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Contents Section l: Musculoskeletal Connective Tissue, System, andIntegument o guys:c u l o s k e l e t a l C h a p t eE r lm . b r y o lM

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g yo:n n e c t i v e T i s s u e C h a p t eH r 2i $ . o l oC

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C h a p t eH r Si s. t o l oMguys: c l e

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Chapter4. Histology: lntegument ...

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Chapter 5.Anatomy: Musculoskeletal

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Chapter 6.Physiology: Musculoskeletal

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a t. h o l o g y C h a p t ePr T Chapter 8.Pharmacology

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ll: Gastrointestinal Section System C h a p t e rEl .m b r y o l o g y Chapter2.Histology Chapter5.Anatomy.... Physiology Chaptera. Chapter5.Pathology.. Chapter 6. Pharmacology

....119 ......125 ...137 ..... 145 ....169 . . .211

ilitshical vii

Section lll: Endocrine System C h a p t le. rH i s t o l o g y

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Chapter2.Anatomy

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Chapter 5. Physiology C h a p t e rP4a. t h o l o g y . . Chapter 5. Pharmacology

. . . . .231 ...265 . . 28.l

Section lV:Reproductive System l. Embryology Chapter

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C h a p t e rH2i.s t o l oM ga y :l e

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Histology: Female ChapterS. Chapter4.Anatomy....

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C h a p t e r 5 . P h y s i o. l o g y

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ga y :l e C h a p t e rP6a. t h o l oM Pathology: Female ChapterT. Chapter 8. Pharmacology Index

viii iliBhical

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......343 ....555 . .379 ....385

I SECTION

System, Musculoskeletal Tlssue, and Connectlve lntegument

Embryology Musculoskeletal thatarisefrom elements frommesenchymal system arederived Thecomponents of theskeletal and intofibroblasts, chondroblasts, crest. Mesenchymal cellsdifferentiate mesoderm andneural respectively. Boneorgans tissue, cartilage, andbonetissue, whichproduce connective osteoblasts, (intramembranous orfrom ossification) tissue in mesenchymal connective develop directly either (endochondral muscles preformed theskeletal differentiate Ingeneral, ossification). cartilage models gives muscle. andsmooth riseto cardiac Thesplanchnic mesoderm mesoderm. fromparaxial (glands, hairs, nails), andtheunderlying oftheepidermis anditsderivatives Theintegument consists isformed frommesenchyme. thedermis fromectoderm, whereas isderived dermis. Theepidermis crest. fromneural originate whichmayoccurin bothlayers, Melanocytes,

SYSTEM SKELETAL A. Origin l. The skeletalsystem develops from paraxial mesoderm, which forms a column of tissue blocks, called the somites, on either side of the neural tube. Each somite becomesdifferentiated into a ventromedial part, the sclerotome, and a dorsolateral part, the dermomyotome. By the end of the fourth week,the sclerotomecellsform embryonic connectivetissue,known as mesenchyme. Mesenchymecells migrate and differentiate to form fibroblasts,chondroblasts,or osteoblasts. 2. Bone organs are formed by two methods: a. Flat bones are formed by a process known as intramembranous ossification, in which bones develop directly within mesenchyme. b. Longbones are formed by a processknown asendochondral ossification, in which mesenchymal cells give rise to hyaline cartilage models that subsequentlybecome ossified. B. Skull formation. The neurocranium provides a protective casearound the brain, and the viscerocranium forms the skeleton of the face. 1. Neurocranium is divided into two portions: a. The membranous neurocranium consistsof flat bones that surround the brain as a vault. The bones appose one another at sutures and fontanelles, which allow overlap of bones during birth and remain membranous until adulthood. Palpation of the anterior fontanelle, where the two parietal and frontal bones meet, provides information about the progressof ossificationand intracranial pressure.

Musculoskeletal System, Connective Tissue, andIntegument

b. The cartilaginous neurocranium (chondrocranium) of the base of the skull is formed by fusion and ossificationof a number of separatecartilagesalong the median plate. 2. Viscerocranium arisesprimarily from the first two pharyngealarches(TableI-1-1). Thble I-f -f . Origins of viscerocranial bones. Pharyngeal Arch Maxilla Zygomatic bone Part of temporal bone

Dorsal part of first arch

Mandible

Ventral part of first arch

Ear ossicles:malleus, incus, stapes

Tip of ventral part of first arch and second arch

Hyoid bone

Arches 3-6

Laryngeal cartilages

C. Appendicular system. The pectoral and pelvic girdles and the limbs comprise the appendicular system. 1. Except for the clavicle,most bones of the systemare endochondral.The limbs begin as mesenchymalbuds with an apical ectodermal ridge covering, which exerts an inductive influence over the mesenchyme. 2. Bone formation occursby ossificationof hyaline cartilagemodels. a. The processbeginsat the end of the embryonic period in the primary ossificationcenters, which are located in the shaft, or diaphysis, of the long bones.At the epiphyses, or bone extremities,ossificationbegins shortly after birth. b. The cartilagethat remainsbetweenthe diaphysisand the epiphysesof a long bone is known as the epiphysial plate. It is the site of growth of long bones until they attain their final size and the epiphysial plate disappears. D. Vertebral column 1. During the fourth week, sclerotomecells migrate medially to surround the spinal cord and notochord.After proliferation of the caudalportion of the sclerotomes,the vertebrae are formed, eachconsistingof the caudalpart of one sclerotomeand cephalicpart of the next. 2. While the notochord persistsin the areasof the vertebral bodies, it degeneratesbetween them, forming the nucleus pulposus. The latter, together with surrounding circular fibers of the annulus fibrosis, forms the intervertebral disc.

MUSCUTAR SYSTEM A. Skeletal (voluntary) system 1. Origin. The dermomyotome further differentiates into the myotome and the dermatome. a. Cells of the myotome migrate ventrally to surround the intraembryonic coelom and the somatic mesoderm of the ventrolateral body wall. These myoblasts elongate, becomespindle-shaped,and fuse to form multinucleatedmuscle fibers.

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Embryology: Musculoskeletal

b. Myofibrils appearin the cytoplasm,and, by the third month, cross-striationsappear. : Individual muscle fibers increasein diameter as myofibrils multiply and become arrangedin groupssurroundedby mesenchyme. c. Individual musclesform. aswell astendonsthat connectmuscleto bone,

: 2. Tlunk rnuscrrlature.By the end of the lifth week body-wall musculaturedividesinto a , dorsalepimere,suppliedby the dorsalprimary ramus of the spinal nerve,and a ventral hypomere,suppliedby the ventral primary ramus a- Epimeremusclesforrn the extensormusclesof the vertebralcolumn, and hypomere ' musclesgiverise to lateraland ventral flexor musculature. b. The hypomeresplitsinto tfuee layers. (1) In the thorax,the threelayersform the extemalintercostal,intemalintercostal,and transrrerse thoracicmuscles. (2) In the abdomen,the threelayersform the extemaloblique,intemal oblique,and transverseabdominalmuscles. 3. Headmusculature a. The extrinsic and intrinsic musclesof the tongue are thought to be derived from occipital myotomesthat migrateforward. b. The extrinsic musclesof tle eyemay derivefrom preoptic myotomesthat originally surround t}reprochordalplate. c. The musclesof nastication, facialexpression,t}te pharynx,and the larynx arederived from different pharyngealarchesand maintain their innervation by the nerveof the archoforigin. 4. Limb muscuLfirre originatesin th€ seventhweekftorn somaticmesodermthat migrates into t";J;;;;;.; into the limb bud. with time, the limb rnusculaturesplits ^ extensorgroups. a. The lirnb is innervatedby spinal nerrrcs,which penetratethe lirnb bud mesodermal condensations. Segmentalbranchesof the spinalnervesfirseto form largedorsaland ventral nerv€s, b. The cutaneousinnervation of the limbs is alsoderivedfrom spinalnervesand reflects I the level at which the limbs arise. B. Smoo0rmusde, The smooth musclecomponentsof the gut, trachea,bronchi, and blood vesselsof the associatedmes€nteriesare derivedfrom splanchnicmesodermsurrounding the gastrointestinaltract. Vesselselsewherein the body obtain their smooth muscleftom I local mesenchyme. C. Cardiacmuscle,like smooth muscle,is derivedftom splanchnicmesoderm

Bdd$ to Genenl Prindples Ihe Pharyngealarch areraie €d inthe deriratives Embryology of General section Principles Book2 (volumelD.

Musculoskeletal System, Connective Tissue, andIntegument

CONGEN ITAIABNORMATITI ES A. Cranioschisis (acrania) is an almost complete absenceof the cranial vault. It is often accompanied by a large spinal defea and is incompatible with life when combined with anencephaly. B. Microcephaly is a bony deformation in which the skull fails to expand secondaryto failure of the brain to grow. C. Amelia (absenceof one or two extremities), meromelia (absenceof an arm or leg with presence of the hand or foot), and micromelia (shortened extremities) are usually rare abnormalities. There were increasedincidencesbetween 1957 and 1962as a result of the administration of thalidomide as a sleepingpill and antinauseant. D. Polydactyly refers to supernumerary digits. It is inherited as a dominant trait. E. Syndactyly is fused or webbed digits. It is due to failure of interdigital mesenchymeto break down. It is inherited as an autosomal dominant or recessivegene. F. Clubfoot is an inward flexing of the sole of the foot while the foot is adducted and the plantar is flexed. It is often combined with syndactyly. G. Congenital dislocation of the hip is an underdevelopment of the acetabulum and head of the femur aswell asa laxity of the hip joint. It occurs most often in femalesand resultsin dislocation after birth. It may be associatedwith breechposture during pregnancy. H. Spina bifida occulta is the failure of dorsal portions of one or two vertebrae,usually in the lumbosacral region, to fuse with one another.It is usually not noticeableat the surfaceexcept as a dimple or tuft of hair and is not associatedwith neurological symptoms. I. Meningocele involves several vertebrae such that the meninges or the spinal cord (myelomeningocele) and its nerves bulge out through the opening covered only by a thin membrane. L Achondroplasia results in dwarfism. It is due to abnormal endochondral ossification in the epiphysealplatesof long bones. K. Acromegaly is an enlargement of the face,hands, and feet due to hyperpituitarism. L. Gigantism is a general excessivegrowth that is also due to hyperpituitarism.

INTEGUMENTARY SYSTEM A. Epidermis 1. Origins. The superficial epidermis and deep connective tissue dermis of the skin have different origins. a. The epidermis arisesfrom the surfaceectoderm covering the entire embryo. b. The dermis arisesfrom underlying mesenchyme,which is derived from dermatome, lateral somatic mesoderm,or neural crest,dependingon the location in the embryo. 2. Differentiation of keratinocytes. In the beginning of the second month, the single layer of embryonic epidermis differentiates into an outer periderm and an inner basal layer. a. Continued mitosis in the basal layer leads to the definitive four-layer arrangement of keratinocytesby the end of the fourth month. b. The cells of the periderm are eventually sloughed off into the amniotic fluid.

Embryology: Musculoskeletal

3. Dermatoglyphics are patterns observedon the finger tips, palms of the hands, and soles of the feet that are due to ridges and hollows of the basal germinative layer and underlying dermis. In children with chromosomal abnormalities, these patterns are abnormal. 4. Melanocytes. Invasion of the epidermis by melanin-secretingdendritic cells of neuralcrest origin is responsiblefor pigmentation of the skin. B. Epidermal derivatives. The germinative layer also gives rise to epidermal derivatives by forming epithelial cord or bud-like ingrowths into the dermis,which secondarilyhollow out by death of the central cells. 1. Hair follicles and associatedsebaceousglands. The dermal root sheath and arrector pili muscle of each follicle are derived from surrounding mesenchyme.Fine lanugo hair, shed at the time of birth, first appearsby the end of the third month. Secretionsfrom the sebaconsistingof ceousglands cover the fetus with a protectivesubstance,the vernix caseosa, secretions. degeneratedepidermis,hair, and fatty sebaceous 2. Sweatglands and mammaryglands. In the mammary gland, the lactiferous ducts develop in the persistingmidthoracic portion of the mammary line, which is a band-like epidermal thickening that extends from the base of the forelimb to the region of the hindlimb when it first appears.The epidermal-derivedepithelial lining of the lactiferous ducts and alveoli are supported by mesenchy-ul connective tissue. 3. Nails appear approximately at the beginning of the sixth month. 4. Teeth. Oral cavity ectoderm givesrise to tooth enamel.Associatedmesenchymegivesrise to the associatedtooth structures. C. Dermis consistsof two layers:an upper papillarylayer, which forms the papillae that contain capillaries and sensory nerve endings and project upward into the epidermal ridges; and a deeperreticular layer, which developsinto denseirregular connectivetissue. D. Abnormalities 1. Ichthyosis involves excessivekeratinization (cornification) of the skin, giving it a scalelike appearance. 2. Nevi are skin malformations, such asbirthmarks or hemangiomas.They are due to localized collectionsof differentiatedcells,such as epidermal,pigmented,vascular,or connective tissue,or any combination thereof. They occur frequently and may be superficialor deep. 3. Hypertrichosis is an excessiveamount of hair as a result of increasedformation of follicles.It may be localizedto the midline region or it may be more generalized. 4. Atrichia is an absenceof hair that is usually associatedwith abnormalities of teeth and nails. 5. Polythelia is a developmentof supernumerarynipples along abnormally persistingfragments of the mammary line. 6. Polymastia is a developmentof supernumerarycompletemammary glands. 7. Inverted nipple is a failure of the original epithelial pit, into which the lactiferous ducts open, to evert.It may alsobe causedby the presenceof a fast-growingtumor in the gland, leading to the retraction of the nipple.

Connective Tissue Histology provides Connective tissue thebodywitha continuous system of support, nutrition, defense, and maintenance. lt makes uptheframework oftissue andorgan structures, andpossesses thetensile strengh to allowtissues to withstand forces. shearing Connective tissue iscomposed of cells embedded in anextracellular matrix, consisting offibers andground substance infiltrated withtissue primary (e.g., fluid.Incontrast to theother tissues epithelum, muscle, nerve) thataremainly cellular greater in composition, connective tissue hasa relatively amount of extracellular components.

CETLS OFCONNECTIVE TISSUE A. Fibroblasts are the most numerous connective tissue cells.They are responsiblefor the synthesisof the matrix components:fibers (i.e., collagen,elastin) and ground substance(glyproteoglycans,glycoproteins). cosaminoglycans, 1. Fibroblastscontain abundant euchromatin, nucleoli, and rough endoplasmicreticulum (RER). 2. They are spindle-shapedcells with large, pale, elongatednuclei and a prominent Golgi apparatus.

Note Cells of connective tissue maybedivided intothree categories: . Cells responsible for synthesis andmaintenance of extracellular matrix (fibroblasts, mesenchyme)

3. Resting(inactive)fibroblasts,sometimescalledfibrocFtes, are smallerand contain a more acidophilic cytoplasm due to a reduced endoplasmicreticulum. Restingfibroblaststhat are stimulated to synthesizenew matrix components, as in wound healing, resume the appearanceof activefibroblasts.

. Cells responsible for storage of andmetabolism of fat(adipose)

4. Myofibroblasts are connectivetissuecellsthat resembleboth fibroblasts and smooth muscle cells.They contain large amounts of the contractile proteins actin and myosin, which are important in contraction of wounds during the healing process.

. Cells withdefense and (mast immune function cells, histiocytes)

B. Mesenchymalcells havethe appearanceof undifferentiated fibroblasts.Thesecellsare found in connectivetissue and in associationwith blood vessels(pericytes).They function as a pluripotential reserveof mesenchy-ul stem cells. C. Adipose cells (adipocytes) are derived from mesenchymal cells or fibroblasts. They are specializedfor the synthesis and storage of lipid. D. Mast cells arelargeround or oval-shapedcellsthat contain largecytoplasmicgranulesand a single round nucleus. 1. The granules have a strong afiinity for basic dyes.With dyes such as toluidine blue, they also stain metachromatically. Mast cell metachromasia is a result of their proteoglycan and heparin content.

Tissue, andIntegument Musculoskeletal System, Connective

ClinicalCorrelate in Mastcellsareinvolved immed iatehypersensitivity Antigens flypel) reactions. canbindto lgEonthesurface of mastcells andinduce the -release of histamine A potentially allergic reaction. fataltypeof immediate hypersensitivity reaction is anaphylactic shock.

Bridgeto Heme/tymph in Blood cellsarediscussed inthe detail phoreticu lar Hematologi{Lym Histology in Organ chapter Bookt (Volume lll). Systems

ln a Nutshell

2. Mast cells are induced to degranulate by mechanical trauma, radiant energy,chemicals, and the binding of allergensto IgE molecules (from plasma cells), attachedto specific receptors on mast cell membranes.This attachment accounts for their role in allergic reactions.Substances releasedfrom mast cellsinclude histamine, eosinophil chemotactic factor of anaphylaxis(ECF-A), leukotrienes,and neutral proteases. 3. Mast cellsresemblebasophilsof the blood (also found in connectivetissue)but are derived from different precursorsin the bone marrow and, thus, are considereda separatecell type. Mast cellsdifferentiatein connectivetissuewhereasbasophilsdifferentiate in bone marrow. E. Formed elements of the blood (i.e., neutrophils, eosinophils,basophils,monocftes, lymphocytes),in responseto tissueinjury and immune reactions,migrate into the connective tissue,where they carry out their respectivefunctions. F. Plasma cells are oval-shapedbasophilic cellswith an eccentricallyplaced nucleus containing clumped chromatin with a "spoked-wheel"appearance.Plasmacellsare derivedfrom B 1y-phocytes. 1. The intenseamount of cytoplasmicbasophiliais due to the extensiveRER that is usedfor the synthesisof large quantities of antibodies. 2. Eachplasmacell producesone specificantibody. G. Macrophagesof connectivetissue(histiocytes) are derived from monocftes that migrate from the blood into the connectivetissues. 1. They contain a small irregular nucleus with a prominent nucleolus and extensivecytoplasm that may contain a variety of particlesand vacuoles.

Precursor cells in bonemarrow --+moflocytes (which circulate - miSration in blood) into --+ mature connective tissue intomacrophages.

2. These cells are active in phagocytosis of particulate matter and are members of the mononuclear phagocyte system (MPS) that also includes osteoclasts,microglia, Langerhanscellsof the epidermis,as well as macrophagesof the liver (Kupffer cells),the lung (dust cells),and immune organs.

In a Nutshell

4. The macrophagerecognizesits prey by the interaction of its membranereceptorwith specific regionsof an antibody or complement that coatsthe foreign particle.

TheMajorFunctions of Macrophages . Ingestion of particles and theirdigestion by lysosomes . Resistance to infection by protozoa, bacteria, viruses, fungi, andmetazoa . Cell-mediated resistance to tumors . Destruction of aged erythrocytes . Antigen presentation to lymphocytes

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3. They act asscavengers by recyclingdamagedand dead cellsand asprotectorsby ingesting and killing bacteriaand foreign substances.

5. They respond to a variety of chemotactic stimuli, including lymphokines (signal moleculesreleasedby lymphocytes). 6. When macrophagesencounterlarge foreign bodies,they fuse togetherto form large cells with multiple nuclei, called multinuclear giant cells. 7. The macrophageis an antigen-presenting cell and, thus, is an important participant in the immune response.This function is reviewed in the BasicImmunology chapter of General PrinciplesBook 1 (Volume I).

Histology: Tissue Connective

EXTRACELLUTAR MATRIX A. Fibrous components (Figure l-2-l).

Note MajorTypes of Collagen

Microfibril

Figure l-2-1.Collagen microfibrils, fibrils, fibers, and bundles.

l . Collagen is the most abundant body protein. It contains many positively chargedamino

acidsand, thus, stainswith eosin.Type I collagen,the most abundant type found in connective tissue,is synthesizedby fibroblasts in the following way: a. Ribosomessynthesizetwo types of peptide chains (cr, and or) that are rich in glycine, lysine,and proline. b. In cisterna of RER, three units (two a, and one crr) bind via disulfide bridges and intertwine to form a triple helix. Component lysines and prolines become hydroxylated in the cisterna to form hydroxylysine and hydroxyproline. c. In the Golgi, sugars(i.e., galactose,glucose)bind to the hydroxylysine,and the "finished" glycoprotein procollagen is secretedfrom the fibroblast. d. Peptidasesoutside the fibroblast excisethe ends of the procollagenmolecule,forming a soluble substancecalled tropocollagen. These helicesaggregateto form low-tensile strength microfibrils. e. Another extracellular enzyme,lysyl oxidase, covalently binds lysine and hydrorylysine residuesto form aldehydes,which cross-link adjacenttropocollagenhelicesto form insoluble,high-tensilestrengthcollagen fibrils. f. Thesefibrils intertwine and form noncovalentbonds with matrix glycoproteinto produce collagen fibers. The characteristiccross-bandingof collagenis due to the overlapping of the parallel end-to-end fibers. Large,white, collagenfibers are visible with the naked eyein tendons,ligaments,and other sheetsof denseconnectivetissue.

TypeI . Mostabundant . Found in dermis, bone, tendon, dentin, fascias, fibrous organ capsules, cartilage Typell . Hyaline andelastic cartilages;intervertebral disc;notochord Type lll . Majorcomponent of reticular fibers . Canco-polymerize with othertypesof collagen . Found insmooth muscle, arteries, liver, spleen, kidney, andlung TypelV . Found in basal lamina of basement membranes TypeV . Placenta, liver, lung;now classified asV/Xtfamily Type Vll . Basement membranes; major component of anchoring fibrils

g. More than two dozen types of collagen have been identified. All have the same tropocollagensubstructurebut differ in their amino acid and hexosecontent. Many

tl

Tissue,and Integument Musculoskeletal System, Connective

cell types, including chondroblasts,smooth muscle cells,and epithelial cells,are also able to synthesizecollagen. 2. Reticular fibers are delicate branching fibers composed mainly of type III collagen. a. They form a delicatesupporting reticulum for cells and tissuesand are abundant in the framework of the spleen,lymph nodes,bone marrow liver, kidney, and endocrine glands. b. Reticularfibers are abundant in embryonic connectivetissue,or mesenchyme,but are replacedby collagenfibers during tissuematuration. c. They are able to react with silver salts (argyrophilia) and thus appear black under the light microscope. d. Becausethey are collagenfibrils, they demonstratethe characteristiccross-bandpattern.

Clinical Correlate Diseases Resulting from Defectsin Collagen Synthesis Ehlers-Danlos Defect: Deficient typelll collagen, faultylysinehydroxylation, or J in procollagen peptidase activity. Increased Symptoms: skin andarticular mobility; elasticity, aortic or intestinal rupture. Scurvy (VitC is Defect:Vit C deficiency forproline cofactor hydroxylase) Symptoms: Ulceration of gums, hemonhages (Ol) Osteogenesis impedecta Defect: Single base substitution in geneforcollagen typeI Symptoms: Spontaneous fractures, insuff cardiac iciency

3. Elastic fibers are abundant in tissuesthat must stretch and recoil, such as skin, lung, blood vessels, and vertebralligaments. a. Like collagen,elastic fibers are synthesizedas subunits by fibroblasts. They are easily distinguishedfrom collagenfibers becausethey are thinner, lack longitudinal striations, and appearyellow to the naked eye. b. Under the light microscope,elasticfibers stain weakly with eosin.They are best seen when stainedpurple-black by specialelasticstains. c. Under the electron microscope,elastin may be resolvedinto its two components: a central pale elastinfiber bulk surrounded by glycoproteinmicrofilaments. d. The amino acid composition of elastinis similar to collagen(i.e.,proline, glycine).In addition, it containstwo specificlysine derivatives,desmosineandisodesmosine,that are mainly responsiblefor the elasticproperties of thesefibers. B. Ground substanceis a hydrated,amorphous,extracellularmaterial that occupiesthe spaces betweencellsand fibers. It is viscousand slippery and it acts as a molecular sievethat permits diffusion of metabolitesbetweentissuesand blood; however,it inhibits the movement and spreadof larger particles such as microorganisms.It consistsmainly of proteoglycans and glycoproteins. 1. Proteoglycans are a complex of glycosaminoglycans (GAGs) and core proteins. with abundant acidic (sulfateand a. GAGsarelong-chainedpolyanionic polysaccharides carboxyl) groups. b. Based on their substituted sugar residues, several GAGs have been identified: hyaluronic acid, heparan sulfate, heparin, keratan sulfate, chondroitin 4-sulfate, chondroitin 6-sulfate,and dermatan sulfate.

Note Cround substance isformed bytwoclasses of components: . Proteoglycans consisting of glycosaminoglycans and proteins . Adhesive glycoproteins

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c. With the exception of hyaluronic acid, GAGs bind to core proteins, forming bottlebrush-like molecules with an exceptional negativecharge density. d. The most abundant GAG is hyaluronic acid, which is a large charged polyanion that overlaps to form dense charged networks. The abundance of negative chargesin this moleculebinds water and is largely responsiblefor the hydrated gel properties of the ground substance.Hyaluronic acid is not stainedby hematorylin-eosin;but in wellpreserved connective tissue, it is metachromatic with toluidine blue and can be demonstratedwith PASstain. 2. Glycoproteins are moleculesof protein with carbohydrateattached.In contrast to proteoglycans,the protein portion in glycoproteinsis usually the most abundant.

Histology: Connective Tissue

a. Severalglycoproteinshavebeen identified that are important in the binding of cellsto the extracellularmatrix. b. Fibronectin, which is synthesizedbyfibroblasts,is a glycoproteinthat containsbinding domains for cells,collagen,and GAGs.It helps mediate normal cell adhesionand migration. c. Thrombospondin, which is synthesizedbyfibroblasts,containsbinding domains for cells,collagen,heparin, and fibronectin.

CTASSIFICATION OFCONNECTIVE TISSUES A. Embryonic connective tissues 1. Mesenchymalconnectivetissue occursthroughout the developingbody and is composed of stellatemesenchymalcells, abundant ground substance,and later, delicate reticular fibers. 2. Mucous connective tissue,found in the umbilical cord, resemblesmesenchymebut contains more collagen fibers and a more viscous,jelly-like ground substancecomposed mainly of hyaluronic acid. B. Adult connective tissues 1. Connective tissue proper a. Looseconnectivetissue is composedof few fibers,an abundant ground substance,and a variety of resident cells aswell as those derived from the blood. Examplesof this type are found in subcutaneousfascia,in the lamina propria of organs,and in mesenteries. b. Dense connective tissue ( 1) Denseregular connectivetissue is composedof parallel arraysof thick collagen fiberswith scantground substanceand cells.It is ableto withstand stressin a definite direction and is found in ligaments,tendons,and the cornea. (2) Dense irregular connective tissue is composed of collagen and elastic fibers interwoven and oriented in many different directions.Examplesof this type are found in the dermis, capsulesof organs, perichondrium of the cartilage,and periosteum of the bone. 2. Reticular connectivetissue is a speciallooseconnectivetissuecomposedof delicatereticular fibers (type III collagen)and reticular cells (fibroblasts),which provide the framework for bone marrow liver, spleen,and lymph nodes. 3. Elastic connective tissue is composedof coarse,parallel elasticfibers or sheetsinterspersed with fibroblasts and, often, delicate collagen fibers. Elastic tissue is found in yellow ligaments of the vertebral column and in walls of hollow organs,such as the large arteries.

In a Nutshell LooseConnective Tissue . Alsoknown asareolar tissue . Abundant ground substance andcells; fewfibers . Found inserosal linings of peritoneal andpleural cavities, andinglands and mucous memDranes Dense Connective Tissue . Predominance ofcollagen fibers; fewercells andless ground substance . Less flexible andmore resistant to stress than loose connective tissue . Found in dermis, ligaments, perichondriu tendons, m andperiosteum.

4. Adipose tissue is looseconnectivetissuein which the adipocytepredominates.It provides insulation as well as an energyreserve. 5. Blood and hematopoietic tissue. See the Hematologic/Lymphoreticular Histology chapterof Organ SystemsBook 1 (Volume III). 6. Cartilage (seebelow) 7. Bone (seebelow)

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Musculoskeletal System, Tissue, andlntegument Connective

CARTITAGE .

Cartilage is a supportive conn€ctive tissue consisting of cells that secretean extracellular matrix composed of fibers embedded in al amorphous ground substance.Cartilage is avascular and is nourished by diffi.rsion of metabolites ftom surrounding blood vessels. A. C€ll6 1. Chondrocytes are round cartilage cells that secrete and maintain the fibers and ground substance that make up the extracellular matrix. a. Chondrocftes occupy microscopic spaces within the extracellular matrix tlat are called lacunae. b. Chondrocytes occur singly or in isogenous groups, resulting from the mitotic diyisions of a single cell. c. Active chondroc)'tes have tle appearanceoftypical protein secretory cells and contain an extensive RER and prominent Golgi apparatus. 2. Chondrogenic cells are undifferentiated mesenchymal cells that are important for the development and growth of cartilage. a. With some exceptions, cartilage is surrounded by a specialized layer of dense connective tissue called the perichondriun. b, The outer portion of the perichondrium is more fibrous, while the inner portion contains mesenchymal cells. These mesenchymal cells can differentiate into chondrogenic cells calleddrondroblasts, whidr are the immediate precursorsto chondro+es. B. Extracellular matrix of cartilage 1..Fibers secretedby chondroc''tes consisting of collagen (mainly type II) and elastin 2. Ground substance,consisting of proteoglycans and glycoproteins a. Proteoglycans of cartilage occur as aggregatesof GAGs and are associatedwith core proteins and hyaluronic acid. (1) These aggregatesassociatewiti cartilage fibers and bind water becauseof their large number of negative charges. (2) These molecular interactions provide cartilage matrix with its unique properties (resistanceto compression) and its firm, yet resili€nt, consistency,

drondronectin' a molecule thatbindschondro!!te Thefirmness ofcartilage depends on: . Electrostatic bondsbetlveen collagen fibersandthe glycosaminoglycn side chainsof matrix proteoSlycans . Thebindingof water(the solvation of u/ater)to the negatively charged proteoSlycn complexes

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" #.:,:"::ilx'to'#*'include C.lpes of cartilage l' Hyaline cartilage is the most commont1ryeof cartilage(FigureI-2-2)' a. Most of the bonesof the axial skeletonand all of the bonesof the appendicularskeleton arefirst laid down in hyalinecartilage,Iaterto be replacedbybone. b. In the adult, hyalinecartilageis retainedastlre articular surfacecoveringofthe bones and the support for tlre upper r€spiratorytract. c. Exceptat articular surfaces,hyzline cartilageis surroundedby a fibrous perichondrium. Perichondriumis essentialfor gro*th and maintenanceof cartilage. d. The extracellularmatrix of hyalinecartilageis a firm gel,consistingof a networkof submicroscopict'?e II collagenfibersembeddedin a hydratedmatrix of groundsubstance.

Histology: Connective Tissue

The efiracellular matrix immediately surrounding the chondrocytes, called the capsule or territorial matrix, is highly basophilic and metachromatic becauseof the high content of polyanionic GAGs.

Fibrouslayer of perichondrium Chondrogeniclayer of perichondrium lntercellular matrix

Chondrocytein lacuna Cell nest

Figure l-2-2. Hyaline cartilage.

2. Elastic cartilage is more opaque than hyaline cartilage and is yellow as a result of the many elastic fibers that it contains. a. It is found in areaswhere elasticity is required, including the external ear, epiglottis, and eustachiantube. b. Collagen fibers (tfpe II) and a perichondrium are also present. 3. Fibrocartilage is a combination of dense,regularly or irregularly arranged type I collagen fibers (dense connective tissue) and cartilage cells, which are enclosed in lacunae and surrounded by scant amounts of hyaline matrix. a. Fibrocartilage is found where increasedtensile strength is needed,such as intervertebral disks, pubic symphysis,and tendon insertions that are adjacent to hyaline cartilage or articular surfaces. b. A perichondrium is not present in fibrocartilage, but chondrocytes arise from existing fibroblasts. D. Growth of cartilage is accomplished via two mechanisms: interstitial growth and appositional growth. 1. Interstitial growth is an enlargement of the internal massof the cartilageby mitotic divisions of existing chondrocytes and continued deposition of the extracellular matrix. a. Interstitial growth, leading to the formation of isogenous groups, usually occurs in soft, young cartilage. b. It is important in the epiphysial plates of developing long bones and accountsfor their growth in length. c. It also occurs in the articular cartilages,where the perichondrium is absent.

t5

Tissue, andlntegument Musculoskeletal System, Connective

2. Appositional growth occurswhen the inner layersof perichondrium cellsdivide and differentiateinto chondroblasts. a. Chondroblastssurround themselveswith matrix and gradually turn into chondrocytes.

In a Nutshell of Cartilage TwoMechanisms Growth lnterstitial . Mitotic of predivision existing chondrorytes . Occurs plates in epiphysial cartilages andarticular growth Appositional . Results fromdifferentiation of perichondrial cells . Occurs oncartilage "surfaces"

b. Appositional growth increasesthe cartilagemassby adding to the surface.

BONE Bone is a supportive connective tissue characterizedby mineralization of its extracellular matrix. Its mineral content servesas an important body reservefor calcium and phosphorus. Bone supports body tissues,protectsvital organs,and contains bone marrow. It also acts as a lever systemwherebyforcesgeneratedduring skeletalmusclecontraction are transformed into body movements. A. Cells 1. Osteoblastsare plump basophilic cellsthat activelysecretebone matrix. 2. Osteocftes are mature bone cellsthat occupy lacunaein the solid matrix and have cytoplasmic extensionsthat extend through canaliculi to reach neighboring lacunaecontaining osteocl.tes.Osteocytesare differentiatedosteoblastssurrounded by newly synthesized matrix. a. Communication betweenosteocytesoccursvia gap junctions.

Mnemonic - B forbuild Osteoblasts bone

b. Osteocytesmaintain bone matrix and, therefore,play an important role in calcium homeostasis. 3. Osteoclastsare large, motile multinucleated cells found on bone surfacesat sites of resorption. They are often found in shallow pits of the bone matrix called Howship lacunae. a. They ariseby the fusion of monocytesand may contain up to 50 or more nuclei. b. Osteoclastserode formed bone by releasingacid and proteolytic enzymes,such ascollagenase,which attack the inorganic and organic bone matrices,respectively. c. Theselarge cells have an acidophilic cytoplasm containing vacuolesand lysosomes. Their rytoplasmic bordet which abuts the surfacesof bone tissue,is elaboratelyfolded and appearsas a striated or ruffled border under the light microscope. d. Osteoclastsare stimulated by parathyroid hormone (PTH) to resorb bone tissue, therebyincreasingserum calcium. e. Osteoclastsare members of the mononuclear phagocytesystem. 4. Osteogeniccells are mesenchymal-likecells in adult bone that differentiate into boneforming osteoblastsfor remodeling and repair. a. They are located in the inner layersof the periosteum and endosteum. b. In developingbones,they are the stem cellsfor bone tissueformation. B. Extracellular matrix 1. Organic matrix consistsof fibers and ground substance. a. Fibersconsistof type I collagenin the form of cross-bandedfibers. b. Ground substanceconsistsof proteogly.ur aggregatescomposedof keratan sulfate, chondroitin sulfate,and hyaluronic acid.

t6

Histology: Connective Tissue

2. lnorganic matrix, which accounts for approximately 50o/oof the dry weight of bone matrix, consistsprimarily of a complexof calcium and phosphatein the form of hydroxyapatite. Calcium carbonate,citrate, fluoride, magnesium,and sodium are also present. C. Organization of bone tissue 1. Immature bone (i.e., nonlamellar,bundle, woven) is newly depositedbone tissue with looselyinterlacedcollagenfibers that contains a high density of osteocytes. 2. Mature bone is a highly structured lamellar arrangementof cellsand extracellularmatrix that is organizedinto osteons,interstitial lamellae,and circumferentiallamellae. a. Osteons (Haversian systems) are composedof concentric lamellaearound a central neurovascularcanal (Haversian canal). Theserylindrical units run more or lessparallel to the long axis of compact bone. b. Interstitial lamellae are wedgesof compact bone located between the cylindrical osteons. c. Circumferential lamellae are parallel lamellar arrays of compact bone tissue surrounding the osteonson the outer surface(outer circumferentiallamellae)and on the inner surface(inner circumferentiallamellae)of bone. 3. Periosteum is a double-layeredtissuemembranebound firmly to the outer bone surface. It consistsof an outer, mostly fibrous, layer and an inner, more cellular,layer that possesses osteogenicpotential. 4. Endosteum is a delicatemembrane of osteogeniccellsthat lines the internal surfacesof bones adjacentto the marrow cavities.

ClinicalCorrelate In Paget disease, thereisa disturbance inthebalance of (an bonehomeo$asis increased rateof bone destruction andconsequent rebuilding) thatleads to the creaiion of wovenor immature bone.People suffering fromPaget arepredisposed to fractures.

Note Primary Functions of Periosteum andEndosteum . Nutrition of bonetissue . Provision of continuous supply of newo$eoblasts

D. Typesofbone l. Cancellous (spongy) bone consistsof delicateanastomoticspiculesor larger trabeculae of bone tissuein the form of a porous meshwork fi.lledwith marrow. 2. Compact (dense)bone consistsof numerous osteons,interstitial lamellae,and circumferential lamellae. E. Organization of long bones 1. Epiphysesare extremitiesof long bones composedof cancellousbone coveredby a thin layer of compact bone. 2. Diaphyses are cylindrical shaftsof long bones composedof compact bone. 3. Metaphysesarethe regionsbetweenthe epiphysesand the diaphysesand consistof a shell of compact bone around a massof cancellousbone. F. Bone formation. Bone organsform by two distinct processes. In intramembranous ossification, bone is formed directly within layers (membranes) of mesenchyme,or primitive connectivetissue.In endochondral ossification, a model of the bone is first laid down in hyaline cartilage,and then the cartilageis replacedby bone. In both processesof bone formation, a temporary, immature nonlamellar tissue appearsfirst and is then replacedby lamellar bone. 1. Intramembranous ossification. Bonesformed in this way are the membrane bones and include certain bones of the skull (i.e., frontal, parietal, temporal, part of the occipital bones),facial bones,the clavicles,and part of the mandible. a. This processbegins in the primary ossification center within the connectivetissue layer.

l7

Tissue, andIntegument Musculoskeletal System, Connective

(1) Mesenchyme cells aggregateand differentiate into osteoblasts,which deposit spiculesof bone matrix in the loose connective tissue. (2) Cells of the connective tissue membrane divide to give rise to more osteoblasts, which contribute to the growth of the ossification center. b. The matrix is calcified after it is secretedby the osteoblastsin the woven bone. After calcification, the spiculesof bone become coated with more osteoblasts,which transform the spiculesinto larger trabeculae.The trabeculaeinterconnect around the blood vesselnetwork in the mesenchymeto form cancellousbone. c. The growth of bone is appositional and osteoblastsbecome trapped in expanding bone to become osteocftes. (Unlike cartilage, bone is able to grow appositionally only.) In lacunae,osteocftes rarely divide, and thus, interstitial growth is impossible. d. The intramembranous bone has two fates: ( 1) It may remain cancellous,in which casethe intertrabecular connectivetissuecavities become filled with bone marrow or fat. (2) It maybecome compact,in which caseappositionalgrowth continuesuntil all of the mesenchyme (except blood vessels)is replaced by bone. In this case,the immature woven bone is replaced by lamellar bone through the concomitant processof resorption and apposition. e. The connectivetissue layer that does not undergo ossification givesrise to the periosteum and endosteum of the bone.

lfot,g ossification, Inendochondral thereis notransformation of cartilage intobone;bone replaces thecartilage tissue model.

2. Endochondral ossification. Bonesformed in this way are the cartilagebones and include most of the long and short bones of the skeleton.Later in development and growth, the cartilage is resorbed and replacedby bone tissue (Figure I-2-3). a. Hyaline cartilage models are formed by differentiated mesenchymalcells called chondroblasts. The mesenchymearound the cartilage model condensesto form the perichondrium. Cartilage models increasein length by interstitial growth (i.e., division of chondroblasts) and in width by appositional growth (i.e., new cartilage cells are contributed by the perichondrium). b. Ossification of the cartilage model begins at the primary ossification center,which is located in the diaphysis of long bones. It begins as the chondrocytes in the region of the primary ossification center hypertrophy, resorb some of the organic matrix, and die, leaving large lacunae. c. A solid mineral phaseof calcium and phosphate is deposited in the remaining matrix to form a calcified cartilage.At the sametime, the cells of the inner layer of perichondrium differentiate into osteoblasts.The perichondrium is now called the periosteum.

t8

Histology: Connective Tissue

Epiphysealbone Restingzone

Proliferativezone

Hypertrophic cadilage zone Calcifiedcartilage

-ugile zone Ossification

Figure l-2-3.Endochondral ossif ication.

d. Osteoblastssecretebone matrix on the surfaceof the calcifed cartilage.Capillaries, osteoclasts, and osteoblastspenetratethe periostealbone to form the primary marrow (central) cavity. e. Cartilage cells adjacentto the primary ossificationcenter then begin to hypertrophy and undergo the samesequenceof events:cell death, calcification of organic matrix, capillary and osteoclastinvasion,and deposition of bone spicules.This processgradually progressesin the cartilagemodel, moving in a direction awayfrom the ossification center.Thus, not all chondroblastsundergo the samechangesat the sametime. There are five distinct zonesin the cartilageskeleton,which representa progressionof cellsfrom the diaphysealprimary ossificationcenteroutward. (1) Ossification z,oneconsistsof osteoblastslaying down bone matrix over calcified cartilage. (2) Calcified cartilage zoneconsistsof cartilagematrix becoming calcified. (3) Hypertrophic cartilage zone consistsof chondrocytesthat appearlarge and have abundant glycogenin their cytoplasm.

Note Growthof a LongBone (l) Proliferation of chondrocytes inthe plate epiphyseal (2) Chondrocytes of the diaphyseal side hypertrophy (3) Matrix calcifies (a) Chondrocytes die (5) Osteoblasts laydown layer of primary bone along thebonespicules (Steps l-5, repeat)

(4) Proliferative zone consists of chondrocytes dividing rapidly to form parallel rows of stackedcellsalong the long axis of bone. (5) Restingr-oneconsistsof hyaline cartilagewithout morphologic cell changes. f. At later stagesof development,usually after birth, secondaryossificationcentersarise in the epiphyses.Growth at thesecentersis radial rather than longitudinal. g. All zoneslocatedbetweenthe diaphysisand epiphysis(in the metaphysisof the bone) are caught between ossification centers.The result is a transversedisk of cartilage, called the epiphyseal plate, which separatesepiphysealbone from diaphysealbone.

t9

Tissue, andIntegument Musculoskeletal System, Connective

( l.) It persists postnatally until longitudinal growth of bone is completed. (2) When the cartilage of the epiphyseal plate stops growing (at approximately age 20), it is replaced by bone tissue.

NOte

. Endochondrar = ossification 1 in len$h . Appositional = ossification I rngirth

G. Growth and remodeling of bones. Bone growth is associatedwith concomitant resorption of preformed tissue and deposition of new tissue. Bone remodeling occurs tlroughout life.

t :rffiJffiffiffirT"lfgbonesgrowinlengthbvthecontinuedinterstitialgrowth a. This radial growth of cartilagetendsto thicken the epiphysealplates;however,subsequent endochondralossificationkeepsthe Plateat about the samethickness,while addingto the length of the bone shaft' proceedat th€ samerate in the two epib. The processof elongationdoesnot necessarily phpeal platesof a long bone. z. Growth in girth. The shaftsof long bonesincreasein width by appositionof new bone subperiosteally. a. At the sametime, bone is removedfrom the internal surfacebeneaththe endosteum so that the bone marrow cavity may increasein diameter. b. Growth in outside diameterresultsftom peripheral apposition of bone. Growth in cavity diameterresultsfrom centralresorptionof bone. H. foints are definedasthe articulation betweentwo bones.Th€rearetwo tfpes of connective tissueioints. l. Synarthrosesarejoints that permit very litde or no movementofbones. a. Syndesnosesare articulationswherebonesarejoined by bandsof denseconnective tissue.This type of joint forms the suturesbetw€enthe growingbonesof the skull but is convertedinto a synostosisin adults. b. Synchondrcsesare ioints where bonesare united by hyaline cartilage.Examplesof this tfpe of ioint arethe epiphysealplatesof growinglong bones. c. Synostosesare joints where bones are united by bone tissue.This type of joint is found in the suturesof the adult skull. d. Symphysesarejoints wherebonesare united by combinationsof hyaline and fibrocartilage.The symphysispubis and intervertebraldisksare consideredsymphyses. 2. Diarthroses arejoints that permit ftee movement.They are presentin the union of long bones,suchasat tle elbowand knee. a. In a diarthrosis,a twoJayeredarticular capsulejoins the extremitiesof long bones. The capsuleis composedof an externalfibrous layerand an internal synoviallayer. (1) The denseconnectivetissue frbrous layer is especiallywell developedin ligamentsand someof tlle tendonsinsertedinto the bone nearthe ioint. (2) The internal synovialmembraneis lined by squamousor cuboidalcellsof mesenchymalorigin calledrynovial cclls. b. The capsuleencloses the articularcavity,which is filled with a hyaluronicacid-richsynovial fluid; this fluid facilitatesthe sliding of the articular surfacesof the bonesat the joint.

20

Muscle Histology Muscle isa tissue specialized forirritability andcontractility. lt iscomposed of elongated cellscalled proteins myofibers thatcontain contractile arranged in rytoplasmic filaments. Muscle cellsattach to bones andsofttissues andarearranged in circular sheets around tubular organs to accomplish mechanical bodymovements uponcontraction. There arethreetypes of muscle: skeletal, cardiac, andsmooth. Skeletal andcardiac muscles areclassified asstriated muscles, based onthe appearance of striations thatrunperpendicular to thelongaxisofthemuscle fiber. Thestriations are dueto thehighly ordered repetitive organization ofthecontractile filaments. Smooth muscle lacks striations dueto a lessstructured, looser arrangement of itscontractile filaments. ln muscle terminology, thesarcolemma refers to themuscle cellmembrane, thesarcoplasm refers to the cytoplasm, andthesarcoplasmic reticulum refers to theendoplasmic reticulum.

SKETETAL MUSCTE Skeletalmuscle is derived from mesodermalsomites.Single-nucleatedmyoblastsfuse to form the multinucleated skeletalmuscle cells (fibers). A. Skeletal muscle cells are long rylindrical fibers. Their multiple ovoid nuclei are located peripherally beneath the sarcolemma. This distinguishes skeletal muscle cells from cardiac muscle cells,which usually have one centrally located nucleus. Each skeletalmuscle fiber is surrounded by a basallamina. 1. Light microscopy. Stainedwith hematorylin and eosin,the sarcoplasmappearshomogeneous or stippled in crosssection and striated in longitudinal section. a. The striations, composed of alternating dark and light bands, are contained in 1-2 pm myofibrils that lie in the sarcoplasmparallel to the long axis of the muscle fiber. Myofibrils are composed of a seriesof sarcomeresthat consist of interdigitating polarizedthin filamentsand bipolar thick filaments (Figure I-3-1). The sarcomeresare the basicunits of contraction of striated muscle. b. The dark bands of the sarcomeresare called A bands becausethey are anisotropic (birefringent) in polarized light. In the center of the A band, a paler region, the H band, is seenin relaxed muscle. c. The light bands of the sarcomereare calledI bands (isotropic), and a dark transverse line, the Zline,bisects eachI band. d. A singlesarcomereis bounded by two Z lines and containsone A band separatingtwo semi-I bands.

2l

Muscle Histology Muscle isa tissue specialized forirritability andcontractility. lt iscomposed of elongated cellscalled proteins myofibers thatcontain contractile arranged in rytoplasmic filaments. Muscle cells attach to bones andsofttissues andarearranged in circular sheets around tubular organs to accomplish mechanical bodymovements uponcontraction. There arethreetypes of muscle: skeletal, cardiac, andsmooth. Skeletal andcardiac muscles areclassified asstriated muscles, based onthe appearance of striations thatrunperpendicular to thelongaxisofthemuscle fiber. Thestriations are dueto thehighly ordered repetitive organization ofthecontractile filaments. Smooth muscle lacks striations dueto a lessstructured, looser arrangement of itscontractile filaments. Inmuscle terminolory, thesarcolemma refers to themuscle cellmembrane, thesarcoplasm refers to the and the sarcoplasmic reticulum refers to the reticulum. endoplasmic rytoplasm,

SKELETAT MUSCTE Skeletalmuscle is derived from mesodermalsomites.Single-nucleatedmyoblastsfuse to form the multinucleated skeletalmuscle cells (fibers). A. Skeletal muscle cells are long rylindrical fibers. Their multiple ovoid nuclei are iocated peripherally beneath the sarcolemma. This distinguishes skeletal muscle cells from cardiac muscle cells,which usually have one centrally located nucleus. Each skeletalmuscle fiber is surrounded by a basallamina. t. tight microscopy. Stainedwith hematorylin and eosin,the sarcoplasmappearshomogeneous or stippled in crosssection and striated in longitudinal section. a. The striations, composed of alternating dark and light bands, are contained in 1-2 pm myofibrils that lie in the sarcoplasmparallel to the long axis of the muscle fiber. Myofibrils are composed of a seriesof sarcomeresthat consist of interdigitating polarizedthin filamentsand bipolar thick filaments (Figure I-3-1). The sarcomeresare the basicunits of contraction of striated muscle. b. The dark bands of the sarcomeresare called A bands becausethey are anisotropic (birefringent) in polarized light. In the center of the A band, a paler region, the H band, is seenin relaxed muscle. c. The light bands of the sarcomereare calledI bands (isotropic), and a dark transverse line, the Zline,bisects eachI band. d. A singlesarcomereis bounded by two Z lines and containsone A band separatingtwo semi-I bands.

2l

Connective Tissue, andlntegument System, Musculoskeletal

AIH z l i ne band band band

Myofibril Sarcomere . lZline lri-----t

A band

Z I band,'

M l i ne

ll'.1

o c o

E (g o

Myosinfilament

I

F-actinfilament \ \ \

Myosinmolecule

f------ra

oe

f,o G-actinmolecules

Heavy Light meromyosin meromyosin Figure l-3-1. Sarcomere structure. 2. Electron microscopy. In skeletalmuscle cells examined with the electron microscope,the repeatingpattern of bands and sarcomeresis due to the arrangementof the myofilaments. a. Thin filaments are composedof the proteins actin, tropomyosin, and troponin. ( 1) Actin is a long fibrous structure (F-actin) composedof two strandsof spherical or globular G-actin monomers twisted in a double helix. The filament is polar and containsmyosin-binding sites on the G-actin monomers.

Note are Actinandtropomyosin filaments, whereas long,thin isa complex of troponin threesubunits.

22

(2) Tropomyosin is a polar molecule containing two polypeptide chainsin the form of an o-helix. The tropomyosin moleculeslie head-to-tail to form filaments that lie in the groovesof the actin helix. (3) Troponin is composed of three polypeptides: TnT binds to tropomyosin at intervals along the thin filament, TnC binds calcium ions, and TnI inhibits actin-myosin interaction. b. Thick filaments are composed of myosin. Myosin is a molecule that contains a tail and two heads.

Histology: Muscle

( 1) The tail fiber is formed from portions of two heavychains,which arewound in a coil. (2) The headsare globular regions formed by the associationof part of one heavy chain with two light chains. Myosin heads function as active sites for AIPase activity and as actin binding sites. c. Actin and myosin together represent55o/oof the total protein in striated muscle. d. Thick filaments occupy the central portions of the sarcomere;thin filaments attach at one end to the ZIine and run parallel to, and between,the thick filaments. (1) I bands are composedof thin filaments only. (2) Abands .ue composedmostly of thick filaments and the thin filamentsbetweenthem. (3) H bands are composedof thick filaments only. B. Connective tissue investments of skeletal muscles and fibers (Figure I-3-2).

Skeletalmuscle

Epimysium

Perimysium

Myofibrils

Nucleus Endomysium Sarcolemma

Figure l-3-2. Connective tissue investments of a striated skeletal muscle.

2!

Tissue, andIntegument System, Connective Musculoskeletal

1. Endomysium is a connective tissue framework composed mainly of reticular fibers that surrounds and supports individual muscle cells. 2. Perimysium is a connective tissue septum that surrounds groups (fascicles) of muscle cells.

Note . Connective notonly tissue bindsmuscle cells together, inthe butalsoassists generation offorceand movement during contraction. . Tendons attach muscles to bones. . Ligaments attach bone to bone.

3. Epimysium is a connective tissue sheath that surrounds an entire muscle. 4. Connectivetissuefibers from the endomysium, perimysium, and epimysium come together at the ends of the long rylindrically shapedmuscle to form a tendon. 5. Skeletalmuscle is a highly vascular tissue; capillaries are located in the connective tissue surrounding all muscle cells. C. Muscle contraction 1. Sliding filament model has been generally acceptedas the explanation of how a muscle cell shortenson contraction. a. According to this theory, the filaments maintain constant lengths during muscle shortening, with thin filaments sliding past thick filaments. b. The sliding movement is due to cross-bridges formed between the actin monomer and the myosin head.Thesecross-bridgesbind the thin and thick filaments during muscle contraction. c. Tensiondevelopmentis proportional to the number of myosin headsoverlappedby thin filaments. 2. Sequenceof events.At the onset of muscle contraction, myosin headsmove out from the thick filament backbone to interact with ATP and actin molecules.

ln a Nutshell Filament Model Sliding isnotcaused by Contraction theshortening of individual bythe filaments, butrather increase intheamount of overlap between thick andthinfilaments.

a. The myosin head movement pulls thin and thick filaments in opposite directions. As the filaments slide, the sarcomeresand myofibrils shorten. The myosin heads then detach from the actin molecules and the rycle is repeated. b. As a consequenceof this action, thin filaments slide into the A band, and the sarcomere and overall muscle shorten. (1) The H band narrows and disappears. (2) The I bands shorten. (3) The Z lines are pulled closertogether. 3. ATP providesthe energyfor muscle contraction in the following manner: a. AlP-bound myosin is active and binds actin. b. This complex is altered when AIP is split by AIPase to liberate energy. 4. Tubules formed by finger-like invaginations of the sarcolemma into the muscle cell surround eachmyofibril to form the transverse (T) tubule system (Figure I-3-3). a. Each tubule lies between the two terminal cisternaeof the sarcoplasmicreticulum to form a triad.

24

Histology: Muscle

Sarcomere I band

Terminalcisterna

Transverse tubules

Figure l-3-3.Striated muscle fiber showing sarcoplasmic reticulum and T-tubulesystem. b. There are two triads in each sarcomere,which are present at the junction between the A and I bands. c. Theseunits serveto couple excitation of muscle cellsto their contraction (excitationcontraction coupling). 5. Muscle contraction is summarizrdas follows: a. Skeletalmuscle cells are innervated by motor neurons located in the CNS. b. The axon of the motor neuron branchesin the muscleto contact severalmuscle cells, forming a motor unit. c. The terminus of each branch forms a specialization at the muscle surface called a motor end plate. d. An action potential from the motor neuron arrives at the motor end plate and causes the releaseof the neurotransmitter acetylcholine onto the surfaceof the muscle. This, in turn, causesdepolarizationof the sarcolemma. e. Electrical impulses travel into the cell via the T tubules and stimulate the sarcoplasmic reticulum via gap junction-like bridges to releaseCa2+. f. Released Caz+ binds to the TnC unit of troponin and induces movement of tropomyosin deep into the actin helix groove. g. As a result of this displacement,the actin filaments can bind to the myosin head, move deeperinto the A band, and the I band then shortens. D. Muscle relaxation 1. The sarcoplasmicreticulum possesses an AlP-driven Ca2+pumping mechanism,which accumulatesCa2+within its membrane system and, thus, reduces the cytoplasmic concentration of Ca2+around the myofilaments. 2. At low Ca2+concentrations,the tropomyosin falls out of the groove of the actin helix in a position where it sterically blocks the myosin-binding site on each actin molecule.

Note Summary of Contraction Mechanism --+ . Depolarization of nerve release of neurotransmitter acetylcholine at junction neuromuscular . Acetylcholine causes depolarization of sarcolemma anditsT tubules . Increased release ofCazr fromSR r fsz*binds toTnCsubunit oftroponin, exposing actin's myosin binding site . Thisallows themyosin headto interact withthe actin's myosin binding site . Myosin headbends (ratchet-motion), pulling actinpastmyosin . Myosin headisreleased onlyafteraddition of new ATPmolecule

2t

Tissue, andIntegument System, Connective Musculoskeletal

MUSCTE SMOOTH A, Smooth rnusde cells are derived ftorn a mesenchymalnetwork of cellscalled myoblasts. nonstriated cells. Ihey areelongated,spindle-shaped, eosinophiliccytoplasm. 1. Theycontaina single centrallylocatednucleusin a homogeneous 2. Eachcell is surroundedby a basallarnina and delicatereticular fibers3. Laversof smooth musclecellsarefound in the walls of blood vesels and hollow viscera. Bandsof smooth rnusclecellscanbe found in the erectorpili musclesof the skin. {. Smoothmusclecellsin a tissueareelectrically coupledwith eachother. a. With the electronmicroscope,areasof adjacentsmooth musclecellscanbe seenwith their cell membranescloselyapposedand forming gapjunctions. b. Similar electricaliunctions occur in cardiacmusclebut not in skeletalmuscle. 5. Smooth musclecells contain actin and myosin filaments,but they are not arrangedin orderly arrayslike thosefound in skeletalmuscle. llota

a. Bundlesofmyofilamentscourseobliquelyin the cell,forming a lattice-likearrangemenl

Densebodiesin smooth musclecellsservethefunction of Z linesin striatedmuscle.

b. A stding filament mechanismof contractionis tlought to occur' c. Thin filamentsinsert into densebodies,locatedwithin smoothrnusclecyoplasm and attachedto their membranes. B. Contraction of smooth muscle is slow and sustained.Individual cellsmay contract completelyor a waveof contractionmay propagatefrom one end of the tissueto the other. 1. Musclecell contraction maybe triggeredby variousstimuli. a. In somestructures(e.g.,ductusdeferens),nervesupplyto smoothmuscleis abundant. b. In the smooth muscleof the intestinal wall, contraction is modulatedby intrinsic rhythrnic depolarizationand by neural input. c. Hormonesmay also causesrnoothmusclecontraction;for example,oxytocin stimulatesuterine contraction, 2. Smoothmusclecellsare able to conc€ntrateCa2+in their cftoplasm. This ion playsan important role in the contractionof thesecells. a. Depolarizationof the cell membraneresultsin an influx of Ca2+from outsidethe cell. reticulum. b. Ca2+is sequestered in eitherthe cellmembraneor in the sparsesarcoplasmic

MUSCLE CARDIAC Cardiac muscle is discussedin the CardiovascularHistology chapter of Organ SystemsBook I (Volume III).

26

Histology: Muscle

SUMMARY OFMUSCLE TYPES Thble I-3-f . Tlpes of muscle. Muscle Type

Description

Skeletal

Bundles of long, cylindrical multinucleated cells

Yes

Strong, quick, discontinuous, voluntary contraction

Cardiac

Elongated, branched individual cells that lie parallel to eachother; intercalated disks between ends of cells

Yes

Strong,quick, continuous, involuntary contraction

Smooth

Fusiformcells

No

Weak,slow, involuntary contraction

Cross Striations

Activity

27

Integument Histology Theintegument consists oftheskin(epidermis anddermis) (sweat andassociated appendages glands, glands, sebaceous hairs, andnails). Considered thelargest bodyorgan, theintegument comprises approximately 16o/o oftotalbodyweight. lt isa highly specialized organ thatfunctions to protect thebodyfrominjury, desiccation, andinfection. lt alsoparticipates in sensory reception, excretion, thermoregulation, andmaintenance ofwater balance.

EPIDERMIS Epiderrnisis the outermostlayerof tJleintegument.It is a stratifiedsquamousorthokeratinized epitheliallayerof ectoderrnalorigin. A. Layersof the epiderrnisftom deepto superficialconsistof four strata. l. Stratum basale (stratum germinatirum) is a proliferative basallayer of columnar-like cellsthat containthe fibrous protein keratin. 2. stratum spinosum is a multilaminar layerof cuboidallike cellsthat are bound togetler by meansof numerouscltoplasmic extensionsand desmosomaljunctions. 3. Stratum granulosum consistsof flat polygonalcellsfilled with basophilickeratohyalin granules.Viewed at the electron microscopiclevel, thesecells also contain numerous membrane-coatinggrarules 4. Stratum corneum is the superficialstratum of deadcellsand consistsof severalto many layersofflat, anucleated,and cornified (keratinized)cells.In the epidermisofthe palms and soles,a thin, transitional zone of flat eosinophilicor pale-staining "r,o.leatei ""u, may occur asthe stratun lucidum. This layeris found only in regionswith a thick stratum corneum.

illnemonic BiG

Stratum Basale (Germinativum)

Sta6

Stratum Spinosum

GNe

Stmtum Gnnulosum

Lotsof Stratum lu.idum -, . charlty Stratum corneum

B. Cellsof the epidermis 1. IGratinoc''tes arethe most numerousand areresponsiblefor the production oftle family of keratin proteinsthat provide the barrier function of the epidermis. 2. Melanocytesare derivativesof neural crestectoderm,They are found in the dermis and arealsoscatteredamongthe keratinocftesin the basallayersof the epiderrnis,Thesedendritic cellsproducethe pigment melanin in the form of melanosomesthat are transferredto keratinocftes. 3. Langerhanscellsaredendritic cellsbut aremembersofthe immune systemand function asantigen-presentingcells.Theyhavealsobeenfound in other parts of the body,including the oral cavity and lymph nodes.

29

Tissue,andIntegument Connective System, Musculoskeletal

ClinicalCorrelate Psoriasis . T in number of proliferating cellsin stratum + stratum spinosum. basale thereisan1 Inaddition, This rateof cellturnover. greater epidermal results in andcontinous thickness oftheepidermis. turnover Addison Disease . J A C T H* t p i g m e n t a t i o n of skin Albinism . Melanocytes areunable to (either melanin synthesize oftyrosinase byabsence or inability of cells activity to takeuptyrosine).

4. Merkel cells are found in the basalepidermis and appearto function in concert with nerve fibers that are closelyassociatedwith them. They appearto have a sensoryfunction. At the electron microscopic level,their cytoplasm contains numerous membrane-bound granules that resemblethose of catecholamine-producingcells.

DERMIS Dermis is a connectivetissue layer of mesodermal origin subjacentto the epidermis and its basementmembrane.The dermis-epidermaljunction, especiallyin thick skin, is characterized by numerous papillary interdigitations of the dermal connectivetissueand epidermal epithelium. This increasesthe surface areaof attachment and brings blood vesselsin closerproximity to the epidermal cells. (The epidermis, like epithelia in general,is devoid of blood vessels.) Histologically,dermis consistsof two identifiable regions. A. Papillary layer, associatedprincipally with the dermal papillae, is the most superficial layer. It consistsof a looselypacked,irregular meshwork of collagenfibrils that contain fine blood vesselsand nerve endings. B. Reticular layer is the deeperdermal layer and consistsof coarsecollagenbundles intertwined with elasticfibers in a gel matrix. This layer is a typical denseirregular connectivetissue.

HYPODERMIS

Vitiligo This layer of loosevascularconnectivetissueis infiltrated with adipocytes and correspondsto the superficial fasciaof gross anatomy.However,since it contains the deepestportions of the . Disorder inwhich melanocytes aredestroyed, cutaneousglandsand hairs, it is alsoan important part of the skin. The hypodermis fastensthe skin to underlying musclesand other structures. to thought to besecondary nedysfu nction, autoimmu leading to depigmentation.

APPENDAGES CUTANEOUS

ClinicalCorrelate Bullous Pemphigoid . Abnormality ofthedermaljunction, leading epidermal to a blistering disorder. Pemphigus . Another blistering disorder; bylossof it iscaused junctions intercellular keratinocvtes. between

Cutaneousappendagesare all derivativesof the epidermis. A. Eccrine (merocrine) sweat glands are simple, coiled, tubular glands that are widely distributed over the body. 1. Secretoryportions are tightly coiled and consistof a single layer of columnar-like pyramidal cells. They extend deep within the dermis or hypodermis, where they are surroundedby myoepithelialcells,which aid in the dischargeof secretionby contraction. 2. Duct portions, composed of two cuboidal cell layers,are corkscrew-shapedand open onto the epidermalsurface.The luminal diameterof the duct is lessthan that of the secretory coil. 3. These glands are important in thermal regulation. When hypotonic sweat is released onto the body surface,heat is lost by water evaporation. 4. Control of the eccrineglandsis mainly by the innervation of cholinergic fibers. B. Apocrine sweatglands are alsosimple,coiled,tubular glandsbut are much lessabundant in their distribution than eccrineglands.They can be found in the axillary, areolar, and anal regions. 1. Secretoryportions of theseglands are composedof a singlelayer of cuboidal or columnar cells.They are larger and have a much wider luminal diameter than eccrine sweat glands.Myoepithelial cells surround the secretorycellswithin the basementmembrane and contract to facilitate secretion.

50

Histology: Integument

2. Duct portiom aresirnilarto thoseof eccrinesweatglandsbut generallyopenonto hair folIiclesinsteadof onto the epidermalsurfaces.

'In a NUbhell

3. Functionsof theseglandsin humansis not at all clear.In other mammals,apocrinesweat glandsarewidely distributedoverth€ bodyandserveavarietyoffirnctions relatedto olfaction and behavior.Specializedapocrine glands in the ear canal (ceruminous glands) producea secretionin conjunctionwith adjacentsebaceous glandsto form the protective earwax(cerumen), Apocrine sweatis normally odorlesswhen secretedbut becomes noticeabledue to ttre activity of cutaneousbacteria,

sLe ::Tlt ,.fn lff:,.|n [o@_Esserrja'yArtkry, doo €v€rywnerq ar€o.r, wihsome and anal erceplionsrcson (e8,slans

4. Control of the apocrineglandsis hormonal and via the innervation of adrenergicfibers. Theseglandsdo not begin to function until puberty.

* n lil']r** opcis

glandsaresirnple,branchedholocrineacinarglands.Theyusuallydischargetheir C. Sebaceous secretionsonto the hair shaft within hair follicles. Theseglands are found in the dermis throughout the skin, excepton tle palrnsand soles.

::*.

Hair foricl*

il;iffil lf:t mainty H,0 producing Nacl, urea, NH'uricacid

l. Seqetorl'portions consistofperipherallylocat€d,flattenedstemcellst}lat resemblebasal keratinocftes.Towardthe centerof the acini, enlargeddifferentiatedcellsare engorged with lipid. Death and ftagmentation of cells nearestthe duct portion result in the holocrine mechanismof secretion.

Inner-cholineqicMrcneqic trdion

2. Duct portions of sebaceous glandsare cornposedof stratified squamousepithelium that is continuouswith the hair canaland epidermalsurface.

I{Ote

3. Functionsinvolvethe lubrication of both hairs and cornified layersof the skin, aswell as resistanceto desiccation.

PrimaryContollingFactorof Sebaceous ClandSecretion

4. Control of sebaceous glandsis hormonal.Enlargementof the acini occursat puberty.

MalFte$osterone

D. Ilairs arelong, filamentousproiectionsconsistingof deadkeratinizedepidermalcells.Each hair derivesftom an epidermalinvaginationcalledthe hair follide, which possesses a terminal hair bulb, locatedin the dermis or hypodermis,from which the hair shaft grows. Bundlesof smoothmusclecells,calledarrector pili musd€s,areattachedto the hair follicle at one end and to the papillar),dermis at the other. C,ontractionof tlese musclesraisethe hairsand dimple the epidermis("gooseflesh").The folliclesand associated sebaceous glands areknown aspiloseboceousunits.

Female-combination of ovarian andadrenal anorogens

E. Nails,like hair, area modified stratum corneumofthe epidermis.They containhard keratin that forms in a manner similar to the formation of hair. Cells continuallv proliferate and keratinizeftom the stratum basaleof the nail natrix

5l

Anatomy Musculoskeletal muscles aswellastheirassociated of theskeleton covers themajorbones Thisextensive chapter group. foreachmuscle arereviewed Blood supply andinnervation andtendons.

SKULL Bonesof the skull may be classifiedasbelonging to the neurocranium (chondrocranium) (i.e., the portion of the skull that surrounds and protectsthe brain) or the viscerocranium (i.e.,the skeletonof the face). A. Osteology 1. Bones of the neurocranium a. Frontal b. Parietal c. Temporal (squamousand petrous portions) d. Occipital e. Ethmoid f. Sphenoid 2. Bones of the viscerocranium a. Maxilla b. Nasal c. Zygomatic d. Mandible e. Vomer f. Lacrimal g. Palatine h. Inferior nasalconcha

t5

Musculoskeletal System, Connective Tissue, andIntegument

B. Articulations. Most skull bones meet at immovable joints calledsutures. The soleexceptionis the temporomandibular joint (TMI), a synovialjoint that has a hinge-gliding movement. 1. The coronal suture is between the frontal and the parietal bones.

Clinical Correlate

2. The sagittal suture is between two parietal bones.

Theanterior fontanelle, or "softspot,"serves asa sitefor prenatal withdrawal of blood samples fromthesuperior sagittal sinus, Theanterior fontanelle usually closes by18 months, andtheposterior fontanelle by6 months.

3. The lambdoid suture is between the parietal and the occipital bones.

Clinical Correlate Thepterion isa landmark for themiddle meningeal artery, whichgrooves theboneofthe skullinternal to thissite.A blowto thelateral aspect, or "temple," oftheskullmay cause theartery to rupture, thereby causing anepidural hemorrhage. lf bloodis allowed to accumulate inthe epidural space, shifting ofthe brainmayoccur, whichcan cause thesharp, freeedgeof thetentorium cerebelli (tentorial incisure) to cutinto brainstemtissue ontheside opposite thein1ury. This pressure mustberelieved quickly, or death ensues.

4. The bregma is the point at which the coronal suture intersects the sagittal suture and is the site of the anterior fontanelle in an infant. 5. The lambda is the point at which the sagittal suture intersectsthe lambdoid suture and is the site of the posterior fontanelle in an infant. 6. The pterion is the point on the lateral aspect of the skull where the greater wing of the sphenoid,parietal,frontal, and temporal bones converge. 7. The temporomandibular joint is betweenthe mandibular fossaof the temporal bone and the condylar head of the mandible.

FACE A. The muscles of facial expressionare derived from the second pharyngeal arch and are supplied by motor branchesof CN VII (TableI-5-1).

Thble I-5-f . Muscles of facial expression. Muscles of the scalp Frontalis Occipitalis Muscles of the ear Anterior auricular Superior auricular Posteriorauricular Muscles of the rim of the orbit Orbicularis oculi Corrugator supercilii Muscles of the nose Procerus Nasalis Muscle of the neck Platvsma

t4

Muscles surrounding the lips Levatorlabii superioris alaequenasi Levator labii superioris Zygomaticus minor Zygomaticus major Levator anguli oris (caninus) Risorius Depressoranguli oris (triangularis) Depressorlabii inferioris (quadratuslabii inferioris) Mentalis Buccinator Orbicularis oris

Anatomy: Musculoskeletal

Superficial temporalartery

ClinicalCorrelate

Temporal Facial artery

Marginalmandibular Mandi bul ar nerve (CN V3)

byan Bellpalsy iscaused paralysis idiopathic ofthe present facial nerve. Patients withaninability to close the of eye,sagging ofthecorner to themouth, aninability voluntarily, and smile drooling, aninabilityto movefoodfrom thevestibule to theoralcavity proper. Thecondition usually resolves spontaneously.

Posteriorauricular

Figure l-5-1.Theface and the parotid gland.

B. The parotid glurd is the largestof the salivary glands and has a denseconnectivetissue capsule (FigureI-5-1). Structuresfound within the substanceof this gland include the following: 1. Motor branches of the facial nerve. CN VII entersthe parotid gland after emergingfrom the stylomastoidforamen at the baseof the skull. 2. Superficial temporal artery and vein. The artery is a terminal branch of the external carotid artery. 3. External carotid artery 4. Retromandibularvein, which is formed from the maxillary and superficial temporal veins 5. Great auricular nerye, which is a cutaneousbranch of the cervicalplexus 6. Auriculotemporal nerve, which is a sensorybranch of Vr. It suppliesthe TMJ and conveyspostganglionicparasympatheticfibers from the otic ganglion to the parotid gland. 7. Parotid (Stensen)duct, which entersthe oral cavity at the level of the maxillary secondmolar 8. Transversefacial artery, a branch of the superficial temporal arrery C. The facial artery is a branch of the external carotid artery in the neck. It terminatesas the angular artery near the bridge of the nose.

Note Thefacial veinhasmany thatcommunicate tributaries withthecavernous sinus. Because theveinshaveno infections valves, extracranial area a triangular arising within ofthe bounded bythebridge andtheangles ofthe nose, mouthmaymove the intracranially to reach Thisareais cavernous sinus. to asthe sometimes referred "danger triangle."

D. The facial vein parallelsthe courseof the facial artery.It terminatesby joining the anterior branch of the retromandibular vein to form the common facial vein.

55

Musculoskeletal System, Connective Tissue, andlntegument

NECK A. Osteology

Thalamus

Superiorsagittal

Tentor ium cere belli C ere bellum

Corpusca

P ons Frontalsinus Cribiformplate of ethmoidbone

External occipital protuberance

Torus tubarius

Internal occipital protuberance

Hard palate

Falxcerebelli

Tongue Atlas

Epiglottis Ma n d i b l e Geniohyoid

Dens of axis

Posterior wallof pharynx

Mylohyoid Thyroidcartilage

Retropharyngeal space

Larynx Oricoidcartilage,arch

Trachea

Laminaof cricoidcartilage

Figure l-5-2.Sagittal section of the head and neck.

Note Movement attheatlantojointcauses occipital flexion andextension, or nodding of "yes"). thehead(e.g., saying Movement attheatlantoaxial jointcauses lateral rotation "no"), (e.g., saying

Note Thehyoidistheonlybonein thehuman bodythatdoesnot directly articulate withatleast oneotherbone.lt isstabilized bytheattachment ofvarious muscles andligaments.

56

1. Cervical vertebrae. There are sevencervicalvertebraeof which the first two are atypical. All cervicalvertebraehaveopeningsin their transverseprocesses, the foramina transversaria, which, when aligned,produce a canal that transmits the vertebral artery and vein. a. Atlas. This is the first cervical vertebra (Cl). It has no body and leavesa spaceto accommodatethe dens of the secondcervicalvertebra. b. Axis. This is the secondcervicalvertebra (C2).It has a tooth-shapedprocess,the dens (odontoid process),which articulateswith the atlasas a pivot joint. Movement at this joint allowslateral rotation of the head. 2 . Hyoid bone is a small U-shapedbone, which is suspendedby musclesand ligamentsat the level of vertebraC3.It occupiesthe angle of the throat that separatesthe neck from the floor of the oral cavity.

3 . Laryngeal prominence is formed by the lamina of the thyroid cartilage.It is more prominent in men than in women and children. 4 . Cricoid cartilage. The arch of the cricoid, another laryngealcartilage,is palpablebelow the thyroid cartilageand superior to the first trachealring (vertebrallevel C6).

Anatomy: Musculoskeletal

B. Triangles of the neck. The neck is divided into a posterior and an anterior triangle by the sternocleidomastoid muscle. These triangles are subdivided by smaller muscles into six smallertriangles (Figure I-5-3).

Submandibular triangle

Mastoidprocess Sternocleidomastoid muscle Occipitaltriangle

CN XI Submentaltriangle

Carotidtriangle Subclaviantriangle

Musculartriangle

Figure l-5-3.Trianglesof the neck.

1. Posterior triangle is bound by the sternocleidomastoid, the clavicle, and the trapezius. The floor of the posterior triangle is formed by the splenius capitis, the levator scapulae, and the medial and posterior scalenemuscles. a. Occipital triangle is located abovethe inferior belly of the omohyoid muscle. Its contents include the following: (1) CN XI is the cranial nerve that suppliesmotor innervation to the trapeziusand sternocleidomastoidmuscles.

Cliniol Conelate presence ofa Theoccasional pressure cervical ribmayexert trunk ofthe onthelower plexus brachial oronthe rib artery. Cervical subclavian type isa particular syndrome syndrome. ofthoracic outlet

(2) Cutaneousbranchesof the cervical plexus are the lesseroccipital, great auricular, transversecervical, and supraclavicular nerves. b. Subclavian (omoclavicular, supraclavicular) triangle is located below the inferior belly of the omohyoid. Its contents include the following: (1) Brachialplexus (supraclavicularportion-roots, trunks), the branchesof which enter this region from behind the scalenusanterior muscle.The branchesinclude the dorsal scapular,long thoracic, subclavius,and suprascapularnerves. (2) The third part of the subclavian artery entersthe subclaviantriangle from behind the scalenus anterior muscle anterior to the brachial plexus. Branches may include the transversecervical and/or suprascapulararteries. (3) The subclavianvein passessuperficid to scalenusanterior muscle. It receivesthe externaljogol"t vein, a superficialvein that crossesthe sternocleidomastoidmuscle.

t7

Musculoskeletal System, Connective Tissue, andIntegument

ClinicalCorrelate prominent Anunusually jugular external vein(known asjugular venous distension may be a sign of heart [JVDI) failure whenaccompanied by pressure a riseinvenous in thesuperior venacava andits tributaries. lt mayalsobea signof obstruction ofthe superior venacavabya tumor.

Bridgeto Cardiovascular (thecarotid A chemoreceptor (the body)anda baroreceptor carotid sinus) arelocated in thewallof thecarotidarteryat or nearitspointof bifurcation. Theformerissensitive to oxygen levels intheblood, whereas thelatter responds to increases in bloodpressure. Visceral afferent impulses from eachof thesereceptors are conveyed byCNlX. Baroreceptors and chemoreceptors arediscussed intheCardiovascular and Respiratory Physiology chapters in Organ Systems Bookt (Volume lll).

2. Anterior triangle is bound by the sternocleidomastoid muscle, the midline of the neck, and the inferior border of the body of the mandible. a. Muscular triangle is bound by the sternocleidomastoid muscle, the superior belly of the omohyoid muscle, and the midline of the neck.Its contents include the infrahyoid (strap) muscles,which function to control movementsof the hyoid bone and larynx during speechand deglutition (swallowing). b. Carotid (vascular) triangle is bound by the sternocleidomastoidmuscle, the superior belly of the omohyoid muscle, and the posterior belly of the digastric muscle. The carotid triangle contains the following: (1) Internal jugular vein (2) Common carotid arterf, bifurcates at the upper border of the thyroid cartilage (i.e., vertebral level C3) to form the internal and external carotid arteries. The external carotid artery has six branches (i.e., the superior thyroid, the ascending pharyngeal,the lingual, the facial, the occipital, and the posterior auricular arteries). Thesesupply structuresof the neck and face (Figure I-5-4). (3) Vagusnerve (CN X) (a) Hypoglossalnerve (CN XII) (5) Internal and external laryngeal branches of the superior laryngeal branch of the vagus nerve. The internal larygeal nerve conveyssensory information from the laryngeal mucosa above the level of the vocal folds, and the external laryngeal nerye supplies motor fibers to the cricothyroid, an intrinsic muscle of the larynx. c. Digastric (submandibular) triangle is bound by the anterior and posterior bellies of the digastricmuscle and the inferior border of the body of the mandible. The floor of this triangle is formed by the hyoglossusand mylohyoid muscles.It contains the submandibular salivary gland. d. Submental triangle is bound by the anterior belly of the digastric muscle, the hyoid bone, and the midline of the neck. The floor of this triangle is formed by the mylohyoid muscle.It containsthe submentally-ph nodes. C. Root of neck This area communicates with the superior mediastinum through the thoracic inlet. Structures of the region include the following: 1. Subclavian artery and vein. The subclavian artery passesposterior to the scalenusanterior muscle,and the vein passesanterior to it. Branchesof the artery include: a. Vertebral artery b. Thyrocervical trunk, which gives rise to the inferior thyroid, the transversecervical, and the suprascapulararteries. c. Internal thoracic artery d. Corticocervical trunk

58

Anatomy: Musculoskeletal

Note

temPoralarterY Superficial

Mnemonic for Branches of External CarotidArtery "Salfops Max"

Transverse facialartery

thyroid Superior Maxillary artery

artery

Facialartery

Descending branch

Externalcarotid

Internalcarotid

artery

artery

pharyngeal Ascending Lingual Occipital Posterior auricular temporal Superficial I terminal Maxillary Jbranches

Lingualartery Superior thyroidartery Vertebral

Inferiorthyroidartery

artery

Commoncarotidartery

Costocervical trunk

First

ClinicalCorrelate

Internal thoracicartery Thyrocervicaltrunk

Subclavianartery

Figure I-5-4.Arteries of the neck. 2. Phrenic nerve is a branch of the cervicalplexus,which arisesfrom C3, C4, and C5. It is the sole motor nerve to the diaphragm. It crossesthe anterior scalenemuscle from lateral to medial to enter the thoracic inlet. 3. Recurrent laryngeal nerve is a branch of the vagus nerve. This mixed nerve conveyssensory information from the laryngealmucosabelow the level of the vocal folds and provides motor innervation to all the intrinsic musclesof the larynx except the cricothyroid muscle. 4. Thoracic duct terminatesat the junction of the left subclavianand the left internal j,tgnlar veins.On the right side of the body, the right lymphatic duct terminatesin a similar fashion. D. Fasciasof the neck 1. Superficial investing fascia enclosesthe platysma, a muscle of facial expression,which has migrated to the neck. 2. Superficial layer of deep investing fascia surrounds the trapezius and sternocleidomastoid muscles. 3. Pharyngeal (visceral) fascia surrounds the pharynx.

nerves Therecurrent laryngeal during thyroid arevulnerable nerves lf oneofthese surgery. quality ofthe isdamaged, the resulting voicemaybechanged, in extreme hoarseness. ClinicalCorrelate Infection withinthepotential between thefascial spaces planes poorly to responds because the treatment antibiotic avascular. spaces areessentially usually therefore Treatment of involves thee$ablishment of theaffected external drainage between the area. Thespace fascial alarandprevertebral (danger is layers space') withthe continuous infection can mediastinum; pass intothe therefore potentially media$inum, resulting ina fatalpericarditis.

59

Musculoskeletal System, Connective Tissue, andlntegument

4. Prevertebral fascia investsthe prevertebral muscles of the neck (i.e., longus colli, longus capitis). This layer givesrise to a derivative known as the alar fascia. E. The major muscle groups and their innervations. A simple method of organizing the musclesof the neck is basedon two basicprinciples: (1) The musclesmay be arrangedin groups, according to their functions; and (2) all musclesin a group share a common innervation with one exceptionin eachgroup.

In a Nutshell MuscleGroupInnervation Exception Tongue

CNXII

Palatoglossus (cNx)

Larynx

Recunent laryngeal branch of vaSus

Cricothyroid (external laryngeal branch of vagus)

Pharynx

CNXand CNXI

Stylopharyngeus(CNlX)

Softpalate

CNXand CNXI

Tensor veli palatini (cNv3)

lnfrahyoid

AnsacervicalisThyrohyoid (branch of cervical of Cl) plexus (Cl, O, C3)

1. Group l: Muscles of the tongue. All intrinsic musclesplus all but one of the extrinsic muscles(i.e., those containing the suffix, glossus)of the tongue are supplied by CN XII. The one exceptionis palatoglossus, which is supplied by CN X. 2. Group 2: Muscles of the larynx. All but one of the intrinsic musclesof the larynx are supplied by the recurrent laryngeal branch of the vagus nerve. The sole exception is the cricothyroid muscle, which is supplied by the external laryngeal branch of the vagus. 3. Group 3: Muscles of the pharyruc All but one of the longitudinal and circular musclesof the pharynx are suppliedby CNs X and XI (cranial portion). The soleexceptionis the stylopharyngeusmuscle,which is supplied by CN IX. 4. Group 4: Muscles of the soft palate. AII but one of the musclesof the palate are supplied by CNs X and XI (cranial portion). The soleexceptionis the tensor veli palatini, which is supplied by CN Vr. 5. Group 5: Infrahyoid muscles.All but one of the infrahyoid musclesare suppliedby the ansa cervicalisof the cervicalplexus(Cl,Cz,and C3). The exceptionis the thyrohyoid,which is suppliedby a branch of Cl. (This branch of Cl alsosuppliesthe geniohyoidmuscle).

THORACIC WAtt A. Osteology 1. There are l2thoracic vertebrae.

Note Thesternal angle isa useful landmark formanythoracic structures andevents:

a. The vertebraehavefacetson their bodies to articulatewith the headsof ribs; eachrib head articulateswith the body of the numerically correspondingvertebraand the one below it. b. The thoracic vertebraehave facetson their transverseprocessesto articulate with the tuberclesof the numerically correspondingribs. 2. Sternum a. The manubrium articulates with the clavicle and the first rib. It meets the bodv of the sternum at the sternal angle, an important clinical landmark.

. Thesecond pairof costal cartilages attaches here, and theribsarecounted from thispoint.

b. The body articulates directly with ribs 2-7; it articulates inferiorly with the xiphoid processat the xiphisternal junction.

. Bifurcation ofthetrachea formstheprimary bronchi.

c. The xiphoid processis cartilaginousat birth and usually ossifiesand unites with the body of the sternum around age40.

. Thesuperior venacavais formed fromtherightand leftbrachiocephalic veins. . Thesternal angle marks the beginning andendofthe aortic arch.

40

3. Ribs and costal cartilages. There are 12 pairs of ribs, which are attached posteriorly to thoracic vertebrae.

Anatomy: Musculoskeletal

Firstrib Clavicle Second rib

Scapula

Manubriumof sternum Sternalangle Body of sternum Costochondral junction

ClinicalCorrelate

Figure l-5-5.Thoracic wall.

a. Ribs l-7 aretermed "true ribs," and attach directly to the sternum by costalcartilages. b. Ribs 8-10 are termed "false ribs," and attach to the costalcartilageof the rib above. c. Ribs 11 and 12 have no anterior attachments,and are therefore classifiedas both "floating ribs" and falseribs. d. The costalgrooveis locatedalong the inferior border of eachrib and providesprotection for the intercostalnerve, artery,and vein. Ribs 1, 2, L0,11, and 12 areatypical. B. Muscles 1. External intercostal muscles a. There are 11 pairs of externalintercostalmuscles.Their fibers run anteriorly and inferiorly in the intercostal spacesfrom the rib above to the rib below. b. Thesemusclesfill the intercostalspacesfrom the tuberclesof ribs posteriorly to the costochondraljunctions anteriorly; they are replacedanteriorly by externalintercostal membranes. 2. Internal intercostal muscles

Ribfractures represent the mostcommon chest injuries andusually result fromdirect blows suchassteering wheel impact, falls, andcrushing injuries to thechest. Since the first2 ribsareprotected bythe clavicle andpectoralis major muscle, andthelast2 ribsare "mobile," theyaretheleast commonly injured. Themiddle onesarethemostcommonly fractured. Insomecases, fractured ribsmaycause damage to theheart, lungs, trachea, bronchi, esophagus, spleen, liver, andkidneys. Note Thefibersof theexternal intercostal muscles runinthe "hands-i n-pockets" direction; thoseoftheinternal intercostal layerrunatright angles to theexternals.

a. There are 11pairs of internal intercostalmuscles.Their fibers run posteriorly and inferiorly in the intercostal spacesdeep to the external layer. b. These muscles filI the intercostal spacesanteriorly from the sternum to the angles of the ribs posteriorly; they are replacedposteriorly by internal intercostalmembranes.

4l

Tissue, andIntegument System, Connective Musculoskeletal

3. Innermost intercostrl muscles a. The deeplayersof th€ intemal int€rcostalmusclesarethe innermostintercostalrnuscles' b. Thesemusclesareseparatedftom the internal intercostalmusdesby intercastalnerves andvesels. .

4. Subcostalismuscles (1) Fibersextendfrom the inner surfaceof the angle of one rib to the rib t}rat is inferior to it. (2) Fibersmay crossmore than one intercostalspace. 5. Tranwersusthoracismuscle (1) Fibersattadr postedorlyto the sternum. (2) Fiberscrossmore than one intercostalspace. (3) Intemal thoracic vessels,branchesof the subclavianarteries,run anterior to thesefibers. C. Intercostal structrf€s

'

1 lntercostal nerves a. Thereare 12 pairsof thoracicnerves:11intercostalpairs,and 1 subcostalpair. b. Intercostaln€rvesarethe ventralprimary rami of thoracicspinalnerves.Thesenerves supplythe skin and musculatureof the thoracic and abdominalwalls. 2. Int€rcostal arteries a. There are 12 pairs of posterior and anterior arteries,11 intercostalpairs, and 1 subcostalpair. b. Anterior intercostalarteries (l) Pairs1-{ are derivedftom the internal thoracicarteries. (2) Pairs7-9 arederivedfiorn the muscr:lophrenicarteries. (3) Thereare no anterior intercostalarteriesin the last two sPaces; thesespacesare suppliedby branchesof the posterior intercostalarteries. c. Posteriorintercostalarteries ( I ) The first two pairs ariseftom the superiorintercostalartery a branchof the costocervicd trunk of the subclavianartery. (2) Nine pairsof intercostaland onepair of subcostalarteriesarisefrom the tloracic aorta.

'

3. Intercostrl veins

andmuscuveinsdrainto theinternalthoracic of theintercostd

F"I1!g|-Cf,g-.-*

" ffi'f;:n'jfifts

Achest tubeisplaced iust i above thelower ribofthe intenpace soasnotto disrupt thenerve, artery, andveinthat lieinthecoshlgroove behind margin theinferior Ofeachrib.

drainto theazygos b. Post€riorbranches rystemof veins.

42

4' Lymphaticdrainageof intercostalspaces nod€s. is to theinternalthoracic(parasternal) a.Anteriordrainage is to thepara-aorticnodesof theposteriormediastinurn' b. Posteriordrainage

Anatomy: Musculoskeletal

ANTERIOR ABDOMINAT WAtt

Lumbar vertebrae

Sacrum

Coccyx Pubic crest

Pubic tubercle

Figure l-5€. The abdominopelvic cavity.

A. Osteology.Unlike the thoracic wall, the bony support of the abdomen is minimal, consisting only of the lumbar vertebraeand portions of the pelvis (the ilium and the pubis). 1. There are five lumbar vertebrae, Ll through L5. 2. The ilium is part of the hip bone or os coxae. The osteology of this bone is presentedin detail in the section on the pelvis.Only the landmarks pertinent to the anterior abdominal wall are listed here. a. Anterior superior iliac spine (ASIS) b. Iliac fossa c. Iliac crest d. Iliac tubercle 3. Pubis (part of os coxae) a. Pubic tubercle b. Pubic crest c. Pubic symphysis

45

andlntegument Tissue, System, Connective Musculoskeletal

B. Surface anatomy 1. Linea alba is a shallow groove that runs vertically in the median plane from the xiphoid to the pubis. It separatesthe right and left rectus abdominis muscles. 2. Lineasemilunaris is a curved line defining the lateral border of the rectus abdominis, a bilateral feature. 3. Inguinal groove indicates the site of the inguinal ligament, the rolled-over, free border of the external oblique aponeurosis. It separatesthe abdomen superiorly from the lower extremity inferiorly. The inguinal ligament extends from the ASIS to the pubic tubercle. C. Planesand regions. There are four planesto define nine regions of the abdomen (Figure l-5-7).

Figurel-5-7.Regionsof the abdomen.RH = righthypochondrium; RL - rightlumbar;LL = leftlumbar; LH = lefthypochondrium; = leftinguinal. Rl = rightinguinal;Ll

1. Subcostalplane (horizontal) passesthrough the inferior margins of the 10th costalcartilages. 2. Tianstubercular plane (horizontal) passesthrough the iliac tubercles(body of L5). 3. Midclavicular lines (vertical) are the two planes that passfrom the midpoint of the clavicle to the midpoint of the inguinal ligament.

M

Anatomy: Musculoskeletal

D. Fascial layers 1. Superficial fascia a. Camper fascia is subcutaneousand variable in thicknessdue to the presenceof fat. b. Scarpa fascia is a deeper membranous layer devoid of fat and is continuous with the fascia lata of the thigh below the inguinal ligament, the dartos fascia of the scrotum or the labia majora, and Colles fascia of the perineum. 2. Deep (innominate) fascia is the investing fascia of the abdominal musculature and is continuous with the externaloblique aponeurosis. E. Muscles 1. External oblique a. The fibers run anteriorly and inferiorly (i.e., the hands-in-pocketsdirection like the externalintercostallayer in the thorax).

ClinicalCorrelate A potential space exists between Scarpa fascia andthe deepinnominate fascia where bloodor urineextravasated froma ruptured membranous urethra mayaccumulate in a patient. male Thespread of fluidislimhed along a line approximately oneinchbelow theinguinal ligament, where Scarpa fascia blends withthe fascia lata.

b. As fibers passmedially,they becomeaponeurotic and contribute to the anterior layer of the rectussheath. c. Inferiorly, the free border of the external oblique aponeurosisforms the inguinal ligament. d. The superficial inguinal ring is an opening in the external oblique aponeurosisjust superior and lateral to the pubic tubercle. e. In men, this layer (externaloblique aponeurosis)givesrise to the external spermatic fascia of the spermaticcord. 2. Internal oblique a. The fibers run posteriorly and inferiorly at right anglesto thoseof the externaloblique like those of the internal intercostallayer in the thorax. b. As the fibers passmedially, they become aponeurotic and split to contribute to the anterior and posterior layersof rectus sheath. c. Inferiorly, thesefibers contribute to the formation of the conjoint tendon. d. In men, this layer (internal oblique aponeurosis)givesrise to the middle spermatic fascia and the cremaster muscle of the spermaticcord. 3. Transversus abdominis a. The muscle fibers run horizontally.As the fibers passmedially,they contribute to the posterior layer of the rectus sheath. b. Inferiorly, the fibers join with those of the internal oblique to form the conjoint tendon. 4. Rectus abdominis a. The fibers run vertically betweenthe pubic symphysisand the xiphoid process. b. The right and left recti musclesare separatedmedially by the linea alba. c. The rectussheathis formed by aponeurotic fibers of three lateral musclelayers. (1) The arcuate line is located one-third of the distancebetween the umbilicus and pubis. It is a landmark for the changein disposition of the aponeuroticfibers.Above the arcuateline, posterior and anterior layersof the rectussheathhaveequal thickness;belowit, all aponeurotic fibers run anterior to the rectusabdominis.

45

Tissue, andlntegument Connective Musculoskeletal System,

ClinicalCorrelate lndirect inguinal hernias are andinvolve oftencongenital anoutpouching of peritoneum through thedeep orviscera just inguinal ring,beginning lateral the to thepointwhere vessels inferior epigastric cross ligament. Direct theinguinal areacquired inguinal hernias asa result of abdominal Theybypass the straining. ringandgo deepinguinal ring. directly to thesuperficial to the Theybeginmedial inferior epigastric vessels and burgeon through theinguinal (Hesselbach) triangle, which isboundbytheinferior epigastric vessels, theinguinal ligament, andthelateral borderoftherectus abdominis.

(2) Superior and inferior epigastricvesselstravel in the posterior layer of the rectus sheath. F. Transversalisfascia 1. The transversalisfascialines the abdominal cavity.It forms the posterior layer of the rectus sheathbelow the arcuateline and the internal spermatic fascia of the spermatic cord. 2. The deep inguinal ring begins as an outpouching of transversalisfasciajust lateral to where the inferior epigastricvesselsintersectthe inguinal ligament. 3. The transversalisfascia is separatedfrom the peritoneum by a layer of fatty areolar extraperitonealconnectivetissue. G. Nerves, blood vessels,and lymphatics 1. Innervation of the skin and musculature of the anterior abdominal wall is via branchesof the ventral primary rami of the lower six thoracic spinal nerves(includes subcostalnerve), plus the iliohypogastricand ilioinguinal branchesof the ventral primary ramus of Ll. 2. The major arterial blood supply to the anterior wall is derived from the superior epigastric branch of the internal thoracic artery as well as the inferior epigastricand the deep circumflex iliac branches of the external iliac artery. 3. Venousdrainage from the anterior wall is to the superficialepigastric,the lateral thoracic veins superiorly, and the greatsaphenousvein inferiorly. a. Lymph from tissuesof the anterior wall drains to axillary nodessuperiorly and to superficial inguinal nodes inferiorly.

WAtt POSTERIOR ABDOMINAT The posterior abdominal wall is locatedbehind the posterior layer of the parietal peritoneum. A. Osteology. The bony structure of the posterior wall includes many of the samefeaturesas the anterior wall of the abdomen and bony landmarks from the thorax and the inferior extremity. 1. Five lumbar vertebrae(L1 through L5) 2. Iliac crest 3. Iliac fossa 4. Twelfth pair of ribs 5. Lessertrochanter of femur B. Muscles

Note

1. The quadratus lumborum extends upward from the iliac crest to the inferior border of the 12th rib. It stabilizesthe 12th rib during inspiration. 2. The psoasmajor arisesfrom the transverseprocessesof the lumbar vertebrae.

Theiliopsoas muscle isthe thatinserts onlymuscle trochanter. onthelesser (Filet mignon comes from thepsoas muscle in cows.)

a. Insertion, along with iliacus,is on the lessertrochanter of the femur. b. It is the chief flexor of the hip. 3. The iliacus originatesfrom the iliac fossa. a. It joins with the psoasmajor to insert on the lessertrochanter. b. Togetherwith psoasmajor, it is known as the iliopsoas.

46

Anatomy: Musculoskeletal

PEwTS A. Osteology 1. Pelvicgirdle is formedanterolaterallyby the pairedhip bones(oscoxae)and is completed posteriorlyby the sacrumand cocc''n a. The oscoxaeis composedof the ilium, the pubis,andthe ischium,includingthe ischial spineand the ischialtuberosity b. Greaterand lessersciaticnotches(foramina) c. Sacrospinous and sacrotuberousligaments 2. Pelviccavity a. Pelvismajor (falsepelvis)lies abovethe pelvicbrim betweenthe iliac fossae.

Oinkal GOrrelab

b. Pelvisminor (true pelvis) is th€ spac€betweenthe pelvic inlet (pelvic brim) and the ouuet.

;"rnesplne isan "* of theischium obstetric landmark inthe administration of anesthesia for a pudendal nerveblockto eliminate sensation inthe

B. Pelvicdiaphragn is the muscularfloor ofthe pelviccavity. 1 Levatoreni hasopeningsto transmit the urethra andthe anusin both sexesand the vagi" na in women.

a.pubococcygeus b. Puboreaalis c.Iliococcygeuscnalinthevicinityofthe 2. coccygeusis the posterior portion of the pelvic diaphragm

lhe : r:ff:T:::'.1{elivery puoenoat neryepasses (Alcock) throughthepudendal ischialspine'

Note

UPPER IIMB A. Pectoral region, axilla, and shoulder 1. Osteology (Figure I-5-S)

Theclavicle isthefirstboneto ossify in fetallifeandisthe mo$frequently fractured boneinthebody.

47

Tissue, andIntegument System, Connective Musculoskeletal

Acromion Coracoidprocess Lessertubercle Greatertubercle Intertubercular groove

Surgical neck

Deltoidtuberosity

Lateral

Medialepicondyle

Capitulum Head of radius

Trochlea

Tuberosity of radi

Coronoidprocess

Radius

Styloidprocess of radius Proximal phalanx

Carpalbones Metacarpalbones

Distal

phalanx

Anteriorview

Figure l-5-8.Osteology of the upper limb.

48

Anatomy: Musculoskeletal

major Pectoralis Serratus anterior

Pectoralis minor Intertubercular groove

Latissimus dorsi Teresmajor Subscapularis Rib

Scapula

Figure l-5-9.Transversesection through the axilla.

a. Sternum has three parts: the manubrium, the body, and the xiphoid process. b. Clavicle is an S-shapedbone, which articulateswith the manubrium of the sternum medially and with the acromion processof the scapulalaterally. c. Scapula landmarks include the acromion process, or point of the shoulder, and the coracoid process,which is an anteriorly projecting "crow's beak."The glenoid fossa of the scapulaarticulateswith the head of the humerus. The subscapular fossa forms the major portion of the anterior surfaceof the scapula.The spine of the scapula,or shoulder blade, is located posteriorly and separatesthe supraspinous fossa above from the infraspinous fossa below. d. Humerus is the bone of the arm. In addition to the head of the humerus, landmarks include the bicipital groove (intertubercular sulcus)and the lateral and medial lips of the bicipital groove. The greater and lesser tuberosities are located inferior to the head of the humerus. The deltoid tuberosity is an elongated,roughened area of the shaft of the humerus. 2. The axilla is a space shaped like a truncated pyramid, which serves as a passageway between the neck and the upper limb. Its apex is formed by the cervicoaxillary canal and is bounded by the clavicle,scapula,and first rib. The baseis formed by the fasciaand haircoveredskin of the armpit.

Nole Thesurgical neckofthe humerus isafrequent siteoffractures. The axillary nerveisatrisk.

a. Walls of the axilla (Figure I-5-9) (1) The anteriorwall is formed by the pectoralismajor and pectoralisminor. The pectoralismajor forms the anterior axillary fold. (2) The posterior wall is formed by the subscapularis, teresmajor, and the latissimus dorsi muscles.The latissimusdorsi forms the posterior axillary fold. (3) The medial wall is formed by the serratusanterior muscle and the underlying ribs and intercostalspaces. ( ) The lateral wall is formed by the bicipital groove of the humerus.

49

System, Connective Tissue, andlntegument Musculoskeletal

ClinicalCorrelate

b. Contents of the axilla ( 1) The axillar'' arter'' is a continuation of the subclavian artery asit passesover the outer border of the first rib. It becomesthe brachial artery at the outer border of the teres major. The axillary artery has six branches.Of these,the most clinically significant are the thoracoacromial, the lateral thoracic, the subscapular,and the posterior humeral circumflex arteries.

trunkof Damage totheupper plexus mayresult thebrachial to flex,abduct, in aninability rotate the andlaterally dueto a weakness of shoulder thedehoid androtator cuff (When thisoccurs muscles. frombirth,it isknownasErb plexus palsy.) Lower brachial theulnarnerve injuries involve andresult in reduced ofthemedial arm, sensation forearm, andhand, aswellas weakness intheforearm and (When this occurs from hand. trauma,ifs knownasKlumpke palsy.)

(2) The axillaryvein follows the samepattern asthe artery.It receivesthe basilic and cephalic veins. (3) The axillary ly-ph nodes drain ly-ph from the upper extremiry the lateral breast, and the superficial portions of the thoracic and upper abdominal wall. The axillary nodes are divided into five groups: apical, central, humeral, pectoral, subscapular.Efferent lymphatics from the last four groups drain to the apical nodes,which then drain to the subclavian ly-ph trunk. (a) The bradrialplexus is the somatic nerve plexus of the upper limb. It is formed from the ventral primary rami of cervical nerves 5-8 and the ventral primary ramus of the first thoracic nerve. The roots of the plexus emerge from between the middle and anterior scalenemuscles in the neck. Th.y combine to form trunks, which divide into anterior and posterior divisions. The divisions pass through the cervicoaxillary canal to reach the axilla and reunite to form lateral, medial, and posterior cords in relation to the second part of the axillary artery.Each trunk divides into nryoterminal branches,which comprise the major nerves of the arm, forearm, and hand (Tablel-5-2).

Thble I-5-2. Major Branches of the brachial plexus. INFRACIAVICUTAR

SUPRACI.AVICUI.A,R

Roots

C5: Dorsal scapular nerve; supplies rhomboids C5, C6, C7: Longthoracic nerve; supplies serratus

Trunl$

Cords

Upper trunk Lateral cord 1. Lateral pectoral nerve; supplies Suprascapularnerve; pectoralismajor supplies supraspinatus and infraspinatus Medial cord 1. Medial pectoral nerve; supplies pectoralis major and minor 2. Medial brachial cutaneous nerve; supplies skin of the medial arm

Branches(Terminal)

1.Musculocutaneousnerve 2.Lateral head of median nerve 1. Medial head of anterior median nerve 2. Ulnar nerve

3. Medial antebrachial cutaneous nerve; supplies skin of the medial forearm C8, T1

Posterior cord 1. Upper subscapularnerve; supplies subscapularis 2. Middle subscapularnerve (thoracodorsalnerve); supplies latissimusdorsi 3. Lower subscapularnerve; supplies teres major

50

1. Radial nerve 2. Axillary nerve

Anatomy: Musculoskeletal

Thble I-5-3. Nerve supply of shoulder muscles. Muscles Acting on the Shoulder Flexors Coracobrachialis Deltoid (anterior segment) Pectoralismajor Extensors Teresmajor Latissimusdorsi Deltoid (posterior segment) Abductors Deltoid (middle segment) Supraspinatus(initial abductor) Adductors Teresmajor Latissimusdorsi Pectoralismajor Teresminor Medial rotators Subscapularis

Nerve Supply Musculocutaneousnerve Axillary nerve Medial and lateral pectoral nerves Lower subscapularnerve Thoracodorsalnerve Axillary nerve

Mnemonic Witha rotator cuffinjury, the pitcher SITS onthebench: supraspinatus, lhfraspinatus, feres minor, subscapularis.

Axillary nerve Suprascapularnerve Lower subscapularnerve Thoracodorsalnerve Medial and lateral pectoral nerves Axillary nerve

Teresmajor Latissimusdorsi Pectoralismajor

Subscapularnerves(upper & lower) Lower subscapularnerve Thoracodorsalnerve Medial and lateral pectoral nerves

Lateral rotators Infraspinatus Teresminor

Suprascapularnerve Axillary nerve

3. Shoulder. The shoulderjoint is a shallowball-and-socketjoint. The head of the humerus is held againstthe glenoid fossaby ligamentsand muscles(TableI-5-3). B. Arm. The portion of the upper extremity betweenthe shoulder and elbow joint is the arm. It is enclosedin alayer of deep fascia.Two septaoriginate from this fasciaand divide the arm into an anterior (preaxial) and a posterior (postaxial) compartment. Flexor musclesoccupy the anterior compartment,and extensorsare found in the posterior compartment (Figure I - s - 10) . 1. Osteology.The bone of the arm is the humerus. a. Radial (spiral) groove is located posteriorly; this shallow depressionis occupied by the radial nerve and the deep brachial (profunda brachii) artery. b. Trochlea is a pulley-shaped feature of the distal humerus, which articulates with the trochlear notch of the ulna.

5l

Tissue, andIntegument System, Connective Musculoskeletal

Coracoid

Acromion

SuprasPinatus GlenoidcavitY

Infraspinatus SubscaPularis

Teresminor

Inferiorangle

Figure l-5-10.Muscles of the rotator cuff (lateral view). c. Capitulum is a rounded processlocated lateral to the trochlea and articulating with the head of the radius. d. Medial and lateral epicondyles are subcutaneous projections from the distal humerus, and give rise to the musclesof the forearm. 2 . Anterior (flexor) compartment of the arm

ClinicalCorrelate "Colfer's (medial elbovV" results froman epicondylitis) inflammation oftheflexor tendons onthemedial ofthehumerus epicondyle (imagine golfing thestandard theelbow). swing, flexing "Tennis (lateral elbow" results froman epicondylitis) inflammation oftheextensor tendons onthelateral epicondyle ofthehumerus (imagine thebackhand swing, extending theelbow).

52

a. Muscles (1) The coracobrachialis is a small muscle arising from the coracoidprocess. (2) The biceps brachii is the principal flexor of the forearm at the elbow joint. The bicepsis also a powerfi.rlsupinator of the forearm. (3) Brachialis lies deep to bicepsbrachii. b. Innervation. All musclesof the flexor compartment of the arm are supplied by the musculocutaneous nerve. 3 . Posterior (extensor) compartment of the arm a. Muscles.The long head of the triceps arisesfrom the scapula;lateral and medial heads of the triceps arisefrom the posterior surfaceof the humerus. b. Innervation. The three headsof the triceps are supplied by the radial nerve. 4 . The cubital fossa is a triangular areaanterior to the elbow.The roof of the cubital fossa is formed by deepfasciaand by the bicipital aponeurosis,which is part of the insertion of the bicepsbrachii. Contents of the cubital fossainclude the following:

Anatomy: Musculoskeletal

a. The median cubital vein is a superficialvein, which communicatesbetweenthe basfic and cephalicveins.It lies superficialto the bicipital aponeurosis. b. The biceps tendon inserts on the radial tuberosity. c. The brachial artery lies medial to the biceps tendon and terminates by dividing into radial and ulnar arteries. d. The median nerve supplies no musclesin the arm but is responsiblefor motor innervation of many musclesof the flexor forearm. 5. Elbow joint. This joint is a hinge joint that includes three articulations. The articulation between the humerus and the bones of the forearm allows flexion and extension at the elbow. The articulation between the radius and the ulna is a pivot, which allows rotation of the radius around the ulna (i.e.,supination and pronation). C. Forearm is the portion of the upper limb between the elbow and the wrist joint. The forearm is enclosedin a layer of deep fascia.The two bones of the forearm, the radius and ulna, aswell as an interosseousmembrane and two fibrous septa,divide the forearm into an anterior (preaxial) compartment and a posterior (postaxial) compartment. 1. Osteology a. Radius (l ) The head articulates with the capitulum of the humerus. (2) The radial tuberosity is the site of insertion of the bicepsbrachii. (3) The dorsal (Lister) tubercleis locatedon the posterior surfaceof the distal aspect of the radius. The tendon of the extensorpollicus longus passesmedial to this prominence. (a) The styloid process is the prominent subcutaneousdistal expansion of the radius.

ClinicalCorrelate Subluxation oftheheadofthe radius occurs inyoung children whoare"pulled along" by theupper limb.Theannular ligament, whichsurrounds the headoftheradius, stretches ortears. Thisisknown as "nursemaid's elbow"

b. Ulna (1) The olecranon,coronoid process,and trochlear notch form the articular surface of the ulna with the humerus. (2) The radial notch is the articular surfacefor the radius. (3) The tuberosity is the site of insertion of the brachialismuscle. (a) The sryloid processis the prominent subcutaneousdistal expansionof the ulna. 2. Anterior (flexor) compartment of the forearm a. Muscles. The eight muscles of the flexor forearm are arranged in three layers, from superficial to deep. (1) First layer includes four muscles,which arise from the medial epicondyle of the humerus. From lateral to medial, they are the pronator teres, the flexor carpi radialis,the palmaris longus, and the flexor carpi ulnaris ('PFPF" muscles). (2) Secondlayer has only one muscle,the flexor digitorum superficialis(sublimus). (3) Third layer has three muscles:the flexor digitorum profundus, the flexor pollicis longus, and the pronator quadratus.

Clinical Correlate Damage to theanterior interosseous nerve, also known asthedeepbranch of themedian nerve, results in theinability to forma round "0" withthethumbandindex finger. The"flatpinch" is caused byimpaired function pollicis oftheflexor longus andlateral twotendons of profundus. flexor digitorum

b. Innervation. The median nerve supplies all the musclesof the anterior compartment of the forearm, except for the flexor carpi ulnaris and the medial (ulnar) half of the flexor digitorum profundus, which are supplied by the ulnar nerve.

55

Musculoskeletal System, Connective Tissue, andIntegument

3. Posterior (extensor) compartment of the forearm a. Muscles. There are 11 musclesin the posterior compartment. They can be classified in three groups accordingto function. (1) Extensors of the hand at the wrist include the extensor carpi radialis longus, extensorcarpi radialis brevis, and extensorcarpi ulnaris. (2) Extensors of the digits are the extensor digitorum, extensor indicis, and extensor digiti minimi. (3) Extensors of the thumb are the abductor pollicis longus, extensorpollicis brevis, and extensorpollicis longus. (4) Additional musclesof the extensorcompartment include the brachioradialisand the supinator. b. Innervation. All musclesof the posterior compartment of the forearm are supplied by the radial nerve.

ClinicalCorrelate is Carpal tunnel syndrome bycompression ofthe caused median nerve withinthe bythecarpal tunnel formed retinaculum. bones andflexor Insevere cases, themuscles of eminence atrophy, and thenar isunable to thepatient oppose thethumb tothe is digits. Thedisorder people in whose common worknecessitates repetitive movements ofthewrist, e.g., keyboard operators.

4. Wrist a. Osteology.The eight bones of the wrist, or carpus,are arrangedin two rows of four. (1) The distal row, medial-to-lateral:hamate,capitate,trapezoid,and trapezium. (2) The proximal row, lateral-to-medial scaphoid,lunate, triquetrum, and pisiform. b. Flexor retinaculum (transversecarpal ligament) is a band of deep fascia, which through which the extendsanteriorly acrossthe carpal bones. It forms a passageway tendons of the flexor musclesand the median nerve enter the palm of the hand. D. Hand 1. Osteology(FigureI-5-11) a. Metacarpals. Five metacarpal bones articulate proximally with the carpal bones and distally with the proximal phalanges.They form the support for the palm of the hand. b. Phalanges. The thumb has two phalanges,proximal and distal. The remaining four digits eachhave three phalanges:proximal, middle, and distal. 2. Intrinsic muscles

ClinicalCorrelate bone-most Scaphoid frequently fractured of carpal bones Lunate bone-most frequ entlydislocated.

a. Thenar muscles (1) Abductor pollicis brevis (2) Flexor pollicis brevis (3) Opponenspollicis b. Hypothenar muscles (1) Abductor digiti minimi (2) Flexor digiti minimi (3) Opponens digiti minimi c. Lumbrical muscles. There are four lumbrical muscles. They flex the digits at the joints and extend at the interphalangealjoints. metacarpophalangeal

54

Anatomy: Musculoskeletal

d. Interosseous muscles. There are seven interosseous muscles. The three palmar interosseiadduct the digits, and the four dorsal interosseiare responsiblefor abduction of the digits.

Distal phalanx Middle phalanx Proximal phalanx

Head Fifth metacarpal Trapezoid

Hookof h Pisiform

Trapezium

Tri Lunate

Tubercle of scaphoid

Right palmar view Figure l-5-11.Osteology of the right hand (palmar view).

3. Innervation a. Motor innervation of intrinsic muscles(Figure I-5-12) (1) The median nerye suppliesthe musclesof the thenar eminence,via the recurrent branch, as well as the first and secondlumbrical muscles. (2) The ulnar nerve supplies the remaining intrinsic musclesof the hand.

55

System, Connective Tissue, andIntegument Musculoskeletal

Note andartery Theulnarnerve thepalm through enter canal. theCuyon

Palmardigital nerves Branchesto first and secondlumbricals

Palmardigitalnerves

'Recurrent branch of mediannerve

Clinical Correlate AllenTest Thistestisusedto determine anastomoses between the radial andulnararteries.

Thenarmuscles Mediannerve Ulnarnerve

Figure l-5-12.Innervation of the palm.

Palmarview

Figure l-5-13.Distribution of cutaneous nerves to the palm and dorsum of the hand.

56

Anatomy: Musculoskeletal

b. Sensoryinnervation of the hand. The median, ulnar, and radial nervesprovide specific areasof the palm and dorsum of the hand with sensoryinnervation (Figure I-5- 13). 4. Blood supply a. The superficial palmar arch is derived mainly from the ulnar artery. b. The deep palmar arch is derived mainly from the radial artery.

TOWER IIMB A. The thigh is the region extending from the inguinal ligament to the knee. The thigh is surrounded by a denselayer of deep investing fascia,called the fascialata. Fibrous septa divide the thigh into three compartments:anterior, medial, and posterior.

lliaccrest Anterior superior iliacspine Anteriorinferior

lliac fossa

Superior ramus of pubis Pubictubercle Crestof pubis

iliacspine

Pecten pubis

Head of femur Greater

Bodyof pubis

trochanter

lntefirochanteric line

Pubicsymphysis Obturator foramen lschialtuberosity

Femur

Lesser trochanter

Adductortubercle Lateral epicondyle

Medialepicondyle Patella

Head of f ibula Neck of f ibula

Tibialtuberosity

Figure l-5-14.Osteology of the lower limb: hip, thigh, and knee.

57

Tissue, andIntegument Connective System, Musculoskeletal

I. Osteology(FigureI-5-14) a. The anterior-superioriliac spineis the superolateralattachmentof the inguinal ligament. b. The pubic tubercle is the inferomedial attachment of the inguinal ligament. c. The ischial tuberosity is the site of origin of the hamstring muscles. d. The greater and lessertrochanters of the femur and the intertrochanteric line are sites of muscleand ligamentousattachments. e. The linea asperaof the femur is the site of insertion for the adductor muscles. f. The adductor tubercle of the femur is the site of insertion for the ischiocondylar portion of the adductor magnus. 2. Anterior thigh muscles. The anterior compartment of the thigh contains postaxial muscles,which are supplied by the femoral nerve: a. The quadricepsfemoris is comprised of the vastus lateralis,vastus medialis, vastus intermedius, and the rectus femoris. The rectus femoris crossesboth the hip and the knee joints. It has a weak flexor action at the hip and a strong extensorfunction at the knee. The three other components of the quadricepsarise from the shaft of the femur. b. The sartoriusmuscle actson both the hip and knee joints, primarily as a flexor.

Note inthelower muscles Postaxial in location; limbareanterior postaxial muscles intheupper posterior in location. limbare of Thisisdueto therotation thelowerlimb,whichbegins andis during thefetalperiod duringthefir$ year. completed

Correlate Clinical hernia, whichenters A femoral through thethighbypassing ringandfemoral thefemoral mayappear asa canal, overthefemoral swelling aninguinal triangle. Unlike inferior hernia, it protrudes to thepubic andlateral tubercle.

58

c. The iliopsoas is the chief flexor of the hip. d. The pectineusmaybe innervated by the obturator nerve aswell asby the femoral nerve. 3. Femoral triangle (Figure I-5-15) a. Boundaries. The femoral triangle is bounded by the inguinal ligament superiorly,the medial border of the sartoriuslaterally,and the medial border of the adductor longus medially. b. Contents (1) The femoral nerve, a mixed branch of the lumbar plexus,contains fibers from L2,L3,and L4; a postaxialnerve,it suppliesthe extensormusclesof the thigh and cutaneousareasof the thigh. The femoral nerve has a long sensorybranch, the saphenousnerve,which suppliesthe kneejoint and the skin on the medial aspect of the foot. (2) The femoral artery, also known as the superficial femoral artery,has three main branches: the profunda femoris, the medial femoral circumflex, and the lateral femoral circumflex arteries.The MFCA and the LFGA are more often branches of the profunda femoris. (3) The deep inguinal lyrtph node (of Cloquet) is locatedin the most medial compartment of the femoral sheath. This compartment is known as the femoral canal, and it communicates with the abdomen via a small opening, called the femoral ring. a. Inguinal lymph nodes a. Superficial nodes (1) Horizontal group. Thesenodes lie along the inguinal ligament. They drain the anterior abdominal wall below the umbilicus; the perineum, including the external genitalia;and the lower one-third of the anal canal.

Anatomy: Musculoskeletal

Anteriorsuperior iliacspine Inguinalligament

Pubic tubercle

Femoralartery Sartorius Adductor longus

Adductor tubercle

Figure l-5-15.Anterior thigh and femoraltriangle.

(2) Vertical group. These nodes follow the great saphenousvein and drain most of the superficial lymphatics of the lower limb. b. Deep nodes. Thesenodes receively-ph from the superficial nodes and from the deep compartment of the leg. Efferent vesselsfrom the deep nodes drain to the external iliac nodes. 5. Medial thigh, or medial compartment, contains musclesresponsiblefor adduction of the thigh. Theseare preaxial muscles,which are innervated by the anterior and posterior divisions of the obturator nerve. They arise from the pubic bone and the ischium. a. Muscles (l) Adductor longus (2) Adductor brevis (3) Adductor magnus (4) Gracilis b. Nerves (1) The anterior division of the obturator nerve, which is a preaxial nerve derived from L2,L3, and L4, suppliesthe pectineus,the hip joint, the adductor longus, the gracilis,and part of the adductor brevis.

59

Tissue, andIntegument Sy$em,Connective Musculoskeletal

(2) The posterior division of the obturator nervesuppliesthe obturator externus,the knee joint, the adductor magnus,and part of the adductor brevis. c. Blood supply (1) Profundafemoris (2) Obturator artery 6. Posterior thigh, or posterior compartment, contains musclesthat extend the thigh at the hip and flex the leg at the knee. These preaxial muscles are known as the "hamstrings." They arise from the ischial tuberosity and are supplied by the tibial division of the sciatic nerve (FigureI-5-16). a. Muscles (1) Semitendinosus (2) Semimembranosus

Rectus femoris muscle

Yi'nitirioi

Femur

Adductor magnus muscle

MeSU_aliaj)

Hamstrings Figure l-5-16.Gompartments of the left thigh (transverse section).

(3) Long headof the bicepsfemoris.The short headof the bicepsarisesfrom the shaft of the femur. It is a postaxial muscle and is, therefore, supplied by the common peroneal division of the sciatic nerve. The ischiocondylar portion of adductor magnus arisesfrom the ischial tuberosity. It inserts on the adductor tubercle and not on the linea asperawith the remaining fibers of adductor magnus.Hence,the ischiocondylar portion of adductor magnus acts as a hamstring. It is, therefore, supplied by the tibial portion of sciatic and not by the obturator nerve.

60

Anatomy: Musculoskeletal

b. Nerves. The sciatic nerve is actually two nerves:the tibial nerve, which is preaxial and supplies the hamstrings as well as the musclesof the calf and the sole of the foot, and the common peronealnerve,which is postaxialand suppliesthe short head of biceps femoris and the musclesof the lateral and anterior compartmentsof the leg. c. Blood supply. The musclesof the posterior compartment receivearterial supply from the perforating branchesof the profunda femoris. B.Hip 1. Gluteal region. The musclesof this region extend,abduct, and rotate the thigh. a. Muscles (1) Gluteus maximus is the extensorof the thigh

Clinical Correlate

(2) Gluteusmedius

Anearlyseparation ofthe sciatic nerve intotibialand peroneal common nerves may resuh inthe"piriformis syndrome," inwhichthe peroneal common nerve enters thegluteal region by passing overoremerging from thesubstance ofthepiriformis muscle. Initsmostextreme form,piriformis syndrome can result in "footdrop"("slap foot").

(3) Gluteusminimus (4) Tensorfascialata (5) Piriformis (6) Small gluteal muscles include the obturator internus, superior and inferior gemelli,and quadratusfemoris. b. Nerves ( 1 ) The sciaticnerve is derived from ventral rami L4-S3. ( 2 ) The superior gluteal nerve supplies the gluteus medius, gluteus minimus, and tensor fascialata. (3) The inferior gluteal nerve suppliesthe gluteusmaximus. ( ) The pudendal nerve is a branch of the sacralplexus (S2, 53, S4). It enters the gluteal region through the greatersciaticforamen, archesover the sacrospinous ligament, and leavesthrough the lessersciaticforamen en route to the ischiorectal fossaand perineum. It travelswith the internal pudendal nerve and artery. c. Blood supply ( 1) Superior gluteal vessels (2) Inferior gluteal vessels (3) Internal pudendal vessels 2. Hip joint. This joint is a ball-and-socketjoint. Locatedat the point at which the head of the femur articulateswith the acetabulumof the os coxae,the hip joint is more stable than the shoulder joint. This stabiliry however,is gained at the expenseof range of motion. The upper limb has a 360" range (i.e.,circumduction), whereasmotion at the hip is limited by the range of medial and lateral rotation. a. Ligaments (1) Iliofemoral ligament (Y ligament of Bigelow) (2) Ischiofemoralligament (3) Pubofemoralligament (a) Ligamentum capitis femoris

ClinicalCorrelate Theprognosis forhealing a hipfracture depends on whether thefracture isintraor extracapsular. Withan intracapsular fractu re,chances aregreater thattheheadof thefemurwillundergo necrosis asa result of interruption of itsblood supply. Anextracapsular (i.e., fracture onenearer the greater trochanter) hasa better chance of healing because muchoftheblood supply willbepreserved.

6l

Tissue, andIntegument System, Connective Musculoskeletal

b. Blood supply. The hip is the central axis of an arterial supply, which arrives from four directions and is known as the cruciateanastomosis. (1) Medial femoral circumflex artery (2) Transversebranch of lateral femoral cutaneousartery (3) Inferior gluteal artery (4) First perforating branch of profunda femoris artery C. Knee 1. Poplitealfossa. This is the diamond-shapedspaceat the back of the knee.Contentsof the popliteal fossainclude the following: a. Poptteal artery and vein. As the superficial femoral vesselspassthrough the adductor hiatus, they becomethe popliteal vessels.The femoral artery lies superficialto the femoral vein in the subsartorial(adductor) canal;however,in the popliteal fossathe relationship is reversedand the artery lies deep to the vein. b. Genicular anastomosis is a network of arteries surrounding the knee joint, which may provide alternate pathwaysfor blood flow if there is a blockageof the main artery. c. Tibial nerve entersthe posterior compartment of the leg. d. Common peroneal nerve follows the medial border of the bicepsfemoris to passlaterally around the neck of the fibula. 2. Knee joint is a hinge-Vpe, synovialjoint. a. Osteology (1) Patella is a sesamoidbone located within the quadricepstendon, which inserts on the tibial tuberosity. (2) Tibia is the bone of the shin. It is the weight-bearingbone of the leg. Its medial and lateral condyles articulate with the femur, and its lateral condyle has a depressionfor articulation with the fibula.

Correlate Clinical ofthepresence of a Because large amount offatinthe popliteal fossa andthe ofthe relatively deeplocation pulsemay artery, a popliteal lt is bedifficult to detect. important to e$ablish the existence ofthispulsebecause itsabsence mayindicate proximal obstruction ofthe artery dueto atherosclerosis.

(3) Fibula. The head of the fibula articulateswith the tibia. A groove in the neck of the fibula indicates the path of the common peroneal nerve. b. Ligamentous and cartilaginous structures (1) The medial collateralligament is a wide, flat ligament that attachesthe medial condyle of the femur to the shaft of the tibia. It is also firmly attached to the medial meniscus. (2) The lateral collateralligament is a discretecord-like structure that attachesthe lateral condyle of the femur to the head of the fibula. (3) The oblique popliteal ligament is an extensionof the semimembranosusinsertion. (a) The anterior cruciate ligament runs from the anterior intercondylar surfaceof the tibia to the lateral femoral condyle. It prevents hyperextension of the knee. (5) The posterior cruciateligament runs from the posterior intercondylar surfaceof the tibia to the medial femoral condyle. It prevents hlperflexion of the knee. (6) The medial semilunar cartilage (medial meniscus) is a nearly circular disk of fibrocartilage that lines the articular surface of the medial tibial condyle. It is attachedto the medial collateral ligament.

62

Anatomy: Musculoskeletal

(7) The lateral semilunar cartilage(lateral meniscus)is a C-shapeddisk of fibrocartilage that lines the articular surfaceof the lateral tibial condyle. It is not attached to the lateral collateral ligament. c. Muscles related to the knee joint (1) The popliteus is a small muscle located posterior to the knee joint. Its tendon inserts on the femur deep to the lateral collateral ligament. It initiates flexion of the knee joint by medially rotating the femur on the tibia. (2) The quadricepsfemoris is an extensorof the knee. (3) The sartorius,gracilis, and semitendinosusmusclesinsert on the medial aspect of the knee as the "pes anserinus." D. The leg is the portion of the lower extremity between the knee and the ankle. Like the thigh, the leg is encasedin a denselayer of deep fascia,the crural fascia.The nvo bones of the leg, the interosseousmembrane between them, and two fibrous septa divide the leg into three compartments. 1. Osteology (Figure I-5-17) a. Tibia. The anterior surface of the tibia is devoid of muscular attachments and is palpable throughout its length as the shin. The lower end of the tibia articulates with the talus and forms a subcutaneousprojection, the medial malleolus. b. Fibula is coveredthroughout its length by muscle. It is palpable only at its head and most distal projection, the lateral malleolus, which articulates with the talus. 2. Posterior compartment a. Muscles. The preaxial muscles of the posterior compartment are arranged in two groups, superficial and deep.They plantar flex the foot. (1) Superficial . Gastrocnemius . Soleus . Plantaris

Clinical Correlate A fracture of theneckof the fibulamaycause common peroneal nerve damage, resulting in "footdrop"-aloss offunction inthemuscles of theanterior compartment of thelegthataresupplied by thedeepperoneal branch of peroneal thecommon nerve. Therefore, therewouldbe difficulty in dorsiflexing the foot.Alsoaffected wouldbe themuscles supplied bythe peroneal superficial nerve: peroneus longus andbrevis, whichevertthefoot.

ClinicalCorrelate Theanterior compartment is limited bythepresence of threefeatures: thetwobones of theleg,theinterosseous membrane, andthecrural fascia. Fluidbuildup withinthis compartment mayoccur asa result of direct trauma, other serious injury, or infection. Thisfluid,whichmaybe bloody, willexertpressure on thedeepperoneal nerve and theanterior tibialblood vessels, resulting in"anterior compartment syndrome." This condition warrants immediate fasciotomy.

65

Tissue, andlntegument Musculoskeletal System, Connective

Neckof fibula

Tuberosity

Lateralmalleolus

Medialmalleolus

Calcaneus

Talus

Cuboid

Navicular Cuneiforms Metatarsals Proximalphalanx Distalphalanx

Figure l-5-17.Osteology of the lower limb: leg and foot. (2) Deep . Tibialis posterior . Flexor digitorum longus . Flexor hallucis longus b. Nerves. The flexor musclesare supplied by the tibial nerve, which also supplies musclesof the plantar surfaceof the foot. c. Blood supply. The posterior tibial artery supplies the posterior compartment of the leg and terminates by dividing into the medial and lateral plantar arteries. 3. Anterior compartment a. Muscles. The postaxial musclesof the anterior compartment act to dorsiflex (i.e., extend) the foot.

il

Musculoskeletal Anatomy:

(1) Tibialis anterior (2) Extensorhallucislongus (3) Extensordigitorum longus (4) Peroneustertius b. Nerves.Motor branchesof the deepperonealnervesupplythe musclesof the anterior compartment.The terminal sensorybranch of the nerveconveyssensoryinformation from tlle dorsum of the foot in the areabetweentlle greatand secondtoes (i.e., fust web space). c. Blood supply, The anterior tibial branch of the posterior tibial artery supptes the anterior compartment.The artery terminateson the dorsum of the foot lateralto the tendon of extensorhallucislongusasthe dorsalispedisartery. 4. Lateral compartment

In a NUbhell

a. Muscles.The major function of the peroneuslongus and the peroneusbrevis, the postaxialmusclesof the lateralcompartment,is to eyert the foot.

compart-Nerve Adery r.d

b, Nerves.The peronealmusclesof the lateralcomPartmentare suppliedby the superficial peronealnerve,which alsoconveyssensoryinformation ftom most of the dorsal

Anterior Deep Anterior peronealtibial bnnch

surface ofthefoot. c. Blood supply.The p€ron€alartery a branch ofthe posterior tibial, suppliesthe lateral compartm€ntof the leg. This artery doesnot enter the lateral compartmentitself but givesof branchesthat piercetlle lateralintermuscu.larseptumto supplythe peronealmuscles.

il,trff::i peroneal Lateral Superficial peroneal pone;or Tibial posterior tibial

E. Anlle. The anHejoint is a rynovial hinge-typejoint locatedbetweenthe tibia, the fibula, and the body of the talus. 1. Osteologf a. The talus is the weight-bearingbone of the foot. b. The calcaneusis the bone of the heel. c. The tuberosityofthe navicularbone is palpableanterior to the medialmalleolusand servesaspart of the attachm€ntof the tibialis posterior muscle. d. The cuboid bone is the most lateralof the smallbonesof the foot. bonesthat articulate proximally with e. The cuneiform bonesare three wedge-shaped of the foot. They areprimarily the navicularboneand distallywith the metatarsals responsiblefor the formation of the transversearch of the foot.

2.Lisamenrs a. Medial The deltoid ligament is the strong, medially located,reinforcementof the anHeioint. It attachesthe medialmalleolusto the talus. b. Irteral

(1)Anteriortaronburar (2) Posteriortalofibular (J'' LiucaneonDuar (4) Anterior and posterior tibiofibular

Cliniol Correlate of theankle Evenion sprains

:fiilf:lTn'Ji',#"**' ligam-enq inversion sprains are morecommonbeouse*n to laterallisamenb aresubiect

*:Tiif,il1ff:iltJH., istireinterior rrgamern followedbYthe talofibular, Repeated injury calcaneofibular results in to theseligamenb joint. instability of theankle

65

Musculoskeletal System, Connective Tissue, andIntegument

F. Foot 1. Osteology a. There are five metatarsalbones. b. Phalanges.The great toe, or hallux, has two phalanges,a proximal and a distal phalanx Eachof the remaining toes (i.e.,digits) hasthree phalanges:proximal, middle, and distal. 2. Ligaments. The plantar calcaneonavicular,or "spring" ligament, supports the head of the talus, which forms much of the medial arch of the foot. 3. Muscles. The musclesof the sole of the foot are arranged in four layers.Thesemusclesare similar to those of the palm of the hand. 4. Nerves. The intrinsic muscles of the sole are supplied by the medial and lateral plantar nerves,which are branches of the posterior tibial nerve. 5. Blood supply. The arterial supply of the sole of the foot is derived from the medial and lateral plantar branches of the posterior tibial artery.

66

Physiology Musculoskeletal potential istransmitted along thesarcolemma Anaction forcontraction. Muscle cells arespecialized (muscle There arethreemajor mechanism. thecontractile that,inturn,activates cellmembrane) (striped isunder theliShtmicroscope), under muscle, whichisstriated skeletal types of muscles. islocated in bloodvessel whichisnotstriated, muscle, smooth voluntary control, andisrapidacting; (having andisslow contractile activity), inherent rhythmic isinvoluntary wallsandinternal organs, of both buthassomecharacteristis muscle likeskeletal muscle, whichisstriated acting; andcardiac mechanisms of skeletal and willdiscuss thecontraction muscle. Thischapter andskeletal smooth Physiology chapter of intheCardiovascular isdiscussed separately muscle; cardiac muscle smooth lll), Book1 S/olume Systems Organ

MUSCTE SKEIETAI Skeletalmuscle is typically composedof many parallel muscle fibers (myofibers) that run the length of the muscle and terminate in tendonsthat attach the fiber to the skeletalsystem.Each myofiber is a multinucleated structure surrounded by the sarcolemma. A. Structural changesduring contraction 1. The shortening of a muscle results from an increasein the extent of thin-thick filament overlap, owing to the sliding of the former over the latter toward the center of the sarcomere.This method of contraction is therefore termed the sliding filament mechanism the lengthsof both thick of musclecontraction.Although the sarcomerelength decreases, (Figure I-6-1). and thin filaments essentiallyremain constant

+l

l-sarcomere+ |+1tztband

1/zt oand+l l*

Contraction .'...'.''.''.'.'''''''.''''''''''''''''''''''''''''* Handl bands shorten

F--+l

H band Relaxedstate

it-

H band Contractedstate

Figure l-6-1.Contraction of the sarcomere.

67

Musculoskeletal System, Connective Tissue,andIntegument

2. Molecular aspectsof contraction (Figure I-6-2). a. Upon stimulation of a myofiber, myosin heads can make connectionswith neighboring thin filaments. b. Once an actomyosin complex is formed, the head undergoes a conformational change(state3), displacingthe thin filament toward the center of the sarcomere. c. The actin-myosin bond is subsequentlybroken (state6) and the cyclemay be repeated aslong asthe muscle remainsstimulated. d. The molecular events in the rycle are driven by the hydrolysis of AIP. The myosin headsin state 1 contain ADP and inorganic phosphate(P,) that remain bound during the binding of the head to the thin filament. Dissociationof the phosphateis thought to acceleratethe tilting step (or power stroke) from state2 to state3. Finally,the ADP dissociatesfrom the attachedtilted state (state4). ATP in the cytoplasm replacesthe previouslybound ADR resulting in the dissociationof the head.

ClinicalCorrelate Rigor Mortis Theabsence ofATP results in theinability ofmyosin heads to bereleased. Theactin-myosin complex becomes stable, leading tomuscular rigidity.

e. The final step involvesthe hydrolysis of the bound AIP with the liberated energy repositioning the myosin head for another rycle. The head in the restingposition (state1), therefore,is consideredto contain stored potential energy,which is expendedduring the power stroke.If ATP supplieswere to run out, all the headswould be trapped in state 4, the so called rigor state.The complex equilibrium involving the actomyosin ATPaseshowsall of the coexistingchemical species. f. Although a single contraction resultsonly in an extremelysmall movement and little force generation,the combination of continuous asynchronouscyclingof many heads and the multiplicity of interprotein connectionsin the myofibriis greatly amplifr the molecular events.

thin filament

Pi

4 Jtoo,

Figure l-6-2.The contractile cycle (mechanochemicalcoupling).

g. There have been recent developmentsinvolving the precisemechanism of contraction at the level of the actin-myosin interaction. There is some evidencethat a single cross bridge cycleinvolving the motion of a myosin head may slide the actin and myosin filament more than the distancebetween two adjacentactive siteson the actin filament. B. Excitation-contraction coupling (EC coupling) refersto the mechanism by which an action potential generated by a motor neuron in the muscle initiates the mechanical events describedabove. 1. An action potential generatedin a muscle fiber is transmitted along the surfacemem-

68

Physiology: Musculoskeletal

brane and down the T tubule to the sarcoplasmic reticulum, resulting in a releaseof the sequesteredCaz+ into the cytoplasm. Cytoplasmic Ca2+rises to approximately 10-sM (FigureI-6-3).

T tubule

Figure l-6-3.Thetransverse tubule system. 2. Ca2+releasedfrom the sarcoplasmicreticulum diffusesinto the myofibrils, where it comes into contact with the thick and thin filaments. 3. When Ca2+binds to the TnC subunit of troponin, it initiates a conformational changein TnC that is transmitted to the other thin-filament proteins, ultimately causinga shift in the position of tropomyosin with respect to the actin surface. The movement of tropomyosin exposesa site on actin that is the binding site for cycling myosin heads. 4. In the absenceof further stimuli, the Ca2+-AIPaseof the sarcoplasmicreticulum rapidly depletesthe cytoplasmicCa2* concentration,causinga return to the inactivatedstateof the thin filament. C. Summary of the contraction sequence 1. Releaseof ACh at the neuromuscularjunction occurs when an action potential reaches the end of the axon; ACh difuses acrossthe gap. 2. The nicotinic acetylcholine receptor at the muscle end plates reactswith ACh, which, in turn, depolarizesthe muscle cell membrane at the motor end plate from the -90 mV resting potential. 3. The threshold is reachedwhen the membrane is sufficiently depolarized,initiating an action potential along the muscle cell membrane that propagatesbidirectionally from the end plate and extendsinto the T tubules. 4. T tubule depolarizationinfluencesthe sarcoplasmicreticulum of the triads, and the sarcoplasmicreticulum releasesCa2* into the cytoplasm. 5. Ca2+binds to troponin-tropomyosin. Myosin heads are now able to bind, and myosin ATPaseis activated.Cross-bridgesattach and detach cyclically at the expenseof AIR and the "rowing motion" causesthick and thin filaments to slide past each other. 6. After a time lag, the sarcoplasmicreticulum actively pumps Ca2+back into the lumen, decreasingavailableCa2+and removing Ca2* from the troponin-tropomyosin complex. The regulatory proteins then rebind to the actin outside the groove, and the actin-myosin interaction is inhibited. A single action potential thus results in a muscle twitch, a brief contraction followed by relaxation. The twitch starts approxim ately2 msecafter the depolarization of the membrane begins,i.e., during repolarization (Figure I-6-4).

69

Musculoskeletal System, Connective Tissue, andIntegument

ClinicalCorrelate TheCa2*re-uptake mechanism ofthesarcoplasmic reticulum is called theryanodine receptor. ln somepeople, thisreceptor is blocked bygeneral anesthetis suchassuccinylcholine. When these aregiven drugs to such patients, isnottakenup Ca2* quickly enough andthe "overcontracf' muscles and generate enormous amounts of heat. Thiscondition iscalled malignant hyperthermia and canbefatalif nottreated with dantrolene.

response electrical {Beginnin.g

ffi time

to peak of contraction)

Figure l-6-4.Relativetiming of action potential and muscle contraction.

D. Muscle mechanics 1. Definitions. An isometric contraction occurs when both ends of a muscle are fixed and no changein length occurs during the contraction, but tension increases.An isotonic contraction occurs when a muscle shortens during contraction while tension remains constant (Figure I-6-5). When both the muscle length and force changeduring the contraction, it is referred to as a dynamic contraction. In a dynamic contraction, the muscle may shorten (concentric contraction) or be pulled out by the load (eccentric contraction). Most physicalactivity includesboth isometric and isotonic contractions.

In a Nutshell Typesof Contraction lsometric: Change inforce butnochange in lengh lsotonic: Change in lenghbutno change inforce Dynamic: Change in both lenghandforce

70

Figure l-6-5.lsotonic contraction. 2. tength-tension relationship. The tension developedby an intact muscle in an isometric contraction varies with the initial length of the muscle fiber; there is an optimal length at which the muscle is able to developmaximum tension (Figure I-6-6). Figure I-6-7 plots the isometric tension developed by a single muscle fiber at different sarcomerelengths. Active tension refers to the difference between the total tension measuredon stimulation and the passivetension (resistanceto stretch) of an unstimulated muscle fiber, i.e., the resting tension. Thus, active tension refers to the tension produced by the active contraction alone.

Musculoskeletal Physiology:

c .o o c o F

Lop,

Length(for an intactmuscle) Figure l-6-6.Length-tension relationship.

a. In part A of the curve in Figure l-6-7, active tension is not developedby the fiber

becausethe sarcomeresare stretchedpast their usual maximum length and there is no overlapbetweenthin and thick filaments (Figure I-6-84); no cross-bridgescan form to generateforce.

c

.o

U' c o o o

1 .2 71 .6 52 .0 2 .2 5 Sarcomerelength(p) Figure l-6-7.Active tension generated as a function of sarcomere length. b. In part B, the sarcomeresbegin to overlap,and the increasein tension is proportional to that form (FigureI-6-88). the extentof overlap,i.e.,to the number of cross-bridges c. Part C of the curve is the plateau tension; no further increasein tension is observed with further shortening becausethe thin filaments overlap the thick filaments up to the bare areasin the central region, in which no cross-bridgesare present(FigureI-6-8C). Increasedshortening only overlapsthe thin filaments with more bare area;hence,no further increasein active tension is generated.The sarcomerelength is optimal for generating tension at approximately 2 mm, the length that correspondsto the in situ resting length of the sarcomeresin the fiber. d. Part D of the curve shows a linear decline in active tension becausethe thin filaments have moved past the bare areasof the thick filaments and begin to overlap one another; thin filaments from opposite halvesthen interfere with eachother (Figure I-6-8D). e. Part E of the curve showsfurther decline in tension at a fasterrate until zero tension is reached.The thick filaments havereachedthe Z lines and begin to crumple asthe Z lines compressthem (FigureI-6-8E).

7l

Musculoskeletal System,Connective Tissue,and Integument

A

r-Fl-Fl-FHFFtIHi

I B

I

Fl-BFr-Hr-r-H-H{

I

nnnr+lnnn

c I II

r-tFH{.|HH{lH{ H-fi-t+{H.|{{{{{J r+#.|flf-fi.|fl#{

D

:

I I

r{++++{H+t+fl+{ r{{.|{.t{H{+il+{.|

Figure l-6-8.A, No overlap of thick and thin filaments; B, initial overlap and tension increase; C, plateau tension; D, initial relaxation of tension; and E, rapid relaxation and thick filament crumbling.

3. Sarcomeresacting in seriesdo not generateadditional force,sincethe forcesact in opposite directions on the two sidesof the Z line and therebycanceleachother (Figure I-6-9). The total force generatedby many sarcomeresin seriesis thus the sameasthat of one sarcomere. a. The displacementprovided by the sarcomeresincreaseswith more sarcomeresin series,sinceeachsarcomereshortensby a given amount. b. Becausethe sarcomeresin seriescontract nearly simultaneously,the speedof shortening is increasedby the arrangementof sarcomeresin series,proportionally to the number so arranged.

72

Physiology: Musculoskeletal

...--->

F--+

-----t-----

tt-

-----+-----r--------l----T------T---

----r---

Note Sarcomeres ofthesame myofibril donotgenerate additive force. Therefore, to generate moreforce, more muscle fibers mustberecruited.

Figure l-6-9.Opposing forces in sarcomeres in series.

4. Sarcomeresacting in parallel generate additional force proportional to the number in this arrangementbecausethe amount of force that is generatedis proportional to the number of cross-linksacting in parallel simultaneously(Figure I-6-10). Thus, the force that a musclegeneratesis proportional to the cross-sectionalareaof the contractilematerial. The tension provided by a muscle can thereforeincreaseby increasingthe cross-sectional areaof eachfibril (adding more filaments in parallel),by increasingthe number of fibrils per muscle fiber (cell), thereby increasingthe number of cross-links(force-generating attachments)acting in parallel.

Figure l-6-10.Sarcomeres in parallel.

5. Isotonic contraction. If a muscle contracts isotonically, it is found that the velocity at which the muscle contractsvaries inverselywith the load it lifts (Figure I-6-11). At zero load, a muscleexhibits a rapid but finite velocity of shortening,which correspondsto the maximum velocity for unloaded cross-bridgerycling. With increasingload, the velocity asymptomatically approachesa value of zero.At zero velociry the contraction becomes isometric. This point representsthe maximum activeforce of the muscle.

E (d

lsometriccontractionmaximumforce

o

o () L

o

TL

Initialvelocityof contraction Figure l-6-11.Force-velocity relationship in skeletal muscle.

73

Musculoskeletal System,Connective Tissue,and Integument

E. Tlpes of skeletal muscle fibers. TWo types of fibers occur interspersedin most muscles, although one type usuallypredominatesin any given muscle.Their properties are summarized in ThbleI-6-1. Thble I-6-f . Properties of fast-twitch and slow-twitch fibers. Propertyand Type

Fast TWitch

Slow TWitch

Color Sarcoplasmicreticulum and T tubules Myosin AIPase Mitochondria

White Many

Red (myoglobin) Few

High Few,(short, rapid movements)

Low Many (sustained contractions)

1. Fast-twitch fibers are white in appearance(hence the term "white muscle"), large in diameter, and usually arranged with relatively few muscle fibers per motor unit. The light color is due to the absenceof red myoglobin. a. Fast-twitch fibers use glycolysisto generateenergy; thus, they usually function under anaerobicconditions. b. These muscle fibers are adapted for rapid contraction: the sarcoplasmic reticulum system and T tubules are extensive and regularly arranged, and the myosin AIPase activity is high.

In a Nutshell FastTwitchVersus SlowTwitch Think ofa chicken: . Whitemeat(whitemuscle) isinthebreast andisused forintermittent flapping of thewings. . Darkmeat(redmuscle) is inthethighs, whichare usedforsustained maintenance of posture.

c. Thesefibers enable fine, careful movements, for example,contraction of the extraocular musclesof the eye. 2. Slow-twitch fibers (or red muscle) are red becauseof the presenceof myoglobin. a. The fibers are smaller in diameter than white muscle fibers,there is lesssarcoplasmic reticulum and fewer T tubules than in white muscle, and the motor end plates are smallerthan those of white muscle. b. Red muscle,such as back muscle,is slower to contract and is adaptedfor long, sustained contractions;oxidative metabolism is used for energy.Largenumbers of mitochondria permit sustainedcontractions,and there is a greaterblood supply. c. Muscle with little sarcoplasmicreticulum contractsslowly,sincelessCa2*is releasedat a slow rate, and contraction takeslonger becauseof the slower removal of Ca2*. Motor units 1. Motor units consist of all the muscle fibers innervated by a single nerve axon (alpha motor neuron). Excitation of the motor neuron of the unit resultsin contraction of all the fibers in the motor unit. a. Eachof the musclefibers of a given motor unit is of the samemuscletype. The nerve exertsa tropic influence on the muscle fibers. b. If the pattern of neural firing is experimentally changed,the muscle changesin type to that determined by the motor nerve.Thus, the firing of any given axon resultsin either slow or fast contraction. c. If the motor nerve is destroyed,all muscle fibers innervated by that neuron atrophy.

74

Physiology: Musculoskeletal

2. Length and tension developedby skeletalmuscle is determined by the rate of firing of the motor neuron. Each muscle fiber has one end plate and is innervated by one motor neuron. a. No activiry occurs in the absenceof motor nerve stimulation (i.e., relaxation).

b. All motor neuron inputs are excitatory,and all reachthreshold; i.e., they all generate the action potential necessaryto initiate contraction. c. Skeletalmusclemotor neuron cell bodies are locatedin the ventral horn of the spinal cord gray matter. (1) A single,rapidly conducting myelinatedaxon directly connectswith the muscle fiber motor end plate. (2) Initiation and coordination of the control occursin the cerebralcortex, cerebellum, specificbrain stem nuclei, and basalganglia,and via reflexes. G. Tr,nitchand tetanus l. Single twitches. Elasticelements(tendons,connectivetissue)within muscleand between the muscle and its attachmentsrepresentslack that must be stretchedbefore the active tension generatedby the muscle can be exerted. a. When contraction is initiated, the active tension first stretchesthe elasticelements. This time delayfor elasticstretchis sufficient for the activetwitch to begin to decline. Thus, the peak tension is never exertedby a singletwitch (Figure I-6-12A).

100

75

E

Unfusedtetanus (colonus)

.9 th

b", lz

(u o

(L

25 Responseto two stimuli

1 Time (sec)

Figure I-6-12.A, twitch amplitudeand relativetiming and amplitudefor force generated (for frog sartorius muscle at 0"C); B, tetanus.

75

Tissue, Musculoskeletal System, Connective andIntegument

ln a Nutshell

b. The force exerted increaseswith the frequenry of twitches, since the slack is exhausted at the beginning and the firll energy of the twitch is then made available.

Tetanus results fromhigh frequency neural stimulation periods over short oftime.

c. The elasticelementsrecoil at the end of one or more twitches,returning the energyinput during initiation; this smooths out the decline of tension at the end of contraction. 2. Tetanus is the summation (fusion) of contractions that occurs when the fiber is stimulated repetitivelywithin a short time, resulting in greater contractions (developmentof more tension) than from a singletwitch. a. Tetanusis causedpartly becausethe elasticelementshavebeen frrlly stretchedfrom the early contractionsso that the maximum tension can be developedby the musclefiber, assumingit is not allowedto relax (FigureI-6-12B). b. Another reasonfor the occurrenceof tetanus involvesthe increasedavailabiliw of Ca2+ over repeatedcontractions. c. Tetanuscan be maintained until fatigue setsin due to an accumulation of lactic acid from anaerobicglycolysis. 3. Graded forces are generatedthrough increasingthe number of motor units (recruitment) and increasingthe firing rate to increasemuscletension (rate coding).

In a Nutshell (intrafusal Muscle spindles fibers) contain a contractile element innervated bygamma motorneurons, anda noncontractile element thatis enveloped bystretch-sensitive afferent neurons.

H. Muscle receptors. TWo tfpes of specializedreceptorsexist in skeletalmuscle: muscle spindles, which are embedded within groups of muscle fibers, and Golgi tendon organs, arrangedin tendons in serieswith the myofibers. 1. Muscle spindles a. Intrafusal fibers are small muscle fibers that are innervated bv small motor neurons called gamma motor neurons. b. Primary, or annulospiral, terminals in muscle spindles are rapidly conducting tfpe Ia fibers that innervate the centersof both the nuclear bag and nuclear chain fibers (the two types of intrafusal muscle fibers, named after the arrangementof nuclei in their equatorialregion). c. The secondary,or flower-spray, terminals are slightly slower conducting tfpe II fibers that innervate only the nuclear chain fibers. d. Motor innervation of intrafusal fibers is through small, slowly conducting gamma fibers (Figure I-6-13). Theseprimarily terminate at the poles of the spindle on the nuclearbag fibers.

Gamma efferents

la afferent ll afferent

Nuclearbag

Nuclearchainfiber

Figure l-6-13.Intrafusal fiber and innervation.

76

Physiology: Musculoskeletal

e. Stretching of a muscle causesstretching and deformation of the muscle spindle, which resultsin a volley of impulsesin the primary endings that synapsedirectly on the alpha motor neurons innervating the extrafusal fibers of the musclein which the spindle is embedded.For example,a contraction of the quadricepsmuscle is elicited when the patellar tendon is tapped and the familiar knee-jerk reflex occurs. f. Primary endings dischargerapidly during the actual lengthening of the muscle and lessrapidly when this increasedlength is maintained (Figure I-6-14). Primary endings thus respondto length aswell asvelocity of stretchof the muscle.

Note Muscle stretch causes an increased rateoffiringfrom spindle afferents. Thisresults in increased firingofalpha m0t0rneurons to cause muscle contraction.

Musclelength la response

ll response

Figure l-6-14.Muscle length changes and responses from la and ll fibers.

g. Secondaryendings dischargerapidly during the entire period of stretch of the muscle; thus secondaryfibers respondprimarily to length.

2. Golgi tendon organs a. The Golgi tendon organ is a receptorin serieswith a discretenumber of skeletalmuscle fibers. When a skeletalmuscle contracts,the tendon in which the muscle inserts lengthensand stretchesthe nerve endings of the afferentfibers, causingthem to fire. b. Golgi tendon organsare arrangedin serieswith extrafusalfibers and are supplied by Ib afferentfibers.Excessive stretchof a musclecausesfiring of Ib fibers,which synapse on inhibitory interneurons,which, in turn, synapseon alpha motor neurons.Excessive stretchthus inhibits muscle contraction, resulting in the inversestretchreflex.This is a protection againstthe possibledamagethat may be causedby excessive stretchingof a muscle. 3 . Golgi tendon organs and the muscle spindleswork in concert during muscle stretching, but function somewhatdifferently from eachother.

ln a Nutshell

a.If a muscleis stretched,both afferentsfire.

. Muscle spindles sense muscle length.

b. If the stretchedmuscle is made to contract actively,the tendon organ further increases its discharge,but the musclespindle decreases or ceasesits rate of discharge;this is becausespindle organs are arranged in parallel and tendon organs are arranged in serieswith the muscle.

. Colgi tendon organs sense muscle tension.

c. Tendon organs are more sensitiveto muscle tension, and muscle spindlesare more sensitiveto musclelength. d. Extrafusalmuscle fibers are controlled by alpha motor neurons,whereasthe control of intrafusal muscle fibers is by smaller gamma motor neurons.Gamma motor neurons regulatethe sensitivity of the spindle afferentsto dynamic and static phasesof stretch.Input through the CNS via gamma motor neurons can thus regulatemuscle tone and contraction.

77

Musculoskeletal System, Tissue, andIntegument Connective

SMOOTH MUSCTE Smooth muscleis involved in regulatingthe internal environment of the body. Smooth muscles are generally smaller than skeletalmusclesand are usually uninucleated. A. Structure of smooth muscle fibers. Smooth muscle fibers have fewer myofibrils per cell and are lessmorphologically organizedthan are skeletalmusclefibers. 1. Densebodies on the cell membraneand in the cytoplasm,analogoustoZ lines,act assites of thin filament insertion. 2. Smooth musclefibers havemuch lessmyosin than skeletalmuscle cellsand no thick filaments. Only small aggregates of myosin bridge the actin filaments. 3. Theyhaveno T-tubule systemand only sparsesarcoplasmicreticulum; most Ca2*appears to enter from the extracellularfluid. 4. Unlike skeletal and cardiac muscle, smooth muscle does not have troponin. Ca2+ is necessaryfor activation of myosin kinases,which in turn mediate excitation-contraction coupling. B. Contraction and relaxation, which occur slowly, probably involve overlap of actin and myosin. Thin filaments inserted into densebodies are pulled closer together by bridging myosin units. Densebodies on the cell surfaceare pulled so that the cell is deformed. 1. Myosin moleculesconsistof two heavychainsand four light chains;the light chainscontain the regulatory subunits. a. After an appropriatesignal,intracellular calcium concentrationsrise,and calcium will bind to calmodulin (FigureI-6-15).

t tcq2*l calmodulin

Ca2{catmodulin I I

myosinlight chainkinase (inactive)

ln a Nutshell Inskeletal muscle, Ca2+ binding to troponin allows actin-myosin interaction. Insmooth muscle, the phosphorylation ofthe myosin lightchain allows actin-myosin interaction.

* ,Ca2*-calmodulinmyosinlightchain kinase(active) ATP I ADP rll

. \* myosin (inactive)

-/

(active)

Figure l-6-15.Contraction and relaxation.

b. Ca2+-calmodulinwill activatemyosin light chain kinase (MLCK). c. MLCK phosphorylatesthe myosin light chain, which allowsthe myosin head to interact with actin. C. Pharmacologicalconsiderations. Knowledgeof the mechanismof smooth musclecontraction easilyexplainswhy autonomic drugs havetheir effects.Arteriolar regulationwill be used for this example. 1. Neutrotransmitters(e.g.,norepinephrine) or drugs (e.g.,phenylephrine)causevasoconstriction by activatingclr-receptors.Thesereceptorsincreaselevelsof inositol triphosphate

78

Physiology: Musculoskeletal

(IP3), which in turn, increasesintracellular Ca2+.This Ca2+ will lead to the cascadeof eventsdescribedculminating in vasoconstriction. 2. Neurotransmitters(e.g.,epinephrine) or drugs (e.g.,isoproterenol)activateBr-receptors that produce vasodilatation by increasing the level of cAMP. cAMP activates cAMPdependent protein kinase, which phophorylates MLCK. This inactivates the enzyme; the myosin light chain cannot be phosphorylated, and vasodilatation occurs. D. Types of smooth muscle 1. Multiunit smooth muscle is characterized by individual muscle fibers having separate innervation for initiation of activity. Muscle fibers are not interconnected by g"p junctions. There is little spontaneousactivity or responseto stretch.This type of muscle allows fine, graded contractions to occur, such as those that occur in the iris of the eye. 2. Unitary (visceral) smooth muscle has many separate fibers that operate as a unit (functional syncytium) becauseof gap junctions (nexus), which are regions of electrical coupling (low electrical resistanceand good current flow). Their fibers are sparselyinnervated by the ANS.

Bridge to Pharmacolry . NEproduces vasoconstriction by -receptors. activating This cr,l increases lP,andtherefore Ca2*levels. Thisleads to theactivation of MLCK. . EPIproduces vasodilatation pr-receptors. byactivating Thisincreases cAMP, which leads to theinactivation of MLCK.

a. Muscle fibers exhibit spontaneousactivity. The resting potential is close to threshold and is unstable. Oscillations of the resting potential, known as slow waves,bring the membrane potential to threshold repeatedlyand rhythmically. Thesechangesare probably due to high Na* permeability. b. Stretch activation occurs,where deformation initiates activity by depolarizingthe cells more rapidly. Muscle fibers are also frequently responsiveto circulating hormones. c. The ANS innervation to some fibers enablesregulation (but not initiation) of contractile activity. d. Contractions in unitary muscle are very slow, sustained, and rhythmic (e.g.,the gastrointestinal tract). They are initiated by action potentials that fire at the end of the slow waves.

79

Muscu loskeletal, nective Con Tissue, Pathology andIntegument Musculoskeletal andskinpathology encompass a broadrange of congenital anomalies, autoimmune diseases, andneoplastic disorders. Thischapter willdiscuss thecharacteristis of eachdisease state, presentations, theirclinical and,whenidentifiable, andtreatments. theircauses

BONE A. Congenitalanomalies 1. Osteogenesis imp€rfecta is a term usedto describeseveralclinical phenotypesof hereditar)' bone ftagilit)'. a. Four types are generallyrecognized.All arerare. (i) Type I shows autosomaldominant inheritance and causesmild-to-rnoderate long bone disease, blue sclerae,deaftress, and litde progressionafter puberty. (2) TypeII is autosonal recessive andoften producesa stillborn infart, or deathafter birth, with generalizedcrumpledbones. (3) Tfpe III is autosomal recessiveand producesprogressiveseveredeformity. Patientshavewhite sclerae. (4) TypeIV is autosomaldominant with variableseverirynormal sclerae,and fracturesof the long bonesand spine. b. Etiology.The caus€in all casesof osteogenesis imperfectaseemsto be a d€f€ctit n" synthesisof type I collagen.Genesfor the peptide chainsof collagenarelocatedon chromosomes17 and 7. Many different typei of lesionshavebee'ndescribed,from chainterminationto aminoacidsubstirution'

!!!!!!91-e!!*!:

;:::$:::;ffi:T* co agensynth*rs. c. Pathology Heritability varis among ( I ) In bones,wovenboneinsteadof trabecularboneand abnormalarrangements61 : thetypes;bluesderae andlaxligamenbare collagenfibers are seen.Jointsshowtigametrtouslaxitl' asa resr.t of abnormal : commonfeatures. collagen. (2) In the eye,somepatientshavean abnormallythin sclerawith a blue hue. (3) In the ears,theremay be fracturedossicles,producingdeaftress. (4) Teethmay be smali and discolored(dentinogenesisimperfecta),there may be mitral valveprolapse,and the dermismaybe abnormallythin

8t

Musculoskeletal System, Connective Tissue, andIntegument

Nole Thedefect inosteopetrosis to be seems aninability of o$eoclasts toresorb bone.

2. Osteopetrosis is a group of hereditary disorders characterizedby increased density and thickening of bone cortex with narrowing of medullary cavities. Bones are brittle and fracture easily.Membranous bones are not affected(e.g.,cranium). It may be associated with anemia,blindness, deafness,hydrocephalus,and cranial nerve palsies.There are two forms of inheritance. a. Autosomal recessivediseaseaffectschildren and produces early death due to anemia as the bones grow and squeezeout the marrow space. b. Autosomal dominant diseaseaffects adults and does not causedeath but may cause increasedfractures and encroach upon cranial nerves as they exit from the skull.

ClinicalCorrelate Achondroplasia isthebe$ known formofdwarfism, characterized byshortlimbs, large body, frontal bossing, and"saddle nose."

3. Achondroplasia is an autosomal dominant diseasecharacterizedby abnormal cartilage synthesis with subsequentdecreasedepiphysealbone formation. It sparesthe cranium and vertebral bones. Clinically, achondroplasia is characterizedby dwarfism with short extremities and a large body and head. 4. Osteochondromatosis is a hereditary disorder characterizedby the formation of multiple exostoses. a. Clinical features (1) Exostosesmay be asymptomatic or produce deformity and compromise the blood supply. (2) Gardner syndrome is a rare genetic disorder in which there is an associationof exostoseswith sebaceouscysts,desmoid tumors, and colonic polyps, which may becomecarcinomas. b. Pathology. Exostosesare bony metaphysealprojections capped with cartilage. They are multiple, often symmetric, and originate from epiphysealcartilage. 5. Enchondromatosis (Ollier disease)is a nonhereditary syndrome characterizedby multiple cartilaginous masseswithin the medullary cavit'' of bone, most commonly in the hands and feet. It often presentswith pain and fractures.These massesmay undergo malignant transformation; half of all chondrosarcomasarisefrom enchondromas.Maffrrccisyndrome is a tamilial associationof enchondromasand hemangiomasof the skin.

Ngte Ino$eoporosis, theboneis formed normally butin decreased amounts.

B. Osteoporosisis a decreasein bone mass,causingfragility of bone. Osteoporosismost commonly occursin postmenopausalwomen. 1. Pathogenesis a. Primarycauses include estrogendeficienry,low density of original bone,lack of exercise,and nutritional factors associatedwith acceleratedbone loss. b. Secondary causesinclude immobilization, endocrinopathies(e.g.,Cushing, thyrotoxicosis),and malnutrition (e.g.,deficienciesof calcium, vitamins C and D, protein). 2. Clinical features

ln a Mbhefl O$eoporosis mayleadto easy fracturing, especially of hips andvertebrae.

a. Patientsmay experiencepain and fractures without obvious trauma. b. X-rays show generalizedradiolucenc)'of bone. c. Laboratory testsrevealnormal serum calcium, phosphorus, and alkaline phosphatase. 3. Pathology. Thinned cortical bone and an enlarged medullary cavity are seen.All bones are affected.Weight-bearing bones (vertebrae,femoral neck) are predisposedto fractures. There is otherwise normal bone histology and a normal ratio of mineraUorganicbony elements(Figure l-7 -I).

82

Pathology

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Figure l-7-1.Osteoporosis of vertebra (microscopic). C. Osteomalacia and rickets l. Etiology. Both diseasesare causedby vitamin D deficiency from chronic renal insufficienry, intestinal malabsorption,or dietary deficiency. 2. Clinical features a. Rickets occursin children prior to closureof the epiphyses,leading to bone deformities and pain. Patientsshow the "rachitic rosary" (deformity of the chestwall asa result of swellingat osteochondraljunctions of ribs), bowing of legs,and fractures. b. Osteomalaciais an impaired mineralization of the osteoid matrix. It causesfractures and bending of bones and widening of osteoid seams. (1) Laboratory tests show low serum calcium and phosphorous and high alkaline phosphatase,which distinguishesthis syndromefrom osteoporosis. (2) X-rays show diffuse radiolucencyof bone.

Note Rickets andosteomalacia aredisorders of o$eoid mineralization; osteoid is produced in normal amounts properly. butisnotcalcified

D. Pagetdisease(osteitisdeformans) is due to excessivebone resorption with replacementby soft, poorly mineralizedmatrix in a disorganizedarray. 1. Ctinical features a. Pagetdiseasemay presentwith pain, deformity, and fractures.It is usuallypolyostotic (affecting many bones), involving the skull, pelvis, femur, and vertebrae.When the skull is involved, impingment of cranial nerves often causesdeafness.Involvement may causebone hypervascularity with increasedwarmth of the overlying skin. b. X-ray showsenlarged,radiolucent bones. c. Laboratory tests show an extremely elevated alkaline phosphatase. 2. Pathology. The diseaseprogressesfrom an osteolyticto an osteoblasticprocess.Resorbed bone is replacedby a vascularconnectivetissue,which later becomesmineralized.There is a mosaic rather than trabecularpattern from persistentosteoid seamsat the margin of new bone. E. Fibrous dysplasia causesfocal areasof fibrous replacementof bone. Incidenceis higher in teenagers,with men more frequently affectedthan women.

8T

Musculoskeletal System, Connective Tissue, andIntegument

1. Clinical features. Monostotic fibrous dysplasia is often asymptomatic or may lead to pathologic fracture.Albright syndrome is an associationof polyostotic fibrous dysplasia, caf6-au-laitspots,and sexualprecocity in women. 2. Pathology. Fibrous dysplasiais usually monostotic, affectingthe long bones,ribs, skull, and facialbones.Fibrosisstartswithin the medullary cavityand remainsencasedin cortical bone. F. Bone abnormalities in hlperparathyroidism (osteitisfibrosa cystica) 1. Pathogenesis.Excessparathyroid hormone activatesosteoclaststo resorbbone and causes the kidney to waste calcium. 2. Clinical features. Osteitis fibrosa cystica occurs more comrnonly in primary hyperparathyroidism,causingbone pain and fractures. 3. Pathology

Note Brown tumors areclassic signs ism. of hyperparathyroid

a. Microscopically, there is an increasednumber of osteoclastswith excessbone resorption and fibrous replacementof marrow causingcystic spacesin trabecularbone and "brown tumors" (areasof organizedhemorrhage). b. Grossly,brown tumors may produce rystic enlargementsof bones. G. Hypertrophic osteoarthropathy 1. Clinical features a. Clinically,hypertrophic osteoarthropathypresentswith painfirl swellingof wrists, fingers,ankles,knees,or elbows.The pathogenesisis unknown. b. This is a periosteal inflammation, and new bone forms at the ends of long bones, metacarpals,and metatarsals. c. Arthritis of adjacentjoints is commonly seen,often with digital clubbing. 2. Etiology. Causesinclude intrathoracic carcinoma (a paraneoplasticsyndrome), sepsis, endocarditis,ryanotic congenitalheart disease,and inflammatory bowel disease.The syndrome regresses when the underlying diseaseis treated. H. Fibrous cortical defect (nonossifring fibroma) is a common developmentalabnormality seenin bones of the lower extremitiesin children. They are non-neoplasticlesionsof bone cortex that are composedof fibrous connectivetissue. 1. Clinical features. Fibrous cortical defect is usually asymptomatic,non-neoplastic,and usually resolvesspontaneously. 2. Pathology. There are irregular, well-demarcated,radiolucent defectsin the bony cortex, with an intact subperiostealshell of bone. In the metaphysis,there are whorls of connective tissue.Occasionally,multinucleatedgiant cellsare seen.This entity must be differentiated from giant cell tumors of bone, which may cross the epiphysis (fibrous cortical defectdoesnot do this). The stromal cellsof giant cell tumors are alsomore atypical,with larger,darker nuclei and lesscytoplasmthan seenin fibrous cortical defect. I. Osteomyelitis 1. Pyogenic osteomylitis a. Etiology. Causedby direct innoculation of bone or by seedingof bone after bacteremia. Organisms include Staphylococcusflnreus, Streptococcas, gonococci, and Haemophilusinfluenzae.Salmonellamay be seenin patients with sickle cell disease. Pseudomonas is common in intravenousdrug usersand diabetics.

84

Pathology

b. Clinical features include fever,localized pain, erythema, and swelling. The x-ray may be normal for up to 2 weeks,then may initially show periosteal elevation. c. Pathology. Suppuration begins within the metaphysealmedullary cavity and penetrates the cortex. Compression by exudateleadsto vascular insufficiency and ischemic necrosis.Specific findings include: (1) Sequestrum,a necrotic bone fragment (2) Involucrum, new bone that surrounds the area of inflammation (3) Brodie abscess,localizedabscessformation in the bone 2. Tuberculous osteomyelitis occurs in 1oloof casesof TB, causing caseatinggranulomas in the bones. The term "Pott disease" refers to spinal involvement. L Tumors 1. Osteoblastic tumors a. Osteoma is a benign growth that frequently involves the skull. ( 1) "Hlperostosis frontalis interna" describesan osteomathat extendsinto the orbit or sinuses. (2) Pathologyshowsdensenormal bone. b. Osteoid osteoma is a benign growth of the diaphysisof long bones,often the tibia or femur. (1) Clinical features include pain that is worse at night and relieved by aspirin. X-rays show a central radiolucencysurrounded by a scleroticrim. (2) Pathology shows a l-cm brown nodule surrounded by densesclerotic cortical bone. Microscopically, the nodule is formed of vascular, woven bone with partially mineralized osteoid. c. Osteoblastoma is similar to a large osteoid osteoma,but is large, painless,often involves vertebrae,and may be malignant. d. Osteosarcomais a malignant bone tumor that producesosteoid and bone. (1) Incidence. Men are affected more often than women, and the tumor usually occursin the secondand third decadeof life.It is the most common bone tumor in older people and is often associatedwith Paget'sdisease.Over one-third of patientswith retinoblastomaalso developosteosarcoma. (2) Pathogenesisis unclear.There is an increasedincidencewith irradiation, Paget disease,and other previous bone pathology. (3) Clinical features. Patients present with localized pain and swelling, weight loss, and anemia. Classicx-ray findings include Codman triangle (periostealelevation) and bone destruction. (4) Pathology. Grossly, osteosarcoma,particularly in teenagers,often affects the metaphysealends of long bones, usually around the knee, producing large necrotic and hemorrhagic mass. Microscopically, the tumor may be sclerotic (with mineralizedosteoid) or osteolytic (with little osteoid).It alsomay contain collagen or cartilage. The classicfinding is anaplastic cells with osteoid, pink, amorphous material that is variably mineralized (FiguresI-7-2 andl-7-3). (5) Prognosis is poor. Patients are treated with amputation and chemotherapy. Metastasisto the lungs is common. Prognosisis improved with aggressive management,such as resectingsinglepulmonary metastases.

85

Musculoskeletal System, Connective Tissue, andIntegument

Figure l-7-2.Osteogenicsarcoma(microscopic).

Figure l-7-3.Osteogenic sarcoma with vertebral collapse (gross). 2. Chondromatous tumors a. Osteochondroma is an exostosisthat forms benign metaphysealgrowths. They may be solitary.Lesionsare identical to those in multiple form (osteochondromatosis). b. Enchondroma is a solitary cartilaginous growth within the spongiosa of bone. Solitary growths are similar to those in multiple form (Ollier disease). c. Chondromyxoid fibroma is a benign,rare tumor affectingyoung men. It forms a firm masswithin the metaphysealmarrow cavity of the tibia or femur. The tumor contains fibrous and mlxomatous tissue,which must be differentiatedfrom a malignant lesion. d. Chondrosarcoma is a malignant tumor of chondroblasts.The agerangeis from 30-60 years.Men are more often affectedthan women.

86

Pathology

(1) Etiology. The tumor may arise de novo or secondaryto a pre-existingenchondroma or exostosis.

ln a NuBhell

(2) Clinical features. Chondrosarcomas are slower growing than osteosarcomas. They typically present with pain and swelling.

Osteochondroma Exo$osis frommisdirected growthof growthplate

(3) Pathology. Tumors typically involve the spine, pelvic bones, and upper extremities. Microscopically, they are characterizedby atypical chondrocytes and chondroblasts,often with multiple nuclei in a lacuna. 3. Giant cell tumor is a malignant neoplasm containing multinucleated giant cells and aqrq7ical stromal cells.This is an uncommon tumor, affecting patients from age2G-50 years. a. Clinical features

Enchondroma growthof benign Solitary cartilage inside bone Chondrosarcoma g Malignantcartilage-producin tumor

(1) Tumors presentas a bulky masswith pain and tenderness. (2) X-rays show an expandingareaof radiolucencywithout a scleroticrim. b. Pathology (1) Grossly,tumors arisein the epiphysealregion of long bones,forming a club-like deformity at the end of the bone. (2) Microscopically, multiple giant cells, resembling osteoclastswithin a matrix of fibroblast-like cells with large, atypical nuclei, occur. a. Ewing sarcoma is a malignant neoplasmof undifferentiated cellsarising within the marrow cavity.It is rare, usually affecting adolescents.Men are affectedmore often than women. a. Etiology. The tumor arisesfrom mesenchymalcellsthat havebeen shown to havesome expressionof neural antigens. b. Clinical features are pain, tendernessand early widespread dissemination. c. Pathology (1) Grossly, the tumor commonly affectsthe pelvis and metaphysesof long tubular bones.Cellserodethrough the cortex and invadesurrounding tissues.Half of the caseshave"onion skin" or concentriclayering of new bone. (2) Microscopically, undifferentiated small cells resembling lymphocytes occur. Surfaceantigensmake the diagnosis.

forNTs A. Arthritis 1. Suppurative arthritis a. Pathogenesis. The primary mechanism of suppurative arthritis is hematogenous seedingof joints during bacteremia,which is more common than direct invasion. H. inlluenzae,and GramStreptococcns, Organismsinclude gonococci,Staphylococcus, negativebacilli. b. Clinical features include tender, swollen, and erythematous joints that require rapid intervention to prevent permanent joint damage.

Nole System ic Iupuserythematosus jointpain. typically includes Because it isa multisystemic immune it is disorder, discussed intheClinical lmmunology chapter of Principles BookI Ceneral (Volume l).

87

Musculoskeletal System, Connective Tissue, andlntegument

ln a Nutshell Arthritis Suppurative . Manife$ed bya tender, red, joint "a sruollen (e.g., hot knee"). . Usually monoarticular, high neutrophil count injoint fluid,andoftendueto staph, strep, andgonococci.

Note Tuberculosis ofthespineis called Pott's disease. lt maybe confused withbrucellosis of thespine.

c. Pathology. This disease is usually monoarticular, affecting a large joint. Characteristicsof typical suppurative infection are cloudy synovial fluid with a high neutrophil count that clots readily. If the organism is very virulent or if it is left untreated, the synovium may ulcerate and infection may erode articular cartilage. 2. Tirberculous arthritis a. Incidence.This form occursmore commonly in children. b. Clinical features include an insidious onset and joint destruction. c. Pathology. It occurs most often in the spine and hip. The synovial lining is covered with tuberclesand granulation tissue.Pannusdevelopsover the articular cartilage and may erodeit. Destruction of joint spaceensueswith fibrosis and calcification,eventually leading to ankylosis. 3. Osteoarthritis (degenerativejoint disease) a. Incidence. Osteoarthritis increaseswith age, affecting women more than men. It affects80o/oof people over 70 yearsold in at leastone joint. b. Pathogenesis ( 1) Aging or wear and tear (biomechanical)is the most important mechanism.Also, chondrocyte injury and abnormal collagen activity (biochemical) contribute; usually,both act together. (2) Predisposingfactors include obesity,previous joint injury, and synovial disease. Most retired football players have at least some osteoarthritis in the knees and ankles. c. Clinical features. There is an insidious onset with joint stiffness,decreasedrange of motion, effrrsions,crepitus,and bony swelling.Symptoms of nerve compressionmay developsecondaryto compressionby osteophytes. (1) Heberden nodes (nodules at the base of terminal phalanges)occur more frequently in women. (2) X-ray showsnarrowing of the joint spacedue to loss of cartilageand osteosclerosis.

In a Nutshell 0steoarthritis . Dueto aging orwearand joints. tearon . Erosion ofarticular cartilage leads to boneeburnation andchipping. . X-rays showthelossofjoint space. . Heberden nodes arefound attheDIPjoint.

88

(3) foint fluid showsfew cellsand normal mucin. d. Pathology (1) The most commonly affectedjoints include vertebrae,hips, knees, and distal interphalangeal(DIP) joints of fingers. (2) Ioint mice are flakes of cartilage in the joint spacefrom erosion. (3) Osteophytes and bone spurs develop. Denuded, sclerotic, subchondral bone may becomeexposedin areas(eburnation). 4. Rheumatoid arthritis is a systemic chronic inflammatory diseasecharacterizedby progressivearthritis. There are many clinical variants. a. Incidence. Women are affected three times more frequently than men. There is a familial predisposition,and the diseasecommonly presentsfrom ages2G-60years. b. Pathogenesis involves an autoimmune reaction with the formation of circulating antibodies (rheumatoid factor) against the Fc fragment of autologous IgG, leading to immune complexes.

Pathology

c. Clinical features (1) Symptoms include low-grade fever,malaise,fatigue, and morning stiffness. (2) Physicalexamination showsjoint swelling,redness,and warmth. In late stages, ankylosis may develop. (3) Synovialfluid showsincreasedcells (usually neutrophils) and poor mucin. (4) There is an elevatedsedimentation rate and hlpergammaglobulinemia. The level of rheumatoid factor may correlate with the severity of the arthritis. (5) X-rays show erosionsand osteoporosis. (6) Systemicfeaturesinclude subcutaneousnodules (20o/opatients),Sj6grensFndrome (l5o/o),glaucoma,pericarditis,vasculitis,hepatosplenomegaly, and adenopathy. d. Pathology (1) The diseaseusually starts in the small joints of the hands and feet but may involve any joint. There is usually symmetric involvement. Patients develop a diffirse proliferative synovitis in which the synovium becomes replaced by pannus, a vascularized mass packed with lymphocytes, macrophages, and plasmacells.Pannuserodesarticular surfaces,bone,joint capsule,and ligaments. Adhesions and ankylosis may result. (2) Rheumatoid nodules are composed of proliferative connective tissue with areas of central necrosis. They may be seen in skin, heart valves, lung, pleura, pericardium, and spleen.Skin nodules are usually on extensor surfaces. (3) Arteries may show acute necrotizing vasculitis due to circulating antigenantibody complexes. e. Other types of rheumatoid arthritis (1) Juvenile rheumatoid arthritis (Still disease) has a peak incidence from 1-3 years.Girls are affected more frequently than boys. It is often preceded by acute febrile illness. There is periarticular swelling, lymphadenopathy, hepatosplenomegaly,and absenceof rheumatoid factor. The course is variable and may resolve. (2) Ank/osing spondylitis occurs predominately in young men with HLA-B27.It is also associatedwith inflammatory bowel disease and usually involves the sacroiliacjoints and spine. (3) Arthritis associatedwith ulcerative colitis occurs in 25o/oof patients with ulcerative colitis. It is not progressiveand resolvesspontaneouslyor with treatment of the ulcerative colitis. There is no pannus formation. (4) Psoriatic arthritis has pathology similar to rheumatoid arthritis but an absence of rheumatoid factor. It is also associatedwith HLA-B27. (5) Felty syndrome is a polyarticular rheumatoid arthritis associatedwith splenomegaly,leukopenia, and leg ulcers.Neutropeniais relatedto splenomegaly, antineutrophil antibodies, and bone marrow failure.

Note Ankylosing spondylitis occurs mainly in HLA-B27-positive patients. Notethatpsoriatic arthritis andReiter syndrome arealsomorecommon inthe presence of HLA-827.

5. Gout. In gout, there is hlperuricemia associatedwith recurrent bouts of acute arthritis, resulting from deposition of monosodium urate in joint tissues.

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a. Types (1) In primarygout (90oloof cases),there is an inborn error of purine metabolism. The metabolic defectis usually not known. Specificenzfme defectsaccount for only about l0o/oof cases(e.g.,Lesch-Nyhansyndrome). (2) Secondarygout is hyperuricemia resulting from a disorder unrelated to purine cell breakdown as in leukemia and polycythemia). metabolism (e.g.,excessive b. Incidence. Most casesare in men, but it occasionallyaffectspostmenopausalwomen. It is familial (primary gout) in about 20o/oof cases.

ln a Nutshell Gout . Coutisthedeposition of leading to uratecrystals painful attacks of acute, Thebigtoeis arthritis. affected. classically . Coutmayresult from overproduction or of uricacid. underexcretion . Tophi arepathognomonic. . Uratecrystals areneedleandnegatively shaped birefringent, In a Nutshell Pseudogout . Calcium pyrophosphate deposition Reitersyndrome . Arthritis, uveitis, and conjunctivitis . Possibly dueto Chlamydia

c. Pathogenesisis an overproduction of uric acid (under 10o/o)or underexcretionof uric acid (over 90o/o). d. Clinical features. There is an asymptomatic period of hyperuricemia (>7 mgldl) followed by acute episodesof joint pain and swelling. After approximately 10 years of recurrent attacks, chronic disabilities ensue (i.e., decreasedrange of motion; joint deformities).Uric acid kidney stonesdevelopin up to 25o/oof patients. e. Pathology. Precipitation of urate crystals in joint fluid causes an acute inflammatory synovitis with synovial edema and leukocytic infiltrate. It usually affectsthe joints of the lower extremities,particularly of the large toe. Formation of tophi (urate deposits surrounded by inflammatory cells, including foreign body giant cells) is pathognomonic. Tophi may form in the helix of ear,bursae,ligaments,and kidney. Chronic changesinclude urate deposition along articular surfaces,pannus formation, erosionof cartilageand bone, adhesions,and anlcylosis.Uric acid crystalsarebestpreservedin tissuesamplesby fixing in ethanol rather than formalin. 6. Pseudogout (chondrocalcinosis) is arthritis secondary to deposition of calcium pyrophosphate crystals in joint fluid. It is associatedwith many metabolic diseases(e.g., Wilson disease,hypothyroidism, diabetesmellitus). The crystals are recognizably different from urate on light microscopy. 7. Reiter syndrome is an associationof arthritis, urethritis, conjunctivitis and mucocutaneous lesions, possibly secondary to Chlamydia infection. The relative risk of this syndrome is raisedapproximately40 times by the presenceof HLA-827. B. Tirmors 1. Synoviosarcoma a. Incidence. This is a rare tumor with a peak incidence in early adulthood, affecting boys and girls equally. b. Clinical features. These tumors form slow-growing, painless masses.They are very aggressivewith early metastasesto the lung and pleura. c. Pathology.Two-thirds of synoviosarcomaform in the lower extremitiesand one-third form in the upper extremities. They arise from synovial lining cells of bursae and tendon sheaths.The picture is often biphasic with a spindle cell fibrosarcomaelement enclosingan epitheloid (glandular) component. 2. Matignant fibrous histiocytoma a. Incidence. This is a relatively common soft tissue malignancy, affecting adult men more than women. b. Pathology.Ttrmors arisein soft tissueor bones.They are locatedin the lower extremities more often than in the upper extremities and in the abdominal cavity. Microscopically, tumors are pleomorphic, composedof fibroblasts,histiocytes,and tumor giant cells.

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C. Other lesions 1. Ganglions are small cystsof tendon sheath or joint capsule,often in the wrist. 2. Tenosynovitis is an inflammation of tendon sheaths and tendons, often secondary to excessstressor trauma. Rare forms include suppurative or tuberculous tenosynovitis. 3. Bursitis is an inflammation of the bursa, often causedby excessivestressor trauma and occasionallybacterial invasion. 4. Pigmented villonodular synovitis is a villous proliferation of synovium colored brown by hemosiderin deposition. It is probably a reactive responseto recurrent trauma and possiblya neoplasticprocessthat doesnot metastasize.

SKELETAI MUSCLE PATHOTOGY A. Clinical features. Signsand physical findings of muscle diseaseinclude myotonia (continuous tonic contraction), weakness,muscle atrophy (wasting),fasciculations(twitching), and pseudohypertrophy.The symptoms and history of muscle diseaseinclude various combinations of the following: 1. Tripping, clumsiness(distal weaknessespecially) 2. Difficulty climbing stairs or rising from chairs (proximal weakness) 3. Family history, which includes three common patterns of inheritance: sex-linked (Xlinked) inheritance, autosomal recessiveinheritance, and autosomal dominant inheritance. B. Diagnosis. Laboratory findings that may help differentiate muscle diseasesinclude: 1. Creatine kinase is elevatedin myositis and some dystrophies. 2. The erythrocyte sed.imentation rate (ESR) may be elevated in myositis or any other inflammation. 3. Serum potassium may be abnormal in periodic paralysisand raised wheneverthere is cell necrosis. 4. Pyruvate or lactate may be abnormal in metabolic, particularly mitochondrial, muscle diseases. 5. Urinarymyoglobin is elevatedif there is acute muscle destruction (e.9.,rhabdomyolysis). 6. Electromyography (EMG) and peripheral nerve conduction velocities (NCVs) may help differentiate neurogenic from myopathic disorders;in general,proximal weaknessis often myopathic, while distal weaknessis often neurogenic. 7. Muscle biopsy is often the definitive diagnostic procedure in myopathic disorders. Diagnosisis made by the presenceor absenceof certain histologic featuresor by staining with enzymaticstains. C. Neurogenic muscle atrophy covers a large class of disorders secondary to loss of normal nerve supply; muscle is lost secondarily. 1. Features of denervated muscle include fiber shrinkage and angulation with nuclear pyknosis. 2. Initially, the histologic picture is of scatteredatrophic fibers, but, since a nerve typically supplies many fibers, a picture of group fiber atrophy eventually becomesapparent. 3. Types I and II fibers show atrophy.

9l

System, Tissue, andIntegument Musculoskeletal Connective

4. Intact neighboring axonsmay sprout and reinnervatefibers,which resultsin a singlefiber tfpe, regardlessof the initial fiber rype. This is known as "fiber-type grouping." Fibers becomeheterogeneouslygrouped together accordingto the "fiber tFpe" (white or red) of the innervating neuron. 5. Ultimately, denervatedmuscleis replacedby connectiveand adiposetissue. 6. Polyarteritisnodosa (PAN) may show musclevascularinfiltration and infarction of muscle and nerve; PAN is particularly notorious for causing mononeuritis multiplex by infarction of multiple peripheral nerves,leadingto neurogenicatrophy.

ln a Nutshell gravis Myasthenia isan autoimmune disease inwhich antibodies aremadeagain$ receptors. NMJacetylcholine it presents with Clinically, muscle weakness that worsens withuse.ftosisis commonly seen.

D. Myasthenia gravis typically affectsyoung women. 1. Pathogenesis.This is an autoimmune disorder causedby IgG directed against the acetylcholine (ACh) receptor. 2. Clinical features include fluctuating weakness.This weaknessinvolves muscles supplied by cranial and peripheral nerveswith no sensoryabnormalities,and it is especiallyprofound late in the day. 3. Diagnosis is establishedby a decrementalresponseto repetitiveelectricalstimulation on EMG or by clinical improvement when a cholinesteraseinhibitor (e.g.,edrophonium) is administered.Muscle biopsy shows group atrophy and, occasionally,mononuclear cell infiltrates. Patients may have thymic abnormalities, including thymoma (10-20o/o)or thymic hyperplasia(70-80o/o).In thesepatients,thymectomy is often curative.

E. Myositides include both polymyositis and dermatomyositis.Both polymyositis and der-

In a Nutshell Themyositides aredisorders thatprobably havean autoimmune etiology. Theyarecharacterized by muscle fascicle atrophy, edema, andnecrosis.

matomyositisare classifiedas autoimmune or collagenvasculardiseases. 1. Incidence. Polymyositisis more common in females. 2. Pathogenesis.These disordersare associatedwith autoantibodies,with a cell-mediated immune response,C2 deficienry,and HLA-DR3. 3. Clinical features a. Neck and proximal limb muscleweakness,dysphagiaand musclepain, tendernessand swellingare all common in polymyositis and in dermatomyositis. b. Dusky erythema of the skin with plaquesover the joints or purple discolorationof the eyelids (heliotrope rash) is also a feature of dermatomyositis. c. Adults with dermatomyositisare at increasedrisk of having internal malignancies, particularly stomach,colon, lung, and breast. d. Laboratory studies show elevated creatine kinase and ESR. Creatinuria can result from breakdown of muscleproteins. e. Electromyographicabnormalitiesreflect abnormal muscle function. 4. Pathology. There is variation in fiber size, peripheral atrophy in fascicles,necrosis, myofiber vacuolation,edema,and perivascularmononuclear cell infiltration. Muscular dystrophies are a heterogeneousgroup of disorders that have a common feature of muscledegeneration.Dystrophic musclesare shrunken,flabby,and pale.Microscopically, there may be vacuolization,cytoplasmicfragmentation,hyalinization,and necrosis. 1. Duchenne muscular dystrophy is the most severefype of muscular dystrophy. a. Pathogenesis. This disorder shows X-linked recessive inheritance. The dystrophin protein, encoded on the X chromosome and normally present in muscle cell membranes,is usually absent. b. Clinical features

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Pathology

( 1) Elevation of creatinekinase and histologic degenerationprecedesclinical features. (2) The classicpresentation is with pelvic girdle weaknessand ataxia. The course is progressive,and children are unable to walk by the ageof 10. (3) Pseudohypertrophy of the calves is characteristic. (4) Myocardial muscle involvement accompaniesother muscle degenerationand may causedeath. (5) Mental retardation is also an associatedfeature.

ClinicalCorrelate Calfpseudohypertrophy (replacement of muscle tissue withadipose andfibrous tissue) ischaracteristic of Duchenne muscular dystrophy.

c. Diagnosis (1) Muscle biopsy revealsfiber degenerationwith connectivetissueproliferation and myophagocytosis;eventually,muscle is replacedby connectivetissueand fat. (2) DNA testsare availablefor the detection of mutations in the dystrophin gene. (3) Heterozygousfemale carriers may have elevatedcreatinekinase and subclinical degeneration,which is detectedby biopsy. 2 . Becker muscular dystrophy a. Pathogenesis.This diseaseshowsboth X-linked recessiveinheritanceor spontaneous mutations in the samegeneas Duchenne dystrophy. b. Clinical features. Patients may walk until age 20 or 25. Cardiac lesions are mild or absent. c. Diagnosis. Creatinekinase is elevated.Muscle biopsy changesare similar to those in Duchenne'sbut lesssevere.

Note Becker muscular dystrophy is essentially a lesssevere form ofDuchenne. InBecker, present dystrophin isusually butisofabnormal size.

3 . Facioscapulohumeral muscular dystrophy (FMD) a. Pathogenesis.Inheritance is autosomal dominant, but spontaneous mutation is common. b. Clinical features. Presenting symptoms usually involve the face, neck, and shoulder muscles.Pelvicmusclesmay be involved at later stages. c. Diagnosis. Muscle biopsy revealsdegenerativechangeswith fibrosis and inflammatory cell infiltration. 4. Limb-girdle muscular dystrophy (tGD) a. Pathogenesis.Inheritance is autosomalrecessive. b. Clinical features. Weaknessbegins in either the pelvic or shoulder girdle and spreads to involve other muscles.Affected individuals may retain ambulation for 25 years or more. c. Diagnosis. Muscle biopsy revealsstriking myofiber size variation with atrophy and hypertrophy. 5 . Myotonic dystrophy a. Pathogenesis.This disorder ariseswith an autosomal dominant pattern or through spontaneousmutations. The geneticdefect for myotonic dystrophy is a trinucleotide repeatin a protein kinaseencodedon chromosome 19. b. Clinical features.It is clinically unique from other dystrophies.Characteristicsinclude weakness,atrophy, and myotonia (tonic contraction of an affectedmuscle with inability to voluntarily relax it). Head and neck musclesare frequently weak and atrophic,

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Tissue, andIntegument Musculoskeletal System, Connective

while limb involvementis usually distal (handsand feet). Patientsmay havecardiac arrhythmias,cataracts,ftontal baldnes, hlryogonadism,and idiosyncraticreactionsin anesthesia. Muscleenzymesand biopsiesmaybe normal. c. CharacteristicpathologicEndingson light microscopy(ring fibers and sarcoplasmic masses)distinguishthis syndrorneftom other forms of musculardystrophy. Bridge-!o Biochemktry glycogen storage Certain diseases affectthe muscular svstem because the accumulation of glycogen impedes normalcellular processes.

enzfmes that result in G. Glycogenosesare diseasescausedby defectsin glycogen-cleaving glycogenaccumulationin varioustissues,including rnuscle, t ' Tlpe II (Pornpedisease) a. Pathogenesis,This diseaseis due to acid maltasedeficiency (a-1,4-glucosidase). Glycogenaccumulatesin the brain, liver, and muscles(including the heart). b. Clinical features include h€patom€galy,cardiomegaly,macroglossia,weakness,and h ?otonia. Presentationis within 3 months of birth, and deathoccursby 8 months. Serumlipid, glucose,and ketonesare normal. An adult form exists,which is milder and presentsasweaknesswithout organomegaly. c. Diagnosisis madeby enzymaticassayof acid maltasein leukocytesor fibroblasts. 2. TypeIII (Cori disease;limit dentrinosis) a. Pathogenesis. This diseaseis dueto a deficiencyin a debranchingenzyme(amylo-1,5glucosidase) . b. Clinical features.Hepatomegalyand growth failure are early features.Theremay be fastinghypoglycemia,ketosis,and elevatedlipids. c. Tleatment. Responseto glucagonor epinephrineis blunted becauseof inability to cleaveglycogenpastbranchingpoints. 3. Type IV (Andersendisease)

ln a Nutshell andexercise Muscle weakness tmoterance arecommon features of $ycogenstorage mvooathies.

a. Pathogenesis.This diseaseis dueto a deficiencyof the branchingenzymeinvolvedin glycogensynthesis. b. Pathology.A polysaccharidesimilar to amylopectinaccumulatesin th€ h€art, liv€r, muscle,and brain. Hepatomegalyis followedby cirrhosisand liver failure. 4. Tlpe V (McArdle disease) a. Pathogenesis,This diseaseis dueto myophosphorylase deficiency.Glycogenaccumulatesin vesicleswithin muscles. b. Clinical features.Muscle cramping and myoglobinuria are usual.There is no lactic acidosisduring exercise,and the glucagonresponseis normal. 5. TypeVII is due to phosphofructokinasedeficiencyand is clinically similar to McArdle disease. H. Congenital nyopathies typically presentearly in life. Clinical featuresinclude hypotonia and slowly progressiveweakness.They may be distinguishedprimarily by histopathologic features. l. In central core disease,denseryIindrical coresextendttle entire length of the fibers. 2. In nemaline myopathy, nemalinebodiesappearto be derivedfrom Z discsand possess crossstriations. 3. Centronuclearmyopathy (myotubular myopathy)usuallyinvolvesfacial and extraocular muscles.Onset may be in infancy, adolescence,or adulthood. The syndrome is

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geneticallyheterogeneous.Nuclei are characteristicallylocated in a central chain, surrounded by vacuoles. I. Werdnig-Hoffrnann disease is not a myopathy but an autosomal recessivedegeneration of the brain stem and spinal cord motor neurons. 1. Clinical features. It may present as neonatal hlpotonia (floppy baby) or decreased intrauterine fetal movement. Intercostal weaknessis frequent. 2. Complications. Respiratorycomplicationsare the usual causeof death. 3. Pathology.There is neuronal loss in anterior horns of the spinal cord as well as the cranial nerve nuclei.

ClinicalCorrelate Werdnig-Hoffman disease is "floppy known as baby syndrome" dueto thelossof neurons innervating both bodily andfacial muscles.

L Myositis ossificanscausesossificationat the site of traumatic hemorrhage.It presentswith pain, swelling,and tenderness.Differentiation from neoplasmscan be made by biopsy. K. Desmoid tumor (aggressivefibromatosis) is an infiltrative, fibrous proliferation, arising from the aponeurosesof skeletalmuscle.They are histologicallybenign and do not metastasizebut can becomelarge,locally invasivemasses.They frequently occur in young women, often in the abdominal wall. There is a possibleassociationwith multiple pregnanciesand previous trauma. Differentiation from sarcomasis made histologicully by the absenceof atypical cells. L. Rhabdomyosarcoma is a malignant neoplasm arising from striated muscle. It is the most common soft tissuesarcomain children. Prognosisdependson the site of origin. Up to 40olo have metastasesat the time of diagnosis. 1. Embryonal rhabdomyosarcoma a. In infanry or childhood, it is most often located in head and neck tissuesand is less aggressive than other forms. b. Sarcoma botryoids is an embryonal rhabdomyosarcoma with a grape-like, soft, polypoid gross appearance.It is usually located in the genitourinary, upper respiratory,or biliary tract. It is extremelyaggressive. M.Skeletal muscle abnormalities in AIDS

Bridgeto Reproductive Sarcoma botryoids is discussed inthe Reproductive Pathology chapter inthisvolume.

1. Incidence. Up to 50oloof HlV-positive individuals have some form of muscular abnormality. 2. The most common fiodirg is similar to polymyositis (i.e., inflammatory infiltrates with macrophagesand muscle fibers showing coagulativeor segmentalnecrosis).The muscle is not directly HlV-positive. Clinically, the picture is also similar to non-HlV-related polymyositis with weakness(primarily proximal in distribution) and EMG and laboratory findings typical of myopathy (increasedserum creatinekinase). 3. Nemaline rod myopathy with atrophy of tfpe I fibers is similar to congenital nemaline myopathy. Weaknessis predominantly proximal in distribution, and the EMG is myopathic. 4. Zidovudine (AZT)-induced myopathy is characterizedby multinucleated cells associated with myositis and by focal infection.

In a Nusthell A myositis-like syndrome may occurinAIDS asa result of infection orAZTtreatment.

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Musculoskeletal System, Connective Tissue, andlntegument

SKIN Note presents Scleroderma withsclerosis oftheskin. in detailin It isdiscussed theClinical lmmunology section of Ceneral Principles l). Bookt 0/olume

A. Epidermal lesions 1. Seborrheickeratoses are benign neoplasms that usually arise in areasexposedto the sun. They are very common in late adulthood. a. Clinical features. Although they are usually left untreated, they may be removed if they become irritated, or for cosmetic purposes.Sudden development of multiple lesionsmay follow an inflammatory dermatitis,hormonal therapy,or may accompany an underlying malignanry. b. Pathology (1) Grossly, lesionsare typically located on the face,back, or trunk. They are typically brown to gray scaly, and greasy. (2) Microscopically, seborrheic keratosis is a squamoproliferative disorder characterized by hyperkeratosis, papillary epidermal hyperplasia, and occasionally, developmentof pseudo horn cysts (epidermal pseudorystsfilled with keratin). Theseare invaginationscreatedbetweenthe papillae of keratin-producing cells.

ln a Nutshell Seborrheic keratoses aregray, greasy scaly, lesions with hyperkeratosis, epidermal papillary hyperplasia, and pseudocyst keratin occasional formation. Theyarebenign.

2. Keratoacanthoma is also a benign squamouslesion, arising in sun-exposedareas.It is most common in middle age. a. Clinical features. Keratoacanthoma is a rapidly growing papule that must be distinguishedfrom squamouscell carcinoma. b. Pathology (1) Grossly, lesions are located on the head and arms. They start as a round pink papule that grows within weeksup to 2 cm with a central depressionfilled with keratin. (2) Microscopically, the squamous cells are well organized and not anaplastic, although mitosesare presentduring the rapid growth phase.A key featureof this neoplasm is a lip of normal, nondysplastic epidermis on both sides of the keratin-filled crater.Keratoacanthomasare said to be composedof large squamous cells with a hyaline, "ground-glass" cytoplasm.

ClinicalCorrelate Skintagsarenormalfindings high onmostpeople; numbers ofthemmay indicate diabetes.

3. Fibroepithelial polyps are benign. Also known as skin tags, theselesions are common in middle agebut may also develop during pregnancy.They are also associatedwith diabetes or intestinal polyposis.They usuallyoccur in intertriginous regionsand on the neck.Skin tagsare composedof benign squamousepithelium covering a fibrovascularcore. 4. Basal cell carcinoma is invasive,but it rarely metastasizes. a. Incidence. It is most common in middle-aged or elderly individuals and those who havefair complexions.They occur on sun-exposedareas. b. Clinical features. Basal cell carcinomas are locally aggressiveand rarely metastasize. Completeexcisionis usuallycurative,but there is approximatelya50o/orecurrencerate from shavebiopsies. c. Pathology (1) Grossly,basalcell carcinomalesionsare locatedon sun-exposedregionsor areas containing pilosebaceousfollicles. Most lesions are on the face.They form pearly grey papuleswith heapedup borders and a central depression(Figure I-7-4).

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Pathology

Figure l-7-4.Basal cell carcinoma (gross).

ln a Nutshell

(2) Microscopically, there are nestsof tumor cellssurrounded by a fibrous stroma. Pallisadingof tumor cellsand retraction from the stroma at the edgesof nestsis a particularly useful microscopiccharacteristic(Figure I-7-5). 5 . Actinic keratosesare premalignant and may developinto squamouscell carcinoma. a. Incidence is highest in fair-skinned people of middle age.It is associatedwith chronic sun exposure.

,."w {:'. *,#;

Basal CellCarcinoma . Dueto sunexposure . Mostcommonly on occur theface . Raremetastases . Nests of tumorcellsin desmoplastic tissue . Pallisading is ofcells characteristic

,i&, b:t V.*

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;fi.fu{";i

Figure l-7-5.Basal cell carcinoma (microscopic).

b. Pathology (1) Grossly, there are rough, crusty,red papulesup to 1 cm in diameter.

97

Musculoskeletal System, Connective Tissue,andlntegument

(2) Microscopically, there are focal regions of atypical epidermis cells that do not invadethe basementmembrane and do not occupy the full thicknessof the epidermis. Disruption of the granular layer and formation of parakeratosisare common. 6 . Squamous cell carcinoma is a malignant tumor that is also found most frequently in sun-exposed areas. a. Incidence. The tumor peaksat 60 yearsof agewith a preponderanceamong women. b. Etiology. Chronic sun exposure and fair complexion are the greatestrisk factors. Chronic skin ulcers or sinus tracts, longterm exposureto hydrocarbons,burns, and radiation also contribute to risk. Papilloma virusesare associatedwith squamouscell carcinomasof the anogenitalregion.

In a Nutshell Squamous cellcarcinoma arises in sun-exposed areas, skinulcers, sinus tracts, or theanogenital region. Crossly, squamous cell carcinoma mayappear in manyforms. "squamous Microscopically, pearls" (formed byatypical keratinocytes) helpmake thediagnosis.

c. Clinical features.When squamouscarcinomaoccurson sun-exposedregions,it rarely metastasizes. When it occurson nonexposedskin, up to 50olometastasize, indicating a fundamentally different biology in the two systems. d. Pathology (1) Grossly, the appearanceis variable, depending on location and invasiveness. Squamouscarcinomasmay be firm, erythematous,scalynodules or oozing ulcers with raisedborders. On mucosal surfaces,th.y may be associatedwith leukoplakia (white plaques),madewhite by the keratin produced (FigureI-7-6).

Figure l-7-6.Squamous cell carcinoma (gross).

( 2 ) Microscopic findings include atypical cells restricted to the epidermis (Bowen diseaseor squamouscell carcinoma in situ) and atypical keratinocytesinvading the dermis (invasivecancer).Arypical keratinocytesmay form squamouspearls, i.e.,laminatedsquamouscellswith central keratinization in an "onion skin" configuration (Figure l-7 -7).

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Pathology

#

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squamous cell carcinoma Figure a-7-7.Well-differentiated with keratin pearls (microscopic).

ln a Nutshell B. Dermal lesions l. Xanthomas a. Incidence. Xanthomas may be idiopathic, or they may be associatedwith hyperlipidemia or malignancies.

arecollections Xanthomas histiorytes of lipid-laden andareoftenassociated withhyperlipidemia.

b. Pathology.They areyellownodules, composedof foamy histiocyteswith eosinophilic cytoplasm.The cellscontain cholesterol,triglycerides,and phospholipids. 2. Capillary hemangiomas (strawberry hemangiomas) a. Clinical features. These lesions usually arise within the first weeks of life and usually resolvespontaneously,starting at 1-3 yearsof age;most are completelygone by age5. b. Pathology.Capillary hemangiomasform a soft, red,lobulated mass,l-6 cm in diameter,composedof thick-walled capillaries. 3. Nevus flammeus (port wine stain) is a common congenitallesion, composedof telangUsuallylocatedon the neck or face,it appearsasa large,flat, irregular pink iectaticvessels. patch that tends to resolvespontaneously. 4. Kaposi sarcomais a malignant mesenchymaltumor (an angiosarcoma),characterizedby an aggressivecoursein patientswith AIDS and by a slower coursein elderly men. C. Pigmentary disorders

ln a Nutshell isan Kaposi sarcoma foundonskin angiosarcoma lt is membranes. andmucous withAIDS and associated herpesvirus caused byhuman typeB (HHVB).

l. Frecklesare areasof increasedmelanin depositionin the basalcell layer of the epidermis. 2. Vitiligo is irregular, completely depigmented patches. a. Incidence is common and may affect any race.Risk is increasedwith a positive family history. b. Etiology is unknown, but it is possiblyautoimmune or relatedto stress. c. Pathology. Microscopically, the skin is devoid of melanocftes in affectedareas.

ln a Nutshell by ischaracterized Vitiligo patchy depigmentation irregular origin dueto ofunknown mela nocyte deficiency.

3. Melasma is irregular patches of hyperpigmentation on the face. It most commonly appearsduring pregnancyand doesnot completelyregress.

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Musculoskeletal System, Connective Tissue, andIntegument

D. Melanocfte tumors l. Nevocellular nevus is a benign tumor of nevus cells and melanocftes. a. Typesof common nevi include junctional, compound, and intradermal.Although the different types may have distinguishing clinical features, histologic examination is neededfor accuratediagnosis. (1) Junctional nevi are recognizedhistologicallyby the presenceof nestsand individual nevus cellsin the lower epidermis, closeto the dermal-epidermal junction. (2) Compound nevi haveboth epidermal and dermal components. (3) Dermal nevi are characterizedby the presenceof mature nevus cellswithin the dermis. In time, the nevus cellsare surrounded by densefibrosis and mav eventually regressaltogether. b. Clinical features (1) The relationship between nevi and melanoma is largely unknown except that both are clearly relatedto sun exposure.Although malignant transformation of nevi is not common, approximately 30o/oof casesof melanoma are associated with nevi. There is also increasedincidence of melanoma associatedwith eiant congenitalpigmented nevi. (2) In most cases,one can distinguish a benign nevus from melanoma on clinical grounds (i.e., colot contour). A nevus is tan to brown and has sharp,well-circumscribedborders.Color is usually uniform, and the lesionsare stablein shape and size. 2. Lentigo maligna (Hutchinson freckle) a. This is a premalignant lesion,occurring on sun-exposedsurfacesin the elderly. b. It is characterizedbyintraepidermalproliferation of atypical melanocytes.Up to 50% progressto invasivemelanoma over the courseof severalyears.

Note Melanomas tendto grow horizontally before spreading vertically. Prognosis relates to depthof invasion.

3. Malignant melanoma a. Incidence. Melanoma peaksby ages40-60. b. Pathology (FiguresI-7-8 and I-7-9) ( 1) tentigo maligna melanoma arisesfrom lentigo maligna with a peak incidenceat age70.It grows horizontally first (radial growth), followed by vertical dermal invasion (nodular growth) and forms a large brown-black patch with an irregular border up to 6 cm in diameter, usually on the face or neck. Small, raised lesions within the patch represent regions of dermal invasion. This form of melanoma has the best prognosis. (2) Superficial spreading melanoma shows extensive horizontal growth with the radiating cells more atypical than those of lentigo maligna. The tumors may form a plaque up to 3 cm with varied coloration and irregular borders.Lesions are most commonly on legs,chest,and back; peak incidenceis by age60.

r00

Pathology

'ffi,!jq'

Figure l-7-8.Melanoma (gross).

Figure l-7-9.Melanoma (microscopic). (3) Nodular melanoma showsextensivedermal invasion and rapid growth. Raised brown-black lesionsmay be found anywhereon the skin or mucosa.Peakincidenceis by age50 and has the worst prognosisof the melanomas. c. Diagnosis. Stagingis by depth of invasion, through the layersof the epidermis and for dermis. Five-yearsurvival ratesrange from 10% for the deepestinvasion to 100o/o the most superficialinvasion.There seemsto be a prognostic cut off at a total thicknessof 0.7 mm. Greaterthan 0.7 mm causesa greaterlikelihood of metastasis.

t0l

Musculoskeletal System, Connective Tissue, andIntegument

d. Treatment is complete excision. Systemic diseaseis treated with chemotherapy or immunotherapy with poor but variable results. Some metastic melanomas resolve spontaneously,and some relapse as internal metastasesmore than a decade after a seeming"cure." E. Primary bullous disease 1. Bullous pemphigoid a. Incidence. This disorder is uncommon; however,it occurs more frequently than other primary bullous diseaseand tends to occur after age60.

ln a Nutshell . Bullous pemphigoid is caused byautoantibodies to ju dermoepidermal nction antigens. . Pemphigus vulgaris isdue to autoantibodies to keratinocyte intercellu lar junction antigens. . Dermatitis herpetiformis isa pruritic vesicular, disease oftenassociated withceliac sprue. lgAisfoundatthe junction. dermoepidermal

b. Clinical features. Bullous pemphigoid causeslarge, tense,pruritic bullae, usually on the lower abdomen, groin, inner thighs, and mouth. Most patients have circulating autoantibodies against the dermoepidermal junction. The diseasefollows a chronic relapsingcourseand is self-limited. c. Pathology. Subepidermalbullae and a linear deposition of IgG and complement at the dermoepidermaljunction on immunofluorescenceis seen. 2. Pemphigus vulgaris a. Incidence is most common from ages40-60. b. Pathogenesis. Autoantibodies against the intercellular junctions between keratinocytes causeacantholysis.The loss of intercellular connections causesan altered cell configuration. c. Clinical features (1) Pemphigus starts with small vesicles,usually on the oral or nasal mucosa, then spreadsto other parts of the body. Bullae are delicateand flaccid. (2) Nikoltky tigt is the development of bullae, causedby rubbing the skin with a finger. Pemphigus may result in erosions;secondaryinfections may lead to 40olo mortdity. Lesions are treated with corticosteroids. d. Pathology.Intraepidermalbullae, acantholysis,intraepidermal IgG, and complement deposition occur. F. Dermatitis herpetiformis 1. Incidence is most common from ages25-30 and is often associatedwith gluten-sensitive enteropathy and specific human HLA haplotypes. 2. Pathogenesis.IgA antibodyis found at the dermoepidermal junction, specifically at the dermal papillaeand in the upper dermis. Somepatientshavecirculating IgA-gluten complexes,which may be trapped in the skin. 3. Clinical features. There is a symmetrical distribution of grouped vesicles,often overlying an urticarial lesion.Vesiclesare intenselypruritic. Patientsexperiencea relapsingcourse. 4. Pathology. Subepidermalbullae and a granular deposition of IgA and complement at the dermoepidermaljunction occur. G. Infectious diseases 1. Impetigo is a superficial skin infection, usually causedby group A p-hemolytic streptococci or staphylococci. It is characterizedby eroded pustules, coveredby honey-colored crusts.Impetigo may lead to poststreptococcalglomerulonephritis.

t02

Pathology

2. Molluscum contagiosumis a poxvirus infection,causingdevelopmentof multiple small, in which viral firm, umbilicated papuleswith a characteristicmicroscopicaPPearance clusterscauseeosinophilicinclusionsin keratinocfes. 3. Verrucre.Wartsarecausedby papillomaviruses,which causeepidermalhlperplasiain a characteristicpapillary configurationwith hlperkeratosisand parakeratosis. 4. Superffcial fungal infections rnay be caused by Trichophyton,Microsporum, and Malassezia-lnfeaionis limited to the cornified layerof the epidermis. a. Tines capitis ("cradlecap") affectsthe scalpin children. b. Tinea corporis infeststhe trunl and extremitiesof children. It usually presentsas expandinground lesionswith erythematouscircinateborders.

Noh Tineacoroorisis alsoknown astingworm',andis actually a tunSalinfeclion.

c. Tineavesicolor causeshlao- or hyperpigmentedgroupsof macules' 'athlete'sfoot." d. Tinea pedis causes 'jock itch." e. Tinea cruris causes f. Tineaunguium (onychomycosis)causesthickeningand discolorationof the nail bed. 5. Scaldedskin syndrome is a pediatric condition causedby an exfoliativetoxin produced by S.aureus.The toxin splitsthe epidermisat the level of the stratum granulosum,causing a global denudationof the skin. H. Hnrersensitivity reactions 1. Urticaria, or hives,are usuallytransient,raised,pruritic, pinl wheals,charact€rizedby dermaledema. 2. Rrzena is a classof very common pruritic skin disorders,characterizedby distinctive clinical and pathologicfeatures. a. Clinical forms ( 1) Atopic dermatitis is of variableand often unknown etiology;usually,there is a family history of atopy (allergy). (2) Contact dermatitis may resultftom allergicor irritant exposure. (3) Lichen simplex chronicus causeschronic, lichenified plaques,probably caused by rubbing. (4) Polymorphouslight eruption is seenafter ultraviolet light exposure. (5) Drug reactions resolvewhent}re offendingdrug is discontinued. (6) Edoliative dermatitis describesscalingand erythemaof the entle skin' b. Pathologictypes ( 1) Acutee€zema(i.e.,contactdermatitis)describesedematous,oozing,red plaques, often witl vesiclesand dermalinflammation. with moist, red (2) Subacuteeczema(i.e.,childhood atopic dermatitis)is associated papulesand plaqueswith epidermalhyperplasiaand derrnalinflammation' (3) Chronic eczema.Dry, scalyplaquesarepresentfor months.Lichenificationcausesaccentuatedskin creasesand thickenedskin. c. Tleatment. Moisturizerscan be usedto control the itching; oral antihistaminesand topical steroidsmay alsobe used.

t05

Musculoskeletal System, Connective Tissue, andIntegument

3. Erythema rnultiforrne a. Pathogenesis.This may be a hnrersensitivityresponseto drugs (e.g.,sulfonamides, penicillins), infections (e.g., herpes, mycoplasma),collagen vascular diseases,or malignancies. In a llubhell Erythema muhiforme isa hypersensitivity reaclion to drugs.StevensJohnson syndrome isthesevere form

b. clinical features.Erythema multiforme is uncommon. There is often symmetrical involvementof the lirnbs' ( l ) In the minor form, tlere arefew lesions,no s),st€micsymptoms;and the disease is selflirnited. (2) In the major form (st€vels-Johnson syndrorne), there is fever, r€spiratory difficulty, widespreadskin involvement(including mucousmembranes),a high risk of sepsis,and a risk of fatality. c. Pathology.A largeerythematouspapulethat dwelops centralvesiculation;erosionis classic.ksions are alsocharacterizedbv edemaand inflammatorv infiltration. I. Psoriasis I . Incidence.One percentof the population of the United Statesis affected.The peakincidenceis 30 yearsof age,and the most commonform is psoriasisvulgaris.

!1 I Nubhell psoriasis . A silveryscalyplaquethat primarily affecbknees , elbows, andthescalp. . Hinologically, it is characterized byepidermal hyperplasia andhyperkeratinization

2. Pathogeresis. The etiology is urrknown, but there is a clear genetic component. Precipitantsincludehormonal changes,infection, andtrauma.Psoriasismayalsobe associatedwith arthritis, enteropathy,and myopathy. 3' clinical featuresof psoriasisvulgaris a. ksions are locatedthroughout the body, especiallyon the nails, knees,elbows,and scalp'They usuallydo not involvemucousmembranesb. lesions arewell-demarcated,coral-coloredplaqueswith white or silver scale. c. The Auspitz sign is seenwhen removalof scaleresultsin pinpoint areasof bleeding. This is characteristicof psoriasis. 4. pathologic featuresofpsoriasis vulgaris a. Hlperkeratinization with parakeratosisappearsin a patc\ distribution. b. Epidermalhyperplasiacausesthickeningand lengtheningofthe reteridges,usuallyto a uniform depth. c. Thinning ofthe surfaceepidermis,particularly overthe dermalpapillae,is characteristic. 5. Treatmentis usuallywith topical steroids and ultraviolet irradiatioL Severe,systemic diseasemaybe treatedwith methotrexate. I. Inflammatorvdisorders l. Acne vulgaris causescomedones,papules,and c)'sts.It may be related to hormones, drugs,diet, irritants, and geneticfactors.An all€rgyto Propionbacteriumacnesis clearly involved. 2' Pitl'riasis rosea a. Incidence.This disorderis common,from ages1G.-40. b. Pathogenesis,Thereis a possibleviral etiology.

t04

Pathology

c. Clinical features. Pityriasis rosea presents first with a "Herald patch," an approximately 4-cm, red, scalingpatch, followed within daysby eruption in "turtle neck-short sleeve"distribution. Lesions are small, pink, oval patchesalong flexural lines (fir tree pattern), appearingin crops.The diseaseis usually self-limited (1-4 months). 3. Rosacea a. Incidence. Rosaceais common from ages30-50. Women are affectedthree times more commonly than men, but the syndrome is more severein men. b. Clinical features. The lesions affect the central face. Erythema and telangiectasias, acneform lesions (i.e., papules, rysts, pustules), and rhinophyma (teleangiectasias and hyperplasiaof nasalsoft tissue) are all seenin various combinations,sometimes causing a severedistortion of the face,particularly the nose.

r05

Musculoskeletal, Tissu€, Connective andlntegument Pharmacology Thenonsteroidal groupof analgesig antipyretic, andanti-inflammatory drugs area heterogeneous organic acids, theprototype being aspirin. Allaspirin-like drugs share certain therapeutic actions and sideeffects, buttherearesomedistinct intheiractivities. differences These drugs aremildanalgesis painof low-to-moderate particularly thatareeffective against intensity, in association with inflammation. Theyareusedclinically asanti-inflammatory inthetreatment agents of rheumatic disorders andgout. fromaninflammatory Coutresults response to thedeposition of sodium uratecrystals inthejoints andperiarticular tissues. Drugs usedinthetreatment of goutactto inhibit synthesis of uricacid, granulocyte increase theurinary excretion of uricacid,inhibit chemotaxis to theinflammatory site,or relieve symptoms of painandinflammation.

SALICYTATES A. Aspirin (acerylsalicylic acid) 1. Pharmacologic properties

Nole Phospholipids I PhosPholiPase Cortico$eroido I

'& Y

a. Pharmacokinetics. Oral preparations are absorbed rapidly in the stomach and small intestine. The half-life of aspirin is approximately 3 hours. b. Metabolism. Aspirin is hydrolyzed to salicylic acid, which binds tightly to plasma proteins. Seventy-fivepercent undergoeshepatic conjugation with glycine. c. Preparations. Aspirin is available in buffered effervescentpreparations, enteric-coated preparations,and rectal suppositories. d. Action. Aspirin relievespain of low intensity (..g., headache,myalgias,arthralgias)by both peripheral and central effects.Unlike opioids, no tolerance or addiction develops. It lowers elevatedbody temperature by inhibition of pyrogen-induced prostaglandin biosynthesisin the CNS. It inhibits the inflammatory responseby blocking the action of cyclooxygenase (COX) and inhibiting prostaglandin synthesis.Aspirin also prolongs bleeding time as a result of altered platelet ryclooxygenasefunction and inhibition of thromboxane production. 2. Indications for use a. Aspirin is used for both rheumatoid arthritis and osteoarthritis. b. Aspirin suppressesthe acute inflammatory processof acute rheumatic fever but has no effect on diseaseprogression.

Arachidonic Acid

NSAtDso i--1

\

/ Cyclooxygenases \ Lipory/ COX-IandC0X-2\ genases

ll

|

/

\\

\lZilenton o

o I le coxibs steroidsr/ ,^glr l

TXA2' / Pro$aglandins Leukotrienes by ReceptorsO -lukasls

Note Therearetwotypesof COX. COX-Iisexpressed in most tissues; C0X-2isexpressed at thesitesof inflammation.

c. Aspirin is used as an analgesicfor headache,arthritis, dysmenorrhea,neuralgia,and myalgia. It is not as effective as narcotic analgesics.

t07

Tissue, Musculoskeletal System, Connective andIntegument

d. Aspirin is indicated for the reduction of fever (antipyresis). e. Aspirin is given to patients after myocardial infarctions and transient ischemic attacks (TIAs) to reducethe risk of reinfarction and stroke. It is also used in some patients for prophylaxis of thrombosis.

Bridge to Biochemistry Acutetoxicityof aspirinresults in uncoupling theelectron fromoxidative transport chain phosphorylation.

3. Side effects and toxicity a. Gastrointestinal effects include gastritis with epigastric distress, nausea,vomiting, abdominal pain, and acute and chronic blood loss secondary to gastric mucosal erosion.Gastrointestinaleffectsare secondaryto a decreasein prostaglandins,which protect the gastrointestinalmucosaand decreasegastric acid production. b. Hypersensitivity syndrome may result in urticaria, rhinitis, or asthma (seenin patients with nasal polyposis). c. Reversiblehepatotoxicity is associatedwith large dosesin juvenile rheumatic diseases and SLE. d. Hemorrhage occurs secondaryto alteredplatelet aggregation.

Note Platelets areirreversibly (other byaspirin inhibited The NSAIDs arereversible). anticoagulant effects ofaspirin arethuslonger lasting. ClinicalCorrelate Aspirin notbe should administered to children and withviral adolescents (because illnesses of therisk of Reye syndrome),

e. Salicylism (i.e., mild chronic intoxication) includes headache,dizziness,tinnitus, hearing loss,drowsiness,nausea,vomiting, and diarrhea. f. Acute salirylate poisoning causeshlperthermia, dehydration, acid-basedisturbances, ketosis,hypokalemia,and acutenoncardiogenicpulmonary edema. g. Aspirin may precipitate renal insufficienry, although this effect is rare. 4. Drug interactions. Aspirin increasesthe bleeding tendency with warfarin and heparin; increasesthe salicylate effect seen with acetazolamideand cimetidine; increaseshypoglycemiawith insulin and sulfonylureas;increasesvalproic acid's effect; and blocks the uricosuric effect of probenecid. B. Diflunisal l. Pharmacologic properties. Diflunisal is a fluorinated derivative of salirylate, although it is not hydrolyzed to salicylate in vivo. Like aspirin, it inhibits cycloorygenaseand has effectssimilar to salirylic acid,but it is much more potent. Its half-life is 8-12 hours. 2. Indications for use.This analgesicis used for mild-to-moderate pain, including musculoskeletalpain and osteoarthritis,especiallywhen antipyrexiais not desired.

Note Diflunisal hasessentially no antipyretic effect sinceit does notentertheCNS.

3. Side effects and toxicity a. Gastrointestinaleffectsinclude nausea,dyspepsia,gastrointestinalbleeding,and diarrhea.Theseeffectsare lessintensethan with aspirin. insomnia,headache,and fatigue. b. Other effectsmay include dizziness,vertigo,neryousness, 4. Drug interactions include an increasedbleeding tendencywith alcohol,warfarin, and heparin. Decreaseddiuretic and antihypertensiveeffectsoccur with thiazides and frrosemide, and an increasedeffect occurswith lithium toxicity. C. Nonacetylated salicylate derivatives, like aspirin, are indicated for the treatment of pain, inflammation, headaches,and fever. 1. Sodium salicylate is probably lesseffective than aspirin. 2. Choline magnesium trisalicylate is a combination of choline salirylate and magnesium salirylate. It may have fewer gastrointestinal side effectsthan other salirylates.It is useful in patients intolerant of aspirin or other nonsteroidal anti-inflammatory agents (NSAIDS).

r08

Pharmacology

3. Salsalateis convertedto salirylic acid, an activemetabolite.Salsalatemay havean advantage over aspirin in that it causeslessgastrointestinalblood loss. D. Selective COX-2 inhibitors: cele- and rofecoxib. The primary difFerencewith NSAIDs are that they causelessgastrointestinalirritation and havelessplateletanti-aggregantproperties. But they increasePT when usedwith warfarin.

ACETIC ACIDDERIVATIVES A. Indomethacin 1. Pharmacologic properties a. Pharmacokinetics.Indomethacinis rapidly absorbedby the gastrointestinaltract following oral administration and reachesa peak plasma concentration in 2-3 hours. It is 90oloplasmaprotein-bound.

ClinicalCorrelate Indomethacin isthe drugof choice for closing a patent ductus arteriosus in a neonate.

b. Metabolism. Indomethacin is converted to inactive metabolites in the liver. c. Action. This drug has potent anti-inflammatory, analgesic,and antipyretic action. It inhibits prostaglandin-formingrycloorygenaseand inhibits the motility of polymorphonuclearleukocytes.It inhibits leukocytephagocytosisof the sodium urate crystals by blocking migration of thesecellsto the site of inflammation. 2. Indications for use a. Indomethacin is used as an analgesicand antipyretic, but the high incidence and severityof side effectslimits its routine use for mild symptoms. b. Its main useis for moderate-to-severe rheumatoid arthritis, osteoarthritis,ankylosing spondylitis, and Bartter syndrome. It is also indicated for tendonitis, bursitis, acute gout, dysmenorrhea,and is the drug of choice for Reiter syndrome. 3. Side effects and toxicity a. Gastrointestinaleffectsare the sameas for aspirin. b. Central nervous system effects include headache,dizziness, vertigo, depression, psychosis,hallucinations,and seizures. c. Hematologic effects include neutropenia, thrombocytopenia, aplastic anemia, and impaired plateletfunction. d. Other effectsinclude hypersensitivity(e.g.,rash,urticaria,asthma),pancreatitis,hepatotoxicity, exacerbationof renal insufficienry, and salt retention. e. Indomethacin is contraindicatedduring pregnancyand in patientswith epilepsy,renal disease,or peptic ulcer disease. 4. Drug interactions. It reducesthe antihypertensiveeffect of furosemide, thiazides, pblockers,captopril, and prazosin.It increaseslithium levelsand prolongs the half-life of digoxin in neonatesand possiblyadults. B. Sulindac 1. Pharmacologic properties a. Pharmacokinetics. Ninery percentis absorbedafter oral administration. It has a long half-life, which allowstwice-daily dosing.

t09

Tissue, andIntegument Musculoskeletal System, Connective

b, Met&bolism. Sulindac undergoesoxidation-reduction reactionsto form an active sulfidemetabolite.Its metabolitesare excretedin urine and feces, c. Action. Sulindacis structurally similar to indomethacinbut lessthan half aspotent. There is no anti-inflammatory activity until it is absorbedand metabolizedto its suifideform. l. Indications for use include rheumatoid arthritis, osteoarthritis,antylosing spondylitis, and acutegouty arthritis. 3. Sid€eff€ctsand toxicitv a. Gastrointestinal effects include abdominal pain, nausea,and constipation.It has fewersideeffectstlan aspirin.There is an increasedrisk of gastrointestinalbleeding when usedwitl warfarin and other anti-inflarnmatorydrugs. b. Central n€rvous system effects include drowsiness,dizziness, headache,and nervousness. c. Odrcr effectsinclude hlpersensitivity reactions(e.g.,skin rash,pruritus) and blood Exacerbationsof renal insuffrciencyand treatedhlpertension arebotl less dyscrasias. Iikely than with other agents.The main advantageof sulindacoverindomethacinis its lack of nephrotoxicity. C. Tolrnetin t. Pharrnacologicproperties a. Pharmacokinetics.Tolmetin is completelyabsorbedafter oral administrationwith a plasmaha.lf-Iifeof I hour andrequiresfrequentdosingto maintain therapeuticlevels. It is 99%bound to plasmaproteins. b. Maebolism. Tolmetin is excretedin conjugatedand unchangedforms in the urine. c. Action. Tolmetin is more potent than aspirin but l€sspotent than indomethacin.

include adult andjuvenile rheumatoid artluitis' l' llJ#frftlse a. Gastrointestinal side effects are most common, alttrough less than with indomethacin. b. OtJrer less common effects include hepatotoxicity, renal toxicity, and hypertension. D. Nabumetone may cause less gastric irritation than indomethacin or naproxen. It exhibits significantly lower gastrointestinal blood loss than aspirin.

PROPIONIC ACIDDERIVATIVES A. Ibuprofen l. Pharrnacologicproperties

l!* lbuprofenhasgreater potency analgesic thanboth aspirinandacetaminophen.

;]tr--,*Tffitriiii"'*il:,Tli:,'$x1L"f;.Tiitlil.T plasmalevels' dosingfour times daily to maintain steady-state

b. Metabolism.It is excretedin urine ashydrorylatedand carboxylatedcompounds. c. Action.Ibuprofen hasanalgesic,antipyretic,and anti-inflammatory actions. l. Indications for useincludedysmenorrhea, musculoskeletal disorders,rheumatoidarthritis, and osteoarthritis.

il0

Pharmacology

3. Sideeff€ctsand toxicity a'Ibuprofenhasfewergastrointestinalsideeffectsthanaspirinorindomethacin b. Other effectsindude thrombocytopenia,skin rashes,dizzines, headache,blurred vision, tinnitus, and exacerbationof renal insufficiency.

:

B. Napro)(€n 1. Pharmacologicproperties

l!9!!

a. Pharmacokinetics.Naproxen is fully absorbedafter oral administration. It has a

plasma halfJife of I2-I5hours andii ee%bound proteins. toplasma

b. Metabolisrn,It is excretedin urine unchangedand asglucuronideconjugates. c. Action. Naproxenhaspotent analgesicactivity in both rhzumatic and nonrheumatic conditions.

itljfrfiffi: f:::ff" theirlonghalf-lives, whic} allowfor les frequentdosing.

2. Indications for use include moderat€-to-severepostoperativepain (e.g. orthopedic surgery dental surgery),postpartum uterine cramps,acute musculoskeletaldisorders, rheumatoidarthritis, osteoarthritis,anJsylosing spondylitis,dpmenorrhea,and acutegoul 3. Sideeffectsand toxicitf a. Gastrointestinaleffectsinclude heartbum, dyspepsia,nausea,vorniting, and gastric bleeding. b. Centralnervouss)'stemsideeffectsincludeheadache, dizziness,ototoxicit)r,dq>ression, andblurredvision. c. Exacerbationof renal insuffciency may alsoorcur.

PYRAZOTONE DERIVATIVES A. Pheny'butazone 1. Pharmacologicproperties a. Pharmacokinetics.Phenylbutazoneis completelyabsorbedfrom the gastrointestinal : tract after oral administration. b. Action. It inhibits prostaglandinbiorynthesis,causingprominent anti-inflammatory effects,although it is not as good an analgesicor antipyretic as the salicylates. Usefulnessas an analgesicand antipyretic agentis limited by the high incidenc.eof toxicity. 2. Indications for use.Phenylbutazonehas a limited role in treatment.It is not a drug of choicebecauseof its toxicity and should not be administeredlong-term. Nonetheless,it is usefirlasa secondaryagentin acutegout and rheumaticdisease. 3. Side€ffectsand toxicit)' a. Gastrointestinaleffectsincludenausea,vomiting, gastritis,diarrhea,andpqrtic ulceratron, b. Other effectsinclude electrolyteand water retention with edemaformation, rashes, aplasticanemi4 agranulocposis,and rarely,thrombocytopenia. c. Contraindications include cardiac,renal,or hepaticdysfunction;peptic r.rlcerdisease; hypertension;and blood dyscrasias. 4. Druginteractions, Phenylbutazone displacesother anti-inflamrnatorydrugs,oral anticoagulants,sulfonamides,and oral hypoglycemicsfrom plasmaproteins.It may inhibit or

ilt

Tissue, andlntegument System, Connective Musculoskeletal

acceleratehepatic metabolism of other drugs. An increasedanticoagulanteffect is seen with warfarin. B. Oxyphenylbutazone is an analog (an active metabolite) of phenylbutazone. Significant accumulationof oxyphenylbutazoneduring chronic administration of phenylbutazonecontributes to the toxic effectsof the parent drug. 1. Pharmacologic properties. There is slow urinary excretionof the glucuronide conjugate. Pharmacologiceffectsare similar to those of phenylbutazone. 2. Indications for use are the sameas for phenylbutazone. 3. Side effectsand toxicity are alsothe sameasphenylbutazone.

NSAIDS OTHER A. Mefenamic acid 1. Pharmacologic properties a. Pharmacokinetics. Mefenamic acid is rapidly absorbed after oral administration. Peakplasma concentrationsoccur in 2 hours with a plasma half-life of 3-4 hours. b. Metabolism. Fifty percentis excretedin the urine as conjugatedmetabolites,and20o/o is excretedin fecesas unconjugatedmetabolites. c. Action.Its anti-inflammatory potencyis half that of phenylbutazone.Analgesiais produced by central and peripheral actions. 2. Indications for use include rheumatic conditions, soft tissue iniuries, musculoskeletal disorders,and dysmenorrhea. 3. Side effects and toxicity a. Gastrointestinal side effects are seenin 25o/oof patients and include dyspepsia,diarrhea, colitis, and gastrointestinalulceration. b. Other effectsinclude autoimmune hemolytic anemiawith long-term use,and exacerbation of renal insufficiency. 4. Drug interactions include an increasedprothrombin time (PT) with warfarin and a decreasedhypoglycemiceffectwith insulin. B. Piroxicam 1. Pharmacologic properties a. Pharmacokinetics. There is rapid oral absorption with peak concentrations in plasma in 3-5 hours. There is enterohepaticcirculation; therefore, the half-life is approximately45 hours, allowing once-a-daydosing. b. Metabolism. Ten percent is excretedunchangedin the urine, while some metabolites are excretedin the urine as well. c. Action. Piroxicam has a similar anti-inflammatory efficacy as aspirin and indomethacin. 2. Indications for use include rheumatoid arthritis, osteoarthritis,and ankylosingspondylitis. 3. Side effectsand toxicity include gastrointestinaleffectssimilar to other NSAIDs.

il2

Pharmacology

NONOPIOID ANATGESICS ANDANTIPYRETICS A. Acetaminoph€n

r- pharmacologicproperties a. Pharmacokinetics.Acetaminophenis rapidly absorbedftom tle gastrointestinaltract following oral administration.Peakplasmavaluesare reachedin I hour with a halflife of l-4 hours. b. Metabolism. It is metabolizedby hepatic microsomalenzymeswith extensivefirstpassdegradation.Most (90-1009o)is recoveredin the urine within 24 hoursafterhepatic conjugationwith glucuronicacid,su.lirric acid,and cysteine. c. Action, Acetaminophenis an effectivealternativeto aspirin as an analgesicand antipyretic,but it has very weak anti-inflammatoryactivity.It is a weakinhibitor of peripheralprostaglandinbiosynthesisand therdore doesnot affectplateletfunction.

!!!1|91!9q!1?.Q Acetaminophen, ratherthan asoirin.istheantiovretic of chotce in children withviral illneses(no riskof Reye syndrome), for patien$on anticoagulanb, andfor Sout pa(en60n uncosunc agens'

2. Indicatioas for use include analgesiaand antipyrexia,especiallywhen aspirin is contraindicated. Note that acetaminophendoesnot havean anti-inflammatory action. 3. Sideeffectsand toxicitf a. Acetaminophencan causea dose-dependent hepaticnecrosis,r€nal tubular necrosis, and hypoglycemiccoma' b. Acute poisoning resultsin nausea,vomiting, anorexia,and abdominal pain. Severe hepatic damage may develop after 2448 hours from a toxic metabolite. Hepatotoicity is decreased if N-acetylqnteine is givenwithin 24 hows ofpoisoning. B. phenacetin

ltl* AcetaminoDhen overdose is treatedwith/V-acetylcysteine, lvtrichhelosto reolenish glutathione depleted stores in theliver.

1. Pharmacologicproperties a. Pharmacokinetics.Most of this drug is rapidly metabolizedto acetaminophenfollowingoral administration. b. Action, Analgesic,antipyretic, and anti-inflammatory activity is similar to acetaminophen. 2. Indications for use,Phenacetinis not in clinical usebecauseof its toxicity. 3. Sideeffectsand toxicit" a. Phenacetin causesrenal tubular necrosis and chronic renal insufficiency. Methemoglobinemiaand hemolytic anemiaare also seenin individuals who havea limited ability to convertphenacetinto acetaminophen. b, Overdosemay caus€cyanosis,respiratorydepression,and cardiacarrest.

ANTIRHEUMATIC OTHER AGENTS A. Diseasenodifying anti-rheumatic drugs (DMARDs) slow diseaseprogressionand maybe usedwith NSAIDSinitially. Hydrorycbloroquineand methotrexateare usedfor mild and severerheumatoidarthritis, respectively. However,new agentstargetingtumor necrosisfactor (TNF) arecurativefor refractorycasesand canbe usedin combination.Theseinclude: 1. Etinerc€pt which binds TNF (recombinantTNF receptor) 2. Infliximab, a monoclonalantibodyto TNF 3. Ieflunomide, a dihydroorotic acid dehydrogenase inhibitor which inhibits lymphocytes' r division and maturation

il5

Tissue, andlntegument Musculoskeletal System, Connective

B. Gold 1. Pharmacologic properties a. Pharmacokinetics. Gold can be administered intramuscularly (e.g., aurothioglucose, gold sodium thiomalate) or orally (e.g.,auranofin). b. Action. Gold inhibits macrophage functioning, including migration and phagocytosis.There is no antipyretic or analgesiceffect. 2. Indications for use. Gold is indicated in rheumatoid arthritis unresponsiveto NSAIDs. It is most effectivetaken early in rapidly progressivediseases. 3. Side effects and toxicity. Most of the following effects,except gastrointestinal effects,are lesslikely to occur with oral auranofin than with intramuscular preparations. a. Gastrointestinaldisturbancesare more common with auranofin, especiallydiarrhea.

Bridgeto GeneglPrinciples

b. Skin effectsinclude erythema, dermatitis, and chrysiasis(grayish-blue skin pigmentation).

isusedinthe Penicillamine disease treatment ofWilson lt biliary cirrhosis. andprimary intheLead isdiscussed Agents Toxicity andChelating Principles chapter of Ceneral ll). Bookz (Volume

c. Mucocutaneous effectsinclude oral ulcers, stomatitis, gastritis, and colitis. d. Renal effectsinclude proteinuria and a reversiblenephrosis. e. Hematologic effectsinclude thrombocytopenia,leukopenia,aplasticanemia,agranulocftosis, and eosinophilia. C. Penicillamine is classedas a chelating agent. Penicillamine decreasesbone destruction in rheumatoid arthritis. Its mechanismof action is unknown but may be relatedto inhibition of collagenformation. Severeside effectslimit its use.

Bridgeto Principles General

D. Chloroquine and hydroxychloroquine are antimalarial agents.Although these drugs have anti-inflammatory actions, seriousside effectslimit their use. The mechanismof action is unknown.

usesof Theantineoplastic arediscussed in methotrexate Agents theAntineopla$ic Principles of Ceneral chapter ll). Bookz (Volume

E. Methotrexate is used primarily as an antineoplastic agent, although it is now approved for treatment of refractory rheumatoid arthritis. Becauseof the much lower doses used in arthritis, side effects are less severethan in cancer therapy. Side effects include hepatic changesand pneumonitis.

TREATMENT OFACUTE GOUT NSAIDs are often preferred in the treatment of acute gout. Although they are as efficacious as colchicine, symptomatic improvement takeslonger. Indomethacin is most commonly used,but naproxen and sulindac may also be employed. Salirylates,such as aspirin, are not used if gout is being treated with probenecid or sulfinpyrazone becausesalicylatesinhibit the uricosuric effect of these drugs. A. Indomethacin (discussedearlier in this chapter) B. Colchicine 1. Pharmacologic properties a. Mechanism of action. Colchicine interferes with microtubules, thus preventing the migration of granulocytesto the inflammatory site. It has no uricosuric effects. b. Routes of administration. Colchicine may be given orally, which causesgreater gastrointestinal toxicity and a slower onset of action, or intravenously, which has a small chanceof anaphylaxis.

il4

Pharmacology

2. Indications for use. Colchicine is used to treat acute attacks of gout, especially when NSAIDs are not tolerated. It is also given prophylactically to prevent recurrent episodesof acutegout. 3. Side effects and toxicity a. Gastrointestinal effects include nausea,vomiting, abdominal pain, and diarrhea, which may necessitatediscontinuation of the drug. b. Effectsof long-term useand high dosesinclude blood dyscrasias(i.e.,aplasticanemia, thrombocytopenia, agranulocytosis),alopecia, neuropathy, myopathy, and hemorrhagic gastroenteritis.

TREATMENT OFHYPERURICEMIA

Bridgeto Biochemistry

A. Allopurinol 1. Pharmacologic properties a. Mechanism of action. Allopurinol is an analog of hypoxanthine that inhibits the conversion of hpoxanthine to uric acid by xanthine oxidase.It lowers both serum and urinary concentrationsof uric acid. b. Pharmacokinetics. Allopurinol is well absorbed orally and metabolized to oxypurinol, a xanthine oxidaseinhibitor with a half-life of 30 hours. 2. Indications for use a. Allopurinol is the drug of choice for most patients with severe hnreruricemia, whether due to gout or other conditions.

"another Allopurinol, meaning purine," isalsoa prodrug that istakenbyHGPRTase and made anallopurinal nucleotide. Thisinturninhibis PRPP amidotransferase, the rat*limiting $epof denovo purine synthesis, resulting in lesspurines made. Therefore, lessisdegraded to uricacid.

b. Acute attacks of gout (1) If a patient is on allopurinol, it should be continued.

Note

(2) If therapy is to be initiated, it should be delayeduntil severaldaysafter the acute episodehas resolvedand the patient is on maintenancedosesof colchicine.

Allopurinol canraise serum levels of someantimetabolites (e.g., azathioprine) by inhibiting theirbreakdown.

3. Side effects and toxicity a. Sideeffectsinclude nausea,diarrhea,and hypersensitivity(e.g.,rash,fever,exfoliative dermatitis). b. Less common side effects include blood dyscrasias,hepatotoxiciry and peripheral neuropathy. 4. Drug interactions. The dose must be reduced in the presence of renal insufficienry. Allopurinol may inhibit the metabolism of oral anticoagulantsand have increasedtoxicity when used with thiazide diuretics. The dosageof mercaptopurine, an antineoplasticthat is metabolizedby xanthine oxidase,must be lowered when administered concomitantly with allopurinol. B. Probenecid l. Pharmacologic properties a. Mechanism of action. Uricosuric agents are organic acids that compete with other acids (including uric acid) at anionic transport sitesin the renal tubule. Low dosesof uricosuric drugs may selectivelyinhibit tubular secretion of uric acid and causesome retention of urate. However, at therapeutic dosestheir predominant effect is to block uric acid reabsorption in the proximal tubule, thereby increasingthe urinary excretion of urate.

Note Allopurinol decreases both serum andurine concentrations of uricacid, whileprobenecid decreases serum levels butincreases urinelevels.

il5

System, Connective Tissue, andIntegument Musculoskeletal

b. Pharmacokinetics. Probenecid is completely reabsorbedin the nephron, metabolized slowly, and excretedin urine. The metabolic byproducts are also uricosuric. 2. Indications for use a. Probenecidis used when allopurinol is not well tolerated. b. During acuteattacks,probenecidshould be continued if the patient is on maintenance therapy but should not be initiated until the acuteattack has subsided. c. It may alsobe used to prevent penicillin elimination and raiseits serum level.

Note of otherweak Thesecretion penicillins, acids, e.g., isreduced by caphalosporins, probenecid, thusincreasing theirhalf-lives.

3. Side effects and toxicity a. Gastrointestinaleffectsinclude nauseaand abdomin"l puitt. b. Hypersensitiviry including rash and fever,may occur. c. Renalcalculi may occur. It should not be used in patients who excretelarge amounts of urate. Patientsshould be instructed to maintain a high fluid intake to help prevent stone formation. d. Nephrotic syndrome and peptic ulceration may occur in rare instances. e. Hemolytic anemia may occur in patients with glucose-6-phosphatedehydrogenase (G6PD) deficiency. f. Severeoverdosescan causeseizuresor fatal respiratory depression.

In a Nutshell DrugsUsedto TreatGout . Colchicine -+ inhibits granuloryte migration by interfering with microtubules . Allopurinol -->inhibits conversion of hypoxanthine to uricacidbyxanthine oxidase . Probenecid -+ blocks uric inthe acidreabsorption proximal tubule (uricosuric) . Sulfinpyrazone + increases of uric urinary excretion acid . NSAIDs + relieve symptoms of painand inflammation

I t6

C. Sulfinpyraznne 1. Pharmacologic properties. Sulfinpyrazone is a derivative of phenylbutazone. Ninety percent is excretedunchangedin the urine. 2. Indications for use. Use for gout is similar to that of probenecid. It may also be used to inhibit platelet aggregationbecauseof its inhibitory action on prostaglandin synthesis. 3. Side effects and toxicity a. Gastrointestinal symptoms are more common with sulfinpyrazone than with probenecid,although gastrointestinalulceration is uncommon. b. Other side effectsinclude rash and renal calculi formation. c. Although the parent compound, phenylbutazone,may, in rare instances,causeblood dyscrasiasand volume overload, these side effects have not been reported with sulfinpyrazone. 4. Drug interactions. Sulfinpyrazone potentiates the effects of insulin, sulfonylureas, sulfonamides,and warfarin.

SECTION II

Gastrol ntestlnaI System

Gastrointestinal Embryology gutisformed Theprimitive asa result of cephalocaudal andlateral foldings oftheembryo. lt is anatomically divided intotheforegufmidgut, andhindgut. Thecranial foregut, fromthe groove, buccopharyngeal membrane to thelaryngotracheal iscovered inthechapter onthe pharyngeal arches andtheirderivatives intheCeneral Principles review book.Theremainder ofthe primitive gutanditsderivatives arereviewed here.Epithelium andglands ofthega$rointe$inal tract andbiliary systems, andtheparenchyma gut oftheliverandpancreas, arederived fromprimitive endoderm. Themuscles, connective tissue, andbloodvessels ofthegutwallarederived from splanchnic mesoderm. Epithelial linings ofthemouthandloweronethird oftheanalcanal arise from theectoderm ofthe$omodeum andproctodeum, respectively.

; i , i I

FOREGUT DERIVATIVES A. Esophagus 1. The esophagusextends from the respiratory diverticulum to the stomach. It becomes elongatedwith the ascentof the pharynx and descentof the heart and lungs. 2. The upper two-thirds of the esophaguscontain striated muscle derived from pharyngeal archesand innervated by the vagus nerve. The lower one-third contains smooth muscle derived from splanchnic mesoderm and innervated by the splanchnic plexus. B. Stomach 1. The stomach appearsin the fourth week as a dilatation of the foregut. During development, the stomach rotates 90" clockn'ise, making its left side anterior and its right side posterior. a. The left side is innervated by the left vagus nerve. b. The right side is innervated by the right vagus nerve. 2. The caudal, or pyloric, part of the stomach moves upward to the right while the cephalic cardiac region moves downward to the left. 3. The greater and lessercurvatures of the stomach ariseby unequal growth of its two sides. a. The posterior part grows fasterthan the anterior part and forms the greatercurvature. b. The anterior part forms the lesser curvature.

il9

System Gasfrointestinal

C. Duodenum 1. The duodenurnis formed by the terminal portion of the foregut and cephalicportion of the midgut. This junction is locatedjust distal to the origin of the liver bud. 2. With the rotation of the stomach,the duodenumbecomesU-shape4is pulledto theright, andcomesto li€ rctroperiton€ally. 3. The duodenumis suppliedby both the celiacand superiormesentericarteries. D. Liver and gallbladder 1. The hepaticdiverticulum (liver bud) appearsasrapidly proliferatingendodermalepithelial cordsat the distal foregutin the middle of the third week. 2, As the liver cordspenetratethe septumtranwersum,the connectionbetweenthe hepatic diverticulum and foregut(duodenum)narrowsto form the bile duct. A ventralgrowth of the bile duct givesrise to the gallbladder and cystic duct. 3. Later in development,liver cordsintermingle with vitelline and umbilical veins to form hepatic stnusoids. 4. Hematopoieticcells,Kupffer cells(macrophages)of the mononuclearphagocytesystem' and connectivetissuestroma (including the fibrous capsuleof the liver) aremesodermal derivatives. 5. Bv the 10th week,nestsof cells,which produce red and white blood cells,are found betweenthe hepaticcellsand the vesseltnat. n formation of blood cellsin the liver declinesduring the last 2 months of intrauterine life, 6. Liver cellsbegin to secretebile during the l2th week E. Pancreasbeginsastwo endodermalduodenalbuds. The dorsal and ventral pancreasand ducts anastomose.The ventral duct remains as the connection to the duodenum. The pancreaticduct. dorsalduct either degenerates or remainsasthe smallaccessory

MIDGUT DERIVATIVES A Primary intestinal loop. Rapid growth of the primary intestinal loop, combined with its herreducedspacewithin the abdominalcavitydueto expansionof the liver,necessitates . niation into the extraembryoniccoelom of the umbilical cord during the sixth week of . dwelopment.Elongationof the small intestinesresultsin the formation of the coiledloops of the jejunum and ileum. The largeintestinefrom the distal part of the ileum to the proximal two-thirds of the transversecolon remainsuncoiled. B. Intestinal rot tion- Within the umbilical cord and during intestinal re-entry into the abdominal cavity in the 10th week,the intestin€srotate a total of 270' counterdockwise around the axisof the superiormesentedcartery. 1. Upon re-entry,tle proximal part of the jejunum comesto lie high on the left side,with the later-retumingloops taking up positionsmore to the right. 2. Last to enter is the cecalswelling,which, becauseof the 270orotation, lies in the right upper region in closecontactwith the right lobe of the liver. a. The cecalswellinggivesris€to the cecumand the appendir b. When the cecumand appendixdescendt}te descendingcolon and hepaticflexureare formed. C. 'Fixation'' of the midgut occursastlle mesenteriesof the intestinesfirsewith the parietal peritoneumof the posterior abdominalwall.

t20

Embryology

HINDGUT DERIVATIVES A. The cloaca is an expandedterminal portion of the hindgut, which is in direct contact with ectoderm at the cloacalmembrane. The ectodermal depressionat the cloacalmembrane is the proctodeum. B. A urorectal septum grows caudally in the angle between the allantois and the hindgut. Its point of fusion with the cloacal membrane is the perineum. The urorectal septum divides the cloaca into an anterior urogenital sinus and a posterior anorectal canal, and thus divides the cloacal membrane into the urogenital membrane and the anal membrane. C. The anal membrane ruptures at about the ninth week, resulting in a direct continuity between the endodermally derived anorectal canal and the ectodermally derived proctodeum (anal pit).Thepectinateline marks the location of this transition.

Amniotic cavity (AM)

Pharyngeal pouches 1

Yolk sac (YS)

Esophagus

Stomach Hepatic diverticulum Yolk stalk

bud

Gall bladder

Foregut

Vitelline duct

f,illdgut

Allantois Cloaca Goelom

Gut tube

Ventral Celiac Dorsal pancreatic artery Inferior Superior pancreatic bud mesenteric mesenteric bud artery artery

Figure Il-1-1.Foregut, midgut, and hindgut with ventral and dorsal mesenteries.

r2l

System Gastrointestinal

Thble II-1-1. Primitive gut derivatives. Borders

Organs Included

Foregut Buccopharyngealmembrane Pharynx, esophagus, stomach,part of duodenum, to anterior intestinal portal liver, gallbladder,pancreas Midgut

Anterior intestinal portal to posterior intestinal portal

Hindgut Posteriorintestinalportal to cloacalmembrane

Blood Supply Celiac artery

Superior Distal duodenum, jejunum, mesenteric ileum, cecum and appendix, artery ascendingcolon, proximal two-thirds of transversecolon Distal one-third of tranverse colon, descendingcolon, sigmoid colon, rectum, upper two-thirds of anal canal

Inferior mesenteric artery

S ITTIT MATFORMATION CONGEN A. Atresias, stenoses,and duplications may occur anywhere along the alimentary tract and often are due to incomplete recanalization following epithelial proliferation and lumen obliteration. 1. In casesof atresia, a thin diaphragm remains acrossthe lumen. 2. Stenosisis marked by a distal narrowing and proximal distention. 3. Duplications may contain mucosathat is very different from that in the segmentof origin. B. Pyloric stenosisis a narrowing of the pyloric lumen, which is due to hlpertrophy of circular smooth muscle in the pyloric region of the stomach.Patientspresent 1-3 weeks after birth with projectile vomiting, constipation,and weight loss.Treatmentsinclude diet management,administration of antispasmodics,and surgicallongitudinal incision through the hypertrophied muscle.It is more common in males. C. Atresia of the gallbladder and bile ducts causespersistent occlusion of the gallbladder or bile ducts. Patientspresent soon after birth with steadilyincreasingjaundice, clay-colored stools,and very dark-colored urine. D. Annular pancreas is an encirclement of the duodenum by pancreatic tissue,which is due to abnormal movement of part of the ventral pancreasto the right of the duodenum rather than to the left. E. Remnants of the vitelline duct 1. Meckel diverticulum is an ileal outpocketing, which may contain gastric and pancreatic tissue.It may becomeinflamed and causesymptoms like those of appendicitis. 2. Umbilical or vitelline fistula is a patent vitelline duct, which allows communication betweenthe umbilicus and the intestinal tract. F. Omphalocele is due to failure of all or part of the intestines to return from the umbilical cord into the abdominal cavity. The viscera outside the abdominal cavity are then covered only by the amnion.

122

Embryology

G. Congenitd umbilical hernia is a herniation of the viscera through a weakenedpart of the abdominal wall where it is not closed completely. Occurring during the fetal period, the sac formed has no muscle or skin and may tear during delivery. H. Malrotation may result in the colon and cecum re-entering the abdominal cavity first and settling on the left. In casesof reversedrotation, the transversecolon passesbehind the duodenum rather than in front of it. I. Congenital megacolon (Hirschsprung disease) is a constriction of a portion of the colon through which the intestinal contents are not moved. It is attributable to the absenceor marked reduction of parasympathetic ganglion cells in that area to which neural crest cells have failed to migrate. As a result, the segment of the gut proximal to the constricted area becomes distended. Symptoms include failure to pass meconium and distention of the abdomen. Tieatment is surgical excision of the distal bowel. It is more common in males. L Imperforate anus may be due to failure of the anal membrane to rupture.

l2t

Gastrointestinal Histology (alimentary) Thegastrointe$inal sy$emconsi$s glands. ofthedige$ive tractanditsassociated Beginning intheoralcavity, thetractcontinues asthepharynx, esophagus, stomach, small intestine, large intestine, rectum, glands, andanalcanal. glands, pancreas, Thelarge consi$ing ofthesalivary liver, andgallbladder, lieoutside thedige$ive tractbutareconnected to it viatheirducts. Theentire tubeislinedbymucosa, or mucous membrane, whichconsists ofa lubricated epithelium withan underlying propria thinlayer of cellular andvascular connective tissue called thelamina thatis generally surrounded bymuscular mucosae.

ORATCAVIIY A.Mucosa oftheoralcavity andofthepharynx aresimilar. l. The qrithelium of the oral cavity is mosdy nonlBasophils ->FSH l-+Gonadotrooes-4 L-+LH I

a. Gonadotropes are large round cellsthat secretefollicle-stimulatinghormone luteinizing hormone (tH).

(FSH) and

b. Thyrotropes produce thyroid-stimulating hormone (TSH). c. Corticotropes produce adrenocorticotropic hormone (ACTH). 3. Chromophobes are cells whose cytoplasm generally remains unstained. They may be either reservestem cells or acidophils and basophils that have degranulatedduring secretion.

I

ISH l+ThyrotropeF-+ L+ Co rt i cotrope s---->ACT H

4. Folliculostellate cells form a network of support-like cells;their function is unknown. C. The pars tuberalis surrounds the infundibulum of the neurohlpophysis. It is composed of highly vascularized cords of epithelial cells forming a thin sheath around the stalk of the infundibulum. The function of this region is unknown.

222

Histology

D. The pars intermedia is presentin humans during fetal life but is greatly reducedor disappearsin adults. 1. This portion is referredto as the intermediatelobe. 2. In other mammals, it is composed of cords of weakly basophilic cells that synthesize melanocyte-stimulatinghormone (MSH). E. Hypothalamohypophysial tract. The median eminence and stalk of the infundibulum and the pars nervosacontain a tract of unmyelinated axons belonging to secretorynerve cells that have their cell bodies in the supraoptic and paraventricular nuclei of the hypothalamus. Thesefibers are collectively known as the hypothalamohypophysial tract. 1. The secretorynerve cells produce the polypeptide hormones oxytocin and antidiuretic hormone (ADH), or vasopressin,which are packagedinto secretorygranules and are moved by axoplasmictransport to the pars nervosa.There they accumulatein nerve terminals near capillaries in clumps called Herring bodies. 2. Thesehormones are secretedby exocytosisupon stimulation of their neurons in the brain. F. Vascular anatomy of the hypophysis is variable, but typically there are two superior hypophysial arteries on each side of the organ: the anterior and posterior superior hypophysialarteries. 1. Thesevesselssupply the median eminenceand the stalk of the infundibulum and form primary looped sinusoidal capillariesthat drain into venous trunks of the hypophysial portal system,which suppliesthe adenohypophysis. 2. The portal systemterminates in the sinusoidal capillariesin the anterior lobe and conducts neurohormonesfrom the median eminenceto the adenohypophysis.

Bridgeto Physiology . Oxytocin induces uterine contractions andstimulates milklet-down. . ADHincreases water resorption inthekidney. Themechanism of action in forADHisdiscussed intheRenal detail Physiology of chapter Book Organ Systems t (Volume lll).

3. The anterior and posterior inferior hypophysialarteriessupply the neurohypophysisand form an arterial circle at the junction to the anterior and posterior lobes. is perfusedvia sinusoidalcapillarieslined 4. The neurohypophysis,likethe adenohypophysis, with fenestratedendothelium.

22t

Endocrine System

Supraopticnucleus Hypothalamic cells that produce releasinghormones

Medianeminence

Hypothalamus

Portalsystem

Anterior pituitarygland Posterior pituitarygland Figu re Ill-1-2.The hypothalamic-pituitary system.

Note

THYROID GTAND

Thethyroid diverticulum arises fromthefloorofthepharynx andenters theneckviathe thyroglossal duct.Thisduct usually disappears, butthyroid tissue andcysts mayremain (e.g., asaccessory thyroids the pyramidal lobe).

A. Overview

In a Nutshell Thyroid Gland . Twolobes connected byanisthmus . Synthesizes T3,T4, andcalcitonin . Tissue composed of follicles whose lumen contains colloid made of thyroglobulin.

224

1. The thyroid is a lobulated gland that consistsof two pear-shapedlateral lobes connected by an isthmus.It is found in the cervicalregion anterior and inferior to the larynx. A pyramidal lobe is frequently presentand points upward from the isthmus near the left lobe. 2. The thyroid synthesizesand secretesthe thyroid hormones triiodothyronine (T3) and tetraiodothyronine (Tl, thyroxine), which regulate cell metabolism, development, growth, and differentiation. T3 and Ta synthesis and releaseis stimulated by thyroidstimulating hormone (TSH) from the adenohypophysis.The gland also releasescalcitonin, which participatesin calcium homeostasis. 3. The stroma of the gland is coveredby a thin fibroelastic capsulefrom which connective tissueseptapenetrate,incompletelydividing the gland into lobules. 4. The parenchyma of the thyroid consistsof follicles, which are lined by a simple cuboidal epithelium surrounding a central lumen. The folliclesare filled with colloid composedof alarge secretoryprotein material calledthyroglobulin. a. During development,the epithelial parenchymalcellsbecomeclumped and form the follicles,the cellsof which secretetheir products into a central lumen calledthe follicular cavity. b. Betweenfollicles,a reticular stroma contains an extensivecapillary bed.

Histology

c. Two cell types occur: follicular cellsand parafollicular cells. (1) Follicular cells are the principal thyroid cells.They are simple cuboidal epithelial cellsthat line the follicular cavity and secretethyroid hormones. Their apical surfacesface the follicular cavity into which thyroglobulin is released,and their basalpoles rest on a basallamina. In periods of increasedactivity,the cells are columnar; their height declinestoward squamousas their activity decreases. The nuclei of follicular cells are rounded, and the cytoplasm is basophilic and PAS-positive,indicating the presenceof glycoprotein. (2) Parafollicular cells, or C cells, are separatedfrom the colloid by follicular cells. Theseare larger cells,which possesslight-staining cytoplasm.The parafollicular cellsare responsiblefor the secretionof calcitonin, a hormone that lowersblood calcium levelsand is secretedinto the capillary bed.

ln a Nutshell -> C cells-+ calcitonin (Ca'.; J blood

B. Synthesis of thyroid hormones 1. Thyroglobulin is synthesizedon membrane-boundribosomesof the rough endoplasmic reticulum (RER), where the nascentpolypeptide is dischargedinto the cisternaeof the endoplasmicreticulum. 2. From the endoplasmic reticulum, the polypeptide is transported to the Golgi, where peripheral sugarresiduesare added. 3. The finished glycoproteinis secretedinto the lumen of the thyroid follicle. 4. The thyroid gland activelyextractsand accumulatesiodide ions from the blood, which are used to iodinate the ryrosine residuesin thyroglobulin. Iodination of tyrosine residues in thyroglobulin occursat the follicular cell surfaceand is catalyzedby thyroid peroxidase enzymeslocalizedin the microvillous border. 5. Under stimulation of TSH, endocytosisof the colloid by follicular cellsoccurs. 6. Endocytotic vesiclesfuse with cytoplasmiclysosomes,resulting in hydrolysisof thyroglobulin and liberation of T3 and Ta. 7. Thyroid hormones are releasedfrom the basal surfacesof foliicular cells into adjacent capillaries. C. Vascular supply. The thyroid is richly supplied by fenestrated capillaries that are closely apposedto the follicular epithelium. 1. The thyroid is supplied by paired superior thyroid arteries (branches of the external carotids) and paired inferior thyroid arteries(branchesof the thyrocervicaltrunks). '(-'l ,aa [ 'r 4 , 2. The thyroid hasmany lymphatic capillaries.

GTANDS PARATHYROID

ln a Nutshell Synthesis of Hormone Stages (l) sv1t!7isofthyroglobulin (2) Uptake of iodide circulatory (3) Activation of iodide peroxidase bythyroid (4) lodination oftyrosine inthyroglobulin residues

Correlate Clinical are abnormalities Thyroid gs. findln common relatively in mayresult Thyroid disease withhigh hyperthyroidism, T3andTa,ot' circulating withlow hypothyroidism, ofT3andTo. amounts

ClinicalCorrelate

A. Overview 1. The parathyroids usually consist of four flat and ovoid glands located behind the thyroid or, occasionally,embeddedwithin it. 2. The stroma of each gland is coveredby a delicateconnectivetissue capsulefrom which septa penetrate and divide the gland into incomplete lobules. Richly vascularized,it contains many reticular fibers.

ofthe Dueto theproximity glands parathyroid to the may removal thyroid, thyroid in hypoparathyroidism, result bylow whichischaracterized caz*andtetanv. serum

225

Endocrine System

Flashback to Embryology

3. The epithelialparenchymal cells,arrangedin irregular cords or clusters,are composedof two cell tnres, which may representdifferent functional statesof a single cell type.

Parathyroid glands arederived fromthepharyngeal pouchesglands thesuperior arederived fromthefoufthpouch, andthe glands inferior arederived fromthethirdpouch. ClinicalCorrelate Hyperparathyroidism . BloodCa"elevated ' BloodPOo'1o*.t.0 . Bonebecomes decalcified, subject to fracture

a. Chief cells are small polyhedral cells with round nuclei. They are generally arranged in cordsbut occasionallyoccur in clumps. They secreteparathyroid hormone (PTH), which is releasedinto the capillary bed. b. Oxyphil cells are larger and much lessnumerous than the chief cells.They appear as eosinophilic cells arranged in three forms: solitary cells,small clumps, or small distinct nodulessurroundedby chief cells.The prominent eosinophilicgranule-likestructures in their cytoplasm are mitochondria. The function of oxyphil cells is unknown. B. Parathyroid hormone (PTH) is synthesizedand secretedby the parathyroid gland. PTH increasesthe serum calcium concentrationby increasingbone resorption, decreasingrenal excretion,and increasinggastrointestinaluptake of calcium (via l,25-hydroxy vitamin D). 1. PTH actsinitially on osteocftesof bone tissue(osteocytic osteolysis) and, subsequently, on osteoblasts, which recruit osteoclasts(osteoclasticresorption) to resorb calcium from bone matrix and make it availableto the circulation. 2. PTH also increasesrenal excretionof phosphate. 3. Secretionof PTH is controlled byblood calcium and magnesiumlevels.For example,low blood calcium levelssignalthe secretionof PTH from the parathyroid glands.This mechanism appearsto be independentof endocrine or neural inputs.

Hypoparathyroidism . Blood Ca,.lowered ' BloodPQ,relevated . Bonebecomes denser, moremineralized

C. Blood supply of the parathyroids is from the superior and inferior thyroid arteries.

GTANDS . Tetany (spastic contractions ADRENAT of muscles andgeneralized A. Overview convulsions) 1. The adrenals are paired glands,eachabout 4-6 cm in length. They are locatedretroperi\i )- I i i ( r i , r toneally,superior to the cranial poles of the kidneys.

i.

li,i

2. The stroma of the adrenal gland consistsof a thick connectivetissuecapsulethat sends trabeculaeof collagenousand reticular fibers into the glandular tissue.

11"

3. The glandular parenchyma is divided into a cortex that secretessteroid hormones and a medulla that secretescatecholamines. B. Adrenal cortex contains cells that synthesizeand secreteglucocorticoids, mineralocorticoids, and certain sex steroid hormones. It is formed by three concentric layersof epithelioid cellsand abundant fenestratedcapillaries.

In a Nutshell -+ inside) (outside Adrenalcortex Zona -) Zona -t Tona glomerulosa fasciculata reticularis JJ J Mineralo- Clucocorticoids Androgens corticoids (cortisol) (DHEA) (aldo$erone) "SALT'

226

"SUCAR"

"SEX"

l. Zonaglomerulosa is the outermost narrow zone in which acidophilic columnar-like cells are arrangedin groups surrounded by capillary networks. a. Thesecellssecretealdosterone,a steroid mineralocorticoidhormone, whosesynthesis and releaseis controlled principally by angiotensinII and plasmapotassiumion (K+) concentration. To a lesserextent,ACTH and atrial natriuretic peptide (ANP), which is secretedfrom the heart, alsostimulatesecretionof aldosterone. b. Aldosterone acts mainly on the distal tubules of the kidney and on the salivary and sweatglandsto promote sodium reabsorption.It also actson the principal cellsof the kidney's collectingduct to secreteK+.

Histology

2. Zonafasciculata is a wide zone with its cells organized in cords, coursing radially inward from the zona glomerulosa and pointed toward the medulla. A longitudinal mesh of sinusoidal capillaries extends the length of the cords. a. The cells are polyhedral or cuboidal and are often binucleated. They contain a high lipid concentration. b. Zonafasciculatacellssecreteglucocorticoids, including the principal hormone cortisol, which havemajor effectson carbohydrate,protein, and lipid metabolism.This zone also secretessome androgensand a minimal amount of estrogens. c. The cellsof this zone are stimulated by the secretionof ACTH from the anterior pituitary. 3. Zonareticularis is a small region at the corticomedullary junction in which the cells of the cords are arranged in irregular networks. This zone secretesdehydroepiandrosterone (DHEA), other l7-ketosteroids,and probably some glucocorticoidsaswell. It is stimulated by ACTH. The zona fasciculata and zona reticularis function together as a unit in some ways (e.g.,some sexsteroidsare made in both fasciculataand reticularis). C. Adrenal medulla consistsof cellsthat are arranged in anastomosingcords intermingled with capillaries and venules. 1. Thesecolumnar cells are oriented with one end facing a capillary and the opposite pole in contact with a venule. Preganglionicsympathetic fibers contact eachcell at the capillary pole. 2. The cells are known aschromaffin cells becausethey are colored by oxidizing agentssuch as potassium dichromate, which turns them brown due to oxidation of the catecholaminesin the cells. 3. The cells produce and secretethe catecholamine hormones epinephrine and norepinephrine, which are stored in their secretorygranules.Glucocorticoidsproduced in the cortex passthrough the medulla and are required by medullary cells for synthesisof catecholamines,especiallyduring stress. 4. The medulla is under sympatheticcontrol, and its hormones function in concertwith the sympathetic flow in the "fight-or-flight" response.In many respects,the medullary cells function as postganglionicsympatheticneurons. D. Blood supplyto the adrenals comesfrom the superior,middle, and inferior suprarenalarteries. E. Innervation of the adrenal glands is mainly sympatheticand is carried via the splanchnicnerves.

to Flashback Embryology Thecellsoftheadrenal from medulla arederived Thecellsof neural crest cells. arederived cortex theadrenal frommesoderm.

In a Nutshell Catecholamines (Epinephrine, Norepinephrine): . t Heartrate . Vasoconstriction (t cardiac t blood output, pressure)

1. These autonomic fibers are the principal means of regulating the release of catecholamines from the medulla.

. t Bloodglucose

2. Although the cortex receivessome fibers, they do not appear to play an important role in regulatingthe releaseof hormones.

ClinicalCorrelate

PANCREAS ENDOCRINE A. Overview. The islets of Langerhans are rounded clustersof endocrine cells dispersedin the pancreaticexocrinetissue. l. There are over one million isletsin the human pancreas,constituting approximatelyl.5o/o of the volume of the pancreas. 2. Theisletsare enclosedin delicatereticular capsules,a few fibers of which penetratethe islets. B. Cells of the islets are polygonal and are arranged in clustersthat are intermingled with sinusoidal capillary networks.

isa Pheochromorytoma thatsecretes neoplasm and epinephrine Thiscauses norepinephrine. hypertension, secondary urinary increased acid(VMA) vanillylmandelic levels levels, andhighplasma lt is treated of catecholamines. such blockers withcr-receptor asphenoxybenzamine.

227

EndocrineSystem

ln a Nutshell

1. When viewed under the electron microscope,thesecells have the structure of cells synthesizingpolypeptides:abundant RER, a prominent Golgi complex, and secretorygranules.

lslebof Langerhans

o cells

p cells

2. Using special staining methods, particularly immunohistochemical procedures,three major cell types havebeen identified in the islets.

6 cells

II

Clucagon Insulin Somatostatin

I

I f ClucoseJ GlucoseJ Glucagon , J Insulin i^ (G.it.. 1,.

''t.c

I

a. cr (A) cells constitute approximately 20o/oof the cellsfound in the endocrine pancreas. They synthesize and secrete the polypeptide hormone glucagon, which acts to increaseblood glucoselevels.cr cellsare found mainly in the periphery of the islets. b. B (B) cells are the major cell type and constitute approximately 60-800/oof the islet cells.They secretethe hormone insulin, which acts to decreaseblood glucoselevels. B cells are found mainly in the center of the islets. c. 6 (D) cells are the least numerous and constitute less than 5o/oof islet cells. They secretethe hormone somatostatin, which actslocally to inhibit the secretionof both insulin and glucagon.6 cellsare found scatteredthroughout the islets.

Clinical Correlate gland Thepineal in humans hasbeenassociated withthe circadian rhythm. Seasonal (SAD) affective disorder and jetlagmayresult from disturbances inthisrhythm.

PINEAT GTAND A. Overview 1. The pineal gland or epiphysis is a pedunculated,cone-shapedbody that is attachedto the roof of the third ventricle by a stalk. a. It is approximately5-8 mm in length and is encapsulatedby pia mater, exceptat its point of attachment. b. Connectivetissuesepta,containing blood vesselsand unmyelinatednerve fibers,originate in the pia mater and penetratethe pineal gland to form irregular lobules around cellular cords and follicles. 2. Maior cell types of the pineal gland consistof pinealocftesand interstitial cells. a. Pinealocftes are epithelial-derived cells with large, irregularly shapednuclei and relatively large nucleoli.

Note A microscopic feature seenin pineal anaging gland is"pineal sand." Thisconsists of calcium phosphate andmagnesium withinanorganic matrix.

228

b. Interstitial cells are characterizedby elongated dark-staining nuclei and are located betweenthe cords of pinealocytesand perivascularareas.Interstitial cellsare comparable to glial cells of the brain. B. Innervation of the pineal gland is by postganglionicsympatheticfibers,which arise in the superior cervicalganglion and terminate on pinealocytes. C. Melatonin, an indoleamine compound, is the principal hormone synthesizedby the pineal gland. The precisefunction of this hormone in humans is unknown. In other mammals,it plays a role in seasonalreproductive rycles; in amphibians, it induces the aggregationof pigment granulesin the melanophores.

Anatomy Endocrine glands, andpancreas. adrenal ofthethyroid, anatomy thegross willhighlight Thischapter Bookt sectionof OrganSystems in theNeuroanatomy of thepituitaryis discussed Theanatomy (Volume lll).

I}IYROIDGTAND The thyroid gland is locat€danterior to the upper trached rings.

!!,$9

A. Arterial supply. The superiorthyroid artery is a branch of the externalcarotid artery and artery. the inferior tlyroid artery is a branch of the thyrocervicaltrunk ftom the sub-clavian 'thyroidea ima" artery may ariseftom the arch of the aortaor one of its branches. A single

glandsare Theparathyroid usuaily fourin numberThE in theDosterior areembedded surface of thelobesof the thyroidgland.

B. Venousdrainage.The superiorand middle thyroid veinsdrain to the int€rnal iugular veins bilaterally.The inferior thyroid veinsusuallyform a commontnurk whidr drainsto the left brachiocephalicvein. C. Lynphatic draimge. The thyroid gland drains primarily to the deepcervicalnodes.

GTANDS ADRENAT A- Adrenal glands are pairedendocrineglandsthat lie on the apicalpolesof the kidnqrc, and arethereforereferredto assuprarenalglands' B. Arterial supply,Like all endocine glands,the adrenalsarevery vascular.All oftheir arteries maybe multiple. 1. The superiorsuprarenalartery is a brandr of the inferior phrenic art€ry. 2. The rniddle suprarenalartery is a branch of the abdominalaorta. 3. The inferior suprarenalartery is a branch of the renalartery' C. Venousdrainage 1. The right suprarenalvein ihains to the inferior venacava. 2. The left suprarenalvein drainsto the left renalvein. D. Lyrnphatic drainagegoesto the superiorlumbar (lateralaortic) nodes. E. Imervation 1. Thepreganglionicsympatheticfiberstravelin the splanchnicnervesandthe celiacplorus. 2. Postganglionicsympatheticcell bodiesform the substanceof the adrenalmedulla.

229

Endocrine System

PANCREAS A. The Pancreas lies retroperitoneally behind the stomach in the transpyloric plane (FigureIII-2-1).

Rightsuprarenal gland

Tail Body Neck Head

Right kidney

Pancreas

Duodenum

Figure lll-2-1.Relations of the pancreas.

ClinicalCorrelate Pancreatic cancer isinsidious andmayor maynotcause jaundice, depending on whether ornotthetumor blocks thebileductsystem. Cancers oftheheadofthe pancreas aremorelikely to produce thanthose of faundice thebody;the latter, therefore, maynotbediagnosed until thetumorislarge enough to cause backpain.

zto

B. The Pancreasis cane-shaped,with a head,body, and tail. The uncinate process,which hooks around the superior mesentericvessels,is continuous with the head of the pancreas. C. Both main and accessoryducts lead from the pancreas.The main duct (of Wirsung) and the common bile duct open into the secondpart of the duodenum at the ampulla of Vater.The accessoryduct (of Santorini) usually opens independently at a secondarypapilla.

Physiology Endocrine primary rolesare whose glands andsecretions ofvarious iscomposed system Theendocrine This andreproduction. promotion, communication, growth maintenance, regulation, metabolic processes aswellastheirinteractions these controlling willfocusonthemajorhormones chapter system, withthenervous associated isclosely system theendocrine Since systems. withotherorgan will be norepinephrine and epinephrine, serotonin, dopamine, including neurotransmitters, specific secretion. rolesin hormone to theirregulatory in relation discussed

SYSTEM OFTHEENDOCRINE ANDORGANIZATION REGUTATION A. Organization of the endocrine system 1. The pituitary glurd (hypophysis) is an unpaired organ that lies just beneaththe brain and is connectedto it by the infundibulum. It is composedof the anterior pituitary and the posterior pituitary. a. The anterior pituitary (adenohlpophysis) is derived embryologically from somatic ectoderm and is devoid of innervation. b. The posterior pituitary (neurohypophysis) is derived from neural ectoderm. The pars nervosa of the posterior pituitary is supplied with nerve tracts directly from the hypothalamus. 2. The hypothalamic-hypophysial portal blood system is the capillary system that connectsthe brain and the anterior pituitary. It originatesin the median eminenceregion of the hypothalamus.The anatomic relationshipsare shown in Figure III-3-1. a. Releasingfactors (RFs) and releasinghormones (RHs) are releasedcloseto the capillary loops of the hypothalamic-hypophysialportal blood system and travel to the anterior pituitary via the portal blood system.Upon reachingthe anterior pituitary, the RHs stimulate the releaseof hormones. Thesehormones, in turn, travel to specific endocrine glandsand causethe synthesisor releaseof specifichormones.

2tl

Endocrine System

Dorsalmedial nucleus

Dorsalhypolhalamicarea Paravenlricular nucleus Laleral hypolhalamic area

Anteriorhypothalamus Venlromedialnucleus Preoptic area Mamrllarybody Supraoplicnucleus

Suprachiasmaticnucleus Optic chiasm Arcualenucleus Median eminence

Superiorhypophysialartery Supraopticand paraventracular nucleinerva lract

Posleriorpituitary {Neurohypophysis)

Long portal vessels

Secondaryportalplexus Anteriorpituitary (Adenohypophysis)

Inferiorhypophysialartery

Figure lll-3-1.Anatomic relationships among the hypotharamus, hypothalamic-hypophysialportal blood system, anterior pituitary, and posterior pituitary.

ln a Nutshell Hypothalamic-Releasin g Hormones . TRH . CRH . CnRH . CHRH . PRH Hypothalamic Inhibitory Hormones . SOmatOStUlin /r:t'1a',! . Prolactin inhibitory factor (dopamine)

252

b. Corticotropin-releasinghormone (CRH), gonadotropin-releasinghormone (GnRH), thyrotropin-releasing hormone (TRH), and growth hormone-releasinghormone (GHRH) are hypothalamic hormones that stimulate pituitary function. CRH controls the releaseof ACTH; GnRH stimulatesthe releaseof LH and FSH; and TRH stimulates the releaseof TSH and prolactin. GHRH stimulatesgrowth hormone secretion. c. Somatostatin inhibits both TSH and growth hormone, whereasdopamine inhibits prolactin secretion. 3 . Neurosecretory cells of the hypothalamus have axons that passthrough the infundibular stalk and terminate either in the pars nervosa or close to the capillary network in the median eminence. Oxytocin and antidiuretic hormone (ADH) are produced by the hypothalamus.They travel via nerve tracts to the pars nervosa,are stored there, and are releasedunder appropriatephysiologicstimulation. 4 . Neurotransmittersinvolved in hypothalamic neurohormone secretionare epinephrine, norepinephrine, dopamine, serotonin (5-hydroxytrlrytamine, 5-HT), acetylcholine (ACh), and y-aminobutyric acid (GABA). Severalpeptidergic neurotransmitters (i.e., neurotensin,substanceR enkephalins,endorphins) also affect neuroendocrinefunction by their effectson hypothalamic hormones and on monoaminergic neurotransmitters.

Physiology

B. Regulation of the endocrine system. There are five distinct mechanisms by which the endocrine system functions. Note that most of the hormones discussedin the following examplesare describedin greater detail later in this chapter. 1. Feedback not involving the hypothalamic-hypophysial axis. The simplest type of endocrinecontrol occurswhen a hormone actson specificcellsand promotes a changein the extracellularfluid, which, in turn, regulatesthe output of the original hormone. For example, parathyroid hormone (PTH) is a peptide produced by the parathyroid glands that regulatesthe concentration of calcium (Cuz*) in the blood, as shown in Figure ril-3-2.

Parathyroid hormone

Figure lll-3-2.Feedback regulation of serum calcium (Ca2*) and parathyroid hormone (PTH).(+) = stimulation;(-) = inhibition. a. The concentration of serum Ca2+in the bloodstream drops (step I in the abovefigure) which stimulatesthe secretionof PTH from the parathyroid (step 2). b. PTH travelsto its target organs(i.e.,kidney,bone, and indirectly to the gut) to stimulate Ca2+absorption and raisethe serum Ca2+level (step 3). c. As the concentrationof serum Ca2+risesin the bloodstream,PTH secretionfrom the parathyroid is inhibited (step4). 2. Endocrine control involving a hormone precursor. A hormone precursor is released into the bloodstreamand is then convertedto an activesubstance.This systemis usedto stimulate the secretionof aldosteronefrom the adrenalcortex. a. Angiotensinogen, an inactivehormone precursor,is secretedinto the bloodstreamby the liver. b. In the blood, the renal enryme renin convertsangiotensinogento another hormone, angiotensin I. c. In the capillariesof the lung, angiotensinI is convertedto angiotensin II by the action of angiotensin-converting enzyme (ACE).

ln a Nutshell (liver) Angiotensinogen J e renin(JCapparatus) Angiotensin I J e ACE(lungs) Angiotensin ll J (adrenal cortex) Aldosterone

d. Angiotensin II stimulatesthe production of aldosterone by the adrenalcortex. e. Aldosteroneactson the kidney and alterselectrolytesecretion,which, in turn,leads to a decreasein renin production by the kidney. 3. Endocrine control involving a dietary precursor. This type of endocrine control occurs when a hormone precursor is derived from the diet or is synthesizedwithin the organism.

2!'

Endocrine System

This precursor goes through successivetransformations in severaladditional sites before becoming biologically active.For example,vitamin D can be either synthesizedin the skin from 7-dehydrocholesterolor ingestedin the diet. It then undergoessuccessive hydroxylations in the liver and kidney to form l,25-dihdroxycholecalciferol (1,25[OH]rDr), the active form of the hormone. 4. Endocrine control involving the hypothalamic-hypophysial axis. This type of control is illustratedin FigureIII-3-3. a. Gonadotropin-releasing hormone (GnRH) is produced in hypothalamic neurons. These neurons terminate in proximity of the capillary network in the median eminenceregion of the hypothalamus. b. After being picked up by this capillary system,GnRH is transported via the hypothalamic-hypophysialportal blood systemto the anterior pituitary where it promotes the synthesisand releaseof luteiniztnghormone (tH) and follicle-stimulatinghormone (FSH). c. LH travelsvia the bloodstream to the testis,where it stimulatesthe production and releaseof testicular steroids (androgens).The androgens,in turn, travel via the blood to the hypothalamusto inhibit the secretionof GnRH, thus functioning in a negativefeedback loop.

Hypothalamus

LH

Anteriorpituitary

LH (_) Long-loop feedbackto hypothalamus androgens)

Shoft-loop feedbackto hypothalamus

LH

(+

Long-loop feedbackto pituitary (androgens)

Testis Figure lll-3-3.Negativefeedback system involving the hypothalamic-hypophysial-testicularaxis. Both long-loopand short-loopfeedbacksystems are shown;(+) = stimulatoryeffects;(-) = inhibitoryeffects; LH = luteinizing hormone;GnRH= gonadotropin-releasing hormone.

214

Physiology

d. Alternately,androgens act directly on the pituitary to decreasethe releaseof LH or FSH by altering the sensitivity of the pituitary cell to GnRH. This is known as direct feedback (pituitary) as compared to indirect feedback (hypothalamic). e. LH could travel via retrogradeblood flow from the pituitary to the hypothalamusto inhibit the synthesisor releaseof GnRH. (1) The effect of LH on the target gland and of the target gland secretionson the hypothalamic-pituitary unit is referred to as long-loop feedback. (2) The effect of LH on the hypothalamusis referredto as short-loop feedback. 5. The interaction between the nervous and endocrine systems is seenwith the releaseof oxFtocin in a lactating woman. a. If the breastis preparedhormonally for lactation,the suckling of an infant sendsneural impulses from the breastto the spinal cord, up into the brain, and eventually,to discretenuclei of the hypothalamus. b. These impulses stimulate the paraventricular nucleus of the hypothalamus to synthesizeand transport oxytocin to the pars nervosaand alsoto causethe releaseof oxytocin from the pars nervosa. c. Oxytocin then travelsvia the bloodstreamto the breast,where it causescontraction of the breast myoepithelial cells,resulting in milk let-down. d. The afferentpart of the arc is nervous,which stimulatesthe synthesis,transport, and releaseof oxytocin. The efferentpart of the arc is endocrine,which is the effectof oxytocin on the breastto induce milk let-down (Figure III-3-4). nucleus Paraventricular

ln a Nutshell

Paraventriculohypophysial nerve tract

OverallOrytocinEffects . Contraction of in myoepithelial cells glands andmilk mammary let-down Anteriorpituitary

pituitary Posterior

. Stimulant of uterine isoftenused contractions; to induce labor

Afferent Oxytoci

Efferent stimulus

(neural)

T,isuckrins

/t \ b* Milklet-down

Figure lll-3-4.Neuroendocrine reflex arc in oxytocin release.

2t5

EndocrineSystem

ANTERIOR PITUITARY HORMONES The hormones synthesizedand secretedby the anterior pituitary are assignedto three basic groups according to their chemical structure.

Note

A. Straight-chain peptides containing disulfide bridges (somatomammotropic group)

groMhrequires Normal normal levels of: . Nutrition

1. Growth hormone (somatotropin, GH) a. Structure. Growth hormone is a protein containing two internal disulfide bridges. It shares similar structural and biologic function with prolactin (PRt) and human placental lactogen (hPt).

.CH

b. Function. Growth hormone stimulates growth in childhood. It acts as an anabolic and anticatabolic agent.It promotes growth in most body tissuesand regulatescell size and number. Growth hormone stimulates the production of somatomedins (insulinlike growth factor, IGF) in the target tissues,which mediate many of growth hormone's key growth actions. Like the insulin receptor, the IGF receptor has tyrosine kinase activity.

. lcF-t . Thyroid hormone . Cortisol . lnsulin

c. Metabolic effects

Clinical Correlate Themajordiseases associated withCHarepituitarydwarfism (insufficient CHsecretion), gigantism (excessive CH growthplates secretion before arefused), andacromegaly (excessive CHsecretion after growthplates arefused). They arediscussed in detail inthe Endocrine Pathology chapter of thisbook.

(1) Increasesprotein synthesiswith a decreasein blood urea and urinary nitrogen. It also increasesprotein synthesisin chondrocftes (increaseslinear growth) with increasedconversion of proline to hydroryproline. Iean bodymass is increased. (2) Decreasessensitivity to insulin; diabetogenic effect. (3) Increased lipolysis results in increased free fatty acids in the bloodstream. Metabolically,this sparesglucoseand protein from being burned as fuel (anticataboliceffect). d. Pattern of secretion. GH is releasedin pulses throughout the day. The most consistent period of secretionoccursapproximatelyone hour after the onset of sleep.GH is releasedfollowing stress,hypoglycemia,vasopressinor r-dopa injection, during exercise,and during sleep. e. Control of secretion (1) GHRH stimulates the production and secretionof growth hormone. (2) Somatostatin blocks the secretion of growth hormone from the anterior pituitary. Recall that besidesthe hypothalamus, somatostatin is also produced in the pancreasand in other tissues.

ln a Nutshell Control of GHSecretion

(3) Somatomedins exert negative feedback by inhibiting GH secretion from the anterior pituitary and promoting somatostatinreleasefrom the hypothalamus.

Hypothalamus

/\

Somatostatin

ol

(+)

Y

GHRH

Y.)

Anterior (+) rPituin" l

-T

u'I

Somatomedins140 mg/t ). 3. Insulin-dependent diabetes mellitus (IDDM, ryPe f ) a. Characterized by an inability of p-cells to produce ad€quste amounts of insulin b. Most commonly caus€dby an autoimmune disorder in which p cells are destroyed c. kss common is a mutation of the gene for preproinsulin d. Genetic and environmental factors may also determine susceptibility to dwelopment of type I diabetes. e. Tieatment is insulin rqtlacement and matching of insulin, diet' and exercise(exercise, like insulin, increasesglucose uptake into cells). 4. Noninsulin-dependent diabetes mellitus (NIDDM, tyPe 2) a. Characterized by an impairment of target cells to respond to insulin; may also have some decreasedsecretory responsein tlte pancreasitself. b. ln most type 2 diabetes,s€rum insulin i6 normal or elwated; the fundamental defect is often in th€ receptor or a PostrecePtordefect (not well understood). c. There is a strong genetic component to the development of tfpe 2 diabetes;autoimmunity does not play a significant role. d. Many type 2 diabetics are overweight; weight loss can decrease the severity of the disease.

to Prom*. classaPPear e. Tre.tmenl Drugsof thesulfonylurea

T:*11:3.':.]'"::-5i:t msullnsecretron. to normalize pancreaticp-cellresponse tissuesandcorrectthe sluSSish

5. Complicationof diabetesrnellitus a. Acute ( 1) With poor control, tfPe I diab€tics€'.hibit hyperglycernnr'glucosuria'dehydration, andketoacidosis.

pharmacology -Bridge --:?: !o - ' Thesulfonylureas are discussed in greater detailintheEndocrine chapter. PharmacoloSy

frrnction-may leadto (2) The drop in fluid volumemaycomprornisecardiovascular circulatoryfailure. (3) Excessive ketoneformation leadsto metabolicacidosisand electrolyteimbalanccs (renal elimination of ketonesmay depleteNa+ or K+ from blood sincethey are excretedasthe ketonesalts). b. Chronic ( I ) Largevesselsshowchangessirnilar to atherosclerosis. (2) Microcirculation exhibits a thickening of basementmembranes,leading to decreasingdeliveryof nutrients to and removalof wasteftom tissues'which, in turn, leadsto tissuedamage. (3) Deteriorationofblood flow to the retina canleadto retinopathy andblindness. (4) D€terioration of blood flow to the extremitiescanleadto possibleamputation. (5) Deteriorationof renalblood flow leadsto kidney failure. (6) Peripheralandautonomicneuropathy

26'.

Endocrine Pathology pathology Endocrine isprimarily concerned withthehypothalamic-pituitary-end organ axis. Knowledge ofthecomplex homeostatic feedback mechanisms affecting thehypothalamus and pituitary iscritical to making anaccurate diagnosis of hyperorhypofunctioning oftheendocrine glands ororgans. Ingeneral, hyperplasia implies of glands anexcess of stimulating hormone, while mayarise independently regulatory adenomas andcarcinomas completely of normal hormone secretion. Hyperplasias arealmost always functional. Incontrast, adenomas varyintheamount of product functional hormone theysecrete; moreover, theirresponses to regulatory varyconsiderably. Carcinomas areusually theleast functional andareusually independent of regulatory hormonal influence. Flashbackto Physiology

HYPOTHATAMUS ANDPITUITARY GTAND A. Lesions of the hnrothalamus 1. Destructive lesions include tumors such as craniopharyngiomas,gliomas,hamartomas, and inflammatory conditions (e.g.,sarcoidosis). 2. Craniopharyngiomas arisefrom ectodermal remnants of Rathkepouch, forming the most common pituitary tumor in children. Pathology shows stratified squamousepithelium with areasof keratinization and rysts. Lamellar bone depositsand calcium may be seen. Malignant transformation is rare.The tumor may be detectedon x-ray by its opaquecalcifications.

produces Thehypothalamus groMhhormone-releasing (CHRH), hormone somatostatin, dopamine, gonadotropi ng n-releasi (CnRH), hormone g n-releasin corticotropi (CRH), hormone antidiuretic (ADH), hormone thyrotropin(IRH), releasing hormone and oxytocin.

B. Anterior pituitary hyperfunction 1. Etiology. Most casesof anterior pituitary hyperfunction are causedby adenomas,which usually secreteprolactin, growth hormone, or adrenocorticotropichormone (ACTH). 2. Clinical syndromes correspondto the hormone secreted. a. Hnrerprolactinemia (amenorrhea-galactorrheasyndrome) results from elevated serum prolactin associatedwith pituitary adenomas(prolactinoma). It is the most common pituitary tumor. In women, it results in amenorrhea and galactorrhea; in men, this tumor may result in galactorrheaand infertility. Other causesof elevated prolactin, such as reserpine,phenothiazines,estrogens,or a hlpothalamic lesion, should be ruled out. b. Excessgrowth hormone

ClinicalCorrelate A pituitarytumormayimpinge ontheopticchiasm, producing a bitemporal (loss hemianopsia of peripheral fields). Make visual a visual field sureto perform you thistumor testif suspect (oranybrainneoplasm).

( 1) Gigantism occurs if there is excessiveGH secretionbefore the growth plates are fused (i.e., before the end of puberty). Excessiveskeletalgrowth may result in heights closeto 9 feet tall.

265

Endocrine System

(2) Acromegaly occurs if there is excessivesecretion after closure of the epiphyseal plates.There is a gradual coarseningof facial features(i.e.,thick lips, protruding jaw, large tongue) and enlargementof the hands and feet. It may be associated with diabetesmellitus, hypertension,osteoporosis,and other symptoms associated with space-occupyinglesions in the pituitary region, such as visual field defects.

Note Hyperplasia or tumorsof the pituitary areassociated with MENtypel.TheMEN syndromes arediscussed at theendofthischapter.

c. Cushing diseaseis causedby ACTH-secretingtumors. Lesionsare usually small and rarely causemasseffect.Cushing diseaseis discussedlater in this section. 3. Pathology of pituitary adenomas a. Gross findings range from microadenomas(5-10 mm) to large masses(10 cm) that may invade surrounding structures. b. Microscopic findings revealuniform cellsin nests,sheets,or cords in a fibrous stroma. (1) Eosinophilic adenomasusually produce growth hormone and are often large. (2) Chromophobe adenomas have few stainablegranulesand often produce prolactin. (3) Basophilic adenomas have periodic acid-Schiff (PAS)-positive granules and often produce ACTH. C. Anterior pituitary hypofunction is usually manifested as panhypopituitarism, resulting from the destruction of at least75o/oof the adenohypophysis. 1. Clinical features include symptoms of hypothyroidism, hypoadrenalism,and hypogonadism. Growth hormone deficiencyin children resultsin primary dwarfism with normal limb and skull proportions. 2. Etiology a. Sheehansyndrome is due to hemorrhagic or ischemic infarction of the pituitary following postpartum hemorrhage with excessive bleeding or shock.It may present with failure to lactatein the postpartum period. b. Empty sella syndrome is due to atrophy of the pituitary. The sellais enlargedon skull x-ray and may mimic a pituitary neoplasm.Surprisingly,it is usually asymptomatic. c. Nonsecreting-chromophobeadenomasmay present with hypopituitarism or symptoms of a space-occupying lesion. d. Tirberculosis(TB), sarcoid,irradiation, and metastases from other neoplasmsmay also causepanhypopituitarism.

In a Nutshell (Dl) Diabetes Insipidus . Polydipsia . Polyuria . Large volumes of dilute (hypotonic) urine . Highserum osmolality . Hypernatremia Central Dl responds to exogenous ADHtherapy; nephrogenic Dl doesnot because renalreceptors do notrespond to ADH.

266

D. Posterior pituitaryhypo-

and hyperfunction

1. Diabetes insipidus (DI) is due to insufficient or absentantidiuretic hormone (ADH). a. Etiology. Disordersinvolving the hypothalamusor neurohypophysis(e.g.,malignanry, meningitis, TB, sarcoid,postsurgicaltrauma to baseof skull) may all causecentral diabetes insipidus. Nephrogenic diabetes insipidus is caused by a lack of renal responseto ADH. b. Clinical features include polydipsia and polyuria with excretion of large volumes of dilute urine, even during statesof dehydration. c. Laboratory results show high serum osmolality and sodium with hemoconcentration due to loss of free water.Patientswith central DI will respondto administration of exogenousADH, while patientswith nephrogenicDI will not.

Pathology

2. The syndrome of inappropriate ADH secretion (SIADH) is due to inappropriate,excessiveADH secretion unrelated to serum osmolaliw. a. Etiology. SIADH may result from: (1) Malignancies associatedwith ectopic ADH production (usually oat cell lung cancer) (2) Central nervous system (CNS) disturbances(e.g.,skull fracture, subarachnoid hemorrhage,stroke) (3) Drug use (e.g.,chlorpropamide, carbamazepine, thiazide diuretics) (4) Certain pulmonary diseases (e.g.,TB or lung abcess). b. Clinical features include fluid retention, weight gain, and lethargy.There is a rangeof CNS disturbances,including seizuresand coma. c. Laboratoryrestrlts show lowserum osmolaliry hnronatremia, and hypertonic urine.

ln a Nutshell SIADH . Fluid retention . Weight gain

ADRENAT GTANDS

. Lethargy

A. Adrenal cortical hyperfunction

. Lowserum osmolality

1. Cushing syndrome is causedby cortisol excess. a. Etiology. Cushing syndrome may take one of four distinct forms, depending on its cause.They are summarizedin Figure III-4-1.

. Hypertonic urine . Hyponatremia

( 1) Pituitary Cushing syndrome (approximately two-thirds of the casesof Cushing). Pituitary or hypothalamicdysfunction is the most common noniatrogeniccause. It is caused by basophilic adenomas,referred to as Cushing disease, or more commonly, by multiple corticotroph microadenomas. Pituitary Cushing syndrome is characterized by bilateral adrenal hyperplasia and elevated serum ACTH. The diagnosis is establishedwhen the administration of high-dose dexamethasone suppressesACTH secretion, causing decreasedserum cortisol and decreasedurinary l7-hydrorycorticosteroid(l7-OHCS) excretion;in normal ACTH secretion. individuals, low-dose dexamethasonesuppresses (2) Adrenal Cushing syndrome is usually caused by an adrenal adenoma. It is characterizedbylowserumACTH and failure of dexamethasonesuppressionof cortical secretion. (3) Ectopic Cushing syndrome is causedby ectopic secretionof ACTH, most commonly by bronchogenic cancer, but also by pancreaticneoplasmsand thymomas. It is characterizedby bilateral adrenal hlperplasia and failure of dexamethasonesuppression. (4) Iatrogenic Cushing syndrome is rather common and is causedby exogenous administration of glucocorticoidsor ACTH. b. Clinical features usually result from excesscortisol but may also be due to excess aldosterone,corticosterone,or adrenalandrogens.The syndrome is most common in women in the 2040-year-old age group. Patients exhibit hnrertension, abnormal glucose tolerance (frank diabetes 20o/o),truncal obesity, muscle wasting in the extremities,moon facies, buffalo hump, cutaneousstriae, osteoporosis, hirsutism and amenorrhea in women, weight gain, edema,weakness,fatigue, susceptibilityto infection and personality disturbances.Children show growth retardation, delayed skeletalmaturation, and precociouspuberty if associatedwith adrenalandrogens.

267

Endocrine System

Cushing Syndrorne t Cortisol Hypertension Truncal obesity I

v

I

+

I

v

V Pituitary Cushing

Adrenal Cushing

+

I V Pituitary adenoma (Cushing disease)

Adrenal adenoma

I

II

I

t

v

t ecrn

J ecrn

from pituitary

Ectopic ACTH

I V Bronchogeniccancer (or other neoplasm)

Iatrogenic

I * Exogenous administration of ACTH or cortisol

II

v

T ecrH I

I

I V

V

Adrenal hyperplasia

Adrenal hyperplasia

I V Suppression of ACTH with highdosedexamethasone

Z Suppression with dexamethasone

I

Z Suppression with dexamethasone

Figure lll-4-1.Summary of Gushing syndrome and its effects. c. Pathology (1) In the pituitary, Crooke hyaline degenerationof basophils results from prolonged feedbackinhibition by cortisol. (2) In the adrenals,there is bilateral cortical hlperplasia, adrenalcortical adenoma, or, rarely, carcinoma in Cushing syndrome due to primary causes.Nodular hyperplasia or atrophy of the adrenal cortex is seen with exogenousACTH or glucocorticoids,respectively. 2. Primary hyperaldosteronism (Conn syndrome) is due to increasedaldosterone secretion, producing sodium retention, increased total plasma volume, increasedrenal artery pressure,and inhibition of renin secretion. a. Etiology. An adrenal adenoma secretingaldosteroneis the most common cause.Other causesinclude idiopathic hyperaldosteronism,in which bilateral cortical nodular hyperplasia of the zona glomerulosa is seen,or, rarely, adrenal carcinoma, glucocorticoidsuppressiblehyperaldosteronism,or congenitalbilateral zona glomerulosahyperplasia. b. Ctinical features include sodium retention, extracellular fluid expansion,and potassium depletion with diastolichypertension,weakness,fatigue,polprria, polydipsia,and headache.

268

Pathology

c. Laboratoryvalues revealhypokalemia, low renin levels, metabolic alkalosis, hlpernatremia, and (fcrradenomas)failure to suppressaldosteronewith salt loading. d. Pathology usually shows a single benign adenoma,which is a well-circumscribed, encapsulated,small lesion composedof lipid-laden clear cells. 3. Secondary hyperaldosteronism a. Etiology. The causesare decreasedrenal blood flow or perfusion pressure,edematous stateswith sodium retention, renin-producing neoplasms,and Bartter syndrome, which is characterizedbyjuxtaglomerular cell hyperplasia,hyper-reninemia,hyperaldosteronism,and failure to thrive; it is often associatedwith low blood pressure. b. Laboratory values include high renin levels, hypernatremia, and hypokalemia. Secretionof aldosteroneis triggeredby elevatedrenin-angiotensinlevels. 4. Congenital adrenal hyperplasia (CAH) a. Etiology. CAH is usuallydue to a congenitalenzymedeficienry of adrenalsteroidsynthesisresulting in cortisol deficiency and marked enlargementof the adrenals. b. Types. The three most common forms all causevirilism and are called adrenogenital syndromes. (1) 2l-hydroxylase deficiency causessimple virilizing CAH (SOotol. There is normal aldosteronefunction and impaired cortisol production. (2) The salt-losing syndrome is due to 2l-hydrorylase deficiency associatedwith aldosteronedeficiency.Infantspresentwith vomiting, dehydration,hyponatremia, and hyperkalemia. (3) ll-Hydroxylase deficiency causesexcessiveandrogen production and buildup of 11-deoxycorticosterone(strong mineralocorticoid), causing virilization, hypertension,and hypokalemia. c. Clinical features of adrenogenital syndromesare virilization in women, sexualprecociry and prematureepiphysealclosure.

ln a Nutshell Hyperaldosteronism

t ruaJK. Metabolic alkalosis

l ' (C onn syndrome) I

2"

Y

Y

v

V

T Aldosterone T Aldosterone secretion by dueto I gland; perfusion or adrenal othercause usually of t renin adenoma secretion

I

Willsee J renin Willsee1 renin

d. Pathology of all types showsdiffirse or nodular bilateral adrenalcortical hyperplasia. B. Adrenal cortical hypofunction l. Acute adrenocortical insufficiency can be causedby: a. Rapid withdrawal of exogenoussteroids in patients with chronic adrenal suppression b. Stress(e.g.,trauma, surgery,infection), Addison disease,or chronic adrenalsuppression causedby administration of exogenouscorticosteroids c. Adrenal apoplexy, such as in the Waterhouse-Friderichsen syndrome: a massive, sudden adrenalhemorrhageusually associatedwith meningococcalsepticemia 2. Chronic or primary adrenocortical insufficiency (Addison disease) a. Etiology. Tuberculosiswas once the most common cause.The most common etiology today is idiopathic (probably autoimmune). Other possibilitiesinclude infections (e.g., fungal, Waterhouse-Friderichsensyndrome), iatrogenic causes,metastases, adrenalhemorrhage,and pituitary insufficienry. b. Pathogenesis.To produce clinical insufficienc,f,90o/oof the adrenal gland must be nonfunctional.

269

Endocrine System

Note Pigmentation oftheskinin Addison isdueto ACTH also having a weakstimulatory ACTH effect on melanorytes. andmelanoryte-stimulating (MSH) hormone share amino acidsequences.

c. Clinical features are due to insufficient cortisol and aldosteronesecretion,leading to weakness,weight loss, anorexia, nausea,vomiting, hypotension, skin pigmentation, hypoglycemia with prolonged fasting, inability to tolerate stress,and abdominal pain. d. Laboratoryvalues show decreasedserum sodium and chloride with metabolic acidosis and increasedserum potassium.Low serum cortisol and urinary 17-OH CS and low l7-ketosteroids,before and after ACTH administration, should alsobe measured. ACTH levels are high. e. Pathology shows bilateral atrophied adrenal glands. In the idiopathic lrpe, there are lymphocytic infiltrates and zonesof fibrosis surrounding islets of remaining epithelial cells. 3. Secondary adrenocortical insufficiency a. Etiology. Causesinclude metastases,irradiation, infection, and infarction, affecting the hypophysial-pituitary axis and resulting in decreasedACTH. b. Clinical features. Secondary insufficiency usually produces less mineralocorticoid malfunction and lesspigmentation. C. Adrenal neoplasms l. Adrenal adenomas a. Clinical features. Adrenal adenomas are mostly asymptomatic and nonsteroidproducing. Steroid-producingadenomasmay produce Conn syndrome, Cushing syndrome, or virilization in women. They may also occur with multiple endocrine neoplasia(MEN) syndromes. b. Pathology. Adrenal adenomas are usually small and unilateral, yellow-orange on cut section, and poorly encapsulated.When adrenal adenomas are large, hemorrhage, rystic degeneration,or calcificationmaybe seen.Nonsteroid-producingadenomasare usually composedof lipid-filled cells;steroid-producingtumors are often mixed with lipid-filled cellsand compact cells. 2. Adrenal carcinomas a. Clinical features. Adrenal carcinoma is relatively rare and usually very malignant. Greaterthan 90oloare steroid-producing(often more than one steroid). b. Pathology. The tumors are often large and yellow with areasof hemorrhage, rystic degeneration,and necrosis. 3. Pheochromocytoma

Mnemonic TheRuleof losfor Pheochromocytoma . l0o/o extra-adrenal . l0o/o bilateral . l0o/o malignant . l0o/o affect children . l0o/o familial

270

a. Etiology. Pheochromocytomais a neoplasmof neural crest-derivedchromaffin cells that secretecatecholamines, resulting in hnrertension. b. Incidence. The highest incidenceis in children and in adults age 30-50. Ten percent are familial, i.e.,are associatedwith MEN IIa and MEN III (aka IIb), neurofibromatosis,or von Hippel-Lindau disease. c. Clinical features are related to catecholaminerelease.Parorysmal or constant hlpertension is the most classicsymptom. Also, sweating,headache,arrhythmias,palpitations, and nervousnessmay be seenin any combination. d. Laboratory values show elevated urinary catecholamines and catacholamine metabolites (e.g.,homovanillic acid, HVA, and vanillylmandelic acid,VIvIA).

Pathology

e. Pathology. Ten percent of tumors are extra-adrenal,l0o/o are bilateral, and 10oloare malignant. Tirmors are well defined and fibrous, creatinga lobulated appearance.The cut surface is light brown, often with areasof hemorrhage and necrosis.Cells are stained with chromium salts (chromaffin reaction) and have a basophilic cytoplasm with secretorygranules. 4. Neuroblastoma is the most common malignant extracranial solid tumor of childhood. Amplification of the N-myc oncogene is a characteristicof neuroblastoma.The more copiesof the oncogene,the more aggressive the tumor.

NoIe Youaremuchmorelikely to seea pheochromocytoma case ontheUSMLE than youeverareto seeonein yourclinical practice.

a. Clinical features. Ttrmors grow rapidly, metastasizewidely (especiallyto bone), and produce elevatedurinary catecholamines.The prognosis is better if patients are less than 1 year old. Tumors may regressin young infants. The presenceof ganglion cells also improvesprognosis. b. Pathology. Neuroblastomaoccurs most frequently in the adrenal medulla but may also arise in the cervical,abdominal, and thoracic sympatheticchain. The tumors are lobulated with a gray cut surface,showing areasof necrosis,hemorrhage,and calcification. Microscopically, malignant small cells are often seen in a rosette pattern around nerve fibrils.

THYROID GTAND A. Overview of hyperthyroidism 1. Etiology. Hyperthyroidism may be seenmost often in Gravesdisease,toxic multinodular goiter, and toxic adenoma.Thyroiditis, thyroid carcinoma,and iodine ingestion are less frequent causes. 2. Pathogenesisis due to increasedcirculating levelsof the thyroid hormones triiodothyronine (Tr) and thyroxine (Tr), causinga hnrermetabolic state. 3. Clinicat features a. Cardiacsymptoms include tachycardia,cardiacpalpitations,cardiomegaly,occasional cardiac arrhythmias (usually atrial fibrillation), and cardiomyopathy. b. The skin is warm, flushed,and moist due to vasodilatation. c. The eyesshow a wide starewith upper lid retraction and lid lag. Exophthalmos is characteristicof Gravesdisease,due to swellingof extraocularmusclesand periorbital tissues. d. Patients also show increasedsweating,heat intolerance,hyperactivity, nervousness, tremor, weight loss,diarrhea,oligomenorrhea,and myopathy. e. Propranolol, a nonselectivebeta blocker, may be given to alleviatethe sympathetic nervous systemsymptoms.

Clinical Correlation Clinical diagnosis of hyperthyroidism maybe difficultin pregnancy, whichis anintrinsically hypermetabolic stateandisoftenassociated withmilddegrees of thyromegaly. Inaddition, the increase inTBGthatresults fromthehighestrogen levels elevates thetotalserum T4, butnotthefreeserum T4.

f. Thyrotoxic storm is a severehypermetabolic state characterizedby tachycardia,fever, cardiacabnormalities,and coma.Twenty-fivepercentof casesare fatal. 4. Diagnosis is basedon low TSH and elevatedTn. Low TSH is most important. B. Overview of hypothyroidism 1. Etiologies a. Congenitalthyroid dysplasiaor hypoplasia b. Hypothalamic or pituitary disease

271

Endocrine System

c. Thyroid conditions causing goiter including iodine deficiency and Hashimoto (autoimmune) thyroiditis d. Surgicalor radiation destruction of gland e. Peripheralresistanceto thyroid hormone 2. Clinical features depend on the age group.

Note Incontrast toprimary hypothyroidism, secondary (pituitary gland failure) and (hypothalmic tertiary failure) hypothyroidism have low (ornormal) TSH levels.

a. Infants lacking sufficient thyroid hormone develop cretinism. The major effects are on skeletaland CNS development (i.e., short stature,retarded bone age,epiphyseal dysgenesis, and mental retardation).Once apparent,the syndromeis irreversible.The initial presentation includes failure to thrive, feeding difficulties, constipation, and somnolence.Children developprotuberant abdomens,wide-set eyes,dry rough skin, broad nose, and delayedepiphysealclosure.Neonatal screeningfor elevatedTSH is essentialfor early detection. b. Older children show short stature, retarded linear growth, and delayed onset of puberty. c. In adults, hypothyroidism causeslethargy, weakness,fatigue, decreasedappetite, weight gain, cold intolerance, hair loss, dry skin, constipation, apathy, myopathy, psychosis,metrorrhagia (irregular uterine bleeding), and acceleratedatherosclerosis with elevated serum cholesterol. Mpredema, a syndrome associatedwith severe hypothyroidism, showsperiorbital puffiness,pale doughy skin due to accumulationof hydrophilic mucopolysaccharides, sparsehair, cardiac enlargement,cardiomyopathy, pleural effrrsions,anemia,and thickened facial features. 3. Diagnosis of primary hypothyroidism is basedon an elevatedTSH and low To. C. Graves disease 1. Incidence. Gravesdiseasepeaksin the third and fourth decadesand is five times more common in women. There is a familial predisposition, and it is associatedwith other autoimmune diseases,such as pernicious anemia and Hashimoto thyroiditis. The incidenceof Gravesdiseaseis increasedin HLA-DR3- and HlA-B8-positive individuals. 2. Pathogenesis is autoimmune, resulting from production of thyroid-stimulating immunoglobulin (TSI) and thyroid growth immunoglobulin, two autoantibodies that causeglandular hyperplasiaand hormone production by binding to TSH receptors. 3. Clinical features are present in varying combinations. a. Thyrotoxicosis has symmetric glandular enlargement. b. Ophthalmopathy is characterizedby lid lag, retraction of the upper lid, proptosis, periorbital edema,and stare.It results from inflammatory infiltration and edema of extraocular musclesand periorbital tissues.It does not alwaysrespond to antithyrotoxicosistreatment. c. Dermopathy is characterizedby thickened edematous nodules or plaques on the lower extremitiesand is presentin 10oloof Gravespatients. 4. Pathology a. Grossly,there is a diffi.rse,moderatesymmetrical enlargementof the gland. b. Microscopically, hypercellulariry producing small follicles with little colloid and papillary infoldings into the lumen, is seen.The stroma exhibits increasedvascularityand variable lymphocytic infiltrate. These changesare not associatedwith an increased incidenceof thvroid cancer.

272

Pathology

D. Hashimoto thyroiditis is a chronic lymphocytic thyroiditis featuring goitrous enlargement of the thyroid gland produced by lymphocytic and plasma cell infiltrates, with the eventual development of hypothyroidism. 1. Etiology is autoimmune. There may be autoantibodies to the TSH receptor, T' Tn, microsomes,and thyroglobulin. 2. Incidence. Hashimoto thyroiditis is the most common type of thyroiditis and is the leading causeof goitrous hypothyroidism in the United States.The highest incidenceis in middleagedwomen, and there is a higher incidencein patientswith a family history of Hashimoto or other autoimmune diseases(e.g., Graves disease,Sj6gren syndrome, systemic lupus erythematosus).The incidence of Hashimoto thyroiditis is increasedin HLA-DR5 and HLA-BS individuals. 3. Clinical features include painless goiter. Hypothyroidism develops,along with malaise, fever,a decreasedTn, and elevatedTSH. 4. Pathology. The gland is enlarged,usually symmetric, and firm. It contains a lymphocftic and plasma cell infiltrate with occasional germinal centers.Acini are partly atrophic, with little colloid and variable fibrosis, increasing as the diseaseprogresses.Follicular epithelium is transformed into Htirthle cells characterizedby an eosinophilic granular cytoplasm.

E. Diffrrse nontoxic goiter is used to describe diffirse enlargement of the gland in euthyroid patients. 1. Incidence a. Endemic goiters havea high incidencein certain geographicregions (e.g.,mountainous regions or regions far from the ocean). They are causedby iodine-deficient diets or increasedintake of goitrogens (e.g.,calcium, fluorides).

In a Nubhell Hyperhyroidism l-lypdyroidlsn (J TSH, (t TsH,J Ty t T3, 1rJ JTJ

I

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. Getrnism inchildren

. Skinmoi$ andflushed

. Lethargy inaduh

. Lidlag

. Fatgue

. Sweating

. Weight gain

. Heat . Cold intolerance intolerance . Weight los

b. Sporadic simple goiter is lesscommon. The incidencein women is much greaterthan in men. 2. Pathogenesis.There arevariableabnormalitieswith thyroid hormone synthesis,resulting in compensatoryhypertrophy and hyperplasiaof follicular epithelium. 3. Pathology. The gland becomeshyperplastic, then accumulatescolloid asymmetrically. Multinodular goiter developsfrom chronic diffirse goiters; it may be toxic or nontoxic and may become very large (Figure III-4-2).

275

Endocrine System

lP*" i

: ,;;TW'',

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Figure lll-4-2.Thyroid:multinodular goiter, microscopic.

1. Clinical features. Glandular enlargement may causestridor, dysphagia,and even superior vena cavasyndrome (masseffect).Fifty percentproduce thyrotoxicosis.Thesetumors must be differentiated from thyroid cancer,particularly asymmetric tumors in euthyroid patients. 2. Pathology. Glands may be as large as 2 kg and nodular with areasof hemorrhage, scarring, and calcification. They are usually asymmetric with areasof colloid-filled acini. G. de Quervain granulomatous subacute thyroiditis 1. Etiology is probably viral. 2. Incidence. It is the second most common form of thyroiditis with the incidence in women greaterthan in men. The diseasepeaksin the secondto fifth decades. 3. Clinical features. Symptoms often begin following a viral syndrome, most commonly mumps and coxsackievirus.The courselasts severalweekswith a tender gland, a goiter in 30o/oof patients, fevet malaise,and dysphagia.Early in the course, the patient may have mild symptoms of thyrotoxicosis; latet patients are usually euthyroid, and the diseasefollows a self-limited course. 4. Pathology a. Grossly, there is moderate irregular enlargementof the gland. b. Microscopically, degeneration of follicular epithelium causesleakageof colloid from follicles, which initiates an inflammatory responsewith foreign body giant cells,histiocytes,and granuloma formation. The degenerationof epithelial cellsis presumably due to a viral infection, but a specificetiology is usually not demonstrated. H. Riedel thyroiditis is a rare diseasecharacterizedby connective tissue proliferation, causing destruction of the thyroid gland and fibrosis of surrounding structures. 1. Incidence is greatestin middle age,and greaterin women than in men. 2. Ctinical features. Fewer than 50oloof patients are hlpothyroid. They may present with stridor, dyspnea,dysphagia,or a painlesslump.

274

Pathology

3. Pathology a. Grossly, the gland is firm and hard, nodular, and irregular; sizevaries. b. Microscopically, complete fibrous replacementof the gland is seen.It may mimic carcinoma. I. Congenital thyroid conditions 1. Agenesis or dysgenesisare frequent causesof cretinism. 2. Thyroglossal duct or cyst may communicate with the skin or base of the tongue. It is formed from nests of incompletely descendedmidline thyroid tissue. 3. Ectopic thyroid nests are usually at the base of the tongue. Prior to removal, it must be documented that the patient has other functioning thyroid tissue.

\ Tumors. Thyroid nodules are very common (F7o/o adults in the U.S.), but thyroid cancer is uncommon (lessthan 2 casesper 1,000nodules).There is a higher incidenceof neoplasiain solitary nodules and in younger patients. 1. Adenomas. Follicular adenoma is the most common. a. Clinical features. Adenomas may causepressuresymptoms, pain, and, rarely, thyrotoxicosis. b. Pathology. There are usually solitary lesions lessthan 3 cm in diameter that are well encapsulatedand compressadjacent thyroid parenchyma. There is a sharp demarcation from surrounding thyroid with a variable amount of colloid, interstitial connective tissue,and acinal size. 2. Cysts make up lV25o/o of solitary nodules and usually represent rystic degenerationof follicular adenomas. 3. Carcinomas representneoplasia of follicular cells (i.e., papillary, follicular, or anaplastic cancer) and/or parafollicular cells (i.e., medullary cancer).Risk factors include radiation and a geneticpredisposition. a. Papillary carcinoma is the most common type. The incidence is higher in women. (1) Pathology. Grossly, there is a papillary branching pattern, which may be rystic or solid. Microscopi..lly, there is a singlelayer of tumor epithelium on a fibrovascular stalk. Nuclei have a characteristicground-glass appearance.Forty percent of tumors contain psammoma bodies. (2) Clinical features. Spread to local nodes is common. Hematogenous spread is rare. Resectionis curative in most cases.Radiotherapywith iodine tlt (131I)is also effective for metastases. b. Follicular carcinoma makes up 20o/oof thyroid cancersand is more malignant than papillary cancer. (1) Patholog''. Tumors are occasionallyencapsulated,with penetration through the capsule.They show an adenomatouspattern with developmentof acini or folliclesthat are lined by large cells compared to those lining normal follicles. Colloid is sparse. (2) Ctinical features. Local invasion and pressure causes dysphagia, dyspnea, hoarseness, and cough.Hematogenousmetastasisto lungs or bonesis common. The prognosis depends on the extent of metastases.The overall 5-year survival is 60010.

In a Nutshell . Papillary carcinoma + lymphnodemetastases . Follicular carcinoma + hematogenous meta$ases

275

System Endocrine

and has a poor prognosis.It is relc. Anaplastic carcinoma is rapid growing, aggressive, atively uncommon and affectsolder patients (60-80 yearsold). (1) Pathology. Tumors are usuallybullq and invasive.They are composedof undifferentiated,anaplastic,and pleomorphic cells.

Note in LabAbnormalities Primary Hyperparathyroidism . tPTH . t ca,r . J Phosphate . t Alkaline phosphatase

(2) Clinical features are early, widespread metastasis and death within 2 years. d. Medullary carcinomas arise from parafollicular cells (C cetls).They are uncommon, and a minority are associatedwith MEN IIa and MEN III (IIb) syndromes.They are composed of nests of cells in an amyloid stroma made of calcitonin. The tumors secretecalcitonin.

PARATHYROID GLANDS A. Primary hyperparathyroidism 1. Etiology

ClinicalCorrelate

a. Parathyroid adenoma is the most common cause,usually involving a single gland.

fibrosa cystica, also Osteitis known asvonRecklinghausen disease of bone, occurs asa primary result ofchronic ism.Cy$ic hyperpa rathyroid changes inboneoccur dueto o$eoclastic resorption. Fibrous replacement ofresorbed bone "brown mayleadto a tumor," a non-neoplastic tumormass.

b. Parathyroid hyperplasia shows diffrrse enlargement of all glands, usually composed of chief cells. c. Parathyroid carcinoma is very rare. It is characterizedby a high mitotic rate, local invasion,and metastases. d. MEN I and MEN IIa include tumors or hyperplasiasof the parathyroids. 2. Clinical features. Patients with elevated serum calcium are often asymptomatic. They may presentwith bone abnormalities secondaryto elevatedparathyroid hormone (e.9., osteomalacia,osteitisfibrosa cystica,subperiostealresorption). Hypercalcemiamay cause metastaticcalcification (e.g,kidney stones). B. Secondary hyperparathyroidism

Note in LabAbnormalities HyperparaSecondary thyroidism .tPTH . J Car. . I Phosphate . t Alkaline phosphatase ClinicalCorrelate DiCeorge isalso syndrome withabsence associated ofthe thymus dueto a common embryologic defect. Tetany occurs shortly afterbirthdue to congenital absence ofthe parathyroid glands. Cardiac structural defects andimmunodeficienol arealsonoted. 276

1. Etiology. Secondaryhyperparathyroidismis usually causedby chronic renal failure, leading to decreasedCa2+ absorption, which in turn results in a feedback loop and increased PTH. Vitamin D deficiencyand malabsorption are lesscommon causes. 2. CLinical features show soft tissue calcification and osteosclerosis.Mild-to-moderate hypocalcemiais characteristic. C. Hypoparathyroidism 1. Etiology. Common causesare removal of glands during thyroidectomy, idiopathic, radioactiveiodine therapy for Gravesdisease,metastaticcancer,and DiGeorgesyndrome. The idiopathic form may be familial and autoimmune. 2. Clinical features include hypocalcemia,hyperphosphatemia, irritabiliry anxiefy, neuromuscular excitability,tetany, intracranial calcifications,lens calcification, dental abnormalities, and cardiacconduction defects. D. Pseudohypoparathyroidism i. Etiology. Pseudohypoparathyroidismis an autosomal recessivedisorder resulting in a kidney unresponsiveto circulating PTH. 2. Clinical features include skeletal abnormalities such as short stature, and shortened fourth and fifth carpalsand metacarpals.

Pathology

E. Hypercalcemia is defined as a persistentserum calcium over 10.4m/dl. 1. Etiology. Hlpercalcemia may be causedby metastaticdiseaseto bone, such as myeloma or epithelial neoplasm, vitamin D intoxication, sarcoidosis,primary or secondary hlperparathyroidism, the milk alkali syndrome,or Pagetdiseaseof bone. 2. Clinical features.Renal stones are often seen;hlperparathyroidism is alsousually associated with hypercalciuria and with hypophosphatemia. Alkaline phosphataseactivity is usually elevated.Patientsmay experiencean altered sensorium, often first noticed as drowsiness. 3. Pathologic features in bone range from obvious metastases to osteoclasttunneling through bony trabeculaein hyperparathyroidism.

Mnemonic (MISHAP) Hypercalcemia Malignancy !ntoxication 5arcoidosis Hyperparathyroidism Alkali syndrome lagetdisease

(rSrETS ENDOCRTNE PANCREAS OFLANGERHANS) A. Diabetes mellitus is causedby inadequate or abnormal insulin secretion,causing impaired glucose utilization, irnd resulting in hyperglycemia, glycosuria, and characteristic systemic pathology. 1. Types a. Insulin-dependent (tt'pe l) diabetes mellitus (IDDM). There is an abrupt onset with patientsprone to ketoacidosis,insulin dependence,and severemetabolic derangements. b. Noninsulin-dependent (t)"e 2) diabetes mellitus (NIDDM). This diseaseconstitutes most casesof idiopathic diabetics.It is characterizedby peripheral insulin resistanceand later,abnormal insulin secretion.Most patientshavecentral obesitywith an onset of diseaseusually after age40. Thesepatients are not prone to ketoacidosis. c. Secondarydiabetes may be causedby destruction of pancreaticislet cellsfrom inflammation, hemochromatosis,tumor, surgery or hormonal disease. 2. Pathogenesis a. IDDM shows a marked, absolute insulin deficienry resulting from diminished p-cell mass. It it therefore characterizedbylowserum insulin levels.There are three etiologic theories;in many casesof IDDM, all three mechanismsmay be operative. (l) A viral infection (e.g.,mumps, coxsackievirusB, rubella, CMV mononucleosis) may lead to destruction of B cells.A subgroup of adult-onset diabeticswith islet cell antibodies and HIA-DR3 are at increasedrisk to becomeinsulin dependent. (2) There is clearly a genetic predisposition becauseof increasedsusceptibility with certain HLA haplotypes. (3) Autoimmune response.Eighty percent of patientswith IDDM haveanti-islet cell antibodies. Relativesof patientswith IDDM often havesimilar antibodies,and this increasestheir risk of developing the disease.Autoantibodies to islet cells may precedethe developmentof the disease. b. MDDM is characterizedby mild-to-moderate insulin deficienry and is not associated with a specificHLA haplotype. There are two theories: (1) Insulin resistance,the impaired ability of tissuesto react to circulating insulin, results from a decreasein the number of cell-surface insulin receptors, for unknown reasons. (2) Delayed or inadequate insulin secretion may develop, probably due to islet exhaustion.

277

Endocrine System

3 . Clinical features a. Predisposingfactors are obesiry pregnancy,trauma, infections,and stress. b. Presentation. Both IDDM and NIDDM may present with polydipsia, polyuria, polyphagia, weight loss, and muscle weakness.Laboratory values may show hnrerglycemia, glycosuria, and hyperlipidemia. c. Acute metabolic complications (1) Diabetic ketoacidosis(DKA) may occur in insulin-dependentdiabetics.It leadsto an oversupply of glucose,fueled by high rates of protein catabolism,lipolysis in adiposetissue,and fatty acid oxidation in liver. The acceleratedrate of fatty acid oxidation producesacetyl-CoAfasterthan it can be burned by the TCA cycle,and the liver conservesthe excessacetyl-CoA by synthesuing ketones.Metabolic acidosisresultsfrom the accumulation of the ketones.The high level of blood glucose leads to dehydration via an osmotic diuresis.Tieatment with insulin normalizes the metabolism of carbohydrate,protein, and fat. Fluids are given to correct the dehydration. (2) Hyperosmolar nonketotic coma occurs in patients with mild adult-onset diabeteswhen blood glucoselevelsexceedapproximately600 mg/dl. It is not clear why ketoacidosisdoes not occur in these patients,but it appearsthat lipolysis occurs to a much lesserextent than in DKA, thereby producing fewer ketones. The treatment of hyperosmolar nonketotic coma is identical to the treatment of DKA. d. Late complications of diabetes. Patientswith long-standing diabetesof either type may developa seriesof long-term complications. ( I ) Atherosclerosis causesstrokes,myocardial infarcts, and gangrene,frequently of the toes. (2) Nephropathy causesproteinuria, hypertension,and edema,and it may lead to renal failure.

ClinicalCorrelate Diabetics arealsoa high-risk group forthefollowing infections:

(3) In the Kimmelstiel-Wilson syndrome, intercapillary glomerulosclerosis with hypertensionand edemalead to proteinuria, beginning approximately20 years after the onset of disease. (4) There is a predispositionto infections (tuberculosis,pyelonephritis,pneumonia, skin infections).

. Klebsiello pneumonia

(5) Neuropathy is usuallya distal,symmetric polyneuropathy("stocking-glove"distribution) but may be a mononeuropathy.In addition to this peripheral neuropathy, diabetics can also have autonomic neuropathy.

. Sinus mucormycosis

(6) Retinopathy may lead to blindness.

. Malignant otitisexterna (Pseu dononosoerug inoso) . Chronic osteomyelitis

4 . Pathology is characterizedby a thickening of basementmembranesby homogeneousor laminated periodic acid-Schiff (PAS)-positive hyaline. Microangiopathy occurs with thickening of capillary basement membranes, causing increased leakage of plasma proteins. a. In the pancreas,visible abnormalitiesmay or may not be present.They may include: ( 1) Decreasein number and sizeof islets (2) Islet-cellhyperplasiaearly in IDDM (3) Lymphocytic infiltrate of islets

278

Pathology

(a) Hyalinization of islets (5) Glycogenaccumulation and degranulationof B cells b. Atherosclerosisbegins within 5 yearsof onset,regardlessof age.Widespreadlesions are prone to calcification,ulceration, and overlying thrombosis, and lead to ischemia (stroke,myocardialinfarction) or aneurysms. c. Arteriolosclerosis is characteized by a severethickening of arteriole walls in every tissue,frequently by hyaline material. d. Kidneys show severeinvolvement, leading to renal failure. Pathologic findings are characterizedbyarteriolosclerosis,glomerular pathology (diffrrseglomerulosclerosis, nodular glomerulosclerosis,exudativelesions),and bacterial infection (pyelonephritis, papillitis). e. Peripheral neuropathy, the most common defect, affectsboth motor and sensory nervesas a result of damageto Schwanncells and myelin, mainly in the lower extremities. It is often associatedwith autonomic neuropathy, causingbladder and bowel dysfunction, gastric atony, impotence, cardiac arrhythmias, and, possibly, sudden death. f. Retinopathy is relatedto duration of disease.Diabetic retinopathy is the fourth leading causeof blindness. (1) Nonproliferative retinopathy is characterizedbymicroaneurysms,with leakage resulting in exudates,edema,and hemorrhage;such a finding is diagnostic of diabetes.Hard protein exudatesare seenin deepretinal layers,and "cotton wool" spots appeardue to microinfarcts in the superficialretina. (2) Proliferative retinopathy is characterizedby neovascularization.It may cause traction bands resulting in retinal detachmentand vitreous hemorrhage. g. Diabeticxanthomas areyellow nodules on the elbowsand kneesresultingfrom lipidfilled macrophagesin the dermis. 5. Prognosis a. NIDDM decreases life spanby approximately8 years.There is a much higher mortality from IDDM. b. Causesof death in decreasingfrequencyare: (1) Myocardial infarction (2) Renalfailure (3) Stroke (4) Ischemicheart disease (5) Infections B. Islet-celltumors (FigureIII-4-3) 1. B-cell tumors. Insulinomas most commonly occur betweenthe agesof 30 and 60. a. Pathogenesis.B-cell tumors produce hlperinsulinemia, causinghypoglycemia. b. Clinical features.Patientsexperienceepisodesof alteredsensorium (i.e., disorientation, dizziness,diaphoresis,nausea,tremulousness,coma) that are relievedby glucoseintake.

279

Endocrine System

c. Pathology. Most tumors are solitary, well-encapsulated,and well-differentiated adenomasof various sizes.Ten percent are malignant carcinomas.

Bridgeto Gastrointestinal Zollinger-Ellison syndrome is discussed in greater detail in theCastrointestinal Pathology chapter ofthisbook.

Figure lll-4-3.lslet-cell adenoma (microscopic).

2. Zollinger-Ellison syndrome is due to a gastrinoma and is often associatedwith MEN tfpe I. a. Pathogenesis.Tumors of pancreaticislet cells secretegastrin, causinggastric hypersecretionof acid. b. Clinical features include intractable peptic ulcer diseaseand severediarrhea. c. Pathology. Sixty percent are malignant. Most tumors are located in the pancreas,with 10oloin the duodenum.

In a Nutshell . MEN| + anterior pituitary, parathyroids, adrenal cortex, pancreas and . MENlla+ adrenal medulla (pheochromorytoma) and parathyroids . MENlll -+ adrenal medulla (pheochromocytoma), (medullary thyroid carcinoma), andmucosal neur0mas

(MEN) MUTTTPTE ENDOCRTNE NEOPTASTA Multiple endocrine neoplasiashowsfamilial, autosomal dominant inheritance with incomplete penetrance.It is characterizedbybenign and malignant tumors of the APUD (amine precursor uptake and decarborylation) cell system. A. MEN I featurestumors of the parathyroids,adrenal cortex, pituitary gland, and pancreas, and is associatedwith peptic ulcersand Zollinger-Ellison syndrome. B. MEN IIa featurestumors of the adrenalmedulla (pheochromocFtoma),medullary carcinoma of thyroid, and parathyroid hyperplasiaor adenoma. C. MEN III (also calledMEN IIb) featuresmedullary carcinoma of the thyroid, pheochromocftoma, and mucosalneuromas. D. Clinical features show varied presentationsthat may include peptic ulcerations, hypoglycemia,hyperparathyroidism,hypertension,and Cushing syndrome.

OVARY ANDTESTIS The pathology of theseendocrine organsis discussedin the ReproductivePathologychapterin this book.

280

Endocrine Pharmacology

Manysynthetic andsemisynthetic hormones andhormone antagonists areusedfordiagnosis and treatment of endocrine andnonendocrine disorders. Thischapter willdiscuss theseimportant endocrine drugs.

HYPOTHALAM IC-PITU ITARYHORMON ES The hypothalamic-pituitary systemis important for regulating the secretion of peripheral hormones,which control growth and development,metabolic function, and reproduction. A. Hypothalamic hormones 1. Growth hormone-releasing hormone (GHRH) stimulates somatotrophs in the anterior pituitary to secretegrowth hormone. a. Indications for use. GHRH is available for diagnosis and therapeutic use in patients with growth hormone deficienry and is effective in specific types of dwarfism. b. Side effects and toxicity.It causespain at the injection site. 2. Somatostatin (growth hormone release-inhibitinghormone, GHIH) is produced in the hypothalamus,in other areasof the central nervous system (CNS), pancreas,gastrointestinal tract, and thyroid.

Note groMh Somatostatin, hormone release-inhibiting (CHIH), hormone and somatotropin release(SRIH) inhibiting hormone areallnames forthe same hormone.

a. Physiologic effects (1) Somatostatin reduces the secretion of growth hormone, gastrin, secretin,vasoactive intestinal peptide, cholecystokinin (CCK), glucagon, insulin, calcitonin, parathyroid hormone (PTH), renin, and thyroid-stimulating hormone (TSH). (2) It acts through cell membrane receptors to reduce calcium influx into the cells. b. Indications for use. Somatostatin's duration of action is too short to be clinically usefrrl.Octreotide, a synthetic somatostatin analog, is longer acting; given subcutaneously, it controls excessivehormone secretion in acromegaly glucagonoma, and insulinoma.

ClinicalCorrelate isusedclinically Octreotide to treatga$rointestinal bleeding andintractable diarrhea.

In a Nutshell

3. Thyrotropin-releasing hormone (TRH) a. Physiologic effects. TRH increasesthe secretion of TSH (thyrotropin) and actson cell membrane receptorsto increasethe activity of adenylateryclase. b. Regulation of secretion. Secretionis regulatedby levelsof thyroid hormones in a negative-feedbackloop.

TRHstimulates thesecretion of thyroid hormones by increasing cyclic adenosine (cAMP). monophosphate

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Endocrine System

4. Corticotropin-releasing hormone (CRH) a. Physiologic effects. CRH acts on the anterior pituitary to increasethe secretion of adrenocorticotropic hormone (ACTH). It binds to cell membrane receptors to increaselevelsof cyclic adenosinemonophosphate(cAMP). The releaseof ACTH is calcium dependent.CRH also stimulatesthe releaseof B-endorphin. b. Indications for use. A synthetic CRH is available for diagnostic studies of pituitary function. 5. Gonadotropin-releasinghormone (GnRH or LH-RH) is produced in the arcuatenucleus of the hypothalamus,which controls the releaseof follicle-stimulatinghormone (FSH) and luteinizinghormone (LH).

Note Leuprolide canbeusedto inhibit FSH andLHrelease.

a. GnRH (gonadorelin), when administered in a pulsatile manner (similar to endogenous secretionpatterns),stimulatesreleaseof FSH and LH and is useful in the diagnosis and treatment of hypogonadism. b. Continuous dosing. When administeredin continuous, steadydoses,gonadotropin releaseis inhibited. Leuprolide and other GnRH analogs (i.e., nafarelin, goserelin, histrelin) are given in continuous dosesto produce a chemical castration in adults with prostatecancer,polyrystic ovary syndrome,uterine fibroids, and endometriosis. Leuprolide is given subcutaneouslyor intramuscularly. Patientsusually worsen slightly before improving becausehormone levels(e.g.,testosterone)initially increaseduring the first week of therapy. 6. Prolactin-inhibiting hormone (PIH)

Bridge to Neruous System Nervous SeetheCentral Pharmacology Sy$em chapter of Organ Systems BookI the flolumelll)to review roleof bromocriptine in thetreatment of Parkinson disease.

In a Nutshell Oxytocin stimulates uterine contractility to: . lnduce labor . Control postpartum bleeding

a. Physiologic and pharmacologic effects. Dopamine has been identified as a PIH. It is not usefulin the treatment of CNS abnormalitiesbecauseof the peripheral sideeffects and the failure of dopamine to crossthe blood-brain barrier effectively.It is also not used to alter prolactin secretion. b. Bromocriptine, a dopaminergic receptor agonist,is effectiveorally in the treatment of hlperprolactinemia, to treat breastengorgement,to inhibit lactation in the postpartum period, and to treat infertility associatedwith excessiveprolactin secretion. B. Posterior pituitaryhormones 1. Oxytocin is synthesizedin the paraventricularnuclei of the hypothalamusand is stored in the posterior pituitary. a. Indications for use. Oxftocin stimulates uterine contractions and is used intravenously to induce or maintain labor at term. It is also usedby intramuscular administration to control postpartum bleeding.It is availableas a nasalspray to causemilk secretionby contracting smooth muscle in the myoepithelial cells of the mammary gland. Dinoprostone, a prostaglandinEz (PGEz),is also used to induce labor. b. Uterine relaxants used to inhibit premature labor include ritodrine and terbutaline, both p2-adrenoceptoragonists. 2. Antidiuretic hormone (ADH) is synthesizedin the supraopticand paraventricularnuclei of the hypothalamusand is storedin the posterior pituitary. a. Physiologic effects (1) ADH increaseswater permeability and, thus, reabsorption of water in the collecting ducts of the kidney. This antidiuretic effect is produced by the action at V2 receptors,leadingto an increasein cAMP. (2) At high doses,ADH alsocausessmooth musclecontraction by stimulation of V1 receptors.

282

Pharmacology

b. Indications for use. The main use of ADH is in treatment of central diabetes insipidus. DDAVP (also called desmopressin),an analog of vasopressinwith no V1 effects,is used clinically to treat diabetesinsipidus. DDAVP is of no use in the treatInent of nephrogenicdiabetesinsipidus becauseof dysfunctionalADH receptors. C. Anterior pituitary hormones 1. Growth hormone (somatotropin) is secretedby anterior pituitary cells (somatotrophs). a. Regulation of secretion is by GH-RH and somatostatin.

ClinicalCorrelate DDAVP isalsouseful in treating orpreventing bleeding complications. lt promotes therelease ofvon Willebrand factor by endothelial cells.

b. Physiologic effects (1) Growth hormone has metabolic and anabolic effects that are mediated by somatomedins,peptidesproduced in the liver. It actson specificcell membrane receptorsto stimulate the releaseof the somatomedins.

(2) Growt*:iilin ("anticatab ") It olic ffi:. ffi ::,t',T#i:?i.:i-:*:::: (3) Its anti-insulin action promotes hyperglycemia;hence,it is diabetogenic. c. Pharmacokinetics. Growth hormone is given subcutaneouslyor intramuscularly and has a half-life of 20-30 minutes.A peak increasein somatomedinsoccurs in24 hours. d. Indications for use. It is used for replacement therapy in children with deficienry of growth hormone and for anaboliceffectsin burn victims. e. Side effects and toxicity. Adversereactions include gigantism in children, acromegaly in adults,and diabetes-likesymptoms. f. Bromocriptine, a dopaminergic receptor agonist, has been used as an adjunct to octreotide to lower plasma levelsof growth hormone in acromegaly.Adversereactions include nauseaand vomiting, arrhythmias,hypotension,and paranoia/psychosis. 2. Prolactin a. Regulation of secretion. The secretion of prolactin is inhibited by dopamine; TRH stimulates secretion. Drugs that increase prolactin secretion include antipsychotics (e.g.,chlorpromazine,haloperidol) and catecholaminedepletors(e.g.,guanethedine). b. Physiologic effects. Prolactin promotes milk production in the postpartum breast. High levelsof prolactin inhibit the releaseof gonadotropin, thus inhibiting ovulation. c. Bromocriptine suppressesprolactin secretion by stimulating dopaminergic receptors. It is usedto treat women with hyperprolactinemia-inducedamenorrheaor galactorrhea. It is also usedto treat pituitary adenomasthat secreteprolactin. 3. Gonadotropic hormones. Secretion of estrogens,progesterone,and testosteroneare under control of the pituitary gonadotropins,FSH and LH, which are regulatedby GnRH from the hypothalamus. GnRH, FSH, and LH are also under negativefeedbackcontrol of the gonadalhormones. a- Follicle-stimulatinghormone (FSH) is a glycoproteinhormone produced and secreted by gonadotropic cells of the anterior pituitary. Secretion is regulated by the concentrationsof reproductivehormones. It actsvia the secondmessengercAMP. (1) In women, FSH causesmaturation of the ovarian follicle; plasmalevelsincrease during the follicular phase of the menstrual cycle, decreaseslowly, and then increase at midcycle; the lowest levels occur during the luteal phase. Together with LH, it causesfinal maturation of the corpus luteum.

In a Nubhell Bromocriptine, a dopaminergic receptor agonisl hasbeenusedto: . Lower serumCHlevels . Lower serum PRLlevels . Inhibit lactation Adverse reactions include nausea, vomiting, arrhythmias, hypotension, andparanoia.

In a Nubhell Infemales, FSHcauses granulosa cellsto synthesize estrogen andcauses follicles to mature. ln males, FSH causes spermatogenesis.

(2) In men, FSH promotes spermatogenesis.

28t

Endocrine System

In a Nutshell . Infemales, theLHsurge triggers ovulation andLH stimulates thecorpus luteum to produce progesterone. . Inmales, LHstimulates testosterone synthesis by Leydig cells.

Note hCCissecreted bythe placenta, anditspresence is diagnostic of pregnanoT.

b. Luteinizing hormone (LH) is a glycoprotein hormone similar in structure to FSH. It is secretedby gonadotrophiccellsof the anterior pituitary. It actsthrough cAMP; LH action on the ovary may alsobe associatedwith increasedinositol 1,4,5-triphosphate(IP3). (1) In women, LH levels peak at midrycle to induce ovulation and the initial formation of the corpus luteum. This pulse is induced by the positive feedbackof estradiol. (2) In men, LH activatesinterstitial cellsto secretetestosterone. c. Human chorionic gonadotropin (hCG) is a glycoprotein hormone secreted by syncytiotrophoblastsof the fetal placenta.It promotes growth of the corpus luteum and preventsmenstruation.It is usedas a pregnancytest, detectableby immunoassay in urine or blood before the first missedmenstrual period. d. Specific agents related to the gonadotropins. Menotropins are a mixture of partially degradedFSH and LH given to infertile women to induce maturation of the follicle. It is usually followed by HCG to induce ovulation. Adversereactionsare due to overstimulation of the ovaries,producing multiple pregnancies,enlargementof the ovaries,and ovarian rysts.In infertile men, menotropins are given after HCG therapy to induce spermatogenesis. 4. Thyroid-stimulating hormone (TSH) is a peptide that binds to cell membrane receptors on the thyroid gland to increaseiodide uptake and the synthesisand secretionof thyroid hormones. Its secretion is enhancedby TRH and is reduced by negative feedback of thyroxine (Ta) and triiodothyronine (T3). a. Physiologic effects.Activation of the TSH receptor produces an increasein cAMR diacylglycerol,IP3, and intracellular calcium. b. Indications for use. TSH is availablefor diagnosisof thyroid function and to increase the uptakeof iodine 131 (13lI) in certaincasesof thyroid carcinoma. 5. Adrenocorticotropic hormone (ACTH, corticotropin) is synthesizedand secretedby the anterior pituitary. Its secretion is stimulated by CRH and is reduced by negativefeedback control of corticosteroids.

Flashback to Pathology primary ACIHcandistinguish fromsecondary adrenal insufficiency. Failure to respond toexogenous AC|Hindicates thattheadrenals themselves (primary). have failed

a. Physiologic effects. ACTH stimulates the human adrenal cortex to secretecortisol and, to a lesserextent, aldosteroneand androgens.ACTH binds to cell membrane receptorsto stimulate adenylatecyclase,leadingto an increasein activity of cholesterol esterase,which catalyzesthe rate-limiting step in steroid hormone synthesis.It also increasesthe cytochrome P-450 enryme system responsiblefor the production of pregnenolone.ACTH actsas a growth factor to the adrenalcortex. b. Indications for use. Usesof ACTH include the diagnosisof primary adrenal insufficiency,therapy of secondaryadrenal insufficiency,and nonendocrine illnesses,such as multiple sclerosis.Cosyntropin, an active synthetic analog, is lessantigenic and is preferred for the diagnosisof adrenalfunction.

THYROID ANDANTITHYROID DRUGS The thyroid gland secretesthree hormones: calcitonin, which is important in calcium homeostasis;and triiodothyronine (Tr) and thyroxine (Ta), which are important in growth and generalmetabolic function.

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Pharmacology

A. Thyroid drugs. Tn and T, are iodine-containing hormones that are analogsof tyrosine. 1. Regulation of thyroid function. Thyroid function is regulatedby TSH, which increases both the synthesisand secretionof thesehormones. TSH secretionis regulatedby negative feedback of the thyroid hormones; it is positively influenced by TRH from the hlpothalamus. 2. Thyroid hormone synthesis a. Iodide is necessaryfor thyroid hormone synthesis.Iodide is obtained from the diet (e.g.,seafood)and is absorbedfrom the gastrointestinaltract. It is taken up by the thyroid gland by an activecotransportprocessinvolving potassium. b. Once in the gl*d, iodide is oxidized via peroxidaseto an active iodine intermediate, which iodinates tyrosine residuesof thyroglobulin (a glycoprotein).An aerobiccondensation of iodinated tyrosine moleculesresultsin production of T, and Tn. Subsequently, proteolysisof thyroglobutin causesreleaseof thyroid hormones into the blood. 3. Kinetic properties. Over 99o/oof T, and T, are bound to plasma proteins, most to thyroid-binding globulin. The hormones are deiodinatedand conjugatedin the liver to form sulfatesand glucuronides.They are excretedin the bile and urine. Tn has a half-life of 6-7 days;T, has a half-life of I-2 days.Some of the circulating Tn is deiodinated to T' the more potent and rapidly acting form. 4. Mechanism of action. Most of the effectsof thyroid hormones stem from activation of nuclear nonhistone protein receptors attached to DNA. Binding of hormone to the receptorleadsto increasedtranscription of messengerRNA (mRNA), thus increasingthe synthesisof specific proteins. T, is ten times more potent for binding to the nuclear receptor.The hormone may also bind to receptorson cell membranesto increaseamino acid and glucoseuptake and to receptorson the inner mitochondrial membrane to regulate energy metabolism.

Flashbackto Physiology Refer backto Figure lll-3-7 to review hormone thyroid biosynthesis.

Flashback to Physiology . T, ismuchmore potent thanTo. . T, hasa shorter half-life thanTo. . T, isboundlessto TBCthanTo.

5. Physiologic effects.Thyroid hormones produce effectsin most major systems,including normal growth and development,increasedbasal metabolic rate, and activation of oxygen consumption. The hormones havea thermogeniceffect (increasedheat production), they causeincreasedplasmaglucoseand free fatty acids,and causea reduction in plasma cholesteroland triglycerides.Increasedcardiovascularactivity, increasedheart rate, and maturation of the CNS are also effectedby thyroid hormones. 6. Specific agents used in the treatment of hypothyroidism. Thyromimetic agents,from animal or synthetic sources,are indicated as replacementtherapy for the treatment of hypothyroidism and to suppressTSH secretion.The levo isomers are more potent in increasing basal metabolic rate. They are all available orally; levothyroxine is also available by injection. Once absorbed,their pharmacokinetic and dynamic properties are identical to endogenousthyroid hormones. Adversereactionsinclude hyperthyroidism (or symptoms of hyperthyroidism), cardiovasculartoxicity (tachyarrhythmias,angina, and infarction are possible),CNS stimulation, and insomnia. a. Levothyroxine sodium is the synthetic levo isomer of T4. It is available for oral or intravenousadministration. It is the preferred drug for treatment of hypothyroidism as a result of better standardizationand stability and long duration. The long half-life of Tn greatly facilitatesmaintenanceof a steadyphysiologic replacementof thyroid hormone. b. Liothyronine sodium is synthetic r-triiodothyronine. It is more difficult to monitor than Tn, is more expensive,and has a shorter duration of action. c. Liotrix is a combination of levothyroxineand liothyronine (at a ratio of 4:1). It hasno advantageover levothyroxine.

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Endocrine System

B. Antithyroid drugs inhibit the formation of thyroid hormones and are used in the treatment of hyperthyroidism. 1. Iodine. Although small amounts of iodine (75-100 pglday) are required for hormone synthesis,high concentrations( 50+ mg/day) produce autoinhibition. a. Pharmacologic properties. Iodine blocks the uptake of iodide by the thyroid, inhibiting synthesisand releaseof thyroid hormones. It alsodiminishesvascularityof the gl*d. b. Indications for use.Iodine is used only preoperatively to shrink the gland in preparation for surgical removal of the thyroid gland, and in the treatment of thyroid storm. It is given as Lugol solution (iodine and potassiumiodide). Effectsare visible within 24 hours. It is no longer used in long-term therapy. c. Side effects and toxicity. Adverse reactions include hypersensitivity and dose-related effects,such as"head cold" symptoms,gastricirritation, and parotitis. Long-term use can lead to sudden disinhibition of hormone synthesis,producing acute hyperthyroidism.

Note Bothmethimazole andPTU inhibit incorporation of iodine intothyroid hormone precursors. However, only PTUinhibits theperipheral conversion ofTo+ Tr.

Clinical Conelate PTUispreferred to methimazole in pregnancy because it ismoreextensively protein-bound (80versus 8o/o formethimazole) andless likely to cross theplacenta.

2. Thioamides: propylthiouracil (PTU) and methimaz,ole a. Mechanism of action. These drugs inhibit the peroxidase enzymes catalyzing the oxidation of iodide and the coupling of iodinated tyrosyl groups, thus reducing the synthesisof thyroid hormones. PTU also inhibits the peripheral deiodination of Ta to T3. There is a delay in onset of clinical effectivenessuntil preformed hormones have been metabolized. b. Indications for use. These drugs are used for control of hyperthyroidism until surgery,in the suppressionof thyroid hormone synthesisuntil the effect of radioactive iodide begins, and in the long-term therapy of mild-to-moderate hyperthyroidism. The drugs are given orally. c. Side effects and toxicit''. Most common adversereactions include mild maculopapular rash, joint pain, headache,nausea,and loss of hair. Although extremely rare, the most serious side effect is agranulocytosis.The drugs cross the placenta and enter breast milk, which can lead to hypothyroidism in the fetus and nursing infant. 3. Radioactiveiodine (t3t1, a. Pharmacologic properties. Given orally or intravenously, l3l1 ir rapidly taken up by the thyroid gland, where it is incorporated into thyroglobulin. With proper doses, 131Ileadsto partial or total destruction of the gland by emission of beta particles. Damageto surrounding tissueis minimal.

Note

b. Indications for use. 131Iis used in the treatment of hyperthyroidism.

Radioactive iodine isvery effective in treatment of hyperthyroidism because the iodine in selectively takenup bythegland's follicular cells.

c. Side effects and toxicity. The major adversereaction due to overdosageis a delayed incidenceof hypothyroidism. 1311r6on1dbe avoidedduring pregnancy.

286

4. Propranolol and other p-adrenergicreceptorblockersare usedasadjuncts in the treatment of hyperthyroidism. They reduce the symptoms of the disease(e.g.,tachycardia,anxiety) until the antithyroid drugs can take effect.Propranol alsoinhibits the peripheral conversion of Ta to T3 via 5'deiodinase.

Pharmacology

DRUGS A1TERING HOMEOSTASIS CALCIUM A. Calcium 1. Physiologic effects a. Calcium concentrationin blood is maintained within narrow limits. Calcium existsin three forms: 50o/oionized, 40o/obound to protein (especiallyto albumin), and 10o/o complexed to anions. Approximately l0-20o/o of. daily intake is absorbed from the proximal intestine, with an equal amount excretedby the kidney. Calcium levels are regulatedby calcitonin, PTH, and vitamin D (TableIII-5-1). Thble III-5-1. Effect of calcitonin, parathyroid hormone (PTH), and vitamin D on calcium homeostasis. Intestinal Absorption of Calcium

Calcitonin J Postprandial

Renal Excretion of Calcium

t

PTH

t Indirectdueto J increase in 1,25(oH)2D3

Vitamin D

t

I (minor)

Bone

Effect on Plasma Calcium

t Mineralization J Resorption

J

l Resorption

1

t Mineralization t Resorption

t

b. Calcium is vital for many cellular functions, including: ( 1) Developmentof bone and teeth (2) Control of enzyme activity (3) Blood coagulation (4) Excitability of nerve and muscle,including cardiac muscle (5) Excitation-contractioncoupling (6) Tiansmembranesignaling/neurotransmitterrelease (7) Cardiovascularfunction 2. Specific agents a. Calcium chloride contains 25o/ocalcium. It is given slowly. High concentrations can causesyncopewith vasodilatationand hypotension.Becauseof the salt, it is not the drug of choicein renal insufficienry. b. Calcium gluconate, containing 9o/ocalcium, is available for oral or intravenous administration. It is used for severetetany. It is also usefrrl for treating severehyperkalemia. c. Calcium carbonate, calcium lactate, and tricalcium phosphate are all used in the treatment of hypocalcemiaand in the prevention and treatment of osteoporosis.

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Endocrine System

B. Phosphate 1. Physiologic effects. Phosphatehelps maintain acid-baseequilibrium, buffers and allows for renal H+ excretion,helps regulatecalcium metabolism,and is an activeintermediate of energymetabolism.Approximately 670/oof an oral doseis absorbedfrom the intestine. Excretion is via the kidney. 2. Indications for use.Various preparationsof sodium phosphateare availablefor a cathartic action and in the treatment of hypercalcemiaand hypophosphatemia. 3. Sideeffectsand toxicity. The major adversereactionof intravenousinfusion for the treatment of hypercalcemiais metastaticcalcificationof soft tissues. C. Parathyroid hormone (PTH) is synthesizedby the parathyroid gland as a preprohormone. 1. Regulation of secretion. Secretionis regulatedby Ca2+concentration in the blood; low freeCa2+stimulatesan increasein PTH secretion. 2. Mechanism of action involves the binding to cell membrane receptors, leading to increasedcAMP. PTH increasesCa2+concentrationbv: a. Increasingcalcium resorption from bone b. Enhancing renal tubular reabsorption of calcium c. Indirectly increasinggastrointestinalabsorption of calcium by enhancingthe production of the activeform of vitamin D 1,25(OH),D? 3. Indications for use a. PTH is a peptide and, thus, must be given parenterally.

ln a Nutshell Calcitonin . Lowers serum calcium . lnhibits boneresorption by osteoclasts . Blocks andphosphate Ca2* release frombone

b. Human PTH is not used clinically becauseadministration of vitamin D and calcium to raise calcium concentrationis safer.A synthetic human hormone is used diagnostically to distinguish between hypoparathyroidism and pseudohypoparathyroidism. Patientswith pseudohypoparathyroidismdo not respond to the synthetichormone. D. Calcitonin is secretedby the parafollicular (C cells) of the thyroid gland. High blood calcium levelsreducethe secretionof calcitonin. 1. Physiologic effects. In general, calcitonin has opposite effects of PTH: it decreasesthe concentration of serum calcium, inhibits bone resorption, and increasesrenal calcium excretion.Although it hasno major effecton the gastrointestinaltract, it may inhibit postprandial calcium absorption. 2. Indications for use include hypercalcemia,hyperparathyroidism, vitamin D toxicity, Paget disease(to reduce bone turnover), bone tumors, and osteoporosis.Human and salmon preparationsare available. 3. Sideeffectsandtoxicity. Adversereactionsinclude hypersensitivityreactionand hypocalcemia. E. Vitamin D 1. Synthesis.Vitamh D, (cholecalciferol) is produced in skin from 7-dehydrocholesterol and requiresthe presenceof ultraviolet light. In the liver, vitamin D, is hydroxylatedto 25-hydroxy-D, (calcifediol),which is convertedin the kidney to 1,25(OH)rD, (calcitriol), the most activeform of the vitamin. PTH increasesthe activity of the hydroxylaseenzyme responsiblefor the final step. 2. Mechanism of action. Calcitriol actsby binding to nuclear receptorsto alter gene expression and initiate protein synthesis.

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Pharmacology

3. Physiologic effects. Vitamin D stimulates intestinal absorption of calcium and phosphate, increasesbone resorption and mineralization, and increasesrenal reabsorptionof calcium and phosphate.The net effect is to increase plasma calcium and phosphate. 4. Indications for use include hypocalcemiadue to rickets,hypoparathyroidism,and osteomalacia. 5. Side effectsand toxicity. The major adversereaction is hypercalcemia. 6. Specific agents. Preparations available orally include: calcitriol, calcifediol, cholecalciferol, dihydrotachysterol (vitamin D2 analog), and ergocalciferol (vitamin Dz). The choiceof agentdependson the causeof the disorder. F. Other agents 1. Glucocorticoids reduce calcium absorption from the gastrointestinaltract and increase renal calcium excretion.They are used in the treatment of hypercalcemia. 2. Diphosphonates (etidronate disodium, pamidronate disodium) are analogs of pyrophosphate used in the treatment of hypercalcemiaof malignancy, Paget disease, osteoporosis,and hyperparathyroidism.They bind to hydroxyapatitecrystals,reducing their formation, growth, and dissolution,thereby reducingbone turnover. 3. Plicamycin (mithramycin) is a cytotoxic antibiotic that inhibits osteoclastfunction and bone resorption by inhibiting DNA-directed RNA synthesis,thereby reducing plasma calcium. It is used to treat Pagetdiseaseand hypercalcemiasecondaryto malignancy. 4. Fluoride stimulatesbone formation when administeredwith calcium. It is accumulated by bones and teeth and stabilizesthe hydroxyapatitecomplex.Fluoride is substitutedfor the hydroxyl group. It is used in the treatment of osteoporosis.Adversereactionsdue to the ability of fluoride to bind calcium include nausea,vomiting, arthralgias,and arthritis. Extreme overdosecan causecardiovascularcollapseor respiratory failure by inducing hypocalcemia. 5. Estrogens inhibit bone resorption and are used in the treatment of postmenopausal osteoporosis. The pharmacology of estrogen is described in the Reproductive Pharmacologychapter of this book.

ISTS ANTAGON ANDTHEIR CORTICOSTEROIDS The term corticosteroidsdesignatessteroid hormones normally secretedby the adrenalcortex; these include glucocorticoids(cortisol), mineralocorticoids(aldosterone),and androgens ( dihydroepiandrosterone, DHEA). A. Glucocorticoids are natural and syntheticsteroidsthat alter glucosemetabolism. 1. Regulation of secretion. Cortisol is the principal naturally occurring hormone in humans, which is synthesizedin the zona fasciculata.Plasmaconcentrationsare highest between6-8 e.v. Synthesisand releaseare stimulated by ACTH, via a negativefeedback mechanism. 2. Mechanism of action. Glucocorticoidsenter target cellsby simple diffrrsion and bind to cytosolicreceptors.The steroid-receptorcomplex is translocatedinto the nucleus,where it regulatesthe synthesisof specificproteins. 3. Physiologic effects a. Glucocorticoidsinfluence carbohydrateand fat metabolismto ensureadequatedelivdecreaseperipheral use of ery of glucoseto the brain: they increasegluconeogenesis, (increased lipolysis). glucose,and increasefree fatty acids

ln a Nutshell bone inhibit Diphosphonates (major of store turnover serum decreasing calcium), levels. calcium Note for Fluoride substitution groups in hydroxyl this makes hydroxyapatite boneandtoothmineral to degradation. resistant ClinicalCorrelate isthe Estrogen replacement preventive for therapy favored Calcium osteoporosis. oftengivenin supplements D withvitamin combination risk reduce thefracture further dueto boneloss. Flashbackto Histology cortex Adrenal outside I | I I I I I V inside

zonuglomerulosa -+ aldosterone (salt) -+ Zonafasciculata (sugar) glu.ocorticoids Zonareticularis --+androgens (sex)

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b. They decreaseabsorption of calcium from the intestineand increaserenal excretionof calcium. c. Glucocorticoidsproduce redistribution of fat from the extremitiesto the trunk and face (buffalo neck). d. Glucocorticoidsfavor protein breakdown and help mobilize amino acids to the liver for gluconeogenesis.

ln a Nutshell Clucocorticoid effects include: . Anti-inflammatory actions . t Serum glucose (enhance gluconeogenesis) . Protein catabolism . lmmune suppression

e. Glucocorticoids have anti-inflamnatory and immunosuppressant activity. They increasecirculating levelsof neutrophils by interfering with adhesion,and they decrease eosinophils,lymphocytes,and monocytes.They decreaselocal edema,fibrin deposition, capillary dilatation, leukocyte migration, and phagocytic activity. Glucocorticoids indirectly inhibit phospholipaseAr-mediated arachidonic acid releaseby increasing the synthesisof lipocortins. The end result is decreasedproduction of prostaglandins, thromboxanes,and leukotrienes. f. Glucocorticoids may also alter mood, sleeppatterns, and EEG activity. 4. Specific agents. Preparations are available for oral, topical, and injectable routes of administration. A comparison of clinically useful corticosteroidsis presentedin Table tII-s-2. ?able lll- 5-2. Commonly used corticosteroids.

Note

Corticosteroids

Cortisone andcortisol have somemineralocorticoid activity, butmuchlessthan aldosterone. Prednisone is activated bytheliverto prednisolone. Beclomethasone potent isa long-acting, glucocorticoid.

Glucocorticoids Short-acting Hydrocortisone (cortisol) Cortisone Intermediate-acting Prednisone Prednisolone Methylprednisolone Triamcinolone Long-acting Dexamethasone

Biologic Half-Life 8-12 hours

18-36 hours

36-54 hours

Mineralocorticoid Fludrocortisone Available as aerosol for treatment of bronchial asthma Beclomethasone Flunisolide

5. Indications for use. In general,drugs with mixed glucocorticoid and mineralocorticoid activity (e.g.,cortisol) are used in replacementtherapy.Intermediate-actingdrugs with minimal mineralocorticoid effect (e.g., prednisone, prednisolone) are used as antiinflammatory and immunosuppressantagentswhen long-term therapy is needed.Doses are gradually reducedwhen the patient is to be taken off the drug. Long-acting,potent steroids (e.g.,dexamethasone)are used mostly for acute,severeconditions. Therapeutic usesof corticosteroidsinclude: a. Replacementtherapy for adrenalinsufficiency

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Pharmacology

b. Treatmentfor: (1) Allergic disorderssuch as anaphylacticreactionsand statusasthmaticus (2) Collagen vascular disorders and other autoimmune conditions, including systemic lupus erythematosus,rheumatoid arthritis, scleroderma,polymyositis, dermatomyositis, polyarteritis nodosa, polymyalgia rheumatica, myasthenia gravis,multiple sclerosis,and temporal arteritis (3) Hematologic disorders,including immunologically mediated aplastic anemia, thrombocytopenicpurpura, acutelymphoblasticleukemia,chronic lymphocytic leukemia, Hodgkin disease,and multiple myeloma (4) Cerebraledema (5) Dermatologic disease (6) Gastrointestinaldisorders,such as inflammatory bowel disease (7) Hypercalcemia (8) Renal disease,including nephrotic syndrome, membranous nephropathy,and focal sclerosis (9) Respiratorydisorders,such assarcoidosis,chronic obstructivepulmonary disease (COPD), hypersensitivity reactions, pneumonitis, and idiopathic pulmonary fibrosis c. Diagnosisof Cushing disease(dexamethasonesuppressiontest) d. Cancerchemotherapy 6. Side effects and toxicity. Adverse reactions depend upon the route of administration (topical versussystemic),dose,and duration of therapy. a. Metabolic disorders, such as hyperglycemia, glycosuria, negative nitrogen balance, fat redistribution, and mineralocorticoid effects (sodium and water retention, hypokalemia,metabolic alkalosis)

ln a Nubhell of Cofticosteroids SideEffects . Hyperglycemia . Hypertension

b. Hypertension (from sodium and water retention and increasedplasmarenin)

. Easy bruising

c. Endocrine disorders,such as suppressionof hypothalamic-pituitary-adrenal axis (leading to adrenalinsufficiency),atrophy of adrenalcortex (from which it may take a year to fully recover),growth retardation in children, and secondaryamenorrhea

. Cataracts

d. Dermatologic disorders,such as hirsutism, skin thickening, poor wound healing, acne, and purpura e. Ocular disorders,such ascataracts(from hyperglycemia)and glaucoma(from salt and water retention)

. Osteoporosis . Myopathy . Dysphoria/psychosis . Cushingoid habitus

f. Gastrointestinaldisorders,such as peptic ulceration, pancreatitis,and perforation of colonic diverticula g. Musculoskeletal disorders, such as myopathy, osteoporosis,and aseptic necrosis (osteonecrosis) h. CNS reactions,including psychiatricsymptoms (elation, mania, psychosis)and pseudotumor cerebri (benign intracranial hypertension) i. Increasedsusceptibilityto infection

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Endocrine System

In a Nutshell Adverse effects of chronic use of syste mic glucocorticoids stemfrom: . Suppression andatrophy of pituitary corticotrophs and adrenal fasciculata and reticularis zones . Symptoms associated with glucocorticoid excess systemic effects These adverse effects canbe minimized by:/) Using topical applications, not possible; systemic, whenever 2) lf systemic useisrequired: . Usea short(