InternalMed_Harrison

InternalMed_Harrison. arTHrOPaTHIES aSSOCIaTED WITH HEMOGLOBINOPaTHIES Sickle Cell Disease Sickle cell disease (Chap. 127) is associated with several musculoskeletal abnormalities (Table 397-1). Children under the ageof 5 yearsmay develop diffuse swelling, tenderness, and warmth of the hands and feet lasting 1–3 weeks. This condition, referred to as sickle cell dactylitis or hand-foot syndrome, has also been observed in sickle cell thalassemia. Dactylitis is believed to result from infarction of the bone marrow and cortical bone leading to periostitis and soft tissue swelling. Radiographs show periosteal elevation, subperiosteal new-bone formation, and areas of radiolucency and increased density involving the metacarpals, metatarsals, and proximal phalanges. These bonechangesdisappearafterseveralmonths.Thesyndromeleaveslittle ornoresidual damage.Becausehematopoiesisceases inthe small bones of the hands and feet with age, the syndrome is rarely seen after age 5.


InternalMed_Harrison

InternalMed_Harrison. Sickle cell crisis is associated with periarticular pain and occasionally with joint effusions. The joint and periarticular area are warm and tender. Knees and elbows are most often affected, but other joints can be involved. Joint effusions are usually noninflammatory. Acute synovial infarction can cause a sterile effusion with high neutrophil counts in synovial fluid. Synovial biopsies have shown mild lining-cell proliferation and microvascular thrombosis with infarctions. Scintigraphic studies have shown decreased marrow uptake adjacent to the involved joint. The treatment for sickle cell crisis is detailed in Chap. 127.


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InternalMed_Harrison. Patients with sickle cell disease seem predisposed to osteomyelitis, which commonly involves the long tubular bones (Chap. 158); Salmonella is a particularly common cause (Chap. 190). Radiographs of the involved site initially show periosteal elevation, with subsequent disruption of the cortex. Treatment of the infection results in healing of the bone lesion. In addition, sickle cell disease is associated with bone infarction resulting from vaso-occlusion secondary to the sickling of red cells. Bone infarction also occurs in hemoglobin sickle cell disease and sickle cell thalassemia (Chap. 127). The bone pain in sickle cell crisis is due to infarction of bone and bone marrow. In children, infarction of the epiphyseal growth plate interferes with normal growth of the affected extremity. Radiographically, infarction of the bone cortex results in periosteal elevation and irregular thickening of the bone cortex. Infarction in the bone marrow leads to lysis, fibrosis, and new bone


InternalMed_Harrison

InternalMed_Harrison. Radiographically, infarction of the bone cortex results in periosteal elevation and irregular thickening of the bone cortex. Infarction in the bone marrow leads to lysis, fibrosis, and new bone formation. Clinical distinction between osteomyelitis and bone infarctions can be difficult; imaging can be helpful.


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InternalMed_Harrison. Avascular necrosis of the head of the femur occurs in ~5% of patients. It also occurs in the humeral head and less commonly in the distal femur, tibial condyles, distal radius, vertebral bodies, and other juxtaarticular sites. Irregularity of the femoral head and other articular surfaces often results in degenerative joint disease. Radiography of the affected joint may show patchy radiolucency and density followed by flattening of the bone. MRI is a sensitive technique for detecting early avascular necrosis as well as bone infarction elsewhere. Total hip replacement and placement of prostheses in other joints may improve function and relieve joint pain in these patients. Septic arthritis is occasionally encountered in sickle cell disease (Chap. 157). Multiple joints may be infected. Joint infection may result from bacteremia due to splenic dysfunction or from contiguous Joint effusions in sickle cell crises Bone changes secondary to marrow hyperplasia


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InternalMed_Harrison. Joint effusions in sickle cell crises Bone changes secondary to marrow hyperplasia Infarction of bone Gouty arthritis Infarction of bone marrow osteomyelitis.ThemorecommonmicroorganismsincludeStaphylococcus aureus,Streptococcus,and Salmonella.Salmonella doesnotcauseseptic arthritis as frequently as it causes osteomyelitis. Acute gouty arthritis is uncommon in sickle cell disease, even though 40% of patients are hyperuricemic. However, it may occur in patients generally not expected to get gout (young patients, female patients). Hyperuricemia is due to overproduction of uric acid secondary to increased red cell turnover as well as suboptimal renal excretion. Attacks may be polyarticular, and diagnostic arthrocentesis should be performed to distinguish infection from gout or synovial infarction.


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InternalMed_Harrison. The bone marrow hyperplasia in sickle cell disease results in widening of the medullary cavities, thinning of the cortices, and coarse trabeculations and central cupping of the vertebral bodies. These changes are also seen to a lesser degree in hemoglobin sickle cell disease and sickle cell thalassemia. In normal individuals red marrow is located mostly in the axial skeleton, but in sickle cell disease red marrow is found in the bones of the extremities and even in the tarsal and carpal bones. Vertebral compression may lead to dorsal kyphosis, and softening of the bone in the acetabulum may result in protrusio acetabuli.


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InternalMed_Harrison. Thalassemia A congenital disorder of hemoglobin synthesis, β thalassemia is characterized by impaired production of β chains (Chap. 127). Bone and joint abnormalities occur in β thalassemia, being most common in the major and intermedia groups. In one study, ~50% of patients with β thalassemia had evidence of symmetric ankle arthropathy characterized by a dull aching pain that was aggravated by weight bearing. The onset came most often in the second or third decade of life. The degree of ankle pain in these patients varied. Some patients experienced self-limited ankle pain that occurred only after strenuous physical activity and lasted several days or weeks. Other patients had chronic ankle pain that became worse with walking. Symptoms eventually abated in a few patients. Compression of the ankle, calcaneus, or forefoot was painful in some patients. Synovial fluid from two patients was noninflammatory. Radiographs of the ankle showed osteopenia, widened medullary spaces, thin


InternalMed_Harrison

InternalMed_Harrison. of the ankle, calcaneus, or forefoot was painful in some patients. Synovial fluid from two patients was noninflammatory. Radiographs of the ankle showed osteopenia, widened medullary spaces, thin cortices, and coarse trabeculations— findings that are largely the result of bone marrow expansion. The joint space was preserved. Specimens of bone from three patients revealed osteomalacia, osteopenia, and microfractures. Increased numbers of osteoblasts as well as increased foci of bone resorption were present on the bone surface. Iron staining was found in the bone trabeculae, in osteoid, and in the cement line. Synovium showed hyperplasia of lining cells, which contained deposits of hemosiderin. This arthropathy was considered to be related to the underlying bone pathology. The role of iron overload or abnormal bone metabolism in the pathogenesis of this arthropathy is not known. The arthropathy was treated with analgesics and splints. Patients also received transfusions to decrease


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InternalMed_Harrison. overload or abnormal bone metabolism in the pathogenesis of this arthropathy is not known. The arthropathy was treated with analgesics and splints. Patients also received transfusions to decrease hematopoiesis and bone marrow expansion.


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InternalMed_Harrison. In patients with β-thalassemia major and β-thalassemia intermedia, other joints are also involved, including the knees, hips, and shoulders. Acquired hemochromatosis with arthropathy has been described in a patient with thalassemia. Gouty arthritis and septic arthritis can occur. Avascular necrosis is not a feature of thalassemia because there is no sickling of red cells leading to thrombosis and infarction.


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InternalMed_Harrison. β-Thalassemia minor (also known as β-thalassemia trait) is likewise associated with joint manifestations. Chronic seronegative oligoarthritis affecting predominantly ankles, wrists, and elbows has been described; the affected patients had mild persistent synovitis without large effusions or joint erosions. Recurrent episodes of acute asymmetric arthritis have also been reported; episodes last <1 week and may affect the knees, ankles, shoulders, elbows, wrists, and metacarpal phalangeal joints. The mechanism underlying this arthropathy is unknown. Treatment with NSAIDs is not particularly effective.


InternalMed_Harrison

InternalMed_Harrison. (See also Chap. 421) Musculoskeletal or cutaneous manifestations may be the first clinical indication of a specific hereditary disorder of lipoprotein metabolism. Patients with familial hypercholesterolemia (previously referred to as type II hyperlipoproteinemia) may have recurrent migratory polyarthritis involving the knees and other large peripheral joints and, to a lesser degree, peripheral small joints. Pain ranges from moderate to incapacitating. The involved joints can be warm, erythematous, swollen, and tender. Arthritis usually has a sudden onset, lasts from a few days to 2 weeks, and does not cause joint damage. Episodes may suggest acute gout attacks. Several attacks occur per year. Synovial fluid from involved joints is not inflammatory and contains few white cells and no crystals. Joint involvement may actually represent inflammatory periarthritis or peritendinitis and not true arthritis. The recurrent, transient nature of the arthritis may suggest rheumatic fever,


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InternalMed_Harrison. crystals. Joint involvement may actually represent inflammatory periarthritis or peritendinitis and not true arthritis. The recurrent, transient nature of the arthritis may suggest rheumatic fever, especially because patients with hyperlipoproteinemia may have an elevated erythrocyte sedimentation rate and elevated antistreptolysin O titers (the latter being quite common). Attacks of tendinitis, including the large Achilles and patellar tendons, may come on gradually and last only a few days or may be acute as described above. Patients may be asymptomatic between attacks. Achilles tendinitis and other joint manifestations often precede the appearance of xanthomas and may be the first clinical indication of hyperlipoproteinemia. Attacks of tendinitis may follow treatment with a lipid-lowering drug. Over time, patients may develop tendinous xanthomas in the Achilles, patellar, and extensor tendons of the hands and feet. Xanthomas have also been reported in the peroneal tendon, the


InternalMed_Harrison

InternalMed_Harrison. drug. Over time, patients may develop tendinous xanthomas in the Achilles, patellar, and extensor tendons of the hands and feet. Xanthomas have also been reported in the peroneal tendon, the plantar aponeurosis, and the periosteum overlying the distal tibia. These xanthomas are located within tendon fibers. Tuberous xanthomas are soft subcutaneous masses located over the extensor surfaces of the elbows, knees, and hands as well as on the buttocks. They appear during childhood in homozygous patients and after the age of 30 in heterozygous patients. Patients with elevated plasma levels of verylow-density lipoprotein (VLDL) and triglycerides (previously referred to as type IV hyperlipoproteinemia)may also have a mild inflammatory arthritis affecting large and small peripheral joints, usually in an asymmetric pattern, with only a few joints involved at a time. The onset of arthritis usually comes in middle age. Arthritis may be persistent or recurrent, with episodes lasting a few days or


InternalMed_Harrison

InternalMed_Harrison. in an asymmetric pattern, with only a few joints involved at a time. The onset of arthritis usually comes in middle age. Arthritis may be persistent or recurrent, with episodes lasting a few days or weeks. Some patients may experience severejointpainor morning stiffness.Joint tenderness and periarticular hyperesthesia may also be present, as may synovial thickening.Jointfluidisusuallynoninflammatoryandwithoutcrystals but may have increased white blood cell counts with predominantly mononuclear cells. Radiographs may show juxtaarticular osteopenia and cystic lesions. Large bone cysts have been noted in a few patients. Xanthoma and bone cysts are also observed in other lipoprotein disorders. The pathogenesis of arthritis in patients with familial hypercholesterolemia or with elevated levels of VLDL and triglycerides is not well understood. NSAIDs or analgesics usually provide adequate relief of symptoms when used on an as-needed basis.


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InternalMed_Harrison. Patients may improve clinically as they are treated with lipid-lowering agents; however, patients treated with an HMG-CoA reductase inhibitor may experience myalgias, and a few patients develop myopathy, myositis, or even rhabdomyolysis. Patients who develop myositis during statin therapy may be susceptible to this adverse effect because of an underlying muscle disorder and should be reevaluated after discontinuation of the drug. Myositis has also been reported with the use of niacin (Chap. 388) but is less common than myalgias. Musculoskeletal syndromes have not clearly been associated with the more common mixed hyperlipidemias seen in general practice.


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InternalMed_Harrison. Musculoskeletal syndromes have not clearly been associated with the more common mixed hyperlipidemias seen in general practice. Neuropathic joint disease (Charcot joint) is a progressive destructive arthritisassociatedwithlossofpainsensation,proprioception,orboth. Normalmuscularreflexesthat modulatejointmovementareimpaired. Without these protective mechanisms, joints are subjected to repeated trauma, resulting in progressive cartilage and bone damage. Today, diabetes mellitus is the most frequent cause of neuropathic joint disease (Fig. 397-1). A variety of other disorders are associated with neuropathic arthritis, including tabes dorsalis, leprosy, yaws, syringomyelia, meningomyelocele, congenital indifference to pain, peroneal muscular atrophy (Charcot-Marie-Tooth disease), and amyloidosis. An arthritis resembling neuropathic joint disease has been reported in


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InternalMed_Harrison. FIGUrE 397-1 Charcot arthropathy associated with diabetes mel-litus. Lateralfootradiographdemonstratingcompletelossofthearchduetobonyfragmentationanddislocationinthemidfoot.(Courtesy of Andrew Neckers, MD, and Jean Schils, MD; with permission.) patients who have received intraarticular glucocorticoid injections, but thisisararecomplicationandwasnotobservedinoneseriesofpatients with knee osteoarthritis who received intraarticular glucocorticoid injections every 3 months for 2 years. The distribution of joint involvement depends on the underlying neurologic disorder (Table 397-2). In tabes dorsalis, the knees, hips, and ankles are most commonly affected; in syringomyelia, the glenohumeral joint, elbow, and wrist; and in diabetes mellitus, the tarsal and tarsometatarsal joints.


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InternalMed_Harrison. The pathologic changes in the neuropathic joint are similar to those found in the severe osteoarthritic joint. There is fragmentation and eventual loss of articular cartilage with eburnation of the underlying bone.Osteophytesarefoundatthejointmargins.Withmoreadvanced disease, erosions are present on the joint surface. Fractures, devitalized bone, intraarticular loose bodies, and microscopic fragments of cartilage and bone may be present.


InternalMed_Harrison

InternalMed_Harrison. At least two underlying mechanisms are believed to be involved in the pathogenesis of neuropathic arthritis. An abnormal autonomic nervous system is thought to be responsible for the dysregulated blood flowtothejoint withsubsequentresorptionofbone.Lossofbone,particularly in the diabetic foot, may be the initial finding. With the loss of deep pain, proprioception, and protective neuromuscular reflexes, the joint is subjected to repeated microtrauma, resulting in ligamental tearsandbonefractures.Theinjurythatfollowsfrequentintraarticular glucocorticoid injections is thought to be due to the analgesic effect of glucocorticoids, leading to overuse of an already damaged joint; the result is accelerated cartilage damage, although steroid-induced cartilage damage be more common in some other animal species than in humans. It is not understood why only a few patients with neuropathy develop clinically evident neuropathic arthritis.


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InternalMed_Harrison. Neuropathic joint disease usually begins in a single joint and then becomes apparent in other joints, depending on the underlying neurologic disorder. The involved joint becomes progressively enlarged as a result of bony overgrowth and synovial effusion. Loose bodies may be palpated in the joint cavity. Joint instability, subluxation, and crepitus occur as the disease progresses. Neuropathic joints may develop rapidly, and a totally disorganized joint with multiple bony fragments may evolve within weeks or months. The amount of pain experienced Meningomyelocele Congenital indifference to pain


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InternalMed_Harrison. Arthritis Associated with Systemic Disease, and Other Arthritides 2244 bythe patient is less than wouldbe anticipatedfrom the degree of joint damage.Patientsmay experiencesuddenjointpainfrom intraarticular fractures of osteophytes or condyles. Neuropathic arthritis is encountered most often in patients with diabetes mellitus, with an incidence of ~0.5%. The onset of disease usually comes at an age of ≥50 years in a patient who has had diabetes for several years, but exceptions occur. The tarsal and tarsometatarsal joints are most often affected, with the metatarsophalangeal and talotibial joints next most commonly involved. The knees and spine are occasionally involved. Patients often attribute the onset of foot pain to antecedent trauma such as twisting of the foot. Neuropathic changes may develop rapidly after a foot fracture or dislocation. The foot and ankle areoftenswollen. Downward collapseofthe tarsal bones leads to convexity of the sole, referred to as a “rocker foot.” Large


InternalMed_Harrison

InternalMed_Harrison. may develop rapidly after a foot fracture or dislocation. The foot and ankle areoftenswollen. Downward collapseofthe tarsal bones leads to convexity of the sole, referred to as a “rocker foot.” Large osteophytes may protrude from the top of the foot. Calluses frequently form over the metatarsal heads and may lead to infected ulcers and osteomyelitis. The value of protective inserts and orthotics, as well as regular foot examination, cannot be overstated. Radiographs may show resorption and tapering of the distal metatarsal bones. The term Lisfranc fracture-dislocation issometimes used to describe thedestructivechangesatthe tarsometatarsal joints.


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InternalMed_Harrison. The diagnosis of neuropathic arthritis is based on the clinical features and characteristic radiographic findings in a patient with underlying sensory neuropathy. The differential diagnosis of neuropathic arthritis depends upon the severity of the process and includes osteomyelitis, avascular necrosis, advanced osteoarthritis, stress fractures, and calcium pyrophosphate deposition disease. Radiographs in neuropathic arthritis initially show changes of osteoarthritis with joint space narrowing, subchondral bone sclerosis, osteophytes, and joint effusions; marked destructive and hypertrophic changes follow later. The radiographic findings of neuropathic arthritis may be difficult to differentiate from those of osteomyelitis, especially in the diabetic foot. The joint margins in a neuropathic joint tend to be distinct, while in osteomyelitis they are blurred. Imaging studies may be helpful, but cultures of tissue from the joint are often required to exclude osteomyelitis. MRI and bone


InternalMed_Harrison

InternalMed_Harrison. joint tend to be distinct, while in osteomyelitis they are blurred. Imaging studies may be helpful, but cultures of tissue from the joint are often required to exclude osteomyelitis. MRI and bone scans using indium 111–labeled white blood cells or indium 111–labeled immunoglobulin G, which will show increased uptake in osteomyelitis but not in a neuropathic joint, may be useful. A technetium bone scan will not distinguish osteomyelitis from neuropathic arthritis, as increased uptake is observed in both. The joint fluid in neuropathic arthritis is noninflammatory; may be xanthochromic or even bloody; and may contain fragments of synovium, cartilage, and bone. The finding of calcium pyrophosphate dihydrate crystals supports the diagnosis of crystal-associated arthropathy. In the absence of such crystals, an increased number of leukocytes may indicate osteomyelitis.


InternalMed_Harrison

InternalMed_Harrison. The primary focus of treatment is to stabilize the joint. Treatment of the underlying disorder, even if successful, does not usually affect established joint disease. Braces and splints are helpful. Their use requires close surveillance, because patients may be unable to appreciate pressure from a poorly adjusted brace. In the diabetic patient, early recognition of Charcot foot and its treatment—prohibition of weight bearing by the foot for at least 8 weeks—may possibly prevent severe disease from developing. Fusion of an unstable joint may improve function and reduce pain, but nonunion is frequent, especially when immobilization of the joint is inadequate.


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InternalMed_Harrison. Hypertrophic osteoarthropathy (HOA) is characterized by clubbing of digits and, in more advanced stages, by periosteal new-bone formation and synovial effusions. HOA may be primary or familial and may begin in childhood. Secondary HOA is associated with intrathoracic malignancies, suppurative and some hypoxemic lung diseases, congenital heart disease, and a variety of other disorders. Clubbing is almost always a feature of HOA but can occur as an isolated manifestation (Fig. 397-2). The presence of clubbing in isolation may be congenital or represent either an early stage or one element in the spectrum of HOA. Isolated acquired clubbing has the same clinical significance as clubbing associated with periostitis. FIGUrE 397-2 Clubbing of the fingers. (Reprinted from the Clinical Slide Collection on the Rheumatic Diseases, © 1991, 1995. Used by permis-sion of the American College of Rheumatology.)


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InternalMed_Harrison. Pathology and Pathophysiology of acquired HOa In HOA, bone changes in the distal extremities begin as periostitis followed by new bone formation. At this stage, a radiolucent area may be observed between the new periosteal bone and the subjacent cortex. As the process progresses, multiple layers of new bone are deposited and become contiguouswiththecortex,withconsequentcorticalthickening.Theouter portion of the bone is laminated in appearance, with an irregular surface. Initially, the process of periosteal new-bone formation involves the proximal and distal diaphyses of the tibia, fibula, radius, and ulna and, lessfrequently,thefemur, humerus,metacarpals,metatarsals, and phalanges. Occasionally, scapulae, clavicles, ribs, and pelvic bones are also affected. The adjacent interosseous membranes may become ossified. The distribution of bone manifestations is usually bilateral and symmetric. The soft tissue overlying the distal third of the arms and legs may be thickened. Proliferation of


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InternalMed_Harrison. may become ossified. The distribution of bone manifestations is usually bilateral and symmetric. The soft tissue overlying the distal third of the arms and legs may be thickened. Proliferation of connective tissue occurs in the nail bed and volar pad of digits, giving the distal phalanges a clubbed appearance. Small blood vessels in the clubbed digits are dilated and have thickened walls. In addition, the number of arteriovenous anastomoses is increased.


InternalMed_Harrison

InternalMed_Harrison. Several theories have been suggested for the pathogenesis of HOA, but many have been disproved or have not explained the condition’s development in all clinical disorders with which it is associated. Previously proposed neurogenic and humoral theories are no longer considered likely explanations for HOA. Studies have suggested a role for platelets in the development of HOA. It has been observed that megakaryocytes and large platelet particles present in the venous circulation are fragmented in their passage through normal lung. In patients with cyanotic congenital heart disease and in other disorders associated with right-to-left shunts, these large platelet particles bypass the lung and reach the distal extremities, where they can interact with endothelial cells. Platelet–endothelial cell activation in the distal portion of the extremities may result in the release of platelet-derived growth factor (PDGF) and other factors leading to the proliferation of connective tissue and


InternalMed_Harrison

InternalMed_Harrison. cell activation in the distal portion of the extremities may result in the release of platelet-derived growth factor (PDGF) and other factors leading to the proliferation of connective tissue and periosteum. Stimulation of fibroblasts by PDGF and transforming growth factor β results in cell growth and collagen synthesis. ElevatedplasmalevelsofvonWillebrandfactorantigenhavebeenfound in patients with both primary and secondary forms of HOA, indicating endothelial activation or damage. Abnormalities of collagen synthesis have been demonstrated in the involved skin of patients with primary HOA. Other factors are undoubtedly involved in the pathogenesis of HOA, and further studies are needed to elucidate this disorder.


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InternalMed_Harrison. Clinical Manifestations Primary or familial HOA, also referred to as pachydermoperiostitis or Touraine-Solente-Golé syndrome, usually begins insidiously at puberty. In a smaller proportion of patients, the onset comes in the first year of life. The disorder is inherited as an autosomal dominant trait with variable expression and is nine times more common among boys than among girls. Approximately one-third of patients have a family history of primary HOA.


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InternalMed_Harrison. Primary HOA is characterized by clubbing, periostitis, and unusual skin features. A small number of patients with this syndrome do not express clubbing. The skin changes and periostitis are prominent features of this syndrome. The skin becomes thickened and coarse. Deep nasolabial folds develop, and the forehead may become furrowed. Patients may have heavy-appearing eyelids and ptosis. The skin is often greasy, and there may be excessive sweating of the hands and feet.Patientsmay alsoexperience acne vulgaris,seborrhea,and folliculitis. In a few patients, the skin over the scalp becomes very thick and corrugated, a feature that has been descriptively termed cutis verticis gyrata. The distal extremities, particularly the legs, become thickened as aconsequence of the proliferation of new bone and soft tissue; when the process is extensive, the distal lower extremities resemble those of an elephant. The periostitis usually is not painful, which it can be in secondary HOA. Clubbing of the


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InternalMed_Harrison. and soft tissue; when the process is extensive, the distal lower extremities resemble those of an elephant. The periostitis usually is not painful, which it can be in secondary HOA. Clubbing of the fingers may be extensive, producing large, bulbous deformities and clumsiness. Clubbing also affects the toes. Patients may experience articular and periarticular pain, especially in the ankles and knees, and joint motion may be mildly restricted by periarticular bone overgrowth. Noninflammatory effusions occur in the wrists, knees, and ankles. Synovial hypertrophy is not found. Associated abnormalitiesobserved in patients with primary HOA include hypertrophic gastropathy, bone marrow failure, female escutcheon, gynecomastia, and cranial suture defects. In patients with primary HOA, the symptoms disappear when adulthood is reached.


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InternalMed_Harrison. HOA secondary to an underlying disease occurs more frequently than primary HOA. It accompanies a variety of disorders and may precede clinical features of the associated disorder by months. Clubbing is more frequent than the full syndrome of HOA in patients with associated illnesses. Because clubbing evolves over months and is usually asymptomatic, it is often recognized first by the physician and not the patient. Patients may experience a burning sensation in their fingertips. Clubbing is characterized by widening of the fingertips, enlargement of the distal volar pad, convexity of the nail contour, and the loss of the normal 15° angle between the proximal nail and cuticle. The thickness of the digit at the base of the nail is greater than the thicknessatthedistalinterphalangealjoint.Anobjectivemeasurement of finger clubbing can be made by determining the diameter at the base of the nail and at the distal interphalangeal joint of all 10 digits. Clubbing is present when the sum of the


InternalMed_Harrison

InternalMed_Harrison. of finger clubbing can be made by determining the diameter at the base of the nail and at the distal interphalangeal joint of all 10 digits. Clubbing is present when the sum of the individual digit ratios is >10. At thebedside, clubbingcanbe appreciated by having the patient place the dorsal surface of the distal phalanges of the fourth fingers together with the nails opposing each other. Normally, an open area is visible betweenthebasesoftheopposingfingernails;whenclubbingispresent, this open space is no longer visible. The base of the nail feels spongy when compressed, and the nail can be easily rocked on its bed. When clubbing is advanced, the finger may have a drumstick appearance, and the distal interphalangeal joint can be hyperextended. Periosteal involvement in the distal extremities may produce a burning or deep-seated aching pain. The pain, which can be quite incapacitating, is aggravated by dependency and relieved by elevation of the affected limbs. Pressure applied over


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InternalMed_Harrison. may produce a burning or deep-seated aching pain. The pain, which can be quite incapacitating, is aggravated by dependency and relieved by elevation of the affected limbs. Pressure applied over the distal forearms and legs or gentle percussion of distal long bones like the tibia may be quite painful.


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InternalMed_Harrison. Patients may experience joint pain, most often in the ankles, wrists, and knees. Joint effusions may be present; usually, they are small and noninflammatory. The small joints of the hands are rarely affected. Severe joint or long bone pain may be the presenting symptom of an underlying lung malignancy and may precede the appearance of clubbing. In addition, the progression of HOA tends to be more rapid when associated with malignancies, most notably bronchogenic carcinoma. Noninflammatory but variably painful knee effusions may occur prior to the appearance of clubbing and symptoms of distal periostitis. Unlike primary HOA, secondary HOA does not commonly include excessive sweating and oiliness of the skin or thickening of the facial skin. Lung abscesses, empyema, bronchiectasis Neoplasms: esophagus, liver, bowel Aneurysm of major extremity arterya Arteriovenous fistula of major extremity vessela


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InternalMed_Harrison. Lung abscesses, empyema, bronchiectasis Neoplasms: esophagus, liver, bowel Aneurysm of major extremity arterya Arteriovenous fistula of major extremity vessela Hyperthyroidism (Graves’ disease) aUnilateral involvement. bBilateral lower-extremity involvement.


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InternalMed_Harrison. Hyperthyroidism (Graves’ disease) aUnilateral involvement. bBilateral lower-extremity involvement. HOA occurs in 5–10% of patients with intrathoracic malignancies, the most common being bronchogenic carcinoma and pleural tumors (Table 397-3). Lung metastases infrequently cause HOA. HOA is also seen in patients with intrathoracic infections, including lung abscesses, empyema, and bronchiectasis, but is uncommon in pulmonary tuberculosis. HOA may accompany chronic interstitial pneumonitis, sarcoidosis, and cystic fibrosis. In cystic fibrosis, clubbing is more common than the full syndrome of HOA. Other causes of clubbing include congenital heart disease with right-to-left shunts, bacterial endocarditis, Crohn’s disease, ulcerative colitis, sprue, and neoplasms of the esophagus, liver, and small and large bowel. In patients who have congenital heart disease with right-to-left shunts, clubbing alone occurs more often than the full syndrome of HOA.


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InternalMed_Harrison. Unilateral clubbing has been found in association with aneurysms of major extremity arteries, with infected arterial grafts, and with arteriovenous fistulas of brachial vessels. Clubbing of the toes but not the fingers has been associated with an infected abdominal aortic aneurysm and patent ductus arteriosus. Clubbing of a single digit may follow trauma and has been reported in tophaceous gout and sarcoidosis. While clubbing occurs more commonly than the full syndrome in most diseases, periostitis in the absence of clubbing has been observed in the affected limb of patients with infected arterial grafts.


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InternalMed_Harrison. Hyperthyroidism (Graves’ disease), treated or untreated, is occasionally associated with clubbing and periostitis of the bones of the hands and feet. This condition is referred to as thyroid acropachy. Periostitis may be asymptomatic and occurs in the midshaft and diaphyseal portionofthe metacarpal andphalangeal bones.Significant hand-joint pain may occur; this pain may respond to successful therapy for thyroid dysfunction. The long bones of the extremities are seldom affected. Elevated levels of long-acting thyroid stimulator are found in the sera of these patients.


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InternalMed_Harrison. Laboratory Findings The laboratory abnormalities reflect the underlying disorder. The synovial fluid of involved joints has <500 white cells/μL, and the cells are predominantly mononuclear. Radiographs show a faint radiolucent line beneath the new periosteal bone along the shaft of long bones at their distal end. These changes are observed most frequently at the ankles, wrists, and knees. The ends of the distal phalanges may show osseous resorption. Radionuclide studies show pericortical linear uptake along the cortical margins of long bones that may precede any radiographic changes. Arthritis Associated with Systemic Disease, and Other Arthritides Myofascial pain most often involves the posterior neck, low back, shoulders, and chest. Chronic pain in the muscles of the posterior


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InternalMed_Harrison. Myofascial pain most often involves the posterior neck, low back, shoulders, and chest. Chronic pain in the muscles of the posterior The treatment of HOA aims to identify the associated disorder and treat it appropriately. The symptoms and signs of HOA may disappear completely with removal of or effective chemotherapy for a tumor or with antibiotic therapy for a chronic pulmonary infection and drainage of the infected site. Vagotomy or percutaneous block of the vagus nerve leads to symptomatic relief in some patients. NSAIDs or analgesics may help control symptoms of HOA.


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InternalMed_Harrison. The reflex sympathetic dystrophy syndrome is now referred to as complex regional pain syndrome, type 1, according to the new classification system of the International Association for the Study of Pain. This syndrome is characterized by pain and swelling, usually of a distal extremity, accompanied by vasomotor instability, trophic skin changes, and the rapid development of bony demineralization. Reflex sympathetic dystrophy syndrome, including its treatment, is covered in greater detail in Chap. 454.


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InternalMed_Harrison. Tietze syndrome is manifested by painful swelling of one or more costochondral articulations. The age of onset is usually before 40, and both sexes are affected equally. In most patients, only one joint is involved, usually the second or third costochondral joint. The onset of anterior chest pain may be sudden or gradual. The pain may radiate to the arms or shoulders and is aggravated by sneezing, coughing, deep inspirations, or twisting motions of the chest. The term costochondritis is often used interchangeably with Tietze syndrome, but some workers restrict the former term to pain of the costochondral articulations without swelling. Costochondritis is observed in patients over age 40; tends to affect the third, fourth, and fifth costochondral joints; and occurs more often in women. Both syndromes may mimic cardiac or upper abdominal causes of pain. Rheumatoid arthritis, ankylosing spondylitis, and reactive arthritis may involve costochondral joints but are distinguished easily by


InternalMed_Harrison

InternalMed_Harrison. syndromes may mimic cardiac or upper abdominal causes of pain. Rheumatoid arthritis, ankylosing spondylitis, and reactive arthritis may involve costochondral joints but are distinguished easily by their other clinical features. Other skeletal causes of anterior chest wall pain are xiphoidalgia and the slipping rib syndrome, which usually involves the tenth rib. Malignancies such as breast cancer, prostate cancer, plasma cell cytoma, and sarcoma can invade the ribs, thoracic spine, or chest wall and produce symptoms suggesting Tietze syndrome. Patients with osteomalacia may have significant rib pain, with or without documented microfractures. These conditions should be distinguishable by radiography, bone scanning, vitamin D measurement, or biopsy. Analgesics, anti-inflammatory drugs, and local glucocorticoid injections usually relieve symptoms of costochondritis/Tietze syndrome. Care should be taken to avoid overdiagnosing these syndromes in patients with acute chest pain syndromes;


InternalMed_Harrison

InternalMed_Harrison. local glucocorticoid injections usually relieve symptoms of costochondritis/Tietze syndrome. Care should be taken to avoid overdiagnosing these syndromes in patients with acute chest pain syndromes; many patients will be tender to overly vigorous palpation of the costochondral joints.


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InternalMed_Harrison. Myofascial pain syndrome is characterized by multiple areas of localized musculoskeletal pain and tenderness in association with tender points. The pain is deep and aching and may be accompanied by a burning sensation. Myofascial pain may be regional and follow trauma, overuse, or prolonged static contraction of a muscle or muscle group, which may occur when an individual is reading or writing at a desk or working at a computer. In addition, this syndrome may be associated with underlying osteoarthritis of the neck or low back. Pain may be referred from tender points to defined areas distant from the area of original tenderness. Palpation of the tender point reproduces or accentuates the pain. The tender points are usually located in the center of a muscle belly, but they can occur at other sites such as costosternal junctions, the xiphoid process, ligamentous and tendinous insertions, fascia, and fatty areas. Tender point sites in muscle have been described as feeling indurated and


InternalMed_Harrison

InternalMed_Harrison. sites such as costosternal junctions, the xiphoid process, ligamentous and tendinous insertions, fascia, and fatty areas. Tender point sites in muscle have been described as feeling indurated and taut, and palpation may cause the muscle to twitch. These findings, however, have been shown not to be unique to myofascial pain syndrome: in a controlled study, they were also present in some “normal” subjects.


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InternalMed_Harrison. neck may involve referral of pain from a tender point in the erector neck muscle or upper trapezius to the head, leading to persistent headaches that may last for days. Tender points in the paraspinal muscles of the low back may refer pain to the buttock. Pain may be referred down the leg from a tender point in the gluteus medius and can mimic sciatica. A tender point in the infraspinatus muscle may produce local and referred pain over the lateral deltoid and down the outside of the arm into the hand. Injection of a local anesthetic such as 1% lidocaine into the tender point site often results in at least transient pain relief. Another useful technique is first to spray an agent such as ethyl chloride from the tender point toward the area of referred pain and then to stretch the muscle. This maneuver may need to be repeated several times. Massage and application of ultrasound to the affected area also may be beneficial. Patients should be instructed in methods to prevent muscle


InternalMed_Harrison

InternalMed_Harrison. This maneuver may need to be repeated several times. Massage and application of ultrasound to the affected area also may be beneficial. Patients should be instructed in methods to prevent muscle stresses related to work and recreation. Posture and resting positions are important in preventing muscle tension. The prognosis in most patients is good. In some patients, regionally localized myofascial pain syndrome may seem to evolve into more generalized fibromyalgia (Chap. 396). Abnormal or nonrestorative sleep is a common accompaniment in these patients and may need to be specifically addressed.


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InternalMed_Harrison. Primarytumors and tumor-like disorders of synovium areuncommon but should be considered in the differential diagnosis of monarticular jointdisease.Inaddition,metastasestoboneandprimarybonetumors adjacent to a joint may produce joint symptoms. Pigmented villonodular synovitis (PVNS) is characterized by the slowly progressive, exuberant, benign proliferation of synovial tissue, usually involving a single joint. The most common age of onset is in the third decade, and women are affected slightly more often than men. The cause of this disorder is unknown. The synovium has a brownish color and numerous large, finger-like villi that fuse to form pedunculated nodules. There is marked hyperplasia of synovial cells in the stroma of the villi. Hemosiderin granules and lipids are found in the cytoplasm of macrophages and in the interstitial tissue. Multinucleated giant cells may be present. The proliferative synovium grows into the subsynovial tissue and invades adjacent cartilage and bone.


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InternalMed_Harrison. The clinical picture of PVNS is characterized by the insidious onset of persistent swelling and pain in affected joints, most commonly the knee. Other joints affected include the hips, ankles, calcaneocuboid joints, elbows, and small joints of the fingers or toes. The disease may also involve the common flexor sheath of the hands or fingers. Less often, tendon sheaths in the wrist, ankle, or foot may be involved. Symptoms of pain, a catching sensation, or stiffness may initially be mild and intermittent and may be present for years before the patient seeks medical attention. Radiographs may show joint space narrowing, erosions, and subchondral cysts. The diagnosis of PVNS is strongly suggested by gradient echo MRI, which reveals a synovial mass lesion of low signal intensity typical of tissue containing hemosiderin (Fig. 397-3). The joint fluid contains blood and is dark red or almost black in color. Lipid-containing macrophages may be present in the fluid. The joint fluid may be


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InternalMed_Harrison. tissue containing hemosiderin (Fig. 397-3). The joint fluid contains blood and is dark red or almost black in color. Lipid-containing macrophages may be present in the fluid. The joint fluid may be clear if hemorrhage has not occurred. Some patients have polyarticular involvement.


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InternalMed_Harrison. The treatment for PVNS is complete synovectomy. With incomplete synovectomy, the villonodular synovitis recurs, and the rate of tissue growth may be faster than it was originally. Irradiation of the involved joint has been successful in some patients. Synovial chondromatosis is a disorder characterized by multiple focal metaplastic growths of normal-appearing cartilage in the synovium or tendon sheath. Segments of cartilage break loose and continue to grow as loose bodies. When calcification and ossification of loose bodies occur, the disorder is referred to as synovial osteochondromatosis. The disorder is usually monarticular and affects young to middle-aged individuals. The knee is most often involved, followed by hip, elbow, and shoulder. Symptoms are pain, swelling, and decreased motion of the joint. Radiographs may show several rounded calcifications within the joint cavity. Treatment is synovectomy; however, as in PVNS, the tumor may recur.


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InternalMed_Harrison. FIGUrE 397-3 Pigmented villonodular synovitis. MRIgradientechosagittalimageshowingamassthatabutstheneckofthetaluswithmarkedlowsignaltypicaloftissuecontaininghemosiderin.(Courtesy of Donald Flemming, MD; with permission.)


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InternalMed_Harrison. Synovial sarcoma is a malignant neoplasm often found near a large joint of both upper and lower extremities, being more common in the lower extremity. It seldom arises within the joint itself. Synovial sarcomas constitute 10% of soft tissue sarcomas. The tumor is believed to arise from primitive mesenchymal tissue that differentiates into epithelial cells and/or spindle cells. Small foci of calcification may be present in the tumor mass. Synovial sarcoma occurs most often in young adults and is more common in men. The tumor presents as a slowly growing deep-seated mass near a joint, without much pain. The area of the knee is the most common site, followed by the foot, ankle, elbow, and shoulder.Other primary sitesincludethebuttocks,abdominal wall, retroperitoneum, and mediastinum. The tumor spreads along tissue planes. The most common site of visceral metastasis is the lung. The diagnosis is made by biopsy. Treatment consists of wide resection of the tumor, including adjacent muscle


InternalMed_Harrison

InternalMed_Harrison. spreads along tissue planes. The most common site of visceral metastasis is the lung. The diagnosis is made by biopsy. Treatment consists of wide resection of the tumor, including adjacent muscle and regional lymph nodes, followed by chemotherapy and radiation therapy. Amputation of the involved distal extremity may be required. Chemotherapy may be beneficial in some patients with metastatic disease. Isolated sites of pulmonary metastasis can be surgically removed. The 5-year survival rate with treatment is variable and depends on the staging of the tumor, ranging from ~25% to ≥60%. Synovial sarcomas tend to recur locally and metastasize to regional lymph nodes, lungs, and skeleton.


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InternalMed_Harrison. In addition to the rare direct metastases of solid cell tumors to the highly vascular synovium, neoplasia arising from nonarticular organ sites can affect joints in other ways. Acute leukemias in children can mimic juvenile inflammatory arthritis with severe joint pain and fever. In adults, chronic and acute myeloid leukemia can infiltrate the synovium in rare instances. The rarely occurring hairy cell leukemia has a peculiar tendency to cause episodic inflammatory oligoarthritis and tenosynovitis; these episodes are dramatic and mimic acute gout attacks. They respond to potent anti-inflammatory therapy with glucocorticoids; with remission of the leukemia, they may abate. Carcinomas can be associated with several paraneoplastic articular syndromes, including HOA (discussed above). Acute palmar fasciitis withpolyarthritisisawell-describedbutrareconditionassociatedwith certain cancers, mainly adenocarcinomas. Clinically, this syndrome is


InternalMed_Harrison

InternalMed_Harrison. including HOA (discussed above). Acute palmar fasciitis withpolyarthritisisawell-describedbutrareconditionassociatedwith certain cancers, mainly adenocarcinomas. Clinically, this syndrome is fairlyabruptinonset,withpaininthemetacarpophalangealandproximal interphalangeal joints of the hands and rapidly evolving contractures of the fingers due to thickening of the palmar (flexor) tendons. A similar syndrome can be seen in diabetics. Paraneoplastic arthritis has been described and may occur in several patterns: asymmetric disease predominantly affecting the lower extremity joints and sym-2247 metric polyarthritis with hand joint involvement. Tumors are often found after the onset of the arthritis, and many patients have a preceding period of malaise or weight loss. The onset is often acute, and patients tend to be older men. These features should raise the specter of an underlying malignancy (or a viral infection such as hepatitis C) as the cause of the arthritis. In one series, the


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InternalMed_Harrison. and patients tend to be older men. These features should raise the specter of an underlying malignancy (or a viral infection such as hepatitis C) as the cause of the arthritis. In one series, the symptoms resolved with successful therapy for the malignancy and did not recur with relapse of the malignancy. Dermatomyositis has a well-described association with neoplasms and may include joint pain and arthritis. Malignancy-associated arthritis may be responsive to NSAIDs and to treatment of the primary neoplasm.


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InternalMed_Harrison. This chapter represents a revised version of the chapter authored by Dr. Bruce C. Gilliland that appeared in previous editions of Harrison’s. Dr. Gilliland passed away on February 17, 2007. He had been a contributor to Harrison’s Principles of Internal Medicine since the 11th edition. periarticular Disorders of the Carol A. Langford A number of periarticular disorders have become increasingly common, due in part to greater participation in recreational sports by individuals of a wide range of ages. Periarticular disorders most commonly affect the knee or shoulder. With the exception of bursitis, hip pain is most often articular or is being referred from disease affecting anotherstructure (Chap 393).Thischapterdiscussessomeofthemore common periarticular disorders.


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InternalMed_Harrison. Bursitis is inflammation ofabursa,whichisa thin-walledsaclinedwith synovial tissue. The function of the bursa is to facilitate movement of tendonsandmusclesoverbonyprominences.Excessivefrictionalforces from overuse, trauma, systemic disease (e.g., rheumatoid arthritis, gout), or infection may cause bursitis. Subacromial bursitis (subdeltoid bursitis) is the most common form of bursitis. The subacromial bursa, which is contiguous with the subdeltoid bursa, is located between the undersurface of the acromion and the humeral head and is covered by thedeltoidmuscle.Bursitisiscausedby repetitiveoverheadmotion and often accompanies rotator cuff tendinitis. Another frequently encountered form is trochanteric bursitis, which involves the bursa around the insertion of the gluteus medius onto the greater trochanter of the femur. Patients experience pain over the lateral aspect of the hip and upperthighand havetendernessoverthe posterioraspect of the greater trochanter. External rotation and


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InternalMed_Harrison. greater trochanter of the femur. Patients experience pain over the lateral aspect of the hip and upperthighand havetendernessoverthe posterioraspect of the greater trochanter. External rotation and resisted abduction of the hip elicit pain. Olecranon bursitis occurs over the posterior elbow, and when the area is acutely inflamed, infection or gout should be excluded by aspirating the bursa and performing a Gram stain and culture on the fluid aswellasexaminingthefluidforuratecrystals. Achilles bursitis involves the bursa located abovethe insertion of thetendon to the calcaneus and results from overuse and wearing tight shoes. Retrocalcaneal bursitis involves the bursa that is located between the calcaneus and posterior surface of the Achilles tendon. The pain is experienced at the back of the heel, and swelling appears on the medial and/or lateral side of the tendon. It occurs in association with spondyloarthritides, rheumatoid arthritis, gout, ortrauma. Ischial bursitis affects the


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InternalMed_Harrison. the heel, and swelling appears on the medial and/or lateral side of the tendon. It occurs in association with spondyloarthritides, rheumatoid arthritis, gout, ortrauma. Ischial bursitis affects the bursa separating the gluteusmediusfromtheischialtuberosityanddevelopsfromprolonged sitting and pivoting on hard surfaces. Iliopsoas bursitis affects the bursa that lies between the iliopsoas muscle and hip joint and is lateral to the femoral vessels. Pain is experienced over this area and is made worse


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InternalMed_Harrison. Periarticular Disorders of the Extremities 2248 by hip extension and flexion. Anserine bursitis is an inflammation of the sartorius bursa located over the medial side of the tibia just below the knee and under the conjoint tendon and is manifested by pain on climbing stairs. Tenderness is present over the insertion of the conjoint tendon of the sartorius, gracilis, and semitendinosus. Prepatellar bursitis occurs in the bursa situated between the patella and overlying skin and is caused by kneeling on hard surfaces. Gout or infection may also occur at this site. Bursitis is typically diagnosed by history and physical examination, but visualization by ultrasound may play a useful role in selected instances for diagnosis and directed guidance of glucocorticoid injection. Treatment of bursitis consists of prevention of the aggravating situation, rest of the involved part, administration of a nonsteroidal anti-inflammatory drug (NSAID) where appropriate for an individual patient, or local


InternalMed_Harrison

InternalMed_Harrison. consists of prevention of the aggravating situation, rest of the involved part, administration of a nonsteroidal anti-inflammatory drug (NSAID) where appropriate for an individual patient, or local glucocorticoid injection.


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InternalMed_Harrison. Tendinitis of the rotator cuff is the major cause of a painful shoulder andiscurrentlythoughttobecausedbyinflammationofthetendon(s). The rotator cuff consists of the tendons of the supraspinatus, infraspinatus, subscapularis, and teres minor muscles, and inserts on the humeral tuberosities. Of the tendons forming the rotator cuff, the supraspinatustendonis the most often affected,probablybecauseofits repeated impingement (impingement syndrome) between the humeral head and the undersurface of the anterior third of the acromion and coracoacromial ligament above as well as the reduction in its blood supply that occurs with abduction of the arm (Fig. 398-1). The tendon oftheinfraspinatusandthatofthelongheadofthebicepsarelesscommonlyinvolved.Theprocessbeginswithedemaandhemorrhageofthe rotatorcuff,whichevolvestofibroticthickeningandeventuallytorotator cuff degeneration with tendon tears and bone spurs. Subacromial bursitis also accompanies this syndrome. Symptoms usually appear after injury


InternalMed_Harrison

InternalMed_Harrison. cuff degeneration with tendon tears and bone spurs. Subacromial bursitis also accompanies this syndrome. Symptoms usually appear after injury or overuse, especially with activities involving elevation of the arm with some degree of forward flexion. Impingement syndrome occurs in persons participating in baseball, tennis, swimming, or occupations that require repeated elevation of the arm. Those over age 40 are particularly susceptible. Patients complain of a dull aching in the shoulder, which may interfere with sleep. Severe pain is experienced when the arm is actively abducted into an overhead position. The arc between 60° and 120° is especially painful. Tenderness is present over the lateral aspect of the humeral head just below the acromion. NSAIDs, local glucocorticoid injection, and physical therapy may relieve symptoms. Surgical decompression of the subacromial space may be necessary in patients refractory to conservative treatment.


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InternalMed_Harrison. FIGUrE 398-1 Coronal section of the shoulder illustrating the relationships of the glenohumeral joint, the joint capsule, the subacromial bursa, and the rotator cuff (supraspinatus tendon). (From F Kozin, in Arthritis and Allied Conditions, 13th ed, WJ Koopman [ed]. Baltimore, Williams & Wilkins, 1997, with permission.) Patients may tear the supraspinatus tendon acutely by falling on an outstretched arm or lifting a heavy object. Symptoms are pain along with weakness of abduction and external rotation of the shoulder. Atrophy of the supraspinatus muscles develops. The diagnosis is establishedbyarthrogram,ultrasound,ormagneticresonanceimaging (MRI).Surgicalrepairmaybenecessaryin patientswhofail torespond to conservative measures. In patients with moderate-to-severe tears and functional loss, surgery is indicated.


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InternalMed_Harrison. Thisconditionischaracterizedbydepositionofcalciumsalts,primarily hydroxyapatite, within a tendon. The exact mechanism of calcification is not known but may be initiated by ischemia or degeneration of the tendon. The supraspinatus tendon is most often affected because it is frequently impinged on and has a reduced blood supply when the arm is abducted. The condition usually develops after age 40. Calcification within the tendon may evoke acute inflammation, producing sudden and severe pain in the shoulder. However, it may be asymptomatic or not related to the patient’s symptoms. Diagnosis of calcific tendonitis can be made by ultrasound or radiograph. Most cases are self-limited and respond to conservative therapy with physical therapy and/or NSAIDs. A subset of patients is refractory and requires ultrasound-guided percutaneous needle aspiration and lavage or surgery.


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InternalMed_Harrison. Bicipital tendinitis, or tenosynovitis, is produced by friction on the tendon of the long head of the biceps as it passes through the bicipital groove. When the inflammation is acute, patients experience anterior shoulder pain that radiates down the biceps into the forearm. Abduction and external rotation of the arm are painful and limited. The bicipital groove is very tender to palpation. Pain may be elicited along the course of the tendon by resisting supination of the forearm with the elbow at 90° (Yergason’s supination sign). Acute rupture of the tendon may occur with vigorous exercise of the arm and is often painful. In a young patient, it should be repaired surgically. Rupture of the tendon in an older person may be associated with little or no pain and is recognized by the presence of persistent swelling of the biceps produced by the retraction of the long head of the biceps. Surgery is usually not necessary in this setting.


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InternalMed_Harrison. In this condition, inflammation involves the abductor pollicis longus and the extensor pollicis brevis as these tendons pass through a fibroussheathattheradialstyloidprocess.Theusualcauseisrepetitive twisting of the wrist. It may occur in pregnancy, and it also occurs in mothers who hold their babies with the thumb outstretched. Patients experience pain on grasping with their thumb, such as with pinching. Swelling and tenderness are often present over the radial styloid process. The Finkelstein sign is positive, which is elicited by having the patient place the thumb in the palm and close the fingers over it. The wrist is then ulnarly deviated, resulting in pain over the involved tendon sheath in the area of the radial styloid. Treatment consists initially of splinting the wrist and an NSAID. When severe or refractory to conservative treatment, glucocorticoid injections can be very effective.


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InternalMed_Harrison. Tendinitis involves the patellar tendon at its attachment to the lower pole of the patella. Patients may experience pain when jumping during basketball or volleyball, going up stairs, or doing deep knee squats. Tenderness is noted on examination over the lower pole of the patella. Treatment consists of rest, icing, and NSAIDs,followed by strengthening and increasing flexibility.


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InternalMed_Harrison. The iliotibial band is a thick connective tissue that runs from the ilium to the fibula. Patients with iliotibial band syndrome most commonly present with aching or burning pain at the site where the band courses over the lateral femoral condyle of the knee; pain may also radiate up the thigh, toward the hip. Predisposing factors for iliotibial band syndrome include a varus alignment of the knee, excessive running distance,poorlyfittedshoes,orcontinuousrunningonuneventerrain. Treatment consists of rest, NSAIDs, physical therapy, and addressing risk factors such as shoes and running surface. Glucocorticoid injection into thearea of tenderness can providerelief, butrunning mustbe avoided for at least 2 weeks after the injection. Surgical release of the iliotibial band has been helpful in rare patients for whom conservative treatment has failed.


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InternalMed_Harrison. Often referred to as “frozen shoulder,” adhesive capsulitis is characterized by pain and restricted movement of the shoulder, usually in the absence of intrinsic shoulder disease. Adhesive capsulitis may follow bursitis or tendinitis of the shoulder or be associated with systemic disorders such as chronic pulmonary disease, myocardial infarction, and diabetes mellitus. Prolonged immobility of the arm contributes to the development of adhesive capsulitis. Pathologically, the capsule of the shoulder is thickened, and a mild chronic inflammatory infiltrate and fibrosis may be present.


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InternalMed_Harrison. Adhesive capsulitis occurs more commonly in women after age 50. Pain and stiffness usually develop gradually but progress rapidly in some patients. Night pain is often present in the affected shoulder, and pain may interfere with sleep. The shoulder is tender to palpation, and both active and passive movement are restricted. Radiographs of the shoulder show osteopenia. The diagnosis is typically made by physical examination but can be confirmed if necessary by arthrography, in that only a limited amount of contrast material, usually <15 mL, can be injected under pressure into the shoulder joint.


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InternalMed_Harrison. In most patients, the condition improves spontaneously 1–3 years after onset. While pain usually improves, many patients are left with some limitation of shoulder motion. Early mobilization of the arm following an injury to the shoulder may prevent the development of this disease. Physical therapy provides the foundation of treatment for adhesive capsulitis. Local injections of glucocorticoids and NSAIDs may also provide relief of symptoms. Slow but forceful injection of contrast material into the joint may lyse adhesions and stretch the capsule, resulting in improvement of shoulder motion. Manipulation under anesthesia may be helpful in some patients.


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InternalMed_Harrison. Lateral epicondylitis, or tennis elbow, is a painful condition involving the soft tissue over the lateral aspect of the elbow. The pain originates ator near the siteof attachment of the commonextensorsto the lateral epicondyle and may radiate into the forearm and dorsum of the wrist. The pain usually appears after work or recreational activities involving repeated motions of wrist extension and supination against resistance. Most patients with this disorder injure themselves in activities other than tennis, such as pulling weeds, carrying suitcases or briefcases, or using a screwdriver. The injury in tennis usually occurs when hitting a backhand with the elbow flexed. Shaking hands and opening doors can reproduce the pain. Striking the lateral elbow against a solid object may also induce pain.


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InternalMed_Harrison. The treatment is usually rest along with administration of an NSAID. Ultrasound, icing, and friction massage may also help relieve pain. When pain is severe, the elbow is placed in a sling or splinted at 90° of flexion. When the pain is acute and well localized, injection of a glucocorticoid using a small-gauge needle may be effective. Following injection, the patient should be advised to rest the arm for at least 1 month and avoid activities that would aggravate the elbow. Once symptoms have subsided, the patient should begin rehabilitation to strengthen and increase flexibility of the extensor muscles before resuming physical activity involving the arm. A forearm band placed 2.5–5.0 cm (1–2 in.) below the elbow may help to reduce tension on the extensor muscles at their attachment to the lateral epicondyle. The patient should be advised to restrict activities requiring forcible extension and supination of the wrist. Improvement may take several months. The patient may continue to


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InternalMed_Harrison. the lateral epicondyle. The patient should be advised to restrict activities requiring forcible extension and supination of the wrist. Improvement may take several months. The patient may continue to experience mild pain but, with care, can usually avoid the return of debilitating pain. Occasionally, 2249 surgical release of the extensor aponeurosis may be necessary.


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InternalMed_Harrison. Medial epicondylitis is an overuse syndrome resulting in pain over the medial side of the elbow with radiation into the forearm. The cause of this syndrome is considered to be repetitive resisted motions of wrist flexion and pronation, which lead to microtears and granulation tissue at the origin of the pronator teres and forearm flexors, particularly the flexor carpi radialis. This overuse syndrome is usually seen in patients >35 years and is much less common than lateral epicondylitis. It occurs most often in work-related repetitive activities but also occurs with recreational activities such as swinging a golf club or throwing a baseball. On physical examination, there is tenderness just distal to the medial epicondyle over the origin of the forearm flexors. Pain can be reproduced by resisting wrist flexion and pronation with the elbow extended. Radiographs are usually normal. The differential diagnosis of patients with medial elbow symptoms includes tears of the pronator teres,


InternalMed_Harrison

InternalMed_Harrison. resisting wrist flexion and pronation with the elbow extended. Radiographs are usually normal. The differential diagnosis of patients with medial elbow symptoms includes tears of the pronator teres, acute medial collateral ligament tear, and medial collateral ligament instability. Ulnar neuritis has been found in 25–50% of patients with medial epicondylitis and is associated with tenderness over the ulnar nerve at the elbow as well as hypesthesia and paresthesia on the ulnar side of the hand.


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InternalMed_Harrison. The initial treatment of medial epicondylitis is conservative, involving rest, NSAIDs, friction massage, ultrasound, and icing. Some patients may require splinting. Injections of glucocorticoids at the painful site may also be effective. Patients should be instructed to rest for at least 1 month. Also, patients should start physical therapy once the pain has subsided. In patients with chronic debilitating medial epicondylitis that remains unresponsive after at least a year of treatment, surgical release of the flexor muscle at its origin may be necessary and is often successful.


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InternalMed_Harrison. Plantar fasciitisis a common cause of footpain in adults,with thepeak incidence occurring in people betweenthe agesof 40and 60 years. The painoriginatesatornearthesiteoftheplantarfasciaattachmenttothe medialtuberosity of the calcaneus.Severalfactorsthatincrease therisk of developing plantar fasciitis include obesity, pes planus (flat foot or absence of the foot arch when standing), pes cavus (high-arched foot), limited dorsiflexion of the ankle, prolonged standing, walking on hard surfaces, and faulty shoes. In runners, excessive running and a change to a harder running surface may precipitate plantar fasciitis.


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InternalMed_Harrison. The diagnosis of plantar fasciitis can usually be made on the basis of history and physical examination alone. Patients experience severe pain with the first steps on arising in the morning or following inactivity during the day. The pain usually lessens with weight-bearing activityduringtheday,onlytoworsenwithcontinuedactivity.Painismade worse on walking barefoot or up stairs. On examination, maximal tendernessis elicitedonpalpation over the inferiorheel corresponding to the site of attachment of the plantar fascia. Imaging studies may be indicated when the diagnosis is not clear. Plain radiographs may show heel spurs, which are of little diagnostic significance. Ultrasonography in plantar fasciitis can demonstrate thickening of the fascia and diffuse hypoechogenicity, indicating edema at the attachment of the plantar fascia to the calcaneus. MRI is a sensitive method for detecting plantar fasciitis, but it is usually not required for establishing the diagnosis.


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InternalMed_Harrison. The differential diagnosis of inferior heel pain includes calcaneal stress fractures, the spondyloarthritides, rheumatoid arthritis, gout, neoplastic or infiltrative bone processes, and nerve compression/ entrapment syndromes. Resolutionofsymptomsoccurswithin12monthsinmorethan80% of patients with plantar fasciitis. The patient is advised to reduce or discontinue activities that can exacerbate plantar fasciitis. Initial treatment consists of ice, heat, massage, and stretching. Orthotics provide medial arch support and can be effective. Foot strapping or taping are commonly performed, and some patients may benefit by wearing a


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InternalMed_Harrison. Periarticular Disorders of the Extremities 2250 night splint designed to keep the ankle in a neutral position. A short Acknowledgmentcourse of NSAIDs can be given to patients when the benefits outweigh This chapter represents a revised version of the chapter authored by the risks. Local glucocorticoid injections have also been shown to be Dr. Bruce C. Gilliland that was in the previous editions of Harrison’s. efficacious but may carry an increased risk for plantar fascia rupture. Dr. Gilliland passed away on February 17, 2007, and had been a Plantar fasciotomy is reserved for those patients who have failed to contributor to Harrison’s Principles of Internal Medicine since the improve after at least 6–12 months of conservative treatment. 11th edition. Approach to the Patient with Endocrine Disorders J. Larry Jameson The management of endocrine disorders requires a broad under-standing of intermediary metabolism, reproductive physiology, bone 399 SEC Tion 1 EnDoCRinology


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InternalMed_Harrison. Approach to the Patient with Endocrine Disorders metabolism, and growth. Accordingly, the practice of endocrinology is intimately linked to a conceptual framework for understanding hormone secretion, hormone action, and principles of feedback control (Chap. 400e). The endocrine system is evaluated primarily by measuring hormone concentrations, arming the clinician with valuable diagnostic information. Most disorders of the endocrine system are amenable to effective treatment once the correct diagnosis is determined. Endocrine deficiency disorders are treated with physiologic hormone replacement; hormone excess conditions, which usually are caused by benign glandular adenomas, are managed by removing tumors surgically or reducing hormone levels medically.


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InternalMed_Harrison. The specialty of endocrinology encompasses the study of glands and the hormones they produce. The term endocrine was coined by Starling to contrast the actions of hormones secreted internally (endocrine) with those secreted externally (exocrine) or into a lumen, such as the gastrointestinal tract. The term hormone, derived from a Greek phrase meaning “to set in motion,” aptly describes the dynamic actions of hormones as they elicit cellular responses and regulate physiologic processes through feedback mechanisms.


InternalMed_Harrison

InternalMed_Harrison. Unlike many other specialties in medicine, it is not possible to define endocrinology strictly along anatomic lines. The classic endocrine glands—pituitary, thyroid, parathyroid, pancreatic islets, adrenals, and gonads—communicate broadly with other organs through the nervous system, hormones, cytokines, and growth factors. In addition to its traditional synaptic functions, the brain produces a vast array of peptide hormones, and this has led to the discipline of neuroendocrinology. Through the production of hypothalamic releasing factors, the central nervous system (CNS) exerts a major regulatory influence over pituitary hormone secretion (Chap. 401e). The peripheral nervous system stimulates the adrenal medulla. The immune and endocrine systems are also intimately intertwined. The adrenal hormone cortisol is a powerful immunosuppressant. Cytokines and interleukins (ILs) have profound effects on the functions of the pituitary, adrenal, thyroid, and gonads. Common endocrine diseases


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InternalMed_Harrison. hormone cortisol is a powerful immunosuppressant. Cytokines and interleukins (ILs) have profound effects on the functions of the pituitary, adrenal, thyroid, and gonads. Common endocrine diseases such as autoimmune thyroid disease and type 1 diabetes mellitus are caused by dysregulation of immune surveillance and tolerance. Less common diseases such as polyglandular failure, Addison’s disease, and lymphocytic hypophysitis also have an immunologic basis.


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InternalMed_Harrison. The interdigitation of endocrinology with physiologic processes in other specialties sometimes blurs the role of hormones. For example, hormones play an important role in maintenance of blood pressure, intravascular volume, and peripheral resistance in the cardiovascular system. Vasoactive substances such as catecholamines, angiotensin II, endothelin, and nitric oxide are involved in dynamic changes of vascular tone in addition to their multiple roles in other tissues. The heart is the principal source of atrial natriuretic peptide, which acts in classic endocrine fashion to induce natriuresis at a distant target organ (the kidney). Erythropoietin, a traditional circulating hormone, is made in the kidney and stimulates erythropoiesis in bone marrow (Chap. 77). The kidney is also integrally involved in the renin-angiotensin axis (Chap. 406) and is a primary target of several hormones, including parathyroid hormone (PTH), mineralocorticoids, and vasopressin. The gastrointestinal tract


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InternalMed_Harrison. involved in the renin-angiotensin axis (Chap. 406) and is a primary target of several hormones, including parathyroid hormone (PTH), mineralocorticoids, and vasopressin. The gastrointestinal tract produces a surprising number of peptide hormones, such as cholecystokinin, ghrelin, gastrin, secretin, and vasoactive intestinal peptide, among many others. Carcinoid and islet tumors can secrete excessive amounts of these hormones, leading to specific clinical syndromes (Chap. 113). Many of these gastrointestinal hormones are also produced in the CNS, where their functions are poorly understood. Adipose tissue produces leptin, which acts centrally to control appetite, along with adiponectin, resistin, and other hormones that regulate metabolism. As hormones such as inhibin, ghrelin, and leptin are discovered, they become integrated into the science and practice of medicine on the basis of their functional roles rather than their tissues of origin.


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InternalMed_Harrison. Characterization of hormone receptors frequently reveals unexpected relationships to factors in nonendocrine disciplines. The growth hormone (GH) and leptin receptors, for example, are members of the cytokine receptor family. The G protein–coupled receptors (GPCRs), which mediate the actions of many peptide hormones, are used in numerous physiologic processes, including vision, smell, and neurotransmission. Endocrine diseases can be divided into three major types of conditions: (1) hormone excess, (2) hormone deficiency, and (3) hormone resistance (Table 399-1).


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InternalMed_Harrison. Syndromes of hormone excess can be caused by neoplastic growth of endocrine cells, autoimmune disorders, and excess hormone administration. Benign endocrine tumors, including parathyroid, pituitary, and adrenal adenomas, often retain the capacity to produce hormones, perhaps reflecting the fact that these tumors are relatively well differentiated. Many endocrine tumors exhibit subtle defects in their “set points” for feedback regulation. For example, in Cushing’s disease, impaired feedback inhibition of adrenocorticotropic hormone (ACTH) secretion is associated with autonomous function. However, the tumor cells are not completely resistant to feedback, as evidenced by ACTH suppression by higher doses of dexamethasone (e.g., high-dose dexamethasone test) (Chap. 406). Similar set point defects are also typical of parathyroid adenomas and autonomously functioning thyroid nodules.


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InternalMed_Harrison. The molecular basis of some endocrine tumors, such as the multiple endocrine neoplasia (MEN) syndromes (MEN 1, 2A, 2B), have provided important insights into tumorigenesis (Chap. 408). MEN 1 is characterized primarily by the triad of parathyroid, pancreatic islet, and pituitary tumors. MEN 2 predisposes to medullary thyroid carcinoma, pheochromocytoma, and hyperparathyroidism. The MEN1 gene, located on chromosome 11q13, encodes a putative tumor-suppressor gene, menin. Analogous to the paradigm first described for retinoblastoma, the affected individual inherits a mutant copy of the MEN1 gene, and tumorigenesis ensues after a somatic “second hit” Type of Endocrine Disorder Examples


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InternalMed_Harrison. Type of Endocrine Disorder Examples Multiple endocrine neoplasia (MEN) Autoimmune Iatrogenic Infectious/inflammatory Activating receptor mutations Hypofunction Pituitary adenomas, hyperparathyroidism, autonomous thyroid or adrenal nodules, pheochromocytoma Adrenal cancer, medullary thyroid cancer, carcinoid Ectopic ACTH, SIADH secretion MEN 1, MEN 2 Graves’ disease Cushing’s syndrome, hypoglycemia Subacute thyroiditis LH, TSH, Ca2+, PTH receptors, Gsα Hashimoto’s thyroiditis, type 1 diabetes mellitus, Addison’s disease, polyglandular failure Radiation-induced hypopituitarism, hypothyroidism, surgical Adrenal insufficiency, hypothalamic sarcoidosis GH, LHβ, FSHβ, vasopressin 21-Hydroxylase deficiency Kallmann syndrome, Turner’s syndrome, transcription factors Vitamin D deficiency, iodine deficiency Sheehan’s syndrome, adrenal insufficiency


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InternalMed_Harrison. Abbreviations: ACTH, adrenocorticotropic hormone; AR, androgen receptor; ER, estrogen receptor; FSH, follicle-stimulating hormone; GHRH, growth hormone–releasing hormone; GnRH, gonadotropin-releasing hormone; GR, glucocorticoid receptor; LH, luteinizing hormone; PPAR, peroxisome proliferator activated receptor; PTH, parathyroid hormone; SIADH, syndrome of inappropriate antidiuretic hormone; TR, thyroid hormone receptor; TSH, thyroid-stimulating hormone; VDR, vitamin D receptor. leads to loss of function of the normal MEN1 gene (through deletion or point mutations).


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InternalMed_Harrison. leads to loss of function of the normal MEN1 gene (through deletion or point mutations). In contrast to inactivation of a tumor-suppressor gene, as occurs in MEN 1 and most other inherited cancer syndromes, MEN 2 is caused by activating mutations in a single allele. In this case, activating mutations of the RET protooncogene, which encodes a receptor tyrosine kinase, leads to thyroid C cell hyperplasia in childhood before the development of medullary thyroid carcinoma. Elucidation of this pathogenic mechanism has allowed early genetic screening for RET mutations in individuals at risk for MEN 2, permitting identification of those who may benefit from prophylactic thyroidectomy and biochemical screening for pheochromocytoma and hyperparathyroidism.


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InternalMed_Harrison. Mutations that activate hormone receptor signaling have been identified in several GPCRs. For example, activating mutations of the luteinizing hormone (LH) receptor cause a dominantly transmitted form of male-limited precocious puberty, reflecting premature stimulation of testosterone synthesis in Leydig cells (Chap. 411). Activating mutations in these GPCRs are located predominantly in the trans-membrane domains and induce receptor coupling to Gsα even in the absence of hormone. Consequently, adenylate cyclase is activated, and cyclic adenosine monophosphate (AMP) levels increase in a manner that mimics hormone action. A similar phenomenon results from activating mutations in Gsα. When these mutations occur early in development, they cause McCune-Albright syndrome. When they occur only in somatotropes, the activating Gsα mutations cause GH-secreting tumors and acromegaly (Chap. 403).


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InternalMed_Harrison. In autoimmune Graves’ disease, antibody interactions with the thyroid-stimulating hormone (TSH) receptor mimic TSH action, leading to hormone overproduction (Chap. 405). Analogous to the effects of activating mutations of the TSH receptor, these stimulating autoantibodies induce conformational changes that release the receptor from a constrained state, thereby triggering receptor coupling to G proteins. Most examples of hormone deficiency states can be attributed to glandular destruction caused by autoimmunity, surgery, infection, inflammation, infarction, hemorrhage, or tumor infiltration (Table 399-1). Autoimmune damage to the thyroid gland (Hashimoto’s thyroiditis) and pancreatic islet β cells (type 1 diabetes mellitus) is a prevalent cause of endocrine disease. Mutations in a number of hormones, hormone receptors, transcription factors, enzymes, and channels can also lead to hormone deficiencies.


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InternalMed_Harrison. Most severe hormone resistance syndromes are due to inherited defects in membrane receptors, nuclear receptors, or the pathways that transduce receptor signals. These disorders are characterized by defective hormone action despite the presence of increased hormone levels. In complete androgen resistance, for example, mutations in the androgen receptor result in a female phenotypic appearance in genetic (XY) males, even though LH and testosterone levels are increased (Chap. 408). In addition to these relatively rare genetic disorders, more common acquired forms of functional hormone resistance include insulin resistance in type 2 diabetes mellitus, leptin resistance in obesity, and GH resistance in catabolic states. The pathogenesis of functional resistance involves receptor downregulation and postreceptor desensitization of signaling pathways; functional forms of resistance are generally reversible.


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InternalMed_Harrison. Because most glands are relatively inaccessible, the physical examination usually focuses on the manifestations of hormone excess or deficiency as well as direct examination of palpable glands, such as the thyroid and gonads. For these reasons, it is important to evaluate patients in the context of their presenting symptoms, review of systems, family and social history, and exposure to medications that may affect the endocrine system. Astute clinical skills are required to detect subtle symptoms and signs suggestive of underlying endocrine disease. For example, a patient with Cushing’s syndrome may manifest specific findings, such as central fat redistribution, striae, and proximal muscle weakness, in addition to features seen commonly in the general population, such as obesity, plethora, hypertension, and glucose intolerance. Similarly, the insidious onset of hypothyroidism— with mental slowing, fatigue, dry skin, and other features—can be difficult to distinguish from similar,


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InternalMed_Harrison. hypertension, and glucose intolerance. Similarly, the insidious onset of hypothyroidism— with mental slowing, fatigue, dry skin, and other features—can be difficult to distinguish from similar, nonspecific findings in the general population. Clinical judgment that is based on knowledge of disease prevalence and pathophysiology is required to decide when to embark on more extensive evaluation of these disorders. Laboratory testing plays an essential role in endocrinology by allowing quantitative assessment of hormone levels and dynamics. Radiologic imaging tests such as computed tomography (CT) scan, magnetic resonance imaging (MRI), thyroid scan, and ultrasound are also used for the diagnosis of endocrine disorders. However, these tests generally are employed only after a hormonal abnormality has been established by biochemical testing.


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InternalMed_Harrison. Immunoassays are the most important diagnostic tool in endocrinology, as they allow sensitive, specific, and quantitative determination of steady-state and dynamic changes in hormone concentrations. Immunoassays use antibodies to detect specific hormones. For many peptide hormones, these measurements are now configured to use two different antibodies to increase binding affinity and specificity. There are many variations of these assays; a common format involves using one antibody to capture the antigen (hormone) onto an immobilized surface and a second antibody, coupled to a chemiluminescent (immunochemiluminescent assay [ICMA]) or radioactive (immunoradiometric assay [IRMA]) signal, to detect the antigen. These assays are sensitive enough to detect plasma hormone concentrations in the picomolar to nanomolar range, and they can readily distinguish structurally related proteins, such as PTH from PTH-related peptide (PTHrP). A variety of other techniques are used to measure specific


InternalMed_Harrison

InternalMed_Harrison. picomolar to nanomolar range, and they can readily distinguish structurally related proteins, such as PTH from PTH-related peptide (PTHrP). A variety of other techniques are used to measure specific hormones, including mass spectroscopy, various forms of chromatography, and enzymatic methods; bioassays are now rarely used.


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InternalMed_Harrison. Most hormone measurements are based on plasma or serum samples. However, urinary hormone determinations remain useful for the evaluation of some conditions. Urinary collections over 24 h provide an integrated assessment of the production of a hormone or metabolite, many of which vary during the day. It is important to assure complete collections of 24-h urine samples; simultaneous measurement of creatinine provides an internal control for the adequacy of collection and can be used to normalize some hormone measurements. A 24-h urine free cortisol measurement largely reflects the amount of unbound cortisol, thus providing a reasonable index of biologically available hormone. Other commonly used urine determinations include 17-hydroxycorticosteroids, 17-ketosteroids, vanillylmandelic acid, metanephrine, catecholamines, 5-hydroxyindoleacetic acid, and calcium.


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InternalMed_Harrison. The value of quantitative hormone measurements lies in their cor-2253 rect interpretation in a clinical context. The normal range for most hormones is relatively broad, often varying by a factor of twoto tenfold. The normal ranges for many hormones are sexand age-specific. Thus, using the correct normative database is an essential part of interpreting hormone tests. The pulsatile nature of hormones and factors that can affect their secretion, such as sleep, meals, and medications, must also be considered. Cortisol values increase fivefold between midnight and dawn; reproductive hormone levels vary dramatically during the female menstrual cycle.


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InternalMed_Harrison. For many endocrine systems, much information can be gained from basal hormone testing, particularly when different components of an endocrine axis are assessed simultaneously. For example, low testosterone and elevated LH levels suggest a primary gonadal problem, whereas a hypothalamic-pituitary disorder is likely if both LH and testosterone are low. Because TSH is a sensitive indicator of thyroid function, it is generally recommended as a first-line test for thyroid disorders. An elevated TSH level is almost always the result of primary hypothyroidism, whereas a low TSH is most often caused by thyrotoxicosis. These predictions can be confirmed by determining the free thyroxine level. In the less common circumstance when free thyroxine and TSH are both low, it is important to consider secondary hypopituitarism caused by hypothalamic-pituitary disease. Elevated calcium and PTH levels suggest hyperparathyroidism, whereas PTH is suppressed in hypercalcemia caused by malignancy or


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InternalMed_Harrison. secondary hypopituitarism caused by hypothalamic-pituitary disease. Elevated calcium and PTH levels suggest hyperparathyroidism, whereas PTH is suppressed in hypercalcemia caused by malignancy or granulomatous diseases. A suppressed ACTH in the setting of hypercortisolemia, or increased urine free cortisol, is seen with hyperfunctioning adrenal adenomas.


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InternalMed_Harrison. It is not uncommon, however, for baseline hormone levels associated with pathologic endocrine conditions to overlap with the normal range. In this circumstance, dynamic testing is useful to separate the two groups further. There are a multitude of dynamic endocrine tests, but all are based on principles of feedback regulation, and most responses can be rationalized based on principles that govern the regulation of endocrine axes. Suppression tests are used in the setting of suspected endocrine hyperfunction. An example is the dexamethasone suppression test used to evaluate Cushing’s syndrome (Chaps. 403 and 406). Stimulation tests generally are used to assess endocrine hypofunction. The ACTH stimulation test, for example, is used to assess the adrenal gland response in patients with suspected adrenal insufficiency. Other stimulation tests use hypothalamic-releasing factors such as corticotropin-releasing hormone (CRH) and growth hormone–releasing hormone (GHRH) to evaluate pituitary


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InternalMed_Harrison. adrenal insufficiency. Other stimulation tests use hypothalamic-releasing factors such as corticotropin-releasing hormone (CRH) and growth hormone–releasing hormone (GHRH) to evaluate pituitary hormone reserve (Chap. 403). Insulin-induced hypoglycemia also evokes pituitary ACTH and GH responses. Stimulation tests based on reduction or inhibition of endogenous hormones are now used infrequently. Examples include metyrapone inhibition of cortisol synthesis and clomiphene inhibition of estrogen feedback.


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InternalMed_Harrison. Many endocrine disorders are prevalent in the adult population (Table 399-2) and can be diagnosed and managed by general internists, family practitioners, or other primary health care providers. The high prevalence and clinical impact of certain endocrine diseases justifies vigilance for features of these disorders during routine physical examinations; laboratory screening is indicated in selected high-risk populations. Approach to the Patient with Endocrine Disorders Approx. Prevalence in Disorder Adultsa Screening/Testing Recommendationsb Chapter(s) Hypogonadism, male Gynecomastia 35% 5–10%, women 0.5–2%, men 1–3%, women 0.1%, men 2–5% palpable >25% by ultrasound 5–10%, women 2–5%, men 0.1–0.5%, women > men 10%, couples 5–10%, women


InternalMed_Harrison

InternalMed_Harrison. Hypogonadism, male Gynecomastia 35% 5–10%, women 0.5–2%, men 1–3%, women 0.1%, men 2–5% palpable >25% by ultrasound 5–10%, women 2–5%, men 0.1–0.5%, women > men 10%, couples 5–10%, women Median age, 51 15% in women with amenorrhea or galactorrhea 0.2%, men 0.03%, women Calculate BMI Measure waist circumference Exclude secondary causes Consider comorbid complications Beginning at age 45, screen every 3 years, or earlier in high-risk groups: Fasting plasma glucose (FPG) >126 mg/dL Random plasma glucose >200 mg/dL An elevated HbA1c Consider comorbid complications Cholesterol screening at least every 5 years; more often in high-risk groups Lipoprotein analysis (LDL, HDL) for increased cholesterol, CAD, diabetes Consider secondary causes Measure waist circumference, FPG, BP, lipids TSH; confirm with free T4 Screen women after age 35 and every 5 years thereafter TSH, free T4


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InternalMed_Harrison. Physical examination of thyroid Fine-needle aspiration biopsy Bone mineral density measurements in women >65 years or in post- menopausal women or men at risk Exclude secondary causes Serum calcium PTH, if calcium is elevated Assess comorbid conditions Investigate both members of couple Semen analysis in male Assess ovulatory cycles in female Specific tests as indicated Free testosterone, DHEAS Consider comorbid conditions Free testosterone, DHEAS Exclude secondary causes Additional tests as indicated FSH PRL level MRI, if not medication-related Careful history, PRL, testosterone Consider secondary causes (e.g., diabetes) Testosterone, LH Often, no tests are indicated Consider Klinefelter’s syndrome Consider medications, hypogonadism, liver disease Karyotype Testosterone Measure serum 25-OH vitamin D Consider secondary causes Karyotype Consider comorbid conditions 411, 412 aThe prevalence of most disorders varies among ethnic groups and with aging. Data based primarily on U.S.


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InternalMed_Harrison. 25-OH vitamin D Consider secondary causes Karyotype Consider comorbid conditions 411, 412 aThe prevalence of most disorders varies among ethnic groups and with aging. Data based primarily on U.S. population. bSee individual chapters for additional information on evaluation and treatment. Early testing is indicated in patients with signs and symptoms of disease and in those at increased risk.


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InternalMed_Harrison. Abbreviations: BMI, body mass index; BP, blood pressure; CAD, coronary artery disease; DHEAS, dehydroepiandrosterone; FSH, follicle-stimulating hormone; HDL, high-density lipoprotein; LDL, low-density lipoprotein; LH, luteinizing hormone; MRI, magnetic resonance imaging; PRL, prolactin; PTH, parathyroid hormone; TSH, thyroid-stimulating hormone. Mechanisms of Hormone Action J. Larry Jameson CLASSES OF HORMONES Hormones can be divided into five major types: (1) amino acid deriva-400e tives such as dopamine, catecholamine, and thyroid hormone; (2) small neuropeptides such as gonadotropin-releasing hormone (GnRH), thyrotropin-releasing hormone (TRH), somatostatin, and vasopressin; (3) large proteins such as insulin, luteinizing hormone (LH), and parathyroid hormone (PTH); (4) steroid hormones such as cortisol and estrogen that are synthesized from cholesterol-based precursors; and (5) vitamin derivatives such as retinoids (vitamin A) and vitamin


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InternalMed_Harrison. D. A variety of peptide growth factors, most of which act locally, share actions with hormones. As a rule, amino acid derivatives and peptide hormones interact with cell-surface membrane receptors. Steroids, thyroid hormones, vitamin D, and retinoids are lipid-soluble and interact with intracellular nuclear receptors, although many also interact with membrane receptors or intracellular signaling proteins as well. Hormones and receptors can be grouped into families, reflecting structural similarities and evolutionary origins (Table 400e-1). The evolution of these families generates diverse but highly selective pathways of hormone action. Recognition of these relationships has proven useful for extrapolating information gleaned from one hormone or receptor to other family members.


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InternalMed_Harrison. The glycoprotein hormone family, consisting of thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), LH, and human chorionic gonadotropin (hCG), illustrates many features of related hormones. The glycoprotein hormones are heterodimers that share the α subunit in common; the β subunits are distinct and confer β-Adrenergic, LH, FSH, TSH GSα, adenylate Stimulation of cyclic AMP procyclase duction, protein kinase A Glucagon, PTH, PTHrP, Ca2+ channels Calmodulin, Ca2+-dependent ACTH, MSH, GHRH, CRH α-Adrenergic, Giα Inhibition of cyclic AMP somatostatin Activation of K+, Ca2+ channels TRH, GnRH Gq, G11 Phospholipase C, diacylglycerol, IP3, protein kinase C, voltage-dependent Ca2+ channels Insulin, IGF-I Tyrosine MAP kinases, PI 3-kinase; AKT kinases, IRS EGF, NGF Tyrosine Raf, MAP kinases, RSK kinases, ras GH, PRL JAK, tyrosine STAT, MAP kinase, PI 3-kinase, kinases IRS-1 Activin, TGF-β, MIS Serine kinase Smads


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InternalMed_Harrison. EGF, NGF Tyrosine Raf, MAP kinases, RSK kinases, ras GH, PRL JAK, tyrosine STAT, MAP kinase, PI 3-kinase, kinases IRS-1 Activin, TGF-β, MIS Serine kinase Smads Abbreviations: IP3, inositol triphosphate; IRS, insulin receptor substrates; MAP, mitogenactivated protein; MSH, melanocyte-stimulating hormone; NGF, nerve growth factor; PI, phosphatidylinositol; RSK, ribosomal S6 kinase; TGF-β, transforming growth factor β. For all other abbreviations, see text. Note that most receptors interact with multiple effectors and activate networks of signaling pathways. specific biologic actions. The overall three-dimensional architecture 400e-1 of the β subunits is similar, reflecting the locations of conserved disulfide bonds that restrain protein conformation. The cloning of the β-subunit genes from multiple species suggests that this family arose from a common ancestral gene, probably by gene duplication and subsequent divergence to evolve new biologic functions.