Arthritis Associated with Systemic Disease, and Other Arthritides

2875CHAPTER 374

surface. Initially, the process of periosteal new bone formation involves

the proximal and distal diaphyses of the tibia, fibula, radius, and ulna

and, less frequently, the femur, 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 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.

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 periosteum. Stimulation of fibroblasts by PDGF

and transforming growth factor β results in cell growth and collagen

synthesis. Elevated plasma levels of von Willebrand factor antigen

have been found 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.

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.

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. Patients may also experience 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 a consequence 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 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 abnormalities observed 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.

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 thickness at the distal interphalangeal joint. An objective measurement 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 the bedside, clubbing can be 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 between the

bases of the opposing fingernails; when clubbing is present, 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 the distal forearms and legs or gentle percussion of distal

long bones like the tibia may be quite painful.

Patients may experience joint pain, most often in the ankles, wrists,

and knees. Joint effusions may be present but are usually 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 onset

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.

HOA occurs in 5–10% of patients with intrathoracic malignancies,

the most common being bronchogenic carcinoma and pleural tumors

(Table 374-3). 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.

Unilateral clubbing has been found in association with aneurysms

of major extremity arteries, with infected arterial grafts, and with

FIGURE 374-2 Clubbing of the fingers. (Photo contributor Alan B. Storrow, MD).

2876 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

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.

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 portion of the metacarpal and phalangeal bones. Significant

hand-joint pain may occur, which 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.

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.

TREATMENT

Hypertrophic Osteoarthropathy

The treatment of HOA aims to identify and treat the associated disorder. 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.

■ COMPLEX REGIONAL PAIN SYNDROME

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. Complex regional

pain syndrome, including its treatment, is covered in greater detail in

Chap. 440.

■ TIETZE SYNDROME AND COSTOCHONDRITIS

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 restrict

the former term to pain of the costochondral articulations without

swelling. Costochondritis is observed in patients aged >40 years; it

tends to affect the third, fourth, and fifth costochondral joints, and

occurs more often in women. Both syndromes may superficially 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 and

causes reproducible pain below the rib cage. 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’s 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, NSAIDs, and local

glucocorticoid injections usually relieve symptoms of costochondritis/

Tietze’s syndrome. Care should be taken to avoid overdiagnosing these

syndromes in patients with acute chest pain syndromes.

■ MYOFASCIAL PAIN SYNDROME

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 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. Myofascial pain most often involves

the posterior neck, low back, shoulders, and chest. Chronic pain in

the muscles of the posterior 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 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

TABLE 374-3 Disorders Associated with Hypertrophic

Osteoarthropathy

Pulmonary

Bronchogenic carcinoma and other neoplasms

Lung abscesses, empyema, bronchiectasis

Chronic interstitial pneumonitis

Cystic fibrosis

Sarcoidosis

Gastrointestinal

Inflammatory bowel disease

Sprue

Neoplasms: esophagus, liver, bowel

Cardiovascular

Cyanotic congenital heart disease

Subacute bacterial endocarditis

Infected arterial graftsa

Aortic aneurysmb

Aneurysm of major extremity arterya

Patent ductus arteriosusb

Arteriovenous fistula of major extremity vessela

Thyroid (thyroid acropachy)

Hyperthyroidism (Graves’ disease)

a

Unilateral involvement. b

Bilateral lower-extremity involvement.

Arthritis Associated with Systemic Disease, and Other Arthritides

2877CHAPTER 374

the affected area also may be beneficial. Patients should be instructed

in methods to prevent muscle stresses related to work and recreation.

The prognosis in most patients is good. In some patients, regionally

localized myofascial pain syndrome may evolve into more generalized

fibromyalgia (Chap. 373). Nonrestorative sleep is a common accompaniment in these patients and may need to be specifically addressed.

■ NEOPLASIAS AND ARTHRITIS

Primary tumors and tumor-like disorders of synovium are uncommon

but should be considered in the differential diagnosis of monarticular

joint disease. In addition, metastases to bone and primary bone tumors

adjacent to a joint may produce joint symptoms.

Pigmented villonodular synovitis (PVNS), likely the same process

causing tenosynovial giant cell tumors, is characterized by the slowly

progressive, benign proliferation of tenosynovial tissue. This usually

involves a single large joint or tendon. The most common age of onset

is in the third decade, and women are affected slightly more often than

men. The proliferating tissue usually displays clonal chromosomal

translocations; most of these aberrations appear to involve the colony

stimulating factor-1 (CSF-1) pathway, which influences the proliferation and maturation of mononuclear cells and macrophages.

The synovium has a brownish color and numerous large, fingerlike

villi that fuse to form pedunculated nodules. There is marked hyperplasia of synovial cells in the stroma of the villi. Hemosiderin and lipids

are found in the cytoplasm of macrophages and in the interstitial tissue.

Multinucleated giant cells may be present. The proliferative synovium

may behave as a simple mass or as a more diffuse invasive tissue growing into the adjacent cartilage and bone.

The clinical picture of PVNS is characterized by the insidious onset

of progressive swelling and pain in affected joints or tendons, most

commonly the knee or flexor tendons of the hand. Other commonly

affected joints include the hips, ankles, calcaneocuboid joints, elbows,

and small joints of the fingers or toes; multifocal form is less common.

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. 374-3).

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.

The treatment for PVNS, if needed, is complete open or arthroscopic synovectomy. Irradiation of the involved joint has been successful in some patients but may cause a delayed malignant transformation.

Treatment directed at inhibiting the CSF-1 pathway activated kinase

has demonstrated efficacy.

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

growths may recur.

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 sites include the buttocks, abdominal wall,

retroperitoneum, and mediastinum. The diagnosis is made by biopsy

and must be distinguished from PVNS. 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 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.

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 systemic inflammatory arthritis with severe joint

pain and fever. In adults, chronic and acute myeloid leukemia rarely

infiltrate the synovium. Hairy cell leukemia has a peculiar tendency

to cause episodic inflammatory oligoarthritis and tenosynovitis; these

episodes are dramatic and mimic acute gout flares. They respond to

potent anti-inflammatory therapy with glucocorticoids; with remission

of the leukemia, they may abate. Lymphomas, usually of T-cell origin,

may also involve the synovium.

Carcinomas can be associated with several paraneoplastic articular

syndromes, including HOA (discussed above). Acute palmar fasciitis

with polyarthritis is a well-described but rare condition associated with

certain cancers, mainly adenocarcinomas. Clinically, this syndrome is

abrupt in onset, with pain in the metacarpophalangeal and proximal

interphalangeal joints of the hands and rapidly evolving contractures of

the fingers due to thickening of the palmar (flexor) tendons. A similar

syndrome, although less dramatic in onset, can occur in diabetics. Paraneoplastic arthritis has been described and may occur in several patterns: asymmetric disease predominantly affecting the lower extremity

joints and symmetric polyarthritiswith 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 question

of an underlying malignancy 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.

Immune checkpoint inhibitors, increasingly used to treat various

malignancies, are now well recognized to frequently elicit severe autoimmune, inflammatory, organ-targeted reactions including myositis,

polymyalgia rheumatica, and polyarthritis.

FIGURE 374-3 Pigmented villonodular synovitis. MRI gradient echo sagittal image

showing a mass that abuts the neck of the talus with marked low signal typical of

tissue containing hemosiderin. (Courtesy of Donald Flemming, MD; with permission.)

2878 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

■ FURTHER READING

Aguilar C et al: Bone and joint disease in sickle cell disease. Hematol

Oncol Clin North Am 19:929, 2005.

Botek G et al: Charcot neuroarthropathy: An often overlooked complication of diabetes. Cleve Clin J Med 77:593, 2010.

Dallos T et al: Idiopathic hand osteoarthritis vs haemochromatosis

arthropathy: A clinical, functional and radiographic study. Rheumatology 52:910, 2013.

Guggenbuhl P et al: Miscellaneous non-inflammatory musculoskeletal conditions. Haemochromatosis: The bone and the joint. Best Pract

Res Clin Rheumatol 25:649, 2011.

Kedar E, Gardner GC: Lipid-associated rheumatologic syndromes.

Rheum Dis Clin North Am 39:481, 2013.

Killinger Z et al: Arthropathy in acromegaly. Rheum Dis Clin North

Am 36:713, 2010.

Pineda C, Martínez-Lavín M: Hypertrophic osteoarthropathy:

What a rheumatologist should know about this uncommon condition. Rheum Dis Clin North Am 39:383, 2013.

Stephan SR et al: Pigmented villonodular synovitis. A comprehensive

review and proposed treatment algorithm. JBJS Rev 4:1, 2016.

Vanderhave KL et al: Musculoskeletal care of the hemophiliac patient.

J Am Acad Orthop Surg 20:553, 2012.

Periarticular disorders are common musculoskeletal abnormalities

that can affect people throughout a wide range of ages. This chapter

discusses some of the more common periarticular disorders.

■ BURSITIS

Bursitis is inflammation of a bursa, which is a thin-walled sac lined

with synovial tissue. The function of the bursa is to facilitate movement of tendons and muscles over bony prominences. Excessive frictional forces 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 the deltoid muscle. Bursitis 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 upper thigh and have tenderness over

the posterior aspect of the greater trochanter. External rotation and

resisted abduction of the hip elicit pain, as will direct pressure applied

to the bursa. 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 as well as examining the fluid for urate crystals. Achilles bursitis

involves the bursa located above the insertion of the tendon 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, or trauma. Ischial bursitis affects the bursa

separating the gluteus medius from the ischial tuberosity and develops

from prolonged sitting and pivoting on hard surfaces. Iliopsoas bursitis

affects the bursa that lies between the iliopsoas muscle and hip joint

375 Periarticular Disorders

of the Extremities

Carol A. Langford

Acromion Subacrominal

bursa

Humerus

Supraspinatus

Scapula

Glenohumeral

joint capsule Inferior (axillary) pouch

Deltoid

Glenoid

Greater

tubercle

"Critical zone" of

supraspinatus

tendon

FIGURE 375-1 Coronal section of the shoulder illustrating the relationships of the

glenohumeral joint, the joint capsule, the subacromial bursa, and the rotator cuff

(supraspinatus tendon). (Reproduced with permission from F Kozin, in WJ Koopman

[ed]: Arthritis and Allied Conditions, 13th ed, Baltimore, Williams & Wilkins, 1997.)

and is lateral to the femoral vessels. Pain is experienced over this area

and is made worse 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 any 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.

■ ROTATOR CUFF TENDINITIS AND

IMPINGEMENT SYNDROME

Tendinitis of the rotator cuff is the major cause of a painful shoulder

and is currently thought to be caused by inflammation of the tendon(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

supraspinatus tendon is the most often affected, probably because of its

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. 375-1). The tendon

of the infraspinatus and that of the long head of the biceps are less

commonly involved. Subacromial bursitis also accompanies this syndrome. Symptoms can appear without a triggering cause or 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 aged >40 years 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.

Periarticular Disorders of the Extremities

2879CHAPTER 375

Although any tendon can be affected, the tendons of the lower extremities are most often impacted, particularly the Achilles tendon. The

pathophysiologic mechanisms responsible for drug-induced tendinopathies remain unknown. Presenting features include pain and

potentially swelling over the tendon, although some patients may first

present with tendon rupture. Ultrasound and MRI can provide information on tendon structure and integrity in support of the diagnosis.

When suspected, the potential agent should be withdrawn and not

reintroduced where possible. Tendon ruptures may require surgery.

■ ILIOTIBIAL BAND SYNDROME

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, poorly fitted shoes, or continuous running on uneven terrain.

Treatment consists of rest, NSAIDs, physical therapy, and addressing

risk factors such as shoes and running surface. Glucocorticoid injection into the area of tenderness can provide relief, but running must be

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.

■ ADHESIVE CAPSULITIS

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 most often

develops in the setting of reduced arm mobility following bursitis or

tendinitis of the shoulder, fractures, or recovery from surgery but can

occur without an antecedent event. It has been associated with systemic

disorders such as diabetes mellitus, chronic pulmonary disease, myocardial infarction, and thyroid disease. Pathologically, the capsule of

the shoulder is thickened, and a mild chronic inflammatory infiltrate

and fibrosis may be present.

Adhesive capsulitis occurs more commonly in women aged

>50 years. 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 movements 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.

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.

■ LATERAL EPICONDYLITIS

Lateral epicondylitis, also known as tennis elbow, is a painful condition

involving the soft tissue over the lateral aspect of the elbow. The pain

originates at or near the site of attachment of the common extensors

to 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.

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 established

by ultrasound, magnetic resonance imaging (MRI), or arthrogram.

Surgical repair may be necessary in patients who fail to respond to

conservative measures. In patients with moderate-to-severe tears and

functional loss, surgery is indicated.

■ CALCIFIC TENDINITIS

This condition is characterized by deposition of calcium salts, 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.

■ BICIPITAL TENDINITIS AND RUPTURE

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

healthy and active patient, it should be repaired surgically as soon as

possible after the rupture occurs. 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.

■ DE QUERVAIN’S TENOSYNOVITIS

In this condition, inflammation involves the abductor pollicis longus and the extensor pollicis brevis as these tendons pass through a

fibrous sheath at the radial styloid process. The usual cause is repetitive

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.

■ PATELLAR TENDINITIS

Tendinitis involves the patellar tendon at its attachment to the lower

pole of the patella. Patients may experience pain when jumping during

sports, 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.

■ DRUG-INDUCED TENDINOPATHIES

With the broadening range of available pharmacologic agents, the

potential for drug-induced tendinopathies has become increasingly

recognized. The drug classes most associated with tendinopathies

include quinolones, glucocorticoids, aromatase inhibitors, and statins.

2880 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

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 experience mild pain but, with

care, can usually avoid the return of debilitating pain. Occasionally,

surgical release of the extensor aponeurosis may be necessary.

■ MEDIAL EPICONDYLITIS

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

aged >35 years and is much less common than lateral epicondylitis. It

occurs most often in work-related repetitive activities and 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, 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.

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.

■ PLANTAR FASCIITIS

Plantar fasciitis is a common cause of foot pain in adults, with the peak

incidence occurring in people between the ages of 40 and 60 years. The

pain originates at or near the site of the plantar fascia attachment to the

medial tuberosity of the calcaneus. Several factors that increase the risk

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.

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

activity only to increase with continued activity. Pain is made worse on

walking barefoot or up stairs. On examination, maximal tenderness is

elicited on palpation over the inferior heel 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.

Resolution of symptoms occurs within 12 months in >80% of

patients with plantar fasciitis. Initial treatment consists of ice, heat,

massage, stretching, and eliminating inciting activities. Orthotics provide medial arch support and can be effective. Some patients may benefit from foot strapping or taping or by wearing a night splint designed

to keep the ankle in a neutral position. A short course of NSAIDs can

be given to patients when the benefits outweigh the risks. Local glucocorticoid injections have also been shown to be efficacious but may

carry an increased risk for plantar fascia rupture. Plantar fasciotomy

is reserved for those patients who have failed to improve after at least

6–12 months of conservative treatment.

■ FURTHER READING

Buchbinder R: Plantar fasciitis. N Engl J Med 350:2159, 2004.

Greis AC et al: Evaluation and nonsurgical management of rotator cuff

calcific tendinopathy. Orthop Clin North Am 46:293, 2015.

Harrison AK, Flatow EL: Subacromial impingement syndrome.

J Am Acad Orthop Surg 19:701, 2011.

Kirchgesner T et al: Drug-induced tendinopathy: From physiology to

clinical applications. Joint Bone Spine 81:485, 2014.

Neviaser AS, Neviaser RJ: Adhesive capsulitis of the shoulder. J Am

Acad Orthop Surg 19:536, 2011.

Section 1 Endocrinology

Endocrinology and Metabolism PART 12

376 Approach to the

Patient with Endocrine

Disorders

J. Larry Jameson

The management of endocrine disorders requires a broad understanding of intermediary metabolism, reproductive physiology, bone

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. 377). 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 established. 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.

SCOPE OF ENDOCRINOLOGY

Classically, the specialty of endocrinology encompasses the study

of glands and the hormones they produce. Over time, the field has

expanded because of the discovery of hormones and growth factors

produced by the brain, gastrointestinal (GI) tract, musculoskeletal system, and other nonglandular organs. 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 GI 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.

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. 378). 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 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. Immune therapies for cancer and various autoimmune diseases can initiate autoimmune endocrine disease

as a side effect of treatment.

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. 63).

The kidney is also integrally involved in the renin-angiotensin axis

(Chap. 386) and is a primary target of several hormones, including

parathyroid hormone (PTH), mineralocorticoids, fibroblast growth

factor 23 (FGF23), and vasopressin. The GI tract produces a vast array

of peptide hormones, such as glucagon-like peptide 1 (GLP1), 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. 84). Many of these GI 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.

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.

PATHOLOGIC MECHANISMS OF

ENDOCRINE DISEASE

Endocrine diseases can be divided into three major types of conditions:

(1) hormone excess, (2) hormone deficiency, and (3) hormone resistance (Table 376-1).

■ CAUSES OF HORMONE EXCESS

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,

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. 386). Similar set point defects are also typical of parathyroid adenomas and autonomously functioning thyroid nodules.

The molecular basis of some endocrine tumors, such as the multiple

endocrine neoplasia (MEN) syndromes (MEN1, 2A, 2B), has provided

important insights into tumorigenesis (Chap. 388). MEN1 is characterized primarily by the triad of parathyroid, pancreatic islet, and

pituitary tumors. MEN2 predisposes to medullary thyroid carcinoma,

pheochromocytoma, and hyperparathyroidism. The MEN1 gene,

located on chromosome 11q13, encodes a 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” 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

MEN1 and most other inherited cancer syndromes, MEN2 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

2882 PART 12 Endocrinology and Metabolism

individuals at risk for MEN2, permitting identification of those who

may benefit from prophylactic thyroidectomy and biochemical screening for pheochromocytoma and hyperparathyroidism.

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. 391). Activating

mutations in these GPCRs are located predominantly in the transmembrane domains and induce receptor coupling to Gs

α 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 Gs

α. When these mutations occur early in development, they cause McCune-Albright syndrome. When they occur

only in somatotropes, the activating Gs

α mutations cause GH-secreting

tumors and acromegaly (Chap. 380).

In autoimmune Graves’ disease, antibody interactions with the

thyroid-stimulating hormone (TSH) receptor mimic TSH action, leading

to hormone overproduction (Chap. 382). Analogous to the effects of activating mutations of the TSH receptor, these stimulating autoantibodies

induce conformational changes in the TSH receptor that release it from

a constrained state, thereby triggering receptor coupling to G proteins.

■ CAUSES OF HORMONE DEFICIENCY

Most examples of hormone deficiency states can be attributed to glandular destruction caused by autoimmunity, surgery, infection, inflammation, infarction, hemorrhage, or tumor infiltration (Table 376-1).

Autoimmune damage to the thyroid gland (Hashimoto’s thyroiditis)

and pancreatic islet β cells (type 1 diabetes mellitus) are examples

of relatively common endocrine diseases. Mutations in a number of

hormones, hormone receptors, transcription factors, enzymes, and

channels can also lead to hormone deficiencies.

■ HORMONE RESISTANCE

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. 388). 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.

■ CLINICAL EVALUATION OF

ENDOCRINE DISORDERS

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, skin 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, nonspecific findings in the general population.

Clinical judgment that is based on knowledge of disease prevalence

TABLE 376-1 Causes of Endocrine Dysfunction

TYPE OF ENDOCRINE DISORDER EXAMPLES

Hyperfunction

Neoplastic

Benign

Malignant

Ectopic

Multiple endocrine neoplasia (MEN)

Autoimmune

Iatrogenic

Infectious/inflammatory

Activating receptor mutations

Pituitary adenomas, hyperparathyroidism, autonomous thyroid or adrenal nodules

Adrenal cancer, medullary thyroid cancer, carcinoid

Ectopic ACTH, SIADH secretion

MEN1, MEN2

Graves’ disease

Cushing’s syndrome, hypoglycemia

Subacute thyroiditis

LH, TSH, Ca2+, PTH receptors, Gs

α

Hypofunction

Autoimmune

Iatrogenic

Infectious/inflammatory

Hormone mutations

Enzyme defects

Developmental defects

Nutritional/vitamin deficiency

Hemorrhage/infarction

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’s syndrome, Turner’s syndrome, transcription factors

Vitamin D deficiency, iodine deficiency

Sheehan’s syndrome, adrenal insufficiency

Hormone Resistance

Receptor mutations

Membrane

Nuclear

Signaling pathway mutations

Postreceptor

GH, vasopressin, LH, FSH, ACTH, GnRH, GHRH, PTH, leptin, Ca2+

AR, TR, VDR, ER, GR, PPARγ

Albright’s hereditary osteodystrophy

Type 2 diabetes mellitus, leptin resistance

Abbreviations: ACTH, adrenocorticotropic hormone; AR, androgen receptor; ER, estrogen receptor; FSH, follicle-stimulating hormone; GH, growth 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.

2883Approach to the Patient with Endocrine Disorders CHAPTER 376

TABLE 376-2 Examples of Prevalent Endocrine and Metabolic Disorders in the Adult

DISORDER APPROXIMATE PREVALENCE IN ADULTSa SCREENING/TESTING RECOMMENDATIONSb CHAPTER(S)

Obesity 40% Obese, BMI ≥30

70% Overweight, BMI ≥25

Calculate BMI

Measure waist circumference

Exclude secondary causes

Consider comorbid complications

402

Type 2 diabetes mellitus >10% Beginning at age 45, screen every 3 years, or earlier in

high-risk groups:

FPG >126 mg/dL

Random plasma glucose >200 mg/dL

An elevated HbA1c

Consider comorbid complications

403

Hyperlipidemia 20–25% 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

407

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.

■ HORMONE MEASUREMENTS AND

ENDOCRINE TESTING

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 hormones,

including mass spectroscopy, various forms of chromatography, and

enzymatic methods; bioassays are now used rarely.

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 ensure

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.

The value of quantitative hormone measurements lies in their correct interpretation in a clinical context. The normal range for most hormones is relatively broad, often varying by a factor of two- to tenfold.

The normal ranges for many hormones are sex- and 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.

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 granulomatous diseases.

A suppressed ACTH in the setting of hypercortisolemia, or increased

urine free cortisol, is seen with hyperfunctioning adrenal adenomas.

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. 380 and 386). 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 hormone reserve (Chap. 380). Insulin-induced hypoglycemia 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.

■ SCREENING AND ASSESSMENT OF

COMMON ENDOCRINE DISORDERS

Many endocrine disorders are prevalent in the adult population

(Table 376-2) and can be diagnosed and managed by general internists, family practitioners, or other primary health care providers.

(Continued)

2884 PART 12 Endocrinology and Metabolism

TABLE 376-2 Examples of Prevalent Endocrine and Metabolic Disorders in the Adult

DISORDER APPROXIMATE PREVALENCE IN ADULTSa SCREENING/TESTING RECOMMENDATIONSb CHAPTER(S)

Metabolic syndrome 35% Measure waist circumference, FPG, BP, lipids 408

Hypothyroidism 5–10%, women

0.5–2%, men

TSH; confirm with free T4 384

Graves’ disease 1–3%, women

0.1%, men

TSH, free T4 383

Thyroid nodules and

neoplasia

2–5% palpable

>25% by ultrasound

Physical examination or ultrasound of thyroid

Fine-needle aspiration biopsy

385

Osteoporosis 5–10%, women

2–5%, men

Bone mineral density measurements in women >65 years

or in postmenopausal women or men at risk

Exclude secondary causes

411

Hyperparathyroidism 0.1–0.5%, women > men Serum calcium

PTH, if calcium is elevated

Assess comorbid conditions

410

Infertility 10%, couples Investigate both members of couple

Semen analysis in male

Assess ovulatory cycles in female

Specific tests as indicated

391,392

Polycystic ovarian

syndrome

5–10%, women Free testosterone, DHEAS

Consider comorbid conditions

392

Hirsutism 5–10% Free testosterone, DHEAS

Exclude secondary causes

Additional tests as indicated

394

Menopause Median age, 51 FSH 395

Hyperprolactinemia 15% in women with amenorrhea or galactorrhea PRL level

MRI, if not medication-related

380

Erectile dysfunction 10–25% Careful history, PRL, testosterone

Consider secondary causes (e.g., diabetes)

397

Hypogonadism, male 1–2% Testosterone, LH 391

Gynecomastia 15% Often, no tests are indicated

Consider Klinefelter’s syndrome

Consider medications, hypogonadism, liver disease

391

Klinefelter’s syndrome 0.2%, men Karyotype

Testosterone

390

Vitamin D deficiency 10% Measure serum 25-OH vitamin D

Consider secondary causes

409

Turner’s syndrome 0.03%, women Karyotype

Consider comorbid conditions

390

a

The prevalence of most disorders varies among ethnic groups and with aging. Data based primarily on U.S. population. b

See 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.

Abbreviations: BMI, body mass index; BP, blood pressure; CAD, coronary artery disease; DHEAS, dehydroepiandrosterone; FPG, fasting plasma glucose; FSH, folliclestimulating hormone; HbA1C, hemoglobin A1C; HDL, high-density lipoprotein; LDL, low-density lipoprotein; LH, luteinizing hormone; MRI, magnetic resonance imaging; PRL,

prolactin; PTH, parathyroid hormone; TSH, thyroid-stimulating hormone.

The high prevalence and clinical impact of certain endocrine diseases

justify vigilance for features of these disorders during routine physical

examinations; laboratory screening is indicated in selected high-risk

populations.

■ FURTHER READING

Endocrine Society: The Endocrine Society Clinical Practice Guidelines. Available from https://www.endocrine.org/

clinical-practice-guidelines.

Golden SH et al: Health disparities in endocrine disorders: Biological,

clinical, and nonclinical factors—an Endocrine Society Scientific

Statement. J Clin Endocrinol Metab 97:E1579, 2012.

Jameson JL, DeGroot LJ (eds): Endocrinology: Adult and Pediatric,

7th ed. Philadelphia, Elsevier, 2016.

Loriaux DL: A Biographical History of Endocrinology. Hoboken, Wiley

Blackwell, 2016.

(Continued)

Hormones function to integrate physiologic systems in the body. The

endocrine system, composed of various glands and the hormones they

produce, interacts with essentially every organ to regulate growth,

metabolism, homeostasis, and reproduction. Because hormones circulate and act via receptors in target tissues, they serve to coordinate

physiologic responses to external or internal cues. For example, the

light-dark cycle, sensed through the visual system, modulates hypothalamic corticotropin-releasing hormone (CRH), which increases

pituitary adrenocorticotropin hormone (ACTH) production, leading

to increased adrenal cortisol production before the time of waking

377 Mechanisms of

Hormone Action

J. Larry Jameson

2885 Mechanisms of Hormone Action CHAPTER 377

confer specific biologic actions. The overall three-dimensional architecture of the β subunits is similar, reflecting the locations of conserved

disulfide bonds that constrain 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.

As hormone families enlarge and diverge, their receptors have

co-evolved to create new biologic functions. Related G protein–coupled

receptors (GPCRs), for example, have evolved for each of the glycoprotein hormones. These receptors are also structurally similar, and

each is coupled predominantly to the Gs

α signaling pathway. However,

there is minimal overlap of hormone binding. For example, TSH binds

with high specificity to the TSH receptor but interacts minimally with

the LH or FSH receptors. Nonetheless, there can be subtle physiologic

consequences of hormone cross-reactivity with other receptors. Very

high levels of hCG during pregnancy stimulate the TSH receptor and

increase thyroid hormone levels, resulting via feedback inhibition in a

compensatory decrease in TSH.

IGF1 and IGF2 have structural similarities that are most apparent

when precursor forms of the proteins are compared. In contrast to the

high degree of specificity seen with the glycoprotein hormones, there

is moderate cross-talk among the members of the insulin/IGF family.

High concentrations of an IGF2 precursor produced by certain tumors

(e.g., sarcomas) can cause hypoglycemia, partly because of binding to

insulin and IGF1 receptors (Chap. 410). High concentrations of insulin

also bind to the IGF1 receptor, perhaps accounting for some of the clinical manifestations seen in conditions with chronic hyperinsulinemia.

Another important example of receptor cross-talk is seen with PTH

and parathyroid hormone–related peptide (PTHrP) (Chap. 410). PTH

is produced by the parathyroid glands, whereas PTHrP is expressed at

high levels during development and by a variety of tumors (Chap. 93).

These hormones have amino acid sequence similarity, particularly

in their amino-terminal regions. Both hormones bind to the PTH1R

receptor that is expressed in bone and kidney. Hypercalcemia and

hypophosphatemia therefore may result from excessive production of

either hormone, making it difficult to distinguish hyperparathyroidism

from hypercalcemia of malignancy solely on the basis of serum chemistries. However, sensitive and specific assays for PTH and PTHrP now

allow these disorders to be distinguished more readily.

Based on their specificities for DNA-binding sites, the nuclear

receptor family can be subdivided into type 1 receptors (glucocorticoid receptor, mineralocorticoid receptor, androgen receptor, estrogen

receptor, progesterone receptor) that bind steroids and type 2 receptors

(thyroid hormone receptor, vitamin D receptor, retinoic acid receptor,

peroxisome proliferator activated receptor) that bind thyroid hormone,

vitamin D, retinoic acid, or lipid derivatives, respectively. Certain functional domains in nuclear receptors, such as the zinc finger DNA-binding domains, are highly conserved. However, selective amino acid

differences within this domain confer DNA sequence specificity. The

hormone-binding domains are more variable, providing great diversity

in the array of small molecules that bind to different nuclear receptors.

With few exceptions, hormone binding is highly specific for a single

type of nuclear receptor. One exception involves the glucocorticoid and

mineralocorticoid receptors. Because the mineralocorticoid receptor

also binds glucocorticoids with high affinity, an enzyme (11β-hydroxysteroid dehydrogenase) in renal tubular cells inactivates glucocorticoids, allowing selective responses to mineralocorticoids such as

aldosterone. However, when very high glucocorticoid concentrations

occur, as in Cushing’s syndrome, the glucocorticoid degradation

pathway becomes saturated, allowing excessive cortisol levels to bind

mineralocorticoid receptors leading to sodium retention and potassium wasting. This phenomenon is particularly pronounced in ectopic

ACTH syndromes (Chap. 386). Another example of relaxed nuclear

receptor specificity involves the estrogen receptor, which can bind an

array of compounds, some of which have little apparent structural similarity to the high-affinity ligand estradiol. This feature of the estrogen

receptor makes it susceptible to activation by “environmental estrogens” such as resveratrol, octylphenol, and many other aromatic hydrocarbons. However, this lack of specificity provides an opportunity to

TABLE 377-1 Examples of Membrane Receptor Families and

Signaling Pathways

RECEPTORS EFFECTORS SIGNALING PATHWAYS

G Protein–Coupled Seven-Transmembrane Receptor (GPCR)

β-Adrenergic, LH,

FSH, TSH

Gs

α, adenylate

cyclase

Stimulation of cyclic AMP

production, protein kinase A

Glucagon, PTH, PTHrP,

ACTH, MSH, GHRH,

CRH

Ca2+ channels Calmodulin, Ca2+-dependent

kinases

α-Adrenergic,

somatostatin

Gi

α Inhibition of cyclic AMP

production

Activation of K+

, Ca2+ channels

TRH, GnRH Gq

, G11 Phospholipase C, diacylglycerol, IP3

, protein kinase

C, voltage-dependent Ca2+

channels

Receptor Tyrosine Kinase

Insulin, IGF-I

EGF, NGF

Tyrosine kinases, IRS

Tyrosine kinases, ras

MAP kinases, PI 3-kinase; AKT

Raf, MAP kinases, RSK

Cytokine Receptor–Linked Kinase

GH, PRL JAK, tyrosine kinases STAT, MAP kinase, PI 3-kinase,

IRS-1

Serine Kinase

Activin, TGF-β, MIS Serine kinase Smads

Abbreviations: IP3

, inositol triphosphate; IRS, insulin receptor substrates;

MAP, mitogen-activated 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.

in the morning. Increased cortisol, in turn, circulates throughout the

body, acting via the nuclear glucocorticoid receptor, to activate numerous genetic programs that influence metabolism, the cardiovascular

system, behavior, and the immune system. This chapter provides an

overview of the different types of hormones and how they function at

the cellular level to control myriad physiologic processes.

CLASSES OF HORMONES

Hormones can be divided into five major types: (1) amino acid derivatives 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 D. A variety of peptide growth factors, such as insulin-like growth factor 1 (IGF1),

share actions with hormones but often act more locally. 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 bind to intracellular nuclear receptors, although

many also interact with membrane receptors or intracellular signaling

proteins as well.

■ HORMONE AND RECEPTOR FAMILIES

Hormones and receptors can be grouped into families, reflecting structural similarities and evolutionary origins (Table 377-1). 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.

The glycoprotein hormone family, consisting of thyroid-stimulating

hormone (TSH), follicle-stimulating hormone (FSH), LH, and human

chorionic gonadotropin (hCG), illustrates many features of evolutionarily related hormones. The glycoprotein hormones are heterodimers

that share the α subunit in common; the β subunits are distinct and