121 Endocrine Diseases and the Musculoskeletal System
Both hypothyroidism and hyperthyroidism are characterized by frequent symptomatic involvement of the musculoskeletal system.
Diseases of the parathyroid gland can manifest in bone and muscle presentations. The most important joint manifestation of primary hyperparathyroidism is calcium pyrophosphate deposition (CPPD) disease.
Cushing’s disease, a subtype (80%) of Cushing’s syndrome, is caused by a pituitary adenoma, which is a benign tumor resulting in excess adrenocorticotropic hormone (ACTH), whereas iatrogenic Cushing’s syndrome is secondary to exogenous high-dosage long-term glucocorticoid therapy. Varied musculoskeletal manifestations may arise, which may be indolent and require high levels of clinical vigilance for detection.
Diabetes mellitus can manifest a variety of musculoskeletal presentations in joints, in long bones, and in connective tissues. Several manifestations are characterized by tissue fibrosis. Abnormal tendon biology may contribute to these presentations. Charcot’s diabetic osteoarthropathy is a severe, destructive form of degenerative arthritis resulting from underlying diabetic neuropathy.
Musculoskeletal manifestations are a common presenting feature of endocrine disease; therefore, a high level of vigilance should be maintained during initial and ongoing assessment of patients with bone, muscle, and soft tissue complaints. Similarly, endocrine disease can arise in the treatment of rheumatic diseases, especially with the use of glucocorticoids. Whereas the underlying mechanisms of many such presentations remain uncertain, their association is sufficiently common as to merit detailed consideration in the history and examination of all new rheumatic disease presentations, and superficial endocrine assessment should form a part of the routine early investigation of new-onset arthralgia and myalgia patients. This chapter addresses some of the more common musculoskeletal elements of endocrine syndromes.
Deficiency of thyroid hormone leads to the state of hypothyroidism. The most common cause is Hashimoto’s thyroiditis, an autoimmune process in which lymphocytic infiltration and fibrous tissue accumulation cause replacement of normal thyroid tissue and thereby gland dysfunction.1 The incidence of autoimmune hypothyroidism (Hashimoto’s thyroiditis) is increased in patients with systemic sclerosis, as well as with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), mixed connective tissue disease, Sjögren’s syndrome, and polymyositis.2 Most patients develop antibodies against thyroid peroxidase and/or thyroglobulin.3 Hashimoto’s thyroiditis is associated with HLA-B8, HLA-DR3, HLA-Aw30, and HLA-DR5.4 Some patients with Hashimoto’s thyroiditis also exhibit antinuclear antibodies, and many have anti-DNA antibodies; despite this, overt SLE is uncommon. Other potential causes of thyroid gland dysfunction include treatment with radioactive iodine (131I) for Graves’ disease and drug-induced hypothyroidism, for example, associated with amiodarone, iodine (i.e., Wolff-Chaikoff effect), or other drugs.5–8 In addition, hereditary disorders of the iodothyronine synthesis pathway (thyroxine [T4] and triiodothyronine [T3]), as well as pituitary tumors and related surgical resections, are possible causes.9,10
Hypothyroidism can cause a broad range of symptoms associated with mild (e.g., fatigue, weight gain, cold intolerance, mental slowing, muscle cramping, bradycardia) to severe complications (e.g., heart enlargement, myxedema coma [rare]). Neuromuscular and musculoskeletal manifestations are observed in many patients. These manifestations can occur at any time in the disease process and include weakness, joint and muscle pain, aching, and stiffness.11 Overall, 30% to 80% of hypothyroid patients manifest neuromuscular symptoms, depending on the severity of hypothyroidism, whereas weakness is observed in almost 30% of patients.12 More rarely, hypothyroid myopathy manifests as a polymyositis-like illness with proximal muscle weakness and an increased creatinine phosphokinase level. It may also present as muscle enlargement (pseudohypertrophy); in adults, this condition is called Hoffmann’s syndrome.13 In children with hypothyroid disease (cretinism), a pattern of proximal weakness and diffuse muscle enlargement is known as Kocher-Debre-Semelaigne syndrome.14 Several case reports describe rhabdomyolysis associated with hypothyroidism; in these cases, hypothyroidism is thought to have been causative.15 Myxedema represents a phenomenon in which thickening of muscle tissue occurs after light percussion in approximately 30% of patients; however, it is not entirely specific for the latter.16 Myxedema is likely caused by delayed calcium reuptake by the sarcoplasmic reticulum, which thereby prolongs muscle contraction. This prolongation of muscle contraction is thought to be related to the development of muscle hypertrophy. A further neuromuscular manifestation concerns peripheral neuropathy. In particular, carpal tunnel syndrome is found in 15% to 30% of patients with hypothyroidism.17
Hyperthyroidism (Graves’ disease) may affect the musculoskeletal system in several ways; the most common manifestation is osteopenia and potentially osteoporosis. The latter may occur in patients with idiopathic Graves’ disease but also in those with iatrogenic hyperthyroidism.18 Failure to recognize the declining need for thyroid replacement with age is a further important cause of iatrogenic hyperthyroidism in older women. For this reason, patients with hypothyroidism who are on thyroid hormone and estrogen therapy should have thyroid-stimulating hormone levels monitored and the dose readjusted to keep the thyroid-stimulating hormone level within the normal range.19 Bone density has been shown to increase after correction of the hyperthyroid state.20
Pretibial myxedema is a syndrome of painless nodules that occur over the pretibial areas; virtually all affected patients have concomitant Graves’ ophthalmopathy.21 Cutaneous lesions vary in size, ranging from nodules with a diameter of 1 cm to very large lesions covering most of the pretibial surface.22 The lesions are colored differently—from pink to a light purple hue—and can be misdiagnosed as erythema nodosum. In contrast to erythema nodosum, however, the lesions are painless. They are caused by the accumulation of hyaluronic acid in the skin and in some cases exhibit a shiny appearance resembling systemic sclerosis or morphea.23
Hyperthyroidism may be associated with changes in the nails, including onycholysis, or elevation of the nail from the nail bed, and clubbing.24 Clubbing usually is part of the condition known as thyroid acropachy, a rare manifestation of hyperthyroidism associated with periostitis around the metacarpal joints and distal soft tissue swelling of the digits.25 This condition is not clearly related to levels of thyroid hormone, and it may be seen after the patient has reverted to the euthyroid state.
Proximal muscle weakness, a common complication of hyperthyroidism, is present in most patients. Most patients have lost weight and have other evidence of loss of muscle mass.26 Proximal muscle weakness reverts rapidly with correction of the hyperthyroid state, suggesting a direct metabolic link to thyroxine effector function. Perhaps related to the proximal myopathy, adhesive capsulitis of the shoulder seems to be increased in patients with hyperthyroidism.27 In these patients, the condition can be insidious and difficult to treat, with frozen-shoulder syndrome often the initial manifestation.
Strong relationships have been noted between Graves’ disease and Hashimoto’s thyroiditis and other rheumatic diseases. Seventy-five percent to 90% of patients with Graves’ disease have antinuclear antibodies, and a proportion also express anti-DNA antibodies, despite the fact that overt SLE is uncommon.3 Graves’ disease is associated with HLA-B8, HLA-A1, HLA-Cw7, and HLA-DR3, and combinations of these antigens correlate with persistent disease.28
Hypoparathyroidism is usually secondary to surgical removal of the parathyroid glands and commonly is characterized by proximal muscle weakness related to the degree of hypocalcemia.29 This condition responds rapidly to treatment with vitamin D and calcium. Other common musculoskeletal manifestations of hypoparathyroidism include osteomalacia and rickets, which are discussed elsewhere. Idiopathic hypoparathyroidism is a rare disorder, seen as part of DiGeorge’s syndrome with thymic hypoplasia.30 Pseudohypoparathyroidism, known as Albright’s hereditary osteodystrophy, is caused by end-organ resistance to the effects of parathyroid hormone.31 Pseudohypoparathyroidism is due to a defect in GNAS1 (guanine nucleotide binding protein, alpha-stimulating activity polypeptide 1).32 Patients show persistent hypocalcemia and hyperphosphatemia, but parathyroid hormone levels are consistently elevated. Type Ia pseudohypoparathyroidism, which is autosomal dominant, is characterized by short stature, calcification of perispinal ligaments, and, usually, mental retardation.33 Patients may present with shortening of the fourth metacarpal and metatarsal bones, and instead of the usual knuckle appearance over the fourth metacarpal head, these individuals have a dimple. Patients affected by type Ib pseudohypoparathyroidism also show resistance to parathyroid hormone but have normal phenotype.34 Type Ia pseudohypoparathyroidism is almost always inherited maternally, and type Ib is inherited paternally.
Primary hyperparathyroidism results from hyperfunction of the parathyroid glands themselves. The condition is characterized by hypersecretion of parathyroid hormone (PTH) caused by adenoma, hyperplasia, or, rarely, carcinoma of the parathyroid glands.35 Secondary hyperparathyroidism comprises the reaction of the parathyroid glands to hypocalcemia caused by pathologic conditions other than parathyroid pathology (e.g., chronic kidney disease).36 The most important joint manifestation of primary hyperparathyroidism is calcium pyrophosphate deposition (CPPD) disease, a disorder with varied clinical manifestations attributed to precipitation of calcium pyrophosphate dihydrate crystals in the connective tissues.37,38 Chondrocalcinosis refers to radiographic evidence of calcification in hyaline and/or fibrocartilage.39 Pseudogout refers to clinically evident acute synovitis that results from shedding of crystals in the joint space after rupture of a CPPD deposit; it is characterized by red, tender, and swollen joints that may resemble gouty arthritis40 (see Chapter 96). CPPD crystal deposition disease is a polyarticular arthritis (i.e., it leads to inflammation of several joints), although it can initially present as monoarthritis.41 Diffuse idiopathic skeletal hyperostosis (DISH) and pseudoankylosing spondylitis are considered additional possible forms of calcium pyrophosphate dehydrate crystal deposition disease (CPPD CDD).42 These syndromes are considered in detail in Chapter 96.
Some patients with long-standing hyperparathyroidism report proximal muscle weakness—a condition rapidly reversed by removal of the parathyroid adenoma.43 In these patients, the muscle enzymes are normal, and electromyography and muscle biopsy reveal a picture most consistent with denervation. In secondary hyperparathyroidism associated with advanced renal disease, numerous bone and articular abnormalities are described.44 The musculoskeletal changes of renal osteodystrophy resulting from secondary hyperparathyroidism include erosive arthritis in the hands, resorption of the distal clavicle, and erosions in the axial skeleton.45 In children, widespread bone deformities of osteitis fibrosa cystica can be very disabling.46 Other musculoskeletal manifestations of advanced renal failure include aluminum-induced osteomalacia33 and β2-microglobulin amyloidosis.47,48
Adrenal Gland Disorders
Primary Cushing’s disease is caused by a pituitary adenoma, which is a benign tumor resulting in excess adrenocorticotropic hormone (ACTH).49,50 It may also arise from adrenal adenomas. Iatrogenic Cushing’s syndrome (hypercortisolism/hyperadrenalism) secondary to exogenous high-dose long-term glucocorticoid therapy is the most common condition involving adrenal hormones that mediates adverse effects on the musculoskeletal system.51 Osteonecrosis, a common late complication of high-dose glucocorticoid therapy, may first become evident months or years after glucocorticoid therapy has been discontinued.52 It is observed less commonly after short courses of therapy, however, or after intermittent high-dose intravenous therapy, although clinical vigilance is required. Because rheumatic patients receiving high-dosage glucocorticoid therapy have associated diseases characterized by joint pain, the risk of osteonecrosis should be considered, particularly in the differential diagnosis. Use of the lowest acceptable dose of glucocorticoids has reduced the risk of osteonecrosis.53,54
Steroid-induced myopathy may be difficult to recognize in patients being treated for primary or secondary inflammatory rheumatic conditions, particularly myopathies.55 However, steroid myopathy is characteristically more severe in the pelvic girdle. It may come on gradually or abruptly, starting with weakness and muscle aching, and can be sufficiently severe to render patients bedbound.56 Biopsy specimens or T2 relaxation times are compatible with muscle fiber atrophy, whereas muscle enzymes are normal.57 Long-acting and fluorinated glucocorticoids are more likely to induce myopathy, and treatment usually requires ultimate discontinuation of glucocorticoids before any improvement is seen; weeks or months may pass before muscle strength begins to return.58
Osteopenia as a secondary effect of hypercortisolism (primary or secondary) is independent of degree or duration of hypercortisolism (adenoma) but may be related to the total dose and duration of glucocorticoid therapy and is more frequent with dosages greater than the equivalent of 7.5 mg/day of prednisone.59,60 Prophylaxis is recommended, and regimens shown to be effective in preventing or treating glucocorticoid-induced osteoporosis must include calcium, vitamin D3, and bisphosphonates.61
Cushing’s disease may be confused with primary musculoskeletal disease, including polymyalgia rheumatica, polymyositis, or statin myopathy, or it may be mistaken for back pain that may arise from osteoporotic fractures or other pathologies.62 In Cushing’s syndrome secondary to ectopic adrenocorticotropic hormone production, glucocorticoid serum levels may be extremely high, inducing severe myopathy and additional complications such as steroid psychosis.63 Several other side effects of glucocorticoids on the musculoskeletal system are less well understood. Some patients describe intense joint pain, frequently most severe in the knees, when high doses of glucocorticoids are started. This pain typically resolves even if the dose is left unchanged.
Adrenal insufficiency is classified into three subtypes based on where the abnormality is based in the hypothalamic-pituitary-adrenal (HPA) axis.62 Primary insufficiency is caused by adrenal gland damage (Addison’s disease). The secondary form is related to insufficient corticotropin (ACTH) from the pituitary gland. The tertiary form is related to insufficient corticotropin-releasing hormone (CRH) generated from the hypothalamus. Acute adrenal insufficiency, or adrenal crisis, is severe and is characterized by shock. Primary adrenal insufficiency (Addison’s disease) is almost exclusively autoimmune (now only rarely related to tuberculosis) and is characterized by weakness, weight loss, abdominal pain, hyperpigmentation, nausea, and hypotension.64 Secondary adrenal insufficiency can be related to destruction of the pituitary gland or to deficiency of ACTH. Classically, it is associated with hemorrhage of the pituitary gland, or thrombosis, or it may be noted during infiltrative processes such as those seen when sarcoidosis affects the pituitary gland. Glucocorticoid use and subsequent withdrawal can cause secondary or tertiary adrenal insufficiency. Iatrogenic Addison’s disease can be subtle because mineralocorticoids are still being produced; salt wasting, hyperkalemia, and postural hypotension are usually less impressive; and hyperpigmentation is not seen because the pituitary is suppressed. Adrenal insufficiency, particularly in such circumstances, can mimic fibromyalgia syndrome.65 Tertiary adrenal insufficiency is most commonly related to withdrawal of glucocorticoids.66 Glucocorticoid-induced adrenal insufficiency can be caused by several mechanisms, including decreased hypothalamic synthesis of CRH, blockade of the actions of CRH on the anterior pituitary, and, after prolonged or profound deficiency of ACTH, adrenal atrophy. As in idiopathic Addison’s disease, features may not be evident unless the individual undergoes a new exogenous stressful condition, such as surgery or infection. Adrenal insufficiency (adrenal crisis) is a rare disorder that usually manifests with gradually evolving clinical symptoms and signs.67 Occasionally, acute adrenal insufficiency (crisis) can become a life-threatening condition as the result of acute interruption of a normal or hyperfunctioning adrenal or pituitary gland, or sudden interruption of adrenal replacement therapy. Addisonian crisis has been seen even in individuals still receiving physiologic or “replacement” doses of glucocorticoids. It should be assumed that individuals taking glucocorticoids at greater than the equivalent of 5 mg/day of prednisone have a pituitary-adrenal axis unable to respond to severe stress (medical and surgical stress, concomitant use of certain medications); consequently, increases in the glucocorticoid dose should be considered in the acute setting.
Musculoskeletal Manifestations and Steroid Deficiency
The so-called steroid withdrawal syndrome consists of widespread arthralgias, myalgias, malaise, and sometimes low-grade fever.68 It may be seen when high-dose glucocorticoids have been used for nonrheumatic conditions, such as asthma or inflammatory bowel disease, and it arises from suppression of the pituitary-adrenal axis. Moreover, abrupt reduction of the dose of glucocorticoid can cause a severe rebound flare of the underlying disease, at least in rheumatic diseases.69 This condition may arise even though the dose of glucocorticoid remains in the pharmacologic range. It is important to recall that treatment with glucocorticoids should not be stopped until endogenous synthesis of glucocorticoids is fully efficient. Administration of low-dose “modified-release” glucocorticoids, which addresses appropriate timing of administration (at night, reflecting HPA circadian rhythms), has been shown to reduce the severity of this syndrome.70–72
Subclinical hypoadrenalism associated with insufficient production of cortisol may arise in conditions of chronic stress (e.g., interpersonal conflict, chronic inflammatory disease state), especially in the elderly.73,74 In this circumstance, a new stressor may induce the development of polymyalgia rheumatica75,76 (see Chapter 88).