Epidemiology and Clinical Features

The most common cause of primary hypothyroidism in the United States is autoimmunity (Hashimoto thyroiditis). The estimated incidence of Hashimoto thyroiditis is 3.6 per 1000 person-years in women and 0.8 per 1000 person-years in men. Other causes include central hypothyroidism (ie, pituitary adenoma or Sheehan syndrome), postpartum thyroiditis, drug-induced causes (ie, lithium), iodine deficiency, and iatrogenesis.

Calcium Pyrophosphate Deposition Disease

Deposition of calcium pyrophosphate dihydrate (CPPD) crystals within the articular cartilage can result in chronic arthropathy (chondrocalcinosis) and/or acute flares of synovitis (pseudogout). Diagnosis is based on the presence of rhomboid intracellular crystals that are weakly positively birefringent under polarized microscopy and/or the presence of intra-articular calcium deposits visualized on radiography.

The association between chondrocalcinosis and hypothyroidism was initially described in a case series of 12 myxedematous patients examined before or within 4 days of thyroid replacement therapy. Musculoskeletal complaints, including joint pain in the hands and knees, were observed. Among the 12 patients, 9 had knee effusions that were typically bilateral. The joint effusions had a characteristically high viscosity and were difficult to ascertain by routine physical examination, often confused for synovial thickening. In addition, synovitis of the wrists, metacarpal joints, and flexor tendon sheaths was noted. Synovial fluid analysis demonstrated the presence of intra- and extracellular positively birefringent crystals consistent with CPPD. However, the presence of chondrocalcinosis was distinguished from acute attacks of pseudogout, which was not observed in most patients.

Subsequently, 4 surveys examining the prevalence of knee chondrocalcinosis among hypothyroid patients compared with healthy patients failed to demonstrate a statistically significant risk association. However, these studies were likely underpowered to detect significant change. A meta-analysis of these studies produced an odds ratio of 1.94 suggesting a small association between the 2 disorders.

In addition to hypothyroidism, CPPD is associated with other metabolic disorders such as hyperparathyroidism, hypomagnesemia, hypophosphatasia, hemachromatosis, gout, Wilson disease, acromegaly, and familial hypocalciuric hypercalcemia. The mechanism whereby an altered metabolic milieu in thyroid disease could contribute to the influx of calcium deposits into the joint is not well understood. Inorganic pyrophosphate levels in synovial fluid have been measured to be lower in hypothyroid patients than normal patients as well as in other disease states associated with CPPD, which does not support the association between the 2 diseases.

Hypothyroid Myopathy

Muscle symptoms may manifest in 25% to 79% of adult patients with hypothyroidism. The symptoms often reported by patients are pain, cramps, stiffness, easy fatigability, and weakness. Physical examination findings may include muscle hypertrophy, proximal muscle weakness, and delayed relaxation phase of deep tendon reflexes. Mounding is a sustained focal contraction of skeletal muscles on striking with a reflex hammer and is a nonspecific finding in hypothyroid myopathy. Mounding may be related, in part, to delayed reuptake of released calcium ion by the sarcoplasmic reticulum.

Hoffman syndrome is a rare clinical disorder of severe hypothyroid myopathy, which manifests with severe muscle stiffness, increased muscle mass (pseudohypertrophy), variable muscle weakness along with elevated levels of creatine kinase (CK). Kocher-Debré-Sémélaigne syndrome is a disorder of infancy associated with the features of cretinism (short stature, enlarged tongue, neurologic impairment in the setting of maternal iodine deficiency) and muscular pseudohypertrophy. Kocher’s original description in 1892 in a young man with cretinism first shed light on the relationship between the thyroid and skeletal muscles. As such, this syndrome is rarely encountered in the era of newborn screening for thyroid disease. There are no painful muscle spasms as in Hoffman syndrome. Muscle enzyme levels are typically elevated, and there is type I fiber atrophy on muscle biopsy.

Serum muscle enzyme levels are frequently elevated in patients with hypothyroid myopathy and are elevated in up to 90% of asymptomatic patients. These enzymes include CK, myoglobin, and lactate dehydrogenase. Although this increase is typically mild (CK<1000 IU/L), numerous reports of a polymyositis-like illness or rhabdomyolysis with dramatic elevations in CK levels do exist in the literature. Correlation between elevated CK levels and thyrotropin-stimulating hormone (TSH) levels has been observed but not with a degree of weakness.

Diagnosis may be supported by electromyography (EMG), which is often normal but helps in distinguishing hypothyroid myopathy from other myopathies. Reported features include repetitive positive waves, increased insertional activity, and fibrillations. On muscle biopsy, there is characteristic atrophy of type II muscle fibers, with relative hypertrophy in type I muscle fibers. Other nonspecific findings include an increase in the percentage of type I fibers, presence of internalized nuclei, and corelike structures. In most cases of hypothyroid myopathy, symptoms resolve within approximately 6 months of therapy with supplemental thyroxine.

Several explanations have been postulated for the effect of thyroid hormones on skeletal muscle tissues. Changes in fiber type from fast to slow contribute to the delayed contraction and relaxation. Alteration in myosin heavy chain gene forms may lead to changes in energy use by the muscle. Impaired glycogenolysis may also be contributory.

Carpal Tunnel Syndrome

Carpal tunnel syndrome (CTS) is an increasingly common neuromuscular disorder with an estimated prevalence of 3.8% in the general population. However, practitioners should remain vigilant of its association with hypothyroidism, diabetes mellitus, and inflammatory disorders. One systematic review of 4908 patients with CTS found a pooled odds ratio of 1.4 (95% CI, 1.0–2.0) for the prevalence of concomitant hypothyroidism compared with healthy controls.

There are 9 flexor tendons and the median nerve coursing through the carpal tunnel ligament on the volar aspect of the wrist. When this compartment is compressed, patients commonly experience pain or paresthesias in the distribution of the median nerve. These symptoms may be worse at night or with flexion at the wrist. There may be weakness or atrophy of the thenar muscles in prolonged cases. Physical maneuvers such as Tinel and Phalen signs or 2-point discrimination may be useful in the diagnosis of CTS. Bilateral CTS has been reported in hypothyroidism. The mechanism for compression is thought to be secondary to the accumulation of glycosaminoglycans (GAGs) within the surrounding tissues.

Electrodiagnostic studies are the gold standard for diagnosing CTS. Therapy may include both medical and surgical options such as wrist splinting, corticosteroid injection, or carpal tunnel release for severe cases. Treatment of underlying hypothyroidism has been shown to ameliorate the course of CTS in most studies, although one article reported ongoing clinical and electrodiagnostic manifestations in hypothyroid patients once they returned to a euthyroid state.

Epidemiology and Clinical Features

Hyperthyroidism may be secondary to a variety of causes including autoimmune, infectious, drug-induced, or iatrogenic. Graves disease, the most common cause of hyperthyroidism worldwide, has an estimated incidence of 100 to 200 cases per annum, with an increased susceptibility in women.

Myopathy

Hyperthyroid myopathy has a similar presentation as hypothyroidism, with proximal muscle manifesting early in the disease course in up to 67% of patients in 1 study. Other complaints, including myalgia or fatigability, are less frequently reported. In contrast with hypothyroidism, serum CK levels are typically normal and myopathic findings on EMG were rare (10% of patients). Symptoms of weakness resolve with a mean 3.6 months of therapy for hyperthyroidism. Muscle biopsy, if ever performed, demonstrates fiber atrophy and fat infiltration.

Pretibial Myxedema

Infiltrative dermopathy, or pretibial myxedema, is a rare manifestation of Graves disease and is a marker for Graves ophthalmopathy (seen in 97% of patients). Clinically, the skin of the lower extremities is typically affected with induration, nonpitting edema, and a peau d’orange appearance in the pretibial areas. The lesions may range in size and are not painful but may be itchy or unsightly. Biopsy of the lesions shows the presence of GAGs and the damage to collagen and elastin fibers. Treatment with topical corticosteroids is effective in 50% of patients unless the lesions are chronic or severe.

It is postulated that GAGs released by skin fibroblasts accumulate in the dermis and subcutis. The triggering event is unknown but may be related to autoantibody stimulation of a cross-reacting thyroid antigen. Another theory relates to aberrant production or degradation of GAGs mediated by prostaglandins. In addition, analysis of the T-cell receptor variable gene region of the involved skin demonstrates a restricted repertoire, suggesting a role for antigen-specific T cells in the development of dermopathy.

Thyroid acropachy, or new periosteal bone formation, leading to clubbing of the fingers and toes may also be seen. Plain radiographs show periosteal reaction. These findings are associated with Graves ophthalmopathy and dermatopathy and may have a higher prevalence in smokers.

Altered Bone Metabolism

Perhaps the most serious musculoskeletal consequence of untreated hyperthyroidism is ongoing rapid bone turnover leading to a decline in bone mineral density (BMD). Excess thyroxine secretion leads to increased bone resorption time with a decrease in mineralization time, leading to net resorptive effect. This effect is likely mediated by indirect osteoblast activation of osteoclasts. Serum calcium levels are increased in hyperthyroidism because of increased bone resorption and similarly hypercalciuria is also present leading to a negative calcium balance. In addition, concentration of bone turnover markers, including serum alkaline phosphatase, osteocalcin, and urinary hydroxyproline, is increased. The amount of both cortical and trabecular bone is decreased.

Comparison of bone densitometry scores of patients with active hyperthyroidism, treated euthyroid patients, and controls highlighted a mean z score ranging from −0.79 to −0.92 (based on the site) in the untreated patients. Euthyroid patients had z scores ranging from −0.23 to −0.74, which are still less than age- and sex-adjusted controls with a z score ranging from 0.09 to 0.36. One long-term study that followed up patients with hyperthyroidism who achieved prolonged euthyroid state demonstrated an increase in lumbar BMD at 5 years suggesting a reversibility of this effect. High triiodothyronine levels during illness positively correlated with a subsequent improvement in BMD. The risk of hip fracture was elevated in a meta-analysis of 5 studies of hyperthyroid patients.

These data suggest that close monitoring of BMD in hyperthyroid patients alongside treatment is essential in preventing osteoporosis. Maintenance of adequate levels of calcium and vitamin D is important. Treatment with alendronate and methimazole may be better than methimazole alone for improvement of BMD.

Epidemiology and Clinical Features

Hyperthyroidism may be secondary to a variety of causes including autoimmune, infectious, drug-induced, or iatrogenic. Graves disease, the most common cause of hyperthyroidism worldwide, has an estimated incidence of 100 to 200 cases per annum, with an increased susceptibility in women.

Myopathy

Hyperthyroid myopathy has a similar presentation as hypothyroidism, with proximal muscle manifesting early in the disease course in up to 67% of patients in 1 study. Other complaints, including myalgia or fatigability, are less frequently reported. In contrast with hypothyroidism, serum CK levels are typically normal and myopathic findings on EMG were rare (10% of patients). Symptoms of weakness resolve with a mean 3.6 months of therapy for hyperthyroidism. Muscle biopsy, if ever performed, demonstrates fiber atrophy and fat infiltration.

Pretibial Myxedema

Infiltrative dermopathy, or pretibial myxedema, is a rare manifestation of Graves disease and is a marker for Graves ophthalmopathy (seen in 97% of patients). Clinically, the skin of the lower extremities is typically affected with induration, nonpitting edema, and a peau d’orange appearance in the pretibial areas. The lesions may range in size and are not painful but may be itchy or unsightly. Biopsy of the lesions shows the presence of GAGs and the damage to collagen and elastin fibers. Treatment with topical corticosteroids is effective in 50% of patients unless the lesions are chronic or severe.

It is postulated that GAGs released by skin fibroblasts accumulate in the dermis and subcutis. The triggering event is unknown but may be related to autoantibody stimulation of a cross-reacting thyroid antigen. Another theory relates to aberrant production or degradation of GAGs mediated by prostaglandins. In addition, analysis of the T-cell receptor variable gene region of the involved skin demonstrates a restricted repertoire, suggesting a role for antigen-specific T cells in the development of dermopathy.

Thyroid acropachy, or new periosteal bone formation, leading to clubbing of the fingers and toes may also be seen. Plain radiographs show periosteal reaction. These findings are associated with Graves ophthalmopathy and dermatopathy and may have a higher prevalence in smokers.

Altered Bone Metabolism

Perhaps the most serious musculoskeletal consequence of untreated hyperthyroidism is ongoing rapid bone turnover leading to a decline in bone mineral density (BMD). Excess thyroxine secretion leads to increased bone resorption time with a decrease in mineralization time, leading to net resorptive effect. This effect is likely mediated by indirect osteoblast activation of osteoclasts. Serum calcium levels are increased in hyperthyroidism because of increased bone resorption and similarly hypercalciuria is also present leading to a negative calcium balance. In addition, concentration of bone turnover markers, including serum alkaline phosphatase, osteocalcin, and urinary hydroxyproline, is increased. The amount of both cortical and trabecular bone is decreased.

Comparison of bone densitometry scores of patients with active hyperthyroidism, treated euthyroid patients, and controls highlighted a mean z score ranging from −0.79 to −0.92 (based on the site) in the untreated patients. Euthyroid patients had z scores ranging from −0.23 to −0.74, which are still less than age- and sex-adjusted controls with a z score ranging from 0.09 to 0.36. One long-term study that followed up patients with hyperthyroidism who achieved prolonged euthyroid state demonstrated an increase in lumbar BMD at 5 years suggesting a reversibility of this effect. High triiodothyronine levels during illness positively correlated with a subsequent improvement in BMD. The risk of hip fracture was elevated in a meta-analysis of 5 studies of hyperthyroid patients.

These data suggest that close monitoring of BMD in hyperthyroid patients alongside treatment is essential in preventing osteoporosis. Maintenance of adequate levels of calcium and vitamin D is important. Treatment with alendronate and methimazole may be better than methimazole alone for improvement of BMD.