Hypothyroid myopathy

INTRODUCTION — Muscle involvement in a variety of forms is a frequent problem in both congenital and adult-onset hypothyroidism [1]. This topic will discuss the clinical manifestations, pathogenesis, and treatment of hypothyroid myopathy. Other neurologic manifestations of hypothyroidism are discussed separately. (See "Neurologic manifestations of hypothyroidism" and "Clinical manifestations of hypothyroidism".)

CONGENITAL HYPOTHYROIDISM — The Kocher-Debre-Semelaigne syndrome describes infants with typical features of cretinism associated with diffuse muscular hypertrophy and muscle weakness that is predominantly proximal. These infants have motor and cognitive developmental delay, constipation, myxedema, enlarged tongue, and coarse hair and skin typical of cretinism. Despite a very muscular, almost muscle-bound appearance, they are in fact weak and often have difficulty with sitting and head control [2]. (See "Iodine deficiency disorders", section on 'Cretinism'.)

Serum creatine kinase (CK) and other muscle enzymes are often elevated in these infants. The electromyogram (EMG) may be normal or show scattered low-amplitude motor unit potentials in involved muscles. Muscle biopsy shows variable muscle fiber size with predominantly type I fiber atrophy. There is also increased interstitial connective tissue related to the duration of the hypothyroidism and abnormal glycogen accumulation. Muscle fiber necrosis and inflammation are not prominent features of this disorder [3].

Treatment with thyroid hormone results in prompt improvement in muscle strength and normalization of serum CK concentrations, even in infants with longstanding congenital hypothyroidism [4].

ADULT HYPOTHYROIDISM — Muscle involvement in adults with hypothyroidism is common; in one small series, 79 percent of patients with newly diagnosed hypothyroidism had muscle complaints (weakness, fatigability, cramps, myalgias), although these symptoms were rarely the presenting symptom [5]. Patients with more severe or longstanding untreated hypothyroidism are more likely to develop clinically significant muscle disease.

Pathogenesis — The pathogenesis of hypothyroid myopathy is not understood. A variety of effects on cellular function and metabolism occurring in hypothyroidism may contribute to the development of muscle symptoms and abnormal muscle function.

Thyroxine (T4) affects energy metabolism. T4 deficiency leads to abnormal glycogenolysis, mitochondrial oxidative metabolism, and triglyceride turnover, which in turn impair muscle function [6-8]. These effects are reflected in selective atrophy of type II fibers, which are more dependent on glycolysis for their energy supply. Type I hypertrophy may be a compensatory response. With severe or prolonged oxidative damage, muscle cell injury and rhabdomyolysis may occur [9,10]. The fact that the degree of weakness often does not correlate with the biochemical severity of hypothyroidism suggests that muscle injury, rather than impaired muscle function alone, plays a prominent role in some patients [5].

Serum muscle enzyme elevations in hypothyroidism, which occur in the absence of weakness, myalgias, or structural muscle abnormalities, appear to be due to changes in muscle cell membrane permeability, although the basis for this change is unknown [11]. Reduced clearance of creatine kinase (CK) probably also plays a role [12].

Animal studies have also studied the role of thyroid hormone in gene expression of several skeletal muscle proteins, including myosin ATPase, AMP-activated protein kinase, and others [4,13-15].

Clinical and laboratory manifestations

Elevated serum creatine kinase — Serum CK elevation occurs in most (57 to 90 percent) patients with hypothyroid myopathy, and small series have suggested enzyme elevations in patients with hypothyroidism without myopathy [16-19]. The degree of CK elevation does not clearly correlate with the severity of other clinical manifestations of muscle disease, but some have found a correlation between CK and serum thyrotropin (TSH) levels [19]. However, in asymptomatic patients, CK elevation is usually mild, less than 10 times greater than normal [12].

CK elevation may be present for several years before clinical manifestations of hypothyroidism appear. Hypothyroidism should be excluded in patients with an unexplained increase in serum CK of skeletal muscle origin.

Myalgia — Nonspecific muscle stiffness or diffuse myalgias, often exacerbated after exercise, are common manifestations of hypothyroidism and may be associated with serum muscle enzyme elevations. In one series, more than 40 percent of patients had neuromuscular complaints at the time of diagnosis [5].

Muscle pseudohypertrophy — Diffuse muscle hypertrophy occurs infrequently in adults. When accompanied by stiffness, weakness, and painful muscle cramps, this is known as Hoffmann syndrome [11]. Affected patients have generalized muscular hypertrophy and variable degrees of weakness. The skin and subcutaneous tissues have a thickened, doughy appearance. Serum muscle enzymes are usually elevated. Signs of hypothyroidism are usually readily apparent and longstanding in this setting.

Proximal myopathy — Some patients develop a slowly progressive, symmetric proximal muscle weakness. Shoulder and hip girdle muscles are most commonly affected. Occasionally hypothyroid myopathy is more fulminant, with marked serum muscle enzyme elevations [16,20-23]. A single case of camptocormia due to hypothyroid myopathy involving primarily paraspinal muscles has been reported [24].

On examination, deep tendon reflexes are characteristically described as "hung-up" due to delayed muscle relaxation. Other coexisting clinical signs and symptoms of hypothyroidism may be present.

Rhabdomyolysis — There have been several case reports of extremely high elevations of serum CK and rhabdomyolysis associated with hypothyroidism [9,10,25-27]. In some cases, rhabdomyolysis appears to have been precipitated by vigorous exercise [9] or concurrent statin therapy [28-30]. Renal failure may occur as a secondary complication. (See "Rhabdomyolysis: Clinical manifestations and diagnosis" and "Clinical features and diagnosis of heme pigment-induced acute kidney injury" and "Statin muscle-related adverse events", section on 'Hypothyroidism, hypovitaminosis D, and other disorders'.)

Myoedema — Myoedema (or "mounding") refers to a small lump rising on the surface of a muscle when it is struck with a percussion hammer. This phenomenon, which is characteristic of hypothyroid myopathy, lasts for 30 to 60 seconds, and is due to a sustained contracture associated with delayed relaxation, because of slow reaccumulation of calcium by the sarcoplasmic reticulum [31-34]. Myoedema is not specific for hypothyroidism as it can also occur in malnutrition.

Electromyography findings — Electromyography (EMG) is normal in approximately half of hypothyroid patients with proximal muscle weakness; in others, it may demonstrate myopathic changes with increased low-amplitude, polyphasic potentials and, rarely, increased insertional activity [5,16,35-37]. Fibrillation potentials are generally absent.

Myoedema elicited with muscle percussion is electrically silent, distinguishing it from myotonia.

Diagnosis — Any of the above clinical symptoms or signs without another known cause should prompt an evaluation for hypothyroidism. TSH is the most sensitive screening test; this should be followed by a thyroxine level if the TSH is elevated (see "Diagnosis of and screening for hypothyroidism in nonpregnant adults"). This can be sufficient to diagnose hypothyroid muscle disease and institute thyroid replacement therapy.

EMG can be helpful, as clinical symptoms and signs do not always distinguish hypothyroid myopathy from inflammatory myositis or other neuromuscular complications. When performed to distinguish hypothyroid myopathy from inflammatory myositis, a lack of fibrillation potentials on EMG with relatively normal appearing motor units suggest the former diagnosis.

Muscle biopsy is not usually required. When performed, the muscle biopsy may be normal or may show a variety of nonspecific changes, including [4,16,17,23,38,39]:

●Type II fiber atrophy

●Type I fiber hypertrophy

●Increased numbers of internal nuclei

●Core-like structures in type I fibers

●Mitochondrial inclusions

●Glycogen accumulation

●Autophagic vacuoles

●Myofibrillar disorganization

●Mild, focal necrosis and degeneration of muscle fibers

●Occasional mild inflammatory infiltrates

Pathologic changes do not correlate well with the severity of the myopathy. They can resolve with treatment. Prominent inflammatory changes may suggest an alternative diagnosis such as polymyositis.

Treatment and prognosis — The symptoms and signs of hypothyroid myopathy respond to thyroid hormone replacement. (See "Treatment of primary hypothyroidism in adults".)

CK levels fall quickly with treatment, normalizing over a few weeks, generally before TSH levels normalize [16,40-42]. Clinical symptoms, particularly weakness, recover more slowly. In one study, muscle complaints resolved in 79 percent of patients over a median time of 5.5 months. At one year, 21 percent of patients continued to complain of weakness [5]. Persistent weakness at six years following initiation of treatment was described in one patient with severe hypothyroid myopathy [43].

SUMMARY AND RECOMMENDATIONS — Muscle disease is a frequent complication of congenital and adult-onset hypothyroidism.

●Myopathy in congenital hypothyroidism – Myopathic weakness in congenital hypothyroidism occurs in association with other manifestations of cretinism, is accompanied by prominent muscle hypertrophy, and responds to thyroid replacement. (See 'Congenital hypothyroidism' above.)

●Clinical manifestations in adults with hypothyroidism – In adults, the severity of muscle disease can range from asymptomatic elevation of serum creatine kinase (CK) to disabling muscle weakness.

Other manifestations include myalgias, muscle hypertrophy, and myoedema. Rhabdomyolysis has been reported but occurs rarely. (See 'Clinical and laboratory manifestations' above.)

●Neurophysiology – Electromyography (EMG) is normal or shows myopathic changes.

●Diagnosis – The presence of typical myopathic symptoms in the setting of hypothyroidism is sufficient to make the diagnosis. Muscle biopsy may not be required but, if performed to exclude other conditions, shows nonspecific changes and only mild, if any, inflammation. (See 'Diagnosis' above.)

●Treatment and prognosis – Thyroid replacement usually leads to resolution of laboratory abnormalities and symptoms over a few to several weeks. Weakness may recover more slowly, over several months, and, in severely affected patients, may persist even longer. (See 'Treatment and prognosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Marc L Miller, MD, who contributed to an earlier version of this topic review.