Myopathies can occur in the setting of a variety of systemic diseases. Previous chapters have discussed inflammatory myopathies that can occur in the setting of connective tissue diseases (e.g., systemic lupus erythematosus, mixed connective tissue disease, Sjögren syndrome, and rheumatoid arthritis) and systemic infections (e.g., HIV). Myopathies occurring as complications of medications (toxic myopathies) are also dealt with elsewhere in the book. In this chapter, we will focus on myopathies related to endocrine disturbances, electrolyte imbalance, nutritional deficiency, and amyloidosis. We also discuss some other less well-defined syndromes such as fibromyalgia.
Myopathies can complicate various endocrinopathies.1,2 In this section, we review myopathies associated with thyroid, parathyroid, adrenal, pituitary, and pancreatic disorders.
Both hyperthyroidism and hypothyroidism can be associated with myopathy. In addition, polyneuropathy and neuromuscular junction disorders can occur with dysthyroid states and these need to be differentiated from one another.
The mean age of onset of thyrotoxicosis is in the fifth decade. The severity of the myopathy does not necessarily relate to the severity of the thyrotoxicosis. Muscle symptoms usually appear several months after the onset of other clinical symptoms associated with mild hyperthyroidism.3 Interestingly, thyrotoxicosis is more common in females; however, thyrotoxic myopathy occurs more commonly in men. Anywhere from 61% to 82% of patients with thyrotoxicosis have some degree of detectable weakness on examination, but only about 5% of patients with thyrotoxicosis present with muscle weakness as their chief complaint.1,3–5
Thyrotoxic myopathy is characterized by proximal muscle weakness and atrophy.2–7 Some individuals have severe shoulder-girdle atrophy and scapular winging.2 Distal extremity weakness can be the predominant feature in approximately 20% of patients.4 Myalgias and fatigue are common. Some patients develop dysphagia, dysphonia, and respiratory distress due to involvement of bulbar, esophageal–pharyngeal muscles, and ventilatory muscles.8,9 Weakness of extraocular muscles and proptosis occur in the setting of Graves’ disease but the sphincters are spared in hyperthyroidism. Rarely, rhabdomyolysis with myoglobinuria can develop in severe thyrotoxicosis.10
Muscle stretch tendon reflexes are often brisk. In addition, fasciculations and myokymia are occasionally seen which probably reflects thyrotoxicosis-induced irritability of anterior horn cells or peripheral nerves.11–13 Peripheral neuropathy in hyperthyroidism is quite rare, but a demyelinating polyneuropathy has been reported.11
Other manifestations of hyperthyroidism include nervousness, anxiety, psychosis, tremor, increased perspiration, heat intolerance, palpitations, insomnia, diarrhea, increased appetite, and weight loss. Common signs include goiter, tachycardia, atrial fibrillation, widened pulse pressure, as well as warm, thin, and moist skin.
Myasthenia gravis can develop in association with Graves’ disease. It can be a challenge distinguishing which neuromuscular symptoms are related to Graves’ disease or to myasthenia gravis. Muscle weakness associated with hyperthyroidism does not fluctuate or significantly improve with anticholinesterase medications.
Thyrotoxicosis is also associated with an unusual form of hypokalemic periodic paralysis. Thyrotoxic periodic paralysis (TPP) may occur sporadically, although a dominantly inherited mutation in a potassium channel has been recently identified in some patients. TPP has been commonly reported in Asians, but it is not restricted to this population.2,5 TPP is also more common in males. The attacks of weakness are similar in onset, frequency, duration, and pattern to familial hypokalemic periodic paralysis (Chapter 32). The one distinguishing feature is that familial hypokalemic periodic paralysis typically has its onset within the first three decades of life, while the onset of TPP usually develops later in adult life. Serum potassium levels tend to be low during the attacks of weakness, but levels can be normal. Muscle strength returns with treatment and normalization of thyroid function. β-adrenergic blocking agents also improve the myopathy.
Serum creatine kinase (CK) levels are usually normal in hyperthyroidism and can even be on the low side. Thyroid stimulating hormone (TSH) level is low in primary hyperthyroidism, while the thyroxine (T4) level and, occasionally, only the triiodothyronine (T3) level are elevated. In TTP serum potassium levels also are usually decreased. Routine motor and sensory nerve conduction studies (NCS) are normal.12,16 Electromyography (EMG) is usually normal, although fasciculation potentials and MUAP multiplets may be evident due to motor nerve hyperactivity.
Routine muscle biopsies are usually unremarkable, however, mild fatty infiltration, muscle fiber atrophy (types 1 and 2), variability in muscle fiber size, scattered isolated necrotic fibers, decreased glycogen, and increased internal nuclei can be noted.12,14–16 Nonspecific ultrastructural findings on electron microscopy (EM) may be seen including Z-band streaming, focal swelling of the T tubules, elongated mitochondria, decreased mitochondria, and subsarcolemmal glycogen deposition.17
In patients with TPP, muscle biopsies can reveal changes similar to that seen in familial hypokalemic periodic paralysis: Vacuoles may be appreciated, on routine light microscopy, while subsarcolemmal blebs filled with glycogen and dilated terminal cisternae of the sarcoplasmic reticulum might be apparent on EM.
The thyroid gland produces T4 that is converted to the more active T3 hormone in the periphery. These thyroid hormones are largely bound to plasma proteins. Free thyroid hormones bind to cytoplasmic receptors on target cells and are internalized into the nucleus, where they regulate the transcription of specific genes. Type 1 muscle fibers have a greater density of these thyroid receptors than do type 2 fibers.18
The pathogenic basis of thyrotoxic myopathy is unknown but is thought to be due to enhanced muscle catabolism. There is an increase in the basal metabolic rate with enhanced mitochondrial consumption of oxygen, pyruvate, and malate.18 Glucose uptake and glycolysis are stimulated in muscle independent of insulin.19 This can lead to an insulin-resistant state with fasting hyperglycemia and glucose intolerance and subsequent depletion of glycogen and reduced ATP production. Insulin resistance also may interfere with insulin’s anabolic effect on amino acid and protein metabolism.20 There is an inadequate level of protein synthesis to meet the demands of accelerated breakdown, which in turn, may be driven by increased lysosomal protease activity.21,22
A mutation in the KCNJ18 gene that encodes an inwardly rectifying potassium channel, Kir2.6 has been discovered in a cohort of TPP patients.23 Mutations were present in up to 33% of the unrelated TPP patients from the United States, Brazil, and France, but in only one of 83 patients from Hong Kong and 0 of 31 Thai patients. Thus, TPP is genetically heterogeneous. The demonstrated mutations appear to lead to muscle membrane inexcitability. In addition, thyroid hormones increase potassium efflux from muscle, which can lead to an increase in the number and activity of sodium-potassium ATPase pumps.24 This, in turn, results in partial depolarization of the muscle membrane, rendering it less excitable. Depolarization-induced sodium-channel inactivation6 and impaired propagation of the action potential across altered T tubules further renders the muscle membrane less excitable.25
Muscle strength improves gradually over several months with treatment of the hyperthyroidism.2 Propranolol can prevent and lessen the attacks of TPP. Unlike the familial form of hypokalemic periodic paralysis, acetazolamide is ineffective in preventing attacks of weakness associated with thyrotoxicosis.
Extraocular muscle weakness associated with Graves’ disease can persist for months or years after treatment. Artificial tears and ophthalmic ointments may be beneficial in preventing drying of the cornea and exposure keratitis that can result from severe lid retraction. Immunosuppression with corticosteroids and cyclosporine can be helpful in some patients but may be associated with significant side effects.26
Approximately one-third of individuals with hypothyroidism develop proximal arm and leg weakness along with myalgias, cramps, and generalized fatigue.2,7,27 Rare patients develop muscle hypertrophy; rhabdomyolysis may occur. Further, ventilatory muscles may be affected in severe cases.28
Delayed relaxation of the muscle stretch reflexes may be demonstrated, particularly at the ankle. This finding is best appreciated by having the patient kneel on a chair or bench while striking the Achilles tendon. Myoedema refers to painless and electrically silent mounding of muscle tissue when firmly percussed and is observed in approximately one-third of affected individuals.29 Myasthenia gravis can also occur in association with hypothyroidism.30
The serum CK levels are elevated as much as 10–100 times of normal. A TSH level should be checked in any patient with idiopathic CK-emia. In primary hypothyroidism, serum T4 and T3 levels are low, while TSH levels are elevated. The motor and sensory NCS are usually normal, unless they have a concomitant polyneuropathy. Needle EMG is also usually normal, although short-duration, low-amplitude polyphasic motor unit action potentials (MUAPs) may be appreciated in severely affected muscles.31–35
Muscle biopsy abnormalities are nonspecific and may include variability in muscle fiber size with atrophy of type 2 and occasionally type 1 fibers, hypertrophic muscle fibers, rare necrotic fibers, increased internalized nuclei, ring fibers, glycogen accumulation, vacuoles, and increased connective tissue.15,36,37 Mitochondrial swellings and inclusions, myofibrillar disarray with central core-like changes, autophagic vacuoles, glycogen accumulation, excess lipid, dilated sarcoplasmic reticulum, and T-tubule proliferation may be appreciated on EM.36
Hypothyroidism leads to reduced anaerobic and mitochondrial aerobic metabolism of carbohydrates and fatty acids decreasing ATP production. 38,39 Hypothyroidism also impairs adrenergic function and produces a concomitant insulin-resistant state. Protein synthesis and catabolism are reduced.
The myopathy improves with treatment of the hypothyroidism. However, some degree of weakness can persist even 1 year after return to a euthyroid state.
Myopathies are common in disorders of calcium and phosphate homeostasis. The regulation of calcium and phosphate levels requires a complex interaction of intestinal, renal, hepatic, endocrine, skin, and skeletal functions.2 Vitamin D regulates calcium absorption in the intestines. There are several forms of vitamin D: (1) vitamin D3 or cholecalciferol, which is derived from the skin; (2) vitamin D2 or ergocalciferol, which is dietary and absorbed through the intestines; and (3) 25-hydroxy-vitamin D, which is made in the liver and converted to the more potent metabolite 1,25-dihydroxy-vitamin D in the kidneys. Parathyroid hormone (PTH) assists in the regulation of serum calcium levels by promoting bone resorption, increasing renal calcium absorption and phosphate excretion, and enhancing 1,25-vitamin D conversion. Diet, intestinal absorption, and renal excretion contribute to serum phosphate levels. Increased PTH leads to increased levels of 1,25-dihydroxy-vitamin D, hypercalcemia, and hypophosphatemia. Persistently elevated PTH results in resorption of minerals within bone and replacement by fibrous tissue, a condition termed “osteitis fibrosa” or “osteitis fibrosa cystica” in severe forms.2
Muscle weakness is very common in osteomalacia, caused by vitamin D deficiency and secondary hyperparathyroidism in adults, occurring in as many as 72% of patients.40 Weakness develops however in only 2–10% of patients with isolated hyperparathyroidism.40,41 The earlier diagnosis and treatment of hyperparathyroidism and osteomalacia have led to fewer and less severe neuromuscular complications than appreciated in the past.40–45
The myopathy associated with primary hyperparathyroidism or osteomalacia is characterized by symmetric proximal weakness and atrophy, which are worse in the lower extremities. Concomitant bone pain is common due to associated microfractures. Involvement of the neck extensor muscles can lead to the so-called “dropped head syndrome.” There are rare reports of hoarseness, dysphagia, ventilatory involvement, and spasticity,41,46–49 although the majority of these cases were likely patients with amyotrophic lateral sclerosis and coincidental hyperparathyroidism.49
Muscle stretch reflexes are often brisk, but plantar responses are flexor. As many as 50% of patients complain of cramps and paresthesia. In addition, in 29–57% of patients there is stocking-glove loss of pain or vibratory sensation and decreased muscle stretch reflexes suggestive of an associated peripheral neuropathy.41 Finally, hypercalcemia can be associated with neurobehavioral abnormalities (memory loss, poor concentration, personality changes, inappropriate behavior including catatonia, anxiety, and hallucinations).
Secondary hyperparathyroidism and muscle weakness can develop in patients with chronic renal failure.50 Multifocal muscle infarcts and myoglobinuria due to calcification of the arteries (calciphylaxis) can develop in this setting.51–53 Calciphylaxis can also occur in patients with renal failure without overt hyperparathyroidism.54
Serum CK levels are usually normal in primary and secondary hyperparathyroidism and osteomalacia. CK may be slightly elevated in patients with muscle infarcts due to calciphylaxis.53 In primary hyperparathyroidism, serum calcium levels are usually elevated and serum phosphate levels are low, while urinary excretion of calcium is low and excretion of phosphate is high. In patients with concurrent hypoalbuminemia, serum calcium levels may be normal, so it is imperative to measure the ionized calcium levels which are typically elevated. Increased urinary excretion of cyclic adenosine monophosphate in the presence of hypercalcemia is also seen in hyperparathyroidism. Serum PTH levels and 1,25-dihydroxy-vitamin D levels are elevated in primary hyperparathyroidism. In contrast, 1,25-dihydroxy-vitamin D levels are low in secondary hyperparathyroidism due to renal failure. Noninvasive imaging techniques, such as ultrasound, thallium/technetium scintigraphy, computed tomography, and magnetic resonance imaging (MRI), may be useful in localizing abnormal parathyroid glands.55
Serum calcium level is low or normal, serum phosphate is variably low, and 25 OH vitamin D levels are also usually low in patients with osteomalacia. 1,25 OH vitamin D levels may be normal, however, as the body attempts to convert remaining vitamin D to this more potent form. Serum PTH levels are elevated in an attempt to normalize serum calcium levels that are reduced in response to vitamin D deficiency. Urinary excretion of calcium is low in an attempt to preserve serum calcium levels (except in cases secondary to renal tubular acidosis), while excretion of phosphate is high in response to secondary hyperthyroidism. In addition, serum alkaline phosphatase levels are elevated in 80–90% of cases of osteomalacia, again due to the body’s attempt to normalize serum calcium by increasing bone resorption.56 Skeletal survey reveals decreased bone density along with loss of trabeculae, blurring of trabecular margins, variably thinned cortices and microfractures that are most evident in the pelvis and proximal femur.42 EMG and NCS are normal unless the patients have a neuropathy related to their renal failure.
Muscle biopsies usually demonstrate nonspecific myopathic features with atrophy predominantly of type 2 fibers, but occasionally also of type 1 fibers. Muscle biopsies may reveal multifocal infarcts and calcium deposition primarily within vessel walls in patients with calciphylaxis.53
Primary hyperparathyroidism can be caused by parathyroid adenomas or hyperplasia as well as pituitary adenomas. Secondary hyperparathyroidism usually occurs in the setting of chronic renal failure which results in the reduction of 1,25-dihydroxy-vitamin D conversion or in malabsorption of vitamin D in disorders such as celiac disease. Vitamin D deficiency leads to diminished intestinal absorption of calcium and decreased renal phosphate clearance, which promotes secondary hyperparathyroidism and osteomalacia. In addition to acquired forms, there are hereditary forms of primary hyperparathyroidism57 and of vitamin D deficiency and osteomalacia.42
The mechanism(s) of weakness in hyperparathyroidism and osteomalacia are not known. PTH stimulates proteolysis in muscle58 and impairs energy production, transfer, and utilization.2,59 In addition, PTH may reduce the sensitivity of contractile myofibrillar proteins to calcium and activate a cytoplasmic protease, thus impairing the bioenergetics of muscle.1 Calcium and phosphate levels do not correlate well with the severity of muscle weakness.40,41,60 Vitamin D also has a direct effect on muscle by increasing muscle adenosine triphosphatase concentration, accelerating amino acid incorporation into muscle proteins,2,61 and enhancing the uptake of calcium by the sarcoplasmic reticulum and mitochondria.62,63
Hyperparathyroidism is diagnosed earlier than in the past because of routine screening of serum calcium levels. Thus, affected individuals are frequently asymptomatic or only mildly affected when they are diagnosed. Medical therapies and surgery are very effective for improvement of muscle weakness when detected within a few months.2,41,55,64
The treatment of choice of symptomatic patients with primary hyperparathyroidism is parathyroidectomy.55 If a patient has a parathyroid adenoma, the affected gland is removed, while additional glands may be biopsied. Individuals with hyperplasia of all four glands generally have subtotal (three and a half glands) parathyroidectomies. Those who are asymptomatic or have significant perioperative risk may be managed medically.64 Secondary hyperparathyroidism improves with vitamin D and calcium replacement or renal transplantation, if it is due to end-stage renal failure.65 Occasionally, subtotal parathyroidectomy may need to be performed in patients with secondary hyperparathyroidism. Likewise, the myopathy associated with osteomalacia responds well to vitamin D and calcium replacement and to treatment of the underlying responsible condition.40,42–44,56,66,67
Some authors have suggested that hyperparathyroidism can cause a neuromuscular syndrome that mimics amyotrophic lateral sclerosis and that patients may improve following resection of parathyroid adenomas.41,47 However, we suspect most of these patients who improved with parathyroidectomy did not have a motor neuron disorder, but rather, hyperparathyroid-related myopathy.49 In our experience, hyperparathyroidism in patients, who meet clinical and electrophysiologic criteria for amyotrophic lateral sclerosis, is rare and coincidental. These patients do not improve with parathyroidectomy.49
Hypoparathyroidism does not typically cause a myopathy, although a few patients do develop mild proximal weakness.68–70 In addition, painless myoglobinuria without objective weakness or tetany has been reported.71 On the other hand, paresthesia and tetany can develop in hypoparathyroidism secondary to hypocalcemia. The examiner may be able to demonstrate Chvostek sign (ipsilateral facial contraction upon tapping the facial nerve at the external auditory meatus) and Trousseau sign (thumb adduction, metacarpophalangeal joint flexion, and interphalangeal joint extension) in these hypocalcemic patients.
Serum CK may be normal or mildly elevated in patients.72,73 Hypoparathyroidism is associated with low serum PTH and calcium levels and high serum phosphate levels. Motor and sensory NCS are normal. Needle EMG may reveal normal insertional activity. Fasciculation potentials result from motor nerve hyperexcitability induced by the hypocalcemia.74–76 Multiplets (clusters of MUAPs activated with voluntary effort with interdischarge intervals between 2 and 20 ms) are another manifestation of nerve hyperexcitability and is the most characteristic electrodiagnostic abnormality seen in hypoparathyroidism or tetany. Otherwise, MUAP morphology and recruitment are normal.
Muscle biopsies may be normal or demonstrate mild variability in fiber size and increased internalized nuclei that reflect previous muscle damage caused by episodes of tetany.2,15 Decreased glycogen phosphorylase activity of muscle biopsy specimens has also been described.1
Hypoparathyroidism is seen in a number of conditions including osteomalacia, complications of surgery, hypomagnesemia or hypermagnesemia, irradiation, drugs, sepsis, infiltrative diseases of the parathyroid, and autoimmune, hereditary, or developmental disorders of the parathyroid glands.77 Decreased PTH leads to reduced synthesis of 1,25-dihydroxyvitamin D, hypocalcemia, and hyperphosphatemia.
The pathogenic mechanism of muscle weakness associated with hypoparathyroidism is poorly understood. Decreased serum calcium concentration causes a shift in the resting membrane potential closer to threshold.71,78–80 Therefore, less current is required to elicit an action potential, which can lead to tetany. Elevated serum CK and mild histologic abnormalities on muscle biopsy are generally considered secondary to muscle damage from tetany.
Muscle weakness improves following correction of the hypocalcemia and hyperphosphatemia with vitamin D and calcium administration.70
The adrenal gland comprises three major regions: (1) zona fasciculata, (2) zona glomerulosa, and (3) zona reticularis.2 The zona fasciculata produces and secretes glucocorticoids, which when produced in excess by an adrenal tumor can cause a myopathy. Mineralocorticoids such as aldosterone are generated by the zona glomerulosa and when produced in excess can cause hypokalemia which in turn leads to muscle weakness. The zona reticularis generates androgens but excess or deficiency of these hormones does not result in a muscle weakness. In contrast, these so-called anabolic steroids may increase muscle strength and mass. In the following section, we discuss myopathies associated with glucocorticoid excess or deficiency.
Steroid myopathy is the most common endocrine-related myopathy. An excess of glucocorticoids may arise directly from adrenal tumors, indirectly from pituitary tumors or from iatrogenic sources (corticosteroid medications).
Approximately 50–80% of patients with Cushing disease develop some degree of proximal weakness prior to treatment.2,81 Distal extremity, oculobulbar, and facial muscles are spared. Patients classically have an increase in truncal adipose tissue, a rounded facial appearance, and thin, frequently ecchymotic and hyperpigmented skin (i.e., the so-called Cushingoid appearance).
The incidence of iatrogenic steroid myopathy is not at all clear. Women appear to be more at risk for developing a steroid myopathy than men, approximately 2:1 but the reasons are unclear. An increased risk of the myopathy is seen with prednisone doses of 30 mg/day or more (or equivalent doses of other corticosteroids).2 Fluorinated corticosteroids have a greater propensity for producing muscle weakness than the nonfluorinated compounds (e.g., risk for myopathy: Triamcinolone > betamethasone > dexamethasone).82 Alternate day therapy may reduce the risk of corticosteroid-induced weakness but this has never been proven in a clinical study. Weakness can develop within several weeks of starting high doses of corticosteroids but more typically develops after chronic administration. In addition, an acute onset of severe generalized weakness can occur in patients receiving high dosages of intravenous corticosteroids (e.g., 1 g of methylprednisolone/day for multiple consecutive days) with or without concomitant administration of neuromuscular blocking agents (see section on acute quadriplegic myopathy/critical illness myopathy in Chapter 35).
Serum CK is normal. Serum potassium can be low and sodium may be elevated. Motor and sensory NCS and EMG are normal.
Muscle biopsy characteristically reveals preferential atrophy of type 2B fibers (Fig. 34-1).15,83 Milder degrees of atrophy and increased lipid deposition of type 1 muscle may be seen as well.
Corticosteroids bind to receptors on target cells and are subsequently internalized into the nuclei, where they regulate the transcription of specific genes. It is not known how corticosteroids lead to muscle dysfunction. Corticosteroids may result in diminished protein synthesis, increased protein degradation, altered carbohydrate metabolism, impaired mitochondrial function, or decreased sarcolemmal membrane excitability (i.e., in the setting of acute quadriplegic myopathy).1,2 In addition, hypokalemia associated with excess corticosteroid can also cause muscle weakness.
In cases of adrenal tumors, treatment is surgical when possible. In patients with iatrogenic steroid myopathy, treatment requires reduction in the corticosteroid dose, switching to an alternate day regimen, and encouraging exercise to prevent concomitant disuse atrophy.2 Experimental studies suggest that insulin-like growth factor-1 may have a prophylactic effect on preventing steroid myopathy.84 Increasing the dietary protein content of the diet is a suggested treatment of unproven benefit.
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