Endocrine Myopathies

Updated: Jul 02, 2021
  • Author: Shireen R Chacko, MBBS; Chief Editor: Nicholas Lorenzo, MD, MHCM, CPE, FAAPL  more...
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Overview

Practice Essentials

A myopathy is considered any abnormal state of striated muscle. Clinically, the patient experiences muscle weakness, pain, cramps, muscle tenderness, and spasms in various degrees.

Diseases of the endocrine system, including the thyroid, parathyroid, adrenal gland, pituitary gland, and the islands of Langerhans of the pancreas, usually result in multisystem signs and symptoms. A myopathy can very often be present, but it rarely is the presenting symptom.

Major categories of endocrine myopathy include those associated with (1) adrenal dysfunction (as in adrenal insufficiency, glucocorticoid excess, and hyperaldosteronism); (2) thyroid dysfunction (as in hypothyroidism or thyrotoxicosis); (3) parathyroid dysfunction (as in hyperparathyroidism or hypoparathyroidism); (4) pituitary dysfunction (as in acromegaly or panhypopituitarism); and (5) pancreatic islands of Langerhans dysfunction (as in diabetic muscle infarction). Steroid myopathy is the most common endocrine myopathy. [1]

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Pathophysiology

A myopathy is defined as an abnormality of the structure or function of skeletal muscle. [2]  Skeletal muscle has a complex structure, composed of intricately organized proteins arranged in a specific manner to allow for muscle contraction. [2]  Contraction of a muscle fiber is initiated by the action of the axon that innervates it, which is then transmitted to the inside of the muscle fiber by a structure called the transverse tubular system that results in the release of calcium from the endoplasmic reticulum. [2]  This calcium then leads to muscle contraction through a series of downstream events in an ATP-dependent process. [2]  Given this complex structure and function, the muscle fiber is susceptible to disturbances by a variety of systemic disorders, including inflammatory disorders, endocrinopathies, electrolyte imbalances, infections, drugs, toxins, and metabolic disorders.  Although endocrinopathies lead to alterations in cellular function and metabolic disturbances that can result in skeletal muscle dysfunction, the exact pathogenesis remains incompletely understood. The etiopathogenesis of specific endocrine myopathies are detailed below.

Adrenal dysfunction

Adrenal disorders associated with skeletal muscle dysfunction include primary adrenal insufficiency, glucocorticoid excess, and hyperaldosteronism. Adrenal hormone excess or deficiency secondary to pituitary disorders may also be associated with skeletal muscle dysfunction.

Primary adrenal insufficiency may be the result of autoimmune, infectious, or metastatic etiologies, with other causes including bilateral adrenal hemorrhage and specific drugs also included in the differential diagnoses. While acute adrenal crisis is associated with severe generalized weakness, [3]  muscle weakness is also a common manifestation of chronic Addison disease. [4]  Patients may also present with myalgias, lower extremity flexion contractures, and hyperkalemic periodic paralysis that improve with hormone replacement. [5, 6, 7]  The exact pathogenesis of this weakness is unclear and whether this represents a true myopathy remains to be elucidated. The postulated mechanisms include circulatory insufficiency, disturbances in carbohydrate metabolism, as well as electrolyte disturbances, namely, hyponatremia and hyperkalemia. [7]  

Glucocorticoid excess caused by Cushing’s syndrome, Cushing’s disease, ectopic adrenocorticotropic hormone (ACTH) production, and exogenous glucocorticoid administration are all associated with muscle weakness and atrophy, with predominant proximal muscle involvement. [7]  Interestingly, other disease states associated with increased glucocorticoid production such as sepsis, acidosis, and cancer, are also associated with muscle damage. [8] ​ Glucocorticoid excess may lead to muscle weakness via inhibition of protein synthesis, increased protein catabolism and altered carbohydrate metabolism. [7, 9, 10]

Hyperaldosteronism caused by pituitary or ectopic overproduction of ACTH, adrenal tumors, or exogenous corticosteroid administration has been associated with muscle weakness that is attributed to the associated hypokalemia. [11, 12] ​ Objective myopathy is rare in hyperaldosteronism, but case reports describe objective muscle weakness, elevated creatine kinase levels, and electromyographic findings of myopathy. [11, 13]

Thyroid dysfunction

Both hyperthyroidism and hypothyroidism are associated with myopathy.

Thyroid hormone deficiency may be congenital or acquired; acquired causes include autoimmune etiologies, iodine-deficient states and post-ablative or post-surgical hypothyroidism. [2]  Central hypothyroidism from hypopituitarism may also occur. [14]  Thyroid hormone deficiency has been commonly associated with neuromuscular symptoms, [15]  probably due to impaired muscle energy metabolism and slow protein turnover that occur with thyroid hormone deficiency. [15, 16, 17]

Thyroid hormone excess, or thyrotoxicosis, may result from Graves disease, toxic multinodular goiter, toxic adenoma, thyroiditis, exogenous thyroid hormone intake and, rarely, excessive thyroid-stimulating hormone (TSH) secretion from the pituitary gland. [14] ​ Thyrotoxic myopathy may  be secondary to a disturbance in the function of the muscle fibers from increased mitochondrial respiration, accelerated protein degradation and lipid oxidation, as well as enhanced beta-adrenergic sensitivity due to excessive amounts of thyroid hormone. [18]

Parathyroid dysfunction and vitamin D deficiency (osteomalacia)

Hypoparathyroidism is most commonly postsurgical, but may also occur due to genetic or autoimmune etiologies. [19]  Resistance to parathyroid hormone (PTH) can occur in hypomagnesemia. [19]  Hypoparathyroidism results in hypocalcemia, which in turn leads to neuromuscular irritability [20]  that manifests as tetany, with or without carpopedal spasm.  

Primary hyperparathyroidism, or hypersecretion of PTH from the parathyroid glands — from parathyroid adenomas, and less commonly from diffuse gland hyperplasia [19]  — has specific effects on skeletal muscle. Increased intracellular calcium, and protein degradation along with reduced calcium sensitivity of troponin, lead to hyperparathyroid myopathy, including muscle weakness and pain. [7]  

Secondary hyperparathyroidism occurs as a result of hypocalcemia from vitamin D deficiency and chronic renal failure. [19]  Elevated PTH levels may lead to hyperparathyroid myopathy by similar mechanisms as in primary hyperparathyroidism. Furthermore, the associated vitamin D deficiency and uremia can result in various downstream effects, resulting in myopathic features as well.  

Osteomalacia, the abnormal mineralization of bone seen in vitamin D deficiency and hypophosphatemia, is associated with myopathy via various mechanisms, including decreased protein synthesis, impaired excitation-contraction coupling, decreased myofibrillar ATPase activity, and impaired calcium uptake ability. [7]  

Pituitary dysfunction

Pituitary disorders, both hyposecretion and hypersecretion of hormones, are associated with myopathy.

Hypopituitarism is usually due to compression of the adenohypophysis from pituitary adenomas and rarely from trauma or infection. The muscle weakness in panhypopituitarism is largely due to the consequent reduction in thyroid and adrenal hormones, although reduced growth hormone levels also play a role. [7]  

Hyperpituitarism results from excessive secretion from tumors arising from specific pituitary cells, such as ACTH and growth hormone from corticotroph and somatotroph adenomas, respectively.

ACTH-secreting pituitary adenoma or Cushing’s disease may result in a proximal myopathy due to excess glucocorticoid secretion. [7, 21]

The muscle weakness in acromegaly has been postulated to occur via reduced membrane excitability and reduced muscle ATPase activity, while a concomitant increased muscle bulk may occur due to the effects of growth hormone on muscle protein metabolism. [7]  Interestingly, there are some reports that dysfunction of the hypothalamic-pituitary-adrenal axis plays a role in the pathogenesis of polymyalgia rheumatica. [22, 23]  

Pancreatic islets of Langerhans dysfunction

Diabetic muscle infarction (spontaneous diabetic myonecrosis) is a rare condition that can occur in patients with type 1 and type 2 diabetes and is thought to represent one of the vascular complications of diabetes. [24, 25]  It can present as painful muscle swelling, typically of the front of the thigh, and the exact pathogenesis is unclear. [25]

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Epidemiology

Patients with endocrine dysfunctions frequently complain of vague fatigue and weakness that may be ignored, leading to delayed diagnosis if this was the sole manifestation. A diagnosis of myopathy is sometimes made without histologic or electrophysiologic confirmation.  Therefore, the true prevalence of endocrine myopathy is difficult to ascertain. [26]  Corticosteroid myopathy remains the most common endocrine-related myopathy.

The prevalence of specific endocrine myopathies is as follows:

  • Exogenous glucocorticoid use: Severe muscle weakness is reported in 2.4-21% of those taking exogenous glucocorticoids for prolonged periods [27]  
  • Cushing’s syndrome: Proximal muscle weakness and wasting is reported in 60% of patients [28]  
  • Cushing’s disease: 50-80% of cases are associated with muscle weakness [29]  
  • Adrenal insufficiency: Weakness and fatigability have been reported in up to 100% of these patients, [30]  with other sources citing a prevalence of severe generalized weakness, cramps, and fatigue in 25-50% of these patients [7]
  • Hyperaldosteronism: Although weakness is a common subjective feature in this condition, objective myopathy appears to be rare [12, 11]  
  • Hypothyroidism: The prevalence of neuromuscular symptoms in these patients varies from 30% to 80% [15]
  • Thyrotoxicosis: 80% of cases of thyrotoxicosis have been reported to have muscle involvement [31]
  • Hypoparathyroidism: Frequently associated with tetany; however, weakness and elevated CK levels appear to be rare [32, 26]  
  • Primary hyperparathyroidism: Approximately 25% of patients with primary hyperparathyroidism develop muscle symptoms [33]  
  • Osteomalacia: Approximately 50% of patients with osteomalacia develop muscle symptoms [7]
  • Acromegaly: 50% of patients have been reported to display myopathic changes on EMG [7]  
  • Diabetic muscle infarction: Extremely rare and since this condition was first described about 45 years ago, fewer than 200 cases have been reported [25]  

Sex- and age-related demographics

Sex-related demographics are as follows:

  • Hyperparathyroid myopathy - Female-to-male ratio 2:1
  • Hyperthyroid myopathy - Female-to-male ratio 1:1
  • Iatrogenic steroid myopathy - Female-to-male ratio 2:1 [34]
  • Hypothyroid myopathy - Female-to-male ratio 5:1
  • Cushing myopathy - Depends on the etiology of Cushing syndrome

Age-related demographics are as follows:

  • Hyperparathyroid myopathy - Peak incidence 40-60 years
  • Hyperthyroid myopathy - Peak incidence 20-60 years
  • Hypothyroid myopathy - Incidence increases after 40 years
  • Cushing myopathy - Peak incidence 20-40 years
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Prognosis

The prognosis depends on the underlying endocrine process. Hyperthyroidism, hypothyroidism, and other endocrine states may be fatal.

Myopathy may be painful, and the pain must be addressed either in the form of symptomatic therapies or curative treatments of the endocrine diseases. Myopathy often abates with correction of underlying disease. Prolonged weakness and partial recovery are common, especially in severe cases and in patients with delayed or suboptimal treatment.

The prognoses for various endocrine myopathies are as follows:

  • Adrenal dysfunction: Although most cases of muscle weakness related to glucocorticoid excess resolve with therapy, there have been reports of persistent symptoms years after treatment. [35, 7]  
  • Thyroid dysfunction: Thyrotoxic myopathy resolves completely with treatment of the underlying endocrinopathy. However, in hypothyroid myopathy, while CK levels fall rapidly with treatment, clinical improvement tends to be slower and less reliable, with one study describing persistent subjective weakness 1 year after treatment in 21% of patients. [36]  
  • Parathyroid dysfunction: In hypoparathyroidism, while the tetany may resolve with correction of hypocalcemia, in patients who have chronic myopathy it will at least partially resolve with calcium and vitamin D supplementation. Secondary hyperparathyroidism is often difficult to treat, but completely treated primary hyperparathyroidism leads to resolution of the associated myopathy. [37, 38, 15]  The myopathy of osteomalacia tends to improve with replacement of vitamin D. [7]  
  • Pituitary dysfunction: In acromegaly, the myopathy resolves with normalization of growth hormone levels. [7]  

Morbidity/mortality

Myopathy may result in weakness and/or pain that may significantly influence the quality of life and impair daily function. Myopathy may also result in muscle atrophy.

Mortality is related to the underlying cause of myopathy. For example, myxedema coma may have a mortality rate between 50% (if treated aggressively) and 100%. [39]

Complications

Clinicians should be aware of the following potential complications that may arise:

  • Hypothyroid myopathy may present acutely with rhabdomyolysis. [40, 41]
  • Respiratory muscle weakness has been reported to occur in various endocrine diseases. [42]
  • Diabetic muscle infarction may be complicated by acute compartment syndrome. [43]  
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Patient Education

For patient education resources, see the following from WebMD:

Also visit the Thyroid & Metabolism Center at eMedicineHealth for additional patient education resources.

 

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