AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Deficiency of thyroid hormone leads to a state called hypothyroidism. Common causes of hypothyroidism include the following:

• Treatment with radioactive iodine I 131 for Graves disease

• Hashimoto disease - An autoimmune process in which lymphocytic infiltration and fibrous tissue accumulation cause replacement of normal thyroid tissue

• Drug-induced hypothyroidism - Known to occur with amiodarone and iodine (ie, Wolff-Chaikoff effect)

• Hereditary disorders of the iodothyronine synthesis pathway (thyroxine [T4] and triiodothyronine [T3])

• Pituitary tumors and related surgical resections

Hypothyroidism can cause several symptoms, ranging from mild (eg, fatigue, weight gain, cold intolerance, mental slowing, muscle cramping) to severe (eg, heart enlargement, myxedema coma [rare]).

Without regard to the cause of hypothyroidism, neuromuscular and musculoskeletal manifestations can be observed in many patients with hypothyroidism. These manifestations can occur at any time in the hypothyroidism disease process. These are usually mild and include weakness, pain, stiffness, or ache.

Hypothyroid myopathy typically manifests as polymyositislike myopathy with proximal muscle weakness and an increased creatine kinase level. But, sometimes, it manifests as muscular enlargement (pseudohypertrophy) and, in adults, is called Hoffmann syndrome. The pattern of proximal weakness with diffuse muscular enlargement in children with hypothyroid disease (cretinism) is referred to as Kocher-Debré-Sémélaigne syndrome.

Several case reports describe rhabdomyolysis associated with hypothyroidism. In these cases, the hypothyroidism was thought to predispose individuals to rhabdomyolysis.

Pathophysiology

Hypothyroidism causes a constellation of changes in the body. The lack of thyroid hormone results in slowed or reduced metabolic function, such as decreased protein turnover and impaired carbohydrate metabolism. These metabolic changes occur in many organ systems, including muscle. Pain with muscle exertion is characteristic of defective carbohydrate metabolism.

Slowed muscle contraction and relaxation, known as hypothyroid myopathy, may be caused by a shift in distribution of muscle fiber type from a fast twitch to a slow twitch. A reduction in muscle mitochondrial oxidative capacity and beta-adrenergic receptors, as well as the induction of an insulin-resistant state, may all cause these changes.

Evidence from a study by Sinclair et al (2005) suggests that a decrease in muscle carnitine in both hypothyroidism and hyperthyroidism may contribute to thyroid myopathy in these people.

The global inhibition of the main oxidative pathways (substrate incorporation, substrate oxidation) and of the respiratory chain within cells also may cause myopathic symptoms. A diminished energetic consumption is related partially to a transition in the myosin isoforms, which express a slower adenosine triphosphatase, and an impairment of the trans-sarcolemmic transports. All these factors may contribute to muscle weakness, fatigue, and exertional pain.

Exercise intolerance could be due to an abnormal recruitment of several metabolic pathways, such as glycolysis, related to the mitochondrial metabolism impairment. Abnormal accumulation of protons and monovalent phosphate ions, which are involved in the actin-myosin interaction, as well as abnormal Ca++ metabolism, also may be causes of reduced exercise tolerance.

Hyponatremia often is seen in patients with hypothyroidism. The decreased number of Na+/K+ adenosine triphosphatase–dependent pumps could imply an abnormal intracellular Na+ level and explain frequent disorders of membrane excitability.

Myoedema is the phenomenon of mounding up of muscle tissue after light percussion. Myoedema occurs in approximately one third of patients with hypothyroidism, but it is not entirely specific for hypothyroidism. Myoedema is thought to be caused by delayed Ca++ reuptake by the sarcoplasmic reticulum, which also prolongs muscle contraction. Although not proven, this type of prolongation of muscle contraction is also thought to cause muscle hypertrophy.

Frequency

United States

Acquired impairment of thyroid function affects about 2% of adult women and about 0.1-0.2% of adult men in North America.

Neonatal hypothyroidism occurs with a frequency of 0.02% in the white population. Among blacks, the frequency falls to 0.003%.

Of individuals with hypothyroidism, 30-80% manifest neuromuscular symptoms, depending on the severity of hypothyroidism. Weakness is observed in one third of patients with hypothyroidism. Carpal tunnel syndrome, although not part of the myopathy, is a peripheral nerve dysfunction found in 15-30% of patients with hypothyroidism.

International

Neonatal screening programs for congenital hypothyroidism in many areas of the world show that hypothyroidism is present in 1 out of every 4000 newborns. In iodine-deficient areas of the world, the incidence of hypothyroidism is 10- to 20-fold higher.

Mortality/Morbidity

Mortality has not been shown to be increased in patients with hypothyroid myopathy. Morbidity is significantly increased, reflected in performance of activities of daily living (ADL) and quality of life.

Race

No predilection for any particular race has been established.

Sex

The incidence of hypothyroidism is much greater in women than in men. Myxedema coma is extremely rare, but its incidence is higher in elderly women, especially those older than 60 years.

Age

Hypothyroidism is seen more commonly in women aged 40-60 years; however, it can be seen in persons of all ages.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Neuromuscular symptoms present in 30-80% of patients with hypothyroidism. These symptoms improve or disappear with correction of the hypothyroid state.
• Patients may complain of muscle cramping, proximal symmetrical muscle weakness, muscle stiffness, and exercise intolerance. These manifestations can occur at any time during the presentation of hypothyroidism.
• With hypothyroid myopathy, slowness of muscle relaxation is noted, as is a slowness of muscle contraction.

Physical

• Deep tendon reflexes are delayed in approximately 85% of patients with hypothyroidism.
• Mounding of the muscle after light percussion (ie, myoedema) occurs in one third of patients with hypothyroidism, but it is not necessarily specific to hypothyroidism.
• Muscle enlargement, stiffness, and cramping are a constellation of findings seen in individuals with hypothyroidism. In adults, these findings are known as Hoffman syndrome. In children, these findings are called Kocher-Debré-Sémélaigne syndrome.
• Myokymia, which may be related to a low sodium level, may be seen.

Causes

See Pathophysiology.

• Hypothyroidism can impair mitochondrial metabolism, which results in a decrease in muscle energy production. A low thyroid hormone level is the main causative factor.



• Certain drugs, such as lipid-lowering drugs, may exacerbate myopathy in patients with hypothyroidism. Lipid-lowering drugs include beta-hydroxy-beta-methylglutaryl-CoA (HMG CoA) reductase inhibitors, such as the following:
• • Atorvastatin (Lipitor)
  
  
  
  • Fluvastatin (Lescol)
  
  
  
  • Simvastatin (Zocor)
  
  
  
  • Pravastatin (Pravachol)
  
  
  
  • Lovastatin (Mevacor)
• Interferon alfa therapy for hepatitis, as well as the infection itself, has been reported to cause a number of immunologic and/or autoimmune adverse effects. Thyroiditis, seen in 10% of patients, may induce hypothyroidism.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Myasthenia gravis

Myasthenia gravis has been associated with Graves disease and hypothyroidism. Patients present with proximal muscle weakness that may be fatigable. Eventually, they can have dysphagia and respiratory distress.

Other metabolic, mitochondrial, and inflammatory myopathies

• Glycogen metabolism deficiencies, which are divided into dynamic and static deficiencies
  • Dynamic myopathies are manifestations with exercise intolerance, pain, muscle cramps, and myoglobinuria.
    • Type V - Phosphorylase (McArdle disease)
      
    • Type VII - Phosphofructokinase (Tarui disease)
      
    • Type VIII - Phosphorylase B kinase
      
    • Type IX - Phosphoglycerate kinase
      
    • Type X - Phosphoglycerate mutase
      
    • Type XI - Lactate dehydrogenase
    
    
  • Static deficiencies are associated with fixed weakness without features of exercise intolerance or myoglobinuria.
    • Type II - Alpha-1,4 glucosidase (acid maltase)
      
    • Type III - Debranching
      
    • Type IV - Branching
    
    
  
  
• Lipid metabolism deficiencies can be accompanied by the following dynamic or static manifestations.
  • Carnitine palmitoyl transferase
    
  • Primary systemic/muscle carnitine deficiency
    
  • Secondary carnitine deficiency (eg, beta-oxidation defects, medications such as valproic acid)
    
  • Purine metabolism deficiencies (eg, myoadenylate deaminase deficiency)
  
  
• Mitochondrial myopathies
  • Pyruvate dehydrogenase complex deficiencies (eg, Leigh syndrome)
    
  • Progressive external ophthalmoplegia
    
  • Kearns-Sayre syndrome
    
  • Mitochondrial encephalopathy with lactic acidosis and strokelike episodes
    
  • Myoclonic epilepsy and ragged red fibers
    
  • Mitochondrial neurogastrointestinal encephalomyopathy
    
  • Mitochondrial depletion syndrome
    
  • Leigh syndrome and neuropathy, ataxia, or retinitis pigmentosa
    
  • Succinate dehydrogenase deficiency
  
  
• Channelopathies are another differential diagnosis for myopathy.
  
• Inflammatory myopathies are another important differential and may be difficult to differentiate from pure endocrine causes, including a heterogenous group of acquired nonhereditary disorders characterized by muscle weakness and inflammation indicated by muscle biopsy.
  • Idiopathic inflammatory myopathies
    • Polymyositis
      
    • Dermatomyositis
      
    • Inclusion body myositis
      
    • Overlap syndromes with other connective tissue disease
      
    • Sarcoidosis and other granulomatous myositis conditions
      
    • Behcet syndrome
      
    • Inflammatory myopathies and eosinophilia
      
    • Focal myositis
      
    • Myositis ossificans
    
    
  • Bacterial infections
    • Staphylococcus aureus
      
    • Escherichia coli
      
    • Yersinia species
      
    • Legionella
      
    • Gas gangrene (Clostridium welchii)
      
    • Leprous myositis
      
    • Lyme disease
    
    
  • Viral infections
    • Acute influenza or other viral infections
      
    • Retrovirus-related myopathies (human immunodeficiency virus, human T-cell leukemia virus type 1)
      
    • Hepatitis B and C
    
    
  • Parasitic infections
    • Trichinosis
      
    • Toxoplasmosis
      
    • Cysticercosis
    
    
  • Fungal infections
    • Candida species
      
    • Cryptococcus species
      
    • Sporotrichosis species
    
    
  
  

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Nerve conduction studies may show both decremental response to low-rate nerve stimulation and incremental response to high-rate nerve stimulation, suggesting some neuromuscular junction abnormality.
• Needle electromyography is usually normal or may be mildly myopathic.
• Increased thyrotropin is seen in primary hypothyroidism, and decreased thyrotropin is seen in pituitary-hypothalamic disease with secondary hypothyroidism.
• Low free T4 and T3 levels, as well as a low total thyroxine level and a free T4 index, are seen. The degree of myopathy is not necessarily correlated to the degree of hypothyroidism.
• The creatine kinase level can be very high (10-100 times normal) in some patients, but it has no correlation with weakness.

Histologic Findings

Histologic findings on muscle biopsy are nonspecific. Pale central regions on nicotinamide adenine dinucleotide with accumulation of periodic acid-Schiff–positive material are seen. Decreased numbers of beta-adrenergic receptors are observed, accompanied by glycogenolysis. Some muscle fiber atrophy is noted, and increased numbers of internal nuclei, glycogen aggregates, and, occasionally, deposition of mucopolysaccharides in the connective tissue are characteristic of hypothyroid myopathy.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Rehabilitation Program

Physical Therapy

Skeletal muscle weakness is the ultimate cause of most clinical problems in myopathy. In a study of patients with slowly progressive myopathies, a 12-week moderate-resistance (30% of maximum isometric force) exercise program resulted in strength gains ranging from 4-20% without any notable deleterious effects. In the same population, a 12-week high-resistance (training at the maximum weight a subject could lift 12 times) exercise program showed no further added benefits when compared with the moderate-resistance program, and there was evidence of overwork weakness in some subjects.

Early intervention with gentle low-impact aerobic exercises may increase muscle efficiency and cardiovascular performance, may fight fatigue and depression, may maintain body weight, and may improve pain tolerance. Activities include walking, swimming, and stationary bicycling.

Occupational Therapy

Occupational therapy may be needed for training in performance of ADL to enable the patient to compensate for proximal muscle weakness. Occupational therapists are able to provide adaptive equipment to assist the patient when performing ADL.

Recreational Therapy

Maintaining the ability to do avocational activities that promote physical fitness and mental health is important.

Medical Issues/Complications

Because there are multiple causes of muscle weakness, patients may not respond well to initial therapy because they have an undiagnosed secondary cause of myopathy. A thorough investigation for all causes is essential.

Consultations

• Physical medicine and rehabilitation specialist
• Endocrinologist
• Neurologist

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Drug Category: Thyroid products

For replacement or supplementation of thyroid levels.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Some patients with hypothyroid myopathy may need a short stay in acute rehabilitation.

Further Outpatient Care

• Outpatient physical therapy is indicated.

In/Out Patient Meds

• Continuation of thyroid supplementation is needed with close monitoring of the levels. Once a normal value has been achieved (normal thyrotropin), levels can be checked annually, unless the patient becomes pregnant or exacerbation of symptoms develops.

Deterrence

• Patients with hypothyroid myopathy should be careful with using cholesterol-reducing agents (ie, HMG CoA reductase inhibitors), such as statins.

Prognosis

• With treatment, the prognosis of hypothyroidism is good. Early diagnosis and prompt introduction of thyroid supplemental treatment is needed. Complete resolution of weakness and other symptoms takes several months of treatment.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to identify the cause of myopathy can lead to potential medical or legal problems. See Medical Issues/Complications.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Barohn R. Metabolic myopathies. In: Cecil RL, Goldman L. Textbook of Medicine. ed. Orlando, Fla: Harcourt Health Sciences; 2000.
• Cakir M, Samanci N, Balci N, Balci MK. Musculoskeletal manifestations in patients with thyroid disease. Clin Endocrinol (Oxf). Aug 2003;59(2):162-7. [Medline].
• Deepak S, Harikrishnan, Jayakumar B. Hypothyroidism presenting as Hoffman's syndrome. J Indian Med Assoc. Jan 2004;102(1):41-2. [Medline].
• Ghilardi G, Gonvers JJ, So A. Hypothyroid myopathy as a complication of interferon alpha therapy for chronic hepatitis C virus infection. Br J Rheumatol. Dec 1998;37(12):1349-51. [Medline].
• Horak HA, Pourmand R. Endocrine myopathies. Neurol Clin. Feb 2000;18(1):203-13. [Medline].
• Kisakol G, Tunc R, Kaya A. Rhabdomyolysis in a patient with hypothyroidism. Endocr J. Apr 2003;50(2):221-3. [Medline].
• Lochmuller H, Reimers CD. Exercise induced myalgia in hypothyroidism. In: Year Book of Sports Medicine. St Louis, Mo: Mosby; 1994:999-1001.
• Miyake I, Hiromatsu Y. [Hypothyroid myopathy]. Ryoikibetsu Shokogun Shirizu. 2001;(36):294-7. [Medline].
• Modi G. Cores in hypothyroid myopathy: a clinical, histological and immunofluorescence study. J Neurol Sci. Apr 1 2000;175(1):28-32. [Medline].
• Monzani F, Caraccio N, Siciliano G, Manca L, Murri L, Ferrannini E. Clinical and biochemical features of muscle dysfunction in subclinical hypothyroidism. J Clin Endocrinol Metab. Oct 1997;82(10):3315-8. [Medline]. [Full Text].
• Pourmand R. Metabolic myopathies. A diagnostic evaluation. Neurol Clin. Feb 2000;18(1):1-13. [Medline].
• Sinclair C, Gilchrist JM, Hennessey JV, Kandula M. Muscle carnitine in hypo- and hyperthyroidism. Muscle Nerve. Mar 31 2005;32(3):357-359. [Medline].
• Takanami I, Imamuma T, Yamamoto Y, et al. The rapid transformation of hyperthyroidism to hypothyroidism complicated by myasthenia gravis. J Thorac Cardiovasc Surg. Sep 1995;110(3):852. [Medline].

Article Last Updated: Apr 6, 2007