Hypothyroid Myopathy

Etiology

Hypothyroid myopathy is a condition that occurs when the thyroid gland does not produce enough thyroid hormones. These hormones play a crucial role in the body's metabolism, including the metabolism of muscles. Consequently, low levels of thyroid hormones can result in muscle weakness, fatigue, and other symptoms. Some common causes of hypothyroidism are listed below.

• Autoimmune disorders: Hashimoto thyroiditis is an autoimmune disorder in which the body's immune system attacks the thyroid gland, leading to hypothyroidism. This disorder stands as the most common cause of hypothyroidism in the developed world.

• Iodine deficiency: Iodine is an essential nutrient that is required for the production of thyroid hormones. Insufficient iodine in the diet can lead to hypothyroidism and hypothyroid myopathy, making it the most prevalent cause worldwide.[3]

• Thyroid surgery or radiation therapy: Surgery or radiation therapy to the thyroid gland can damage the gland or reduce its function, resulting in hypothyroidism and hypothyroid myopathy.[4]

• Medications: Certain medications, such as lithium, can interfere with the production of thyroid hormones.

• Congenital hypothyroidism: An underactive thyroid gland at birth can cause significant developmental delays and physical deficiencies. 

• Aging: The natural aging process may cause a decline in thyroid function.[5]

Overall, hypothyroid myopathy is caused by a lack of thyroid hormones in the body, which can be due to a variety of factors such as autoimmune disorders, iodine deficiency, thyroid surgery, medications, congenital hypothyroidism, and aging.

Epidemiology

Hypothyroidism is one of the most commonly diagnosed medical conditions, affecting up to 12% of Americans during their lifetime.[6] Women are affected more often compared to men, and it can manifest at any age, although it is commonly observed between the ages of 40 and 70. No specific racial predilection has been identified in studies regarding this condition. The prevalence of hypothyroidism also increases with age, with older adults being more affected compared to younger individuals.

Pathophysiology

The pathophysiology of hypothyroid myopathy is not fully understood. Thyroid hormones significantly influence cellular metabolism, and their deficiency causes impairment of the cell's normal functioning. Serum T3 is a primary regulator of skeletal muscle mitochondrial function.[7] Hypothyroid myopathy is likely secondary to metabolism alterations resulting in aberrant glycogen and oxidative metabolism in the actin-myosin unit.[8] Thyroxine (T4) deficiency results in a reduced mitochondrial oxidative capacity, abnormal glycogenolysis, and an insulin-resistant state of the cell. Consequently, there is a selective atrophy of type 2 muscle fibers (fast-twitching type) as they depend on glycolysis for energy, leading to the slowing of muscle contraction observed clinically in patients with hypothyroidism.[7] Oxidative damage also likely causes muscle cell injury and rhabdomyolysis.[9]

Muscle hypertrophy is believed to be a compensatory response to the accumulation of glycosaminoglycans in the muscle. An increase in connective tissue and muscle fibers also contributed to this hypertrophy. There is also a decrease in muscle carnitine in patients with thyroid dysfunction, causing myopathic symptoms. The muscle involvement in hypothyroidism is caused by alterations in muscle fibers from fast-twitching type 2 to slow-twitching type 1 fibers, deposition of glycosaminoglycans, poor contractility of actin-myosin units, low myosin ATPase activity, and low ATP turnover in skeletal muscle.[10]

Notably, the degree of muscle weakness does not always correlate with the severity of thyroid hormone deficiency, suggesting that besides impaired muscle function, structural muscle injury might have a role in the pathogenesis of myopathy in some cases. Changes in muscle cell membrane permeability can result in elevated levels of serum muscle enzyme in the absence of symptoms or structural abnormalities, and reduced clearance of these enzymes can also contribute to muscle injury.

Animal studies have shown that thyroid hormones regulate the gene expression of skeletal muscle proteins such as myosin ATPase, strengthening the role of thyroid hormone deficiency in the pathogenesis of hypothyroid myopathy.

Histopathology

Microscopic examination of hypothyroid myopathy may reveal the following findings:

• Muscle fiber atrophy: Decrease in the size of muscle fibers due to inadequate thyroid hormone levels, leading to muscle weakness.

• Increased connective tissue: Accumulation of connective tissue within the muscle, which can contribute to muscle stiffness and weakness.

• Fiber type changes: Shift in muscle fiber types, with a decrease in fast-twitch fibers (Type II) and an increase in slow-twitch fibers (Type I). This alteration can affect muscle function and endurance.

• Vacuolar changes: Presence of vacuoles within muscle fibers, which may contain cellular debris or lipid droplets. These vacuoles can disrupt muscle structure and function.

• Myopathic changes: Features such as fiber necrosis (death of muscle fibers), regeneration (attempted repair of muscle tissue), and inflammatory infiltrates (immune cells infiltrating muscle tissue). These changes are typically observed in more severe cases of hypothyroid myopathy.

• Glycogen accumulation: Increased glycogen storage within muscle fibers due to impaired glycogenolysis, leading to muscle stiffness and weakness.

• Reduced oxidative enzyme activity: Decreased activity of oxidative enzymes in muscle fibers, which can impair energy production and muscle function.

These microscopic findings collectively contribute to the characteristic muscle weakness and dysfunction observed in hypothyroid myopathy. However, the specific findings can vary depending on the severity and duration of hypothyroidism and individual patient factors.

Toxicokinetics

Endocrine disruptors impact various metabolic pathways, but effects on the thyroid axis are especially concerning due to hypothyroidism's effects on infant and childhood development. The Organization for Economic Co-operation and Development (OECD) and the United States Environmental Protection Agency (EPA) testing strategies for identifying developmental thyroid toxicants primarily rely on serum tetraiodothyronine (T4) measurements in rodents, paralleling the clinical monitoring of pregnant women and newborns. The use of T4 measurements is historically based on the idea that hormone measurements are linearly related to receptor occupancy, thus defining thyroid hormone action. However, significant research findings in thyroid biology have challenged this dogma. Although some xenobiotic exposures may reduce thyroid hormone actions, these observations may not be applicable at all life stages.[11][12] Once testing identifies specific thyroid hormone molecular pathway disruption, toxic effects on the thyroid gland causing hypothyroid myopathy can be addressed more specifically.[6]

History and Physical

Neuromuscular manifestations of hypothyroidism frequently occur in conjunction with the common systemic symptoms, such as fatigue, weight gain, cold intolerance, and dry skin.[13] Decreased or absent deep tendon reflexes are common. Rarely, muscle and nerve dysfunction may manifest as the initial symptom of hypothyroidism, highlighting the importance of considering thyroid dysfunction when evaluating new neuromuscular symptoms.

Hypothyroid myopathy presents with nonspecific symptoms of myalgias, muscle cramps, fatigue, and muscle weakness, particularly exacerbated with exertion and exercise. Typical features of hypothyroid myopathy are described below.

Myalgia, a common manifestation of hypothyroidism, presents as nonspecific muscle stiffness or diffuse pain, often exacerbated after exercise. This symptom may be associated with elevated levels of serum muscle enzyme.[2]

Proximal myopathy is characterized by a slowly progressive, symmetric proximal muscle weakness.[14] Shoulder and hip girdle muscles are most commonly affected. Occasionally, hypothyroid myopathy is more fulminant, with markedly elevated serum muscle enzymes. On examination, deep tendon reflexes are characteristically described as hung-up due to delayed muscle relaxation.

Muscle pseudohypertrophy infrequently occurs in adults. Patients can have generalized muscular hypertrophy and variable degrees of weakness. The skin and subcutaneous tissues have a thickened, doughy appearance. Serum muscle enzymes are typically elevated. Signs of hypothyroidism are typically readily apparent and long-standing in this setting.[15][16]

Two associated syndromes related to muscle pseudohypertrophy include:

• Kocher-Debre-Semelaigne syndrome manifests in childhood and is associated with generalized muscular hypertrophy, myxoedema, short stature, and developmental delay.[17]

• Hoffmann syndrome typically occurs in adults and is characterized by pseudohypertrophy, painful spasms, proximal muscle weakness, and stiffness. This syndrome is generally observed in primary hypothyroidism and very rarely with secondary hypothyroidism. The cause of muscle pseudohypertrophy in Hoffmann syndrome is postulated to be due to the deposition of glycosaminoglycans and increased muscle fiber size. The muscles commonly involved are tongue, arm, and leg muscles.[18]

Rhabdomyolysis is a potential complication of hypothyroidism and can lead to extremely high levels of serum creatine kinase and rhabdomyolysis.[19] In some cases, this condition can be triggered by vigorous exercise, trauma, electrolyte abnormalities, alcohol consumption, or concurrent statin therapy. Renal failure may occur as a secondary complication.[20]

Myoedema refers to a small lump rising on the surface of a muscle after light pressure, such as with a percussion hammer. This phenomenon, characteristic of hypothyroid myopathy, lasts for 30 to 60 seconds due to a sustained contracture associated with delayed relaxation because of the slow reaccumulation of calcium by the sarcoplasmic reticulum.[15][21]

Acute compartment syndrome, characterized by increased pressure within a muscle compartment leading to vascular compromise, is a rare complication of hypothyroidism. Although its causative mechanisms are not clear, its syndrome can be triggered by strenuous exercise and statin or alcohol use.[22]

Evaluation

Hypothyroidism is a prerequisite for diagnosing hypothyroid myopathy and is diagnosed by measuring thyroid-stimulating hormone (TSH) and T4 levels in the blood. The most common laboratory finding in hypothyroid myopathy is an elevation in serum creatine kinase levels. However, this is not specific to myopathy, and patients may experience elevated levels of creatine kinase for many years before developing the myopathy.

Physical evaluation may include a 6-minute walking test, hand grip strength test, and timed chair standing test. These tests primarily assess proximal muscle strength.[23]

Electromyography (EMG) can demonstrate low or small amplitude potentials, which could help with diagnosis. However, this is normal in half of the patients, so a normal test does not preclude the diagnosis. Compared to myositis, there is a lack of fibrillation potentials on EMG with relatively normal motor units.[24] However, when Hoffman syndrome is present, chronic denervation can also lead to fibrillation and sharp waves.[7]

Although muscle biopsy is not necessary for diagnosis, if performed, it may show swollen and pale muscle tissue with loss of striations and increased separation between the muscle fibers due to mucinous depositions. Type I muscle fiber hypertrophy, type 2 muscle fiber atrophy, focal necrosis, and degeneration of muscle fibers may also be noted.[25] Moreover, increased numbers of internal nuclei, mitochondrial inclusions, glycogen accumulation, autophagic vacuoles, and myofibrillar disorganization are other nonspecific histopathological features that may be observed on the muscle biopsy.

Treatment / Management

The synthetic form of the thyroid hormone thyroxine (T4), levothyroxine, is the primary medication used for hypothyroidism and its associated myopathy. Levothyroxine, with a half-life of 7 days, is slowly absorbed and rapidly equilibrates in its distribution volume. However, it takes approximately 6 weeks for complete equilibration of the free thyroxine levels and to notice the clinical effects of levothyroxine. Dosage adjustments are made by monitoring free thyroxine and TSH levels, aiming for normalization within approximately 2 months. The myopathy typically improves within 2 to 3 weeks, but months may be required to resolve completely. See StatPearls' companion reference, "Hypothyroidism," for more information.

Management of hypothyroidism is the mainstay of treating hypothyroid myopathy.[14] The initial dose of levothyroxine is typically 1.6 mcg/kg body weight per day, although it may be lower for older patients or those with coronary heart disease. The dose timing is essential, and the medication should be taken on an empty stomach with water, ideally 30 to 60 minutes before a meal. If a patient has persistent symptoms after 2 to 3 weeks, they should be re-evaluated, and serum-free T4 and TSH levels should be remeasured in 3 weeks. The maintenance dose may vary based on the cause of hypothyroidism. Serum TSH levels are measured annually or more often with an abnormal result or a change in the patient's status.(B3)

According to a study, T4 requirements correlate more with lean body mass than total body weight. The study also found that the average full replacement dose after thyroidectomy varied depending on the patient's body mass index (BMI). Patients with a BMI of less than 25 kg/m² had an average dose of 1.76 mcg/kg body weight, whereas those with a BMI between 25 and 29 kg/m² had an average dose of 1.47 mcg/kg. Patients with a BMI between 30 and 34 kg/m² had an average dose of 1.42 mcg/kg, whereas those with a BMI between 35 and 39 kg/m² had an average dose of 1.27 mcg/kg. Patients with a BMI over 40 kg/m² had an average dosage of 1.28 mcg/kg.[26]

Adrenal insufficiency should be ruled out before initiating hormonal replacement therapy to avoid an adrenal crisis that could be life-threatening.[27] With adequate thyroid hormone replacement and restoration of normal thyroid function, most patients gradually resolve most of the neuromuscular symptoms. Creatine kinase levels fall quickly with thyroxine replacement within a few weeks and may resolve before TSH normalization. Hence, this can be used as a surrogate to monitor treatment response in the initial stages, as the myopathic symptoms can take up to 6 months to resolve completely. Most of the symptoms resolve within a year of adequate hormone replacement.[14](A1)

Differential Diagnosis

The differential diagnosis of hypothyroid myopathy includes:

• Acid maltase deficiency
• Acute poliomyelitis
• Amyotrophic lateral sclerosis
• Becker muscular dystrophy
• Inclusion body myositis
• Polymyositis
• Post-polio syndrome
• Peripheral neuropathy

Toxicity and Adverse Effect Management

Although generally well-tolerated, levothyroxine can occasionally lead to adverse effects, particularly if the dosage is too high or if there are underlying medical conditions. The following list describes how the adverse effects of levothyroxine are managed in the context of hypothyroid myopathy.

• Symptom assessment: Patients should be monitored for palpitations, tremors, anxiety, insomnia, heat intolerance, sweating, weight loss, and diarrhea.

• Thyroid function tests: Regular monitoring of thyroid function tests, including TSH and T4, and dosage adjustment as needed is essential.

• Gradual titration: Dosage adjustments should be made gradually to minimize the risk of abrupt changes in thyroid hormone levels, which can exacerbate symptoms or lead to adverse effects.

• Review of medications and supplements: Certain medications and supplements can interfere with levothyroxine absorption or metabolism. Reviewing the patient's medication list and adjusting doses or avoiding interactions when possible can help optimize treatment outcomes.

  When intravenous (IV) steroids or biological agents are required in patients with hypothyroid myopathy, careful monitoring and management of potential adverse effects are essential because both IV steroids and some biological agents can affect thyroid function. 

• Management of underlying conditions: Patients with underlying medical conditions such as cardiovascular disease, osteoporosis, or diabetes may require special consideration when prescribing levothyroxine.

Consultation With Endocrinologists

In cases where dosage adjustment or management of adverse effects is challenging, consultation with an endocrinologist or thyroid specialist may be warranted. These specialists can provide expertise in managing complex cases of hypothyroidism and associated myopathy.

Management of Steroid-Induced Myopathy

Steroid-induced myopathy is a potential adverse effect of IV steroids, characterized by muscle weakness and wasting. In individuals with hypothyroid myopathy, the combination of steroid-induced myopathy and underlying muscle weakness from hypothyroidism can exacerbate symptoms. Management may include physical therapy, exercise programs tailored to individual capabilities, and optimizing thyroid hormone replacement therapy to address underlying hypothyroidism.

Medical Oncology

Thyroid dysfunction and associated hypothyroid myopathy are common adverse events observed with the use of immune checkpoint inhibitors.[28] Immune checkpoint inhibitors commonly affect the endocrine system, leading to autoimmunity while treating the neoplastic process.[29] The thyroid dysfunction can present as hypothyroidism or, more rarely, thyrotoxicosis.[30]

Staging

Staging

Hypothyroid myopathy typically does not have a formal staging system similar to some other medical conditions. However, its severity can vary widely among individuals and may be assessed based on the degree of muscle weakness, functional impairment, and associated symptoms. A general framework for understanding the severity or staging of hypothyroid myopathy is as follows:

• Mild: Patients with mild hypothyroid myopathy may experience subtle muscle weakness, fatigue, and stiffness, which may not significantly impact their daily activities. They may notice symptoms such as difficulty climbing stairs, lifting objects, or participating in physical activities.

• Moderate: Muscle weakness and fatigue may be more pronounced in moderate cases, affecting the individual's ability to perform routine tasks. They may experience difficulty with activities requiring muscle strength and endurance, such as walking longer distances, standing from a seated position, or carrying groceries.

• Severe: Severe hypothyroid myopathy is characterized by profound muscle weakness and fatigue, significantly impairing mobility and functional independence. Patients may struggle to perform basic activities of daily living, such as dressing, bathing, or climbing stairs, and may require assistance or mobility aids.

• Complications: In some cases, hypothyroid myopathy can lead to complications such as falls, fractures (due to muscle weakness and impaired bone health), or respiratory compromise (due to weakness of respiratory muscles).

The severity of hypothyroid myopathy can be influenced by factors such as the duration and extent of thyroid hormone deficiency, the presence of other medical conditions or comorbidities, and individual variations in muscle function and response to treatment.

Prognosis

In general, the prognosis for hypothyroid myopathy is good with prompt and appropriate treatment.[14] Most patients experience muscle strength and function improvement with thyroid hormone replacement therapy. However, the recovery process may take some time, and patients may need to continue treatment for an extended period.

The prognosis may be poor in severe cases, particularly when diagnosis is delayed or when the patient has other underlying medical issues. In such cases, patients may experience permanent muscle damage, leading to muscle strength and function loss.

Complications

Hypothyroid myopathy may progress and lead to symptoms and complications listed below. 

Muscle cramps: Hypothyroid myopathy can cause muscle cramps due to prolonged contraction of already weak muscles.

Reduced mobility: Muscle weakness and fatigue caused by hypothyroid myopathy can reduce mobility, making it difficult to perform daily activities such as walking, climbing stairs, and standing up from a seated position.

Increased risk of falls: Reduced mobility can lead to an increased risk of falls, especially in older adults. Falls can result in injuries such as fractures, further reducing mobility and quality of life.

Respiratory complications: Severe hypothyroid myopathy can weaken the muscles involved in breathing, leading to respiratory complications such as shortness of breath and difficulty breathing.

Cardiovascular complications: Hypothyroid myopathy can also affect the heart muscles, leading to cardiovascular complications such as an increased risk of heart failure and arrhythmias.

Psychological impact: Chronic muscle weakness and fatigue associated with hypothyroid myopathy can have a significant psychological impact, leading to depression, anxiety, and decreased self-esteem.

Long-term disability: In severe cases of hypothyroid myopathy, persistent muscle weakness and functional impairment may result in long-term disability, requiring ongoing support and assistance with daily activities.