Thyrotoxic periodic paralysis

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Thyrotoxic periodic paralysis

Thyrotoxic periodic paralysis

Thyrotoxic periodic paralysis also called TPP or Thyrotoxic Hypokalemic Periodic Paralysis (Thyrotoxic HypoKPP) is a very rare life-threatening complication of thyrotoxicosis (too much thyroid hormone) or hyperthyroidism (overactive thyroid) that is characterized by episodes (also known as “attacks”) of muscle weakness and muscle paralysis (periodic paralysis) due to hypokalemia (low blood potassium levels) caused by massive intracellular shift of potassium by the excessive thyroid hormones 1, 2, 3, 4, 5, 6, 7, 8, 9. (Kalemic refers to potassium; hypo means too little; hypokalemia means too little potassium in your blood). The attack is often precipitated by exercise, high carbohydrate meals, and occasionally fasting 10. The attacks may occur daily to yearly. Episodes of muscle weakness may last for a few hours or several days. During the attacks, you will be alert and can answer questions. Normal muscle strength returns between attacks. With repeat attacks, you may develop muscle weakness. The cause of thyrotoxicosis is most often attributable to Graves disease and patients typically have symptoms of thyrotoxicosis for months leading up to the episodes of paralysis 10.

Your thyroid gland is part of the endocrine system. Your thyroid gland is located in your neck and produces several hormones (triiodothyronine [T3], and thyroxine [T4]) that help control growth, digestion, and metabolism. A complex set of mechanisms control the rate of thyroid gland activity. Too much thyroid hormone called hyperthyroidism or thyrotoxicosis is due to an overactive thyroid gland. Hyperthyroidism is not a specific disease, but a symptom of an underlying condition or disease. The causes of hyperthyroidism include Graves’ disease; tumors of the thyroid or other endocrine glands; inflammation or infection of the thyroid (thyroiditis); taking too much thyroid hormone (thyrotoxicosis factitia); and taking too much iodine. Graves’ disease accounts for 85% of all cases of hyperthyroidism. Graves disease (like Hashimoto’s thyroiditis) sometimes occurs with other autoimmune disorders, including type 1 diabetes mellitus, vitiligo, premature graying of hair, pernicious anemia, connective tissue disorders, and polyglandular deficiency syndrome. Heredity increases the risk of Graves disease, although the genes involved are unknown.

Thyroid hormones regulate the sodium-potassium pump (Na+-K+-ATPase pump) at a transcriptional and post-transcriptional level and also induce the release of catecholamines via beta 2 receptors, furthermore stimulating the Na+-K+-ATP pump 11. Thyrotoxic periodic paralysis patients were shown to have 80% more Na+-K+-ATPase pump activity than other thyrotoxic patients 6. The Na+ K+-ATPase pump maintains the gradient of a higher concentration of sodium ion (Na+) extracellularly and a higher level of potassium ion (K+) intracellularly 12. The Na+ K+ ATPase pumps 3 sodium ions (Na+) out of the cell and 2 potassium ions (K+) that into the cell, for every single ATP consumed 12. The sustained concentration gradient of a higher concentration of sodium extracellularly and a higher level of potassium intracellularly is crucial for physiological processes in many organs and has an ongoing role in stabilizing the resting membrane potential of the cell, regulating the cell volume, and cell signal transduction 13. The overactivity of Na+-K+-ATP pump drives serum potassium into the intracellular compartment causing hyperpolarization, hypokalemia and muscle weakness 14. In addition, insulin and testosterone increase the activity of the Na+-K+-ATP pump, which might explain the higher prevalence of thyrotoxic periodic paralysis in males and the manifestation of symptoms after an intense workout and a high-carbohydrate meal 6.

Thyrotoxic periodic paralysis in most cases are hereditary (some cases may occur sporadically) and is commonly reported in Asian men (Japanese, Chinese, Vietnamese, Korean, and Filipino) between 20–40 years of age, but it is rare in children and adolescents 15, 16, 5. Most people who develop high thyroid hormone levels are not at risk of thyrotoxic periodic paralysis and the incidence has been reported at a rate of approximately 2% in hyperthyroidism patients 17. Thyrotoxic periodic paralysis also occurs more frequently in those of Native American and Latin American descent, but only occasionally in those of European descent (0.1 to 0.2% in American Caucasians) 18, 19.

Although thyrotoxic periodic paralysis is rare in children and adolescents, some cases of thyrotoxic periodic paralysis in adolescents have been reported from China, Korea, and in other ethnic groups 20. Most recently, the reported cases of thyrotoxic periodic paralysis have been attributable to Graves’ disease, although autoimmune thyroiditis can be a very rare cause of thyrotoxic periodic paralysis in children and adolescents 5.

To date, genes that have been studied in relation to thyrotoxic periodic paralysis include the KCNJ18 and KCNJ2 genes. The KCNJ18 gene (also called potassium inwardly rectifying channel subfamily J member 18) located in chromosome 17p11.2 (short arm of chromosome 17), which encodes for the inwardly rectifying potassium (Kir) channel Kir2.6, is known to be more common in Western countries, and has been reported at rates of 33.3% in Caucasian populations, primarily among individuals with Brazilian heritage, 25.9% in Singaporeans, and 1.2% in people from Hong Kong 21, 22. In contrast, in recent studies, genetic variants of the KCNJ2 gene have been reported to affect the development of thyrotoxic periodic paralysis in Korean and Chinese populations 23, 24. These ethnic genetic differences might explain the difference in the incidence of thyrotoxic periodic paralysis.

The most common cause of thyrotoxic periodic paralysis is Graves disease (toxic diffuse goiter) affecting 96% of thyrotoxic periodic paralysis patients. However, thyrotoxic periodic paralysis can occur in any type of thyrotoxicosis (including administration of excessive amounts of exogenous thyroid hormone or thyrotoxicosis factitia [hyperthyroidism resulting from intentional or accidental over ingestion of thyroid hormone]) or hyperthyroidism (e.g., multinodular goiter, thyroiditis, single autonomous hyperfunctioning “hot” nodule [toxic nodular adenoma], excess iodine ingestion) can trigger attacks of thyrotoxic periodic paralysis in susceptible subjects 25, 26, 27, 28, 29, 30, 31, 32. In general, autoimmune thyroid diseases such as Graves’ disease are more common in pubertal girls than boys. However, the incidence of thyrotoxic periodic paralysis is higher in boys than in girls 33. Unusual is also the disproportional occurrence of thyrotoxic periodic paralysis in men compared to women (26: 1), despite Graves’ disease being predominantly encountered in women 25.

Only 17 to 50% of thyrotoxic periodic paralysis patients exhibit clinical signs of hyperthyroidism, making the diagnosis even more challenging 25. The sudden onset muscle paralysis due to hypokalemia (due to acute potassium ions (K+) shift into the intracellular space) in the context of thyrotoxicosis can lead to cardiac arrhythmias and respiratory failure if not recognized and treated on time 6.

The diagnosis of thyrotoxic periodic paralysis is often delayed, possibly due to a lack of awareness and the rarity of the condition; approximately half of the patients have had history of an episode before the diagnosis was made 34. The diagnosis is delayed on average for 14 months 35.

Early diagnosis of thyrotoxic periodic paralysis is essential, as the condition is potentially reversible by oral or intravenous potassium treatment, leading to rapid resolution without lasting weakness 27, 35. Overlooking the diagnosis may result in respiratory failure and cardiac arrhythmias including QT prolongation, Torsades de points, and ventricular arrhythmias 2. Potassium chloride (KCl) supplementation is essential but often not enough to control thyrotoxic periodic paralysis 36. The management of thyrotoxic periodic paralysis is further complicated by the thin line between refractory hypokalemia and rebound hyperkalemia, both predisposing to serious cardiac events 37.

Treatment of thyrotoxic periodic paralysis includes correction of hypokalemia and maintenance of an normal thyroid (euthyroid) status. Immediate intravenous (IV) infusion with potassium chloride (KCl) is needed to prevent major heart arrhythmias and to foster muscle paralysis recovery 22. However, another study has reported that there is lack of correlation between recovery time of muscle paralysis and the dose of infused potassium chloride (KCl) 38. Despite intravascular hypokalemia, the total body potassium level is normal. Therefore, potassium chloride (KCl) infusion should be administered with caution. Potassium chloride (KCl) infusion causes rebound hyperkalemia in up to 70% of cases, and as a result, fatal arrhythmias may occur 5. Rebound hyperkalemia can be prevented by lower doses of potassium chloride (KCl) and close cardiac monitoring is necessary 39.

A beta blocker like propranolol is an alternative treatment that can reduce paralysis without rebound hyperkalemia. Because thyrotoxic periodic paralysis does not usually recur once an normal thyroid (euthyroid) state has been attained, adequate control of hyperthyroidism is important after the acute phase 33. Currently, antithyroid drugs remain the mainstay treatment of the overactive thyroid (hyperthyroidism). Once the underlying thyroid problem is corrected with medication, radiation or surgery, the symptoms of thyrotoxic periodic paralysis usually disappear.

What triggers attacks of thyrotoxic periodic paralysis?

The same factors which trigger attacks of hypokalemic periodic paralysis will trigger attacks of thyrotoxic periodic paralysis if thyroid levels are too high. Meals high in starchy and sweet foods may trigger an attack. Taking thyroid hormones may trigger an attack. Sleep or resting after vigorous exercise may trigger an attack. For a more complete discussion on triggers see Hypokalemic Periodic Paralysis.

How do I avoid having attacks?

Your doctor will treat the underlying thyroid disorder, which will eventually cure your thyrotoxic periodic paralysis. In the meantime you should determine what triggers your attacks and avoid those triggers. Medication is usually necessary until the thyroid problem is brought under control.

Thyrotoxic periodic paralysis causes

Thyrotoxic periodic paralysis may be caused by any causes of hyperthyroidism, including Graves disease (most common), toxic multinodular goiter, toxic adenoma, thyroiditis, amiodarone-induced thyrotoxicosis, iodine-induced thyrotoxicosis, excess exogenous thyroxine use and thyrotropin (TSH) producing pituitary adenoma 40, 3, 41, 42. A rare cause of thyrotoxic periodic paralysis is thyrotoxicosis factitia or exogenous thyrotoxicosis from surreptitious use of thyroid hormone. Ragesh et al. 43 described a case of thyrotoxic periodic paralysis secondary to consumption of nutraceuticals containing triiodothyronine (T3).

To date, genes that have been studied in relation to thyrotoxic periodic paralysis include the KCNJ18 and KCNJ2 genes. The KCNJ18 gene (also called potassium inwardly rectifying channel subfamily J member 18) located in chromosome 17p11.2 (short arm of chromosome 17), which encodes for the inwardly rectifying potassium (Kir) channel Kir2.6, is known to be more common in Western countries, and has been reported at rates of 33.3% in Caucasian populations, primarily among individuals with Brazilian heritage, 25.9% in Singaporeans, and 1.2% in people from Hong Kong 21, 22. In contrast, in recent studies, genetic variants of the KCNJ2 gene have been reported to affect the development of thyrotoxic periodic paralysis in Korean and Chinese populations 23, 24. These ethnic genetic differences might explain the difference in the incidence of thyrotoxic periodic paralysis.

Common factors triggering attacks of periodic paralysis include the consumption of carbohydrate-rich foods, strenuous physical activity, high salt or sodium intake, stresses (surgical, infectious, psychological), trauma, and drugs (diuretics, estrogens, acetazolamide, epinephrine, laxatives, corticosteroids, non-steroidal anti-inflammatory drugs, licorice, fluoroquinolones, aminoglycosides, and ecstasy) 41, 44, 45, 46, 47, 48, 49.

Thyrotoxic periodic paralysis pathophysiology

The underlying pathophysiology of thyrotoxic periodic paralysis is poorly understood, however the mechanism of thyrotoxic periodic paralysis involves two major factors: the occurrence of hypokalemia and associated muscle paralysis 50. The hypokalemia in thyrotoxic periodic paralysis results from a rapid and massive shift of potassium from the extracellular to the intracellular compartment, mainly into muscles induced by an increased adrenergic sensitization of Na + /K + –ATPase pump. Potassium is the most abundant cation (positively charged ion) in the intracellular fluid (ICF). Potassium (K+) is actively transported into the intracellular fluid (ICF) by the Na + /K + –ATPase pump, which also transports the sodium (Na+) in to the extracellular fluid (ECF). This is expressed in various tissues including the liver, muscle and kidney 51, 52. The Na-K-ATP pump is under the influence of various hormones, which can modulate its activity. The outward flow of potassium is regulated by the inward rectifying K channels (Kir) (4). These two channels working in tandem, keep the potassium levels tightly controlled.

Thyroid hormones stimulate the Na+–K+ ATPase pump in skeletal muscle by binding to the thyroid response elements (TRE) which are upstream of the genes for Na-K pump, and increase its activity by both transcriptional and post transcriptional modification 53, 54, 55. Thyrotoxic periodic paralysis patients have 80% more Na+–K+ ATPase pump activity as compared to thyrotoxic patients 56. Therefore, there is no pure potassium depletion in the body 22.

Catecholamines can also act on stimulating the activity of Na+–K+ ATPase pump through the beta-adrenergic receptors. Insulin, a high carbohydrate meal, exercise and testosterone can increase the activity of Na+–K+ ATPase pump while estrogen decreases it, this may be partly responsible for the male preponderance of thyrotoxic periodic paralysis 57, 58, 59, 60. In addition, insulin and catecholamines can inhibit the inwardly rectifying potassium (Kir) channels decreasing the transport of potassium into extracellular fluid (ECF). Mutations in the KCNJ 18 gene, which encode for the Kir channels, have been found in approximately 33% of patients with thyrotoxic periodic paralysis 61. This massive influx of potassium along with decreased outflow leads to hypokalemia and thyrotoxic periodic paralysis.

Although serum potassium levels are usually decreased in thyrotoxic periodic paralysis, in exceptionally rare circumstances normal serum potassium levels (normokalemia) can lead to normokalemic thyrotoxic periodic paralysis 62. Patients who initially showed normokalemic thyrotoxic periodic paralysis also eventually progressed to hypokalemia 62. However, the pathogenesis of normokalemic thyrotoxic periodic paralysis remains unclear 5.

Genetic and environmental factors may possibly play a role 63, 22. Thyrotoxic periodic paralysis is known to be a channelopathy caused by mutations of the ion channel of the cell membrane and masked under normal thyroid (euthyroid) conditions 9.

Figure 1. Pathogenesis of hypokalemia in thyrotoxicosis

Pathogenesis of hypokalemia in thyrotoxicosis
[Source 3 ]

Thyrotoxic periodic paralysis symptoms

Thyrotoxic periodic paralysis symptoms involve attacks of muscle weakness or paralysis. Between attacks, normal muscle function returns. Attacks often begin after symptoms of hyperthyroidism have developed. Hyperthyroid symptoms may be subtle. The attacks may occur daily to yearly. Episodes of muscle weakness may last for a few hours or several days.

The muscle weakness or paralysis 64:

  • Comes and goes
  • Lasts from a few hours up to several days (rare)
  • Occurs more often in the legs than the arms
  • Is most common in the shoulders and hips
  • Is triggered by heavy, high-carbohydrate, high-salt meals
  • Is triggered during rest after exercise

Other rare symptoms may include any of the following 64:

  • Trouble breathing
  • Speech problems
  • Trouble swallowing
  • Vision changes

Thyrotoxic periodic paralysis is characterized by episodes of sudden onset of muscle weakness. The severity of the episodes can range from weakness to complete paralysis and the duration can range from a few hours to 3 days 65. Eye muscles, muscles in the head and neck and respiratory muscle weakness is rare, but has been reported 66, 22. During the attacks, you will be alert and can answer questions. Typically, the weakness starts in the proximal muscles of the lower extremities; however, it involves all four extremities in 80% of cases 67. Normal muscle strength returns between attacks. With repeat attacks, you may develop muscle weakness.

Heavy meals, alcohol, exercise, high salt diet, stress, infections, menstruation and glucocorticoids have all been known to precipitate the paralytic episodes 3. Most of these attacks happen at night, likely related to prior alcohol or heavy meals and thereby was given the old name “nocturnal palsy.” Manoukian et al. 38 noted that 84% of thyrotoxic periodic paralysis patients presented to the emergency room between 1 am to 8 am. Thyrotoxic periodic paralysis is seen mostly in males aged 20–40 years, although it can be seen in adolescents and children 68, 66, 47, 69.

The severity of muscle paralysis is correlated with the degree of hypokalemia, but not with clinical signs and symptoms of hyperthyroidism or thyroid hormone levels 33. However, in approximately 75% of patients with thyrotoxic periodic paralysis have it as the presenting symptom of their hyperthyroidism 70.

Symptoms of hyperthyroidism include 64:

  • Excessive sweating
  • Fast heart rate
  • Fatigue
  • Headache
  • Heat intolerance
  • Increased appetite
  • Insomnia
  • Having bowel movements more often
  • Feeling strong heartbeat (palpitations)
  • Tremors of the hand
  • Warm, moist skin
  • Weight loss

Signs of hyperthyroidism may include:

  • warm, moist skin,
  • tremor,
  • tachycardia,
  • widened pulse pressure, and
  • atrial fibrillation.

Many common symptoms of hyperthyroidism are due to enhanced sensitivity to adrenergic hormones, such as nervousness, palpitations, hyperactivity, increased sweating, heat hypersensitivity, fatigue, increased appetite, weight loss, insomnia, weakness, and frequent bowel movements (occasionally diarrhea). Hypomenorrhea (infrequent menstruation or abnormally low bleeding, less than 30 ml per menstrual cycle) may be present.

Older patients, particularly those with toxic nodular goiter, may present atypically (apathetic or masked hyperthyroidism) with symptoms more akin to depression or dementia. Most do not have exophthalmos or tremor. Atrial fibrillation, syncope, altered sensorium, heart failure, and weakness are more likely. Symptoms and signs may involve only a single organ system.

Eye signs include stare, eyelid lag, eyelid retraction, and mild conjunctival injection and are largely due to excessive adrenergic stimulation. They usually remit with successful treatment. Infiltrative ophthalmopathy, a more serious development, is specific to Graves disease and can occur years before or after hyperthyroidism. It is characterized by orbital pain, lacrimation, irritation, photophobia, increased retro-orbital tissue, exophthalmos, and lymphocytic infiltration of the extraocular muscles, causing ocular muscle weakness that frequently leads to double vision.

Infiltrative dermopathy, also called pretibial myxedema (a confusing term, because myxedema suggests hypothyroidism), is characterized by nonpitting infiltration by proteinaceous ground substance, usually in the pretibial area. It rarely occurs in the absence of Graves ophthalmopathy. The lesion is often itchy and reddish in its early stages and subsequently becomes brawny. Infiltrative dermopathy may appear years before or after hyperthyroidism.

Thyrotoxic periodic paralysis is very rare in children and adolescents and is even more unusual in girls. In addition, although there are aggravating factors, such as a high carbohydrate meal and exercise, that are associated with the occurrence of thyrotoxic periodic paralysis, thyrotoxic periodic paralysis can occur without such factors.

Thyrotoxic periodic paralysis complications

Untreated thyrotoxic periodic paralysis can lead to:

  • Difficulty breathing, speaking, or swallowing during attacks (rare)
  • Heart arrhythmias during attacks
  • Muscle weakness that gets worse over time

Thyrotoxic periodic paralysis diagnosis

Diagnosis of thyrotoxic periodic paralysis is based on recurrent clinical features of thyrotoxic periodic paralysis and blood test results suggestive of hyperthyroidism (abnormal thyroid hormone levels) and hypokalemia (low potassium level during attacks). Your doctor will do blood tests to check the levels of various thyroid hormones including:

  • TSH (thyroid stimulating hormone) levels,
  • T3 (triiodothyronine),
  • T3 resin uptake (T3RU) and
  • T4 (thyroxine).

Other test results:

  • Abnormal electrocardiogram (ECG) might be present during attacks. The most common electrocardiogram (EKG) changes include ST depression, sinus tachycardia, U waves, and AV blocks 71. Very rarely, patients can present with prolonged QT interval or ventricular tachyarrhythmias.
  • Abnormal electromyogram (EMG) during attacks. Electromyograms (EMG) might show a myopathic pattern with decreased duration of muscle action potentials, reduced amplitude, and an increase in polyphasic potentials. These changes might completely disappear during remission 72.
  • Low serum potassium during attacks, but normal between attacks. During an attack of weakness your doctor will do a blood test to check the level of potassium. In thyrotoxic periodic paralysis, the level of potassium is low during attacks but normal between attacks. Diagnosis also involves ruling out disorders caused by low potassium.
  • A muscle biopsy may sometimes be taken.

Your doctor may try to trigger an attack by giving you insulin and sugar. The sugar is glucose, which reduces potassium level. Or you may be given thyroid hormone. The following signs may be seen during the attack:

  • Decreased or no reflexes
  • Heart arrhythmias
  • Low potassium in the bloodstream (potassium levels are normal between attacks)

Between attacks, the examination is normal. Or, there may be signs of hyperthyroidism. These include an enlarged thyroid changes in the eyes, tremor, or hair and nail changes.

Previously reported cases with thyrotoxic periodic paralysis had only mildly elevated serum thyroid hormone levels. Ko et al. 73 have reported that only 10% of patients have mild thyrotoxic symptoms. Therefore, thyrotoxic periodic paralysis should be distinguished from other causes of acute paralysis such as familial hypokalemic periodic paralysis, Guillain-Barré syndrome, myasthenic crisis, and conditions that produce spinal cord compression 39.

Hypokalemia is the hallmark feature of thyrotoxic periodic paralysis, most of the time, potassium less than 3 mmol/L 74. As the hypokalemia is the result of transcellular shift, urinary potassium is < 20 mmol/lt and urine potassium creatinine ratio is <2 mmol/lt, consistent with renal conservation of potassium (5, 29). Other electrolyte disorders like hypomagnesemia and hypophosphatemia due to transcellular shift are observed. Urine calcium is high due to increased filtration and decreased reabsorption, whereas urine phosphate excretion is decreased. Lin et al. found that a urine calcium/phosphate ratio of >1.4 detected thyrotoxic periodic paralysis with a sensitivity of 100% and specificity of 96% (7). thyrotoxic periodic paralysis occurs in the hyperthyroid state and thyroid studies show a high thyroxine (T4) and suppressed TSH. However, the severity of the paralysis is not directly related to the degree of severity of hyperthyroidism (31). Electrocardiograms (EKG) are abnormal in 83–100% of patients with thyrotoxic periodic paralysis (29, 32). Besides signs of hypokalemia, (U waves, ST segment depression and T wave flattening), atrioventricular block and arrhythmias (supraventricular arrhythmias, atrial fibrillation and ventricular arrhythmias) have also been reported. thyrotoxic periodic paralysis needs to be differentiated from familial hypokalemic periodic paralysis (FHPP), which presents with episodic muscular weakness as well. However, it affects Caucasians with equal sex distribution. FHPP is autosomal dominant and a family history of hypokalemic paralysis is often positive (33). Thyroid studies in thyrotoxic periodic paralysis show hyperthyroidism, whereas in FHPP they are normal.

In one study of 19 men with thyrotoxic periodic paralysis initial serum potassium (K) levels upon admittance to hospital ranged from 1.1 to 3.4 mmol/L (mean, 1.90.5 mmol/L). Serum magnesium (Mg) level was measured in 18 episodes during paralysis and in 13 episodes after paralysis. During paralysis episodes, all patients had low or low-normal magnesium (Mg) levels (0.60-0.80 mmol/L 1.5-1.9 mg/dL). Only two patients received supplemental magnesium sulphate, but magnesium (Mg) levels increased by 0.1 mmol/L or more (0.24 mg/dL) in all patients who had it checked. Serum creatine phosphokinase levels were obtained in 18 episodes during paralysis. Twelve patients had elevated creatine phosphokinase values, 5 of which were of 1000 U/L or more. Serum alkaline phosphatase levels were mildly elevated in 12 of 16 patients, ranging from 118 to 268 U/L (normal, 39-117 U/L).

Diagnosis of hyperthyroidism is based on history, physical examination, and thyroid function tests. Serum TSH (thyroid stimulating hormone) measurement is the best test because TSH is suppressed in hyperthyroid patients except in the rare instance when the cause is a TSH-secreting pituitary adenoma or pituitary resistance to the normal inhibition by thyroid hormone.

Free T4 (thyroxine) is increased in hyperthyroidism. However, T4 can be falsely normal in true hyperthyroidism in patients with a severe systemic illness (similar to the falsely low levels that occur in euthyroid sick syndrome) and in T3 (triiodothyronine) toxicosis. If free T4 level is normal and TSH is low in a patient with subtle symptoms and signs of hyperthyroidism, then serum T3 should be measured to detect T3 toxicosis; an elevated level confirms that diagnosis.

The cause can often be diagnosed clinically (eg, the presence of signs specific to Graves disease). If not, radioactive iodine uptake by the thyroid may be measured by using iodine-123. When hyperthyroidism is due to hormone overproduction, radioactive iodine uptake by the thyroid is usually elevated. When hyperthyroidism is due to thyroiditis, iodine ingestion, or overtreatment with thyroid hormones, radioactive iodine uptake is low.

TSH receptor antibodies can be measured to evaluate for Graves disease. Measurement is done in pregnant women with a history of Graves disease during the 3rd trimester of pregnancy to assess the risk of neonatal Graves disease; TSH receptor antibodies readily cross the placenta to stimulate the fetal thyroid. Most patients with Graves disease have circulating antithyroid peroxidase antibodies, and fewer have antithyroglobulin antibodies.

Inappropriate TSH secretion is uncommon. The diagnosis is confirmed when hyperthyroidism occurs with elevated circulating free T4 and T3 concentrations and normal or elevated serum TSH.

If thyrotoxicosis factitia is suspected, serum thyroglobulin can be measured; it is usually low or low-normal—unlike in all other causes of hyperthyroidism.

Thyrotoxic periodic paralysis treatment

Potassium should also be given during the attack, most often by mouth, however not all patients respond to potassium alone and recent evidence suggests that combining potassium and propranolol is a more effective therapy. If weakness is severe, you may need to get potassium through a vein (IV). Note: You should only get intravenous (IV) potassium if your kidney function is normal and you are monitored in the hospital. The ultimate goal of treatment is to reduce your thyroid hormone levels and restore normal thyroid status.

Weakness that involves the muscles used for breathing or swallowing is an emergency. You must be taken to a hospital. Serious irregularity of heartbeat also occur during attacks.

Acute treatment recommended that 30 mEq of potassium chloride (KCl) be given every 2 hours orally for 6 hours and then every 4 hours with careful monitoring until recovery begins, with a maximum oral dose of 90 mEq in 24 hours 50, 75. Some experts suggestions include replacing at a rate of less than 10 mEq orally. Because thyrotoxic periodic paralysis patients may develop rebound hyperkalemia, Manoukian et al 38 recommends that potassium replacement therapy should be cautious and should not exceed 90 mEq of potassium chloride (KCl) per 24 hours unless there is a reason for potassium (K) loss, such as diarrhea, vomiting, or diuretic use.

In the Manoukian study (19 patients) all patients remained attack free as long as they took methimazole and propranolol hydrochloride or after radioiodine (iodine-131) treatment 38. Eighteen patients were eventually treated with radioiodine (iodine-131) therapy. None of the patients had paralytic episodes after a euthyroid state was achieved. Nonselective beta-blockers such as propranolol may be useful to prevent attacks of paralysis once patients begin taking antithyroid medications but are not yet euthyroid.

Your doctor may also recommend a diet low in carbohydrates and salt to prevent attacks. Precipitating factors like strenuous exercise and high carbohydrate meals should be avoided 76. Glucose infusions need to be avoided as they can raise insulin levels and worsen hypokalemia. Prophylactic administration of potassium chloride (KCl) to prevent thyrotoxic periodic paralysis is not effective and therefore not recommended 70.

You may be given beta-blocker medicines to reduce the number and severity of attacks while your hyperthyroidism is brought under control. Non-selective beta-blockers have been shown to improve neuromuscular symptoms by reducing the intracellular shift of phosphate and potassium 77. Intravenous propranolol 1 mg every 10 minutes up to 3 doses can be given in patients unresponsive to potassium replacement 78, 79, 80. Oral propranolol (40 mg four time daily) is also effective as prophylaxis, preventing further episodes of thyrotoxic periodic paralysis 81. However, propranolol needs to be administered with caution in case of a heart block, as it can result in severe bradycardia and cardiovascular collapse 82.

Definitive treatment of hyperthyroidism, either with radioiodine ablation or with thyroidectomy, results in resolution of thyrotoxic periodic paralysis. Use of antithyroid medications alone resulted in a relapse attack in 56% patients within 7 months 34.

Treatment of hyperthyroidism

Treatment of hyperthyroidism depends on cause but may include 83:

  • Radioactive iodine
  • Methimazole or propylthiouracil
  • Beta-blockers
  • Iodine
  • Surgery

Radioactive sodium iodine (iodine-131, radioiodine)

In the United States, iodine-131 is the most common treatment for hyperthyroidism. Radioiodine is often recommended as the treatment of choice for Graves disease and toxic nodular goiter in all patients, including children. Dosage of iodine-131 is difficult to adjust because the response of the gland cannot be predicted; some physicians give a standard dose of 8 to 15 millicurie. Others adjust the dose based on estimated thyroid size and the 24-hour uptake to provide a dose of 80 to 120 microcurie/g thyroid tissue.

When sufficient iodine-131 is given to cause euthyroidism, about 25 to 50% of patients become hypothyroid 1 year later, and the incidence continues to increase yearly. Thus, most patients eventually become hypothyroid. However, if smaller doses are used, incidence of recurrence is higher. Larger doses, such as 10 to 20 millicurie, often cause hypothyroidism within 6 months, and thus ablative therapy (ie, iodine-131) has become the preferred approach.

Radioactive iodine is not used during lactation because it can enter breast milk and cause hypothyroidism in the infant. It is not used during pregnancy because it crosses the placenta and can cause severe fetal hypothyroidism. There is no proof that radioiodine increases the incidence of tumors, leukemia, thyroid cancer, or birth defects in children born to previously hyperthyroid women who become pregnant later in life.

Methimazole and propylthiouracil

These antithyroid drugs block thyroid peroxidase, decreasing the organification of iodide, and impair the coupling reaction. Propylthiouracil in high doses also inhibits the peripheral conversion of T4 to T3.

Methimazole is the preferred drug. The usual starting dosage of methimazole is 5 to 20 mg orally 2 or 3 times a day. Normalization of TSH lags normalization of T4 and T3 levels by one or more weeks. Therefore, when T4 and T3 levels normalize, the dosage is decreased to the lowest effective amount, usually methimazole 2.5 to 10 mg once a day in order to avoid inducing hypothyroidism. Control generally is achieved in 2 to 3 months. Maintenance doses of methimazole may be continued for one or many years depending on the clinical circumstances. Carbimazole, which is used widely in Europe but is unavailable in the US, is rapidly converted to methimazole. The usual starting dose is similar to that of methimazole; maintenance dosage is 2.5 to 10 mg orally once a day or 2.5 to 5 mg twice a day.

Because of severe liver failure in some patients < age 40, especially children, propylthiouracil is recommended only in special situations (eg, in the 1st trimester of pregnancy, in thyroid storm). The usual starting dose of propylthiouracil is 100 to 150 mg orally every 8 hours. Rapid control can be achieved by increasing the dosage of propylthiouracil to 150 to 200 mg every 8 hours. Such dosages or higher ones (up to 400 mg every 8 hours) are generally reserved for severely ill patients, including those with thyroid storm, to block the conversion of T4 to T3. Maintenance dosing with propylthiouracil is 50 mg twice a day or 3 times a day

About 20 to 50% of patients with Graves disease remain in remission after a 1- to 2-year course of either drug. The return to normal or a marked decrease in gland size, the restoration of a normal serum TSH level, and less severe hyperthyroidism before therapy are good prognostic signs of long-term remission. The concomitant use of antithyroid drug therapy and levothyroxine does not improve the remission rate in patients with Graves disease. Because toxic nodular goiter rarely goes into remission, antithyroid drug therapy is given only in preparation for surgical treatment or iodine-131 therapy.

Adverse effects include rash, allergic reactions, abnormal liver function (including hepatic failure with propylthiouracil), and, in about 0.1% of patients, reversible agranulocytosis. Patients allergic to one drug can be switched to the other, but cross-sensitivity may occur. If agranulocytosis occurs, the patient cannot be switched to the other drug; other therapy (eg, radioiodine, surgery) should be used.

  • If agranulocytosis occurs with one of the antithyroid peroxidase drugs (methimazole or propylthiouracil), avoid using another drug in the same class; use another therapy (eg, radioiodine, surgery) instead.

Potential adverse effects or other characteristics vary between the two drugs and guide the indications for each. Methimazole need only be given once a day, which improves adherence. Furthermore, when methimazole is used in dosages of < 20 mg a day, agranulocytosis is less common; with propylthiouracil, agranulocytosis may occur at any dosage.

Methimazole has been used successfully in pregnant and nursing women without fetal or infant complications, but rarely methimazole has been associated with scalp and gastrointestinal defects in neonates and with a rare embryopathy. Because of these complications, propylthiouracil is used in the 1st trimester of pregnancy.

Propylthiouracil is preferred for the treatment of thyroid storm, because the high dosages used (over 800 mg a day) partially block the peripheral conversion of T4 to T3 in addition to decreasing production in the thyroid.

The combination of high-dose propylthiouracil and dexamethasone, also a potent inhibitor of T4 to T3 conversion, can relieve symptoms of severe hyperthyroidism as seen in patients with thyroid storm and restore the serum T3 level to normal within a week.

Beta-blockers

Symptoms and signs of hyperthyroidism due to adrenergic stimulation may respond to beta-blockers; propranolol has had the greatest use, but atenolol or metoprolol may be preferable.

Other manifestations typically do not respond.

Manifestations typically responding to beta-blockers: Tachycardia, tremor, mental symptoms, eyelid lag; occasionally heat intolerance and sweating, diarrhea, proximal myopathy

Manifestations typically not responding to beta-blockers: goiter, exophthalmos, weight loss, bruit, increased oxygen consumption, and increased circulating thyroxine levels

Propranolol is indicated in thyroid storm. It rapidly decreases heart rate, usually within 2 to 3 hours when given orally and within minutes when given intravenously. Esmolol should be used only in the intensive care unit because it requires careful titration and monitoring. Beta-blockers are also indicated for tachycardia with hyperthyroidism, especially in older patients, because antithyroid drugs usually take several weeks to become fully effective. Calcium channel blockers may control tachyarrhythmias in patients in whom beta-blockers are contraindicated.

Iodine

Iodine in pharmacologic doses inhibits the release of T3 and T4 within hours and inhibits the organification of iodine, a transitory effect lasting from a few days to a week, after which inhibition usually ceases. Iodine is used for emergency management of thyroid storm, for hyperthyroid patients undergoing emergency nonthyroid surgery, and (because it also decreases the vascularity of the thyroid) for preoperative preparation of hyperthyroid patients undergoing thyroidectomy. Iodine generally is not used for routine treatment of hyperthyroidism. The usual dosage is 2 to 3 drops (100 to 150 mg) of a saturated potassium iodide solution orally 3 times a day or 4 times a day or sodium iodide in 1 L 0.9% saline solution 0.5 to 1 g IV given slowly once a day.

Complications of iodine therapy include inflammation of the salivary glands, conjunctivitis, and rash.

Surgery

Surgery is indicated for patients with Graves disease whose hyperthyroidism has recurred after courses of antithyroid drugs and who refuse iodine-131 therapy, patients who cannot tolerate antithyroid drugs, patients with very large goiters, and in some younger patients with toxic adenoma and multinodular goiter. Surgery may be done in older patients with giant nodular goiters.

Surgery usually restores normal function. Postoperative recurrences vary between 2 and 16%; risk of hypothyroidism is directly related to the extent of surgery. Vocal cord paralysis and hypoparathyroidism are uncommon complications. Saturated solution of potassium iodide 3 drops (about 100 to 150 mg) orally 3 times a day should be given for 10 days before surgery to reduce the vascularity of the gland. Methimazole must be given first because the patient should be euthyroid before iodide is given. Dexamethasone can be added to rapidly restore euthyroidism. Surgical procedures on the anterior neck are more difficult in patients who previously underwent thyroidectomy or radioiodine therapy.

Treatment of infiltrative dermopathy and ophthalmopathy

In infiltrative dermopathy in Graves disease, topical corticosteroids or corticosteroid injections into the lesions may decrease the dermopathy. Dermopathy sometimes remits spontaneously after months or years.

Ophthalmopathy should be treated jointly by the endocrinologist and ophthalmologist and may require selenium, corticosteroids, orbital radiation, and surgery. Surgical thyroidectomy may help resolve or prevent progression of ophthalmopathy. Teprotumumab, an insulin-like growth factor 1 (IGF-1) receptor inhibitor, is very effective therapy for moderately severe ophthalmopathy 84. Radioiodine therapy may accelerate progression of ophthalmopathy when ophthalmopathy is active, and is thus contraindicated in this active phase.

Thyrotoxic periodic paralysis prognosis

Thyrotoxic periodic paralysis responds well to treatment. Treating hyperthyroidism will prevent attacks. It may even reverse muscle weakness.

If an attack is not treated and your breathing muscles are affected, death can occur.

Chronic attacks over time can lead to muscle weakness. This weakness can continue even between attacks if the thyrotoxicosis is not treated.

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