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Thyrotoxic Periodic Paralysis
Introduction
Thyrotoxic periodic paralysis (TPP) is an uncommon but dangerous complication seen in thyrotoxic patients. It is characterized by hypokalemia associated with acute proximal symmetrical lower limb weakness and can progress to involve all four limbs and the respiratory musculature. The mechanisms of hypokalemia are incompletely understood. The prevailing theories include increased Na-K ATPase pump activity and mutations in genes encoding Kir channels in skeletal muscle. It is often confused with familial periodic paralysis (FPP) due to the similarity in presentation but can be differentiated based on the presence of thyrotoxic features and biochemical testing. Commonly recorded and described in East Asian males, the incidence of TPP has been rising in the West and other parts of the world. Knowledge regarding identification, early treatment, and prevention of future episodes of TPP is essential in mitigating this potentially lethal complication.
Etiology
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Etiology
Any cause of hyperthyroidism can lead to thyrotoxic periodic paralysis. They include Grave disease (most common), toxic nodular goiter, solitary toxic nodule, iodine-induced thyrotoxicosis, excess exogenous thyroxine use, thyroiditis, thyrotropin-secreting pituitary adenoma, and amiodarone-induced thyrotoxicosis.[1][2]
Common factors triggering attacks of periodic paralysis include the consumption of carbohydrate-rich foods, strenuous physical activity, high salt/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).[1][3][4][5][6][7][8]
Epidemiology
TPP has been well-documented in the Asian population. Reported incidences vary from 1.9% in Japanese thyrotoxic patients to 1.8% in Chinese thyrotoxic patients.[9][6] Data on the incidence rate in the West is mostly unknown, with one study reporting a rate between 0.1% to 0.2% in thyrotoxic patients in North America.[4] Recently, however, the incidence of TPP in Western countries has increased, whereas the incidence in Japan has reduced.[10][11]
Cases of TPP have also been reported in children, Europeans, Hispanics, Indians, Malaysians, Vietnamese, Saudis, Polynesians, and the Turkish populations.[12][13][8][14] Several studies have shown thyrotoxic males have a much higher incidence of TPP compared to females, albeit the higher incidence of thyrotoxicosis in females.[15][5][16][17][18] The incidence among Japanese thyrotoxic patients was recorded as 4.3% in males and 0.04% in females.[19] In the Chinese, thyrotoxic males demonstrated an incidence of 13% compared to 0.13% in thyrotoxic females.[6] It usually manifests around the age of 30-50.[6][20][21][22]
Pathophysiology
The mechanism of TPP involves two major factors: the occurrence of hypokalemia and associated muscle paralysis. Skeletal muscles house the largest share of total body potassium in the body (2600mmol) and play a vital role in maintaining extracellular potassium homeostasis. This balance is maintained by the sarcolemmal Na-K ATPase pumps and K channels. The former regulates the intracellular movement of potassium, whereas the latter, including the inward rectifying (Kir) and delayed rectifying potassium channels, regulates the extracellular movement of potassium.[23]
Thyrotoxicity can contribute to hypokalemia by a direct increase in the genetic transcription of genes coding for the Na-K ATPase pump as well as an increase in the pump's intrinsic activity.[24][25] Thyroid hormones also cause Beta-2 adrenergic stimulation and a rise in sensitivity to circulating catecholamines, resulting in an increase in Na-K pump activity.[26]
Hyperinsulinemia seen in attacks of TPP may also contribute to a depletion in extracellular potassium.[27][28] Increased Androgen levels, characteristically seen in males, have been associated with increased Na-K pump activity as well.[29] Loss-of-function mutations in the genes encoding muscle-specific Kir channels (Kir2.6), can prevent the flow of potassium out of skeletal muscle cells, disrupting potassium homeostasis.[30] These mutations have been identified in up to a third of TPP patients.[31] Furthermore, insulin and catecholamines have also been shown to inhibit Kir channels.[32] Following the reduction in extracellular potassium, the sarcolemmal membrane depolarizes, rather than hyperpolarizing. This paradoxical effect leads to the inactivation of sarcolemmal sodium channels, causing the pathognomonic paralysis of skeletal muscles.[33][34] Thyroid hormones have been shown to upregulate transcription oKir channels.
History and Physical
Patients usually present with sudden onset of episodic muscle weakness, more in the proximal muscle compared to distal, along with myalgias. Weakness is also more common in lower extremities compared to upper extremities. Paralytic symptoms usually appear after symptoms of hyperthyroidism appear. They might also present with palpitations, tachycardia, dyspnea, dysphagia, and speech and visual changes. Some patients might present with rhabdomyolysis.[35] Patients might also present with other hyperthyroid symptoms, including heat intolerance, hyper defecation, goiter, and exophthalmos.[36] On examination, they might have ectopic heartbeats, tachycardia, decreased or lack of reflexes. Usually, patients regain strength in between attacks, but weakness can persist with recurrent attacks. Attacks are more common in early mornings and usually precipitated after a heavy carbohydrate meal or after strenuous exercise.[37]
Evaluation
Hypokalemia is present in most of the patients. Hypomagnesemia and Hypophosphatemia are also present in some patients which might be one of the distinguishing features from other forms of familial periodic paralysis.[38] Abnormal thyroid hormones like elevated T4, or elevated T3 and low thyrotropin (TSH) might be present. The thyroid uptake scan might show increased uptake.
Abnormal electrocardiograms with arrhythmias might be present. The most common Electrocardiogram (EKG) changes include ST depression, sinus tachycardia, U waves, and AV blocks.[39] Very rarely, they can present with prolonged QT interval or ventricular tachyarrhythmias. Electromyograms 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.[40]
Treatment / Management
Here are important treatment goals:
- The goal is to quickly supplement potassium along with the reduction of thyroid hormones. We need to monitor for the risk of rebound hyperkalemia and hyperphosphatemia during the recovery phase.
- Intravenous potassium replacement is preferred, especially when patients present with severe symptoms, especially arrhythmias. Acute treatment suggestion is with 30 mEq of potassium given orally, every two hours until recovery begins, with a maximum oral dose of 90 mEq in 24 hours. Some suggestions include replacing at a rate of less than 10 mEq orally.
- Prophylactic potassium supplementation between attacks has not shown to be beneficial.[37]
- Non-selective beta-blockers have been shown to improve neuromuscular symptoms by reducing the intracellular shift of phosphate and potassium.[41] Intravenous propranolol 1 mg every 10 minutes up to 3 doses can be given in patients unresponsive to potassium replacement.[42]
- Medications that induce hypokalemia like glucocorticoids should be carefully monitored and should be avoided if possible in these patients. The ultimate goal is to reduce thyroid hormone levels and restore euthyroid status.
- Antithyroid drugs, radioactive iodine, and or surgery might be necessary based on the etiology of hyperthyroidism.
- Precipitating factors like strenuous exercise and high carbohydrate meals should be avoided.[43] (B3)
Differential Diagnosis
Other muscular disorders like myasthenia gravis, Guillain Barre syndrome, transverse myelitis, botulism, tick paralysis, and other familial periodic paralysis syndromes should be ruled out when patients present with acute muscle weakness.[35]
Deterrence and Patient Education
Patient education is one of the very important steps in treating and preventing the disease.
Patients should be educated about symptoms, including muscle weakness, arrhythmias, and symptoms related to hyperthyroidism, including heat intolerance, goiter, hyper defecation, and exophthalmos. They should avoid heavy meals, intense exercise, high sodium intake, etc.
Patients are instructed to go to the nearest emergency room if they experience any of the symptoms of thyrotoxic periodic paralysis.
Enhancing Healthcare Team Outcomes
Thyrotoxic periodic paralysis is a sporadic form of hypokalemic periodic paralysis, which most commonly presents as sudden onset weakness in the proximal muscles. It is a reversible condition that can be treated with quick replacement of potassium and normalization of thyroid hormones. Interprofessional communication by the total team is essential to timely treat these patients and minimize complications.
Pharmacists should be very vigilant when dispensing intravenous potassium, and they should clearly label the instructions about how to infuse the drug, as it can cause complications, including local skin reactions to severe complications like fatal arrhythmias if given too fast. Nursing staff should double-check the instructions on electrolyte infusion bags to prevent complications. The patients need to be carefully monitored for any rebound symptoms from hyperkalemia and hyperphosphatemia. The discharge staff should provide educational materials for patients and family members upon discharge, as this can be a recurrent condition.
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