Hypokalemia in Thyrotoxic Periodic Paralysis: Implication for Nephrology Practice

The aim of this article was to review the clinical presentation, pathogenesis, and management of thyrotoxic periodic paralysis (TPP). A MEDLINE search was conducted for articles published during the last 40 yr based on the key words thyrotoxic periodic paralysis and hypokalemic periodic paralysis. A total of 281 primary articles and 168 references of the retrieved articles were also reviewed. TPP is a common complication of hyperthyroidism in Asian men but is increasingly seen in Western countries. Hypokalemia and muscle paralysis results from a sudden intracellular shift of potassium and is not due to potassium deficiency. Clinical features of hyperthyroidism in patients with TPP may be subtle. Immediate potassium supplementation prevents serious cardiopulmonary complications and may hasten the recovery of muscle weakness. Nonselective beta-adrenergic blockers can ameliorate and prevent recurrence of the paralytic attacks. This episodic paralysis will remit with definitive control of hyperthyroidism. Increased sodium-potassium ATPase pump activity and enhanced insulin response in patients with TPP is postulated to contribute to the hypokalemia. The genetic predisposition for TPP is not entirely clear. Association of polymorphisms of the calcium channel alpha1-subunit gene with TPP has been noted. Due to population mobility, TPP is increasingly common in Western countries. Early diagnosis and prompt treatment prevent life-threatening complications associated with hypokalemia and muscle weakness. Assaying of thyroid function in patients with hypokalemic paralysis distinguishes TPP from other forms of hypokalemic periodic paralysis.

Thyrotoxic hypokalemic periodic paralysis (TPP) is characterized by acute attacks of weakness, hypokalemia, and thyrotoxicosis of various etiologies. These transient attacks resemble those of patients with familial hypokalemic periodic paralysis (hypoKPP) and resolve with treatment of the underlying hyperthyroidism. Because of the phenotypic similarity of these conditions, we hypothesized that TPP might also be a channelopathy. While sequencing candidate genes, we identified a previously unreported gene (not present in human sequence databases) that encodes an inwardly rectifying potassium (Kir) channel, Kir2.6. This channel, nearly identical to Kir2.2, is expressed in skeletal muscle and is transcriptionally regulated by thyroid hormone. Expression of Kir2.6 in mammalian cells revealed normal Kir currents in whole-cell and single-channel recordings. Kir2.6 mutations were present in up to 33% of the unrelated TPP patients in our collection. Some of these mutations clearly alter a variety of Kir2.6 properties, all altering muscle membrane excitability leading to paralysis.

Although hypokalemic periodic paralysis is a common complication of hyperthyroidism among Asian populations, it is an uncommon problem in the United States. The recent experience in an American medical center with 7 patients with thyrotoxic periodic paralysis (TPP) is reviewed. Compared to most descriptions of this disorder, which tend to reflect the international experience with this disease, patients with TPP in the United States reflect the ethnic makeup of the local population: the predisposition of patients of Asian origin is very evident, but whites are more frequently affected than most previous reports have recognized. Hispanics and American Indians also appear to be at increased risk, and blacks have also been affected. Except for the fact that hyperthyroidism is an absolute requirement for expression of the disease, TPP is identical to familial periodic paralysis (FPP) in its clinical presentation. TPP affects predominantly males (to an even greater degree than FPP), is rarely associated with a positive family history, and has a later onset of presentation than FPP (reflecting the need for hyperthyroidism to occur before the disorder can be expressed). Graves disease is the most common cause of hyperthyroidism in affected patients, but any cause of thyrotoxicosis (including administration of excessive amounts of exogenous thyroid hormone) can trigger attacks of TPP in susceptible subjects. Clinical features of thyroid disease may be very subtle or virtually nonexistent; as a result, thyroid function tests should be routinely monitored in patients with features of hypokalemic paralysis. The pathophysiology of the disorder is not well understood. Definitive treatment of hyperthyroidism leads to cessation of periodic hypokalemic paralysis, but symptoms can return with recurrence of the hyperthyroid condition. Potassium administration during an acute attack will shorten the duration of the episode, and treatment with propranolol, potassium supplementation, or spironolactone may prevent attacks in some patients.