Thyrotoxic Hypokalemic Periodic Paralysis
Thyrotoxic periodic paralysis (THKPP) is an uncommon disorder characterized by simultaneous thyrotoxicosis, hypokalemia, and paralysis that occurs primarily in males of Asian descent, including patients of Japanese, Chinese, Vietnamese, Korean and Filipino ancestry.
Kilpatrick et al. (1994) found six reports of thyrotoxic hypokalemic periodic paralysis in African-Americans and described four additional cases, all in males. They concluded that the disorder may be more frequent in blacks than previously suspected and should be considered when patients present with unexplained hypokalemia, muscular weakness, and rhabdomyolysis.
Patients with THKPP 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, THKPP is identical to Hypokalemic periodic paralysis in its clinical presentation but THKPP is rarely associated with a positive family history. 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 THKPP 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 HypoKPP. The thyrotoxicosis may be mild. Attacks can be precipitated by high carbohydrate intake, sleep (onset of paralysis usually occurs during sleep), unusual exertion, infection, diarrhea, thyroid hormone or alcohol abuse.
A number of researchers have reported that the serum insulin level is sharply elevated prior to the attack of paralysis in THKPP. Increased sodium-potassium ATPase pump activity and enhanced insulin response in patients with THKPP is postulated to contribute to the hypokalemia. Spontaneous or induced attacks do not occur in persons whose hyperthyroidism has been corrected.
Patients typically present with an acute episode of paralysis involving the muscles of the extremities and limb girdles. The lower limbs are more frequently and severely involved than the upper. Weakness may be asymmetrical. Proximal strength is more severely impaired than distal strength.
A specific genetic basis is suggested by the fact that although occasional cases occur in Caucasians the disorder is seen predominantly in Asians. It is primarily found in males, although the occasional female patient presents. THKPP may be due to a genetic peculiarity of muscle membranes. Multiple cases in families have been observed but the mode of inheritance is not clear. (note: one genetic mutation has now been identified. This may not account for all cases of THKPP, but it does strongly suggest a genetic cause for all cases.)
Genetics and Inheritance
Potassium Channel; In 2010, Ryan et al. identified mutations in KCNJ 18 (Kir 2.6); Chromosome 17p11.2 as the cause of about 1/3 of cases of susceptibility to Thyrotoxic HypoKPP. Specific mutations include: Arg399X, Gln407X, T354M; Lys366Arg; Arg205His; I144fs (c.428 delC)
In one study of 19 men with THKPP initial serum K levels upon admittance to hospital ranged from 1.1 to 3.4 mmol/L (mean, 1.90.5 mmol/L). Serum 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 Mg levels (0.60-0.80 mmol/L 1.5-1.9 mg/dL). Only two patients received supplemental magnesium sulphate, but 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).
Elevated total thyroxine, triiodothyronine resin uptake, and total triiodothyronine levels. Radioiodine scan for Graves disease and adenomas
Consistent with Hypokalemia or Thyrotoxicosis; During paralysis, sinus tachycardia, diffuse ST-T changes, flattening of T waves, prolonged QT intervals, and U waves. Sinus arrest and second-degree atrioventricular block also have been described in patients with THKPP, ventricular fibrillation and ventricular tachycardia.
The mainstay of emergency treatment has always been potassium replacement, however not all patients respond to potassium alone and recent evidence suggests that combining potassium and propranolol is a more effective therapy. It has been recommended that 27 mEq of KCl be given every 2 hours orally for 6 hours and then every 4 hours with careful monitoring. Because THKPP patients may develop rebound hyperkalemia, (Manoukian et al 1999) recommends that K+ replacement therapy should be cautious and should not exceed 90 mEq of KCl per 24 hours unless there is a reason for 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 131 treatment. Eighteen patients were eventually treated with radioiodine 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. For information on management of the Hypokalemic aspect of THKPP see Hypokalemic Periodic Paralysis.
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