3.3.2 Thyrotoxic periodic paralysis

The association of thyrotoxicosis and periodic paralysis was first described in 1902 in a white patient. However, it soon became evident that thyrotoxic periodic paralysis (TPP) affects mainly Asian populations, in particular Chinese and Japanese, although isolated cases have also been reported in other ethnic groups such as white, Hispanic, African-American, and American Indian populations. The incidence of TPP in non-Asian thyrotoxic patients is around 0.1%, whereas in Chinese and Japanese thyrotoxic patients, TPP affects 1.8% and 1.9%, respectively (1–3). Despite a higher incidence of thyrotoxicosis in women, TPP affects mainly men, with a male to female ratio ranging from 17:1 to 70:1, according to different series. In the Chinese population, TPP affects 13% of male and 0.17% of female thyrotoxic patients. In the Japanese population, TPP was reported to occur in 8.2% of male and 0.4% of female thyrotoxic patients in the 1970s, but in 1991 the reported incidence had decreased to 4.3% and 0.04%, respectively (4).

TPP patients are usually between 20 and 40 years of age, similar to the age distribution for thyrotoxicosis. The paralytic attacks are characterized by transient recurrent episodes of muscle weakness. Attacks involve proximal more than the distal muscles, with an initial involvement of the lower limbs and subsequently the truncal muscles, and finally all four limbs. The degree of weakness varies from mild weakness to total flaccid paralysis and hyporeflexia. Some patients may experience prodromal symptoms of aches, cramps, or stiffness in the affected muscles. Weakness usually affects skeletal muscles only. However, total paralysis of respiratory, bulbar, and ocular muscles has been reported in severe cases (5–7). Recovery is usually complete, but the duration of paralysis can vary from a few hours in a mild attack to 36–72 h in a severe attack. Electromyographic studies have confirmed the myopathic changes with intact peripheral nerve function. The presentation of TPP may be confused with Guillain–Barré syndrome, acute spinal cord compression, myelitis, and hysteria. The attacks of weakness are similar to those of familial hypokalaemic periodic paralysis (FHPP) except for the presence of hyperthyroidism. While FHPP is an autosomal dominant condition affecting mainly white people, TPP is a sporadic disease found mainly in Asian men, and familial cases of TPP are extremely rare.

High carbohydrate loads and strenuous exercise are well-recognized precipitating factors for TPP (8). The paralytic attacks do not occur during exercise but occur during the resting period that follows strenuous exercise, and the attacks may be aborted by continuation of exercise. In subtropical cities such as Hong Kong, attacks are most common during the summer season. This seasonal variation is probably associated with an increased intake of sugary drinks as well as outdoor activities and exercise in summer. In tropical cities, such as Singapore, seasonal variation is not seen. Attacks usually occur in the middle of the night or early morning, which coincides with a period of rest following a heavy meal or exercise. Paralysis can be induced in these patients with high carbohydrate loads with or without insulin infusion, strenuous exercise, or even thyroxine therapy. However, attacks cannot be induced once the patient has become euthyroid.

Hypokalaemia is the hallmark of TPP. Plasma potassium concentrations have been reported to be as low as 1.1 mmol/l. Some patients may have a near to normal plasma potassium concentration if they are admitted during the recovery phase of the attack. Mortality due to cardiac arrhythmia associated with the hypokalaemia has been reported. The complication of rhabdomyolysis may occur in a severe attack. Potassium concentration returns to normal when the patient recovers spontaneously from the weakness. The degree of hypokalaemia and the severity of weakness have no correlation with the severity of hyperthyroidism and the serum thyroid hormone concentration. Indeed, many patients have relatively few symptoms of hyperthyroidism and TPP may be their only manifestation of thyrotoxicosis. Apart from hypokalaemia, patients may also experience mild to moderate hypophosphataemia and hypomagnesaemia. These are also a result of intracellular shift as these electrolyte abnormalities would return to normal spontaneously when the patient recovers from the paralysis.

The underlying cause of hyperthyroidism in the majority of TPP patients is Graves’ disease. However, TPP can also be associated with thyroiditis (either spontaneous or induced by interferon therapy), toxic nodular goitre, toxic adenoma, thyroid-stimulating hormone (TSH)-secreting pituitary tumour, and even overdosage of thyroid hormone. TPP is usually the early presentation of the underlying thyroid disease. In the case of Graves’ disease, TPP can also be a presenting feature of relapse of the disease. Paralysis only occurs when the patient is thyrotoxic and not when euthyroid.

Muscle biopsies from patients with TPP have revealed a variety of abnormalities. The most consistent finding is proliferation and focal dilation of the sarcoplasmic reticulum and transverse tubular system, with prominent vacuoles arising from the sarcoplasmic reticulum (9). It is uncertain whether these vacuoles represent coalescence of dilated sarcoplasmic reticulum or sequestrated areas of focal myofibrillar necrosis.

The pathogenesis of TPP remains unclear. Hypokalaemia is due to a rapid and massive shift of plasma potassium from the extracellular into the intracellular compartment, mainly into the muscles, and is not due to depletion through losses in urine or faeces. This massive shift of potassium is believed to be due to increased Na⁺,K⁺-ATPase pump activity in these patients. It is known that thyroid hormone can increase Na⁺,K⁺-ATPase activity in skeletal muscle, liver, and kidney, and also induce influx of plasma potassium into the intracellular space (10). A thyroid hormone responsive element has been described in the promoter region of the α1- and β1-subunits of the Na⁺,K⁺-ATPase pump. The action of thyroid hormone on Na⁺,K⁺-ATPase activity is believed to be mediated through both transcriptional and post-transcriptional levels. Thyroid hormone also increases the number and sensitivity of β-adrenergic receptors. The increased β-adrenergic stimulation further increases Na⁺,K⁺-ATPase activity, which may explain why nonselective β-blockers can prevent attacks of TPP. The finding that selective β₁ antagonists do not protect patients from paralytic attacks is consistent with the specific role of the β₂ receptor in mediating the catecholamine-induced increase in Na⁺,K⁺-ATPase activity in skeletal muscle (11).

As it is difficult to determine potassium transport in intact skeletal muscles during TPP and in between attacks, most studies have resorted to measurement of the potassium flux and sodium pump activity in peripheral tissues such as the red blood cells, leucocytes, and platelets. Various groups have shown that the number of Na⁺,K⁺-ATPase pumps, as well as Na⁺,K⁺-ATPase-mediated cation influx, were increased in leucocytes (12) and platelets (13) in thyrotoxic patients with or without TPP when compared to healthy controls. However, TPP patients have significantly higher pump capacity and activity than those with plain thyrotoxicosis. When thyrotoxicosis is controlled, the Na⁺,K⁺-ATPase activity in TPP patients returns to levels similar to those of healthy individuals.

Insulin stimulates Na⁺,K⁺-ATPase and plays a permissive role for the potassium shift in TPP. Serum insulin levels vary widely in spontaneous attacks or during induction of paralysis, but hyperinsulinaemia during the attack or after glucose challenge has been reported in TPP (14). The hyperinsulinaemic response may explain the association of the paralysis with heavy meals or sweet snacks. Exercise releases potassium from muscle while rest promotes influx of potassium, which may explain why mild exercise may abort an attack. It would thus appear that TPP patients have an underlying predisposition for activation of Na⁺,K⁺-ATPase activity, and that thyroid hormone and insulin enhance the exaggerated response of the pump activity in these people. It is of interest to note that Na⁺,K⁺-ATPase activity is possibly increased by androgens and inhibited by oestrogens, and this may explain the male predilection for TPP (15).

A number of genetic association studies on TPP have been reported. Associations with the HLA genotypes HLA-B46, HLA-DR9, and HLA-DQBl*0303 were reported in Hong Kong Chinese, HLA-A2, HLA-Bw22, HLA-AW19, and HLA-B17 in Singapore Chinese, and HLA-DRW8 in Japanese populations (16). However, it is uncertain whether these associations were related to the genetic predisposition to Graves’ disease rather than to TPP, especially when the majority of these TPP patients had an underlying autoimmune thyroid disease.

In view of the similar presentations between TPP and FHPP, the role of the voltage-dependent calcium channel or dihydropyridine-sensitive L-type calcium channel receptor (Ca_v1.1), which is associated with FHPP 1, was studied in TPP patients. None of the few mutation hot spots associated with FHPP was present in Asian or non-Asian patients with TPP (17, 18). However, certain single nucleotide polymorphisms (SNPs) of Ca_v1.1, including nucleotide (nt) 476, intron 2 nt 57, and intron 26 nt 67, were associated with TPP in southern Chinese (18). The location of these SNPs lies at or close to the thyroid hormone responsive element (TRE) of the gene, and it is likely that they affect the binding affinity of thyroid hormone responsive element (TRE) and modulate the stimulation of thyroid hormone on the Ca_v1.1 gene. Similarly, isolated case reports with mutations in other skeletal muscle ionic channels were reported in white individuals but were not identified in other populations.

In view of the insulin resistance and increased Na⁺,K⁺-ATPase activity and increased adrenergic response observed in TPP patients, the genes encoding for the α1-, α2-, β1-, β2-, and β4-subunits of Na⁺,K⁺-ATPase and β-adrenergic receptor were examined. Ryan et al. (19) have recently reported that one in three patients with TPP carries a mutation of a gene encoding an inwardly rectifying potassium (Kir) channel Kir 2.6, suggesting that TPP might be a channelopathy like FHPP.

Treatment of TPP consists of two components: (1) the acute management of the paralytic attack and (2) the definitive treatment of hyperthyroidism. During the paralysis associated with marked hypokalaemia, treatment with intravenous potassium can hasten the recovery of muscle function and prevent cardiac arrhythmia. However, the serum potassium level has to be monitored closely, as rebound hyperkalaemia may occur when the potassium is being shifted back into the extracellular compartment. The use of oral potassium supplements during the early phase of weakness can sometimes help to prevent further progression to complete paralysis. Whereas potassium replacement is most effective during paralysis, regular potassium supplements are not effective for prophylaxis against further paralytic attack. Further attacks of paralysis can be prevented by the administration of spironolactone or propranolol. The most effective agent is propranolol, a nonselective β-blocker. At a dosage of 40 mg 4 times a day, propranolol can prevent paralysis induced by high carbohydrate load in about two-thirds of those with a history of TPP (20). The selective β₁ antagonist metoprolol does not protect patients from paralytic attacks. Thyroxine and acetazolamide have been reported to reduce the frequency of attacks in FHPP, whereas the reverse is the case with TPP.

Patients should be advised to avoid the factors that may precipitate the attack, including heavy carbohydrate intake, alcohol ingestion, and excessive exertion. However, since patients will not have further paralytic attacks when they are euthyroid, adequate control of hyperthyroidism is necessary. Definitive treatment of the hyperthyroidism with radioactive iodine or thyroidectomy is indicated. It has to be noted that TPP may occur after radioactive iodine therapy when the patient is still thyrotoxic, and addition of antithyroid drugs for several weeks after radioactive iodine therapy may be necessary to establish a euthyroid state. When treatment leads to hypothyroidism, careful monitoring of the thyroxine replacement therapy is essential to avoid overtreatment, which may lead to a recurrence of paralytic attacks.