Pathophysiology

Although the mechanism of thyrotoxic periodic paralysis remains uncertain, the two main ingredients that produce a paralytic attack are thyrotoxicosis and hypokalemia. It has been shown [32] that Na+,K+-ATPase activity in patients with thyrotoxic periodic paralysis was significantly higher than in healthy subjects or in thyrotoxic patients without a history of paralysis despite similar degree of hyperthyroidism. Compared with thyrotoxic patients without paralysis, patients with thyrotoxic periodic paralysis respond to thyrotoxicosis with a smaller decrement in erythrocyte Na+,K+-ATPase activity, however, the difference is too small to represent a useful genetic marker for this disease entity.[33] There are high levels of immunoreactive insulin during spontaneous attacks in thyrotoxic periodic paralysis.[34] An increase in plasma glucose concentration together with abnormally high levels of serum immunoreactive insulin was observed preceding a spontaneous attack of paralysis, and the affinity of erythrocyte insulin receptors was decreased during the attack.[35] In thyrotoxic periodic paralysis, patients have been found to have hyperinsulinemia, and this is accompanied by increased Na+,K+-ATPase activity.[36] Precipitation of an attack by a carbohydrate diet was associated with only a modest fall in level of plasma potassium but with a marked rise in total blood cell potassium.[37]

It has been observed that b-blockade with propranolol prevents paralysis, and this suggests that the development of paralysis is partly influenced by the hyperadrenergic state characteristic of thyrotoxicosis.[38] Studies in skeletal muscle have shown that CA++-ATPase activity and the calcium uptake by sarcoplasmic reticulum decrease during the attack of paralysis but revert to normal after the attack. [39] The decrease in the activity of the calcium pump was proportional to the severity of paralysis and the degree of hypokalemia.[39]

Studies suggest that chronically elevated plasma aldosterone levels may contribute to the occurrence of periodic paralysis of thyrotoxicosis in some patients, especially when further stimulated by a prompt increase in endogenous corticotropin as the result of severe stress, or even a normal or diurnal rise. [40] In 17 hyperthyroid patients without paralysis, neurophysiologic evaluation of untreated hyperthyroid patients showed abnormalities mainly in the proximal muscles, and these findings suggest the presence of an initial axonal type of mild polyneuropathy.[41] In a study of 7 patients with thyrotoxic periodic paralysis by using glucose and insulin infusion, a paralytic attack developed within 90 minutes in 6 of 7 patients. [42]

These results suggest that hyperaldosteronism may not be a trigger for the induced paralytic attack but may be a phenomenon due to volume depletion and a change in potassium homeostasis induced by glucose and insulin infusion.[42]

Electromyographic studies in eight Chinese patients with thyrotoxic periodic paralysis showed that most had a myopathic pattern during an attack of paralysis that disappeared during remission. [43] The myopathic changes were a decrease in duration of muscle action potentials, an increase in polyphasic potentials, a satisfactory interface pattern with reduced amplitude, and a reduced amplitude of the evoked muscle action potential on nerve stimulation.[43] Peripheral nerve function was normal in these cases, and it was concluded that the weakness in thyrotoxic periodic paralysis is myopathic and that the peripheral nerve function during paralysis is normal.[43]

Light microscopy of the biopsied quadriceps muscles during paralysis in 17 patients with thyrotoxic periodic paralysis showed no abnormalities in 23.5%, sarcolemmal nuclear proliferation in 35.5%, atrophy of muscle fibers in 29.4%, central nuclei in 23.5%, fatty infiltration in 17.6%, vacuolation in 11.8%, and sarcoplasmic masses in 11.8%.[44] These muscles were also examined by electron microscopy in 10 patients; the main changes observed were vacuolation in 90%, mitochondrial abnormalities in 100%, glycogen granules accumulation in 100%, disruption of the myofibers in 50%, and changes in the T system in 40%.44 The light and electron microscopic changes in the skeletal muscles during paralysis were not well-correlated with the severity of the muscle weakness of hypokalemia.[44]

In another study,[45] electron microscopic examination of muscle biopsy specimens made it possible to assume that in thyrotoxic periodic paralysis, the action of the thyroid hormone not only causes impairment

1

of the mineral metabolism, but also brings about changes in the structure of the membranes of the sarcolemma and T system, which leads to disturbances of conductance of action potential into the fiber. These changes affect the function of the end cisterns and lead to distortion of the processes of conjugation of excitation-contraction with resulting development of paresis and paralysis of muscles.[45]

In animal studies,[46] thyroid hormone appears to regulate Na channels in cultured rat skeletal myotubes by two opposing mechanisms, (1) direct stimulation of Na channel synthesis and (2) indirect decrease in synthesis mediated by an increase in cytosolic Ca[2]+. The results indicate that thyroid hormone may play an important role in developmental expression of Na channels in excitable tissue. [46] In rats, triiodothyronine induced upregulation of the concentration on Na+ channels and Na+,K+ pumps, which was associated with a progressive loss of contractile endurance.[47] These observations are important for an understanding of the fatigue associated with hyperthyroidism and add further support to the hypothesis that muscle endurance depends on the leak-to-pump ratio for Na+.[47] In rat soleus muscle, thyroid hormone at physiologic doses seems to be the major endocrine factor determining the concentration of Na+,K+ pumps in skeletal muscle,[48] and endurance is a function of the ratio between the concentration of Na+ channels and Na+,K+ pumps.[49] In rat skeletal muscle, the stimulation of the Na/H antiport by physiologic concentrations of thyroid hormones results in a dose-dependent increase in intracellular pH.[50]

These findings suggest that thyroid hormones may have an active role in the recovery from muscular acidosis through direct stimulation of the Na/H antiport.[50]

Studies of the interaction of the thyroid state and skeletal myosin heavy chain expression in rats suggest that for patients with nerve damage and/or paralysis, both muscle mass and biochemical properties can also be affected by the thyroid state.[51] In rat heart, the status of sarcolemmal Ca[2]+ transport processes is regulated by thyroid hormones, and the modification of Ca[2]+ fluxes across the sarcolemmal membrane may play a crucial role in the development of thyroid state-dependent contractile changes in the heart.[52]

In hyperthyroid cats with hypokalemia and skeletal muscle weakness manifested as ventroflexion of the neck, correction of the hypokalemia led to recovery in muscle strength.[53]

In the rat brain, Na+,K+-ATPase activity has been noted to be significantly greater in males than in females,[54] and testosterone induces an increase in the Na+,K+-ATPase activity.[55] Other studies in rats showed that hepatic Na+,K+- ATPase activity is inhibited by estrogen.[56] Progesterone or progesterone derivatives also inhibited Na+,K+-ATPase activity in the canine kidney[57] and in the guinea pig heart and brain.[58] These effects of sex hormones on the Na+,K+ pump may contribute to the predisposition for thyrotoxic periodic paralysis in men.

Genetics

Unlike familial hypokalemic periodic paralysis, thyrotoxic periodic paralysis is not usually associated with family history. There is, however, an association with the presence of HLA-DRw8, and data suggest that this gene may play a significant role in the susceptibility to thyrotoxic periodic paralysis among Japanese men.[59] In a pair of monozygous adolescent male twins with hyperthyroidism, one had thyroiditis while the other had muscle weakness and paralysis.[60] The finding of HLA antigens A2BW22 and AW19B17 in Chinese patients with thyrotoxic periodic paralysis but not in patients without the disorder raises the possibility that these haplotypes may serve as genetic markers.[61] In a black patient, phenotyping revealed neither of the two genetic markers previously observed among Chinese patients with thyrotoxic periodic paralysis, indicating that the haplotypes do not serve as markers for the disorder in black patients.[27] Although the HLA system has been suggested to provide a link to a presumed immunogenetic etiology of the thyrotoxic periodic paralysis, this seems to be an unlikely explanation in view of the numerous patients with the disorder whose thyrotoxicosis is not related to autoimmune mechanism. The high incidence of the disorder in Asians suggests that the basic defect may be genetically determined, but the defect manifests itself only when challenged by thyrotoxicosis.[2]

Treatment

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The definitive therapy for thyrotoxic periodic paralysis is the management of the thyrotoxic state by medical therapy, surgery, or radioactive iodine therapy. The resolution of periodic paralysis with restoration of euthyroidism has been acknowledged as a universal finding.[2] The Na+,K+-ATPase activity in RBCs was found to be impaired in Graves' disease, and thioamide treatment restored the normal activity.[62] One case was an exception, however, because the periodic paralysis persisted even when the patient's clinical and laboratory features suggested a euthyroid state. This patient continued to have symptoms of periodic paralysis when he progressed to hypothyroidism after radioactive iodine ablation.[63]

Once the paralytic attack has started, administration of potassium is standard therapy, and recovery of the periodic paralysis may be hastened.[64] Although the serum potassium level will eventually normalize spontaneously as potassium moves from the intracellular space to the extracellular space, the administration of potassium is not done to correct the hypokalemia. It is given mainly to prevent cardiac arrhythmias that potentially can be life-threatening. Potassium is usually administered intravenously, even though there is no proven benefit or advantage in using this method of administration.

As potassium is released from the cells into the circulation during the recovery phase of the paralytic attack, aggressive potassium administration can lead to hyperkalemia, as happened in our case 2 patient with a potassium level of 6.1 mmol/L after receiving a dose of only 60 mEq KCl. A patient who had a potassium level of 1.9 mEq/L progressed to a level of 6.4 mEq/L after receiving 100 mEq KCl intravenously over 10 hours.20 In cases with associated hypophosphatemia, as in our patients' cases and those of Norris et al[13] and Guthrie et al,[15] it has been observed that serum phosphate levels returned to normal after giving only potassium.

After initiating the definitive therapy for the thyrotoxicosis, patients should be advised to avoid precipitating factors while awaiting normalization of the thyrotoxic state. Others have advocated supplementation with oral potassium to prevent attacks of paralysis in some patients, though this approach is not consistently effective. Acetazolamide has been used in the familial hypokalemic periodic paralysis; however, in one case a Hispanic man was given acetazolamide for his thyrotoxic periodic paralysis, which had been mistakenly diagnosed as familial hypokalemic periodic paralysis, and this resulted in near-total body paralysis 2 weeks later.[18] In some cases, the efficacy of using spironolactone[2] or aldosterone antagonist SC942065 in preventing paralytic attacks is well-documented. b-Adrenergic blockade induced with propranolol therapy has resulted in marked relief of the episodes of paralysis[38] and is probably the most useful preventive therapy until a euthyroid state is achieved.

Summary

Thyrotoxic periodic paralysis is a thyroid-related disorder manifested as recurrent episodes of hypokalemia and muscle weakness lasting from hours to days. The onset of paralytic attacks coincides with the onset of thyrotoxicosis, which could be due to various causes. This condition predominantly affects men and usually occurs in the third to fifth decades of life. The usual precipitating factors are ingestion of a high-carbohydrate meal and strenuous physical activity followed by rest. Although the mechanism of thyrotoxic periodic paralysis remains uncertain, the two main ingredients to produce a paralytic attack are thyrotoxicosis and hypokalemia. The high incidence of thyrotoxic periodic paralysis among Asian people suggests that the basic defect may be genetically determined, but the defect manifests itself only when challenged by thyrotoxicosis. Propranolol and spironolactone have been used to prevent paralytic attacks, but the definitive therapy is management of the thyrotoxicosis. Potassium administration is mainly done to prevent cardiac arrhythmias and to hasten the recovery of the paralyzed muscles. Our cases are the ninth and tenth reports of thyrotoxic periodic paralysis in blacks.

Hypokalemic periodic paralyses (PROGNOSIS)o Untreated patients may experience fixed proximal weakness, which may interfere with

activities. o Several deaths have been reported, mostly related to aspiration pneumonia or inability to

clear secretions.

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Treatment is often necessary for acute attacks of hypokalemic PP but seldom for hyperkalemic PP. Prophylactic treatment is necessary when the attacks are frequent.

Hypokalemic periodic paralyses o During attacks, oral potassium supplementation is preferable to IV supplementation. The

latter is reserved for patients who are nauseated or unable to swallow. Oral potassium salts at a dose of 0.25 mEq/kg should be given every 30 minutes until the weakness improves. Avoiding IV fluids is prudent. IV potassium chloride 0.05-0.1 mEq/kg body weight in 5% mannitol as a bolus is preferable to continuous infusion. Continuous ECG monitoring and sequential serum potassium measurements are mandatory.

o For prophylaxis, acetazolamide is administered at a dose of 125-1500 mg/day in divided doses. Dichlorphenamide 50-150 mg/day has been shown recently to be equally effective. Potassium-sparing diuretics like triamterene (25-100 mg/d) and spironolactone (25-100 mg/d) are second-line drugs to be used in patients in whom the weakness worsens or in those who do not respond to carbonic anhydrase inhibitors. As these diuretics are potassium sparing, potassium supplements may not be necessary.

o Thyrotoxic PP: Treatment consists of controlling thyrotoxicosis and beta-blocking agents.

Potassium supplementation, propranolol, and spironolactone may be helpful during the attacks, as well as prophylaxis. Propranolol in doses of 20-40 mg twice a day may be sufficient to control recurrent attacks of periodic paralysis.

(DIET)-Hypokalemic PP: Low-carbohydrate and low-sodium diet may decrease the frequency of attacks.

Lab Studies

Hypokalemic periodic paralyses o Serum potassium level decreases during attacks, but not necessarily below

normal. Creatine phosphokinase (CPK) level rises during attacks. In a recent study, transtubular potassium concentration gradient (TTKG) and potassium-creatinine ratio (PCR) distinguished primary hypokalemic PP from secondary PP resulting from a large deficit of potassium. Values of more than 3.0 mmol/mmol (TTKG) and 2.5 mmol/mmol (PCR) indicated secondary hypokalemic PP.

o

o ECG may show sinus bradycardia and evidence of hypokalemia (flattening of T waves, U waves in leads II, V2, V3, and V4, and ST segment depression).

Hypokalemic PP Hyperkalemic PP

Serum potassium

Mildly depressed; may reach 1-5 mEq/L

Increases from baseline but may not increase beyond normal range

Serum CPK Moderately elevated during attacks Mildly elevated during attacks

ECG BradycardiaFlat T waves, U waves, ST segment depression

Tall T waves

4