Thyrotoxic periodic paralysis is a rare complication of thyrotoxicosis that constitutes an endocrine emergency. Periodic paralysis without a familial history in a patient with hyperthyroidism is a strong clinical clue to the diagnosis, especially when accompanied by concomitant hypokalemia. Restoration of a euthyroid state by pharmacologic means, along with early, aggressive correction of hypokalemia, can effectively prevent an acute paralytic attack.¹

Case Presentation

A 44-year-old construction worker (originally from Ecuador) presented to the emergency department with 6 hours of weakness in his legs. Five years ago, he was diagnosed with Graves' disease and was initially treated with oral propylthiouracil, 200 mg 3 times daily. A year ago, he had a radioactive thyroid ablation procedure, after which he remained euthyroid without medications for 6 months. No one in his family had ever had a similar illness.

He denied the use of recreational drugs and did not have any other known medical condition. He has been taking aspirin for headaches whenever necessary. Initial evaluation in the emergency department revealed an alert and oriented man. Vital signs were within normal limits, except for a high blood pressure of 156/92 mm Hg. Physical examination showed flaccidity in both legs, power 1/5, with abolished deep-tendon reflexes, and minimal perception to pinprick in the legs. Examination of the arms was normal.

Laboratory test results showed low serum potassium at 1.8 mmol/L (normal, 3.5-5.5 mmol/L). Complete blood cell count and urine electrolyte analysis were within normal range. Computed tomography of the brain and x-ray of the chest were normal. Electrocardiography (ECG) showed a normal sinus rhythm, with diminished P wave and first-degree heart block.

After reviewing potential diagnoses—including acute bilateral lower-extremity peripheral neuropathy, myopathy, and periodic paralysis secondary to hypokalemia—acute bilateral lower-extremity peripheral neuropathy was established as the initial diagnosis. The patient was admitted to the intensive care unit for observation and was monitored for possible progression to respiratory muscle paralysis. Intravenous (IV) potassium chloride was infused at 20 mEq/hour.

After 5 hours of IV infusion, his plasma potassium level rose to 2.2 mmol/L and the serum magnesium level was 2.4 mg/dL (normal, 1.8-3.0 mg/dL). Although alert, the man started showing signs of labored breathing and exhaustion. Pulse oximetry demonstrated arterial oxygen saturation decline from 99% to 87%. Flaccidity was now evident in his arms, with power declination to 2/5 and diminished deep-tendon reflexes. Endotracheal intubation was performed, and the patient was supported with assist-control mechanical ventilation for impending respiratory muscle paralysis and respiratory failure.

Follow-up tests revealed: serum thyroid-stimulating hormone, 0.0 mIU/mL (normal, 0.5-5.0 mIU/mL); serum total thyroxine, 37.5 µg/dL (normal, 5.5-12.5 µg/dL); and serum total triiodothyronine, 227 ng/dL (normal, 70-200 ng/dL). The patient was started on methimazole (Tapazole), 4 mg every 8 hours, by nasogastric tube. Serum potassium levels were monitored every hour. At 12 hours after admission, his serum potassium concentration was stable, ranging between 3.9 and 4.2 mmol/L.

The patient remained alert and was able to move his arms and legs, regaining 5/5 power and normal deep-tendon reflexes. Repeat ECG findings were normal, with no signs of first-degree heart block. He was successfully weaned off the ventilator and remained stable. The IV potassium replacement was stopped, and maintenance oral potassium replacement of 20 mEq/day was started. Based on his response to therapy, a definitive diagnosis of thyrotoxic hypokalemic periodic paralysis was established.

After 24 hours, the patient was asymptomatic and ambulatory. His serum potassium level at discharge was 4.9 mmol/L.

Discussion

Characteristic features
Periodic paralysis associated with the thyrotoxic state is a rare and peculiar disorder that affects only skeletal muscles. The degree of paralysis varies from one attack to another. Severe episodes can cause paralysis of all skeletal muscles, including those controlling respiration. Smooth muscles are seldom affected, and cardiovascular dysfunction is not observed in this disorder. The ECG abnormalities in our patient were caused by his hypokalemic state.

The cardinal feature of a typical attack is muscle weakness, usually symmetrical paralysis beginning in the proximal muscles of the legs.¹ Hypokalemia (potassium level <3.0 mmol/L) associated with hyperthyroidism is also common.¹

A typical attack of thyrotoxic periodic paralysis lasts from a few hours to several days. Most attacks occur in the morning or evening.¹ In contrast to familial periodic paralysis, in which the first attack occurs before the age of 10 years, patients with thyrotoxic periodic paralysis are usually aged 20 to 40 years.¹

Asians are disproportionately affected by this condition, with one study showing Asians were at 159-fold higher risk compared with white Europeans.² There is an overwhelming male predominance, with a male-to-female ratio of 77:20.³ The condition has been reported worldwide, including in the United Kingdom, the United States (in whites and African Americans), and South America.^4-6

A low serum potassium level has been noted in the majority of patients with thyrotoxic periodic paralysis. Thyrotoxicosis is associated with normal regulation of body sodium, potassium, and cell volume. Administration of thyroid hormone has been shown to increase the fractional excretion of potassium.⁷ Compared with other body tissues, human renal tissue contains a higher concentration of messenger RNA for the thyroid receptors alpha-1, alpha-2, and beta. An alteration of thyroid-receptor expression may be an important mechanism that controls the tissue effects of the hormone, as the thyroid hormone levels in the serum increase.⁸

Differential diagnosis of hypokalemia
A basic understanding of the potential processes leading to low serum potassium levels in patients with thyrotoxic periodic paralysis can help identify the most probable cause from the 3 differential diagnostic categories:

1. Reduced intake of potassium
2. Transcellular shift of potassium
3. Loss of potassium (nonrenal or renal).

A detailed dietary history can provide enough information to determine if the patient's total daily potassium intake is low. However, reduced dietary intake is usually not the sole cause of hypokalemia, as the kidneys will drastically reduce potassium excretion under such circumstances.

A transcellular shift of potassium is a common cause of hypokalemia, especially in hospitalized patients, and can be caused by an underlying disorder or a medical intervention (Table). Movement of potassium into cells will produce hypokalemia, without changing total body potassium.

An excess loss of potassium from the kidneys, gastrointestinal (GI) tract, or skin can occur. Urinary potassium excretion of < 15 mmol/L in a 24-hour urine sample points toward GI or integumentary loss. Measurements of serum bicarbonate help identify the presence of a metabolic acid-base disorder. Metabolic acidosis suggests lower GI potassium loss as a result of diarrhea, colonic villous adenoma, vasoactive intestinal peptide-secreting tumors, or laxative abuse. The presence of metabolic alkalosis is more suggestive of vomiting, aspiration of gastric contents via a nasogastric tube, remote diuretic use, or excessive sweating.

Urinary potassium excretion in excess of 15 mmol/L indicates increased potassium loss via the kidneys. Estimation of the transtubular potassium gradient (TTKG) helps to assess the extent of net potassium secretion in distal renal tubules. This gradient can be calculated using the formula depicted in the Figure.

Figure—Estimating transtubular potassium gradient in excess renal potassium excretion. [K+]p = concentration of potassium in plasma; [K+]u = concentration of potassium in urine; OSMp = plasma osmolality; OSMu = urine osmolality; TTKG = transtubular potassium gradient.

A TTKG value of less than 2 suggests an increased distal flow of potassium, which is observed in salt-wasting nephropathies or with the use of conventional or osmotic diuretics. A value greater than 4 suggests enhanced potassium secretion in the distal tubule. Again, determination of serum bicarbonate concentration helps identify a concomitant metabolic acid-base disorder.

The presence of metabolic acidosis (when 24-hour urinary potassium excretion is >15 mmol/L) suggests possible diabetic ketoacidosis, proximal (type 2) or distal (type 1) renal tubular acidosis, or the use of drugs such as lipid-based amphotericin B or amphotericin B desoxycholate. The presence of metabolic alkalosis (with 24-hour urinary potassium excretion >15 mmol/L) requires further assessment for hypertension.

Clinical syndromes associated with hypertension in patients with hyperkalemia include mineralocorticoid excess states (because of primary hyperaldosteronism), secondary hyperaldosteronism (as in uncontrolled hypertension, hypovolemia, renal artery stenosis), Liddle's syndrome, licorice intake, congenital adrenal hyperplasia, and Cushing's syndrome. In patients with hyperkalemia, clinical states presenting without hypertension include vomiting, Bartter's syndrome, hypomagnesemia, and diuretic abuse.

Most of the calorigenic effects of thyroid hormones are mediated by enhanced sodium-potassium adenosine triphosphatase (ATPase) activity. Evidence suggests an abnormality of sodium-potassium transport in patients with thyrotoxic periodic paralysis.⁹ Such patients have been shown to have hyperinsulinemia and increased sodium-potassium ATPase pump activity compared with controls.¹⁰ Another proposed pathophysiology involves the creation of an intracellular blockade of potassium by excess levels of thyroid hormone.¹¹

Risk factors
Precipitating factors of hypokalemic thyrotoxic periodic paralysis include strenuous exercise followed by rest, excessive ingestion of carbohydrate-rich food, administration of insulin or epinephrine, trauma, exposure to cold temperatures, infection, menstruation, and emotional stress.¹ Our patient was a construction worker, and his major caloric intake was from corn-based preparations (ie, high carbohydrate content). Since altered potassium metabolism is responsible for the episodes of periodic muscle paralysis that occur in thyrotoxic patients, patients with familial forms of hypokalemic periodic paralysis should be investigated for evidence of thyrotoxicosis.

Physicians should remember that Asian and Hispanic patients with thyrotoxicosis are particularly susceptible to periodic paralysis. It is also important to remember that although hypokalemia is common during the acute paralytic episode, between attacks plasma potassium and total body potassium stores remain within normal limits.¹²

Treatment
Management is aimed at the acute attack as well as treatment of the underlying condition to prevent future attacks. Rapid administration of oral or IV potassium chloride can abort an attack and prevent cardiovascular and respiratory complications.¹ However, this approach places the patient at risk of rebound hyperkalemia (serum potassium, >5.0 mmol/L), which reportedly occurs in more than 40% of patients.¹³ Thus potassium chloride should be used cautiously and administration limited to < 90 mEq/L per 24 hours, provided that no other condition is causing the potassium loss, such as diarrhea, vomiting, or diuretic therapy.¹³ Antithyroid treatment was reported to cure thyrotoxicosis in one case, with complete resolution of periodic paralysis.¹¹ Treatment of thyrotoxicosis with antithyroid medications restores the euthyroid state and prevents periodic paralysis.¹

It has also been suggested that if a paralytic attack continues, potassium salts should be used in addition to antithyroid therapy.¹¹ Several reports indicate that the nonselective beta-blocker propranolol HCl (Inderal), at an oral dose of 3 mg/kg, results in rapid resolution of acute symptoms, including paralysis, hypokalemia, and hypophosphatemia.^5,14,15

Conclusion

Thyrotoxic periodic paralysis is a rare complication of thyrotoxicosis that must be regarded as an endocrine emergency. Clinical clues to this condition include a presentation of periodic paralysis without a family history, along with a history of hyperthyroidism. Emphasis should be placed on evaluating patients for coexistent hypokalemia. Pharmacologic agents, such as methimazole or propylthiouracil, should be considered to restore a euthyroid state in addition to early and aggressive correction of hypokalemia to effectively manage an acute paralytic attack.

References

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