In the latest Case Record of the Massachusetts General Hospital, a 37-year-old man was admitted to this hospital because of 12 hours of muscle pain and weakness, resulting in the inability to rise from bed. Brief episodes of similar symptoms had occurred during the past month. He reported blurred vision, gynecomastia, and weight loss.
Potassium is the most abundant cation in the body. Because of active potassium uptake by the sodium-potassium pump (Na+/K+-ATPase) across cell membranes, approximately 98% of total-body potassium is intracellular. The remaining 2%, approximately 60 mmol of potassium, constitutes the extracellular pool. Typical potassium intake on a Western diet is 50 to 100 mmol per day; therefore, robust mechanisms are needed to prevent dangerous increases in the potassium level of the extracellular fluid, in the short-term and over time. Sudden increases can be prevented by increased cellular uptake by means of Na+/K+-ATPase, a process that is stimulated by insulin and catecholamines.
• How does one approach a diagnosis of hypokalemia?
The kidneys can reduce urinary potassium excretion below 20 mmol per day, thus, hypokalemia due solely to inadequate intake is uncommon. Most hypokalemia relates to excessive potassium loss. The clinician’s challenge is to differentiate renal from nonrenal potassium wasting. When hypokalemia occurs suddenly, the clinician must also consider whether transcellular potassium shift, and not total-body potassium depletion, is responsible. Since 98% of total-body potassium is intracellular, relatively small changes in its distribution can cause clinically important changes extracellular fluid potassium level. Renal causes can be further subdivided into aldosterone-mediated renal losses (e.g. Conn’s syndrome or Cushing’s syndrome, both of which can cause hypokalemia and hypertension) and non-aldosterone mediated renal losses (such as with the use of diuretics or in a distal renal tubular acidosis). Nonrenal potassium loss is typically either cutaneous (related to heat exposure or prolonged exertion) or from the GI tract.
• What is the best way to make a diagnosis of renal potassium loss?
In the absence of known diuretic use, assessment of urine potassium excretion is critical for establishing renal potassium wasting. Urine potassium loss of more than 20 mmol over a 24-hour period in a patient with hypokalemia indicates ongoing, excessive renal potassium secretion. When a 24-hour urine collection is impractical, a spot urine sample that reveals a potassium level of more than 15 mmol per liter is suggestive of an excessive loss of renal potassium. Conversely, a urinary potassium loss of less than 20 mmol in 24 hours or a spot urine potassium loss of less than 15 mmol per liter indicates previous renal potassium loss (e.g., prior use of diuretics), nonrenal potassium loss, or transcellular potassium shift.
Morning Report Questions
Q: What is the etiology of hypokalemia in hypokalemic periodic paralysis?
A: Although any cause of severe hypokalemia can result in marked muscle weakness, most cases associated with acute paralysis are due to transcellular shift, rather than net potassium loss. A history of recurrent, transient episodes of muscle weakness, ranging from mild weakness to complete paralysis, is highly suggestive of acute swings in the transcellular distribution of potassium. On rare occasions, transcellular shift resulting from exogenous stimuli can result in severe hypokalemia. For example, abuse of an adrenergic agent such as pseudoephedrine can cause hypokalemia through catecholamine-induced stimulation of the transmembrane Na+/K+-ATPase; such abuse would also present with hypertension, tachycardia, and tremor. Barium intoxication is another rare cause of hypokalemic paralysis resulting from the transcellular shift of potassium. More commonly, however, a transcellular shift that results in hypokalemic paralysis represents a diagnosis of either familial hypokalemic periodic paralysis or thyrotoxic periodic paralysis (TPP).
Q: How does thyrotoxic periodic paralysis (TPP) differ from hypokalemic periodic paralysis?
A: Clinically, attacks of familial hypokalemic periodic paralysis and TPP are indistinguishable and are characterized by aches in the proximal muscles, cramping, and weakness that can progress to paralysis; hypokalemia is a hallmark of both presentations. In both cases, attacks can be precipitated by carbohydrate-heavy meals because of insulin’s stimulatory effects on the Na+/K+-ATPase. Attacks also occur during periods of rest, particularly after strenuous exercise, as potassium released during activity is reabsorbed by skeletal muscle. Other overlapping characteristics include a male predominance, normal acid-base status, and a low serum phosphate level (also due to transcellular shift). Familial hypokalemic periodic paralysis is an autosomal dominant genetic disorder due to mutations in ion channels of the skeletal-muscle sarcolemma. TPP is generally viewed as an acquired disorder, defined by the presence of hyperthyroidism (of any cause), although signs and symptoms of excess thyroid hormone may be subtle or even absent at presentation. The pathogenesis of TPP remains unclear, but thyroid hormone is known to increase the expression and activity of the Na+/K+-ATPase, perhaps unmasking an underlying predisposition for an increased transcellular shift of potassium in select persons. Familial hypokalemic periodic paralysis is usually manifested in patients who are less than 20 years of age, whereas TPP tends to have a disease onset between the ages of 20 and 50 years. TPP may be associated with the following cardinal features of hyperthyroidism: systolic hypertension with a wide pulse pressure, tachycardia, tremor, and weight loss. Gynecomastia may also be seen, as it is a well-recognized complication of hyperthyroidism and is attributable to a relative increase in circulating free estradiol.