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Definition, Diagnosis, and Clinical Features

Hypokalemia is defined as a decrease in serum potassium concentration 3.5 mmol/L (severe: 2.5 mmol/L), hyperkalemia as an increase 5.0 mmol/L (severe: 6 mmol/L). Internal and external disorders of potassium balance cannot be distinguished by measurement of serum potassium concentration and have to be analyzed as described below.

Diagnosis

When analyzing potassium disorders the potential of an artifact in serum potassium measurement should always be considered. Whereas the measurement of potassium concentration with ion-selective electrodes is very reliable, preanalytical conditions can have a major influence on the results.

Pseudohyperkalemia occurs when cytolysis occurs in-vitro. This is observed with very high cell numbers (thrombocytosis, chronic myelogenous leukemia), with in-vitro hemolysis (long transport times), and with difficult blood draws. Conversely, pseudohypokalemia can occur via transcellular shift into cells after intravenous insulin application shortly before a blood draw, but also with high cell numbers and long transport times at room temperature.

Renal potassium excretion can be estimated by the measurement of urinary potassium concentration (UK). However, it is important to recall that urinary potassium excretion is also influenced by renal sodium and water excretion. Therefore, a change in urinary potassium concentration is more difficult to interpret in the context of such concomitant disorders.

Clinical Features

Because of the mentioned functions of potassium as the main intracellular cation, symptoms of potassium disorders are mainly characterized by alteration in neuromuscular excitability. In general, hypokalemia leads to an increase in the membrane potential and therefore to reduced excitability, whereas hyperkalemia leads to a decreased membrane potential and increased excitability. The symptoms and signs for both disorders are summarized in table below. The typical ECG alterations with hypokalemia and hyperkalemia are depicted in the figure below.

READ ALSO: Hypokalemia ECG Changes [With Examples]

Hypokalemia

An overview on causes of hypokalemia are presented in the images below.

Symptoms and Signs of Hypokalemia

Hypokalemia Due to Reduced Potassium Intake

This type of hypokalemia occurs with all variations of malnutrition and/or malabsorption. Examples are kwashiorkor, anorexia/bulimia, chronic alcoholism, and generalized malabsorption in the context of celiac sprue, or Crohn disease, etc. However, the potassiumsparing mechanism of the kidney is very efficient. Therefore, hypokalemia usually only occurs with concomitant renal potassium loss, e. g., with the additional use of diuretics.

Hypokalemia Due to Transcellular Shifts (Disorders of Internal Balance)

Two main pathogenetic situations can be distinguished:

• Massively enhanced cell proliferation that uses up all available potassium: examples are rapidly growing lymphomas or acute leukemias. The same mechanism plays a role in the treatment of severe forms of pernicious anemia and of severe malnutrition. The latter situation was termed “refeeding syndrome” and was first described in World War II in patients leaving concentration camps, but it was later also observed in severely ill patients with severe malnutrition after a long stay in intensive care units.

• Potassium shift from the extracellular to the intracellular space with constant cell proliferation: this mechanism occurs with insulin therapy (especially in the context of diabetic coma), alkalosis, endogenous and exogenous catecholamines, hyperthyroidism, and with certain drugs (e. g., theophylline). The same mechanism plays a role in a rare genetic disease called familial periodic hypokalemic paralysis. Various mutations in sodium, calcium, and potassium channels were described as a potential cause of this syndrome. The common denominator is the occurrence of hypokalemia with paralytic symptoms in association with adrenergic stimuli (e. g., physical exercise) and with insulin secretion (after carbohydrate-rich meals).

Hypokalemia Due to Enhanced Potassium Loss

Under physiologic conditions only 10% of potassium excretion occurs via extrarenal routes, mainly the gastrointestinal tract. Diarrhea of various origins (infectious, malabsorption, etc.) can lead to massively enhanced extrarenal potassium loss and subsequent hypokalemia. In rarer cases, certain drugs can also be responsible (abuse of laxatives, overdose of potassiumbinding ion exchangers). In order to distinguish renal and extrarenal potassium loss, urinary potassium concentration should be measured.

Renal potassium loss is by far the most common cause of hypokalemia.

As mentioned above, only two parameters influence renal potassium excretion: distal sodium delivery and overall mineralocorticoid activity. Hence, in the context of hypokalemia with renal potassium loss, we can distinguish between disorders with enhanced distal sodium delivery (ECV contraction and hypotension) and disorders with primary mineralocorticoid excess (ECV expansion and hypertension).

Hypokalemia with Normal or Reduced Blood Pressure (Enhanced Distal Sodium Delivery)

Distal sodium delivery is enhanced with diuretic therapy (all classes of diuretics except potassium-sparing drugs). It occurs most often with the use of loop and thiazide diuretics. Distal sodium delivery also increases with the presence of high anion concentrations in the urine that use sodium as the cation for excretion. Examples are bicarbonate in the context of metabolic alkalosis and proximal renal tubular acidosis and also therapy with highdose penicillin. Finally, magnesium deficiency blocks sodium reabsorption in the loop of Henle and therefore leads to enhanced distal sodium delivery and concomitant potassium loss.

A variety of genetic disorders of sodium transport lead to enhanced distal sodium delivery and potassium loss. The genetic defect in various types of Bartter syndrome is located in the loop of Henle and is comparable to chronic treatment with loop diuretics. The disorder is usually severe and manifests in early childhood. In contrast, the defect in Gitelman syndrome is located in the distal tubule and is comparable to chronic thiazide treatment. Hypomagnesemia is usually a prominent feature of this disorder, which is less severe and often diagnosed only in adulthood.

Hypokalemia with Hypertension (MineralocorticoidExcess)

Hyperaldosteronism leads to ECV expansion, hypertension,and hypokalemia. This includes acquired forms of hyperreninemic hyperaldosteronism in the context of renal artery stenosis as well as hyporeninemic hyperaldosteronism with an aldosterone-producing adenoma of the adrenal cortex (Conn syndrome) or with bilateral diffuse hyperplasia of the adrenal cortex.

A rare, but interesting, disease should be considered in the differential diagnosis of hyporeninemic hyperaldosteronism.The disorder is called glucocorticoid suppressible hyperaldosteronism. Pathogenetically, anew fusion gene appears, which is comprised of aldosterone synthase linked to the promoter region of11-hydroxylase (11-HSD2). This promoteris under the control of ACTH. Therefore, ACTH stimulates aldosterone instead of cortisol production. Since aldosterone does not allow for negative feedback on ACTH production, this disease leads to mineralocorticoid excess, which can be treated by exogenous application of dexamethasone.

A variety of diseases are associated with mineralocorticoid excess, but with low aldosterone levels (sometimes called “pseudohyperaldosteronism”). Acquired forms occur with hypercortisolism (central or adrenal Cushing syndrome) and acquired 11-HSD2deficiency with licorice consumption. Genetic forms are activating mutations in the distal sodium channel (Liddle syndrome) or in the mineralocorticoid receptor as well as the inborn 11-HSD2 deficiency (also-called“apparent mineralocorticoid excess,” AME).

Treatment of Hypokalemia

• Mild, asymptomatic:
  • Oral potassium chloride supplementation
  • Correct contributing factors (e.g., diuretics, GI losses, hypomagnesemia)

• Moderate to severe or symptomatic (<3.0 mmol/L, arrhythmias, muscle weakness):
  • Intravenous potassium chloride
    • Peripheral line: usually 10–20 mmol/hour
    • Central line: higher rates if needed, with continuous ECG monitoring

• Magnesium repletion:
  • Essential, as hypomagnesemia impairs potassium correction

• Underlying cause:
  • Identify and treat to prevent recurrence

Hyperkalemia

An overview of the causes of hyperkalemia is shown in the images below.

Differential Diagnosis of Hyperkalemia

Hyperkalemia Due to Excessive Potassium Intake

Excessive potassium intake occurs via food or drugs. Food rich in potassium includes chocolate and various types of fruits (bananas, grapes, oranges, dried fruit). Overdose of therapeutically administered potassium chloride or potassium citrate can lead to hyperkalemia aswell as infusion of blood and certain drugs (e. g., highdose penicillin).

As with hypokalemia, it is also true for hyperkalemia that changes in intake only lead to relevant potassium disorders when renal potassium excretion is impaired at the same time, i. e., preexistent chronic renal insufficiency.

Hyperkalemia Due to Transcellular Shifts (Disorders of Internal Balance)

Analogous to hypokalemia, two main pathogenetic mechanisms can be distinguished:

• Massive cytolysis: classic examples are massive hemolysis, rhabdomyolysis including malignant hypothermia, and tumor lysis syndrome associated with chemotherapy of acute leukemias or rapidly growing lymphomas. In these situations combined electrolyte disorders including hyperkalemia, hyperphosphatemia, hypocalcemia, and hyperuricemia are typically found.

• A potassium shift from the intracellular to the extracellular space occurs with metabolic and respiratory acidosis, insulin deficiency, drugs (-blockers, digoxin, depolarizing muscle relaxing agents [e. g., succinylcholine]). A rare genetic disorder, familial periodic hyperkalemic paralysis, is caused by a mutation in a sodium channel and leads to exercise-induced hyperkalemia with paralytic symptoms.

Hyperkalemia Due to Reduced Potassium Excretion

Since 90% of potassium is excreted by the kidneys, hyperkalemia due to reduced potassium excretion is always of renal origin. As mentioned above, two parameters, distal sodium delivery and mineralocorticoid activity, determine renal potassium excretion. Therefore, hyperkalemia disorders with reduced distal sodium delivery can be distinguished from disorders with primary mineralocorticoid deficit.

Hyperkalemia Due to Disorders with Reduced Distal Sodium Delivery.

The classical examples for this condition are all forms of intrarenal and postrenal acute and chronic renal insufficiency. The loss of nephrons leads to a reduced glomerular filtration rate and subsequently to a reduction of natriuresis with sodium and water retention and hypertension. The concomitant metabolic acidosis of renal failure exacerbates the hyperkalemia. In contrast, volume depletion in the context of prerenal renal failure does not lead to hyperkalemia, since potassium excretion is enhanced by secondary hyperaldosteronism.

Gordon syndrome (pseudohypoaldosteronism type 2) is a congenital disease with reduced distal sodium delivery. The activating mutation of a protein kinase in the distal tubule leads to increased sodium reabsorption in this nephron segment, a situation functionally comparable to an “inverse Gitelman syndrome.”

Hyperkalemia Due to Mineralocorticoid Deficiency

Pathogenetically, disorders of aldosterone deficiency can be distinguished from disorders with aldosterone resistance. Total destruction of the adrenal cortex leads to a condition with hyperreninemic hypoaldosteronism. It results in combined mineralocorticoid and glucocorticoid deficiency (Addison disease) including hyperkalemic acidosis, hypotension, and hyponatremia. Certain drugs lead to a selective blockade of the aldosterone axis (e. g., ACE inhibitors, angiotensin receptor blockers, heparin).

In contrast, hyporeninemic hypoaldosteronism is classically observed in the context of diabetic and interstitial nephropathies or treatment with nonsteroidal antirheumatic drugs. The typical constellation is the combination of hyperkalemia with renal tubular acidosis type 4, hypertension, and slightly impaired renal function. Pathogenetically, a damage of the juxtaglomerular apparatus is postulated.

Genetic variants of hypoaldosteronism occur with different forms of adrenogenital syndrome as well as with isolated aldosterone synthase deficiency.

Disorders with mineralocorticoid resistance but high levels of aldosterone should be differentiated from true hypoaldosteronism. Acquired mineralocorticoid resistance occurs in the context of various nephropathies with damage to the collecting ducts (e. g., tubulointerstitial nephropathies, sickle cell disease, amyloidosis, obstructive nephropathy). Certain drugs, e. g., potassium-sparing diuretics (amiloride), mineralocorticoid- receptor blockers (spironolactone), and digoxin, interfere with potassium excretion in distal nephron. Finally, genetic disorders with mineralocorticoid resistance are known as pseudohypoaldosteronism type 1A (inactivating mutation of the mineralocorticoid receptor) and type 1B (inactivating mutation of the distal sodium channel).

Treatment of Hyperkalemia

• Cardiac stabilization (if ECG changes or severe hyperkalemia):
  • IV calcium gluconate or calcium chloride

• Shift potassium intracellularly (temporizing measures):
  • Insulin + glucose
  • β2-adrenergic agonists
  • Sodium bicarbonate (in metabolic acidosis)

• Potassium elimination:
  • Loop diuretics
  • Cation-exchange resins (sodium zirconium cyclosilicate, patiromer)
  • Hemodialysis for refractory or life-threatening cases

• Underlying cause:
  • Stop/adjust contributing drugs (e.g., RAAS inhibitors, K⁺-sparing diuretics)
  • Manage renal dysfunction or other precipitating conditions

References

• Clark BA, Brown RS. Potassium homeostasis and hyperkalemic syndromes. Endocrin Metab Clin North Am 1995; 24:573–91.
• Gennary FJ. Hypokalemia. N Eng J Med 1998; 339:451–7.
• Halperin ML. Electrolyte quintet: potassium. Lancet 1998; 352: 135–40.
• Shaer AJ. Inherited primary renal tubular hypokalemic alkalosis: a review of Gitelman and Bartter syndromes. Am J Med Sci 2001; 322:316–32.
• Stewart PM. Mineralocorticoid hypertension. Lancet 1999; 353: 1341–7.
• Warnock DG. Renal genetic disorders related to K and Mg. Ann Rev Physiol 2002; 64:845–76.