Acid-base and electrolyte abnormalities with diarrhea

INTRODUCTION — Diarrhea can cause a variety of fluid volume, acid-base, and electrolyte abnormalities. The alterations in serum chemistries that can occur, their etiologic mechanisms, and the issues related to diagnosis and treatment are reviewed in this topic.

FLUID AND ELECTROLYTE CONTENT OF NORMAL STOOL — The composition of normal and diarrheal stool must be known in order to understand the consequences of diarrhea:

●Normal stool has an alkaline pH.

●Sodium and potassium salts are the primary stool solutes. The sodium plus potassium concentration in stool usually ranges between 130 and 150 mEq/L. Other cations, such as calcium and magnesium, are present at much lower concentrations.

●The main inorganic stool anions are bicarbonate (approximately 30 mEq/L), chloride (approximately 10 to 20 mEq/L), and a small amount of phosphate and sulfate.

●Various organic acid anions (eg, propionate and butyrate, approximately 80 to 90 mEq/L) account for most of the anions in normal stool [1-4].

Organic acid anions represent "decomposed bicarbonate" and can also be considered "potential bicarbonate." When bicarbonate salts enter the colon and encounter strong organic acids, such as lactic and butyric acid, which have been produced by bacterial fermentation of non-absorbed food, mainly carbohydrates, the bicarbonate is titrated by the dissociated hydrogen ions to form carbon dioxide and water (ie, decomposition of bicarbonate). What remain are sodium and potassium salts of the organic acid anions. These organic acid anions also represent "potential bicarbonate" because, if they are absorbed, they will be converted back to bicarbonate by the body. Thus, losing these organic anions in the stool as sodium or potassium salts has the same acid-base effect as losing sodium or potassium bicarbonate.

●Stool water osmolality is similar to the osmolality of serum (approximately 300 mOsm/kg). Although the stomach is capable of maintaining an osmotic gradient, more distal segments of the bowel are permeable to water, and therefore, the luminal contents are in osmotic equilibrium with the serum by the time the fluid has passed the ligament of Treitz [1-4].

It must be emphasized that, normally, only approximately 100 mL of water is excreted in the stool each day. Thus, despite the high stool electrolyte concentrations, only approximately 4 mEq of sodium and 9 mEq of potassium are lost in normal stool each day, and the total daily loss of bicarbonate plus organic acid anion salts is only approximately 11 mEq/day [1,2,4].

FLUID, ELECTROLYTE, AND NON-ELECTROLYTE CONTENT OF DIARRHEA — When diarrhea develops, stool osmolality remains similar to serum (approximately 300 mOsm/L). Depending upon the etiology of the diarrhea, osmotically active solutes in diarrheal stool may be electrolytes, magnesium salts, phosphate salts, substances derived from carbohydrates such as mannitol, sorbitol, or lactulose, the bacterial fermentation products of these substances (ie, lactic, butyric, acetic acid, and others), large synthetic molecules such as polyethylene glycol (PEG), and combinations of these substances. Some forms of diarrhea may be primarily due to fat malabsorption (ie, steatorrhea); stool volumes in such patients are generally small but may increase markedly if the steatorrhea is also associated with carbohydrate malabsorption.

The origin of osmotically active molecules in stool may be endogenous, exogenous, or both. Examples of diarrhea due to loss of endogenous osmotic molecules include:

●Cholera toxin or enteropathic Escherichia coli causes secretory diarrhea by increasing intestinal secretion of sodium, potassium, chloride, and bicarbonate, and by variably impairing their reabsorption. These ions are then eliminated with enough water to create stool with an osmolality of approximately 300 mOsm/L. The diarrhea generated by Clostridioides difficile infection (CDI) can also have a major secretory etiology.

●Certain tumors secrete hormones such as vasoactive intestinal peptide (VIP) that can cause marked gastrointestinal electrolyte secretion and massive, watery, electrolyte-rich diarrhea.

●A mutation in a gastrointestinal chloride-bicarbonate exchanger causes the loss of endogenous chloride salts and a chloride-rich diarrhea (congenital chloridorrhea).

Examples of diarrhea due to loss of exogenous osmotic molecules include:

●Ingestion of poorly absorbed carbohydrates, such as lactose (in lactase-deficient patients), lactulose, sorbitol, or mannitol, generates diarrhea that is relatively electrolyte poor.

●Ingestion of high doses of magnesium or phosphate salts overwhelm gastrointestinal absorptive processes, thereby causing diarrhea in which the major osmotically active agent is the ingested salt.

ACID-BASE, ELECTROLYTE, AND VOLUME ABNORMALITIES ASSOCIATED WITH DIARRHEA — Common derangements that can result from diarrhea include the following:

●Hypovolemia, which can reduce glomerular filtration rate, and, when severe, generate shock (see 'Hypovolemia' below)

●Metabolic acidosis (see 'Metabolic acidosis' below)

●Hypokalemia (see 'Hypokalemia' below)

Less commonly, the following abnormalities may be seen:

●Hypernatremia (see 'Hypernatremia' below)

●Metabolic alkalosis (see 'Metabolic alkalosis' below)

Hypovolemia — Because stool water is relatively isotonic and typically electrolyte-rich, large-volume diarrhea can generate marked volume depletion. Volume depletion will stimulate ADH secretion, and if excessive quantities of water are ingested, hyponatremia may develop. (See "Causes of hypotonic hyponatremia in adults".)

The treatment of severe hypovolemia is discussed in detail elsewhere. (See "Treatment of severe hypovolemia or hypovolemic shock in adults".)

Metabolic acidosis — The most common acid-base disorder that develops in patients with diarrhea is metabolic acidosis. Although some bicarbonate is present in stool, it is usually the loss of salts of organic acid anions (eg, propionate, lactate, acetate, and butyrate) that is the most important cause of metabolic acidosis in patients with diarrhea. The loss of large quantities of sodium or potassium salts of organic acid anions (which represent potential bicarbonate) is physiologically equivalent (from an acid-base perspective) to losing equal quantities of sodium or potassium bicarbonate. Because potential bicarbonate usually exceeds actual bicarbonate in diarrheal stool, the stool pH can be acidic. Thus, stool pH is generally of little importance in the determination of how diarrhea will impact systemic acid-base balance. A better index is the mathematical difference between the sum of the stool sodium plus potassium concentration and the stool chloride concentration; this difference approximates the concentration of stool bicarbonate plus organic acid anion salts (potential bicarbonate).

Diarrhea caused by cholera is more commonly associated with high stool concentrations of true bicarbonate. These patients generally have markedly reduced oral intake and therefore limited delivery of carbohydrate and other substrates to the colon. Thus bacterial fermentation products that would react with bicarbonate are limited.

In addition to the loss of potential and actual bicarbonate salts, several other factors often contribute to the metabolic acidosis that develops in patients with diarrhea:

●Hypovolemia will reduce the glomerular filtration rate and accelerate renal salt reabsorption. The resulting decrease in sodium delivery to the distal tubule impairs renal acid excretion. (See "Overview and pathophysiology of renal tubular acidosis and the effect on potassium balance" and 'Evaluating the renal response to metabolic acidosis in patients with diarrhea' below.)

●Severe hypovolemia reduces tissue perfusion and can generate an element of lactic acidosis. (See "Causes of lactic acidosis".)

●If the diarrhea is associated with prolonged anorexia and fasting, ketoacidosis may develop. (See "Fasting ketosis and alcoholic ketoacidosis".)

Serum anion gap in patients with metabolic acidosis due to diarrhea — Patients with large-volume diarrhea who lose a large amount of bicarbonate and potential bicarbonate (eg, propionate, butyrate, lactate, citrate salts) will generally develop a normal anion gap (ie, hyperchloremic) acidosis. (See "Approach to the adult with metabolic acidosis".)

However, severe diarrhea with volume depletion can also cause a high anion gap acidosis as a result of the following [5,6]:

●Lactic acidosis, which can result from decreased tissue perfusion when severe hypovolemia develops.

●Hyperphosphatemia, which can result from the combination of a reduced glomerular filtration rate and acidemia-induced release of intracellular phosphate into the extracellular fluid.

●Reduced kidney function can increase the concentration of other "unmeasured" acid anions.

●Increased serum albumin concentration, which can result from hemoconcentration; negative charges on albumin constitute a large part of the anion gap, and therefore, high albumin concentrations elevate the anion gap.

Thus, in patients with diarrhea, the fall in the serum bicarbonate concentration may be partially balanced by a rise in chloride concentration and partially by a rise of the anion gap [6]. (See "The delta anion gap/delta HCO3 ratio in patients with a high anion gap metabolic acidosis".)

Evaluating the renal response to metabolic acidosis in patients with diarrhea — The normal renal response to metabolic acidosis is to increase acid excretion. Initially, urine pH falls and titratable acid excretion increases. If the acidosis persists, then renal ammonia synthesis and excretion also increase. In general, if the metabolic acidosis persists for more than several days, the ammonia excretory response to metabolic acidosis exceeds the increase in titratable acid. (See "Urine anion and osmolal gaps in metabolic acidosis", section on 'Brief overview of renal acid excretion'.)

If kidney function and kidney perfusion are normal, then the kidney can largely compensate for major losses of bicarbonate and potential bicarbonate that occur in patients with diarrhea. However, if the diarrhea generates hypovolemia, this will simultaneously reduce glomerular filtration and markedly enhance proximal renal tubule sodium and chloride reabsorption. The resulting decrease in distal tubule sodium chloride delivery reduces renal acid secretion and excretion. (See "Overview and pathophysiology of renal tubular acidosis and the effect on potassium balance".)

The renal response to metabolic acidosis in patients with diarrhea can be evaluated by measuring the changes in creatinine concentration, the urine pH, and the urine sodium concentration. Calculation of the urine anion or osmolal gap may also be helpful in assessing the renal response to diarrhea-induced metabolic acidosis. (See 'Urine pH and urine ammonium and sodium concentrations' below.)

Urine pH and urine ammonium and sodium concentrations — Acute metabolic acidosis should increase distal tubule hydrogen ion secretion and initially reduce urine pH below 5.5. However, if the acidosis persists and becomes chronic, a major increase in urine ammonium excretion will develop. This large increase in urine ammonium will increase the urine pH. The development of potassium depletion and hypokalemia will further increase renal ammonia generation and excretion. High urine ammonia (NH₃) concentrations bind hydrogen ions (H⁺) to form ammonium (NH₄⁺) and thereby raise the urine pH:

Thus, a relatively high urine pH in a patient with chronic metabolic acidosis does not necessarily indicate the existence of a renal acidification defect. (See "Urine anion and osmolal gaps in metabolic acidosis", section on 'Urine anion gap'.)

If the urine pH is relatively high (greater than 5.5) in a patient with diarrhea and metabolic acidosis, measurement or estimation of urine ammonium excretion can be used to determine if the renal response is appropriate. If urine ammonium measurements are not available, a helpful surrogate marker for urine ammonium is the calculated urine osmolal gap [7]. This calculation indirectly estimates the urine ammonium concentration. A high urine ammonium concentration is consistent with a normal renal response to metabolic acidosis, despite a high urine pH. (See "Urine anion and osmolal gaps in metabolic acidosis".)

If the renal response to metabolic acidosis is inadequate, then the urine sodium concentration should be measured. If it is less than 25 mEq/L, inadequate distal sodium chloride delivery due to hypovolemia may be the cause of inadequate renal distal tubule acid secretion and excretion. The evaluation of renal acidification should be repeated after volume status has been restored.

Hypokalemia — The potassium concentration in stool water is normally relatively high. Although the potassium concentration falls as stool volume increases, large-volume diarrhea commonly results in hypokalemia due to stool potassium loss. Hypokalemia can occur with all forms of diarrhea but is especially common with diarrhea due to cholera, certain pancreatic islet cell tumors (VIPomas), villous adenomas, congenital chloride-wasting diarrhea, and laxative abuse [2,3,8]. Some patients with intestinal pseudo-obstruction secrete large amounts of potassium into the colonic fluid and develop marked hypokalemia [9]. (See "Causes of hypokalemia in adults", section on 'Increased gastrointestinal losses'.)

Two common causes of hyperchloremic (ie, normal anion gap) metabolic acidosis and hypokalemia are diarrhea and proximal or distal tubule RTA. The hypokalemia of diarrhea is mainly caused by stool potassium loss (and reduced intake), while the hypokalemia of proximal or distal tubule RTA is due to renal potassium loss. The hypokalemia that develops in patients with congenital chloride-wasting diarrhea is an exception to this paradigm; it is largely due to renal potassium losses. In most cases, measurement of urinary potassium excretion may help to distinguish between gastrointestinal and renal losses of potassium (see "Overview and pathophysiology of renal tubular acidosis and the effect on potassium balance" and "Evaluation of the adult patient with hypokalemia"):

●The hypokalemia that develops in patients with hyperchloremic metabolic acidosis due to proximal or distal tubule RTA is largely due to renal potassium loss, and the urine potassium concentrations are generally greater than 25 mEq/L.

●By contrast, when hypokalemia is due to gastrointestinal loss, the kidney conserves potassium, and the urine potassium concentration is typically less than 25 mEq/L. When severe hypovolemia results in secondary hyperaldosteronism, the urine potassium concentration may increase above 25 mEq/L. However, under those conditions, the urine volume will be low, and therefore, daily urinary potassium excretion will be quite low despite the relatively high potassium concentration. The daily potassium excretion rate can be measured with a 24-hour urine collection or estimated using the urine potassium-to-creatinine ratio [10].

Hypernatremia — Diarrhea is sometimes due to the presence of non-electrolyte, osmotically active substances in the stool, such as carbohydrates or organic anion salts generated by bacterial metabolism of carbohydrates. This can occur in patients with malabsorption, or after ingestion of nonabsorbable carbohydrates such as mannitol, sorbitol, or lactulose. In addition, ingestion of other non-carbohydrate, non-electrolyte substances such as polyethylene glycol (PEG) can also generate diarrhea. These osmotically active substances obligate enough water to maintain the osmolality of the gastrointestinal lumen and stool at approximately 300 mOsm/L (ie, similar to serum).

Since the osmolality of stool water in these conditions is largely due to non-electrolytes, the diarrhea represents the loss of electrolyte-free water. Large-volume diarrhea due to these mechanisms, with large electrolyte-free water loss, can generate hypernatremia [1-3,11,12]. However, the development of hypernatremia is uncommon in such patients if they have access to water and are able to respond normally to thirst. Hypernatremia may develop in those who do not experience or respond to thirst normally, such as patients with impaired mental status or infants who experience thirst but require others to provide fluid intake. (See "Etiology and evaluation of hypernatremia in adults".)

Metabolic alkalosis — Although uncommon, some patients with diarrhea develop metabolic alkalosis rather than metabolic acidosis. This occurs in a rare disease called congenital chloride wasting diarrhea (congenital chloridorrhea) (see 'Congenital chloride wasting diarrhea' below). It can also develop in patients who chronically abuse laxatives. (See 'Laxative abuse' below.)

Congenital chloride wasting diarrhea — Metabolic alkalosis and hypokalemia occur in patients with congenital chloride wasting diarrhea (congenital chloridorrhea). This disorder is due to a mutation in the "down-regulated in adenoma," or the DRA, gene that encodes an intestinal Cl^-/HCO3^- exchanger (SLC26A3) that normally absorbs chloride from the intestinal lumen and secretes bicarbonate.

The mutation markedly reduces the activity of this chloride-bicarbonate exchanger and results in very high stool chloride concentrations (>100 mEq/L). The stool chloride concentration generally exceeds the sum of the stool sodium and potassium concentrations. The difference between stool chloride and the sum of sodium and potassium is largely ammonium (NH4) and organic cations. The excretion of chloride salts of NH4 and organic cations in the stool generates a systemic alkali load and results in metabolic alkalosis [13,14]. These patients also become hypokalemic and potassium depleted because they lose potassium (with bicarbonate) in the urine. The mechanism of urinary potassium loss in this disorder is similar to that responsible for the loss of urine potassium that occurs with vomiting and other gastric fluid losses. (See "Causes of hypokalemia in adults", section on 'Upper gastrointestinal losses'.)

The etiology and treatment of this disorder are discussed in greater detail elsewhere. (See "Approach to chronic diarrhea in neonates and young infants (<6 months)", section on 'Evaluation for suspected congenital diarrheas and enteropathies'.)

Laxative abuse — Chronic laxative abuse can produce chronic hypovolemia and hypokalemia. Such patients may develop metabolic acidosis, metabolic alkalosis, or have no systemic acid-base disorder [15-17].

When metabolic alkalosis develops, it is probably generated by the combination of severe hypokalemia, potassium depletion, and hypovolemia. Hypokalemia generates and maintains metabolic alkalosis via a number of mechanisms (see "Potassium balance in acid-base disorders"):

●Hypokalemia causes a shift of potassium from the intracellular fluid (ICF) to the extracellular fluid (ECF) and simultaneous movement of hydrogen ions from the ECF into the ICF. This produces a relative intracellular acidosis (including acidification of the cells of the proximal and distal tubules) and increases the extracellular bicarbonate concentration.

●Intracellular acidosis in proximal tubule cells increases ammonia generation and secretion into the renal tubule.

●Intracellular acidosis in distal tubule cells stimulates hydrogen ion secretion, which increases renal excretion of both titratable acid and ammonium. Hydrogen ion secretion causes bicarbonate reabsorption and bicarbonate generation (figure 1).

●Hypokalemia also increases distal tubule acidification by stimulating hydrogen-potassium exchange via the distal tubule H-K-ATPase exchanger, which reabsorbs and thereby conserves potassium when it secretes hydrogen ions (figure 1) [18].

●Although several reports hypothesize that severe hypokalemia may produce an acquired form of intestinal chloridorrhea, this remains unproven [14]. (See 'Congenital chloride wasting diarrhea' above.)

Another important consideration is that a patient who surreptitiously ingests laxatives may also be surreptitiously taking diuretics, which can generate metabolic alkalosis.

Thus, occult, or surreptitious, laxative abuse should be considered when patients present with unexplained hypokalemia. Their acid-base status may be normal, or they may have a metabolic acidosis (usually hyperchloremic) or a metabolic alkalosis. (See "Evaluation of the adult patient with hypokalemia".)

If the laxative contains magnesium salts, then hypermagnesemia may develop. Magnesium-induced diarrhea can occasionally develop in patients who ingest magnesium-rich antacids or food supplements [11,17]. (See "Factitious diarrhea: Clinical manifestations, diagnosis, and management".)

If surreptitious laxative-related diarrhea is suspected, stool and/or urine can be analyzed for laxatives. However, the assays for senna and bisacodyl, two common ingredients in readily available laxatives, are unreliable [19]. Although a room search for laxatives (and diuretics) can be diagnostic, it is a procedure which raises significant legal and ethical issues. (See "Factitious diarrhea: Clinical manifestations, diagnosis, and management", section on 'Evaluation'.)

TREATMENT — The treatment of diarrhea and the common, associated acid-base and electrolyte abnormalities are discussed in other topics:

●Treatment of diarrhea (see "Approach to the adult with acute diarrhea in resource-limited settings" and "Approach to the adult with acute diarrhea in resource-abundant settings" and "Oral rehydration therapy")

●Treatment of hypovolemia (see "Treatment of hypovolemia (dehydration) in children in resource-abundant settings" and "Maintenance and replacement fluid therapy in adults" and "Treatment of severe hypovolemia or hypovolemic shock in adults")

●Treatment of metabolic acidosis (see "Approach to the child with metabolic acidosis" and "Approach to the adult with metabolic acidosis")

●Treatment of hypokalemia (see "Clinical manifestations and treatment of hypokalemia in adults")

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Fluid and electrolyte disorders in adults".)

SUMMARY

●Knowledge of the composition of normal stool water and of diarrheal stool water is necessary to understand the impact of diarrhea on body fluids, electrolytes, and acid-base status. (See 'Fluid and electrolyte content of normal stool' above and 'Fluid, electrolyte, and non-electrolyte content of diarrhea' above.)

●Common derangements that can result from diarrhea include the following (see 'Acid-base, electrolyte, and volume abnormalities associated with diarrhea' above):

•Hypovolemia, which, if combined with excessive water ingestion, can result in hyponatremia (see 'Hypovolemia' above)

•Metabolic acidosis, usually with a normal anion gap (see 'Metabolic acidosis' above)

•Hypokalemia (see 'Hypokalemia' above)

●Less commonly, the following abnormalities may be seen in patients with diarrhea (see 'Acid-base, electrolyte, and volume abnormalities associated with diarrhea' above):

•Hypernatremia, which can occur in patients with electrolyte-poor diarrhea who do not experience or respond to thirst normally (see 'Hypernatremia' above)

•Metabolic alkalosis, which can be seen in patients with congenital chloride wasting diarrhea and in some patients who chronically abuse laxatives (see 'Metabolic alkalosis' above)

●The treatment of diarrhea and the common, associated acid-base and electrolyte abnormalities are discussed elsewhere. (See "Approach to the adult with acute diarrhea in resource-limited settings" and "Approach to the adult with acute diarrhea in resource-abundant settings" and "Oral rehydration therapy" and "Treatment of hypovolemia (dehydration) in children in resource-abundant settings" and "Maintenance and replacement fluid therapy in adults" and "Treatment of severe hypovolemia or hypovolemic shock in adults" and "Approach to the child with metabolic acidosis" and "Approach to the adult with metabolic acidosis" and "Clinical manifestations and treatment of hypokalemia in adults".)