Clinical manifestations and evaluation of metabolic alkalosis

INTRODUCTION — Metabolic alkalosis, which is usually accompanied by hypokalemia, is defined as a disorder that causes elevations in the serum bicarbonate concentration and arterial pH. In a patient with an uncomplicated (simple) metabolic alkalosis, both parameters are above normal. However, this may not be present in patients with mixed acid-base disorders. (See "Simple and mixed acid-base disorders".)

The pathogenesis of metabolic alkalosis requires, sequentially, both the development or generation of alkalosis (related to the source of the additional bicarbonate) and the maintenance of the metabolic alkalosis (related to why the disorder persists and is not corrected by renal excretion of the excess bicarbonate). These issues are discussed in detail in other topics (see "Pathogenesis of metabolic alkalosis" and "Causes of metabolic alkalosis") but are briefly reviewed here:

●An elevation in the serum bicarbonate concentration is due to excessive hydrogen ion loss in the urine or gastrointestinal tract; hydrogen ion movement into cells; administration of sodium or potassium bicarbonate or the sodium or potassium salt of an organic anion, such as citrate or lactate, that is metabolized and thereby generates bicarbonate; and/or volume contraction around a relatively constant amount of extracellular bicarbonate (called a contraction alkalosis). This is called the "generation phase" of metabolic alkalosis.

●An inability to excrete the excess bicarbonate in the urine is due to intravascular volume contraction, reduced effective arterial blood volume (including heart failure and cirrhosis), chloride depletion, hypokalemia, kidney function impairment, or combinations of these factors. This is called the "maintenance phase" of metabolic alkalosis [1-3].

Patients with metabolic alkalosis usually develop respiratory compensation characterized by hypoventilation and an elevation in arterial PCO2. This lowers the arterial pH toward normal. However, the beneficial pH effect of hypoventilation is blunted because the elevation in arterial PCO2 increases renal acid excretion, producing a further rise in serum bicarbonate [4]. These issues are discussed in detail elsewhere. (See "Simple and mixed acid-base disorders", section on 'Response to metabolic alkalosis' and "Simple and mixed acid-base disorders", section on 'Compensatory respiratory and renal responses'.)

The clinical manifestations and evaluation of the patient with metabolic alkalosis will be reviewed here. The causes, pathogenesis, and treatment of metabolic alkalosis are presented separately. (See "Causes of metabolic alkalosis" and "Pathogenesis of metabolic alkalosis" and "Treatment of metabolic alkalosis".)

CLINICAL FEATURES

Symptoms — Patients with metabolic alkalosis may be asymptomatic or may complain of symptoms that are primarily related to the alkalemia, to the underlying etiology of the metabolic alkalosis, or to accompanying electrolyte abnormalities. Symptoms can, for example, be due to volume depletion (which may produce lassitude, easy fatigability, muscle cramps, and postural dizziness) and hypokalemia (which may produce muscle weakness, cardiac arrhythmias, and, if persistent, polyuria and polydipsia due to impaired urinary concentrating ability and/or direct stimulation of thirst). (See "Etiology, clinical manifestations, and diagnosis of volume depletion in adults", section on 'Symptoms related to volume depletion' and "Clinical manifestations and treatment of hypokalemia in adults", section on 'Manifestations of hypokalemia'.)

Clinical manifestations directly related to the metabolic alkalosis are uncommon. This is in contrast to paresthesias, carpopedal spasm, and lightheadedness that often occur in acute respiratory alkalosis (see "Hyperventilation syndrome in adults"). This difference is probably related to several factors. Metabolic alkalosis probably causes a smaller change in intracellular pH and brain pH than acute respiratory alkalosis because rapid shifts in arterial CO2 tension are almost immediately transmitted throughout the total body water, including the intracellular fluid compartment, the brain, and the cerebrospinal fluid. By contrast, alterations in blood HCO3 concentration cause slower and less pronounced pH changes within the intracellular compartments and across the blood-brain barrier.

Muscular spasms, tetany, and paresthesia can occur with severe metabolic alkalosis [5-7], but these findings are most likely to occur when the ionized calcium and magnesium concentrations are also reduced (as in Bartter syndrome, Gitelman syndrome, chronic diuretic use). Severe metabolic alkalosis can cause agitation, disorientation, seizures, and coma [5-8], especially when metabolic alkalosis develops in patients with chronic liver disease. In such patients, the alkaline systemic pH will increase the blood concentration of unionized nitrogen compounds such as ammonia, which enhances their penetration into the central nervous system and thereby enhances neurotoxicity. (See "Hepatic encephalopathy in adults: Treatment", section on 'Commonly used treatments'.)

Physical examination — Abnormal findings on physical examination, when present, reflect the cause of the metabolic alkalosis. Hypovolemic patients (eg, vomiting, diuretic therapy for hypertension) may have signs of extracellular and intravascular volume depletion, such as reduced skin turgor, low-estimated jugular venous pressure, and postural hypotension. By contrast, patients with effective arterial blood volume depletion due to heart failure or cirrhosis who develop metabolic alkalosis (most often due to diuretic therapy) may have peripheral edema, ascites, and/or, in heart failure, pulmonary edema.

Arterial blood gases — Metabolic alkalosis is associated with a respiratory compensation that should raise the PCO2 by approximately 0.7 mmHg for every 1 mEq/L elevation in the plasma bicarbonate concentration, thereby minimizing the increase in arterial pH. These issues are discussed in detail elsewhere. (See "Simple and mixed acid-base disorders", section on 'Response to metabolic alkalosis' and "Simple and mixed acid-base disorders", section on 'Compensatory respiratory and renal responses'.)

EVALUATION

The cause is usually apparent from the history — The most common causes of metabolic alkalosis are external loss of gastric secretions due to vomiting or nasogastric suction and diuretic therapy. These and other causes of metabolic alkalosis (table 1) are often apparent from the history. (See "Causes of metabolic alkalosis".)

When the cause is not apparent from the history — The etiology of metabolic alkalosis is not always apparent from the history. Several examples include:

●Patients who are unwilling or unable to report vomiting or diuretic ingestion. Self-induced vomiting and surreptitious diuretic or laxative abuse associated with the anorexia nervosa-bulimia nervosa spectrum are relatively common and must always be considered in patients with unexplained metabolic alkalosis, especially in women. Dental pathology (due to hydrochloric acid-induced decalcification), parotitis, and chronic traumatic lesions on the fingers and hands strongly suggest a diagnosis of surreptitious vomiting. (See "Bulimia nervosa and binge eating disorder in adults: Medical complications and their management", section on 'Dental' and "Bulimia nervosa and binge eating disorder in adults: Medical complications and their management", section on 'Skin'.)

●The history may not be helpful in patients with metabolic alkalosis due to primary mineralocorticoid excess syndromes (most often, primary aldosteronism), disorders that mimic mineralocorticoid excess including glycyrrhizic acid (licorice) ingestion, ectopic adrenocorticotropic hormone (ACTH) syndrome, the syndrome of apparent mineralocorticoid excess, and genetic disorders involving renal tubular transport such as Bartter, Gitelman, or Liddle's syndrome. Primary aldosteronism and its mimics are usually associated with hypertension and mild volume expansion due to the stimulatory effect of aldosterone on sodium reabsorption, whereas patients with vomiting, diuretic therapy, Bartter syndrome, and Gitelman syndrome usually present with volume contraction and relatively low blood pressure. (See "Causes of metabolic alkalosis" and "Pathophysiology and clinical features of primary aldosteronism" and "Inherited hypokalemic salt-losing tubulopathies: Pathophysiology and overview of clinical manifestations" and "Apparent mineralocorticoid excess syndromes (including chronic licorice ingestion)" and "Genetic disorders of the collecting tubule sodium channel: Liddle syndrome and pseudohypoaldosteronism type 1".)

●Diarrhea typically generates a metabolic acidosis. However, certain conditions associated with diarrhea may produce a metabolic alkalosis:

•Laxative abuse, which is often denied by the patient. (See "Factitious diarrhea: Clinical manifestations, diagnosis, and management".)

•Villous adenoma. (See "Acid-base and electrolyte abnormalities with diarrhea".)

•Congenital chloridorrhea, which is a rare hereditary disorder that produces hypokalemia and metabolic alkalosis as a result of chronic, watery, chloride-rich diarrhea. The cause is a mutation in the solute carrier family 26 member 3 (SLC26A3) gene. This gene directs synthesis of an intestinal chloride-bicarbonate exchanger located in the apical mucosa of the lower intestinal tract. It normally reabsorbs chloride and secretes bicarbonate into the intestinal lumen. The exchanger has several different names including the "intestinal chloride-bicarbonate exchanger," the "chloride diarrhea anion exchanger (CLD)," and the "downregulated-in-adenoma (DRA)" transporter. (See "Acid-base and electrolyte abnormalities with diarrhea" and "Approach to chronic diarrhea in neonates and young infants (<6 months)", section on 'Congenital diarrheas and enteropathies'.)

•The alkalosis in these conditions is in part related to relatively high stool chloride and potassium concentrations, resulting in potassium depletion and hypokalemia. The loss of ammonium chloride and other organic chloride salts in the stool generates systemic bicarbonate. Intermittently, the renal loss of bicarbonate together with secondary hyperaldosteronism also generates renal potassium losses. Hypokalemia stimulates the generation and excretion of ammonium chloride by the kidney, which generates systemic bicarbonate [1,9-11]. In addition, hypokalemia causes potassium to move from the intracellular to the extracellular fluid, and this transcellular potassium flux moves extracellular hydrogen ions into cells to maintain electroneutrality. These ion fluxes simultaneously increase the plasma bicarbonate concentration but lower the intracellular pH. In renal tubular cells, this intracellular acidosis promotes hydrogen secretion into the lumen and, therefore, bicarbonate reabsorption and generation (figure 1) [12]. The pathophysiology of ion fluxes is discussed in detail separately. (See "Pathogenesis of metabolic alkalosis", section on 'Hypokalemia'.)

Diagnostic approach in unexplained metabolic alkalosis — When the etiology of metabolic alkalosis is not apparent from the history and physical examination, measurement of a spot urine chloride, urine sodium, and urine pH can be helpful.

Disorders associated with a low urine chloride concentration (less than 20 mEq/L)

Vomiting or nasogastric suction — The spot urine chloride concentration is persistently low in metabolic alkalosis due to vomiting or nasogastric suction, reflecting both hypovolemia and the associated hypochloremia (unless the patient is also ingesting diuretics) [13,14]. This reflects the extracellular fluid volume contraction and chloride depletion that exist in these patients. In contrast, the urine sodium concentration often fluctuates in these patients. The hypovolemia stimulates renal tubule sodium reabsorption, reducing the urine sodium concentration. However, the urine sodium concentration may increase intermittently despite persistent volume contraction because the high serum bicarbonate concentration and high-filtered bicarbonate load will intermittently exceed the renal bicarbonate reabsorptive capacity. When this occurs, the loss of bicarbonate into the urine must be accompanied by an equimolar quantity of cations, mainly sodium and potassium [13-15]. At these times, the urine pH is high, generally greater than 6.5, and the urine sodium and potassium concentrations increase. However, the urine chloride concentration remains low. This is further described by the following sequence:

Gastric alkalosis is usually effectively treated with intravenous isotonic saline plus potassium infusion. When saline expands the extracellular volume, sodium bicarbonate is excreted in the urine and the infused chloride is retained. The bicarbonate concentration falls and the chloride concentration increases. Restoration of the extracellular volume is signaled by a rise in the urine chloride concentration.

Diuretic-induced alkalosis — Diuretics that block sodium chloride reabsorption (thiazide and loop diuretics) produce a high urine chloride concentration when they are active. However, the urine chloride concentration falls to low levels when the diuretic effect has dissipated. Thus, patients who surreptitiously take diuretics will often have wide swings in the urine chloride concentration from day to day as the diuretic effect waxes and wanes. This finding in a patient with metabolic alkalosis is virtually diagnostic of diuretic use.

Other causes of metabolic alkalosis associated with low urine chloride concentration — The urine chloride can be low with other forms of metabolic alkalosis associated with extracellular fluid volume contraction and chloride depletion. As examples, the urine chloride is usually low when metabolic alkalosis develops in patients with laxative abuse, cystic fibrosis with excessive sweating (loss of a large volume of chloride-rich sweat) [16], congenital chloride diarrhea [17], and in infants given a chloride-deficient synthetic formula [18].

Settings in which the urine chloride is not low (greater than 20 mEq/L) — In contrast to the low urine chloride concentration in most patients with metabolic alkalosis who are hypovolemic, the urine chloride concentration is not low (greater than 20 mEq/L and often greater than 40 mEq/L) when metabolic alkalosis exists in patients who are volume expanded due to the various forms of primary mineralocorticoid excess or a disorder that mimics mineralocorticoid excess. Examples include:

●Primary hyperaldosteronism

●Liddle's syndrome

●Excess licorice ingestion (glycyrrhizic acid)

●Apparent mineralocorticoid excess syndrome

Such patients are usually hypertensive. These disorders and the diagnostic approach to the patient with hypertension and hypokalemia are discussed elsewhere. (See "Pathophysiology and clinical features of primary aldosteronism" and "Diagnosis of primary aldosteronism" and "Genetic disorders of the collecting tubule sodium channel: Liddle syndrome and pseudohypoaldosteronism type 1" and "Apparent mineralocorticoid excess syndromes (including chronic licorice ingestion)".)

Another group of disorders that generate metabolic alkalosis associated with persistently high urine chloride concentrations are those caused by genetic mutations that mimic the effect of loop and/or thiazide diuretics. (Bartter and Gitelman syndromes are the classic examples.) The mutations producing these disorders directly or indirectly reduce the activity of the sodium and chloride transporters that are inhibited by loop or thiazide diuretics. However, unlike diuretics, which are usually taken intermittently, these defects are persistent. Thus, they generate persistent renal salt wasting and a persistently high renal chloride concentration despite systemic volume contraction. Such patients are relatively hypovolemic and hypotensive (table 1). (See "Inherited hypokalemic salt-losing tubulopathies: Pathophysiology and overview of clinical manifestations".)

In addition, marked potassium depletion with severe hypokalemia (serum potassium concentration less than 2 mEq/L) can cause metabolic alkalosis with a high urine chloride concentration. It is believed that the severe potassium depletion can reversibly impair renal tubular chloride reabsorption, leading to a rise in urinary chloride excretion that is independent of volume status. This form of metabolic alkalosis does not improve with sodium chloride volume expansion but resolves with potassium repletion [19].

Utility of urine chemistries in metabolic alkalosis — The usefulness of the urine chloride concentration was illustrated in a study that included 25 adult patients with unexplained metabolic alkalosis and hypokalemia: The final diagnosis was diuretic abuse in 5, surreptitious vomiting in 8, and suspected Bartter or Gitelman syndrome in 12 [20]. The following findings were noted:

●The mean urine chloride concentration was 1.3 mEq/L in the patients with surreptitious vomiting, 76 mEq/L with diuretic abuse, and 230 mEq/L with suspected Bartter or Gitelman syndrome. The urine chloride concentration in those with diuretic abuse would be expected to be much lower if measured after the diuretic effect had worn off.

●The mean urine sodium concentration was 73 mEq/L with diuretic abuse and 160 mEq/L with suspected Bartter syndrome. The mean urine sodium concentration was 90 mEq/L in the patients with surreptitious vomiting, illustrating that the urine sodium concentration may be elevated despite hypovolemia in some patients with metabolic alkalosis.

Hypokalemia — Patients with metabolic alkalosis frequently have concurrent hypokalemia. This is usually due to urinary potassium losses, even in patients with vomiting (the potassium concentration in gastric secretions is only 5 to 10 mEq/L and, therefore, not high enough to generate hypokalemia) [15]. The increase in sodium bicarbonate delivery to the cortical collecting tubule (where potassium is secreted) combines with increased aldosterone activity (due to either hypovolemia or primary excess) to promote sodium reabsorption and potassium (and proton) secretion at this site (figure 2). The physiology is reviewed in detail elsewhere. (See "Potassium balance in acid-base disorders", section on 'Metabolic alkalosis'.)

SUMMARY

●Metabolic alkalosis, which is usually accompanied by hypokalemia, is defined as a disorder that causes elevations in the serum bicarbonate concentration and arterial pH. The pathogenesis of metabolic alkalosis requires both the development and generation of alkalosis (related to the source of the additional bicarbonate) and the maintenance of the metabolic alkalosis (related to why the disorder persists and is not corrected by renal excretion of the excess bicarbonate) (see 'Introduction' above):

•An elevation in the serum bicarbonate concentration is due to hydrogen ion loss in the urine or gastrointestinal tract; hydrogen ion movement into cells; the administration of sodium or potassium bicarbonate or the sodium or potassium salt of an organic anion, such as citrate or lactate, that is metabolized and thereby generates bicarbonate; and/or volume contraction around a relatively constant amount of extracellular bicarbonate (called a contraction alkalosis). This is called the "generation phase" of metabolic alkalosis.

•An inability to excrete the excess bicarbonate in the urine is due to intravascular volume depletion, reduced effective arterial blood volume (including heart failure and cirrhosis), chloride depletion, hypokalemia, kidney function impairment, or combinations of these factors. This is called the "maintenance phase" of metabolic alkalosis.

●Patients with metabolic alkalosis may be asymptomatic or may complain of symptoms that are primarily related to either the underlying etiology of the alkalosis (eg, volume depletion) or accompanying electrolyte abnormalities (eg, hypokalemia). Metabolic alkalosis due to Bartter or Gitelman syndrome or chronic diuretic use can be associated with neuromuscular irritability, spasms, and tetany. This may also occur with severe metabolic alkalosis of other etiologies. Abnormal findings on physical examination, when present, may reflect the cause of the metabolic alkalosis. (See 'Clinical features' above.)

●The two most common causes of metabolic alkalosis are loss of gastric secretions due to vomiting or nasogastric suction and diuretic therapy. These and other causes of metabolic alkalosis (table 1) are often apparent from the history. However, the etiology of metabolic alkalosis is not always apparent from the history. Several examples include (see 'When the cause is not apparent from the history' above):

•Patients who are unwilling or unable to report vomiting or diuretic ingestion such as those with self-induced vomiting and or surreptitious diuretic or laxative abuse.

•Patients with metabolic alkalosis due to primary mineralocorticoid excess syndromes (most often, primary aldosteronism), disorders that mimic mineralocorticoid excess such as glycyrrhizic acid (licorice) ingestion, ectopic adrenocorticotropic hormone (ACTH) syndrome, the syndrome of apparent mineralocorticoid excess, and genetic disorders involving renal tubular electrolyte transport such as Bartter, Gitelman, or Liddle's syndrome.

•Patients with certain causes of chloride-rich diarrhea, villous adenoma, and congenital chloridorrhea.

●When the etiology of metabolic alkalosis is not apparent from the history and physical examination, measurement of the urine chloride, urine sodium, and urine pH can be helpful. (See 'Diagnostic approach in unexplained metabolic alkalosis' above.)

●The spot urine chloride concentration is always appropriately low (less than 20 mEq/L and often below 10 mEq/L) when metabolic alkalosis is due to vomiting or nasogastric suction, reflecting hypovolemia, chloride depletion, and hypochloremia. Although the spot urine sodium concentration is also often reduced to less than 20 mEq/L as a result of the volume depletion, it is less reliable than the urine chloride because it increases intermittently when bicarbonaturia occurs (and sodium and potassium are excreted to maintain electroneutrality). Under those conditions, the urine pH exceeds 7. However, the urine chloride concentration is persistently reduced whether or not bicarbonaturia exists, and it is therefore a superior indicator of volume status. (See 'Vomiting or nasogastric suction' above.)

●Metabolic alkalosis with a low urine chloride also occurs in patients who use diuretics (but only after the diuretic effect has dissipated). Thus, patients who surreptitiously take diuretics will often have wide swings in the urine chloride concentration as the diuretic effect waxes and wanes. This finding in a patient with metabolic alkalosis is virtually diagnostic of diuretic use. (See 'Diuretic-induced alkalosis' above.)

●The urine chloride concentration may be low when metabolic alkalosis develops in patients with laxative abuse, cystic fibrosis with excessive sweating (loss of a large volume of chloride-rich sweat), congenital chloride diarrhea, and in infants given a chloride-deficient synthetic formula. (See 'Other causes of metabolic alkalosis associated with low urine chloride concentration' above.)

●In contrast to the low urine chloride concentration in most patients with metabolic alkalosis who are hypovolemic, the urine chloride concentration is not low (it is usually greater than 40 mEq/L) in patients who are taking loop or thiazide diuretics when the drug is still active and inhibiting renal tubule sodium and chloride reabsorption. Similarly, disorders resulting from genetic mutations that cause persistent renal salt wasting, such as Bartter or Gitelman syndrome, also result in elevated urine chloride concentration. These patients will be volume contracted and relatively hypotensive. They are functionally similar to persistently acting loop or thiazide diuretics (table 1). (See 'Settings in which the urine chloride is not low (greater than 20 mEq/L)' above.)

●Metabolic alkalosis with a relatively high urine chloride concentration also occurs in patients with any form of primary mineralocorticoid excess or with the disorders that mimic mineralocorticoid excess (table 1). Under these conditions, the patients are generally volume expanded and hypertensive. (See 'Settings in which the urine chloride is not low (greater than 20 mEq/L)' above.)