What causes chloride-resistant metabolic alkalosis?

Updated: Dec 10, 2020
  • Author: Christie P Thomas, MBBS, FRCP, FASN, FAHA; Chief Editor: Vecihi Batuman, MD, FASN  more...
  • Print

Causes of chloride-resistant alkalosis can be divided into those associated with hypertension and those associated with hypotension or normotension. The former may result from primary hyperaldosteronism, as well as a variety of acquired and hereditary disorders. An adrenal adenoma (most common), bilateral adrenal hyperplasia, or an adrenal carcinoma may cause primary hyperaldosteronism. [5]

Another cause of primary hyperaldosteronism is glucocorticoid-remediable aldosteronism (see Hyperaldosteronism, Familial, Type 1 [OMIM]), an autosomal dominant disorder, in which ectopic production of aldosterone in the zona fasciculata of the adrenal cortex occurs. In this case, aldosterone production is controlled by adrenocorticotropic hormone (ACTH) rather than angiotensin II and potassium, its principal regulators. This type of primary hyperaldosteronism responds to glucocorticoid therapy, which inhibits aldosterone secretion by suppressing ACTH.

The mineralocorticoid receptor (MR) in the collecting duct usually is responsive to both aldosterone and cortisol. Cortisol has a higher affinity for the MR and circulates at a higher concentration than aldosterone. Under physiological conditions, however, the enzyme 11-beta-hydroxysteroid dehydrogenase type 2 (11B-HSD2) inactivates cortisol to cortisone in the collecting duct, allowing aldosterone free access to its receptor.

Deficiency of this enzyme leads to occupation and activation of the MR by cortisol, which, like aldosterone, then stimulates the ENaC. Cortisol behaves as a mineralocorticoid under these circumstances.

11B-HSD2 deficiency may be inherited as an autosomal recessive trait (see Cortisol 11-Beta-Ketoreductase Deficiency [OMIM]), manifesting as syndrome of apparent mineralocorticoid excess (AME). The enzyme may be inhibited by glycyrrhizic acid, which is found in licorice and chewing tobacco, or carbenoxolone, which is a synthetic derivative of glycyrrhizinic acid. Deficiency or inhibition of 11B-HSD2 causes hypertension with low renin and low aldosterone, hypokalemia, and metabolic alkalosis. Serum cortisol is within the reference range because the negative feedback of cortisol on adrenocorticotropic hormone (ACTH) is intact.

Active use of thiazides or loop diuretics in hypertension is the most common cause of metabolic alkalosis in hypertensive patients. The mechanism of alkalosis is discussed above.

The enhanced mineralocorticoid effect in Cushing syndrome is caused by occupation of the MR by the high concentration of cortisol. Hypokalemia and metabolic alkalosis are more common in Cushing syndrome caused by ectopic ACTH production (90%) than in other causes of Cushing syndrome (10%). This difference is related to the higher concentration of plasma cortisol and the defective 11B-HSD activity found in ectopic ACTH production.

Liddle syndrome (see Liddle Syndrome [OMIM]) is a rare autosomal dominant disorder arising from a gain-of-function mutation in the beta (SCNN1B) or gamma subunit (SCNN1G) of the ENaC in the collecting duct. The channel behaves as if it is permanently open, and unregulated reabsorption of Na+ occurs, leading to volume expansion and hypertension. This unregulated Na+ reabsorption is responsible for secondary renal hydrogen ion and potassium ion losses and persists despite suppression of aldosterone.

Significant unilateral or bilateral renal artery stenosis stimulates the renin-angiotensin-aldosterone system, leading to hypertension and hypokalemic metabolic alkalosis.

Renin- or deoxycorticosterone-secreting tumors are rare. In renin-secreting tumors, excessive amounts of renin are secreted by tumors in the juxtaglomerular apparatus, stimulating aldosterone secretion. In the latter, deoxycorticosterone (DOC), rather than aldosterone, is secreted by some adrenal tumors and has mineralocorticoid effects.

Mutation in mineralocorticoid receptor (see Hypertension, Early-Onset, Autosomal Dominant, with Severe Exacerbation in Pregnancy [OMIM]) is a form of early-onset hypertension with autosomal dominant inheritance that has now been linked to a specific mutation of the MR. This mutation results in constitutive activation of the MR, making the MR responsive to progesterone.

Activation of MR leads to unregulated sodium ion reabsorption via the collecting duct sodium ion channel, with accompanying hypokalemia and alkalosis. The disease is characterized by severe exacerbations of hypertension during pregnancy, and spironolactone can exacerbate hypertension.

Congenital adrenal hyperplasia (CAH; see Adrenal Hyperplasia, Congenital, Due to 11-Beta-Hydroxylase Deficiency [OMIM] and Adrenal Hyperplasia, Congenital, Due to 17-Alpha-Hydroxylase Deficiency [OMIM]) can be caused by deficiency of either 11-beta-hydroxylase or 17-alpha-hydroxylase. Both enzymes are involved in the synthesis of adrenal steroids.

Deficiency of either enzyme leads to increased levels of the mineralocorticoid 11-deoxycortisol, while cortisol and aldosterone production is impaired. 11-Hydroxylase deficiency differs from 17-hydroxylase deficiency by the presence of virilization.

Chloride-resistant alkalosis (urine chloride >20 mEq/L) with hypotension or normotension may be a manifestation of Bartter syndrome (see Hypokalemic Alkalosis with Hypercalciuria [OMIM]), an inherited autosomal recessive disorder. In Bartter syndrome, impaired reabsorption of sodium ions and chloride ions in the thick ascending loop of Henle leads to their increased delivery to the distal nephron.

The impaired reabsorption of sodium chloride in the loop of Henle is secondary to loss of function mutations of 1 of several transporters in this site of the nephron: (1) the furosemide-sensitive Na+/K+/2Cl- cotransporter (NKCC2); (2) the basolateral chloride ion channel (CLCNKB); (3) the inwardly rectifying apical potassium ion channel (ROMK1); (4) barttin (BSND), the beta-subunit of the chloride channels, CLC-Ka and CLC-Kb; and (5) the calcium sensing receptor (CaSR).

Mutations of CLCNKB cause classic Bartter syndrome, while mutations of the other 2 transporters manifest with the antenatal form of Bartter syndrome. [6] Edema and hypertension are absent, and hypercalciuria is common because the impaired reabsorption of sodium chloride inhibits the paracellular reabsorption of calcium. Because loop diuretics inhibit the Na+/K+/2Cl- transporter, the electrolyte abnormalities observed in Bartter syndrome and with loop diuretic use are similar.

Gitelman syndrome (see Potassium and Magnesium Depletion [OMIM]) is an inherited autosomal recessive disorder in which loss of function of the thiazide-sensitive sodium/chloride transporter (NCCT) in the distal convoluted tubule occurs. The subsequent increased distal solute delivery and salt wasting with stimulation of the renin-angiotensin-aldosterone system lead to hypokalemic metabolic alkalosis. Other features of the syndrome are hypocalciuria and hypomagnesemia. The electrolyte abnormalities resemble those caused by thiazide diuretics.

Pure hypokalemia (ie, severe potassium ion depletion) causes mild metabolic alkalosis, but, in combination with hyperaldosteronism, the alkalosis is more severe. Possible mechanisms of alkalosis in hypokalemia are enhanced proximal bicarbonate reabsorption, stimulated renal ammonia genesis, impaired renal chloride reabsorption, reduced GFR (in animals), and intracellular acidosis in the distal nephron with subsequent enhanced hydrogen secretion.

Magnesium depletion (ie, hypomagnesemia) may lead to metabolic alkalosis. The mechanism probably involves hypokalemia, which is usually caused by or associated with magnesium depletion.

Did this answer your question?
Additional feedback? (Optional)
Thank you for your feedback!