Classification and diagnostic approach to metabolic alkalosis

Generally speaking, metabolic alkalosis is a neglected and poorly understood beast. Perhaps there is an impression that it is somehow less dangerous and thus less interesting than metabolic acidosis. The acid-base enthusiast must become familiar with this process.

Exogenous strong cation excess

Sodium bicarbonate or citrate administration

β-lactam associated metabolic alkalosis

Exotic buffer substances, eg THAM

Milk-alkali syndrome and hypercalcemia in general

Primary derangement of homeostatic mechanisms

Failure of bicarbonate excretion in end-stage renal failure

Hypoalbuminaemia

Enteric chloride depletion

Dietary chloride restriction

Gastric loss of chloride ions

Chloride loss due to villous adenoma

Renal chloride depletion

Diuretic-induced metabolic alkalosis

Post-hypercapneic state

Bartter's syndrome and Gitelman's syndrome

Pseudo-Bartter's syndrome of cystic fibrosis

Hypokalemia

Hypomagnesaemia

Mineralocorticoid excess

Renin-secreting adenoma

Renal artery stenosis and malignant hypertension

Primary hyperaldosteronism

Licorice overindulgeance

Corticosteroids and fludrocortisone

Cushing syndrome

Causes of congential hyperadrenalism

Liddle syndrome

Again, I reproduce a table to list the various causes of metabolic alkalosis according to the findings of one's clinical examination history and biochemistry.

Causes of Metabolic Alkalosis; Organised by Diagnostic Features
Classification	Causes and pathophysiology	Literature reference
Easily excluded historical features:
Excess antacid consumption	Milk-alkali syndrome	[reference]
Calcium oversupplementation	Hypercalcemia-associated metabolic alkalosis	[reference]
β-lactam use	β-lactam associated metabolic alkalosis (particularly Tazocin)	[reference]
Cystic fibrosis	Pseudo-Bartter's syndrome of cystic fibrosis	[reference]
No specific historical features, and a normal urinary chloride (i.e. renal chloride conservation)
Recent (ceased) diuretic therapy	Diuretic-induced metabolic alkalosis (particularly due to loop diuretics)	[reference]
Vomiting or high NGT output	Gastric chloride ion depletion	[reference]
Post-hypercapneic alkalosis	Delay in the renal compensation to a rapid change (for the better!) in ventilation	[reference]
Villous adenoma	Chloride loss due to an unusual chloride-secreting phenotype of the adenoma	[reference]
A high urinary chrloride, WITHOUT hypertension
Ongoing diuretic therapy	That is why the urinary chloride is high and the blood pressure is normal.	[reference]
Bartter's syndrome	Failure of chloride reabsorption	[reference]
Gitelman's syndrome	Failure of chloride reabsorption	[reference]
Hypokalemia	Whatever the cause, low K⁺ causes increased renal chloride excretion	[reference]
Hypomagnesemia	Generally seen together with hypokalemia, and mainly in alcohol withdrawal	[reference]
Hypertension with a high urinary chrloride, and with high serum renin activity: RAAS (renin -angiotensin-aldosterone system) hyperactivity
Ongoing diuretic therapy	The diuretics have caused volume depletion and RAAS activation	[reference]
Renal artery stenosis	RAAS is activated by poor renal perfusion	[reference]
Renin-secreting adenoma	RAAS is activated directly by oversecretion of renin	[reference]
Malignant hypertension	RAAS is hyperactive for whatever reason, also causing malignant hypertension	[reference]
Hypertension with a high urinary chrloride, and WITHOUT high renin or high aldosternone levels
Cushing syndrome	Excess cortisol activates mineralocorticoid receptors	[reference]
Corticosteroid use	Exogenous steroids activate mineralocorticoid receptors	[reference]
Liddle's Syndrome	Hyperactivity of the amiloride-sensitive sodium channel (ENaC)	[reference]
Licorice overindulgeance	Inhibition of cortisol metabolism by glycorrhizin	[reference]
Hyperaldosteronism: a high urinary chrloride, with hypertension and with high serum aldosterone levels
Primary hyperaldosteronism	Eg. Conn's Syndrome (primary adrenal adenoma)	[reference]
Congential adrenal hyperplasia	Eg. 17α-hydroxylase deficiency	[reference]
Aldosterone synthase hyperactivity	Ectopic expression of the enzynme due to a case of genetic chimaerism	[reference]

The diagnostic pathway can therefore be reduced into a flowchart:

The approach to metabolic alkalosis

Background history

History of congential adrenal hypoplasia
History of cystic fibrosis
History of CCF (suggesting chronic exposure to diuretics)
History of uncontrolled hypertension (malignant hypertension or renal artery stenosis)

Recent history

Recent antacic consumption
Recent use of calcium supplements
β-lactam antibiotic use
Massive abuse of licorice
History of diarrhoea (villous adenoma) or vomiting (chloride loss)
History of recent hypercapneic respiratory failure

Examination

Clinically, findings consistent with severe hypertension (eg. retinal changes)
Renal artery stenosis bruit
Peripheral oedema (suggesting chronic exposure to diuretics)

Biochemistry

Serum potassium
Serum magnesium
Urinary chloride
Serum renin levels
Serum aldosterone levels

References

Medarov, Boris I. "Milk-alkali syndrome." Mayo Clinic Proceedings. Vol. 84. No. 3. Elsevier, 2009.

Waked, Alain, Abdallah Geara, and Badiaa El-Imad. "Hypercalcemia, metabolic alkalosis and renal failure secondary to calcium bicarbonate intake for osteoporosis prevention-‘modern’milk alkali syndrome: a case report." Cases journal 2 (2009).

Zietse, Robert, Roeland Zoutendijk, and E. J. Hoorn. "Fluid, electrolyte and acid–base disorders associated with antibiotic therapy." Nature Reviews Nephrology 5.4 (2009): 193-202.

Zaki, Syed Ahmed, and Vijay Lad. "Piperacillin-tazobactam-induced hypokalemia and metabolic alkalosis." Indian journal of pharmacology 43.5 (2011): 609.

Kennedy, J. D., et al. "Pseudo-Bartter's syndrome in cystic fibrosis." Archives of disease in childhood 65.7 (1990): 786-787.

Mersin, S. S., et al. "Urinary chloride excretion distinguishes between renal and extrarenal metabolic alkalosis." European journal of pediatrics 154.12 (1995): 979-982.

Eiam-Ong, Somchai, Neil A. Kurtzman, and Sandra Sabatini. "Effect of furosemide-induced hypokalemic metabolic alkalosis on renal transport enzymes." Kidney Int 43 (1993): 1015-1020.

Luke, Robert G., and John H. Galla. "It is chloride depletion alkalosis, not contraction alkalosis." Journal of the American Society of Nephrology 23.2 (2012): 204-207.

Fujita, Kazushige. "(2) Clinical Study on Elevation of pH (Alkalemia) in Chronic Respiratory Failure, Especially Associated with Chronic Hypercapnia."Japanese Journal of Medicine 15.2 (1976): 154-155.

Cogan, Martin G. "Chronic hypercapnia stimulates proximal bicarbonate reabsorption in the rat." Journal of Clinical Investigation 74.6 (1984): 1942.

Khanna, Apurv, and Neil A. Kurtzman. "Metabolic alkalosis." studies 28 (2006): 29.

Eiam-ong, S. O. M. C. H. A. I., et al. "Effect of respiratory acidosis and respiratory alkalosis on renal transport enzymes." American Journal of Physiology 267 (1994): F390-F390.

STARR, ALBERT, STERLING MUELLER, and JOHN R. McKITTRICK. "Villous adenoma of the colon associated with severe hypopotassemia." AMA archives of surgery 73.6 (1956): 995-998.

Favero, Marta, et al. "Bartter’s and Gitelman’s diseases." Best Practice & Research Clinical Rheumatology 25.5 (2011): 637-648.

Rastergar, A., and M. Soleimani. "Hypokalaemia and hyperkalaemia."Postgraduate medical journal 77.914 (2001): 759-764.

Amlal, Hassane, Khalid Habo, and Manoocher Soleimani. "Potassium deprivation upregulates expression of renal basolateral Na+-HCO3− cotransporter (NBC-1)." American Journal of Physiology-Renal Physiology279.3 (2000): F532-F543.

Al-Ghamdi, Saeed MG, Eugene C. Cameron, and Roger AL Sutton. "Magnesium deficiency: pathophysiologic and clinical overview." American Journal of Kidney Diseases 24.5 (1994): 737-752.

Wolfe, Sidney M., and Maurice Victor. "The relationship of hypomagnesemia and alkalosis to alcohol withdrawal symptoms." Annals of the New York Academy of Sciences 162.2 (1969): 973-984.

Bunchman, Timothy E., and Alan R. Sinaiko. "Renovascular hypertension presenting with hypokalemic metabolic alkalosis." Pediatric Nephrology 4.2 (1990): 169-170.

Baruch, Dominique, et al. "Diagnosis and treatment of renin-secreting tumors. Report of three cases." Hypertension 6.5 (1984): 760-766.

Laragh, John H., et al. "Aldosterone secretion and primary and malignant hypertension." Journal of Clinical Investigation 39.7 (1960): 1091.

Christy, Nicholas P., and John H. Laragh. "Pathogenesis of hypokalemic alkalosis in Cushing's syndrome." New England Journal of Medicine 265.22 (1961): 1083-1088.

Schambelan, M., P. E. Slaton Jr, and E. G. Biglieri. "Mineralocorticoid production in hyperadrenocorticism: Role in pathogenesis of hypokalemic alkalosis." The American journal of medicine 51.3 (1971): 299-303.

GLYNN, RUSSELL D., et al. "Effects of glucocorticoid steroids on renal and systemic acid-base metabolism." (1980).

Palmer MD, Biff F., and Robert J. Alpern MD. "Liddle’s syndrome." The American journal of medicine 104.3 (1998): 301-309.

Lin, Shih-Hua, et al. "An unusual cause of hypokalemic paralysis: chronic licorice ingestion." The American journal of the medical sciences 325.3 (2003): 153-156.

Epstein, M. T., et al. "Liquorice toxicity and the renin-angiotensin-aldosterone axis in man." British medical journal 1.6055 (1977): 209.

Kassirer, Jerome P., et al. "On the pathogenesis of metabolic alkalosis in hyperaldosteronism." The American journal of medicine 49.3 (1970): 306-315.

Speiser, Phyllis W., and Perrin C. White. "Congenital adrenal hyperplasia." New England Journal of Medicine 349.8 (2003): 776-788.

LIfton, Richard P., et al. "A chimaeric llβ-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension." (1992): 262-265.

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