The differential diagnosis of syndromes involving hypokalemia, metabolic alkalosis, and hypertension

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While there are a number of conditions which can cause the combination of hypokalemia and metabolic alkalosis there are a limited number of disease processes which lead to hypokalemia, metabolic alkalosis, AND hypertension. In order to have hypertension in this setting, the pathological disease process must involve increased sodium (and water) reabsorption which leads to volume expansion and elevated blood pressure. The list of these diseases includes:

1. Liddle’s syndrome. Autosomal dominant condition caused by a gain-of-function mutation in the epithelial sodium channel (ENaC) which results in increased Na+ reabsorption.

2. Licorice ingestion and the Syndrome of Apparent Mineralocorticoid Excess (SAME). Ingestion of large amounts of licorice (or licorice-containing tobacco or gun) can lead to inhibition of the enzyme 11-beta-hydroxysteroid dehydrogenase, which converts cortisol into the cortisone in aldosterone target tissues (e.g. collecting ducts). Since cortisol has an equal affinity for the mineralocorticoid receptor compared to aldosterone, it would act as the primary mineralocorticoid if it were not converted into the inactive cortisone. The compound in licorice that is responsible for this enzyme inhibitory activity is glycyrrhetinic acid, which also has some mild mineralocorticoid activity. The mechanism is similar in SAME, in which one has mutations in the 11-beta-hydroxysteroid dehydrogenase enzyme that prevent proper conversion of cortisol into cortisone.

3. Renal artery stenosis and renin secreting tumors. Both of these etiologies are the result of elevated production and secretion of renin leading to hyperaldosteronism.

4. Adrenal hyperfunction. This category includes causes of primary hyperaldosteronism, including adrenal adenoma, adrenal hyperplasis, and adrenal carcinoma.

All of these conditions essentially result in or mimic hyperaldosteronism and can be partly differentiated on the basis of the response of the renin-angiotensin-aldosterone system to the disease processes:

Liddle’s — low renin, low aldo
Licorice and SAME — low renin, low aldo
Renal artery stenosis and renin-secreting tumors — high renin, high aldo
Adrenal hyperfunction — low renin, high aldo


  1. Thanks for these d/d's on your blog. They are quite informative. I am linking to your post

  2. we can add to the differential diagnosis of hypermineralocorticism with low renin low aldo , Geller syndrome wich is a gain-of-function mutation of mineralocorticoid receptor .

  3. I agree with above comment.
    In order to differentiate between Liddle's and SAME, urinary cortisol to cortisone ratio is helpful.

  4. Great review. Often a highly pimped subject among fellows. Few corrections to the renin/aldo remarks.

    Liddle's should be low renin, low aldo. The volume expansion associated with autonomous Na reabsorption should shut off renin.

    RAS and renin-secreting tumors should be high renin, high aldo as its the aldo that is causing the volume expansion.

    Adrenal hyperfunction would be low renin, high aldo in cases of excess mineralocorticoid production. If it was due to Cushings, it would be low renin, low aldo.

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