The Biology and Diagnosis of AME

Understanding the biology of Apparent Mineralocorticoid Excess (AME) requires looking at how the body processes hormones. While high blood pressure is the most visible symptom, the “engine room” of the problem is in the kidney, where a specific enzyme failure changes how the body handles salt and potassium ^[1][2].

The Biology of “Apparent” Excess

In a healthy body, the hormone aldosterone signals the kidneys to hold onto salt and release potassium. AME is called “apparent” excess because while the body acts like it has too much aldosterone, the actual levels of aldosterone in the blood are often very low ^[3].

The culprit is cortisol, your body’s primary stress hormone. Cortisol is very similar in structure to aldosterone. In the kidneys, there is an enzyme called 11β-HSD2 (encoded by the HSD11B2 gene) that acts as a filter ^[4]. It normally converts active cortisol into inactive cortisone. When this enzyme is missing or broken due to a genetic mutation or chemical exposure, cortisol stimulates the kidney’s receptors, “pretending” to be aldosterone ^[5][2]. The kidney responds by aggressively reabsorbing sodium (salt) and water while dumping potassium into the urine ^[6][7].

The Diagnostic Lab Profile

To evaluate AME, doctors look for a specific “signature” in the blood and urine. Because the body is already overwhelmed by the false signal from cortisol, it shuts down its own natural salt-regulating system to compensate ^[8].

• Suppressed Renin: Renin is an enzyme that starts the process of salt retention. In AME, renin levels drop to nearly zero because the body is already holding onto far too much salt ^[8][7].
• Low Aldosterone: Unlike other forms of high blood pressure, aldosterone is usually very low or undetectable in AME ^[2][9].
• Hypokalemia: This is the medical term for low potassium. The kidneys are “leaking” potassium into the urine, which can cause muscle weakness or fatigue ^[7][10].
• Metabolic Alkalosis: This occurs when the blood becomes too alkaline (high pH) due to the way the kidneys are processing electrolytes ^[8][10].

The Biochemical Evidence: The Cortisol/Cortisone Ratio

The most definitive biochemical test for 11β-HSD2 deficiency is a urine sample to measure the ratio of cortisol metabolites to cortisone metabolites (like THF+5αTHF/THE). In AME, the amount of free cortisol or its metabolites is abnormally high compared to cortisone metabolites because the conversion process is broken ^[11][3].

What this test can and cannot tell you: An abnormal ratio shows the enzyme is failing, but it does not definitively prove genetic AME by itself—licorice or certain drugs can also cause this pattern. It also does not mean the body is producing too much total cortisol overall, just that the kidneys are failing to convert it.

Important Note: Laboratory reports can be confusing. Some labs report the cortisol-to-cortisone ratio (which will be high in AME), while others report the cortisone-to-cortisol ratio (which will be low in AME). Always verify which way the ratio is oriented with your specialist ^[8][11].

Distinguishing AME from Similar Conditions

AME belongs to a group of conditions involving low-renin hypertension. Because many of these look similar, doctors use a differential diagnosis matrix to tell them apart:

While Liddle Syndrome and AME look nearly identical on basic blood tests (both have low renin and low aldosterone), Liddle is caused by mutations in ENaC genes and only AME shows the abnormal cortisol-to-cortisone ratio ^[2][10].

Confirming the Diagnosis with Genetic Testing

Genetic testing for the HSD11B2 gene is used to investigate the molecular cause.

• Because AME is autosomal recessive, finding pathogenic variants on both copies of the gene supports classic AME ^[12].
• However, genetic testing can sometimes yield a Variant of Uncertain Significance (VUS) or fail to find a variant due to technical limitations. A clinical diagnosis evaluates the labs and the genetics together ^[3][13].

Common Diagnostic Data Points

While not every person must have all tests completed before treatment begins, a full diagnostic workup often includes:

1. Plasma Renin Activity (PRA) or Direct Renin Concentration (DRC) (should be suppressed) ^[8].
2. Serum Aldosterone level (should be low) ^[2].
3. Serum Potassium and Bicarbonate (to check for hypokalemic alkalosis) ^[8].
4. Urinary Steroid Profile (specifically the ratio of cortisol metabolites to cortisone metabolites) ^[3].
5. Molecular Genetic Analysis of the HSD11B2 gene ^[12].
6. Kidney Ultrasound (to check for nephrocalcinosis, or calcium deposits) ^[3].