**Core Concept**
The Syndrome of Apparent Mineralocorticoid Excess (SAME) is a rare genetic disorder characterized by excessive mineralocorticoid activity, leading to hypertension, hypokalemia, and metabolic alkalosis. This condition arises due to the inability to distinguish between cortisol and aldosterone, which are both mineralocorticoids, and cortisol's mineralocorticoid activity is not normally suppressed.

**Why the Correct Answer is Right**
The correct answer is D. Lack of Inactivation of cortisol to cortisone. In normal physiology, cortisol is inactivated to cortisone by the enzyme 11-beta hydroxysteroid dehydrogenase type 2 (11-beta HSD2) in the collecting ducts of the kidneys. In patients with SAME, this enzyme is deficient or non-functional, allowing cortisol to remain active and bind to mineralocorticoid receptors, mimicking the effects of aldosterone. This leads to excessive sodium reabsorption, potassium excretion, and water retention, resulting in hypertension and hypokalemia.

**Why Each Wrong Option is Incorrect**
**Option A:** Increased aldosterone production is not the primary cause of SAME, as aldosterone levels are typically normal or decreased in this condition.

**Option B:** Lack of inactivation of aldosterone is not relevant to SAME, as aldosterone is inactivated by a different enzyme, 11-beta HSD1.

**Option C:** Increased cortisol production is not the primary cause of SAME, as cortisol levels are typically normal or decreased in this condition.

**Clinical Pearl / High-Yield Fact**
It's essential to remember that SAME is a rare but important diagnosis to consider in patients with hypertension and hypokalemia, particularly those with a family history of the condition. The diagnosis is often made by demonstrating the inability to suppress aldosterone or cortisol production in response to low sodium intake, and genetic testing can confirm the presence of a mutation in the HSD11B2 gene.

✓ Correct Answer: D. Lack of Inactivation of cortisol to cortisone