Pellagra (niacin/tryptophan deficiency) can occur despite adequate dietary niacin in patients with Hartnup disease. What is the precise mechanism?

• A Hartnup disease causes hepatic niacin oxidase overactivity, rapidly degrading absorbed niacin
• B Hartnup disease involves defective intestinal and renal neutral amino acid transport (SLC6A19 mutation); impaired tryptophan absorption from gut prevents its conversion to niacin via the kynurenine pathway ✓
• C SLC6A19 mutation blocks NAD+ synthesis from nicotinic acid in the liver directly
• D Hartnup disease causes intestinal bacteral overgrowth that degrade tryptophan to indole before absorption

Explanation

Hartnup disease is caused by mutations in SLC6A19 (B0AT1), the neutral amino acid transporter in brush border of intestine and proximal renal tubule. This impairs absorption of neutral amino acids including tryptophan from the gut. Since tryptophan is the endogenous precursor for niacin synthesis via the kynurenine pathway (60 mg tryptophan → 1 mg niacin, requiring B6 and B2 as cofactors), reduced tryptophan absorption effectively causes secondary niacin deficiency. The classic pellagra triad (dermatitis, diarrhea, dementia) emerges on a low-protein diet. Aminoaciduria (neutral aminoaciduria) from tubular failure is the other diagnostic feature.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

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