protoporphyria

Protoporphyria refers to a group of inherited disorders of heme biosynthesis in which protoporphyrin IX accumulates in red blood cells and other tissues. The most common forms are erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP); a liver-focused variant can occur with hepatic involvement.

In EPP, reduced activity of ferrochelatase, the enzyme that inserts iron into protoporphyrin IX to form heme, is usually due to mutations in the FECH gene. In XLP, gain-of-function mutations in the ALAS2 gene increase production of precursor molecules that lead to protoporphyrin IX accumulation. Both conditions cause photosensitivity, but they differ in inheritance patterns and biochemistry. EPP often presents in childhood with a burning, painful sensation on sun exposure; XLP presents similarly and may be associated with iron deficiency.

Symptoms are predominantly related to skin and, less commonly, liver. Skin reactions include immediate burning, stinging, redness, and swelling after light exposure, especially to visible light in the blue range. Blistering is less common than in other porphyrias. In a subset of patients, protoporphyrin accumulates in the liver, leading to cholestasis, elevated liver enzymes, and, rarely, progressive liver disease.

Diagnosis rests on laboratory tests showing elevated free erythrocyte protoporphyrin and increased protoporphyrin in plasma, with porphyrin analysis in urine or feces aiding subtype classification. Genetic testing confirms FECH or ALAS2 mutations.

Management focuses on minimizing sun exposure and protecting the skin with clothing and shielding light-filtering sunscreens. Iron status should be monitored, as iron deficiency can influence symptoms in some patients. Avoidance of hepatotoxic drugs and regular liver monitoring are advised when liver involvement is present. Treatment is supportive, with liver transplantation considered only in rare cases of severe hepatic disease.