Genetic testing to distinguish X-linked protoporphyria from erythropoietic protoporphyria informed iron replacement therapy leading to reversal of severe protoporphyric hepatopathy.

Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are cutaneous porphyrias characterized by excess protoporphyrin IX (PPIX), leading to photosensitivity and, in a minority of patients, progressive hepatobiliary injury. Although XLP and EPP have similar clinical presentations and management, they differ in their response to iron repletion. A reduction in PPIX levels has been demonstrated in XLP, whereas this effect has not been consistently observed in EPP. Data on the role of iron supplementation in XLP-associated liver dysfunction are limited to a single pediatric case report and a pilot study that included only two adult patients with XLP. Here, we describe a 64-year-old man with a history of presumed EPP who underwent liver transplantation for decompensated cirrhosis attributed to protoporphyric hepatopathy and possible alcohol-related disease, who presented with recurrence of hepatopathy and photosensitivity. Serial erythrocyte PPIX levels increased from 3250 to 4368 and then to 5561 μg/dL with multiple liver biopsies confirming marked porphyrin deposition without rejection. During evaluation for bone marrow transplant, genetic testing revealed a pathogenic ALAS2 variant, confirming XLP. Oral iron replacement was started after the diagnosis of iron deficiency anemia. Although the underlying cause of iron deficiency was not fully investigated, given the urgent need to address the XLP-related symptoms, iron supplementation was initiated and resulted in rapid improvement in photosensitivity and liver chemistries. This was accompanied by a marked reduction in erythrocyte PPIX levels to 1940 μg/dL. This case demonstrates the importance of genetic testing, as iron repletion may serve as a disease-modifying therapy for XLP-associated hepatopathy, even after liver transplantation.