EPP Pathophysiology, Prevalence, and Why Accurate Protoporphyrin Testing Matters

Welcome back to another Dermatology Times Case-Based Peer Perspectives series. In "EPP Pathophysiology, Prevalence, and Why Accurate Protoporphyrin Testing Matters," Dr. Herbert Bonkovsky opens the series on erythropoietic protoporphyria (EPP) with an overview of its biology, prevalence, and diagnostic challenges.

Dr. Bonkovsky begins with the biology of the disease, explaining that classical EPP results from a critical drop in ferrochelatase, the final enzyme in the heme synthesis pathway. Symptoms appear only when enzyme activity falls by at least 75%, which usually requires a missense, nonsense, or deletion allele on one chromosome. The partner allele is typically a hypomorphic intron 3 variant, a T-to-C change at position minus 48, that lowers activity by about 25%.

Developing red cells make roughly 80% of the body's daily heme, the liver about 15%, and other tissues about 5%. The bone marrow is therefore the main source of excess protoporphyrin. That protoporphyrin deposits in skin capillaries and nearby cells and is activated by blue light near 410 nanometers, generating reactive oxygen species that cause acute pain and swelling. Standard sunscreens do not block this wavelength, and once a full reaction has begun there is no effective treatment, so prevention is the priority.

Dr. Bonkovsky estimates prevalence at about 1 in 100,000 or somewhat higher, and biobank data suggest that pathogenic variants may be more common than expected. The test of first choice is a whole blood or red cell protoporphyrin, but he warns that large commercial laboratories run a flawed assay that actually measures zinc protoporphyrin. Samples should instead go to the Mayo Medical Laboratories, which run the accurate assay. Plasma protoporphyrin is reliable at several labs but unstable, so it must be drawn under subdued light, shielded from light within 30 minutes, and kept refrigerated.

The next episode in this series, "EPP Misdiagnosis and Long-Term Liver, Iron, and Vitamin D Complications," features Dr. Bonkovsky on the long road to diagnosis and the liver, iron, and vitamin D consequences of missed EPP.