EPP & XLP are rare genetic disorders of the heme biosynthetic pathway1
The porphyrias are a group of lifelong metabolic disorders, each resulting from a defect in 1 of 8 enzymes involved in heme synthesis. Porphyrias can be broadly classified as acute or cutaneous, depending on the predominant clinical features.2
Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are cutaneous porphyrias caused by defects in either the final enzyme (FECH) or first enzyme (ALAS2) of heme synthesis, respectively. Both disorders are primarily characterized by painful cutaneous phototoxicity after light exposure, usually beginning in infancy or early childhood.1,3
Estimated global prevalence4,5
1:57,000 to 1:200,000
More recent data using a biomedical database found a prevalence estimating 1:17,000.1
Estimated US
prevalence6
~6,000 patients with EPP
XLP accounts for
approximately 10%
of
these cases.3
Both EPP and XLP lead to the accumulation of protoporphyrin IX (PPIX), causing the characteristic phototoxicity in addition to other systemic complications that can develop.1
Beneath the surface: PPIX-induced pathophysiology
EPP and XLP are caused by genetic mutations that result in accumulation of photoreactive PPIX3
Disrupted heme synthesis2,3,7
- As a precursor of heme, PPIX is normally present at low levels in all living cells
- Mutations in FECH (EPP) or ALAS2 (XLP) disrupt enzymatic activity in the heme biosynthetic pathway, leading to excess PPIX accumulation in the bone marrow and erythrocytes
PPIX buildup in the liver can cause hepatobiliary dysfunction and damage9,10
PPIX accumulation in hepatocytes and bile canaliculi lies at the core of hepatobiliary complications in EPP and XLP11
PPIX deposition and biliary obstruction9,10
Excess PPIX is excreted by the liver into bile, where it becomes insoluble and can crystallize, forming stones and obstructing bile flow.
Escalating hepatobiliary dysfunction3,10
Biliary obstruction impairs PPIX excretion, resulting in further PPIX accumulation and escalating PPIX-mediated liver damage.
PPIX-induced liver damage9
Ultrastructural liver damage in hepatocyte nuclei, endoplasmic reticulum, and plasma membranes is an early and consistent finding in EPP and XLP, even in patients without clinically evident liver dysfunction.