Goals: The goal of this study was to define molecular determinants of liver di sease in erythropoietic protoporphyria (EPP).Background: EPP is a genetic disord er in which deficient ferrochelatase activity causes excessive production of pro toporphyrin,which is excreted in bile. Some patients develop liver disease that necessitates transplantation. Study: Ferrochelatase gene analysis was done in 25 families with EPP to identify mutations and a polymorphism(IVS3-48c) that caus es low gene expression. Expression of multiple hepatic genes was also examined b y DNA microarray analysis in patients who had liver transplantation to identify genes with altered regulation.Results: Heterozygous ferrochelatase mutations wer e found in 43 individuals. In 94%of 31 symptomatic patients, 15 of whom had liv er disease, the polymorphism was also present in the nonmutant allele. Explanted liver of patients who had transplantation showed significant change in expressi on of several genes involved in wound healing, organic anion transport, and oxid ative stress. Conclusions: Patients with EPP who develop liver disease usually h ave amutation in one ferrochelatase allele that alters enzyme function, together with a polymorphism in the nonmutant allele that causes low gene expression. Th is results in significant increase in the hepatobiliary excretion of protoporphy rin, which can dam- age the liver through both cholestatic injury and oxidative stress. Goals: The goal of this study was to define molecular determinants of liver diase in erythropoietic protoporphyria (EPP). Background: EPP is a genetic disord er in which deficient ferrochelatase activity causes excessive production of pro toporphyrin, which is excreted in bile. Some Patients develop liver disease that necessitates transplantation. Study: Ferrochelatase gene analysis was done in 25 families with EPP to identify mutations and a polymorphism (IVS3-48c) that caus es low gene expression. Expression of multiple hepatic genes was also examined by DNA microarray analysis in patients who had liver transplantation to identify genes with altered regulation. Results: Heterozygous ferrochelatase mutations found in 43 individuals. In 94% of 31 symptomatic patients, 15 of whom had liv er disease, the polymorphism was also present in the nonmutant allele Explanted liver of patients who had transplantation showed significant change in expressi on of several genes involved in woun d healing, organic anion transport, and oxidative stress. Conclusions: Patients with EPP who develop liver disease usually h ave amutation in one ferrochelatase allele that alters enzyme function, together with a polymorphism in the nonmutant allele that causes low gene expression. Th is results in significant increase in the hepatobiliary excretion of protoporphy rin, which can dam- age the liver through both cholestatic injury and oxidative stress.