Pathophysiologic mechanisms underlying cutaneous photosensitivity and hepatic failure in erythropoietic protoporphyria (EPP) and related porphyric disorders will be investigated. EPP is currently being recognized in increasing numbers of cases, but its pathophysiology remains undetermined or controversial. Whether bone marrow or hepatic tissue or both, are major sites of the excess protoporphyrin (PP) synthesis will be studied in vitro and in vivo, in animal models and patients. Whether ferrochelatase deficiency is a primary or secondary defect of this disease will be evaluated in a mitogen transformed lymphocyte culture system utilizing lymphocytes from EPP patients. Rodent liver systems will be used to evaluate the kinetics of hepatic protoporphyrin clearance and/or deposition from a circulating blood pool; and factors which may influence these kinetics (including some with potential for therapeutic benefit) will be studied in the same systems. In vivo testing of therapeutic modalities of potential benefit in EPP will be performed using the griseofulvin-induced murine protoporphyria model. Clinical trials of anion exchange resins for removal of protoporphyrin from circulation in EPP patients will be conducted after metabolic balance studies to establish the dynamics of protoporphyrin production and excretion without therapy are completed. Serial measurement of erythrocyte, plasma and stool protoporphyrin; rates of diffusion of protoporphyrin from erythrocytes; serum carotene and hemopexin values will be performed over several years in EPP patients, seeking correlations with severity of cutaneous photosensitivity, propensity for liver damage and seasonal influences on circulating porphyrin burden.
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