Homeostasis of Iron and Hepcidin in Erythropoietic Protoporphyria and X-Linked Protoporphyria: 621

Introduction: Erythropoietic protoporphyria (EPP) and X-Linked protoporphyria (XLP) are genetic deficiencies of heme synthesis that result in excess production of protoporphyrin that typically manifests as severe photosensitivity during infancy. Patients with these disorders often have iron deficiency anemia, the mechanism of which is not well understood. The aim of this study was to determine whether hepcidin, a well-known regulator of iron homeostasis, is inappropriately increased in EPP/XLP patients resulting in decreased enteral iron absorption and iron deficiency anemia. Methods: Eight patients with EPP, 1 patient with XLP, and 9 controls were given 660 mg of ferrous sulfate. Prior to dosing, baseline blood, and urine samples were collected. Post-dose blood and urine samples were collected at hours 2, 4, 6, and 8. CBC, serum ferritin, iron, transferrin, and TIBC were analyzed at baseline. Serum iron, serum and urine hepcidin, and erythropoietin were analyzed at baseline and subsequent time points. Results: EPP/XLP participants had lower hemoglobin (mean 13.89+/-0.88 g/dL vs. 15.33+/-0.69 g/dL, p=0.0007) and ferritin (mean 31.56+/-20.19 ng/mL vs. 115.22 +/- 62.31 ng/mL, p=0.0007) levels at baseline compared to controls. Serum iron levels were not significantly different between EPP/XLP (mean predose 69.20+/-13.72 mcg/dL, 2 hr post 179.22+/-26.46, 4 hr post 231.8+/-33.29, 6 hr post 217.80+/- 31.62, 8 hr post 209.80+/-31.92) and control (mean predose 99.44+/-26.76 mcg/dL, 2 hr post 165.44+/- 48.17, 4 hr post 272.45+/-33.51, 6 hr post 252.56+/-39.23, 8 hr post 215.33+/-53.06) participants. Serum hepcidin was significantly higher in the control group (4 hr post 26.61+/-4.06 nmol/L, 8 hr post 34.62+/- 3.93, p<0.0001) than the EPP/XLP group (4 hr post 3.79+/-1.51 nmol/L, 8 hr post 5.79+/-2.15). Urine hepcidin was significantly increased in the control group (4 hr post 2.50+/-0.46 nM/mM, 8 hr post 6.63+/-1.33) vs. EPP/XLP (4 hr post 0.85+/-0.57 nM/mM, 8 hr post 1.44+/-0.62, p<0.0001). Erythropoietin levels did not show a significant change (p=0.431) over time for either control or EPP/XLP subjects. Conclusion: Contrary to our hypothesis, serum and urine hepcidin are not inappropriately increased in EPP/XLP subjects at baseline and do not increase over time as serum iron increases after oral ferrous sulfate. Future studies should explore possible urine or biliary-fecal losses of excess iron or if excess protoporphyrin decreases iron as a protective mechanism against free/toxic levels of iron.