Long-term phlebotomy successfully alleviated hepatic iron accumulation in a ferroportin disease patient with a mutation in SLC40A1: a case report

Abstract

Background Hereditary hemochromatosis is a heterogenous group of inherited iron-overload conditions that is characterized by increased intestinal absorption and deposition in vital organs. Hepcidin is a soluble regulator that acts to attenuate both intestinal iron absorption and iron release from reticuloendothelial macrophages through internalization of ferroportin-1, an iron exporter. Ferroportin disease is hereditary hemochromatosis which is affected by SLC40A1, a gene coding ferroportin-1, and phenotypically classified into two forms (classical and nonclassical). In nonclassical form, ferroportin mutations are responsible for a gain of function with full iron export capability but insensitivity to downregulation by hepcidin. Here, we report a case of nonclassical ferroportin disease. Case presentation A 46-year-old Japanese man showed elevated serum iron (284 μg/dl), ferritin (1722 ng/ml), transferrin saturation ratio (91.3%), and hepcidin-25 level (139.6 ng/ml). Magnetic resonance imaging (MRI) demonstrated a marked reduction in the signal intensity of the liver in T1- and T2-weighted images. The liver histology exhibited a large amount of iron that had accumulated predominantly in hepatocytes. We identified a heterozygous 1520A > G (p.H507R) mutation in the SLC40A1 gene. Phlebotomy (400 ml at a time) was monthly performed for 3 years in this patient. Importantly, the serum hepcidin level (1.0 ng/ml) was normal when the serum ferritin level was normal and hepatic iron accumulation was remarkably reduced after 3 years of phlebotomy. Conclusions The present case demonstrated for the first time that there was a correlation between hepatic iron levels as measured by MRI and serum hepcidin levels through long-term phlebotomy in a patient with ferroportin disease with the p.H507R mutation of in SLC40A1.

A Revised Classification of Primary Iron Overload Syndromes

“…Anonymized information of the patients with the prehepatic class of ACP and ILA is summarized in Tables 1 and 2, 16,18,[30][31][32][33][34] and that of HC and SLC40A1-PIOSs is shown in Table 3. [16][17][18][19][20]22,24,25,[35][36][37][38][39][40] The clinical features of new patients in each disease category are described briefly, and the characteristics of each category are summarized in Table 4. [18][19][20][21]23 One of the five patients was newly enrolled in ACP of prehepatic PIOSs (Table 1).…”

“…Three patients with SLC40A1-PIOSs were reported in the first version 18 and five were newly enrolled in the revised version (Table 2). [36][37][38][39] Phenotypically, they were divided into five patients with SLC40A1-HC and three with FP-D. Four new patients with SLC40A1-HC were already complicated with multiorgan damage at presentation. All five patients with SLC40A1-HC had high serum ferritin and Hep25 levels and also had advanced chronic liver diseases associated with combined parenchymal and reticuloendothelial iron loading.…”

“…may fail to detect the disease-causing mutation in the postulated gene. 40 Patients with HC have excellent tolerance for standard phlebotomy 3,4,25 Milder phlebotomy may be recommended for SL40A1-HC 3,38 and other phenotypes. 3 New oral iron chelators are now available for patients intolerant of phlebotomy.…”

Iron and liver cancer: an inseparable connection

“…Ferroportin disease prevents iron export from cells, resulting in hyperferritinaemia, normal-to-low Tf saturation and iron accumulation predominantly in reticuloendothelial cells [54]. FPN1-associated haemochromatosis exhibits full iron export capability but insensitivity to downregulation by hepcidin, leading to increased Tf saturation and iron accumulation in hepatocytes, in addition to hyperferritinaemia [55,56]. A recent cryogenic electron microscopy analysis identified two metal-binding sites within the N and C domain of ferroportin and that C domain metal-binding site is important for hepcidin binding.…”