Molecular diagnostic and pathogenesis of hereditary hemochromatosis

Abstract

Hereditary hemochromatosis (HH) is an autosomal recessive disorder characterized by enhanced intestinal absorption of dietary iron. Without therapeutic intervention, iron overload leads to multiple organ damage such as liver cirrhosis, cardiomyopathy, diabetes, arthritis, hypogonadism and skin pigmentation. Most HH patients carry HFE mutant genotypes: homozygosity for p.Cys282Tyr or p.Cys282Tyr/p.His63Asp compound heterozygosity. In addition to HFE gene, mutations in the genes that encode hemojuvelin (HJV), hepcidin (HAMP), transferrin receptor 2 (TFR2) and ferroportin (SLC40A1) have been associated with regulation of iron homeostasis and development of HH. The aim of this review was to identify the main gene mutations involved in the pathogenesis of type 1, 2, 3 and 4 HH and their genetic testing indication. HFE testing for the two main mutations (p.Cys282Tyr and p.His63Asp) should be performed in all patients with primary iron overload and unexplained increased transferrin saturation and/or serum ferritin values. The evaluation of the HJV p.Gly320Val mutation must be the molecular test of choice in suspected patients with juvenile hemochromatosis with less than 30 years and cardiac or endocrine manifestations. In conclusion, HH is an example that genetic testing can, in addition to performing the differential diagnostic with secondary iron overload, lead to more adequate and faster treatment.

Keywords: HFE; HJV; hemochromatosis; high-resolution melting; molecular diagnostic; primary iron overload.

Figure 1

Normal (A) and hemochromatosis (B) conditions. A1: HFE, HJV, and TFR2 modulates hepcidin synthesis by hepatocytes; A2: normal hepcidin levels; A3: hepcidinferroportin interaction with internalization and ferroportin degradation in enterocytes; A4: normal iron absorption. B1: HFE or HJV or TFR2 gene mutations alter hepcidin synthesis modulation; B2: lower hepcidin levels; B3: decreased hepcidin-ferroportin interaction and increased ferroportin activity; B4: iron overload observed in types 1, 2 and 3 hemochromatosis. TFR2: transferrin receptor 2; TFR1: transferrin receptor 1, HFE: HFE protein; HJV: hemojuvelin.

Figure 2

Representation of diagnostic strategy for patients suspected hereditary hemochromatosis (HH). * Recommendations report TS > 45%, SF > 200 μg/L in females and > 300 μg/L in males; or in advanced stages: TS > 50% in females and TS > 60% in males, in the absence of secondary causes [79,80]. ** Some patients with primary iron overload may not present mutation during this genetic approach. Very rare mutations in other genes can be involved [15,81]. Abbreviations: TS: transferrin saturation; SF: serum ferritin; JH: juveline hemochromatosis. + means positive result, and − means negative result.