Haemochromatosis revisited

Haemochromatosis is a genetic disease caused by hepcidin deficiency, responsible for an increase in intestinal iron absorption. Haemochromatosis is associated with homozygosity for the HFE p.Cys282Tyr mutation. However, rare cases of haemochromatosis (non-HFE haemochromatosis) can also be caused by pathogenic variants in other genes (such as HJV, HAMP, TFR2 and SLC40A1). A working group of the International Society for the Study of Iron in Biology and Medicine (BIOIRON Society) has concluded that the classification based in different molecular subtypes is difficult to be adopted in clinical practice and has proposed a new classification approaching clinical questions and molecular complexity. The aim of the present review is to provide an update on classification, pathophysiology and therapeutic recommendations.     

Analysis of the HFE gene (C282Y, H63D and S65C) mutations in a general Chinese Han population

Hereditary hemochromatosis (HH) is one of the most common autosomal recessive genetic disorders of iron metabolism in white populations, which leads to inappropriately high iron absorption. C282Y, H63D, and S65C are three major missense mutations of the hemochromatosis gene (HFE). In the present study, C282Y, H63D, and S65C mutations in 395 normal Chinese Han populations from Zhejiang province were investigated. No C282Y, S65C mutations, and H63D homozygote was observed, while the genotype frequency of H63D heterozygote was 4.6% and the allelic frequency 2.3% in this population. This was the first report to analyze the prevalence of C282Y, H63D, and S65C mutations in the HFE gene in a Chinese Han population. Low incidence of the HFE gene mutations could be a reason for the rarity of HH in the Chinese Han population studied.     

HFE gene mutations in patients with acute leukemia

An increased incidence of HFE gene mutations has been described in hematologic malignancies. In the present study, we investigated the allelic frequency of HFE gene mutations in 154 adult patients with acute leukemia (AL) [107 acute myeloid leukemia (AML), 20 acute promyelocytic leukemia (APL) and 27 acute lymphoblastic leukemia (ALL)]. The allelic frequency of the H63D mutation was 29% in AL patients and 25% in the healthy controls [P = 0.41; odds ratio (OR) = 1.20; 95% confidence interval (CI) = 0.77 - 1.93]. No difference was found between controls and AML or APL patients, whereas the H63D mutation was significantly more frequent in ALL than controls (44% vs. 25%, P = 0.04; OR = 2.37; 95% CI = 1.05 - 5.36). The overall comparison of the mutation among the three subtypes of AL demonstrated a higher allelic frequency in ALL (P = 0.02). In conclusion, our data demonstrate a correlation between the presence of the H63D mutation and the occurrence of ALL in adult patients.     

Is genetic screening for hemochromatosis worthwhile?

Hereditary hemochromatosis is an iron overload disorder and is the most common recessive disease in Caucasians. About 80% of hemochromatosis patients are homozygous for the C282Y mutation in the HFE gene. Since iron accumulation can be prevented by phlebotomy, there is increasing interest in screening populations for hemochromatosis. Hemochromatosis is a disease that meets all the criteria for screening as set by the World Health Organization (WHO) or the US preventive services task force criteria for a screening program. However, there is no consensus on the value of a screening program for hemochromatosis. Moreover, there is no agreement on whether this screening should be based on the phenotype i.e. biochemical levels of serum iron parameters or on the genotype i.e. based on the presence of mutations in the HFE gene. Other important concerns are the lack of important data in evaluating screening as well as the psychosocial impact of a screening program. The present review analyses the current situation from a genetic-epidemiological perspective. We conclude that general population screening may be helpful to identify high-risk groups or individuals in the early stage of the disease so that treatment can be started. We suggest a two-phase screening program based on the first instance on serum iron levels and then a genetic test to only those with elevated serum iron parameters.     

Klinische und genetische Aspekte der hereditären Hämochromatose

Hereditary hemochromatosis (HH) is an autosomal recessive disease in which increased iron absorption causes iron overload and irreversible tissue damage. As laboratory parameters for measuring HH lack specificity, and HH remains asymptomatic for a long time, methods for genetic screening are highly valuable. Mutations in two genes, hfe and TfR2, have recently been found to be responsible for HH. The mutation C282Y in the hfe gene is detected in 70-95% of German and Austrian HH patients. Mutations in the TfR2 gene have been detected only very recently, and results of larger epidemiological studies are not yet available. Molecular methods permit molecular diagnosis and genetic screening.     

HFE,the MHC and hemochromatosis: paradigm for an extended function for MHC class I

HFE was discovered as the hereditary hemochromatosis (HH) gene. It is located on chromosome 6 (6p21.3), 4Mb telomeric to the HLA-A locus, and its product has a structure similar to MHC class I molecules. HFE encodes two frequent mutations: C282Y and H63D. One of these (C282Y) is present in a large proportion of Caucasian HH patients. HFE has a tissue distribution compatible with a role in iron absorption (intestine), recycling (macrophages) and transport to the fetus (placenta).     

Prevalence of HFE mutations in California newborns

Advances in molecular diagnostics have led to an increased interest in expanding population-based screening to include genetic diseases that occur outside the newborn period. Hereditary hemochromatosis may be a candidate for large-scale screening in populations with a high prevalence of the common HFE mutations. To determine race-specific frequencies of the HFE mutations, C282Y and H63D, the authors applied an automated, high-throughput genotyping method to dried blood spot samples from a representative population of California newborns. In this sample of 3989 newborns, C282Y and H63D allele frequencies were highest in white (C282Y: 5.5 ± 0.5%; H63D: 13.4 ± 0.76%) and Hispanic (C282Y: 1.8 ± 0.29%; H63D: 11.9 ± 0.72%) newborns, and lowest in black (C282Y: 1.3 ± 0.25%; H63D: 3.0 ± 0.38%) and Asian (C282Y 0.5 ± 0.16%; H63D 2.9 ± 0.37%) newborns. The estimated prevalence of C282Y homozygotes in this multiracial population is 1.4/1000. As additional genetic and environmental risk factors for HHC are identified, neonatal screening may become an acceptable strategy to follow susceptible individuals and prevent clinical disease.     

Intron 2 [IVS2, T-C +4] HFE gene mutation associated with S65C causes alternative RNA splicing and is responsible for iron overload.

A patient with congenital liver fibrosis revealed a high transferrin saturation index and iron overload on liver biopsy. He did not carry the most frequent HFE mutations: C282Y or H63D. Heterozygosity was detected for S65C. Unknown HFE mutations were also sought using a combined denaturing high performance liquid chromatography (DHPLC)/direct sequence approach and another point mutation, a transition T-C (nt 4910), at the fourth base of the donor splice site of intron 2 [HFE, intervening sequence (IVS) 2, T-C +4] was found. Family screening revealed that a daughter carried both S65C and [IVS2, T-C +4]. CONCLUSION:: The existence in our proband of a partly-altered HFE protein in the region encoded by exon 2 might be responsible for the histologically-demonstrated iron overload.