Impact of HFEgenetic testing on clinical presentation of hereditary hemochromatosis: new epidemiological data

Abstract

BackgroundHereditary hemochromatosis (HH) is a common inherited disorder of iron metabolism in Northern European populations. The discovery of a candidate gene in 1996 (HFE), and of its main mutation (C282Y), has radically altered the way to diagnose this disease. The aim of this study was to assess the impact of the HFE gene discovery on the clinical presentation and epidemiology of HH.MethodsWe studied our cohort of 415 patients homozygous for the C282Y allele and included in a phlebotomy program in a blood centre in western Brittany, France.ResultsIn this cohort, 56.9% of the patients were male and 21.9% began their phlebotomy program before the implementation of the genetic test. A significant decrease in the sex ratio was noticed following implementation of this DNA test, from 3.79 to 1.03 (p < 10-5), meaning that the proportion of diagnosed females relatives to males greatly increased. The profile of HH patients at diagnosis changed after the DNA test became available. Serum ferritin and iron values were lower and there was a reduced frequency of clinical signs displayed at diagnosis, particularly skin pigmentation (20.1 vs. 40.4%, OR = 0.37, p < 0.001) and hepatomegaly (11.0 vs. 22.7%, OR = 0.42, p = 0.006). In contrast, fatigue became a more common symptom at diagnosis (68.0 vs. 51.2%, OR = 2.03, p = 0.004).ConclusionThis study highlights the importance of the HFE gene discovery, which has simplified the diagnosis of HH and modified its clinical presentation and epidemiology. This study precisely measures these changes. Enhanced diagnosis of HFE-related HH at an early stage and implementation of phlebotomy treatment are anticipated to maintain normal life expectancy for these patients.

The molecular genetics of haemochromatosis

“…We have recently shown that HFE C282Y mutation testing has modified the epidemiology of haemochromatosis, with the sex ratio reduced to close to 1.0 and a weaker clinical expression than observed previously. 132 However, we should also be aware that the C282Y homozygous genotype is not fully penetrant and that its expression depends on the complex interplay of genetic and nongenetic factors. Several investigations are focusing on discovery of the genetic factors that enable us to identify more precisely those C282Y homozygous patients at increased risk of developing clinical features.…”

Prevalence of C282Y and H63D mutations in the HFE gene of Brazilian individuals with clinical suspicion of hereditary hemochromatosis

“…3,5 As it was expected, when assessed together, there was no statistical difference in the genotypic frequencies of C282Y and H63D between genders due to the fact that both are autosomally inherited.…”

“…2,3,4 It is unquestionable that C282Y is the main mutation responsible for HH in all studied populations, as the majority of published reports worldwide cite its prevalence in more than 80% of individuals with clinical manifestations of HH, 1,[4][5][6]12,15,17,23 thus several other diagnostic guides are based on the result of C282Y mutation genic testing. 2,6,7,15 It is not different for the Brazilian population, as in the paper by Bittencourt et al, 1 homozygous individuals for this mutation present an earlier onset for pathological aspects compared to heterozygous individuals with an onset at an earlier age than the wild allele, 282CC.…”

“…The fifth decade is, in particular, the most common period among women for the onset of signs and symptoms. 5,6 Classical hereditary hemochromatosis (Type 1) is associated to the presence of genetic variations in the HFE gene located in the short arm of the 6p21.3 chromosome. 1,9,10 An average of 20 mutations have been identified in this gene; 5 nevertheless, there are two missense mutations, C282Y and H63D, which are more commonly associated to HH.…”

“…Clinical manifestations predominate in men (two to three times more common in men than in women) while the absence of this phenotype is common in women due to monthly blood loss which decreases iron deposits in the body. 2,5,6 HH presents a long term latency 7 and is divided into 3 stages: from 0 to 20 years old, in which there is no iron accumulation; from 20 to 40, in which there is an iron overload, however, with no physiological damage, and over 40, when there is an iron overload and damage to organs, initially with fibrosis and/or hepatic cirrhosis. 8 Generally, clinical manifestations appear between the ages of 40 and 60.…”