Hemochromatosis: genetics helps to define a multifactorial disease

Abstract

Hereditary hemochromatosis (HH) is a common autosomal recessive disorder that can result in iron overload and a wide range of clinical complications, including hepatic cirrhosis, diabetes mellitus, hypopituitarism, hypogonadism, arthritis, and cardiomyopathy. People with HH can be detected at an asymptomatic stage of the disease by abnormalities in serum iron measures. Early detection is desirable, because periodic phlebotomy provides effective treatment for iron overload and may prevent complications of the disorder. The natural history of HH is poorly understood, however, and the proportion of people detected by screening who will develop serious complications of HH is unknown. The genetics of HH may help to resolve these questions. The gene, HFE, and two mutations, C282Y and H63D, have been identified; the C282Y mutation has a higher penetrance than the H63D mutation, and appears to result in a greater loss of HFE protein function. Most people with HH are C282Y homozygotes, a small proportion are compound heterozygotes or H63D homozygotes, and some have no identifiable HFE mutation or are HFE heterozygotes, suggesting that additional mutations associated with HH are yet to be found. Gender and environmental agents, such as alcohol and dietary iron, influence phenotypic expression of HH. The severity of HH is thus determined by an interaction between genotype and modifying factors. HFE mutations also appear to increase the likelihood of iron overload in inherited anemias and to promote the clinical manifestations of porphyria cutanea tarda. HH is an important paradigm for medical genetics because it offers an opportunity to explore the complexity of gene–gene and gene–environment interactions.

Hereditary hemochromatosis beyond hyperferritinemia: Clinical and laboratory investigation of the patient’s profile submitted to phlebotomy in two reference centers in southern Brazil

“…Both in the scientific and healthcare environments, much is discussed about the variability in gene penetrance among the investigated variants, with C282Y being suggested as the one with the greatest causal effect, resulting in a greater loss of function of the encoded protein ( Burke et al, 1998 ; Rossi et al, 2008 ; Rametta et al, 2020 ). Therefore, a stratification of possible genotypes was considered, in which C282Y in homozygosity and in compound heterozygosity with H63D and S65C were allocated in a group with possible differentiated clinical impact (group 1), followed by the other genotypes with at least one variant detected (group 2), and a third group which was negative for the variants investigated (group 3).…”

The voice of haemochromatosis journeys in regional Australia – A qualitative study exploring self-management

“…1,2 The majority (approximately 90%) of individuals affected by haemochromatosis are homozygous for the C282Y mutation; H63D mutations are also associated with haemochromatosis, but to a lesser degree. 3,4 Haemochromatosis presents variably between individuals. The most frequently reported symptoms include fatigue, joint pain, skin discolouration and loss of libido.…”

“…Once iron levels have been depleted, patients may variably need to continue regular venesections depending on their individual cases. 3,7 Although venesection is the mainstay treatment of haemochromatosis, it is also considered reasonable for individuals to make dietary choices to decrease iron intake. However, there are no formal dietary guidelines for haemochromatosis.…”

Cardiomyopathies

“…254 Iron-overload cardiomyopathy, an important and potentially reversible cause of HF, involves diastolic dysfunction, increased susceptibility to dysrhythmias, and a late-stage DCM. 259 It appears that biochemical markers and tissue biopsy, which have traditionally been used to diagnose and guide therapy, are not sensitive enough to detect early cardiac iron deposition. Hereditary hemochromatosis is one of the most common autosomal-recessive disorders among Caucasians, because the genotype at risk for hemochromatosis accounts for 1:200-400 individuals of Northern European ancestry.…”