Aetiology
The most common type of haemochromatosis (type 1) involves mutations in the HFE gene, which is sometimes referred to as the haemochromatosis gene and is on the short arm of chromosome 6.[25] In the initial description of the discovery of the HFE gene, most of the subjects with haemochromatosis were found to be homozygous for the C282Y mutation, with a smaller proportion having a single copy of C282Y along with single copy of a second HFE mutation, H63D. Unlike C282Y, the H63D mutation is found in people of many different ethnicities.[26] An S65C mutation in the HFE gene has been studied but appears not to play a causative role in iron loading.[4][7] Homozygosity for C282Y is the most common disease-associated genotype in patients with clinically apparent haemochromatosis.[4][7][8]
More recent studies have led to a re-appraisal of the role of the H63D mutation. It has been known for some time that some compound heterozygotes (C282Y/H63D) have increased iron studies, but consequences of iron overload are rare in patients with this genotype.[27] When C282Y/H63D compound heterozygotes (and H63D homozygotes) are found to have iron overload, it is usually in the context of other conditions known to cause alterations in iron metabolism (e.g., alcoholism or dysmetabolic syndrome [obesity, hypertension, hyperlipidaemia, type 2 diabetes mellitus, and hyperuricaemia]). H63D is, therefore, no longer regarded as a disease-causing mutation but is rather a variant that can predispose to mild alterations in iron status.[4][7]
Individuals with phenotypic penetrance (the proportion of individuals carrying a particular variant of a gene who express an associated trait) are at risk of developing iron overload-related disease (IORD). Phenotypic penetrance is identified by elevated serum iron markers (transferrin saturation and/or serum ferritin) and varies between men and women. One study showed significantly greater serum ferritin levels and transferrin saturation in C282Y homozygotes than in those with other genotypes, with elevated ferritin levels being found in 82% of male and 55% of female untreated C282Y homozygotes.[11] The proportion of those with phenotypic penetrance at risk of developing IORD has been the subject of controversy. The available data indicate that less than half of C282Y homozygotes with significant iron burdens develop clinically significant consequences. Women in particular appear to be at low risk of IORD.[23][28] Several studies have documented that the risk of IORD, including cirrhosis, is low in C282Y homozygotes whose serum ferritin is below 2250 picomols/L (1000 nanograms/mL).[29][30][31] Apart from sex, other factors may modulate the tendency to iron accumulation as well as influencing the likelihood of IORD. These include as-yet unidentified genetic mutations, environmental factors such as blood loss or donation, alcohol use, diet, and infections such as viral hepatitis.[32]
Rarely, haemochromatosis occurs due to mutations in the genes encoding in hepcidin, ferroportin-1, transferrin receptor 2, or haemojuvelin.[4][7]
Pathophysiology
HFE participates in the sensing and regulation of body iron stores via modulation of the expression of the iron-regulatory hormone, hepcidin. In C282Y homozygotes, hepatic hepcidin gene expression is inappropriately low, which permits ongoing duodenal absorption of iron despite replete iron stores.[33] In addition, under low-hepcidin conditions, macrophages continually release iron derived from erythrophagocytosis. These phenomena probably account for the elevation in serum iron and transferrin saturation that is characteristic of haemochromatosis.
In patients with advanced, fully penetrant haemochromatosis, iron accumulates in multiple organs including liver, heart, anterior pituitary, pancreas, joints, and other organs.[4][7][8] The clinical manifestations of haemochromatosis are presumed to be the direct result of the pro-oxidant effects of excess iron in these organs. The relationship between excess iron and organ damage is most clearly established in the liver (where significant fibrosis occurs only with substantial iron burdens) and in the heart. In these organs, removal of excess iron improves organ function and can lead to reversal of fibrosis.[34] Although diabetes is often attributed to pancreatic damage from iron accumulation, data have shown that the prevalence of diabetes among C282Y homozygotes is not increased compared with the general population, except in the setting of cirrhosis, where there is a known association of diabetes with cirrhosis of various aetiologies.[28][30] Nonetheless, control of diabetes may improve following removal of excess iron. In contrast, phlebotomy does not consistently lead to improvement in joint symptoms.[35][36][37]
Classification
The American College of Gastroenterology[4]
There are four main types of haemochromatosis.
Type 1 (HFE gene mutations)
Autosomal-recessive disorder as a result of mutations of the HFE gene on chromosome 6. Accounts for the majority of cases.
Type 1A hereditary haemochromatosis (homozygote, mutations in HFE C282Y); type 1B hereditary haemochromatosis (compound heterozygote, mutations in HFE C282Y and H63D); type 1C hereditary haemochromatosis (mutations in HFE S65C).
Patients with type 1A or type 1B haemochromatosis present with arthropathy, skin pigmentation, liver damage, diabetes mellitus, endocrine dysfunction, cardiomyopathy, hypogonadism.
Patients with type 1C haemochromatosis may have elevations in serum iron/ferritin, with no evidence of tissue iron deposition.
Type 2 (Juvenile haemochromatosis)
Autosomal-recessive disorder as a result of a mutation of the haemojuvelin gene (type 2A juvenile hereditary haemochromatosis) or hepcidin gene (type 2B juvenile hereditary haemochromatosis).
Type 2A locus is 1p21; type 2B locus is 19q13.
Early onset (<30 years); hypogonadism and cardiomyopathy prevalent.
Type 3 (Transferrin receptor 2 gene mutations)
Type 3 hereditary haemochromatosis is an autosomal-recessive disorder resulting from a mutation in transferrin receptor 2 gene (7q22).
Patients present with arthropathy, skin pigmentation, liver damage, diabetes mellitus, endocrine dysfunction, cardiomyopathy, hypogonadism.
Type 4 (Ferroportin [FPN] disease)
Autosomal-dominant disorder as a result of a mutation of the ferroportin-1 (SLC40A1) gene (2q32).
Type 4A hereditary haemochromatosis (FPN disease, loss of function for FPN excretion): characterised by iron deposition in the spleen, lower tolerance to phlebotomy, and anaemia.
Type 4B hereditary haemochromatosis (non-classical FPN disease, gain of function): associated with fatigue and joint pain.
The International Society for the Study of Iron in Biology and Medicine (BIOIRON Society)[5]
BIOIRON Society has developed an alternative method of classification, which it feels will be easier to use in clinical practice than the existing classification.[5] Its proposed new classification, published in 2022, involves both clinical and molecular considerations, and excludes Ferroportin disease due to its distinct phenotype.[5] This proposed new classification includes the categories: HFE-related, non-HFE-related, digenic (mutations in two different genes involved in iron metabolism), and molecularly undefined.[5]
French recommendations for the management of HFE haemochromatosis: Haute Autorité de Santé[6]
The following staging system can be used to guide therapy:
Stage 0: C282Y homozygosity with normal serum transferrin saturation and ferritin and no clinical symptoms
Stage 1: C282Y homozygosity with increased transferrin saturation (>45%), normal ferritin, and no clinical symptoms
Stage 2: C282Y homozygosity with both increased transferrin saturation (>45%) and serum ferritin (>300 micrograms/L in men, >200 micrograms/L in women), but no clinical symptoms
Stage 3: C282Y homozygosity with increased transferrin saturation (>45%) and serum ferritin (>300 micrograms/L in men, >200 micrograms/L in women), as well as clinical symptoms affecting the quality of life that are attributed to this disease (e.g., asthaenia, impotence, and arthropathy)
Stage 4: C282Y homozygosity with increased transferrin saturation (>45%) and serum ferritin (>300 micrograms/L in men, >200 micrograms/L in women), and clinical symptoms manifesting organ damage predisposing to early death (e.g., cirrhosis with risk of hepatocellular carcinoma, insulin-dependent diabetes, and cardiomyopathy).
Use of this content is subject to our disclaimer