Version May 2024
INTRODUCTION — This topic reviews the genetics and functions of the HFE gene and other genes associated with hereditary hemochromatosis (HH) syndromes, including some of the more challenging clinical questions related to the likelihood of iron overload in individuals with HFE variants, the extent and sequence of testing in an individual with iron overload who does not have a common variant in HFE, and the role of screening at-risk populations.
Separate topics discuss evaluation and management of hereditary hemochromatosis and other causes of iron overload:
●General evaluation of iron overload – (See "Approach to the patient with suspected iron overload".)
●Diagnosis of HH – (See "Clinical manifestations and diagnosis of hereditary hemochromatosis".)
●Management of HH – (See "Management and prognosis of hereditary hemochromatosis".)
●Screening of at risk relatives – (See "Management and prognosis of hereditary hemochromatosis", section on 'Testing and counseling first-degree relatives'.)
●Iron chelation – (See "Iron chelators: Choice of agent, dosing, and adverse effects".)
HFE GENE FUNCTION — Understanding of HFE gene function continues to evolve. The following describes some of the major observations:
●The HFE gene was identified in 1996 by positional cloning, 20 years after hereditary hemochromatosis (HH) was recognized as a monogenic disorder linked to the major histocompatability complex (MHC) cluster [1-4]. The gene was originally called HLA-H. Later, the name HFE was adopted (H for "high" and Fe as the chemical symbol for iron; the H could also stand for "hereditary" or "homeostatic") [5,6]. The original description of the gene also identified the most common HFE mutation, which is presumed to represent an ancestral founder mutation that occurred >4000 years ago in Northern Europe [7,8]. (See 'C282Y' below.)
●Subsequent studies confirmed the high frequency of two HFE variants, C282Y (referred to as 845A for the nucleotide sequence) and H63D (referred to as 187G), in diverse populations with European ancestry including individuals from France, Australia, Italy, and Germany [9-13].
●Crystal structure and domain analysis of the HFE protein revealed it to be a cell surface protein with three extracellular domains and a similar structure to class I MHC molecules (figure 1) [14]. The HFE protein binds to beta-2-microglobulin (β2-microglobulin) on the cell surface, but unlike MHC molecules, it does not bind or "present" small peptides [15,16]. The C282Y mutation interferes with HFE binding to beta-2-microglobulin and prevents membrane localization [17,18].
●On the surface of cells, HFE interacts with the transferrin receptor 1 (TfR1) [19,20]. HFE and diferric transferrin compete for binding to the same region of TFR1 [20].
●HFE is ubiquitously expressed, but its main function is in hepatocytes where it positively regulates hepcidin. The mechanism is not completely understood, but it has been proposed that HFE may act via a bone morphogenetic protein (BMP) pathway, by stabilizing the BMP type I receptor ALK3 (activin receptor-like kinase 3) on the cell surface to increase hepcidin transcription and reduce serum iron levels [21]. Pathogenic variants in HFE such as C282Y produce a protein that can no longer stabilize ALK3 and in turn are unable to activate the BMP pathway. (See 'HFE variants in hereditary hemochromatosis' below.)
Support for the role of HFE in the liver comes from observations of increased iron uptake in hepatocytes from HFE-knockout mice and individuals with HFE mutations [22,23]. In a series of 18 individuals with HH who underwent liver transplantation, hepcidin levels were low before transplant and normalized after transplant, presumably due to normal HFE expression in hepatocytes [24]. A mouse model of tissue-specific HFE gene deletion in the intestine did not demonstrate an appreciably altered iron balance, suggesting that normal HFE expression in hepatocytes is sufficient to regulate intestinal iron absorption [25]. In contrast, a mouse model of conditional HFE gene deletion in hepatocytes resulted in hemochromatosis [26]. Additional details are presented separately. (See "Regulation of iron balance", section on 'Iron sensing and signaling pathway'.)
●Hepcidin controls iron absorption in the intestine and iron release from macrophages via its binding to ferroportin [27].
●In the placenta, the HFE-beta-2-microglobulin-TfR1 complex may facilitate iron transport to the fetus [28].
●Evidence is increasing for a role for HFE in immune function, perhaps via regulation of the T cell repertoire or by negatively regulating antigen presentation [29]. This is only one aspect of multiple intersections between iron metabolism and immunity [30].
HFE VARIANTS IN HEREDITARY HEMOCHROMATOSIS
Overview of genotypes — Hereditary hemochromatosis (HH) due to pathogenic variants in HFE (MIM 235200) is an autosomal recessive disorder; in the vast majority of cases, affected individuals have biallelic HFE mutations. HFE-related HH has also been referred to as "type 1" HH, although the complex type-numerical HH classification has been supplanted by a more clinically focused HH classification [31].
The most common HH genotype is homozygosity for the C282Y variant (C282Y/C282Y). The H63D variant can contribute to a minority of cases in compound heterozygosity with C282Y (C282Y/H63D), generally in combination with other causes of liver disease that contribute to iron overload, such as alcohol, hepatitis C virus (HCV) infection, or nonalcoholic fatty liver disease (NAFLD) [31,32]. Other point mutations or HFE gene deletion are less common. (See 'Rare HFE variants' below.)
The distribution of these genotypes within HH populations of individuals with European ancestry is as follows [10-13,33-35]:
●C282Y/C282Y – 80 to 100 percent.
●C282Y/H63D – 2 to 7 percent.
In unselected series of individuals with European ancestry, the prevalence of homozygous HFE C282Y is approximately 1 in 150 to 1 in 300 (0.44 percent) [36,37].
Observation of iron overload in C282Y heterozygotes (C282Y/wildtype) may represent association rather than causation, as the risk of developing HH is similar to the general population. These individuals may have another HFE variant, a pathogenic variant in another gene, or iron overload from another cause such as excess alcohol consumption [34,38-40]. In cases of severe iron overload in a C282Y heterozygote, without evident acquired causes of iron overload, disease variants in other genes may be suspected. (See 'Non-HFE hemochromatosis' below and "Approach to the patient with suspected iron overload", section on 'Causes of iron overload'.)
The likelihood of developing iron overload with each of the genotypes is discussed below. (See 'Likelihood of developing iron overload' below.)
C282Y — The C282Y variant is the most common finding in individuals with HH. Homozygosity for C282Y is found in approximately 80 to 100 percent of individuals with clinical iron overload from a genetic cause. (See 'Overview of genotypes' above.)
The C282Y variant has a tyrosine instead of a cysteine at position 282 of the HFE protein. This is caused by a point mutation (a guanine to adenine [G to A] transition) at nucleotide 845 of the HFE gene [41]. This change disrupts the interaction of the HFE protein with beta-2-microglobulin (β2-microglobulin), which in turn causes HFE to be sequestered in the cytoplasm and prevents it from being transported to the cell surface and carrying out its normal function [41]. Interestingly, b2-microglobulin knockout mice also develop iron overload [15,16,42]. (See 'HFE gene function' above.)
As noted separately, the C282Y variant is especially common in White people of northern European ancestry, with a population frequency of 4 to 7 percent, and heterozygosity for this variant may have been selected for during evolution. The population frequency is lower in other groups including Native Americans, individuals with Hispanic ethnicity, and individuals with African ancestry, and it is extremely rare in people with East Asian ancestry and individuals with Mexican ancestry (<0.1 percent) [36]. (See "Clinical manifestations and diagnosis of hereditary hemochromatosis", section on 'Epidemiology' and "Clinical manifestations and diagnosis of hereditary hemochromatosis", section on 'Genotype-phenotype correlations'.)
H63D — The H63D variant is also seen in individuals with HH, although much less commonly than C282Y. Compound heterozygosity (C282Y/H63D) is seen in a few percent of individuals with HH, usually with mild, non-progressive iron overload and in the presence of other contributory factors such as liver disease from excess alcohol intake, HCV infection, or NAFLD; such other factors need to be searched for and corrected whenever possible [31,32,35,43]. (See 'Overview of genotypes' above.)
The H63D variant has a histidine instead of an aspartate at position 63 of the HFE protein, caused by a point mutation (a cytosine to guanine [C to G] transition) at nucleotide 187 of the HFE gene [41]. This change appears to reduce the interaction between HFE and TfR1, but it does not abolish HFE localization to the cell surface or interaction with beta-2-microglobulin. (See 'HFE gene function' above.)
Rare HFE variants — A number of other rare HFE variants have been described, especially in individuals with non-northern European ancestry.
●Point mutations – A study that genotyped a cohort of 206 individuals with HH who did not have the common C282Y/C282Y genotype found "private" variants in HFE in 13 unrelated individuals [44]. Some of these were point mutations that created a premature stop codon (Y52*; E168*; L270R*; A271V*; H341L*); others affected the protein sequence (D141Y; K166N), and their causality is less proven. Affected individuals typically had biallelic variants (eg, they were compound heterozygotes for one of these HFE mutations along with C282Y).
The HFE S65C variant has been reported to be associated with mild iron overload, only when expressed in combination with C282Y [33]. However, this genotype is no longer considered a hemochromatosis susceptibility genotype since it requires other contributory factors to produce even mild iron overload.
●Gene deletion – Homozygous deletion of the HFE-containing region of chromosome 6p has also been described in individuals with HH. This genotype is the most common cause of HH in Sardinia, apparently due to a founder effect [45-48].
Genetic modifiers of HFE — The penetrance of HFE C282Y (development of clinical iron overload in homozygous individuals) is likely to be modified by a number of genetic factors, some of which remain to be elucidated [49,50].
●BMP2 – Variants in the gene that encodes bone morphogenetic protein 2 (BMP2, also called BMP2A) may modify the phenotype of HFE C282Y hemochromatosis [49,51,52]. BMP2 is a ligand for BMP receptors and a regulator of hepcidin, as discussed separately. (See "Regulation of iron balance", section on 'Iron sensing and signaling pathway'.)
●BMP6 - Heterozygous mutations affecting the BMP6 propeptide have been associated with inappropriately reduced hepcidin levels and mild iron overload in some but not all populations [53-55].
●GNPAT – A variant in the GNPAT gene is associated with increased iron in individuals who are homozygous for HFE C282Y [56].
●PCSK7 – A variant in PCSK7 has been reported to lead to liver fibrosis in individuals with HFE-associated hemochromatosis [57].
●Other iron regulatory genes – Variants in the genes for hepcidin (HAMP) or hemojuvelin (HJV) were associated with an increased risk of clinically significant iron overload in individuals with HFE mutations [58-60].
●Polygenic risk scores – A 2022 study involving a series of 2890 C282Y homozygous individuals from the United Kingdom Biobank found that polygenic risk scores (PRS) built up with 128 non-HFE common variants associated with markers of increased iron significantly increased the clinical penetrance of iron overload (odds ratio [OR] for top 20 percent of PRS versus the bottom 20 percent, 4.90, 95% CI 1.63-14.73), pointing out the complexity of the overall genetic background [61].
All such factors may modify other forms of HH, although HFE HH is the most common form of HH.
NON-HFE HEMOCHROMATOSIS — The majority of individuals with hereditary hemochromatosis (HH) are homozygous for HFE C282Y. (See 'HFE variants in hereditary hemochromatosis' above.)
However, some individuals have pathogenic variants in other genes including HJV, HAMP, and TFR2. These rare types of HH are collectively called non-HFE hemochromatosis [30].
A 2018 systematic review of non-HFE HH cases was used to create a non-HFE HH database [62]. Major findings included a generally younger age at diagnosis for non-HFE HH (in the 20s for HJV and HAMP variants and in the early 30s for TRF2 variants, compared with the 40s for HFE-related HH), higher serum ferritin levels and transferrin saturation (TSAT) in the non-HFE patients, and greater likelihood of clinical complications in the non-HFE patients, especially cardiac involvement and hypogonadism.
The younger age of presentation compared with classical (HFE-related) HH has been reported in other studies and has led to the term juvenile hemochromatosis for individuals with disease variants in the HJV and HAMP genes [35,63,64]. (See 'Juvenile hemochromatosis' below.)
Some of these gene variants and their clinical characteristics and inheritance patterns are summarized in the table (table 1). A general discussion of how these genes regulate systemic iron balance is presented separately. (See "Regulation of iron balance".)
Other genetic disorders are characterized by iron overload in the brain (eg, hereditary aceruloplasminemia, neuroferritinopathy) or high serum ferritin without systemic iron overload; these are discussed separately. (See "Bradykinetic movement disorders in children", section on 'Neurodegeneration with brain iron accumulation' and "Approach to the patient with suspected iron overload", section on 'Other causes of high ferritin'.)
Juvenile hemochromatosis — Juvenile hemochromatosis refers to HH that presents in childhood, adolescence, or early adulthood (before age 30 years) [65]. This phenotype, formerly called "type 2" HH, is typically associated with variants in the genes for hemojuvelin (HJV) or hepcidin (HAMP). The prevalence is extremely low, and many case reports describe fatal outcomes due to delayed diagnosis and severe organ iron deposition [66]. In several cases, parents were reported to be consanguineous.
Hemojuvelin (HJV) — Juvenile HH due to variants in HJV (previously called HFE2) (MIM 602390) is an autosomal recessive disorder [67-70]. HH due to an HJV mutation has been formerly referred to as "type 2A" HH. This form of juvenile HH has been reported in a number of Italian, Greek and Canadian pedigrees (people of French origin from the geographically isolated Saguenay Lac St Jean region), where several different HJV variants have been described [68,71-73]. Affected individuals are more likely to present with cardiomyopathy, reduced glucose tolerance, and hypogonadism, rather than severe liver disease [35,74]. HJV mutations are reported also in middle-aged individuals of Asian ancestry; however, all had severe clinical complications.
Hemojuvelin, a glycosylphosphatidylinositol (GPI) anchor-linked protein, appears to be involved in the BMP pathway that upregulates hepcidin, acting as a BMP coreceptor [75-78]. (See 'Hepcidin (HAMP)' below.)
Hepcidin (HAMP) — Juvenile HH due to variants in HAMP (hepcidin antimicrobial peptide, also called LEAP1) (MIM 613313) is an autosomal recessive disorder. HH due to a pathogenic variant in HAMP was formerly referred to as "type 2B" HH. This form of juvenile HH has been reported in individuals from Italy, Greece, and Portugal, and in individuals from Asia with high degree of consanguinity [79-82].
Low levels of hepcidin result in markedly increased intestinal iron absorption and iron release from macrophages, highlighting the essential role for hepcidin in regulating iron balance. (See "Regulation of iron balance", section on 'Hepcidin'.)
Transferrin receptor 2 (TFR2) — HH due to variants in TFR2 (MIM 604250) is a rare autosomal recessive disorder. HH due to TFR2 mutations has been also referred to as "type 3" HH. This disorder has been reported in individuals from Italy, France, Spain, Portugal, and Japan [35,83-87]. The clinical phenotype appears to be of intermediate severity between classical and juvenile HH [35,86-88].
The function of the TfR2 protein involves binding to diferric transferrin and iron sensing; unlike TfR1, TfR2 does not import iron and has a lower affinity for diferric transferrin. In the liver, TfR2 is involved in hepcidin regulation [89,90]; patients with TFR2 variants and a mouse model of TFR2 inactivation show low hepcidin levels [91] and have iron overload [83,84,86]. (See "Regulation of iron balance", section on 'Transferrin receptor 2'.)
Ferroportin (SLC40A1; FPN1) — HH due to variants in SLC40A1 (also called FPN1) (MIM 606069) is an extremely rare autosomal dominant disorder. HH due to a pathogenic variant in SLC40A1 has also been referred to as "type 4" HH or ferroportin disease. This may represent a cause of HH in individuals of African or Chinese ancestry [92-94]. Cases in individuals with European ancestry have also been reported [95-99].
There appear to be two different phenotypes [92]:
●Macrophage-type – Loss-of-function mutations of ferroportin are thought to produce a molecule that either does not traffic appropriately to the cell surface or that has limited ability to export iron (figure 2).
This results in excess accumulation of iron in macrophages, with resulting high serum ferritin, normal to reduced transferrin saturation (TSAT), and mild anemia [100-102]. In young females, hypochromic microcytic anemia may develop that is responsive to iron supplementation [35]. This has also been called macrophage-type (M-type) and is now considered the real ferroportin disease, which is no longer included among HH because of the distinct phenotype [31,92].
●Hepatic-type (non-classical) – Gain-of-function mutations produce a ferroportin protein that is resistant to hepcidin and retains full iron export capability (figure 2) [103-105]. The mutation may affect the binding site for hepcidin (C326) or occurs in its proximity [106]. Iron overload is similar to classic HH [92].
This results in increased TSAT, high levels of ferritin and hepcidin, and hepatic iron overload, similar to or more severe than classical HH [31]. Liver biopsy has shown increased hepatocyte iron. In ferroportin disease, unlike classical hemochromatosis, the iron is considerably more prominent in Kupffer cells than in hepatocytes, and fibrosis is primarily sinusoidal [35,97-99,107].
Ferroportin is the iron transport channel mainly expressed in macrophages and hepatocytes and on the basolateral surface of intestinal enterocytes that is blocked by hepcidin. Ferroportin has also been implicated in the transport of other ions such as manganese [108]. (See "Regulation of iron balance", section on 'Ferroportin'.)
PIGA — A 2022 study identified variants in PIGA in three patients with an unusual phenotype resembling the juvenile hemochromatosis phenotype, with the addition of severe neurologic abnormalities (early-onset epilepsy, severe developmental delay, and intellectual disability) [109]. All three were males and were diagnosed during childhood due to neurologic findings; they were also found to have evidence of iron overload and low hepcidin levels.
PIGA, located on the X chromosome, encodes the phosphatidylinositol glycan anchor biosynthesis class A protein, the first enzyme in the pathway that adds a glycophosphatidylinositol (GPI) anchor to certain plasma membrane proteins to maintain their cell surface attachment. The hemojuvelin protein is GPI-anchored, suggesting this may be the mechanism by which these PIGA variants cause reduction of hepcidin and iron overload. The mechanism of the neurologic findings remains unexplained; however, homologues of hemojuvelin (repulsive guidance molecules [RGMs]) are expressed on normal neuronal cells and are GPI-anchored; low levels of ceruloplasmin, which is also GPI-anchored on glial cells, may contribute.
Germline PIGA variants are associated with other congenital anomalies (multiple congenital anomalies-hypotonia-seizures syndrome-2 [MCAHS2]). Acquired somatic PIGA variants in hematopoietic stem cells are seen in paroxysmal nocturnal hemoglobinuria (PNH); the lack of a GPI anchor causes deficiency of certain complement regulatory proteins on the surface of circulating red blood cells (RBCs), leading to chronic hemolytic anemia. Individuals with germline pathogenic variants in PIGA have no biochemical or clinical signs of PNH, likely because the constitutional (germline) variants allow some residual protein function, at variance with the somatic null mutations. (See "Pathogenesis of paroxysmal nocturnal hemoglobinuria", section on 'PIGA gene mutation' and "Pathogenesis of paroxysmal nocturnal hemoglobinuria", section on 'GPI anchor'.)
CLINICAL IMPLICATIONS
Likelihood of developing iron overload
Role of HFE genotype in iron overload and complications — HFE-related HH is an autosomal recessive disorder with reduced clinical penetrance. Biallelic HFE C282Y mutations are necessary for the development of clinical iron overload but not sufficient; the majority of individuals with biallelic HFE mutations will not develop clinical iron overload [61,110].
The risk of iron overload in HFE C282Y homozygotes is variably estimated in unselected populations to be as low as 1 percent in females to as high as 28 percent in males (table 2). This means that as high as 72 to 99 percent of individuals with biallelic HFE C282Y mutations will not develop clinical iron overload, especially females and individuals with a negative family history [111,112].
Individuals who develop severe iron overload are also at risk for complications such as liver disease (cirrhosis and liver cancer), heart disease (heart failure and arrythmias), endocrine dysfunction, and others. (See "Clinical manifestations and diagnosis of hereditary hemochromatosis", section on 'Manifestations of organ iron overload'.)
In contrast, non-HFE hemochromatosis has a much higher clinical prevalence. In cases of severe iron overload in an HFE C282Y heterozygote, pathogenic variants in one of the non-HFE genes may be suspected. (See 'Non-HFE hemochromatosis' above.)
Heterozygotes for HFE C282Y have a similar risk of developing iron overload as the general population. This risk is not zero, as some individuals in the general population have iron overload due to as-yet undiscovered causes, but it is extremely low. (See "Clinical manifestations and diagnosis of hereditary hemochromatosis", section on 'Genotype-phenotype correlations' and "Management and prognosis of hereditary hemochromatosis", section on 'Heterozygous individuals'.)
The documentation of iron overload depends on the means of assessment (eg, questionnaire versus liver imaging or biopsy). Biochemical evidence of iron overload (increased serum transferrin saturation [TSAT] and ferritin) is more common:
●A 2022 United States biobank study involving 445,521 participants identified 2890 C282Y homozygous individuals (0.7 percent) [113]. Only 12 percent of C282Y homozygous males were diagnosed with hemochromatosis at baseline, and only 33 percent of males and 21 percent of females were diagnosed with hemochromatosis by the end of the 14-year follow-up, at mean ages of 69 and 70 years, respectively [61].
●A population study that identified HFE C282Y homozygotes and used patient questionnaires to determine whether they had symptoms of clinical iron overload found that only 1 of 152 (<1 percent) were affected [114]. This study did not include iron studies or other measures of iron overload.
●A population study that genotyped 9174 individuals from the Copenhagen City Heart Study identified 23 HFE C282Y homozygotes [115]. Many had high TSAT and ferritin levels, but none developed clinically overt hemochromatosis over 25 years of follow-up.
●In the Hemochromatosis and Iron Overload Screening (HEIRS) study, which screened 101,168 primary care participants for iron overload, 333 HFE C282Y homozygotes were detected (prevalence, 0.3 percent); of these, 75 (23 percent) had previously been diagnosed with HH [116].
●A population-based study from Australia that performed HFE testing on over 30,000 individuals of northern European descent who were between the ages of 40 and 69 years identified 203 C282Y homozygotes (prevalence, 0.65 percent) [111]. During approximately 12 years of follow-up, iron overload and at least one complication (cirrhosis, liver fibrosis, hepatocellular cancer, abnormal liver function tests, and/or classical HH arthropathy) was seen in approximately 28 percent of the C282Y homozygous men and 1 percent of the C282Y homozygous women.
A related study from some of the same authors looked more closely using liver biopsy in 672 asymptomatic individuals who were homozygous for HFE C282Y [117]. Hepatic iron overload was identified in 56 percent of males and 35 percent of females, hepatic fibrosis was seen in 18 percent of males and 5 percent of females, and cirrhosis was seen in 6 percent of males and 2 percent of females. More than half of the individuals in this cohort were identified because they had a family member with HH, which could bias the results towards individuals with a greater likelihood of clinically significant iron overload than would be seen in the general population, although results were generally similar regardless of the indication for HFE testing.
Further discussion of genetic and acquired factors that can influence disease penetrance are discussed separately. (See "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)", section on 'Penetrance and expressivity'.)
Additional risk factors — The population data summarized above (see 'Role of HFE genotype in iron overload and complications' above) can provide a general sense of disease penetrance, but there are a number of potentially useful considerations in estimating the likelihood of iron overload in an individual with biallelic HFE mutations [118-120].
●Family history – A positive family history of HH-associated iron overload is probably a surrogate for other genetic contributions to increased iron absorption. A study that identified 214 HFE C282Y homozygous relatives of individuals with HH (mostly siblings) found that up to 43 percent of males and 10 percent of females had a clinical complication of iron overload such as elevated hepatic transaminases, hemochromatotic arthropathy, hepatic fibrosis, or cirrhosis [121]. The average age at the time of testing was 41 years for men and 44 years for women, and the risk for disease complications was higher in men over age 40 and women over age 50. Data such as these provide the rationale for evaluating all first-degree relatives of individuals with HH, typically after they reach adulthood. (See "Management and prognosis of hereditary hemochromatosis", section on 'Testing and counseling first-degree relatives'.)
●Age and sex – Males and postmenopausal women have a higher risk of developing iron overload because they do not lose iron during monthly menstrual cycles or pregnancy. The risk of HH increases with age due to progressive accumulation of iron over time. (See "Clinical manifestations and diagnosis of hereditary hemochromatosis", section on 'Typical presentations'.)
●Alcohol use or other comorbidities – Alcohol intake is often a consideration in individuals with HH-associated liver disease and appears to increase the risk of progression to cirrhosis. In one study involving C282Y/H63D compound heterozygotes, complications of iron overload only developed in those with excess alcohol use or another comorbidity such as diabetes or hepatic steatosis [122]. (See "Management and prognosis of hereditary hemochromatosis", section on 'Limiting alcohol'.)
●Genetic modifiers – Several iron regulatory genes have been identified that may modify risk. (See 'Genetic modifiers of HFE' above.)
●Other genetic conditions– Beta-thalassemia may cause ineffective erythropoiesis, which in turn increases intestinal iron absorption. A small study found that compared with controls with the same HFE genotype, individuals who were also carriers of beta-thalassemia trait developed iron overload at an earlier age and had a higher degree of iron overload and related complications (heart failure, hypogonadism, liver disease) [123]. This might be related to the well-known mechanism of hepcidin inhibition by erythroferrone that is increased in beta-thalassemia [124]. (See "Diagnosis of thalassemia (adults and children)", section on 'Iron overload'.)
Sequence of testing in individuals with iron overload — A diagnosis of HH generally requires clinical iron overload as well as a relevant HFE genotype. (See "Clinical manifestations and diagnosis of hereditary hemochromatosis", section on 'Diagnostic criteria'.)
Thus, testing for HFE mutations is appropriate in individuals with increased TSAT, increased serum ferritin, or other evidence of iron overload. This is especially true for those who do not have another cause of iron overload such as beta-thalassemia or transfusional iron overload, but it may also be appropriate in individuals who do have other causes of iron overload, those with other causes of liver disease such as porphyria cutanea tarda, and/or those with unexplained increases in hepatic transaminases.
Typically, initial HFE genotyping panels test for the C282Y and H63D variants. Homozygosity for C282Y or compound heterozygosity for these two variants accounts for the vast majority of individuals with HH.
For individuals with negative initial HFE genotyping, there are several options for subsequent evaluations. Regardless of the genotype, clinically significant iron overload should be treated (ie, the absence of an HFE mutation is not a reason to withhold treatment). (See "Management and prognosis of hereditary hemochromatosis", section on 'Iron removal'.)
Options for further testing include the following:
●For an individual with a known familial genotype that includes variants other than C282Y and H63D, it may be reasonable to test for the familial variant(s) alone. This is especially true if there are first-degree relatives for whom this genotyping information may help guide management.
●For individuals who have developed iron overload at a younger age (eg, before age 40 in men or before menopause in women) or those from non-European backgrounds, it may be reasonable to test for less common HFE variants and variants in other genes (see 'Non-HFE hemochromatosis' above). This is especially true if genotyping information would be helpful for first-degree relatives. Sequential testing versus the use of a gene panel is individualized based on patient features and available testing resources. Testing for specific variants in the relevant gene(s) versus gene sequencing using a next generation sequencing (NGS) approach is also individualized based on available resources [125,126].
●For individuals who do not wish to pursue further testing, it is reasonable to treat for non-HFE iron overload without documenting the underlying genotype. This is especially true for those in whom additional testing would incur additional costs and burdens without additional benefit. (See "Management and prognosis of hereditary hemochromatosis", section on 'Iron removal'.)
●For those with a high ferritin without evidence of iron overload (ie, no elevation in TSAT and/or no evidence of iron deposition on magnetic resonance imaging [MRI] or tissue biopsy), evaluation for other conditions that increase serum ferritin (eg, chronic inflammatory conditions, liver injury) may be appropriate. (See "Approach to the patient with suspected iron overload", section on 'Other causes of high ferritin'.)
Testing of first-degree relatives — First-degree relatives of individuals with HH should be tested for the familial mutation(s) and for iron overload (eg, with iron studies). Important considerations, such as delaying testing until adulthood, are discussed separately. (See "Clinical manifestations and diagnosis of hereditary hemochromatosis", section on 'Asymptomatic first-degree relatives' and "Management and prognosis of hereditary hemochromatosis", section on 'Testing and counseling first-degree relatives'.)
ROLE OF POPULATION SCREENING — There is general agreement that routine population screening for hereditary hemochromatosis (HH) using genetic testing is not cost-effective, and we suggest routine genetic testing not be performed in average-risk individuals in the general population (those who lack evidence of iron overload and have a negative family history for HFE-related HH). This is consistent with most guidelines and consensus documents, which advise against unselected population screening for mutations in HFE or other hemochromatosis genes [127,128].
Additional reasons cited for avoiding routine population screening have included the unclear prevalence of clinically significant disease, the lack of demonstrated benefits to screening that outweigh risks and costs, possible reluctance of insurance carriers to pay the costs of phlebotomy in asymptomatic individuals, possible genetic discrimination (documented in some reports), and unnecessary interventions and/or anxiety, and difficulty communicating results to large numbers of individuals [129-134]. Further, no studies have established whether population screening impacts patient-important outcomes such as liver disease or heart disease from HH.
The HFE C282Y variant has a relatively high prevalence, and, in contrast to the general population, screening may be reasonable for certain populations who are at higher risk for developing iron overload (eg, men and postmenopausal women) [135]. If high-risk individuals are screened, phenotypic testing with iron studies (ferritin and transferrin saturation [TSAT]) rather than HFE genotyping may be the best screening test. Cost-effectiveness studies have found the expense of screening for HH using iron studies to be reasonable considering the number of individuals who would not otherwise have been identified [136,137].
HFE testing is often appropriate for individuals with iron overload and almost always appropriate for at-risk relatives (eg, first degree relatives) of an individual with HH. In these cases, genetic testing can facilitate identification of other affected family members, as discussed separately. (See "Clinical manifestations and diagnosis of hereditary hemochromatosis", section on 'HFE genetic testing' and "Management and prognosis of hereditary hemochromatosis", section on 'Testing and counseling first-degree relatives'.)
Some individuals may present with results of HFE genetic testing even without an indication for screening, and they may ask about whether additional testing or interventions are needed. If HFE testing reveals an HH-associated genotype, a family history should be elicited and iron studies should be performed, and the HFE genotype should be interpreted in context with this other information. A finding of one or more HFE mutations by itself is not sufficient for the diagnosis of HH; the genotype only confers a susceptibility to iron overload, and many individuals with HFE mutations will never manifest the disorder [138]. (See 'Likelihood of developing iron overload' above.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hemochromatosis".)
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●Basics topics (see "Patient education: Hemochromatosis (The Basics)")
●Beyond the Basics topics (see "Patient education: Hereditary hemochromatosis (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●HFE gene – The HFE gene encodes a protein that regulates hepcidin production by hepatocytes. Pathogenic variants in HFE, primarily C282Y, can lead to increased iron absorption that sometimes causes tissue iron overload. (See 'HFE gene function' above and "Regulation of iron balance".)
●Hereditary hemochromatosis – Hereditary hemochromatosis (HH) is an autosomal recessive disorder with variable penetrance. Homozygosity for HFE C282Y is generally required for clinical iron overload, but many of these individuals will never develop HH (table 2). Rarely, compound heterozygosity with the H63D variant (C282Y/H63D) or HFE gene deletion may be associated with iron overload, usually mild. In such cases, secondary causes of iron overload and liver disease (excess alcohol, hepatitis C virus, nonalcoholic fatty liver disease) should be sought and treated. Heterozygosity for HFE C282Y generally produces an unaffected carrier state with similar risk of iron overload as the general population. In some heterozygotes, concomitant liver disease may cause abnormal iron studies. (See 'HFE variants in hereditary hemochromatosis' above.)
●Other iron regulatory genes – Rarely, iron overload can be caused by variants in other iron regulatory genes, referred to as non-HFE hemochromatosis. Juvenile hemochromatosis, which typically presents in childhood, adolescence, or young adulthood, may be due to mutations in HJV (encodes hemojuvelin) or HAMP (encodes hepcidin). Other genes, inheritance patterns, and clinical features are discussed above. (See 'Non-HFE hemochromatosis' above.)
●Risk of iron overload – The risk of iron overload in an HFE C282Y homozygote (C282Y/C282Y) is challenging to estimate. Population studies have reported risks from 1 percent in females to 28 percent in males (table 2). Positive family history, male sex, older age, and excess alcohol use can all increase the likelihood of iron overload. (See 'Likelihood of developing iron overload' above.)
●Role of genetic testing – Individuals with iron overload should be tested for HFE C282Y and H63D or for a familial mutation (if known). Other testing may be appropriate for individuals who present at a younger than average age (before age 40 in males or before menopause in females) or those from non-European backgrounds, especially if genotype information would be helpful for first-degree relatives. For individuals who do not wish to pursue testing, it is reasonable to treat iron overload without documenting the genotype, especially if testing would incur significant costs and burdens without altering management. (See 'Sequence of testing in individuals with iron overload' above.)
●First-degree relatives – First-degree relatives of individuals with HH should be tested, typically with iron studies as well as genotyping. This is generally deferred to adulthood. An exception is a sibling of an individual with juvenile hemochromatosis, who may require testing at a younger age. (See "Clinical manifestations and diagnosis of hereditary hemochromatosis", section on 'Asymptomatic first-degree relatives' and "Management and prognosis of hereditary hemochromatosis", section on 'Testing and counseling first-degree relatives'.)
●Population screening – For asymptomatic individuals with a negative family history and no iron overload, we suggest not routinely screening for HH (Grade 2C). Screening may be reasonable in selected populations, especially White males of northern European ancestry. Iron studies (ferritin and transferrin saturation [TSAT]) rather than HFE genotyping may be the best screening test. (See 'Role of population screening' above.)
●Differential diagnosis – The differential diagnosis of a high ferritin and other causes of iron overload are discussed separately. (See "Approach to the patient with suspected iron overload", section on 'Other causes of high ferritin' and "Approach to the patient with suspected iron overload" and "Clinical manifestations and diagnosis of hereditary hemochromatosis".)
●Management of HH – Management and prognosis of HH and testing of first-degree relatives are discussed separately. (See "Management and prognosis of hereditary hemochromatosis".)
ACKNOWLEDGMENTS — UpToDate gratefully acknowledges Stanley L Schrier, MD (deceased), who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Hematology.
The UpToDate editorial staff also acknowledges the extensive contributions of Bruce R Bacon, MD, and William C Mentzer, MD, to earlier versions of this and many other topic reviews.
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