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HFE-Associated Hereditary Hemochromatosis

and , AC, MD, PhD.

Author Information
University of Queensland School of Medicine
Brisbane, Queensland, Australia
, AC, MD, PhD
Royal Brisbane & Women’s Hospital and University of Queensland
Brisbane, Queensland, Australia

Initial Posting: ; Last Update: September 17, 2015.

Summary

Clinical characteristics.

HFE-associated hereditary hemochromatosis (HFE-HH) is characterized by inappropriately high absorption of iron by the gastrointestinal mucosa. The phenotypic spectrum of HFE-HH is now recognized to include:

  • Those with clinical HFE-HH, in which manifestations of end-organ damage secondary to iron storage are present;
  • Those with biochemical HFE-HH, in which the only evidence of iron overload is increased transferrin-iron saturation and increased serum ferritin concentration;
  • Non-expressing p.Cys282Tyr homozygotes, in whom neither clinical manifestations of HFE-HH nor iron overload is present.

Clinical HFE-HH is characterized by excessive storage of iron in the liver, skin, pancreas, heart, joints, and testes. In untreated individuals, early symptoms may include: abdominal pain, weakness, lethargy, and weight loss; the risk of cirrhosis is significantly increased when the serum ferritin is higher than 1,000 ng/mL; other findings may include progressive increase in skin pigmentation, diabetes mellitus, congestive heart failure, and/or arrhythmias, arthritis, and hypogonadism. Clinical HFE-HH is more common in men than women.

Diagnosis/testing.

The diagnosis of clinical HFE-HH in individuals with clinical findings consistent with HFE-HH and the diagnosis of biochemical HFE-HH are typically based on finding elevated transferrin-iron saturation 45% or higher and serum ferritin concentration above the upper limit of normal (i.e., >300 ng/mL in men and >200 ng/mL in women) and two pathogenic variants on confirmatory HFE molecular genetic testing. Although serum ferritin concentration may increase progressively over time in untreated individuals with HFE-HH, it is not specific for HFE-HH, and therefore cannot be used alone for identification of individuals with HFE-HH.

Management.

Treatment of manifestations: Clinical HFE-HH: treatment by phlebotomy (removal of blood) to maintain serum ferritin concentration at ≤50 ng/mL. Biochemical HFE-HH: start phlebotomy when serum ferritin concentration is >500 ng/mL. Non-expressing p.Cys282Tyr homozygotes: phlebotomy is not required, as these individuals do not have iron overload.

Prevention of secondary complications: Vaccination against hepatitis A and B.

Surveillance:

  • Clinical HFE-HH: Once the serum ferritin concentration is <50 ng/mL, routine monitoring of serum ferritin concentration every three to four months; routine screening for hepatocellular cancer (HCC) in individuals who have cirrhosis.
  • Biochemical HFE-HH and non-expressing p.Cys282Tyr homozygotes: Begin annual measurement of serum ferritin concentration when ferritin concentration exceeds normal levels.

Agents/circumstances to avoid: Medicinal iron, mineral supplements, excess vitamin C, and uncooked seafood; alcohol consumption in those with hepatic involvement.

Evaluation of relatives at risk: Offer molecular genetic testing to the adult sibs of a proband homozygous for p.Cys282Tyr to allow early diagnosis and surveillance.

Genetic counseling.

HFE-HH is inherited in an autosomal recessive manner.

Risk to sibs: When both parents of an affected individual are heterozygous for the HFE pathogenic variant, the risk to sibs of inheriting two HFE pathogenic variants is 25%. However, because the carrier frequency for an HFE pathogenic variant in persons of European origin is high (11%, or 1/9), on occasion one parent of an affected individual has two abnormal HFE alleles. In such instances, the risk to each sib of inheriting two HFE pathogenic variants is 50%.

Risk to offspring: Offspring of an individual with HFE-HH inherit one HFE pathogenic variant from the affected parent. Because of the 1/9 chance that the other parent is a carrier for a mutant HFE allele, the risk to the offspring of inheriting two HFE pathogenic variants is approximately 5%.

Prenatal testing: Although prenatal testing would be technically feasible for pregnancies at 25% or more risk, such requests would be highly unusual because HFE-HH is an adult-onset, treatable disorder with low clinical penetrance.

Diagnosis

The American Association for the Study of Liver Disease (AASLD) has published practice guidelines for diagnosis and management of hemochromatosis [Bacon et al 2011] (full text).

Suggestive Findings

Diagnosis of HFE-associated hereditary hemochromatosis (HFE-HH) should be suspected in individuals with

Clinical signs of advanced iron overload, including:

  • Hepatomegaly
  • Hepatic cirrhosis
  • Hepatocellular carcinoma
  • Diabetes mellitus
  • Cardiomyopathy
  • Hypogonadism
  • Arthritis (especially involving the metacarpophalangeal joints)
  • Progressive increase in skin pigmentation

Biochemical evidence of iron overload demonstrating elevated serum transferrin-iron saturation (TS) and elevated serum ferritin concentration.

  • Transferrin-iron saturation (TS) is an early and reliable indicator of risk for iron overload in HFE-HH; the TS is not age-related in adults and does not correlate with the presence or absence of clinical findings.
  • Approximately 80% of individuals with HFE-HH have had a fasting serum transferrin-iron saturation of at least 60% (men) or at least 50% (women) on two or more occasions in the absence of other known causes of elevated transferrin-iron saturation.
  • Serum ferritin concentration generally increases progressively over time in individuals with untreated clinical HFE-HH; however, an elevated serum ferritin concentration alone is not specific for iron overload as it is an acute phase reactant and may be caused by inflammatory or neoplastic disorders (especially when the serum TS is normal).

    Commonly accepted ferritin values for the upper limit of normal (from the HEIRS study) are <300 ng/mL in males and <200 ng/mL in females [Adams et al 2005].
  • No “typical” range for ferritin values for persons with HFE-HH has been defined: it may range from normal to several thousand.

An algorithm for screening for HFE-associated hemochromatosis has been developed (see Figure 1).

Figure 1.

Figure 1.

Algorithm for screening for HFE-associated hemochromatosis using LFT (liver function test) and TS (transferrin saturation)

Originally published in Eijkelkamp et al [2000]; reused with permission

Establishing the Diagnosis

The diagnosis of HFE-HH is established in a proband with the identification of biallelic pathogenic variants in HFE (see Table 1).

Molecular testing approaches can include:

Table 1.

Summary of Molecular Genetic Testing Used in HFE-HH

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method
Genotype% of Individuals with HH 2, 3
HFETargeted analysis for pathogenic variants 4p.[Cys282Tyr]+[Cys282Tyr]~60%-90% 5
p.[Cys282Tyr]+[His63Asp]3%-8% 5
p.[His63Asp]+[His63Asp]~1% 6
Sequence analysis 7Other 8Rare 8
Gene-targeted deletion/duplication analysis 9OtherRare 10
1.

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene.

2.

In populations of European origin [Ramrakhiani & Bacon 1998]

3.
4.

Typically includes the p.Cys282Tyr and p.His63Asp pathogenic variants. Note: Pathogenic variants included in a panel may vary by laboratory.

5.
6.

Although biochemically defined abnormalities may be present in p.[His63Asp]+[His63Asp], characteristic clinical manifestations are rare [Gochee et al 2002].

7.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

8.

Typically compound heterozygous for the p.Cys282Tyr pathogenic variant and a second rare pathogenic variant. A number of private pathogenic variants have been described, including p.Glu168Ter and p.Trp169Ter, found with an allele frequency respectively of 25% and 8.4% in individuals with hemochromatosis in two northern regions of Italy [Piperno et al 2000].

9.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used can include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

10.

Full HFE gene deletion is the most common cause of hemochromatosis in the Sardinian population [Le Gac et al 2010].

Clinical Characteristics

Clinical Description

Three phenotypes of HFE-associated hereditary hemochromatosis (HFE-HH) are now recognized:

  • Clinical HFE-HH (individuals with end-organ damage [e.g., advanced cirrhosis, cardiac failure, skin pigment changes, or diabetes] secondary to iron storage)
  • Biochemical HFE-HH (individuals with evidence of iron overload as determined by transferrin-iron saturation and serum ferritin concentration only)
  • Non-expressing p.Cys282Tyr homozygotes (p.Cys282Tyr homozygotes without clinical or biochemical evidence of iron overload [i.e., normal serum ferritin concentration])

Individuals with HFE-HH may be identified because of signs and symptoms related to iron overload (i.e., clinical HFE-HH); however, most frequently they are identified before symptoms develop, either through detection of abnormal iron-related studies (i.e., biochemical HFE-HH) or by molecular genetic testing used in their evaluation as family members at risk for HFE-HH (non-expressing p.Cys282Tyr homozygotes).

The difference between clinical HFE-HH and biochemical HFE-HH must be understood in the interpretation of population studies evaluating morbidity related to HH. Several large-scale screening studies in the general population have demonstrated that most individuals homozygous for the p.Cys282Tyr pathogenic variant do not have clinical HFE-HH; however, a significant proportion of individuals with this genotype (especially males) have biochemical HFE-HH.

Factors influencing disease manifestation

  • Gender. Reports suggest that of p.Cys282Tyr homozygotes, a higher proportion of males than females (28% vs 1%) have definite disease manifestation of hemochromatosis [Allen et al 2008].
  • Detection through screening. When identified through iron studies or screening of at-risk family members, 75%-90% of individuals with HFE-HH are asymptomatic.
    • Normal serum ferritin concentration at diagnosis is usually associated with lack of symptom development [Yamashita & Adams 2003].
    • Clinical disease appears to be more common among at-risk sibs of clinically affected individuals.

Clinical HFE-HH

Individuals with clinical HFE-HH have inappropriately high absorption of iron from a normal diet by the gastrointestinal mucosa, resulting in excessive parenchymal storage of iron, which may result in damage in a number of end-organs and, potentially, organ failure.

Age of onset. Symptoms related to iron overload usually appear between age 40 and 60 years in males and after menopause in females. Occasionally, HFE-HH manifests at an earlier age, but hepatic fibrosis or cirrhosis is rare before age 40 years.

Early signs. Often the first signs of clinical HFE-HH are arthropathy (joint stiffness and pain) involving the metacarpophalangeal joints, progressive increase in skin pigmentation resulting from deposits of melanin and iron, diabetes mellitus resulting from pancreatic iron deposits, and cardiomyopathy resulting from cardiac parenchymal iron stores. Hepatomegaly may or may not be present early in the disease; however, asymptomatic individuals can occasionally have hepatomegaly on physical examination. Males may have impotence from pituitary dysfunction. In women hypogonodism leads to diminished libido and possibly infertility. Abdominal pain, weakness, lethargy, and weight loss are common, but nonspecific, findings.

Alcohol consumption worsens the symptoms in HFE-HH [Scotet et al 2003]. Moderate to heavy alcohol consumption increases the risk of cirrhosis by 10% [Fletcher et al 2002].

With progression of the disease, liver cirrhosis may develop and be complicated by portal hypertension, hepatocellular carcinoma, and end-stage liver disease [Kowdley et al 2005]. The HEIRS study found an odds ratio of 3.3 for liver disease among men homozygous for p.Cys282Tyr [Adams et al 2005]. In addition, as stated above, cirrhosis is much more common among p.Cys282Tyr homozygotes who consume more than 60 g of alcohol per day compared to those who drink less [Fletcher et al 2002].

By the time cirrhosis or liver failure is recognized, approximately 50% of individuals have diabetes mellitus and 15% have congestive heart failure or arrhythmias.

Life expectancy. Individuals diagnosed and treated prior to the development of cirrhosis have normal life expectancy; those identified after the development of cirrhosis have a decreased life expectancy even with iron depletion therapy [Adams et al 2005] primarily due to the development of hepatocellular cancer.

Prognosis. Individuals with cirrhosis who are treated have a better outcome than those who are not; however, treatment does not eliminate the 10%-30% risk for hepatocellular carcinoma (HCC) and cholangiocarcinoma years after successful iron depletion in those subjects with cirrhosis.

Failure to deplete iron stores after 18 months of treatment is a poor prognostic sign. With iron depletion, dysfunction of some affected organs (liver and heart) can improve; however, endocrine abnormalities and arthropathy improve in only 20% of those treated.

Death in individuals with clinical HFE-HH is usually caused by liver failure, cancer, congestive heart failure, or arrhythmia.

Biochemical HFE-HH

Controversy exists among experts as to whether individuals who have biochemical HFE-HH in the absence of clinical HFE-HH are at increased risk for development of complications of iron overload and whether they are candidates for phlebotomy treatment (see Management).

Ferritin levels at diagnosis. Bardou-Jacquet and colleagues concluded that HFE Cys282Tyr homozygotes with a serum ferritin at diagnosis between the upper limit of normal and 1000 μg/L have reduced mortality compared to the general population owing to phlebotomy therapy [Bardou-Jacquet et al 2015a, Bardou-Jacquet et al 2015b, Bardou-Jacquet et al 2015c]. Conversely, an Australian consortium believes the benefits of phlebotomy for p.Cys282Tyr homozygotes with mildly elevated serum ferritin remains unproven without a randomized study [Delatycki et al 2015].

Prospective follow up of a few individuals in some studies has been inconclusive as to whether iron overload is progressive. The evidence at present suggests that although serum ferritin concentration may rise in these individuals over time, end-organ damage is uncommon but is more frequently observed in men homozygous for p.Cys282Tyr than females homozygous for p.Cys282Tyr [see Yamashita & Adams 2003, Andersen et al 2004, Olynyk et al 2004, Allen et al 2008, Gurrin et al 2008].

Modifying factors. It has been assumed for many years that additional modifying factors or genes are required for expression of hemochromatosis in p.Cys282Tyr homozygotes. An international consortium has recently identified a modifying gene known as GNPAT which is over-expressed in men homozygous for p.Cys282Tyr expressing severe iron overload [McLaren et al 2015].

Non-Expressing p.Cys282Tyr Homozygotes

Three longitudinal population-based screening studies showed that 38%-50% of p.Cys282Tyr homozygotes may develop iron overload (i.e., elevated serum ferritin concentration) and 10%-33% may eventually develop hemochromatosis-related symptoms [Whitlock et al 2006] (i.e., nonspecific symptoms that may include fatigue and arthralgia) or end-organ damage (e.g., diabetes mellitus, cirrhosis, and/or cardiomyopathy). The vast majority developing end-organ damage are male [European Association for the Study of the Liver 2010].

Therefore, while “non-expressing homozygotes” are unlikely to develop end-organ damage over time, a substantial proportion of males who have biallelic p.Cys282Tyr variants may develop progressive iron overload or symptoms of iron overload [Yamashita & Adams 2003, Gurrin et al 2008, Gurrin et al 2009, Allen et al 2010, Gan et al 2011].

Heterozygotes

Some individuals who are heterozygous for either the HFE p.Cys282Tyr or p.His63Asp pathogenic variant tend to have elevated serum transferrin-iron saturation (TS) and ferritin concentrations that exceed normal; however, they do not develop complications of iron overload [Bulaj et al 1996, Allen et al 2008].

Although a threshold serum TS of 45% may be more sensitive than the higher values used in the past for detecting HFE-HH, it may identify heterozygotes who are not at risk of developing clinical findings [McLaren et al 1998].

In the large study in Danish men, Pedersen & Milman [2009] showed that:

  • Among p.Cys282Tyr/wild type (wt) heterozygotes, 9% had elevated serum TS (≥50%), 9% had elevated ferritin (≥300 ng/mL), and 1.2% had elevation of both serum TS and ferritin.
  • Among p.His63Asp/wt heterozygotes, 8% had elevated serum TS, 12% had elevated ferritin, and 2% had elevation of both serum TS and ferritin.

Note: The abnormalities in iron studies observed in p.Cys282Tyr heterozygotes do not necessarily reflect a hemochromatosis-associated phenotype.

Genotype-Phenotype Correlations

Homozygotes for p.Cys282Tyr are at greater risk for iron overload than p.Cys282Tyr/p.His63Asp compound heterozygotes.

Penetrance

Penetrance in HFE-HH refers to the percentage of adults (males and females separately) homozygous or compound heterozygous for HFE pathogenic variants who exhibit either clinical HFE-HH or biochemical HFE-HH:

  • p.Cys282Tyr homozygotes. Penetrance for biochemically defined iron overload among p.Cys282Tyr homozygotes is relatively high, but not 100%. In contrast, accumulating data suggest that penetrance for clinically defined iron overload is quite low. In the absence of unbiased data, penetrance of clinical endpoints of iron overload cannot yet be determined for individuals homozygous for p.Cys282Tyr; however, penetrance was as low as 2% in the large study by Beutler et al [2002]. Currently, no test can predict whether an individual homozygous for p.Cys282Tyr will develop clinical HFE-HH.
  • p.Cys282Tyr/p.His63Asp compound heterozygotes. The penetrance for this genotype is low: only approximately 0.5%-2.0% of such individuals develop clinical evidence of iron overload [Gurrin et al 2009].
    • Many p.Cys282Tyr/p.His63Asp compound heterozygotes who develop clinical evidence of iron overload appear to have a complicating factor (e.g., fatty liver, viral hepatitis) that leads to iron overload.
    • Male p.Cys282Tyr/p.His63Asp compound heterozygotes also were more likely to report a history of liver disease in the HEIRS study (odds ratio 1.7 p=0.05) [Adams et al 2005].
  • p.His63Asp homozygotes. The penetrance for this genotype is even lower than the penetrance of the p.[Cys282Tyr]+[His63Asp] genotype. Although biochemically defined abnormalities may be present, characteristic clinical manifestations are rare [Gochee et al 2002].

Nomenclature

HFE-HH has been variably described in the past as hereditary hemochromatosis, primary hemochromatosis, genetic hemochromatosis, and "bronze diabetes."

More recently, after the identification of other forms of iron overload associated with pathogenic variants in other iron-related genes, HFE-HH has been described as HFE-hemochromatosis or type 1 hemochromatosis.

Prevalence

The prevalence of individuals homozygous for the variant p.Cys282Tyr is approximately 3:1000 to 5:1000, or 1:200 to 1:400 [Adams et al 2005]:

  • The frequency of homozygotes among African Americans is rare (1:7000), with 2.3% of that population being heterozygotes.
  • Homozygosity for the p.Cys282Tyr variant is extremely rare among Asians; heterozygotes have an estimated frequency of 1:1000.
  • Hispanics have homozygote and heterozygote frequencies of 0.027% and 3.0%, respectively.

The p.His63Asp variant rarely causes clinical problems in the homozygous or compound heterozygous (p.[Cys282Tyr]+[His63Asp]) state and is relatively common in the heterozygous state in most populations (northern Europeans: 25%; Hispanics: 18%; African Americans: 6%; Asians: 8.5%).

Considering the high frequency of heterozygotes for the p.Cys282Tyr and p.His63Asp alleles, approximately one third of the northern European population is heterozygous for either one or the other of these two variant alleles.

Differential Diagnosis

HFE-associated hereditary hemochromatosis (HFE-HH) (sometimes called type 1 HH) needs to be distinguished from several much rarer primary iron overload disorders as well as from secondary iron overload disorders.

Primary overload disorders are characterized by increased absorption of iron from a normal diet. The following first two forms of hemochromatosis result from hepcidin deficiency. Thus the clinical manifestations are identical to p.Cys282Tyr hemochromatosis but more severe:

  • Juvenile hereditary hemochromatosis (sometimes called type 2 HH) has an earlier age of onset and more severe clinical manifestations than type 1 HH. Hepatocellular cancer has not been reported, possibly because of the short life span in this disorder. Pathogenic variants have been identified in two genes, giving rise to two clinically indistinguishable "subtypes": type 2A, caused by pathogenic variants in HJV encoding hemojuvelin; and type 2B, caused by pathogenic variants in HAMP. Inheritance is autosomal recessive [Roetto et al 1999, Camaschella et al 2000, De Gobbi et al 2002].
  • TFR2-related hereditary hemochromatosis (sometimes called type 3 HH) has a similar presentation to HFE-HH. Age of onset is earlier and progression is slower than in juvenile HH. It is caused by pathogenic variants in TFR2, which encodes transferrin receptor 2.

    TFR2-related hereditary hemochromatosis is rare; it has primarily been reported in Italy. Inheritance is autosomal recessive [Mattman et al 2002].
  • Ferroportin (SLC40A1)-related iron overload (ferroportin disease, type 4 hemochromatosis, HFE4) (OMIM 606069) is also a disorder of iron overload, but unlike juvenile and HFE-HH, macrophages are iron laden. Onset is late and, in contrast to all other varieties of hemochromatosis, iron storage affects reticuloendothelial rather than parenchymal cells [Montosi et al 2001, Njajou et al 2001]. HFE4 presents in adulthood. It is caused by pathogenic variants in SLC40A1, which encodes ferroportin. Inheritance is autosomal dominant [Pietrangelo 2004].
  • African iron overload (OMIM 601195) results from a predisposition to iron overload that is exacerbated by excessive intake of dietary iron. It is particularly prevalent among Africans who drink a traditional beer brewed in non-galvanized steel drums. Mutation of other yet-to-be-defined iron-related genes predisposes to this condition. A specific pathogenic variant (p.Gln248His) in SLC40A1 (NM_014585.5) encoding ferroportin has been associated with a tendency to iron overload in Africans and African Americans [McNamara et al 2005, Rivers et al 2007]. Another probable pathogenic variant (p.Asp270Val) in SLC40A1 was discovered in an African American man with mild iron overload [Lee et al 2012].
  • Neonatal hemochromatosis is a severe, often fatal iron overload syndrome that usually presents at birth. Iron overload occurs in utero. Inheritance is unknown, but autosomal recessive and mitochondrial inheritance have been postulated. No locus has been identified. A recent paper suggests that pathogenic variants in DGUOK, the gene which encodes deoxyguanosine kinase, may lead to a phenotype resembling this condition [Pronicka et al 2011]. See DGUOK-Related Mitochondrial DNA Depletion Syndrome, Hepatocerebral Form.

Secondary iron overload disorders

  • Liver diseases associated with parenchymal liver disease include conditions such as alcoholic liver disease, acute viral hepatitis or chronic hepatitis C, neoplasms, porphyria cutanea tarda, and inflammatory disorders, such as rheumatoid arthritis.
  • A very common liver disease, nonalcoholic fatty liver disease (NAFLD) (OMIM 613282) may frequently lead to elevated serum ferritin level and may be associated with increased hepatic iron deposition [Nelson et al 2011, Kowdley et al 2012].
  • Iron overload can result from ingested iron in foods, cooking ware, and medicines, as well as parenteral iron from iron injections or transfusions for a chronic anemia (e.g., beta-thalassemia, sickle cell disease).

See Hemochromatosis: OMIM Phenotypic Series, to view genes associated with this phenotype in OMIM.

Management

The American Association for the Study of Liver Disease (AASLD) has published practice guidelines for diagnosis and management of hemochromatosis [Bacon et al 2011] (full text). The European Association for the Study of the Liver (EASL) published Clinical Practice Guidelines on the Management of hemochromatosis [European Association for the Study of the Liver 2010] (full text).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with HFE-associated hereditary hemochromatosis (HFE-HH), the following evaluations are recommended at initial diagnosis:

  • Serum ferritin concentration to establish disease status and prognosis (see Figure 2)
  • For p.Cys282Tyr homozygotes:
    • Liver biopsy remains the gold standard for establishing or excluding cirrhosis.
    • Liver biopsy is recommended for those with serum ferritin >1,000 ng/mL or elevated AST and ALT to evaluate for advanced hepatic fibrosis [Morrison et al 2003, Bacon et al 2011].
    • Liver biopsy is not recommended for those with serum ferritin concentration <1,000 ng/mL and normal ALT and AST because their risk for advanced hepatic fibrosis is low [Bacon et al 2011].
  • MRI to estimate parenchymal iron content by utilizing the paramagnetic properties of iron:
  • Biomagnetic liver susceptometry (BLS) to estimate liver iron by measuring the change in magnetic flux as a hemochromatosis patient moves through a stable magnetic field, generating a voltage in the SQUID sensor [Fischer & Harmatz 2009]. As BLS is not widely available it is not included in diagnosis or management guidelines for hemochromatosis.
  • Consultation with a medical geneticist and/or genetic counselor
Figure 2.

Figure 2.

Use of serum ferritin concentration to help direct management

Treatment of Manifestations

The American Association for the Study of Liver Disease (AASLD) has published practice guidelines for diagnosis and management of hemochromatosis [Bacon et al 2011] (full text). The European Association for the Study of the Liver (EASL) published Clinical Practice Guidelines on the Management of hemochromatosis [European Association for the Study of the Liver 2010] (full text).

Clinical HFE-HH

Therapeutic phlebotomy is indicated in the presence of symptoms of iron overload or evidence of end-organ damage (e.g., advanced cirrhosis, cardiac failure, skin pigment changes, or diabetes):

  • Periodic phlebotomy is a simple, inexpensive, safe, and effective treatment.
    • Each unit of blood (400-500 mL) with a hematocrit of 40% contains approximately 160-200 mg of iron.
    • Each mL of packed red blood cells contains 1 mg of iron.
  • The usual therapy is removal of the excess iron by weekly phlebotomy (i.e., removal of a unit of blood) until the serum ferritin concentration is 50 ng/mL or lower. Twice-weekly phlebotomy may be occasionally useful to accelerate iron depletion.
  • Weekly phlebotomy is carried out until the hematocrit is 75% of the baseline hematocrit.
  • At this point, if the serum ferritin concentration is ≥50 ng/mL despite a significant reduction in hematocrit, the interval at which phlebotomy is performed needs to be spaced further apart. Once the serum ferritin concentration is ≤100 ng/mL, serum ferritin concentration should be quantified in all affected individuals after each additional one or two treatments [Barton et al 1998].
  • The serum ferritin concentration is the most reliable and inexpensive way to monitor therapeutic phlebotomy.
  • Maintenance therapy is aimed at maintaining serum ferritin concentration <50 ng/mL and transferrin-iron saturation <50%. On average, men require removal of twice as many units of blood as women. Subsequent phlebotomies to prevent reaccumulation of iron can be carried out approximately every three to four months for men and once or twice a year for women.
  • Iron chelation therapy is not recommended unless an individual has an elevated serum ferritin concentration and concomitant anemia that makes therapeutic phlebotomy impossible. However, this is uncommon in individuals with HFE-HH.
  • Therapeutic phlebotomy improves fibrosis except in cases of cirrhosis [Powell et al 2006].

Orthotopic liver transplantation is the only treatment for end-stage liver disease from decompensated cirrhosis. However, the post-transplant survival among untreated individuals with HFE-HH is poor [Crawford et al 2004, Kowdley et al 2005]. Although one study suggested that outcomes may have improved, this report did not enroll persons with documented HFE-HH but rather used a database [Yu & Ioannou 2007].

Biochemical HFE-HH

Both the EASL and AASLD guidelines recommend therapeutic phlebotomy for persons with biochemical HFE-HH (i.e., those who have increased body iron stores in the absence of clinical evidence of iron overload). See European Association for the Study of the Liver [2010] (full text) and Bacon et al [2011] (full text). The exact serum ferritin concentration at which therapeutic phlebotomy should be initiated is not clear, the European Association for Study of Liver suggests performing phlebotomy once serum ferritin concentration is higher than 500 ng/mL.

Non-Expressing p.Cys282Tyr Homozygotes

These individuals do not have iron overload and thus do not need phlebotomy.

Prevention of Primary Manifestations

See Treatment of Manifestations.

Prevention of Secondary Complications

Individuals with iron overload should be advised against ingestion of shellfish or raw fish.

Vaccination against hepatitis A and B is advised [Tavill 2001].

Surveillance

Clinical HFE-HH

Once the serum ferritin concentration is <50 ng/mL, monitor serum ferritin concentration every three to four months.

It is reasonable to perform follow-up T2* MRI for assessment of cardiac iron among persons with a history of cardiac involvement or known cardiac iron deposition.

Since cirrhosis is a crucial stage in the natural history of hemochromatosis, the diagnosis of cirrhosis is important because management changes. Individuals with cirrhosis should be followed regularly and screened for hepatocellular cancer (HCC) [Tavill 2001]. The AASLD Practice Guidelines recommend imaging every six months with good ultrasonography [Sherman 2010]. This may be accompanied with measurement of alpha fetoprotein. Noninvasive methods that use results derived from values of serum markers such as HepaScore® and FibroMeter™ can also be used to assess the stage of liver fibrosis [Martínez et al 2011].

Although the gold standard for the diagnosis of cirrhosis is biopsy, FibroScan® has been shown to have good sensitivity and specificity for cirrhosis [Tsochatzis et al 2011]. FibroScan (also known as transient elastography) quantifies fibrosis with ultrasound in a non-invasive manner [Tsochatzis et al 2011]. The results from a meta-analysis suggested a cut-off value for diagnosis of cirrhosis of 13.01 kPa [Friedrich-Rust et al 2008]. Individuals with normal transient elastography (TE) values on FibroScan would not need a biopsy while individuals with intermediate or high TE values should have biopsies to confirm cirrhosis. These results should be interpreted in conjunction with clinical and biochemical parameters.

Note: The AASLD Guidelines recommend that individuals with cirrhosis undergo surveillance regardless of whether or not they have been iron depleted [Bacon et al 2011] (full text).

Biochemical HFE-HH

Begin annual measurement of serum ferritin concentration when ferritin concentration exceeds normal levels [European Association for the Study of the Liver 2010] (full text).

Non-Expressing p.Cys282Tyr Homozygotes

Begin annual measurement of serum ferritin concentration when ferritin concentration exceeds normal levels [European Association for the Study of the Liver 2010].

Agents/Circumstances to Avoid

Avoid the following:

  • Medicinal iron, mineral supplements, excess vitamin C, and uncooked seafood
  • Alcohol consumption in those with hepatic involvement

Evaluation of Relatives at Risk

It is appropriate to clarify the status of apparently asymptomatic adult sibs and offspring of individuals homozygous for p.Cys282Tyr in order to identify those who would benefit from prompt initiation of treatment and preventive measures.

The following strategy is appropriate:

1.

Offer molecular genetic testing to the adult sibs of an individual homozygous for p.Cys282Tyr.

2.

Perform iron studies (i.e., transferrin iron saturation and serum concentration of ferritin) on those sibs who are homozygous for p.Cys282Tyr.

3.

Begin phlebotomy therapy if serum ferritin concentration is elevated above the upper limits of normal and if the proband has clinical HFE-HH. Note: Sibs of probands with clinical HFE-HH appear to have a higher prevalence of clinical HFE-HH than asymptomatic individuals detected through screening programs.

Note: Genotype-based testing has been found to be cost effective in most individuals because it has excellent negative predictive value. However, genotype-based testing has a low positive predictive value because many p.Cys282Tyr homozygotes and compound heterozygotes will not express the disease [El-Serag et al 2000, Beutler et al 2002].

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

No guidelines exist; common practice is to withhold phlebotomy during pregnancy.

Therapies Under Investigation

The oral iron chelator, deferasirox (Exjade®) has been studied in a Phase I/II study in patients with hemochromatosis. Final results of this trial suggest that deferasirox is effective at reducing iron burden within an acceptable safety profile [Phatak et al 2010]. It has not yet been approved for use in treating hemochromatosis.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

HFE-associated hereditary hemochromatosis (HFE-HH) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • Most parents of individuals with HFE-HH are heterozygotes (i.e., carriers of one HFE pathogenic variant).
    • Heterozygotes do not develop iron overload but may occasionally have abnormal serum iron studies [Bulaj et al 1996]. (See Clinical Description, Heterozygotes).
  • On occasion, one parent has biallelic HFE pathogenic variants and may have clinical HFE-HH (i.e., presence of significant end-organ damage including advanced cirrhosis, cardiac failure, skin pigment changes, or diabetes). Thus, it is appropriate to evaluate the parents of an individual with HFE-HH by molecular genetic testing (for the p.Cys282Tyr and p.His63Asp pathogenic variants) or by serum iron studies (i.e., transferrin iron saturation (TS) and serum concentration of ferritin).

    Note: The occurrence of an autosomal recessive disorder in two generations of a family without consanguinity (called "pseudodominance") is attributed to the high carrier frequency of HFE pathogenic variants in persons of European origin (see Prevalence).

Sibs of a proband

  • If both parents are heterozygous, each sib of an affected individual has at conception a 25% chance of inheriting both HFE pathogenic variants, a 50% chance of inheriting one HFE pathogenic variant, and a 25% chance of inheriting neither HFE pathogenic variant.
  • When one parent is homozygous for p.Cys282Tyr and the other parent is heterozygous for an HFE pathogenic variant, each sib of an individual with HFE-HH has a 50% chance of inheriting both HFE pathogenic variants and a 50% chance of inheriting one HFE pathogenic variant.

Offspring of a proband

  • Unless an individual with HFE-HH has children with an affected individual or a heterozygote (carrier), his/her offspring will be obligate heterozygotes for an HFE pathogenic variant.
  • The risk that a northern European reproductive partner of an individual with HFE-HH is heterozygous for the p.Cys282Tyr pathogenic variant is approximately 1/9. Thus, the risk to the offspring of a proband of being homozygous for this pathogenic variant is approximately 5% (i.e., 1/9 x 1/2 = 1/18).

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier of an HFE pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the HFE pathogenic variants in the family.

Molecular genetic testing can be offered to the reproductive partner of a person with HFE-HH to determine if their offspring are at risk for HFE-HH.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Testing of asymptomatic individuals younger than age 18 years who are at risk for adult-onset disorders for which no treatment exists is not considered appropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.

It is appropriate to consider testing symptomatic individuals regardless of age in a family with an established diagnosis of HFE-HH.

For more information, see also the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers or affected.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Population Screening

Population screening has been considered because of the high prevalence of HFE-HH, the lack of clinical findings early in the course of the disease, the lack of specificity of clinical findings once they appear, the low cost of diagnosis, the relatively simple and effective early treatment, and the high cost and low success rate of treatment when the diagnosis is established late. For logistical reasons, however, population screening is still not recommended.

Genotype-based population screening of HFE-HH is not recommended because penetrance appears to be low and the natural history of untreated individuals cannot be predicted. See European Association for the Study of the Liver [2010] (full text) and Bacon et al [2011] (full text).

Biochemical-based screening (using the serum iron markers transferrin iron saturation and serum concentration of ferritin) should be considered especially among men older than age 30 years who are of northern European descent [Phatak et al 2008, European Association for the Study of the Liver 2010, Bacon et al 2011].

Prenatal Testing

Because the HFE pathogenic variants have been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of this gene or custom prenatal testing.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the HFE pathogenic variants have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

HFE-Associated Hereditary Hemochromatosis: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for HFE-Associated Hereditary Hemochromatosis (View All in OMIM)

235200HEMOCHROMATOSIS, TYPE 1; HFE1
613609HFE GENE; HFE

Gene structure. HFE is approximately 13 kb in size and comprises seven exons [Feder et al 1996, Albig et al 1998]; HFE gives rise to at least eleven alternative transcripts encoding four to seven exons. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. At least 28 distinct pathogenic variants have been reported; most are missense or nonsense. Two missense variants account for the vast majority of disease-causing alleles in the population:

  • p.Cys282Tyr removes a highly conserved cysteine residue that normally forms an intermolecular disulfide bond with beta-2-microglobulin, and thereby prevents the protein from being expressed on the cell surface.
  • p.His63Asp may alter a pH-dependent intramolecular salt bridge, possibly affecting interaction of the HFE protein with the transferrin receptor.

In addition, p.Ser65Cys has been seen in combination with p.Cys282Tyr in individuals with iron overload [Bacon et al 2011]. Unlike individuals heterozygous for the common pathogenic variants, no p.Ser65Cys/wt heterozygotes had elevation of both serum TS and ferritin.

Table 2.

Selected HFE Pathogenic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.187C>Gp.His63AspNM_000410​.3
NP_000401​.1
c.193A>Tp.Ser65Cys
c.502G>Tp.Glu168Ter
c.506G>Ap.Trp169Ter
c.845G>Ap.Cys282Tyr

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. The largest predicted primary translation product is 348 amino acids, which gives rise to a mature protein of approximately 321 amino acids after cleavage of the signal sequence. The HFE protein is similar to HLA Class I molecules at the level of the primary structure [Feder et al 1996] and tertiary structure [Lebrón et al 1998]. The mature protein is expressed on the cell surface as a heterodimer with beta-2-microglobulin, and this interaction is necessary for normal presentation on the cell surface. The normal HFE protein binds to transferrin receptor 1 on the cell surface and may reduce cellular iron uptake; the exact means by which the HFE protein regulates iron uptake is as yet unclear [Fleming et al 2004].

Abnormal gene product. The p.Cys282Tyr pathogenic variant destroys a key cysteine residue that is required for disulfide bonding with beta-2-microglobulin. As a result, the HFE protein does not mature properly and becomes trapped in the endoplasmic reticulum and Golgi apparatus, leading to decreased cell-surface expression. The mechanistic basis for the phenotypic effect of other HFE pathogenic variants is not clear at present.

References

Published Guidelines/Consensus Statements

  1. Bacon BR, Adams PC, Kowdley KV, Powell LW, Tavill AS; American Association for the Study of Liver Diseases. Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. Available online. 2011. Accessed 9-14-15.
  2. Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available online. 2013. Accessed 9-14-15. [PubMed: 23428972]
  3. European Association for the Study of the Liver. EASL clinical practice guidelines for HFE hemochromatosis. Available online. 2010. Accessed 9-14-15.
  4. National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available online. 2012. Accessed 9-14-15.

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Chapter Notes

Author History

Robin L Bennett, MS; University of Washington (2000-2015)
Kris V Kowdley, MD; Virginia Mason Medical Center (2000-2015)
Arno G Motulsky, MD; University of Washington (2000-2015)
Lawrie Powell, AC, MD, PhD (2015-present)
Rebecca Seckington (2015-present)
Jonathan F Tait, MD, PhD; University of Washington School of Medicine (2000-2011)

Revision History

  • 17 September 2015 (me) Comprehensive update posted live
  • 19 April 2012 (me) Comprehensive update posted live
  • 4 December 2006 (me) Comprehensive update posted to live Web site
  • 13 July 2005 (kk) Revision: sequence analysis of entire coding region clinically available
  • 13 September 2004 (kk) Author revisions
  • 7 October 2003 (me) Comprehensive update posted to live Web site
  • 3 April 2000 (me) Review posted to live Web site
  • October 1998 (kk) Original submission
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