Hfe Hemochromatosis
Summary
Clinical characteristics.
HFE hemochromatosis is characterized by inappropriately high absorption of iron by the small intestinal mucosa. The phenotypic spectrum of HFE hemochromatosis includes:
- Persons with clinical HFE hemochromatosis, in whom manifestations of end-organ damage secondary to iron overload are present;
- Individuals with biochemical HFE hemochromatosis, in whom transferrin-iron saturation is increased and the only evidence of iron overload is increased serum ferritin concentration; and
- Non-expressing p.Cys282Tyr homozygotes, in whom neither clinical manifestations of HFE hemochromatosis nor iron overload are present.
Clinical HFE hemochromatosis is characterized by excessive storage of iron in the liver, skin, pancreas, heart, joints, and anterior pituitary gland. In untreated individuals, early symptoms include: abdominal pain, weakness, lethargy, weight loss, arthralgias, diabetes mellitus; and increased risk of cirrhosis when the serum ferritin is higher than 1,000 ng/mL. Other findings may include progressive increase in skin pigmentation, congestive heart failure, and/or arrhythmias, arthritis, and hypogonadism. Clinical HFE hemochromatosis is more common in men than women.
Diagnosis/testing.
The diagnosis of HFE hemochromatosis in a proband is established by identification of biallelic HFE pathogenic variants on molecular genetic testing.
Management.
Treatment of manifestations:
- Clinical HFE hemochromatosis: induction treatment by phlebotomy to achieve serum ferritin concentration ≤50 ng/mL.
- Biochemical HFE hemochromatosis: start phlebotomy when serum ferritin concentration is >300 ng/mL.
- Non-expressing p.Cys282Tyr homozygotes: phlebotomy is not indicated, because these individuals do not have iron overload.
Prevention of secondary complications: Vaccination against hepatitis A and B.
Surveillance:
- Clinical HFE hemochromatosis: Once the serum ferritin concentration is ≤50 ng/mL, monitor serum ferritin concentration every three to four months. Maintain serum ferritin <300 ng/mL (men) and <200 ng/mL (women) thereafter; perform standard screening for primary liver cancer in individuals who have cirrhosis.
- Biochemical HFE hemochromatosis and non-expressing p.Cys282Tyr homozygotes: Begin annual measurement of serum ferritin concentration when serum ferritin concentration exceeds 300 ng/mL (men) and 200 ng/mL (women).
Agents/circumstances to avoid: Medicinal iron, mineral supplements, excess vitamin C, and uncooked seafood; alcohol consumption in those with hepatic involvement; and daily ingestion of more than 500 mg of supplemental ascorbic acid / vitamin C.
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 hemochromatosis is inherited in an autosomal recessive manner.
Risk to sibs: When both parents of a person with hemochromatosis are heterozygous for an HFE p.Cys282Tyr variant, the risk to sibs of inheriting two HFE p.Cys282Tyr variants is 25%. Because the HFE p.Cys282Tyr heterozygote prevalence in persons of European origin is high (11%, or 1/9), some parents of HFE p.Cys282Tyr homozygotes have two abnormal HFE alleles. If one parent is heterozygous and the other parent homozygous for two abnormal HFE alleles, the risk to each sib of inheriting two HFE pathogenic alleles is 50%.
Risk to offspring: Offspring of an individual with HFE hemochromatosis inherit one HFE p.Cys282Tyr variant from the parent with HFE hemochromatosis. Because the chance that the other parent is a heterozygote for HFE p.Cys282Tyr is 1/9, the risk that the offspring will inherit two HFE p.Cys282Tyr variants is approximately 5%.
Prenatal testing: Although prenatal testing for a pregnancy at increased risk is possible once the HFE pathogenic variants have been identified in an affected family member, prenatal testing is not usually performed because HFE hemochromatosis is an adult-onset, treatable disorder with low clinical penetrance.
Diagnosis
The European Association for the Study of the Liver (EASL) published clinical practice guidelines including diagnosis of HFE hemochromatosis [European Association for the Study of the Liver 2010]. The American Association for the Study of Liver Disease (AASLD) has published practice guidelines for diagnosis of hemochromatosis [Bacon et al 2011] (full text). Experts at the 2017 Hemochromatosis International meeting published an objective and practical set of recommendations for treatment of persons with hemochromatosis and p.Cys282Tyr homozygosity based on published scientific studies and guidelines in a form suitable for patients and other persons without medical training [Adams et al 2018].
Suggestive Findings
HFE hemochromatosis should be suspected in individuals with a combination of the following clinical signs of advanced iron overload, biochemical evidence of hemochromatosis, and/or family history of HFE hemochromatosis.
Clinical signs of advanced iron overload
- Diabetes mellitus
- Progressive increase in skin pigmentation
- Hepatomegaly
- Hepatic cirrhosis
- Arthropathy (especially involving the metacarpophalangeal joints)
- Primary liver cancer (hepatocellular carcinoma, cholangiocarcinoma)
- Cardiomyopathy
- Hypogonadism (usually hypogonadotropic)
Biochemical evidence of hemochromatosis
- Elevated serum transferrin-iron saturation (TS) is an early and reliable indicator of risk for iron overload in HFE hemochromatosis; TS is not age-related in adults and is not significantly associated with the presence or absence of clinical findings or increased serum ferritin levels.Approximately 80% of individuals with HFE hemochromatosis have had a fasting serum TS of at least 60% (men) or at least 50% (women) on two or more occasions in the absence of other known causes of elevated TS.
- Elevated serum ferritin concentration. Serum ferritin generally increases progressively over time in individuals with untreated clinical HFE hemochromatosis. An elevated serum ferritin concentration alone is not specific for iron overload because serum ferritin is an acute-phase reactant and elevated serum ferritin levels may be caused by non-iron liver disorders or inflammatory or neoplastic disorders (especially when the serum TS is normal).Commonly accepted normal serum ferritin values from the HEIRS Study are <300 ng/mL in men and <200 ng/mL in women [Adams et al 2005].
- No "typical" range for serum ferritin values for persons with HFE hemochromatosis has been defined. Values range from subnormal to several thousands.
An algorithm for screening for HFE hemochromatosis has been developed (see Figure 1).
Figure 1.
Algorithm for screening for HFE hemochromatosis using LFTs (liver function tests) and TS (transferrin saturation) Originally published in Eijkelkamp et al [2000]; reused with permission
Establishing the Diagnosis
The diagnosis of HFE hemochromatosis is established in a proband with the identification of biallelic pathogenic variants in HFE, typically p.Cys282Tyr, by molecular genetic testing (see Table 1).
Molecular testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (chromosomal microarray analysis, exome sequencing, exome array, genome sequencing) depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of HFE hemochromatosis is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of HFE hemochromatosis has not been considered are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
When the phenotypic and laboratory findings suggest the diagnosis of HFE hemochromatosis, molecular genetic testing approaches can include single-gene testing or use of a multigene panel.
Single-gene testing
- Targeted analysis for HFE p.Cys282Tyr and p.His63Asp can be performed first.Note: Other pathogenic variants common in some populations have been described:
- Northern Italian: p.Glu168Ter and p.Trp169Ter [Piperno et al 2000]
- French: p.Ser65Cys [Bacon et al 2011]
- Vietnamese: c.1006+1G>A [Barton et al 2015]
- Perform sequence analysis of HFE, followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.Note: HFE whole-gene deletion has been found to be the most common pathogenic variant in the Sardinian population [Le Gac et al 2010].
A multigene panel that includes HFE and other genes of interest (see Differential Diagnosis) may be used to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
When the diagnosis of HFE hemochromatosis is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in HFE Hemochromatosis
| Gene 1 | Method | Proportion of Pathogenic Variants 2 Detectable by Method |
|---|---|---|
| HFE | Targeted analysis | ~99% 3 |
| Sequence analysis 4 | ~99% 5 | |
| Gene-targeted deletion/duplication analysis 6 | Rare 7 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Individuals of European ancestry; approximately 60%-90% of individuals of European ancestry with HFE hemochromatosis are homozygous for variant p.Cys282Tyr, 1% are homozygous for p.His63Asp, and 3%-8% are compound heterozygous for p.Cys282Tyr / p.His63Asp [Feder et al 1996, Morrison et al 2003, Barton et al 2015].
- 4.
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.
- 5.
Population-specific pathogenic variants have been described, including p.Glu168Ter and p.Trp169Ter, found with allele frequencies of 25% and 8.4% (respectively) in individuals with hemochromatosis in two northern regions of Italy [Piperno et al 2000]. The prevalence of HFE p.Ser65Cys is greatest in French populations. The HFE splice site variant c.1006+1G>A occurs in Vietnamese with and without phenotypic evidence of iron overload [Barton et al 2015]. HFE gene deletion is the most common pathogenic HFE allele in the Sardinian population [Le Gac et al 2010].
- 6.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may 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.
- 7.
ALU-mediated HFE gene deletion is the most common cause of hemochromatosis in the Sardinian population [Le Gac et al 2010].
Clinical Characteristics
Clinical Description
HFE hemochromatosis comprises three phenotypes:
- Clinical HFE hemochromatosis (individuals with end-organ damage [e.g., cirrhosis, diabetes, cardiac failure, skin hyperpigmentation] secondary to iron storage)
- Biochemical HFE hemochromatosis (individuals with elevated transferrin saturation [TS], not otherwise explained) with evidence of iron overload (elevated serum ferritin concentration)
- Non-expressing p.Cys282Tyr homozygotes (p.Cys282Tyr homozygotes without clinical or biochemical evidence of iron overload [i.e., normal serum ferritin concentration])
Some individuals with HFE hemochromatosis may be identified because they have signs and symptoms related to iron overload (i.e., clinical HFE hemochromatosis). Other individuals are diagnosed with HFE hemochromatosis before symptoms develop, either through detection of abnormal iron-related studies (i.e., biochemical HFE hemochromatosis) or by molecular genetic testing used in their evaluation as family members at risk for HFE hemochromatosis (expressing or non-expressing p.Cys282Tyr homozygotes).
The difference between clinical and biochemical HFE hemochromatosis must be understood in the interpretation of population studies evaluating morbidity related to HFE hemochromatosis. Several large-scale screening studies in the general population have demonstrated that most individuals homozygous for p.Cys282Tyr do not have clinical HFE hemochromatosis. A significant proportion of individuals with homozygosity for p.Cys282Tyr (especially men) have biochemical HFE hemochromatosis.
Factors influencing disease manifestation
- Gender. Among p.Cys282Tyr homozygotes, a higher proportion of men than women (28% vs 1%) have manifestations 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 hemochromatosis are asymptomatic.
- Normal serum ferritin concentration at diagnosis is usually associated with lack of symptom development [Yamashita & Adams 2003].
- Clinical disease is more common among p.Cys282Tyr homozygous sibs of clinically affected p.Cys282Tyr homozygotes than among p.Cys282Tyr homozygotes identified outside of family studies.
Clinical HFE Hemochromatosis
Individuals with clinical HFE hemochromatosis have inappropriately high absorption of iron from a normal diet by the mucosa of the small intestine, resulting in excessive parenchymal storage of iron, which may result in damage to target organs and, potentially, organ failure.
Age of onset. Symptoms related to iron overload usually appear between age 40 and 60 years in men and after menopause in women. Occasionally, HFE hemochromatosis 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 hemochromatosis 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 HFE hemochromatosis. Some asymptomatic individuals have hepatomegaly on physical examination. Some men, typically those with severe iron overload, have erectile dysfunction, hypotestosteronemia, loss of muscle mass, and osteoporosis due to hypogonadotropic hypogonadism. In women, hypogonadism leads to diminished libido, amenorrhea, and infertility in some individuals. Abdominal pain, weakness, lethargy, and weight loss are common nonspecific findings [Edwards & Barton 2018].
The HEIRS Study found an odds ratio of 3.3 for liver disease among men homozygous for p.Cys282Tyr [Adams et al 2005]. With progressive iron overload, cirrhosis may develop and be complicated by portal hypertension, primary liver cancer, and end-stage liver disease [Kowdley et al 2005]. Alcohol consumption worsens the symptoms in HFE hemochromatosis [Scotet et al 2003]. Approximately 50% of individuals with cirrhosis or liver failure also have diabetes mellitus and approximately 15% have congestive heart failure or cardiac arrhythmias. Cirrhosis is more common among p.Cys282Tyr homozygotes who consume more than 60 g of alcohol per day [Fletcher et al 2002]. Age, diabetes, alcohol consumption, and severity of iron overload increase the risk of cirrhosis, after adjusting for other factors [Barton et al 2018].
Life expectancy. Individuals diagnosed and treated prior to the development of cirrhosis have normal life expectancy. Those diagnosed 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 treated. Treatment of patients with cirrhosis to achieve iron depletion does not eliminate the 10%-30% risk of primary liver cancer (e.g., hepatocellular carcinoma, cholangiocarcinoma).
Failure to deplete iron stores after 18 months of treatment is a poor prognostic sign that reflects iron overload severity in most individuals and insufficient phlebotomy therapy in other individuals. With iron depletion, dysfunction of some organs (liver and heart) can improve. Endocrine abnormalities and arthropathy improve in 20% of treated individuals.
Death in individuals with clinical HFE hemochromatosis is often caused by liver failure, primary liver cancer, extrahepatic cancers, congestive heart failure, or arrhythmia.
Biochemical HFE Hemochromatosis
It is controversial whether individuals who have biochemical HFE hemochromatosis in the absence of clinical HFE hemochromatosis are at increased risk of developing complications of iron overload and are therefore candidates for phlebotomy treatment (see Management).
Ferritin levels at diagnosis. Bardou-Jacquet and colleagues concluded that HFE p.Cys282Tyr homozygotes with a serum ferritin at diagnosis between the upper limit of normal and 1,000 μg/L have lower mortality than the general population due to phlebotomy therapy [Bardou-Jacquet et al 2015a, Bardou-Jacquet et al 2015b, Bardou-Jacquet et al 2015c]. Conversely, an Australian consortium concluded that the benefits of phlebotomy for p.Cys282Tyr homozygotes with mildly elevated serum ferritin remain unproven without a randomized study with long-term follow-up [Delatycki et al 2015].
Prospective follow-up study of a few HFE Cys282Tyr homozygotes found that iron overload is not progressive in all individuals. Although serum ferritin concentration may rise in these individuals over time, end-organ damage is uncommon and is more frequently observed in men than women [Allen et al 2008, Gurrin et al 2008].
Modifying factors. It has been assumed for many years that additional modifying factors or pathogenic variants in non-HFE genes are required for expression of hemochromatosis in some p.Cys282Tyr homozygotes. An international consortium identified a modifying variant p.Asp519Gly in GNPAT in p.Cys282Tyr homozygotes, which occurs with greater frequency in men and women with severe iron overload in the absence of heavy alcohol consumption than in those without severe iron overload [McLaren et al 2015, Barton et al 2017]. GNPAT p.Asp519Gly was not an independent risk factor for cirrhosis in men and women with p.Cys282Tyr homozygosity who underwent liver biopsy [Barton et al 2018].
Non-Expressing p.Cys282Tyr Homozygotes
Non-expressing homozygotes are unlikely to develop end-organ damage. Women represent a higher proportion of non-expressing homozygotes than men [Allen et al 2010, Gan et al 2011].
Three longitudinal population-based screening studies showed that 38%-50% of p.Cys282Tyr homozygotes develop iron overload (i.e., elevated serum ferritin concentration) and 10%-33% eventually develop hemochromatosis-related symptoms [Whitlock et al 2006] (i.e., nonspecific symptoms such as fatigue and arthralgia) or end-organ damage (e.g., cirrhosis, diabetes mellitus, and/or cardiomyopathy). The majority of HFE p.Cys282Tyr homozygotes who develop end-organ damage and corresponding manifestations are men [Allen et al 2010, European Association for the Study of the Liver 2010, Gan et al 2011].
Heterozygotes
Some individuals who are heterozygous for either HFE p.Cys282Tyr or p.His63Asp have elevated serum TS and serum ferritin concentrations, but they do not develop complications of iron overload [Bulaj et al 1996, Allen et al 2008].
Although a threshold TS of 45% may be more sensitive than higher values for detecting HFE hemochromatosis, TS of 45% may also identify heterozygotes who are not at risk of developing other clinical abnormalities [McLaren et al 1998].
In a large study of Danish men, Pedersen & Milman [2009] showed that:
- Among p.Cys282Tyr 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 heterozygotes, 8% had elevated serum TS, 12% had elevated ferritin, and 2% had elevation of both TS and ferritin.
Genotype-Phenotype Correlations
Homozygotes for p.Cys282Tyr are at greater risk of developing iron overload than p.Cys282Tyr/p.His63Asp compound heterozygotes.
Penetrance
Penetrance of HFE hemochromatosis refers to the percentage of adults (men and women separately) homozygous or compound heterozygous for HFE pathogenic variants who exhibit either clinical or biochemical hemochromatosis:
- p.Cys282Tyr homozygotes. Penetrance for biochemically defined iron overload among p.Cys282Tyr homozygotes is relatively high, but not 100%. In contrast, penetrance of clinically defined iron overload is low. Penetrance of clinical endpoints of iron overload have not been determined for individuals homozygous for p.Cys282Tyr. 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 hemochromatosis.
- p.Cys282Tyr/p.His63Asp compound heterozygotes. The penetrance of this genotype is low: 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 have a concomitant factor (e.g., fatty liver, viral hepatitis) that may increase iron absorption, enhance liver injury, or increase TS and serum ferritin levels due to hepatocellular injury.
- Male p.Cys282Tyr/p.His63Asp compound heterozygotes in the HEIRS Study were more likely to report a history of liver disease (odds ratio 1.7, p=0.05) [Adams et al 2005].
- p.His63Asp homozygotes. The penetrance of this genotype is lower than the penetrance of the p.Cys282Tyr/p.His63Asp genotype. Although biochemically defined abnormalities may be present, clinical manifestations characteristic of iron overload are rare [Gochee et al 2002].
Nomenclature
HFE hemochromatosis has been variably described in the past as hereditary hemochromatosis, primary hemochromatosis, genetic hemochromatosis, and bronze diabetes with cirrhosis.
After the description of other types of iron overload associated with pathogenic variants in non-HFE iron-related genes, HFE hemochromatosis was described as either HFE hemochromatosis or type 1 hemochromatosis. It is preferred to specify hemochromatosis according to gene or genotype. Using the term "hereditary" for hemochromatosis of known pathogenic genotype is redundant.
Prevalence
Among most populations of northern European ancestry, the prevalence of individuals homozygous for HFE p.Cys282Tyr is 2:1,000 to 5:1,000 [Barton et al 2015]. In non-Hispanic whites in North America, the prevalence of p.Cys282Tyr homozygotes is 1:200 to 1:400 [Adams et al 2005].
Among African Americans, p.Cys282Tyr homozygotes are rare (1:6,781). The prevalence of heterozygotes is 1:775.
Among Asians, p.Cys282Tyr homozygotes are very rare (1:25,000). The prevalence of heterozygotes is 1:1,000.
Among Hispanics, the prevalence of p.Cys282Tyr homozygotes and heterozygotes is 0.027% and 3.0%, respectively.
Heterozygosity for p.His63Asp is common in most populations (northern Europeans: 25%; Hispanics: 18%; African Americans: 6%; Asians: 8.5%).
Approximately one third of northern European whites are heterozygous for either p.Cys282Tyr or p.His63Asp.
Differential Diagnosis
HFE hemochromatosis differs from rarer primary iron overload disorders and secondary iron overload disorders.
Primary iron overload disorders (summarized in Table 2) are characterized by increased absorption of iron from a normal diet in subjects without severe anemia. Juvenile hereditary hemochromatosis and TFR2-related hereditary hemochromatosis result from hepcidin deficiency and thus the clinical manifestations of these disorders are similar to but more severe than those of hemochromatosis associated with HFE p.Cys282Tyr homozygosity.
Table 2.
Primary Iron Overload Disorders in the Differential Diagnosis of HFE Hemochromatosis
| Disorder | Gene(s) | MOI | Clinical Features of Differential Diagnosis Disorder | |
|---|---|---|---|---|
| Overlapping w/HFE Hemochromatosis | Distinguishing from HFE Hemochromatosis | |||
| Juvenile hereditary hemochromatosis | HJV HAMP | AR |
|
|
| TFR2-related hereditary hemochromatosis | TFR2 | AR |
|
|
| Ferroportin-associated iron overload (OMIM 606069) | SLC40A1 | AD | In gain-of-function (hepcidin resistance) subtype:
| In loss-of-function (classic) subtype:
|
| Aceruloplasminemia | CP | AR | Progressive iron deposition in liver & pancreas causes cirrhosis & diabetes. |
|
| BMP6-related iron overload (OMIM 112266) | BMP6 | AD |
|
|
| African iron overload (OMIM 601195) | ? | ? |
|
|
? = unknown; AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; RE = reticuloendothelial cells; TS = transferrin saturation
Secondary Iron Overload Disorders
Liver diseases include alcoholic liver disease, acute viral hepatitis, or chronic viral hepatitis C (uncommon), neoplasms, porphyria cutanea tarda, and inflammatory disorders such as rheumatoid arthritis.
A very common liver condition, nonalcoholic fatty liver disease (NAFLD) (OMIM 613282), frequently causes elevated serum ferritin levels and is sometimes associated with increased hepatic iron deposition.
Iron overload can result from ingested iron in foods, cooking ware, and medicines, in addition to parenteral iron from iron injections or transfusions for chronic anemia (e.g., beta-thalassemia, sickle cell disease, hereditary sideroblastic anemia, pyruvate kinase deficiency, hereditary spherocytosis, myelodysplastic syndrome with refractory anemia).
Iron absorption is increased in some subtypes of heritable anemia, especially severe beta-thalassemia and hereditary sideroblastic anemia.
Neonatal hemochromatosis is a severe liver disease that develops in utero and is associated with extrahepatic siderosis. Gestational alloimmune liver disease is the cause of fetal liver injury resulting in nearly all cases [Feldman & Whitington 2013]. Maternal alloimmunity accounts for the occurrence of neonatal hemochromatosis in two or more offspring of the same mother. Antenatal therapy with high-dose intravenous IgG initiated at either 18 or 14 gestational weeks prevents poor outcome of pregnancies at risk for neonatal hemochromatosis [Whitington et al 2018]. There is little evidence that neonatal hemochromatosis is a heritable disorder attributed to an as-yet-unidentified gene. Some investigators have suggested that pathogenic variants in DGUOK lead to phenotypes that resemble that of neonatal hemochromatosis (see Deoxyguanosine Kinase Deficiency).
See Hemochromatosis: OMIM Phenotypic Series, to view genes associated with this phenotype in OMIM.
Management
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]. The American Association for the Study of Liver Disease (AASLD) published practice guidelines for diagnosis and management of hemochromatosis [Bacon et al 2011] (full text). Experts at the 2017 Hemochromatosis International meeting published an objective and practical set of recommendations on treatment of persons with hemochromatosis and p.Cys282Tyr homozygosity based on published scientific studies and guidelines in a form suitable for patients and other persons without medical training [Adams et al 2018].
Evaluations Following Initial Diagnosis
To establish the extent of iron overload and optimal management of persons diagnosed with HFE hemochromatosis, the evaluations summarized in this section (if not performed as part of the evaluation at diagnosis) are recommended:
- Serum ferritin concentration to establish iron overload status and prognosis (see Figure 2)
- For p.Cys282Tyr homozygotes:
- Liver biopsy remains the "gold standard" for establishing or excluding cirrhosis.
- Liver biopsy to evaluate for advanced hepatic fibrosis is recommended for individuals with serum ferritin >1,000 ng/mL or elevated serum AST and ALT levels [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 serum ALT and AST levels because their risk for advanced hepatic fibrosis is low [Bacon et al 2011, Barton et al 2018].
- MRI to estimate parenchymal iron content by utilizing the paramagnetic properties of iron:
- A specialized MRI technique with excellent sensitivity for estimation of hepatic iron concentration has been approved by the FDA for clinical use [St Pierre et al 2005]. This method of quantitative MRI (R2) accurately measures liver iron concentration (LIC) within a sufficiently wide concentration range. Compared with liver biopsy, R2-LIC is noninvasive and significantly reduces biopsy sampling error [Fischer & Harmatz 2009]. In addition, T2*-weighted MRI measurement of liver iron is now widely available [Brittenham et al 2003, Cheong et al 2005, Ptaszek et al 2005].
- Cardiac iron concentration can be monitored using similar techniques and may be of prognostic value [Fischer & Harmatz 2009, Ramazzotti et al 2009].
Figure 2.
Use of serum ferritin concentration to direct management
Clinical HFE Hemochromatosis
Therapeutic phlebotomy is indicated in the presence of symptoms of iron overload or evidence of end-organ damage (e.g., cirrhosis, cardiac failure, skin hyperpigmentation, diabetes, or hypogonadotropic hypogonadism):
- Periodic phlebotomy is a simple, inexpensive, safe, and effective treatment.
- Each unit of blood (500 mL) with a hematocrit of 40% removes 200 mg of iron.
- Each mL of packed red blood cells contains 1 mg of iron.
- The usual therapy is weekly phlebotomy (i.e., removal of a unit of blood) until the serum ferritin concentration is ≤50 ng/mL. Twice-weekly phlebotomy is useful to accelerate iron depletion in some patients. Some persons, especially women, tolerate phlebotomy therapy less frequently (every 10-14 days) or at lower volume per phlebotomy.
- Phlebotomy is performed at intervals until the hematocrit is 75% of the baseline hematocrit.
- The serum ferritin concentration is the most reliable and inexpensive way to monitor therapeutic phlebotomy. If the serum ferritin concentration is ≥50 ng/mL despite a significant reduction in hematocrit, the frequency at which phlebotomy is performed needs to be increased. After the serum ferritin concentration is ≤100 ng/mL, serum ferritin concentration should be quantified after each additional one or two treatments [Barton et al 1998]. On average, men require removal of twice as many units of blood to achieve iron depletion as women.
- Maintenance phlebotomy to prevent reaccumulation of excess iron is indicated for men whose serum ferritin levels exceed 300 ng/mL and for women whose serum ferritin levels exceed 200 ng/mL [Adams & Barton 2010].Whether lowering TS should be a target of phlebotomy therapy is debatable. Elevated TS in HFE hemochromatosis is caused by increased iron export from macrophages due to hepcidin deficiency and is not a marker of iron overload. Attempting to achieve and maintain low TS in p.Cys282Tyr homozygotes may result in iron deficiency and associated manifestations [Barton & Bottomley 2000].
- Individuals with HFE hemochromatosis rarely need iron chelation therapy. Iron chelation therapy is not recommended unless an individual has an elevated serum ferritin concentration and concomitant anemia, inadequate venous access