Hereditary Hemochromatosis

How to Cite This Chapter: Agarwal A, Verhovsek M, Mach T. Hereditary Hemochromatosis. McMaster Textbook of Internal Medicine. Kraków: Medycyna Praktyczna. Accessed April 23, 2024.
Last Updated: September 25, 2022
Last Reviewed: September 25, 2022
Chapter Information

Definition, Etiology, PathogenesisTop

Hereditary hemochromatosis (HH) is a genetically determined disease in which excessive absorption of iron in the small intestine leads to iron overload. Iron deposition in parenchymal organs (especially in the liver, heart, pancreas, pituitary gland, skin, and joints) results in tissue and organ damage. HH is more common in individuals of Northern European descent. The disease is caused by mutations in the HFE gene (HFE-related hereditary hemochromatosis) (HFE-HH) or other genes encoding hemojuvelin, hepcidin, transferrin receptor 2, or ferroportin (non–HFE-related hemochromatosis).

HFE-HH is an autosomal recessive disease resulting in an abnormality in the membrane protein, which stimulates hepatic synthesis of hepcidin, thus affecting the regulation of gastrointestinal iron absorption and macrophage release of iron. In ≥90% of patients it is caused by a mutation at C282Y in the HFE gene. In the remaining cases, mutations at other sites in the HFE gene, including H63D and S65C, are implicated. Homozygosity for a mutation at the C282Y confirms the diagnosis of HH; compound heterozygosity at C282Y and H63D is associated with a possibility, although with a lower likelihood, of developing iron overload. Mutations at H63D or S65C in the absence of a mutation at C282Y are generally not associated with an increased risk of iron overload.

The following 5 pathophysiologic mechanisms are implicated in primary hemochromatosis:

1) Altered HFE protein function.

2) Decreased expression of hepcidin for iron regulation.

3) Increased upper intestinal absorption of dietary iron.

4) Dysregulated iron retention by macrophages.

5) Tissue injury and fibrogenesis related to iron overload, particularly liver damage.

Clinical Features and Natural HistoryTop

HH is classified into the following stages:

1) Stage 1: Genetic disorder with no increase in iron stores but with genetic susceptibility.

2) Stage 2: Genetic disorder with phenotypic evidence of iron overload but no end-organ damage.

3) Stage 3: Genetic disorder with iron overload and end-organ damage.

The prevalence of clinically overt HFE-HH is higher in men than in women. The onset of symptoms is usually >40 years of age in men and >50 years (after menopause) in women. Disease penetrance of HH is low. Only 2% to 10% of individuals homozygous for HFE C282Y mutations develop clinically significant iron overload.

Early manifestations include fatigue, loss of libido, and arthralgia (most commonly affecting the hands and wrists). Later signs and symptoms result from chronic hepatitis or cirrhosis, cardiomyopathy, pancreatic damage (diabetes mellitus in ~70% of patients), accumulation of iron and melanin in the skin (increased pigmentation and bronze discoloration), and hormonal abnormalities (hypopituitarism, mainly gonadotropic, and rarely hypothyroidism). However, increasingly patients are being identified in the asymptomatic stage if ferritin testing is included in routine blood screening tests. Untreated hemochromatosis is progressive. Approximately a third of patients with cirrhosis develop hepatocellular carcinoma (HCC).

Juvenile hemochromatosis, caused by mutations in genes encoding hepcidin or hemojuvelin, has a more severe and rapid course. The onset of symptoms (hypogonadism and heart failure) occurs between the ages of 15 and 20 years.


Diagnostic Tests

1. Blood tests: Elevated ferritin levels (>300 in men and >200 in women) and significantly elevated transferrin saturation (>45%). The absence of both findings excludes HH with a good negative predictive value (97%). Ferritin levels >1000 should lead to a higher index of suspicion of an underlying end-organ damage. Transaminases may be elevated with hepatic iron overload.

Genetic studies: HFE mutation testing for C282Y, H63D, and S65C using a polymerase chain reaction (PCR) assay may confirm the diagnosis of HH. The studies are indicated in individuals with elevated ferritin and transferrin saturation levels, especially with unexplained liver disease, and for first-degree relatives of patients with HH.

2. Imaging studies: Magnetic resonance imaging (MRI) is the preferred imaging modality. Hepatic iron concentration may be evaluated with MRI. Elastography may also be used to assess the extent of liver fibrosis.

3. Histologic examination: Most patients do not require liver biopsy if the initial biochemical workup, genetic testing, and imaging are consistent with the diagnosis of HH. Biopsy is generally reserved for individuals with significantly elevated ferritin levels (>1000), with suspected hepatic fibrosis or cirrhosis, or where the diagnosis is in question. When conducted, histologic examination of liver biopsy specimens may assist in determining the stage of the disease and grading fibrosis (for prognostication), assessing hepatocyte iron content, fibrosis, and cirrhosis, and determining the degree and cellular distribution of iron loading.

Differential Diagnosis

1. High ferritin with normal transferrin saturation:

1) Other causes of liver disease including alcoholic liver disease, viral hepatitis, nonalcoholic steatohepatitis, and Wilson disease.

2) Nonhepatic inflammatory conditions: Chronic infections (eg, osteomyelitis, tuberculosis), connective tissue disease (eg, systemic lupus erythematosus, rheumatoid arthritis), and malignancy.

2. Secondary iron overload states.


1. Phlebotomy is the treatment of choice to remove excess iron from the body. Early identification and initiation of phlebotomy preemptively before the development of cirrhosis or diabetes mellitus significantly reduces hemochromatosis-related morbidity and mortality. Phlebotomy reduces tissue iron stores and improves survival in the precirrhotic and prediabetic settings, quality of life, cardiac function, diabetes control, physical symptoms (abdominal pain, skin pigmentation, arthropathy, testicular atrophy), and biochemical and structural liver abnormalities (elevated transaminases, hepatic fibrosis, portal hypertension).

Symptomatic patients and those with existing end-organ damage should be treated rapidly and with close ongoing reassessment to prevent progressive organ damage. Asymptomatic individuals with homozygous disease and biochemical or biopsy-proven evidence of iron overload, particularly those with a significant family history of iron overload, should be treated. Individuals with compound heterozygosity or other HFE variants are less likely to develop iron overload–related complications; annual monitoring of iron indices and evidence of end-organ sequelae is a reasonable approach in this setting, as is early initiation of phlebotomy.

Phlebotomy is routinely performed in quantities up to 500 mL (equivalent to ~250 mg of iron) every 1 to 2 weeks until the ferritin level is reduced to 50 to 100 microg/L and transferrin saturation is <50%. Complete blood counts and ferritin levels should be checked prior to each phlebotomy, ensuring that the hemoglobin level does not fall below 110 g/L. It remains the treatment of choice when compared with red blood cell (RBC) removal (erythrocytapheresis).Evidence 1Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the risk of bias, imprecision, and indirectness. Buzzetti E, Kalafateli M, Thorburn D, Davidson BR, Tsochatzis E, Gurusamy KS. Interventions for hereditary haemochromatosis: an attempted network meta-analysis. Cochrane Database Syst Rev. 2017 Mar 8;3:CD011647. doi: 10.1002/14651858.CD011647.pub2. Review. PubMed PMID: 28273330; PubMed Central PMCID: PMC6464659. The initial course of phlebotomy treatment should be continued until the target ferritin level is reached, with most patients subsequently requiring maintenance phlebotomy every 2 to 4 months, guided by serial serum hemoglobin, hematocrit, and ferritin levels. In many jurisdictions patients with HH are encouraged to donate blood to the public blood supply, provided they meet other donor criteria.

2. Chelation with deferoxamine, deferiprone, or deferasirox may be considered as second-line therapy for patients unable to tolerate or refractory to phlebotomy (eg, anemia, heart failure). One should consider possible retinal or auditory toxicity (deferoxamine), agranulocytosis (deferiprone), and liver or renal toxicity (deferasirox) when initiating therapy.

3. In patients treated with phlebotomy, reduction of meat consumption or other dietary iron intake is not necessary. Alcohol intake should be limited (<20 g/d; in patients with cirrhosis total abstinence is recommended) and avoidance of iron and vitamin C supplements is advised, including avoidance of cooking with iron pots and skillets. Patients should avoid uncooked seafood, given the risk of Listeria, Yersinia, or Vibrio infections with elevated iron states.

4. All patients should receive hepatitis A and B vaccinations. All patients with cirrhosis should receive pneumococcal and influenza vaccinations.

5. Patients with decompensated cirrhosis or focal hepatocellular carcinoma may be considered for liver transplant.


In the course of treatment, serum hemoglobin, hematocrit, and ferritin levels should be assessed prior to each phlebotomy; the target ferritin level is 50 to 100 microg/L. Transferrin saturations should be measured after every 10 to 12 phlebotomies (every ~3 months). During maintenance therapy, ferritin may be assessed before every second phlebotomy.

Screening with iron studies, with or without HFE mutation analysis, should be done for all first-degree relatives of patients with HH. For children identified through a proband (first identified patient), testing of the other parent is indicated to evaluate homozygosity or heterozygosity; further testing is warranted in homozygosity and not warranted in heterozygosity (unless there is compound heterozygosity).

Ongoing screening for cirrhosis and development of HCC should be arranged for patients regardless of whether phlebotomy is used.


Approximately one-third of untreated patients survive 5 years from diagnosis. Effective treatment (before the onset of cirrhosis and other irreversible complications) is associated with survival similar to that of the general population.

We would love to hear from you

Comments, mistakes, suggestions?

We use cookies to ensure you get the best browsing experience on our website. Refer to our Cookies Information and Privacy Policy for more details.