Hereditary Hemochromatosis

How to Cite This Chapter: Agarwal A, Verhovsek M, Mach T. Hereditary Hemochromatosis. McMaster Textbook of Internal Medicine. Kraków: Medycyna Praktyczna. Accessed January 19, 2022.
Last Updated: July 21, 2019
Last Reviewed: July 21, 2019
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, that is, accumulation of iron in the parenchymal organs (especially in the liver, heart, pancreas, other endocrine glands, and joints) resulting in tissue and organ damage. HH can be 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 condition. In ≥80% of patients it is caused by the C282Y mutation in the gene encoding hemochromatosis protein (HFE), a membrane protein. This protein is one of the factors stimulating hepatic synthesis of hepcidin, an acute phase protein that inhibits gastrointestinal iron absorption and release of iron from macrophages. Clinical penetration of this mutation is low (~28% in men and ~1% in women, which is attributed to the protective effects of blood loss during menstruation and iron demands of pregnancy). In the remaining cases, HFE-HH is caused by other mutations in the HFE gene (eg, H63D or S65C).

The following 4 pathophysiologic mechanisms are implicated in primary hemochromatosis:

1) Increased upper intestinal absorption of dietary iron.

2) Decreased expression of hepcidin for iron regulation.

3) Altered HFE protein function.

4) 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 in women. 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 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 and significantly elevated transferrin saturation (>45%). In hepatic iron overload elevated serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels may be seen.

2. Imaging studies: Features of cirrhosis and its complications. In advanced disease computed tomography (CT) and magnetic resonance imaging (MRI) reveal increased hepatic iron content. Elastography may be used to assess the severity of liver fibrosis.

3. Histologic examination of liver biopsy specimens is not necessary if ferritin is <1000 microg/L. If ferritin is >1000 microg/L, biopsy may be required for determining the stage of the disease and grading fibrosis (for prognosis evaluation). It may be used to assess hepatocyte iron content, fibrosis, and cirrhosis. The decision to biopsy should involve the patient, a hematologist, and a hepatologist. If biopsy is performed, hepatic iron concentration and histopathologic iron staining may help determine the degree and cellular distribution of iron loading.

4. Genetic studies confirm the diagnosis of HH by demonstrating specific mutations using a polymerase chain reaction (PCR) assay. The studies are indicated in (1) patients with simultaneously elevated serum ferritin levels (>200 microg/L in women, >300 microg/L in men), elevated transferrin saturation (>45%), and unexplained chronic liver disease; (2) first-degree relatives of patients with HH.

Diagnostic Criteria

Diagnostic criteria for HFE-HH:

1) Iron overload confirmed by elevation of serum ferritin and transferrin saturation (>45%).

2) Documented homozygosity for the C282Y mutation of the HFE gene in a patient with high transferrin saturation and high serum ferritin level (this is the diagnostic gold standard in HFE-HH) or compound heterozygosity for the C282Y/H63D mutations. Other polymorphisms of the HFE gene (including homozygosity for the H63D mutation) should be interpreted with caution as they are less likely to have clinical significance. Alternative causes for high ferritin levels should be investigated.

3) Liver biopsy is not required for diagnosis and usually not performed unless the diagnosis is in doubt.

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), 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. Symptomatic patients and those with existing end-organ damage should be treated to prevent progressive organ damage. Asymptomatic individuals with homozygous disease and biochemical or biopsy-proven evidence of iron overload should be treated. 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).

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 ng/mL (microg/L) and transferrin saturation is <50%. Phlebotomies should be done weekly, as tolerated, targeting the above serum ferritin levels and stopped at levels lower than these. 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. Hematocrit and hemoglobin (Hb) levels should be allowed to decrease by a maximum of 20% from their prior level between phlebotomies. Complete blood count (CBC) and ferritin should be checked before each phlebotomy (at Hb <10 g/dL the frequency of phlebotomies should be reduced; Hb before phlebotomy should be within the normal reference range or at minimum 11-­12 g/dL). The initial course of phlebotomy treatment should be continued until the target ferritin level is reached, with most patients requiring maintenance phlebotomy every 2 to 4 months, guided by serial serum Hb, 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. In patients treated with phlebotomy, reduction of meat consumption is not necessary. Alcohol intake should be limited (<20 g/d; in patients with cirrhosis total abstinence is needed) and avoidance of iron and vitamin C supplements is advised, including avoidance of cooking with iron pots and skillets. Data suggesting beneficial effects of controlling iron intake are very limited.Evidence 2Low 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 of effects. Moretti D, van Doorn GM, Swinkels DW, Melse-Boonstra A. Relevance of dietary iron intake and bioavailability in the management of HFE hemochromatosis: a systematic review. Am J Clin Nutr. 2013 Aug;98(2):468-79. doi: 10.3945/ajcn.112.048264. Epub 2013 Jun 26. Review. PubMed PMID: 23803887

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


In the course of treatment, serum Hb and hematocrit should be assessed prior to each phlebotomy and ferritin levels (target, 50-100 microg/L) should be assessed prior to each phlebotomy or monthly. Transferrin saturation should be measured after every 10 to 12 phlebotomies (approximately every 3 months). During maintenance therapy ferritin should be assessed before every second phlebotomy.

Screening with iron studies and HFE mutation analysis should be done for all first-degree relatives of patients with HH. Genotypic and phenotypic testing should be performed simultaneously. 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.

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