> Table of Contents > Hemochromatosis
Robert A. Marlow, MD, MA
image BASICS
Hemochromatosis is a hereditary disorder in which the small intestine absorbs excessive iron (1,2).
  • Early clinical features include arthralgia, fatigue, and decreased libido.
  • Late effects include cirrhosis of the liver, diabetes, hypermelanotic pigmentation of the skin, and heart failure.
  • Because there is no mechanism to excrete excess iron, the excess is stored in muscle and in organs, including the liver, pancreas, and heart, eventually resulting in severe damage to the affected organs.
  • Liver damage ultimately may result in hepatocellular carcinoma.
  • System(s) affected: endocrine/metabolic
  • Synonym(s): bronze diabetes; Troisier-Hanot-Chauffard syndrome
  • Predominant age: Metabolic abnormality is congenital, but symptoms usually present in the 5th and 6th decades.
  • Predominant sex: gene frequency: male = female, although clinical signs are more frequent in men (3)
  • 3/1,000 people (heterozygote frequency, 1/10) (4)
  • The most common genetic abnormality in the United States
Pediatric Considerations
Rarely, iron overload may occur as early as 2 years of age. The disorder can be diagnosed before iron overload is clinically apparent.
  • Type 1 hemochromatosis is caused by mutations in the HFE gene, type 2 by mutations in either the HFE2 gene or HAMP gene, type 3 by mutations in the TFR2 gene, and type 4 by mutations in the SLC40A1 gene. The cause of neonatal hemochromatosis is unknown.
  • The mechanism for increased iron absorption in the face of excessive iron stores is not clear. Iron metabolism appears normal in this disease except for a higher level of circulating iron.
  • Iron overload may be caused by thalassemia, sideroblastic anemia, liver disease, excess iron intake, or chronic transfusion.
  • Genetically heterogeneous disorder of iron overload; types 1, 2, and 3 are autosomal recessive; type 4 is autosomal dominant. Neonatal hemochromatosis is rare.
  • Penetrance is incomplete; expressivity is variable.
  • Factors contributing to variable expressivity include different mutations in the same gene, mitigating or exacerbating genes, and environmental factors.
  • The disease is a genetic disorder.
  • Affected individuals should not ingest iron supplements, eat raw shellfish, or eat large quantities of iron-rich food, such as red meat.
  • Alcohol increases the absorption of iron. (As many as 41% of patients with symptomatic disease are alcoholic.)
  • Loss of blood, such as that which occurs during menstruation and pregnancy, delays the onset of symptoms.
  • Family members of affected individuals should be screened.
  • Pregnant women with the disorder should avoid iron supplements.
See “Complications.”
  • Hepatomegaly (83%)
  • Increased skin pigmentation (75%)
  • Loss of body hair (20%)
  • Splenomegaly (13%)
  • Peripheral edema (12%)
  • Jaundice (10%)
  • Gynecomastia (8%)
  • Ascites (6%)
  • Testicular atrophy
  • Hepatic tenderness
  • Repeated transfusions
  • Hereditary anemias with ineffective erythropoiesis
  • Alcoholic cirrhosis
  • Porphyria cutanea tarda
  • Atransferrinemia
  • Excessive ingestion of iron (rare)
  • Transferrin saturation (serum iron concentration ÷ total iron-binding capacity × 100): >70% is virtually diagnostic of iron overload; ≥45% warrants further evaluation. Iron supplements and transfusions may elevate serum iron.
  • Serum ferritin: >300 &mgr;g/L for men and postmenopausal women and 200 &mgr;g/L for premenopausal women (7); may be elevated by inflammatory reactions, other forms of liver disease, certain tumors (e.g., acute granulocytic leukemia), and rheumatoid arthritis
  • After the diagnosis is established
    • Obtain an oral glucose tolerance test or hemoglobin A1C to rule out diabetes and an echocardiogram to rule out cardiomyopathy.
    • Consider abdominal US to assess for cirrhosis.
    • Decreased FSH
    • Decreased LH
    • Decreased testosterone
    • Increased serum glutamic-oxaloacetic transaminase
    • Hypoalbuminemia
  • If the diagnosis is uncertain after laboratory testing, MRI may be helpful to assess hepatic iron (1).
Diagnostic Procedures/Other
  • Liver biopsy for stainable iron is the standard for diagnosis. Presence or absence of cirrhosis also can be ascertained. However, with the availability of genetic testing, liver biopsy is not frequently necessary to confirm the diagnosis (7)[C].
  • DNA PCR testing for HFE gene mutations C282Y and H63D: present in 85-90% of patients
  • Homozygosity for the C282Y mutation or compound heterozygosity for C282Y and H63D with biochemical evidence for iron overload can confirm the diagnosis (8).
Test Interpretation
  • Increased hepatic parenchymal iron stores
  • Hepatic fibrosis and cirrhosis with hepatomegaly
  • Pancreatic enlargement
  • Excess hemosiderin in liver, pancreas, myocardium, thyroid, parathyroid, joints, skin
  • Cardiomegaly
  • Joint deposition of iron
  • None. Only when phlebotomy is not feasible or in the presence of severe heart disease should the iron-chelating agent deferoxamine (Desferal) be considered.
  • Hepatitis A and hepatitis B immunizations should be done if there is no evidence of previous exposure (9).

  • Remove excess iron by repeated phlebotomy once or twice weekly to establish and maintain a mild anemia (hematocrit of 35-39%) (7)[C].
  • When the patient finally becomes iron-deficient, a lifelong maintenance program of 2 to 6 phlebotomies a year to keep storage iron normal; maintain serum ferritin 50 to 100 &mgr;g/L.
Admission Criteria/Initial Stabilization
Outpatient treatment
Full activity unless there is significant heart disease
Patient Monitoring
  • Measure hematocrit before each phlebotomy; skip phlebotomy if hematocrit is <36%.
  • Schedule an additional phlebotomy when hematocrit is >40%.
  • When anemia becomes refractory, repeat transferrin saturation and serum ferritin to confirm depletion of iron stores.
  • When iron stores are depleted, 2 to 6 phlebotomies a year should keep iron stores normal; maintain serum ferritin 50 to 100 &mgr;g/L.
  • During maintenance therapy, measure transferrin saturation and serum ferritin yearly.
  • An iron-poor diet is not of significant benefit.
  • Avoid alcohol, iron-fortified foods, iron-containing supplements, and uncooked shellfish (increased susceptibility to Vibrio sp.).
  • Restrict vitamin C to small doses between meals.
  • Tea chelates iron and may be drank with meals.
  • Iron Disorders Institute, PO Box 675, Taylors, SC 29687
  • American Hemochromatosis Society, Inc., PO Box 950871, Lake Mary, FL 32795-0871
  • Patients diagnosed before cirrhosis develops and treated with phlebotomy have a normal life expectancy.
  • Life expectancy is reduced in patients with cirrhosis and DM and in those who require >18 months of phlebotomy therapy to return iron stores to normal.
  • Patients with ferritin levels <1,000 &mgr;g/L are unlikely to have cirrhosis (3,10).
  • Cirrhosis
  • Hepatoma (only in patients with cirrhosis)
  • DM
  • Cardiomyopathy
  • Arthritis
  • Hypogonadism
1. van Bokhoven MA, van Deursen CT, Swinkels DW. Diagnosis and management of hereditary haemochromatosis. BMJ. 2011;342:c7251.
2. Sood R, Bakashi R, Hegade VS, et al. Diagnosis and management of hereditary haemochromatosis. Br J Gen Pract. 2013;63(611):331-332.
3. Allen KJ, Gurrin LC, Constantine CC, et al. Iron-overload-related disease in HFE hereditary hemochromatosis. N Engl J Med. 2008;358(3): 221-230.
4. Brandhagen DJ, Fairbanks VF, Baldus W. Recognition and management of hereditary hemochromatosis. Am Fam Physician. 2002;65(5): 853-860.
5. Bacon BR, Adams PC, Kowdley KV, et al. Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology. 2011;54(1):328-343.
6. Crownover BK, Covey CJ. Hereditary hemochromatosis. Am Fam Physician. 2013;87(3):183-190.
7. Qaseem A, Aronson M, Fitterman N, et al. Screening for hereditary hemochromatosis: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2005;143(7):517-521.
8. Cherfane CE, Hollenbeck RD, Go J, et al. Hereditary hemochromatosis: missed diagnosis or misdiagnosis? Am J Med. 2013;126(11):1010-1015.
9. Alexander J, Kowdley KV. Hereditary hemochromatosis: genetics, pathogenesis, and clinical management. Ann Hepatol. 2005;4(4):240-247.
10. Janssen MC, Swinkels DW. Hereditary haemochromatosis. Best Pract Res Clin Gastroenterol. 2009;23(2):171-183.
Additional Reading
  • Bardou-Jacquet E, Brissot P. Diagnostic evaluation of hereditary hemochromatosis (HFE and non-HFE). Hematol Oncol Clin North Am. 2014;28(4):625-635.
  • Ekanayake D, Roddick C, Powell LW. Recent advances in hemochromatosis: a 2015 update: a summary of proceedings of the 2014 conference held under the auspices of Hemochromatosis Australia. Hepatol Int. 2015;9(2):174-182.
  • Salgia RJ, Brown K. Diagnosis and management of hereditary hemochromatosis. Clin Liver Dis. 2015;19(1):187-198.
  • U.S. Preventive Services Task Force. Screening for hemochromatosis: recommendation statement. Ann Intern Med. 2006;145(3):204-208.
  • E83.110 Hereditary hemochromatosis
  • E83.118 Other hemochromatosis
  • E83.111 Hemochromatosis due to repeated red blood cell transfusions
Clinical Pearls
  • The best laboratory tests available to screen a patient initially for hemochromatosis are serum ferritin and transferrin saturation. An elevated transferrin saturation is the earliest abnormality in hemochromatosis. Ferritin is a sensitive measure of iron overload but can be elevated in a variety of infectious and inflammatory conditions without iron overload being present.
  • Liver biopsy need not be done to confirm the diagnosis or to check for cirrhosis if the patient is homozygous for C282Y or is heterozygous for C282Y/H63D. If the patient's serum ferritin is <1,000 &mgr;g/L, LFTs are normal, and hepatomegaly is not present, cirrhosis is very unlikely, so liver biopsy is not needed.
  • Initially, a patient with hemochromatosis should have a phlebotomy weekly until the serum ferritin is 50 to 100 &mgr;g/L, and the transferrin saturation falls to <30%. Then, lifelong maintenance therapy of 2 to 6 phlebotomies a year is mandatory to keep the ferritin 50 to 100 &mgr;g/L and the transferrin saturation <50%.
  • Most patients with hemochromatosis go undiagnosed. Because treatment with phlebotomy will prevent all complications when begun early, physicians should consider the diagnosis of hemochromatosis much more frequently. However, the U.S. Preventive Services Task Force recommends against routine screening of asymptomatic average-risk populations.