Introduction
Background
Hemochromatosis is characterized by a progressive increase in total body iron stores with abnormal iron deposition in multiple organs.1 Primary hemochromatosis is a genetic disorder, whereas secondary hemochromatosis can be the result of a variety of disorders, most commonly chronic hemolytic anemias.2
Pathophysiology
Primary hemochromatosis (also termed hereditary hemochromatosis or idiopathic hemochromatosis) is an autosomal recessive disorder.3,4 This disease is the result of an abnormality, usually a single site mutation, in the HFE gene, which is located near the HLA complex and produces a glycoprotein. In such cases, affected patients have lower levels of hepcidin, a hepatic peptide hormone that negatively regulates iron efflux from the intestines into the blood. The normal HFE glycoprotein interacts with the transferrin receptor and decreases the affinity of this receptor for iron-bound transferrin.5 The mutated HFE glycoprotein does not have this interaction and allows cellular uptake of iron-based transferrin. In addition, these patients have an increase in intestinal iron absorption. Patients with primary hemochromatosis have increased total body iron stores of up to 20-40 g, whereas normal patients have iron stores of 1-3 g.6,7
T2-weighted gradient echo axial image in a patient with hemochromatosis demonstrates diffuse abnormal low signal intensity of the liver. The pancreas and spleen appear normal.
Noncontrast CT scan in a 47-year-old man with sickle cell disease who had undergone multiple transfusions demonstrates diffuse increased attenuation of the liver, representing abnormal iron deposition. The spleen is small and calcified from autosplenectomy.
In primary hemochromatosis, the liver is the main organ for abnormal iron deposition, consisting of ferritin and hemosiderin. Early deposition is located in periportal hepatocytes. This progresses to perilobular fibrosis with iron deposition in the biliary epithelium, Kupffer cells, and fibrous septa. In patients with advanced disease, the liver is cirrhotic with broad fibrous septa surrounding large areas of relatively normal liver parenchyma. Other sites of abnormal iron deposition include the pancreas and heart.
Patients who receive multiple blood transfusions also develop iron overload, occasionally termed hemosiderosis or secondary hemochromatosis.1,8,9,10,11,12,13 Iron from the transfused erythrocytes is deposited in the reticuloendothelial system in the liver, spleen, and bone marrow. Abnormal iron accumulation in the reticuloendothelial system does not damage the affected organs and, thus, is of little clinical significance.
In patients who have received more than 40 units of blood, the reticuloendothelial system is typically saturated with iron (10 g), and additional iron deposits are seen in the parenchymal cells of the liver, pancreas, and heart. The abnormal parenchymal iron deposition can cause organ dysfunction, similar to that seen in primary hemochromatosis. Iron chelation therapy is used in patients who receive large numbers of transfusions to remove excess iron and prevent organ damage.1,8,9,10,11,12
Patients with thalassemia have increased demand for iron in the bone marrow because of ineffective erythropoiesis. This results in increased absorption of iron. In patients without transfusions, the excess iron is deposited in hepatocytes, not in Kupffer cells. If patients are transfusion-dependent, they also may have abnormal iron deposition in the reticuloendothelial system.
Bantu siderosis, a condition found in parts of Africa, causes abnormal iron deposition in the liver. The disorder occurs in patients who drink a large amount of locally brewed beer, which is iron-laden. In addition, these patients have a genetic predisposition for increased iron absorption. These patients have abnormal iron deposition in both parenchymal cells (hepatocytes) and the reticuloendothelial system (Kupffer cells).
Frequency
International
Homozygous hemochromatosis occurs in 0.4-1% of persons of Northern European origin and is much less common in other populations.
Mortality/Morbidity
Patients with primary hemochromatosis who do not have cirrhosis have the same life expectancy as normal persons. Patients with cirrhosis and primary hemochromatosis have a poor prognosis. One third of deaths from hemochromatosis are the result of hepatocellular carcinoma. Other complications of cirrhosis, such as decreased liver function and varices, also account for a significant number of deaths from hemochromatosis. Cardiomyopathy and diabetes are uncommon causes of death in patients with hemochromatosis; however, patients with hemochromatosis and diabetes have a worse prognosis than other patients with hemochromatosis. The presence of arthropathy does not affect the prognosis in patients with hemochromatosis.
Race
Hemochromatosis occurs predominantly in white populations of Northern European origin.
Sex
Male-to-female ratio is 1.8:1.
Presentation
In primary hemochromatosis, the liver is the main organ for abnormal iron deposition and, if left untreated, may lead to cirrhosis. In addition to liver dysfunction in patients with cirrhosis from primary hemochromatosis, approximately 30% develop hepatocellular carcinoma. Hepatocellular carcinoma is not commonly seen in patients with hemochromatosis without cirrhosis.
The pancreas also is commonly involved by primary hemochromatosis. Patients with early hemochromatosis (noncirrhotic) frequently have insulin resistance, while patients with cirrhosis and hemochromatosis often have type 1 diabetes mellitus.
Patients with primary hemochromatosis often have hyperpigmentation of the skin.
Arthropathy occurs in 25-50% of patients with primary hemochromatosis and classically occurs in the second and third metacarpophalangeal joints. Arthropathy may occur early in the course of the disease.
Later in the course of the disease, approximately 40% of males develop pituitary hypogonadism with subsequent sexual impotence and loss of libido.
Cardiac involvement includes cardiomyopathy and arrhythmias and is a common cause of death in patients with primary hemochromatosis. Cardiac transplantation may be necessary in patients with severe cardiomyopathy.
Treatment involves frequent phlebotomy, particularly during the period after initial diagnosis. Symptoms such as hepatomegaly, skin pigmentation, lethargy, and abdominal pain are significantly improved with phlebotomy, but arthritis is not affected by therapy. Mild abnormalities of glucose metabolism improve with therapy, but type 1 diabetes mellitus is not affected by therapy. Hepatic fibrosis and cardiac dysfunction also improve after therapy.8
Screening for hemochromatosis can be performed with measurement of serum ferritin and transferring saturation. Definitive diagnosis of primary hemochromatosis can be made with genetic testing3 or liver biopsy with quantitative determination of liver iron concentration.14,15,16,17,18
Preferred Examination
MRI is the best imaging examination to evaluate abnormal iron deposition in the liver. CT is less sensitive than MRI but can demonstrate increased iron if it is severe.
Limitations of Techniques
Although quantification of iron deposition in the liver is possible with MRI, calibration of each MR scanner is necessary. Therefore, quantitative MRI for iron deposition is not available at many institutions.
Differential Diagnoses
More on Hemochromatosis |
 Overview: Hemochromatosis |
| Imaging: Hemochromatosis |
| Follow-up: Hemochromatosis |
| Multimedia: Hemochromatosis |
| References |
| Further Reading |
| Next Page » |
References
Schranz M, Talasz H, Graziadei I, Winder T, Sergi C, Bogner K, et al. Diagnosis of hepatic iron overload: a family study illustrating pitfalls in diagnosing hemochromatosis. Diagn Mol Pathol. Mar 2009;18(1):53-60. [Medline].
Pietrangelo A. Inherited metabolic disease of the liver. Curr Opin Gastroenterol. Apr 1 2009;[Medline].
Picot J, Bryant J, Cooper K, Clegg A, Roderick P, Rosenberg W, et al. Psychosocial aspects of DNA testing for hereditary hemochromatosis in at-risk individuals: a systematic review. Genet Test Mol Biomarkers. Feb 2009;13(1):7-14. [Medline].
Phatak PD, Sham RL, Raubertas RF. Prevalence of hereditary hemochromatosis in 16031 primary care patients. Ann Intern Med. Dec 1 1998;129(11):954-61. [Medline].
Gao J, Chen J, Kramer M, Tsukamoto H, Zhang AS, Enns CA. Interaction of the hereditary hemochromatosis protein HFE with transferrin receptor 2 is required for transferrin-induced hepcidin expression. Cell Metab. Mar 2009;9(3):217-27. [Medline].
Deugnier Y, Bourgain C, Mosser J. [Acquired and genetic factors influencing the penetrance of HFE haemochromatosis]. Bull Acad Natl Med. May 2008;192(5):873-81; discussion 881. [Medline].
Bartolo C, McAndrew PE, Sosolik RC. Differential diagnosis of hereditary hemochromatosis from other liver disorders by genetic analysis: gene mutation analysis of patients previously diagnosed with hemochromatosis by liver biopsy. Arch Pathol Lab Med. Jul 1998;122(7):633-7. [Medline].
Mair SM, Weiss G. New pharmacological concepts for the treatment of iron overload disorders. Curr Med Chem. 2009;16(5):576-90. [Medline].
Howard JM, Ghent CN, Carey LS. Diagnostic efficacy of hepatic computed tomography in the detection of body iron overload. Gastroenterology. Feb 1983;84(2):209-15. [Medline].
Jensen PD, Jensen FT, Christensen T. Evaluation of transfusional iron overload before and during iron chelation by magnetic resonance imaging of the liver and determination of serum ferritin in adult non-thalassaemic patients. Br J Haematol. Apr 1995;89(4):880-9. [Medline].
Villari N, Caramella D, Lippi A. Assessment of liver iron overload in thalassemic patients by MR imaging. Acta Radiol. Jul 1992;33(4):347-50. [Medline].
McLeod C, Fleeman N, Kirkham J, Bagust A, Boland A, Chu P, et al. Deferasirox for the treatment of iron overload associated with regular blood transfusions (transfusional haemosiderosis) in patients suffering with chronic anaemia: a systematic review and economic evaluation. Health Technol Assess. Jan 2009;13(1):iii-iv, ix-xi, 1-121. [Medline].
Flyer MA, Haller JO, Sundaram R. Transfusional hemosiderosis in sickle cell anemia: another cause of an echogenic pancreas. Pediatric Radiology. 1993;23(2):140-2.
Wang X, Leiendecker-Foster C, Acton RT, Barton JC, McLaren CE, McLaren GD, et al. Heme carrier protein 1 (HCP1) genetic variants in the Hemochromatosis and Iron Overload Screening (HEIRS) Study participants. Blood Cells Mol Dis. Mar-Apr 2009;42(2):150-4. [Medline].
Pedersen P, Milman N. Genetic screening for HFE hemochromatosis in 6,020 Danish men: penetrance of C282Y, H63D, and S65C variants. Ann Hematol. Jan 22 2009;[Medline].
Phatak PD, Bonkovsky HL, Kowdley KV. Hereditary hemochromatosis: time for targeted screening. Ann Intern Med. Aug 19 2008;149(4):270-2. [Medline].
Adams PC, Reboussin DM, Barton JC, Acton RT, Speechley M, Leiendecker-Foster C, et al. Serial serum ferritin measurements in untreated HFE C282Y homozygotes in the Hemochromatosis and Iron Overload Screening Study. Int J Lab Hematol. Aug 2008;30(4):300-5. [Medline].
Acton RT, Barton JC, Passmore LV, Adams PC, McLaren GD, Leiendecker-Foster C, et al. Accuracy of family history of hemochromatosis or iron overload: the hemochromatosis and iron overload screening study. Clin Gastroenterol Hepatol. Aug 2008;6(8):934-8. [Medline].
Kawamoto S, Soyer PA, Fishman EK. Nonneoplastic liver disease: evaluation with CT and MR imaging. Radiographics. Jul-Aug 1998;18(4):827-48. [Medline].
Alustiza JM, Artetxe J, Castiella A, et al. MR quantification of hepatic iron concentration. Radiology. Feb 2004;230(2):479-84. [Medline].
Bonkovsky HL, Rubin RB, Cable EE. Hepatic iron concentration: noninvasive estimation by means of MR imaging techniques. Radiology. Jul 1999;212(1):227-34. [Medline].
Gandon Y, Guyader D, Heautot JF. Hemochromatosis: diagnosis and quantification of liver iron with gradient-echo MR imaging. Radiology. Nov 1994;193(2):533-8. [Medline].
Siegelman ES, Mitchell DG, Outwater E. Idiopathic hemochromatosis: MR imaging findings in cirrhotic and precirrhotic patients. Radiology. Sep 1993;188(3):637-41. [Medline].
Siegelman ES, Mitchell DG, Semelka RC. Abdominal iron deposition: metabolism, MR findings, and clinical importance. Radiology. Apr 1996;199(1):13-22. [Medline].
Villeneuve JP, Bilodeau M, Lepage R. Variability in hepatic iron concentration measurement from needle- biopsy specimens. J Hepatol. Aug 1996;25(2):172-7. [Medline].
Further Reading
Clinical guidelines
Screening for hemochromatosis: recommendation statement.
United States Preventive Services Task Force - Independent Expert Panel. 2006. 5 pages. NGC:004959
Screening for hereditary hemochromatosis: a clinical practice guideline from the American College of Physicians.
American College of Physicians - Medical Specialty Society. 2005 Oct 4. 5 pages. NGC:004540
AASLD practice guidelines: evaluation of the patient for liver transplantation.
American Association for the Study of Liver Diseases - Private Nonprofit Research Organization. 2000 Jan (revised 2005 Jun). 26 pages. NGC:004333
Clinical trials
Treatment of Hemochromatosis
Erythrocyte Apheresis Versus Phlebotomy in Hemochromatosis
Oral Nifedipine to Treat Iron Overload
Related eMedicine topics
Hemochromatosis (Dermatology)
Hemochromatosis (Gastroenterology)
Hemochromatosis, Neonatal
Transfusion-Induced Iron Overload
Keywords
hemochromatosis, haemochromatosis, hereditary hemochromatosis, primary hemochromatosis, secondary hemochromatosis, idiopathic hemochromatosis, hemosiderosis, iron overload, iron toxicity
