Introduction
Background
Hemochromatosis is characterized by a progressive increase in total body iron stores with abnormal iron deposition in multiple organs. Primary hemochromatosis is a genetic disorder, whereas secondary hemochromatosis can be the result of a variety of disorders, most commonly chronic hemolytic anemias.
Pathophysiology
Primary hemochromatosis (also termed hereditary hemochromatosis or idiopathic hemochromatosis) is an autosomal recessive disorder. 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. The normal HFE glycoprotein interacts with the transferrin receptor and decreases the affinity of this receptor for iron-bound transferrin. 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 of uncertain etiology. 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.
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. 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, 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.
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 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.
Screening for hemochromatosis can be performed with measurement of serum ferritin and transferring saturation. Definitive diagnosis of primary hemochromatosis can be made with genetic testing or liver biopsy with quantitative determination of liver iron concentration.
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
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References
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Further Reading
Keywords
hereditary hemochromatosis, primary hemochromatosis, secondary hemochromatosis, idiopathic hemochromatosis, hemosiderosis
