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Primary hemochromatosis
is an inherited disorder characterized by excessive iron accumulation causing
tissue damage. Symptoms do not develop until organ damage, often
irreversible, develops. Symptoms include fatigue, hepatomegaly,
bronze skin pigmentation, loss of libido, arthalgias, and manifestations
of cirrhosis, diabetes, or cardiomyopathy. Diagnosis is based on
serum iron studies and gene assay. Treatment is with serial phlebotomies.
Etiology
and Pathophysiology
Nearly all primary hemochromatosis is caused by a mutation of the HFE gene. Non-HFE primary hemochromatosis is uncommon and includes ferroportin disease, juvenile hemochromatosis, and the very rare neonatal hemochromatosis, hypotransferrinemia, and aceruloplasminemia. The clinical consequences of iron overload are the same in all types.
Over 80% of HFE-related hemochromatosis is caused by the homozygous C282Y or C282Y/H63D compound heterozygote mutation. The disorder is autosomal recessive, with a homozygous frequency of 1:200 and a heterozygous frequency of 1:8 in Northern Europeans. It is uncommon in blacks and rare in Asians. Of patients with clinical hemochromatosis, 83% are homozygous. The mechanism for iron overload is increased iron absorption from the GI tract, leading to chronic deposition of iron in the tissue. Hepcidin, a recently identified liver-derived peptide, is the critical control mechanism for iron absorption. Hepcidin, along with the normal HFE gene, prevents excessive iron absorption and storage in the normal individual.
Total body iron content can reach as high as 50 g, compared with the normal levels of about 2.5 g in women and 3.5 g in men. Iron deposition in organs catalyzes generation of reactive free hydroxyl radicals.
Symptoms and Signs
Symptoms are uncommon before middle age. Of affected men, 80 to 90% have total body iron stores > 10 g before symptoms develop. In women, symptoms are uncommon before menopause, because iron loss during menses and pregnancy provides some protection.
Because iron accumulates in multiple sites, symptoms can develop referable to many possible organs or systemically. In women, fatigue and nonspecific constitutional symptoms develop early; in men, cirrhosis or diabetes is often the initial presentation. Hypogonadism is common in both sexes as well and may predate other manifestations. Liver disease is the most common complication, and in cases that progress to cirrhosis, about 20 to 30% progress further to hepatocellular carcinoma. Ten to 15% of untreated patients develop heart failure; 90%, excessive skin pigmentation; 65%, diabetes and its potential sequelae (nephropathy, retinopathy, neuropathy); and 25 to 50%, arthropathy.
Diagnosis
Hemochromatosis is suspected in patients with typical symptoms, particularly unexplained hepatic abnormalities, and in patients with a family history. Because symptoms develop only after tissue injury, diagnosis before symptoms develop is desirable (but difficult). If hemochromatosis is suspected, testing includes serum iron, serum transferrin saturation, serum ferritin, and gene assay.
Serum iron is increased (> 300 mg/dL). Serum transferrin saturation is usually > 50% and often > 90%. Serum ferritin is increased. Gene assay establishes the diagnosis; nongenetic mechanisms of iron overload, such as congenital hemolytic states (eg, sickle cell anemia, thalassemia) must be ruled out. Hepatic iron content can be estimated with a high-intensity MRI where available. Because cirrhosis markedly affects prognosis, a liver biopsy is done if serum ferritin is unexpectedly high (eg, > 1000, but cutoffs should be adjusted for age, which can increase levels, and for elevated liver enzymes, which can decrease levels). Liver iron content can also be measured to further confirm tissue iron deposition.
First-degree relatives of people with primary hemochromatosis should be screened. Testing for C282Y and H63D identifies > 95% of cases.
Treatment
Phlebotomy is the simplest method of excess iron removal in most cases. It prolongs survival but does not prevent hepatocellular carcinoma. As soon as the diagnosis is made, about 500 mL/wk of blood (about 250 mg of iron) is removed weekly until serum iron levels are normal and transferrin saturation is < 50%. Weekly phlebotomy may be needed for several years. When iron levels are normal, further phlebotomy can be performed to maintain transferrin saturation at < 30%. Diabetes, cardiac abnormalities, erectile dysfunction, and other secondary manifestations are treated as indicated.
Ferroportin
Disease
Ferroportin disease occurs largely in southern Europeans. It results from an autosomal dominant mutation in the SLC 40 A1 gene. It manifests in the 1st decade of life as increased serum ferritin with low or normal transferrin, with progressive saturation of transferrin in the 3rd to 4th decades. Clinical manifestations are milder than in HFE disease, with modest liver disease and mild anemia. Tolerance to vigorous phlebotomy is poor; serial monitoring of Hb and transferrin saturation is required.
Juvenile
Hemochromatosis
This is a rare autosomal recessive disease due to mutations in the HJV gene affecting the transcription protein hemojuvelin. It often presents in adolescents. Ferritin levels are > 1000, and transferrin saturation is > 90%. Symptoms and signs include progressive hepatomegaly and hypogonadotropic hypogonadism.
Transferrin and
Ceruloplasmin Deficiency
(Hypotransferrinemia/atransferrinemia; Aceruloplasminemia)
In transferrin deficiency, absorbed iron that enters the portal system as nontransferrin-bound iron is deposited in the liver. Subsequent transfer to sites of RBC production is reduced because of the transferrin deficiency. In ceruloplasmin deficiency, lack of ferroxidase results in defective conversion of Fe2
+ to Fe3
+, which is necessary for binding to transferrin; this impairs the movement of iron from intracellular stores to plasma transport, resulting in tissue iron accumulation.
These transport defects are suspected in patients with iron overload that develops at an early age or when overload is found but genetic testing results are normal. Diagnosis is based on measurement of serum transferrin (ie, iron-binding capacity) and ceruloplasmin (see Mineral Deficiency and Toxicity: Inherited Copper Toxicity). Treatment is experimental.
An autosomal recessive form of hemochromatosis occurs with mutations in transferrin receptor 2, a protein that appears to control saturation of transferrin. Symptoms and signs are similar to HFE hemochromatosis.
Last full review/revision November 2005
Content last modified November 2005
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