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HEMOCHROMATOSIS symptoms, diagnosis and treatment


Hemochromatosis is an autosomal recessive disease caused in most cases by a mutation in the HFE gene on chromosome 6. The HFE protein is thought to play an important role in the process by which duodenal crypt cells sense body iron stores, and a mutation of the gene leads to increased iron absorption from the duodenum. A decrease in the synthe­sis or expression of hepcidin, the principal iron regulatory hormone, is thought to be a key pathogenic factor in all forms of hemochromatosis.

Hemochromatosis is characterized by increased accu­mulation of iron as hemosiderin in the liver, pancreas, heart, adrenals, testes, pituitary, and kidneys. Cirrhosis is more likely to develop in affected persons who drink alco­hol excessively or have obesity-related hepatic steatosis than in those who do not. Eventually, hepatic and pancre­atic insufficiency, heart failure, and hypogonadism may develop; overall mortality is increased slightly. Heterozy­gotes do not develop cirrhosis in the absence of associated disorders such as viral hepatitis or NAFLD.

Signs and symptoms

The onset of clinical disease is usually after age 50 years— earlier in men than in women; however, because of wide­spread liver biochemical testing and iron screening, the diagnosis is usually made long before symptoms develop.

Early symptoms are nonspecific (eg, fatigue, arthralgia). Later clinical manifestations include arthropathy (and ulti­mately the need for joint replacement surgery in some cases), hepatomegaly and evidence of hepatic dysfunction, skin pigmentation (combination of slate-gray due to iron and brown due to melanin, sometimes resulting in a bronze color), cardiac enlargement with or without heart failure or conduction defects, diabetes mellitus with its complications, and erectile dysfunction in men.


Population studies have shown an increased prevalence of liver disease but not of diabetes mellitus, arthritis, or heart disease in C282Y homozygotes.

In patients in whom cirrhosis develops, bleeding from esophageal varices may occur, and there is a 15–20% frequency of hepatocellular carcinoma.

Affected patients are at increased risk of infection with Vibrio vulnificus, Listeria monocytogenes, Yersinia entero­colitica, and other siderophilic organisms.

The risk of porphyria cutanea tarda is increased in persons with the C282Y or H63D mutation, and C282Y homozygotes have twice the risk of colorectal and breast cancer than persons without the C282Y variant.


Laboratory findings include mildly abnormal liver tests (AST, alkaline phosphatase), an elevated plasma iron with greater than 45% transferrin saturation, and an elevated serum ferritin (although a normal iron saturation or a nor­mal ferritin does not exclude the diagnosis). Affected men are more likely than affected women to have an elevated ferritin level.

Testing for HFE mutations is indicated in any patient with evidence of iron overload. Interestingly, in persons with an elevated serum ferritin, the likelihood of detecting C282Y homozygosity decreases with increasing ALT and AST levels, which are likely to reflect hepatic inflammation and secondary iron overload.

MRI and CT may show changes consistent with iron over­load of the liver, and MRI can quantitate hepatic iron stores and help assess the degree of hepatic fibrosis.

Differential diagnosis

In patients who are homozygous for C282Y, liver biopsy is often indicated to determine whether cirrhosis is present. Biopsy can be deferred, however, in patients in whom the serum ferritin level is less than 1000 mcg/L, serum AST level is normal, and hepatomegaly is absent; the likelihood of cirrhosis is low in these persons.

The combination of a serum ferritin level of 1000 mcg/L or more and a serum hyaluronic acid level of 46.5 mcg/L or more has been reported to identify all patients with cirrhosis, with a high specificity. Risk factors for advanced fibrosis include male sex, excess alcohol consumption, and diabetes mellitus. Liver biopsy is also indicated when iron overload is sus­pected even though the patient is neither homozygous for C282Y nor a C282Y/H63D compound heterozygote.

In patients with hemochromatosis, the liver biopsy character­istically shows extensive iron deposition in hepatocytes and in bile ducts, and the hepatic iron index—hepatic iron content per gram of liver converted to micromoles and divided by the patient’s age—is generally higher than 1.9. Only 5% of patients with hereditary hemochromatosis identified by screening in a primary care setting have cirrhosis.

Iron studies and HFE testing are recommended for all first-degree family members of a proband; children of an affected person (C282Y homozygote) need to be screened only if the patient’s spouse carries the C282Y or H63D mutation. General population screening for hemochroma­tosis is not recommended because the clinical penetrance of C282Y homozygosity and morbidity and mortality from hemochromatosis are low. Patients with otherwise unex­plained chronic liver disease, chondrocalcinosis, erectile dysfunction, and type 1 diabetes mellitus (especially late-onset) should be screened for iron overload.


Affected patients are advised to avoid foods rich in iron (such as red meat), alcohol, vitamin C, raw shellfish, and supplemental iron.

Weekly phlebotomies of 1 or 2 units (250–500 mL) of blood (each containing about 250 mg of iron) is indicated in all symptomatic patients, those with a serum ferritin level of at least 1000 mcg/L, and those with an increased fasting iron saturation and should be contin­ued for up to 2–3 years to achieve depletion of iron stores. The hematocrit and serum iron values should be monitored. When iron store depletion is achieved (iron saturation less than 50% and serum ferritin level 50–100 mcg/L), phlebotomies (every 2–4 months) to maintain serum fer­ritin levels between 50 mcg/L and 100 mcg/L are continued, although compliance has been reported to decrease with time.

Administration of a proton pump inhibitor, which reduces intestinal iron absorption, decreases the maintenance phlebotomy volume requirement.

In C282Y homozygous women, a body mass index greater than 28 is associated with a lower phlebotomy requirement, possibly because hepcidin levels are increased by overweight. Complications of hemochromatosis—arthropathy, diabetes mellitus, heart disease, portal hypertension, and hypopituitarism—also require treatment.

The chelating agent deferoxamine is indicated for patients with hemochromatosis and anemia or in those with secondary iron overload due to thalassemia who can­not tolerate phlebotomies. The drug is administered intra­venously or subcutaneously in a dose of 20–40 mg/kg/day infused over 24 hours and can mobilize 30 mg of iron per day; however, treatment is painful and time-consuming.

Two oral chelators, deferasirox, 20 mg/kg once daily, and deferiprone, 25 mg/kg three times daily, have been approved for treatment of iron overload due to blood transfusions and may be appropriate in persons with hemochromatosis who cannot tolerate phlebotomy; how­ever, these agents have a number of side effects and drug-drug interactions.


The course of hemochromatosis is favorably altered by phlebotomy therapy. Hepatic fibrosis may regress, and in precirrhotic patients, cirrhosis may be prevented. Cardiac conduction defects and insulin requirements improve with treatment.

More severe joint symptoms are associated with persistent increases in the transferrin saturation, even if the serum ferritin level is maintained below 50 mcg/L. In patients with cirrhosis, varices may reverse, and the risk of variceal bleeding declines, although the risk of hepatocel­lular carcinoma persists.

In those with an initial serum ferritin level greater than 1000 mcg/L (2247 pmol/L), the risk of death is fivefold greater than in those with a serum ferritin of 1000 mcg/L (2247 pmol/L) or less. In treated patients, only those with a serum ferritin greater than 2000 mcg/L (4494 pmol/L) have increased mortality, mainly related to liver disease. Since 1997, posttransplant survival rates have been excellent. Following liver trans­plantation, serum iron studies and hepcidin levels are normal, and phlebotomy is not required.


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