Recently discovered genetic mutations, modern diagnostic techniques, and fresh approaches to therapy change the outlook on hemochromatosis.

Ben, age 46, visited his primary-care clinician with complaints of joint pains and impotence. He had also noticed that his skin seemed to be turning darker. Over the past three years, Ben has had several office visits at which he complained of fatigue and weakness. The doctor examined Ben and took a family and personal history. Ben’s father died at 55 of an MI, and his mother is alive and well. One brother died at age 53 of esophageal varices. Autopsy showed iron overload in the liver. A remaining brother and sister are living and apparently well.

The patient’s laboratory studies included an elevated serum ferritin of 1,200 ng/mL, hematocrit 46%, and liver aminotransferase enzymes twice the normal value. Based on the laboratory and examination findings, as well as the family history, the clinician suspected that Ben might have hemochromatosis.

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What is hemochromatosis?

Hemochromatosis describes a number of hereditary conditions characterized by iron overload. It is the most common genetic disorder in populations of European ancestry. The discovery in 1996 of the HFE gene, the most common mutated gene in hemochromatosis, has enabled population screening and new diagnostic strategies. The subsequent discovery of other genes involved in iron metabolism has led to the proposed classification of five types of the disease:

Type 1—HFE hemochromatosis is the most frequent form, representing >90% of cases. It is due to mutations in the HFE gene and affects only Caucasians. Among northern Europeans, one of every 300-400 individuals is thought to be homozygous for this mutation.
Type 2—Juvenile hemochromatosis results from mutation in the hemojuvelin gene or the hepcidin gene.
Type 3—Transferrin receptor 2 hemochromatosis is caused by mutations in the transferrin receptor gene.
Type 4—Ferroportin disease results from mutations of the ferroportin gene.
Type 5—Other rare genetic disorders resulting in iron overload, including mutations in the ceruloplasmin gene, transferrin gene, or the divalent metal transporter gene.

The majority of cases involving primary iron overload are due to HFE hemochromatosis. This diagnosis is often overlooked in the general population and needs to be distinguished from secondary causes of iron overload, such as transfusional iron overload, alcoholic liver disease, and porphyria cutanea tarda.

How is the diagnosis made?

Hemochromatosis should be considered in any patient with one or more of the following symptoms: arthralgias, impotence, hyperpigmentation, liver function abnormalities, diabetes, or cardiomyopathy in the presence of an elevated serum ferritin. Serum ferritin may also be elevated due to hepatitis B or C infection, alcoholic liver disease, and non-alcoholic fatty liver disease. Liver biopsy may be helpful in ascertaining the exact etiology.

Anytime hemochromatosis is suspected, evaluation of transferrin saturation is mandatory. A normal transferrin saturation excludes HFE hemochromatosis except in the setting of an inflammatory state. Saturation values >45% in women and >50% in men have been successfully used to detect individuals with HFE hemochromatosis. Ben’s transferrin saturation was 90%, lending support to this diagnosis.

If suspicion of hemochromatosis remains heightened, order genetic testing for mutations in the HFE gene. More than 90% of classical hemochromatosis cases have a single base change that results in the substitution of tyrosine for cysteine at position 282 of the HFE protein (C282Y). The mutation probably originated in a single Celtic or Viking ancestor in northwestern Europe more than 2,000 years ago. Homozygosity for C282Y mutation confirms the diagnosis of type 1 hemochromatosis. Substitution of aspartic acid for histidine at position 63 (H63D) may dispose homozygotes and compound heterozygotes (C282Y/H63D) to iron overload. Simple heterozygotes for C282Y or H63D almost never have HFE hemochromatosis.

How severe is the disease?

If you diagnose hemochromatosis, quantify the degree of iron overload by measuring the serum ferritin. A ferritin level 1,000 severe excess. Levels >1,000 are most likely to be associated with significant clinical complications.

Liver biopsy has been considered the gold standard to quantify the degree of iron overload. Besides determining the amount of iron excess, biopsy provides valuable information about liver pathology, such as cirrhosis or fibrosis, or coexisting conditions, such as alcoholic hepatitis or steatohepatitis. Biopsy also provides information about the distribution of iron in the liver (hepatocyte or macrophage).

Recently MRI has been used to quantify hepatic iron. This approach obviates the need for an invasive procedure and may more accurately estimate total liver iron because it eliminates the potential sampling errors inherent in a tissue biopsy. A machine using a 1.5T magnet and the appropriate algorithm software must be employed for an accurate assessment.

Therapy of HFE hemochromatosis

While there are some lifestyle modifications patients can make, correction of iron overload is achieved primarily through phlebotomy. Advise patients to avoid foods rich in vitamin C, as ascorbic acid increases both intestinal absorption of iron and release from storage pools. Patients should also avoid vitamin supplements containing iron. Encourage patients to keep ethanol intake at a minimum to avoid damage to the liver. Modification of diet is otherwise not necessary.

Phlebotomy should be promptly instituted when the serum ferritin exceeds 300 in men and 200 in women. This can be done weekly or as tolerated by the patient. The volume re-moved should be weight-based at 7 mL/kg. This is equivalent to taking a unit of whole blood from a 70-kg individual. Measure hemoglobin before each treatment and serum ferritin after every two venesections. The goal is to decrease the serum ferritin to a level £50. Maintenance treatment is advocated by most experts, using phlebotomy of one or two units every four to six months to maintain the ferritin at 50.

Serum aminotransferases should return to baseline after several phlebotomies, and hyperpigmentation should decrease during this time. Joint pains may resolve, but this is not always the case and the arthritis may persist. Insulin-dependent diabetes mellitus will not resolve, and cirrhosis of the liver may be irreversible. Any effects on cardiac function should stabilize.

Juvenile hereditary hemochromatosis (type 2) and transferrin receptor 2 hemochromatosis (type 3) both respond well to phlebotomy and should be managed in a fashion similar to HFE hemochromatosis. Patients with ferroportin disease (type 4) may not be able to tolerate phlebotomy due to the risk of developing anemia. Type 5 forms of hemochromatosis are often associated with anemia; these cases should be treated with parenteral desferrioxamine to chelate the excess iron.

Future therapy for hemochromatosis may include the oral iron chelator deferasirox (Exjade) as an additional measure to remove excess iron in patients with severe organ damage. More long-term drug safety information needs to be accrued, as concerns about nephrotoxicity of this agent have arisen.

Studies have implicated the peptide hepcidin as the central regulator of iron balance. Hepcidin deficiency is thought to play a key role in iron overload in all forms of hemochromatosis. The development of hepcidin agonists may reverse this process.

Screening and prevention

The severity of the clinical disease combined with the ease of screening and benefit of early treatment mandate screening and prevention in appropriate populations. Any individual who has symptoms potentially related to hemochromatosis should be screened with transferrin saturation followed by serum ferritin determinations.

First-degree relatives of individuals who have been identified as C282Y homozygous and have hemochromatosis should be evaluated with HFE genetic testing as well as transferrin saturation and ferritin. Some homozygotes have normal iron stores. These individuals should be monitored periodically for development of iron overload.

Mass screening of Caucasian populations has not been adopted to date. First, the cost-effectiveness of testing has been questioned. In addition, the incomplete penetrance of the homozygous state further calls into question the value of such an approach. Family screening is a more effective way to evaluate for hemochromatosis.

Dr. Flamm is assistant professor of clinical medicine, College of Physicians & Surgeons, Columbia University Medical Center, New York City.

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