Pathophysiology Diagnosis and Management of Hereditary Hemochromatosis

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Hereditary hemochromatosis (HH) is a relatively common homozygous recessive disorder with variable penetrance due to a cysteine to tyrosine substitution at amino acid 282 (C282Y) of the HFE protein.1 The HH genotype can be detected in approximately 1:250-1:400 Caucasians, but less than 1% of HFE homozygotes and compound heterozygotes appear to have a clinically significant iron overload phenotype.3-7 The incidence of the C282Y mutation in non-Caucasian populations is very low. But many other genetic causes of iron overload occur at much lower rates in both Caucasians and non-Caucasians as a result of mutations in other iron-metabolism proteins. However, the wide availability of molecular testing has made the identification of C282Y and H63D HFE mutations an important part of the evaluation of iron-overloaded Caucasian patients and has replaced HLA testing. The H63D mutation is relevant only if there is heterozygosity for C282Y, since "compound heterozygotes" are at risk for iron overload. Heterozygotes for C282Y and heterozygotes and homozygotes for the H63D mutation alone are not at risk.

In normal individuals, all dietary iron is absorbed from the duodenum and proximal jejunum where enterocytes regulate the amount of iron transported across the basolateral membrane into the body on the basis of the body's iron requirements.5 Unneeded iron is sequestered within the enterocyte as cellular ferritin and is lost into the GI tract as the

Pathophysiology, Diagnosis, and Management of Hereditary Hemochromatosis 103

enterocyte migrates to the villus tip and is sloughed. However, in HH the ability to regulate this process is lost and there is abnormally high duodenal absorption of dietary iron over the subject's lifetime. There may also be dysregulation of iron sequestration within macrophages throughout the body. These defects lead to iron deposition and damage to a number of organs, including the liver, pancreas, heart, pituitary, and synovium.

Much new and exciting information has been learned about absorption, transport, and cellular iron regulation since the mid-1990s, with the molecular identification not only of the HFE protein but also of most of the iron uptake and transport proteins. Excellent detailed reviews are available.5,6 Hepcidin is a 25-amino-acid liver-derived peptide that negatively regulates intestinal iron absorption and also regulates macrophage iron metabolism. Patients with HH have inappropriately low serum hepcidin. But how the mutant HFE protein causes this situation is still unclear. Decreased hepatic hepcidin production might also explain the mild iron overload often seen in patients with various liver diseases such as alcoholic and hepatitis C-induced liver disease.

The appropriate way to screen for HH is to determine serum iron and total iron-binding capacity (TIBC), with calculation of the percent transferrin saturation.7 Because of the diurnal variation in serum iron concentrations, fasting morning specimens are recommended. HH is suspected if the transferrin saturation is >60% in men and >50% in women. Ferritin, an important iron-binding and intracellular iron storage protein, should also be measured in the serum of patients with suspected HH. Serum ferritin is not an iron transport protein, and the presence of ferritin in the serum probably represents protein that "leaks" out of macrophages that are processing iron. Serum ferritin does not become elevated early in HH and only increases with heavy iron loading when iron spills over from hepatocytes into the reticuloendothelial system. In non-HH patients, serum ferritin is increased with acute hepatocyte damage (acute hepatitis) or if there is a systemic inflammatory reaction or certain hematologic malignancies. Therefore, an elevated serum ferritin value should be interpreted with caution. But in most HH patients serum ferritin is a good reflection of total body iron stores and is used to monitor iron reduction therapy.

Iron loading in HH can affect several organs, with the manifestations of end-organ damage usually appearing in the 40s-60s age range in men and slightly later in women. Women are somewhat protected since they lose iron over many years with menses. In the liver, iron overload can lead first to occult, then clinically evident cirrhosis, and eventually to development of malignant hepatoma. In the pancreas, iron loading of the islets of Langerhans causes glucose intolerance or frank diabetes. Cardiomyopathies and arrhythmias can develop with iron deposition in cardiac myocytes. Testicular atrophy and impotence occur in men as a result of decreased gonadotropin production by the iron-loaded pituitary. Women can develop secondary amenorrhea. Chondrocalcinosis develops in joint synovia and leads to a pseudogout picture. Hyperpigmentation of skin may be observed, but is actually due to increased melanin rather than iron deposition. Because each of these manifestations more often are caused by factors other than HH, a physician must cultivate a high index of suspicion for the disease and utilize screening tests.

On finding a high percent transferrin saturation and homozygosity for the C282Y mutation, the degree of hepatic injury is assessed with a liver biopsy with special stains for iron deposits (Prussian blue or Perls' stain) and by quantitative determination of iron content of liver tissue. If the patient is relatively young, <age 30, liver biopsy is probably not necessary as long as all other liver tests are normal. An "iron index" can be calculated from the iron content of liver (in mmol/g of dry liver) divided by the age of the subject, and an index >1.9 is usually found in HH homozygotes. But the importance of calculating the iron index is much less now that HFE genetic testing is available. Once the diagnosis of HH is made on the basis of laboratory (including HFE analysis), biopsy, and clinical results, one should not forget to screen siblings with iron studies and HFE molecular testing. It is less important to screen children who are obligate heterozygotes as they generally have no significant risk of iron overload (unless the patient's spouse is an HFE heterozygote or homozygote).

Fortunately for iron-overloaded HH patients, phlebotomy therapy is a highly effective method for lowering body iron stores. Every 500 mL of blood removed contains ~250 mg of iron. Phlebotomies are usually instituted every 1 -2 weeks while keeping the patient on a high-protein and folate-supplemented diet. Immediately prior to the phlebotomy, patients should have a light snack and take in fluids. The removed blood can be used by blood banks (although some centers post "warnings" that the blood was obtained for therapeutic reasons). The goal of phlebotomy therapy is to lower the serum ferritin to <100ng/mL (< 100 mg/L) and a transferrin saturation around 30% and then find a phlebotomy frequency (usually every 2-4 months) that keeps the ferritin and transferrin saturation within normal range without causing iron deficiency or anemia. Treated precir-rhotic HH patients have been shown to have a normal life expectancy. But once cirrhosis or diabetes develops, HH patients have markedly shortened lifespans. Occasionally HH patients require liver transplantation, but often do poorly afterwards because of cardiac problems and infections.

The importance of identifying HH in patients who present with cirrhosis, diabetes, cardiomyopathy, chondrocalcinosis, or impotence cannot be overstressed because iron removal therapy is safe and generally effective if instituted early. Usually cirrhosis, diabetes, and impotence are not reversible. If homozygotes are recognized early, prior to development of symptoms of end-organ damage, preventive (prophylactic) treatment is easily initiated by prescribing regular blood donation to reduce the rate of iron loading. Serum iron determination as part of a fasting morning chemistry screening panel was shown to help in early identification of iron-overloaded homozygotes and was cost-effective.8 In this study identifying serum irons of > 180 mg/dL led to further testing in 1% of patients that included transferrin saturation and ferritin. Eight of 127 identified patients were recommended for a liver biopsy, with four unsuspected cases of clinically significant HH discovered. However, only a few large institutions such as the KaiserPermanente Health Care System have adopted screening for iron overload.5 Screening with HFE mutational analysis is too expensive and will not identify patients who are iron-overloaded because of the low penetrance of this mutation.

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