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Hereditary Haemochromatosis

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Hereditary Haemochromatosis CLINICAL Hereditary Katie Allen haemochromatosis Diagnosis and management of women develop significant iron overload related Background disease (haemochromatosis).2 Iron accumulation Hereditary haemochromatosis is a common inherited disorder in which excessive iron is in genetically at risk individuals occurs gradually absorbed and which, over time, may cause organ damage. Genetic predisposition leads to over many decades. The stages of iron loading disease in some but not all cases. progression are now characterised as: Objective • genetic predisposition without iron indices This article discusses the presentation, testing, treatment and management of hereditary abnormality (C282Y homozyogtes) haemochromatosis. • iron overload (raised serum ferritin [SF] in Discussion the presence of a raised fasting transferrin Hereditary haemochromatosis is autosomal recessive and is more common in people of saturation [TS]) without symptoms Celtic or northern European descent. Although more than 90% of cases of hereditary • iron overload with hereditary haemochromatosis haemochromatosis are due to C282Y homozygosity (carrying two copies of the C282Y (HH) associated symptoms (such as arthritis and gene) not all C282Y homozygous individuals will progress through all stages of disease fatigue), and development. Clinical disease is less common in females due to physiological blood loss • iron overload with organ damage, in particular from menstruation and pregnancy. Most importantly, early diagnosis and treatment cirrhosis.3 of hereditary haemochromatosis prevents complications and results in a normal life expectancy. Venesection is a simple and effective way to both prevent and manage the In patients with haemochromatosis, iron potential sequelae of iron overload, which include severe fatigue, arthritis, impotence, accumulation occurs because there is disordered raised alanine aminotransferase/aspartate aminotransferase, fibrosis or cirrhosis, and increased iron absorption across the diabetes, and cardiomyopathy. intestinal mucosa, which is compounded by the fact that there are no compensatory Keywords: liver diseases; genetics; haemochromatosis mechanisms of iron excretion that can be activated as the body lacks an active iron excretory mechanism. Iron depletion normally occurs through After the discovery of the HFE gene in cell attrition from gastrointestinal mucosal 19961 it was initially believed that every cell turnover and through physiological and individual with two abnormal copies of pathological mechanisms of blood loss. The basic the gene (C282Y homozygote) would defect in HFE associated hemochromatosis is develop iron overload related disease, a lack of cell surface expression of HFE (due to consistent with haemochromatosis. the C282Y mutation). The normal (wild-type) HFE Haemochromatosis is defined as iron protein forms a complex with beta-2 microglobulin overload leading to end organ damage and transferrin receptor 1 (TfR1), and the C282Y through the interaction between mutation completely abrogates this interaction. As environmental and genetic factors and not a result, the mutant HFE protein remains trapped the presence of genetic predisposition. intracellularly, reducing TfR1 mediated iron uptake by the intestinal crypt cell. This impaired TfR1 It has now been shown that although 60–80% of mediated iron uptake leads to upregulation of the C282Y homozygotes develop abnormal iron indices divalent metal transporter (DMT1) on the brush in their lifetime, only 28% of men and less than 1% border of the villus cells, causing inappropriately 938 Reprinted from AUSTRALIAN FAMILY PHYSICIAN VOL. 39, NO. 12, DECEMBER 2010 Hereditary haemochromatosis – diagnosis and management CLINICAL increased intestinal iron absorption.4 delayed presentation in women, which occurs more it is also an acute phase reactant and can be Hepcidin, a peptide synthesised primarily by the frequently after menopause. The most common elevated nonspecifically on occasions (eg. alcohol liver, has been identified as the central regulator in symptoms of early sequelae are fairly nonspecific consumption, chronic inflammation and other liver iron homeostasis, although how genetic changes in and include lethargy, arthralgia and loss of libido.7 diseases). Haemochromatosis is unlikely if the SF is the HFE gene impact on the regulation of this key Patients with more severe iron overload may very high but the TS is normal, and in this situation molecule remains unclear.5 develop liver disease with fibrosis or cirrhosis, SF is more likely to be elevated as an acute phase There is recent evidence supporting a role for arthritis, gonadal failure, diabetes mellitus, cardiac reactant. In such cases testing the HFE gene may be HFE as an important component of a larger iron- failure and arrhythmias. Hepatocellular carcinoma helpful to exclude HH. sensing complex that involves interactions with has been reported to develop in about 30% of If both fasting TS and SF are increased, diferric transferrin, TfR1 and TfR2 at the plasma patients with untreated cirrhosis due to HH. Physical haemochromatosis should be suspected, even if membrane of hepatocytes. Defective HFE protein examination may be normal if the predisposition to there are no clinical symptoms or abnormal liver prevents formation of a functional iron sensor iron overload is diagnosed early, but if present, the function tests. In this situation, the HFE gene test and signal transduction effector complex leading most common physical signs are hepatomegaly or should be ordered. With the exception of arthritis, to dysregulated hepcidin expression and the signs of cirrhosis, testicular atrophy, or joint swelling suspicious symptoms are unlikely to be due to development of hereditary haemochromatosis. and tenderness (Figure 1).7 It should be noted that haemochromatosis if the SF is in the normal range. Genetic predisposition to HH is now frequently HH is not a common cause of cirrhosis and that Patients with SF >1000 µg/L or elevated alanine diagnosed in individuals who remain asymptomatic nonalcoholic steatohepatitis, alcoholic liver disease aminotransferase/aspartate aminotransferase (ALT/ but who have been found to have abnormal iron and chronic viral hepatitis each contribute more AST) are at significant risk of liver cirrhosis and studies, or in those with a family history of HH significantly to the burden of disease from cirrhosis should be immediately referred to a hepatologist for who have undergone family testing for the gene. in the Australian population.8 assessment for percutaneous liver biopsy. Patients usually develop elevated ST saturation Diabetes mellitus is usually present only in Genetic testing and SF levels before significant symptoms occur. patients with advanced disease.7 ‘Bronzed diabetes’ The accumulation of iron is a slow process, is (golden skin pigmentation in a newly diagnosed For first and second degree relatives of an index often silent in the early stages, and only when iron diabetic) was historically regarded as a classic case, HFE gene testing should be undertaken to stores reach toxic levels does tissue injury develop. presentation of HH before the discovery of the screen for disease. Alterations in the HFE gene Assessment of iron overload status has traditionally gene, but is rarely seen now due to early increased are the most common cause for developing been undertaken using percutaneous liver biopsy awareness and more aggressive testing for genetic haemochromatosis. Most laboratories test for two but there is now a noninvasive reasonably accurate predisposition. different genetic changes in the HFE genes: measure of liver iron loading status through • C282Y – the amino acid tyrosine is substituted magnetic resonance imaging (MRI) of the liver using Testing for hereditary for a cysteine at position 282, and a newly patented technique called Ferriscan®.6 haemochromatosis • H63D – the amino acid aspartate is substituted Which tests on whom, and when they should be for a histidine at position 63. Clinical presentation performed are outlined in Table 1 and 2. In the majority of patients who present with overt Implications of genetic testing Iron studies signs of haemochromatosis, the first symptoms No alterations found in the HFE gene develop between the ages of 30–60 years. In patients presenting with signs or symptoms Menstruation and pregnancy account for the suspicious of HH, a fasting TS (ratio of serum If iron studies are normal, haemochromatosis is iron and iron binding capacity) and SF unlikely to develop. All patients with iron overload concentration should be undertaken. In very require follow up, regardless of HFE gene test result, early disease, TS may be elevated before a as in a small percentage of cases a different gene rise in SF. Transferrin saturation is abnormal may be responsible. when it is >45% for men and >55% for C282Y homozygote (C282Y/C282Y) women. Serum ferritin is abnormal when it is >200 µg/L in premenopausal women Not all individuals with this genotype will develop and >300 µg/L in men and postmenopausal severe iron overload related disease, however women. These tests should be performed in 60–80% will develop abnormal iron studies during the morning after an overnight fast. their lifetime.7 If iron overload is present, lifelong An increased TS reflects increased venesection is required. Cirrhosis is unlikely if the Figure 1. HH associated arthritis most absorption of Fe (the underlying biological ferritin level is <1000 µg/L, the ALT level is normal, usually
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