Type 1 haemochromatosis

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Inherited as an autosomal recessive trait, this is one of the most common genetic conditions found in populations of northern European origin. In the UK, about one in eight people are carriers of the C282Y mutation of the HFE gene, and about 1 in 200 are homozygous for this mutation. Homozygosity is strongly associated with GH, with about 90% of patients with genetic iron overload having this genotype. Digenetic disease has been described - patients being heterozygous for HFE C282Y and a mutation in the HAMP (hepcidin) gene. In homozygotes, there is a gradual accumulation of iron, leading to tissue damage, which may present as cirrhosis of the liver, diabetes, hypogonadism, arthritis and a slate-grey skin pigmentation. Hepatocellular carcinoma develops in 25% of established cases with cirrhosis. Most patients present between the ages of 40 and 60 years, but the clinical penetrance is low (see p. 48). Full pheno-typic expression of the disorder is dependent upon other factors, including dietary iron intake, blood loss and probably other genetic factors modifying the genotype. Menstrual losses account for a lower frequency and generally delayed onset in women.

Nature of the defect

A defect in the regulation of intestinal iron absorption, at the stage of either mucosal iron uptake or mucosal transfer, is probable, but the molecular basis of the disorder is only now beginning to be understood. The responsible gene is known to be located on the short arm of chromosome 6, close to the human leucocyte antigen A locus (HLA-A), and association with HLA-A3 and, to a lesser extent, B7 suggested a founder mutation in a chromosome carrying the A3, B7 haplotype. Subsequent linkage analyses using multiple genetic markers have supported this suggestion, and positional cloning led to the identification of a novel MHC class I-like gene, 4 Mb telomeric to the HLA A locus. The gene, HFE, contains seven exons, and in over 80% of patients there is homozygosity for a missense mutation. This mutation, G to A at nucleotide 845, results in a cysteine to tyrosine substitution at amino acid 282 (C282Y) in exon 4. A second variant in exon 2 (187C^G) results in a histidine to aspartic acid substitution at amino acid 63 (His63Asp or H63D). This is carried by about 20% of the general population. In the UK, about 90% of patients presenting with haemochromatosis are homozygous for HFE C282Y, and another 4% are compound heterozygotes for the two mutations. HFE was therefore a strong candidate for the haemochromatosis gene and this was confirmed by the demonstration that HFE knockout mice and mice homozygous for the C282Y mutation develop iron overload.

How this abnormality might give rise to the iron loading has been the subject of much debate. After the demonstration that in some cell lines the normal HFE protein binds to the transferrin receptor and reduces iron uptake from transferrin, it was speculated that this would be the mechanism leading to increased iron absorption. It was difficult to explain, however, how increased iron uptake from transferrin in developing intestinal epithelial cells, as a result of the failure of expression of the mutated HFE protein, causes increased iron absorption. Moreover, duodenal mucosal iron levels in haemochromatosis are normal or reduced. More recently, it has been shown that hepcidin release from the liver requires expression of HFE and that in mice lacking HFE or expressing the C282Y protein hepcidin expression is low (Chapter 3). Hepcidin is a negative regulator of iron absorption possibly by binding ferroportin and causing its internalization. Lack of hepcidin upregulates expression of a number of iron transport proteins in the intestinal mucosa, thus increasing iron uptake and absorption. Hepcidin also controls iron release from macrophages. This explains the findings in the early stages of haemochromatosis - increased iron absorption, a raised serum iron and a paucity of iron in macrophages. Most recent data suggest that HFE, transferrin receptor 2 and hemojuvelin defects result in reduced hepcidin secretion.

HFE mutation frequencies worldwide

Genotypes have been reported for over 50 000 subjects throughout the world. The C282Y mutation is confined to populations of European origin and within Europe is most frequent in the north. The highest frequencies for the allele are found in Ireland,

Figure 4.1 Frequency of chromosomes carrying the C282Y mutation in regions of Europe (from Worwood 2004 with permission).

Where C282y

Figure 4.1 Frequency of chromosomes carrying the C282Y mutation in regions of Europe (from Worwood 2004 with permission).

Scotland, Wales, Brittany and Scandinavia (Figure 4.1) and the lowest frequencies in southern Italy and Greece. The H63D mutation is found throughout the world but is most common in Europe, where allele frequencies vary from 10% to 20% with a mean of 15%. The only other variant found throughout Europe is Ser65Cys (S65C), which has a frequency of about 2%. Other HFE gene mutations associated with iron accumulation have been described - mostly in individual families.

HFE mutations and iron status

The haemochromatosis gene may have increased in frequency because of a selective advantage for heterozygotes - protection against iron deficiency anaemia. Homozygotes would be unlikely to suffer the effects of iron overload before reproducing. About 25% of heterozygotes, identified by HLA typing of family members of haemochromatosis patients, have either a raised transferrin saturation or a raised serum ferritin. Coexistent disease may be the explanation for raised ferritin concentrations in many heterozygotes for HFE C282Y. In population surveys, slight but significantly higher values for serum iron and transferrin saturation have been found in heterozygotes for either C282Y or H63D compared with subjects lacking these mutations. The differences in ferritin levels are smaller and not significant. In compound heterozygotes, and those homozygous for H63D, there are greater differences in both transferrin saturation and serum ferritin although signification accumulation is rare. In heterozygotes for C282Y or H63D, haemoglobin levels are slightly higher than in subjects lacking mutations, but it has not been clearly demonstrated that this leads to a lower prevalence of anaemia among women carrying either mutation. There is little information about S65C, but in combination with C282Y or H63D it may be associated with mild iron accumulation.

HFE mutations and morbidity

Although advanced haemochromatosis is characterized by diabetes, arthritis and cirrhosis, there is little evidence that possession of HFE mutations is a risk factor for these conditions except through iron overload. The frequency of homozygosity or heterozygosity for C282Y or H63D mutations is not generally increased in patients with arthritis, diabetes and heart disease. Homozygosity for C282Y is more frequent in patients with cirrhosis and hepatoma than in the general population. In one study, homozygosity for C282Y was increased in patients with type 1, late-onset diabetes. Alcohol is a definite risk factor for the development of cirrhosis in patients homozygous for C282Y. The significance of other genetic modifiers remains uncertain.

m mt

Figure 4.2 Radiograph of hand - patient with haemochromatosis showing loss ofjoint space and erosion of cartilage at the metacarpophalangeal joints.

Diagnosis: clinical

The variety of clinical presentations and their lack of specificity for haemochromatosis means that a high degree of clinical suspicion is needed. Fatigue, diabetes mellitus, gonadal failure and arthritis may be present for several years before the diagnosis is made. Arthritis particularly affects the second and third metacarpophalangeal joints (Figure 4.2), and destructive arthropathy of hip and knee joints occurs in 10% of patients. There is chondrocalcinosis with pyrophosphate deposition in the joints. Abdominal pain may result from hepatic enlargement or hepa-tocellular carcinoma. Grey skin pigmentation results from excess melanin deposition.

Diagnosis: iron status

Transferrin saturation and serum ferritin

In asymptomatic subjects, iron accumulation is indicated by a raised transferrin saturation (> 55% for men and > 50% for women). Most men and about 50% of women who are homozygous for HFE C282Y will have a raised transferrin saturation. As iron accumulates, the serum ferritin concentration rises, and values of > 200 |ig/L (women) and 300 |ig/L (men) suggest iron overload. Serum ferritin concentrations largely reflect iron turnover in phagocytic cells and do not provide an early indication of iron accumulation in liver parenchymal cells. Thus, measurement of transferrin saturation is essential for early detection of iron loading. In patients with infection, inflammation or malignancy, or undergoing surgery, transferrin saturation may, however, be depressed and the serum ferritin concentration elevated. In most cases, genotyping will confirm the diagnosis of GH.

Liver biopsy

In patients homozygous for C282Y with normal serum transaminase activity, serum ferritin concentration < 1000 |g/L and without hepatomegaly there is no need for a liver biopsy in order to make a diagnosis of GH. A liver biopsy is essential to assess tissue damage in patients with evidence of liver disease or a serum ferritin concentration > 1000 | g/L. In patients with an unexplained raised transferrin saturation and serum ferritin, who are not homozygous for C282Y, a liver biopsy may be required to confirm iron overload (Figure 4.3a and b).

Part of the liver biopsy should be washed to remove extraneous blood before wrapping in aluminium foil and drying to constant weight for chemical measurement of iron concentration. Values in excess of 80 |mol/g dry weight (4.5 mg/g dry weight) indicate iron overload. In the differential diagnosis of GH, where there is a progressive increase in iron with age, it is useful to express the result as the 'hepatic iron index' (|mol iron/g dry weight divided by age in years). An elevated index (> 2.0) generally separates patients with homozygous GH from heterozygotes or those with alcoholic liver disease. The hepatic iron index may be helpful in distinguishing iron overload due to GH from the more modest iron overload that can occur secondary to chronic liver disease (usually alcoholic). As alcohol is one of the factors that may enhance the phenotypic expression of GH, this diagnostic distinction is important.

Desferrioxamine-induced iron excretion The measurement of urine iron excretion following a single i.m. injection of 0.5 g of desferrioxamine (DFX) is still occasionally useful in the assessment of possible iron overload, particularly when clinical considerations rule out the more definitive liver biopsy. Urinary excretion of iron greater than 2 mg in 24 h indicates increased iron stores. A number of other factors influence iron chelation by DFX (p. 54) and, although hepatocytes are an important site of action of the drug, reticuloendothelial iron is also a major source of urine iron excretion in response to the drug. The value of the test as a measure of parenchymal iron overload is therefore limited.

Perll Stain Urine
Figure 4.3 Liver histology (Perls' stain). (a) Liver biopsy for a patient with type 1 haemochromatosis, showing staining predominantly in parenchymal cells. (b) Liver biopsy for a patient with type 4 haemochromatosis, showing iron staining predominantly in Kupffer cells.

Mobilization of iron by phlebotomy to calculate iron stores

This is carried out by once-weekly venesection (450 mL of blood) until the serum ferritin concentration is < 20 |ig/L and transferrin saturation is < 16%. Haemoglobin (Hb) levels should be measured weekly and the rate of venesection reduced if anaemia develops. Serum ferritin should be monitored monthly. The transferrin saturation should be measured weekly when the ferritin concentration drops below 50 |g/L. Once storage iron has been removed the serum ferritin concentration will be less than 15 |g/L, the transferrin saturation < 16% and anaemia will develop. The amount of iron removed at each venesection is calculated by weighing the blood bag before and after venesection (density of blood is 1.05 g/mL) and assuming that 450 mL of blood (Hb concentration = 13.5 g/dL) contains 200 mg of iron. Iron absorption should be allowed for at a rate of 3 mg per day (20 mg per week). With these assumptions, 25 weekly venesections will remove 4.5 g of iron. The amount of storage iron measured by the technique in normal adults has been shown to be about 750 mg in men and 250 mg in women.

Non-invasive methods (see also p. 51)

The superconducting quantum interface device (SQUID) bio-susceptometry technique is sensitive, accurate and reproducible. It depends on the paramagnetic properties of haemosiderin and ferritin. Unlike magnetic resonance imaging (MRI), it does not distinguish parenchymal from reticuloendothelial iron, but the result closely correlates with chemical estimation of liver iron, except when fibrosis is present. Machines are expensive to build and run and at present there are only four worldwide (none in the UK).

Although MRI techniques are being increasingly used as indirect measures of both liver and heart iron (see p. 52), they require special analytical skills and have not been generally applied to type 1 haemochromatosis.

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