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January 1998 • Volume 27 • Number 1

Editorial
Mutations in the Hemochromatosis Gene, Porphyria Cutanea Tarda, and Iron Overload

George H. Elder, M.D. [MEDLINE LOOKUP]
Mark Worwood, Ph.D. [MEDLINE LOOKUP]

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SEE ARTICLE ON PAGE 181

It has long been thought that the inheritance of one or more human leukocyte antigen (HLA)-linked hemochromatic genes may contribute to iron overload in diseases other than genetic hemochromatosis (GH).¹ Porphyria cutanea tarda (PCT) has always been a prime candidate for this association. Patients with this disorder present with fragile skin and subepidermal bullae and often show some evidence of hepatocyte damage, although cirrhosis is unusual.² Mild to moderate iron overload is present in 60% to 70% of cases.^3,4 PCT seems to be provoked in most patients by alcohol, estrogens, viruses (notably hepatitis C virus and human immunodeficiency virus), or a combination of these factors. It is rarely associated with clinically overt GH.^2,5

The underlying metabolic abnormality is decreased activity of uroporphyrinogen decarboxylase, one of the enzymes of the heme biosynthesis, in the liver. Clinical and experimental studies suggest that this enzyme is reversibly inactivated by an iron-dependent process.⁶ Depletion of hepatic iron stores by venesection, or by other means, leads to clinical remission and reversal of the metabolic defect, even in those without iron overload.² In animal models of PCT, the inactivation process is both dependent on iron and accelerated by iron overload.^7,8

Although development of PCT in response to hepatocyte damage by these agents is believed to be determined by inherited factors, few genes that contribute to this predisposition have been identified. Most patients have the sporadic (type I) form of PCT in which the enzyme defect is restricted to the liver and in which causative mutations at the uroporphyrinogen decarboxylase locus have been excluded.⁹ Even in the 20% or so of patients from families showing autosomal dominant inheritance of half-normal enzyme activity in all tissues (familial or type II PCT), further inactivation of the enzyme in the liver seems necessary for clinical expression.^6,9,10

About 75% of patients with genetic hemochromatosis carry the HLA-A3 allele compared with 25% of controls. Some studies of the frequency in PCT of this and other alleles defining the ancestral hemochromatosis haplotype (HLA-A3, D6S265-1, D6S105-8, D6S1260-4) have shown an association,^3,4,11,12 whereas others have not.^13-16 In 1996 Feder et al.¹⁷ cloned a strong candidate for the hemochromatosis HFE gene which was located 4.5 Megabases telomeric to the HLA-A locus and encoded an HLA-class Ib protein. They found that about 85% of chromosomes from patients with GH carry a point mutation in the HFE gene which replaces cysteine at amino acid position 282 with tyrosine (C282Y). A second mutation which replaces histamine 63 by aspartic acid (H63D) is common in the population (gene frequency 0.15); however, by itself it is not associated with iron overload. The wild-type and H63D proteins are expressed on the cell surface and bind

₂ microglobulin (like most class I–HLA proteins) but the mutant C282Y protein neither reaches the cell surface nor binds

₂ microglobulin.¹⁸ The two mutations are in complete linkage disequilibrium. Compound heterozygotes, which comprise about 1% of the general population, may develop iron overload and even clinical hemochromatosis.^19-21

The C282Y mutation is responsible for much of the iron overload in populations of European descent. All GH patients in Queensland,²² 92% in both Brittany²³ and the UK,¹⁹ about 83% in the USA,^17,21 71% in France generally,²⁴ and 61% in Italy²⁵ are C282Y homozygotes. In parts of Northern Europe, the gene frequency in the general population approaches 10% but falls to 3% in Greece and to only 0.5% in Italy. The mutation seems to be absent from the native populations of Asia, Africa, the Middle East, and the Americas.²⁶

Early in 1997, Roberts et al.²⁷ reported that 44% of 41 British patients with sporadic PCT carried at least one copy of the C282Y mutation. This association has since been confirmed in patients with sporadic PCT from the Netherlands,²⁸ the USA,²⁹ Australia,³⁰ and, for patients of European descent, South Africa.³¹ It is also present in familial PCT.^28,32

In this issue of HEPATOLOGY , Sampietro et al.³³ report that the association between the C282Y mutation and sporadic PCT is not found in Italian patients. The allele frequency in 68 male patients (1.5%) was not increased in comparison with two control groups: 28 students and hospital staff (0.7%), and because hepatitis C virus infection is common in Italian patients with PCT, 50 patients with chronic hepatitis caused by hepatitis C virus (2%). Though the frequency of this mutation in the general population and in GH is lower than in Britain, this finding is unexpected particularly as the range of iron stores in Italian patients with PCT does not differ from patients elsewhere.^3-5 Even more unexpectedly, the frequency of the other mutation in the HFE gene, H63D, was significantly increased as it was present on 28.7% of HFE alleles in the PCT group compared with 12.8% and 12% in the two control groups. There was no relationship between the presence of this mutation and the degree of iron storage. To our knowledge, this is the first report of an association of this mutation alone with a disease.

Five of the Italian patients without HFE mutations but with iron overload carried the ancestral hemochromatosis haplotype, one of which was homozygous. The authors point out that there may be another gene, linked to the ancestral haplotype, that causes hemochromatosis. Patients homozygous for the ancestral haplotype are reported to accumulate more iron than other patients do with GH in both Queensland³⁴ and Italy.³⁵ In the study by Roberts et al.,²⁷ four chromosomes with the ancestral haplotype also lacked the C282Y mutation. However, in Britain, this mutation is only carried by 50% of chromosomes with the ancestral haplotype and there may not be any other iron loading genes associated with it.³⁶

Is the frequency of the H63D mutation increased in other populations with PCT? The C282Y mutation has predominated in all other series reported to date.^27-32 As the two mutations are in complete linkage disequilibrium, calculating the frequency of the H63D chromosome after eliminating those carrying the C282Y mutation has been advocated.^17,37 This calculation did not reveal any significantly higher frequency in 107 British patients with sporadic PCT.^27,32 Further studies of HFE mutations in PCT from other countries where the population frequency of the C282Y mutation is lower than in Northern Europe are awaited with interest.

What conclusions may be drawn from these studies of PCT? The main one is that HFE mutations confer susceptibility to PCT. The mechanism is far from clear. PCT is rare in heterozygotes for each mutation. Presumably the C282Y mutation promotes iron accumulation and may, thereby, accelerate the onset of disease in those who are already predisposed. The relationship between the presence of this mutation and iron storage in PCT has not yet been established. Sampietro et al. suggest that the H63D mutation may cause a subtle change in iron metabolism caused by the accumulation of toxic iron species which accelerates inactivation of uroporphyrinogen decarboxylase. Hepatitis C virus infection is much more common in Italian patients with PCT than in British patients with PCT.⁵ The authors hypothesize that hepatitis C virus infection and the H63D mutation might synergize to produce clinically manifest PCT, whereas the C282Y mutation might more efficiently trigger PCT independently of viral liver disease.

Will there be other diseases in which these mutations play a role? In some populations hemochromatosis is common, and, therefore, it is inevitable that some patients with iron overload secondary to hematological disorders will also carry a gene for hemochromatosis.¹ Of two brothers with pyridoxine-responsive sideroblastic anemia, one carried both the C282Y and H63D mutations and had accumulated more iron than his brother with a normal genotype.³⁸ More extensive investigations of HFE mutations in such patients are awaited.

A final unexpected finding from these studies has been the high proportion of PCT patients who are C282Y homozygotes (21% in Britain). In countries where this mutation is common, patients with PCT should be screened for its presence. Homozygotes should be treated by venesection and monitored to ensure that iron does not reaccumulate, and their families should be investigated. In GH it is suggested that the transferrin saturation should be kept below 55% and that the serum ferritin below 100 µg/L. Similar standards should apply to PCT.