Prevalence of hepatitis C virus infection in porphyria cutanea tarda
Article Outline
Porphyria cutanea tarda (PCT) is the most common type of porphyrias [1], [2]. Usually the disease manifests with dermatological signs, including skin fragility and vesciculo-bullous eruption on the hand and face, which become evident after exposure to sunlight. These dermatological manifestations are caused by deposits of uroporphyrin and partially decarboxylated porphyrins in the skin. The source of these compounds is the liver because of a reduced activity of uroporphyrinogen decarboxylase (URO-D), an enzyme involved in the heme biosynthetic pathway. Two different forms of PCT have been described, the familial type which is transmitted as an autosomal dominant trait and accounts for about 20% of the cases and the sporadic/acquired form. In the familial type the activity of URO-D is half the normal in all tissues, while in the sporadic type the reduced activity of URO-D is restricted to the liver. However the partial deficiency of URO-D, is a ‘sine qua non’ condition but not sufficient to have overt PCT since in pedigrees with familial PCT most individuals who carry mutant URO-D do not express the porphyric phenotype unless exposed to triggering factors [3]. Estimates of the prevalence of overt PCT vary from 1 in 5000 to 25 000, whereas it is impossible to estimate the prevalence of patients potentially affected since the disease is totally silent until triggering factors make it clinically manifest. Besides cutaneous manifestations, which usually are the first overt clinical signs of PCT, evidence of chronic liver disease, detectable by biochemical tests, is present in almost all patients.
Factors which cause hepatic injury in PCT are the same that trigger clinical manifestations of the disease. Exposure to toxic compounds and, in particular, alcohol abuse is recognized to be a triggering factor for PCT. In fact alcohol has long been considered one of the more prevalent etiopathogenic factors for PCT. Among drugs, estrogens have repeatedly been demonstrated to be involved in PCT and the more common use for postmenopausal replacement therapy and contraception has lead to an increased occurrence of PCT in women.
Several pieces of evidence indicate that iron also plays a major role in the pathogenesis of PCT. Iron overload is detected in the large majority of patients, phlebotomy is followed by reversal of clinical manifestations of PCT and administration of iron produces relapse [3]. In addition, in experimental studies, iron addition to culture cells interferes with URO-D activity very likely because of oxidation of uroporphyrinogen [4], [5]. After the identification of the gene responsible for hereditary hemochromatosis (HH) several Authors searched for HFE gene mutations in patients with PCT from different geographical areas. Almost invariably an increased prevalence of HFE mutations was detected although in most of the countries the more prevalent mutation was the C282Y [3]. In Italy the prevalence of the H63D mutation, usually associated with only a very mild increase of iron, if any, was found to be significantly increased compared to controls [6].
Virus infections have been included among the potential PCT triggering factors. Initial reports of hepatitis B infection [7] and anecdotal cases of human immunodeficiency virus (HIV) infection [8] have been later overwhelmed by the evidence of a strong association between hepatitis C virus (HCV) infection and PCT [3], [9]. This was initially reported in Mediterranean countries including Italy, Spain and France and later also in the United States. These findings prompted the search for HCV infection in patients with PCT all over the world but results were uneven, with countries such as Ireland, Germany, and New Zealand having almost absent HCV infection. Thus, prevalence of HCV infection in patients with PCT ranged between 90 and 0%.
The finding of this unexpected strong association gave rise to a series of questions: does PCT predispose to HCV infection or, oppositely, HCV infection predispose to PCT, or do both HCV infection and PCT share common pathogenic events? As a matter of fact no sure answer has yet been found. However, studies in patients with HCV infection without evidence of PCT ruled out that HCV infection is able by itself to derange the heme synthesis pathway since only a small minority of patients studied had an increase in urinary porphyrins, and the prevalence of PCT among HCV-infected patients has been reported between 1 and 5% [3], [10], [11]. On the other hand, all patients are very likely first infected with HCV and only later manifest PCT. Thus the most reasonable explanation is that some unidentified factors favor both HCV infection and PCT manifestation.
Very recently El-Saref and colleagues [10] analyzed the relationship between HCV and extrahepatic conditions and unequivocally pointed out that PCT is an extrahepatic manifestation of HCV infection. They provided evidence in a hospital-based case-control study, which analyzed a large series of patients with HCV infection, compared to randomly chosen controls without HCV infection that HCV infection was associated with PCT, vitiligo, lichen planus, cryoglobulinemia, membranoproliferative glomerulonephritis, and non-Hodgkin's lymphoma. The strongest association was between HCV infection and PCT with a 12-fold increase in PCT among cases (HCV-infected) as compared to control patients (non-HCV-infected).
In the present issue of the Journal Gisbert and colleagues [12] present a systematic review and meta-analysis on the prevalence of HCV infection in patients with PCT. The exhaustive analysis of the literature allowed these authors to define that the prevalence of HCV infection in these patients is approximately 50%, much higher than that reported in general population. Interestingly the weighted mean prevalence of HCV infection was 57% in the sporadic form and 26% in the familial one, despite the same environmental exposure in the two forms. Interestingly, family background of PCT has been described to be significantly less frequent among patients infected with HCV [13]. These differences underline that acquired triggering factors are more important for clinical manifestation of the sporadic than of the familial form, possibly for the more marked URO-D deficiency in the latter. Half-normal activity of hepatic URO-D is present in heterozygotes for URO-D mutation while in the sporadic form protein concentration is normal though enzyme activity is reduced. It has been suggested that acquired risk factors contribute to the generation of liver-specific inhibitors of URO-D and compounds which induce specific isoforms of P450 that can trigger PCT both in human and rodents.
Gisbert and colleagues [12] noted a striking geographical variation in the association between HCV and PCT, and suggested that genetic and environmental factors may account for these differences and be involved in the pathogenesis of the disease.
The role of environmental differences is evident. In some geographical areas the prevalence of HCV infection in patients with PCT is much lower than in Mediterranean countries, but when these figures are compared to those of matched control populations a 10-fold increase in the prevalence of HCV infection is observed in patients with PCT than in controls [14], [15], [16]. These data indicate that the differences in the prevalence of HCV infection reflect the different epidemiology of HCV infection in the various countries more than a different predisposition of patients with PCT to become infected with HCV. It is very likely that in case of an increased diffusion of HCV infection in these geographical areas the differences in the prevalence of HCV infection in PCT patients would be nullified.
Interestingly, HCV genotype 1b was reported to be present in 90% of Italian with PCT, a prevalence significantly higher than that observed in age-matched patients with HCV infection without PCT [17]. However, no genotype-specific association was reported in other countries. Thus it is not yet defined whether a preferential association between a given HCV type and PCT occurs or, alternatively, whether the association between a given HCV type and PCT merely reflects a different epidemiology of HCV genotypes in different countries.
It has repeatedly been reported that autoimmune phenomena responsible for liver diseases are much more frequent in patients from northern Europe than in Mediterranean countries. A mutual exclusion between HCV infection and autoimmune liver disease has also been indirectly suggested, with a higher prevalence of autoimmunity in countries at low prevalence of HCV infection. Patients from northern Europe, where HCV infection is not frequent, could be more susceptible to some autoimmune-mediated mechanisms able to facilitate the generation of liver-specific inhibitors of URO-D that trigger PCT.
Whatever the triggering agent, an interaction between environmental and genetic factors appears to be required for phenotypic expression of PCT.
Patients with PCT from different countries could carry gene mutations/polymorphisms able to interfere with PCT clinical manifestation. As previously reported, iron plays a key role in PCT and a high prevalence of HFE gene mutations has been detected in almost all studies with differences between patients of northern European ancestry and those of Mediterranean origin [3]. In a study performed in the United States [18] the contributing role of HFE gene mutations and acquired risk factors in the pathogenesis of PCT was investigated. The authors reported that in their series of patients with PCT, HCV infection was present in 59%, alcohol abuse in 46%, and 63% of the female patients were taking estrogens. Of the PCT patients tested, 19 were homozygous for the C282Y mutation and 7% were compound heterozygous. The authors concluded that homozygosity for the C282Y mutation and HCV infection were the greatest risk factors for the expression of PCT. However, in most of the patients several coexistent risk factors were present. Interestingly, a recent study from South Africa [19] emphasizes that in PCT the etiological importance of genetic factors and viral infection is population-dependent. In this study a racially mixed population of patients with PCT drawn from three ethnic groups was investigated for HFE gene mutations and viral infections. HFE mutations, highly prevalent in South African controls of European origin, were completely absent in African patients and very rare in cases of mixed or Asian origin. HCV infection did not appear to be associated with PCT while HIV was more prevalent in patients with PCT than in controls, but the high background prevalence of HIV infection in some sectors of the South African population did not allow the authors to define the strength of this association.
Given the high prevalence of iron overload in patients with PCT and several reports of a link between iron and PCT, other genes besides the HFE, involved in iron metabolism, could play a role in the pathogenesis of this disease. Interestingly, in a series of French patients with PCT, of whom 28% were HCV positive, an association was found between PCT and a polymorphism of the human transferrin receptor-1 gene whose product is functionally associated with the HFE protein [20].
Another gene which could play a role in PCT is tumor necrosis factor α (TNFα). The gene product is a proinflammatory cytokine, which contributes to the regulation of iron metabolism through different mechanisms. It has been reported that TNFα stimulates the synthesis of ferritin and of the transferrin receptor in different cell types, inhibits iron release from peritoneal macrophages and decreases plasma iron uptake in erythroid precursors [21]. Preliminary data from our group [22] indicate that TNFα polymorphisms influence susceptibility to PCT. Patients with PCT had a lower prevalence of the TNFα 238 promoter polymorphism and those who carried the polymorphisms (238 and/or 308) had a higher number of known risk factors for PCT, implying a possible protective effect exerted by TNF polymorphisms. Thus genetic factors (HFE gene, possibly TNF and transferrin receptor 1, URO-D and other not yet identified genes) the relevance of which differs in different geographic areas appear to contribute to the pathogenesis of PCT possibly by modulating the expression of the URO-D defect.
On the other hand, the existence of an interaction between HCV and iron is very well known. Mild to moderate iron overload is detected in at least 30–40% of patients with HCV-related chronic hepatitis, patients with increased iron have a lower probability of responding to interferon therapy, and considerable evidence indicates that patients with increased iron and/or who are positive for HFE mutations have a more severe evolution of the liver disease [23], [24]. In addition, in HCV-related chronic hepatitis iron depletion leads to a marked reduction of ALT levels which in a proportion of patients may reach even normal values [23]. Necroinflammatory events secondary to HCV infection may contribute to biochemical or tissue iron excess, or at least to alterations in the normal cellular iron compartmentalization. HCV by itself may be able to interfere with the usual iron motion within hepatocytes. The functions of the recently identified genes, which control cell iron uptake, storage and export could be altered by HCV, resulting in an excess of iron in cytosol with a damage of URO-D. This could be facilitated by the recently demonstrated homology between HCV and iron protein biology, which could imply a tight interaction between genes involved in iron metabolism and HCV [25]. This could be followed by an increased oxidative stress in hepatocytes with URO-D damage. Moreover, it has been reported that experimental iron overload enhances HCV pathogenicity, resulting in a synergistic effect facilitating overt PCT manifestation.
In countries where HCV infection is rare other factors, for example alcohol, could play a synergistic role with iron increasing the production of intracellular toxic compounds able to interfere with URO-D function. Thus on a genetic background consisting in a reduced concentration/activity of URO-D, different acquired factors, interacting with potential modifying genes, could trigger PCT clinical manifestations.
In conclusion, the paper by Gisbert and colleagues [12] outlines that HCV infection is the most prevalent triggering factor for PCT in countries where the prevalence of this viral infection is high. This is confirmed in studies in which PCT is identified as the most frequent extrahepatic manifestation of HCV infection. Iron seems to play a key role in triggering PCT, possibly interfering with HCV and/or other acquired triggering factors. Genetic factors, among which the best candidates are those involved in iron metabolism, could facilitate PCT occurrence by enhancing hepatocyte cytosol damage, resulting in a reduced concentration/activity of URO-D.
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PII: S0168-8278(03)00399-4
doi:10.1016/S0168-8278(03)00399-4
© 2003 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.
