Prevalence of hepatitis C virus infection in porphyria cutanea tarda: systematic review and meta-analysis

Journal of Hepatology 39 (2003) 620–627 www.elsevier.com/locate/jhep

Prevalence of hepatitis C virus infection in porphyria cutanea tarda: systematic review and meta-analysis Javier P. Gisbert*, Luisa Garcı´a-Buey, Jose´ Marı´a Pajares, Ricardo Moreno-Otero Servicio de Gastroenterologı´a y Hepatologı´a, Universidad Auto´noma de Madrid, Hospital Universitario de la Princesa, Diego de Leo´n, 62. 28006 Madrid, Spain

See Editorial, pages 635– 638 Background/Aims: To conduct a systematic review and meta-analysis on the prevalence of hepatitis C virus (HCV) infection in porphyria cutanea tarda (PCT). Methods: Studies evaluating prevalence of HCV infection in patients with PCT were considered. Bibliographical searches were conducted in several electronic databases. Studies comparing HCV prevalence in PCT (cases) and in a reference group (controls) were included in the meta-analysis, combining the Odds Ratios (OR) of the individual studies. Results: Fifty studies including 2,167 patients were identified. Mean HCV prevalence by serology was 47%, and 50% with polymerase chain reaction (PCR). HCV prevalence markedly varied depending on the country and the type of PCT (57% in the sporadic and 26% in the familial form). Eight case-contol studies were identified. Seven studies compared HCV prevalence in PCT vs. healthy controls: 40% vs. 0.24%, respectively (OR=275; 95% confidence interval=104-725). Heterogeneity disappeared when only studies evaluating HCV infection by PCR were included. Conclusions: HCV prevalence in patients with PCT is approximately 50%, much higher than that reported in general population, suggesting a possible etiopathogenic role of HCV in PCT. The striking geographical variation in this association suggests that genetic and/or environmental factors may also be involved in the pathogenesis of this disorder. q 2003 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. Keywords: Hepatitis C virus; Meta-analysis; Porphyria cutanea tarda; Systematic review

1. Introduction Hepatitis C virus (HCV) infection is a major public health problem worldwide, with a global prevalence of 170 million people affected [1]. The enormous burden of chronic HCV infection over the next two decades has been estimated mainly concerning the consequences of liver disease [2], but no definite information exists regarding the incidence and outcome of related extrahepatic conditions. HCV has been associated with several extrahepatic manifestations, including essential mixed cryoglobulinemia, membranoproliferative glomerulonephritis, non-Hodgkin’s lymphoma, and some dermatological conditions such as lichen planus, vitiligo and porphyria cutanea tarda (PCT) [3,4]. Received 9 April 2003; received in revised form 25 June 2003; accepted 26 June 2003 Abbreviations: HCV, hepatitis C virus; PCT, porphyria cutanea tarda; PCR, polymerase chain reaction. * Corresponding author. Tel.: þ 34-915202254; fax: þ34-914022299. E-mail address: [email protected] (J.P. Gisbert).

PCT, the most common form of porphyria, is caused by reduced activity of uroporphyrinogen decarboxilase [5,6]. In the sporadic form of the disease, the enzyme activity is decreased to 50% in the hepatocytes only, whereas in the less common familial form, the enzymatic defect is also present in other cells types, such as erithrocytes [7]. However, this enzymatic defect itself is not sufficient to produce a PCT phenotype because most persons with this degree of decrease have no symptoms or signs of PCT [5,6]. The extrinsic factors that modulated this expression include alcohol consumption, estrogens, and iron overload [5,6]. The onset of PCT is characterized by the development of cutaneous lesions, increased skin fragility, bruising, and the appearance of vesicles and bullae that may become hemorrhagic. Liver disease is seen in almost all cases of PCT, the cause of which is incompletely known [5,6]. Extensive epidemiological evidence favors the pathogenic implications of HCV. Thus, the prevalence of HCV infection has been reported to be increased in patients with PCT, although considerable geographical variation is observed [3,8]. The aim of our study was to

0168-8278/03/$30.00 q 2003 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. doi:10.1016/S0168-8278(03)00346-5

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conduct a systematic review on the prevalence of HCV infection in PCT, and to perform a meta-analysis of studies comparing the prevalence of HCV infection in patients with PCT and in respective controls.

2. Patients and methods 2.1. Criteria for considering studies 2.1.1. Types of studies and participants Studies evaluating the prevalence of HCV infection in patients with PCT were considered. Only case-control studies comparing the prevalence of HCV infection in patients with PCT and in respective controls were eligible for inclusion in the meta-analysis.

2.1.2. Types of outcome measures The outcome considered in this review was ‘prevalence of HCV infection’.

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2.3.4. Data synthesis The outcome considered in this study was ‘prevalence of HCV infection’. The mean percentage of patients with HCV infection was calculated and expressed as weighted mean [and corresponding 95% confidence interval (95% CI)] to make due allowance for the number of patients included in each study. For the meta-analysis, the homogeneity of effects throughout studies was appraised using a homogeneity test based on the chi-square test. Due to the low power of this test, a minimum cut-off P value of 0.1 was established as a threshold of homogeneity: lower values indicated heterogeneity, and prevented us from relying on the combination of the study results. Meta-analysis was performed combining the odds ratios (OR) of the individual studies in a global OR, using a random effect model (DerSimonian and Laird). Significance and 95% CI are provided for the combined OR. All calculations were performed with the freeware program Review Manager 4.2.2.

2.3.5. Subanalysis/sensitivity analysis Subanalyses were planned depending on the country of the study, type of PCT (sporadic or familial), diagnosis of HCV infection, type of control group, and quality of the study (based on the inclusion of matched controls and the prospective/retrospective design of the study).

2.2. Search strategy for identification of studies

3. Results

Bibliographical searches were performed in MEDLINE (January 1966 to January 2003), EMBASE (January 1988 to January 2003) and CINAHL (January 1982 to January 2003) electronic databases, and in the Cochrane Controlled Trials Register (the Cochrane Library issue 1, 2003), looking for the following words (all fields):. (‘Hepatitis C virus’ OR ‘hepatitis C’ OR ‘virus C’ OR HCV) AND Porphyria. Abstracts of the articles selected in each of these multiple searches were reviewed and those meeting the inclusion criteria were recorded. Reference lists from trials selected by electronic searching were hand searched to identify further relevant trials. Articles published in any language were included.

Three studies identified with the search strategy were excluded from the calculations of this systematic review because all of the included patients were HIV-positive [11 – 13]. Thus, the 50 studies identified assessing the prevalence of HCV infection in patients PCT and fulfilling the inclusion criteria are summarized in Table 1 [14–64]. Weighted mean prevalence of HCV infection by serology calculated from 2167 patients included in those studies was 47% (95% CI ¼ 45–49%). HCV prevalence (by serology) in PCT patients depending on the country of the study is summarized in the table, and the weighted mean in those countries including most studies was: Australia (24%), Czech Republic (22%), France (31%), Italy (83%), Spain (71%), Japan (85%), and USA (66%). When PCR was the method used to diagnose HCV infection, weighted mean prevalence, calculated from a total of 1164 patients, was 50% (47–53%). Table 2 summarizes those studies which have evaluated, in the same protocol, the prevalence of HCV infection in patients with PCT depending on the type (sporadic or familial) of presentation [15, 17, 19, 20, 26, 33, 38, 53]. From this table, a weighted mean prevalence of 57% (53 –71%) is calculated in the sporadic form, while in the familial form this figure was of only 26% (17 –34%). The characteristics of studies included in the meta-analysis comparing the prevalence of HCV infection in patients with PCT and in respective controls are summarized in Table 3 [18, 23, 26, 39, 42, 51, 59, 65]. The overall prevalence of HCV in PCT in eight studies was 45% (40–49%). Seven studies compared HCV prevalence in PCT and in healthy controls [18,26,39,42,51,59,65], with respective figures of 40% and 0.24%, results being summarized in Fig. 1. The OR for this association was 275 (104–725), results being heterogeneous (test for heterogeneity chi-square, P ¼ 0:0048). However, heterogeneity disappeared when only studies evaluating HCV infection by PCR (and not only by serology) were included

2.3. Methods of the review 2.3.1. Selection of studies Only studies that clearly stated information about the number of PCT patients included and infected with HCV were selected. For the meta-analysis, case-control studies comparing prevalence of HCV infection in cases (PCT) and controls (any other group of patients different from PCT; see subanalysis section following) were included. Studies with all patients having human immunodeficiency virus (HIV) were excluded, as an association between PCT and HIV infection has been described [9], which may introduce a selection bias.

2.3.2. Assessment of study quality The performance of matching (by age, sex, etc.) and the design (prospective or retrospective) of case-control studies included in the metaanalysis was assessed [10].

2.3.3. Data extraction Regarding studies evaluating HCV prevalence in patients with PCT, the following variables were extracted in a predefined data extraction form (see Table 1): author, country of the study, number of patients with PCT, and prevalence of HCV infection. In addition, in studies included in the metaanalysis, the following variables were extracted (see Table 2): author, country of the study, diagnosis of HCV infection [serology or polymerase chain reaction (PCR)], HCV infection in PCT (number and percentage), type of controls (healthy subjects, dermatological lesions different from PCT, etc.), matching (by age, sex, etc.), design (prospective or retrospective study), and HCV infection in controls (number and percentage). Publications identified as duplicates were excluded; when more than one version of the same trial was retrieved, only the most recent data were considered.

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Table 1 Prevalence of hepatitis C virus (HCV) infection in patients with porphyria cutanea tarda (PCT) Author (ref.)

Country

PCT type

Andreone et al. [14] Antonov et al. [15] Bonkovsky et al. [16] Bulaj et al. [17] Chuang et al. [18] Cribier et al. [19,20] Dabrowska et al. [21] Dabrowska et al. [22] Carpintero et al. [23] Dereure et al. [24] Egger et al. [25] Fargion et al. [26] Fargion et al. [27] Fernandez-Miranda et al. [28] Ferri et al. [29] Ferri et al. [30] Fracanzani et al. [31] Gisbson et al. [32] Herrero et al. [33] Hussain et al. [34] Koester et al. [35] Kondo et al. [36] Lacour et al. [37] Lamoril et al. [38] Lamoril et al. [39] Lim et al. [40] Lopez-Morante et al. [41] Malina et al. [42] Malina et al. [43] Mancini et al. [44] Martin-Vivaldi et al. [45] Martinelli et al. [46] McCrossin et al. [47] Moran et al. [48] Murphy et al. [49] Nagi et al. [50] Navas et al. [51] Piperno et al. [52] Quecedo et al. [53] Rivanera et al. [54] Salmon et al. [55] Siersema et al. [56] Sinclair et al. [57] Skowron et al. [58] Sto¨lzel et al. [59] Stransky et al. [60] Stuart et al. [61] Tannapfel et al. [62] Tsukazaki et al. [63] Wolf et al. [64]

Italy Bulgaria USA USA USA France Poland Poland Spain France USA Italy Italy Spain Italy Italy Italy Australia Spain Scotland USA Japan France France France USA Spain Czech Republic Czech Republic Italy Spain Brazil Australia Spain Ireland Hungary Spain Italy Spain Italy New Zealand The Netherlands USA France Germany Czech Republic Australia Germany Japan Chile

S S and F NS S and F NS S and F NS NS S and F S and F NS S and F NS NS S NS NS NS S and F NS NS S S S and F S S NS NS NS NS NS NS NS S and F NS NS S NS NS NS NS NS NS NS S and F NS S and F S S S and F

Prevalence of HCV infection by serology n/N (%) 6/9 (67%) 40/77 (52%) 39/70 (56%) 42/71 (59%) 16/17 (94%) 7/13 (54%) 7/9 (78%) 29/36 (80%) 20/36 (56%) 29/39 (74%) 56/74 (76%) 56/63 (89%) 42/64 (66%) 21/23 (91%) 21/23 (91%) 48/53 (90%) 26/112 (23%) 75/100 (75%) 11/12 (92%) 5/5 (100%) 22/26 (85%) 10/13 (76%) 26/124 (21%) 18/65 (28%) 3/4 (75%) 4/10 (40%) 20/92 (22%) 14/60 (23%) 23/31 (76%) 4/5 (80%) 15/23 (65%) 3/13 (25%) 18/26 (69%) 2/20 (20%) 31/34 (91%) 7/12 (58%) 85/132 (64%) 1/25 (4%) 7/38 (18%) 16/21 (76%) 14/56 (25%) 9/111 (8%) 14/66 (21%) 7/27 (26%) 28/190 (15%) 17/20 (85%) 9/17 (53%)

Prevalence of HCV infection by PCR n/N (%) 8/9 (89%) 39/70 (56%)

7/13 (54%) 12/29 (41%) 29/36 (80%) 20/36 (56%) 49/74 (66%) 43/63 (68%) 35/64 (55%) 17/22 (77%) 18/23 (77%) 48/53 (90%)

11/12 (92%)

26/124 (21%) 18/65 (28%)

23/31 (76%) 15/23 (65%) 18/26 (69%) 2/20 (20%) 6/19 (32%) 21/32 (65%) 46/55 (83%) 34/40 (84%) 0/25 (0%)

9/111 (8%) 14/66 (21%) 7/27 (26%) 12/15 (80%)

PCR, polymerase chain reaction; S, sporadic; F, familial; NS, not stated. Weighted mean prevalence of HCV infection by serology in a total of 2167 patients was 47% (95% confidence interval ¼ 45–49%), and by PCR in 1164 patients it was 50% (95% confidence interval ¼ 47 –53%).

[39,51,59]; in this case, the OR was 82 (15–437), and the P value for the test for heterogeneity chi-square was 0.39. When subanalysis was performed depending on the inclusion of matched controls, an OR of 42 (6–314) was calculated when

only age- and sex-matched healthy controls were included [39, 59]. Finally, two studies compared HCV prevalence in PCT and in dermatological lesions different from PCT [18,23], with respective figures of 85% and 2.9% (OR ¼ 117, 19–720).

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Table 2 Prevalence of hepatitis C virus (HCV) infection in patients with porphyria cutanea tarda (PCT) depending on the type (sporadic or familial) of presentation Author (ref.)

Country

HCV diagnosis

Prevalence of HCV infection n/N (%) in the sporadic form

Prevalence of HCV infection n/N (%) in the familial form

Antonov et al. [15] Bulaj et al. [17] Cribier et al. [19,20] Fargion et al. [26] Herrero et al. [33] Lamoril et al. [38] Quecedo et al. [53]

Bulgaria USA France Italy Spain France Spain

Serology Serology Serology and PCR Serology Serology Serology and PCR Serology

36/57 (63%) 35/56 (63%) 7/12 (58%) 53/70 (76%) 75/95 (79%) 22/83 (26%) 76/113 (67%)

4/20 (20%) 7/15 (47%) 0/1 (0%) 3/4 (75%) 0/5 (0%) 4/41 (9.8%) 9/19 (47%)

PCR, polymerase chain reaction. Mean prevalence of HCV infection in the sporadic form was 57% (95% confidence interval ¼ 53–71%), and in the familial form it was 26% (95% confidence interval ¼ 17–34%).

4. Discussion Epidemiological data suggest a strong association between HCV and PCT, as mean prevalence of HCV

infection calculated from 2167 patients in the 50 studies included in our systematic review was 47% (Table 1). Furthermore, the high prevalence of HCV in PCT was confirmed in the case-control studies included in our

Table 3 Prevalence of hepatitis C virus (HCV) infection in cases [patients with porphyria cutanea tarda (PCT)] and in respective controls Author (ref.)

Country

HCV diagnosis

HCV infection in PCT n/N (%)

Type of controls

Carpintero et al. [23]

Spain

Serology and PCR

29/36 (80%)

Chuang et al. [18]

USA

Serology

16/17 (94%)

18/65 (28%)

(1) Alcoholic liver disease (2) Dermatological lesions different from PCT, with no liver disease (1) Healthy controls (blood donors) (2) Dermatological lesions different from PCT (psoriasis treated with methotrexate) (1) Healthy controls (blood donors) (2) Alcoholic liver disease (3) Hospitalized patients without liver disease (1) Healthy controls (blood donors and hospital employees) (2) Other conditions different from liver or dermatological diseases Healthy controls

20/92 (22%)

Healthy controls

31/34 (91%) by serology 21/32 (65%) by PCR 9/111 (8%)

Healthy controls (blood donors) Healthy controls (recruited in a dental practice, with no evidence of PCT or autoimmune diseases)

DeCastro et al. [65]

Fargion et al. [26]

Spain

Italy

Lamoril et al. [39]

France

Malina et al. [42] Navas et al. [51]

Czech Republic Spain

Sto¨lzel et al. [59]

Germany

a

Serology

Serology

Serology and PCR Serology Serology and PCR Serology and PCR

21/34 (62%)

56/74 (76%)

PCR, polymerase chain reaction; P, prospective; R, retrospective. This study was also geographical residence- and occupation-matched.

Matching

Design

HCV infection in controls n/N (%)

R

(1) 3/26 (11%) (2) 1/29 (3.4%)

R

(1) 255/149,756 (0.17%) (2) 0/5 (0%)

R

(1) 156/19,788 (0.79%) (2) 7/40 (17%) (3) 8/138 (5.8%)

No

R

(1) 2/205 (1%) (2) 3/70 (4%)

Age- and sex-matcheda

R

Age- and sex-matched No

R

0/108 (0%)

R

23/14,651 (0.16%)

No

P

Age- and sex-matched

R

0/20 (0%) by serology 0/20 (0%) by PCR 0/111 (0%)

No No

No No No

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Fig. 1. Meta-analysis of case-control studies comparing the prevalence of hepatitis C virus (HCV) infection in patients with porphyria cutanea tarda (PCT) and in healthy controls.

meta-analysis (Table 3). Thus, when comparing HCV prevalence in PCT patients and in healthy controls, the OR for this association was as high as 275. In addition, both biochemical [19 – 21,33,46,53,58,65 – 67] and histological [26,33,52,53,64,67] parameters have been reported to be worse in PCT infected than in non-infected patients, suggesting that HCV infection may be considered not only as a precipitating factor for the disease but, probably, also as an aggravating factor for its associated liver damage. In summary, the remarkably high prevalence of HCV prevalence in PCT suggests that the virus could have a pathogenic role in inducing PCT or increasing the susceptibility of patients to other triggering factors such as iron overload or alcohol abuse. From another point of view, the reported prevalence of PCT (or PCT-like abnormality in the pattern of urinary porphyrin excretion) among HCV-infected patients has been less than 5% in a recent study [16], or even less than 1% in other studies published afterwards [4,68]. Therefore, despite the aforementioned association of HCV infection and PCT, most patients with chronic HCV infection do not develop PCT, suggesting that routine porphyrin testing of all HCV-infected patients is not indicated, but should be limited to those with features suggestive of PCT. A marked study and geographic variability exists for the relationship between HCV and PCT. For example, in our study, HCV prevalence in PCT patients from Australia, Czech Republic and France was about 20– 30%, while the corresponding figure for Japan and countries in southern Europe such as Italy and Spain was considerably higher (ranging from 71 to 85%) (Table 1). HCV prevalence in North American PCT patients (66%) was between these extremes, although closer to southern Europe. Other authors have reported the following spectrum of HCV prevalence depending on the geographical area: northern Europe (17%), Australia/New Zealand (20%), and southern Europe (65%)(18). This varying regional prevalence suggests that there are other factors (environmental, genetic, etc.) that may have to be present in combination with HCV in order to

trigger PCT. Regarding environmental factors, sun exposure, which is greater in southern compared to northern Europe, could be involved in the development of the clinical symptoms in PCT; however, considering their relatively intense geographic sun exposure, this would not explain, for example, the differences between incidences in southern Europe and Australia. Other risk factors, such as excess alcohol use, are also more frequent in some geographical areas. Finally, differences in distribution of the types of PCT among the studies may also explain some of the reported variability. In this respect, we calculated a mean HCV prevalence of 57% in the sporadic form of PCT, while in the familial form this figure was of only 26% (Table 2); in the same way, family background of PCT has been described to be significantly less frequent among patients infected with HCV [64]. From the virological perspective, factors contributing also to the geographical variability observed in our study may be: (i) the prevalence of HCV infection in the general population, due to the fact that HCV appears to be associated with PCT mainly in southern Europe, where HCV is highly prevalent. (ii) HCV genotype, as it has been demonstrated that different HCV genotypes may have variable degrees of pathogenetic potential for the development of liver disease; although some studies have reported a single genotype of HCV (type Ib) to be present in nearly 90% of PCT patients, significantly exceeding the frequency on the same genotype in control group (patients with HCVassociated chronic liver disease, but without PCT) [69], other authors have found no correlation between specific genotype and PCT [19,20,38,61,70]. (iii) The method used to diagnose HCV infection, as the detection of HCV antibodies without HCV RNA analysis may overestimate the true rate of HCV infection, due to the fact that anti-HCV reactivity can be non-specific in some cases and do not necessarily indicate existence of an active replication of HCV; however, we found a similar prevalence of HCV both with serological and with molecular (PCR) methods

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(47% and 50%, respectively, Table 1). Nevertheless, in our meta-analysis comparing HCV in PCT and in healthy controls, statistical heterogeneity disappeared when only studies evaluating HCV infection by PCR (and not only by serology) were included, in which case the association between both factors was considerably lower (the OR decreased from 275 to 82). The selection of the control group in comparative studies is of the greatest importance. Most of studies included in our meta-analysis included healthy subjects as control group (e.g. blood donors). However, blood donors may not represent a proper control group since they have a lower seroprevalence than the population at large. The low HCV infection rate in this group would bias towards an exaggerated difference when compared with PCT patients. Therefore, we have also considered other control groups, such as dermatological lesions different from PCT, then calculating a lower OR for this association (but still very high, of 117). It should be stressed that only few case-control studies included in our review were matched with respect to age, sex or other variables. Nevertheless, when subanalysis was performed depending on the inclusion of matched controls, an OR as high as 42 was still calculated when only age- and sex-matched healthy controls were included. On the other hand, some retrospective studies have been performed using cohorts of PCT patients attending hepatology departments, and this recruitment bias may lead to an overestimation of the prevalence of HCV infection. A disadvantage of case-control studies with retrospective design (which was the case of almost all studies included in our meta-analysis) in establishing causation is their inability to determine whether the HCV exposure occurred before or after onset of disease (PCT). In this respect, the association between exposure to HCV and PCT can be explained in either two ways: (i) HCV-infected patients have increased risk of developing PCT; and alternatively, (ii) patients with PCT have increased risk of HCV infection. It may be that the high HCV prevalence reported in some studies with PCT patients might result from HCV infection during phlebotomy aimed to induce iron depletion [51]. However, some studies have found that frequency of phlebotomies did not differ significantly between HCV-infected and non-infected PCT patients [38, 51], and that most of HCV-positive PCT patients with significant risk factors of HCV infection were exposed to the virus before the onset or PCT [16,38,65]; in these patients, HCV infection always preceded the clinical expression and diagnosis of PCT. The increased prevalence of HCV infection might be somewhat related to increased alcohol consumption, due to the fact that anti-HCV positivity has been reported in up to 25% of chronic alcoholic patients [71]. However, data exist demonstrating similar alcohol intake in HCV-positive and -negative PCT patients [38]. Finally, interventional studies may give us important information for or against a causal link between HCV

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and PCT. Favorable response of PCT, with decrease or even normalization of urinary porphyrin level, serum liver enzymes and ferritin, and disappearance of skin lesions, has been reported in case reports after successful interferon therapy [72 –74], although the absence of significant changes in HCV load suggests that, in some cases, the resolution of PCT may not be related to the virus per se, but to other mechanisms [75]. Furthermore, several authors did not confirm these favorable findings [19,20,76,77], or have observed even de novo occurrence of PCT in a patient during interferon/ribavirin therapy [78], indicating that the role of antiviral therapy in HCVassociated PCT has yet to be defined. At this time, nevertheless, if HCV is present in the setting of hepatic iron overload, the use of antiviral therapy together with phlebotomy in patients with the sporadic form of PCT has been recommended [6,8,79]. It is unclear if phlebotomy is beneficial in the small number of patients with PCT and normal hepatic iron concentration; in this setting, interferon in combination with ribavirin if HCV is present may be worthwhile [79]. As some authors have pointed out [4], recognition of the type and magnitude of comorbid extrahepatic disorders in HCV-infected patients is important for at least three reasons. First, this knowledge may increase the awareness of health care providers, leading to early diagnosis and treatment of this disease. Second, some of these disorders may improve in response to antiviral treatment for HCV. And third, persons with these extrahepatic disorders can be targeted for HCV testing. Consequently, patients with PCT should be tested for HCV infection, and, conversely, signs and symptoms of PCT should be sought in patients with chronic HCV infection [3]. Nevertheless, due to the fact that the information of epidemiological and case-control studies is limited and that epidemiological parallelisms do not always reveal a causal link, more prospective studies are necessary on this issue as well as on therapeutic approaches. In addition, the striking geographical variation in the association between PCT and HCV, suggesting that different genetic, environmental and viral factors are probably involved in the pathogenesis of these disorders, needs further investigation. A better understanding of the role that HCV plays in PCT will permit the use of more efficacious antiviral options aimed at the prevention and treatment of HCV-associated PCT.

Acknowledgements We are indebted to Brenda Ashley for assistance with the English. Supported in part by a Grant from the Instituto de Salud Carlos III (C03/02).

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