Porphyria cutanea tarda and hepatitis C virus infection

We studied the prevalence of hepatitis C virus (HCV) infection in 20 Japanese patients with sporadic-type porphyria cutanea tarda (PCT). Seventeen of the 20 patients (85%) had anti-HCV antibodies. Biochemical remission was observed in nine patients, six of whom still had positive HCV RNA copies. These results suggest that HCV infection is a triggering factor for PCT in Japan. However, continuous HCV infection seems to exert little influence on the maintenance of abnormal porphyrin metabolism. Hepatocellular carcinoma (HCC) developed in five of the 17 HCV-positive patients, three of whose PCT was in remission. Four of these patients showed chronic active hepatitis or cirrhosis on liver biopsy. PCT patients with HCV infection should be followed up long-term because of the possibility of HCC. To evaluate the risk of HCC, liver biopsy may be required, even when the patient is in biochemical remission.     

Does chloroquine therapy of porphyria cutanea tarda influence liver pathology?

Background  Porphyria cutanea tarda (PCT) is regularly associated with changes in liver tissue. On the other hand, systematic investigations are lacking on whether there is a correlation between the severity of liver damage and chloroquine treatment.
Patients and methods  During a 20-year period, liver biopsies were obtained in 89 patients with PCT confirmed by biochemical analysis of urine and feces and low-dose chloroquine therapy. Seventeen patients with alcohol-induced liver disease were excluded. In 8 of 63 patients, only a single biopsy was available. Classification of liver damage was performed according to the Riedel score. Electron microscopy was available from 24 patients. In a second group of patients, the HFE status was investigated and Berlin blue stains of liver biopsies were performed.
Results  There was no correlation between the duration of cutaneous symptoms and liver pathology. After 12 months chloroquine treatment, 45 patients (81%) disclosed an improvement of liver pathology, nine (16%) had no change, and a worsening was observed in one patient (3%). All patients achieved a complete clinical and biochemical remission. In 13 of 16 patients with a relapse, there was again a deterioration of liver damage. Patients with HFE mutations had a significant higher risk ( P  < 0.05) for hepatic siderosis.
Conclusions  The severity of liver damage was not correlated with the disease duration. Chloroquine treatment resulted in PCT remission (clinical and biochemical) and in 81% to an improvement of liver morphology.     

The association of hepatitis C viral infection with porphyria cutanea tarda in the Lothian region of Scotland

Porphyria cutanea tarda (PCT) is believed to be associated with reduced hepatic uroporphyrinogen decarhoxylase activity and risk factors such as alcohol abuse and medication with oral contraceptives and certain other drugs. Recently it has been suggested that hepatitis C virus (HCV) infection may also he associated with PCT. We have therefore reviewed the prevalence of HCV infection in a series of patients with PCT in the Lothian region of Scotland. We identified 12 patients with PCT, all of whom had abnormal liver function tests. Liver histology revealed chronic active hepatitis in six patients, micronodular cirrhosis in lour patients, hepatocellular carcinoma in one patient and normal findings in one HIV positive patient. Out of 12 patients tested, 11 were positive for anti-HCV antibodies by second generation enzyme linked immunosorbent assay (ELISA 2), and by recombinant immunoblot assay (RIBA 2); positive serology was confirmed by polymerase chain reaction (PCR). In a second group of 14 patients with chronic HCV infection matched for age and sex with the PCT patients, all had normal urinary uroporphyrin excretion. We have thus confirmed in Scotland early reports from Spain and Italy that PCT is strongly associated with HCV infection. This could explain the development of inflammatory changes in the liver and progression of liver disease in patients with PCT. Porphyrin metabolism, however, appears normal in patients with chronic HCV infection without PCT.     

Iron, genes, and viruses: the porphyria cutanea tarda triple threat

Porphyria cutanea tarda (PCT) is a vesiculobulIous disorder often associated with estrogens, hepatitis C virus (HCV), alcoholism, hereditary hemochromatosis (HH), and human immunodeficiency virus. Hepcidin, a peptide hormone produced by the liver, has been associated with iron metabolism in 3 common precipitating factors for PCT: HCV, HH, and alcohol consumption. We present the case of a patient with erosions and noninflammatory bullae on his hands and forearms who received a diagnosis of PCT. On further examination, the patient was found to be positive for 3 precipitating factors: HCV, an HH gene mutation, and alcohol use. For patients with PCT, it is important to perform phenotypic screening for HCV and HH. Targeting hepcidin with replacement therapy to decrease iron may be a treatment of not only HCV, HH, and alcoholic cirrhosis, but also PCT.     

The management of porphyria cutanea tarda

Porphyria cutanea tarda (PCT), the commonest of all porphyrias, is usually characterized by blisters and fragility of skin in light-exposed areas. It can be clinically indistinguishable from other disorders including variegate porphyria and the diagnosis can only be made by rigorous biochemical analysis. PCT does not cause acute attacks of porphyria. It is usually an acquired condition caused by inhibition of the uroporphyrinogen decarboxylase enzyme in the liver. Hereditary haemochromatosis, hepatitis C virus infection, alcohol, oestrogens and a family history of PCT are the major risk factors for the condition and should be searched for specifically in all patients. Liver disease, including hepatocellular carcinoma, is common in patients with PCT, and should be investigated for at presentation by means of a liver biopsy where possible. Patients with severe hepatic pathology or longstanding untreated PCT need to be monitored for the development of hepatocellular carcinoma in the long term. Low dose twice weekly chloroquine is the mainstay of treatment, but venesection should be used in patients with severe iron overload or hepatitis C-related liver disease. Subsequently, long-term follow-up is needed in all patients to monitor for relapse.     

Porphyria cutanea tarda and hepatitis C virus: a case-control study and meta-analysis of the literature.

BACKGROUND: Porphyria cutanea tarda (PCT) and hepatitis C virus (HCV) infection have been associated in several reports with the prevalence of HCV exhibiting considerable regional variation. However, most reports were confounded by selection bias and a regional prevalence of HCV in the populations studied. In the United States, only a few cases of this association have been reported to date. OBJECTIVE: We concluded a study to evaluate the association between PCT and HCV in a US population. We used a case-control study design to control the systemic error that may occur during a selecting process or sampling procedure. METHODS: We reviewed the medical records of Wishard Memorial Hospital, a county hospital serving metropolitan Indianapolis, Indiana, to perform a retrospective case-control study of 26 patients with PCT (as case) against 149,756 regional volunteer blood donors (as control-1) and 51 patients receiving methotrexate for psoriasis (as control-2). HCV antibody titers and other liver abnormalities were our main outcome measures. We then performed a weighted meta-analysis of 17 reports that had at least 17 patients in their study populations. RESULTS: Sixteen (94%) of 17 PCT patients tested for HCV were antibody positive. Among blood donors, only 255 or 0.17% were HCV antibody positive (P < 10(-5), two-sided chi-square test). Of 5 psoriasis patients tested for HCV, none were HCV antibody positive (P = .0002, two-sided Fisher's exact test). For geographic comparison, meta-analysis of the literature demonstrated a varying regional prevalence of HCV in PCT patients as follows: Northern Europe 17%, Australia/New Zealand 20%, and Southern Europe 65%. CONCLUSION: Although a marked geographic variation was found in the worldwide prevalence of HCV in PCT patients, a very large percentage of US patients with PCT had HCV infection. Our results emphasize the need for clinicians to actively look for HCV in patients with PCT.     

Relationship between Porphyria Cutanea Tarda (PCT) and Viral Hepatitis

Recent reports have revealed the high prevalence of serological markers of viral hepatitis in porphyria cutanea tarda (PCT). We present two cases of PCT associated with hepatitis C and discuss the relationship between PCT and viral hepatitis. Case 1: A 50-year-old Japanese male noticed blisters, erosions, and fragility on sun-exposed areas of his skin in November of 1990. He had no history of excessive alcohol intake. He had been taking analgesics for eighteen years. Case 2: A 64-year-old Japanese male was referred in October of 1989 because of pigmentation on sun-exposed areas of his skin. He had been drinking alcohol excessively for 43 years. The hepatitis C virus (HCV) antibody was present in each case. Tests for the HCV antibody and hepatitis B serological markers were run in 5 other patients. HCV antibody was present in 3 of them. The two cases negative for the HCV antibody exhibited the hepatitis B antibody. We speculated that viral hepatitis infection may play an important role in precipitating PCT in cases with a history of a long term excessive intake of alcohol or chemicals.     

Porphyrin metabolism in hepatitis C infection

Hepatitis C virus has been implicated as a major precipitating factor in porphyria cutanea tarda (PCT). To determine whether hepatitis C infection alone is sufficient to induce PCT, we screened two groups of patients with hepatitis C infection. The first group comprised women who had become HCV positive secondary to immunization with anti-D immunoglobulin (group 1). Group 2 included males and females who were HCV positive but HIV negative secondary to intravenous drug abuse. Though both groups had very abnormal liver function tests, we found no significant abnormalities in porphyrin metabolism in these groups of patients. Therefore, in this study population, we conclude that HCV infection alone is insufficient to cause porphyrin metabolic derangement.     

The prevalence of HFE C282Y gene mutation is increased in Spanish patients with porphyria cutanea tarda without hepatitis C virus infection

OBJECTIVES: To investigate the role of C282Y and H63D mutations, and hepatitis C virus (HCV) infection in the pathogenesis of porphyria cutanea tarda (PCT). DESIGN: Prospective case-control study. SETTING: A large clinical and research institute for the study and treatment of cutaneous diseases in Barcelona, Spain. PATIENTS: Ninety-nine consecutive patients with PCT and one hundred and twenty-six control patients (76 healthy subjects and 50 patients chronically infected with HCV), were recruited. MAIN OUTCOME MEASURES: The frequency of the C282Y and H63D mutations in patients with PCT vs. controls and the relationship of these mutations with HCV infection, and iron status, as judged by serum iron, liver iron and ferritin levels. RESULTS: C282Y mutation was significantly increased in PCT patients. This mutation was more frequent among non-HCV-infected patients. Increased ferritin levels and hepatic iron overload were also observed in PCT patients with heterozygous C282Y state. H63D mutation was only significantly increased among PCT patients with chronic hepatitis C infection. No significant iron overload was observed in patients with H63D mutation. CONCLUSIONS: This study confirms the high frequency of C282Y mutation in patients with PCT and its relationship with iron overload. The C282Y mutation has a relevant role in Spanish patients with PCT not associated with HCV chronic infection. On the other hand, the prevalence of the H63D mutation seems not to be increased in patients with PCT. The possibility of an association between HCV infection and H63D mutation in inducing PCT can be hypothesized.     

Porphyria cutanea tarda, hepatitis C, alcoholism, and hemochromatosis: a case report and review of the literature

Porphyria cutanea tarda (PCT) is associated with estrogen, certain medications, alcohol abuse, hepatitis viruses, and iron overload. Numerous studies have demonstrated an increased incidence of hepatitis C in patients with PCT; therefore, hepatitis screening should be routinely performed on these patients. On the other hand, although studies have long suspected hereditary hemochromatosis (HH) to be an underlying condition of PCT, many physicians have a low index of suspicion. Also, diagnosis of HH has been difficult until recently, when the gene mutation was identified. We present a case of a patient with PCT, hepatitis C, and alcoholism who was homozygous for the HH gene mutation.     

Is non‐alcoholic steatohepatitis a predisposing factor to porphyria cutanea tarda?

Porphyria cutanea tarda (PCT) is a disease caused by a deficiency of the fifth enzyme of the heme biosynthetic pathway in the liver that manifests in the skin as blistering and fragility of predominantly sun‐exposed skin. It occurs in individuals with environmental and/or genetic risk factors such as estrogen use, hepatitis C infection and hemochromatosis gene mutations. This report highlights a case of PCT which manifested in an individual with non‐alcoholic fatty liver disease (non‐alcoholic steatohepatitis; NASH). We propose that NASH may have been a contributing factor for the development of PCT in our patient.     

Porphyria cutanea tarda,C282Y,H63D and S65C HFE gene mutations and hepatitis C infection: a study from southern France

BACKGROUND: To evaluate the role of genetic factors in the pathogenesis of porphyria cutanea tarda (PCT) and their association with chronic hepatitis C. OBJECTIVE: To investigate the relations between hemochromatosis gene (HFE) mutations and PCT in the south of France and their links with chronic hepatitis C virus (HCV) infection. METHODS: The genotype for the C282Y, H63D and S65C mutations of HFE was determined in 33 patients with PCT, 46 patients with HCV infection but without PCT and 58 controls. Iron status and HCV, HBV and HIV serologies were studied in all patients. RESULTS: A statistically significant increase in the C282Y mutation was found in PCT patients. No difference was found for H63D or S65C mutations. The prevalence of HCV infection was higher in PCT patients than controls. CONCLUSIONS: C282Y mutations and HCV infection but not H63D or S65C mutations are PCT-triggering or associated factors in the south of France.     

Porphyria cutanea tarda. A rare cutaneous manifestation of hepatic tumors.

Porphyria cutanea tarda (PCT), the most common form of porphyria, may be one of the rare cutaneous manifestations of hepatic tumors, benign, malignant, or metastatic. The liver damage associated with PCT may predispose to the development of hepatocellular carcinoma. Our experience and a review of the literature suggest that in patients with PCT in whom the usual precipitating factors are absent, or in patients with PCT of long duration and an unexplained exacerbation, liver scan is indicated to rule out the presence of a hepatic tumor.     

Increased serum hepcidin levels in patients with porphyria cutanea tarda

Background Increased iron stores‐ are common in porphyria cutanea tarda (PCT) patients, but the pathophysiological pathways remain unknown. Down‐regulation of hepcidin, a peptide which regulates systemic iron homeostasis, has been demonstrated in different conditions associated with PCT, such as haemochromatosis, chronic hepatitis C (CHC) and excessive alcohol intake. However, serum hepcidin levels have not yet been studied in PCT patients. Objective To measure the serum hepcidin levels in patients with PCT, CHC and control patients, and to assess the association of hepcidin with serum markers of inflammation, iron overload and oxidative stress. Methods Hepcidin levels were measured by a competitive enzyme‐linked immunosorbent assay in serum samples of patients presenting PCT (n = 30), CHC (n = 31) and healthy volunteers (n = 52). Results  The mean of serum hepcidin levels was significantly higher in the PCT group (129.6 ng/mL) in comparison with the mean values in the CHC (41.3 ng/mL) and control (70.8 ng/mL) groups. The serum concentration of ferritin and interleukin‐6 (IL‐6) was also significantly higher in the PCT group, and correlated strongly with the hepcidin levels. The PCT patients with hepatitis C virus (HCV) infection showed significantly higher hepcidin levels than the group of CHC patients without porphyria. Conclusion Serum hepcidin levels are increased in patients with PCT suggesting that the mechanisms regulating iron homeostasis in PCT differ from those involved in other related disorders, such as haemochromatosis, HCV infection or alcohol abuse.     

Hepatitis B serum markers in porphyria cutanea tarda

Hepatitis B virus (HBV) infection was studied in 100 patients with porphyria cutanea tarda (PCT). The overall prevalence of HBV serologic markers was 57%: 6 patients had HBsAg, 9 had antiHBc alone, 2 had antiHBc associated with antiHBe and the remaining 40 patients had antiHBs. The seropositivity frequency was significantly related to the age of patients and to previous venesection treatment but was unrelated to previous hepatitis or risk factors, amount of alcohol consumption, abnormalities of serum iron levels, liver function tests, or hepatosiderosis. Seropositive patients showed more severe histological abnormalities than seronegative patients. Our results indicate that PCT should be considered a high risk disorder for HBV infection and that this agent may play an important role in aggravating the underlying liver damage.     

Sclerodermiform porphyria

We give a retrospective survey on the clinical, histological, biochemical, and pathogenetical aspects of sclerodermiform changes rarely accompanying porphyria cutanea tarda (PCT). Sclerodermiform changes were seen in 12 patients (2% of all our PCT cases). In these patients, no correlation was found between the severity of the dermatological signs and symptoms and the degree of disturbance in the porphyrin metabolism. Biochemical remission was not accompanied by improvement of the sclerodermiform changes. The proportion of porphyrins with 4 or 5 COOH-groups was higher than that of PCT patients without sclerosis. The findings are consistent with the view that the development of sclerodermiform changes cannot be merely explained by phototoxic reactions, but the "dark-effect" of the porphyrins may also play an important role in the pathogenesis.     

HFE mutations and transferrin receptor polymorphism analysis in porphyria cutanea tarda: a prospective study of 36 cases from southern France

BACKGROUND: Porphyria cutanea tarda (PCT) is associated in most cases with iron overload, which may participate in decreased activity of uroporphyrinogen decarboxylase in the liver. The aetiology of this iron overload remains unknown; however, it has been demonstrated that mutations of HFE, the genetic haemochromatosis gene, might be present in a significant proportion of Anglo-Saxon and Italian patients. Furthermore, transferrin receptor polymorphism may influence the affinity of this receptor to its ligand with a subsequent increase of cellular iron absorption and storage. OBJECTIVES: To evaluate the incidence and spectrum of HFE mutations and the relative frequency of the two main alleles of transferrin receptor in patients with PCT originating from southern France, and to evaluate the relationship of these genetic data with iron status, and with hepatitis B and C and human immunodeficiency virus (HIV) infections. METHODS: Thirty-six consecutive patients with either sporadic or familial PCT were prospectively included between 1997 and 2000. Search for the presence of the three main mutations of the HFE gene and identification of the transferrin receptor alleles were performed using polymerase chain reaction followed by enzymatic digestion. Iron parameters and viral status for hepatitis B and C viruses and HIV were determined. RESULTS: Seven patients (19%) showed heterozygous C282Y mutation, but no C282Y homozygote was present; five patients (14%) carried homozygous H63D mutation, while eight (22%) were heterozygous for this mutation. One patient was heterozygous for the S65C mutation (3%). Iron parameters demonstrated overload in all patients, without a clear difference between patients with and without deleterious mutations of the HFE gene. Infection by hepatitis C virus was documented in 20 patients (56%), and was significantly less frequent in patients with deleterious HFE mutations. The profile of transferrin receptor alleles in PCT patients did not show significant variation compared with the general population. CONCLUSIONS: This study confirms the high frequency of HFE mutations in patients with PCT and supports the hypothesis that HFE gene abnormalities might play a significant part in the PCT pathomechanism, probably through iron overload; by contrast, transferrin receptor polymorphisms do not appear to play a significant part in iron overload in PCT.     

PORPHYRIA CUTANEA TARDA AND HUMAN IMMUNODEFICIENCY VIRUS INFECTION

Porphyria cutanea tarda (PCT), a relatively uncommon disease, has recently been reported in patients infected with the human immunodeficiency virus (HIV). Although PCT and HIV infection may co-exist by chance, the increasing number of reported cases suggest that HIV or an associated factor triggers the development of PCT in predisposed individuals. We report four additional cases of PCT in HIV seropositive patients and review the previously reported cases. The possible links between PCT and HIV are discussed. We believe the diagnosis of PCT should prompt investigation for HIV infection in all patients.     

Microscopic abnormalities in the liver of two patients with Porphyria variegate

In contrast to Porphyria cutanea tarda (PCT), which is characterized by constant hepatic involvement, the liver seems to be unaltered in Porphyria variegate (PV). However, the authors have found microscopic alterations in the liver of 2 patients with PV (mild inflammation and fibrosis of the portal tracts and the presence of iron deposits in one of the cases). Although these changes could be attributed to other causes, the hypothesis of possible liver involvement in PV is not excluded.     

High prevalence of HFE gene mutations in patients with porphyria cutanea tarda in the Czech Republic

Background  Iron overload and hepatitis C virus (HCV) infection are independent factors which are thought to play a role in the pathogenesis of porphyria cutanea tarda (PCT).
Objectives  To determine the prevalence of the HFE gene mutations p.Cys282Tyr (C282Y), p.His63Asp (H63D) and p.Ser65Cys (S65C), the p.Tyr250X (Y250X) mutation of the TFR2 gene, and HCV infection in patients with PCT in the Czech population, and to make comparison of the iron status among the respective genotypes.
Methods  Iron metabolism indices, results of mutational analysis and serological markers of HCV infection were examined in 63 patients with PCT.
Results  The HFE gene mutations were detected in 70% of patients with PCT compared with 35% in the control group ( P  <   0·001). Mean serum ferritin levels were increased in all genotypes, the highest being in homozygotes for the p.Cys282Tyr mutation. HCV infection was detected in only 8% of patients with PCT.
Conclusions  There was a very high prevalence of the p.Cys282Tyr and p.His63Asp mutations observed in patients with PCT accompanied by mild degrees of iron overload, which was genotype dependent.