Association between hepatitis C virus and porphyria cutanea tarda.

Porphyria cutanea tarda (PCT) arises from a deficiency of uroporphyrinogen decarboxylase (UROD) in the liver. Several exogenous risk factors are associated with the acquired form of the disease. In Southern Europe, PCT is strongly linked to hepatitis C virus (HCV) infection to the point that a high prevalence of viral infection in some geographic areas generated an increase of PCT cases as a complication. In spite of the association, PCT is a rare complication of HCV infection, thus suggesting the existence of susceptibility factors operating in only some patients. Investigation of liver specimens of PCT patients showed iron accumulation, which albeit moderate, was higher in comparison with HCV-infected patients without PCT. Measurements of hepcidin in serum of HCV-infected patients with and without PCT and calculation of hepcidin/ferritin ratio were compatible with the hypothesis that HCV induced inadequate response of hepcidin to iron accumulation. Administration of direct-acting antivirals (DAA) to HCV-infected patients with active PCT showed that eradication of the virus was followed by resolution of PCT and rapid disappearance of urinary porphyrins. This suggests a direct participation of the virus in the oxidative mechanism leading to UROD inhibition. If clinical evolution of HCV- PCT-patients is placed within a time-frame, rapid PCT resolution by DAA is in striking contrast with a long-delay (in most cases of decades) between viral infection and appearance of overt porphyria. This could be explained if HCV infection (a): enhanced an oxidative environment in the vicinity of UROD and (b): facilitated iron accumulation through hepdicin down-regulation. Thus, only when iron accumulation reached a threshold, inhibition of UROD attained a critical level. However, the enigma is why only a minority of HCV-infected patients develop PCT. If additional risk factors (i.e. alcohol abuse) are not concurring, it should be concluded that modifier genes or epigenetic mechanisms related to iron homeostasis, facilitate iron progressive accumulation in only a minority susceptible patients.

Extrahepatic Manifestations of Hepatitis C: A Meta-analysis of Prevalence, Quality of Life, and Economic Burden.

BACKGROUND & AIMS: Hepatitis C virus (HCV) infection has hepatic and extrahepatic manifestations with various costs and impairments to health-related quality of life (HRQL). We performed a meta-analysis to determine the prevalence of extrahepatic manifestations in patients with HCV infection, how these impair HRQL, and their costs. METHODS: We performed systematic reviews of the literature using MEDLINE, CINAHL, and the Cochrane Systematic Review Database, from 1996 through December 2014, to identify studies of the following extrahepatic manifestations of HCV infection: mixed cryoglobulinemia, chronic kidney or end-stage renal disease, type 2 diabetes, B-cell lymphoma, lichen planus, Sjögren's syndrome, porphyria cutanea tarda, rheumatoid-like arthritis, or depression. We performed a separate meta-analysis for each condition to determine prevalence rates of extrahepatic manifestations of HCV infection and their effects on HRQL. We determined the annual costs (inpatient, outpatient, and pharmacy) associated with extrahepatic manifestations of HCV infection. RESULTS: In an analysis of data from 102 studies, we found the most common extrahepatic manifestations to be diabetes (in 15% of patients) and depression (in 25% of patients). HRQL data showed that HCV infection had negative effects on overall physical and mental health. Total direct medical costs of extrahepatic manifestations of HCV infection, in 2014 US dollars, were estimated to be $1506 million (range, $922 million-$2208 million in sensitivity analysis). CONCLUSIONS: In a systematic review and meta-analysis we determined the prevalence, risks, and costs associated with extrahepatic manifestations of HCV infection. These estimates should be added to the liver-related burden of disease to obtain a more accurate assessment of the total burden of chronic HCV infection. Prospective, real-world studies are needed to increase our understanding of the total clinical and economic effects of HCV infection and treatment on patients and society.

Hepatitis C virus and its cutaneous manifestations: treatment in the direct-acting antiviral era.

New all-oral direct-acting antivirals (DAA) have changed the hepatitis C virus (HCV) treatment landscape. Given that dermatologists frequently encounter HCV-infected patients, knowledge of the current treatment options and their utility in treating HCV-associated dermatologic disorders is important. In addition to highlighting the new treatment options, we review four classically HCV-associated dermatologic disorders - mixed cryoglobulinaemia (MC), lichen planus (LP), porphyria cutanea tarda (PCT) and necrolytic acral erythema (NAE) - and examine the role for all-oral direct-acting antiviral (DAA) regimens in their treatment. A literature search of English-language publications was conducted of the PubMed and EMBASE databases using search terms including 'hepatitis C', 'direct acting antivirals', 'cutaneous', 'mixed cryoglobulinemia', 'necrolytic acral erythema', 'lichen planus', 'porphyria cutanea tarda', 'rash', as well as specific drug names, related terms and abbreviations. Currently, limited data exist on the use of DAAs in HCV-infected patients with cutaneous side-effects, although treatment of the underlying HCV is now recommended for nearly all patients, with the new drugs offering much-improved dosage schedules and side-effect profiles. The most data exist for MC, in which several studies suggest that DAAs and achievement of sustained virologic response (SVR) improve cutaneous symptoms. Studies of both older and newer regimens are limited by their small size, retrospective nature, lack of appropriate controls and wide variability in study protocols. Given the strong association, screening for HCV should be considered in patients with MC, LP, PCT and NAE.

Hepatitis C, porphyria cutanea tarda and liver iron: an update.

Porphyria cutanea tarda (PCT) is the most common form of porphyria across the world. Unlike other forms of porphyria, which are inborn errors of metabolism, PCT is usually an acquired liver disease caused by exogenous factors, chief among which are excess alcohol intake, iron overload, chronic hepatitis C, oestrogen therapy and cigarette smoking. The pathogenesis of PCT is complex and varied, but hereditary or acquired factors that lead to hepatic iron loading and increased oxidative stress are of central importance. Iron loading is usually only mild or moderate in degree [less than that associated with full-blown haemochromatosis (HFE)] and is usually acquired and/or mutations in HFE. Among acquired factors are excessive alcohol intake and chronic hepatitis C infection, which, like mutations in HFE, decrease hepcidin production by hepatocytes. The decrease in hepcidin leads to increased iron absorption from the gut. In the liver, iron loading and increased oxidative stress leads to the formation of non-porphyrin inhibitor(s) of uroporphyrinogen decarboxylase and to oxidation of porphyrinogens to porphyrins. The treatment of choice of active PCT is iron reduction by phlebotomy and maintenance of a mildly iron-reduced state without anaemia. Low-dose antimalarials (cinchona alkaloids) are also useful as additional therapy or as alternative therapy for active PCT in those without haemochromatosis or chronic hepatitis C. In this review, we provide an update of PCT with special emphasis upon the important role often played by the hepatitis C virus.

Resolution of subclinical porphyria cutanea tarda after hepatitis C eradication with direct-acting anti-virals.

BACKGROUND: Hepatitis C virus (HCV) is a risk factor for porphyria cutanea tarda (PCT), a rare disease originating in the liver characterised by overproduction of porphyrins. Although hepatitis C infection is highly prevalent among patients with porphyria, only a minority of hepatitis C patients develop PCT. AIMS: To explore the presence of porphyrin abnormalities in a cohort of asymptomatic hepatitis C-infected patients and the impact of anti-viral therapy. METHODS: Eighty-four consecutive patients with HCV infection treated with direct-acting antivirals after 1 January 2018 were longitudinally evaluated for the presence of porphyrin abnormalities. Those patients with biochemical abnormalities at baseline were additionally evaluated at follow-up. Porphyrins in urine were screened by fluorometry and isomer separation was performed by liquid chromatography. RESULTS: In five patients, all of them asymptomatic, porphyrin profile abnormalities were detected: three presented significant increased urinary porphyrins with a typical PCT profile, and two showed normal levels of urinary porphyrins, but abnormal porphyria-like profiles. Urine evaluation after hepatitis C cure showed complete normalisation of the urinary porphyrins in all patients, confirming the biochemical cure of the disease. CONCLUSIONS: We document the existence of rare cases of hepatitis C-infected patients with significant uroporphyrinuria in the absence of dermatological manifestations. Anti-viral therapy normalises the biochemical disorder, preventing patients from presenting PCT associated complications.

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.

Dermatologic Manifestations of Chronic Hepatitis C Infection.

Chronic hepatitis C virus (HCV) infection is associated with various extrahepatic manifestations, including dermatologic involvement mostly caused by immune complexes. Mixed cryoglobulinemia has a strong relationship with HCV with 95% of these patients being infected with HCV. Lichen planus is a disease of the squamous epithelium and may affect any part of the skin, with 4% to 24% of patients with lichen planus reported to have chronic HCV infection. Porphyria cutanea tarda is the most common form of porphyria, and it is thought that HCV interferes with iron stores, which can promote porphyria cutanea tarda. Finally, necrolytic acral erythema is a rare, psoriasis-like disease closely associated with HCV.

Overview of hepatitis C and skin.

Hepatitis C (HCV) is the most common cause of chronic liver disease and hepatocellular carcinoma, as well as the leading indication for liver transplantation in the Western world. For many patients, cutaneous manifestations may be the only, the earliest, or the most apparent sign of the underlying infection. The dermatologic manifestations of HCV infection are reviewed.

[Development of porphyria cutanea tarda in a chronic hepatitis C patient with indetectable viremia under treatment with peg-interferon plus ribavirin]. / Aparición de porfiria cutánea tarda durante el tratamiento con peg-interferón más ribavirina en un paciente con hepatitis C crónica con viremia indetectable.

Porphyria cutanea tarda (PCT) is considered an extra-hepatic manifestation of HCV infection. The frequency of this association varies according to different authors and the mechanism by which the virus can trigger this disease is not yet clear. We present a 47-year-old-man with chronic hepatitis C genotype 1b who, during the treatment with peg-interferón alfa 2b plus ribavirina, with no detectable viremia at weeks 12th, 24th, and 48th, developed dermatological photosensitive lesions at week 44th. With a presumptive diagnosis of PCT a cutaneous/skin biopsy was performed as well as a porphyrin dosage with urine porphyirins of 4185 microg/24 hs (nv<250). The chromatographic analysis revealed the typical PCT pattern thus confirming the diagnosis. The hemochromatosis HFE gen evaluation showed heterozigotus character mutations (H63D and C282Y) a frequent association in patients with iron overload and PCT. The antiviral treatment of the HCV infection can improve the clinical-humoral manifestations of PCT. The novo occurrence of PCT was recently reported during chronic hepatitis C treatment with interferón and ribavirin, but no cases of late appearance of PCT in patients with no detectable viremia were reported. The mutation of the gen HFE in our patient and the hemolysis caused by ribavirin can be related to the development of the disease, but the iron overload because of ribavirin use is also controversial. This is another example of the complexity of this association.

Porphyria cutanea tarda in a HIV- positive patient.

This is a case report about Porphyria cutanea tarda (PCT) and its relationship with the infection caused by the human immunodeficiency virus (HIV). Cutaneous porphyria is an illness caused by enzymatic modification that results in partial deficiency of uroporphyrinogen decarboxylase (Urod), which may be hereditary or acquired. Several studies suggest that HIV infection associated with cofactors might trigger the development of porphyria cutanea tarda. In this case report, we present a patient infected with HIV, who after the introduction of antiretroviral therapy (ART) enjoyed clinical improvement of porphyria cutanea tarda symptoms.

Porphyria cutanea tarda and human immunodeficiency virus: two cases associated with hepatitis C.

Hepatitis C virus (HCV) was recently recognized as a probable etiologic factor for porphyria cutanea tarda (PCT). A review of the literature revealed 40 cases of PCT associated with the human immunodeficiency virus (HIV). In most of these cases, hepatitis C status was unknown. We describe two patients with PCT who were coinfected with HIV and HCV and discuss the interaction of these two viruses. A diagnosis of PCT, especially in a young patient, should prompt investigation for underlying HIV and HCV infection. Porphyrin studies should be performed in any patient with HIV and photosensitivity. Clinicians should be aware of the infectious risk associated with the vesicles and erosions in these patients.

Porphyria cutanea tarda and hepatitis C viral infection. A clinical and virologic study.

BACKGROUND AND DESIGN: The role of hepatitis C virus (HCV) infection in porphyria cutanea tarda (PCT) is probable since the global HCV antibody prevalence among patients with PCT is about 70%. The purpose of this study was to evaluate the virologic characteristics in 12 patients with sporadic PCT and in one patient with familial PCT. Anti-HCV antibodies were detected by enzyme-linked immunosorbent assay and confirmed by recombinant immunoblot assay. Hepatitis B virus and antihuman immunodeficiency virus markers were also determined. The polymerase chain reaction was performed to detect the following: (1) both positive and negative HCV RNA strands, (2) HCV RNA titer, and (3) HCV RNA genotype. RESULTS: Seven of the 12 patients with sporadic PCT were HCV positive, and the patient with familial PCT was HCV negative. The age at onset of PCT was significantly lower in HCV-positive patients than in HCV-negative patients. The HCV RNA was detected in all patients who had HCV antibodies, and the replicative intermediate of HCV was detected in three of them. The positive RNA titer ranged from 1:10 to 1:10(6). Four patients were infected by HCV genotype I, two by genotype II, and one patient was coinfected by type I and type II. Three of the seven HCV-positive patients also had HBV antibodies, but HBV DNA was never detected. All patients were negative for the human immunodeficiency virus. CONCLUSIONS: The HCV infection rate was high (58%) in this series, and all HCV-infected patients had HCV RNA, reflecting an active replication of the virus. The young age at onset of PCT suggests that HCV is a major triggering factor of PCT. Nevertheless, the clinical changes of PCT were not related to the virologic findings, suggesting an indirect role of HCV.

Etiopathogenetic role of hepatitis C virus in mixed cryoglobulinemia, chronic liver diseases and lymphomas.

Hepatitis C virus (HCV) infection has been found in the majority of patients with mixed cryoglobulinemia (MC) in studies conducted in different countries. In our series of 110 MC patients the frequency of HCV markers was significantly high (91%) compared with other rheumatic diseases (6.4%) and with healthy Italian controls (1.2%). Moreover, HCV RNA was detected in 81% of the peripheral lymphocytes from MC patients. Comparable percentages of HCV infection were detectable in other disorders, i.e. porphyria cutanea tarda (77%) and autoimmune hepatitis type 1 (77%). The HCV infection of peripheral lymphocytes suggests that this virus could be the triggering factor for the lymphoproliferation underlying MC. In a number of patients with MC the evolution from a benign lymphoproliferation to frank B-cell lymphoma was observed. In these subjects HCV RNA in the sera and in fresh and cultured peripheral lymphocytes was constantly detected. The same phenomenon has been observed in patients with long-lasting type C chronic hepatitis. Interestingly, HCV infection has also been recorded in 32% of idiopathic B-cell non-Hodgkin's lymphomas. Taken together, the above findings suggest that HCV can cause benign B-cell proliferation with the consequent production of various autoantibodies, including rheumatoid factor and mixed cryoglobulins. These serological abnormalities characterise different clinical disorders, including the appearance of lymphoma in a not negligible number of individuals.

Hepatitis C virus infection detected by viral RNA analysis in porphyria cutanea tarda.

The high prevalence (62%) of anti-HCV in patients with porphyria cutanea tarda (PCT) found in a recent study prompted us to speculate that hepatitis C virus (HCV) infection could contribute to liver damage in this disease. The relationship between a positive serologic test and infectivity remains elusive, as anti-HCV false-positive reactivity has been described in some patients with chronic liver disease. Hence, it needs to be established if HCV infection plays a role in the pathogenesis of liver injury, or anti-HCV positivity may be an epiphenomenon in PCT patients. The aim of this study was to evaluate the existence of true HCV infection by verifying the presence of serum viral RNA in patients with PCT. HCV RNA was studied in sera from 36 patients with clinical and biochemical features of PCT using a polymerase chain reaction technique. Additionally, 26 patients with chronic alcoholic liver disease and 29 patients with different dermatological lesions but with no liver disease were studied as control groups. HCV RNA was positive in 29 of 36 patients (80.5%) with anti-HCV positive PCT. For alcoholic liver disease and dermatological disease controls the values for HCV RNA were 11.5% and 3.4%, respectively. HCV infection was found to be significantly higher in patients with PCT than in controls (P < 0.001), demonstrating that most subjects with clinically expressed PCT have true HCV infection. These data support the hypothesis that liver damage in some patients with PCT may be attributed to prolonged HCV infection, suggesting that treatment for chronic hepatitis C could be indicated.

Interferon treatment of porphyria cutanea tarda associated with chronic hepatitis type C.

We evaluated the efficacy of interferon in the treatment of a 61 year-old male patient with porphyria cutanea tarda associated with hepatitis C virus infection. After initiation of intravenous administration of interferon-beta, urinary excretion of uroporphyrin and coproporphyrin, serum transaminase, gamma-glutamyl transpeptidase levels and ferritin were gradually increased. However, after completion of interferon-beta administration for 6 weeks, urinary excretion of uroporphyrin and coproporphyrin, serum enzymes and ferritin were significantly decreased correspondent with diminished hepatitis C virus RNA titer. These results suggest that interferon may be beneficial for the treatment of porphyria cutanea tarda due to hepatitis C virus infection.

[Skin manifestations related to hepatitis C viruses]. / Les manifestations dermatologiques associées au virus de l'hépatite C.

The hepatitis C virus causes both hepatic and extrahepatic disorders, particularly as regards dermatology. The link between essential mixed cryoglobulinemias and the C virus infection has been clearly evidenced., whereas its frequency seems low in other systemic vasculitis such as polyarteritis nodosa. Similarly, the link between C virus hepatopathy and porphyria cutanea tarda is now proven. Lichen planus is also described as being associated with this virus, but further epidemiological studies are required to determine the exact prevalence of lichen in C virus hepatopathy cases. Finally, various cutaneous disorders, such as urticaria, erythema multiforme, dermo-hypodermitis, etc, occasionally arise during acute or chronic hepatitis C.