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.

The effect of sustained virological response on the risk of extrahepatic manifestations of hepatitis C virus infection.

BACKGROUND AND AIM: Chronic HCV infection is associated with several extrahepatic manifestations (EHMs). Data on the effect of sustained virological response (SVR) on the risk of EHMs are limited. METHODS: We conducted a retrospective cohort study using data of patients from the US Veterans Affairs HCV Clinical Case Registry who had a positive HCV RNA test (10/1999-08/2009). Patients receiving interferon-based antiviral therapy (AVT) were identified. SVR was defined as negative HCV RNA at least 12 weeks after end of AVT. Risks of eight incident EHMs were evaluated in Cox regression models. RESULTS: Of the 160 875 HCV-infected veterans, 31 143 (19.4%) received AVT, of whom 10 575 (33.9%) experienced SVR. EHM risk was reduced in the SVR group compared with untreated patients for mixed cryoglobulinaemia (adjusted HR (aHR)=0.61; 95% CI 0.39 to 0.94), glomerulonephritis (aHR=0.62; 95% CI 0.48 to 0.79), porphyria cutanea tarda (PCT) (aHR=0.41; 95% CI 0.20 to 0.83), non-Hodgkin's lymphoma (NHL) (aHR=0.64; 95% CI 0.43 to 0.95), diabetes (aHR=0.82; 95% CI 0.76 to 0.88) and stroke (aHR=0.84; 95% CI 0.74 to 0.94), but not for lichen planus (aHR=1.11; 95% CI 0.78 to 1.56) or coronary heart disease (aHR=1.12; 95% CI 0.81 to 1.56). Risk reductions were also observed when patients with SVR were compared with treated patients without SVR for mixed cryoglobulinaemia, glomerulonephritis, PCT and diabetes. Significant reductions in the magnitude of aHRs towards the null with increasing time to initiation of AVT after HCV diagnosis were observed for glomerulonephritis, NHL and stroke. CONCLUSIONS: Risks of several EHMs of HCV infection are reduced after AVT with SVR. However, early initiation of AVT may be required to reduce the risk of glomerulonephritis, NHL and stroke.

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.

[Porphyria cutanea tara]. / Porphyria cutanea tarda.

Porphyria cutanea tara (PCT) has a prevelance of about 40 new diagnoses per 1 million people per year and is the most frequently occurring type of porphyria worldwide. Inhibition of the uroporphyrinogen decarboxylase (UROD) is the main cause of the disease, which can be the result of a heterozygous or homozygous mutation of the UROD gene; however, xenobiotics or other diseases may play an important role for the precipitation of the disease. Risk factors include alcohol, estrogen, iron overload, and hemochromatosis, hepatitis C or poisoning, e.g., with polyhalogenated aromatic compounds such as hexachlorobenzene. Signs and symptoms are blisters, skin fragility, erosions hyperpigmentation, sclerodermoid plaques. Therapy includes sun protection, prevention of risk factors, phlebotomy, and chloroquine.

Porphyrias in Norway.

BACKGROUND: Porphyria is an umbrella term for a group of largely hereditary diseases that are due to defective haem synthesis. The diseases have a varied and partly overlapping range of symptoms and presentations. The commonest forms of porphyria are porphyria cutanea tarda, acute intermittent porphyria and erythropoietic protoporphyria. The purpose of this study is to provide an overview of the prevalence and pathological manifestations of porphyrias in Norway. MATERIAL AND METHOD: Information on all patients registered with the Norwegian Porphyria Centre (NAPOS) up to 2012 was used to estimate the prevalence and incidence of porphyrias in Norway. Figures on symptoms, precipitating factors and follow-up routines were obtained from the Norwegian Porphyria Registry, which includes 70% of Norwegians registered with NAPOS as having porphyria. RESULTS: The prevalence of porphyria cutanea tarda was approximately 10 : 100,000 and that of acute intermittent porphyria approximately 4 : 100,000. The total incidence of all porphyrias was approximately 0.5-1 : 100,000 per year. Diagnostic delay, i.e. the time passing between the onset of symptoms and diagnosis, varied from 1-17 years depending on the type of porphyria. There was wide variation in the frequency with which patients with the various types of porphyria went for medical check-ups. INTERPRETATION: The prevalence of acute intermittent porphyria and porphyria cutanea tarda appears to be higher in Norway than in most other countries. Data from the Norwegian Porphyria Registry makes it possible to demonstrate differences in treatment and follow-up of porphyria patients and may be used to initiate necessary measures.

Familial and sporadic porphyria cutanea tarda: characterization and diagnostic strategies.

BACKGROUND: Porphyria cutanea tarda (PCT) occurs in sporadic (sPCT) and familial (fPCT) forms, which are generally clinically indistinguishable and have traditionally been differentiated by erythrocyte uroporphyrinogen decarboxylase (UROD, EC 4.1.1.37) activity. We used UROD gene sequencing as the reference standard in assessing the diagnostic accuracy of UROD activity, evaluating the mutation spectrum of the UROD gene, determining the frequency and disease attributes of PCT and its subtypes in Norway, and developing diagnostic models that use clinical and laboratory characteristics for differentiating fPCT and sPCT. METHODS: All consecutive patients with PCT diagnosed within a 6-year period were used for incidence calculations. UROD activity analysis, UROD gene sequencing, analysis of hemochromatosis mutations, and registration of clinical and laboratory data were carried out for 253 patients. RESULTS: Fifty-three percent of the patients had disease-relevant mutations, 74% of which were c.578G>C or c.636+1G>C. The UROD activity at the optimal cutoff had a likelihood ratio (LR) of 9.2 for fPCT, whereas a positive family history had an LR of 19. A logistic regression model indicated that low UROD activity, a high uroporphyrin-heptaporphyrin ratio, a young age at diagnosis, male sex, and low alcohol consumption were predictors of fPCT. The incidence of PCT was 1 in 100 000. CONCLUSIONS: Two commonly occurring mutations are responsible for the high frequency of fPCT in Norway. UROD activity has a high diagnostic accuracy for differentiating the 2 PCT types, and a model that takes into account both clinical information and laboratory test results can be used to predict fPCT.

Experience in management of porphyria cutanea tarda in a tertiary referral Brazilian hospital from 2002 to 2017.

BACKGROUND: Porphyria cutanea tarda (PCT) is the most common porphyria worldwide. The known acquired precipitating factors that induce PCT include alcoholism, hepatitis C virus infection, human immunodeficiency virus infection, and estrogen intake. Hereditary hemochromatosis is considered an inherited risk factor. The aim of this study was to describe and analyze precipitating factors and family history, with emphasis on PCT management. METHODS: A retrospective study of 87 patients with PCT was conducted between January 2002 and December 2017. RESULTS: A male predominance of 1.8 : 1 was found. The median age at diagnosis was 49 years (range 18-71). Family history of PCT was observed in 19.5% of patients. Two or more acquired precipitating factors were present in 42.5%. Patients were treated with antimalarial monotherapy (72.4%), antimalarial combined with phlebotomy (22.9%), and only with phlebotomy (4.6%). Acquired precipitating factors and inherited factors were not associated with treatment group. There was a difference in 24 h-UP normalization rate between treatment groups; combined therapy takes longer than antimalarial monotherapy, 38 months versus 15 months, respectively (CI 95%, 6.5-63.5 vs. 12.9-17) (log-rank test, P = 0.004). CONCLUSION: Precipitating factors did not seem to be associated with treatment choice; however, all acquired and inherited precipitating factors should be investigated, and the choice between phlebotomy and/or antimalarials should be individualized. All dermatologists treating PCT patients should observe transferrin saturation and ferritin levels to search for underlying hereditary hemochromatosis.

[The combination of carbohydrate and porphyrinic exchange disturbances: is it a chance or regularity?].

The subjects of the study were 399 patients with internal diseases and metabolic disturbances. Carbohydrate exchange parameters (fasting level of capillary blood glucose and glucose tolerance test), and porphyrin fractions in urine (uroporphyrin, coproporphyrin), and feces (protoporphyrin, coproporphyrin) were measured. Hepatic type of porphyrinic dysmetabolism was registered in 201 (50.4%) patients. Out of these patients, 38 had disturbances corresponding to the criteria of symptomatic elevation of fecal porphyrin level, 28 had secondary coproporphyrinuria, 40 had latent, and 95 had manifest late cutaneous porphyria. In patients with normal porphyrinic exchange, the frequency of carbohydrate exchange disturbances did not exceed 6%, while in patients with different variants of porphyrinic dysmetabolism it was almost 40%. The results show that patients with hepatic type of porphyrinic dysmetabolism should be considered to have a higher risk of the development of diabetes mellitus and other carbohydrate disorders.

The role of inherited and acquired factors in the development of porphyria cutanea tarda in the Argentinean population.

BACKGROUND: Inherited and environmental factors are implicated in the expression of porphyria cutanea tarda (PCT); the contribution of each factor depends on the population. OBJECTIVE: To provide a review of PCT cases diagnosed in Argentina over 24 years and evaluate the role of different precipitating factors in its pathogenesis. Methods Plasma and urinary porphyrin levels and erythrocyte uroporphyrinogen decarboxylase (URO-D) activity were determined. Potential precipitating factors were identified in each patient. Additional tests for hepatitis C virus (HCV) and hemochromatosis gene mutations were carried out. RESULTS: Several factors (mainly alcohol abuse in men and estrogen ingestion in women), alone or combined were identified in our patients. Prevalence of HCV infection was 35.2%. Inherited URO-D deficiency occurs in 25.0% of cases. H63D was the most common hemochromatosis gene mutation. High incidence of PCT associated with HIV infection was found. CONCLUSIONS: PCT is multifactorial. Therefore, knowledge of all risk factors in each patient is important for the management of the disease.

Lack of association between porphyria cutanea tarda and alpha 1-antitrypsin deficiency.

OBJECTIVE: To determine whether alpha 1-antitrypsin deficiency is involved in the pathogenesis of chronic liver disease in patients with porphyria cutanea tarda and in their recently described high prevalence of hepatitis C virus infection. DESIGN: Consecutive patients diagnosed as having porphyria cutanea tarda and chronic liver disease. SETTING: A northern Italian hospital. METHODS: alpha 1-antitrypsin phenotypes were characterized by isoelectric focusing and the results confirmed by DNA analysis in 63 Italian patients with porphyria cutanea tarda. RESULTS: alpha 1-antitrypsin phenotypes different from the normal one were found in 13% of the patients. This prevalence did not differ from that in control subjects (9%). Clinical characteristics of patients with porphyria cutanea tarda with normal or altered alpha 1-antitrypsin phenotype, including age of presentation of the disease, prevalence of hepatitis C virus infection, liver histology, prevalence of iron overload and hepatocellular carcinoma occurrence, did not differ significantly. CONCLUSION: alpha 1-antitrypsin does not seem to play a role in the pathogenesis of chronic liver disease and hepatitis C virus infection in patients with porphyria cutanea tarda. Patients in whom the two defects coexist do not have a more severe disease.

Incidence of hereditary porphyria cutanea tarda (PCT) in a sample of the Italian population.

The determination of the enzymatic activity of URO-D in erythrocytes is the screening method used for differentiation between hereditary and non-hereditary forms of porphyria cutanea tarda (PCT). The aim of the present work was to establish the relative frequencies of the symptomatic and hereditary forms by the determination of the URO-D enzyme in the PCT patients who were regularly treated at the Centre for Porphyrins in our Institute. In the course of this work we also examined the statistical properties of the distributions of both normal and porphyric subjects, so as to be able to suggest values for discriminating between normal subjects and the various types of porphyric subjects.

Overt and hidden coinfection with hepatitis B and C viruses in chronic liver disease and porphyria cutanea tarda.

The aim of this study was to assess the rate of hepatitis B virus (HBV) and hepatitis C virus (HCV) coinfection ("the coinfection") in chronic liver disease (CLD) and to reveal overt and hidden HBV infection in patients with antibodies to HCV (anti-HCV). A total of 209 untreated patients (64 with chronic hepatitis B, 79 with chronic hepatitis C and 66 with porphyria cutanea tarda (PCT)) were screened for serological markers of HBV and HCV infection in serum by third generation enzyme-linked immunosorbent assay (ELISA) methods and for HBV DNA and HCV RNA in serum by polymerase chain reaction (PCR). The rate of the overt coinfection in chronic hepatitis B was very low (2/64, 3%). However, in chronic hepatitis C, the rate of the hidden coinfection with HBV was relatively high (19/79, 24%); these patients had higher alanine transaminase (ALT) and asparagine transaminase (AST) levels in serum and a more advanced liver disease. In PCT patients, the rates of HBV and HCV infections were the same, 21% (14/66). In the PCT patients infected with HBV or HCV, the rate of the coinfection was 33% (7/21). The PCT patients with the coinfection had a high serum ALT level and the worst histological picture in the liver. The hidden HBV infection was more frequent than the overt one. The possibility of the overt or hidden coinfection in CLD renders a detailed analysis of all serum samples for both viruses mandatory. Vaccination against HBV infection should be offered to anti-HCV-positive individuals as well as to PCT patients not showing antibodies to HBV (anti-HBV).

Health effects of chronic high exposure to hexachlorobenzene in a general population sample.

Hexachlorobenzene, an organochlorine compound that accumulates in humans, is widespread throughout the environment. In this study, we describe the health status of inhabitants of a rural village that surrounds an electrochemical factory characterized by high levels of hexachlorobenzene in the air. During 1994, we conducted a cross-sectional study of 1 800 inhabitants in the south of Catalonia, Spain, who were older than 14 y of age. We obtained information on lifestyles and occupational and medical histories via questionnaire. Self-reported health outcomes were validated against clinical records and cancer registry data. Serum levels of hexachlorobenzene were very high in males who worked in the electrochemical factory (geometric mean = 54.6 ng/ml in randomized participants). Levels were lower among subjects who had never worked in the electrochemical factory (females, 14.9 ng/ml; males, 9.0 ng/ml). Levels of other organochlorine compounds (i.e., beta-hexachlorocy-clohexane, 2,2-bis[p-chlorophenyl]-1,1-dichloroethylene) were in the same range found in other communities. Perceived health, prevalence of self-reported common chronic conditions, and porphyria cutanea tarda, thyroid pathology, Parkinson's disease, cancer, and reproductive outcomes were within the ranges observed in other studies. Employment in the plant, however, was associated with having any of the a priori selected health outcomes that were potentially related to exposure to hexachlorobenzene (odds ratio for cancer prevalence = 1.9; 95% confidence interval = 0.5, 7.6). Our population of workers and nonworkers had the highest levels of hexachlorobenzene ever described. The results suggest that exposure to hexachlorobenzene did not affect the general health status of the this population, but it was associated with specific health effects of the most highly exposed subjects.

[Prevalence of porphyria cutanea tarda in Madrid and relationship between urine porphyrin and ethanol intake in a multiple linear regression model]. / Prevalencia de porfiria cutánea tarda en Madrid y asociación entre la porfirinuria y el consumo de etanol en un modelo de regresión lineal múltiple.

BACKGROUND: The application of a simple fluorometric analytical method enabled us to quantify the urinary porphyrin excretion and to establish the prevalence of porphyria cutanea tarda (PCT) in the town of Madrid, Spain, in a cross-sectional study. PATIENTS AND METHODS: The study assessed 1,613 subjects from three districts in Madrid, in whom further variables potentially related to porphyrinuria such as ethanol intake or -in women-oral contraceptive use were measured and recorded. RESULTS: The estimated prevalence of the disease was 1.24 cases per 1,000 inhabitants (95% confidence interval 0.15-4.47 per thousand). After excluding from the study sample all cases with existent disease, an analysis was performed to ascertain an unilateral tolerance interval for urinary porphyrin concentration in the adult population; this level was established at 181.2 micrograms/l. The effect of ethanol intake on porphyrinuria was considered significant using a multiple linear regression model adjusted for the control variables gender, age and body mass index. In fertile women, contraceptive use did not attain statistical significance when that variable was included in a multiple regression model. CONCLUSIONS: A high prevalence has been estimated for PCT in the Madrid population. A significant association was further found between alcohol intake and porphyrinuria in non-porphyric adults.

[Porphyria cutanea tarda and hepatitis C virus infection. Clinical and virological study]. / Porphyrie cutanée tardive et infection par le virus de l'hépatite C. Etude clinique et virologique.

INTRODUCTION: The role of hepatitis C virus (HCV) infection in porphyria cutanea tarda (PCT) is probable since the global antibody prevalence among PCT patients is about 70 p. 100. The purpose of this study was to evaluate the virological characteristics in 12 patients with sporadic PCT and one with familial PCT. METHODS: Anti-HCV antibodies were detected by enzyme-linked immunosorbent assay and confirmed by recombinant immunoblot assay. Hepatitis B virus (HBV) and anti-human immunodeficiency virus (HIV) markers were also determined. The polymerase chain reaction (PCR) was performed in order to detect: 1) both positive and minus HCV 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 of onset of PCT was significantly lower in HCV positive patients than in HCV negative patients (p < 0.02). The HCV RNA was detected in all patients who had HCV antibodies, and the replicative intermediate of HCV was detected in 3 of them. The positive RNA titer ranged from 1/10 to 1/10(6). Four patients were infected by HCV genotype I, 2 by genotype II and 1 patient was coinfected by type I and type II. Three of the 7 HCV positive patients also had HBV antibodies, but HBV DNA was never detected. All patients were HIV negative. DISCUSSION: The HCV infection rate was high in this series (58 p. 100), and all HCV infected patients had HCV RNA, reflecting an active replication of the virus. The young age of onset of PCT suggests that HCV is a major triggering factor of PCT. Nevertheless, the clinical changes of PCT were not related to the virological findings, suggesting an indirect role of HCV.

[Role of the hemochromatosis gene in prophyria cutanea tarda. Prospective study of 56 cases]. / Rôle du gène de l'hémochromatose (HFE) dans la porphyrie cutanée tardive. Etude prospective de 56 cas.

BACKGROUND: The cause of iron overload in prophyria cutanea tada is unknown. The aim of this work was to determine the frequency of the hemochromatosis gene (HFE) in 56 patients with porphyria cutanea tarda. We analyzed the relationship between HFE mutations and biochemical abnormalities in porphyria cutanea tarda and the interaction with other triggering factors of porphyria cutanea tarda (alcohol abuse, hepatitis C, drugs). PATIENTS AND METHODS: Hepatitis C, alcohol abuse, drug intake and HFE mutations were determined in 56 patients with porphyria cutanea tarda (44 men and 12 women). Iron status was determined from transferrin saturation, serum iron, and serum ferritin. Liver metabolism was determined from liver chemistries: alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transpeptidase. RESULTS: Thirty-nine patients (69.4 p. 100) carried HFE mutations, 18 (32.1 p. 100) were H63D heterozygous, 4 (7.1 p. 100) were H63D homozygous, 9 (16 p. 100) C282Y heterozygous, 8 (14.2 p. 100) compound C282Y/H63D heterozygous and none were C282Y homozygous. Comparison between porphyria cutanea tarda with and without mutations showed that compound C282Y/H63D heterozygous status was significantly linked to iron overload: transferrin saturation=0.61 vs 0.39 (p=0.0001) and serum iron=32.9 vs 22.4 (p=0.0046). H63D homozygous status was linked to iron overload but non-significantly: transferrin sturatin=0.53 vs 0.39 (p=0.06). The class with high iron overload (transferrin saturation > 0.45) was not linked with triggering factors of porphyria cutanea tarda. Hepatatic cytolysis was linked to alcohol abuse and hepatitis C but not to HFE mutations. DISCUSSION: The frequencies of HFE mutations in Lyons France are halfway between Anglo-Saxon and Italian papers, highlighting the Celtic origin of C282Y mutation. Compound heterozygous and to a lesser degree H63D homozygous status explained the highest iron overload in our patients. This favors clinical expression of porphyria cutanea tarda. This iron overload due to HFE mutations is a new triggering factor of porphyria cutanea tarda independent of classical triggering factors: mutation of the erythrocytic uroporpyrinogen decarbocylase gene, alcohol abuse, hepatitis C, and drugs.

Cutaneous porphyrias part I: epidemiology, pathogenesis, presentation, diagnosis, and histopathology.

The porphyrias are a group of disorders characterized by defects in the heme biosynthesis pathway. Many present with skin findings including photosensitivity, bullae, hypertrichosis, and scarring. Systemic symptoms may include abdominal pain, neuropsychiatric changes, anemia, and liver disease. With advances in DNA analysis, researchers are discovering the underlying genetic causes of the porphyrias, enabling family members to be tested for genetic mutations. Here we present a comprehensive review of porphyria focusing on those with cutaneous manifestations. In Part I, we have included the epidemiology, pathogenesis, presentation, diagnosis, and histopathology. Treatment and management options will be discussed in Part II.