Molecular genetic association of rs8099917 and rs1800795 polymorphisms in the progression of hepatitis Delta virus liver disease

Background: The relationship between viral infections and host factors holds high hopes for identifying the role of Interferon Lambda 3 (IFNL3) and Interleukin 6 (IL-6) polymorphisms in the development of Chronic Liver Disease (CLD) in patients infected with hepatitis Delta virus (HDV) in the Western Brazilian Amazon. Methods: Cross-sectional study conducted with a cohort of 40 chronic HDV patients, 27 with CLD and 13 without evident liver damage. Biological samples from the participants were analyzed using the polymerase chain reaction (PCR) technique, followed by sequencing by the automated Sanger method. Results: The rs8099917 T allele, from the IFNL3 gene, showed a higher frequency in both groups; however, it was not possible to establish an association with HDV infection [OR = 1.42 (0.42 - 4.75; p = 0.556 (95% CI). For IL-6, the rs1800795 G allele was superior to rs1800795 C. Analyzing both distributions in the studied groups, any association with HDV was absent (p > 0.05). Conclusion: The results suggest that the rs8099917 T/G (IFNL3) and rs1800795 G/C (IL-6) polymorphisms are not associated with the evolution of HDV in the studied population.

Transplante hepático na hepatite delta: experiência da América do Sul / Liver transplantation in hepatitis delta: south america experience

ABSTRACT BACKGROUND: The Amazon region is one of the main endemic areas of hepatitis delta in the world and the only one related to the presence of genotype 3 of the delta virus. OBJECTIVE: To analyze the profile, mortality and survival of cirrhotic patients submitted to liver transplantation for chronic hepatitis delta virus and compare with those transplanted by hepatitis B virus monoinfection. METHODS: Retrospective, observational and descriptive study. From May 2002 to December 2011, 629 liver transplants were performed at the Walter Cantídio University Hospital, of which 29 patients were transplanted due to cirrhosis caused by chronic delta virus infection and 40 by hepatitis B chronic monoinfection. The variables analyzed were: age, sex, MELD score, Child-Pugh score, upper gastrointestinal bleeding and hepatocellular carcinoma occurrence before the transplantation, perioperative platelet count, mortality and survival. RESULTS: The Delta Group was younger and all came from the Brazilian Amazon Region. Group B presented a higher proportion of male patients (92.5%) compared to Group D (58.6%). The occurrence of upper gastrointestinal bleeding before transplantation, MELD score, and Child-Pugh score did not show statistical differences between groups. The occurrence of hepatocellular carcinoma and mortality were higher in the hepatitis B Group. The survival in 4 years was 95% in the Delta Group and 75% in the B Group, with a statistically significant difference (P=0.034). Patients with hepatitis delta presented more evident thrombocytopenia in the pre-transplantation and in the immediate postoperative period. CONCLUSION: The hepatitis by delta virus patients who underwent liver transplantation were predominantly male, coming from the Brazilian Amazon region and with similar liver function to the hepatitis B virus patients. They had a lower incidence of hepatocellular carcinoma, more marked perioperative thrombocytopenia levels and frequent episodes of upper gastrointestinal bleeding. Patients with hepatitis by delta virus had lower mortality and higher survival than patients with hepatitis B virus.

RESUMO CONTEXTO: A região Amazônica é uma das principais áreas endêmicas da hepatite delta no mundo e a única relacionada com a presença do genótipo 3 do vírus delta. OBJETIVO: Analisar o perfil, mortalidade e sobrevida dos pacientes cirróticos submetidos a transplante hepático por hepatite crônica pelo vírus delta e comparar com os transplantados pela monoinfecção do vírus da hepatite B. MÉTODOS: Estudo retrospectivo, observacional e descritivo. Entre maio de 2002 a dezembro de 2011, foram realizados 629 transplantes de fígado no Hospital Universitário Walter Cantídio, dos quais 29 pacientes foram transplantados por cirrose causada pela infecção crônica do vírus delta e 40 pela monoinfecção crônica da hepatite B. As variáveis analisadas foram: origem, idade, sexo, escore de MELD, classificação de Child-Pugh, ocorrência de hemorragia digestiva alta e carcinoma hepatocelular antes do transplante, número de plaquetas perioperatória, mortalidade e sobrevida. RESULTADOS: O Grupo Delta foi mais jovem e todos oriundos da região Amazônica Brasileira. O Grupo B apresentou maior proporção de pacientes do sexo masculino (92,5%) em relação ao Grupo D (58,6%). A ocorrência de hemorragia digestiva alta antes do transplante, escore de MELD e classificação de Child-Pugh não obtiveram diferenças estatísticas entre os grupos. A ocorrência de carcinoma hepatocelular e a mortalidade foram maiores no grupo com hepatite B. A sobrevida em 4 anos foi de 95% no Grupo delta e 75% no Grupo B com diferença estatisticamente significante (P=0,034). Pacientes com hepatite delta, apresentaram mais acentuada plaquetopenia no pré-transplante e no pós-operatório imediato. CONCLUSÃO: Os pacientes com hepatite por vírus delta submetidos ao transplante hepático eram predominantemente homens, vindos da região da Amazônia brasileira e com função hepática semelhante a dos pacientes com vírus da hepatite B. Apresentavam menor incidência de carcinoma hepatocelular, níveis de trombocitopenia perioperatória mais acentuados e episódios frequentes de hemorragia digestiva alta. Os pacientes com hepatite por vírus delta apresentaram menor mortalidade e maior sobrevida que os pacientes com vírus da hepatite B.

Interferon- alpha treatment of children and young adults with chronic hepatitis delta virus [HDV] infection

To determine the response of one-year interferon-alpha therapy in hepatitis delta virus [HDV] infection in children and young adults at a tertiary care hospital, Karachi, Pakistan. An observational study. Sarwar Zuberi Liver Centre [SZLC], Medical Unit IV, Civil Hospital, Karachi / Dow University of Health Sciences [DUHS], from June 2009 to July 2010. Paediatric patients [< 18 years age] and young adults [18-35 years] presenting were screened for hepatitis B virus [HBV] and HDV sero-markers. HDV anti-body positive by ELISA were further screened for hepatitis D ribonucleic acid [HDV-RNA] by real time PCR. HDV RNA PCR positive patients were treated with INF- alpha [children 6 MIU/m2/day and adults 5 MIU/day] for a period of one year. Patients were assessed monthly. Haematological parameters and ALT were monitored during treatment. Clinical progress [side effects] and negative HDV RNA were used as response criteria. Overall 49 patients were HDV RNA positive [children: n=15, mean age 15 +/- 2.92 years adults: n=34, mean age 27 +/- 4 years]. Eighty percent were male. Treatment was given to 25 patients [children: n=11, adults: n=14]. HBV genotype D was the predominant in all HDV RNA positive patients [73%]. Eighty percent [20/25] were HDV-RNA negative after one year of treatment, and remaining patients are still under treatment. Side effects were tolerated well and children continued regular activity. Haematological parameters were unremarkable. Children maintained their pre-treatment centile for height and weight [growth parameters]. ALT levels were significantly decreased post-treatment. Conventional INF- was safe in children with HDV infection in terms of side effects and growth parameters. Eighty percent were HDV-RNA negative one year after treatment. Further follow-up 2 years post-treatment will give conclusive results

Frequency of hepatitis C and D super infection in patients with hepatitis B related complex liver disorders

To determine the frequency of super infection of hepatitis C and D in patients with hepatitis B related complex liver disorders and the distribution of HBV genotypes in these patients. Descriptive study. The Gastroenterology Unit of PMRC in JPMC, Karachi, from July 2006 to June 2007. All patients registered for HBV associated infections were selected. Blood was drawn from 180 patients who fulfilled the inclusion criteria. Those with an incomplete test profile were excluded. All clinical conditions were investigated through liver function tests, coagulation profile, and findings at abdominal ultrasonography, upper gastrointestinal endoscopy and liver biopsy. Liver cirrhosis and hepatocellular carcinoma [HCC] were diagnosed either on the basis of histology, or on a combination of radiological, endoscopic and laboratory data. Hepatitis B virus DNA was extracted from serum, and subjected to a nested PCR using the type specific primers for HBV genotype. Descriptive statistics were used for frequency and mean determination. The 129 patients finally selected for statistical analysis included 108 [84%] males and 21 [16%] females. The age ranged from 6- 68 years [mean=31.5 +/- 12.39 years]. There were 70 [54.2%] patients of non-cirrhotic, chronic hepatitis [CLD], 38 [29.4%] carriers, 12 [9.3%] cirrhotics and 9 [6.9%] HCC patients. Among the 129 patients, 45 [34.9%] were positive for double infection with HDV. These included 35 CLD cases, 7 cirrhotic and 3 carriers, 4 [3.1%] patients were positive for double infection with HCV including one with CLD, 2 with cirrhosis and one with HCC. Triple infection with HBV/HDV/HCV was present in 4 [3.1%] patients who had CLD. Approximately 59% [n=76] patients were not coinfected, though 9 had developed HCC. The genotype distribution of HBV was observed as D in 98 [76%] patients, A in 24 [18.6%], and AD mix in 7 [5.4%]. Genotypes B, C, E or F were not found. Accordingly, genotype D strains were the predominant strains among all categories. The frequency of super infection of hepatitis C and D was found to be highest in HBV cirrhosis patients compared to patients having chronic liver disease [non-cirrhotics] and carriers. Genotype D of hepatitis B virus was found dominant in all hepatitis B related complex liver disorders

Treatment outcome in patients of hepatitis B with hepatitis D: experience of 4 years at a tertiary care centre in Pakistan

To determine HBV suppression in patients with dual HBV and HDV infection after 48 weeks with 10.0 MID of interferon-a 2b. Quasi experimental study. Civil Hospital, Karachi and Lyari General Hospital, Karachi, from July 2003 to June 2005. All HBsAg positive patients were screened for anti-HDV, all positives were included. Baseline investigations, liver chemistries and HBsAg; HBeAg; anti-HBcore IgM; HBV DMA quantitative PCR were done. Patients with hepatocellular carcinoma and decompensated cirrhosis were excluded. Patients were treated with Interferon-a 10.0 MID sc t.i.w. for 48 weeks. HBeAg and quantitative HBV DNA was done at week 0, 24 and 48 while CBC and SGPT were done monthly. HBV suppression was defined as levels <400 copies/ml. Fifty-two patients were selected for intervention, including 34 males and 18 females. At the end of therapy after 48 weeks, HBV DNA suppression was achieved in 51.9% and HBeAg became undetectable in 53.8% of patients. Twenty -one patients with HBV suppression still had raised SGPT. HDV should be screened in all patients eligible for HBV treatment

Diagnosis and treatment of viral liver fibrosis

This review summarized the diagnostic value of fibrosis biomarkers and the efficacy of anti-viral treatments on fibrosis progression. Non-invasive biomarkers can facilitate the screening and management of chronic hepatitis C and B. Screening for significant fibrosis is mandatory as very effective anti-viral treatments are available, permitting to stop or to reduce the fibrosis progression. The reduction of fibrosis progression will decrease the mortality due to complications of cirrhosis. In patients with chronic hepatitis C, pegylated interferons combined with ribavirin are effective in reducing fibrosis progression. In patients with chronic hepatitis B, lamivudine, adefovir and pegylated interferon are also effective in reducing fibrosis progression. In patients with chronic hepatitis Delta, pegylated interferon is also effective in reducing fibrosis progression

Parasite persistence in treated chagasic patients revealed by xenodiagnosis and polymerase chain reaction

Polymerase chain reaction (PCR) was compared with xenodiagnosis performed 20 years after trypanocidal chemotherapy to investigate parasite clearance. Eighty-five seropositive individuals for Chagas disease presenting a positive xenodiagnosis were treated with specific drugs; 37 in the acute phase and 48 in the chronic phase. Fifteen chronic assymptomatic patients received a placebo. Treatment in the acute phase led to PCR negative results in 73 percent of the cases, while xenodiagnosis was negative in 86 percent. In the chronic phase, PCR was negative in 65 percent of the patients and 83 percent led to xenodiagnosis negative results. Regarding the untreated group (placebo), 73 percent gave negative results by xenodiagnosis, of which 36 percent were positive by PCR. Individuals that were considered seronegative (n=10), presented unequivocally negative results in the PCR demonstrating the elimination of parasite DNA. Seventeen individuals had their antibodies titers decreased to such a level that the final results were considered as doubtful and 16 of them presented negative PCR. The molecular method represents a clear advantage over conventional techniques to demonstrate persistent infections in Chagas disease patients that underwent chemotherapy

Prevalence of anti-delta antibodies in central India.

A total of 238 sera samples from cases of hepatitis, renal failure, thalassaemia, healthy health care workers (HCWs) & asymptomatic HBsAG carriers coming from central India from July 1992 to June 1998, were screened for anti-delta antibodies. Among 238 subjects, 206 were reactive for hepatitis B surface antigen (HBsAg) while 32 were HBsAg non-reactive. The prevalence of anti-delta antibodies was low (1.9%) among 54 patients of acute viral hepatitis (AVH) while it was higher (5.7%) among 52 patients of chronic liver disease (CLD). The anti-delta antibodies positivity among 34 patients with hepatic failure was around 15% and all of them were FHF patients. Among multitransfused subjects such as chronic renal failure (CRF) the prevalence of anti-delta antibodies was low (2.3%). None of the apparently healthy HBsAg reactive HCWs and asymptomatic HBV carriers were reactive for anti-delta antibodies. Similarly anti-delta antibodies could not be detected in HBsAg negative viral hepatitis patients. There is a wide variation in the prevalence of anti-delta antibodies in different parts of India. However, overall prevalence of anti-delta antibodies appears to be lower in the Indian population in comparision to western countries.

La miocardiopatia chagasica: perspectiva histórica / Chagasic myocardiopathy: historical perspective

El conocimiento sobre la enfermedad de Chagas ha tenido considerables avances desde la descripción de Carlos Chagas en el año 1909. Esta enfermedad causada por el Trypanosoma cruzi y transmitida habitualmente al ser humano por insectos hematófagos (triatomideos), afecta a unos 18 millones de personas y se estima que alrededor de 100 millones están expuestos a contraerla. El riesgo de adquirir la enfermedad está directamente relacionado a factores económico-sociales y culturales. En la historia natural de la enfermedad se pueden reconecer tres períodos perfectamente definidos: el período agudo que aparece inmediatamente después de la infección inicial (en general en niños de zonas endémicas), que es clínicamente manifesto en un nuy bajo porcetaje (5 a 10 por ciento) con síntomas inespecíficos (fiebre, dolores articulares, quebrantamiento general, adenopatias, esplenomegalia, dermatopatías) o más específicos como el complejo oftalmoganglionar. Las manifestaciones cardíacas del período agudo son las de una miocarditis no severa y reversible en la mayoría de los casos. Excepcionalmente, se observa miocarditis aguda grave y mortal por insuficiencia cardíaca, tromboembolismo o arritmias. Al estadío agudo le sigue un período de 10 a 20 años denominado período indeterminado en el cual no existe evidencia clínica alguna de la enfermedad (en el 100 por ciento de los casos) salvo la serología positiva. Durante el período indeterminado la prueba de ajmalina y la biopsia endomiocárdica son los métodos de diagnóstico que permitirían "detectar" con mayor precocidad a aquellos pacientes candidatos a padecer una miocardiopatía. Después de este período, un 20 a 30 por ciento de los casos desarrolla signos y síntomas de una miocardiopatía dilatada que evoluciona lentamente (10 a 20 años) a formas de severidad variable caracterizadas, en las etapas más avanzadas, por la presencia de insuficiencia cardíaca global, tromboembolismo y arritmias. La muerte súbita es frecuentes y a veces ocurre en estadíos no demasiado avanzados de la miocarditis. El cuadro anátomopatológico corresponde al de una panmiocarditis microfocal diseminada. Se observa por lo general agrandamiento global del corazón con la particularidad de encontrar aneurismas apicales en un alto porcentaje (40-50 por ciento) con trombos intracavitarios. El compromiso de otras vísceras (megaesófago y megacolon) es más frecuente en el Brasil.

Genomic and phylogenetic analysis of hapatitis C virus strains from Argentina

HCV genomic characterization was performed by nucleotide sequence analysis (n=50) combined with restriction fragment length polymorphism (RFLP) of the 5'UTR region in 82 isolates coresponding to different Argentine groups. Genotype 1 was detected in 70.7 percent of the samples (58 out of 82), genotype 2 in 21.9 percent (18 of 82) and genotypes 3 in the remaining 6 sera (7.3 percent). HCV ib subtype contributed with 35.3 percent to the whole population studied (29 of 82) and was detected in 6 out of 21 sporadic cases. Besides their epidemiological significance, these results should be taken into account when future vaccines are considered on the basis of geographical HCV genotypic prevalence.

Hepatitis crónica viral: diagnóstico, evolución y tratamiento / Cronic viral hepatitis: diagnosis, natural history and treatment

La infección crónica por los virus de la hepatitis B, C y D puede prvocar un proceso necro-inflamatorio hepático persistente y progresivo. La hepatitis crónica viral constituye una de las primeras causas de enfermedad hepática avanzada a nivel mundial. Por lo general asintomátivca, solo se hace clínicamente aparente cuando ya existe cirrosis o sus complicaciones. Se sospecha frecuentemente al detectarse elevación de las transaminasas. La evolucíon es muy variable pero un grupo significativo de pacientes progresan hacia cirrosis y hepatocarcinoma, generalmente en cuestión de décadas. El diagnóstico se basa fundamentalmente en el laboratorio en especial en los marcadores virales, pudiendo ser útiles los hallazgos de la biopsia. El tratamiento aceptado es con interferón que inhibe la replicación viral y reduce la lesión hepática, sin embargo, esto solo sucede en un subgrupo de enfermos, siendo frecuentes las recaídas especialmente en las infecciones provocadas por el virus C. Se están investigando nuevas modalidades terapéuticas entre las cuales destaca el uso de antivirales como los nucleósidos análogos utilizados por lo general combinados con interferón

Chronic viral hepatitis.

Among hepatitis A to E viruses, hepatitis B, C, and D viruses can cause chronic hepatitis, in both children and adults. Hepatitis B virus (HBV) infection is the most prevalent and important one. Perinatal transmission accounts for about 40-45% of chronic HBV infection in hyperendemic areas. Horizontal transmission through intramuscular injection using non-sterile needles and intrafamilial spread accounts for the other half of carriers. During the natural course of HBV infection, the host gradually clears HBV and hepatitis B e antigen (HBeAg), liver damage and elevation of aminotransferases occur during the process of HBV clearance. The most effective way to eliminate HBV infection is immunoprophylaxis starting since birth. It can prevent both HBV and hepatitis D virus (HDV) infections. Hepatitis C virus (HCV) infection in children occurs mainly in high risk children, such as those who received blood product or injection using non-sterile needles, or infants of HCV viremic mothers, etc. Screening of blood product reduced markedly the prevalence of post-transfusion HCV infection, but the prevention of sporadic cases requires HCV vaccination which is still under investigation.

HDV prevalence and its relation to the pattern of hepatitis B virus in transfused patients

This study was designed in order to assess the prevalence of HDV and its relation to B virus markers among blood recipients and to attempt to determine different risk factors. Our work was conducted in blood recipients of Mansoura University Hospital; they comprise 353 patients with history of blood transfusion. Thirty fine females with age ranged from 19 to 65 years [mean 34.9 years], and 314 males with age ranged from 13 to 73 years [mean 41.6 years]. Besides, 150 volunteer blood donors [controls] were randomly selected from blood bank, 93 males with age ranged from 14 to 57 years [mean 26.84] and 57 females with age ranged from 18 to 48 years [mean 26.6 years]. Hepatitis D Virus. Anti-HDV is significantly prevalent among HBsAg blood recipients [8 1.8%] as compared to controls [10%]. Significant increase in prevalence of anti-HDV [94.1%] were found among recipients with common use of glass syringes and history of jaundice. The majority of HDV infection [96.3%] was due to superinfection rather than coinfection. Combined HBV and HDV infection aggravated the course of the disease as evidenced from liver function tests even in the presence of anti HBe [a marker of good prognosis]. Study of different profiles of HBV can serve as useful guides to monitor infection or recovery, state of infectivity and prognostic significance. As a large number of blood recipients are capable of transmitting HBV [30.7%], all newly admitted patients to hospital should have tested to HBV markers [namely HBsAg, anti-HBs and anti-HBs], so adequate steps can be taken to protect their contacts from infection. The high prevalence of anti-HDV among both blood donors and recipients is an indication that our locality is hyperendemic for HDV and I.V. injection is an important route of delta transmission among HBV carriers. HDV infection is a characteristic feature of patients with frequent history of jaundice which could represent the clinical expression of superinfection with delta agent in silent HBsAg carriers. Delta infection may cause severe illness despite serological markers of inactive HBV infection due to the cumulative effect of both viruses on the liver. So anti-HDV assay should be added to the battery of tests used to evaluate hepatitis patients

Hepatitis fulminante en la Sierra Nevada: una forma de superinfección del virus delta con el virus de la hepatitis B / Fulminant hepatitis in La Sierra Nevada: a type of Delta superinfection with hepatitis B virus

Durante septiembre de 1980 a octubre de 1983, se realizó un estudio seroepidemiológico para hepatitis A y B, en 258 personas en una ciudad (Santa Marta) población de 250.000 y tres pequeños municipios (Santa Rosalía, Julio Zawady y Aracataca), poblaciones de 768.800 y 5.000 habitantes respectivamente. La presencia de hepatitis A se encontró en un 77 a 93 por ciento (IgG Hepatitis A). Hbs Ag o Anti-Hbs Ag en 30.5 por ciento de la población en dos municipios (Santa Rosalía y Julio Zawady), en 2,5 por ciento en el municipio de Aracataca y 48.5 por ciento en la ciudad de Santa Marta. La presencia del agente Delta (Anti-Delta en el suero) se determinó también en estas mismas poblaciones, encontrándose ausente en la ciudad y uno de los municipios (Aracataca), en contraste con una prevalencia de 13,7 por ciento y 22 por ciento en Julio Zawady y Santa Rosalía (P:0.0001). Se escluyeron por historia clínica, antecedentes de drogadicción, transfusiones, o prácticas homosexuales, como mecanismos de transmisión de los virus B y delta. En veinte pacientes con diagnóstico histopatológico de hepatitis fulminante y en quienes se descartaron otras etiologías se demostró la presencia serológica de los virus de la hepatitis B y Delta. De estos veinte, diez provenían de Julio Zawady y los otros diez de Santa Rosalía. La evolución clínica de esta enfermedad fue indistinguible de otras causas de falla hepática aguda. La mortalidad de estas formas fulminantes de hepatitis alcanzaron hasta un 65 por ciento. Los corticoides no modificaron el curso de esta enfermedad. La población joven mostró mayor compromiso y peor diagnóstico (P: 0.033). La hepatitis fulminante de la Sierra Nevada de Santa Marta es el resultado de la superinfección con el virus Delta sobre la infección virus B. La aparición simultánea de casos intrafamiliares sugiere una relación importante entre los grupos comprometidos, aunque la forma exacta de transmisión permanece aún desconocida