Unexpected distribution of hepatitis B genotypes in patients with kidney disease: comparison with immunocompetent subjects.

Hepatitis B virus (HBV) infection has a high prevalence among hemodialysis and renal transplant patients. Data regarding genotype distribution in these populations are scarce and are still under investigation. The aim of this study was to evaluate the distribution of HBV genotypes in end-stage renal disease (ESRD)-patients and renal transplant patients and to compare with the distribution observed in immunocompetent patients from the same geographic region. From a population of 213 patients evaluated initially, 120 patients with detectable HBV-DNA were included in the study and submitted to genotype determination by amplification of S gene by nested PCR followed by sequencing method. Among 41 hemodialysis patients the most frequent genotype was D (83%), followed by genotype A (10%), C (5%), and F (2%). Genotype D was also the most prevalent (73%) among 33 renal transplant patients, followed by genotype A (18%), F (6%), and B (3%). This distribution was similar in these two groups of patients and for the comparative analysis they were considered in the kidney disease group. Compared to immunocompetents, patients with kidney disease (ESRD and renal transplant patients) showed a distinct distribution, with a higher prevalence of genotype D (78% vs. 17%, P < 0.001) whereas genotype A was the most prevalent among immunocompetent patients (70% vs. 14%, P < 0.001). In conclusion, the higher frequency of genotype A in immunocompetent patients and of genotype D in patients with renal disease suggest a higher capacity of environmental transmission or a better adaptability of this genotype in patients with a different pattern of immunologic response.

Changing pattern of chronic hepatitis C in renal transplant patients over 20 years.

BACKGROUND: The prevalence and clinical epidemiological profile of hepatitis C virus (HCV) infection have changed over time. AIM: This study aimed to evaluate these changes in renal transplant recipients (RTx) comparing two different decades. MATERIALS AND METHODS: RTx with HCV referred to RTx from 1993 to 2003 (A) and from 2004 to 2014 (B) were studied retrospectively. The demographic and clinical characteristics and different outcomes were compared between groups A and B. Variables that were statistically different were tested for inclusion in a multivariate Cox proportional hazard model predicting patient survival within the group. RESULTS: Among 11 715 RTx, the prevalence of HCV was 7% in A and 4.9% in B. In the more recent period (B), the mean age was older (46.2 vs. 39.5 years), with more males (72 vs. 60.7%), larger number of deceased donors (74 vs. 55%), higher percentage of previous RTx (27 vs. 13.7%), less frequent history of blood transfusion (81 vs. 89.4%), lower prevalence of hepatitis B virus coinfection (4.7 vs. 21.4%), and higher percentage of cirrhotic patients (13 vs. 5%). Patients of group B more frequently underwent treatment of HCV (29 vs. 9%), less frequently used azathioprine (38.6 vs. 60.7%) and cyclosporine (11.8 vs. 74.7%), and more frequently used tacrolimus (91 vs. 27.3%). In the outcomes, graft loss showed no difference between periods; however, decompensation was more frequent (P = 0.007) and patients' survival was lower in the more recent period (P = 0.032) compared with the earlier one. CONCLUSION: The profile of RTx with HCV has changed over the last 20 years. Despite a decrease in the prevalence of HCV, new clinical challenges have emerged, such as more advanced age and a higher prevalence of cirrhosis.

Hepatitis C among predialysis patients: prevalence and characteristics in a large cohort of patients.

BACKGROUND: The factors associated with hepatitis C virus (HCV) infection in predialysis patients need to be better investigated. The aims of this study were to evaluate the prevalence, risk factors, clinical, biochemical and virological characteristics of chronic HCV infection in predialysis patients. METHODS: Anti-HCV antibodies were determined in a large cohort of predialysis patients. Epidemiological and laboratorial characteristics of HCV infection were evaluated in predialysis patients and this group was matched to a control group consisting of predialysis patients without viral infection (1:3) and compared in terms of risk factors and alanine aminotransferase (ALT) levels. Logistic regression analysis was applied to identify variables independently associated with chronic HCV infection. RESULTS: A total of 1,041 patients (61% males) with a mean age of 61 +/- 15 years and mean creatinine clearance of 36 +/- 18 ml/min were included. Forty-one (3.9%) patients were anti-HCV positive and, of these, 39 (95%) presented viremia. Predialysis patients with HCV more frequently showed a history of blood transfusion before 1992 (66.7 vs. 10.3%; p < 0.001) and major surgeries (53.8 vs. 17.1%; p < 0.001), a higher proportion of undetermined etiology of kidney disease (43.6 vs. 17.1%; p = 0.001), and higher ALT levels (1.3 vs. 0.4 xULN; p < 0.001). History of blood transfusion before 1992 (p < 0.001; OR: 19), intravenous drug abuse (p = 0.002; OR: 69) and ALT levels (p < 0.001; OR: 50) were the variables that were independently associated with chronic HCV infection. The accuracy of ALT in detecting HCV infection was 92%. The most prevalent HCV genotype was 1b (48.7%) and 56.5% of patients presented high HCV viral load. CONCLUSION: Chronic HCV infection among predialysis patients is related to increased parenteral exposure. Elevated ALT levels suggest the need for HCV screening as part of the predialysis care since ALT seems to be a good marker of this infection.

Hepatitis C in chronic kidney disease: predialysis patients present more severe histological liver injury than hemodialysis patients?

BACKGROUND: The characteristics of hepatitis C virus (HCV) infection in predialysis patients are poorly understood and they could be different from hemodialysis patients. AIMS: To evaluate the demographics, laboratory and histological characteristics of chronic HCV infection in predialysis patients and to compare them with those observed in hemodialysis patients. METHODS: Thirty-nine predialysis patients with chronic HCV infection were compared to HCV-infected hemodialysis patients (ratio of 1:3) in terms of demographics, laboratory and histological characteristics. The fibrosis progression rate (FPR) was calculated as the ratio between fibrosis stage and duration of infection. RESULTS: Predialysis patients were older (57 +/- 10 vs. 45 +/- 12 years; p < 0.001), presented a higher proportion of elevated alanine aminotransferase (71.8 vs. 41.0%; p = 0.001) and aspartate aminotransferase (64.1 vs. 26.5%; p < 0.001), a higher proportion of interface hepatitis (66.7 vs. 47%; p = 0.033) and more advanced fibrosis (71.8 vs. 16.2%; p = 0.001). Among patients with estimated duration of infection, predialysis patients presented a longer duration of infection (22 vs. 6 years; p < 0.001) and no difference in FPR was observed between groups (p = 0.692). CONCLUSION: Although predialysis patients with HCV infection present more severe histological injury than hemodialysis patients, this finding probably reflects a longer duration of infection with no evidence supporting that hepatitis C presents a more aggressive course in this group.

Prevalence of naturally occurring protease inhibitor resistance-associated variants in hemodialysis and renal transplant patients with hepatitis C virus infection.

Background NS3 protease inhibitors (PIs) were the first direct antiviral agents used for the treatment of hepatitis C virus. The combination of second-wave PIs with other direct antiviral agents enabled the use of interferon-free regimens for chronic kidney disease patients on dialysis and renal transplant (RTx) recipients, populations in which the use of interferon and ribavirin is limited. However, the occurrence of PI resistance-associated variants (RAVs), both baseline and induced by therapy, has resulted in the failure of many treatment strategies. Methods The aim of this study was to estimate the prevalence of PI RAVs and of the Q80K polymorphism in chronic kidney disease patients on hemodialysis and RTx recipients. Direct sequencing of the NS3 protease was performed in 67 patients (32 hemodialysis and 35 RTx).Results RAVs to PIs were detected in 18% of the patients: V55A (9%), V36L (1.5%), T54S (1.5%), S122N (1.5%), I170L (1.5%), and M175L (1.5%). Only 1.5% of the patients carried the Q80K polymorphism. The frequency of these mutations was more than two times higher in patients infected with GT1a (25%) than GT1b (9.7%) (P=0.1). The mutations were detected in 20% of treatment-naive patients and in 15.6% of peginterferon/ribavirin-experienced patients (P=0.64). Furthermore, no mutation that would confer high resistance to PIs was detected.Conclusion The Q80K polymorphism was rare in the population studied. The occurrence of RAVs was common, with predominance in GT1a. However, the variants observed were those associated with a low level of resistance to PIs, facilitating the use of these drugs in this special group of patients.

ASSOCIATION OF THE NUTRITIONAL PROFILE WITH HISTOLOGICAL FINDINGS OF PATIENTS WITH GENOTYPE 1 CHRONIC HEPATITIS C INFECTION.

BACKGROUND: Different factors are responsible for the progression of hepatic fibrosis in chronic infection with hepatitis C virus, but the role of nutritional factors in the progression of the disease is not clearly defined. This study aimed to evaluate the nutritional status and dietary profile among patients with chronic hepatitis C who were candidates for treatment and its association with histopathological features. METHODS: A crossectional study was conducted on treatment-naïve patients with chronic hepatitis C genotype 1, between 2011 and 2013. The following assessments were performed before treatment: liver biopsy, anthropometric measurements and qualitative/quantitative analysis of food intake. RESULTS: Seventy patients were studied. The majority of patients was classified as obese (34%) or overweight (20%) according to body mass index [BMI] and as at risk for cardiovascular diseases by waist circumference (79%). Unhealthy food intake was presented by 59% according to qualitative parameters and several patients showed an insufficient intake of calories (59%), excessive intake of protein (36%) and of saturated fat (63%), according to quantitative analysis. With respect to histology, 68% presented activity grade ≥2, 65% had steatosis and 25% exhibited fibrosis stage >2. Comparative analysis between anthropometric parameters and histological features showed that elevated waist circumference was the only variable associated to hepatic steatosis ( P =0.05). There was no association between qualitative and quantitative food intake parameters with histological findings. CONCLUSION: In this study, most of the patients with hepatitis C presented inadequate qualitative food intake and excessive consumption of saturated fat; in addition, excess of abdominal fat was associated to hepatic steatosis. Therefore, nutritional guidance should be implemented prior to treatment in patients with chronic hepatitis C, in order to avoid nutritional disorders and negative impact on the management of patients.

Practical Considerations of Real Life of Hepatocellular Carcinoma in a Tertiary Center of Brazil

ABSTRACT Background. Hepatocellular carcinoma (HCC) is the most common malignancy that develops in cirrhotic livers. Its clinical and epidemiological characteristics and mortality rates vary according to geographical region. The objective of this study was to evaluate the clinical profile, epidemiological characteristics, laboratory parameters, treatment and survival of patients with HCC. Material and methods. Patients with HCC seen between 2000 and 2012 were studied. The Kaplan-Meier method was used for survival analysis according to variables in question. Results. The study included 247 patients with a mean age of 60 ± 10 years. There was a predominance of males (74%). The main etiologies of HCC were HCV infection (55%), excessive alcohol consumption (12%), and HBV infection (8%). Liver cirrhosis was present in 92% of cases. The mean tumor number and diameter were 2 and 5 cm, respectively. Patients meeting the Milan criteria corresponded to 43% of the sample. Liver transplantation was performed in 22.4% of patients of the Milan subset and in 10% of the whole sample. The overall mean survival was 60 months, with a 1-, 3- and 5-year survival probability of 74%, 40% and 29%, respectively. Lower survival was observed among patients with alcoholic etiology. Survival was higher among patients submitted to liver transplantation (P < 0.001), TACE (P < 0.001), or any kind of treatment (P < 0.001). However, no difference was found for surgical resection (P = 0.1) or sorafenib (P = 0.1). Conclusion. Patients with HCC were mainly older men diagnosed at an advanced stage. Treatment was associated with better overall survival, but few patients survived to be treated.

ASSOCIATION OF THE NUTRITIONAL PROFILE WITH HISTOLOGICAL FINDINGS OF PATIENTS WITH GENOTYPE 1 CHRONIC HEPATITIS C INFECTION

Background - Different factors are responsible for the progression of hepatic fibrosis in chronic infection with hepatitis C virus, but the role of nutritional factors in the progression of the disease is not clearly defined. This study aimed to evaluate the nutritional status and dietary profile among patients with chronic hepatitis C who were candidates for treatment and its association with histopathological features. Methods - A crossectional study was conducted on treatment-naïve patients with chronic hepatitis C genotype 1, between 2011 and 2013. The following assessments were performed before treatment: liver biopsy, anthropometric measurements and qualitative/quantitative analysis of food intake. Results - Seventy patients were studied. The majority of patients was classified as obese (34%) or overweight (20%) according to body mass index [BMI] and as at risk for cardiovascular diseases by waist circumference (79%). Unhealthy food intake was presented by 59% according to qualitative parameters and several patients showed an insufficient intake of calories (59%), excessive intake of protein (36%) and of saturated fat (63%), according to quantitative analysis. With respect to histology, 68% presented activity grade ≥2, 65% had steatosis and 25% exhibited fibrosis stage >2. Comparative analysis between anthropometric parameters and histological features showed that elevated waist circumference was the only variable associated to hepatic steatosis ( P =0.05). There was no association between qualitative and quantitative food intake parameters with histological findings. Conclusion - In this study, most of the patients with hepatitis C presented inadequate qualitative food intake and excessive consumption of saturated fat; in addition, excess of abdominal fat was associated to hepatic steatosis. Therefore, nutritional guidance should be implemented prior to treatment in patients with chronic hepatitis C, in order to avoid nutritional disorders and negative impact on the management of patients.

Contexto - Diferentes fatores são responsáveis pela progressão da fibrose na infecção crônica pelo vírus da hepatite C, mas o papel dos fatores nutricionais na progressão da doença não está definido. Este estudo teve como objetivo avaliar o estado nutricional e o perfil dietético de pacientes com hepatite C crônica candidatos a tratamento e sua associação com achados histopatológicos. Métodos - Foi conduzido um estudo transversal em pacientes com hepatite C crônica genótipo 1 virgens de tratamento, entre 2011 e 2013. Foram analisados, antes do tratamento, os seguintes aspectos: biópsia hepática, medidas antropométricas e análise qualitativa e quantitativa do consumo alimentar. Resultados - Setenta pacientes foram estudados. A maioria dos pacientes apresentava obesidade (34%) ou sobrepeso (20%) de acordo com índice de massa corporal e risco para doenças cardiovasculares de acordo com a circunferência da cintura elevada (79%). Na análise qualitativa do consumo alimentar, 59% apresentavam uma dieta inadequada. Conforme análise quantitativa, 59% tinham consumo insuficiente de calorias, 36% consumo excessivo de proteínas e 63% consumo excessivo de gorduras saturadas. Com relação à histologia, 68% apresentavam grau de atividade inflamatória ≥2, 65% mostraram esteatose hepática e 25% possuíam grau de fibrose >2. Na análise comparativa entre as medidas antropométricas e achados histológicos, somente a circunferência da cintura elevada mostrou associação com esteatose hepática ( P =0,05). Não houve associação entre consumo alimentar qualitativo e quantitativo com parâmetros histológicos. Conclusão - A maioria dos pacientes apresentava consumo alimentar inadequado de acordo com parâmetros qualitativos e consumo excessivo de gordura saturada, além de excesso de gordura abdominal, que esteve associada à esteatose hepática. Portanto, aconselhamento nutricional deveria ser implementado em pacientes candidatos a tratamento para hepatite C crônica visando evitar distúrbios nutricionais que podem impactar negativamente no manejo dos pacientes.

Clinical and laboratory characteristics of acute hepatitis C in patients with end-stage renal disease on hemodialysis.

BACKGROUND: Patients with end-stage renal disease (ESRD) undergoing hemodialysis are a risk group for hepatitis C virus (HCV) infection. The characteristics of acute hepatitis C infection in this population are not well known. GOALS: To evaluate the clinical and laboratory characteristics of acute hepatitis C in ESRD patients treated with hemodialysis. STUDY: ESRD patients on hemodialysis with acute hepatitis C, characterized by elevated alanine aminotransferase (ALT) followed by anti-HCV seroconversion were studied. RESULTS: Thirty-six patients (58% females, 44+/-12 y), with a mean time on hemodialysis of 2 years, were included. Only 2 (6%) patients had jaundice. ALT elevation was observed in all patients. Median peak ALT was 4.7 x upper limit of normal. The median interval between ALT elevation and anti-HCV seroconversion was 1 month (0 to 8). None of the patients with detectable HCV-RNA showed spontaneous clearance of viremia within 12 weeks of follow-up. Three (8%) patients presented ALT elevation followed by anti-HCV seroconversion with undetectable HCV-RNA. CONCLUSIONS: Acute hepatitis C is frequently asymptomatic in ESRD patients on hemodialysis and should be suspected in all patients presenting elevated ALT. Determination of HCV-RNA is important for the confirmation of infection. Anti-HCV seroconversion seems to occur early and spontaneous clearance of HCV-RNA is uncommon.

Efficacy and tolerance of interferon-alpha in the treatment of chronic hepatitis C in end-stage renal disease patients on hemodialysis.

BACKGROUND: Patients with end-stage renal disease (ESRD) show a high prevalence of hepatitis C, with a negative impact on the survival on hemodialysis and after renal transplantation. We evaluated the efficacy and tolerance of interferon-alpha (IFN-alpha) in HCV-infected ESRD patients on dialysis. METHODS: Forty-six HCV-RNA-positive ESRD patients were studied. IFN-alpha regimen consisted of 3 million units three times a week for 12 months, and the patients were followed up for 6 months. End-of-treatment, and sustained biochemical and virological responses were evaluated and tolerance was assessed monthly. RESULTS: A sustained virological response (SVR) was observed in 10/46 patients (22%) and in 10/29 who completed the treatment (34%). Alanine aminotransferase was elevated in 63% of the patients at the beginning of the study and returned to normal levels within the first month in all patients with SVR. Treatment was discontinued because of side effects in 11/46 patients (24%) and six patients (13%) were lost to follow-up. CONCLUSIONS: IFN-alpha monotherapy for hepatitis C in dialysis patients shows a high frequency of adverse effects. However, the SVR is high (34%) in patients who complete treatment, emphasizing the importance of careful selection and close follow-up in order to minimize and control possible side effects.

Hepatitis C virus infection in renal transplant patients: a comparative study with immunocompetent patients.

The behavior of hepatitis C in states of immunodeficiency is poorly understood and it is still unclear whether the characteristics of hepatitis C virus (HCV) infection in renal transplant patients differ from those observed in immunocompetent subjects. The aim of this study was to compare the biochemical and histologic characteristics of chronic HCV infection between renal transplant and immunocompetent patients. Forty-one HCV-RNA-positive renal transplant patients and 41 immunocompetent controls matched for gender, age at infection and time of infection were included in the study. The groups were compared regarding laboratory and histologic variables. Renal transplant patients showed lower alanine aminotransferase (ALT) levels (p = 0.005) and higher levels of gamma-glutamyltransferase (p = 0.003), alkaline phosphatase (p < 0.001), and direct bilirubin (p < 0.001) when compared with controls. Histologic analysis revealed less intense portal (p < 0.001) and periportal (p = 0.046) inflammatory infiltrate in renal transplant patients but a larger proportion of cases with confluent necrosis (p = 0.043). No difference in the presence of septal fibrosis, hepatic steatosis, bile duct injury and siderosis was observed. However, there was a difference in the presence of lymphoid aggregates, which were less frequent in the renal transplant group (p < 0.001). In conclusion, the characteristics of hepatitis C in renal transplant patients differ from that observed in immunocompetent patients. In renal transplant patients, HCV infection is biochemically characterized by lower ALT levels and higher frequency of cholestasis. Regarding histology, despite lower frequency of lymphoid aggregates and less intense portal/periportal inflammatory infiltrate, a greater lobular damage was observed. The impact of these differences on the progression of fibrosis remains to be established.

Iron overload in patients with chronic hepatitis C virus infection: clinical and histological study.

BACKGROUND: Recently it has been found that iron is an important element in the natural history of hepatitis C. Serum markers of iron stores are frequently increased in chronic hepatitis C virus (HCV)-infected carriers but the real impact of the hepatic iron overload is poorly understood. The purpose of the present paper was to determine the prevalence of iron overload and to study the relationship between hepatic iron concentration (HIC) and clinical, biochemical and histological characteristics in chronic HCV-infected carriers. METHODS: Patients presenting with anti-HCV and HCV-RNA were included. Hepatic iron concentration was determined in liver tissue by atomic absorption spectrophotometry. The association between HIC and age, gender, risk factor of transmission, duration of infection, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, iron and serum ferritin, transferrin saturation, HCV-RNA level, grading of inflammatory activity, staging of fibrosis, hepatic steatosis, and stainable iron was analyzed. Statistical analysis included the Mann-Whitney test and a multiple linear regression model. RESULTS: Ninety-six patients (58% male) with a mean age of 44 +/- 10 years were studied. Serum iron, ferritin and transferrin saturation were elevated in 28%, 27% and 12.5% of patients, respectively. Stainable iron was detected in few patients (15.6%). Higher grades of stainable iron (2 and 3) were observed in only 7%. The HIC (>30 mmol/g dry weight) was elevated in five patients (5%). Neither grading nor staging were related to HIC. Higher HIC were observed in male patients (P < 0.001), in patients with elevated serum ferritin (P = 0.001) and in patients with stainable iron (grades 2 and 3; P = 0.001). Multiple linear regression analysis showed that only stainable iron was independently correlated with HIC (P = 0.003). CONCLUSIONS: Iron overload in chronically HCV-infected patients was uncommon and hepatic iron content seemed not to be related to the liver damage process. In the eventuality of iron overload, histochemical liver iron is a useful marker to estimate HIC.

Cirrose hepática / Hepatic cirrhosis

A cirrose é o estágio final da fibrose hepática avançada que resulta na perda da arquitetura normal do órgão e que tem inúmeras causas, sendo as principais hepatite B e C crônicas e alcoolismo. A formação da fibrose se dá por um remodelamento anormal da matriz extracelular em resposta à lesão crônica do fígado. A avaliação clínica dos pacientes cirróticos inclui questionamento sobre fatores de risco e um exame físico minucioso para detecção de estigmas de doença hepática crônica. O diagnóstico inclui avaliação laboratorial, métodos de imagem, endoscopia digestiva alta e biópsia hepática. As principais complicações da cirrose ocorrem em decorrência da hipertensão porta que se instala no processo evolutivo. Hemorragia varicosa, ascite, peritonite bacteriana espontânea, encefalopatia hepática, síndrome hepatorrenal e hepatocarcinoma estão entre as complicações mais temidas no ambiente cirrótico e são responsáveis por alta mortalidade. Para avaliação prognóstica, os modelos mais utilizados são os de Child-pugh e MELD. O manuseio da cirrose é complexo e requer tratamento da causa subjacente, controle e prevenção das complicações, boa nutrição, abstinência alcoólica, rastreamento do hepatocarcinoma e transplante hepático que se constitui no tratamento definitivo desta doença.