Autonomic dysfunction is common in liver cirrhosis and is associated with cardiac dysfunction and mortality: prospective observational study

ABSTRACT BACKGROUND: Although autonomic dysfunction has been shown to be associated with liver cirrhosis, the prevalence and prognostic implications are unclear. Abnormal heart rate variability (HRV), a measure of autonomic function, has not been well investigated in cirrhosis. OBJECTIVE: To evaluate the prevalence of high-risk HRV parameters in a cohort of cirrhotic patients and their association with cardiac dysfunction and mortality. DESIGN AND SETTING: Prospective observational study conducted in the Federal University of São Paulo. METHOD: A cohort of 120 patients, comprising 17 healthy controls and 103 cirrhotic outpatients, was evaluated and followed for 10 months. HRV analysis was based on 24-hour Holter monitoring and defined using time-domain and frequency-domain parameters. RESULTS: The HRV parameters were statistically lower in cirrhotic patients than in healthy subjects. High-risk HRV parameters were prevalent, such that 64% had at least one high-risk parameter. Time-domain parameters correlated with Child scores (P < 0.0001). In regression models, HRV parameters were independent predictors of diastolic dysfunction and mortality. During 10 months of follow-up, there were 11 deaths, all of patients with at least one high-risk HRV parameter. Kaplan-Meier analysis estimated low survival rates among patients with standard deviation of normal-to-normal RR intervals (SDNN) < 100. CONCLUSION: Reduced HRV is prevalent in liver cirrhosis and is related to cardiac dysfunction, severity of liver disease and mortality. Abnormal high-risk HRV parameters are prevalent among cirrhotic patients and are also predictors of mortality. Our findings highlight the need for a more careful cardiac evaluation of cirrhotic patients.

Autonomic dysfunction is common in liver cirrhosis and is associated with cardiac dysfunction and mortality: prospective observational study.

BACKGROUND: Although autonomic dysfunction has been shown to be associated with liver cirrhosis, the prevalence and prognostic implications are unclear. Abnormal heart rate variability (HRV), a measure of autonomic function, has not been well investigated in cirrhosis. OBJECTIVE: To evaluate the prevalence of high-risk HRV parameters in a cohort of cirrhotic patients and their association with cardiac dysfunction and mortality. DESIGN AND SETTING: Prospective observational study conducted in the Federal University of São Paulo. METHOD: A cohort of 120 patients, comprising 17 healthy controls and 103 cirrhotic outpatients, was evaluated and followed for 10 months. HRV analysis was based on 24-hour Holter monitoring and defined using time-domain and frequency-domain parameters. RESULTS: The HRV parameters were statistically lower in cirrhotic patients than in healthy subjects. High-risk HRV parameters were prevalent, such that 64% had at least one high-risk parameter. Time-domain parameters correlated with Child scores (P < 0.0001). In regression models, HRV parameters were independent predictors of diastolic dysfunction and mortality. During 10 months of follow-up, there were 11 deaths, all of patients with at least one high-risk HRV parameter. Kaplan-Meier analysis estimated low survival rates among patients with standard deviation of normal-to-normal RR intervals (SDNN) < 100. CONCLUSION: Reduced HRV is prevalent in liver cirrhosis and is related to cardiac dysfunction, severity of liver disease and mortality. Abnormal high-risk HRV parameters are prevalent among cirrhotic patients and are also predictors of mortality. Our findings highlight the need for a more careful cardiac evaluation of cirrhotic patients.

Iron Overload in Renal Transplant Patients: The Role of Hepcidin and Erythropoietin.

Renal transplant patients may present important serum iron overload (IO), which can persist for long periods after transplantation, but its mechanisms are not fully understood. We raised the hypothesis that post-transplant hypererythropoietinemia might induce reduction in serum hepcidin, favoring iron absorption. The aims of this study were to determine the prevalence of IO and associated factors in transplant patients and to evaluate erythropoietin and hepcidin levels in patients with and without IO. A total of 168 patients were included, with a median time of dialysis and transplantation of 28 and 65 months, respectively. Most patients (85%) received large amounts of parenteral iron (3600 mg iron) during the dialysis period. Median ferritin was 427 ng/mL, and transferrin saturation was 33%. IO was present in 26 patients (15%). A comparison of patients with and without IO showed a predominance of male and nonwhite patients in the former group (P < .001 and .002, respectively). The total amount of iron used before transplantation and hemoglobin levels were higher in the group with IO (P = .023 and .046, respectively). Hepcidin was higher in the group with IO (P < .0001), whereas erythropoietin did not differ between groups. There was no correlation between serum levels of hepcidin and erythropoietin (r = -0.001). In conclusion, factors associated with IO were male sex, higher hemoglobin levels, and the amount of iron received before transplantation. IO was not the result of reduction in hepcidin secondary to hypererythropoietinemia. The elevated levels of serum hepcidin were possibly secondary to IO, mediated by mechanisms that are independent of the hepcidin-erythropoietin axis.

Prevalence of resistance-associated substitutions to direct-acting antiviral agents in hemodialysis and renal transplant patients infected with hepatitis C virus.

BACKGROUND: Direct-acting antiviral agents (DAAs) permit the use of interferon (IFN)-free regimens to treat hepatitis C (HCV) in patients with chronic kidney disease (CKD) on hemo-dialysis (HD) or renal transplant (RTx) recipients, with excellent response rates and safety. However, the occurrence of basal or therapy-induced resistance-associated substitutions (RASs) to DAAs can result in treatment failure. The aim of this study was to estimate the prevalence of RASs to NS3A, NS5A and NS5B inhibitors, and particularly the Q80K polymorphism, in CKD patients on HD and RTx recipients infected with HCV. PATIENTS AND METHODS: HD and RTx patients infected with HCV-genotype 1 (GT1) were subjected to sequencing of the NS3, NS5A and NS5B regions. RESULTS: Direct sequencing of NS3 protease, NS5A and NS5B was performed in 76 patients (HD, n=37; RTx, n=39). The overall prevalence of RASs was 38.2%, but only 5.3% of the patients had mutations in more than one region. Substitutions were detected in NS3A (17.8%), NS5A (21.9%) and NS5B (8.4%). Q80K was detected in 1.5 % of the patients. Highly inhibitory RASs were uncommon (L31M, 2.6%; L159F+C316N, 2.6%). RASs were more prevalent in HCV-GT1a (42.9%) than in HCV-GT1b (32.4%), P=0.35. RASs were detected in 52.4% of treatment-naive patients and 27.8% of peg-IFN/ribavirin-experienced patients (P=0.12). The presence of RASs was associated with time of RTx (P=0.01). CONCLUSION: The Q80K polymorphism was uncommon in our sample of HD and RTx patients. Despite the high prevalence of naturally occurring RASs, most of the substitutions detected were associated with a low level of resistance to DAAs.

Prevalence of hepatitis delta virus among hemodialysis and renal transplant patients.

INTRODUCTION: Hepatitis B virus infection is an important cause of liver disease in hemodialysis patients and renal transplant recipients. Hepatitis Delta virus is a defective virus transmitted by the same route of hepatitis B virus, which requires the helper function of hepatitis B virus. Data about hepatitis B virus/hepatitis delta virus coinfection are scarce and there are no studies regarding the coinfection among hemodialysis patients and renal transplant in our country. OBJECTIVE: This study aimed to investigate the prevalence of hepatitis delta virus infection among hemodialysis patients and renal transplant recipients. METHODS: Cross-sectional study analyzing virological markers of hepatitis B virus and hepatitis delta virus infection and biochemical and clinical features of liver disease of patients infected with hepatitis B virus in hemodialysis and renal transplant. RESULTS: A total of 117 HBsAg-positive patients (46 hemodialysis and 71 renal transplant) were included. The mean age was 48.5 ± 11.8 years and 67% were males. Antiviral therapy was given to 74% of patients. Liver function tests were within the normal range. HBeAg-positive was found in 35% of patients and median hepatitis B virus DNA was 2.98 log (IU/mL). Cirrhosis was detected in 26.5% of patients. The prevalence of anti-hepatitis delta virus total antibody (+) was 1.7% (2/117). None of the 2 patients had active hepatitis delta virus infection, since all samples tested negative for hepatitis delta virus-RNA. CONCLUSION: The results suggest a low prevalence rate of coinfection B and D in hemodialysis and renal transplant recipients in this population.

Hematological and dermatological adverse events during hepatitis C treatment with peg-interferon and ribavirin / Eventos adversos hematológicos e dermatológicos durante o tratamento da hepatite C com interferon peguilado e ribavirina

Objective: To evaluate frequency and impact of adverse events, mainly the hematological and dermatological ones, on sustained virological response, and compliance to hepatitis C treatment. Methods: Patients were treated according to the guidelines of the Brazilian Ministry of Health. Variables associated with hematological and dermatological adverse events were: age, gender, stage of fibrosis, type of Pegylated interferon, dose reductions, temporary discontinuation and early interruption of treatment. Results: Two hundred and twenty two patients were studied (58% females; age 49±11 years). Dose reductions, temporary interruptions, and early discontinuations were observed in 21%, 8% and 9.5% of patients, respectively. The main adverse events were hematological (anemia, neutropenia and thrombocytopenia) and dermatological (pruritus and alopecia). Anemia (Hemoglobin <10g/dL) was associated with female gender (p<0.001), advanced fibrosis (p=0.047) and dose reductions (p<0.001); neutropenia with advanced fibrosis (p=0.003) and temporary discontinuation (p=0.002); thrombocytopenia with advanced fibrosis (p<0.001) and pegylated interferon α2a (p=0.05). Pruritus and alopecia were associated to female gender (p=0.008 and p=0.02) and treatment interruption (p=0.029 and p=0.02).Conclusion: Hematological and dermatological adverse events are frequent in hepatitis C patients treated with pegylated interferon and ribavirin. However, despite frequent dose reductions and interruptions, these adverse events did not affect the sustained virological response.

Objetivo: Avaliar a frequência e o impacto de eventos adversos, principalmente hematológicos e dermatológicos, na resposta virológica sustentada e na aderência ao tratamento para hepatite C. Métodos: Os pacientes foram tratados de acordo com diretriz do Ministério da Saúde. Variáveis associadas com eventos adversos hematológicos e dermatológicos foram: idade, sexo, grau de fibrose, tipo de interferon peguilado, reduções de dose, descontinuação temporária e interrupção precoce do tratamento. Resultados: Foram estudados 232 pacientes (58% mulheres; idade 49±11 anos). Reduções de dose, interrupções temporárias e descontinuações precoces foram observadas em 21%, 8% e 9,5% dos pacientes, respectivamente. Os principais eventos adversos foram hematológicos (anemia, neutropenia e plaquetopenia) e dermatológicos (prurido e alopecia). Anemia (hemoglobina <10g/dL) se associou a sexo feminino (p<0,001), fibrose avançada (p=0,047) e reduções de doses (p<0,001); neutropenia com fibrose avançada (p=0,003) e interrupção temporária (p=0,002); plaquetopenia com fibrose avançada (p<0,001) e interferon peguilado α2a (p=0,05). Prurido e alopecia se associaram ao sexo feminino (p=0,008 e p=0,02) e interrupção do tratamento (p=0,029 e p=0,02). Conclusão: Eventos adversos hematológicos e dermatológicos foram frequentes em pacientes tratados com interferon peguilado e ribavirina. Entretanto, a despeito de frequentes reduções de dose e interrupções, estes eventos adversos não afetaram a resposta virológica sustentada.

High incidence of tuberculosis in patients treated for hepatitis C chronic infection.

Brazil is one of the 22 countries that concentrates 80% of global tuberculosis cases concomitantly to a large number of hepatitis C carriers and some epidemiological risk scenarios are coincident for both diseases. We analyzed tuberculosis cases that occurred during α-interferon-based therapy for hepatitis C in reference centers in Brazil between 2001 and 2012 and reviewed their medical records. Eighteen tuberculosis cases were observed in patients submitted to hepatitis C α-interferon-based therapy. All patients were human immunodeficiency virus-negative. Nine patients (50%) had extra-pulmonary tuberculosis; 15 (83%) showed significant liver fibrosis. Hepatitis C treatment was discontinued in 12 patients (67%) due to tuberculosis reactivation and six (33%) had sustained virological response. The majority of patients had a favorable outcome but one died. Considering the evidences of α-IFN interference over the containment of Mycobacterium tuberculosis, the immune impairment of cirrhotic patients, the increase of tuberculosis case reports during hepatitis C treatment with atypical and severe presentations and the negative impact on sustained virological response, we think these are strong arguments for latent tuberculosis infection screening before starting α-interferon-based therapy for any indication and even to consider IFN-free regimens against hepatitis C when a patient tests positive for latent tuberculosis infection.

Reativação de leishmaniose durante tratamento de hepatite b crônica com alfainterferona 2b / Leishmaniasis reactivation during treatment of chronic hepatitis B with interferon alpha 2b - case report

Descreve-se aqui um caso de reativação de leishmaniose cutaneomucosa durante o tratamento com alfainterferona 2b (IFN) para hepatite B crônica (HBV). Relato do caso: Paciente masculino, 52 anos, natural da Bahia, procedente de São Paulo onde vivia há 30 anos, encaminhado por HBV. Na história epidemiológica, referiu-se a uma viagem há cinco anos para Porto Seguro-BA, sem apresentar outros fatores de risco. No exame físico para admissão, não havia evidências de doença hepática crônica. Sorologias pré-tratamento: HBsAg e HBeAg positivos, biópsia A0F0 (Metavir). Foi submetido a tratamento com IFN 5 milhões de UI/dia por 24 semanas. No final, apresentava-se HBV DNA detectável, sem soroconversão de HBeAg, porém evoluiu no quarto mês de tratamento com perda ponderal de 10 kg, astenia, sinais e sintomas de sinusite sem melhora clínica após antibioticoterapia. Foi encaminhado para a otorrinolaringologia com rouquidão persistente, destruição de septo nasal, com áreas de crostas, necrose local, alargamento nasal e lesão em palato mole, cuja biópsia mostrou processo inflamatório granulomatoso com necrose caseosa, sugestivo de leishmaniose. Sorologia para leishmaniose IgG 1/80 (IFI) e intradermorreação de Montenegro de 30 mm. Indicado antimoniato de meglumina IV por 30 dias, obteve melhora da rouquidão e das lesões de palato. Conclusão: O quadro clínico sugere reativação da leishmaniose induzida pelo IFN. Acredita-se que este seja o primeiro relato na literatura de reativação de leishmaniose muco-cutânea por uso de IFN, semelhantemente ao que ocorre com a tuberculose. Screening para leishmaniose deve ser realizado em paciente de região endêmica no pré-tratamento com IFN diante da possibilidade de reativação de infecção latente

Does hepatitis B virus coinfection have any impact on treatment outcome in hepatitis C patients on hemodialysis?

BACKGROUND: HBV/HCV coinfection is a common finding among hemodialysis patients. However, there is scarce information concerning the impact of HBV coinfection on the response to treatment of HCV-infected patients on hemodialysis. AIM: We aimed to compare the rate of sustained virologic response (SVR) to treatment with interferon-alfa (IFN) between hemodialysis patients with HBV/HCV coinfection and those with HCV-monoinfection. MATERIAL AND METHODS: HCV-infected patients on hemodialysis treated with IFN were included. Patients coinfected by HBV/HCV were compared to HCV-monoinfected patients, regarding clinical and biochemical features and rates of SVR. RESULTS: One hundred and eleven patients were treated. HBV/HCV coinfection was observed in 18/111 patients (16%). Coinfected patients were younger (p = 002), had more time on dialysis (p = 0.05) and showed a tendency to present a higher prevalence of septal fibrosis (p = 0.06). The analysis by intention to treat showed SVR of 56% among coinfected patients and 18% in HCV-monoinfected patients (p = 0.004). CONCLUSION: In conclusion, end-stage renal disease patients with HBV/HCV coinfection exhibit higher rate of SVR to HCV treatment than HCV-monoinfected patients. It is possible that factors related to the host immune response and viral interaction could explain the better response observed among coinfected patients.

Management of hepatitis C in patients with chronic kidney disease.

Hepatitis C virus (HCV) infection is highly prevalent among chronic kidney disease (CKD) subjects under hemodialysis and in kidney transplantation (KT) recipients, being an important cause of morbidity and mortality in these patients. The vast majority of HCV chronic infections in the hemodialysis setting are currently attributable to nosocomial transmission. Acute and chronic hepatitis C exhibits distinct clinical and laboratorial features, which can impact on management and treatment decisions. In hemodialysis subjects, acute infections are usually asymptomatic and anicteric; since spontaneous viral clearance is very uncommon in this context, acute infections should be treated as soon as possible. In KT recipients, the occurrence of acute hepatitis C can have a more severe course, with a rapid progression of liver fibrosis. In these patients, it is recommended to use pegylated interferon (PEG-IFN) in combination with ribavirin, with doses adjusted according to estimated glomerular filtration rate. There is no evidence suggesting that chronic hepatitis C exhibits a more aggressive course in CKD subjects under conservative management. In these subjects, indication of treatment with PEG-IFN plus ribavirin relies on the CKD stage, rate of progression of renal dysfunction and the possibility of a preemptive transplant. HCV infection has been associated with both liver disease-related deaths and cardiovascular mortality in hemodialysis patients. Among those individuals, low HCV viral loads and the phenomenon of intermittent HCV viremia are often observed, and sequential HCV RNA monitoring is needed. Despite the poor tolerability and suboptimal efficacy of antiviral therapy in CKD patients, many patients can achieve sustained virological response, which improve patient and graft outcomes. Hepatitis C eradication before KT theoretically improves survival and reduces the occurrence of chronic graft nephropathy, de novo glomerulonephritis and post-transplant diabetes mellitus.

Acute exacerbation of chronic hepatitis B virus infection in renal transplant patients

Introduction: There is scarce information regarding clinical evolution of HBV infection in renal transplant patients. Aims: To evaluate the prevalence of acute exacerbation in HBV-infected renal transplant patients and its association with the time after transplantation, presence of viral replication, clinical evolution, and use of antiviral prophylaxis. Materials and methods: HBV infected renal transplant patients who underwent regular follow-up visits at 6-month intervals were included in the study. The criteria adopted to characterize exacerbation were: ALT >5 × ULN and/or >3 × baseline level. Predictive factors of exacerbation evaluated were age, gender, time on dialysis, type of donor, post-transplant time, ALT, HBeAg, HBV-DNA, HCV-RNA, immunosuppressive therapy, and use of antiviral prophylaxis. Results: 140 HBV-infected renal transplant patients were included (71% males; age 46 ±10 years; post-renal transplant time 8 ±5 years). During follow-up, 25% (35/140) of the patients presented exacerbation within 3.4 ±3 years after renal transplant. Viral replication was observed in all patients with exacerbation. Clinical and/or laboratory signs of hepatic insufficiency were present in 17% (6/35) of the patients. Three patients died as a consequence of liver failure. In univariate analysis variables associated with exacerbation were less frequent use of prophylactic/preemptive lamivudine and of mycophenolate mofetil. Lamivudine use was the only variable independently associated with exacerbation, with a protective effect. Conclusions: Acute exacerbation was a frequent and severe event in HBV-infected renal transplant patients. Prophylactic/preemptive therapy with antiviral drugs should be indicated for all HBsAg-positive renal transplant patients. .

Acute exacerbation of chronic hepatitis B virus infection in renal transplant patients.

INTRODUCTION: There is scarce information regarding clinical evolution of HBV infection in renal transplant patients. AIMS: To evaluate the prevalence of acute exacerbation in HBV-infected renal transplant patients and its association with the time after transplantation, presence of viral replication, clinical evolution, and use of antiviral prophylaxis. MATERIALS AND METHODS: HBV infected renal transplant patients who underwent regular follow-up visits at 6-month intervals were included in the study. The criteria adopted to characterize exacerbation were: ALT >5× ULN and/or >3× baseline level. Predictive factors of exacerbation evaluated were age, gender, time on dialysis, type of donor, post-transplant time, ALT, HBeAg, HBV-DNA, HCV-RNA, immunosuppressive therapy, and use of antiviral prophylaxis. RESULTS: 140 HBV-infected renal transplant patients were included (71% males; age 46 ± 10 years; post-renal transplant time 8 ± 5 years). During follow-up, 25% (35/140) of the patients presented exacerbation within 3.4 ± 3 years after renal transplant. Viral replication was observed in all patients with exacerbation. Clinical and/or laboratory signs of hepatic insufficiency were present in 17% (6/35) of the patients. Three patients died as a consequence of liver failure. In univariate analysis variables associated with exacerbation were less frequent use of prophylactic/preemptive lamivudine and of mycophenolate mofetil. Lamivudine use was the only variable independently associated with exacerbation, with a protective effect. CONCLUSIONS: Acute exacerbation was a frequent and severe event in HBV-infected renal transplant patients. Prophylactic/preemptive therapy with antiviral drugs should be indicated for all HBsAg-positive renal transplant patients.

Poor response to hepatitis C treatment in elderly patients.

INTRODUCTION: Treatment of genotype 1 chronic hepatitis C in elderly patients has been associated with low rates of a sustained virological response (SVR), but the reasons are unclear. OBJECTIVE: To determine the SVR rate in patients ≥ 60 years with genotype 1 chronic hepatitis C treated with Peg-IFN and ribavirin, and to identify risk factors related to treatment response in this specific group of patients. Material and methods. Patients were divided into < 60 years (non-elderly) and ≥60 years (elderly) and were compared regarding clinical, laboratory and histological characteristics and response to treatment. RESULTS: A total of 231 patients were included in the study. The elderly group (n=89) presented a predominance of women, more advanced hepatic disease, higher glucose, cholesterol and LDL levels, lower hemoglobin levels, and a larger proportion of overweight subjects. The SVR rate was lower (25% vs 46%) and anemia, ribavirin dose reduction and use of filgrastim and erythropoietin were more frequent in elderly patients. Negative predictive factors of SVR in the whole group (n = 231) were glucose ≥ 100 mg/dL and age ≥ 60 years. In the elderly group, only pretreatment variables (lower serum glucose and higher hemoglobin levels) were associated with SVR. CONCLUSION: The SVR rate was low in elderly patients. However, this poor response was not due to poor tolerance, but mainly to pretreatment conditions. Among elderly patients, the best candidates for hepatitis C treatment are those with elevated pretreatment hemoglobin levels and adequate glycemic control.

Is early virological response as predictive of the hepatitis C treatment response in dialysis patients as in non-uremic patients?

OBJECTIVE: The aim of the present study was to determine whether hepatitis C virus (HCV) RNA present at week 12 is a good predictor of the response to interferon (IFN) monotherapy in hemodialysis patients with hepatitis C. METHODS: Hemodialysis patients with hepatitis C who were treated between 1997 and 2008 with IFN monotherapy for 48 weeks without dose reduction were included. The predictive value of HCV RNA at week 12 for achieving a sustained virological response (SVR) was determined. RESULTS: Forty patients (mean age 47±9 years; 75% males and 80% with genotype 1) were included. Septal fibrosis or cirrhosis was observed in 38% of these patients. Twelve (30%) of the 40 patients achieved SVR. HCV RNA was undetectable at week 12 in 68%. The positive predictive value of HCV RNA at week 12 was 45% and the negative predictive value was 100%. CONCLUSIONS: The presence of HCV RNA at week 12 had a high negative predictive value for SVR in hemodialysis patients with chronic hepatitis C treated with IFN for 48 weeks. Therefore, if HCV RNA is detected at week 12, treatment should be discontinued due to the low probability of a sustained response.

Spontaneous bacterial peritonitis: How to deal with this life-threatening cirrhosis complication?

Spontaneous bacterial peritonitis (SBP) is one of the most common and life-threatening complications of cirrhosis. It occurs in 10% to 30% of patients admitted to hospital and recent studies tend to demonstrate that SBP incidence seems to be decreasing in its frequency. A bacterial overgrowth with translocation through the increased permeable small intestinal wall and impaired defense mechanisms is considered to be the main mechanism associated with its occurrence. The Gram-negative aerobic bacteria are the major responsible for SBP episodes and Gram-positive bacteria, mainly Staphylococcus aureus, are being considered an emergent agent causing SBP. The prompt diagnosis of SBP is the key factor for reduction observed in mortality rates in recent years. The clinical diagnosis of SBP is neither sensitive nor specific and the search for new practical and available tools for a rapid diagnosis of SBP is an important endpoint of current studies. Reagent strips were considered a promising and faster way of SBP diagnosis. The prompt use of empirical antibiotics, mostly cefotaxime, improves significantly the short-term prognosis of cirrhotic patients with SBP. The recurrence rate of SBP is high and antibiotic prophylaxis has been recommended in high-risk settings. Unfortunately, the long-term prognosis remains poor.