Drug-Induced Acute-on-Chronic Liver Failure in Asian Patients.

OBJECTIVES: Acute insults from viruses, infections, or alcohol are established causes of decompensation leading to acute-on-chronic liver failure (ACLF). Information regarding drugs as triggers of ACLF is lacking. We examined data regarding drugs producing ACLF and analyzed clinical features, laboratory characteristics, outcome, and predictors of mortality in patients with drug-induced ACLF. METHODS: We identified drugs as precipitants of ACLF among prospective cohort of patients with ACLF from the Asian Pacific Association of Study of Liver (APASL) ACLF Research Consortium (AARC) database. Drugs were considered precipitants after exclusion of known causes together with a temporal association between exposure and decompensation. Outcome was defined as death from decompensation. RESULTS: Of the 3,132 patients with ACLF, drugs were implicated as a cause in 329 (10.5%, mean age 47 years, 65% men) and other nondrug causes in 2,803 (89.5%) (group B). Complementary and alternative medications (71.7%) were the commonest insult, followed by combination antituberculosis therapy drugs (27.3%). Alcoholic liver disease (28.6%), cryptogenic liver disease (25.5%), and non-alcoholic steatohepatitis (NASH) (16.7%) were common causes of underlying liver diseases. Patients with drug-induced ACLF had jaundice (100%), ascites (88%), encephalopathy (46.5%), high Model for End-Stage Liver Disease (MELD) (30.2), and Child-Turcotte-Pugh score (12.1). The overall 90-day mortality was higher in drug-induced (46.5%) than in non-drug-induced ACLF (38.8%) (P = 0.007). The Cox regression model identified arterial lactate (P < 0.001) and total bilirubin (P = 0.008) as predictors of mortality. DISCUSSION: Drugs are important identifiable causes of ACLF in Asia-Pacific countries, predominantly from complementary and alternative medications, followed by antituberculosis drugs. Encephalopathy, bilirubin, blood urea, lactate, and international normalized ratio (INR) predict mortality in drug-induced ACLF.

The present and future disease burden of hepatitis C virus infections with today's treatment paradigm - volume 3.

The total number, morbidity and mortality attributed to viraemic hepatitis C virus (HCV) infections change over time making it difficult to compare reported estimates from different years. Models were developed for 15 countries to quantify and characterize the viraemic population and forecast the changes in the infected population and the corresponding disease burden from 2014 to 2030. With the exception of Iceland, Iran, Latvia and Pakistan, the total number of viraemic HCV infections is expected to decline from 2014 to 2030, but the associated morbidity and mortality are expected to increase in all countries except for Japan and South Korea. In the latter two countries, mortality due to an ageing population will drive down prevalence, morbidity and mortality. On the other hand, both countries have already experienced a rapid increase in HCV-related mortality and morbidity. HCV-related morbidity and mortality are projected to increase between 2014 and 2030 in all other countries as result of an ageing HCV-infected population. Thus, although the total number of HCV countries is expected to decline in most countries studied, the associated disease burden is expected to increase. The current treatment paradigm is inadequate if large reductions in HCV-related morbidity and mortality are to be achieved.

Antibody and markers of T-cell activation illuminate the pathogenesis of HCV immune restoration disease in HIV/HCV co-infected patients commencing ART.

Some HIV/hepatitis C virus co-infected patients beginning ART experience Immune Restoration Disease (IRD) manifested as a rise in serum alanine transaminase. This was investigated in HIV/HCV co-infected individuals (n=50) commencing ART in Jakarta (Indonesia). Samples were collected at weeks 0, 4, 8, 12, 24 and at HCV IRD. Nine patients experienced HCV IRD (incidence=9.2 per 1000 person-weeks). These resolved without changing treatment. Markers of T-cell activation (sCD26, sCD30) and immune recruitment (CXCL10) increased in many HCV IRD cases, so T-cells may mediate HCV IRD. Total anti-HCV antibody (core, NS3, NS4) remained lower in HCV IRD cases, but levels of antibody to core were not lower in HCV IRD cases. Rises in HCV RNA on ART were independent of HCV IRD, but there was a negative correlation between baseline HCV RNA and total anti-HCV antibody. High levels of antibody may protect against HCV IRD, via lower HCV antigen loads.

Grade 3-4 liver enzyme elevation during HAART in HIV and hepatitis C co-infected adults.

AIM: To evaluate the incidence of grade 3-4 LEE in HIV/HCV co-infected patients after the introduction of HAART, the clinical significance to the patients and to determine any factors that could predict its development. METHODS: A retrospective cohort study of HIV/HCV co-infected adults in Pokdisus AIDS Clinic Cipto Mangunkusumo Hospital was conducted. All patients were antiretroviral naive and had never had interferon therapy before. Patients who started taking fist line combination therapy in Indonesia (NNRTI based regimen) from January 2004 to August 2006 and who were followed up for at least 6 months later were included in this study. RESULTS: A total of 59 grade 3-4 LEE (any ALT increase by > 5 times ULN or any increase of 100 U/L from baseline) developed in 284 patients during the follow up (20.8%). The median onset of grade 3-4 LEE was 20 weeks (min-max 2-80). Only 27.1% accompanied with symptoms. Two patients developed decompensated liver diseases, one of them ended with death. In 5 patients, grade 3-4 LEE coincided with nevirapine or efavirenz-related rashes. Fifty-two patients (88.1%) continued their antiretroviral regimen throughout the entire episode of grade 3-4 LEE. The median peak level of ALT was 2311 IU/L (IQR, 174-327). CONCLUSION: Lower baseline ALT was the only factor significantly correlated with grade 3-4 LEE in this study.

Liver failure determines the outcome in patients of acute-on-chronic liver failure (ACLF): comparison of APASL ACLF research consortium (AARC) and CLIF-SOFA models.

BACKGROUND AND AIMS: Acute-on-chronic liver failure (ACLF) is a progressive disease associated with rapid clinical worsening and high mortality. Early prediction of mortality and intervention can improve patient outcomes. We aimed to develop a dynamic prognostic model and compare it with the existing models. METHODS: A total of 1402 ACLF patients, enrolled in the APASL-ACLF Research Consortium (AARC) with 90-day follow-up, were analyzed. An ACLF score was developed in a derivation cohort (n = 480) and was validated (n = 922). RESULTS: The overall survival of ACLF patients at 28 days was 51.7%, with a median of 26.3 days. Five baseline variables, total bilirubin, creatinine, serum lactate, INR and hepatic encephalopathy, were found to be independent predictors of mortality, with AUROC in derivation and validation cohorts being 0.80 and 0.78, respectively. AARC-ACLF score (range 5-15) was found to be superior to MELD and CLIF SOFA scores in predicting mortality with an AUROC of 0.80. The point scores were categorized into grades of liver failure (Gr I: 5-7; II: 8-10; and III: 11-15 points) with 28-day cumulative mortalities of 12.7, 44.5 and 85.9%, respectively. The mortality risk could be dynamically calculated as, with each unit increase in AARC-ACLF score above 10, the risk increased by 20%. A score of ≥11 at baseline or persisting in the first week was often seen among nonsurvivors (p = 0.001). CONCLUSIONS: The AARC-ACLF score is easy to use, dynamic and reliable, and superior to the existing prediction models. It can reliably predict the need for interventions, such as liver transplant, within the first week.

Detection of esophageal varices in liver cirrhosis using non-invasive parameters.

AIM: recent guidelines recommend that all cirrhotic patients without previous variceal hemorrhage undergo endoscopic screening to detect esophageal varices. The aim of this study is to evaluate clinical, laboratory and ultrasound parameters to detect esophageal varices. METHODS: this is a cross sectional study. Fourty seven consecutive cirrhotic patients without history of variceal hemorrhage underwent upper endoscopy. Physical examination, laboratory and ultrasonography to find portal vein diameter and anterioposterior splenic measurement of each patient were also recorded. RESULTS: esophageal varices was detected in 36 of the 47 patients (76.6%). Using bivariate analysis we found that a platelet count of 82,000/ul (90.9% sensitivity; 41.7% specificity), portal vein diameter of 1.15 cm (75% sensitivity; 54.5% pecificity) and an anteroposterior splenic measurement of 10.3 cm (83.3% sensitivity; 63.6% specificity) were predictive factors for esophageal varices in liver cirrhosis. CONCLUSION: our data show that platelet count, portal vein diameter and anteroposterior splenic measurement can be used as non invasive parameters to detect esophageal varices in cirrhotic patients.

Hepatitis C virus RNA detection and HCV genotype in patients with chronic non-A, non-B hepatitis in Jakarta.

Antibody response in HCV infection may be variable and the variability of the serological response could be due to the differences in HCV strains. Since the distribution of hepatitis C virus genotype has been found to be geographically dependent, it is important to determine the distribution of HCV genotype in various countries with high prevalence of chronic non-A, non-B hepatitis. In this study, serum HCV RNA was examined in 53 patients suspected of chronic non-A, non-B hepatitis with an anti-HCV test as determined by currently available assay. HCV viremia was detected in 48 patients (90.6%). These patients had elevated serum ALT level at the time of HCV RNA determination. Using specific genotype probes, all isolates were classified into three different genotypes. Double and triple infections were also noted. HCV genotype 1b is the predominant genotype found in chronic hepatitis C patients in Jakarta.

Hepatitis C virus variants from Jakarta, Indonesia classifiable into novel genotypes in the second (2e and 2f), tenth (10a) and eleventh (11a) genetic groups.

Hepatitis C virus (HCV) isolates from 126 hepatitis patients in Jakarta, Indonesia were genotyped by PCR with genotype-specific primers deduced from the HCV core gene. Fifty-five isolates (44%) were classified as genotype II/1b, 15 (12%) as 1c, 33 (26%) as III/2a, and 1 (1%) as V/3a, while the remaining 22 (17%) were not classifiable into any of the five common genotypes (I/1a, II/1b, III/2a, IV/2b and V/3a) or 1c. Sequences of a part of the NS5b region [1093 bp (nucleotides 8279-9371)] of the 22 isolates of unclassifiable genotype were subjected to pair-wise comparison and phylogenetic analysis along with those of 62 isolates of 25 genotypes in nine genetic groups. Seven of the isolates were classified into 2e and two into 2f, representing novel genotypes in genetic group 2, while ten and three were classified into two new genetic groups, 10 and 11, respectively, and their genotypes were provisionally designated 10a and 11a. The isolates of genotype 10a (JK049) and 11a (JK046) were sequenced in full. Comparison of 24 HCV genomes including those of JK049 and JK046, over the entire genome and subgenomic regions, supported the classification of HCV into 11 genetic groups.

Seroepidemiology of HBV and HCV infection in Jakarta, Indonesia.

A total of 545 serum samples were consecutively collected from patients with acute hepatitis, chronic hepatitis, liver cirrhosis, hepatocellular carcinoma, chronic hemodialysis and voluntary blood donors to study the seroepidemiology of HBV and HCV infection in Jakarta. Fourteen out of 243 or 5.8% samples from blood donors were HBsAg-positive, while HCV-antibodies (anti-C100 and/or anti-CP9 and/or anti-CP10) positivity rate was found in 59 out of 243 or 24.3%. Out of 91 donors aged 29 years or younger, 15 (16.5%) donors turned positive for HCV-antibody (-ies), while out of 152 donors aged 30 years or above, 44 (28.9%) donors were anti-HCV-positive, showing a higher HCV-antibody prevalence among higher age group. Among 88 acute hepatitis patients, 33 (37.5%) cases, 10 (11.4%) cases, 15 (17.0%) cases and 30 (34.1%) cases were diagnosed as hepatitis A, hepatitis B, acute exacerbation of HCV carriers, and NANB hepatitis respectively. HCV-antibodies were found in 15 (45.5%) of hepatitis A cases and 6 (40.0%) of acute exacerbation of HBV carrier cases, but found only in 9 (30.0%) of acute NANB hepatitis cases. Positivity rates of HCV-antibodies among 23 chronic hepatitis, 80 liver cirrhosis and 64 hepatocellular carcinoma cases were 78.3%, 75.0% and 65.6% respectively, while 30.4%, 30.0% and 45.3% of the respective groups were positive for HBs antigen. Among 47 hemodialysis cases, 97.9% and 6.4% were positive for HCV antibodies and HBs antigen respectively. It was concluded that: (1) HBV infection rate is high among blood donors and patients with acute and chronic liver diseases. (2) HCV infection rate is high among blood donors.(ABSTRACT TRUNCATED AT 250 WORDS)