Barjesh Chander Sharma

Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific Association for the study of the liver (APASL)

The Asian Pacific Association for the Study of the Liver (APASL) set up a working party on acute-on-chronic liver failure (ACLF) in 2004, with a mandate to develop consensus guidelines on various aspects of ACLF relevant to disease patterns and clinical practice in the Asia-Pacific region. Experts predominantly from the Asia–Pacific region constituted this working party and were requested to identify different issues of ACLF and develop the consensus guidelines. A 2-day meeting of the working party was held on January 22–23, 2008, at New Delhi, India, to discuss and finalize the consensus statements. Only those statements that were unanimously approved by the experts were accepted. These statements were circulated to all the experts and subsequently presented at the Annual Conference of the APASL at Seoul, Korea, in March 2008. The consensus statements along with relevant background information are presented in this review.

Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update

Worldwide, some 240 million people have chronic hepatitis B virus (HBV), with the highest rates of infection in Africa and Asia. Our understanding of the natural history of HBV infection and the potential for therapy of the resultant disease is continuously improving. New data have become available since the previous APASL guidelines for management of HBV infection were published in 2012. The objective of this manuscript is to update the recommendations for the optimal management of chronic HBV infection. The 2015 guidelines were developed by a panel of Asian experts chosen by the APASL. The clinical practice guidelines are based on evidence from existing publications or, if evidence was unavailable, on the experts’ personal experience and opinion after deliberations. Manuscripts and abstracts of important meetings published through January 2015 have been evaluated. This guideline covers the full spectrum of care of patients infected with hepatitis B, including new terminology, natural history, screening, vaccination, counseling, diagnosis, assessment of the stage of liver disease, the indications, timing, choice and duration of single or combination of antiviral drugs, screening for HCC, management in special situations like childhood, pregnancy, coinfections, renal impairment and pre- and post-liver transplant, and policy guidelines. However, areas of uncertainty still exist, and clinicians, patients, and public health authorities must therefore continue to make choices on the basis of the evolving evidence. The final clinical practice guidelines and recommendations are presented here, along with the relevant background information.

Beneficial effects of tumor necrosis factor-α inhibition by pentoxifylline on clinical, biochemical, and metabolic parameters of patients with nonalcoholic steatohepatitis

BACKGROUND:Tumor necrosis factor-α (TNF-α) has been incriminated to play an important role in the pathogenesis of nonalcoholic steatohepatitis (NASH). Pentoxifylline, a TNF-α inhibitor could prove useful in treating patients with NASH.METHODS:Eighteen patients (mean age, 34 ± 7.8 yr) with histologically proven NASH and with persistently elevated ALT (>1.5 times) were given pentoxifylline at a dosage of 400 mg t.i.d. for 6 months. No lipid-lowering agent or antioxidants were concurrently advised.RESULTS:Impaired fasting glycemia, impaired glucose tolerance, diabetes mellitus, and hypertriglyceridemia were noted in 6, 35, 17, and 53% of the patients, respectively.After 6 months of therapy, fatigue improved (55.6 vs 20%, P = 0.016), but serum triglyceride (182 ± 66 vs 160 ± 55 mg/dl, P = 0.397), cholesterol (173 ± 46 vs 162 ± 40 mg/dl, P = 0.440), and body mass index (BMI) (27.3 ± 3.1 vs 26 ± 3.1 kg/m2, P = 0.087) remained unchanged. Mean AST (66 ± 29 vs 33 ± 11 IU/l, p < 0.0001) and ALT (109 ± 44 vs 47 ± 20 IU/l, p < 0.0001) reduced significantly. ALT normalized in 23% at month 1 (P = 0.125), 35% at month 2 (P = 0.125), and 60% at month 6 (P = 0.008) of treatment. The insulin resistance index assessed by homeostatic metabolic assessment (HOMAIR) improved (5.1 ± 3.4 vs 2.6 ± 2, p = 0.046) and the serum TNF-α reduced significantly after therapy (22.15 ± 2.49 vs 17 ± 2.58 pg/ml, p = 0.011). The drug was well tolerated.CONCLUSIONS:In patients with NASH, pentoxifylline therapy effectively achieved significant clinical and biochemical improvement with reduction in HOMAIR. These benefits are possibly mediated through suppression of TNF-α.

Secondary Prophylaxis of Hepatic Encephalopathy: An Open-Label Randomized Controlled Trial of Lactulose Versus Placebo

BACKGROUND & AIMS Hepatic encephalopathy (HE) is associated with a poor prognosis. Lactulose is used for the treatment of HE. There is no study on the prevention of recurrence of HE using lactulose. METHODS Consecutive cirrhotic patients who recovered from HE were randomized to receive lactulose (HE-L group) or placebo (HE-NL group). All patients were assessed by psychometry (number connection test [NCT-A and B], figure connection test if illiterate [FCT-A and B], digit symbol test [DST], and object assembly test [OAT]), critical flicker frequency test, and blood ammonia at inclusion. Primary end point was development of overt HE. RESULTS Of 300 patients with HE who recovered, 140 (46.6%) met the inclusion criteria and were included. There was a high prevalence of abnormal psychometry test results (NCT-A, 67.5%; NCT-B, 62.5%; DST, 70%; and OAT, 80%), and FCT-A and B were abnormal in 10 of 14 patients. Critical flicker frequency was <38 Hz in 77 patients (55%). Twelve (19.6%) of 61 patients in the HE-L group and 30 (46.8%) of 64 in the HE-NL group (P = .001) developed HE over a median follow-up of 14 months (range, 1-20 months). Readmission rate due to causes other than HE (HE-L vs HE-NL, 9:6; P = NS) and deaths (HE-L vs HE-NL, 5:11; P = .18) in 2 groups were similar. Recurrence of overt HE was significantly associated with 2 or more abnormal psychometric tests after the recovery of an episode of HE (r = 0.369, P = .02). CONCLUSIONS Lactulose is effective for prevention of recurrence of HE in patients with cirrhosis.

Consensus on extra-hepatic portal vein obstruction

Abstract: The Asian Pacific Association for the Study of the Liver (APASL) had set up a working party on portal hypertension in 2002 with a mandate to develop consensus on various aspects of portal hypertension. The first of these consensuses has been developed on extra‐hepatic portal vein obstruction (EHPVO). It was discussed and prepared by the experts in this field from the Asian region and was presented at the annual meeting of the APASL, at Bali in August 2005. This article summarizes all the consensus statements approved by the APASL on various aspects of EHPVO.

Granulocyte Colony–Stimulating Factor Mobilizes CD34+ Cells and Improves Survival of Patients With Acute-on-Chronic Liver Failure

BACKGROUND & AIMS Acute-on-chronic liver failure (ACLF) develops in patients with chronic liver disease and has high mortality. Mobilization of bone marrow-derived stem cells with granulocyte colony-stimulating factor (G-CSF) could promote hepatic regeneration. METHODS Consecutive patients with ACLF were randomly assigned to groups given 5 μg/kg G-CSF subcutaneously (12 doses; group A, n = 23) or placebo (group B, n = 24) plus standard medical therapy. We assessed survival until day 60; Child-Turcotte-Pugh (CTP), Model for End-Stage Liver Disease (MELD), and Sequential Organ Failure Assessment (SOFA) scores; and the development of other related complications. RESULTS After 1 week of treatment, group A had higher median leukocyte and neutrophil counts than group B (P < .001). Sixteen patients in group A (69.6%) and 7 in group B (29%) survived; the actuarial probability of survival at day 60 was 66% versus 26%, respectively (P = .001). Treatment with G-CSF also reduced CTP scores in group A by a median of 33.3% compared with an increase of 7.1% in group B (P = .001), along with MELD (median reduction of 15.3% compared with an increase of 11.7% in group B; P = .008) and SOFA scores (median reduction of 50% compared with an increase of 50% in group B; P = .001). The percentages of patients who developed hepatorenal syndrome, hepatic encephalopathy, or sepsis were lower in group A than in group B (19% vs 71% [P = .0002], 19% vs 66% [P = .001], and 14% vs 41% [P = .04], respectively). After 1 month of treatment, G-CSF increased the number of CD34(+) cells in the liver (by 45% compared with 27.5% in group B; P = .01). CONCLUSIONS G-CSF therapy more than doubles the percentage of patients with ACLF who survive for 2 months; it also significantly reduces CTP, MELD, and SOFA scores and prevents the development of sepsis, hepatorenal syndrome, and hepatic encephalopathy.

Tenofovir improves the outcome in patients with spontaneous reactivation of hepatitis B presenting as acute-on-chronic liver failure.

Spontaneous reactivation of chronic hepatitis B (CHB) is an important cause of acute‐on‐chronic liver failure (ACLF). Antiviral drugs may help reduce the high morbidity and mortality in such patients, especially in places where liver transplant is not available. The aim was to evaluate the efficacy of tenofovir and to determine the predictors of mortality in patients with spontaneous reactivation of CHB with ACLF. Consecutive patients of ACLF due to spontaneous reactivation of CHB were randomized to receive either tenofovir or placebo. The primary endpoint was survival at 3 months. Of the 90 patients with ACLF of different etiologies, 27 (26%) were due to reactivation of CHB and were enrolled. The median baseline hepatitis B virus (HBV) DNA level was 9 × 105 IU/mL. Fourteen patients received tenofovir and 13 placebo. At 3 months the probability of survival was higher in the tenofovir than the placebo group (8/14 [57%] versus 2/13 [15%], respectively; P = 0.03). The cause of death in the 15 patients was progressive liver failure leading to multiorgan failure. Liver transplantation could not be offered due to its nonavailability. In the surviving patients, there was a significant improvement in the Child‐Turcotte Pugh (CTP) and model for endstage liver disease (MELD) scores and significant decline in the HBV DNA levels in the tenofovir group, whereas these parameters did not change significantly in the placebo group. More than 2 log reduction in HBV DNA levels at 2 weeks was found to be an independent predictor of survival. Conclusion: Tenofovir significantly reduces HBV‐DNA levels, improves CTP and MELD scores, and reduces mortality in patients with severe spontaneous reactivation of CHB presenting as ACLF. Reduction in HBV‐DNA levels at 2 weeks should be a desirable goal and is a good predictor of survival. (HEPATOLOGY 2011;.)

Beneficial effects of pentoxifylline on hepatic steatosis, fibrosis and necroinflammation in patients with non‐alcoholic steatohepatitis

Background and Aim:  Inhibition of tumor necrosis factor (TNF)‐α is a logical approach to manage patients with non‐alcoholic steatohepatitis (NASH). Pentoxifylline reduces TNF‐α and alanine aminotransferase (ALT) levels in patients with NASH. The aim of the present paper was to study if pentoxifylline can improve histological injury in patients with NASH.

An open-label randomized controlled trial of lactulose and probiotics in the treatment of minimal hepatic encephalopathy.

Background and aim Minimal hepatic encephalopathy (MHE) is associated with poor quality of life and increased work disability. Treatment with lactulose and probiotics has shown some benefit. We compared lactulose with probiotics and a combination of lactulose plus probiotics in the treatment of MHE. Patients and methods One hundred and ninety cirrhotic patients without overt encephalopathy [Childs A grade 71 patients (37.4%), Childs B grade 72 patients (37.9%), Childs C grade 47 patients (24.7%)] were evaluated by psychometry (number connection tests A and B or figure connection tests A and B) and P300 auditory event-related potential (P300ERP). MHE was diagnosed by abnormal psychometry and/or P300ERP. Patients were randomized to receive lactulose [group A (n=35): dose 30–60 ml/day], probiotics [group B (n=35): dose 1 capsule three times/day, each capsule contained Streptococcus faecalis 60 million, Clostridium butyricum 4 million, Bacillus mesentricus 2 million, lactic acid bacillus 100 million] and lactulose plus probiotics [group C (n=35)] for 1 month. Response was defined by normalization of the abnormal test parameters. Results MHE was diagnosed in 105 (55.2%) patients. Of the 105 patients, 75 (71%) had both abnormal psychometry and P300ERP, whereas 90 (86%) had abnormal psychometry alone, and 89 patients (85%) had abnormal P300ERP alone. Significant improvement was seen in abnormal psychometry tests (group A: n=31 vs. n=12, group B: n=29 vs. n=14, group C: n=30 vs. n=10), P300ERP (group A: 376.8±22.3 vs. 344.3±30.6 ms, group B: 385.4±28.5 vs. 355.5±27.9 ms, group C: 387.7±27.5 vs. 347.7±31.5 ms) and venous ammonia levels (group A: 102.3±63.1 vs. 69.3±33.3 μmol/l, group B: 108.2±37.5 vs. 75.7±33.0 μmol/l, group C: 96.3±27.7 vs. 68.7±28.4 μmol/l) in lactulose, probiotics and a combination of lactulose plus probiotics groups after treatment. Normalization of abnormal psychometry and P300ERP was seen in 54.8, 51.6 and 56.6% of patients treated with lactulose, probiotics and lactulose plus probiotics groups, respectively. Conclusion A total of 55% of the patients with cirrhosis had MHE. Lactulose or probiotics or combinations of both are equally effective in the treatment of MHE.

A randomized, double-blind, controlled trial comparing rifaximin plus lactulose with lactulose alone in treatment of overt hepatic encephalopathy.

OBJECTIVES:Hepatic encephalopathy (HE) is associated with poor prognosis in cirrhosis. Drugs used in the treatment of HE are primarily directed at the reduction of the blood ammonia levels. Rifaximin and lactulose have shown to be effective in HE. We evaluated the efficacy and safety of rifaximin plus lactulose vs. lactulose alone for treatment of overt HE.METHODS:In this prospective double-blind randomized controlled trial, 120 patients with overt HE were randomized into two groups: (group A lactulose plus rifaximin 1,200 mg/day; n=63) and group B (lactulose (n=57) plus placebo). The primary end point was complete reversal of HE and the secondary end points were mortality and hospital stay.RESULTS:A total of 120 patients (mean age 39.4±9.6 years; male/female ratio 89:31) were included in the study. 37 (30.8%) patients were in Child–Turcotte–Pugh (CTP) class B and 83 (69.2%) were in CTP class C. Mean CTP score was 9.7±2.8 and the MELD (model for end-stage liver disease) score was 24.6±4.2. At the time of admission, 22 patients (18.3%) had grade 2, 40 (33.3%) had grade 3, and 58 (48.3%) had grade 4 HE. Of the patients, 48 (76%) in group A compared with 29 (50.8%) in group B had complete reversal of HE (P<0.004). There was a significant decrease in mortality after treatment with lactulose plus rifaximin vs. lactulose and placebo (23.8% vs. 49.1%, P<0.05). There were significantly more deaths in group B because of sepsis (group A vs. group B: 7:17, P=0.01), whereas there were no differences because of gastrointestinal bleed (group A vs. group B: 4:4, P=nonsignificant (NS)) and hepatorenal syndrome (group A vs. group B: 4:7, P=NS). Patients in the lactulose plus rifaximin group had shorter hospital stay (5.8±3.4 vs. 8.2±4.6 days, P=0.001).CONCLUSION:Combination of lactulose plus rifaximin is more effective than lactulose alone in the treatment of overt HE.