Shiv Kumar Sarin

Asian Pacific Association for the Study of the Liver consensus recommendations on hepatocellular carcinoma

IntroductionThe Asian Pacific Association for the Study of the Liver (APASL) convened an international working party on the management of hepatocellular carcinoma (HCC) in December 2008 to develop consensus recommendations.MethodsThe working party consisted of expert hepatologist, hepatobiliary surgeon, radiologist, and oncologist from Asian-Pacific region, who were requested to make drafts prior to the consensus meeting held at Bali, Indonesia on 4 December 2008. The quality of existing evidence and strength of recommendations were ranked from 1 (highest) to 5 (lowest) and from A (strongest) to D (weakest), respectively, according to the Oxford system of evidence-based approach for developing the consensus statements.ResultsParticipants of the consensus meeting assessed the quality of cited studies and assigned grades to the recommendation statements. Finalized recommendations were presented at the fourth APASL single topic conference on viral-related HCC at Bali, Indonesia and approved by the participants of the conference.

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.

Profile, spectrum and significance of HBV genotypes in chronic liver disease patients in the Indian subcontinent

Background and Aim Certain hepatitis B virus (HBV) genotypes have been alleged to be associated with the development of cirrhosis and hepatocellular carcinoma (HCC), and the response to interferon therapy in Taiwanese patients. We undertook to study the prevalence and significance of HBV genotypes in the Indian subcontinent.

A randomized controlled trial of cyanoacrylate versus alcohol injection in patients with isolated fundic varices

OBJECTIVE:Treatment of bleeding gastric varices (GVs) is still controversial, mainly because of anecdotal studies or inclusion of patients with GVs located at different sites that have variable incidences of bleeding. A prospective study was undertaken to compare the efficacy and safety of GV sclerotherapy using alcohol and GV obturation using cyanoacrylate glue.METHODS:Thirty-seven consecutive patients with portal hypertension and endoscopic evidence of isolated GVs, 17 presenting with histories of active bleeding, were randomized to receive endoscopic intervention either with alcohol (n = 17) or with cyanoacrylate glue (n = 20) injection. Variceal obliteration, rebleeding, or death was the endpoint.RESULTS:The glue was significantly more effective in achieving variceal obliteration than alcohol (100% vs 44%, p < 0.05). Furthermore, this could be achieved in a significantly shorter period (2.0 ± 1.6 vs 4.7 ± 3.2 wk, p < 0.05) and with a smaller volume of the agent. Cyanoacrylate glue injection could achieve arrest of acute GV bleeding more often than alcohol (89% vs 62%), and the need for rescue surgery was less; the difference was, however, not significant. Six patients died from uncontrolled GV bleeding, four being in the alcohol group. During a mean follow-up of 15.4 ± 3.7 months there was no recurrence of GVs in either group.CONCLUSIONS:Our results show that cyanoacrylate is more effective and achieves GV obliteration faster than injection sclerotherapy with alcohol. It also appears to be more useful in controlling acute GV bleeding, with less of a need for rescue surgery.

Maternal and Fetal Outcomes in Pregnant Women with Acute Hepatitis E Virus Infection

Context Hepatitis E virus (HEV) infection causes severe liver disease in pregnant women. Contribution In a case series of 220 pregnant women with jaundice and acute viral hepatitis, the authors observed that women with HEV infection more often died and had more obstetric complications and worse fetal outcomes than did women with other forms of viral hepatitis. Caution The series was restricted to symptomatic women at a referral center. Implication Infection with HEV not only causes more severe liver disease in pregnant women but also appears to contribute to worse obstetric and fetal outcomes compared with other forms of viral hepatitis. The Editors Hepatitis E virus (HEV) is a single-stranded RNA virus that causes large-scale epidemics and sporadic cases of acute viral hepatitis in developing countries (1, 2). Infection with HEV also poses a significant risk for acute viral hepatitis to travelers in endemic areas (3). The main source of transmission of HEV is contaminated drinking water (4, 5). In men and nonpregnant women, the disease is usually self-limited and has a low case-fatality rate (<0.1%) (6). However in pregnant women, HEV infection is more severe, often leading to fulminant hepatic failure and death in up to 15% to 20% of cases. This high mortality rate was first reported in an epidemic setting in the early 1980s (7) and was reported again in a sporadic setting in 2003 (8). Information is limited and conflicting on the effect of HEV infection on maternal, obstetric, and fetal outcomes (9, 10). Therefore, we describe the prevalence and clinical outcomes of acute viral hepatitis in a series of HEV-infected pregnant women and compare their maternal, obstetric, and fetal outcomes with those of pregnant women without HEV infection. Methods Setting and Participants The study was conducted at the Department of Obstetrics and Gynecology, Lady Hardinge Medical College, and Shrimati Sucheta Kriplani Hospital, New Delhi, India (a large tertiary care hospital), in collaboration with the Department of Gastroenterology, G.B. Pant Hospital, New Delhi. Consecutive pregnant women at any gestational stage who presented between January 2003 and July 2005 with acute viral hepatitis were systematically assessed for hepatitis virus infection by using liver function tests and serologic analysis. Acute viral hepatitis was diagnosed (7) by a serum bilirubin level of 34 mol/L or greater (2 mg/dL); a serum alanine aminotransferase level 2.5 times the upper limit of normal or greater; and positivity for any hepatotropic virus by using the following serologic tests: hepatitis B surface antigen; antibody to hepatitis C virus; and IgM antibodies to hepatitis A virus, hepatitis B core antigen, hepatitis delta virus, and HEV. We excluded patients with negative results on viral serologic examination, those with dual viral infection, those with clinical evidence of other causes of jaundice (such as biliary obstruction, the HELLP syndrome [hemolytic anemia, elevated liver enzyme level, low platelet count], acute fatty liver of pregnancy, hemolytic jaundice, and drug-induced jaundice), and those with clinical or laboratory evidence of chronic liver disease. Women who met the case definition of acute viral hepatitis were managed in a separate hepatitis hospital ward. Management depended on whether the patients acute viral hepatitis was complicated by fulminant hepatic failure, which was diagnosed when hepatic encephalopathy developed in a patient with acute viral hepatitis within 4 weeks of the onset of jaundice (11). Patients without fulminant hepatic failure were given standard care and were monitored for signs and complications of acute viral hepatitis (fever, edema, ascites, paralytic ileus, nasal and gastrointestinal hemorrhage, high leukocyte count, high creatinine concentration, hepatic encephalopathy, clinically significant coagulation defect [international normalized ratio> 2.0], hypoglycemia, hyponatremia, hypernatremia, hypokalemia, hyperkalemia, and hypocalcemia), and obstetric complications (antepartum, intrapartum, or postpartum hemorrhage; premature rupture of membranes; and intrauterine death). If their condition improved, patients were discharged and instructed to return for regular outpatient follow-up visits until delivery. Patients with fulminant hepatic failure were managed with supportive care in the intensive care unit because liver transplantation facilities are not available in the hospital. They were monitored for increased intracranial tension along with other medical and obstetric complications. They received 20% mannitol, lactulose, antibiotics, parenteral nutrition, and ventilatory support, as needed. Women without fulminant hepatic failure who had fetal distress, meconium staining of amniotic fluid, no progress of labor, or obstructed labor underwent cesarian section. Termination of pregnancy was considered in cases of intrauterine death, severe intrauterine growth retardation, a nonreactive nonstress test result, postdated pregnancy, and premature rupture of membrane at term only if the patient had improving liver function and a coagulation profile that could be further corrected by giving fresh frozen plasma. Termination of pregnancy was not considered for women with fulminant hepatic failure. All women with manifestations of bleeding were infused with fresh frozen plasma and packed red cells. In keeping with the policy of our institutions, the study did not require institutional review board approval or documented informed consent from patients for study participation because patients received care according to a standard clinical protocol, their care was not influenced by their inclusion in the study, and data were collected and recorded according to ethical standards and norms in India and were analyzed with total anonymity of patients. Statistical Analysis We used the t test and the MannWhitney U test to compare normally distributed data and non-normally distributed data, respectively, of HEV-infected and nonHEV-infected patients. The chi-square test was used to compare discrete values between groups. A P value less than 0.05 was considered significant. Relative risk was calculated for all complications in HEV-infected pregnant women versus nonHEV-infected pregnant women. Statistical analyses were done by using SPSS, version 13.0 (SPSS, Chicago, Illinois). Role of the Funding Source The study received no external funding. Results Patients Of the 33385 pregnant women who were admitted during the study period, 316 (0.9%) presented with jaundice. Ninety-two were excluded for causes of jaundice other than viral hepatitis (intrahepatic cholestasis of pregnancy [41 women], the HELLP syndrome [6 women], acute fatty liver of pregnancy [3 women], drug hepatotoxicity [7 women], hemolytic jaundice [14 women], choledocholithiasis [6 women], and unknown cause [15 women]), and 4 were excluded for dual viral infection. The remaining 220 pregnant women with jaundice met the inclusion criteria for acute viral hepatitis. None had evidence of autoimmune disease. Table 1 shows patient characteristics. The mean maternal age was 22.4 years (SD, 3.2). Sixty-one women (28%) were in the second trimester of pregnancy (mean gestational age, 26.2 weeks [SD, 2.0]) and 159 (72%) were in the third trimester (mean gestational age, 34.2 weeks [SD, 2.6]). The mean duration of jaundice before hospitalization was 4.9 days (SD, 2). Table 1. Patient Characteristics* Cause of Hepatitis Infection with HEV was the most common cause of acute viral hepatitis (132 participants [60%]) (Table 1). Hepatitis B virus (HBV) infection was the most common cause of nonHEV acute viral hepatitis (72 participants [33%]). Fewer HEV-infected patients than nonHEV-infected patients were in their third trimester of pregnancy, corresponding to a lower mean gestational age for HEV-infected patients (31 weeks [SD, 4.1] vs. 33 weeks [SD, 4.4]; P= 0.004) (Table 1). The median duration of jaundice did not differ between HEV-infected women and nonHEV-infected women (4 days [range, 1 to 15 days] vs. 4.5 days [range, 2 to 10 days]; P= 0.68). Fulminant Hepatic Failure Ninety-one women (41%) had fulminant hepatic failure, of whom 54 (59%) had fulminant hepatic failure on admission and 37 (41%) developed fulminant hepatic failure during hospitalization. Fulminant hepatic failure was more common among HEV-infected women than nonHEV-infected women (73 of 132 [55%] vs. 18 of 88 [20%]; relative risk, 2.7 [CI, 1.7 to 4.2]; P< 0.001) (Table 1) and among HEV-infected women in their third trimester (46 of 88 [52%] vs. 11 of 71 [15%] noninfected women; relative risk, 3.4 [CI, 1.9 to 6.0]; P< 0.001). The frequency of fulminant hepatic failure did not statistically significantly differ between HEV-infected women and nonHEV-infected women in their second trimester (27 of 44 [61%] vs. 7 of 17 [41%]; P= 0.26). Jaundice before hospital admission was of longer duration in women with fulminant hepatic failure than in those without fulminant hepatic failure (5.4 days [SD, 2.6] vs. 4.6 days [SD, 1.5]; P= 0.010). In women who developed fulminant hepatic failure, the mean interval from onset of jaundice to onset of encephalopathy was 108 hours (SD, 58) and was similar in HEV-infected and nonHEV-infected women (112 hours [SD, 60] vs. 93 hours [SD, 50]; P= 0.18). The mean duration of encephalopathy before admission was 20 hours (SD, 15) and was similar in HEV-infected and nonHEV-infected women. Maternal Mortality and Complications of Infection Maternal mortality was higher in HEV-infected women and occurred exclusively in women with fulminant hepatic failure (Table 2). Signs and complications of infection that differed by HEV status were an international normalized ratio greater than 2.0, nasal or gastrointestinal hemorrhage, leukocyte count of 11109 cells/L or greater, high serum creatinine concentration (34 mol/L [2 mg/dL]), ascites, and signs of increased intracranial tension. Differenc

Beneficial effects of terlipressin in hepatorenal syndrome: a prospective, randomized placebo-controlled clinical trial.

Background and Aim:  Hepatorenal syndrome (HRS) occurs in about 18% of cirrhotic patients with ascites and is characterized by intense renal vasoconstriction, low glomerular filtration rate and preserved tubular function and normal renal histology. The aim of the present study was to examine the effects of terlipressin on renal function, systemic hemodynamics and clinical outcome in patients with HRS.

Hepatocellular carcinoma (HCC): a global perspective

Peter Ferenci (chair) (Austria) Michael Fried (Switzerland) Douglas Labrecque (USA) J. Bruix (Spain) M. Sherman (Canada) M. Omata (Japan) J. Heathcote (Canada) T. Piratsivuth (Thailand) Mike Kew (South Africa) Jesse A. Otegbayo (Nigeria) S.S. Zheng (China) S. Sarin (India) S. Hamid (Pakistan) Salma Barakat Modawi (Sudan) Wolfgang Fleig (Germany) Suliman Fedail (Sudan) Alan Thomson (Canada) Aamir Khan (Pakistan) Peter Malfertheiner (Germany) George Lau (Hong Kong) F.J. Carillo (Brazil) Justus Krabshuis (France) Anton Le Mair (The Netherlands)

Prospective randomized trial of endoscopic sclerotherapy versus variceal band ligation for esophageal varices: influence on gastropathy, gastric varices and variceal recurrence

BACKGROUND/AIMS Endoscopic variceal ligation and endoscopic sclerotherapy are both recommended for the prevention of variceal rebleeding. To compare their efficacy, their influence on gastric varices and the development of portal gastropathy, 95 patients with variceal bleeding were studied. METHODS The patients were randomized to receive weekly endoscopic sclerotherapy using alcohol (n=48) or endoscopic variceal ligation (n=47). The endoscopic sclerotherapy and endoscopic variceal ligation groups were comparable in etiology, severity of liver disease and grade of varices. RESULTS In the arrest of acute bleed, endoscopic sclerotherapy and endoscopic variceal ligation were comparable (86% vs. 80%, p=ns). Endoscopic variceal ligation as compared to endoscopic sclerotherapy, obliterated esophageal varices in fewer sessions (4.1+/-1.2 vs. 5.2+/-1.8, p<0.01) and a shorter time (4.4+/-1.3 vs. 6.9+/-3.4 wk, p<0.01). Three (6.4%) patients bled after endoscopic variceal ligation and 10 (20.8%) after endoscopic sclerotherapy (p<0.05). The actuarial percentage of variceal recurrence during a follow-up of 8.5+/-4.4 months, was higher after endoscopic variceal ligation than endoscopic sclerotherapy (28.7% vs 7.5%, p<0.05). Esophageal stricture formation after endoscopic sclerotherapy occurred in five (10.4%) patients, but in none after endoscopic variceal ligation. Significantly more patients developed gastropathy after endoscopic sclerotherapy than ligation (20.5% vs. 2.3%; p=0.02). Endoscopic sclerotherapy (52%) and endoscopic variceal ligation (59%) were equally effective in obliterating the lesser curve gastric varices. Six patients died: three in each group. CONCLUSIONS (i) Endoscopic sclerotherapy and endoscopic variceal ligation were equally effective in controlling acute bleed; (ii) endoscopic ligation achieved variceal obliteration faster and in fewer treatment sessions; (iii) endoscopic variceal ligation had a significantly lower rate of development of portal gastropathy and rebleeding, (iv) while both techniques influenced gastric varices equally, there was significantly higher esophageal variceal recurrence after endoscopic variceal ligation than sclerotherapy.

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.