Erratum to 'Indian National Association for the Study of Liver Consensus Statement on Acute Liver Failure (Part-2): Management of Acute Liver Failure' [J Clin Exp Hepatol 10 (2020) 477-517].

[This corrects the article DOI: 10.1016/j.jceh.2020.04.011.].

Indian National Association for the Study of Liver Consensus Statement on Acute Liver Failure (Part-2): Management of Acute Liver Failure.

Acute liver failure (ALF) is not an uncommon complication of a common disease such as acute hepatitis. Viral hepatitis followed by antituberculosis drug-induced hepatotoxicity are the commonest causes of ALF in India. Clinically, such patients present with appearance of jaundice, encephalopathy, and coagulopathy. Hepatic encephalopathy (HE) and cerebral edema are central and most important clinical event in the course of ALF, followed by superadded infections, and determine the outcome in these patients. The pathogenesis of encephalopathy and cerebral edema in ALF is unique and multifactorial. Ammonia plays a crucial role in the pathogenesis, and several therapies aim to correct this abnormality. The role of newer ammonia-lowering agents is still evolving. These patients are best managed at a tertiary care hospital with facility for liver transplantation (LT). Aggressive intensive medical management has been documented to salvage a substantial proportion of patients. In those with poor prognostic factors, LT is the only effective therapy that has been shown to improve survival. However, recognizing suitable patients with poor prognosis has remained a challenge. Close monitoring, early identification and treatment of complications, and couseling for transplant form the first-line approach to manage such patients. Recent research shows that use of dynamic prognostic models is better for selecting patients undergoing liver transplantation and timely transplant can save life of patients with ALF with poor prognostic factors.

Indian National Association for the Study of the Liver Consensus Statement on Acute Liver Failure (Part 1): Epidemiology, Pathogenesis, Presentation and Prognosis.

Acute liver failure (ALF) is an infrequent, unpredictable, potentially fatal complication of acute liver injury (ALI) consequent to varied etiologies. Etiologies of ALF as reported in the literature have regional differences, which affects the clinical presentation and natural course. In this part of the consensus article designed to reflect the clinical practices in India, disease burden, epidemiology, clinical presentation, monitoring, and prognostication have been discussed. In India, viral hepatitis is the most frequent cause of ALF, with drug-induced hepatitis due to antituberculosis drugs being the second most frequent cause. The clinical presentation of ALF is characterized by jaundice, coagulopathy, and encephalopathy. It is important to differentiate ALF from other causes of liver failure, including acute on chronic liver failure, subacute liver failure, as well as certain tropical infections which can mimic this presentation. The disease often has a fulminant clinical course with high short-term mortality. Death is usually attributable to cerebral complications, infections, and resultant multiorgan failure. Timely liver transplantation (LT) can change the outcome, and hence, it is vital to provide intensive care to patients until LT can be arranged. It is equally important to assess prognosis to select patients who are suitable for LT. Several prognostic scores have been proposed, and their comparisons show that indigenously developed dynamic scores have an edge over scores described from the Western world. Management of ALF will be described in part 2 of this document.

Immunoglobulin G4 related pancreaticobiliary disease: Report of two cases highlighting the diagnostic criteria.

Two cases of immunoglobulin (IgG4)-related biliary and pancreaticobiliary disease are reported to define its diagnostic features. Case 1 presented with obstructive jaundice and showed IgG4-related disease (RD) involving right and left hepatic duct, common bile duct and gallbladder. Case 2 presented as periampullary mass. Both patients underwent surgical intervention. However, certain clinical and radiological features were present in these cases indicative of the possibility of IgG4-RD.

Clinical profile, etiology and therapeutic outcome in 324 hepatocellular carcinoma patients at a tertiary care center in India.

OBJECTIVE: To study the profile and outcome of therapy for hepatocellular carcinoma (HCC) in India. METHODS: Data analysis of HCC patients enrolled in liver clinic between 1990 and 2005. RESULTS: We registered 324 HCC patients [males 284 (88%), mean age 52.4 +/- 13.1 years]. The etiology of HCC was: hepatitis B virus 165 (51%), hepatitis C virus 38 (12%), alcohol 20 (6%), combined 31 (10%) and unknown 70 (21%). Serum alpha-fetoprotein was >400 ng in 36%, portal vein invasion was seen in 40% and distant metastases in 13%. Therapy was offered to 141 (43.5%) patients, but survival data was available in only 130 (93%) of them. Treatment given and median survival time was as follows: surgical resection, 19 months (n = 14); transarterial chemoembolization, 11 months (n = 23); transarterial rhenium therapy, 26 months (n = 7); radiofrequency ablation, 24 months (n = 4); acetic acid ablation, 13 months (n = 17); oral chemotherapy, 26 months (n = 33), and combination therapy, 26 months (n = 32). Vascular invasion, Okuda staging and therapy were independent factors associated with survival. Treated patients had longer median survival compared to untreated ones (16 months vs. 7 months, p < 0.05). CONCLUSIONS: Hepatitis B infection is the predominant cause of HCC in India. Serum alpha-fetoprotein was diagnostic in only one third of our patients. Most patients present late, when curative therapies are not possible. Treated patients had better survival than untreated ones.

HBV genotypes in India: do they influence disease severity?

AIMS: Association of HBV genotypes (especially A and D) with severity of liver disease is controversial. We studied the influence of HBV genotypes on liver disease severity among Indian patients. METHODS: We selected 247 HBV infected patients (42 acute hepatitis, 87 carriers, 44 chronic hepatitis B [CHB], 35 liver cirrhosis [LC] and 40 hepatocellular carcinoma [HCC]). Genotyping of stored sera was performed using genotype-specific enzyme-linked immunosorbent assay (ELISA) and restriction fragment length polymorphism (RFLP). The distribution of genotypes in disease states of differing clinical, histological and biochemical severity were compared. RESULTS: The most common genotype was D (162/237, 68.3%), followed by A (61, 25.7%) and C (14, 5.9%). The distribution of HBV genotypes between patients with acute hepatitis and CHB (carriers + CHB + LC + HCC), or between carriers and disease states (CHB + LC + HCC), or between mild chronic infection (carriers + CHB) and complications of chronic HBV infection (LC + HCC) was similar. Eighty-seven patients had liver biopsy; the median histological activity index (HAI) and fibrosis stage at baseline were similar between genotype groups (four [1-9] genotype A [n = 28]), three (2-4) genotype C (n = 4) and four (1-10) genotype D (n = 55); P = 0.33 for HAI score; (0.5 [0-6] genotype A, 0.5 [0-4] genotype C and 1 [0-6] genotype D; P = 0.92 for fibrosis stage). The response to therapy was similar between the genotypes. CONCLUSION: Clinical, histological severity and therapeutic responses are similar among patients with HBV genotypes A and D.

Non-alcoholic fatty liver disease may not be a severe disease at presentation among Asian Indians.

AIM: To evaluate the clinical and biochemical profile of patients with non alcoholic fatty liver disease (NAFLD) and to assess their histological severity at presentation. METHODS: Consecutive patients presenting to the liver clinic of All India Institute of Medical Sciences (AIIMS) with raised transaminases to at least 1.5 times upper limit of normal, and histologically confirmed non-alcoholic fatty liver disease were included. Patients who had significant alcohol intake or positive markers of other liver diseases or who were taking drugs known to produce fatty liver were excluded. The clinical, biochemical and histological profile of this group was studied. RESULTS: Fifty-one patients with NAFLD formed the study population. Their median age and BMI were 34(17-58) years and 26.7(21.3-32.5) kg/m(2) respectively and 46 (90.1%) were males. The majority of the patients had mild inflammation, either grade 1 [32 (63%)] or grade 2 [16 (31%)] and only 3 (6%) patients had severe (grade 3) inflammation. Twenty-three (45%), 19 (37%), 8(16%) and 1(2%) patient had stage 0, 1, 2 and 3 fibrosis respectively on index biopsy and none had cirrhosis. On univariate analysis, triglyceride levels more than 150 mg % (OR = 7.1; 95% CI: 1.6-31.5, P = 0.002) and AST/ALT ratio>1 (OR = 14.3; 95% CI: 1.4-678.5, P = 0.008) were associated with high grades of inflammation and none was associated with advanced fibrosis. On multivariate logistic regression analysis, hypertriglyceridemia >150 mg% was the only factor independently associated with presence of high grade of inflammation (OR = 1.6; 95% CI: 1.3-22.7, P = 0.02), while none was associated with advanced fibrosis. Triglyceride levels correlated positively with inflammatory grade (r = 0.412; P = 0.003). CONCLUSION: NAFLD in North Indian patients is a disease of young over-weight males, most of whom are insulin resistant and they tend to have a mild histological disease at presentation.

Gallbladder cancer in India: a dismal picture.

BACKGROUND: Gallbladder cancer (GBC) is one of the most common gastrointestinal malignancies. The data regarding GBC are, however, limited. METHODS: Records of 634 patients with GBC over a 10-year period were examined with regard to the clinical presentation, investigative findings, treatment, operative findings and outcome. RESULTS: The mean age of patients was 51 +/- 11 years and men : women ratio was 0.36:1.00. Pain, jaundice and hepatomegaly were seen in 81.0%, 76.0% and 61.5% patients, respectively. On imaging, a mass replacing the gallbladder was seen in 73% patients. Gallstones were present in 54% patients. Surgery was carried out in 291 (46%) patients and endoscopic treatment in 72 (19%) patients but no intervention was carried out in the remaining patients because of disseminated disease. Among the patients who were operated on, 2.0% had stage I GBC, 3.4% stage II, 17.5% stage III, 47.0% stage IVa and 29.8% stage IVb. Radical resection was possible in 133 (46%) patients. The 30-day mortality was 10% with most (90%) deaths in patients with stage IV disease. The median survival after simple cholecystectomy and radical surgery was 33.5 and 12.0 months, respectively. However, among those who underwent debulking, palliative bypass or exploratory laparotomy alone, the survival ranged between 1 and 3 months. Logistic regression analysis showed that only radical resection improved the long-term survival (P < 0.05). CONCLUSIONS: The majority of patients with GBC in India have advanced unresectable disease. Detection of GBC at an early stage is incidental and rare but is associated with long-term survival. Radical surgery, when feasible, is the only option for achieving long-term survival.

Vitamin E-based therapy is effective in ameliorating transaminasemia in nonalcoholic fatty liver disease.

BACKGROUND: Comparative trials of ursodeoxycholic acid (UDCA), vitamin E and weight management programs among patients with nonalcoholic fatty liver disease (NAFLD) are lacking. AIM: To find an effective single agent or combination of agents for management of NAFLD. METHODS: In this retrospective study, consecutive patient with histologically confirmed NAFLD with raised ALT were included. The patients received either weight management (exercise and therapeutic lifestyle changes [TLC] diet with a target to reduce body weight 10% in 6 months) (group I) ; weight management + UDCA (300 mg BID) (group II); or weight management + UDCA + vitamin E (400 mg OD) (group III). Outcome measure was normalization of ALT. RESULTS: 42 patients (18, 12 and 12 in groups I, II and III, respectively) were included between 1996 and 2004. All patients in group III normalized their ALT levels, which was significantly higher than numbers in group I (8/18) and group II (5/12); (p=0.003). Post treatment ALT was significantly lower in group III (28.6 [9.3]) as compared to group I (59.3 [32.2]) and group II (49.0[31.8]); (p=0.01). Type of therapy received was the only factor predictive of ALT normalization. CONCLUSION: Combination regimen containing vitamin E appears to be effective in normalizing ALT among NAFLD patients.

Role of polymerase chain reaction and liver biopsy in the evaluation of patients with asymptomatic transaminitis: implications in diagnostic approach.

BACKGROUND AND AIM: Detection of an asymptomatic rise in the hepatic aminotransferase (ARHA) value has become a distinct and frequent clinical problem. We evaluated a three-step diagnostic algorithm in such patients for maximum yield. METHODS: Consecutive patients with an ARHA value 1.5-fold the upper limit of normal for at least 4 weeks and who were apparently healthy were included in the study. Each patient underwent standard biochemical investigations and a stepwise investigative protocol. In the first step, serological markers for hepatitis viruses, serum ferritin, 24-h urinary copper, alpha-1-antitrypsin phenotyping, and autoimmune markers were carried out. In step two, patients who tested negative for all the above markers had polymerase chain reaction (PCR) analysis for hepatitis B virus (HBV)-DNA and hepatitis C virus (HCV)-RNA. Patients without a diagnosis despite the above investigations underwent a liver biopsy as part of step three. RESULTS: Of 105 patients with ARHA, 38 were excluded for various reasons and 67 were included for the final analysis. The mean age was 35.11 +/- 11.96 years and 56 patients were men. The mean body mass index was 24.17 +/- 3.2 kg/m(2). The stepwise diagnostic algorithm achieved a diagnosis in 65/67 (97%) patients. Non-alcoholic steatohepatitis (NASH) and chronic viral hepatitis were the most common diagnoses, in 24 (36%) patients each. Using the diagnostic algorithm a diagnosis was reached in 34% of patients with only serological and biochemical investigations, whereas PCR for HBV and HCV could further detect the presence of active HBV or HCV viremia in 21% (14/97) and a liver biopsy was necessary to establish the diagnosis in 28/67 (42%) patients. CONCLUSIONS: A stepwise diagnostic algorithm in patients with ARHA resulted in an optimal use of PCR and invasive tests such as liver biopsy. Cryptic HBV and HCV infection was frequent among these patients and PCR was necessary in such cases. NASH and chronic viral hepatitis were the most frequent causes of ARHA.

Molecular adsorbent and re-circulating system.

The molecular adsorbent recirculating system (MARS) is a non-biological artificial liver support system. Used for almost a decade, there are only two randomized controlled trials on the efficacy of MARS till date. A number of uncontrolled studies have documented a marked improvement in the biochemical parameters of patients after MARS. Although MARS seems to be an effective and promising tool in the management of liver failure, its cost needs to be reduced to enable it use in a member of indications.

Treatment of hepatitis C virus infection in patients of northern India.

BACKGROUND AND AIM: The purpose of the present study was to evaluate the therapeutic response of north Indian patients with chronic hepatitis C (CH-C) to two different treatment regimens of interferon and ribavirin. METHODS: Consecutive patients with a diagnosis of CH-C attending the Liver Clinic at the All India Institute of Medical Sciences, New Delhi between April 1999 and April 2002 were included in the study. A competitive reverse transcription-polymerase chain reaction (RT-PCR) method developed in the authors' laboratory was used for quantification of hepatitis C virus (HCV)-RNA. Genotyping of HCV was also determined. The clinical, biochemical, virological and histological parameters were used to assess the therapeutic response among a clinical cohort of patients with chronic hepatitis C. They were treated with two different protocols (interferon [IFN]-alpha-2b, 3 million units daily and ribavirin 10.6 mg/kg daily in two divided doses for 6 months or IFN-alpha-2b, 3 million units thrice weekly and ribavirin 10.6 mg/kg daily for 6 months). RESULTS: Sixty-five patients with CH-C were included in the study. Blood transfusion (n = 28, 43%) and community-acquired (n = 23, 35%) HCV infections were the commonest. The mean HCV load was high (24.14 +/- 12.5 x 10(8) copies/mL). Genotype 2 and 3 were prevalent in 80% (41/51) of the patients. Forty-five patients received 3 million units of IFN thrice weekly and 20 received the same dose daily. All received the same dose of ribavirin. A sustained virological response (SVR) of 95% (19/20) was achieved among patients receiving daily IFN, whereas 64.4% (29/45) of those who received IFN thrice weekly had SVR. The virological relapse was significantly lower among patients who received daily IFN than in those treated with thrice weekly IFN (n = 1/20, 5% vs 10/39, 25.6%; P = 0.015). The proportion of patients receiving daily IFN among those achieving SVR (19/48, 40%) was significantly higher than the proportion of patients receiving similar therapy among patients without SVR (1/17, 6%; P = 0.02). CONCLUSIONS: Transfusion and community-acquired HCV infection were the major causes of CH-C. Genotype 2 and 3 HCV were most prevalent among these patients. Despite high viral load, these patients responded well to a combination of daily IFN-alpha-2b and ribavirin.

Prophylactic phenytoin does not improve cerebral edema or survival in acute liver failure--a controlled clinical trial.

BACKGROUND/AIMS: Seizure activity in patients with acute liver failure (ALF) may increase cerebral oxygen requirements and worsen cerebral edema. Recently, prophylactic phenytoin has been recommended to suppress sub-clinical seizure activity evident on electroencephalographic monitoring. To determine the clinical utility of prophylactic phenytoin therapy in patients with ALF. METHODS: Forty two patients with ALF were randomized. Twenty two patients were given prophylactic phenytoin and 22 patients acted as controls. The baseline clinical and biochemical features were similar in the two groups and patients with > or =2 poor prognostic variables were equally represented. RESULTS: Sixteen patients in the phenytoin group, and 15 in the control group developed cerebral edema (P=0.38). Mechanical ventilation was required in 10 and 12 patients in the phenytoin and control groups, respectively, (P=0.77). Seizures occurred in 5 (22.7%) control patients and 5 (25%) phenytoin treated patients (P=0.86). Fourteen (70%) patients randomized to phenytoin and 15 (68.2%) control patients died (P=0.89). CONCLUSIONS: Seizure was common in patients with ALF. Prophylactic use of phenytoin did not prevent cerebral edema, seizures or need for mechanical ventilation, and did not improve survival.

Predictors of unsuccessful mechanical lithotripsy and endoscopic clearance of large bile duct stones.

BACKGROUND: Mechanical lithotripsy is used to break large bile duct stones. This study investigated the predictors of unsuccessful mechanical lithotripsy. METHODS: Consecutive patients with bile duct stones underwent endoscopic retrograde cholangiography, sphincterotomy, and basket removal of stones. Mechanical lithotripsy was performed for stones of large size (>15 mm diameter) that precluded extraction intact. Success was defined as complete clearance of the duct. Various predictive factors, including size and number of stones, stone impaction, serum bilirubin, presence of cholangitis, and bile duct diameter were analyzed in relation to the success or failure of lithotripsy. RESULTS: A total of 669 patients underwent endoscopic retrograde cholangiography for suspected choledocholithiasis, which was found in 401 patients. Of the latter patients, 87 had large stones that required mechanical lithotripsy. Lithotripsy was successful in 69 (79%) patients. Impaction of the stone(s) in the bile duct was the only significant factor that predicted failure of lithotripsy and consequent failure of bile duct clearance. Other factors, including stone size, were not significant. CONCLUSIONS: Mechanical lithotripsy is successful in about 79% of patients with large bile duct stones. The only significant factor that predicts failure of mechanical lithotripsy is stone impaction in the bile duct.

Acute liver failure: prognostic markers.

Acute liver failure (ALF) is defined as liver failure occurring within one month of the occurrence of jaundice. The disease has a grim prognosis, with a mortality of 65% to 85%. The management of ALF has till recently been conservative, and newer therapeutic modalities like bioartificial liver, hepatocyte transplant, and extracorporeal liver assist devices have not yet been proven to be successful. Liver transplant has changed the gloomy outlook of the disease, and post-transplant survival rates of 60%-70% have been reported from most centers. However liver transplant is expensive, necessitates life-long immunosupression, and is limited by a global shortage of available organs. It is thus necessary to select patients who are at greatest risk of death for liver transplantation. Prognostic criteria are based primarily either on clinical and laboratory (coagulation tests, serum bilirubin) parameters, or on other parameters like liver volume. Prognostic criteria have been developed both from the East and the West; these are essentially similar except that the Western criteria take into account etiology (drug overdose being the main cause of ALF there) as well as jaundice-encephalopathy interval as factors for prognostication. The King's College criteria were one of the first prognostic systems; it has two parts for both paracetamol as well as non paracetamol ALF. The criteria from our institute found prothrombin time >25 s, serum bilirubin >15 mg/dL, age >40 years, and cerebral edema to be bad prognostic markers. Criteria from the PGIMER, Chandigarh found age >50 years, raised intracranial pressure, prothrombin time >100 s, and onset of HE more than seven days after the jaundice as poor prognostic markers. All these clinical criteria have similar sensitivity and specificity.

Vaccination for hepatitis A virus is not required for patients with chronic liver disease in India.

BACKGROUND: Hepatitis A virus (HAV) vaccination is recommended worldwide for patients with chronic liver disease to prevent decompensation due to superinfection with HAV. India being endemic for HAV, the prevalence of pre-existing antibodies against HAV due to subclinical exposure to the virus in childhood among patients with chronic liver disease may be high and, therefore, vaccination may not be needed. However, data are lacking on the prevalence of HAV antibody among patients with chronic liver disease in India. METHODS: Two hundred fifty-four patients attending the Liver Clinic at the All India Institute of Medical Sciences, New Delhi during the past 5 years and diagnosed to have either chronic hepatitis due to the hepatitis B virus (n = 76), hepatitis C virus (n = 84) or cirrhosis of the liver due to the hepatitis B (n = 47) or C (n = 47) virus were tested for the presence of IgG anti-HAV antibody in their sera (using a commercial ELISA kit). RESULTS: Two hundred forty-eight (97.6%) patients tested positive for IgG anti-HAV. The prevalence of anti-HAV positivity was similar among patients with chronic hepatitis B (74, 97.4%), chronic hepatitis C (82, 97.6%), cirrhosis of the liver due to the hepatitis B (46, 97.8%) and hepatitis C (46, 97.8%) virus. CONCLUSION: Vaccination against HAV is not required among patients with chronic liver disease in India as there is a very high prevalence of pre-existing antibodies in these patients.

Post cholecystectomy hemobilia: transcatheter embolization of pseudoaneurysms with homemade steel coils.

Two patients presented with hemobilia, one and two months following cholecystectomy. Angiography demonstrated pseudoaneurysms arising form the gastroduodenal and right hepatic arteries. Percutaneous transcatheter embolization of the pseudoaneurysms was successfully performed in both patients using homemade steel coils.