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.].

Prognostic, clinical, and therapeutic importance of RANTES-CCR5 axis in hepatitis A infection: A multiapproach study.

Fulminant hepatic failure (FHF) is a lethal manifestation of hepatitis A virus (HAV) infection, whose underlying mechanisms are poorly understood. We aimed to evaluate the importance of the modulation of the RANTES-chemokine receptor type 5 (CCR5) signaling axis and its immunomodulatory effects in directing hepatitis A disease pathogenesis using an in silico, in vitro and patient cohort-based approach. In silico interaction studies were performed using computation approaches with suitable software. Differential expression of relevant cytokines and immune cell markers were studied using real-time quantitative reverse transcription PCR (qRT-PCR), enzyme-linked immunosorbent assay, and flow-cytometry-based methods. In the HepG2 cell line, we studied inflammatory responses and susceptibility to HAV infection following RANTES stimulation and antibody blockade of CCR5. The HAV-VP3 region exhibited high interaction in CCR5: HAV complexes. RANTES levels were significantly increased in FHF cases. Reduced monocyte and T-cell activation were observed in FHF cases. RANTES expression inversely correlated with viremia but positively correlated with proinflammatory responses. Hyper Th1-biased immune responses, marked by high interleukin (IL)-12/IL-10 ratio were observed in FHF cases, which were also characterized by upregulated tumor necrosis factor-alpha (TNF-α) expression and reduced interferon-gamma expression. In vitro, RANTES was protective against HAV infection but resulted in upregulated TNF-α expression. Although viral load increased upon the regulation of inflammatory responses by CCR5 blocking, it was still significantly lower compared to control HAV-infected cells. Our study suggests the importance of RANTES-CCR5 signaling and linked-immunomodulation in HAV disease pathogenesis, as well as highlights the utility of CCR5 antagonists as a risk-reduction strategy in FHF patients. Our findings, therefore, have important implications for the management of high-risk HAV infections.

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.

2019 Update of Indian National Association for Study of the Liver Consensus on Prevention, Diagnosis, and Management of Hepatocellular Carcinoma in India: The Puri II Recommendations.

Hepatocellular carcinoma (HCC) is one of the major causes of morbidity, mortality, and healthcare expenditure in patients with chronic liver disease in India. The Indian National Association for Study of the Liver (INASL) had published its first guidelines on diagnosis and management of HCC (The Puri Recommendations) in 2014, and these guidelines were very well received by the healthcare community involved in diagnosis and management of HCC in India and neighboring countries. However, since 2014, many new developments have taken place in the field of HCC diagnosis and management, hence INASL endeavored to update its 2014 consensus guidelines. A new Task Force on HCC was constituted that reviewed the previous guidelines as well as the recent developments in various aspects of HCC that needed to be incorporated in the new guidelines. A 2-day round table discussion was held on 5th and 6th May 2018 at Puri, Odisha, to discuss, debate, and finalize the revised consensus statements. Each statement of the guideline was graded according to the Grading of Recommendations Assessment Development and Evaluation system with minor modifications. We present here the 2019 Update of INASL Consensus on Prevention, Diagnosis, and Management of Hepatocellular Carcinoma in India: The Puri-2 Recommendations.

Indian National Association for the Study of the Liver-Federation of Obstetric and Gynaecological Societies of India Position Statement on Management of Liver Diseases in Pregnancy.

Liver diseases occurring during pregnancy can be serious and can progress rapidly, affecting outcomes for both the mother and fetus. They are a common cause of concern to an obstetrician and an important reason for referral to a hepatologist, gastroenterologist, or physician. Liver diseases during pregnancy can be divided into disorders unique to pregnancy, those coincidental with pregnancy, and preexisting liver diseases exacerbated by pregnancy. A rapid differential diagnosis between liver diseases related or unrelated to pregnancy is required so that specialist and urgent management of these conditions can be carried out. Specific Indian guidelines for the management of these patients are lacking. The Indian National Association for the Study of the Liver (INASL) in association with the Federation of Obstetric and Gynaecological Societies of India (FOGSI) had set up a taskforce for development of consensus guidelines for management of patients with liver diseases during pregnancy, relevant to India. For development of these guidelines, a two-day roundtable meeting was held on 26-27 May 2018 in New Delhi, to discuss, debate, and finalize the consensus statements. Only those statements that were unanimously approved by most members of the taskforce were accepted. The primary objective of this review is to present the consensus statements approved jointly by the INASL and FOGSI for diagnosing and managing pregnant women with liver diseases. This article provides an overview of liver diseases occurring in pregnancy, an update on the key mechanisms involved in its pathogenesis, and the recommended treatment options.

Impact of maternal nutrition in hepatitis E infection in pregnancy.

BACKGROUND AND AIM: The basis of host response in hepatitis E virus (HEV)-related liver disease during pregnancy-is still unclear. The study aims to evaluate anthropometric parameters and biochemical nutritional parameters in hepatitis E infection during pregnancy and correlate it with severity of the disease. METHODS: A total of consecutive 267 pregnant women with jaundice were recruited. The jaundiced patients were classified as acute viral hepatitis (AVH) or acute liver failure (ALF). The study group included 144 pregnant women with HEV infection and 144 healthy asymptomatic age and gestational age-matched pregnant women as controls. Nutritional factors were evaluated on basis of anthropometric parameters and biochemical factors. Serum prealbumin and folate were assayed by ELISA kit. RESULTS: All nutritional parameters were significantly lower in pregnant women with HEV infection as compared with healthy pregnant controls. Some of the nutritional parameters significantly lower in ALF pregnant patients compared to AVH pregnant patients in HEV group. Linear regression analysis of the AVH group showed that serum total protein and mid-upper arm circumference (MUAC) were significant predictors for bilirubin, body mass index (BMI) could significantly predict viral load level, and total protein, prealbumin, folate, and tricep skin fold thickness (TSFT) could significantly predict prothrombin time. In ALF group, serum prealbumin could significantly predict bilirubin levels and MUAC could significantly predict prothrombin time. CONCLUSION: Malnutrition might confer a higher predisposition for HEV infection during pregnancy and is associated with increased severity of disease in terms of occurrence of ALF.

Does angiotensin-converting enzyme-1 (ACE-1) gene polymorphism lead to chronic kidney disease among hypertensive patients?

BACKGROUND: Hypertension is one of the important contributing factors linked with both causation and development of kidney disease. It is a multifactorial, polygenic, and complex disorder due to interaction of several risk genes with environmental factors. The present study was aimed to explore genetic polymorphism in ACE-1 gene as a risk factor for CKD among hypertensive patients. METHODS: Three hundred patients were enrolled in the study. Ninety were hypertensive patients with CKD taken as cases, whereas 210 hypertensive patients without CKD were taken as controls. Demographic data including age, sex, Body mass index (BMI), and other risk factors were also recorded. DNA was extracted from blood by salting out method. Genotyping of ACE gene was done by PCR technique. All the statistical analysis was done by using Epi Info and SPSS version 16 software (SPSS Inc., Chicago, IL). RESULTS: Mean age was higher in the control group (p < 0.05). Variables among two groups were compared out of which age, BMI, hemoglobin (Hb) was found to be statistically significant whereas other variables like systolic blood pressure, triglyceride and low-density lipoprotein were not. Blood urea and serum creatinine levels were statistically significant in the two genotypes (p < 0.05). Total and HDL cholesterol were statistically significant for DD genotype of ACE gene (OR = 1.42, 95% CI = 0.72-2.81). Similarly, the risk for CKD among hypertensive patients was also associated with D allele of ACE gene (OR = 1.25, 95% CI = 0.86-1.79). CONCLUSION: It is concluded that ACE-DD genotype may be a risk factor for the causation and development of chronic kidney failure among hypertensive patients.

Reduced glutathione in hepatitis E infection and pregnancy outcome.

AIM: To study reduced glutathione (GSH) as a marker of oxidative stress in hepatitis E virus (HEV) infection during pregnancy, and to clarify its association with pregnancy outcome. METHODS: A total of 30 pregnant and 30 non-pregnant women with HEV infection were enrolled in the present study, along with 30 age- and gestation-matched healthy pregnant controls. Serum GSH was measured using commercially available enzyme-linked immunoassay kit. RESULTS: Significantly lower GSH was observed in HEV-infected pregnant women than in healthy pregnant controls (10.44 ng/mL vs 19.77 ng/mL; P < 0.01). No significant association was observed between GSH and pregnant women and non-pregnant women with HEV infection (P = 0.54). Serum GSH ≤10.88 ng/mL was more likely to be associated with HEV infection during pregnancy, with sensitivity and specificity of 73.3%. Lower GSH was observed in pregnant women with HEV infection having preterm delivery and low birthweight newborns compared with healthy pregnant women (P < 0.01 and P < 0.05, respectively). Serum GSH was lower in pregnant women with HEV infection who had stillbirth compared with those having live births (7.21 ng/mL vs 6.12 ng/mL, P = 0.60). CONCLUSION: Oxidative stress is present in HEV infection during pregnancy, as shown by low GSH, and is associated with adverse pregnancy outcomes. Serum GSH ≤10.88 ng/mL during pregnancy can be used for risk stratification for HEV infection.

Frequency of nucleotide sequence variations in the internal ribosome entry site region of hepatitis C virus RNA isolated from responding and non-responding patients with hepatitis C virus genotype 3 infection.

Located within 5' untranslated region of HCV RNA is internal ribosome entry site (IRES) which directs cap-independent translation of viral polyprotein. Mutations in IRES sequence have been shown to cause changes in efficiency of protein translation in vitro in few instances. No study has been done to investigate association between frequency of nucleotide sequence variations in IRES region of HCV-3 RNA and response to pegylated interferon-α plus ribavirin therapy. Hence, this study was planned to analyze relationship between frequency of nucleotide sequence variations of HCV-3 IRES region and response to therapy. Twenty-seven HCV-3 patients were studied, of whom 19 responded to therapy and 8 did not. Alanine aminotransferase and aspartate aminotransferase levels were significantly lower in responders compared to non-responders. HCV RNA detection and genotyping was performed by nested-PCR and RFLP respectively. Viral load quantification in pre and post therapy samples was done by real time PCR. The viral load was significantly lower in the patients after treatment as compared to before treatment. HCV IRES region from pre-treatment sera of 27 HCV-3 infected patients was amplified by nested PCR and sequenced. Secondary structure of IRES region of HCV-3 was predicted using the M fold Web Server. Mutational analysis revealed hot spot of mutations in HCV-3 IRES region from 40-80 and 210-280 nucleotides. Though more mutations were found in non-responders as compared to responders, this difference was statistically insignificant. Therefore, in addition to IRES region of HCV-3, some other host and viral factors may contribute to therapy outcome.

Profile of Acute Liver Failure from North-east India and Its Differences from other Parts of the Country.

BACKGROUND: Acute liver failure (ALF) is a critical illness with a large number of viral and nonviral causes. Clinical course and etiologies in the Asian countries are different from those reported from the Western world and mortality is high. There may even be intracountry variations in large countries like India, which have differing culture, ethnicity, and environment. Data from North-east part of India is lacking. MATERIALS AND METHODS: Acute liver failure cases (>14 years of age) seen over a period of 8 years (n = 255) were studied at a Government Medical College in Assam for their etiological and other demographic profile. Viral serology was carried out and revalidated at a laboratory in New Delhi. RESULTS: Majority of cases were <30 years of age. Commonest etiology was nonviral (non-ABCE). Amongst viral causes, hepatitis A and E were common, while hepatitis B virus (HBV) was rare. Unknown herbal medication use was very frequent in our cases with a significantly higher mortality. Mortality was highest in cases in 3rd decade of life. Statistically, international normalized ratio (INR) was the strongest predictor of death. CONCLUSION: Unlike the rest of India, hepatitis virus is not the major cause of ALF in our part; hepatitis A being commoner than hepatitis E, and B is rare. Unknown herbal medications are major cause of mortality and is important medicosocial issue. Our study highlights the differences in the profile of ALF from other Indian and western studies, possibly due to sociocultural factors prevalent in this part. HOW TO CITE THIS ARTICLE: Das AK, Begum T, Kar P, Dutta A. Profile of Acute Liver Failure from North-east India and Its Differences from other Parts of the Country. Euroasian J Hepato-Gastroenterol 2016;6(2):111-115.

The Indian National Association for Study of the Liver (INASL) Consensus on Prevention, Diagnosis and Management of Hepatocellular Carcinoma in India: The Puri Recommendations.

Hepatocellular carcinoma (HCC) is one of the major causes of morbidity, mortality and healthcare expenditure in patients with chronic liver disease. There are no consensus guidelines on diagnosis and management of HCC in India. The Indian National Association for Study of the Liver (INASL) set up a Task-Force on HCC in 2011, with a mandate to develop consensus guidelines for diagnosis and management of HCC, relevant to disease patterns and clinical practices in India. The Task-Force first identified various contentious issues on various aspects of HCC and these issues were allotted to individual members of the Task-Force who reviewed them in detail. The Task-Force used the Oxford Center for Evidence Based Medicine-Levels of Evidence of 2009 for developing an evidence-based approach. A 2-day round table discussion was held on 9th and 10th February, 2013 at Puri, Odisha, to discuss, debate, and finalize the consensus statements. The members of the Task-Force reviewed and discussed the existing literature at this meeting and formulated the INASL consensus statements for each of the issues. We present here the INASL consensus guidelines (The Puri Recommendations) on prevention, diagnosis and management of HCC in India.

GSTM1 and GSTT1 polymorphism and susceptibility to esophageal cancer in high- and low-risk regions of India.

Glutathione transferases, a super family of dimeric phase II metabolic enzymes play a vital role in biotransformation of many substances. This study evaluates the influence of genetic polymorphism of GSTM1 and GSTT1 gene loci on esophageal cancer risk in Assam and Delhi from India. DNA from blood samples of esophageal cancer cases (203,112) and controls (286,150) from Assam and Delhi, respectively, were extracted. GSTM1 and GSTT1 polymorphisms were analyzed by multiplex PCR procedure. Differences in proportions were tested using Pearson's chi-square test with odds ratio (OR) and 95 % confidence interval (CI). Risk of esophageal cancer was approximately twice in individuals having homozygous GSTM1 (OR-2.1, 95 % CI, 1.44-3.13) and GSTT1 null genotypes (OR-1.7,95 % CI, 0.99-2.77) in Assam, and around three times in GSTT1 null genotype (OR-2.9, 95 % CI, 1.56-5.27) in Delhi population. GSTM1 null genotype seems to play a protective role (OR-0.7, 95 % CI, 0.39-1.27) in Delhi. A significant association of GSTM1 null genotype with esophageal cancer was observed in a younger age group in Assam (OR-2.7, 95 % CI, 1.48-5.01), and in Delhi population association was observed in smokers with GSTT1 null genotype (OR-2.5, 95 % CI, 1.04-6.07), and alcoholics having GSTM1 null genotype (OR-2.6, 95 % CI, 0.99-6.77). Significant association of GSTM1 null genotype in Assam was observed between cancer cases and controls in fermented betel nut chewers only (OR-2.8, 95 % CI, 1.19-6.72), whereas, smoking and alcohol failed to show any correlation with GSTM1/GSTT1 genotypes. Cancer development is not only due to exogenous or endogenous carcinogens but depends on their interaction with genes that are involved in the detoxification of these carcinogens.

Waldenstrom macroglobulinemia presenting with pancreatic mass: a case report and review of literature.

CONTEXT: Waldenstrom macroglobulinemia is a rare lymphoplasmacytic lymphoma characterized by a wide range of clinical presentations related to direct tumor infiltration and the production of IgM. Most commonly it presents with cytopenia, hepatosplenomegaly, lymphadenopathy, constitutional symptoms, and hyperviscosity syndrome. CASE REPORT: We report a case of Waldenstrom macroglobulinemia in an 60-year-old female who initially presented with intermittent abdominal pain. The patient had no peripheral lymphadenopathy. On extensive investigation she was found to have pancreatic mass. The diagnosis of Waldenstrom macroglobulinemia was established after cytomorphology and immunohistochemical analysis of the patient's bone marrow revealed the presence of a lymphoid/lymphoplasmacytoid-like bone marrow infiltrate along with an elevated serum IgM level. The patient responded both clinically and serologically to chemotherapy. This case is unusual because the patient lacked all common clinical features of Waldenstrom macroglobulinemia with exception of anemia. CONCLUSION: To our knowledge this is the first report of a patient with Waldenstrom macroglobulinemia presenting with a pancreatic mass adding to the spectrum of clinical presentations seen in this disease. This adds to the wide variety of gastrointestinal related clinical presentations of Waldenstrom macroglobulinemia and points to the need for considering Waldenstrom macroglobulinemia along with other lymphoid neoplasms in the differential diagnosis of pancreatic lesions.

Randomised placebo-controlled double blind multicentric trial on efficacy and safety of Lactobacillus acidophilus LA-5 and Bifidobacterium BB-12 for prevention of antibiotic-associated diarrhoea.

AIMS: To evaluate the effectiveness, safety and tolerability of a probiotic formulation containing Lactobacillus acidophilus LA-5 and Bifidobacterium BB-12 in the prevention of antibiotic associated diarrhoea (AAD). METHODS AND MATERIAL: A double-blind randomised placebo controlled multicentric trial was conducted in adults who were prescribed a seven-day course of oral antibiotic (either cefadroxil or amoxycillin) for a documented indication. The effectiveness of a 14-day therapy (concomitant with antibiotic course and seven days thereafter) of the probiotic formulation in preventing AAD was evaluated. Safety profile was assessed by monitoring of all treatment emergent adverse events and tolerability on a global well being scale. RESULTS: The incidence of AAD in the probiotic group was 10.8% compared to 15.6% in the placebo group, the difference being statistically non-significant (p = 0.19). The relative risk for AAD was 0.7 with the 95% CI being 0.4 to 1.2. The diarrhoea duration in the probiotic group was two days with an interquartile range of 1- 3 days and was significantly less (p = 0.01) than the placebo group which was four days with an interquartile range of 3 - 5.5 days. Subgroup analysis of subjects with AAD showed that the incidence of severe diarrhoea (watery stools) was 96% in the placebo group (25 out of 26) compared to 31.6% (6 out of 19) in the probiotic group and this difference was significant statistically (p < 0.001). Four mild, non-serious, adverse events were detected (2.0%) in the probiotic group but there were none in the placebo group. CONCLUSION: This randomised controlled trial shows that prophylactic administration of the probiotic formulation containing Lactobacillus acidophilus LA-5 and Bifidobacterium BB-12, did not effectively lower the incidence of AAD in adults. However, compared to placebo the duration of diarrhoea in the probiotic group was significantly reduced. Its tolerability and safety profile were good.

Sweet's syndrome in a patient with infective endocarditis: a rare clinical entity.

Sweet's syndrome, also known as acute febrile neutrophilic dermatosis, has been associated with malignancy, autoimmune disease and collagen vascular disease. The association of infective endocarditis and Sweet's syndrome is rare. The authors report a case of Sweet's syndrome in a patient with infective endocarditis. Infective endocarditis should be excluded in patients of rheumatic heart disease presenting with Sweet's syndrome. Alternatively, Sweet's syndrome should be considered as a differential diagnosis when a patient with infective endocarditis develops skin lesions.

Treatment of Chronic Hepatitis due to Hepatitis C Virus (CH-C) in India: A Randomized Controlled Trial Comparing Daily Interferon-alfa-2b and Ribavirin with Daily Interferon-alfa-2b and Glycyrrhizin-A Multicenter Study.

BACKGROUND AND AIM: Pegylated-interferon-alfa (PEG-IFN-α) with ribavirin is an established treatment in chronic hepatitis due to hepatitis C virus (HCV) (CH-C). Such treatment is expensive and in resource-poor countries such as India, alternative less expensive therapy is needed. METHODS: Multicenter randomized controlled trial comparing two treatment regimens (interferon-alfa-2b [IFN-α-2b] 3 million unit/day [MU/day] and ribavirin 1000 mg/day [I+R] vs IFN-α-2b 3 MU/day and glycyrrhizin 250 mg [I+G]) in CH-C. Viral, host characteristics and therapeutic responses were assessed (ICMR-6 months trial for chronic hepatitis-CTRI/2008/091/000105). RESULTS: One hundred and thirty-one patients meeting the inclusion criteria were randomized to I + G (n=64) or I+R (n=67) during the period February 2002 to May 2005. About 85% (I+G=53, I+R=58) completed 6 months of treatment and 89% of them (I+G=46, I+R=53) completed 6 months of follow-up after completion of treatment. Hepatitis C virus genotype 3 was the major type detected (71% patients). The mean log10 viral load (copies/mL), histological activity index, and fibrosis stage for all patients were 5.1 ± 0.98, 5 ± 2, and 2± 1.5, respectively. Sustained viral response (SVR) was significantly higher in I + R group than in I + G group (65.7% vs 46.9%, OR=2.2, P = 0.03). Treatment with I + G was associated with significantly lower frequencies of leukopenia (2% vs 17%, P <0.01) and anemia (8% vs 40%, P <0.001) as compared to treatment with I + R. CONCLUSION: Genotype 3 HCV infection with low viral load is prevalent in India. Daily IFN with ribavirin showed significantly better responses. Leukopenia and anemia were significantly more in ribavirin group. Responses observed with IFN + ribavirin were similar to the reported response rates with PEG-IFN suggesting that this modality may be considered as a cheaper alternative of treatment for chronic hepatitis C.

Hepatic myelopathy in a patient with decompensated alcoholic cirrhosis and portal colopathy.

Cirrhotic or hepatic myelopathy is a rare neurological complication of chronic liver disease usually seen in adults and presents as a progressive pure motor spastic paraparesis which is usually associated with overt liver failure and a surgical or spontaneous systemic portocaval shunt. We describe the development of progressive spastic paraparesis, in a patient with alcoholic cirrhosis with portal hypertension and portal colopathy who presented with the first episode of hepatic encephalopathy. The patient had not undergone any shunt procedure.