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Autoimmune Hepatitis (AIH) is a chronic liver disease Characterized by interface hepatitis, lymphoplasmacytic infiltrate, and hepatic rosettes. HIV infection is a state of immunosuppression; hence, the possibility of AIH is relatively rare, especially in patients with low CD4 counts. Therefore, we present an interesting case series of four patients with autoimmune liver disease with myriad presentations for the first time from India . We propose that despite the rarity of this presentation with immunosuppression, one should never miss such a treatable cause of liver disease leading to good clinical outcomes., (© 2022 Indian National Association for Study of the Liver. Published by Elsevier B.V.)

Background: Single-stranded RNA has the potential to form secondary structures that may result in intrastrand misalignment of repeats and may be responsible for DNA mutation. Two amplicons obtained from amplification of hepatitis E virus (HEV) gene by reverse transcription and nested polymerase chain reaction (RT-nPCR) were of unexpected size and had the same misalignment. They did not contain the target region between the internal priming sites but contained two fragments flanking the target region joined by a 12-base sequence instead. Objectives: To determine whether the unexpected amplicons obtained were due to secondary structures present in the HEV RNA. Study design: HEV RNA sequences were obtained from the GenBank database and the software dnasis was used to predict the presence of secondary structures within the amplification target regions. The free energy barriers of the secondary structures, which indicate their stability, were also calculated. Conventional RT-nPCR protocol was subsequently modified to eliminate RNA secondary structures. Results: An extensive stem-loop structure was predicted to exist between the two internal priming sites of the HEV RNA by the dnasis software. Its free energy barrier was found to be significant and might have resulted in the deletion of the target region located between the internal priming sites. Increased temperature and addition of dimethyl sulphoxide (DMSO) in the reverse transcription step gave the expected amplicon after the nested polymerase chain reaction. Conclusion: Spontaneous secondary structure formation can influence the outcome of RNA gene amplification and should be considered an important factor when designing primers and adopting protocols for RNA gene amplification. [Copyright &y& Elsevier]

Background & Aims: HEV variants such as swine genotypes within Paslahepevirus species balayani (HEV-A) and rat HEV ( Rocahepevirus ratti ; HEV-C1) cause chronic hepatitis E in immunocompromised individuals. There are few reliable and accessible small animal models that accurately reflect chronic HEV infection. We aimed to develop an immunocompromised rat model of chronic hepatitis E infection., Methods: In this animal model infection study, rats were immunosuppressed with a drug combination (prednisolone, tacrolimus, and mycophenolate mofetil) commonly taken by transplant recipients. Rats were challenged with human- and rat-derived HEV-C1 strains or a human-derived HEV-A strain. Viral load, liver function, liver histology, humoural, and cellular immune responses were monitored., Results: A high-dose (HD) immunosuppressive regimen consistently prolonged human- and rat-derived HEV-C1 infection in rats (up to 12 weeks post infection) compared with transient infections in low-dose (LD) immunosuppressant-treated and immunocompetent (IC) rats. Mean HEV-C1 viral loads in stool, serum, and liver tissue were higher in HD regimen-treated rats than in LD or IC rats ( p <0.05). Alanine aminotransferase elevation was observed in chronically infected rats, which was consistent with histological hepatitis and HEV-C1 antigen expression in liver tissue. None (0/6) of the HD regimen-treated, 5/6 LD regimen-treated, and 6/6 IC rats developed antibodies to HEV-C1 in species-specific immunoblots. Reversal of immunosuppression was associated with clearance of viraemia and restoration of HEV-C1-specific humoural and cellular immune responses in HD regimen-treated rats, mimicking patterns in treated patients with chronic hepatitis E. Viral load suppression was observed with i.p. ribavirin treatment. HD regimen-treated rats remained unsusceptible to HEV-A infection., Conclusions: We developed a scalable immunosuppressed rat model of chronic hepatitis E that closely mimics this infection phenotype in transplant recipients., Lay Summary: Convenient small animal models are required for the study of chronic hepatitis E in humans. We developed an animal model of chronic hepatitis E by suppressing immune responses of rats with drugs commonly taken by humans as organ transplant rejection prophylaxis. This model closely mimicked features of chronic hepatitis E in humans., Competing Interests: SS has received speaker’s honoraria from Abbott Medical Laboratories. The other authors report that there are no competing interests to declare. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2022 The Author(s).)

Cyproterone acetate (CPA), a hydroxyprogesterone derivative, is used to treat advanced prostate cancer and infrequently in women for acne, breast cancer and hirsutism. Transient mild elevation in levels of liver enzymes is reported in 10-30% of patients, and acute liver failure (ALF) is uncommon. Here, we discuss the first case of CPA-induced ALF from India and the available literature., (© 2021 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Hepatitis E is one of the leading causes of acute viral hepatitis worldwide. Chronic infection with hepatitis E is less common and limited to immunosuppressed patients and is usually due to genotype 3 of the virus. Genotype 1, the most prevalent strain in the South Asian region, is seldom known to be associated with chronic hepatitis. Here we describe a case of chronic hepatitis E with genotype 1 in a post-liver transplant setting. In the index case, previously compensated cryptogenic cirrhosis was decompensated by an acute hepatitis E infection, which necessitated liver transplantation because of acute chronic liver failure. This later progressed to chronicity. This case may have significant implications in management, especially in the post-liver transplant setting., Competing Interests: The authors have none to declare., (© 2020 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Hepatic involvement in systemic lupus erythematosus (SLE) is common but described infrequently. Liver is usually never the primary organ to be affected in lupus. Again hepatic involvement probably does not carry much prognostic importance though it may correlate with lupus activity. We here report a case of 21-year-old man with no prior comorbidity or addiction who presented to us with acute hepatic illness with jaundice. He also had malar rash and arthralgia. Viral markers were negative. Antinuclear antibody and anti-double-stranded DNA (dsDNA) were strongly positive. Liver biopsy was consistent with autoimmune hepatitis, whereas skin biopsy was suggestive of SLE. He had a brisk and complete recovery with prompt use of immunosuppressive agents (corticosteroids and azathioprine). Cyclophosphamide was started latter in view of lupus nephritis. This is probably the fourth reported case of SLE presenting as acute hepatic illness with jaundice., (© 2020 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background/aims: Hematopoietic stem cell transplantation (HSCT) is an established curative modality for various hematological malignancies and other diseases. Hepatobiliary dysfunction and subsequent sequelae constitute a common cause of morbidity and mortality in post-transplant scenario. However, data among Indian HSCT recipients is lacking., Methods: One hundred and one HSCT recipients (37 prospective and 64 retrospective) were followed up for hepatobiliary dysfunction in the post-transplant period. The causes for hepatobiliary dysfunction were categorized as sinusoidal obstruction syndrome (SOS), formerly known as veno-occlusive disease (VOD); acute and chronic graft-versus- host disease (GVHD); drug-induced liver injury (DILI); viral infections and miscellaneous causes including bacterial, fungal and unknown causes based on clinical and laboratory evidence., Results: Among the 101 transplants, 56.44% ( n  = 57) were allogenic transplants, and 43.56% ( n  = 44) were autologous transplants. Hepatobiliary dysfunction was observed among 71 (70.30%) patients in first 30 days and overall, among 78 (77.23%) patients. Incidence of hepatobiliary dysfunction was higher among allogenic transplant patients compared to autologous transplants (91.23% vs. 59.09%, p  < 0.001). The most common cause of hepatobiliary dysfunction reported was Drug-induced liver injury (DILI). In most cases, however, hepatobiliary dysfunction was multifactorial. Sinusoidal obstruction syndrome (15.79%), acute liver GVHD (31.58%), chronic liver GVHD (33.33%) and viral infection/reactivation (26.32%) were reported only in allogenic transplant patients. 15 (14.85%) patients died of which 14 patients had hepatobiliary dysfunction, commonest cause being infections., Conclusion: Our study reported a higher incidence of hepatobiliary dysfunction among Indian population post HSCT and was associated with significant mortality. In majority of the cases, the cause is multifactorial and pose a diagnostic dilemma and challenges in therapy., (© 2020 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Sickle hepatopathy is an umbrella term describing various pattern of liver injury seen in patients with sickle cell disease. The disease is not uncommon in India; in terms of prevalence, India is second only to Sub-Saharan Africa where sickle cell disease is most prevalent. Hepatic involvement in sickle cell disease is not uncommon. Liver disease may result from viral hepatitis and iron overload due to multiple transfusions of blood products or due to disease activity causing varying changes in vasculature. The clinical spectrum of disease ranges from ischemic injury due to sickling of red blood cells in hepatic sinusoids, pigment gall stones, and acute/chronic sequestration syndromes. The sequestration syndromes are usually episodic and self-limiting requiring conservative management such as antibiotics and intravenous fluids or packed red cell transfusions. However, rarely these episodes may present with coagulopathy and encephalopathy like acute liver failure, which are life-threatening, requiring exchange transfusions or even liver transplantation. However, evidence for their benefits, optimal indications, and threshold to start exchange transfusion is limited. Similarly, there is paucity of the literature regarding the end point of exchange transfusion in this scenario. Liver transplantation may also be beneficial in end-stage liver disease. Hydroxyurea, the antitumor agent, which is popularly used to prevent life-threatening complications such as acute chest syndrome or stroke in these patients, has been used only sparingly in hepatic sequestrations. The purpose of this review is to provide insights into epidemiology of sickle cell disease in India and pathogenesis and classification of hepatobiliary involvement in sickle cell disease. Finally, various management options including exchange transfusion, liver transplantation, and hydroxyurea in hepatic sequestration syndromes will be discussed in brief., (© 2020 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background/objectives: Acute liver failure (ALF) is rare and associated with poor outcomes. The outcomes of ALF and predictors of outcome may vary as per the etiology. There are limited data on the predictors of spontaneous survival among patients with ALF of non-A-E hepatitis or cryptogenic etiology. We aimed to assess clinical course, complications, and outcome of non-A-E etiology ALF., Methods: In this prospective analysis, all consecutive ALF patients (n = 1555; January 1986-June 2018) were analyzed. Non-A-E-ALF was defined as ALF that could not be attributed to known etiologies such as drugs, viral hepatitis, autoimmune hepatitis, and Wilson's disease. Clinical course, complications, and outcomes of non-A-E-ALF patients who did not undergo liver transplantation were analyzed. Unadjusted and adjusted odds ratios (ORs) were calculated., Results: Non-A-E-ALF constituted 34.6% (n = 538) of all ALF patients, whereas hepatitis E virus (HEV), hepatitis B virus (HBV), and anti-tuberculosis therapy (ATT) accounted for 29.5% (n = 459), 8.6% (n = 134), and 7.4% (n = 115), respectively. Among non-A-E-ALF patients, mean age was 28.8 ± 12.0 years, 50.9% females, majority (63.1%) had hyperacute presentation, and 79.2% had advanced encephalopathy at presentation. The frequency of cerebral edema in non-A-E-ALF (53.3%) was higher than that in HEV-ALF (41.2%) and ATT-ALF (44.2%), P < 0.001. The survival rate in non-A-E-ALF (37.5%) was poorer than HEV-ALF (54.9%) and was comparable to that in HBV (35.8%) and ATT (29.6%) induced ALF. The baseline prothrombin time prolongation (odds ratio [OR] 1.041; 95% confidence intervals [CI], 1.017-1.065) and infection (OR 2.366; 95%CI, 1.107-5.055) were independent predictors of outcome in non-A-E-ALF. The 3-days acute liver failure early dynamic model had the best value in predicting the outcome., Conclusions: Non-A-E-ALF accounts for one-third of all cases of ALF and is associated with poor spontaneous survival., Competing Interests: The authors have none to declare, (© 2020 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Acute liver failure (ALF) is the leading cause for emergency liver transplantation (LT) all over the world. We looked at the profile of cases who required LT for ALF from a single centre to identify the possible predictors of poor outcomes., Methodology: During the 10-year period starting from 2007, 320 cases of ALF were treated at our institution, of which 70 (median age 24 years, Male:Female 1:2) underwent LT. Retrospective analyses of these 70 patients were performed., Results: Etiology was identifiable in 73% (n = 51) of cases (yellow phosphorous [YP] poisoning [n = 16], Hepatitis A virus [HAV] [n = 15], Hepatitis B virus [HBV] [n = 5], Hepatitis E virus [HEV] [n = 1], anti-tubercular therapy [ATT] induced [n = 6], acute Wilson's [n = 3], and autoimmune [n = 5]]. Upon meeting King's College Hospital criteria, 69 had live donor LT (61 right lobe grafts, three left lobe grafts, five left lateral segment grafts) and one had deceased donor LT. Among these, there were five auxiliary partial orthotopic grafts and four ABO-incompatible transplants. Overall, 90-day mortality was 35.7% (n = 25), predominantly due to sepsis. Significant risk factors for mortality on multivariate analysis included indeterminate etiology, pre-op renal dysfunction, and Grade IV hepatic encephalopathy (HE). Cumulative 10-year survival of the remaining survivors was 95.6% (n = 45)., Conclusion: LT for ALF carries high perioperative mortality (35.7%) in those presenting with indeterminate etiology, pre-op renal dysfunction, and Grade IV HE. Nevertheless, if they survive the perioperative period, long-term survival is excellent., Competing Interests: The authors have none to declare., (© 2019 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved.)

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., Competing Interests: The authors have none to declare., (© 2020 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Acute-on-chronic liver failure (ACLF) results in very high mortality in children. We aimed to evaluate the role of granulocyte colony-stimulating factor (GCSF) on short-term outcome of children with ACLF in a nontransplant unit., Methods: Children (aged > 1 year) diagnosed with ACLF over a 15 month period were randomised. Group A was given GCSF therapy along with standard medical care (SMC - details in supplementary data) and group B was given only SMC. The outcome was evaluated as survival at 30 and 60 days of therapy., Result: Thirty-one children with ACLF were enrolled, with a mean age of 6.92 ± 4.3yrs. A total of 15 patients were randomised to group A and 16 to group B. The overall mortality was 54.83%. The intervention group showed survival rates of 80%, 66.67% and 53.3%, whereas the control group had survival rates of 43.75%, 37.5% and 37.5% at 14, 30 and 60 days, respectively. A significant survival benefit was noted on day 14 (p = 0.043) of therapy in group A with significant difference in Child-Turcotte-Pugh (CTP) and pediatric end-stage liver disease (PELD) scores in the two groups. After an initial rise in group A, the granulocyte counts fell to become comparable in the two groups by day 30 and 60, indicating that the effect of GCSF therapy wears off over time. There was no significant difference in the overall survival, median/mean CTP, PELD and MCS (Modified Cliff sequential organ failure assesment (SOFA)) scores on day 30 and 60. Mean (%) CD 34 + cells level showed a rise on day 7 in group A but was statistically insignificant., Conclusion: The present study shows that GCSF therapy at 5 mcg/kg/day for 5 days seems to be ineffective in improving the survival outcome on day 30 and 60 of therapy. Studies with larger number of children enrolled and longer duration of therapy are required. (CTRI/2017/11/010420)., Competing Interests: The authors have none to declare., (© 2019 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Objective: The study was designed to examine the hypothesis whether the course and severity of hepatitis E virus (HEV)-related liver disease is worse during pregnancy., Method: The prospective study included 1088 patients (550 pregnant; 538 nonpregnant) with clinically and biochemically confirmed acute viral hepatitis (AVH) or acute liver failure (ALF) and were subjected to a complete panel of hepatitis serology., Results: In the pregnant cohort, HEV was the cause of infection in 80.36% (442/550) of cases, whereas non-HEV accounted for 19.63 (108/550) of cases. In the ALF pregnant group, the prevalence of HEV was observed in 73.38% (102/139) of cases, whereas other viruses accounted for 26.61% (37/139) of illness. Ninety-eight of 129 (75.96%) cases of HEV-infected pregnant women died, whereas non-HEV infection was responsible for only 31 of 129 (24.04%) cases' death in comparison. Serum viral load in the ALF group was also significantly higher than that in the AVH group in the pregnant (24578.6 ± 12410.3 vs. 6821.9 ± 1832.7, respectively) cohort and nonpregnant cohort (583.6 ± 187.34 vs. 298.68 ± 65.77, respectively)., Conclusion: HEV infection has a higher incidence, more severe course, and greater mortality in the pregnant cohort than in the nonpregnant cohort., (© 2019 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: The present study is planned to assess etiologies, course, and outcome in patients with acute-on-chronic liver failure (ACLF)., Methods: Two hundred and eight (182 males and 26 females) patients of ACLF fulfilling modified Asia Pacific Association For Study Of Liver Consensus criteria 2009 admitted to the gastroenterology department of SMS Medical College and hospital, Jaipur, between October 2015 and December 2017 were included. We evaluated etiology of underlying chronic disease and the acute event precipitating decompensation in ACLF., Results: Most common etiology of chronic liver disease (CLD) was alcohol with 133 (63.94 %) patients. Viral hepatitis, cryptogenic cirrhosis, autoimmunity, nonalcoholic steatohepatitis, and Wilson disease as causes of CLD were present in 32 (15.4%), 29 (13.94%), 9 (4.3%), 3 (1.4%), and 2 (1%) cases, respectively. Alcohol, sepsis, bleeding, reactivation of hepatitis B, hepatitis E, antitubercular drugs, and autoimmune hepatitis as the causes of acute event were present in 100 (48.08%), 34 (16.35%), 19 (9.1%), 17 (8.2 %), 15 (7.2%), 13 (6.25%), and 2 (0.96%) patients, respectively. In 8 (3.85%) patients, the precipitating event could not be known. Mortality (in-hospital) in this study was 37.5%. Higher model for end-stage liver disease score and high Child-Turcotte-Pugh score score were significantly associated with mortality (P <0.001). Patients with higher ACLF grade were associated with higher mortality. Alcohol as a cause of CLD was significantly associated with mortality (p=0.0146, 95% confidence interval between 3.802 and 30.979). There was no significant difference regarding acute precipitating events between survivors and nonsurvivors., Conclusions: Alcohol was the most common cause for chronic etiology as well as acute precipitating event. Alcohol as a cause of CLD was significantly associated with mortality., (© 2019 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: This is a case-control study aimed at evaluating clinical as well as molecular risk factors for occurrence of ATT induced hepatitis in Northern Indian population., Methods: 100 patients of tuberculosis were recruited from both Outdoor patient department and wards of Lok Nayak Hospital, New Delhi. 40 out of 100 patients who developed ATT induced hepatitis were taken as test group and 60 out of 100 patients who didn't develop liver dysfunction on ATT were taken as controls and studied and compared for clinical factors such as age, gender, nutritional status, HBsAg carrier, chronic hepatitis C and HIV infection. Molecular factors i.e. NAT2 acetylator status, GSTT1 and M1 null mutations were also determined in all of the patients in each group and compared., Results: Mean body weight and serum albumin were significantly lower in the ATT induced hepatitis patients as compared to the control group. No preferential association was observed between age and gender with ATT induced hepatitis. HBsAg carrier (OR-6.5; P  = 0.03), HIV infection (OR-5.1; P  = 0.01), slow acetylator phenotype (OR-3.85; P  = 0.02), GSTM1 null mutation (OR-2.72; P  = 0.02) and GSTT1 null mutation (OR-3.12; P  = 0.02) were found to be positively co-related to ATT induced hepatitis according to the univariate analysis. HBsAg carrier (OR-23.18; P  = 0.01), HIV infection (OR-16.92; P  = 0.02), Slow acetylator phenotype (OR-70.90; P  = 0.001), GSTM1 null mutation (OR-37.03; P  = 0.002) and GSTT1 null mutation (OR-8.19; P  = 0.014) were also found to be independently increasing the risk of ATT induced hepatitis using multivariate analysis., Conclusion: The present study established a positive co-relation between malnutrition, HBsAg carrier, HIV infection, NAT2 slow acetylators, GSTM1 null mutation, GSTT1 null mutation and ATT induced hepatitis.

Hepatitis B Virus (HBV) reactivation in patients receiving chemotherapy, biologicals, immunosupressants, or corticosteroids is emerging to be an important cause of morbidity and mortality in patients with current or prior exposure to HBV infection. These patients suffer a dual onslaught of illness: one from the primary disease for which they are receiving the culprit drug that led to HBV reactivation, and the other from HBV reactivation itself. The HBV reactivation not only leads to a compromised liver function, which may culminate into hepatic failure; it also adversely impacts the treatment outcome of the primary illness. Hence, identification of patients at risk of reactivation before starting these drugs, and starting treatment aimed at prevention of HBV reactivation is the best strategy of managing these patients. There are no Indian guidelines on management of HBV infection in patients receiving chemotherapy, biologicals, immunosupressants, or corticosteroids for the treatment of rheumatologic conditions, malignancies, inflammatory bowel disease, dermatologic conditions, or solid-organ or bone marrow transplantation. The Indian National Association for Study of the Liver (INASL) had set up a taskforce on HBV in 2016, with a mandate to develop consensus guidelines for management of various aspects of HBV infection, relevant to India. In 2017 the taskforce had published the first INASL guidelines on management of HBV infection in India. In the present guidelines, which are in continuation with the previous guidelines, the issues on management of HBV infection in patients receiving chemotherapy, biologicals, immunosupressants, or corticosteroids are addressed.

Coinfections contribute significantly to diagnostic challenges of acute febrile illnesses, especially in endemic areas. The confusion caused by overlapping clinical features impedes timely management. Herein, we report an unusual, previously unreported case of a pregnant woman suffering from a coinfection of scrub typhus and hepatitis E virus. A 25-year-old, 31-week pregnant woman presented with jaundice for 5 days and altered sensorium for 2 days. She had features of both viral acute liver failure (ALF) and tropical infections mimicking ALF, including hyperbilirubinemia, coagulopathy, anemia, thrombocytopenia, intravascular hemolysis, and hepatosplenomegaly. Etiological workup revealed rare coinfection of hepatitis E and scrub typhus. Despite all supportive measures, the patient succumbed to her illness (i.e., absent brainstem reflexes and intracranial bleed secondary to coagulopathy) and had poor fetal outcome, which resulted in stillbirth. ALF in a pregnant woman is a medical and obstetric emergency. It can result from varied etiologies that though differ in their incidence, mode of occurrence, and pregnancy outcome, can clinically masquerade as each other, causing diagnostic dilemma. This unusual case report highlights the significance of keeping all such possibilities in mind while managing a pregnant woman with ALF, especially in a country like India where maternal and perinatal mortality rates, the core indicators of national health, are still among the highest in the world.

Introduction: The hepatitis B virus (HBV), HCV, and HEV may occur as singly or concurrently in patients of different kind of liver disease. The rapid, reliable, and cost-effective screening of these pathogens is required for the large epidemiological studies. Therefore, a study has been planned to develop a multiplex Reverse Transcriptase-PCR assay which can be used for the screening of maximum number of pathogens at a time., Methodology: To develop multiplex Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) assay for simultaneous detection of HBV, HCV, and HEV; the serum samples of 54 patients who were positive either singly or in co-infection with for HBV, HCV, and HEV serologically were screened by uniplex PCR/RT-PCR followed by multiplex RT-PCR for HBV, HCV, and HEV using specific primers. These primers can detect most genotypes of these viruses. Multiplex RT-PCR was done in one tube for the identification of viral DNA/RNA using a mixture of three pairs of specific primers for hepatitis B, C, and E viruses. Representative positive samples of these viruses by uniplex/multiplex RT-PCR were also confirmed by sequencing followed by alignment with reference strains sequence., Results: The specificity of multiplex PCR was 100% with high sensitivity 89%, 87%, and 74% for HBV, HCV, and HEV respectively. The sensitivity and specificity of RT-multiplex PCR demonstrated a good correlation with that of uniplex PCR., Conclusion: The study suggests that multiplex RT-PCR can serve as a simple and reliable assay for rapid, sensitive, and cost-effective method for simultaneous detection of super-infections with HEV particularly in Asian countries as a cause of decompensation of chronic liver disease.

Background and Objectives: Acute-On-Chronic liver failure (ACLF) is an emerging entity. The present study was undertaken to analyze the clinical profile and natural course of ACLF patients., Patients and Methods: ACLF was defined as per Asia Pacific Association for the Study of Liver consensus criteria 2009. Patients fulfilling these criteria with some deviations were included and prospectively evaluated for clinical profile, etiologies of acute decompensation (AD) and underlying chronic liver disease, and short-term natural course [3 months]., Results: Out of 123 patients with ACLF (mean age: 45.83 ± 12.05 years; male:female 109:14), 45.53% cases had prior history of AD, and 54.47% presented for the first time as ACLF. Etiologies of cirrhosis were alcohol, cryptogenic, and chronic hepatitis B virus infection in 65.04%, 23.57%, and 11.38% cases, respectively. Recent history of alcohol intake (within 4 weeks) [42.27%] followed by bacterial infections [36.58%] were the common etiologic precipitants for AD. Only 87 (70.73%) out of 123 cases could be followed up for a duration of 3 months; 62 (71.26%) cases died by 3 months. Most deaths occurred in the alcoholics compared to nonalcoholics [(43/53) 81.13% vs. (19/34) 55.88%; P = 0.01]. No significant difference in mortality rate was observed between ACLF cases with history of prior AD compared to newly diagnosed ACLF cases [30/40 (75%) vs. 32/47 (68.09%); P = 0.477]. The prognostic markers [MELD, MELD-Na, CTP] were not significantly different between survivors and nonsurvivors., Conclusion: ACLF patients in our population had high short-term mortality rates with majority of deaths in alcoholics. Alcohol intake and bacterial infections were mainly responsible for AD in our study.

Background: Liver biopsy (LB) has been used as diagnostic modality in liver diseases (LD). Over last two decades, there has been remarkable improvement in understanding of natural history, molecular diagnostics of viral hepatitis, genetic of LD, and also limitations of LB. There is current trend in avoiding LB in the management of various LDs., Aim: To determine utility of LB in clinical practice., Material and Methods: In a prospective study, 2413 patients of LD were followed up, 219 (9%) were acute, and remaining 2194 (90.9%) were chronic LD. Patients were evaluated by biochemical parameters, virological studies, and imaging endoscopy as and when required. LB was performed in 176 (7.2%) patients when no conclusion could be drawn from the noninvasive workup. Patients with platelet count <50,000/cm(2), ascites, and overt bleeding were excluded. Patients with international normalization ratio (INR) more than 1.5 were not excluded. No prophylactic use of fresh frozen plasma and platelet transfusion was done. There was no major complication related to the procedure. Indications for LB were as follows: cryptogenic LD 38 cases, hepatitis B infection 35, suspected autoimmune hepatitis 30, mass lesion in the liver and lymphoma 29, evaluation of portal hypertension 15, elevated liver enzymes 11, hepatitis C infection 9, and drug-induced LD 4, and miscellaneous 5 cases which were primary biliary cholangitis, primary sclerosing cholangitis, cholestatic LD, sarcoidosis, and amyloidosis., Results: LB changed the diagnosis in 55 (31.2%). These were cryptogenic LD in 24 cases, portal hypertension 15, elevated liver enzymes 11, and 5 others. In remaining, LB confirmed clinical diagnosis and helped in making management decisions., Conclusion: LB was required in 7.2% of patients with chronic LD. In 31.2% cases, LB changed the diagnosis. LB was a safe procedure even in presence of low platelet count and abnormal INR.

Hepatitis E virus (HEV) infection may cause acute hepatitis and lead to hepatic failure in developing and developed countries. We studied HEV seroprevalences in patients with hepatitis B virus (HBV) infection to understand the consequences of HEV superinfection in a Vietnamese population. This cross-sectional study was conducted from 2012 to 2013 and included 1318 Vietnamese patients with HBV-related liver diseases and 340 healthy controls. The case group included patients with acute (n = 26) and chronic hepatitis B (n = 744), liver cirrhosis (n = 160), hepatocellular carcinoma (n = 166) and patients with both liver cirrhosis and hepatocellular carcinoma (n = 222). Anti-HEV IgG and IgM antibodies were assessed in patients and controls by ELISA. HEV-RNA was identified by PCR assays and sequencing. Seroprevalences of anti-HEV IgG among hepatitis B patients and controls were 45% and 31%, respectively (adjusted P = 0.034). Anti-HEV IgM seroprevalences were 11.6% and 4.7% in patients and controls, respectively (adjusted P = 0.005). Seroprevalences were higher among the elder individuals. When stratifying for patient groups, those with liver cirrhosis had the highest anti-HEV IgG (52%) and anti-HEV IgM (19%) seroprevalences. Hepatitis B patients with current HEV infection had abnormal liver function tests compared to patients with past or without HEV infection. One HEV isolate was retrieved from a patient with both liver cirrhosis and hepatocellular carcinoma and identified as HEV genotype 3. This study indicates high prevalences of HEV infection in Vietnamese HBV patients and among healthy individuals and shows that HEV superinfection may influence the outcome and progression of HBV-related liver disease.

The purpose of this study was to evaluate the diagnostic efficiency for hepatocellular carcinoma (HCC) with the combined analysis of alpha-l-fucosidase (AFU), alpha-fetoprotein (AFP) and thymidine kinase 1 (TK1). Serum levels of AFU, AFP and TK1 were measured in: 116 patients with HCC, 109 patients with benign hepatic diseases, and 104 normal subjects. The diagnostic value was analyzed using the logistic regression equation and receiver operating characteristic curves (ROC). Statistical distribution of the three tested tumor markers in every group was non-normally distributed (Kolmogorov-Sminov test, Z = 0.156-0.517, P < 0.001). The serum levels of AFP and TK1 in patients with HCC were significantly higher than those in patients with benign hepatic diseases (Mann-Whitney U test, Z = -8.570 to -5.943, all P < 0.001). However, there was no statistically significant difference of AFU between these two groups (Mann-Whitney U test, Z = -1.820, P = 0.069). The levels of AFU were significantly higher in patients with benign hepatic diseases than in normal subjects (Mann-Whitney U test, Z = -7.984, P < 0.001). Receiver operating characteristic curves (ROC) in patients with HCC versus those without HCC indicated the optimal cut-off value was 40.80 U/L for AFU, 10.86 μg/L for AFP and 1.92 pmol/L for TK1, respectively. The area under ROC curve (AUC) was 0.718 for AFU, 0.832 for AFP, 0.773 for TK1 and 0.900 for the combination of the three tumor markers. The combination resulted in a higher Youden index and a sensitivity of 85.3%. The combined detection of serum AFU, AFP and TK1 could play a complementary role in the diagnosis of HCC, and could significantly improve the sensitivity for the diagnosis of HCC.

Background: Acute viral hepatitis (AVH) is usually a self-limiting illness. Diabetics are prone to develop liver diseases and liver regeneration is impaired in them. Natural course of AVH in diabetics has not been assessed and may be severe., Design: Observational prospective study to evaluate natural course of AVH in patients with and without diabetes mellitus. Consecutive patients with AVH were included and categorized in to those with or without diabetes. Etiology, complications, mortality and recovery parameters of AVH were identified and compared between two groups., Results: 131 consecutive AVH between March 2007 and March 2009 were evaluated; 12 diabetics and 83 non-diabetics (n = 95) were included for analysis. Hepatitis E was the commonest cause (n = 55, 57.89%) in the whole cohort. However, Hepatitis B virus (HBV) as the etiology was significantly higher among diabetics than in non-diabetics (58.33% vs. 25.3%, P = 0.02). In contrast, hepatitis E was the etiology in 61.44% of non-diabetics. Frequency of severe hepatitis was significantly higher in diabetics than in non-diabetics (5/12; 41.67% vs. 9/83; 10.64%, P < 0.005). 5 of 14 (36%) with severe hepatitis were diabetics. Liver failure and death occurred in 2 (16%) diabetics, while none among the non-diabetics had liver failure. Multiple variable logistic regression analysis revealed that acute hepatitis B (OR 4.7 (95% CI 1.34-16.47)) and diabetes (OR 4.0 (95% CI 0.96-16.47)) were associated with severe hepatitis., Conclusion: Patients with diabetes are at risk to contact HBV infection and severe hepatitis.

Hepatitis E virus (HEV) is the most common cause of acute viral hepatitis (AVH) globally. It causes large scale epidemics of AVH across the low- and middle income countries in Asia and Africa, and also causes sporadic cases of AVH in the same geographical region. AVH due to HEV is usually an acute, self-limiting illness, similar in clinical presentation to AVH caused by hepatitis A virus (HAV). When HEV causes AVH in patients of chronic liver disease it may worsen rapidly to a syndrome called acute-on-chronic liver failure (ACLF) leading to very high mortality. Acute deterioration of liver function in a patient with compensated chronic liver disease is the characteristic feature of ACLF. The typical disease course of patients with ACLF is the appearance of organ failure, which progresses to multi-organ failure and death. Many publications have reported HEV as one of the leading causes for ACLF from Asia and Africa, where HEV is endemic. The mortality rate of HEV-related ACLF (HEV-ACLF) ranges from 0% to 67% with a median being 34%. These patients require admission in the intensive care unit and they benefit from a team approach of clinicians with expertise in both hepatology and critical care. The goals of treatment are to prevent further deterioration in liver function, reverse precipitating factors, and support failing organs. Liver transplantation is required in selected patients to improve survival and quality of life. One preliminary report suggests that ribavirin may be an effective and safe drug for treatment of HEV-ACLF however this requires validation in large trials.

Hepatitis E virus is a positive strand RNA virus with three open reading frames which is transmitted predominantly through the fecal contamination of water and food. It is the most common cause of acute liver failure in endemic areas. Pregnant women especially from the Indian subcontinent and Africa are at increased risk of contracting acute HEV infection as well as developing severe complications including ALF. Transmission of HEV occurs from mother to unborn child. Both maternal and fetal complications may occur, including abortion, fetal demise, preterm labor and maternal or neonatal death. The precise reasons for increased susceptibility to HEV infection during pregnancy and associated severe disease are still an enigma. Management is supportive and termination of pregnancy is not recommended as a general rule. Prevention of infection is of vital importance, as availability of clean drinking water can reduce the burden of this disease in the community. There is a need for future research to focus on prevention of ALF in pregnancy and to study the disease pathogenesis, which is not explicitly understood at present. The availability of a vaccine may alter the natural course of the disease in this select population which is at risk.

Background: High mobility group box1 (HMGB1) and poly(ADP-ribose) polymerase1 (PARP1) proteins repair cellular DNA damage. Reduced expression of the corresponding genes can lead to an impaired DNA damage repair mechanism. Intracellular replication of hepatitis B virus (HBV) in such conditions can favor the integration of viral DNA into host genome leading to the development of hepatocellular carcinoma (HCC)., Objective: This study was performed to assess the expression of HMGB1 and PARP1 mRNAs in conjunction with the estimation of HBV replication intermediate pregenomic RNA (PgRNA) in various phases of HBV infection., Materials: Eighty eight patients and 26 voluntary blood donors as controls were included in the study. Patients were grouped in to acute (AHB; n = 15), inactive carriers (IC; n = 36), cirrhosis (Cirr; n = 25) and hepatocellular carcinoma (HCC; n = 12). Serum HBV DNA was quantified by real time polymerase chain reaction (PCR) assay. Expression of HMGB1, PARP1 and PgRNA were evaluated using peripheral blood mononuclear cells (PBMCs) derived RNA by reverse transcription PCR (RT-PCR) and densitometry., Results: Significant reduction of HMGB1 and PARP1 gene expressions (P < 0.05) were observed in patients than controls with more explicit decline of PARP1 (P = 0.0002). Both genes were significantly downregulated (P < 0.001) in ICs than controls. In ICs, HMGB1 was significantly lowered than cirrhosis (P = 0.002) and HCC (P = 0.0006) while PARP1 declined significantly (P = 0.04) than HCC. Level of PgRNA was comparable in all the disease categories., Conclusion: In conclusion, our findings indicate impaired DNA damage repair mechanisms in HBV infected cells of ICs. This, along with low viral load but higher level of PgRNA in this group is suggestive of the diversion of HBV replication pathway that might facilitate viral DNA integration in to host genome. Intrusion of HBV PgRNA reverse transcription in early stage of infection might appear advantageous to thwart the development of HCC.

It is now well accepted that hepatitis E virus (HEV) infection can induce chronic hepatitis and cirrhosis in immunosuppressed patients. Chronic genotype-3 HEV infections were first reported in patients with a solid-organ transplant. Thereafter, cases of chronic HEV infection have been reported in patients with hematological disease and in those who are human immunodeficiency virus (HIV)-positive. HEV-associated extra-hepatic manifestations, including neurological symptoms, kidney injuries, and hematological disorders, have been also reported. In transplant patients, reducing the dosage of immunosuppressive drugs allows the virus to be cleared in some patients. In the remaining patients, as well as hematological patients and patients who are HIV-positive, anti-viral therapies, such as pegylated interferon and ribavirin, have been found to be efficient in eradicating HEV infection. This review summarizes our current knowledge of chronic HEV infection, its treatment, and the extra-hepatic manifestations induced by HEV.

Hepatitis E is a disease caused by infection with hepatitis E virus (HEV). The virus has four genotypes, named 1 to 4, with one shared serotype. Genotypes 1 and 2 infect only humans, whereas genotypes 3 and 4 primarily infect several mammalian animals, with occasional transmission to humans. Evidence of infection with HEV has been found in most parts of the world, with two distinct epidemiological patterns. In areas with high disease endemicity, primarily developing countries in Asia and Africa, the disease occurs as outbreaks and as sporadic cases of acute hepatitis, and is caused exclusively by infection with genotypes 1 or 2 HEV, which is acquired through fecal-oral route, usually through contamination of water supplies. The disease in these areas occurs most commonly in young adults, and is particularly severe in pregnant women and persons with pre-existing chronic liver disease; chronic infection has not been reported. In areas with lower endemicity, which are mainly developed areas with robust water supply and sanitation systems, occasional sporadic cases of locally-acquired genotype 3 or 4 HEV infection are observed. The affected persons are often elderly and have other coexisting illnesses. The reservoir of infection in these areas is believed to be in animals, such as pigs, wild boar and deer, with zoonotic transmission to humans, possibly through consumption of undercooked meat. Also, in these areas, persistent HEV infection has been well documented among immunosuppressed persons such as organ transplant recipients, and is believed to lead to chronic liver injury, including liver cirrhosis. Further work is needed to better understand the biological basis underlying these widely-differing epidemiological patterns.

Hepatitis E virus (HEV) infection is a common cause of acute hepatitis in India and other developing countries. The data regarding the neurologic manifestation of HEV infection are limited. The neurologic disorders including Guillain-Barré syndrome, polyradiculopathy, neuralgic amyotrophy, encephalitis, bilateral brachial neuritis, ataxia/proximal myopathy, and acute transverse myelitis have been described. Bell's palsy and other cranial nerve involvement in hepatitis A virus (HAV) and HEV infection are rare. We present the second case of Bell's palsy associated with HEV.

Cytomegalovirus (CMV) is the most common viral infection in solid organ transplant recipients. Symptomatic infection usually presents with fever, pneumonia, colitis, or cytopenia. We describe a case of symptomatic CMV infection in a liver transplant recipient presenting with atypical symptoms of only persistent nausea and vomiting, in the absence of classical symptoms and signs; thus, highlighting the importance of high index of suspicion of CMV in immunocompromised patients, keeping in mind the high morbidity and mortality associated with this disease.