Efficacy of long-term albumin therapy in the treatment of decompensated cirrhosis.

BACKGROUND AND AIMS: Decompensated liver cirrhosis has a poor prognosis, with a median overall survival of two to four years, which is worse than for many oncological disorders. These patients are highly susceptible to infections due to increased systemic inflammation leading to kidney failure and death. The aim was to study the efficacy of albumin in reducing episodes of decompensation, preventing bacterial infection, kidney dysfunction and mortality. METHOD: Study involved patients with Child B or C cirrhosis with an albumin level below 3.0 g/dL, who were administered 20% human albumin weekly with standard medical treatment (SMT) for three months or till serum albumin levels were 4.0 g/dL (whichever is earlier) and compared with age and sex-matched controls who received only SMT. The primary end-point was six-month mortality and the secondary end-points were reduction in infections, kidney dysfunction, ascites recurrence, hepatic encephalopathy (HE), gastrointestinal (GI) bleed and complications of cirrhosis. RESULTS: From September 2021 to January 2023, 88 cases and 86 controls were taken and followed up for six months. Overall, six-month survival was not statistically significant between groups (95.1% vs. 91.9%; p = 0·330). The incidence of recurrence of ascites (34.09% vs. 59.3%, p < 0.001), kidney dysfunction (6.8% vs. 24.4%, p < 0.001), HE (15.9% vs, 37.2%, p = 0.015), spontaneous bacterial peritonitis (SBP) (3.4% vs 17.4%, p = 0.002) and non-SBP infections (7.9% vs. 18.6%, p = 0.038) were significantly less in cases as compared with controls; however, GI bleed (14.8% vs. 17.4%, p = 0.632) was not statistically significant. CONCLUSION: Long-term human albumin acts as a disease-modifying treatment in patients with decompensated cirrhosis.

2023 Update of Indian National Association for Study of the Liver Consensus on Management of Intermediate and Advanced Hepatocellular Carcinoma: The Puri III Recommendations.

Hepatocellular carcinoma (HCC) presents significant treatment challenges despite considerable advancements in its management. The Indian National Association for the Study of the Liver (INASL) first published its guidelines to aid healthcare professionals in the diagnosis and treatment of HCC in 2014. These guidelines were subsequently updated in 2019. However, INASL has recognized the need to revise its guidelines in 2023 due to recent rapid advancements in the diagnosis and management of HCC, particularly for intermediate and advanced stages. The aim is to provide healthcare professionals with evidence-based recommendations tailored to the Indian context. To accomplish this, a task force was formed, and a two-day round table discussion was held in Puri, Odisha. During this event, experts in their respective fields deliberated and finalized consensus statements to develop these updated guidelines. The 2023 INASL guidelines offer a comprehensive framework for the diagnosis, staging, and management of intermediate and advanced HCC in India. They represent a significant step forward in standardizing clinical practices nationwide, with the primary objective of ensuring that patients with HCC receive the best possible care based on the latest evidence. The guidelines cover various topics related to intermediate and advanced HCC, including biomarkers of aggressive behavior, staging, treatment options, and follow-up care.

To evaluate the prevalence of spontaneous portosystemic shunts in decompensated cirrhosis patients and its prognostic significance.

INTRODUCTION: Spontaneous portosystemic shunts (SPSS) are frequent in liver cirrhosis and their prevalence increases as liver function deteriorates, probably as a consequence of worsening portal hypertension, but without achieving an effective protection against cirrhosis complications. This study was conducted to detect the prevalence of portosystemic shunts in liver cirrhosis patients and analyze its prognostic role. METHOD: We conducted a prospective observational study, where 92 patients with decompensated cirrhosis were evaluated based on history, physical examination, biochemical tests and abdominal computed tomography (CT) angiography findings. A follow-up was done after six months for the development of cirrhosis-related complications. RESULTS: Of the 92 cirrhotic patients, 57.6% had SPSS (large SPSS + small SPSS) detected by multi-detector computed tomographic angiography. Overall, we found large SPSS in 24 (26.1%) patients, small SPSS in 29 (31.5%) patients and no shunt in 39 (42.4%) patients. Among the shunts, the splenorenal shunt is the most frequent type (25, 27.2%) followed by the paraumbilical shunt (20.7%). Previous decompensating events, including hepatic encephalopathy, ascites, spontaneous bacterial peritonitis and gastrointestinal bleed, were experienced more frequently by the large SPSS group followed by the small SPSS and without SPSS groups. Regarding follow-up, decompensating episodes of hepatic encephalopathy developed more frequently in patients with large SPSS (41.7%) than in patients with small SPSS (24.1%) followed by patients without SPSS (12.8%). CONCLUSION: In summary, all cirrhotic patients should be studied with radiological imaging to detect the presence of portosystemic shunts. In several cases, patients with large SPSS had a more impaired liver function and more frequent complications of portal hypertension. So, these patients would probably benefit from a closer surveillance and more intensive therapy.

Altered expression of endosomal Toll-like receptors and HBeAg seropositivity may act synergistically towards the vertical transmission of HBV.

PROBLEM: Hepatitis B is one of the leading causes of mortality in India. Despite the mass vaccination programme, the burden of the infection is still increasing due to its vertical transmission. Asymptomatic nature of hepatitis B virus (HBV) infection owing to immune tolerance among pregnant women is a major issue in this regard. METHOD OF STUDY: As such, this study aims to investigate the potential role of altered Toll-like receptor (TLR) expression (TLR-3, 7 and 9) along with peripheral blood HBeAg status in attaining differential cord blood (CB) HBV DNA status. RESULT: Expression analysis reveals an overall downregulation of expression with mean ± SD value 1.14 ± 1.05, 0.86 ± 0.5 and 0.71 ± 0.4 (TLR 3, 7 and 9, respectively) upon comparison with healthy women. Further stratification based on CB HBV DNA status; the downregulation of expression was found to be significantly (p < .05) associated with positive CB HBV DNA status apart from peripheral HBeAg status. One hundred percent HBeAg positive parturiting women exhibit positive CB HBV DNA. Pearson's correlation analysis reveals a positive correlation between CB HBV DNA status and altered TLR expression, HBeAg status and mother HBV DNA status and as such can be associated with the potential risk of HBV vertical transmission. CONCLUSION: This study suggests that the downregulation of TLR 3, 7 and 9 may be a risk factor for potential vertical transmission of HBV.

Epidemiology, Genotyping, Mutational and Phylogenetic Analysis of Hepatitis B Virus Infection in North-east India.

BACKGROUND/OBJECTIVE: Hepatitis B virus (HBV) infection is a major public health problem globally. Northeast India is home to indigenous tribes with different ethnicity and high rates of drug abuse and HIV infection. The study was designed to estimate the burden of HBV infection across various spectrums of liver diseases from this region. HBV genotypes and subgenotypes play a role in the chronicity of disease, response to treatment and its progression. As very limited data are available from this region, we tried to elucidate the role of HBV genotypes, HBV mutants and their phylogenetic analysis. METHOD: We designed a prospective multicentric study, and included 7464 liver disease cases, 7432 blood donors and 650 health care workers, who were screened for HBV infection. HBV DNA positive patients were genotyped and subjected to surface protein, precore and core mutation and phylogenetic analysis. RESULTS: The prevalence of HBV infection with respect to different types of liver diseases, blood donors and health care workers was 9.9% (1550/15,546). 49.5% (768/1550) cases were found to be HBV DNA positive. The most common genotype was found to be genotype D 74.2% (570/768), followed by genotype C 6.5% (50/768), A 4.4% (34/768) and I 0.9% (7/768). CONCLUSION: This study highlights the high hepatitis B burden in Northeast India, reflecting lacunae in health care needs of the region. Also, the different genotype distribution and presence of mutations may translate into different rates of liver disease progression, prognosis and ultimately, clinical significance. However, further prospective cohort study from Northeast India is warranted, to elucidate the clinical significance of multiple genotypes and mutation in this unique population.

Single-nucleotide polymorphisms in dendritic cell (dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin) gene of hepatocellular carcinoma patients from India.

OBJECTIVE: Hepatocellular carcinoma (HCC) is one of the major causes of morbidity and mortality in the world. Numerous genomic and proteomic studies have been carried out across the globe to understand cancer biology related to HCC. Dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN) is also known as cluster of differentiation 209. The current study was designed to investigate the association of mutation in DC-SIGN promoter region in HCC patients and healthy controls and to analyze the association of these mutations as a risk factor for HCC development from India. MATERIALS AND METHODS: total of 40 cases of HCC and 40 healthy controls without any underlying liver diseases were included in the study. A total of 5 ml of peripheral blood samples were collected, and genomic DNA was isolated using phenol-chloroform method. Polymerase chain reaction amplification was carried out for DC gene, and the amplicons were subjected to direct sequencing (Macrogen, Korea). Mutations were analyzed comparing these sequences with those published sequences from the database using bioinformatics software. RESULTS: A total of eight point mutations were observed in the HCC cases. The natures of mutation observed were deletion, transition, and transversion. All mutations were located in the 19th chromosome at nine different loci (51,079, 51,493, 51,561, 51,124, 51,125, 51,127, 51,169, 51,170, and 51,172). CONCLUSION: Mutation in the promoter region of the DC-SIGN gene may be a possible risk factor for the development of HCC in India. The findings of the study reveal the possible role of these mutants with HCC, and future large-scale prospective studies will further validate the findings of the current study.

A 5-year Single-Center Experience of Hepatitis E Virus Infection During Pregnancy.

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.

Expression Analysis of MicroRNA-21 and MicroRNA-122 in Hepatocellular Carcinoma.

BACKGROUND/OBJECTIVE: Hepatocellular carcinoma (HCC) is a multistep process starting from chronic hepatitis (CH) that progress through cirrhosis to HCC. The expression level of microRNA (miRNA) was found to be deregulated in HCC. The study was designed to find out whether the expression level of miR-21 and miR-122 was deregulated in HCC compared to controls without HCC. METHODS: Real-time quantitative polymerase chain reaction was performed to find out the miRNA expression level using Ct value followed by statistical analysis where P value ≤ 0.05 was considered as significant. RESULTS: Overexpression of miR-21 and miR-122 in HCC was detected. All changes in the expression level of miR-21 and miR-122 were due to HCC compared with healthy control, CH, and liver cirrhosis. Hence miR-21 and miR-122 are suitable to differentiate HCC with an efficient diagnostic power of sensitivity, specificity, and expression level, but they might not have any role in patients' survival. CONCLUSION: miR-21 and miR-122 could be considered as potential markers of HCC screening molecule in addition to other approved markers. However the current study is limited to expression levels of miRNAs from serum; therefore, it needs further validated study in a large group of population to fulfill all the criteria of a biomarker.

Clinical and Molecular Risk Factors of Anti-tubercular Therapy Induced Hepatitis.

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.

A guide to the management of hepatitis E infection during pregnancy.

INTRODUCTION: Hepatitis E virus (HEV) infection has distinct features, depending upon the genotype and geographical area. HEV genotypes 1 and 2 are endemic to various developing countries causing epidemics of acute viral hepatitis with human to human transmission. On the other hand, HEV genotypes 3 and 4 prevalent in developed countries commonly lead to subclinical infection and are transmitted zoonotically. HEV infection typically causes acute self-limiting illness associated with low morbidity and mortality. Infection with HEV genotype 1 or 2 in pregnancy, especially in the third trimester may lead to severe illness and fulminant liver failure. Poor maternal and fetal outcomes have been reported. Areas covered: This review highlights the various aspects of HEV infection in pregnancy including diagnosis, management, and prevention. Expert commentary: Treatment is mainly supportive with diligent monitoring and intensive care. Therapeutic termination of pregnancy cannot be recommended based to the available literature. Early liver transplantation (LT) should be considered in these patients although the indications and timing of LT are still controversial. Prevention of HEV infection or illness by improved sanitation and active/passive immunization needs further research.

Role of oestrogen and its receptors in HEV-associated feto-maternal outcomes.

BACKGROUND: Pregnant women infected with HEV develops adverse pregnancy outcomes like, abortions, intrauterine fetal death, still births, neonatal deaths, preterm delivery and maternal mortality. AIM: To correlate oestrogen and its receptors ESR1α and ESR2ß levels with HEV-associated feto-maternal outcomes. MATERIAL & METHODS: A total of 142 pregnant women with HEV infection and 142 pregnant controls were included in study from Department of Obstetrics & Gynaecology and Department of Medicine, Maulana Azad Medical College (MAMC) and associated Lok Nayak Hospital (LNH), New Delhi. Three millilitre of blood sample was collected in plain for quantification of oestrogen, and its receptors ESR1α and ESR2ß using commercially available third-generation ELISA kits. RESULTS: The levels of oestrogen, ESR1α and ESR2ß were considerably higher in HEV-infected pregnant women (20.11 ± 18.19 ng/mL, 10.58 ± 3.27 ng/mL, 10.42 ± 4.71 ng/mL respectively) than pregnant controls (11.74 ± 6.42 ng/mL, 9.11 ± 1.63 ng/mL, 9.01 ± 1.18 ng/mL respectively)(P < 0.0001). It was found that oestrogen levels were significantly higher in pregnant women infected with HEV who had preterm delivery, low birth weight babies and fetal loss (19.64 ± 17.60 ng/mL, 19.71 ± 17.63 ng/mL, 33.62 ± 23.20 ng/mL respectively) than who had full term delivery, average birth weight babies and live babies (11.71 ± 8.77 ng/mL, 11.99 ± 9.44 ng/mL, 16.58 ± 14.98 ng/mL respectively)(P < 0.05). A significant negative correlation was observed between baby birth weight and oestrogen levels in HEV-infected pregnant women. CONCLUSION: The high level of oestrogen plays an important role in preterm delivery, low birth weight babies and fetal mortality in pregnant women with HEV infection through placental dysfunction. Moreover, oestrogen level is a significant predictor for preterm delivery and maternal mortality and ESR2ß levels is a significant predictor for maternal mortality in pregnant women infected with HEV.

Synthetic therapeutics for the treatment of hepatitis B during pregnancy.

INTRODUCTION: Hepatitis B infection in pregnancy mandates careful monitoring and specialized management according to the phase of hepatitis B infection. Perinatal transmission may be prevented by antiviral therapy in mothers with high viral load and timely immunoprophylaxis of the infant. AREAS COVERED: This review focuses on the current first-line therapies for treating hepatitis B in pregnancy, timing of therapy, and prevention of perinatal transmission. Strategies to manage disease at the various phases and potential emerging therapies in phase III of development are also covered. Medline/PubMed and Cochrane databases were searched systematically from 1990 to April 2018 with the relevant articles selected for the review. EXPERT OPINION: Universal antenatal screening for hepatitis B and strict immunoprophylaxis for infants form the cornerstones to prevent hepatitis B virus (HBV) perinatal transmission. Tenofovir is the preferred drug for treatment in pregnancy in view of its good efficacy and high barrier to resistance. Most of the data on antivirals are from cohort studies which are prone to bias and more randomized controlled trials (RCTs) are needed to establish the benefits and safety of these drugs in pregnancy. Various novel drugs are in the pipeline which may pave the way for a cure in the near future.

HLA-DQA1 & DQB1 variants associated with hepatitis B virus-related chronic hepatitis, cirrhosis & hepatocellular carcinoma.

Background & objectives: Clinical outcome after hepatitis B virus (HBV) exposure varies extremely from spontaneous clearance to chronic hepatitis B and often progresses to liver cirrhosis (LC) and hepatocellular carcinoma (HCC). Host genetic factor plays an important role in the regulation of immune response. This study was aimed to investigate whether HLA class II DQA1 and DQB1 gene polymorphism were associated with chronic hepatitis B infection and in the development of HBV-related LC and HCC. Methods: DQA1 and DQB1 allele polymorphism were studied in 187 patients with HBV-related liver diseases (which included 73 chronic hepatitis B, 84 LC and 30 HCC patients) and 109 controls who had spontaneously recovered from HBV infection using polymerase chain reaction amplification with sequence-specific primers. Results: Our data suggested that DQA1*0101/2/4 [odds ratio (OR)=2.78; Pc=0.003], DQA1*0103 (OR=2.64; Pc=0.0007) and DQB1*0302/3 (OR=2.15; Pc=0.01) were associated with the protection from chronic HBV infection, whereas DQB1*0402 (OR=0.25; Pc=0.001) showed susceptible effect on chronic HBV infection. DQB1*0601 (OR=3.73; Pc=0.006) conferred protective effect from developing LC; similarly, DQB1*0302/3 (OR=5.53; Pc=0.05) and DQB1*0402 (OR=0.00; Pc=0.001) conferred protective effect from developing HCC. However, DQA1*0601 and DQB1*0503 showed susceptible effect on chronic HBV infection; these associations were no longer significant after Bonferroni correction. Interpretation & conclusions: Our results revealed HLA-DQA1*0101/2/4 - DQA1*0103 - DQB1*0302/3 and DQB1*0601 as protective and DQB1*0402 as risk alleles. The study suggests that various subtypes of HLA-DQA1 and DQB1 are associated with both HBV clearance and development of chronic HBV infections.

Expression Analysis of Serum microRNA-34a and microRNA-183 in Hepatocellular Carcinoma

Background/objective: HCC is a multistep process starting from chronic hepatitis that progress through cirrhosis to HCC. MicroRNA expression level was found to be deregulated in HCC. To find out whether the expression level of miR-34a and miR-183 was deregulated in HCC compared to controls without HCC. Methods: Real time quantitative PCR was done to find out the miRNA expression level in terms of Ct value followed by statistical analysis. Results: Over-expression of miR-183 and under-expression of miR-34a in HCC was detected. All changes in expression level of miR-34a and miR-183 were found to be due to HCC compared to controls without HCC. So both miR-34a and miR-183 were suitable to differentiate HCC from Cirrhosis and chronic hepatitis with an efficient diagnostic power of sensitivity, specificity and expression level. But they might not have any role in patients' survival. Conclusion: miR- 34a and miR-183 might be considered as potential markers of HCC screening molecule in addition to other approved panel of marker. Our study warrants further expression level study.