Subclinical hepatitis E virus genotype 1 infection: The concept of "dynamic human reservoir".

Hepatitis E virus (HEV) is hyperendemic in South Asia and Africa accounting for half of total Global HEV burden. There are eight genotypes of HEV. Among them, the four common ones known to infect humans, genotypes 1 and 2 are prevalent in the developing world and genotypes 3 and 4 are causing challenge in the industrialized world. Asymptomatic HEV viremia in the general population, especially among blood donors, has been reported in the literature worldwide. The clinical implications related to this asymptomatic viremia are unclear and need further exploration. Detection of viremia due to HEV genotype 1 infection, apparently among healthy blood donors is also reported without much knowledge about its infection rate. Similarly, while HEV genotype 3 is known to be transmitted via blood transfusion in humans and has been subjected to screening in many European nations, instances of transmission have also been documented albeit without significant clinical consequences. Epidemiology of HEV genotype 1 in endemic areas often show waxing and waning pattern. Occasional sporadic occurrence of HEV infection interrupted by outbreaks have been frequently seen. In absence of known animal reservoir, where HEV exists in between outbreak is a mystery that needs further exploration. However, occurrence of asymptomatic HEV viremia due to HEV genotype 1 during epidemiologically quiescent period may explain that this phenomenon may act as a dynamic reservoir. Since HEV genotype 1 infection cannot cause chronicity, subclinical transient infection and transmission of virus might be the reason it sustains in interepidemic period. This might be the similar phenomenon with SARS COVID-19 corona virus infection which is circulating worldwide in distinct phases with peaks and plateaus despite vaccination against it. In view of existing evidence, we propose the concept of "Dynamic Human Reservoir." Quiescent subclinical infection of HEV without any clinical consequences and subsequent transmission may contribute to the existence of the virus in a community. The potential for transmitting HEV infection by asymptomatic HEV infected individuals by fecal shedding of virus has not been reported in literature. This missing link may be a key to Pandora's box in understanding epidemiology of HEV infection in genotype 1 predominant region.

INASL-SAASL Consensus Statements on NAFLD Name Change to MAFLD.

There is an ongoing debate on the change of terminology of non-alcoholic fatty liver disease (NAFLD) to metabolic associated fatty liver disease (MAFLD). Experts from the Indian National Association for Study of the Liver (INASL) and the South Asian Association for Study of the Liver (SAASL) involved in diagnosing, managing, and preventing NAFLD met in March 2022 to deliberate if the name change from NAFLD to MAFLD is appropriate, as proposed by a group of experts who published a "consensus" statement in 2020. Proponents of name change to MAFLD opined that NAFLD does not reflect current knowledge, and the term MAFLD was suggested as a more appropriate overarching term. However, this "consensus" group which proposed the name change to MAFLD did not represent the views and opinions of gastroenterologists and hepatologists, as well as perceptions of patients across the globe, given the fact that change of nomenclature for any disease entity is bound to have multidimensional impact on all aspects of patient care. This statement is the culmination of the participants' combined efforts who presented recommendations on specific issues concerning the proposed name change. The recommendations were then circulated to all the core group members and updated based on a systematic literature search. Finally, all the members voted on them using the nominal voting technique as per the standard guidelines. The quality of evidence was adapted from the Grades of Recommendation, Assessment, Development and Evaluation system.

Holistic Approach in the Management of Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD), in a few decades, is expected to be the commonest cause of end-stage liver disease and liver cancer surpassing all other etiologies. Urbanization and modern lifestyle have led to global epidemic of NAFLD with alarming prevalence rates across the globe. Its multisystemic involvement manifests as metabolic syndrome, diabetes, cardiovascular disease, end-stage liver disease, and hepatic and extrahepatic malignancies. The absence of promising therapy for halting disease progression in NAFLD is a challenge that is not only limited to liver disease but also other organs involved. It is unrealistic to expect any significant impact of pharmacotherapies in overall survival of NAFLD patients, given that the morbidity and mortality in these patients are contributed by conditions other than that of liver. Liver-centric approach in managing NAFLD will be futile unless the problem is dealt in a holistic manner. Lifestyle modifications have been repeatedly appraised in prevention and treatment of various diseases linked to metabolic syndrome including NAFLD. Despite being inexpensive and highly efficacious in prevention and treatment of different manifestations of NAFLD, lifestyle intervention often fails to gather sufficient interest among patients and physicians alike. This review intends to highlight pleiotropic nature of this disease, limitations of currently available pharmacotherapies and evidence that emphasizing lifestyle intervention is the only way to holistically deal in patients with NAFLD. How to cite this article: Shrestha A, Pradhananga S. Holistic Approach in the Management of Nonalcoholic Fatty Liver Disease. Euroasian J Hepato-Gastroenterol 2022;12(Suppl 1):S51-S58.

NAFLD vs MAFLD: South Asian NAFLD Patients don't Favor Name Change.

Aim: There have been vociferous attempts to change the name of Nonalcoholic Fatty Liver Disease (NAFLD) to Metabolic Associated Fatty Liver Disease (MAFLD). Of the many arguments put forth in support of this, an important one is the presumed demand by patient groups insisting on the change. However, this claim does not have credible evidence to support it. Therefore, we decided to conduct a survey among South Asian NAFLD patients to understand their perspectives with regard to the change in nomenclature. Materials and Methods: The study was conducted at multiple centers across South Asia from January 2021 to June 2021. Patients were surveyed using an 8-question survey questionnaire and responses were categorized by multiple-choice format. Results: Of 218 patients surveyed, 80.3% of the patients were not aware of the entity "NAFLD" before they were first diagnosed. Although 74.3% of patients admitted to being questioned about alcohol intake at the time of the first diagnosis, 75.9% of female patients were not questioned regarding this. After being labelled NAFLD, 92.1% of patients were never questioned again about alcohol intake. While 86.3% of patients found the term "NAFLD" consoling, 83% did not feel that "Non" in NAFLD trivialized their problem. In addition, only 6.9% of patients were scared of developing cardiovascular disease. Conclusion: The term "NAFLD" destigmatizes patients of the taboo associated with alcohol use. It was found to be consoling to most patients and they did not feel it trivialized their problem. A change of name without considering patients' perspectives and peculiarities specific to different populations will have enormous ramifications for both patients and physicians. Clinical significance: Our survey clearly shows that patients are happy with the term "NAFLD" and it effectively destigmatizes them from the taboo of alcohol. This would lead to higher compliance with management and greater patient participation in future studies and trials. How to cite this article: Singh SP, Anirvan P, Butt AS, et al. NAFLD vs MAFLD: South Asian NAFLD Patients don't Favor Name Change. Euroasian J Hepato-Gastroenterol 2022;12(Suppl 1):S1-S4.

'First week' is the crucial period for deciding living donor liver transplantation in patients with acute-on-chronic liver failure.

BACKGROUND AND AIMS: Acute-on-chronic liver failure (ACLF) is a rapidly progressive illness with high short-term mortality. Timely liver transplant (LT) may improve survival. We evaluated various indices for assessment of the severity of liver failure and their application for eligibility and timing of living donor LT (LDLT). METHODS: Altogether 1021 patients were analyzed for the severity and organ failure at admission to determine transplant eligibility and 28 day survival with or without transplant. RESULTS: The ACLF cohort [mean age 44 ± 12.2 years, males 81%) was of sick patients; 55% willing for LT at admission, though 63% of them were ineligible due to sepsis or organ failure. On day 4, recovery in sepsis and/or organ failure led to an improvement in transplant eligibility from 37% at baseline to 63.7%. Delay in LT up to 7 days led to a higher incidence of multiorgan failure (p < 0.01) contributing to 23% of the first week and 55% of all-cause 28-day mortality. In a matched cohort analysis, the actuarial survival with LT (n = 41) and conditional survival in the absence of transplant (n = 191) were comparable, when the condition, i.e., transplant was adjusted. The comparison curve showed differentiation in survival beyond 7 days (p < 0.01). CONCLUSIONS: ACLF is a rapidly progressive disease and risk stratification within the first week of hospitalization is needed. 'Emergent LT' should be defined in the first week in the ACLF patients; the transplant window for improving survival in a live donor setting.

Implications of Birth-Dose Vaccination against Hepatitis B Virus in Southeast Asia.

The World Health Organization (WHO) South-East Asia Regional Office (SEARO) covers 11 countries with a combined population of about 2 billion people, making it the most populous of the six WHO regions. In 1992, the WHO advocated including the hepatitis B vaccine in the Expanded Program of Immunization (EPI) and vaccinating all infants and children three times within 1 year of birth (HepB3). Recently, the WHO advocate birth-dose hepatitis B vaccination (HepB-BD) as soon as possible after birth, preferably within 24 hours. In 2016, the SEARO endorsed a regional hepatitis B control goal with a target of hepatitis B surface antigen (HBsAg) seroprevalence of ≤1% among children aged ≥5 years by 2020. Of the 11 SEARO countries, four achieved this target on schedule. Out of these four countries, two countries (Bangladesh and Nepal) have not adopted HepB-BD in EPI program. On the other hand, the coverage of HepB3 is not satisfactory in some SEARO countries, including India which adopted HepB-BD but could not achieve the overall target of SEARO. Thus, it is a point of debate whether emphasis should be placed on proper implementation of HepB3 or whether a new agenda of HepB-BD should be incorporated in developing countries of SEARO. The article discusses strengthening and expanding the Hepatitis B vaccination program in SEARO countries with an emphasis on HepB and HepB-BD programs.

Impact of metabolic risk factors on the severity and outcome of patients with alcohol-associated acute-on-chronic liver failure.

BACKGROUND: Metabolic risk factors may impact the severity and outcome of alcoholic liver disease. The present study evaluated this effect in patients with alcohol-associated acute-on-chronic liver failure (ACLF). METHODOLOGY: One thousand two hundred and sixteen prospectively enrolled patients with ACLF (males 98%, mean age 42.5 ± 9.4 years, mean CTP, MELD and AARC scores of 12 ± 1.4, 29.7 ± 7 and 9.8 ± 2 respectively) from the Asian Pacific Association for the Study of the Liver (APASL) ACLF Research Consortium (AARC) database were analysed retrospectively. Patients with or without metabolic risk factors were compared for severity (CTP, MELD, AARC scores) and day 30 and 90 mortality. Information on overweight/obesity, type 2 diabetes mellitus (T2DM), hypertension and dyslipidaemia were available in 1028 (85%), 1019 (84%), 1017 (84%) and 965 (79%) patients respectively. RESULTS: Overall, 392 (32%) patients died at day 30 and 528 (43%) at day 90. Overweight/obesity, T2DM, hypertension and dyslipidaemia were present in 154 (15%), 142 (14%), 66 (7%) and 141 (15%) patients, respectively, with no risk factors in 809 (67%) patients. Patients with overweight/obesity had higher MELD scores (30.6 ± 7.1 vs 29.2 ± 6.9, P = .007) and those with dyslipidaemia had higher AARC scores (10.4 ± 1.2 vs 9.8 ± 2, P = .014). Overweight/obesity was associated with increased day 30 mortality (HR 1.54, 95% CI 1.06-2.24, P = .023). None of other metabolic risk factors, alone or in combination, had any impact on disease severity or mortality. On multivariate analysis, overweight or obesity was significantly associated with 30-day mortality (aHR 1.91, 95% CI 1.41-2.59, P < .001), independent of age, CTP, MELD and AARC scores. CONCLUSION: Overweight/obesity and dyslipidaemia increase the severity of alcohol-associated ACLF, and the former also increases the short-term mortality in these patients.

Drug-Induced Acute-on-Chronic Liver Failure in Asian Patients.

OBJECTIVES: Acute insults from viruses, infections, or alcohol are established causes of decompensation leading to acute-on-chronic liver failure (ACLF). Information regarding drugs as triggers of ACLF is lacking. We examined data regarding drugs producing ACLF and analyzed clinical features, laboratory characteristics, outcome, and predictors of mortality in patients with drug-induced ACLF. METHODS: We identified drugs as precipitants of ACLF among prospective cohort of patients with ACLF from the Asian Pacific Association of Study of Liver (APASL) ACLF Research Consortium (AARC) database. Drugs were considered precipitants after exclusion of known causes together with a temporal association between exposure and decompensation. Outcome was defined as death from decompensation. RESULTS: Of the 3,132 patients with ACLF, drugs were implicated as a cause in 329 (10.5%, mean age 47 years, 65% men) and other nondrug causes in 2,803 (89.5%) (group B). Complementary and alternative medications (71.7%) were the commonest insult, followed by combination antituberculosis therapy drugs (27.3%). Alcoholic liver disease (28.6%), cryptogenic liver disease (25.5%), and non-alcoholic steatohepatitis (NASH) (16.7%) were common causes of underlying liver diseases. Patients with drug-induced ACLF had jaundice (100%), ascites (88%), encephalopathy (46.5%), high Model for End-Stage Liver Disease (MELD) (30.2), and Child-Turcotte-Pugh score (12.1). The overall 90-day mortality was higher in drug-induced (46.5%) than in non-drug-induced ACLF (38.8%) (P = 0.007). The Cox regression model identified arterial lactate (P < 0.001) and total bilirubin (P = 0.008) as predictors of mortality. DISCUSSION: Drugs are important identifiable causes of ACLF in Asia-Pacific countries, predominantly from complementary and alternative medications, followed by antituberculosis drugs. Encephalopathy, bilirubin, blood urea, lactate, and international normalized ratio (INR) predict mortality in drug-induced ACLF.

Short article: Association between liver fibrosis and hepatitis E seroprevalence among HIV-positive individuals in Nepal.

OBJECTIVE: Hepatitis E virus (HEV) seropositivity may confer an increased risk of liver fibrosis in immunosuppressed individuals. We studied this effect in HIV-infected individuals in Nepal, a country hyperendemic for HEV. PARTICIPANTS AND METHODS: We prospectively evaluated 200 HIV-positive individuals. Serum samples were tested for components of fibrosis scores and cytokeratin-18. RESULTS: Of 200 patients, 43% were HEV-immunoglobulin G+. The mean fibrosis-4 score was 8.02 in the HEV-positive and 1.17 in the HEV-negative group (P<0.001). The mean nonalcoholic fatty liver disease score was 2.12 in the HEV-positive and -2.53 in the HEV-negative group (P=0.02). The mean aminotransferase-platelet ratio index score was 0.37 in the HEV-positive and 0.38 in the HEV-negative group (P=0.9). The mean cytokeratin-18 levels were 119.9 in the HEV-positive group and 158.6 in the HEV-negative group (P=0.08). CONCLUSION: We found higher fibrosis-4 and nonalcoholic fatty liver disease scores in HEV-HIV-positive individuals, suggesting an increased liver fibrosis profile in this group. Further studies using liver stiffness measurements should be carried out.

Liver Cancer in Nepal.

Hepatocellular carcinoma (HCC) is highly incidental in South Asian countries. Nepal, however, has low incidence for HCC owing to low prevalence for hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. Nepal lacked national cancer registry until 2003. Though there has been some effort in having one, the current registry incorporates twelve centers and may not properly represent the total cancer burden in the country. Serology for HBV and HCV is seen to be positive in nearly 25 to 30% and 5 to 10% of HCCs respectively. Clinical characteristics of HCCs in Nepal have been discussed in this mini-review and it features poor performance status and advanced stage at presentation, making only a small fraction of these subjects eligible for curative treatment options. Most of the standard treatment modalities are available in Nepal and appear to be reasonably affordable as compared with other developed nations. How to cite this article: Shrestha A. Liver Cancer in Nepal. Euroasian J Hepato-Gastroenterol 2018;8(1):63-65.

Current Treatment of Acute and Chronic Hepatitis E Virus Infection: Role of Antivirals.

Hepatitis E virus (HEV) infection results in nearly 20 million new infections, resulting in 70,000 deaths globally each year. Previously thought as a disease limited to developing nations with poor sanitation and hygiene, it is increasingly recognized that even the most developed nations are not spared. A clear dichotomy in epidemiology of HEV is noted between developing and industrialized nations. The HEV genotypes 1 and 2 are common in Asia and Africa and are transmitted mainly by contaminated drinking water. Sporadic as well as large-scale epidemics of acute hepatitis have been noted with HEV genotype 1 infection in developing countries of Asia and Africa. On the contrary, HEV genotypes 3 and 4 are common in industrialized nations and unlike genotypes 1 and 2, they are transmitted by consumption of raw meat products, fruits, and blood transfusion. Large epidemics have not been reported with HEV genotypes 3 and 4 and manifestation is usually indolent, though severe acute hepatitis has been reported. How to cite this article: Shrestha A, Gupta BP, Lama TK. Current Treatment of Acute and Chronic Hepatitis E Virus Infection: Role of Antivirals. Euroasian J Hepato-Gastroenterol 2017;7(1):73-77.

Prevalence and risk of hepatitis E virus infection in the HIV population of Nepal.

BACKGROUND: Infection with the hepatitis E virus (HEV) can cause acute hepatitis in endemic areas in immune-competent hosts, as well as chronic infection in immune-compromised subjects in non-endemic areas. Most studies assessing HEV infection in HIV-infected populations have been performed in developed countries that are usually affected by HEV genotype 3. The objective of this study is to measure the prevalence and risk of acquiring HEV among HIV-infected individuals in Nepal. METHODS: We prospectively evaluated 459 Human Immunodeficiency Virus (HIV)-positive individuals from Nepal, an endemic country for HEV, for seroprevalence of HEV and assessed risk factors associated with HEV infection. All individuals were on antiretroviral therapy and healthy blood donors were used as controls. RESULTS: We found a high prevalence of HEV IgG (39.4%) and HEV IgM (15.3%) in HIV-positive subjects when compared to healthy HIV-negative controls: 9.5% and 4.4%, respectively (OR: 6.17, 95% CI 4.42-8.61, p < 0.001 and OR: 3.7, 95% CI 2.35-5.92, p < 0.001, respectively). Individuals residing in the Kathmandu area showed a significantly higher HEV IgG seroprevalance compared to individuals residing outside of Kathmandu (76.8% vs 11.1%, OR: 30.33, 95% CI 18.02-51.04, p = 0.001). Mean CD4 counts, HIV viral load and presence of hepatitis B surface antigen correlated with higher HEV IgM rate, while presence of hepatitis C antibody correlated with higher rate of HEV IgG in serum. Overall, individuals with HEV IgM positivity had higher levels of alanine aminotransferase (ALT) than IgM negative subjects, suggesting active acute infection. However, no specific symptoms for hepatitis were identified. CONCLUSIONS: HIV-positive subjects living in Kathmandu are at higher risk of acquiring HEV infection as compared to the general population and to HIV-positive subjects living outside Kathmandu.

Immune therapy for hepatitis B.

Although several antiviral drugs are now available for treatment of patients with chronic hepatitis B (CHB), sustained off-treatment clinical responses and containment of CHB-related complications are not achieved in majority of CHB patients by antiviral therapy. In addition, use of these drugs is endowed with substantial long term risk of viral resistance and drug toxicity. The infinite treatment regimens of antiviral drugs for CHB patients are also costly and usually unbearable by most patients of developing and resource-constrained countries. Taken together, there is a pressing need to develop new and innovative therapeutic approaches for CHB patients. Immune therapy seems to be an alternate therapeutic approach for CHB patients because impaired or distorted or diminished immune responses have been detected in most of these patients. Also, investigators have shown that restoration or induction of proper types of immune responses may have therapeutic implications in CHB. Various immunomodulatory agents have been used to treat patients with CHB around the world and the outcomes of these clinical trials show that the properties of immune modulators and nature and designing of immune therapeutic regimens seem to be highly relevant in the context of treatment of CHB patients. In this review, the general properties and specific features of immune therapy for CHB have been discussed for developing the guidelines of effective regimens of immune therapy for CHB.

First report of hepatitis E virus viremia in healthy blood donors from Nepal.

The aim of this study was to detect the prevalence of hepatitis E virus (HEV) in healthy blood donors so as to decipher the maintenance of (HEV) reservoir if any. Five hundred and eighty-one blood samples along with clinical information were collected from central blood bank, Kathmandu between February and March 2014. Samples were tested for hepatitis B virus surface antigen, anti-hepatitis C virus antibodies, anti-hepatitis A virus IgM, HEV antigen, HEV viral load and anti-HEV antibodies (IgM and IgG) by ELISA. Only those samples positive with anti-HEV IgM were tested for HEV RNA by reverse transcriptase nested PCR. Age adjusted prevalence of IgM anti HEV and IgG anti HEV were 3.6 and 8.3 % respectively. No significant difference in Median ALT levels was noted between HEV RNA positive and negative subjects. Sequence analysis of HEV shows all genotype belongs to genotype 1a. Phylogenetic analysis shows the virus has homology of 95 % with strain from India and Nepal outbreak of April 2014. This study sheds light on how inter epidemic reservoirs can be maintained in healthy population with asymptomatic cases. This raises an important question regarding nature of HEV as well as its tendency to circulate in blind sight and also cause periodic outbreaks in endemic setting like Kathmandu.

Viral Hepatitis in Nepal: Past, Present, and Future.

Over the last four decades, the diagnosis and therapy of viral hepatitis has evolved substantially all over the world. Although Nepal is a developing nation, it has been keeping pace with these developments in terms of the implementation of diagnostic and therapeutic strategies. However, because of a lack of infrastructure and logistics, Nepal still depends on its neighboring countries for molecular diagnostics in viral hepatitis B and C. Though most of the recent antivirals for hepatitis B and directly acting antivirals for hepatitis C are available at a highly subsidized cost, affordability still remains an issue. A lack of comprehensive national program for hepatitis B and C has been a major barrier for access to health care in patients with chronic viral hepatitis. Similarly, hepatitis E still remains an important public health issue with major epidemics at periodic intervals. Recent developments in understanding hepatitis E virus have unveiled important aspects of the virus, particularly with regard to why these epidemics occur. In this manuscript we try to elaborate the evolution in understanding, diagnosing, and treating viral hepatitis in Nepal. HOW TO CITE THIS ARTICLE: Shrestha A. Viral Hepatitis in Nepal: Past, Present, and Future. Euroasian J Hepato-Gastroenterol 2016;6(1):59-61.

Epidemiology of Viral Hepatitis and Liver Diseases in Nepal.

Geographical and ethnic diversity in Nepal has led to interesting epidemiology of viral hepatitis and liver diseases. Before the epidemic of Biratnagar that occurred in April to June 2014, Kathmandu was the only known endemic region for hepatitis E virus infection (HEV), where at least four previous epidemics have been documented since 1973. Due to rapid urbanization with still low socioeconomic condition, other major cities are appreciated to be at increasing risk of outbreaks. Characteristics of HEV epidemics and genetic changes of HEV during last decade have been studied. While hepatitis A virus infection was only common during childhood till recent years, it is re-emerging as an important etiology of acute hepatitis in young adults. Nepal is classified as low endemic region for hepatitis B virus infection (HBV) with overall seroprevalence of 1.1%. But, some ethnic groups and geographical areas have high prevalence rates. Despite low endemicity, HBV accounts for majority of cases of hepatocellular carcinoma and liver cirrhosis in the country. Similarly, though hepatitis C virus (HCV) is present in only 0.4% of general population, high seroprevalence was found among intravenous drug abusers many of them with HIV coinfection. Apart from hepatitis viruses, alcohol use also contributes significantly to liver cirrhosis and chronic liver failure. A unique form of hepatic venous outflow obstruction called 'hepatic vena cava syndrome' has been identified as an important etiology of liver cirrhosis and hepatocellular carcinoma. HOW TO CITE THIS ARTICLE: Shrestha A. Epidemiology of Viral Hepatitis and Liver Diseases in Nepal. Euroasian J Hepato-Gastroenterol 2015;5(1):40-42.