A multisociety Delphi consensus statement on new fatty liver disease nomenclature.

The principal limitations of the terms NAFLD and NASH are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favor of a change in nomenclature and/or definition. A modified Delphi process was led by three large pan-national liver associations. The consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. A total of 236 panelists from 56 countries participated in 4 online surveys and 2 hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83%, and 78%, respectively. Seventy-four percent of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms "nonalcoholic" and "fatty" were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction-associated steatotic liver disease. There was consensus to change the definition to include the presence of at least 1 of 5 cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic steatotic liver disease. A new category, outside pure metabolic dysfunction-associated steatotic liver disease, termed metabolic and alcohol related/associated liver disease (MetALD), was selected to describe those with metabolic dysfunction-associated steatotic liver disease, who consume greater amounts of alcohol per week (140-350 g/wk and 210-420 g/wk for females and males, respectively). The new nomenclature and diagnostic criteria are widely supported and nonstigmatising, and can improve awareness and patient identification.

Determinants of clinical response to empirical antibiotic treatment in patients with cirrhosis and bacterial and fungal infections- Results from the ICA 'Global study' [EABCIR-Global Study].

BACKGROUND AND AIMS: The administration of an appropriate empirical antibiotic treatment is essential in cirrhosis and severe bacterial infections. We aimed to investigate the predictors of clinical response of empirical antibiotic treatment in a prospective cohort of patients with cirrhosis and bacterial and fungal infections included in the International Club of Ascites(ICA) "Global Study". METHODS: Hospitalized patients with cirrhosis and bacterial/fungal infection were prospectively enrolled at 46 centers. Clinical response to antibiotic treatment was defined according to changes in markers of infection/inflammation, vital signs, improvement of organ failure, and results of cultures. RESULTS: From October 2015 to September 2016, 1302 patients were included at 46 centres. A clinical response was achieved only 61% of cases. Independent predictors of lack of clinical response to empirical treatment were C-reactive protein (OR=1.16;95%CI=1.02-1.31),blood leukocyte count (OR=1.39;95%CI=1.09-1.77), serum albumin (OR=0.70;95%CI=0.55-0.88), nosocomial infections (OR=1.96;95%CI=1.20-2.38), pneumonia (OR=1.75;95%CI=1.22-2.53),and ineffective treatment according to antibiotic susceptibility test (OR=5.32;95%CI=3.47-8.57). Patients with lack of clinical response to first-line antibiotic treatment had a significantly lower resolution rate of infections (55%vs. 96%;p<0.001), a higher incidence of second infections (29%vs. 15%;p<0.001),shock (35%vs. 7%;p<0.001) and new organ failures (52%vs. 19%;p<0.001) than responders. Clinical response to empirical treatment was an independent predictor of 28-day survival (sHR=0.20;95%CI=0.14-0.27). CONCLUSION: Four out of 10 patients with cirrhosis do not respond to the first-line antibiotic therapy, leading to lower resolution of infections and higher mortality. Broader-spectrum antibiotics and strategies targeting systemic inflammation may improve prognosis in patients with high degree of inflammation, low serum albumin levels and severe liver impairment. LAY SUMMARY: In a large, hospitalized cohort of patients with cirrhosis and infection at 46 multinational sites, lack of clinical response to empirical antibiotics was noted in four out of each ten patients. The non-response varied according to the geographic area and prevalence of multidrug/extensively drug resistant organisms with lowest response noted in the Asian countries particularly the Indian subcontinent. Severe systemic inflammation, as indicated by high white cell count, serum C-reactive protein levels low serum albumin concentration, presence of pneumonia, nosocomial infection and ineffective treatment were independent predictors of lack of clinical response to empirical antibiotic regimens. Patients with non-response to empirical regimen had worse clinical outcomes and this was identified as an independent predictor of higher in-hospital and 28-day mortality. Additional care and novel antibiotic protocols are an unmet need in cirrhosis patients, especially those with higher degree of inflammation, lower serum albumin levels and more severe liver impairment.

Journey of Women in Gastroenterology in South Asian Countries: From Training to Leadership.

Women in gastroenterology are underrepresented all over the world and in South Asia, the numbers are even fewer. Women doctors in South Asia have their unique set of problems that they have to deal with. They are trained well and are keen to publish but are not considered good enough. They do not get the same opportunities as their male colleagues. There is more expectation from women doctors to look after their families and children. We can correct this discrepancy by giving more opportunities, arranging flexible training, deserving promotions, leadership roles, equal pay, and research mentors for women doctors in gastroenterology in South Asia, and educating our society to treat women doctors, at par with men. How to cite this article: Kedia D, Kamani L, Begum MR, et al. Journey of Women in Gastroenterology in South Asian Countries: From Training to Leadership. Euroasian J Hepato-Gastroenterol 2023;13(1):41-43.

Use of albumin infusion for cirrhosis-related complications: An international position statement.

Background & Aims: Numerous studies have evaluated the role of human albumin (HA) in managing various liver cirrhosis-related complications. However, their conclusions remain partially controversial, probably because HA was evaluated in different settings, including indications, patient characteristics, and dosage and duration of therapy. Methods: Thirty-three investigators from 19 countries with expertise in the management of liver cirrhosis-related complications were invited to organise an International Special Interest Group. A three-round Delphi consensus process was conducted to complete the international position statement on the use of HA for treatment of liver cirrhosis-related complications. Results: Twelve clinically significant position statements were proposed. Short-term infusion of HA should be recommended for the management of hepatorenal syndrome, large volume paracentesis, and spontaneous bacterial peritonitis in liver cirrhosis. Its effects on the prevention or treatment of other liver cirrhosis-related complications should be further elucidated. Long-term HA administration can be considered in specific settings. Pulmonary oedema should be closely monitored as a potential adverse effect in cirrhotic patients receiving HA infusion. Conclusions: Based on the currently available evidence, the international position statement suggests the potential benefits of HA for the management of multiple liver cirrhosis-related complications and summarises its safety profile. However, its optimal timing and infusion strategy remain to be further elucidated. Impact and implications: Thirty-three investigators from 19 countries proposed 12 position statements on the use of human albumin (HA) infusion in liver cirrhosis-related complications. Based on current evidence, short-term HA infusion should be recommended for the management of HRS, LVP, and SBP; whereas, long-term HA administration can be considered in the setting where budget and logistical issues can be resolved. However, pulmonary oedema should be closely monitored in cirrhotic patients who receive HA infusion.

A multisociety Delphi consensus statement on new fatty liver disease nomenclature.

The principal limitations of the terms NAFLD and NASH are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favor of a change in nomenclature and/or definition. A modified Delphi process was led by three large pan-national liver associations. The consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. A total of 236 panelists from 56 countries participated in 4 online surveys and 2 hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83%, and 78%, respectively. Seventy-four percent of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms "nonalcoholic" and "fatty" were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction-associated steatotic liver disease. There was consensus to change the definition to include the presence of at least 1 of 5 cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic steatotic liver disease. A new category, outside pure metabolic dysfunction-associated steatotic liver disease, termed metabolic and alcohol related/associated liver disease (MetALD), was selected to describe those with metabolic dysfunction-associated steatotic liver disease, who consume greater amounts of alcohol per week (140-350 g/wk and 210-420 g/wk for females and males, respectively). The new nomenclature and diagnostic criteria are widely supported and nonstigmatising, and can improve awareness and patient identification.

A multisociety Delphi consensus statement on new fatty liver disease nomenclature.

The principal limitations of the terms NAFLD and NASH are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favour of a change in nomenclature and/or definition. A modified Delphi process was led by three large pan-national liver associations. The consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. A total of 236 panellists from 56 countries participated in 4 online surveys and 2 hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83%, and 78%, respectively. Seventy-four percent of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms "nonalcoholic" and "fatty" were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction-associated steatotic liver disease (MASLD). There was consensus to change the definition to include the presence of at least 1 of 5 cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic steatotic liver disease. A new category, outside pure metabolic dysfunction-associated steatotic liver disease, termed metabolic and alcohol related/associated liver disease (MetALD), was selected to describe those with metabolic dysfunction-associated steatotic liver disease, who consume greater amounts of alcohol per week (140-350 g/wk and 210-420 g/wk for females and males, respectively). The new nomenclature and diagnostic criteria are widely supported and non-stigmatising, and can improve awareness and patient identification.

Gender Differences in Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) has currently emerged as the most common liver disorder in both developed and developing countries. It has been observed that NAFLD exhibits sexual dimorphism, and there is limited understanding on the sex differences in adults with NAFLD. Nonalcoholic fatty liver disease shows marked differences in prevalence and severity with regards to gender. There are considerable biological disparities between males and females attributed to differences in the chromosomal makeup and sex hormone levels, distinct from the gender differences resulting from the sociocultural influences that lead to differences in lifestyle, which have a significant impact on the pathogenesis of this complex disorder. A multitude of factors contributes to the gender disparities seen and need to be researched in-depth to better understand the mechanisms behind them and the therapeutic measures that can be taken. In this article, we will review the gender disparities seen in NAFLD, as well as recent studies highlighting certain gender-specific factors contributing to its varying prevalence and severity. How to cite this article: Nagral A, Bangar M, Menezes S, et al. Gender Differences in Nonalcoholic Fatty Liver Disease. Euroasian J Hepato-Gastroenterol 2022;12(Suppl 1):S19-S25.

Nonalcoholic Fatty Liver Disease in Diabetics: The Role of Hepatologist.

Diabetes mellitus is one of the most prevalent metabolic diseases worldwide, causing an enormous burden on the economies of both developed and developing nations. Nonalcoholic fatty liver disease (NAFLD) is very closely associated with diabetes, and the two diseases are known to cause an increase in morbidity and mortality. Timely referral of a diabetic with NAFLD to a hepatologist can definitely delay disease progression and the related complications. Despite the magnitude, there are no guidelines that recommend a screening algorithm that must be followed for evaluating NAFLD in at-risk diabetics at the primary care level and their further referral to hepatologists. Nonalcoholic fatty liver disease management needs heightened awareness among primary care physicians/endocrinologists and hepatologists, and a collaborative care approach is paramount in these patients. Certain antidiabetic drugs are found to be beneficial in the treatment of NAFLD patients with diabetes, however, none of them are FDA approved. How to cite this article: Khandelwal R, Dassanayake AS, Singh SP. Nonalcoholic Fatty Liver Disease in Diabetics: The Role of Hepatologist. Euroasian J Hepato-Gastroenterol 2022;12(Suppl 1):S37-S40.

Oncogenic potential of ATAD2 in stomach cancer and insights into the protein-protein interactions at its AAA + ATPase domain and bromodomain.

ATAD2 has recently been shown to promote stomach cancer. However, nothing is known about the functional network of ATAD2 in stomach carcinogenesis. This study illustrates the oncogenic potential of ATAD2 and the participation of its ATPase and bromodomain in stomach malignancy. Expression of ATAD2 in stomach cancer is analyzed by in silico and in vitro techniques including western blot and immunofluorescence microscopy of stomach cancer cells (SCCs) and tissues. The oncogenic potential of ATAD2 is examined thoroughly using genetic alterations, driver gene prediction, survival analysis, identification of interacting partners, and analysis of canonical pathways. To understand the protein-protein interactions (PPI) at residue level, molecular docking and molecular dynamics simulations (1200 ns) are performed. Enhanced expression of ATAD2 is observed in H. pylori-infected SCCs, patient biopsy tissues, and all stages and grades of stomach cancer. High expression of ATAD2 is found to be negatively correlated with the survival of stomach cancer patients. ATAD2 is a cancer driver gene with 37 mutational sites and a predictable factor for stomach cancer prognosis with high accuracy. The top canonical pathways of ATAD2 indicate its participation in stomach malignancy. The ATAD2-PPI in stomach cancer identify top-ranked partners; ESR1, SUMO2, SPTN2, and MYC show preference for the bromodomain whereas NCOA3 and HDA11 have preference for the ATPase domain of ATAD2. The oncogenic characterization of ATAD2 provides strong evidence to consider ATAD2 as a stomach cancer biomarker. These studies offer an insight for the first time into the ATAD2-PPI interface presenting a novel target for cancer therapeutics. Communicated by Ramaswamy H. Sarma.

Association and functional significance of genetic variants present in regulatory elements of SERPINB5 gene in gallbladder cancer.

SERPINB5 is a mammary serine protease inhibitor, which is involved in various cellular functions. The aberrant expression of SERPINB5 is reported in many cancers along with GBC but limited information is available about its role in genetic predisposition for GBC. We carried out case-control study in 206 cases and 219 controls. Promoter SNPs were genotyped by Sanger's sequencing. In-silico promoter analysis and luciferase reporter assay were done to elucidate the role of promoter variants in regulation of SERPINB5 expression. Out of four SNPs, three SERPINB5 promoter variants showed association with GBC in different models. The 'C' allele of variant rs17071138 was found to be significantly associated with GBC (p = 0.017). The 'T' allele of rs3744940 significantly increased the risk for GBC in dominant (p = 0.035) and additive models (p = 0.005). Also, rs3744941 'T' allele increased the risk for GBC by dominant (p = 0.042) as well as additive models (p = 0.016). In-silico promoter analysis and luciferase reporter assay revealed the probable regulatory role of the SERPINB5 promoter variant rs17071138 on the expression. Overall, our study reveals the genetic association of SERPINB5 promoter variants with GBC and possible role of rs17071138 in the regulation of expression.

Narrative review of current and emerging pharmacological therapies for nonalcoholic steatohepatitis.

Nonalcoholic steatohepatitis (NASH) is the most common cause of chronic liver disease today, and it has now emerged as the leading etiology of end-stage liver disease requiring liver transplantation. It is a progressive form of non-alcoholic fatty liver disease which can not only progress to cirrhosis of liver and hepatocellular carcinoma (HCC), but is associated with increased cardiovascular risks too. Despite all the advances in the understanding of the risk factors and the pathogenetic pathways involved in the pathogenesis and progression of NASH, an effective therapy for NASH has not been developed yet. Although lifestyle modifications including dietary modifications and physical activity remain the mainstay of therapy, there is an unmet need to develop a drug or a combination of drugs which can not only reduce the fatty infiltration of the liver, but also arrest the development and progression of fibrosis and advancement to cirrhosis of liver and HCC. The pharmacologic therapies which are being developed target the various components believed to be involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD)/NASH which includes insulin resistance, lipid metabolism oxidative stress, lipid peroxidation, inflammatory and cell death pathways, and fibrosis. In this review, we summarize the current state of knowledge on pharmacotherapy of NASH, and also highlight the recent developments in the field, for optimizing the management and treatment of NASH.

Management of Helicobacter pylori infection: The Bhubaneswar Consensus Report of the Indian Society of Gastroenterology.

The Indian Society of Gastroenterology (ISG) felt the need to organize a consensus on Helicobacter pylori (H. pylori) infection and to update the current management of H. pylori infection; hence, ISG constituted the ISG's Task Force on Helicobacter pylori. The Task Force on H. pylori undertook an exercise to produce consensus statements on H. pylori infection. Twenty-five experts from different parts of India, including gastroenterologists, pathologists, surgeons, epidemiologists, pediatricians, and microbiologists participated in the meeting. The participants were allocated to one of following sections for the meeting: Epidemiology of H. pylori infection in India and H. pylori associated conditions; diagnosis; treatment and retreatment; H. pylori and gastric cancer, and H. pylori prevention/public health. Each group reviewed all published literature on H. pylori infection with special reference to the Indian scenario and prepared appropriate statements on different aspects for voting and consensus development. This consensus, which was produced through a modified Delphi process including two rounds of face-to-face meetings, reflects our current understanding and recommendations for the diagnosis and management of H. pylori infection. These consensus should serve as a reference for not only guiding treatment of H. pylori infection but also to guide future research on the subject.

SERPINB5 Genetic Variants rs2289519 and rs2289521 are Significantly Associated with Gallbladder Cancer Risk.

Serine protease inhibitor b5 (SERPINB5) is a tumor suppressor gene that plays a critical role in various cellular processes. In gallbladder cancer (GBC), SERPINB5's aberrant expression is reported but its role in genetic predisposition is not known. We enrolled 270 cases and 296 controls and genotyped them for single nucleotide polymorphisms (SNPs) using direct DNA sequencing, followed by genotype-phenotype analysis in GBC and other cancer cell lines. Luciferase assay was done to determine the role of rs2289521 SNP on expression regulation. We found that two SERPINB5 variants rs2289519 and rs2289521 are significantly associated with GBC and contribute to genetic predisposition. The TT genotype of variant rs2289519 was found to be significantly associated (p = 0.008) with GBC in a recessive model. C allele of rs2289521 increased the risk for GBC significantly at genotypic (CT, p = 0.026) and allelic (p = 0.04) levels. In silico analysis and luciferase assay uncovered the probable regulatory role of the rs2289521 variant on expression. Genotype-phenotype correlation in GBC and breast cancer cell lines showed reduced expression of SERPINB5 in the presence of C allele that was consistent with the result of luciferase assay. Overall, our study reveals the genetic association of two SERPINB5 variants with GBC and rs2289521's possible role in the regulation of expression.

Genetic association of MMP14 promoter variants and their functional significance in gallbladder cancer pathogenesis.

Gallbladder cancer (GBC) is relatively rare but shows high frequency in certain geographical regions and ethnic groups, which include Northern and Eastern states of India. Previous studies in India have indicated the possible role of genetic predisposition in GBC pathogenesis. Although matrix metalloproteinase-14 (MMP14) is known modulator of tumour microenvironment and tumorigenesis and TCGA data also suggests its upregulation yet, its role in genetic predisposition for GBC is completely unknown. We explored MMP14 promoter genetic variants as risk factors and their implication in expression modulation and the pathogenesis of GBC. We genotyped all single nucleotide polymorphisms of MMP14 promoter by Sanger's sequencing in approximately 300 GBC and 300 control study subjects of Indian ethnicity and, in 26 GBC tissue samples. Protein expression of MMP14 in GBC tissue samples was checked by immunohistochemistry. In vitro luciferase reporter assay was carried out to elucidate role of promoter genetic variants on expression levels in two different cell lines. MMP14 promoter variants, rs1003349 (p value = 0.0008) and rs1004030 (p value = 0.0001) were significantly associated with GBC. Luciferase reporter assay showed high expression for risk alleles of both the SNPs. Genotype-phenotype correlation for rs1003349 and rs1004030, in patient sample, confirmed that risk allele carriers had higher expression levels of MMP14; moreover, the correlation pattern matched with genetic association models. Overall, this study unravels the association of MMP14 promoter SNPs with GBC which contribute to pathogenesis by increasing its expression.

Acute kidney injury in hospitalized cirrhotic patients: Risk factors, type of kidney injury, and survival.

BACKGROUND AND AIM: Acute kidney injury (AKI) is a common complication of chronic liver disease (CLD). We performed a prospective study to evaluate the risk factors and spectrum of AKI among decompensated cirrhosis (DC) patients and the impact of AKI on survival. METHODS: This study was conducted in consecutive DC patients hospitalized in SCB Medical College between December 2016 and October 2018. AKI was defined as per ICA criteria. Demographic, clinical, and laboratory parameters and outcomes were compared between patients with and without AKI. RESULTS: A total of 576 DC subjects were enrolled, 315 (54.69%) of whom had AKI; 34% (n = 106) had stage 1A, 28% (n = 90) stage 1B, 21% (n = 65) stage 2, and 17% (n = 54) stage 3 AKI. Alcohol was the predominant cause of CLD (66.7%). In 207 (65.7%) patients, diuretic/lactulose/nonsteroidal anti-inflammatory drugs use was noted, and infection was present in 190 (60.3%) patients. Compared to those without AKI, patients with AKI had higher leucocyte count, higher serum urea and creatinine, higher Child-Turcotte-Pugh, higher Model of End-Stage Liver Disease (MELD) scores (P < 0.001), longer hospital stay, and lower survival at 28 days and 90 days (P < 0.001). Besides, in patients with stages 1A to 3 AKI, there were differences in overall survival at 28 days (P < 0.001) and 90 days (P < 0.001). CONCLUSIONS: Over half of DC patients had AKI, and alcohol was the most common cause of cirrhosis in them. Use of AKI-precipitating medications was the most common cause of AKI, followed by bacterial infection. AKI patients had increased prevalence of acute-on-chronic liver failure and had prolonged hospitalization and lower survival both at 28 days and 90 days.