Ammonia is associated with liver-related complications and predicts mortality in acute-on-chronic liver failure patients.

The relationship between ammonia and liver-related complications (LRCs) in acute-on-chronic liver failure (ACLF) patients is not clearly established. This study aimed to evaluate the association between ammonia levels and LRCs in patients with ACLF. The study also evaluated the ability of ammonia in predicting mortality and progression of LRCs. The study prospectively recruited ACLF patients based on the APASL definition from the ACLF Research Consortium (AARC) from 2009 to 2019. LRCs were a composite endpoint of bacterial infection, overt hepatic encephalopathy (HE), and ascites. A total of 3871 cases were screened. Of these, 701 ACLF patients were enrolled. Patients with LRCs had significantly higher ammonia levels than those without. Ammonia was significantly higher in patients with overt HE and ascites, but not in those with bacterial infection. Multivariate analysis found that ammonia was associated with LRCs. Additionally, baseline arterial ammonia was an independent predictor of 30-day mortality, but it was not associated with the development of new LRCs within 30 days. In summary, baseline arterial ammonia levels are associated with 30-day mortality and LRCs, mainly overt HE and ascites in ACLF patients.

Clinical Features, Laboratory Characteristics and Outcome from Oral Contraceptives-induced Liver Injury in 43 Consecutive Patients and a Brief Review of Published Reports.

Background: Hormonal oral contraceptive (OC) agents such as estrogen or progesterone, either as single agents or in combination, and a non-hormonal drug like ormeloxifene are used for various conditions. However, estrogen and progesterone-containing OC as well as ormeloxifene are seldom associated with hepatotoxicity. We prospectively studied the clinical, demographic, liver injury pattern, complications, and outcome of the hepatotoxicity from OC and ormeloxifene. Methods: We analyzed and compared the aforementioned characteristics among consecutive patients with OC and ormeloxifene-induced drug-induced liver injury (DILI) from two university hospitals in India. Cases fulfilling established DILI criteria and the Roussel Uclaf causality assessment method were identified and followed up until recovery/death. Results: We identified 43 (3.5%) amongst 1226 patients with DILI; 19 (44%) from estrogen and progesterone combination, 21 (49%) from progesterone monotherapy, and 3 (7%) due to ormeloxifene. Seven cases were identified from 1998 to 2014 and 36 cases from 2015 to 2023. All were due to oral tablets. The mean age was 36 years (range 21-75). Nineteen patients (44%) developed jaundice and 5 (11.6%) developed itching. The liver injury pattern was hepatocellular in 19 (44%), mixed in 13 (30%), and cholestatic in 11 (26%). Four patients (9%) died, three from acute liver failure and one due to acute on chronic liver failure. Liver biochemical tests normalized after a mean of 66 days after stopping the implicated agents. Contrastingly, literature search yielded 24 cases of progesterone DILI reported between 1962 and 2019 with no mortality. Conclusion: In contrast to published literature on oral contraceptives, a majority of oral contraceptive-induced DILI in our series were from progesterone monotherapy and a smaller number with ormeloxifene, that often resulted in clinically significant jaundice or liver test abnormalities and rarely in fatality.

Barriers to seeking treatment for alcohol use disorders among males in a tertiary care center in South India - a cross-sectional study.

BACKGROUND: There are limited studies on barriers to seeking treatment for Alcohol Use Disorders (AUD) among males in tertiary care centers in India and abroad. Identification of these factors can aid in addressing the barriers to seeking treatment for AUD in low-and-middle-income countries. OBJECTIVE: To investigate the barriers to seeking treatment for AUD among males in a tertiary care center in South India. METHODS: The study design was cross-sectional. We employed a semi-structured interview proforma, Barriers Questionnaire (Alcohol), and assessed the age of onset of initiation of alcohol, problem drinking, and AUD. RESULTS: The majority (73.3%) belonged to Low-Barrier group. Individual items such as "Denial of Alcoholism", "avoid others counseling", "don't like to talk in groups", "Worried about what others will think for taking help or made fun of by others", "Self or Family embarrassed of taking treatment", "cannot afford treatment due to various reasons", "Fear of losing job", "Fear of losing friends" and "Fear of seeing people" were significantly higher in High-Barrier group. CONCLUSIONS: Our study has helped to identify some of the important impediments. Psychoeducation and reducing the stereotypes related to the treatment of AUD can increase trust in the treatment process, resulting in greater help-seeking, early intervention, and improved quality of life.

A study of genetic variants, genetic risk score and DNA methylation of PNPLA3 and TM6SF2 in alcohol liver cirrhosis.

BACKGROUND: Genetic and epigenetic factors are associated with the development of alcohol-associated liver disease (AALD). The single nucleotide polymorphisms (SNPs), rs738409 in Patatin-like phospholipase domain-containing protein (PNPLA3) and rs58542926 in Transmembrane 6 Superfamily Member 2 (TM6SF2) are strongly associated with AALD in different global populations, Hence, we analyzed the genetic risk score for these variants and deoxyribonucleic acid (DNA) methylation levels of the PNPLA3 and TM6SF2 genes among cases (alcohol liver cirrhosis) and controls (heavy drinkers without cirrhosis). METHOD: We studied patients with alcohol use disorder (AUD) with cirrhosis (AUD-C + ve, n = 136) and without cirrhosis (AUD-C-ve, n = 107) drawn from the clinical services of St. John's Medical College Hospital (SJMCH) (Gastroenterology and Psychiatry) and Centre for Addiction Medicine (CAM), National Institute of Mental Health and Neurosciences, (NIMHANS). Genotype data was generated for rs738409 (PNPLA3) and rs58542926 (TM6SF2) and used to calculate unweighted genetic risk score (uGRS) and weighted genetic risk scores (wGRS). DNA methylation levels were estimated by pyrosequencing at PNPLA3 and TM6SF2 loci. RESULTS: Overall we observed a significantly higher genetic risk score (weighted genetic risk score, wGRS) in individuals with alcohol use disorder compared to control population (p = < 0.01). Further, uGRS and wGRS were associated with the diagnosis of cirrhosis, even after correcting for age of onset, quantity and frequency of drinking. We also found hypomethylation at CpG2 of TM6SF2 gene in AUD-C + ve compared to AUD-C-ve (P = 0.02). CONCLUSION: We found that a genetic risk score based on SNPs in the PNPLA3 and TM6SF2 genes was significantly associated with cirrhosis in patients with AUD, suggesting a potential utility in identifying patients at risk and providing pre-emptive interventions. These may include interventions that aim to alter DNA methylation, which may be one of the mechanisms through which elevated genetic risk may influence the development of cirrhosis.

Hypomethylation of Long Interspersed Nucleotide Elements and Aldehyde Dehydrogenase in Patients of Alcohol Use Disorder with Cirrhosis.

Alcohol use disorder (AUD) and cirrhosis are key outcomes of excessive alcohol use, and a genetic influence in these outcomes is increasingly recognized. While 80-90% of heavy alcohol users show evidence of fatty liver, only 10-20% progress to cirrhosis. There is currently no clear understanding of the causes of this difference in progression. The aim of this study is to evaluate genetics and epigenetics at the aldehyde dehydrogenase (ALDH2) locus in patients with AUD and liver complications. Study participants were inpatients from the clinical services of Gastroenterology and Psychiatry at St. John's Medical College Hospital (SJMCH) and the National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India. Men diagnosed as having AUD with cirrhosis (AUDC+ve, N = 136) and AUD without cirrhosis (AUDC-ve, N = 107) were assessed. FibroScan/sonographic evidence was used to rule out fibrosis in the AUDC-ve group. Genomic DNA was used for genotyping at the ALDH2 (rs2238151) locus. A subset of 89 samples was used for DNA methylation (AUDC+ve, N = 44; and AUDC-ve, N = 45) analysis at long interspersed nucleotide element 1 (LINE-1) and ALDH2 cytosine-phosphate-guanine (CpG) loci by pyrosequencing. ALDH2 DNA methylation was significantly lower in the AUDC+ve group compared with the AUDC-ve group (p < 0.001). Lower methylation was associated with a risk allele (T) of the ALDH2 locus (rs2238151) (p = 0.01). Global (LINE-1) DNA methylation levels were also significantly lower in the AUDC+ve group compared with the AUDC-ve group (p = 0.01). Compromised global methylation (LINE-1) and hypomethylation at the ALDH2 gene was observed in patients with cirrhosis compared with those without cirrhosis. DNA methylation could be explored as a biomarker for cirrhosis and liver complications.

Nomenclature, diagnosis and management of drug-induced autoimmune-like hepatitis (DI-ALH): An expert opinion meeting report.

Drug-induced liver injury (DILI) can mimic almost all other liver disorders. A phenotype increasingly ascribed to drugs is autoimmune-like hepatitis (ALH). This article summarises the major topics discussed at a joint International Conference held between the Drug-Induced Liver Injury consortium and the International Autoimmune Hepatitis Group. DI-ALH is a liver injury with laboratory and/or histological features that may be indistinguishable from those of autoimmune hepatitis (AIH). Previous studies have revealed that patients with DI-ALH and those with idiopathic AIH have very similar clinical, biochemical, immunological and histological features. Differentiating DI-ALH from AIH is important as patients with DI-ALH rarely require long-term immunosuppression and the condition often resolves spontaneously after withdrawal of the implicated drug, whereas patients with AIH mostly require long-term immunosuppression. Therefore, revision of the diagnosis on long-term follow-up may be necessary in some cases. More than 40 different drugs including nitrofurantoin, methyldopa, hydralazine, minocycline, infliximab, herbal and dietary supplements (such as Khat and Tinospora cordifolia) have been implicated in DI-ALH. Understanding of DI-ALH is limited by the lack of specific markers of the disease that could allow for a precise diagnosis, while there is similarly no single feature which is diagnostic of AIH. We propose a management algorithm for patients with liver injury and an autoimmune phenotype. There is an urgent need to prospectively evaluate patients with DI-ALH systematically to enable definitive characterisation of this condition.

Global burden of liver disease: 2023 update.

Liver disease accounts for two million deaths annually and is responsible for 4% of all deaths (1 out of every 25 deaths worldwide); approximately two-thirds of all liver-related deaths occur in men. Deaths are largely attributable to complications of cirrhosis and hepatocellular carcinoma, with acute hepatitis accounting for a smaller proportion of deaths. The most common causes of cirrhosis worldwide are related to viral hepatitis, alcohol, and non-alcoholic fatty liver disease. Hepatotropic viruses are the aetiological factor in most cases of acute hepatitis, but drug-induced liver injury increasingly accounts for a significant proportion of cases. This iteration of the global burden of liver disease is an update of the 2019 version and focuses mainly on areas where significant new information is available like alcohol-associated liver disease, non-alcoholic fatty liver disease, viral hepatitis, and hepatocellular carcinoma. We also devote a separate section to the burden of liver disease in Africa, an area of the world typically neglected in such documents.

APASL-ACLF Research Consortium-Artificial Intelligence (AARC-AI) model precisely predicts outcomes in acute-on-chronic liver failure patients.

BACKGROUND AND AIMS: We hypothesized that artificial intelligence (AI) models are more precise than standard models for predicting outcomes in acute-on-chronic liver failure (ACLF). METHODS: We recruited ACLF patients between 2009 and 2020 from APASL-ACLF Research Consortium (AARC). Their clinical data, investigations and organ involvement were serially noted for 90-days and utilized for AI modelling. Data were split randomly into train and validation sets. Multiple AI models, MELD and AARC-Model, were created/optimized on train set. Outcome prediction abilities were evaluated on validation sets through area under the curve (AUC), accuracy, sensitivity, specificity and class precision. RESULTS: Among 2481 ACLF patients, 1501 in train set and 980 in validation set, the extreme gradient boost-cross-validated model (XGB-CV) demonstrated the highest AUC in train (0.999), validation (0.907) and overall sets (0.976) for predicting 30-day outcomes. The AUC and accuracy of the XGB-CV model (%Δ) were 7.0% and 6.9% higher than the standard day-7 AARC model (p < .001) and 12.8% and 10.6% higher than the day 7 MELD for 30-day predictions in validation set (p < .001). The XGB model had the highest AUC for 7- and 90-day predictions as well (p < .001). Day-7 creatinine, international normalized ratio (INR), circulatory failure, leucocyte count and day-4 sepsis were top features determining the 30-day outcomes. A simple decision tree incorporating creatinine, INR and circulatory failure was able to classify patients into high (~90%), intermediate (~60%) and low risk (~20%) of mortality. A web-based AARC-AI model was developed and validated twice with optimal performance for 30-day predictions. CONCLUSIONS: The performance of the AARC-AI model exceeds the standard models for outcome predictions in ACLF. An AI-based decision tree can reliably undertake severity-based stratification of patients for timely interventions.

Clinical and Liver Biochemistry Phenotypes, and Outcome in 133 Patients with Anti-seizure Drug-Induced Liver Injury.

AIMS AND OBJECTIVE: Anti-seizure drugs that cause idiosyncratic drug-induced liver injury (DILI) are an important cause of morbidity and mortality in individuals exposed to these drugs. The clinical and demographic characteristics, the liver injury pattern, the outcome, and the agents responsible for hepatotoxicity have not been thoroughly studied. We investigated the aforementioned characteristics in a large cohort of DILI registry patients. METHODS: Patients with anti-seizure DILI were studied from a large single-center DILI registry between 1998 and 2021. DILI was defined by international working group criteria with at least a probable relation with RUCAM. Immunoallergic features and organ-specific contribution to outcome were investigated. RESULTS: Anti-seizure drugs accounted for 133 patients (12.5%) among 1067 patients with idiosyncratic DILI. Compared to other agents, patients with anti-seizure DILI were younger (31 vs 41 years; p = 0.31), were more often females (52% vs 46%; p = 0.19) and had a lower frequency of jaundice (41% vs 59%, p = 0.001), MELD score (14.5 vs 16.5; p = 0.02) and mortality (9.8% vs 15.7%, p = 0.03). Anti-seizure DILI exhibited a greater frequency of hypersensitivity skin rashes (75% vs 22%, p < 0.001), including DRESS (51% vs 13%, p < 0.001) and SJS/TEN (19% vs1%, p < 0.001). A total of 18 different anti-seizure agents were responsible for DILI, largely contributed by carbamazepine (n = 36), phenytoin (n = 71), phenobarbitone (n = 8) and valproate (n = 14) which accounted for 89% of cases and 85% of 13 deaths. CONCLUSIONS: Anti-seizure DILI are caused predominantly by first generation drugs. Newer agents account for < 10% of cases. Hypersensitivity reaction is the most common phenotypic presentation. Both severity and mortality are lower with anti-seizure DILI.

AARC score determines outcomes in patients with alcohol-associated hepatitis: a multinational study.

BACKGROUND AND AIM: Acute-on-chronic liver failure (ACLF) is a severe form of alcoholic hepatitis (SAH). We aimed to study the natural course, response to corticosteroids (CS), and the role of the Asian Pacific Association for the Study of Liver (APASL) research consortium (AARC) score in determining clinical outcomes in AH patients. METHODS: Prospectively collected data from the AARC database were analyzed. RESULTS: Of the 1249 AH patients, (aged 43.8 ± 10.6 years, 96.9% male, AARC score 9.2 ± 1.9), 38.8% died on a 90 day follow-up. Of these, 150 (12.0%) had mild-moderate AH (MAH), 65 (5.2%) had SAH and 1034 (82.8%) had ACLF. Two hundred and eleven (16.9%) patients received CS, of which 101 (47.87%) were steroid responders by day 7 of Lille's model, which was associated with improved survival [Hazard ratio (HR) 0.15, 95% CI 0.12-0.19]. AARC-ACLF grade 3 [OR 0.28, 0.14-0.55] was an independent predictor of steroid non-response and mortality [HR 3.29, 2.63-4.11]. Complications increased with degree of liver failure [AARC grade III vs. II vs I], bacterial infections [48.6% vs. 37% vs. 34.7%; p < 0.001); extrahepatic organ failure [66.9% vs. 41.8% vs. 35.4%; p < 0.001] respectively. The AARC score better discriminated 90-day mortality. Harrell's C-index was 0.72 compared to other scores. CONCLUSION: Nearly 4 of 5 patients with AH present with ACLF. Such patients have a higher risk of infections, organ failures, lower response to CS, and higher mortality. Patients with AH and ACLF with AARC grade 3 should be considered for an early liver transplant.

Idiosyncratic Drug-Induced Liver Injury Associated With and Without Drug Reaction With Eosinophilia and Systemic Symptoms.

INTRODUCTION: Immunoallergic drug-induced liver injury (DILI) presenting with features of drug reaction with eosinophilia and systemic symptoms (DRESS) is a distinct phenotype. We describe the clinical characteristics, hepatitis pattern, severity, complications, and implicated medications in DILI patients with and without DRESS. METHODS: Using established criteria, we analyzed DILI registry patients with and without DRESS from 1998 to 2021. RESULTS: DILI associated with DRESS (DwD) comprised 179 among 943 cases (19%) of DILI. Compared with the cohort without DRESS, patients with DwD are more often women and have shorter latency, lesser degrees of injury ( P < 0.01), and lower mortality (7.8%) than those without DRESS (16%). Antiepileptic drugs (36%), sulfonamides (19%), antituberculosis drugs (14%), antibiotics (10%), and antiretroviral drugs (8%) account for 87% of the cases of DwD. DISCUSSION: A limited number of drugs cause DwD, representing a fifth of patients with DILI. DwD is characterized by lesser degrees of liver injury and mortality likely because of earlier presentation.

Acute variceal bleeding portends poor outcomes in patients with acute-on-chronic liver failure: a propensity score matched study from the APASL ACLF Research Consortium (AARC).

BACKGROUND AND AIMS: Limited data exist regarding outcomes of acute variceal bleeding (AVB) in patients with acute-on-chronic liver failure (ACLF), especially in those with hepatic failure. We evaluated the outcomes of AVB in patients with ACLF in a multinational cohort of APASL ACLF Research Consortium (AARC). METHODS: Prospectively maintained data from AARC database on patients with ACLF who developed AVB (ACLF-AVB) was analysed. This data included demographic profile, severity of liver disease, and rebleeding and mortality in 6 weeks. These outcomes were compared with a propensity score matched (PSM) cohort of ACLF matched for severity of liver disease (MELD, AARC score) without AVB (ACLF without AVB). RESULTS: Of the 4434 ACLF patients, the outcomes in ACLF-AVB (n = 72) [mean age-46 ± 10.4 years, 93% males, 66% with alcoholic liver disease, 65% with alcoholic hepatitis, AARC score: 10.1 ± 2.2, MELD score: 34 (IQR: 27-40)] were compared with a PSM cohort selected in a ratio of 1:2 (n = 143) [mean age-44.9 ± 12.5 years, 82.5% males, 48% alcoholic liver disease, 55.7% alcoholic hepatitis, AARC score: 9.4 ± 1.5, MELD score: 32 (IQR: 24-40)] of ACLF-without AVB. Despite PSM, ACLF patients with AVB had a higher baseline HVPG than without AVB (25.00 [IQR: 23.00-28.00] vs. 17.00 [15.00-21.75] mmHg; p = 0.045). The 6-week mortality in ACLF patients with or without AVB was 70.8% and 53.8%, respectively (p = 0.025). The 6-week rebleeding rate was 23% in ACLF-AVB. Presence of ascites [hazard ratio (HR) 2.2 (95% CI 1.03-9.8), p = 0.026], AVB [HR 1.9 (95% CI 1.2-2.5, p = 0.03)], and MELD score [HR 1.7 (95% CI 1.1-2.1), p = 0.001] independently predicted mortality in the overall ACLF cohort. CONCLUSION: Development of AVB confers poor outcomes in patients with ACLF with a high 6-week mortality. Elevated HVPG at baseline represents a potential risk factor for future AVB in ACLF.

Erratum to 'Indian National Association for the Study of Liver Consensus Statement on Acute Liver Failure (Part-2): Management of Acute Liver Failure' [J Clin Exp Hepatol 10 (2020) 477-517].

[This corrects the article DOI: 10.1016/j.jceh.2020.04.011.].

Leflunomide-induced liver injury: Differences in characteristics and outcomes in Indian and US registries.

BACKGROUND: Leflunomide, a disease-modifying anti-rheumatic drug, has been associated with elevations of serum aminotransferases. Herein, we describe the clinical, laboratory features and outcomes of 17 patients with leflunomide/teriflunomide hepatotoxicity from two large drug-induced liver injury (DILI) registries. METHODS: Consecutive, adjudicated cases of leflunomide (n = 16)-or teriflunomide (n = 1)-related DILI from a single centre in Bangalore, India and the multicentre US Drug-Induced Liver Injury Network (DILIN) were reviewed. RESULTS: Nine (0.8%) of the 1070 Indian patients and 8 (0.5%) of the 1400 DILIN patients fulfilled the criteria for DILI because of leflunomide- or teriflunomide. 89% of the Indian cases were women and all were associated with severe cutaneous adverse reaction (SCAR) and a median drug latency of 49 days, whereas 37.5% of the DILIN cases were female, none exhibited SCAR and the median drug latency was 166 days. Hepatocellular injury (70%) was more common in women than men (92% vs. 20%) and was associated with younger mean age (41 vs. 59 years), higher peak INR (2.3 vs. 1.2) and higher mortality (58% vs. 0%). Mortality was observed in six patients from India (2 of the three with myocarditis) and one received liver transplantation from the USA. CONCLUSION: Leflunomide-induced liver injury is predominantly hepatocellular. Leflunomide hepatotoxicity is more likely accompanied by SCAR, a short latency and a higher mortality in the Indian cohort, with a predominance of females, compared to US DILIN patients. The differences in skin involvement, immunoallergic features and outcomes among subjects from India vs. the USA suggest that genetic or environmental factors are important in the pathogenesis of liver injury.

Association of human leukocyte antigen-B*13:01 with dapsone-induced liver injury.

Human leukocyte antigens (HLA) have been linked to adverse drug reactions. Generally, HLA association is phenotype specific and is related to either liver or skin injury. HLA-A*13:01 has been linked to dapsone-induced severe cutaneous drug reactions and its role in drug-induced liver injury (DILI) is unclear. In our series, all of the four patients with immunoallergic dapsone DILI were carrying HLA-B*13:01 compared to its prevalence of 1-12% among Indians. HLA-B*13:01 plays a role not only in dapsone-induced severe cutaneous adverse reaction (SCAR) but also in dapsone-induced liver injury with immunoallergic features and highlights the role of adaptive immune response in the pathogenesis of both liver and skin injury and associated other organ involvement.