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.

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.

Asian Pacific association for the study of liver (APASL) guidelines: hepatitis B virus in pregnancy.

Hepatitis B virus (HBV) infection still remains a major public health issue in the Asia-Pacific region. Most of the burden of HBV-related disease results from infections acquired in infancy through perinatal or early childhood exposure to HBV in Asia-Pacific. Hepatitis B during pregnancy presents unique management issues for both the mother and fetus. These APASL guidelines provide a comprehensive review and recommendations based on available evidence in the literature, for the management of females with HBV infection through every stage of pregnancy and postpartum. These also address the concerns, management challenges, and required follow-up of children born to hepatitis B-positive mothers.

APASL clinical practice guideline on hepatitis B reactivation related to the use of immunosuppressive therapy.

BACKGROUND & AIM: Hepatitis B reactivation related to the use of immunosuppressive therapy remains a major cause of liver-related morbidity and mortality in hepatitis B endemic Asia-Pacific region. This clinical practice guidelines aim to assist clinicians in all disciplines involved in the use of immunosuppressive therapy to effectively prevent and manage hepatitis B reactivation. METHODS: All publications related to hepatitis B reactivation with the use of immunosuppressive therapy since 1975 were reviewed. Advice from key opinion leaders in member countries/administrative regions of Asian-Pacific Association for the study of the liver was collected and synchronized. Immunosuppressive therapy was risk-stratified according to its reported rate of hepatitis B reactivation. RECOMMENDATIONS: We recommend the necessity to screen all patients for hepatitis B prior to the initiation of immunosuppressive therapy and to administer pre-emptive nucleos(t)ide analogues to those patients with a substantial risk of hepatitis and acute-on-chronic liver failure due to hepatitis B reactivation.

Dynamic assessments of hepatic encephalopathy and ammonia levels predict mortality in acute-on-chronic liver failure.

BACKGROUND: We evaluated the dynamics of hepatic encephalopathy (HE) and ammonia estimation in acute-on-chronic liver failure (ACLF) patients due to a paucity of evidence. METHODS: ACLF patients recruited from the APASL-ACLF Research Consortium (AARC) were followed up till 30 days, death or transplantation, whichever earlier. Clinical details, including dynamic grades of HE and laboratory data, including ammonia levels, were serially noted. RESULTS: Of the 3009 ACLF patients, 1315 (43.7%) had HE at presentation; grades I-II in 981 (74.6%) and grades III-IV in 334 (25.4%) patients. The independent predictors of HE at baseline were higher age, systemic inflammatory response, elevated ammonia levels, serum protein, sepsis and MELD score (p < 0.05; each). The progressive course of HE was noted in 10.0% of patients without HE and 8.2% of patients with HE at baseline, respectively. Independent predictors of progressive course of HE were AARC score (≥ 9) and ammonia levels (≥ 85 µmol/L) (p < 0.05; each) at baseline. A final grade of HE was achieved within 7 days in 70% of patients and those with final grades III-IV had the worst survival (8.9%). Ammonia levels were a significant predictor of HE occurrence, higher HE grades and 30-day mortality (p < 0.05; each). The dynamic increase in the ammonia levels over 7 days could predict nonsurvivors and progression of HE (p < 0.05; each). Ammonia, HE grade, SIRS, bilirubin, INR, creatinine, lactate and age were the independent predictors of 30-day mortality in ACLF patients. CONCLUSIONS: HE in ACLF is common and is associated with systemic inflammation, poor liver functions and high disease severity. Ammonia levels are associated with the presence, severity, progression of HE and mortality in ACLF patients.

APASL practical recommendations for the management of hepatocellular carcinoma in the era of COVID-19.

BACKGROUND: COVID-19 has been giving the devastating impact on the current medical care system. There are quite many guidelines on COVID-19, but only a few on the management of hepatocellular carcinoma (HCC) during COVID-19 pandemic. AIMS: We develop these recommendations to preserve adequate clinical practice for the management of HCC. METHODS: Experts of HCC in the Asia-Pacific region exchanged opinions via webinar, and these recommendations were formed. RESULTS: Close contact should be minimized to reduce possible exposure of both medical staff and patients to the novel coronavirus. To prevent transmission of the virus, meticulous hygiene measures are important. With the decrease in regular medical service, the medical staff may be mobilized to provide COVID-19-related patient care. However, diagnosis and treatment of HCC should not be delayed because of COVID-19 pandemic. The management of HCC should be the same as in non-pandemic circumstances. HCC is highly malignant, thus it is recommended not to delay curative treatment such as surgery and ablation. However, a kind of triage is necessary even among patients with HCC when resources are insufficient for all to be treated. Curative treatments should be periodized and cytoreductive or non-curative treatment such as vascular interventions and systemic therapy may be postponed until it can be performed safely with sufficient resources. For patients with confirmed or suspected to be infected with the novel coronavirus, diagnosis and treatment should be postponed until the virus is eliminated or they are confirmed as not being infected with it. CONCLUSIONS: These are collection of measures implemented by front-line medical professionals. We would evolve these recommendations over time as more real-world data becomes available.

Correction to: Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific association for the study of the liver (APASL): an update.

The article Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific association for the study of the liver (APASL): an update, written by [Shiv Sarin], was originally published electronically on the publisher's internet portal (currently SpringerLink) on June 06, 2019 without open access.

Complications constitute a major risk factor for mortality in hepatitis B virus-related acute-on-chronic liver failure patients: a multi-national study from the Asia-Pacific region.

BACKGROUND AND AIM: Cirrhosis is a controversial determinant of mortality in HBV-related acute-on-chronic liver failure (HBV-ACLF). The present study aimed to explore the effects of cirrhosis and the associated risk factors, especially its complications, on the outcome of HBV-ACLF. METHODS: A prospective-retrospective cohort of 985 patients was identified from the APASL-ACLF Research Consortium (AARC) database and the Chinese Study Group. Complications of ACLF (ascites, infection, hepatorenal syndrome, hepatic encephalopathy, upper gastrointestinal bleeding) as well as cirrhosis and the current main prognostic models were measured for their predictive ability for 28- or 90-day mortality. RESULTS: A total of 709 patients with HBV-ACLF as defined by the AARC criteria were enrolled. Among these HBV-ACLF patients, the cirrhotic group showed significantly higher mortality and complications than the non-cirrhotic group. A total of 36.1% and 40.1% of patients met the European Association for the Study of Liver (EASL)-Chronic Liver Failure consortium (CLIF-C) criteria in the non-cirrhotic and cirrhotic groups, respectively; these patients had significantly higher rates of mortality and complications than those who did not satisfy the CLIF-C criteria. Furthermore, among patients who did not meet the CLIF-C criteria, the cirrhotic group exhibited higher mortality and complication rates than the non-cirrhotic group, without significant differences in organ failure. The Tongji prognostic predictor model score (TPPMs), which set the number of complications as one of the determinants, showed comparable or superior ability to the Chinese Group on the Study of Severe Hepatitis B-ACLF score (COSSH-ACLFs), APASL-ACLF Research Consortium score (AARC-ACLFs), CLIF-C organ failure score (CLIF-C OFs), CLIF-C-ACLF score (CLIF-C-ACLFs), Model for End-Stage Liver Disease score (MELDs) and MELD-sodium score (MELD-Nas) in HBV-ACLF patients, especially in cirrhotic HBV--ACLF patients. Patients with two (OR 4.70, 1.88) or three (OR 8.27, 2.65) complications had a significantly higher risk of 28- or 90-day mortality, respectively. CONCLUSION: The presence of complications is a major risk factor for mortality in HBV-ACLF patients. TPPM possesses high predictive ability in HBV-ACLF patients, especially in cirrhotic HBV-ACLF patients.

APASL HCV guidelines of virus-eradicated patients by DAA on how to monitor HCC occurrence and HBV reactivation.

In the direct-acting antiviral (DAA) era for hepatitis C virus (HCV) infection, sustained virological response (SVR) is very high, but close attention must be paid to the possible occurrence of hepatocellular carcinoma (HCC) and reactivation of hepatitis B virus (HBV) in patients with co-infection who achieved SVR in short term. HCC occurrence was more often observed in patients with previous HCC history. We found occurrence of HCC in 178 (29.6%) of 602 patients with previous HCC history (15.4 months mean follow-up post-DAA initiation) but, in contrast, in only 604 (1.3%) of 45,870 patients without previous HCC history (18.2 months mean follow-up). Thus, in these guidelines, we recommend the following: in patients with previous HCC history, surveillance at 4-month intervals for HCC by ultrasonography (US) and tumor markers should be performed. In patients without previous HCC history, surveillance at 6- to 12-month intervals for HCC including US is recommended until the long-term DAA treatment effects, especially for the resolution of liver fibrosis, are confirmed. This guideline also includes recommendations on how to follow-up patients who have been infected with both HCV and HBV. When HCV was eradicated in these HBsAg-positive patients or patients with previous HBV infection (anti-HBc and/or anti-HBs-positive), it was shown that HBV reactivation or HBV DNA reappearance was observed in 67 (41.4%) of 162 or 12 (0.9%) of 1317, respectively. For these co-infected patients, careful attention should be paid to HBV reactivation for 24 weeks post-treatment.

Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific association for the study of the liver (APASL): an update.

The first consensus report of the working party of the Asian Pacific Association for the Study of the Liver (APASL) set up in 2004 on acute-on-chronic liver failure (ACLF) was published in 2009. With international groups volunteering to join, the "APASL ACLF Research Consortium (AARC)" was formed in 2012, which continued to collect prospective ACLF patient data. Based on the prospective data analysis of nearly 1400 patients, the AARC consensus was published in 2014. In the past nearly four-and-a-half years, the AARC database has been enriched to about 5200 cases by major hepatology centers across Asia. The data published during the interim period were carefully analyzed and areas of contention and new developments in the field of ACLF were prioritized in a systematic manner. The AARC database was also approached for answering some of the issues where published data were limited, such as liver failure grading, its impact on the 'Golden Therapeutic Window', extrahepatic organ dysfunction and failure, development of sepsis, distinctive features of acute decompensation from ACLF and pediatric ACLF and the issues were analyzed. These initiatives concluded in a two-day meeting in October 2018 at New Delhi with finalization of the new AARC consensus. Only those statements, which were based on evidence using the Grade System and were unanimously recommended, were accepted. Finalized statements were again circulated to all the experts and subsequently presented at the AARC investigators meeting at the AASLD in November 2018. The suggestions from the experts were used to revise and finalize the consensus. After detailed deliberations and data analysis, the original definition of ACLF was found to withstand the test of time and be able to identify a homogenous group of patients presenting with liver failure. New management options including the algorithms for the management of coagulation disorders, renal replacement therapy, sepsis, variceal bleed, antivirals and criteria for liver transplantation for ACLF patients were proposed. The final consensus statements along with the relevant background information and areas requiring future studies are presented here.

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.

Cardioprotective effect of caffeic acid phenethyl ester on cardiac contusion following blunt chest trauma in rats.

We investigated the effects of caffeic acid phenethyl ester (CAPE) on cardiac damage after blunt chest injury. Forty male adult Wistar albino rats were divided into four groups; control, cardiac contusion, cardiac contusion + CAPE, and CAPE. CAPE, 10 mmol/kg, was administered intraperitoneally for 7 days following cardiac contusion. Heart tissue and blood were obtained at the end of the experimental period. Cardiac histopathology was determined using hematoxylin & eosin (H & E) staining. Expression of tumor necrosis factor-alpha (TNF-α) in cardiomyocytes was determined using immunohistochemistry. Cardiac apoptosis was determined using the TUNEL method. Serum creatine kinase (CK), creatine kinase-muscle/brain (CK-MB) and lactate dehydrogenase (LDH) levels were determined using spectrophotometric methods. The serum cardiac troponin I (C-TI) level was measured using the ELISA method. Myofibril loss was detected in the cardiomyocytes of the cardiac contusion group. Increased apoptosis and TNF-α expression were observed in the cardiac contusion group compared to the control group. Increased CK, CK-MB, LDH and C-TI levels were found in the cardiac contusion group. We found that CAPE administration improved myocardial function. Compared to the cardiac contusion group, CK, CK-MB, LDH and C-TI levels decreased significantly in the cardiac contusion + CAPE group. Administration of CAPE significantly inhibited apoptosis and cardiac TNF-α expression. Our findings demonstrate the therapeutic effects of CAPE for cardiac contusion damage after blunt chest trauma.

APASL clinical practice recommendation: how to treat HCV-infected patients with renal impairment?

Chronic hepatitis C virus (HCV) infection is common among patients with chronic kidney disease (CKD) and those on hemodialysis due to nosocomial infections and past blood transfusions. While a majority of HCV-infected patients with end-stage renal disease are asymptomatic, some may ultimately experience decompensated liver diseases and hepatocellular carcinoma. Administration of a combination of elbasvir/grazoprevir for 12 weeks leads to high sustained virologic response (SVR) rates in patients with HCV genotypes (GTs) 1a, 1b or 4 and stage 4 or 5 CKD. Furthermore, a combination of glecaprevir/pibrentasvir for 8-16 weeks also results in high SVR rates in patients with all HCV GTs and stage 4 or 5 CKD. However, these regimens are contraindicated in the presence of advanced decompensated cirrhosis. Although sofosbuvir and/or ribavirin are not generally recommended for HCV-infected patients with severe renal impairment, sofosbuvir-based regimens may be appropriate for those with mild renal impairment. To eliminate HCV worldwide, HCV-infected patients with renal impairment should be treated with interferon-free therapies.

Health-related Quality of Life of Liver Donors: A Prospective Longitudinal Study.

Living donor liver transplantation is a widely accepted option to treat liver diseases in several indications. Risk of liver donation is being discussed and quality of life of donors is also studied. Changes and the change pattern of quality of life were analyzed in this prospective longitudinal study. PATIENTS AND METHODS: Fifty-five donors were included. The Medical Outcomes Study Short Form 36 (SF-36) was fulfilled either in-person or during a telephone interview each donor preoperatively and at the end of the third, sixth, and 12th months. RESULTS: Physical subdomain scores of SF-36 decreased significantly in the third postoperative month compared to preoperative score. The scores recovered in the sixth postoperative month, except for the bodily pain domain. The pain score recovered at the end of the 12th month. While social functioning score among mental subdomains of SF-36 temporarily decreased and recovered at postoperative 12th month, other mental subdomain scores and mental composition summary scores did not show a significant change. CONCLUSION: The quality of life of living liver donors is not permanently affected by donation. There are well-defined changes in the physical aspects of the quality of life that all seem to recover within 1 year. Donors should be preoperatively informed about this temporary change as well as complications.

Liver failure determines the outcome in patients of acute-on-chronic liver failure (ACLF): comparison of APASL ACLF research consortium (AARC) and CLIF-SOFA models.

BACKGROUND AND AIMS: Acute-on-chronic liver failure (ACLF) is a progressive disease associated with rapid clinical worsening and high mortality. Early prediction of mortality and intervention can improve patient outcomes. We aimed to develop a dynamic prognostic model and compare it with the existing models. METHODS: A total of 1402 ACLF patients, enrolled in the APASL-ACLF Research Consortium (AARC) with 90-day follow-up, were analyzed. An ACLF score was developed in a derivation cohort (n = 480) and was validated (n = 922). RESULTS: The overall survival of ACLF patients at 28 days was 51.7%, with a median of 26.3 days. Five baseline variables, total bilirubin, creatinine, serum lactate, INR and hepatic encephalopathy, were found to be independent predictors of mortality, with AUROC in derivation and validation cohorts being 0.80 and 0.78, respectively. AARC-ACLF score (range 5-15) was found to be superior to MELD and CLIF SOFA scores in predicting mortality with an AUROC of 0.80. The point scores were categorized into grades of liver failure (Gr I: 5-7; II: 8-10; and III: 11-15 points) with 28-day cumulative mortalities of 12.7, 44.5 and 85.9%, respectively. The mortality risk could be dynamically calculated as, with each unit increase in AARC-ACLF score above 10, the risk increased by 20%. A score of ≥11 at baseline or persisting in the first week was often seen among nonsurvivors (p = 0.001). CONCLUSIONS: The AARC-ACLF score is easy to use, dynamic and reliable, and superior to the existing prediction models. It can reliably predict the need for interventions, such as liver transplant, within the first week.

Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update.

There is great geographical variation in the distribution of hepatocellular carcinoma (HCC), with the majority of all cases worldwide found in the Asia-Pacific region, where HCC is one of the leading public health problems. Since the "Toward Revision of the Asian Pacific Association for the Study of the Liver (APASL) HCC Guidelines" meeting held at the 25th annual conference of the APASL in Tokyo, the newest guidelines for the treatment of HCC published by the APASL has been discussed. This latest guidelines recommend evidence-based management of HCC and are considered suitable for universal use in the Asia-Pacific region, which has a diversity of medical environments.

Systemic inflammatory response syndrome in acute-on-chronic liver failure: Relevance of 'golden window': A prospective study.

BACKGROUND AND AIM: Systemic inflammatory response syndrome (SIRS) is an early marker of sepsis and ongoing inflammation and has been reported in large proportion of acute-on-chronic liver failure (ACLF) patients. Whether sepsis is the cause or the result of liver failure is unclear and is vital to know. To address this, the study investigated the course and outcome of ACLF patients without SIRS/sepsis. METHODS: Consecutive ACLF patients were monitored for the development of SIRS/sepsis and associated complications and followed till 90 days, liver transplant or death. RESULTS: Of 561 patients, 201 (35.8%) had no SIRS and 360 (64.2%) had SIRS with or without infection. New onset SIRS and sepsis developed in 74.6% and 8% respectively in a median of 7 (range 4-15) days, at a rate of 11% per day. The cumulative incidence of new SIRS was 29%, 92.8%, and 100% by days 4, 7, and 15. Liver failure, that is, bilirubin > 12 mg/dL (odds ratio [OR] = 2.5 [95% confidence interval {CI} = 1.05-6.19], P = 0.04) at days 0 and 4, and renal failure at day 4 (OR = 6.74 [95%CI = 1.50-13.29], P = 0.01), independently predicted new onset SIRS. Absence of SIRS in the first week was associated with reduced incidence of organ failure (20% vs 39.4%, P = 0.003), as was the 28-day (17.6% vs 36%, P = 0.02) and 90-day (27.5% vs 51%,P = 0.002) mortality. The 90-day mortality was 61.6% in the total cohort and that for those having no SIRS and SIRS at presentation were 42.8% and 65%, respectively (P < 0.001). CONCLUSION: Liver failure predicts the development of SIRS. New onset SIRS in the first week is an important determinant of early sepsis, organ failure, and survival. Prompt interventions in this 'golden window' before development of sepsis may improve the outcome of ACLF.

APASL consensus statements and recommendations for hepatitis C prevention, epidemiology, and laboratory testing.

The Asian Pacific Association for the Study of the Liver (APASL) convened an international working party on "APASL consensus statements and recommendations for management of hepatitis C" in March 2015 to revise the "APASL consensus statements and management algorithms for hepatitis C virus infection" (Hepatol Int 6:409-435, 2012). The working party consisted of expert hepatologists from the Asian-Pacific region gathered at the Istanbul Congress Center, Istanbul, Turkey on 13 March 2015. New data were presented, discussed, and debated during the course of drafting a revision. Participants of the consensus meeting assessed the quality of the cited studies. The finalized recommendations for hepatitis C prevention, epidemiology, and laboratory testing are presented in this review.