Acute-on-chronic liver failure (ACLF) is a condition associated with high mortality in the absence of liver transplantation. There have been various definitions proposed worldwide. The first consensus report of the working party of the Asian Pacific Association for the Study of the Liver (APASL) set in 2004 on ACLF was published in 2009, and the "APASL ACLF Research Consortium (AARC)" was formed in 2012. The AARC database has prospectively collected nearly 10,500 cases of ACLF from various countries in the Asia-Pacific region. This database has been instrumental in developing the AARC score and grade of ACLF, the concept of the 'Golden Therapeutic Window', the 'transplant window', and plasmapheresis as a treatment modality. Also, the data has been key to identifying pediatric ACLF. The European Association for the Study of Liver-Chronic Liver Failure (EASL CLIF) and the North American Association for the Study of the End Stage Liver Disease (NACSELD) from the West added the concepts of organ failure and infection as precipitants for the development of ACLF and CLIF-Sequential Organ Failure Assessment (SOFA) and NACSELD scores for prognostication. The Chinese Group on the Study of Severe Hepatitis B (COSSH) added COSSH-ACLF criteria to manage hepatitis b virus-ACLF with and without cirrhosis. The literature supports these definitions to be equally effective in their respective cohorts in identifying patients with high mortality. To overcome the differences and to develop a global consensus, APASL took the initiative and invited the global stakeholders, including opinion leaders from Asia, EASL and AASLD, and other researchers in the field of ACLF to identify the key issues and develop an evidence-based consensus document. The consensus document was presented in a hybrid format at the APASL annual meeting in Kyoto in March 2024. The 'Kyoto APASL Consensus' presented below carries the final recommendations along with the relevant background information and areas requiring future studies.

Plasma exchange (PLEX) improves survival in patients with rodenticidal hepatotoxicity. However, predictors of treatment response are unknown. We aimed at assessing predictors of response to PLEX treatment in these patients. Patients with rodenticidal hepatotoxicity from 2014 to 2023 managed in our department were included in this study. Kochi criteria (model for end-stage liver disease [MELD] score ≥ 36 or international normalized ratio [INR] ≥ 6 with hepatic encephalopathy [HE]) derived specifically for rodenticidal hepatotoxicity (PubMed IDentifier [PMID]: 26310868) were used to assess need for liver transplantation. We analyzed predictors of survival at one month. ∆Bilirubin, ∆MELD score and ∆INR were calculated as percentage change of the parameter after third PLEX session (or after last PLEX if < 3 PLEX sessions done) from baseline pre-PLEX value. Of 200 patients with rodenticidal hepatotoxicity, 114 patients were treated with low-volume PLEX (PLEX-LV). No patient had liver transplantation. Of 78 patients who fulfilled Kochi criteria, 32 patients were PLEX-LV eligible and underwent PLEX-LV (M: 10; age: 20.5, 7–70 years; median, range; acute liver failure: 24). Twenty-two (69 ≥ 20

Low-volume plasma exchange (PLEX) and low-dose steroid improve survival in severe alcoholic hepatitis. We aimed to compare one-year survival of very severe alcoholic hepatitis (VSAH) patients treated with centrifugal PLEX (cPLEX), membrane PLEX (mPLEX) or standard medical treatment (SMT). We retrospectively analyzed survival in consecutive VSAH patients treated at our department from November 2017 to September 2021. PLEX patients received low-volume PLEX along with low-dose steroid (tab. prednisolone 10 mg or 20 mg daily). To adjust for baseline differences between the three treatment (cPLEX, mPLEX or SMT) groups, propensity score (PS) matching was done. Acute-on-chronic liver failure (ACLF) was defined as per European Association for the Study of the Liver (EASL). The primary study outcome was one-year transplant-free survival of PS-matched VSAH patients treated with cPLEX compared to SMT. Of 101 PLEX-eligible VSAH patients, 30 patients were treated with cPLEX, 21 with mPLEX and 50 with SMT. On comparing 30 PS-matched patients each in the cPLEX group vs. the SMT group, transplant-free survival in the cPLEX group was 86.7

Background: Idiosyncratic drug-induced liver injury (iDILI) causing acute liver failure (ALF) carries high shortterm mortality and patients who meet King's College criteria for liver transplantation have 1-month survival of 34% without liver transplantation (PMID: 20949552). We present our experience with low-volume plasma exchange (PLEX-LV, 50% of estimated plasma volume exchanged per session) and low-dose steroid to treat iDILI ALF. Methods: We retrospectively analysed data of patients with iDILI (diagnosed as per RUCAM score), treated with PLEX-LV and low-dose steroid (prednisolone: 10 mg OD, with rapid taper) in our department from 2016 to 2022. Baseline and dynamic parameters (post-PLEX) were assessed as predictors of 1-month liver transplantayears, median (range); MELD score: 30.5 (19-43)] underwent PLEX-LV for ALF during the study period. Causative agents were complementary and alternative medications (36%), antiepileptics (18%) antimicrobials (14%), antitubercular drugs (14%), antifungal drugs (9%) and others (9%). All patients had jaundice and encephalopathy; 9 patients also had ascites. None of the patients underwent liver transplantation. Study patients underwent 3 (1-7) PLEX sessions and 1.4 (0.6-1.6) litres of plasma was exchanged per session. One-month transplant-free survival was 59% (13/22) in the study population and 63% (12/19) among patients who fulfilled Kings College criteria for liver transplantation. Reduction of $25% in plasma von Willebrand factor (VWF) levels after PLEX-LV predicted improved survival (HR: 0.09, 95% CI: 0.01-0.65; AUROC: 0.81; 95% CI: 0.6-1.0). Conclusion: Low-volume PLEX and low-dose steroid appears a promising treatment option in patients with iDILI-induced ALF not opting for liver transplantation. Dynamic changes in VWF level after PLEX predict 1-month survival in these patients. ( J CLIN EXP HEPATOL 2024;14:101303)

Ingestion of phosphorus-containing rodenticide is an important cause of acute liver failure (ALF) in agrarian communities in southern and western India. In Tamil Nadu (TN), it was estimated that among 1584 cases of rodenticide hepatotoxicity (RH), 554 (35%) had died in 2019.1Govindarajan R. Ramamoorthy G. Shanmugam R.M. et al.Rodenticide ingestion is an important cause of acute hepatotoxicity in Tamil Nadu, southern India.Indian J Gastroenterol. 2021; 40: 373-379Crossref PubMed Scopus (12) Google Scholar As highlighted recently in The Lancet Gastroenterology and Hepatology, high mortality in low-resource settings is attributable to lack of access to urgent liver transplantation.2Vento S. Cainelli F. Acute liver failure in low-income and middle-income countries.Lancet Gastroenterol Hepatol. 2023; 8: 1035-1045Summary Full Text Full Text PDF PubMed Scopus (0) Google Scholar Annually, only about 50–75 ALF patients undergo urgent liver transplantation in India.3Acharya S.K. Acute liver failure: Indian perspective.Clin Liver Dis (Hoboken). 2021; 18: 143-149Crossref PubMed Scopus (0) Google Scholar Specific criteria to list RH patients for urgent liver transplantation (model for end-stage liver disease score ≥36 or baseline prothrombin time–international normalized ratio ≥6 with hepatic encephalopathy) were proposed from Kochi in Kerala state. No patient fulfilling these criteria survived with standard medical management alone.4Saraf V. Pande S. Gopalakrishnan U. et al.Acute liver failure due to zinc phosphide containing rodenticide poisoning: clinical features and prognostic indicators of need for liver transplantation.Indian J Gastroenterol. 2015; 34: 325-329Crossref PubMed Scopus (35) Google Scholar High volume plasma exchange (PLEX) is an alternate treatment in ALF due to paracetamol overdose.5Larsen F.S. Schmidt L.E. Bernsmeier C. et al.High-volume plasma exchange in patients with acute liver failure: an open randomised controlled trial.J Hepatol. 2016; 64: 69-78Summary Full Text Full Text PDF PubMed Scopus (424) Google Scholar We had previously reported, in Vellore, TN, survival in six out of eight (75%) children with RH, meeting Kochi criteria for transplantation and no contraindication to PLEX, treated with low volume (0.5 × estimated plasma volume per session) PLEX.6Thomas L. Chandran J. Goel A. et al.Improving transplant-free survival with low-volume plasma exchange to treat children with rodenticide induced hepatotoxicity.J Clin Exp Hepatol. 2023; 13: 252-258Summary Full Text Full Text PDF PubMed Scopus (10) Google Scholar When expanded to include all children and adults with RH who met Kochi criteria for liver transplantation treated with low volume PLEX, from January 2014 to September 2023, 1-month survival rate was 22/32, 68.7% (unpublished data). In Vellore, low volume PLEX is standard of care for ALF due to RH. It was adopted as the Health Department's policy in TN.7Handbook of Poisoning ManagementPrimary care to tertiary care. (National Health Mission, Tamil Nadu).www.nhm.tn.gov.in/sites/default/files/2023-02/Hand%20book%20Poisoning%20management_1.pdfDate accessed: December 15, 2023Google Scholar The TN Government adopted a set of interventions to manage RH, including timely access to PLEX in case of ALF (Fig. 1). Protocols for non-transplant management of rodenticide ingestion were prepared by the Tamil Nadu Chapter of the Indian Society of Gastroenterology (TN-ISG)8Eapen C.E. Balasubramanian V. Ramamoorthy G. et al.Management of rodenticide poisoning: Tamil Nadu chapter of Indian Society of Gastroenterology guidelines.Gastroenterol Hepatol Endosc Pract. 2022; 2: 1-6Crossref Google Scholar and the TN Government.7Handbook of Poisoning ManagementPrimary care to tertiary care. (National Health Mission, Tamil Nadu).www.nhm.tn.gov.in/sites/default/files/2023-02/Hand%20book%20Poisoning%20management_1.pdfDate accessed: December 15, 2023Google Scholar Poisonings constitute one of six thrust areas of the TN Accident and Emergency Care Initiative (TAEI) of the National Health Mission (NHM). Under the aegis of TAEI-NHM, an expert group (called Working Group) was asked to propose solutions to address rodenticide poisoning. Furthermore, the authors visited Thanjavur (TN district with the highest RH case burden) and interacted with those who survived RH as well as farmers, shop owners selling rodenticides and concerned district regulatory authority personnel. All stakeholders were sensitised about the high number of deaths, especially amongst the youth due to easy access to rodenticide and its use as a poison for suicide, and ways to curb this. The Working Group recommended stringent regulations to restrict rodenticide sale and a model of care for rodenticide poisoning within the patient's own district. Initial assessment and resuscitation is feasible at the nearest primary health centre and monitoring at the nearest secondary level hospital. Those who develop RH would be taken to the district government medical college (GMC) hospital, where those who fulfil defined criteria undergo low volume PLEX. This referral chain is the "Hub and Spoke" model. Legislation was passed to curb unrestricted access to rodenticide. Online sensitisation and training were periodically imparted to doctors, nurses, and technicians from TAEI centres (taluk [sub-district], district and state level). Initially, dedicated teams from GMC hospitals with high case load started PLEX services for RH, after onsite training in the TAEI-NHM management protocol. This subsequently expanded to include more specially trained teams in district government hospitals offering PLEX to treat RH patients. The aim is for each of the 38 districts in TN state to have a similar facility. By repurposing of existing resources, the plasmapheresis machines acquired during the COVID-19 pandemic are now used to treat RH patients. In 2 years (2022–23), in the state of Tamil Nadu (population 72 million), only three patients with RH accessed urgent liver transplantation.9Personal Communication from Dr N Gopalakrishnan, Member Secretary, Transplant Authority of Tamil Nadu (TRANSTAN).Google Scholar During the same period, 1237 RH patients underwent PLEX under the TAEI-NHM programme. The effectiveness of this "Hub and Spoke" model needs to be analysed further. A cost analysis of low volume PLEX as compared to liver transplantation needs to be carried out; it is likely that PLEX will be a fraction of the cost of transplantation. Equally, the donor pool for PLEX (plasma) is more readily available than for transplant (organ). This "Hub and Spoke" model could be replicable in other resource-constrained settings for saving lives of patients with ALF of diverse aetiologies. CEE, AG, UZ, and KN conceptualized the paper. TAEI Team - SPS, KN, SMT, SR, JJ, AM, CP, NS, SC, and SK were involved in project administration. UD and VJ supervised the project and paper. VA, SKE, CEE, AG, and UZ were involved in data curation, formal analysis and the manuscript preparation. VA, SKE, AG, CEE, UZ, DD, GKC, SV, VD, IA, DRV, SK, KP, EJ, KPPA, DDA, SJ, and SG were involved in the clinical care of patients. All contributors reviewed and approved the final draft of the manuscript. None. T. Jacob John, Professor of Clinical Virology (Retired), Christian Medical College, Vellore. Download .docx (.01 MB) Help with docx files CMC Vellore Collaborative Group

Background:Data on non-O1/non-O139 Vibrio cholera (NOVC) infection in liver disease is limited. We studied the clinical features and outcome of patients with cirrhosis with non-NOVC bacteraemia and/or spontaneous bacterial peritonitis (SBP) when compared to non-extended spectrum beta lactamase (non-ESBL) Escherichia coli (E. coli). Methods:Hospital information system of patients with cirrhosis admitted with bacteraemia and/or SBP from 2010 to 2020 was searched to include patients with NOVC infection. Non-ESBL E. coli bacteraemia/bacterascites were chosen as a comparator group, matched for the date of admission within 5 days of index case. Propensity score matching (PSM) was done for patient's age and Child score to compare outcome at discharge between NOVC-infected and E. coli-infected cirrhotic patients. Results:There were 2545 patients admitted with bacteraemia and/or SBP during the study period; 29 had NOVC isolated (M:F = 23:6; age: 39, 18-54 years; median, range; model for end-stage liver disease [MELD] score: 25, 12-38; Child score: 11, 10-12.5) from either blood (26), ascites (3), or both (8). Of these, 26 isolates were pan-sensitive to antibiotic sensitivity tests. Fifty-three patients with non-ESBL E. coli were isolated (M: F = 43:10; age: 48; 18-69 years; MELD score: 25, 20-32; Child score:12,11-13) from blood (31), ascites (17), or both (5) within the selected time frame. Of these, 48 isolates were sensitive to the empirical antibiotics initiated.After PSM, in comparison with 29 non-ESBL E. coli patients (age: 41, 18-55 years; MELD score: 24, 19-31; Child score: 12, 11-13), NOVC patients had higher incidence of circulatory failure at admission (14 [49 %] vs 4 [13 %]; P: 0.01) and significantly higher in-hospital mortality (15 [52 %] vs 6 [20 %];P: 0.028]. Conclusions:Bacteraemia due to non-O1/non-O139 strains of V. cholera, is an uncommon cause of bacteraemia or bacterascites in patients with cirrhosis and is associated with high incidence of circulatory failure and significant mortality.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Sir, A 61-year-old man presented with low backache and severe proximal muscle weakness of 2-year duration. He also had an increased urinary frequency for the past 3 years, and he was evaluated elsewhere and diagnosed to have adenocarcinoma of prostate based on an elevated prostate specific antigen and biopsy of gland. He received radiation therapy (30 Gy in 10 fractions) prior to visiting our centre. On examination, there was no bony deformity. He had significant proximal myopathy of lower limbs; there was no other focal neurological deficit. There was no history of fractures. The rest of the systemic examination was normal. His serum total prostate specific antigen was 1137 ng/ml. The radiograph of the lumbar spine demonstrated osteosclerotic vertebrae [Figure 1], and Technetium-99m methylene diphosphonate (MDP) scan revealed disseminated osseous metastasis [Figure 2]. A computed topography (CT) scan of the thorax, abdomen, and pelvis done elsewhere had shown the prostatic mass and right axillary lymphadenopathy. The biopsy from the axillary lymph node was reported as a metastatic acinar adenocarcinoma. Further evaluation for the cause of proximal myopathy demonstrated normal fasting corrected serum calcium (8.6 mg/dL) with low phosphate levels (1.4 mg/dL) and normal serum creatinine (0.8 mg/dL). He had an elevated alkaline phosphatase (551 U/L) with 25(OH) vitamin D of 17 ng/mL and a normal PTH (37 pg/mL). In addition, he had a low renal threshold of phosphate reabsorption (TmP/GFR 1.8 mg/dL). His FGF-23 level was markedly elevated (587 RU/mL), confirming the fibroblast growth factor 23 (FGF-23)-mediated phosphaturia and hypophosphatemic osteomalacia secondary to metastatic prostate adenocarcinoma.Figure 1: Radiograph of lumbar spine showing osteosclerotic vertebraFigure 2: Technetium-99m methylene diphosphonate (MDP) scan showing disseminated osseous metastasisHe was subsequently initiated on phosphate supplementation and calcitriol. For the metastatic prostate cancer, he underwent bilateral orchidectomy and was later initiated on androgen biosynthesis inhibitor abiraterone along with prednisolone. As the patient had wished for follow-up at his hometown, a repeat FGF-23 level was not available. Prostate cancer is the second most common urological malignancy associated with paraneoplastic syndromes. The endocrine paraneoplastic syndromes associated include syndrome of inappropriate antidiuretic hormone (SIADH), Cushing’s syndrome, PTH-rP-mediated hypercalcaemia, and rarely tumour-induced osteomalacia.[1,2] Tumour-induced osteomalacia (TIO), also known as oncogenic osteomalacia, occurs as a consequence of overproduction of FGF-23 by a tumour, resulting in several skeletal manifestations, which include osteomalacia in adults and rickets in children. FGF-23, through its action on sodium-dependent phosphate transport proteins NPT2A and NPT2C in the kidney, reduces tubular re-absorption of phosphate and in turn leads to low serum phosphate levels. FGF-23 also down-regulates renal 1,25(OH) vitamin D synthesis as well as PTH production and secretion.[3] The down-regulation of 1,25(OH) vitamin D may also contribute to reduced intestinal absorption of phosphate. The most common cause of oncogenic osteomalacia is mixed connective tissue types of mesenchymal tumours. The manifestations associated with TIO may also often be subtle and lead to significant time lag from symptom onset to diagnosis.[4] Oncogenic osteomalacia was diagnosed in our patient only after metastatic prostate cancer was detected and an initial bout of radiation therapy executed, clearly demonstrating the importance of being aware of the varied manifestations of both metastatic prostate cancer and symptom complex of TIO. Although commonly associated with small benign tumours, TIO can rarely be a secondary paraneoplastic manifestation of advanced metastatic cancers, including prostate cancer as seen in the present patient. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Liver transplant outcomes have improved over the years, and currently, the quality of life and long-term well-being of these patients needs to be improved. Improving bone health goes a long way toward achieving this objective. Poor bone health (osteopenia and osteoporosis) although prevalent, is often overlooked owing to its asymptomatic nature. It can be complicated by debilitating fracture affecting quality of life. It is recommended to assess and optimize bone health prior to liver transplant. Multiple factors contribute to poor bone health in a liver transplant recipient and it is vital to understand and ameliorate these. A careful and targeted approach with inputs from multidisciplinary team involving transplant physician, endocrinologist, occupational therapist, nutritionist, and nursing personnel may often be required. In this review, we aim to concisely discuss the various aspects related to prevalence, pathophysiology, evaluation, treatment, and follow-up of bone disease among liver transplant recipients. ( J CLIN EXP HEPATOL 2023;13:1130-1139)

Background and Aim: Low volume plasma exchange (PLEX) with low dose steroid improves 1-year survival in severe alcoholic hepatitis (SAH) patients. Methods: We retrospectively analyzed data in SAH patients (DF >32) admitted to our unit between November 2017 to September 2021. PLEX was performed after informed consent. Patients unwilling for PLEX got standard medical treatment (SMT). Type of PLEX (centrifugal or membrane) was decided on a case-to-case basis, patients after September 2020 mostly underwent centrifugal PLEX (c.PLEX). PLEX patients received oral prednisolone (10 mg daily, 1 month). Results: Of 109 SAH patients [all males, age: 42 (23-66) years; median, range, serum bilirubin: 24.2 (4.6-53.6) mg%, MELD: 31 (20-58), DF: 88.3 (46.7- 425.9); plasma von Willebrand factor: 732 (187-1486) U/dl], 33 patients underwent c.PLEX, 23 underwent membrane PLEX (m. PLEX) and 53 had SMT. Baseline characteristics were similar in the both PLEX groups. Patients in SMT group had higher MELD score at admission (p-0.005). PLEX parameters were similar in c.PLEX [sessions: 3 (1-7); exchange per session: 1.4 (1.2-1.6) liters] and m.PLEX [sessions:3 (1-5); exchange:1.4 (0.5-1.5)liters]. Plasma removal efficiency was higher in c.PLEX [56 (43-87)%] as compared to m.PLEX [20(10-40)%] (p-value <0.00001) and flow rate was slower [35 (25-50) ml/min, 125 (100-150) ml/min respectively] (p<0.00001). During 1-year follow up, 78 patients died, 29 were alive and 2 had liver transplantation. One-year transplant-free survival estimate (standard error) was significantly better in c.PLEX group: 54.6% (9.2) compared to m.PLEX: 5.2% (5) and SMT: 18.1% (5.4). Hazard ratio (HR) of c.PLEX compared to m.PLEX was 0.25 (0.12-0.53) and adjusted HR of c.PLEX compared to SMT was 0.35 (0.19-0.64). Conclusions: SAH patients treated with c.PLEX had better 1 year survival compared to m.PLEX or SMT. We suggest centrifugal PLEX as the preferred type of PLEX (with low dose steroid) to treat SAH patients.

Background: Alcohol-related acute on chronic liver failure (A-ACLF) patients have high short-term mortality and are poor candidates for steroid therapy. Plasma exchange (PLEX) improves survival in ACLF patients. We analyzed our experience with low volume PLEX (50% of plasma volume exchanged per session) and low dose steroids to treat A-ACLF patients. Methods: We retrospectively compared the efficacy of low volume PLEX and lowdose steroids with standard medical treatment (SMT) in A-ACLF patients treated at our center between November 2017 to June 2019. The primary study outcome was one-year survival. Results: Twenty-one A-ACLF patients in PLEX group [age 40 (29-56) years, median (range); MELD score 31 (29-46)] and 29 A-ACLF patients in SMT group [age 41.5 (28-63) years, MELD score 37 (21-48)] were studied. All 50 study patients had severe alcoholic hepatitis [mDF 84.7 (50-389)]. PLEX group patients had 3 (1-7) PLEX sessions with 1.5 (1.4-1.6) liters of plasma exchanged per session and oral Prednisolone 20 mg daily, tapered over 1 month. Kaplan Meier analysis showed better survival over 1 year in the PLEX group compared to the SMT group (P = 0.03). There was renal dysfunction in 10 patients in the PLEX group, which normalized in six patients after PLEX. Conclusion: In this preliminary report, compared to SMT, low volume PLEX and low dose steroid improved survival over one year in A-ACLF patients with severe alcoholic hepatitis. In patients with renal dysfunction, 60% showed improvement in renal function with PLEX. Studies with a larger number of patients are needed to validate these results.