Emergency Liver Transplantation Research Articles

Multimodal decoding of human liver regeneration.

The liver has a unique ability to regenerate1,2; however, in the setting of acute liver failure (ALF), this regenerative capacity is often overwhelmed, leaving emergency liver transplantation as the only curative option3-5. Here, to advance understanding of human liver regeneration, we use paired single-nucleus RNA sequencing combined with spatial profiling of healthy and ALF explant human livers to generate a single-cell, pan-lineage atlas of human liver regeneration. We uncover a novel ANXA2+ migratory hepatocyte subpopulation, which emerges during human liver regeneration, and a corollary subpopulation in a mouse model of acetaminophen (APAP)-induced liver regeneration. Interrogation of necrotic wound closure and hepatocyte proliferation across multiple timepoints following APAP-induced liver injury in mice demonstrates that wound closure precedes hepatocyte proliferation. Four-dimensional intravital imaging of APAP-induced mouse liver injury identifies motile hepatocytes at the edge of the necrotic area, enabling collective migration of the hepatocyte sheet to effect wound closure. Depletion of hepatocyte ANXA2 reduces hepatocyte growth factor-induced human and mouse hepatocyte migration in vitro, and abrogates necrotic wound closure following APAP-induced mouse liver injury. Together, our work dissects unanticipated aspects of liver regeneration, demonstrating an uncoupling of wound closure and hepatocyte proliferation and uncovering a novel migratory hepatocyte subpopulation that mediates wound closure following liver injury. Therapies designed to promote rapid reconstitution of normal hepatic microarchitecture and reparation of the gut-liver barrier may advance new areas of therapeutic discovery in regenerative medicine.

Macrophage activation markers are associated with infection and mortality in patients with acute liver failure.

Acute liver failure is a multisystem disorder with a high mortality and frequent need for emergency liver transplantation. Following massive innate immune system activation, soluble markers of macrophage activation are released during liver damage and their association with disease severity and prognosis requires exploration. Patients ALF from the United States Acute Liver Failure Study Group (USALFSG, n = 224) and King's College Hospital (n = 40) together with healthy controls (HC, n = 50) were recruited. Serum from early (Days 1-3) and late (>Day 3) time points were analysed for MAMs by enzyme-linked immunosorbent assay correlated to markers of illness severity and 21-day spontaneous survival. Surface expression phenotyping was performed via Flow Cytometry on CD14+ monocytes. All MAMs serum concentrations were significantly higher in ALF compared to controls (p < .0001). sCD206 concentration was higher in early and late stages of the disease in patients with bacteraemia (p = .002) and infection in general (p = .006). In MELD-adjusted multivariate modelling, sCD206 and sCD163 were independently associated with mortality. CD14+ monocyte expression of CD206 (p < .001) was higher in patients with ALF compared with controls and correlated with SOFA score (p = .018). sCD206 was independently validated as a predictor of infection in an external cohort. sCD206 is increased in serum of ALF patients with infections and poor outcome and is upregulated on CD14+ monocytes. Later measurements of sCD163 and sCD206 during the evolution of ALF have potential as mechanistic predictors of mortality. sCD206 should be explored as a biomarker of sepsis and mortality in ALF.

CHALF Score: A Novel Tool to Rapidly Risk Stratify Children in Need of Liver Transplant Evaluation During Acute Liver Failure.

Pediatric acute liver failure (PALF) can require emergent liver transplantation (LT, >25%) or lead to death (~15%). Existing models cannot predict clinical trajectory or survival with native liver (SNL). We aimed to create a predictive model for PALF clinical outcomes based on admission variables. A retrospective, single-center PALF cohort (April 2003 to January 2022) was identified using International Classification of Disease codes, selected using National Institutes of Health PALF Study Group (PALFSG) criteria, and grouped by clinical outcome (SNL, LT, or death). Significant admission variables were advanced for feature selection using least absolute shrinkage and selection operator regression with bootstrapping (5000×). A predictive model of SNL versus LT or death was created using logistic regression and validated using PALFSG data. Our single-center cohort included 147 patients (58% SNL, 32% LT, 10% expired), while the PALFSG validation cohort included 492 patients (50% SNL, 35% LT, 15% expired). Admission variables associated with SNL included albumin (odds ratio [OR], 16; P < 0.01), ammonia (OR, 2.37; P < 0.01), and total bilirubin (OR, 2.25; P < 0.001). A model using these variables predicted SNL versus LT or death with high accuracy (accuracy [0.75 training, 0.70 validation], area under the curve [0.83 training, 0.78 validation]). A scaled score (CHLA-acute liver failure score) was created that predicted SNL versus LT or death with greater accuracy (C statistic 0.83) than Pediatric End-Stage Liver Disease (C statistic 0.76) and admission liver injury unit (C statistic 0.76) scores. The CHLA-acute liver failure score predicts SNL versus LT or mortality in PALF using admission laboratories with high accuracy. This novel, externally validated model offers an objective guide for urgent referral to a pediatric LT center.

Genetic aetiologies of acute liver failure.

Acute liver failure (ALF) is a rare, rapidly evolving, clinical syndrome with devastating consequences where definitive treatment is by emergency liver transplantation. Establishing a diagnosis can be challenging and, historically, the cause of ALF was unidentified in up to half of children. However, recent technological and clinical advances in genomic medicine have led to an increasing proportion being diagnosed with monogenic aetiologies of ALF. The conditions encountered include a diverse group of inherited metabolic disorders each with prognostic and treatment implications. Often these disorders are clinically indistinguishable and may even mimic disorders of immune regulation or red cell disorders. Rapid genomic sequencing for children with ALF is, therefore, a key component in the diagnostic work up today. This review focuses on the monogenic aetiologies of ALF.

Liver transplantation in viral and autoimmune liver diseases

Despite substantial progress in the management of viral and autoimmune liver diseases, these entities remain relevant indications for liver transplantation. To provide an overview of the current knowledge regarding the management of viral and autoimmune liver diseases before and after liver transplantation. Selective literature search, including current guidelines and abstracts of key scientific meetings. Viral and autoimmune liver disease can be effectively treated in most cases, which has resulted in an overall decline in liver transplantations for this indication group. However, hepatitisD infection and primary sclerosing cholangitis remain difficult-to-treat liver diseases in some patients and may progress to end-stage liver disease despite best possible management. Viral or autoimmune hepatitis can lead to fulminant liver failure requiring emergency liver transplantation. In patients who are transplanted due to viral or autoimmune liver disease, specific measures to prevent recurrence of these diseases after transplantation are mandatory. In view of effective treatment modalities for chronic hepatitisB andC, even liver grafts from donors infected with these viruses can be considered for liver transplantation under certain circumstances.

Lansoprazole Ameliorates Isoniazid-Induced Liver Injury.

Isoniazid is a first-line drug in antitubercular therapy. Isoniazid is one of the most commonly used drugs that can cause liver injury or acute liver failure, leading to death or emergency liver transplantation. Therapeutic approaches for the prevention of isoniazid-induced liver injury are yet to be established. In this study, we identified the gene expression signature for isoniazid-induced liver injury using a public transcriptome dataset, focusing on the differences in susceptibility to isoniazid in various mouse strains. We predicted that lansoprazole is a potentially protective drug against isoniazid-induced liver injury using connectivity mapping and an adverse event reporting system. We confirmed the protective effects of lansoprazole against isoniazid-induced liver injury using zebrafish and patients' electronic health records. These results suggest that lansoprazole can ameliorate isoniazid-induced liver injury. The integrative approach used in this study may be applied to identify novel functions of clinical drugs, leading to drug repositioning.

A Comprehensive Review of the Diagnosis and Management of Acute Liver Failure

Acute liver failure (ALF) is a rare and specific form of severe hepatic dysfunction characterized by coagulopathy and hepatic encephalopathy in a patient with no known liver disease. ALF carries a high morbidity and mortality. Careful attention should be given to hemodynamics and metabolic parameters along with the active surveillance of infections. Timely transfer and supportive management are important in an intensive care unit in a liver transplant center. Identifying patients who will and will not improve with medical management and may need emergent liver transplantation is critical. In this review, we provide a comprehensive update on the etiology, diagnosis, and management of ALF.

Insuficienţa hepatică acută ca formă de debut în boala Wilson în adolescenţă

Introduction. Wilson’s disease (WD) is an autosomal re­ces­sive disease of copper metabolism involving the liver, the nervous system and other organs. In children, the main form is represented by liver disease, with a very variable pre­sen­ta­tion, from mild elevation of transaminases to acute liver failure. In adolescence, mainly in girls, WD can pre­sent as nonimmune hemolytic anemia with acute liver fai­lure (ALF). This case report aims to raise awareness about the ALF as a severe presentation form in WD. Case pre­sen­ta­tion. We report the case of a 13-year-old girl who was admitted to our hospital with abdominal pain and jaun­dice. The laboratory parameters revealed hemolytic ane­mia, a mild increase of transaminases, a very high bi­li­ru­bin level, and severe coagulopathy. The ceruloplasmin level was 6 mg/dl. The diagnosis was Wilson’s disease with non-­im­mune hemolytic anemia and acute liver failure. The ge­ne­tic results confirmed the WD diagnosis; our patient pre­sen­ted homozygous status for p.Lys844Ter (c.2530A&gt;T) va­riant of the ATP7B gene. Chelating therapy was started with D-penicillamine alongside supportive therapy, and we re­ferred her to liver transplantation, which was performed with success five days later. Conclusions. Acute liver fai­­lure is a rare but very severe form of Wilson’s disease, with a high risk of death without liver transplantation. Early diagnosis and referral to a specialized center for the consideration of liver transplantation are vital in these patients. Chelating therapy could be lifesaving, and extracorporeal liver support could be used until the emergency liver transplantation is available.

Mechanisms and aetiology-dependent treatment of acute liver failure.

This review compiles the mechanisms of acute liver failure (ALF) as well as the current and potential therapeutic approaches, including aetiology-specific treatment, and the issues encountered with such approaches. On a cellular level, ALF is characterized by massive hepatocyte death due to different types of cellular demise. Compensatory hyperplasia and functional recovery are possible when the regenerative capacity is sufficient to sustain hepatic function. ALF has a high mortality of about 30% and can lead to death in a very short time despite maximum therapeutic intervention. Besides aetiology-specific therapy and intensive care, the therapeutic option of emergency liver transplantation has significantly improved the prognosis of patients with ALF. However, due to limiting factors such as organ shortage, many patients die on the waiting list. In addition to graft assessment, machine perfusion may have the potential to recondition marginal organs and thus expand the organ donor pool.

Indeterminate etiology of acute liver failure in North America: Less common, still grave prognosis.

The etiology of acute liver failure (ALF) remains one of the most important factors in determining prognosis and predicting outcomes. In a significant proportion of ALF cases, however, the etiology remains unknown and is categorized as indeterminate ALF (IND-ALF). In this study, we summarize findings from patients with IND-ALF from 32 transplant centers across the United States, and we compare laboratory, prognostic, and outcome data for patients with IND-ALF. Between 1998 and 2019, 3364 adult patients with ALF or acute liver injury (ALI) from 32 liver transplant centers were enrolled in the ALFSG registry. The primary clinical outcome of interest was 21-day transplant-free survival (TFS). Of the 3364 patients enrolled in the ALFSG registry, 3.4 % (n=114) were adjudicated as true indeterminate. On multivariate analysis, patients with a lower bilirubin, lower INR, lack of use of mechanical ventilation and no clinical features of coma at baseline had a higher odds ratio of transplant free survival. The number of deaths were similar between patients withtrue-INDALF versus patients withindeterminableALF (29.8%vs. 27.2%), with almost half of the patients requiring liver transplant (42.1%vs. 45.7%). We illustrate the poor prognoses that true-IND-ALF and indeterminable ALF carry and the need for emergency liver transplantation in most cases.

Liver Transplantation for Acute Liver Failure During Pregnancy: Case Report and Literature Review

Liver failure during pregnancy is a rare and highly fatal condition frequently resulting from the patient's pre-existing chronic liver disease. There is no established protocol for managing this condition, and physicians tend to adopt a conservative approach due to concerns about the impact of liver transplantation on fetal development. However, conservative treatment may exacerbate the condition, increasing the risk of fetal and miscarriage deaths. In this study, we present a case of acute-on-chronic liver failure resulting from chronic hepatitis during the 19th week of gestation. Despite undergoing conservative treatment, the fetus tragically died, but the patient achieved an excellent clinical outcome after emergency liver transplantation. We also conducted a systematic review of the literature on liver transplantation during pregnancy from the last decade, examining the causes of liver failure and transplantation during pregnancy. Our research complied with the principles outlined in the Declaration of Helsinki and the Istanbul Declaration.

Integrated Serum Metabolomics and Network Pharmacology Approach to Reveal the Potential Mechanisms of Diwuyanggan Prescription in the Prevention of Acute Liver Injury

Objective: Acute liver injury (ALI) has become a major reason for emergency liver transplantation mortality worldwide. Diwuyanggan (DWYG), a hospital preparation of traditional chinese medicine, does a satisfactory job of treating liver disease, but its pharmacological mechanisms should be further investigated. Thus, we aimed to unravel the mechanisms of DWYG against ALI through a comprehensive approach integrating metabolomics and network pharmacology analysis in this study. Methods: An untargeted metabolomics based on ultra-high pressure liquid chromatography together with quadrupole time of flight mass spectrometry was applied to identify differential metabolites between normal mice and thioacetamide (TAA)-induced ALI mice. By utilizing network pharmacology, potential targets against ALI caused by TAA were excavated. Subsequently, the key targets were validated by real-time polymerase chain reaction assays. Results: DWYG alleviated TAA-induced ALI. Furthermore, 28 differential metabolites were identified with an association between ALI pathological processes and DWYG effects. The pathways involved in bile acid, glycerophospholipid, fatty acid, sphingolipid, tryptophan, and tyrosine metabolism. Then, we found 127 active compounds in DWYG and 26 hub genes associated with the treatment of ALI according to network pharmacology. Besides, according to Kyoto Encyclopedia of Genes and Genome analysis, sphingolipid signaling pathway was deemed as one of the main signaling pathways involved in DWYG anti-ALI, which was in agreement with the metabolomics findings. Further, a combined analysis was performed focusing on 7 key targets, including mitogen-activated protein kinase 1, mitogen-activated protein kinase 8, caspase 3, peroxisome proliferator-activated receptor gamma, albumin, carboxylesterase 1 and glucocerebrosidase, along with their related core metabolites and pathways. Confirmatory experiment further showed that DWYG could reverse the abnormal mRNA expression of these targets in TAA mice. Conclusion: This study revealed direct evidence for the preventive effect of DWYG against ALI and the related pharmacological mechanisms.

M6A Regulator-mediated RNA Methylation Modulates Immune Microenvironment of Hepatitis B Virus-related Acute Liver Failure.

Acute liver failure (ALF) is a rare and complicated disease with a high mortality rate. Emergency liver transplantation is the only treatment method that can improve the ALF prognosis. However, its clinical application remains limited owing to the aggressive nature of liver transplantation, limited donors, and high postoperative mortality. The study investigated the effect of m6A on the immune microenvironment of hepatitis B virus-related ALF (HBV-ALF). In this study, the gene expression data of 47 normal people and 42 HBV-ALF patients were downloaded from the Gene Expression Omnibu (GEO) database. The known 23 m6A regulators which mediated RNA modification patterns were compared and analyzed in these two groups, and the gene diagnosis model of HBV-ALF patients was established based on the analysis results. In addition, we used unsupervised clustering to identify different m6A RNA methylation modification patterns in HBV-ALF based on m6A regulators, and evaluated the immune infiltration and biological differences in these subtypes. In addition, the relationship between m6A genes and immune cell activation in HBV-ACLF patients was explored by immune infiltration analysis. Nineteen m6A regulators mediated RNA methylation (m6A regulators for short) were differentially expressed in HBV-ALF and control groups. m6A regulators could well distinguish control samples from HBV-ALF samples, and m6A regulators might be used as a basis for diagnosing HBV-ALF patients. Immune cells such as activated CD8 T cells, activated B cells, and activated CD4 T cells might play important roles in HBV-ALF, and m6A regulators were closely associated with immune cell infiltration. ALKBH15, CBLL1, IGF2BP2, IGF2BP3, and ZC3H13 were significantly associated with immune cells. Considering 23 m6A regulators, HBV-ALF patients could be classified into two subtypes (cluster 1 and cluster 2) based on different immune cell infiltration. m6A regulators of the IGFBP and YHDF families have extremely different levels in these two subtypes. Differential immune cell infiltration among these subtypes was observed, a total of 913 differentially expressed genes among different m6A modification patterns was identified, and their biological functions were explored. m6A modification might play a crucial role in the diverse and complex immune microenvironment of HBV-ALF patients.

Global disparities in mortality and liver transplantation in hospitalised patients with cirrhosis: a prospective cohort study for the CLEARED Consortium

Cirrhosis, the end result of liver injury, has high mortality globally. The effect of country-level income on mortality from cirrhosis is unclear. We aimed to assess predictors of death in inpatients with cirrhosis using a global consortium focusing on cirrhosis-related and access-related variables. In this prospective observational cohort study, the CLEARED Consortium followed up inpatients with cirrhosis at 90 tertiary care hospitals in 25 countries across six continents. Consecutive patients older than 18 years who were admitted non-electively, without COVID-19 or advanced hepatocellular carcinoma, were enrolled. We ensured equitable participation by limiting enrolment to a maximum of 50 patients per site. Data were collected from patients and their medical records, and included demographic characteristics; country; disease severity (MELD-Na score); cirrhosis cause; medications used; reasons for admission; transplantation listing; cirrhosis-related history in the past 6 months; and clinical course and management while hospitalised and for 30 days post discharge. Primary outcomes were death and receipt of liver transplant during index hospitalisation or within 30 days post discharge. Sites were surveyed regarding availability of and access to diagnostic and treatment services. Outcomes were compared by country income level of participating sites, defined according to World Bank income classifications (high-income countries [HICs], upper-middle-income countries [UMICs], and low-income or lower-middle-income countries [LICs or LMICs]). Multivariable models controlling for demographic variables, disease cause, and disease severity were used to analyse the odds of each outcome associated with variables of interest. Patients were recruited between Nov 5, 2021, and Aug 31, 2022. Complete inpatient data were obtained for 3884 patients (mean age 55·9 years [SD 13·3]; 2493 (64·2%) men and 1391 (35·8%) women; 1413 [36·4%] from HICs, 1757 [45·2%] from UMICs, and 714 [18·4%] from LICs or LMICs), with 410 lost to follow-up within 30 days after hospital discharge. The number of patients who died while hospitalised was 110 (7·8%) of 1413 in HICs, 182 (10·4%) of 1757 in UMICs, and 158 (22·1%) of 714 in LICs and LMICs (p<0·0001), and within 30 days post discharge these values were 179 (14·4%) of 1244 in HICs, 267 (17·2%) of 1556 in UMICs, and 204 (30·3%) of 674 in LICs and LMICs (p<0·0001). Compared with patients from HICs, increased risk of death during hospitalisation was found for patients from UMICs (adjusted odds ratio [aOR] 2·14 [95% CI 1·61-2·84]) and from LICs or LMICs (2·54 [1·82-3·54]), in addition to increased risk of death within 30 days post discharge (1·95 [1·44-2·65] in UMICs and 1·84 [1·24-2·72] in LICs or LMICs). Receipt of a liver transplant was recorded in 59 (4·2%) of 1413 patients from HICs, 28 (1·6%) of 1757 from UMICs (aOR 0·41 [95% CI 0·24-0·69] vs HICs), and 14 (2·0%) of 714 from LICs and LMICs (0·21 [0·10-0·41] vs HICs) during index hospitalisation (p<0·0001), and in 105 (9·2%) of 1137 patients from HICs, 55 (4·0%) of 1372 from UMICs (0·58 [0·39-0·85] vs HICs), and 16 (3·1%) of 509 from LICs or LMICs (0·21 [0·11-0·40] vs HICs) by 30 days post discharge (p<0·0001). Site survey results showed that access to important medications (rifaximin, albumin, and terlipressin) and interventions (emergency endoscopy, liver transplantation, intensive care, and palliative care) varied geographically. Inpatients with cirrhosis in LICs, LMICs, or UMICs have significantly higher mortality than inpatients in HICs independent of medical risk factors, and this might be due to disparities in access to essential diagnostic and treatment services. These results should encourage researchers and policy makers to consider access to services and medications when evaluating cirrhosis-related outcomes. National Institutes of Health and US Department of Veterans Affairs.

Biomolecular map of albumin identifies signatures of severity and early mortality in acute liver failure

Acute liver failure (ALF) is associated with high mortality. Alterations in albumin structure and function have been shown to correlate with outcomes in cirrhosis. We undertook a biomolecular analysis of albumin to determine its correlation with hepatocellular injury and early mortality in ALF. Altogether, 225 participants (200 patients with ALF and 25 healthy controls [HC]) were enrolled. Albumin was purified from the baseline plasma of the training cohort (ALF, n= 40; survivors, n= 8; non-survivors, n= 32; and HC, n= 5); analysed for modifications, functionality, and bound multi-omics signatures; and validated in a test cohort (ALF, n= 160; survivors, n= 53; non-survivors, n= 107; and HC, n= 20). In patients with ALF, albumin is more oxidised and glycosylated with a distinct multi-omics profile than that in HC, more so in non-survivors (p <0.05). In non-survivors, albumin was more often bound (p <0.05, false discovery rate <0.01) to proteins associated with inflammation, advanced glycation end product, metabolites linked to arginine, proline metabolism, bile acid, and mitochondrial breakdown products. Increased bacterial taxa (Listeria, Clostridium, etc.) correlated with lipids (triglycerides [4:0/12:0/12:0] and phosphatidylserine [39:0]) and metabolites (porphobilinogen and nicotinic acid) in non-survivors (r2 >0.7). Multi-omics signature-based probability of detection for non-survival was >90% and showed direct correlation with albumin functionality and clinical parameters (r2 >0.85). Probability-of-detection metabolites built on the top five metabolites, namely, nicotinic acid, l-acetyl carnitine, l-carnitine, pregnenolone sulfate, and N-(3-hydroxybutanoyl)-l-homoserine lactone, showed diagnostic accuracy of 98% (AUC 0.98, 95% CI 0.95-1.0) and distinguish patients with ALF predisposed to early mortality (log-rank <0.05). On validation using high-resolution mass spectrometry and five machine learning algorithms in test cohort 1 (plasma and paired one-drop blood), the metabolome panel showed >92% accuracy/sensitivity and specificity for prediction of mortality. In ALF, albumin is hyperoxidised and substantially dysfunctional. Our study outlines distinct 'albuminome' signatures capable of distinguishing patients with ALF predisposed to early mortality or requiring emergency liver transplantation. Here, we report that the biomolecular map of albumin is distinct and linked to severity and outcome in patients with acute liver failure (ALF). Detailed structural, functional, and albumin-omics analysis in patients with ALF led to the identification and classification of albumin-bound biomolecules, which could segregate patients with ALF predisposed to early mortality. More importantly, we found albumin-bound metabolites indicative of mitochondrial damage and hyperinflammation as a putative indicator of <30-day mortality in patients with ALF. This preclinical study validates the utility of albuminome analysis for understanding the pathophysiology and development of poor outcome indicators in patients with ALF.

Evaluation of transcranial Doppler use in patients with acute liver failure listed for emergency liver transplantation.

Acute liver failure (ALF) is characterized by hepatic encephalopathy (HE) often due to intracranial hypertension (ICH). The risk/benefit-balance of intraparenchymal pressure catheter monitoring is controversial during ALF. Perform an evaluation of transcranial Doppler (TCD) use in patients with ALF listed for emergency liver transplantation. Single center retrospective cohort study including all patients registered on high emergency LT list between 2012 and 2018. All TCD measurements performed during ICU stay after listing and after LT (when performed) were recorded. TCD was considered abnormal when pulsatility index (PI) was >1.2. Among 106 patients with ALF, forty-seven (44%) had a TCD while on list. They had more severe liver and extrahepatic organ failure. When performed, TCD was abnormal in 51% of patients. These patients more frequently developed ICH events (45% vs. 13%, p=.02) and more frequently required increase in sedative drugs and vasopressors. While 22% of patients with normal TCD spontaneously survived, all of those with abnormal TCD died or were transplanted (p=.02). All transplanted patients who had abnormal exams normalized their TCD within 2 (1-2)days after LT. TCD may be a useful non-invasive tool for ICH detection and management, then guide sedation withdrawal.

PIRO-CIC model can predict mortality and futility of care in critically ill cirrhosis patients in the intensive care unit.

Dynamic assessment of critically ill patients with cirrhosis (CICs) is required for accurate prognostication. Development of a dynamic model for prediction of mortality and decision on futility of care in CICs. In a prospective cohort study, we developed the PIRO-CIC model(predisposition,injury,response,organ failure forcriticallyillcirrhotics)] in a derivative cohort (n = 360) and validated it (n = 240) for patients admitted to the Liver ICU. Decompensated cirrhosis admitted to ICU. The model was developed usingCox-regression analysis, and futility was performed by decision-curve analysis. CICs aged 48 ± 11.5years, 87% males, majority being alcoholics, were enrolled, of which 73.5% were alive at one month. Factors significant forPcomponent were INR [hazard ratio 1.12, 95% confidence interval 1.07-1.18] and CystatinC [2.25, 1.70-2.97]; forIcomponent were sepsis [4.69, 1.90-11.57], arterial lactate[1.40, 1.02-1.93] and alcohol as etiology [2.78, 1.85-4.18];forRcomponent-systemic inflammatory response syndrome [1.97, 1.14-3.42] and urine neutrophil-gelatinase-associated lipocalin [HR 2.37, 1.59-3.53]; forOcomponent-low PaO2/FiO2 ratio and need of mechanical ventilation [7.41, 4.63-11.86].The PIRO-CIC model predicted one-month mortality with a C-index of 0.83 in the derivation and 0.80 in the validation cohorts. It predicted futility of care better than other prognostic scores. The immediate risk of mortality increased by 39% with each unit increase in PIRO-CIC score. Not applicable for acute-on-chronic liver failure and patients requiring emergency liver transplant. Assessment and stratification of CICs with the dynamic PIRO-CIC model could determine one-month mortality and futility in the first week. Targeted and aggressive management of coagulation, kidneys, sepsis, and severe systemic inflammation may improve outcomes of CICs.

S3158 Supplement Gone Wrong: Drug-Induced Liver Injury Caused by Artemisinin

Introduction: Drug-induced liver injury (DILI) is defined as hepatic dysfunction caused by prescription medications, supplements, or xenobiotics after alternative causes have been excluded. As one of the leading causes of acute liver failure, DILI should be considered when patients present with hepatic dysfunction. We present a case of symptomatic DILI secondary to artemisinin use. Case Description/Methods: A 78-year-old Chinese man with no medical history presented to the hepatology clinic with 10 weeks of jaundice, weakness, and pruritis. He started taking Artemisinin/ Bioperine 12 weeks ago to prevent COVID-19 but stopped 3 weeks ago. He denied abdominal pain, a family history of liver disease, substance/alcohol use, and taking other concomitant drugs. Physical examination revealed scleral icterus and no other signs of chronic liver disease. Laboratory studies showed total bilirubin 11 mg/dL, alkaline phosphatase 293 U/L, aspartate transaminase 170 U/L, and alanine transaminase 196 U/L with negative workup for hepatitis A, B, and C. CT abdomen and MRCP were unremarkable for liver or biliary pathology. Further serological workup was negative and follow-up labs revealed normalization of liver enzymes and bilirubin. Given the patient’s improvement, liver biopsy was not pursued. The patient was instructed to avoid supplements unless prescribed by a physician. Discussion: DILI is a global issue with an estimated annual incidence rate of 13.9 to 24.0 per 100,000 persons. Diagnosing DILI is important as it can cause acute liver injury and liver failure in certain cases. Since COVID-19 emerged, supplement use has increased given claims of boosting the immune system. Artemisinin is an herb used in traditional Chinese medicine with antimalarial activity investigated to be a possible COVID-19 treatment, but no current evidence exists to support it being effective against COVID-193. Our patient’s supplement also contained Bioperine, a black pepper extract, which is likely benign. Contrarily, artemisinin is a well-described cause of idiosyncratic acute liver injury and hepatotoxicity, causing self-limited mild to moderate transaminitis but also severe cases requiring emergent liver transplantation. Our patient’s unrevealing workup, his spontaneous improvement correlating with supplement discontinuation, and RUCAM score of 7 led to high suspicion of DILI secondary to artemisinin. Providers should always ask patients about supplement use and consider DILI when patients present with liver injury. Table 1. - The patient’s laboratory values, including total bilirubin, alkaline phosphatase (ALP), aspartate transaminase (AST), and alanine transaminase (ALT) improved after stopping Artemisinin/Bioperine Total bilirubin (mg/dL) ALP (U/L) AST (U/L) ALT (U/L) Initial labs with PCP 11 293 170 196 Repeat labs with PCP 5.6 143 75 98 3 weeks after stopping supplement 2.4 85 34 41

Design for a Multicentre Prospective Cohort for the Assessment of Platelet Function in Patients with Hepatitis-B-Virus-Related Acute-on-Chronic Liver Failure.

BackgroundAcute-on-chronic liver failure (ACLF) has high short-term mortality and lacks sufficient medical therapy. Available algorithms are unable to precisely predict short-term outcomes or safely stratify patients with ACLF as emergent liver transplantation candidates. Therefore, a personalized prognostic tool is urgently needed.PurposePlatelet function and its clinical significance in ACLF patients with chronic hepatitis B virus (HBV) infection have not been investigated. This study aimed to assess changes in platelet function using thromboelastography (TEG) and platelet mapping (TEG-PM) in HBV-related ACLF patients.MethodsChronic liver disease patients with acute decompensation or acute hepatic injury were recruited. The derivation cohort enrolled HBV-related patients at Nanfang Hospital. HBV-related and non-HBV-related patients were both enrolled in internal and external validation cohorts at seven university hospitals. TEG and TEG-PM were performed at baseline in the derivation cohort and baseline, day 7, and day 14 in the validation cohorts. The primary outcome was all-cause 28-day mortality. Status check and new-onset complications were recorded during the 3-month follow-up, but status check will extend to 5 years.Conclusion and Future PlansIn this study, 586 participants were enrolled, including 100 in derivation cohort, 133 in internal validation cohort, and 353 in external validation cohort. Biomaterials, including plasma, serum, urine, and some explanted liver tissues, were collected from these patients. A 3-month follow-up with survival status was completed. The baseline characteristics indicated that 51% of the patients had adenosine diphosphate (ADP)-hyporesponsive circulating platelets. The prognostic potential of platelet function will be explored in the derivation cohort (HBV-related ACLF patients) and further substantiated in the validation cohorts (HBV-related and non-HBV-related ACLF patients). Biosamples are currently used to explore the underlying mechanisms related to ADP-hyporesponsive platelets. The ongoing proteomic and metabolic analyses will provide new insights into the pathogenesis of extrahepatic organ failures in ACLF patients.

Management of Acute Liver Failure: Update 2022.

Abbreviated pathogenesis and clinical course of the acute liver failure syndrome. The pathogenesis and clinical course of the syndrome of acute liver failure (ALF) differs depending upon the etiology of the primary liver injury. In turn, the severity of the liver injury and resulting synthetic failure is often the primary determinant of whether a patient is referred for emergency liver transplantation. Injuries by viral etiologies trigger the innate immune system via pathogen-associated molecular patterns (PAMPs), while toxin-induced (and presumably ischemia-induced) injuries do so via damage-associated molecular patterns (DAMPs). The course of the clinical syndrome further depends upon the relative intensity and composition of cytokine release, resulting in an early proinflammatory phenotype (SIRS) and later compensatory anti-inflammatory response phenotype (CARS). The outcomes of overwhelming immune activation are the systemic (extrahepatic) features of ALF (cardiovascular collapse, cerebral edema, acute kidney injury, respiratory failure, sepsis) which ultimately determine the likelihood of death.Acute liver failure (ALF) continues to carry a high risk of mortality or the need for transplantation despite recent improvements in overall outcomes over the past two decades. Optimal management begins with identifying that liver failure is indeed present and its etiology, since outcomes and the need for transplantation vary widely across the different etiologies. Most causes of ALF can be divided into hyperacute (ischemia and acetaminophen) and subacute types (other etiologies), based on time of evolution of signs and symptoms of liver failure; the former evolve in 3 to 4 days and the latter typically in 2 to 4 weeks. Both involve intense release of cytokines and hepatocellular contents into the circulation with multiorgan effects/consequences.Management involves optimizing fluid balance and cardiovascular support, including the use of continuous renal replacement therapy, vasopressors, and pulmonary ventilation. Early evaluation for liver transplantation is advised particularly for acetaminophen toxicity, which evolves so rapidly that delay is likely to lead to death.Vasopressor support, high-grade hepatic encephalopathy, and unfavorable (subacute) etiologies heighten the need for urgent listing for liver transplantation. Prognostic scores such as Kings Criteria, Model for End-Stage Liver Disease, and the Acute Liver Failure Group prognostic index take these features into account and provide reasonable but imperfect predictive accuracy. Future treatments may include liver support devices and/or agents that improve hepatocyte regeneration.