Background/Aims Acute liver failure (ALF) has high mortality predominantly due to compromised immune system and increased vulnerability to bacterial and fungal infections.
Methods Plasma lipidome and fungal peptide-based community (mycobiome) analysis were performed in discovery cohort (ALF=40, healthy=5) and validated in a validation cohort of 230 patients with ALF using high-resolution-mass-spectrometry, artificial neural network (ANN) and machine learning (ML).
Results Untargeted lipidomics identified 2,013 lipids across 8 lipid group. 5 lipid-species—phosphatidylcholine (PC)[15:0/17:0], PC[20:1/14:1], PC[26:4/10:0], PC[32:0] and TG[4:0/10:0/23:6]—significantly differentiated ALF-NS (FC>10, P<0.05, FDR<0.01). Mycobiome alpha/beta diversity was significantly higher and showed 4 phyla and >20 species significantly dysregulated in ALF-NS linked with lipid metabolism, fatty acid elongation in ER, and others (P<0.05). Lipid and mycobiome diversity values in ALF-NS were strongly correlated (r2>0.7, P<0.05). Multi-modular correlation network showed striking associations between lipid, fungal peptide modules, and clinical parameters specific to ALF-NS (P<0.05). Cryptococcus amylolentus CBS6039 and Penicillium oxalicum 1142 directly correlated with phosphatidylcholine, triglycerides, and severity in ALF-NS (r2>0.85, P<0.05). POD-fungus and POD-lipids showed direct association with infection, necrosis, and hepatic encephalopathy (Beta>1.2, P<0.05). POD-lipid (AUC=0.969 and HR=1.99 [1.02–2.04]) superseded POD-fungus and severity indices for early-mortality prediction. Finally, significant increase in PC (15:0/17:0) level showed highest normalized importance, and ANNs and ML predicted early mortality with >95% accuracy, sensitivity, and specificity. Interestingly, fungal surveillance protein Clec7a was significantly downregulated (>2-fold), leading to a notable increase in fungal infection-mediated choline/phosphatidylcholine and associated enzymes (FC>1.5; Kennedy cycle). This contributed to phosphatidic acid-mediated hyper-inflammation in ALF-NS.
Conclusions In ALF, the plasma lipidome and mycobiome are dysregulated. Increased circulating phosphatidylcholine could stratify ALF predisposed to early mortality or require emergency liver transplantation.
Do Seon Song, Hee Yeon Kim, Young Kul Jung, Tae Hyung Kim, Hyung Joon Yim, Eileen L Yoon, Ki Tae Suk, Jeong-ju Yoo, Sang Gyune Kim, Moon Young Kim, Young Chang, Soung Won Jeong, Jae Young Jang, Sung-Eun Kim, Jung-Hee Kim, Jung Gil Park, Won Kim, Jin Mo Yang, Dong Joon Kim, Korean Acute-on-Chronic Liver Failure (KACLiF) study group, Ashok Kumar Choudhury, Vinod Arora, Shiv Kumar Sarin, APASL ACLF Research Consortium (AARC) for APASL ACLF working party
Clin Mol Hepatol 2024;30(3):388-405. Published online April 11, 2024
Background/Aims Quick sequential organ failure assessment (qSOFA) is believed to identify patients at risk of poor outcomes in those with suspected infection. We aimed to evaluate the ability of modified qSOFA (m-qSOFA) to identify high-risk patients among those with acutely deteriorated chronic liver disease (CLD), especially those with acute-onchronic liver failure (ACLF).
Methods We used data from both the Korean Acute-on-Chronic Liver Failure (KACLiF) and the Asian Pacific Association for the Study of the Liver ACLF Research Consortium (AARC) cohorts. qSOFA was modified by replacing the Glasgow Coma Scale with hepatic encephalopathy, and an m-qSOFA ≥2 was considered high.
Results Patients with high m-qSOFA had a significantly lower 1-month transplant-free survival (TFS) in both cohorts and higher organ failure development in KACLiF than those with low m-qSOFA (Ps<0.05). Subgroup analysis by ACLF showed that patients with high m-qSOFA had lower TFS than those with low m-qSOFA. m-qSOFA was an independent prognostic factor (hazard ratios, HR=2.604, 95% confidence interval, CI 1.353–5.013, P=0.004 in KACLiF and HR=1.904, 95% CI 1.484– 2.442, P<0.001 in AARC). The patients with low m-qSOFA at baseline but high m-qSOFA on day 7 had a significantly lower 1-month TFS than those with high m-qSOFA at baseline but low m-qSOFA on day 7 (52.6% vs. 89.4%, P<0.001 in KACLiF and 26.9% vs. 61.5%, P<0.001 in AARC).
Conclusions Baseline and dynamic changes in m-qSOFA may identify patients with a high risk of developing organ failure and short-term mortality among CLD patients with acute deterioration.
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Acute-on-chronic liver failure is an acute deterioration of liver function manifesting as jaundice and coagulopathy with the development of ascites, with a high probability of extrahepatic organ involvement and high 28-day mortality. The pathogenesis involves extensive hepatic necrosis, which is associated with severe systemic inflammation and subsequently causes the cytokine storm, leading to portal hypertension, organ dysfunction, and organ failure. These patients have increased gut permeability, releasing lipopolysaccharide (LPS) and damage-associated molecular patterns (DAMPS) in the blood, leading to hyper-immune activation and the secretion of cytokines, followed by immune paralysis, causing the development of infections and organ failure in a proportion of patients. Early detection and the institution of treatment, especially in the "Golden Window" period of 7 days, gives an opportunity for reversal of the syndrome. Scores like the Asian Pacific Association for the Study of the Liver (APASL) ACLF research consortium (AARC) score, a model for end stage liver disease (MELD), and the CLIF Consortium acute-on-chronic liver failure (CLIF-C ACLF) score can help in the prediction of mortality. Treatment strategy includes treatment of acute insult. Patients should be considered for early transplant with MELD score >28, AARC score >10, high-grade hepatic encephalopathy, and in the absence of >2 organ failure or overt sepsis to improve survival of up to 80% at five years. Patients, with no option of transplant, can be treated with emerging therapies like faecal microbial transplant, plasma exchange, etc., which need further evaluation.
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Background/Aims Liver cirrhosis is an important cause of morbidity and mortality globally. Every episode of decompensation and hospitalization reduces survival. We studied the clinical profile and long-term outcomes comparing alcohol-related cirrhosis (ALC) and non-ALC.
Methods Cirrhosis patients at index hospitalisation (from January 2010 to June 2017), with ≥1 year follow-up were included.
Results Five thousand and one hundred thirty-eight cirrhosis patients (age, 49.8±14.6 years; male, 79.5%; alcohol, 39.5%; Child-A:B:C, 11.7%:41.6%:46.8%) from their index hospitalization were analysed. The median time from diagnosis of cirrhosis to index hospitalization was 2 years (0.2–10). One thousand and seven hundred seven patients (33.2%) died within a year; 1,248 (24.3%) during index hospitalization. 59.5% (2,316/3,890) of the survivors, required at least one readmission, with additional mortality of 19.8% (459/2,316). ALC compared to non-ALC were more often (P<0.001) male (97.7% vs. 67.7%), younger (40–50 group, 36.2% vs. 20.2%; P<0.001) with higher liver related complications at baseline, (P<0.001 for each), sepsis: 20.3% vs. 14.9%; ascites: 82.2% vs. 65.9%; spontaneous bacterial peritonitis: 21.8% vs. 15.7%; hepatic encephalopathy: 41.0% vs. 25.0%; acute variceal bleeding: 32.0% vs. 23.7%; and acute kidney injury 30.5% vs. 19.6%. ALC patients had higher Child-Pugh (10.6±2.0 vs. 9.0±2.3), model for end-stage liver-disease scores (21.49±8.47 vs. 16.85±7.79), and higher mortality (42.3% vs. 27.3%, P<0.001) compared to non-ALC.
Conclusions One-third of cirrhosis patients die in index hospitalization. 60% of the survivors require at least one rehospitalization within a year. ALC patients present with higher morbidity and mortality and at a younger age.
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Predictive Factors for the Prognosis of Alcoholic Liver Cirrhosis Anca Trifan, Horia Minea, Adrian Rotaru, Carol Stanciu, Remus Stafie, Ermina Stratina, Sebastian Zenovia, Robert Nastasa, Ana-Maria Singeap, Irina Girleanu, Cristina Muzica, Laura Huiban, Tudor Cuciureanu, Stefan Chiriac, Catalin Sfarti, Camelia Cojocariu Medicina.2022; 58(12): 1859. CrossRef
Alcohol-related cirrhosis: The most challenging etiology of cirrhosis is more burdensome than ever Marta Tonon, Salvatore Piano Clinical and Molecular Hepatology.2021; 27(1): 94. CrossRef
Severe alcoholic hepatitis (SAH) remains a disease with high mortality. Steroid is the main stay and has been shown to give modest 28-day survival benefit in carefully selected patients, but no 90-day survival benefit. Since non-responders have high incidence of infections and increased mortality, it would be worthwhile to identify them before starting steroid therapy. A high and rising bilirubin, urinary acetyl carnitine >2,500 ng/mL, high asiloglycoprotein positive microparticles, and specific features in liver biopsy could predict steroid non-response at baseline. There is an ever-growing need to find new and effective therapies for SAH patients. Besides aggressive nutrition, granulocyte colony stimulating factor, fecal microbiota transplantation, and plasma exchange appear promising therapies and provide a hope for steroid ineligible or steroid non-responsive patients. Suppression of hepatic inflammation, preventing new bacterial or fungal infections, and enhancing liver regeneration will remain the key targets for next generation therapies.
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Predicting steroid response in acute alcohol-associated hepatitis: Beyond biomarkers of alcohol consumption Jin-Wei Zhang World Journal of Hepatology.2025;[Epub] CrossRef
Severity of Acute Portal Hypertension Determines the Clinical Outcomes in Severe Alcoholic Hepatitis Ankur Jindal, Manoj K. Sharma, Rajan Vijayaraghavan, Shasthry SM, Guresh Kumar, Shiv K. Sarin Digestive Diseases and Sciences.2024; 69(1): 298. CrossRef
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Background/Aims The aim of this study was to study the efficacy and safety of zolpidem for sleep disturbances in patients with cirrhosis.
Methods Fifty-two Child-Turcotte-Pugh (CTP) class A or B cirrhotics with Pittsburgh Sleep Quality Index >5 were randomized to either zolpidem 5 mg daily (n=26) or placebo (n=26) for 4 weeks.
Results The therapy of 4 weeks was completed by 23 patients receiving zolpidem (3 stopped treatment due to excessive daytime drowsiness) and 24 receiving placebo (2 refused to continue the study). In the zolpidem group, after 4 weeks of therapy, there was significant increase in total sleep time (TST) and sleep efficiency compared to baseline and improvement in polysomnographic parameters of sleep initiation and maintenance (i.e., decrease in sleep latency time, decrease in wake time, and decreases in number of arousals and periodic limbs movements per hour of sleep), without any significant change in sleep architecture.
Conclusions Four weeks of 5 mg daily zolpidem in CTP class A or B cirrhosis patients with insomnia led to significant increases in TST and sleep efficiency and improvement in polysomnographic parameters of sleep initiation and maintenance without any significant change in sleep architecture.
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