Palliative care for end-stage liver disease and acute on chronic liver failure:A systematic review

BACKGROUND End stage liver disease(ESLD)represents a growing health concern characterized by elevated morbidity and mortality,particularly among individual ineligible for liver transplantation.The demand for palliative care(PC)is pronounced in patients grappling with ESLD and acute on chronic liver failure(ACLF).Unfortunately,the historical underutilization of PC in ESLD patients,despite their substantial needs and those of their family caregivers,underscores the imperative of seamlessly integrating PC principles into routine healthcare practices across the entire disease spectrum.AIM To comprehensively investigate the evidence surrounding the benefits of incorporating PC into the comprehensive care plan for individuals confronting ESLD and/or ACLF.METHODS A systematic search in the Medline(PubMed)database was performed using a predetermined search command,encompassing studies published in English without any restrictions on the publication date.Subsequently,the retrieved studies were manually examined.Simple descriptive analyses were employed to summarize the results.RESULTS The search strategies yielded 721 references.Following the final analysis,32 fulllength references met the inclusion criteria and were consequently incorporated into the study.Meticulous data extraction from these 32 studies was undertaken,leading to the execution of a comprehensive narrative systematic review.The review found that PC provides significant benefits,reducing symptom burden,depressive symptoms,readmission rates,and hospital stays.Yet,barriers like the appeal of transplants and misconceptions about PC hinder optimal utilization.Integrating PC early,upon the diagnosis of ESLD and ACLF,regardless of transplant eligibility and availability,improves the quality of life for these patients.CONCLUSION Despite the substantial suffering and poor prognosis associated with ESLD and ACLF,where liver transplantation stands as the only curative treatment,albeit largely inaccessible,PC services have been overtly provided too late in the course of the illness.A comprehensive understanding of PC's pivotal role in treating ESLD and ACLF is crucial for overcoming these barriers,involving healthcare providers,patients,and caregivers.

Chronic Liver Failure-Sequential Organ Failure Assessment is better than the Asia-Pacific Association for the Study of Liver criteria for defining acute-on-chronic liver failure and predicting outcome

AIM: To compare the utility of the Chronic Liver Failure-Sequential Organ Failure Assessment (CLIF-SOFA) and Asia-Pacific Association for the Study of Liver (APASL) definitions of acute-on-chronic liver failure (ACLF) in predicting short-term prognosis of patients with ACLF.

Potent antiviral therapy improves survival in acute on chronic liver failure due to hepatitis B virus reactivation

Acute on chronic liver failure(ACLF)is a disease entity with a high mortality rate.The acute event arises from drugs and toxins,viral infections,bacterial sepsis,interventions(both surgical and non-surgical)and vascular events on top of a known or occult chronic liver disease.ACLF secondary to reactivation of chronic hepatitis B virus is a distinct condition;the high mortality of which can be managed in the wake of new potent antiviral therapy.For example,lamivudine and entecavir use has shown definite short-term survival benefits,even though drug resistance is a concern in the former.The renoprotective effects of telbivudine have been shown in a few studies to be useful in the presence of renal dysfunction.Monotherapy with newer agents such as tenofovir and a combination of nucleos(t)ides is promising for improving survival in this special group of liver disease patients.This review describes the current status of potent antiviral therapy in patient with acute on chronic liver failure due to reactivation of chronic hepatitis B,thereby providing an algorithm in management of such patients.

Acute-on-chronic liver failure：recent update

Acute on chronic liver failure（ACLF） was first described in 1995 as a clinical syndrome distinct to classic acute decompensation.Characterized by complications of decompensation,ACLF occurs on a background of chronic liver dysfunction and is associated with high rates of organ failure and significant short-term mortality estimated between45%and 90%.Despite the clinical relevance of the condition,it still remains largely undefined with continued disagreement regarding its precise etiological factors,clinical course,prognostic criteria and management pathways.It is concerning that,despite our relative lack of understanding of the condition,the burden of ACLF among cirrhotic patients remains significant with an estimated prevalence of 30.9%.This paper highlights our current understanding of ACLF,including its etiology,diagnostic and prognostic criteria and pathophysiology.It is evident that further refinement of the ACLF classification system is required in order to detect high-risk patients and improve short-term mortality rates.The field of metabolomics certainly warrants investigation to enhance diagnostic and prognostic parameters,while the use of granulocyte-colony stimulating factor is a promising future therapeutic intervention for patients with ACLF.

Development of a novel score for the diagnosis of bacterial infection in patients with acute-on-chronic liver failure

BACKGROUND The diagnosis of bacterial infection is difficult in patients with acute-on-chronic liver failure(ACLF).AIM To evaluate the diagnostic accuracy of widely used parameters for bacterial infection in ACLF and to develop a simple scoring system to improve diagnostic efficiency.METHODS This was a retrospective study.Procalcitonin(PCT),white blood cells(WBC),proportion of neutrophils(N%),and C-reactive protein(CRP)were examined.Logistic regression was used to select variables for the scoring models and receiver operating characteristic curve(ROC)analysis was used to evaluate the diagnostic value of different indices.RESULTS This study included 386 patients with ACLF,169(43.78%)of whom had bacterial infection on admission.The area under the ROC(AUROC)of PCT,CRP,WBC and N%for the diagnosis of bacterial infection ranged from 0.637 to 0.692,with no significant difference between them.Logistic regression showed that only N%,PCT,and CRP could independently predict infection.A novel scoring system(infection score)comprised of N%,PCT and CRP was developed.The AUROC of the infection score was 0.740,which was significantly higher than that for the other four indices(infection score vs N%,PCT,CRP,and WBC,P=0.0056,0.0001,0.0483 and 0.0008,respectively).The best cutoff point for the infection score was 4 points,with a sensitivity of 78.05%,a specificity of 55.29%,a positive predictive value of 57.91%and a negative predictive value of 76.16%.CONCLUSION The infection score is a simple and useful tool for discriminating bacterial infection in ACLF.

Effects of plasma from patients with acute on chronic liver failure on function of cytochrome P450 in immortalized human hepatocytes

BACKGROUND: The bioartificial liver is anticipated to be a promising alternative choice for patients with liver failure. Toxic substances which accumulate in the patients' plasma exert deleterious effects on hepatocytes in the bioreactor, and potentially reduce the efficacy of bioartificial liver devices. This study was designed to investigate the effects of plasma from patients with acute on chronic liver failure (AoCLF) on immortalized human hepatocytes in terms of cytochrome P450 gene expression, drug metabolism activity and detoxification capability. METHODS: Immortalized human hepatocytes (HepLi-2 cells) were cultured in medium containing fetal calf serum or human plasma from three patients with AoCLF. The cytochrome P450 (CYP3A5, CYP2E1, CYP3A4) expression, drug metabolism activity and detoxification capability of HepLi-2 cells were assessed by RT-PCR, lidocaine clearance and ammonia elimination assay. RESULTS: After incubation in medium containing AoCLF plasma for 24 hours, the cytochrome P450 mRNA expression of HepLi-2 cells was not significantly decreased compared with control culture. Ammonia elimination and lidocaine clearance assay showed that the ability of ammonia removal and drug metabolism remained stable. CONCLUSIONS: Immortalized human hepatocytes can be exposed to AoCLF plasma for at least 24 hours with no significant reduction in the function of cytochrome P450. HepLi-2 cells appear to be effective in metabolism and detoxification and can be potentially used in the development of bioartificial liver. (Hepatobiliary Pancreat Dis Int 2010; 9:611-614)

Efficacy of plasma exchange in adjuvant treatment of chronic and acute liver failure

Objective:To study and evaluate the clini1cal effect of plasma exchange in the adjuvant treatment of chronic and acute liver failure.Methods:Totally 60 patients with chronic and acute liver failure in our department were divided into two groups.The control group received comprehensive treatment and the plasma exchange group received plasma exchange.The changes of total bilirubin(TBIL),PT percentage activity(PTA),alanine aminotransferase(ALT),aspartate aminotransferase(AST),albumin(ALB),interleukin-6(IL-6),procalcitonin(PCT)and C-reactive protein(CRP)were measured after treatment,and were assessed in terms of the degree of relief of clinical symptoms.Results:TBIL,ALB,Alt,AST,IL-6,PCT and CRP in the two groups decreased and PTA increased compared with those before treatment,but the curative effect of the treatment group was better than that of the control group(P<0.05).The total effective rate of the treatment group was 80.0%,which was higher than 46.6%of the treatment group(P<0.05).Conclusion:Plasma exchange can help to improve the liver function,remove a large number of inflammatory factors,promote the recovery of liver function and improve the prognosis of patients with chronic and acute liver failure.

Modified EASL-CLIF criteria that is easier to use and perform better to prognosticate acute-on-chronic liver failure

BACKGROUND We have recently shown that the European Association for the Study of the Liver-Chronic Liver Failure Consortium(EASL-CLIF)criteria showed a better sensitivity to detect acute-on-chronic liver failure(ACLF)with a better prognostic capability than the North American Consortium for the Study of End-Stage Liver Disease criteria.AIM To simplify EASL-CLIF criteria for ease of use without sacrificing its sensitivity and prognostic capability.METHODS Using the United Network for Organ Sharing data(January 11,2016,to August 31,2020),we modified EASL-CLIF(mEACLF)criteria;the modified mEACLF criteria included six organ failures(OF)as in the original EASL-CLIF,but renal failure was defined as creatinine≥2.35 mg/dL and coagulation failure was defined as international normalized ratio(INR)≥2.0.The mEACLF grades(0,1,2,and≥3)directly reflected the number of OF.RESULTS Of the 40357 patients,14044 had one or more OF,and 9644 had ACLF grades 1-3 by EASL-CLIF criteria.By the mEACLF criteria,15574 patients had one or more OF.The area under the receiver operating characteristic(AUROC)for 30-d allcause mortality by OF was 0.842(95%CI:0.831-0.853)for mEACLF and 0.835(95%CI:0.824-0.846)for EASL-CLIF(P=0.006),and AUROC for 30-d transplantfree mortality by OF was 0.859(95%CI:0.849-0.869)for mEACLF and 0.851(95%CI:0.840-0.861)for EASL-CLIF(P=0.001).The AUROC of 30-d all-cause mortality by ACLF grades was 0.842(95%CI:0.831-0.853)for mEACLF and 0.793(95%CI:0.781-0.806)for EASL-CLIF(P<0.0001).The AUROC of 30-d transplant-free mortality by ACLF was 0.859(95%CI:0.848-0.869)for mEACLF and 0.805(95%CI:0.793-0.817)for EASL-CLIF(P<0.0001).CONCLUSION Our study showed that EASL-CLIF criteria for ACLF grades could be simplified for ease of use without losing its prognostication capability and sensitivity.

The Pathogenesis of Acute on Chronic Hepatitis B liver Failure

Acute-on-chronic liver failure is a characteristic clinical liver syndrome, which should be differentiated from acute liver failure, acute decompensated liver cirrhosis and chronic liver failure. The pathogenesis of ACLF is not fully understood yet. Viral factors and immune injury have been reported to be the two major pathogenesis. This paper reviewed the researches on the pathogenesis of acute on chronic hepatitis B liver failure in recent years, to provide theoretical basis for prompt and accurate diagnosis and treatment of this syndrome. This would benefit for the prognosis and raise the survival rate of patients.

Comparison of fungal vs bacterial infections in the medical intensive liver unit:Cause or corollary for high mortality?

BACKGROUND Due to development of an immune-dysregulated phenotype,advanced liver disease in all forms predisposes patients to sepsis acquisition,including by opportunistic pathogens such as fungi.Little data exists on fungal infection within a medical intensive liver unit(MILU),particularly in relation to acute on chronic liver failure.AIM To investigate the impact of fungal infections among critically ill patients with advanced liver disease,and compare outcomes to those of patients with bacterial infections.METHODS From our prospective registry of MILU patients from 2018-2022,we included 27 patients with culture-positive fungal infections and 183 with bacterial infections.We compared outcomes between patients admitted to the MILU with fungal infections to bacterial counterparts.Data was extracted through chart review.RESULTS All fungal infections were due to Candida species,and were most frequently blood isolates.Mortality among patients with fungal infections was significantly worse relative to the bacterial cohort(93%vs 52%,P<0.001).The majority of the fungal cohort developed grade 2 or 3 acute on chronic liver failure(ACLF)(90%vs 64%,P=0.02).Patients in the fungal cohort had increased use of vasopressors(96%vs 70%,P=0.04),mechanical ventilation(96%vs 65%,P<0.001),and dialysis due to acute kidney injury(78%vs 52%,P=0.014).On MILU admission,the fungal cohort had significantly higher Acute Physiology and Chronic Health Evaluation(108 vs 91,P=0.003),Acute Physiology Score(86 vs 65,P=0.003),and Model for End-Stage Liver Disease-Sodium scores(86 vs 65,P=0.041).There was no significant difference in the rate of central line use preceding culture(52%vs 40%,P=0.2).Patients with fungal infection had higher rate of transplant hold placement,and lower rates of transplant;however,differences did not achieve statistical significance.CONCLUSION Mortality was worse among patients with fungal infections,likely attributable to severe ACLF development.Prospective studies examining empiric antifungals in severe ACLF and associations between fungal infections and transplant outcomes are critical.

Chronic Liver Failure after Treatment with Infliximab for Ankylosing Spondylitis in a Patient with Hepatitis B

A 50-year-old man with ankylosing spondylitis was treated successfully with infliximab,who was also a HBV carrier for about twenty-five years.After injection with infliximab for four times,he developed jaundice and HBV DNA was detectable in serum.Serum aminotransferase and total bilirubin levels were higher than normal.Then he was hospitalized and treated with entacavir and Chinese herb medicine.But his liver damage aggravated and was diagnosed as acute on chronic liver failure.Finally,liver transplantation was carried out and he was cured successfully.

HBsAg levels in HBeAg-positive chronic hepatitis B patients with different immune conditions

AIM: To investigate hepatitis B surface antigen (HBsAg) levels in patients with HBeAg-positive chronic hepatitis B (CHB) and different immune conditions.

PD-1 Involvement in Peripheral Blood CD8+T Lymphocyte Dysfunction in Patients with Acute-on-chronic Liver Failure

Background and Aims:Programmed cell death-1(PD-1)plays an important role in downregulating T lymphocytes but the mechanisms are still poorly understood.This study aimed to explore the role of PD-1 in CD8^(+)T lymphocyte dysfunction in hepatitis B virus(HBV)-related acute-on-chronic liver failure(ACLF).Methods:Thirty patients with HBV-ACLF and 30 healthy controls(HCs)were recruited.The differences in the numbers and functions of CD8^(+)T lymphocytes,PD-1 and glucose transporter-1(Glut1)expression from the peripheral blood of patients with HBV-ACLF and HCs were analyzed.In vitro,the CD8^(+)T lymphocytes from HCs were cultured(HC group)and the CD8^(+)T lymphocytes from ACLF patients were cultured with PD-L1-IgG(ACLF+PD-1 group)or IgG(ACLF group).The numbers and functions of CD8^(+)T lymphocytes,PD-1 expression,glycogen uptake capacity,and Glut1,hexokinase-2(HK2),and pyruvate kinase(PKM2)expression were analyzed among the HC group,ACLF group and ACLF+PD-1group.Results:The absolute numbers of CD8^(+)T lymphocytes in the peripheral blood from patients with HBVACLF were lower than in the HCs(p<0.001).The expression of PD-1 in peripheral blood CD8^(+)T lymphocytes was lower in HCs than in patients with HBV-ACLF(p=0.021).Compared with HCs,PD-1 expression was increased(p=0.021)and Glut1 expression was decreased(p=0.016)in CD8^(+)T lymphocytes from the HBV-ACLF group.In vitro,glycogen uptake and functions of ACLF CD8^(+)T lymphocytes were significantly lower than that in HCs(p=0.017;all p<0.001).When PD-1/PD-L1 was activated,the glycogen uptake rate and expression levels of Glut1,HK2,and PKM2 showed a decreasing trend(ACLF+PD-1 group compared to ACLF group,all p<0.05).The functions of CD8^(+)T lymphocytes in the ACLF+PD-1 group[using biomarkers of Ki67,CD69,IL-2,interferon-gamma,and tumor necrosis factor-alpha-were lower than in the ACLF group(all p<0.05).Conclusions:CD8^(+)T lymphocyte dysfunction is observed in patients with HBV-ACLF.PD-1-induced T lymphocyte dysfunction might involve glycolysis inhibition.

Update on diagnosis and management of sepsis in cirrhosis: Current advances

Sepsis and septic shock are catastrophic disease entities that portend high mortality in patients with cirrhosis.In cirrhosis,hemodynamic perturbations,immune dysregulation,and persistent systemic inflammation with altered gut microbiota in the background of portal hypertension enhance the risk of infections and resistance to antimicrobials.Patients with cirrhosis develop recurrent lifethreatening infections that progress to multiple organ failure.The definition,pathophysiology,and treatment options for sepsis have been ever evolving.In this exhaustive review,we discuss novel advances in the understanding of sepsis,describe current and future biomarkers and scoring systems for sepsis,and delineate newer modalities and adjuvant therapies for the treatment of sepsis from existing literature to extrapolate the same concerning the management of sepsis in cirrhosis.We also provide insights into the role of gut microbiota in initiation and progression of sepsis and finally,propose a treatment algorithm for management of sepsis in patients with cirrhosis.

Letter to editor‘prognostic significance of hepatic encephalopathy in patients with cirrhosis treated with Rifaxamin’

The present letter to editor is related to Bohra A et al Prognostic significance of hepatic encephalopathy in patients with cirrhosis treated with current standards of care.World J Gastroenterol 2020;26(18):2221-2231.Hepatic encephalopathy(HE)is a significant and frequent major decompensating event in cirrhosis.However clinical studies examining the clinical outcome of HE are lacking despite its high prevalence.

Transjugular intrahepatic portosystemic shunt vs conservative treatment for recurrent ascites:A propensity score matched comparison

BACKGROUND Transjugular intrahepatic portosystemic shunt(TIPS) placement is an effective intervention for recurrent tense ascites. Some studies show an increased risk of acute on chronic liver failure(ACLF) associated with TIPS placement. It is not clear whether ACLF in this context is a consequence of TIPS or of the pre-existing liver disease.AIM To better understand the risks of TIPS in this challenging setting and to compare them with those of conservative therapy.METHODS Two hundred and fourteen patients undergoing their first TIPS placement for recurrent tense ascites at our tertiary-care center between 2007 and 2017 were identified(TIPS group). Three hundred and ninety-eight patients of the same time interval with liver cirrhosis and recurrent tense ascites not undergoing TIPS placement(No TIPS group) were analyzed as a control group. TIPS indication,diagnosis of recurrent ascites, further diagnoses and clinical findings were obtained from a database search and patient records. The in-hospital mortality and ACLF incidence of both groups were compared using 1:1 propensity score matching and multivariate logistic regressions.RESULTS After propensity score matching, the TIPS and No TIPS groups were comparable in terms of laboratory values and ACLF incidence at hospital admission. There was no detectable difference in mortality(TIPS: 11/214, No TIPS 13/214). During the hospital stay, ACLF occurred more frequently in the TIPS group than in the No TIPS group(TIPS: 70/214, No TIPS: 57/214, P = 0.04). This effect was confined to patients with severely impaired liver function at hospital admission as indicated by a significant interaction term of Child score and TIPS placement in multivariate logistic regression. The TIPS group had a lower ACLF incidence at Child scores < 8 points and a higher ACLF incidence at ≥ 11 points. No significant difference was found between groups in patients with Child scores of 8 to 10 points.CONCLUSION TIPS placement for recurrent tense ascites is associated with an increased rate of ACLF in patients with severely impaired liver function but does not result in higher in-hospital mortality.