PROGNOSTIC FACTORS OF LIVER TRANSPLANTATION FOR ACUTE-ON-CHRONIC LIVER FAILURE.

BACKGROUND: Liver transplantation (LT) is the only treatment that can provide long-term survival for patients with acute-on-chronic liver failure (ACLF). Although several studies identify prognostic factors for patients in ACLF who do not undergo LT, there is scarce literature about prognostic factors after LT in this population. AIM: Evaluate outcomes of ACLF patients undergoing LT, studying prognostic factors related to 1-year and 90 days post-LT. METHODS: Patients with ACLF undergoing LT between January 2005 and April 2021 were included. Variables such as chronic liver failure consortium (CLIF-C) ACLF values and ACLF grades were compared with the outcomes. RESULTS: The ACLF survival of patients (n=25) post-LT at 90 days, 1, 3, 5 and 7 years, was 80, 76, 59.5, 54.1 and 54.1% versus 86.3, 79.4, 72.6, 66.5 and 61.2% for patients undergoing LT for other indications (n=344), (p=0.525). There was no statistical difference for mortality at 01 year and 90 days among patients with the three ACLF grades (ACLF-1 vs. ACLF-2 vs. ACLF-3) undergoing LT, as well as when compared to non-ACLF patients. CLIF-C ACLF score was not related to death outcomes. None of the other studied variables proved to be independent predictors of mortality at 90 days, 1 year, or overall. CONCLUSIONS: LT conferred long-term survival to most transplant patients. None of the studied variables proved to be a prognostic factor associated with post-LT survival outcomes for patients with ACLF. Additional studies are recommended to clarify the prognostic factors of post-LT survival in patients with ACLF.

Patients hospitalized with alcohol-related liver disease and prior bariatric surgery are more prone to develop acute-on-chronic liver failure.

BACKGROUND & AIMS: Patients with a history of bariatric surgery (BS) are susceptible to developing alcohol use disorder. We and others have previously shown that these patients can develop severe alcohol-related liver disease (ARLD). Our aim was to describe the demographics, co-morbidities and mortality of a hospitalized population diagnosed with alcohol-related liver disease, in relation to BS. METHODS: We included 299 patients hospitalized with ARLD at the Ghent University Hospital between 1 January 2018 and 31 December 2022. Clinical, biochemical and outcome data were retrospectively retrieved from the most recent hospitalization. Statistical analysis was performed using the t test, Mann-Whitney U and χ2 tests. RESULTS: Thirteen per cent (39/299) of patients admitted with ARLD had a history of bariatric surgery, of whom 25 (64.1%) had undergone Roux-en-Y gastric bypass. Patients with a history of BS were predominantly female (76.9%), in contrast to the non-BS population (29.2%) (p < .0001), and despite being significantly younger (p < .0001) and had a similar survival (61.5% vs. 58.1%). Bariatric surgery and older age at diagnosis were both significantly associated with poorer transplant-free survival. The cause of death was acute-on-chronic liver failure in 73.3% of BS patients, compared to only 19.2% of those without a history of BS (p < .0001). The weekly amount of alcohol consumed (p = .012) and duration of use (p < .0001) were significantly lower/shorter in the BS population. CONCLUSIONS: BS patients hospitalized with ARLD are predominantly younger women with a lower cumulative alcohol consumption compared to those without prior BS. BS impacted transplant-free survival, with ACLF as the predominant cause of death in these patients.

Candesartan cilexetil ameliorates NOSTRIN-NO dependent portal hypertension in cirrhosis and ACLF.

In decompensated cirrhosis, the severity of portal hypertension (PHT) is associated with increased hepatic endothelial nitric oxide synthase (eNOS) trafficking inducer (Nostrin), but the mechanism remains unclear. AIM: To investigate: (1) Whether in cirrhosis-PHT models, ± superimposed inflammation to mimic acute-on-chronic liver failure (ACLF) modulates hepatic nitric oxide synthase trafficking inducer (NOSTRIN) expression, nitric oxide (NO) synthesis, and/or endothelial dysfunction (ED); and (2) Whether the "angiotensin II type 1 receptor blocker" candesartan cilexetil (CC) affects this pathway. CD-1 mice received intraperitoneal carbon tetrachloride injections (CCl4 15% v/v in corn oil, 0.5 mL/kg) twice weekly for 12 wk to induce cirrhosis. After 12 wk, mice were randomized to receive 2-wk oral administration of CC (8 mg/kg) ± LPS. At sacrifice, plasma (biochemical indicators, cytokines, and angiotensin II) and liver tissues (histopathology, Sirius-red stains, and molecular studies) were analysed. Moreover, Nostrin gene knockdown was tested in human umbilical vein endothelial cells (HUVECs). When compared to naïve animals, CCl4-treated animals showed markedly elevated hepatic Nostrin expression (P < 0.0001), while hepatic peNOS expression (measure of eNOS activity) was significantly reduced (P < 0.05). LPS challenge further increased Nostrin and reduced peNOS expression (P < 0.05 for both) in cirrhotic animals. Portal pressure and subsequent hepatic vascular resistance were also increased in all cirrhotic animals following LPS challenge. In CCl4 ± LPS-treated animals, CC treatment significantly reduced Nostrin (P < 0.05) and increased hepatic cGMP (P < 0.01). NOSIP, caveolin-1, NFκB, and iNOS protein expression were significantly increased in CCl4-treated animals (P < 0.05 for all). CC treatment non-significantly lowered NOSIP and caveolin-1 expression while iNOS and NFκB expression was significantly reduced in CCl4 + LPS-treated animals (P < 0.05 for both). Furthermore, Nostrin knockdown significantly improved peNOS expression and associated NO synthesis and reduced inflammation in HUVECs. This study is the first to indicate a potential mechanistic role for the Nostrin-eNOS-NO pathway in cirrhosis and ACLF development. Moreover, this pathway provides a potential therapeutic target given the ameliorative response to Candesartan treatment.

Granulocyte colony-stimulating factor with or without stem or progenitor cell or growth factors infusion for people with compensated or decompensated advanced chronic liver disease.

BACKGROUND: Advanced chronic liver disease is characterised by a long compensated phase followed by a rapidly progressive 'decompensated' phase, which is marked by the development of complications of portal hypertension and liver dysfunction. Advanced chronic liver disease is considered responsible for more than one million deaths annually worldwide. No treatment is available to specifically target fibrosis and cirrhosis; liver transplantation remains the only curative option. Researchers are investigating strategies to restore liver functionality to avoid or slow progression towards end-stage liver disease. Cytokine mobilisation of stem cells from the bone marrow to the liver could improve liver function. Granulocyte colony-stimulating factor (G-CSF) is a 175-amino-acid protein currently available for mobilisation of haematopoietic stem cells from the bone marrow. Multiple courses of G-CSF, with or without stem or progenitor cell or growth factors (erythropoietin or growth hormone) infusion, might be associated with accelerated hepatic regeneration, improved liver function, and survival. OBJECTIVES: To evaluate the benefits and harms of G-CSF with or without stem or progenitor cell or growth factors (erythropoietin or growth hormone) infusion, compared with no intervention or placebo in people with compensated or decompensated advanced chronic liver disease. SEARCH METHODS: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, three other databases, and two trial registers (October 2022) together with reference-checking and web-searching to identify additional studies. We applied no restrictions on language and document type. SELECTION CRITERIA: We only included randomised clinical trials comparing G-CSF, independent of the schedule of administration, as a single treatment or combined with stem or progenitor cell infusion, or with other medical co-interventions, with no intervention or placebo, in adults with chronic compensated or decompensated advanced chronic liver disease or acute-on-chronic liver failure. We included trials irrespective of publication type, publication status, outcomes reported, or language. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane procedures. All-cause mortality, serious adverse events, and health-related quality of life were our primary outcomes, and liver disease-related morbidity, non-serious adverse events, and no improvement of liver function scores were our secondary outcomes. We undertook meta-analyses, based on intention-to-treat, and presented results using risk ratios (RR) for dichotomous outcomes and the mean difference (MD) for continuous outcomes, with 95% confidence intervals (CI) and I2 statistic values as a marker of heterogeneity. We assessed all outcomes at maximum follow-up. We determined the certainty of evidence using GRADE, evaluated the risk of small-study effects in regression analyses, and conducted subgroup and sensitivity analyses. MAIN RESULTS: We included 20 trials (1419 participants; sample size ranged from 28 to 259), which lasted between 11 and 57 months. Nineteen trials included only participants with decompensated cirrhosis; in one trial, 30% had compensated cirrhosis. The included trials were conducted in Asia (15), Europe (four), and the USA (one). Not all trials provided data for our outcomes. All trials reported data allowing intention-to-treat analyses. The experimental intervention consisted of G-CSF alone or G-CSF plus any of the following: growth hormone, erythropoietin, N-acetyl cysteine, infusion of CD133-positive haemopoietic stem cells, or infusion of autologous bone marrow mononuclear cells. The control group consisted of no intervention in 15 trials and placebo (normal saline) in five trials. Standard medical therapy (antivirals, alcohol abstinence, nutrition, diuretics, ß-blockers, selective intestinal decontamination, pentoxifylline, prednisolone, and other supportive measures depending on the clinical status and requirement) was administered equally to the trial groups. Very low-certainty evidence suggested a decrease in mortality with G-CSF, administered alone or in combination with any of the above, versus placebo (RR 0.53, 95% CI 0.38 to 0.72; I2 = 75%; 1419 participants; 20 trials). Very low-certainty evidence suggested no difference in serious adverse events (G-CSF alone or in combination versus placebo: RR 1.03, 95% CI 0.66 to 1.61; I2 = 66%; 315 participants; three trials). Eight trials, with 518 participants, reported no serious adverse events. Two trials, with 165 participants, used two components of the quality of life score for assessment, with ranges from 0 to 100, where higher scores indicate better quality of life, with a mean increase from baseline of the physical component summary of 20.7 (95% CI 17.4 to 24.0; very low-certainty evidence) and a mean increase from baseline of the mental component summary of 27.8 (95% CI 12.3 to 43.3; very low-certainty evidence). G-CSF, alone or in combination, suggested a beneficial effect on the proportion of participants who developed one or more liver disease-related complications (RR 0.40, 95% CI 0.17 to 0.92; I2 = 62%; 195 participants; four trials; very low-certainty evidence). When we analysed the occurrences of single complications, there was no suggestion of a difference between G-CSF, alone or in combination, versus control, in participants in need of liver transplantation (RR 0.85, 95% CI 0.39 to 1.85; 692 participants; five trials), in the development of hepatorenal syndrome (RR 0.65, 95% CI 0.33 to 1.30; 520 participants; six trials), in the occurrence of variceal bleeding (RR 0.68, 95% CI 0.37 to 1.23; 614 participants; eight trials), and in the development of encephalopathy (RR 0.56, 95% CI 0.31 to 1.01; 605 participants; seven trials) (very low-certainty evidence). The same comparison suggested that G-CSF reduces the development of infections (including sepsis) (RR 0.50, 95% CI 0.29 to 0.84; 583 participants; eight trials) and does not improve liver function scores (RR 0.67, 95% CI 0.53 to 0.86; 319 participants; two trials) (very low-certainty evidence). AUTHORS' CONCLUSIONS: G-CSF, alone or in combination, seems to decrease mortality in people with decompensated advanced chronic liver disease of whatever aetiology and with or without acute-on-chronic liver failure, but the certainty of evidence is very low because of high risk of bias, inconsistency, and imprecision. The results of trials conducted in Asia and Europe were discrepant; this could not be explained by differences in participant selection, intervention, and outcome measurement. Data on serious adverse events and health-related quality of life were few and inconsistently reported. The evidence is also very uncertain regarding the occurrence of one or more liver disease-related complications. We lack high-quality, global randomised clinical trials assessing the effect of G-CSF on clinically relevant outcomes.

Spur cells in liver cirrhosis are predictive of acute-on-chronic liver failure and liver-related mortality regardless of severe anaemia.

Chronic anaemia in advanced liver disease is a frequent finding. The aim was to explore the clinical impact of spur cell anaemia, a rare entity typically associated with end-stage of the disease. One-hundred and nineteen patients (73.9% males) with liver cirrhosis of any etiology were included. Patients with bone marrow diseases, nutrients deficiencies and hepatocellular carcinoma were excluded. In all patients, a blood sample was collected to check for the presence of spur cells on blood smear. A complete blood biochemical panel was recorded together with Child-Pugh (CP) score and Model for End-Stage Liver Disease (MELD) score. For each patients, clinically relevant events, such as acute-on-chronic liver failure (ACLF) and 1 year liver-related mortality, were registered. Patients were then grouped according to the percentage of spur cells at smear (> 5%, 1-5%, < 1%). Severe anaemia was defined as haemoglobin levels lower than 8 g/dL. 9.2% of subjects had > 5% spur cells, only 2 had evidence of haemolysis. In patients with > 5% spur cells, haemoglobin and albumin were lower compared with the other sub-group, while MELD score, CP score, International Normalized Ratio, ferritin, creatinine and unconjugated bilirubin were higher. Patients with more spur cells were more decompensated and developed more frequently ACLF. ACLF and liver-related mortality were significantly and independently associated with the presence of > 5% spur cells but not with baseline severe anaemia. Cirrhotic patients have a fairly high prevalence of spur cells, not always associated with severe haemolytic anaemia. The presence of spur red cells is per se associated with a worse prognosis and, therefore, should be always evaluated to prioritize patients for intensive management and eventually liver transplantation.

Chronic anaemia is a frequent finding in liver cirrhosis and spur cell anaemia has been shown to be an uncommon non-immune haemolytic disease typically related to advanced-liver disease. In our study, spur cell anaemia (spur cells >5%) was found in almost 10% of outpatient cirrhotics and was significantly related to more decompensated disease, higher incidence of ACLF and 1 year liver-related mortality. More importantly, the vast majority of patients with high percentage of spur cells did not have severe anaemia. Therefore, spur cells should be searched for in patients with advanced liver disease by a simple blood smear evaluation, even in the absence of significant anaemia, because of relevant prognostic impact and in order to prioritize patients to intensive management and possibly liver transplantation.

Machine learning can guide suitability of consultation and patient referral through telemedicine for hepatobiliary diseases.

BACKGROUND AND AIM: Telemedicine is an evolving tool to provide health-care services. We evaluated the suitability of telemedicine to deliver effective consultation for hepatobiliary disorders. METHODS: In this prospective study spanning over a year, we interviewed hepatologists delivering the teleconsultations through a pre-validated questionnaire. A consult was deemed suitable based on the physician's judgment in the absence of unplanned hospitalization. We evaluated factors determining the suitability through inferential statistics and machine learning models, namely, extreme gradient boosting (XGB) and decision tree (DT). RESULTS: Of 1118 consultations, 917 (82.0%) were deemed suitable. On univariable analysis, patients with skilled occupation, higher education, out-of-pocket expenses, and diseases such as chronic hepatitis B, C, and non-alcoholic fatty liver disease (NAFLD) without cirrhosis were associated with suitability (P < 0.05). Patients with cirrhosis (compensated or decompensated), acute-on-chronic liver failure (ACLF), and biliary obstruction were likely unsuitable (P < 0.05). XGB and DT models predicted suitability with an area under the receiver operating curve of 0.808 and 0.780, respectively. DT demonstrated that compensated cirrhosis with higher education or skilled occupation with age < 55 years had 78% chance of suitability whereas hepatocellular carcinoma, decompensated cirrhosis, and ACLF patients were unsuitable with a 60-95% probability. In non-cirrhotic liver diseases, hepatitis B, C, and NAFLD were suitable, with a probability of 89.7%. Biliary obstruction and previous failure of teleconsultation were unsuitable, with a probability of 70%. Non-cirrhotic portal fibrosis, dyspepsia, and dysphagia not requiring intervention were suitable (probability: 88%). CONCLUSION: A simple decision tree can guide the referral of unsuitable and the management of suitable patients with hepatobiliary diseases through telemedicine.

Prognostic and therapeutic significance of microbial cell-free DNA in plasma of people with acute decompensation of cirrhosis.

BACKGROUND & AIMS: Although the effect of bacterial infection on cirrhosis has been well-described, the effect of non-hepatotropic virus (NHV) infection is unknown. This study evaluated the genome fragments of circulating microorganisms using metagenomic next-generation sequencing (mNGS) in individuals with acute decompensation (AD) of cirrhosis, focusing on NHVs, and related the findings to clinical outcomes. METHODS: Plasma mNGS was performed in 129 individuals with AD of cirrhosis in the study cohort. Ten healthy volunteers and 20, 39, and 81 individuals with stable cirrhosis, severe sepsis and hematological malignancies, respectively, were enrolled as controls. Validation assays for human cytomegalovirus (CMV) reactivation were performed in a validation cohort (n = 58) and exploratory treatment was instituted. RESULTS: In the study cohort, 188 microorganisms were detected in 74.4% (96/129) of patients, including viruses (58.0%), bacteria (34.1%), fungi (7.4%) and chlamydia (0.5%). A NHV signature was identified in individuals with AD, and CMV was the most frequent NHV, which correlated with the clinical effect of empirical antibiotic treatment, progression to acute-on-chronic liver failure, and 90-day mortality. The NHV signature in individuals with acute-on-chronic liver failure was similar to that in those with sepsis and hematological malignancies. CMV was detected in 24.1% (14/58) of patients in the validation cohort. Of the 14 cases with detectable CMV by mNGS, nine were further validated by real-time PCR or pp65 antigenemia testing. Three patients with CMV reactivation received ganciclovir therapy in an exploratory manner and experienced clinical resolutions. CONCLUSIONS: The results of this study suggest that NHVs may play a pathogenic role in complicating the course of AD. Further validation is needed to define whether this should be incorporated into the routine management of individuals with AD of cirrhosis. IMPACT AND IMPLICATIONS: A non-hepatotropic virus (NHV) signature, which was similar to that in individuals with sepsis and hematological malignancies, was identified in individuals with acute decompensation of cirrhosis. The detected viral signature had clinical correlates, including clinical efficacy of empirical antibiotic treatment, progression to acute-on-chronic liver failure and short-term mortality. Cytomegalovirus reactivation, which is treatable, may adversely affect clinical outcomes in some individuals with decompensated cirrhosis. Routine screening for NHVs, especially cytomegalovirus, may be useful for the management of individuals with acute decompensation of cirrhosis.

[Cutaneous hyperpigmentation as a manifestation in acute on chronic liver failure]. / Hiperpigmentación cutánea como manifestación poco reconocida en falla hepática aguda sobre crónica.

Background: The acquired cutaneous pigmentation represents a little recognized clinical manifestation in liver disorders, both acute and chronic, and can occur in the exacerbation processes of preexisting hepatopathies, as in the context of acute-on-chronic liver failure. Several hypotheses about the increase in pigment at skin and mucous membranes have been developed; some try to explain it as a defect in the degradation of melanin with secondary accumulation at tissues; others, on the other hand, describe it as a consequence of the release of fibroblast growth factors like endothelial growth factor and hepatocyte growth factor, which are produced under the stimulation of liver regeneration and cause a melanogenesis stimulation. The aim of this article is to study pigmentary skin changes in the background of liver diseases. Clinical cases: We described two clinical cases of patients with acuteon chronic liver failure secondary to different clinical scenarios are presented, who have in common the development of acquired pigmentary skin changes. Conclusion: In hepatopathies, the cutaneous hyperpigmentation is a sign with unknown etiology, so further studies are required to know the accurate pathophysiology. Reporting this finding is useful for physicians, since timely identification can help in the early diagnosis of underlying liver diseases.

Introducción: la hiperpigmentación cutánea adquirida representa una manifestación clínica poco reconocida en los trastornos hepáticos, tanto agudos como crónicos, y puede presentarse tanto en procesos de agudización de hepatopatías preexistentes como en el contexto de la falla hepática aguda sobre crónica. Se han desarrollado diversas hipótesis sobre el aumento de pigmento a nivel piel y mucosas, algunas tratan de explicarlo por un defecto en la degradación de la melanina, lo cual genera su acumilación en los tejidos; otras, en cambio, describen la liberación de factores de crecimiento derivados de fibroblastos, como el factor de crecimiento endotelial y el factor de crecimiento de hepatocitos, los cuales son producidos bajo el estímulo de la regeneración hepática y, a su vez, provocan una estimulación de la melanogénesis. El objetivo de este trabajo es estudiar la hiperpigmentación cutánea en el contexto de enfermedades hepáticas. Casos clínicos: se presentan dos casos clínicos de pacientes con falla hepática aguda sobre crónica secundaria a diferentes escenarios clínicos, quienes tienen en común el desarrollo pigmentación cutánea adquirida. Conclusiones: en las enfermedades hepáticas, la hiperpigmentación cutánea es un hallazgo presente cuya etiología aún no es dilucidada, por lo que se requieren más estudios para conocer la fisiopatología exacta. El reporte de este hallazgo es de utilidad para el personal médico, ya que la identificación oportuna puede ayudar a el diagnóstico temprano de hepatopatías subyacentes.

Prevalence and clinical characteristics of autoimmune liver disease in hospitalized patients with cirrhosis and acute decompensation in China.

BACKGROUND: Autoimmune liver disease (AILD) has been considered a relatively uncommon disease in China, epidemiological data for AILD in patients with cirrhosis and acute decompensation (AD) is sparse. AIM: To investigate the prevalence, outcome and risk factors for AILD in cirrhotic patients complicated with AD in China. METHODS: We collected data from patients with cirrhosis and AD from two prospective, multicenter cohorts in hepatitis B virus endemic areas. Patients were regularly followed up at the end of 28-d, 90-d and 365-d, or until death or liver transplantation (LT). The primary outcome in this study was 90-d LT-free mortality. Acute-on-chronic liver failure (ACLF) was assessed on admission and during 28-d hospitalization, according to the diagnostic criteria of the European Association for the Study of the Liver (EASL). Risk factors for death were analyzed with logistic regression model. RESULTS: In patients with cirrhosis and AD, the overall prevalence of AILD was 9.3% (242/2597). Prevalence of ACLF was significantly lower in AILD cases (14%) than those with all etiology groups with cirrhosis and AD (22.8%) (P < 0.001). Among 242 enrolled AILD patients, the prevalence rates of primary biliary cirrhosis (PBC), autoimmune hepatitis (AIH) and PBC-AIH overlap syndrome (PBC/AIH) were 50.8%, 28.5% and 12.0%, respectively. In ACLF patients, the proportions of PBC, AIH and PBC/AIH were 41.2%, 29.4% and 20.6%. 28-d and 90-d mortality were 43.8% and 80.0% in AILD-related ACLF. The etiology of AILD had no significant impact on 28-d, 90-d or 365-d LT-free mortality in patients with cirrhosis and AD in both univariate and multivariate analysis. Total bilirubin (TB), hepatic encephalopathy (HE) and blood urea nitrogen (BUN) were independent risk factors for 90-d LT-free mortality in multivariate analysis. The development of ACLF during hospitalization only independently correlated to TB and international normalized ratio. CONCLUSION: AILD was not rare in hospitalized patients with cirrhosis and AD in China, among which PBC was the most common etiology. 90-d LT-free mortality were independently associated with TB, HE and BUN.

Albuminuria as a predictor of mortality in type II diabetic patients after living-donor liver transplantation.

PURPOSE: Diabetes mellitus (DM) increases the risk of morbidity and mortality after liver resection. Albuminuria is associated with a higher risk for all-cause and cardiovascular mortality. This study evaluated albuminuria as a predictor of the outcome of living donor liver transplantation (LDLT) in patients with pre-existing DM. METHODS: This retrospective study involved 103 type II diabetic patients with end-stage liver disease who received LDLT. Preoperative spot urine albumin: creatinine ratio was used to determine the degree of albuminuria. The primary outcome measure was the impact of urinary albumin excretion on the 3-year mortality rate after LDLT in this diabetic cohort. RESULTS: Hepatitis C virus infection was the main cause of cirrhosis. Albuminuria was detected in 41 patients (39.8%); 15 had macroalbuminuria, while 26 had microalbuminuria. Patients with microalbuminuria were significantly older than those with macroalbuminuria and normal albumin in urine. After 3 years, twenty-four patients (23.3%) died within 3 years after LT. Myocardial infarction was the leading cause of death (25%). Albuminuria was an independent factor affecting 3-year mortality with an odds ratio of 5.17 (95% CI: 1.86-14.35). CONCLUSION: Preoperative albuminuria is an independent factor affecting mortality within 3 years after LDLT in type II diabetic patients. Myocardial infarction was the leading cause of death in 25% of cases, followed by hepatocellular carcinoma recurrence, sepsis, and graft failure.KEY MESSAGESDiabetes mellitus (DM) increases the risk of morbidity and mortality after liver resection.Albuminuria is associated with a higher risk for all-cause and cardiovascular mortality.Preoperative albuminuria is a significant predictor of mortality within 3 years after LDLT in diabetic patients.

Gadoxetic acid-enhanced MRI-derived functional liver imaging score (FLIS) and spleen diameter predict outcomes in ACLD.

BACKGROUND & AIMS: Functional liver imaging score (FLIS) - derived from gadoxetic acid-enhanced MRI - correlates with liver function and independently predicts liver-related mortality in patients with chronic liver disease (CLD), while splenic craniocaudal diameter (SCCD) is a marker of portal hypertension. The aim of this study was to investigate the accuracy of a combination of FLIS and SCCD for predicting hepatic decompensation, acute-on-chronic liver failure (ACLF), and mortality in patients with advanced CLD (ACLD). METHODS: We included 397 patients with CLD who underwent gadoxetic acid-enhanced liver MRI. The FLIS was calculated by summing the points (0-2) of 3 hepatobiliary-phase features: hepatic enhancement, biliary excretion, and portal vein signal intensity. Patients were stratified into 3 groups according to liver fibrosis severity and presence/history of hepatic decompensation: non-ACLD, compensated ACLD (cACLD), and decompensated ACLD (dACLD). RESULTS: SCCD showed excellent intra- and inter-reader agreement. Importantly, SCCD was an independent risk factor for hepatic decompensation in patients with cACLD (per cm; adjusted hazard ratio [aHR] 1.13; 95% CI 1.04-1.23; p = 0.004). Patients with cACLD and a FLIS of 0-3 points and/or a SCCD of >13 cm were at increased risk of hepatic decompensation (aHR 3.07; 95% CI 1.43-6.59; p = 0.004). In patients with dACLD, a FLIS of 0-3 was independently associated with an increased risk of ACLF (aHR 2.81; 95% CI 1.16-6.84; p = 0.02), even after adjusting for other prognostic factors. Finally, a FLIS and SCCD-based algorithm was independently predictive of transplant-free mortality and stratified the probability of transplant-free survival (TFS) in ACLD (p <0.001): FLIS 4-6 and SCCD ≤13 cm (5-year TFS of 84%) vs. FLIS 4-6 and SCCD >13 cm (5-year TFS of 70%) vs. FLIS 0-3 (5-year TFS of 24%). CONCLUSION: The FLIS and SCCD are simple imaging markers that provide complementary information for risk stratification in patients with compensated and decompensated ACLD. LAY SUMMARY: Magnetic resonance imaging (MRI) can be used to assess the state of the liver. Previously the functional liver imaging score, which is based on MRI criteria, was developed as a measure of liver function and to predict the risk of liver-related complications or death. By combining this score with a measurement of spleen diameter, also using MRI, we generated an algorithm that could predict the risk of adverse liver-related outcomes in patients with advanced chronic liver disease.

[A female patient with liver failure and pseudocirrhosis]. / Een patiënte met leverfalen en pseudocirrose.

BACKGROUND: Acute-on-chronic liver failure encompasses an acute deterioration of liver function in patients with pre-existent cirrhosis. Sometimes the clinical picture of acute-on-chronic liver failure is misleading and may not be secondary to primary liver disease, as described in our case. CASE DESCRIPTION: A 65-year-old woman with cirrhosis was transferred to our transplantation centre because of suspected acute-on-chronic liver failure. Given her medical history of breastcancer and suspicious laboratory results, we performed a liver biopsy. This showed diffuse metastases of mammary carcinoma. Earlier CT-scans showed features of cirrhosis without signs of malignancy: a misleading phenomenon called pseudocirrhosis. CONCLUSION: Diffuse malignant hepatic infiltration can resemble cirrhosis and acute-on-chronic liver failure, both in clinical presentation as in imaging. Liver transplantation is contraindicated in malignant liver failure. To assure a solid indication for transplantation, a liver biopsy has to be considered, even in emergency situations.

Decreasing von Willebrand Factor Levels Upon Nonselective Beta Blocker Therapy Indicate a Decreased Risk of Further Decompensation, Acute-on-chronic Liver Failure, and Death.

BACKGROUND & AIMS: Nonselective beta blockers (NSBBs) exert beneficial effects beyond lowering hepatic venous pressure gradient (HVPG), which may be particularly relevant in patients with decompensated cirrhosis (DC), in whom bacterial translocation and bacterial-induced systemic inflammation drive the development of complications such as acute-on-chronic liver failure (ACLF). We evaluated whether NSBB-related changes in von Willebrand factor (VWF) may serve as a biomarker for these effects. METHODS: In this retrospective analysis, 159 prospectively characterized patients with clinically stable DC (ie, without acute decompensation) who underwent paired HVPG/VWF assessments before/on NSBB therapy were classified as 'VWF-responders' (as defined by a ≥5% decrease in VWF) versus 'VWF-non-responders.' RESULTS: There were no major differences in baseline characteristics between VWF-responders (61%) and VWF-non-responders. VWF-responders showed more pronounced decreases in inflammation (procalcitonin), whereas rates of HVPG-response were similar. In line, NSBB-related changes in VWF correlated with the dynamics of bacterial translocation/inflammation (lipopolysaccharide-binding protein, C-reactive protein, and procalcitonin), rather than those of HVPG. Interestingly, VWF-responders also showed less pronounced NSBB-related decreases in mean arterial pressure, suggesting an amelioration of systemic vasodilatation. Finally, VWF-response was associated with decreased risks of further decompensation (adjusted hazard ratio [aHR], 0.555; 95% confidence interval [CI], 0.337-0.912; P = .020), ACLF (aHR, 0.302; 95% CI, 0.126-0.721; P = .007), and liver-related death (aHR, 0.332; 95% CI, 0.179-0.616; P < .001) in Cox regression models adjusted for prognostic factors including changes in HVPG. CONCLUSIONS: Decreases in VWF upon NSBB therapy reflect their anti-inflammatory activity, are accompanied by less pronounced adverse effects on systemic hemodynamics, and are independently associated with a decreased risk of further decompensation, ACLF, and death. VWF-response may discriminate between decompensated patients who benefit from NSBB treatment and have a favorable prognosis versus patients with poor outcomes.

Hepatitis E virus infection in a patient with alcohol related chronic liver disease: a case report of acute-on-chronic liver failure.

BACKGROUND: The hepatitis E virus (HEV) infection has been described as a causing factor for acute-on-chronic-liver-failure (ACLF) in patients with underlying chronic liver disease (CLD), such as chronic hepatitis or cirrhosis, which could end in the failure of one or more organs and high short-term mortality. There are scarce data about the association of HEV in patients with chronic liver disorders in South America. CASE PRESENTATION: A 56-year-old hypertensive male with a history of type 2 diabetes was diagnosed with alcohol-related-liver cirrhosis in February 2019. A year later, the patient was admitted to hospital due to fatigue, jaundice and acholia. No evidence of hepatitis A virus, hepatitis B virus, hepatitis C virus, Epstein-Barr virus, herpes zoster virus and cytomegalovirus infections were found. Nevertheless, in February and March, 2020 the patient was positive for HEV-IgM and HEV-IgG, and HEV genotype 3 RNA was detected in sera. Afterwards, he presented grade I hepatic encephalopathy and, therefore, was diagnosed with acute hepatitis E-on-chronic liver disease. The patient reported a recent travel to the Argentine coast, where he consumed seafood. Besides, he reveled to have consumed pork meat and had no history of blood transfusion. CONCLUSION: This report describes a unique case of hepatitis E virus infection in a patient with alcohol-related cirrhosis. This is the first report of a patient with HEV-related ACLF in Argentina and it invokes the importance of HEV surveillance and treatment among patients with CLD, such as alcohol-related cirrhosis.

Insuficiência hepática crônica agudizada está independentemente associada com menor sobrevida em pacientes com peritonite bacteriana espontânea / Acute-on-chronic liver failure is independently associated with lower survival in patients with spontaneous bacterial peritonitis

ABSTRACT BACKGROUND: Spontaneous bacterial peritonitis (SBP) is a decompensation of cirrhosis with an in-hospital mortality ranging from 20% to 40%. OBJECTIVE: The purpose of this study is to analyze if EASL-CLIF definition of acute-on-chronic liver failure (ACLF) is able to predict mortality in cirrhotic patients with SBP. METHODS: Historical cohort study conducted in a public tertiary care teaching hospital. Data from medical records from January 2009 to July 2016 were obtained by searching the hospital electronic database for samples of ascites collected in the period. Electronic and physical medical records were analyzed and patients were included if they were over 18-years old, with cirrhosis and an ascites fluid compatible with SBP: 69 patients were included. Liver-specific scores were calculated and Kaplan-Meier survival analysis was used for univariate analysis and a stepwise approach to the Cox regression for multivariate analysis. RESULTS: All cause mortality was 44%, 56.5% and 74% for 28-, 90- and 365-day, respectively. The prevalence of ACLF was 58%. Of these, 65% grade 1, 17.5% grade 2 and 17.5% grade 3. In multivariate analysis, the use of proton-pump inhi­bitors, alanine transaminase lower than 40 U/L, hemoglobin higher than 9 g/dL, absence of ACLF and lower CLIF-SOFA and MELD scores were independently associated with higher survival for both 28- and 90-day interval. CONCLUSION: The presence of ACLF and higher CLIF-SOFA scores were independently associated with higher 28- and 90-day mortality in cirrhotic patients admitted due to SBP.

RESUMO CONTEXTO: A peritonite bacteriana espontânea (PBE) é uma descompensação da cirrose com uma mortalidade intra-hospitalar de 20% a 40%. OBJETIVO: O objetivo deste estudo é analisar se a definição de insuficiência hepática crônica agudizada (IHCA) como definido pelo consórcio EASL-CLIF é capaz de predizer mortalidade em pacientes cirróticos com PBE. MÉTODOS: Coorte histórica conduzida em um hospital de ensino público terciário. Foram obtidos dados de prontuários médicos de janeiro de 2009 até julho de 2016, buscando no banco de dados eletrônico do hospital por todas as amostras de ascite coletadas no período. Prontuários eletrônicos e físicos foram analisados e os pacientes com mais de 18 anos com cirrose e líquido de ascite compatível com PBE foram incluídos. Foram incluídos 69 pacientes. Escores específicos para o fígado foram calculados e a análise de sobrevida de Kaplan-Meier foi utilizada para a análise univariada, e uma abordagem progressiva para a regressão logística de Cox foi usada para a análise multivariada. RESULTADOS: A mortalidade por todas as causas foi 44%, 56,5% e 74% para 28-, 90- e 365-dias, respectivamente. A prevalência de IHCA foi de 58%. Desses, 65% grau 1, 17,5% grau 2 e 17,5% grau 3. Na análise multivariada, o uso de inibidores da bomba de prótons, alanina transaminase menor que 40 U/L, hemoglobina acima de 9 g/dL, ausência de IHCA e menores valores dos escores CLIF-SOFA e MELD foram independentemente associados com maior sobrevida para ambos intervalos de 28- e 90-dias. CONCLUSÃO: A presença de IHCA e maiores valores de CLIF-SOFA foram independentemente associados em maior mortalidade para pacientes cirróticos admitidos por PBE no intervalo de 28- e 90-dias.

COVID-19 and Pneumocystis jirovecii Pulmonary Coinfection-The First Case Confirmed through Autopsy.

Background: Establishing the diagnosis of COVID-19 and Pneumocystisjirovecii pulmonary coinfection is difficult due to clinical and radiological similarities that exist between the two disorders. For the moment, fungal coinfections are underestimated in COVID-19 patients. Case presentation: We report the case of a 52-year-old male patient, who presented to the emergency department for severe dyspnea and died 17 h later. The RT-PCR test performed at his admission was negative for SARS-CoV-2. Retesting of lung fragments collected during autopsy revealed a positive result for SARS-CoV-2. Histopathological examination showed preexisting lesions, due to comorbidities, as well as recent lesions: massive lung thromboses, alveolar exudate rich in foam cells, suprapleural and intra-alveolar Pneumocystisjirovecii cystic forms, and bilateral adrenal hemorrhage. Conclusion: COVID-19 and P.jirovecii coinfection should be considered, particularly in critically ill patients, and we recommend the systematic search for P. jirovecii in respiratory samples.

Metabolic associated fatty liver disease and acute-on-chronic liver failure: common themes for common problems.

Metabolic associated fatty liver disease (MAFLD) affects 20-30% of the worldwide population and is becoming the most common cause of chronic liver disease, cirrhosis and hepatocellular carcinoma (HCC). MAFLD is the hepatic expression of metabolic dysfunction correlated with a variety of metabolic comorbidities including obesity, dyslipidemia, hypertension and type 2 diabetes (T2DM). Obesity, altered gut permeability, chronic inflammation and dysbiosis related to MAFLD might predispose patients with cirrhosis to the development of acute-on-chronic liver failure (ACLF); however, this relationship remains unclear. ACLF is a syndrome with high short-term mortality, presenting with acute hepatic decompensation associated with organ failures in patients with underlying chronic liver disease with or without an identifiable precipitating event. While this syndrome can occur in any patient with cirrhosis, the increasing prevalence of cirrhosis due to MAFLD is of great concern because, in a recent analysis, MAFLD was the fastest rising cause of cirrhosis associated with ACLF among patients listed for LT in the US. In this review, we will discuss the current knowledge on MAFLD and the development of ACLF.

Amelioration of systemic inflammation in advanced chronic liver disease upon beta-blocker therapy translates into improved clinical outcomes.

OBJECTIVE: Systemic inflammation promotes the development of clinical events in patients with advanced chronic liver disease (ACLD). We assessed whether (1) non-selective beta blocker (NSBB) treatment initiation impacts biomarkers of systemic inflammation and (2) whether these changes in systemic inflammation predict complications and mortality. DESIGN: Biomarkers of systemic inflammation, that is, white blood cell count (WBC), C reactive protein (CRP), interleukin-6 (IL-6) and procalcitonin (PCT) were determined at sequential hepatic venous pressure gradient (HVPG) measurements without NSBB and under stable NSBB intake. The influence of NSBB-related changes in systemic inflammation on the risk of decompensation and liver-related death was analysed using competing risk regression. RESULTS: Our study comprised 307 stable patients with ACLD (Child-A: 77 (25.1%), Child-B: 161 (52.4%), Child-C: 69 (22.5%), median HVPG: 20 (IQR 17-24) mm Hg) including 231 (75.2%) with decompensated disease.WBC significantly decreased upon NSBB therapy initiation (median: -2 (IQR -19;+13)%, p=0.011) in the overall cohort. NSBB-related reductions of WBC (Child-C: -16 (-30;+3)% vs Child-B: -2 (-16;+16)% vs Child-A: +3 (-7;+13)%, p<0.001) and of CRP (Child-C: -26 (-56,+8)% vs Child-B: -16 (-46;+13)% vs Child-A: ±0 (-33;+33)%, p<0.001) were more pronounced in advanced stages of cirrhosis. The NSBB-associated changes in WBC correlated with changes in CRP (Spearman's ρ=0.228, p<0.001), PCT (ρ=0.470, p=0.002) and IL-6 (ρ=0.501, p=0.001), but not with changes in HVPG (ρ=0.097, p=0.088).An NSBB-related decrease in systemic inflammation (ie, WBC reduction ≥15%) was achieved by n=91 (29.6%) patients and was found to be an independent protective factor of further decompensation (subdistribution HR, sHR: 0.694 (0.49-0.98), p=0.038) in decompensated patients and of liver-related mortality in the overall patient cohort (sHR: 0.561 (0.356-0.883), p=0.013). CONCLUSION: NSBB therapy seems to exert systemic anti-inflammatory activity as evidenced by reductions of WBC and CRP levels. Interestingly, this effect was most pronounced in Child-C and independent of HVPG response. An NSBB-related WBC reduction by ≥15% was associated with a decreased risk of further decompensation and death.

The Risk of Acute Kidney Injury in Hepatitis B Virus-Related Acute on Chronic Liver Failure with Tenofovir Treatment.

AIMS: Tenofovir (TDF) is an antiviral drug with potential risk of kidney injury. The study is aimed at comparing the incidence of acute kidney injury (AKI) between TDF and entecavir (ETV) treatment in hepatitis B virus- (HBV-) related acute on chronic liver failure (ACLF). METHODS: Treatment-naive patients with HBV-related ACLF were included. Propensity score matching was used to balance the baseline characteristics between ETV and TDF groups. The risk of AKI and the efficacy of TDF and ETV were compared. RESULTS: A total of 95 cases with HBV-related ACLF were included in this study, with 74.74% of male and a mean age of 47.01 ± 14.71 years. The antiviral therapy was initiated within 2 days after admission, with 39 cases on the TDF group and 56 on the ETV group. Patients in the TDF group had higher AST, hemoglobin, and serum sodium levels and lower MELD-Na score. After propensity matching, 39 cases of TDF and 39 of ETV were included in the final analysis. No difference was found in the changes of creatinine and cystatin C from baseline to 4 weeks after treatment between ETV and TDF groups. AKI was developed in 1 (2.56%) patient in the ETV group and 2 (5.13%) in the TDF group within one month (P = 0.556). Survival analysis revealed no significant difference in the 6-month mortality between the two groups (P = 0.813). Cox analysis showed that the type of antiviral drug or the development of AKI was not an independent risk factor for the outcomes. CONCLUSIONS: Compared to ETV, TDF did not increase the risk of AKI nor the mortality in patients with HBV-related ACLF in the short time.