Acute-on-chronic liver failure in cirrhosis

The definition of acute-on-chronic liver failure (ACLF) remains contested. In Europe and North America, the term is generally applied according to the European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF) Consortium guidelines, which defines this condition as a syndrome that develops in patients with cirrhosis and is characterized by acute decompensation, organ failure and high short-term mortality. One-third of patients who are hospitalized for acute decompensation present with ACLF at admission or develop the syndrome during hospitalization. ACLF frequently occurs in a closed temporal relationship to a precipitating event, such as bacterial infection or acute alcoholic, drug-induced or viral hepatitis. However, no precipitating event can be identified in approximately 40% of patients. The mechanisms of ACLF involve systemic inflammation due to infections, acute liver damage and, in cases without precipitating events, probably intestinal translocation of bacteria or bacterial products. ACLF is graded into three stages (ACLF grades 1–3) on the basis of the number of organ failures, with higher grades associated with increased mortality. Liver and renal failures are the most common organ failures, followed by coagulation, brain, circulatory and respiratory failure. The 28-day mortality rate associated with ACLF is 30%. Depending on the grade, ACLF can be reversed using standard therapy in only 16–51% of patients, leaving a considerable proportion of patients with ACLF that remains steady or progresses. Liver transplantation in selected patients with ACLF grade 2 and ACLF grade 3 increases the 6-month survival from 10% to 80%

Acute-on-Chronic Liver Failure: Definition, Diagnosis, and Clinical Characteristics

Acute-on-chronic liver failure (ACLF) is a recently recognized syndrome in cirrhosis characterized by acute decompensation (AD), organ failure(s), and high short-term mortality. Organ failure(s) is defined by the Chronic Liver Failure-Sequential Organ Failure (CLIF-SOFA) score or by its simplified version Chronic Liver Failure-Organ Failure Assessment (CLIF-OF) score. They include six types of organ failure: liver, renal, coagulation, cerebral, respiratory, and circulatory. One third of patients hospitalized with AD present with ACLF at admission or develop ACLF during hospitalization. Acute-on-chronic liver failure frequently occurs in a closed relationship to a precipitating event. According to the number of organ failures, ACLF is graded into three stages: ACLF-1 = single renal failure or single nonrenal organ failure if associated with renal dysfunction and/or cerebral dysfunction; ACLF-2 = two organ failures; and ACLF-3 = three to six organ failures, with increasing 28-day mortality rate (from 23%–74%). Acute-on-chronic liver failure may develop at any phase during the clinical course of the disease. Patients without prior AD develop a severe form of ACLF

A High-Value, Low-Cost Bubble Continuous Positive Airway Pressure System for Low-Resource Settings: Technical Assessment and Initial Case Reports

Acute respiratory infections are the leading cause of global child mortality. In the developing world, nasal oxygen therapy is often the only treatment option for babies who are suffering from respiratory distress. Without the added pressure of bubble Continuous Positive Airway Pressure (bCPAP) which helps maintain alveoli open, babies struggle to breathe and can suffer serious complications, and frequently death. A stand-alone bCPAP device can cost $6,000, too expensive for most developing world hospitals. Here, we describe the design and technical evaluation of a new, rugged bCPAP system that can be made in small volume for a cost-of-goods of approximately$350. Moreover, because of its simple designﾗconsumergrade pumps, medical tubing, and regulators—it requires only the simple replacement of a ,$1 diaphragm approximately every 2 years for maintenance. The low-cost bCPAP device delivers pressure and flow equivalent to those of a reference bCPAP system used in the developed world. We describe the initial clinical cases of a child with bronchiolitis and a neonate with respiratory distress who were treated successfully with the new bCPAP device

Diagnostic and mechanistic implications of serum free light chains, albumin and alpha-fetoprotein in hepatocellular carcinoma

Background: Mass spectroscopy analysis suggested low serum albumin and high immunoglobulin free light chain (sFLC) levels may have diagnostic value in hepatocellular carcinoma (HCC). Our aims were to apply quantitative assays to confirm these observations, determine their diagnostic utility, and investigate the mechanisms involved. Methods: Albumin, sFLC, routine liver and renal function tests were measured in patients with chronic liver disease with (n=102) and without (n=113) HCC. The discriminant performance was compared with the current standard serological test alpha-fetoprotein (AFP) using receiver operating characteristic (ROC) and area under the curve (AUC) analyses. Results: sFLC and serum albumin were each confirmed to have discriminatory utility in HCC with AUC values of 0.7 and 0.8, respectively. sFLC were strongly correlated with gammaglobulin levels and both these were inversely related to serum albumin levels. The discriminatory utility of sFLC was retained after adjusting for renal and liver function. Conclusions: Serum levels of sFLC and albumin were strongly associated with HCC as predicted by mass spectroscopy. Discrimination of HCC by AFP was improved by the addition of either albumin or sFLC. Larger prospective studies are required to determine how AFP, sFLC and albumin might be combined in a useful diagnostic approach for HCC

Validating a novel score based on interaction between ACLF grade and MELD score to predict waitlist mortality

Background and Aim: Among candidates listed for liver transplant (LT), MELD score may not capture acute on chronic liver failure (ACLF) severity. Data on interaction between ACLF and MELD score in predicting waitlist (WL) mortality are scanty. / Methods: UNOS database (01/2002 to 06/2018) on LT listings for adults with cirrhosis and ACLF (without HCC) was analyzed. ACLF grades 1, 2, 3a, and 3b- were defined using modified EASL-CLIF criteria. / Results: Of 18,416 candidates with ACLF at listing (mean age 54 years, 69% males, 63% Caucasians), 90-d WL mortality (patient death or being too sick for LT) was 21.6% (18%, 20%, 25%, and 39% for ACLF grades 1, 2, 3a, and 3b respectively). Fine and Gray regression model identified interaction between MELD and ACLF grade, with higher impact of ACLF at lower MELD score. Other variables included candidate’s age, gender, liver disease etiology, listing MELD, ACLF grade, obesity, and performance status. A score developed using parameter estimates from the interaction model on the derivation cohort (N=9181) stratified the validation cohort (N=9235) to four quartiles Q1 (score 15.50). WL mortality increased with each quartile from 13%, 18%, 23%, and 36% respectively. Observed versus expected deciles on WL mortality in validation cohort showed good calibration (goodness of fit P=0.98) and correlation (R=0.99). / Conclusion: Among selected candidates who are in ACLF at listing, MELD score and ACLF interact in predicting cumulative risk of 90-d WL mortality, with higher impact of ACLF grade at lower listing MELD score. Validating these findings in large prospective studies will support to factor in both MELD and ACLF in prioritizing transplant candidates and allocation of liver grafts

γ-Glutamyltransferase, but not markers of hepatic fibrosis, is associated with cardiovascular disease in older people with type 2 diabetes mellitus: the Edinburgh Type 2 Diabetes Study

AIMS/HYPOTHESIS: We examined the association of prevalent and incident cardiovascular disease (CVD) with chronic liver disease in a cohort of community-based people with type 2 diabetes, in order to clarify the relationship between these two important conditions. METHODS: 1,066 participants with type 2 diabetes aged 60–75 years underwent assessment of a range of liver injury markers (non-specific injury, steatosis, steatohepatitis, fibrosis, portal hypertension). Individuals were followed up for incident cardiovascular events. RESULTS: At baseline there were 370/1,033 patients with prevalent CVD, including 317/1,033 with coronary artery disease (CAD). After a mean follow-up of 4.4 years there were 44/663 incident CVD events, including 27/663 CAD events. There were 30/82 CVD-related deaths. Risk of dying from or developing CVD was no higher in participants with steatosis than in those without (HR 0.90; 95% CI 0.40, 2.00; p > 0.05). The only notable relationship was with γ-glutamyltransferase (GGT) (incident CVD: adjusted HR for doubling GGT 1.24 [95% CI 0.97, 1.59] p = 0.086; incident CAD: adjusted HR 1.33 [95% CI 1.00, 1.78] p = 0.053), suggesting that in our study population, chronic liver disease may have little effect on the development of, or mortality from, CVD. CONCLUSIONS/INTERPRETATION: An independent association between GGT and CVD warrants further exploration as a potentially useful addition to current cardiovascular risk prediction models in diabetes. However, overall findings failed to suggest that there is a clinical or pathophysiological association between chronic liver disease and CVD in elderly people with type 2 diabetes. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00125-015-3575-y) contains peer-reviewed but unedited supplementary material, which is available to authorised users

H2S biosynthesis and catabolism: new insights from molecular studies

Hydrogen sulfide (H2S) has profound biological effects within living organisms and is now increasingly being considered alongside other gaseous signalling molecules, such as nitric oxide (NO) and carbon monoxide (CO). Conventional use of pharmacological and molecular approaches has spawned a rapidly growing research field that has identified H2S as playing a functional role in cell-signalling and post-translational modifications. Recently, a number of laboratories have reported the use of siRNA methodologies and genetic mouse models to mimic the loss of function of genes involved in the biosynthesis and degradation of H2S within tissues. Studies utilising these systems are revealing new insights into the biology of H2S within the cardiovascular system, inflammatory disease, and in cell signalling. In light of this work, the current review will describe recent advances in H2S research made possible by the use of molecular approaches and genetic mouse models with perturbed capacities to generate or detoxify physiological levels of H2S gas within tissue

Trends in liver transplantation for primary biliary cirrhosis in the Netherlands 1988-2008

Background: A decrease in the need for liver transplantations (LTX) in Primary Biliary Cirrhosis (PBC), possibly related to treatment with ursodeoxycholic acid (UDCA), has been reported in the USA and UK. The aim of this study was to assess LTX require

Human serum fetuin A/α2HS-glycoprotein level is associated with long-term survival in patients with alcoholic liver cirrhosis, comparison with the Child-Pugh and MELD scores

BACKGROUND: Serum concentration of fetuin A/α2HS-glycoprotein (AHSG) is a good indicator of liver cell function and 1-month mortality in patients with alcoholic liver cirrhosis and liver cancer. We intended to determine whether decreased serum AHSG levels are associated with long-term mortality and whether the follow-up of serum AHSG levels can add to the predictive value of the Child-Pugh (CP) and MELD scores. METHODS: We determined serum AHSG concentrations in 89 patients by radial immunodiffusion. Samples were taken at the time of enrolment and in the 1(st), 3(rd), 6(th), and the 12(th )month thereafter. RESULTS: Forty-one patients died during the 1-year follow-up period, 37 of them had liver failure. Data of these patients were analysed further. Deceased patients had lower baseline AHSG levels than the 52 patients who survived (293 ± 77 vs. 490 ± 106 μg/ml, mean ± SD, p < 0.001). Of all laboratory parameters serum AHSG level, CP and MELD scores showed the greatest difference between deceased and survived patients. The cutoff AHSG level 365 μg/ml could differentiate between deceased and survived patients (AUC: 0.937 ± 0.025, p < 0.001, sensitivity: 0.865, specificity: 0.942) better than the MELD score of 20 (AUC: 0.739 ± 0.052, p < 0.001, sensitivity: 0.595, specificity: 0.729). Initial AHSG concentrations < 365 μg/ml were associated with high mortality rate (91.4%, relative risk: 9.874, 95% C.I.: 4.258–22.898, p < 0.001) compared to those with ≥ 365 μg/ml (9.3%). Fourteen out of these 37 fatalities occurred during the first month of observation. During months 1–12 low AHSG concentration proved to be a strong indicator of mortality (relative risk: 9.257, 95% C.I.: 3.945–21.724, p < 0.001). Multiple logistic regression analysis indicated that decrease of serum AHSG concentration was independent of all variables that differed between survived and deceased patients during univariate analysis. Multivariate analysis showed that correlation of low serum AHSG levels with mortality was stronger than that with CP and MELD scores. Patients with AHSG < 365 μg/ml had significantly shortened survival both in groups with MELD < 20 and MELD ≥ 20 (p < 0.0001 and p = 0.0014, respectively). CONCLUSION: Serum AHSG concentration is a reliable and sensitive indicator of 1-year mortality in patients with alcoholic liver cirrhosis that compares well to the predictive value of CP score and may further improve that of MELD score

Limitations of the MELD score in predicting mortality or need for removal from waiting list in patients awaiting liver transplantation

<p>Abstract</p> <p>Background</p> <p>Decompensated cirrhosis is associated with a poor prognosis and liver transplantation provides the only curative treatment option with excellent long-term results. The relative shortage of organ donors renders the allocation algorithms of organs essential. The optimal strategy based on scoring systems and/or waiting time is still under debate.</p> <p>Methods</p> <p>Data sets of 268 consecutive patients listed for single-organ liver transplantation for nonfulminant liver disease between 2003 and 2005 were included into the study. The Model for End-Stage Liver Disease (MELD) and Child-Turcotte-Pugh (CTP) scores of all patients at the time of listing were used for calculation. The predictive ability not only for mortality on the waiting list but also for the need for withdrawal from the waiting list was calculated for both scores. The Mann-Whitney-U Test was used for the univariate analysis and the AUC-Model for discrimination of the scores.</p> <p>Results</p> <p>In the univariate analysis comparing patients who are still on the waiting list and patients who died or were removed from the waiting list due to poor conditions, the serum albumin, bilirubin INR, and CTP and MELD scores as well as the presence of ascites and encephalopathy were significantly different between the groups (p < 0.05), whereas serum creatinine and urea showed no difference.</p> <p>Comparing the predictive abilities of CTP and MELD scores, the best discrimination between patients still alive on the waiting list and patients who died on or were removed from the waiting list was achieved at a CTP score of ≥9 and a MELD score of ≥14.4. The sensitivity and specificity to identify mortality or severe deterioration for CTP was 69.0% and 70.5%, respectively; for MELD, it was 62.1% and 72.7%, respectively. This result was supported by the AUC analysis showing a strong trend for superiority of CTP over MELD scores (AUROC 0.73 and 0.68, resp.; p = 0.091).</p> <p>Conclusion</p> <p>The long term prediction of mortality or removal from waiting list in patients awaiting liver transplantation might be better assessed by the CTP score than the MELD score. This might have implications for the development of new improved scoring systems.</p