Severe Cholestasis Predicts Recurrent Primary Sclerosing Cholangitis Following Liver Transplantation.

BACKGROUND AIMS: Primary sclerosing cholangitis (PSC) may reoccur following liver transplantation (LT) and the diagnosis established once imaging studies demonstrate the diagnostic cholangiographic appearance. To evaluate whether the development of recurrent PSC (rPSC) is associated with cholestasis soon after LT, we studied whether changes in hepatic biochemistry within the first 12 months were linked with the development of rPSC and graft loss. METHODS: We conducted a retrospective cohort analysis of 158 transplant recipients with PSC in Canada, and 549 PSC transplant recipients from the United Kingdom. We evaluated serum liver tests within 12 months after LT and the subsequent development of a cholangiographic diagnosis of rPSC as a time-dependent covariate using Cox regression. Severe cholestasis was defined as either alkaline phosphatase> 3xupper limit of normal or total bilirubin> 100 µmol/L. RESULTS: Patients who developed rPSC were more likely to have severe cholestasis versus those without at 3 months (20.5% vs 8.2%, p=0.011), at 6 months (17.9% vs. 10.0%, p=0.026) and 12 months (15.4% vs. 7.8%, p=0.051) in the Canadian cohort and at 12 months in the UK cohort (27.9% vs. 12.6%, p<0.0001). By multivariable analysis, development of severe cholestasis in the Canadian cohort at 3 months (HR=2.41, p=0.046) and in the UK cohort at 12 months (HR=3.141, p<0.0001) were both associated with rPSC. Severe cholestasis at 3 months in the Canadian cohort was predictive of graft loss (HR=3.88, p=0.0001). CONCLUSIONS: The development of cholestasis within 3 to 12 months following LT was predictive of rPSC and graft loss.

Post liver transplantation delirium assessment using the CAM-ICU-7 scale: A cohort analysis.

Background: We applied the Confusion Assessment Method (CAM)-Intensive Care Unit (ICU)-7 delirium scale to patients who underwent liver transplant (LT). Methods: Retrospective cohort including patients who underwent LT for cirrhosis admitted to the ICU from June 2013 to June 2016 at the University of Alberta Hospital, Canada. Delirium was assessed using the CAM-ICU-7 scale (0-7 points) twice daily on days one and 3 post LT, with the highest score being considered. Primary endpoint was hospital mortality. Results: Among all patients, 101/150 (67.3%) were men and mean age was 52.4 (SD 11.8) years. On days 1 and 3 post LT, mean CAM-ICU-7 scores were 1.8 (SD 1.3) and 1.6 (SD 1.8), respectively. Therefore, on days 1 and 3 post LT, 38/150 (25.3%) and 26/95 (27.4%) patients had delirium. While delirium on day 3 post LT was associated with higher hospital mortality (11.5% versus 0%; p = 0.019), it was not associated with length-of-hospital stay (29.2 versus 34.4 days; p = 0.36). Following adjustment for APACHEII score, delirium on day 3 post LT was associated with higher odds of hospital mortality (adjusted odds ratio [aOR] 1.89 [95% CI 1.02-3.50]). Following adjustment for Glasgow Coma Scale and mechanical ventilation, serum creatinine was associated with higher odds of delirium on day 3 post LT (aOR 2.02 [95% CI 1.08-3.77]). Conclusions: Using the CAM-ICU-7 scale, delirium was diagnosed in a fourth of patients who underwent LT. Delirium on day 3 post LT was associated with higher odds of hospital mortality.

The Prediction of In-Hospital Mortality in Decompensated Cirrhosis with Acute-on-Chronic Liver Failure.

Acute-on-chronic liver failure (ACLF) is a condition in cirrhosis associated with organ failure (OF) and high short-term mortality. Both the European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF) and North American Consortium for the Study of End-Stage Liver Disease (NACSELD) ACLF definitions have been shown to predict ACLF prognosis. The aim of this study was to compare the ability of the EASL-CLIF versus NACSELD systems over baseline clinical and laboratory parameters in the prediction of in-hospital mortality in admitted patients with decompensated cirrhosis. Five NACSELD centers prospectively collected data to calculate EASL-CLIF and NACSELD-ACLF scores for admitted patients with cirrhosis who were followed for the development of OF, hospital course, and survival. Both the number of OFs and the ACLF grade or presence were used to determine the impact of NACSELD versus EASL-CLIF definitions of ACLF above baseline parameters on in-hospital mortality. A total of 1031 patients with decompensated cirrhosis (age, 57 ± 11 years; male, 66%; Child-Pugh-Turcotte score, 10 ± 2; Model for End-Stage Liver Disease [MELD] score, 20 ± 8) were enrolled. Renal failure prevalence (28% versus 9%, P < 0.001) was more common using the EASL-CLIF versus NACSELD definition, but the prevalence rates for brain, circulatory, and respiratory failures were similar. Baseline parameters including age, white cell count on admission, and MELD score reasonably predicted in-hospital mortality (area under the curve, 0.76). The addition of number of OFs according to either system did not improve the predictive power of the baseline parameters for in-hospital mortality, but the presence of NACSELD-ACLF did. However, neither system was better than baseline parameters in the prediction of 30- or 90-day outcomes. The presence of NACSELD-ACLF is equally effective as the EASL-CLIF ACLF grade, and better than baseline parameters in the prediction of in-hospital mortality in patients with cirrhosis, but not superior in the prediction of longer-term 30- or 90-day outcomes.

Exercise Only Works If You Do It! The Holy Grail of Adherence.

Exercise interventions in patients with cirrhosis have been shown to improve muscle mass and strength, aerobic capacity, fatigue, and quality of life. There are gaps, however, including limited data on patients with decompensated cirrhosis and home-based routines. This editorial comments on the randomized controlled trial by Lai et al. investigating a home-based exercise intervention in patients with cirrhosis and its impact on physical frailty. Although the trial yielded negative results, the lessons learned should help refine and propel future work.

Health-Related Quality of Life: A Rapid Predictor of Hospitalization in Patients With Cirrhosis.

OBJECTIVES: Patients with cirrhosis experience a worsened quality of life; this may be quantified by the use of health-related QoL (HRQoL) constructs, such as the chronic liver disease questionnaire (CLDQ) and EuroQoL Group-visual analog scale (EQ-VAS). In this multicenter prospective study, we aimed to evaluate HRQoL as a predictor of unplanned hospital admission/early mortality, identify HRQoL domains most affected in cirrhosis, and identify predictors of low HRQoL in patients with cirrhosis. METHODS: Multivariable logistic regression was used to determine independent association of HRQoL with primary outcome and identify predictors of low HRQoL. HRQoL was also compared with population norms. RESULTS: In this cohort of 402 patients with cirrhosis, mean model for end-stage liver disease was 12.5 (4.9). More than 50% of the cohort had low HRQoL, considerably lower than population norms. HRQoL (measured by either CLDQ or EQ-VAS) was independently associated with the primary outcome of short-term unplanned hospitalization/mortality. Every 1-point increase in the CLDQ and every 10-point increase in the EQ-VAS reduced the risk of reaching this outcome by 30% and 13%, respectively. Patients with cirrhosis had lower HRQoL scores than population norms across all domains of the CLDQ. Younger age, female sex, current smoker, lower serum albumin, frailty, and ascites were independently associated with low CLDQ. DISCUSSION: Patients with cirrhosis experience poor HRQoL. HRQoL is independently associated with increased mortality/unplanned hospitalizations in patients with cirrhosis and could be an easy-to-use prognostic screen that patients could complete in the waiting room before their appointment.

Child-Pugh Classification: Time to Abandon?

The Child-Pugh classification is one of the commonest and oldest bedside tools utilized in estimating prognosis in patients with cirrhosis. However, its usage as a risk prediction tool or indeed a decision-making tool should be revisited. In this review, we discuss some inherent issues with the Child-Pugh classification and present a few contexts in which the current usage of Child-Pugh warrants reassessment, elaborating on its utility in acute variceal bleeding, specifically its role in decision-making on early transjugular intrahepatic portosystemic shunt, as well as its use in the context of hepatocellular carcinoma and drug development and dose adjustment.

Graft Dysfunction and Management in Liver Transplantation.

Graft dysfunction of the liver allograft manifests across a spectrum in both timing posttransplantation and clinical presentation. This can range from mild transient abnormalities of liver tests to acute liver failure potentially leading to graft failure. The causes of graft dysfunction can be divided into those resulting in early and late graft dysfunction. Although nonspecific, liver biochemistry abnormalities are still the mainstay investigation used in monitoring for dysfunction. This article provides a summary of the main causes and management strategies for liver graft dysfunction in the early through late posttransplant stages.

Frailty in Patients With Cirrhosis.

PURPOSE OF REVIEW: This review gives an overview of the evolving concept of physical frailty in patients with cirrhosis. As well as summarizing the available metrics that have been used to diagnose it, this review also examines the major recent trials that have investigated frailty in patients with cirrhosis. The complex relationship between sarcopenia and frailty is explored, and strategies to optimize frailty, such as including pharmacological and non-pharmacological therapies, are discussed. RECENT FINDINGS: Though there is heterogeneity between studies on how physical frailty in cirrhosis has been assessed, it is nonetheless becoming increasingly apparent that frailty in cirrhosis contributes to poor outcomes. A growing body of evidence strongly supports that frailty, as an entity distinct from comorbidity or measurable by laboratory-based liver disease severity, contributes to pre-transplant mortality and unplanned hospital admissions. If taken into account, frailty may improve pre-transplant mortality risk prediction. Physical frailty in cirrhosis may be objectively assessed by a number of validated metrics though at present, we lack a uniform consensus on the most appropriate tool. Early identification of frailty may allow optimization of the patient with the potential to avoiding adverse outcomes. Further studies are awaited validating and exploring optimal approaches to diagnosing and reversing frailty.

Acute Liver Failure from Tumor Necrosis Factor-α Antagonists: Report of Four Cases and Literature Review.

BACKGROUND: Tumor necrosis factor-α antagonists (anti-TNF-α) have been associated with drug-induced liver injury. However, cases of anti-TNF-α-associated acute liver failure have only been rarely reported. AIMS: To identify cases of anti-TNF-α-associated acute liver failure and evaluate patterns of liver injury and common characteristics to the cases. METHODS: The United States Acute Liver Failure Study Group database was searched from 1998 to 2014. Four subjects were identified. A PubMed search for articles that reported anti-TNF-α-associated acute liver failure identified five additional cases. RESULTS: The majority of individuals affected were female (eight of nine cases). Age of individual ranged from 20 to 53 years. The most common anti-TNF-α agent associated with acute liver failure was infliximab (n = 8). The latency between initial drug exposure and acute liver failure ranged from 3 days to over a year. Of the nine cases, six required emergency LT. Liver biopsy was obtained in seven cases with a preponderance toward cholestatic-hepatitic features; none showed clear autoimmune features. CONCLUSIONS: Anti-TNF-α-associated acute liver failure displays somewhat different characteristics compared with anti-TNF-α-induced drug-induced liver injury. Infliximab was implicated in the majority of cases. Cholestatic-hepatitic features were frequently found on pre-transplant and explant histology.

The impact of obesity in cirrhotic patients with septic shock: A retrospective cohort study.

BACKGROUND & AIMS: The prevalence of obesity in cirrhosis is rising. The impact of obesity in critically ill cirrhotic patients with sepsis/septic shock has not been evaluated. This study aimed to examine the relationship between obesity and mortality in cirrhotic patients admitted to the intensive care unit with septic shock. METHODS: A retrospective cohort study of all cirrhotic patients with septic shock (n = 362) and a recorded body mass index (BMI) from an international, multicentre (CATSS) database (1996-2015) was performed. Patients were classified by BMI as per WHO categories. Primary outcome was in-hospital mortality. Multivariate logistic regression analyses were carried out to determine independent associations with outcome. RESULTS: In this analysis, mean age was 56.4 years, and 62% were male. Median BMI was 26.3%, and 57.7% were overweight/obese. In-hospital mortality was 71%. Obese patients were more likely to have comorbidities of cardiac disease, lung disease and diabetes. Compared to survivors (n = 105), non-survivors (n = 257) had significantly higher MELD and APACHEII scores and higher requirements for renal replacement therapy and mechanical ventilation (P < .03 for all). Using multivariable logistic regression, increase in BMI (OR 1.07, P = .034), time delay to appropriate antimicrobials (OR 1.16 per hour, P = .003), APACHEII (OR 1.12 per unit, P = .008) and peak lactate (OR 1.15, P = .028) were independently associated with in-hospital mortality. CONCLUSIONS: Septic shock in cirrhosis carries a high mortality. Increased BMI is common in critically ill cirrhotic patients and independently associated with increased in-hospital mortality.

Management of Cerebral Edema in Acute Liver Failure.

Advances in medical care of the acute liver failure patient have led to a significant reduction in mortality related to the condition. Nevertheless, cerebral edema and ensuing brain herniation remains one of the top causes of demise in acute liver failure. Controversy remains regarding the utility of invasive intracranial pressure monitoring as well as usage of novel treatment modalities including therapeutic hypothermia. This review provides a brief summary into the pathophysiology and risk factors for developing cerebral edema in the context of acute liver failure; this review particularly provides a practical focus on general management of the patient with established cerebral edema as well as specific intracranial pressure-lowering strategies.

Intrahepatic vascular changes in non-alcoholic fatty liver disease: Potential role of insulin-resistance and endothelial dysfunction.

Metabolic syndrome is a cluster of several clinical conditions characterized by insulin-resistance and high cardiovascular risk. Non-alcoholic fatty liver disease is the liver expression of the metabolic syndrome, and insulin resistance can be a frequent comorbidity in several chronic liver diseases, in particular hepatitis C virus infection and/or cirrhosis. Several studies have demonstrated that insulin action is not only relevant for glucose control, but also for vascular homeostasis. Insulin regulates nitric oxide production, which mediates to a large degree the vasodilating, anti-inflammatory and antithrombotic properties of a healthy endothelium, guaranteeing organ perfusion. The effects of insulin on the liver microvasculature and the effects of IR on sinusoidal endothelial cells have been studied in animal models of non-alcoholic fatty liver disease. The hypotheses derived from these studies and the potential translation of these results into humans are critically discussed in this review.