Juan Córdoba

HCV-related fibrosis progression following liver transplantation: increase in recent years

BACKGROUND/AIMS The natural history and predictors of HCV-related disease severity post-transplantation are uncertain. The aims of this study were to define the natural history of post-transplantation HCV infection by assessing the rate of fibrosis progression, to determine if the post-transplantation natural history differs from that observed pre-transplantation, and to identify predictors of post-transplantation disease progression. METHODS Post-transplantation biopsies (mean: 3+/-1.6/patient) from 284 patients were scored according to histologic stage, using the method of Desmet et al. Change in fibrosis score (fibrosis progression/year) post-transplantation was used as the primary outcome. Predictors analyzed included viral factors (genotype and viral load at transplantation), patient demographics, year of transplantation, country of transplantation, pre-transplantation fibrosis progression, immunosuppression and laboratory data. RESULTS There was a linear association between change in fibrosis score and time from transplantation, with a median rate of fibrosis progression per year of 0.3 (0.004-2.19/year). Using parametric time-to-event analysis, the expected median duration to cirrhosis was 10 years. The rate of post-transplantation fibrosis progression was significantly higher than pre-transplantation (0.2/year (0.09-0.8) p<0.0001), and higher in Spanish than US centers (0.48 (0.01-2.19) vs 0.28 (0.004-2.08); p=0.09) despite similar progression rates prior to transplantation. Variables independently associated with post-transplantation progression included year of transplantation (p=0.0001), race (p=0.02), number of methyl-prednisolone boluses (p=0.03), and HCV RNA levels at transplantation (p=0.01). CONCLUSIONS HCV-related disease progression is accelerated in immunocompromised compared to immunocompetent patients, with a progressive increase in patients who have recently undergone liver transplantation. Changes in patient management post-transplantation over time and between transplant centers may account for the increase in fibrosis progression observed in recent years.

Acute-on-Chronic Liver Failure Is a Distinct Syndrome That Develops in Patients With Acute Decompensation of Cirrhosis

BACKGROUND & AIMS Patients with cirrhosis hospitalized for an acute decompensation (AD) and organ failure are at risk for imminent death and considered to have acute-on-chronic liver failure (ACLF). However, there are no established diagnostic criteria for ACLF, so little is known about its development and progression. We aimed to identify diagnostic criteria of ACLF and describe the development of this syndrome in European patients with AD. METHODS We collected data from 1343 hospitalized patients with cirrhosis and AD from February to September 2011 at 29 liver units in 8 European countries. We used the organ failure and mortality data to define ACLF grades, assess mortality, and identify differences between ACLF and AD. We established diagnostic criteria for ACLF based on analyses of patients with organ failure (defined by the chronic liver failure-sequential organ failure assessment [CLIF-SOFA] score) and high 28-day mortality rate (>15%). RESULTS Of the patients assessed, 303 had ACLF when the study began, 112 developed ACLF, and 928 did not have ACLF. The 28-day mortality rate among patients who had ACLF when the study began was 33.9%, among those who developed ACLF was 29.7%, and among those who did not have ACLF was 1.9%. Patients with ACLF were younger and more frequently alcoholic, had more associated bacterial infections, and had higher numbers of leukocytes and higher plasma levels of C-reactive protein than patients without ACLF (P < .001). Higher CLIF-SOFA scores and leukocyte counts were independent predictors of mortality in patients with ACLF. In patients without a prior history of AD, ACLF was unexpectedly characterized by higher numbers of organ failures, leukocyte count, and mortality compared with ACLF in patients with a prior history of AD. CONCLUSIONS We analyzed data from patients with cirrhosis and AD to establish diagnostic criteria for ACLF and showed that it is distinct from AD, based not only on the presence of organ failure(s) and high mortality rate but also on age, precipitating events, and systemic inflammation. ACLF mortality is associated with loss of organ function and high leukocyte counts. ACLF is especially severe in patients with no prior history of AD.

Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study Of Liver Diseases and the European Association for the Study of the Liver

The AASLD/EASL Practice Guideline Subcommittee on Hepatic Encephalopathy are: Jayant A. Talwalkar (Chair, AASLD), Hari S. Conjeevaram, Michael Porayko, Raphael B. Merriman, Peter L.M. Jansen, and Fabien Zoulim. This guideline has been approved by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver and represents the position of both associations.

Bacterial infections in cirrhosis: A position statement based on the EASL Special Conference 2013

Bacterial infections are very common and represent one of the most important reasons of progression of liver failure, development of liver-related complications, and mortality in patients with cirrhosis. In fact, bacterial infections may be a triggering factor for the occurrence of gastrointestinal bleeding, hypervolemic hyponatremia, hepatic encephalopathy, kidney failure, and development of acute-on-chronic liver failure. Moreover, infections are a very common cause of repeated hospitalizations, impaired health-related quality of life, and increased healthcare costs in cirrhosis. Bacterial infections develop as a consequence of immune dysfunction that occurs progressively during the course of cirrhosis. In a significant proportion of patients, infections are caused by gram-negative bacteria from intestinal origin, yet gram-positive bacteria are a frequent cause of infection, particularly in hospitalized patients. In recent years, infections caused by multidrug-resistant bacteria are becoming an important clinical problem in many countries. The reduction of the negative clinical impact of infections in patients with cirrhosis may be achieved by a combination of prophylactic measures, such as administration of antibiotics, to reduce the occurrence of infections in high-risk groups together with early identification and management of infection once it has developed. Investigation on the mechanisms of altered gut microflora, translocation of bacteria, and immune dysfunction may help develop more effective and safe methods of prevention compared to those that are currently available. Moreover, research on biomarkers of early infection may be useful in early diagnosis and treatment of infections. The current manuscript reports an in-depth review and a position statement on bacterial infections in cirrhosis.

Value of the critical flicker frequency in patients with minimal hepatic encephalopathy

Minimal hepatic encephalopathy (MHE) is mainly diagnosed using psychometric tests such as the psychometric hepatic encephalopathy score (PHES). Despite the clinical and social relevance of MHE, psychometric testing is not widespread in routine clinical care. We assessed the usefulness of the critical flicker frequency (CFF), for the diagnosis of MHE and for the prediction of the development of overt episodes of HE. The normal range of PHES in the Spanish population was evaluated in a control group. Subsequently, 114 patients with cirrhosis and 103 healthy controls underwent both PHES and CFF tests. A diagnosis of MHE was made when the PHES was lower than −4 points. Patients were followed‐up every 6 months for a total of 1 year. CFF did not correlate with age, education, or sex in the control group. The mean CFF was significantly lower in patients with MHE versus non‐MHE or controls. Mean CFF correlated with individual psychometric tests as well as PHES (r = 0.54; P < 0.001). CFF <38 Hz was predictive of further bouts of overt HE (log‐rank: 14.2; P < 0.001). There was a weak correlation between mean CFF and Child‐Pugh score but not with model for end‐stage liver disease score. In multivariate analysis using Cox regression, CFF together with Child‐Pugh score was independently associated with the development of overt HE. Conclusion: CFF is a simple, reliable, and accurate method for the diagnosis of MHE. It is not influenced by age or education and could predict the development of overt HE. (HEPATOLOGY 2007;45:879–885.)

The development of low-grade cerebral edema in cirrhosis is supported by the evolution of 1H-magnetic resonance abnormalities after liver transplantation

BACKGROUND/AIMS Liver failure may cause brain edema through an increase in brain glutamine. However, usually standard neuroimaging techniques do not detect brain edema in cirrhosis. We assessed magnetization transfer ratio and (1)H-magnetic resonance (MR) spectroscopy before and after liver transplantation to investigate changes in brain water content in cirrhosis. METHODS Non-alcoholic cirrhotics without overt hepatic encephalopathy (n=24) underwent (1)H-MR of the brain and neuropsychological tests. (1)H-MR results were compared with those of healthy controls (n=10). In a subgroup of patients (n=11), the study was repeated after liver transplantation. RESULTS Cirrhotic patients showed a decrease in magnetization transfer ratio (31.5+/-3.1 vs. 37.1+/-1.1, P<0.01) and an increase in glutamine/glutamate signal (2.22+/-0.47 vs. 1.46+/-0.26, P<0.01). The increase in glutamine/glutamate signal was correlated to the decrease in magnetization transfer ratio and to neuropsychological function. Following liver transplantation, there was a progressive normalization of magnetization transfer ratio, glutamine/glutamate signal and neuropsychological function. Accordingly, correlations between these variables were lost after liver transplantation. CONCLUSIONS Cirrhotic patients show reversible changes in magnetization transfer ratio that are compatible with the development of low-grade cerebral edema. Minimal hepatic encephalopathy and low-grade cerebral edema appear to be the consequences of the metabolism of ammonia in the brain.

Quality of life and cognitive function in hepatitis C at different stages of liver disease

BACKGROUND/AIMS Hepatitis C has been associated with a decrease in quality of life and with neurological abnormalities. The aim of our study was to investigate the relationship between quality of life and cognitive function. METHODS Quality of life, clinical variables and neuropsychological function were evaluated in 120 patients with hepatitis C (mild chronic hepatitis, compensated cirrhosis and decompensated cirrhosis) and in healthy controls (n=40, in each group). RESULTS Patients with chronic hepatitis or compensated cirrhosis showed a decrease in quality of life, in spite of unimpaired neuropsychological tests. Patients with decompensated cirrhosis exhibited a further decrease in quality of life and neuropsychological abnormalities. The decrease in quality of life was associated with the severity of liver failure, neuropsychological abnormalities and treatment with beta-blockers or diuretics. However, in the multivariable analysis, only treatment with beta-blockers or diuretics (which was limited to decompensated cirrhosis) was independently associated with quality of life. CONCLUSIONS Hepatitis C causes a decrease in quality of life even in the absence of major cognitive impairment. The mechanisms that worsen quality of life are unknown. However, in cirrhotic outpatients with prior decompensations, treatment with beta-blockers or diuretics appears to have an important effect on quality of life.

Review article: the design of clinical trials in hepatic encephalopathy - an International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) consensus statement

Aliment Pharmacol Ther 2011; 33: 739–747

New assessment of hepatic encephalopathy

Hepatic encephalopathy (HE) is a common complication of cirrhosis that requires careful appraisal of the clinical manifestations, evaluation of the underlying neurological disorders, and assessment of liver function and the portal-systemic circulation. This article reviews recent developments in the assessment of HE and discusses the controversy regarding the use of a categorical or a continuous approach in measuring the severity of this condition. New scales facilitate effective monitoring and assessment of episodic HE. Neuropsychological test batteries and neurophysiological tests are of value for evaluating cognitive function in outpatients and can establish the diagnosis of minimal HE, and the severity of low-grade HE. These tools allow better evaluation of the origin of cognitive complaints and help in estimating the risk of accidents. It is now possible to complete the evaluation with measurement of the effects of cognitive impairment on daily living. In difficult cases, imaging of the brain and portal-systemic circulation with magnetic resonance imaging is especially helpful. Based on these studies, neurological signs and symptoms can be attributed to HE in patients with mild liver disease and in those with complex neurological manifestations. The new methods presented are also valuable for investigating the neurological manifestations occurring after liver transplantation.

Clinical Course of acute-on-chronic liver failure syndrome and effects on prognosis.

Acute‐on‐chronic liver failure (ACLF) is characterized by acute decompensation (AD) of cirrhosis, organ failure(s), and high 28‐day mortality. We investigated whether assessments of patients at specific time points predicted their need for liver transplantation (LT) or the potential futility of their care. We assessed clinical courses of 388 patients who had ACLF at enrollment, from February through September 2011, or during early (28‐day) follow‐up of the prospective multicenter European Chronic Liver Failure (CLIF) ACLF in Cirrhosis study. We assessed ACLF grades at different time points to define disease resolution, improvement, worsening, or steady or fluctuating course. ACLF resolved or improved in 49.2%, had a steady or fluctuating course in 30.4%, and worsened in 20.4%. The 28‐day transplant‐free mortality was low‐to‐moderate (6%‐18%) in patients with nonsevere early course (final no ACLF or ACLF‐1) and high‐to‐very high (42%‐92%) in those with severe early course (final ACLF‐2 or ‐3) independently of initial grades. Independent predictors of course severity were CLIF Consortium ACLF score (CLIF‐C ACLFs) and presence of liver failure (total bilirubin ≥12 mg/dL) at ACLF diagnosis. Eighty‐one percent had their final ACLF grade at 1 week, resulting in accurate prediction of short‐ (28‐day) and mid‐term (90‐day) mortality by ACLF grade at 3‐7 days. Among patients that underwent early LT, 75% survived for at least 1 year. Among patients with ≥4 organ failures, or CLIF‐C ACLFs >64 at days 3‐7 days, and did not undergo LT, mortality was 100% by 28 days. Conclusions: Assessment of ACLF patients at 3‐7 days of the syndrome provides a tool to define the emergency of LT and a rational basis for intensive care discontinuation owing to futility. (Hepatology 2015;62:243‐252)