Puneeta Tandon

Severe muscle depletion in patients on the liver transplant wait list: Its prevalence and independent prognostic value

As detected by cross‐sectional imaging, severe muscle depletion, which is termed sarcopenia, holds promise for prognostication in patients with cirrhosis. Our aims were to describe the prevalence and predictors of sarcopenia in patients with cirrhosis listed for liver transplantation (LT) and to determine its independent prognostic significance for the prediction of waiting‐list mortality. Adults listed for LT who underwent abdominal computed tomography/magnetic resonance imaging within 6 weeks of activation were retrospectively identified. The exclusions were hepatocellular carcinoma, acute liver failure, prior LT, and listing for multivisceral transplantation or living related LT. Sixty percent of the 142 eligible patients were male, the median age was 53 years, and the median Model for End‐Stage Liver Disease (MELD) score at listing was 15. Forty‐one percent were sarcopenic; sarcopenia was more prevalent in males versus females (54% versus 21%, P < 0.001) and increased with the Child‐Pugh class (10% for class A, 34% for class B, and 54% for class C, P = 0.007). Male sex, the dry‐weight body mass index (BMI), and Child‐Pugh class C cirrhosis (but not the MELD score) were independent predictors of sarcopenia. Sarcopenia was an independent predictor of mortality (hazard ratio = 2.36, 95% confidence interval = 1.23‐4.53) after adjustments for age and MELD scores. In conclusion, sarcopenia is associated with increased waiting‐list mortality and is poorly predicted by subjective nutritional assessment tools such as BMI and subjective global assessment. If this is validated in larger studies, the objective assessment of sarcopenia holds promise for prognostication in this patient population. Liver Transpl 18:1209–1216, 2012.

The Efficacy and Safety of Bile Acid Binding Agents, Opioid Antagonists, or Rifampin in the Treatment of Cholestasis-Associated Pruritus

OBJECTIVES:The objective of this review was to evaluate the efficacy and safety of rifampin, opioid antagonists, or bile acid binding agents in the treatment of cholestasis-related pruritus (CAP) from available randomized controlled trial evidence.METHODS:In addition to a comprehensive gray literature search, the Cochrane Library, MEDLINE, EMBASE, PubMed, and Web of Science were searched. Only full-text RCTs in participants (>75% adult) with CAP on at least one of the three medications were included. The primary outcome was change in pruritus score, recorded as a continuous or dichotomous outcome. Two independent reviewers performed trial selection and quality assessment.RESULTS:From 487 citations, 12 RCTs were included. Rifampin (standardized mean difference [SMD] –1.62, 95% CI –3.05 to –0.18) and opioid antagonists (SMD –0.68, 95% CI –1.19 to –0.17) significantly reduced CAP. The two cholestyramine studies were too heterogeneous to pool. Although cholestyramine (P = 0.35) and rifampin (P = 0.96) were not associated with greater side effects compared with placebo, opioid antagonists were (number needed to harm = 2.6, 95% CI 1.4–25).CONCLUSIONS:The available RCTs are small, few in number, and use varying scales for measuring pruritus. Although both opioid antagonists and rifampin demonstrated a reduction in pruritus, there were insufficient data to judge the efficacy of cholestyramine. Opioid antagonists were associated with transient side effects in a significant proportion of patients. A longer well-designed randomized controlled trial is needed to confirm the efficacy of bile acid binding agents and accurately assess adverse events.

Severe muscle depletion predicts postoperative length of stay but is not associated with survival after liver transplantation: Sarcopenia After Liver Transplantation

Muscle depletion or sarcopenia is associated with increased mortality in patients with cirrhosis; how it affects mortality after liver transplantation requires further study. In this study, we aimed to establish whether sarcopenia predicts increased morbidity or mortality after liver transplantation. We analyzed 248 patients with cirrhosis who had a computed tomography (CT) scan including the third lumbar vertebra before liver transplantation. Data were recovered from medical charts, the skeletal muscle cross‐sectional area was measured with CT, and sarcopenia was defined with previously published sex‐ and body mass index–specific cutoffs. One hundred sixty‐nine patients (68%) were male, and the mean age at transplantation was 55 ± 1 years. The etiologies of cirrhosis were hepatitis C virus (51%), alcohol (19%), autoimmune liver diseases (15%), hepatitis B virus (8%), and other etiologies (7%). Sarcopenia was present in 112 patients (45%), and it was more frequent in males (P = 0.002), patients with ascites (P = 0.02), and patients with higher bilirubin levels (P = 0.05), creatinine levels (P = 0.02), international normalized ratios (P = 0.04), Child‐Pugh scores (P = 0.002), and Model for End‐Stage Liver Disease scores (P = 0.002). The median survival period after liver transplantation was 117 ± 17 months for sarcopenic patients and 146 ± 20 months for nonsarcopenic patients (P = 0.4). Sarcopenic patients had longer hospital stays (40 ± 4 versus 25 ± 3 days; P = 0.005) and a higher frequency of bacterial infections within the first 90 days after liver transplantation (26% versus 15%, P = 0.04) in comparison with nonsarcopenic patients. In conclusion, sarcopenia is one of the most common complications in patients with cirrhosis and is predictive of longer hospital stays and a higher risk of perioperative bacterial infections after liver transplantation, but it is not associated with increased mortality. Liver Transpl 20:640–648, 2014.

A MELD-Based Model to Determine Risk of Mortality Among Patients With Acute Variceal Bleeding

BACKGROUND & AIMS Patients with cirrhosis with acute variceal bleeding (AVB) have high mortality rates (15%-20%). Previously described models are seldom used to determine prognoses of these patients, partially because they have not been validated externally and because they include subjective variables, such as bleeding during endoscopy and Child-Pugh score, which are evaluated inconsistently. We aimed to improve determination of risk for patients with AVB. METHODS We analyzed data collected from 178 patients with cirrhosis (Child-Pugh scores of A, B, and C: 15%, 57%, and 28%, respectively) and esophageal AVB who received standard therapy from 2007 through 2010. We tested the performance (discrimination and calibration) of previously described models, including the model for end-stage liver disease (MELD), and developed a new MELD calibration to predict the mortality of patients within 6 weeks of presentation with AVB. MELD-based predictions were validated in cohorts of patients from Canada (n = 240) and Spain (n = 221). RESULTS Among study subjects, the 6-week mortality rate was 16%. MELD was the best model in terms of discrimination; it was recalibrated to predict the 6-week mortality rate with logistic regression (logit, -5.312 + 0.207 • MELD; bootstrapped R(2), 0.3295). MELD values of 19 or greater predicted 20% or greater mortality, whereas MELD scores less than 11 predicted less than 5% mortality. The model performed well for patients from Canada at all risk levels. In the Spanish validation set, in which all patients were treated with banding ligation, MELD predictions were accurate up to the 20% risk threshold. CONCLUSIONS We developed a MELD-based model that accurately predicts mortality among patients with AVB, based on objective variables available at admission. This model could be useful to evaluate the efficacy of new therapies and stratify patients in randomized trials.

Risk factors for recurrence of autoimmune hepatitis after liver transplantation

Autoimmune hepatitis has been reported to recur after liver transplantation. The aim of our study was to evaluate the risk factors associated with recurrence of autoimmune hepatitis. Forty‐six patients that underwent liver transplantation because of end‐stage liver disease secondary to autoimmune hepatitis were studied. Recurrence of autoimmune hepatitis was diagnosed in 11 of the 46 (24%) patients, and the overall 5‐year probability of recurrence was 18%. By univariate Cox analysis, the features before liver transplantation associated with a higher risk of recurrence were concomitant autoimmune disease [hazard ratio (HR), 3.74; 95% confidence interval (CI), 1.05–13.36; P = 0.04], high aspartate aminotransferase (HR, 1.09; 95% CI, 1.03–1.14; P = 0.002), high alanine aminotransferase (HR, 1.09; 95% CI, 1.03–1.20; P = 0.003), and high immunoglobulin G (IgG; HR, 1.25; 95% CI, 1.11–1.41; P = 0.0003). Moreover, patients with recurrence had a higher frequency of moderate to severe inflammatory activity (HR, 5.3; 95% CI, 1.55–18.79; P = 0.008) and plasma cell infiltration in the liver explant (HR, 5.8; 95% CI, 1.52–22.43; P = 0.01). In the multivariate Cox analysis, only the presence of moderate to severe inflammation (HR, 6.9; 95% CI, 1.76–26.96; P = 0.006) and high IgG levels before liver transplantation (HR, 7.5; 95% CI, 1.45–38.45; P = 0.02) were independently associated with the risk of autoimmune hepatitis recurrence. In conclusion, patients with concomitant autoimmune disease, high aspartate aminotransferase, alanine aminotransferase, and IgG before the transplant, or moderate to severe inflammatory activity or plasma cell infiltration in the liver explant have a higher risk of recurrent disease. These findings suggest that recurrence of autoimmune hepatitis may reflect incomplete suppression of disease activity prior to liver transplantation. Liver Transpl 15:1254–1261, 2009.

Managing the post-liver transplantation anastomotic biliary stricture: multiple plastic versus metal stents: a systematic review.

BACKGROUND Anastomotic biliary strictures (ABSs) are common after liver transplantation, especially with living donors. The strategy of balloon dilation and multiple plastic stents (MPSs) is effective in treating ABSs, but requires multiple ERCPs with the associated risks, cost, and patient burden. Covered self-expandable metal stents (SEMSs) have been increasingly used in this setting. However, it is not clear whether there are definite advantages of using SEMSs over MPSs. OBJECTIVE To compare the efficacy and safety of MPSs and SEMSs in ABS after orthotopic liver transplantation (OLT) and living donor liver transplantation (LDLT). DESIGN Systematic review by searching MEDLINE and EMBASE databases. PATIENTS OLT and LDLT patients. INTERVENTIONS MPSs versus SEMSs. MAIN OUTCOME MEASUREMENTS Stricture resolution and adverse event rates. RESULTS Eight studies (446 patients) using MPSs in OLT, 3 studies (120 patients) using MPSs in LDLT, and 10 studies (200 patients) using SEMSs fulfilled the inclusion and exclusion criteria. The stricture resolution rates were highest (94%-100%) when MPS duration was 12 months or longer. The stricture resolution rates with SEMSs in OLT patients were also high when stent duration was 3 months or longer (80%-95%) compared with a duration less than 3 months (53%-88%). Although the overall adverse event rates were low, the overall SEMS migration rate was significant at 16%. LIMITATIONS No randomized, controlled trials were identified; only small case series using either MPSs or SEMSs were included. CONCLUSIONS Although SEMSs appeared to be a promising option in the endoscopic management of ABSs after liver transplantation, current evidence does not suggest a clear advantage of SEMS use over MPSs for this indication.

The 3‐month readmission rate remains unacceptably high in a large North American cohort of patients with cirrhosis

In smaller single‐center studies, patients with cirrhosis are at a high readmission risk, but a multicenter perspective study is lacking. We evaluated the determinants of 3‐month readmissions among inpatients with cirrhosis using the prospective 14‐center North American Consortium for the Study of End‐Stage Liver Disease cohort. Patients with cirrhosis hospitalized for nonelective indications provided consent and were followed for 3 months postdischarge. The number of 3‐month readmissions and their determinants on index admission and discharge were calculated. We used multivariable logistic regression for all readmissions and for hepatic encephalopathy (HE), renal/metabolic, and infection‐related readmissions. A score was developed using admission/discharge variables for the total sample, which was validated on a random half of the total population. Of the 1353 patients enrolled, 1177 were eligible on discharge and 1013 had 3‐month outcomes. Readmissions occurred in 53% (n = 535; 316 with one, 219 with two or more), with consistent rates across sites. The leading causes were liver‐related (n = 333; HE, renal/metabolic, and infections). Patients with cirrhosis and with worse Model for End‐Stage Liver Disease score or diabetes, those taking prophylactic antibiotics, and those with prior HE were more likely to be readmitted. The admission model included Model for End‐Stage Liver Disease and diabetes (c‐statistic = 0.64, after split‐validation 0.65). The discharge model included Model for End‐Stage Liver Disease, proton pump inhibitor use, and lower length of stay (c‐statistic = 0.65, after split‐validation 0.70). Thirty percent of readmissions could not be predicted. Patients with liver‐related readmissions consistently had index‐stay nosocomial infections as a predictor for HE, renal/metabolic, and infection‐associated readmissions (odds ratio = 1.9‐3.0). Conclusions: Three‐month readmissions occurred in about half of discharged patients with cirrhosis, which were associated with cirrhosis severity, diabetes, and nosocomial infections; close monitoring of patients with advanced cirrhosis and prevention of nosocomial infections could reduce this burden. (Hepatology 2016;64:200–208)

Renin-angiotensin-aldosterone inhibitors in the reduction of portal pressure: a systematic review and meta-analysis.

BACKGROUND & AIMS Renin-angiotensin-aldosterone antagonists [ACE inhibitors (ACEi), angiotensin receptor blockers (ARB), aldosterone antagonists (AA)] are potential therapies for portal hypertension. We evaluated the efficacy and safety of RAAS inhibitors in hepatic venous pressure gradient (HVPG) reduction. METHODS We included full-text controlled trials in patients with cirrhosis and portal hypertension. The primary outcome was mean change in HVPG between treatment and control. Two independent reviewers performed trial selection and quality assessment. An individual patient meta-analysis based on the data of three studies was performed. RESULTS From 193 citations, 19 controlled trials (n=678) were included. When compared to placebo, ARB/ACEi resulted in significant HVPG reduction. The best quality trials compared ARB/ACEi to beta-blockers (BB). Pooled individual patient data for three of four of these trials showed that BB decreased the HVPG more than ARB/ACEi. In patients with Child Pugh A cirrhosis, the HVPG reduction with ARB/ACEi (-17%; 95% CI: -28 to -6), was similar to that of BB (-21%; 95% CI: -32 to -9). Significant variation in the comparison groups of AA trials precluded pooling. There was no difference in adverse events in any group but selected studies noted adverse hemodynamic effects in decompensated patients on ARB/ACEi. CONCLUSIONS ARB/ACEi reduce portal pressure in patients with Child Pugh A cirrhosis without adverse events. The efficacy and safety in this group may be secondary to a targeted effect on the local hepatic RAAS system, as compared to decompensated patients who risk hypotension and renal insufficiency due to activation of the systemic RAAS. Further studies should determine the potential of these drugs as an alternative or adjunct to BB.

A shorter duration of pre-transplant abstinence predicts problem drinking after liver transplantation.

OBJECTIVES:Liver transplantation for alcoholic liver disease (ALD) can be complicated by abusive or “problem” drinking (PD) after transplant. There are limited data for evaluating the effect of pre-transplant abstinence on post-transplant PD. Few existing studies have included a substantial number of patients with co-existing causes of hepatic dysfunction, and the effect of PD on survival in recent European studies has been controversial. We hypothesized that a longer duration of pre-transplant abstinence would lead to less PD after transplantation. Accordingly, the objectives of this study are to analyze a North American cohort of patients with ALD with or without a secondary diagnosis of liver disease to estimate (i) the incidence of PD and its predictors, as well as (ii) the effect of PD on patient survival.METHODS:We conducted a retrospective review of all patients transplanted for ALD surviving for more than 3 months after transplant. PD was defined as either any drinking (AD) to the point of intoxication or drinking above the toxic threshold (>20 g/day in women and >40 g/day in men) on at least two separate occasions. We used Coxs proportional hazards regression to estimate risk ratios and Kaplan–Meier curves with log-rank analysis to compare survival.RESULTS:Of 213 eligible transplant patients, 42 were excluded. Of the 171 remaining patients, 78% were male; mean age was 52 years. Overall 53% of patients had co-existing causes of liver dysfunction. The mean follow-up was 64.8 months. The median pre-transplant abstinence was 19 months. In all patients, the risk of AD was 24% and PD 13%. Pre-transplant abstinence duration was the only independent predictor of PD after transplant. For every 1-month increment in pre-transplant abstinence, there was a 5% decrease in the adjusted relapse rate. There was no survival difference noted between problem drinkers and non-drinkers.CONCLUSIONS:The risk of PD decreased with increasing pre-transplant abstinence. Our data support pre-transplant abstinence as an important predictor of post-transplant recidivism; however, the optimal period of abstinence remains unclear. Patients with <18 months of abstinence may benefit from more intensive follow-up and rehabilitation after transplant.

The natural history of inflammatory bowel disease and primary sclerosing cholangitis after liver transplantation – a single-centre experience

OBJECTIVE To describe the natural history of primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) after liver transplant, the predictors of PSC and IBD recurrence, and the interaction of these disease processes. METHODS Data regarding patients who received liver transplants for PSC at the University of Alberta Hospital (Edmonton, Alberta) from 1989 to 2006 were retrospectively reviewed. Recurrent PSC (rPSC) was defined by the Mayo Clinic criteria. Cox proportional hazards modelling and Kaplan-Meier statistics were used. RESULTS Fifty-nine patients were studied, with a median follow-up of 68 months. A total of 71.2% of patients were diagnosed with IBD pretransplant. Clinical IBD severity post-transplant compared with severity pretransplant was unchanged in 67%, worse in 26.5% and improved in 6.1% of patients. Twenty-five per cent of patients developed rPSC posttransplant. The occurrence of at least one episode of acute cellular rejection (hazard ratio 5.7; 95% CI 1.3 to 25.8) and cytomegalovirus mismatch (hazard ratio 4.2; 95% CI 1.1 to 15.4) were found to be significant predictors of rPSC. Although not statistically significant, there was no rPSC in patients without pre- or post-transplant IBD, and in only one patient with a colectomy. Actuarial patient survival rates at one, five and 10 years posttransplant were 97%, 86% and 79%, respectively. Although a significant proportion of patients experienced worsening IBD post-transplantation, the presence or severity of IBD did not influence rPSC or patient survival. CONCLUSION Acute cellular rejection and cytomegalovirus mismatch were both identified as independent predictors of rPSC. The impact of steroids and the ideal immunosuppressive regimen for the control of both IBD and PSC post-transplant requires further examination in prospective studies.