Brett E. Fortune

Risk of waitlist mortality in patients with primary sclerosing cholangitis and bacterial cholangitis.

Patients with primary sclerosing cholangitis (PSC) are at increased risk for bacterial cholangitis because of biliary strictures and bile stasis. A subset of PSC patients suffer from repeated episodes of bacterial cholangitis, which can lead to frequent hospitalizations and impaired quality of life. Although waitlist candidates with PSC and bacterial cholangitis frequently receive exception points and/or are referred for living donor transplantation, the impact of bacterial cholangitis on waitlist mortality is unknown. We performed a retrospective cohort study of all adult waitlist candidates with PSC who were listed for initial transplantation between February 27, 2002 and June 1, 2012 at the University of Pennsylvania and the University of Colorado–Denver. During this period, 171 PSC patients were waitlisted for initial transplantation. Before waitlisting, 38.6% (66/171) of the patients had a history of bacterial cholangitis, whereas 28.0% (44/157) of the patients with at least 1 Model for End‐Stage Liver Disease update experienced cholangitis on the waitlist. During follow‐up, 30 patients (17.5%) were removed from the waitlist for death or clinical deterioration, with 46.7% (14/30) developing cholangiocarcinoma. Overall, 12 of the 82 waitlist candidates (14.6%) who ever had an episode of cholangitis were removed for death or clinical deterioration, whereas 18 of the 89 candidates (20.2%) without cholangitis were removed (P = 0.34 for a comparison of the 2 groups). No patients were removed because of bacterial cholangitis. In multivariate competing‐risk models, a history of bacterial cholangitis was not associated with an increased risk of waitlist removal for death or clinical deterioration (subhazard ratio = 0.67, 95% confidence interval = 0.65–0.70, P < 0.001). In summary, waitlist transplant candidates with PSC and bacterial cholangitis do not have an increased risk of waitlist mortality. The data call into question the systematic granting of exception points or referral for living donor transplantation due to a perceived risk of increased waitlist mortality. Liver Transpl 19:250–258, 2013.

Post-transplant survival is improved for hepatitis C recipients who are RNA negative at time of liver transplantation

Hepatitis C virus (HCV) infection recurs universally in patients who are viremic at liver transplantation and likely accounts for the diminished post‐transplant graft and patient survival. We evaluated whether undetectable HCV RNA pretransplant improves graft and patient survival after transplantation. Cases, defined by HCV listing diagnosis and positive HCV antibody, were selected from the Scientific Registry of Transplant Recipients database and further grouped as HCV RNA‐positive (n = 4978) or negative (n = 445) based upon pretransplant testing. Controls were non‐HCV recipients (n = 2995). RNA‐negative cases had significantly better 5‐year graft (72% vs. 64%) and patient (79% vs. 69%) survival than RNA‐positive cases (P < 0.01 for both), and similar survival as controls (Graft: 72% vs. 74%, Patient: 79% vs. 80%; P > 0.05 for both). Nonproportional hazards modeling of RNA‐positive cases identified a subgroup with rapid progression leading to early graft loss and death. Multivariable analyses confirmed that a positive HCV RNA prior to transplantation was a significant independent predictor of graft loss and death. In conclusion, HCV patients who have undetectable RNA at the time of liver transplantation experience improved long‐term graft and patient outcomes. We speculate that the post‐transplant survival of HCV recipients could be improved by safe and tolerable pretransplant antiviral strategies.

Optimal timing for hepatitis C therapy in US patients eligible for liver transplantation: a cost‐effectiveness analysis

Recurrence of hepatitis C virus (HCV) following liver transplantation (LT) is universal for those with ongoing viraemia and is associated with higher rates of allograft failure and death. However, the optimal timing of HCV treatment for patients awaiting transplant remains unclear.

Linking a Hepatology Clinical Service Line to Quality Improvement

As health care delivery reform continues in the United States, the need for care integration is increasingly obvious. Long-term mitigation of cost trends will likely require care coordination of patients with multiple comorbidities, since about 5% of patients account for almost 50% of health care costs. Successful care coordination of this type of patient begins with accurate patient identification and then tracking of selected patients across the care continuum, both dependent on an all-inclusive health system electronic medical record. This month’s Practice Management article describes innovative work at Yale University School of Medicine and Yale New Haven Hospital. There, clinicians worked with experts in the hospital’s Cost and Value Department to identify all patients with liver disease and then track their clinical care and resource use over a 12-month period. These data then were used to categorize patients into medically logical subpopulations where targeted clinical interventions could be applied to affect patient and financial outcomes.

Child-Turcotte-Pugh Class is Best at Stratifying Risk in Variceal Hemorrhage: Analysis of a US Multicenter Prospective Study

Goals/Background: Data on acute variceal hemorrhage (AVH) in the United States is limited and the best method to stratify risk is not clear. Taking advantage of a prospective US cohort study, we aimed to (1) describe clinical outcomes of AVH and their predictors; (2) compare predictors of 6-week mortality. Study: Prospective 15-center US cohort of patients with cirrhosis presenting with endoscopically proven AVH, all of whom received antibiotics, vapreotide (a somatostain analog) infusion and endoscopic band ligation. Patients were enrolled between August 2006 and April 2008. Primary outcome was 6-week mortality. Secondary outcome was 5-day treatment failure. The prognostic value of Child-Turcotte-Pugh (CTP) class, Model for End-stage Liver Disease (MELD) score and a recent recalibrated MELD were compared. Results: Seventy eligible patient were enrolled; 18 (26%) patients died within 6-weeks of index bleed. Demographic, clinical, and laboratory data were compared between survivors and nonsurvivors. Multivariate models showed that admission CTP or the MELD score (separately) were independent predictors of survival. The discriminative values of CTP (area under receiver operating characteristic: 0.75) and MELD (area under receiver operating characteristic: 0.79) were good and not significantly different (P=0.27). However, calibration (correlation between observed and predicted mortality) test was significantly better for CTP than for MELD, with the recently described recalibrated MELD model having the worst agreement. Predicted mortality for CTP-A was <10%, CTP-B 10% to 30%; and CTP-C >33%. Conclusions: AVH mortality of 26% in the United States is in the upper range limit compared with recent series but may be due to inclusion of patients with more advanced cirrhosis. CTP score has the best overall performance in the prediction of 6-week mortality and is best at stratifying risk.

The clinical and molecular epidemiology of pre-transplant vancomycin-resistant enterococci colonization among liver transplant recipients.

Vancomycin‐resistant enterococci (VRE) infections cause significant morbidity in liver transplant recipients. The epidemiology and impact of pre‐transplant colonization with VRE among patients who undergo liver transplantation are poorly understood. We conducted an observational cohort study to identify risk factors and outcomes associated with pre‐transplant VRE colonization and described the molecular diversity among VRE strains colonizing patients who undergo liver transplantation. Perirectal VRE surveillance cultures were performed prior to transplantation. Repetitive sequence‐based polymerase chain reaction (rep‐PCR) testing was used to identify clonality among VRE isolates. Of 61 patients who underwent pre‐transplant VRE surveillance and subsequent liver transplantation, 27 (44%) were colonized with VRE. In multivariate analysis, pre‐transplant VRE colonization was associated with central venous catheterization (OR 9.4, 95% confidence interval [CI]= 1.3–70.2, p = 0.03) and rifaximin use (OR 15.4, 95% CI 1.5–159.7, p = 0.02). Pre‐transplant VRE colonization was associated with more hospital days post‐transplant (26.6 vs. 16.1 d, p = 0.04). Of VRE‐colonized patients analyzed with rep‐PCR, 68% were colonized with the same strain as another patient in the cohort. Active surveillance identifies VRE‐colonized patients who may benefit from targeted antimicrobial prophylaxis and enhanced infection prevention measures to prevent VRE spread. The relationship between rifaximin receipt and VRE colonization warrants further study. The identification of similar VRE isolates may suggest linked transmission during pre‐transplant hospitalizations, which should be further investigated in prospective studies.

Liver transplantation for hepatocellular carcinoma: a surgical perspective.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality in the world. Early detection and timely treatment of HCC is critical for better patient outcomes. Curative therapy consists of surgical hepatic resection or liver transplantation (LTx); however, both are restricted to explicit selective criteria. Liver resection is the gold standard of treatment for noncirrhotic patients but can be done in only a small fraction of cirrhotic patients depending on synthetic dysfunction, degree of portal hypertension, and number and location(s) of tumor(s). Therefore, the best treatment modality in cirrhotic patients with HCC is LTx as it will cure both HCC and the underlying cirrhosis. The limitation to offer transplant to all cirrhotic patients with HCC is the shortage of available donor organs. While these patients are waiting for transplant, their tumors may progress and develop distant metastases and may lead to patients losing their candidacy for LTx. Various ablation therapies can be used to treat HCC, prevent tumor progression, and thus, avoid patients losing the option of LTx. Future directions to improve HCC patient outcomes include advancement in tumor gene analysis and histopathology for better prediction of tumor behavior, improved immunosuppression regimens to reduce tumor recurrence in the posttransplant setting, and efficient use of an expanded donor pool that includes living donor organs. This paper will review the current methods of HCC diagnosis, selection for either hepatic resection or LTx, and will also summarize posttreatment outcomes. We will suggest future directions for the field as we strive to improve outcomes for our HCC patients.

Ascites, refractory ascites and hyponatremia in cirrhosis

Abstract Ascites is the most common complication related to cirrhosis and is associated with increased morbidity and mortality. Ascites is a consequence of the loss of compensatory mechanisms to maintain the overall effective arterial blood volume due to worsening splanchnic arterial vasodilation as a result of clinically significant portal hypertension. In order to maintain effective arterial blood volume, vasoconstrictor and antinatriuretic pathways are activated, which increase overall sodium and fluid retention. As a result of progressive splanchnic arterial vasodilation, intestinal capillary pressure increases and results in the formation of protein-poor fluid within the abdominal cavity due to increased capillary permeability from the hepatic sinusoidal hypertension. In some patients, the fluid can translocate across diaphragmatic fenestrations into the pleural space, leading to hepatic hydrothorax. In addition, infectious complications such as spontaneous bacterial peritonitis can occur. Eventually, as the liver disease progresses related to higher portal pressures, loss of a compensatory cardiac output and further splanchnic vasodilation, kidney function becomes compromised from worsening renal vasoconstriction as well as the development of impaired solute-free water excretion and severe sodium retention. These mechanisms then translate into significant clinical complications, such as refractory ascites, hepatorenal syndrome and hyponatremia, and all are linked to increased short-term mortality. Currently, liver transplantation is the only curative option for this spectrum of clinical manifestations but ongoing research has led to further insight on alternative approaches. This review will further explore the current understanding on the pathophysiology and management of ascites as well as expand on two advanced clinical consequences of advanced liver disease, refractory ascites and hyponatremia.

Corticosteroids Versus Pentoxifylline for Severe Alcoholic Hepatitis: A Sequential Analysis of Randomized Controlled Trials.

Introduction: Despite the significant morbidity and mortality associated with alcoholic hepatitis, a consensus or generally accepted therapeutic strategy has not yet been reached. The purpose of this analysis was to evaluate the effects of corticosteroids and pentoxifylline on short-term mortality, incidence of hepatorenal syndrome, and sepsis in patients with severe alcoholic hepatitis. Materials and Methods: We conducted a comprehensive search of the Cochrane library, PUBMED, Scopus, EMBASE, and published proceedings from major hepatology and gastrointestinal meetings from January 1970 to June 2015. All relevant articles irrespective of language, year of publication, type of publication, or publication status were included. Two independent reviewers extracted data and scored publications; a third investigator adjudicated discrepancies. The &kgr; scores were measured to assess the agreement between the 2 initial reviewers. The review and meta-analyses were performed following the recommendations of The Cochrane Collaboration. Conventional meta-analysis and Trial sequential analysis were performed. GRADEpro version 3.6 was used to appraise the quality of epidemiologic evidence. Results: A total of 14 studies satisfied inclusion criteria comparing corticosteroids, pentoxifylline, or placebo. Compared with placebo, corticosteroids reduced 28-day mortality (RR=0.53; 95% CI, 0.33-0.84; P=0.006). There was no statistically significant difference in short-term mortality between pentoxifylline and placebo (RR=0.74; 95% CI, 0.46-1.18; P=0.21). Neither corticosteroids nor pentoxifylline impacted the incidence of hepatorenal syndrome or sepsis. Trial sequential analysis confirmed the results of our conventional meta-analysis. Conclusions and Relevance: Corticosteroids demonstrated a decrease in 28-day mortality in patients with severe alcoholic hepatitis. The evidence from this study is insufficient to support any recommendations regarding the mortality benefit of pentoxifylline in severe alcoholic hepatitis.

Early weight changes after liver transplantation significantly impact patient and graft survival.

Background and aim Associations between pre-liver transplantation (pre-LT) BMI and post-LT survival are well described; however, there are few data assessing the associations between the commonly observed post-LT BMI changes and survival. We investigated the impact of early post-LT BMI change on post-LT patient and graft survival. Methods Using United Network for Organ Sharing data, we identified 2968 adult primary LT recipients who were not overweight pre-LT (BMI >16 to ⩽25 kg/m2), and who had BMI recorded at 2 years post-LT. Delta BMI was defined as the BMI difference between pre-LT and 2 years post LT. Recipients were grouped into three categories: BMI gain (increase by >1 BMI point), BMI loss (decrease by >1 BMI point), and BMI stable (maintained BMI within 1 point). Associations between delta BMI and patient and graft survival were evaluated using Kaplan–Meier and multivariable Cox regression analyses. Results BMI gain was common (54%) and associated with significantly greater 5-year patient and graft survival (90 and 89%, respectively), compared with recipients who had either BMI loss (77 and 74%, respectively, P<0.0001 for both) or were BMI stable (83%, P=0.04 and 82%, P=0.007, respectively). In multivariable analyses, increasing delta BMI was found to be inversely associated with risk for death and graft loss [hazard ratio 0.89 (95% confidence interval 0.86–0.91), P<0.001; and hazard ratio 0.88 (95% confidence interval 0.86–0.91), P<0.001, respectively]. Conclusion This study of a large national liver transplant database demonstrated that post-LT BMI gain was associated with better patient and graft survival, whereas BMI loss was associated with reduced patient and graft survival.