Barry Schlansky

Waiting time predicts survival after liver transplantation for hepatocellular carcinoma: A cohort study using the United Network for Organ Sharing registry

Recipients of liver transplantation (LT) for hepatocellular carcinoma (HCC) have an 8% to 20% risk of HCC recurrence. Single‐center studies suggest that a period of waiting after HCC therapy may facilitate the selection of patients at low risk for post‐LT HCC recurrence and mortality. We evaluated whether a longer waiting time after Model for End‐Stage Liver Disease (MELD) prioritization for HCC predicts longer post‐LT survival. From the United Network for Organ Sharing registry, we selected 2 groups registered for LT between March 2005 and March 2009: (1) HCC patients receiving MELD prioritization and (2) non‐HCC patients. Patients were stratified by their MELD status at LT (a marker of time on the wait list after HCC MELD prioritization) and were followed from LT until death or censoring through October 2012. By comparing post‐LT survival to intention‐to‐treat (ITT) survival from registration, we assessed predictors of post‐LT survival and estimated the benefit of LT. The median MELD scores at LT were 22 (HCC) and 24 (non‐HCC). A higher MELD score at LT was independently associated with lower post‐LT mortality in the HCC group [hazard ratio (HR) = 0.84, 95% confidence interval (CI) = 0.73‐0.98] and higher post‐LT mortality in the non‐HCC group (HR = 1.20, 95% CI = 1.15‐1.25). Compared with the HCC group, the non‐HCC group had lower post‐LT mortality [relative risk (RR) = 0.85, log‐rank P < 0.01] but higher ITT mortality (RR = 1.25, log‐rank P < 0.01) because of a 33 percentage point lower probability of undergoing LT. In conclusion, a longer waiting time before LT for HCC predicted longer post‐LT survival in a national transplant registry. Delaying LT for HCC may reduce disparities in ITT survival and access to LT among different indications and thereby improve system utility and organ allocation equity for the overall pool of LT candidates. Liver Transpl 20:1045–1056, 2014.

Higher Mortality and Survival Benefit in Obese Patients Awaiting Liver Transplantation.

Background Over 85% of US centers adhere to practice guidelines that consider morbid obesity to be a contraindication to liver transplantation (LT). The relationship of morbid obesity with LT outcomes and survival benefit in the current era is unknown. Methods We investigated the association of body mass index with waitlist and post-LT outcomes, and survival benefit, using the United Network for Organ Sharing registry. We categorized body mass index as follows: 18.5 to 29.9 kg/m2, normal/overweight; 30 to 34.9 kg/m2, obese; 35 to 39.9 kg/m2, severely obese; and ≥40 kg/m2, morbidly obese, and evaluated waitlist outcomes using competing risk regression and post-LT outcomes and survival benefit using Cox regression. Results 3.9% of 80 221 waitlisted and 3.5% of 38 177 transplanted patients were morbidly obese. Waitlist mortality was higher for morbidly obese than normal/overweight patients (subdistribution hazard ratio, 1.16; 95% confidence interval [CI]:1.08-1.26), but post-LT mortality and graft failure were comparable (hazard ratio [HR], 1.01; 95% CI, 0.86-1.19; and HR, 1.15; 95% CI, 0.95-1.40). Morbidly obese patients also benefited more from LT (88% mortality reduction vs 80% for normal/overweight). Morbid obesity predicted higher post-LT mortality before 2007 (HR, 1.18; 95% CI, 1.04-1.34), but not afterward (HR, 0.98; 95% CI, 0.81-1.18). Conclusions Morbid obesity is associated with higher mortality on the LT waitlist, but no longer predicts inferior outcomes after LT. Morbidly obese patients should be considered potential candidates for LT.

Guideline adherence and outcomes in esophageal variceal hemorrhage: comparison of tertiary care and non-tertiary care settings.

Background: Implementation of consensus guidelines for esophageal variceal hemorrhage yields improved outcomes. We evaluated guideline adherence and outcomes after variceal hemorrhage at a university hospital (UH) and a staff-model health maintenance organization (HMO). Study: Factors associated with short-term bleeding, infection, and death were retrospectively identified in UH (n=160) and HMO (n=123) patients with esophageal variceal hemorrhage from January 2000 to December 2006. A second analysis of factors associated with long-term rebleeding was conducted in patients who survived ≥14 days without rebleeding. Results: UH patients were younger, with more severe liver disease and overall illness (P<0.01). UH patients more often received vasoactive agents and prophylactic antibiotics (P<0.01), however the rate of endoscopic therapy did not differ. Infections at 14-days were similar (18.2% vs. 13.0%, P=0.25), but UH patients had greater in-hospital rebleeding (16.4% vs. 5.7%, P<0.01) and mortality (15.2% vs. 4.1%, P<0.01). Poor liver function and overall illness predicted infection, rebleeding, and death (adjusted odds ratio 2.75 to 13.39). Long-term rebleeding occurred in 36.1% of UH patients and 25.9% of HMO patients. Secondary prophylaxis reduced late rebleeding (hazard ratio 0.37 to 0.41). Poor liver function did not predict late rebleeding. Adherence to secondary prophylaxis was greater at the HMO (P<0.05), but late rebleeding did not differ (36% vs. 26%, P=0.13). Conclusions: Irrespective of practice setting, poor liver function and critical illness predicted short-term bleeding, infection, and death after esophageal variceal hemorrhage, and secondary prophylaxis prevented long-term rebleeding. Differing guideline adherence did not influence outcomes between tertiary care and non-tertiary care centers.

Implications of expanded medicaid eligibility for patient outcomes after liver transplantation: Caveat emptor

Since passage of the Social Security Amendments in 1965, Medicaid has functioned as the primary source of health insurance for low-income Americans. The Patient Protection and Affordable Care Act (ACA) of 2010 placed a significant focus on Medicaid, changing it from a disability care program to an early intervention, prevention-based program and recommending an expansion in Medicaid eligibility to adults with incomes at or below 138% of the federal poverty line (

Comparative Effectiveness of Medical Therapies for Severe Alcoholic Hepatitis: Guidance at Last?

16,242 for an individual or

The Braden Scale, a standard tool for assessing pressure ulcer risk, predicts early outcomes after liver transplantation

33,465 for a family of 4 in 2016). However, the Supreme Court ruled in National Federation of Independent Business v. Sebelius that Medicaid expansion was optional for the states, and 25 states opted out when the law was implemented in January 2014. As of publication, nearly 3 million people in nonexpansion states are both ineligible for Medicaid and below the minimum income requirements for subsidized private insurance, a “coverage gap” representing over half of uninsured Americans that disproportionately affects racial and ethnic minorities. In this issue of Liver Transplantation, Tumin et al. report a study of the effect of Medicaid expansion on health insurance coverage after liver transplantation (LT). The authors used a difference-in-difference (DID) approach to estimate the time-dependent change in post-LT Medicaid enrollment or loss of insurance in patients who were insured at the time of LT, according to residence in a Medicaid expansion or nonexpansion state. DID is a methodological tool common in social sciences research that compares the risk of an outcome in persons exposed to a health policy with the risk in persons excluded from the policy, after first confirming that both groups had the same baseline risk before the policy was enacted. DID methodology evaluates the effect of a health policy by controlling for background changes (secular trends) in the outcome that occur over time. The post-LT setting is a lens for understanding the impact of Medicaid expansion in a highly selected population with complex medical needs. LT is a specialized and expensive procedure that is rarely available to uninsured patients because (1) insurance coverage is generally required to finance the transplant and (2) uninsured status or an inability to pay for post-LT care, established risk factors for nonadherence to immunosuppressant medications, missed clinic appointments, and allograft rejection, are exclusions for LT eligibility. Historically, less than 1% of US solid organ transplants have been performed for uninsured patients. In the present study, a similarly low proportion of patients undergoing LT before Medicaid expansion were uninsured at the time of LT. Medicaid expansion surprisingly did not reduce insurance loss in the post-LT period, despite pervasive longterm unemployment after LT (75% at 2 years in a recent study), a presumptive risk factor for losing employer-sponsored commercial insurance. The low incidence of post-LT insurance loss may have masked a risk difference if the effect size were small, as only 1% of patients were uninsured through 3 years of post-LT follow-up. Alternatively, this result might be explained by a concurrent rise in non-Medicaid insurance enrollment, driven by ACA provisions such as the prohibition on exclusion for preexisting medical conditions, the individual insurance mandate, or the availability of subsidies for private insurance. The low incidence of insurance loss in LT recipients also might reflect the rigor of transplant Abbreviations: ACA, Patient Protection and Affordable Care Act; DID, difference-in-difference; LT, liver transplantation.

Promise and Pitfalls of Using α-Fetoprotein in Liver Transplantation Allocation for Hepatocellular Carcinoma

76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 Sby progressive inflammatory injury to hepatocytes and associated liver failure arising from prolonged, heavy alcohol consumption. The diagnosis carries a 1-month mortality of 30%–60%, which is particularly striking because severe alcoholic hepatitis disproportionally affects young and otherwise healthy individuals. The burden of illness seems to be increasing in several countries worldwide and the economic impact is significant, both from the perspectives of the health care system and society at large. Although several pharmacologic agents and combinations of agents have demonstrated a mortality benefit for severe alcoholic hepatitis in randomized clinical trials, their efficacy relative to one another is unknown because head-to-head trials have been infeasible. In this issue of Gastroenterology, Singh et al report a comprehensive meta-analysis of pharmacotherapies for severe alcoholic hepatitis that employs a novel, “network” approach to estimate the relative efficacy of drug regimens that were not directly compared in individual trials. Network meta-analysis methodology incorporates both conventional (direct) meta-analysis and indirect comparisons based on the transitive property (if A 1⁄4 B, and B 1⁄4 C, then A 1⁄4 C) to compare and rank interventions for a common outcome. The network meta-analysis provides a methodologic tool to evaluate comparative effectiveness in an area where clinical equipoise and major research gaps exist. Although meta-analyses of randomized, clinical trials are widely acknowledged to offer the strongest support for evidence-based decision making, the validity of the results is largely dependent on the included studies. One must ask, “Is the whole greater than the sum of its parts?” In this study, 8 of 10 trials of corticosteroids versus placebo were performed >15 years ago, whereas most trials of the other interventions were completed within the last decade. The standard of care for severe alcoholic hepatitis has changed dramatically over time, and the inclusion of studies with historic death rates may overestimate the present-day mortality risk. Moderate to high study heterogeneity in the outcomes was also identified for several interventions. Finally, although the quality of evidence was similar for the various interventions, the quality of evidence was judged to be “low” or “very low” for the majority. To their credit, the authors rigorously adhered to established guidelines for the conduct of network meta-analysis, and performed robust

Portal Biliopathy Causing Recurrent Biliary Obstruction and Hemobilia

The Braden Scale is a standardized tool to assess pressure ulcer risk that is reported for all hospitalized patients in the United States per requirements of the Center for Medicare and Medicaid Services. Previous data have shown the Braden Scale can predict both frailty and mortality risk in patients with decompensated cirrhosis. Our aim was to evaluate the association of the Braden Scale score with short‐term outcomes after liver transplantation (LT). We performed a retrospective cohort study of deceased donor LT recipients at 2 centers and categorized them according to the Braden Scale at hospital admission as low (>18), moderate (16‐18), or high risk (<16) for pressure ulcer. We created logistic and Poisson multiple regression models to evaluate the association of Braden Scale category with in‐hospital and 90‐day mortality, length of stay (LOS), nonambulatory status at discharge, and discharge to a rehabilitation facility. Of 341 patients studied, 213 (62.5%) were low risk, 59 (17.3%) were moderate risk, and 69 (20.2%) were high risk. Moderate‐ and high‐risk patients had a greater likelihood for prolonged LOS, nonambulatory status, and discharge to a rehabilitation facility, as compared with low‐risk patients. High‐risk patients additionally had increased risk for in‐hospital and 90‐day mortality after LT. Multiple regression modeling demonstrated that high‐risk Braden Scale score was associated with prolonged LOS (IRR, 1.56; 95% confidence interval [CI], 1.47‐1.65), nonambulatory status at discharge (odds ratio [OR], 4.15; 95% CI, 1.77‐9.71), and discharge to a rehabilitation facility (OR, 5.51; 95% CI, 2.57‐11.80). In conclusion, the Braden Scale, which is currently assessed in all hospitalized patients in the United States, independently predicted early disability‐related outcomes and greater LOS after LT. Liver Transplantation 23 1153–1160 2017 AASLD.

Influence of spontaneous splenorenal shunts on clinical outcomes in decompensated cirrhosis and after liver transplantation

Serum α-fetoprotein (AFP) testing is no longer recommended for hepatocellular carcinoma (HCC) screening or diagnosis.1 However, AFP remains a valuable tool to monitor treatment response in the 60% to 75% of patients with AFP-producing tumors,1-3 and as a prognostic marker for recurrence after a liver transplant (LT).4-6 Although low or decreasing AFP levels at the time of LT predict a lower risk of recurrence, studies have not distinguished HCCs with low AFP levels as a result of cancer treatment from HCCs that do not produce AFP. Thus, it is uncertain whether conventional predictors of recurrence of HCC after LT extend to the subgroup of non-AFP–producing tumors, or whether the lack of AFP production indicates a distinct cancer behavior and prognosis. In this issue of JAMA Surgery, Agopian et al7 report the outcomes of patients with HCC who are known to have normal AFP levels for their entire period on the liver transplantation waitlist. Risk factors for recurrence of HCC after LT in patients with non-AFP–producing tumors reaffirmed those previously reported for patients with HCC, in general, including increasing size/number of tumors and vascular invasion, with a few exceptions (poor histologic differentiation and receipt of liver-directed treatment were not predictive). About one-third of patients with HCC who underwent LT had nonAFP–producing tumors, and this group had less frequent explant vascular invasions or poor differentiation and higher overall and recurrence-free survival rates compared with patients with AFP-producing tumors. However, the analysis cannot confirm that AFP production signifies a more aggressive cancer, which is prone to unfavorable outcomes, because the patients with non-AFP– producing tumors and the patients with AFP-producing tumors were not directly compared with adjustment for important confounders. The patients with non-AFP–producing tumors underwent more liver-directed treatment sessions and combined modality treatments, which could explain their less advanced explant HCCs and, consequently, their lower risk of recurrence after LT, rather than the absence of AFP independently predicting these outcomes. The comparison of explant outcomes is also problematic because no validated method exists to pathologically assess HCC after liverdirected treatment. The notion that non-AFP–producing tumors represent an indolent cancer phenotype would be strengthened by showing a consistent association between the absence of AFP and a less advanced explant pathology, with adjustment for confounders in the roughly 25% of patients with HCC who had not received liver-directed treatment. Despite these uncertainties, the study by Agopian et al7 provides a novel epidemiologic account of an understudied but not uncommon HCC variant and raises the question as to what is the most efficient and ethical strategy for allocating organs to patients with HCC. Evidence supports a role for AFP in identifying patients with a poor prognosis after LT, but it remains elusive how to incorporate AFP status into liver allocation policy, which prioritizes patients by medical urgency (risk of death or dropout). The recently implemented 6-month delay for the prioritization of LT recipients with HCC by use of the Model for End-Stage Liver Disease allocation system serves a function similar to that of AFP status, excluding patients likely to have poor outcomes after LT (aggressive cancers more often progress, and the patients drop off the waitlist during the delay), but its primary intent is to equalize dropout risks for HCC and non-HCC indications, conforming to urgency-based allocation. Adding an LT exclusion based on AFP status to the 6-month delay could disrupt this balance and overly disadvantage patients with HCC who most urgently need an LT, but it might be acceptable using a threshold that prevents futile transplants—an AFP level of 1000 ng/mL (to convert to micrograms per liter, multiply by 1.0) at the time of LT was recently proposed, based on a nearly 50% recurrence risk with higher values.6 As the incidence of HCC surges despite a relatively fixed donor pool, the inclusion of AFP status into the allocation policy could facilitate the redistribution of scarce organs to patients with or without HCC likely to benefit the most.

Bleeding ‘downhill’ esophageal varices associated with benign superior vena cava obstruction: case report and literature review

A 63-year-old man with extrahepatic portal vein thrombosis presented with biliary obstruction and hemobilia after a liver biopsy. Balloon sweep of the common bile duct removed clotted blood, and cholangiogram showed a common bile duct narrowing, treated with biliary stenting. A percutaneous biliary catheter was later required for recurrent biliary obstruction and hemobilia, and repeat cholangiogram confirmed portal biliopathy—a large peri-biliary varix was compressing the common bile duct, causing biliary obstruction and intermittent portal hypertensive hemobilia. A transjugular intrahepatic portosystemic shunt was inserted, followed by embolization of the peri-biliary varix. Delayed diagnosis of portal biliopathy may lead to significant patient morbidity.