Trotter, James F.

Background and Aims: Liver transplant is a specialized treatment for a spectrum of indications that use a scarce resource. Transplant is guided by principles of justice, equity, and benefit, with a constant conflict between competing interests. Organs are a national resource with a goal of equitable distribution across sites. An AASLD guideline for the evaluation and selection of appropriate candidates for transplant has been available since 2005. Methods: A multidisciplinary writing group of liver transplant experts and a librarian convened over 24 months. The writing group reviewed the literature, generated guideline recommendations, and rated the level of evidence for each recommendation based on the Oxford Center for Evidence-Based Medicine. The group categorized the strength of recommendations based on the level of evidence, risk-benefit ratio, and patient preferences. Conclusions: Liver transplant is a lifesaving procedure that should be offered to selected patients with clear indications and a reasonable prospect of benefit. The evaluation is designed to identify those in need, to outline hurdles to a successful outcome, and to develop an effective transplant plan. The goal of this document is to provide a template for this process.

Background and Aims Compared to other chronic diseases, patients with chronic liver disease (CLD) have significantly higher inpatient mortality; accurate models to predict inpatient mortality are lacking. Serum lactate (LA) may be elevated in patients with CLD due to both tissue hypoperfusion as well as decreased LA clearance. We hypothesized that a parsimonious model consisting of Model for End‐Stage Liver Disease (MELD) and LA at admission may predict inpatient mortality in patients with CLD. Approach and Results We examined all patients with CLD in two large and diverse health care systems in Texas (North Texas [NTX] and Central Texas [CTX]) between 2010 and 2015. We developed (n = 3,588) and validated (n = 1,804) a model containing MELD and LA measured at the time of hospitalization. We further validated the model in a second cohort of 14 tertiary care hepatology centers that prospectively enrolled nonelective hospitalized patients with cirrhosis (n = 726). MELD‐LA was an excellent predictor of inpatient mortality in development (concordance statistic [C‐statistic] = 0.81, 95% confidence interval [CI] 0.79‐0.82) and both validation cohorts (CTX cohort, C‐statistic = 0.85, 95% CI 0.78‐0.87; multicenter cohort C‐statistic = 0.82, 95% CI 0.74‐0.88). MELD‐LA performed especially well in patients with specific cirrhosis diagnoses (C‐statistic = 0.84, 95% CI 0.81‐0.86) or sepsis (C‐statistic = 0.80, 95% CI 0.78‐0.82). For MELD score 25, inpatient mortality rates were 11.2% (LA = 1 mmol/L), 19.4% (LA = 3 mmol/L), 34.3% (LA = 5 mmol/L), and >50% (LA > 8 mmol/L). A linear increase (P < 0.01) was seen in MELD‐LA and increasing number of organ failures. Overall, use of MELD‐LA improved the risk prediction in 23.5% of patients compared to MELD alone. Conclusions MELD‐LA (bswh.md/meldla) is an early and objective predictor of inpatient mortality and may serve as a model for risk assessment and guide therapeutic options.

Liver transplantation (LT) for alcohol associated hepatitis (AH) remains controversial. We convened a consensus conference to examine various aspects of LT for AH. The goal was not to unequivocally endorse LT for AH; instead, it was to propose recommendations for programs that perform or plan to perform LT for AH. Criteria were established to determine candidacy for LT in the setting of AH and included the following: (1) AH patients presenting for the first time with decompensated liver disease that are nonresponders to medical therapy without severe medical or psychiatric comorbidities; (2) a fixed period of abstinence prior to transplantation is not required; and (3) assessment with a multidisciplinary psychosocial team, including a social worker and an addiction specialist/mental health professional with addiction and transplantation expertise. Supporting factors included lack of repeated unsuccessful attempts at addiction rehabilitation, lack of other substance use/dependency, acceptance of diagnosis/insight with a commitment of the patient/family to sobriety, and formalized agreement to adhere to total alcohol abstinence and counseling. LT should be avoided in AH patients who are likely to spontaneously recover. Short‐term and longterm survival comparable to other indications for LT must be achieved. There should not be further disparity in LT either by indication, geography, or other sociodemographic factors. Treatment of alcohol‐use disorders should be incorporated into pre‐ and post‐LT care. The restrictive and focused evaluation process described in the initial LT experience for AH worldwide may not endure as this indication gains wider acceptance at more LT programs. Transparency in the selection process is crucial and requires the collection of objective data to assess outcomes and minimize center variation in listing. Oversight of program adherence is important to harmonize listing practices and outcomes.

Background and Aims Among patients with cirrhosis awaiting liver transplantation, prediction of wait‐list (WL) mortality is adjudicated by the Model for End Stage Liver Disease–Sodium (MELD‐Na) score. Replacing serum creatinine (SCr) with estimated glomerular filtration rate (eGFR) in the MELD‐Na score may improve prediction of WL mortality, especially for women and highest disease severity. Approach and Results We developed (2014) and validated (2015) a model incorporating eGFR using national data (n = 17,095) to predict WL mortality. Glomerular filtration rate (GFR) was estimated using the GFR assessment in liver disease (GRAIL) developed among patients with cirrhosis. Multivariate Cox proportional hazard analysis models were used to compare the predicted 90‐day WL mortality between MELD‐GRAIL‐Na (re‐estimated bilirubin, international normalized ratio [INR], sodium, and GRAIL) versus MELD‐Na. Within 3 months, 27.8% were transplanted, 4.3% died on the WL, and 4.7% were delisted for other reasons. GFR as estimated by GRAIL (hazard ratio [HR] 0.382, 95% confidence interval [CI] 0.344‐0.424) and the re‐estimated model MELD‐GRAIL‐Na (HR 1.212, 95% CI 1.199‐1.224) were significant predictors of mortality or being delisted on the WL within 3 months. MELD‐GRAIL‐Na was a better predictor of observed mortality at highest deciles of disease severity (≥ 27‐40). For a score of 32 or higher (observed mortality 0.68), predicted mortality was 0.67 (MELD‐GRAIL‐Na) and 0.51 (MELD‐Na). For women, a score of 32 or higher (observed mortality 0.67), the predicted mortality was 0.69 (MELD‐GRAIL‐Na) and 0.55 (MELD‐Na). In 2015, use of MELD‐GRAIL‐Na as compared with MELD‐Na resulted in reclassification of 16.7% (n = 672) of patients on the WL. Conclusion Incorporation of eGFR likely captures true GFR better than SCr, especially among women. Incorporation of MELD‐GRAIL‐Na instead of MELD‐Na may affect outcomes for 12%‐17% awaiting transplant and affect organ allocation.

OBJECTIVES: In a population-based study, we examined time trends in chronic liver disease (CLD)-related hospitalizations in a large and diverse metroplex. METHODS: We examined all CLD-related inpatient encounters (2000–2015) in Dallas–Fort Worth (DFW) using data from the DFW council collaborative that captures claims data from 97% of all hospitalizations in DFW (10.7 million regional patients). RESULTS: There were 83,539 CLD-related hospitalizations in 48,580 unique patients across 84 hospitals. The age and gender standardized annual rate of CLD-related hospitalization increased from 48.9 per 100,000 in 2000 to 125.7 per 100,000 in 2014. Mean age at hospitalization increased from 54.0 (14.1) to 58.5 (13.5) years; the proportion of CLD patients above 65 years increased from 24.2% to 33.1%. HCV-related hospitalizations plateaued, whereas an increase was seen in hospitalizations related to alcohol (9.1 to 22.7 per 100,000) or fatty liver (1.4 per 100,000 to 19.5 per 100,000). The prevalence of medical comorbidities increased for CLD patients: coronary artery disease (4.8% to 14.3%), obesity (2.8% to 14.6%), chronic kidney disease (2.8% to 18.2%), and diabetes (18.0% to 33.2%). Overall hospitalizations with traditional complications of portal hypertension (ascites, varices, and peritonitis) remained stable over time. However, hospitalization with complications related to infection increased from 54.7% to 66.4%, and renal failure increased by sevenfold (2.7% to 19.5%). CONCLUSIONS: CLD-related hospitalizations have increased twofold over the last decade. Hospitalized CLD patients are older and sicker with multiple chronic conditions. Traditional complications of portal hypertension have been superseded by infection and renal failure, warranting a need to redefine what it means to have decompensated CLD.

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.

Abstract Rationale Portopulmonary hypertension (PPHTN) occurs in 6% of liver transplant candidates. The pathogenesis of this complication of portal hypertension is poorly understood. Objectives To identify genetic risk factors for PPHTN in patients with advanced liver disease. Methods We performed a multicenter case-control study of patients with portal hypertension. Cases had a mean pulmonary artery pressure &gt;25 mm Hg, pulmonary vascular resistance &gt;240 dynes·s−1·cm−5, and pulmonary capillary wedge pressure ≤15 mm Hg. Controls had a right ventricular systolic pressure &lt; 40 mm Hg (if estimated) and normal right-sided cardiac morphology by transthoracic echocardiography. We genotyped 1,079 common single nucleotide polymorphisms (SNPs) in 93 candidate genes in each patient. Measurements and Main Results The study sample included 31 cases and 104 controls. Twenty-nine SNPs in 15 candidate genes were associated with the risk of PPHTN (P &lt; 0.05). Multiple SNPs in the genes coding for estrogen receptor 1, aromatase, phosphodiesterase 5, angiopoietin 1, and calcium binding protein A4 were associated with the risk of PPHTN. The biological relevance of one of the aromatase SNPs was supported by an association with plasma estradiol levels. Conclusions Genetic variation in estrogen signaling and cell growth regulators is associated with the risk of PPHTN. These biologic pathways may elucidate the mechanism for the development of PPHTN in certain patients with severe liver disease.