Scott W. Biggins

Hyponatremia and mortality among patients on the liver-transplant waiting list.

BACKGROUND Under the current liver-transplantation policy, donor organs are offered to patients with the highest risk of death. METHODS Using data derived from all adult candidates for primary liver transplantation who were registered with the Organ Procurement and Transplantation Network in 2005 and 2006, we developed and validated a multivariable survival model to predict mortality at 90 days after registration. The predictor variable was the Model for End-Stage Liver Disease (MELD) score with and without the addition of the serum sodium concentration. The MELD score (on a scale of 6 to 40, with higher values indicating more severe disease) is calculated on the basis of the serum bilirubin and creatinine concentrations and the international normalized ratio for the prothrombin time. RESULTS In 2005, there were 6769 registrants, including 1781 who underwent liver transplantation and 422 who died within 90 days after registration on the waiting list. Both the MELD score and the serum sodium concentration were significantly associated with mortality (hazard ratio for death, 1.21 per MELD point and 1.05 per 1-unit decrease in the serum sodium concentration for values between 125 and 140 mmol per liter; P<0.001 for both variables). Furthermore, a significant interaction was found between the MELD score and the serum sodium concentration, indicating that the effect of the serum sodium concentration was greater in patients with a low MELD score. When applied to the data from 2006, when 477 patients died within 3 months after registration on the waiting list, the combination of the MELD score and the serum sodium concentration was considerably higher than the MELD score alone in 32 patients who died (7%). Thus, assignment of priority according to the MELD score combined with the serum sodium concentration might have resulted in transplantation and prevented death. CONCLUSIONS This population-wide study shows that the MELD score and the serum sodium concentration are important predictors of survival among candidates for liver transplantation.

Serum sodium predicts mortality in patients listed for liver transplantation.

With the implementation of the model for end‐stage liver disease (MELD), refractory ascites, a known predictor of mortality in cirrhosis, was removed as a criterion for liver allocation. Because ascites is associated with low serum sodium, we evaluated serum sodium as an independent predictor of mortality in patients with cirrhosis who were listed for liver transplantation and whether the addition of serum sodium to MELD was superior to MELD alone. This is a single‐center retrospective cohort of all adult patients with cirrhosis listed for transplantation from February 27, 2002, to December 26, 2003. Listing laboratories were those nearest the listing date ±2 months. Of the 513 patients meeting inclusion criteria, 341 were still listed, while 172 were removed from the list (105 for transplantation, 56 for death, 11 for other reasons). The median serum sodium and MELD scores were 137 mEq/L (range, 110‐155) and 15 (range, 6‐51), respectively, at listing. Median follow‐up was 201 (range, 1‐662) days. The risk of death with serum sodium < 126 mEq/L at listing or while listed was increased, with hazard ratios of 7.8 (P < .001) and 6.3 (P < .001), respectively, and the association was independent of MELD. The c‐statistics of receiver operating characteristic curves for predicting mortality at 3 months based upon listing MELD with and without listing serum sodium were 0.883 and 0.897, respectively, and at 6 months were 0.871 and 0.905, respectively. In conclusion, serum sodium < 126 mEq/L at listing or while listed for transplantation is a strong independent predictor of mortality. Addition of serum sodium to MELD increases the ability to predict 3‐ and 6‐month mortality in patients with cirrhosis. (HEPATOLOGY 2005;41:32–39.)

Survival Benefit‐Based Deceased‐Donor Liver Allocation

Currently, patients awaiting deceased‐donor liver transplantation are prioritized by medical urgency. Specifically, wait‐listed chronic liver failure patients are sequenced in decreasing order of Model for End‐stage Liver Disease (MELD) score. To maximize lifetime gained through liver transplantation, posttransplant survival should be considered in prioritizing liver waiting list candidates. We evaluate a survival benefit based system for allocating deceased‐donor livers to chronic liver failure patients. Under the proposed system, at the time of offer, the transplant survival benefit score would be computed for each patient active on the waiting list. The proposed score is based on the difference in 5‐year mean lifetime (with vs. without a liver transplant) and accounts for patient and donor characteristics. The rank correlation between benefit score and MELD score is 0.67. There is great overlap in the distribution of benefit scores across MELD categories, since waiting list mortality is significantly affected by several factors. Simulation results indicate that over 2000 life‐years would be saved per year if benefit‐based allocation was implemented. The shortage of donor livers increases the need to maximize the life‐saving capacity of procured livers. Allocation of deceased‐donor livers to chronic liver failure patients would be improved by prioritizing patients by transplant survival benefit.

Survival in infection-related acute-on-chronic liver failure is defined by extrahepatic organ failures

Infections worsen survival in cirrhosis; however, simple predictors of survival in infection‐related acute‐on‐chronic liver failure (I‐ACLF) derived from multicenter studies are required in order to improve prognostication and resource allocation. Using the North American Consortium for Study of End‐stage Liver Disease (NACSELD) database, data from 18 centers were collected for survival analysis of prospectively enrolled cirrhosis patients hospitalized with an infection. We defined organ failures as 1) shock, 2) grade III/IV hepatic encephalopathy (HE), 3) need for dialysis and mechanical ventilation. Determinants of survival with these organ failures were analyzed. In all, 507 patients were included (55 years, 52% hepatitis C virus [HCV], 15.8% nosocomial infection, 96% Child score ≥7) and 30‐day evaluations were available in 453 patients. Urinary tract infection (UTI) (28.5%), and spontaneous bacterial peritonitis (SBP) (22.5%) were the most prevalent infections. During hospitalization, 55.7% developed HE, 17.6% shock, 15.1% required renal replacement, and 15.8% needed ventilation; 23% died within 30 days and 21.6% developed second infections. Admitted patients developed none (38.4%), one (37.3%), two (10.4%), three (10%), or four (4%) organ failures. The 30‐day survival worsened with a higher number of extrahepatic organ failures, none (92%), one (72.6%), two (51.3%), three (36%), and all four (23%). I‐ACLF was defined as ≥2 organ failures given the significant change in survival probability associated at this cutoff. Baseline independent predictors for development of ACLF were nosocomial infections, Model for Endstage Liver Disease (MELD) score, low mean arterial pressure (MAP), and non‐SBP infections. Independent predictors of poor 30‐day survival were I‐ACLF, second infections, and admission values of high MELD, low MAP, high white blood count, and low albumin. Conclusion: Using multicenter study data in hospitalized decompensated infected cirrhosis patients, I‐ACLF defined by the presence of two or more organ failures using simple definitions is predictive of poor survival. (Hepatology 2014;60:250–256)

Impact of Pretransplant Hyponatremia on Outcome Following Liver Transplantation

Hyponatremia is associated with reduced survival in patients with cirrhosis awaiting orthotopic liver transplantation (OLT). However, data are sparse regarding the impact of hyponatremia on outcome following OLT. We investigated the effect of hyponatremia at the time of OLT on mortality and morbidity following the procedure. The study included 2,175 primary OLT recipients between 1990 and 2000. Serum sodium concentrations obtained immediately prior to OLT were correlated with subsequent survival using proportional hazards analysis. Morbidity associated with hyponatremia was assessed, including length of hospitalization, length of intensive care unit (ICU) admission, and occurrence of central pontine myelinolysis (CPM). Out of 2,175 subjects, 1,495 (68.7%) had normal serum sodium (>135 mEq/L) at OLT, whereas mild hyponatremia (125‐134 mEq/L) was present in 615 (28.3%) and severe hyponatremia (<125 mEq/L) in 65 (3.0%). Serum sodium had no impact on survival up to 90 days after OLT (multivariate hazard ratio = 1.00, P = 0.99). Patients with severe hyponatremia tended to have a longer stay in the ICU (median = 4.5 days) and hospital (17.0 days) compared to normonatremic recipients (median ICU stay = 3.0 days, hospital stay = 14.0 days; P = 0.02 and 0.08, respectively). There were 10 subjects that developed CPM, with an overall incidence of 0.5%. Although infrequent, the incidence of CPM did correlate with serum sodium levels (P < 0.01). Conclusion: Pre‐OLT serum sodium does not have a statistically significant impact on survival following OLT. The incidence of CPM correlates with hyponatremia, although its overall incidence is low. Incorporation of serum sodium in organ allocation may not adversely affect the overall post‐OLT outcome. (HEPATOLOGY 2009;49:1610–1615.)

Retransplantation for Hepatitis C: Results of a U.S. Multicenter Retransplant Study

It is widely perceived that outcomes are relatively poor following retransplantation (reTX) for recurrent of hepatitis C virus (HCV) infection. Transplant centers debate the utility of offering another liver to these patients. A U.S. study group was formed to retrospectively compare survival after reTX in patients with recurrent HCV (histologically proven) and those transplanted for other indications greater than 90 days after first transplantation, from 1996 to 2004. Patients were divided into 3 groups; group 1: HCV reTX (n = 43), group 2: non‐HCV reTX (n = 73), and group 3: recurrent HCV but no reTX (n = 156). They were predominantly male, Caucasian, with mean age of 47.2 yr. The commonest indications for non‐HCV reTX were chronic rejection (36%), hepatic artery thrombosis (31%) and recurrent primary sclerosing cholangitis (17%). Duration of hospitalization, number of intensive care unit (ICU) days, and time interval from listing to transplantation or reTX were similar between reTX groups. The 1‐yr and 3‐yr survival rates after reTX were also similar for HCV reTX and non‐HCV reTX groups (1 yr, 69% vs. 73%; 3 yr, 49% vs. 55%). Model for End‐Stage Liver Disease (MELD) scores were not predictive of survival from reTX. However, with a MELD score of >30 in the non HCV group, survival was <50%. In the recurrent HCV not undergoing reTX group, 30% were reevaluated for reTX but only 15% were listed for reTX and the 3‐yr survival was 47%. The most common reasons for not listing for reTX were recurrent HCV within 6 months (22%), fibrosing cholestatic hepatitis (19%), and renal dysfunction (9%). In conclusion, patients retransplanted for recurrent HCV had similar 1‐yr and 3‐yr survival when compared to patients undergoing reTX for other indications. MELD scores were not predictive of post‐reTX survival. Survival was <50% in the non‐HCV reTx group with MELD score of >30. Many patients with recurrent HCV are not considered for reTX and die from recurrent disease. Liver Transpl 13:1246–1253, 2007.

Predictors of endoscopic treatment outcomes in the management of biliary problems after liver transplantation at a high-volume academic center

BACKGROUND Biliary tract problems are the most common complications after liver transplantation. ERCP is increasingly being used to address posttransplantation biliary problems. OBJECTIVE To identify predictors of endoscopic treatment outcomes in the management of post-liver transplantation complications. SETTING AND PATIENTS All adult patients who underwent liver transplantation at the University of California, San Francisco between January 1999 and December 2008 were reviewed. DESIGN A multivariate regression analysis. MAIN OUTCOME MEASUREMENTS Identification of donor and recipient factors as well as technical considerations that predicted success or failure in the endoscopic management of posttransplantation biliary complications. RESULTS In 1062 patients who underwent liver transplantation, there were 224 biliary complications. ERCP was the primary treatment modality and was successful in the majority of patients treated. Patients with biliary complications who had take-back surgery for a nonbiliary indication during the first month after liver transplantation (odds ratio [OR], 0.32; P = .03), particularly for bleeding (OR, 0.18; P = .02), were less likely to respond to endoscopic therapy. Those who received a graft from a donor after cardiac death (OR, 0.15; P = .02) or a living donor (OR, 0.11; P < .01) were also less likely to respond to endoscopic therapy. Take-back surgery for a nonbiliary indication in the first month after liver transplantation was also identified as a novel risk factor for the development of biliary complications (OR, 1.80; P = .02). LIMITATIONS Retrospective design. CONCLUSIONS ERCP can be used to treat the majority of posttransplantation biliary problems. However, endoscopic therapy is less efficacious in the treatment of complications associated with ischemia.

Low, rather than high, body mass index confers increased risk for post‐liver transplant death and graft loss: Risk modulated by model for end‐stage liver disease

With increasing attention being paid to optimizing patient outcomes, it has been proposed that liver transplantation (LT) for individuals with elevated body mass index (BMI) values and high Model for End‐Stage Liver Disease (MELD) scores may adversely affect post‐LT outcomes. We investigated the impact of BMI on post‐LT outcomes in the context of MELD at LT. Using United Network for Organ Sharing data, we identified all adult (≥18 years) primary LT recipients from March 1, 2002 to September 30, 2011. BMI categories included the following: underweight, normal, overweight, class I obese, class II obese, and class III obese (<18.5; 18.5‐24.9; 25‐29.9; 30‐34.9; 35‐39.9; ≥40 kg/m2, respectively). One‐year post‐LT death and graft loss were modeled using Cox regression, including interactions between BMI and MELD. A total of 45,551 adult recipients were identified: 68% male; median (interquartile range [IQR]) age 55 years (IQR, 49‐60 years); MELD, 19 (IQR, 13‐26); and donor risk index, 1.39 (IQR, 1.12‐1.69). Representations in the BMI categories were underweight (n = 863, 2%), normal (n = 13,262, 29%), overweight (n = 16,329, 36%), class I obese (n = 9639, 21%), class II obese (n = 4062, 9%), and class III obese (n = 1396, 3%). In adjusted analyses, elevated BMI was not associated with increased risk for death or graft loss. Among the underweight, there were significant interactions between BMI and MELD with respect to death (P = 0.02) and graft loss (P = 0.01), with significantly increased risks for death (hazard ratio [HR], 1.70; 95% confidence interval [CI], 1.38‐2.09; P = 0.006) and graft loss (HR, 1.45; 95% CI, 1.21‐1.74; P = 0.02) among those with low MELD (≤26), compared to normal BMI recipients with low MELD. In conclusion, overweight and obese LT recipients do not have increased risk of death or graft loss regardless of MELD. Underweight patients are at increased risk for poor outcomes post‐LT, specifically underweight recipients with low MELD have increased risk for death and graft loss. Mechanisms underlying this phenomenon warrant further investigation. Liver Transpl 21:1286‐1294, 2015.

Inequities of the Model for End-Stage Liver Disease: an examination of current components and future additions.

Purpose of reviewThe aim of this article is to examine the limitations of the Model for End-Stage Liver Disease (MELD) components and summarize data on promising new predictor variables. Recent findingsPromising modifications to MELD have been aimed at identifying more accurate measurements of the current MELD components and at improving survival prediction in earlier stages of cirrhosis. Incorporation of new measurements of cholestasis, coagulopathy and renal dysfunction should improve accuracy and reliability of MELD in predicting mortality in end stage liver disease. Direct bilirubin may be a more specific surrogate marker of liver disease than total bilirubin and further investigation of its use in liver mortality risk models in warranted. The recently developed liver-specific international normalized ratio may mitigate thromboplastin-related variation in international normalized ratio measurements. The incorporation of more accurate assessments of renal function into MELD should improve prognostic accuracy and would avert systematic biases associated with serum creatinine. Hepatic venous pressure gradient and serum sodium are promising predictors of liver-related mortality that may warrant further consideration. SummaryModification to MELD, particularly if intended for use in liver transplant allocation, should be based upon objective, reliable, reproducible and readily available predictors; and be able to withstand rigorous model development and validation.

Ascites improves upon plus serum sodium model for end-stage liver disease (MELD) for predicting mortality in patients with advanced liver disease

Background  The clinical impact of ascites has historically been well recognized; however, its value is unclear in the context of current prognostic models.