Carl L. Berg

Liver and Intestine Transplantation in the United States 1998–2007

Liver transplantation numbers in the United States remained constant from 2004 to 2007, while the number of waiting list candidates has trended down. In 2007, the waiting list was at its smallest since 1999, with adults ≥50 years representing the majority of candidates. Noncholestatic cirrhosis was most commonly diagnosed. Most age groups had decreased waiting list death rates; however, children <1 year had the highest death rate. Use of liver allografts from donation after cardiac death (DCD) donors increased in 2007. Model for end‐stage liver disease (MELD)/pediatric model for end‐stage liver disease (PELD) scores have changed very little since 2002, with MELD/PELD <15 accounting for 75% of the waiting list. Over the same period, the number of transplants for MELD/PELD <15 decreased from 16.4% to 9.8%. Hepatocellular carcinoma exceptions increased slightly. The intestine transplantation waiting list decreased from 2006, with the majority of candidates being children <5 years old. Death rates improved, but remain unacceptably high. Policy changes have been implemented to improve allocation and recovery of intestine grafts to positively impact mortality. In addition to evaluating trends in liver and intestine transplantation, we review in depth, issues related to organ acceptance rates, DCD, living donor transplantation and MELD/PELD exceptions.

Identification of a human heme exporter that is essential for erythropoiesis

FLVCR, a member of the major facilitator superfamily of transporter proteins, is the cell surface receptor for feline leukemia virus, subgroup C. Retroviral interference with FLVCR display results in a loss of erythroid progenitors (colony-forming units-erythroid, CFU-E) and severe anemia in cats. In this report, we demonstrate that human FLVCR exports cytoplasmic heme and hypothesize that human FLVCR is required on developing erythroid cells to protect them from heme toxicity. Inhibition of FLVCR in K562 cells decreases heme export, impairs their erythroid maturation and leads to apoptosis. FLVCR is upregulated on CFU-E, indicating that heme export is important in primary cells at this stage. Studies of FLVCR expression in cell lines suggest this exporter also impacts heme trafficking in intestine and liver. To our knowledge, this is the first description of a mammalian heme transporter.

Coagulopathy does not fully protect hospitalized cirrhosis patients from peripheral venous thromboembolism

OBJECTIVE:Despite the endogenous coagulopathy of cirrhosis, some patients with cirrhosis experience thrombophilic states. This study aims to determine the incidence and predictors of venous thromboembolism (VTE), such as deep vein thrombosis (DVT) and pulmonary embolism, in hospitalized patients with cirrhosis.METHODS:A retrospective case-control study was performed in a tertiary-care teaching hospital over an 8-yr period. A total of 113 hospitalized patients with cirrhosis with a documented new VTE were compared to controls. Risk factors for VTE were determined using univariate and multivariate statistical analyses.RESULTS:Approximately 0.5% of all hospitalized patients with cirrhosis had a VTE. Traditional markers of coagulation such as INR and platelet count were not predictive of VTE. In the univariate analysis, serum albumin level was significantly lower in cases than controls (2.85 vs. 3.10 g/dL, respectively, p = 0.01). In the multivariate analysis, serum albumin remained independently predictive of VTE, with an odds ratio of 0.25 (95% CI 0.10–0.56).CONCLUSIONS:Approximately 0.5% of admissions involving cirrhosis patients resulted in a new thromboembolic event. Low serum albumin was strongly predictive of increased risk for developing VTE, independent of international normalized ratio or platelet count. Serum albumin deficiency may indicate low levels of endogenous anticoagulants.

Model for End-Stage Liver Disease (MELD) Predicts Nontransplant Surgical Mortality in Patients With Cirrhosis

Objective:We sought to determine the ability of the Model for End-Stage Liver Disease (MELD) score to predict 30-day postoperative mortality for patients with cirrhosis undergoing nontransplant surgical procedures. Summary Background Data:The Child-Pugh class historically has been used by clinicians to assist in management decisions involving patients with cirrhosis. However, this classification scheme has a number of limitations. Recently, MELD was introduced. It has been shown to be highly predictive of mortality in a variety of clinical scenarios. Methods:Adult patients with a diagnosis of cirrhosis undergoing nontransplant surgical procedures between January 1, 1996, and January 1, 2002, at a single center were analyzed. The preoperative MELD score was calculated for all patients, and the MELDs performance in predicting 30-day mortality was determined using multivariate regression techniques. Results:A total of 140 surgical procedures were identified and analyzed. The 30-day mortality rate was 16.4%. The mean admission MELD score for the patients who died (23.3, 95% confidence interval 19.6–27.0) was significantly different from those patients surviving beyond 30 days (16.9, 15.6–18.2), P = 0.0003. The c-statistic for MELD score predicting 30-day mortality was 0.72. Further subgroup analysis of 67 intra-abdominal surgeries showed an in-hospital mortality of 23.9%. The mean MELD score for patients dying (24.8, 20.4–29.3) was significantly different from survivors (16.2, 14.2–18.2), P = 0.0001. The c-statistic for this subgroup was 0.80. Conclusions:The MELD score, as an objective scale of disease severity in patients with cirrhosis, shows promise as being a useful preoperative predictor of surgical mortality risk.

Hepatocellular carcinoma recurrence and death following living and deceased donor liver transplantation

We examined mortality and recurrence of hepatocellular carcinoma (HCC) among 106 transplant candidates with cirrhosis and HCC who had a potential living donor evaluated between January 1998 and February 2003 at the nine centers participating in the Adult‐to‐Adult Living Donor Liver Transplantation Cohort Study (A2ALL). Cox regression models were fitted to compare time from donor evaluation and time from transplant to death or HCC recurrence between 58 living donor liver transplant (LDLT) and 34 deceased donor liver transplant (DDLT) recipients. Mean age and calculated Model for End‐Stage Liver Disease (MELD) scores at transplant were similar between LDLT and DDLT recipients (age: 55 vs. 52 years, p = 0.21; MELD: 13 vs. 15, p = 0.08). Relative to DDLT recipients, LDLT recipients had a shorter time from listing to transplant (mean 160 vs. 469 days, p < 0.0001) and a higher rate of HCC recurrence within 3 years than DDLT recipients (29% vs. 0%, p = 0.002), but there was no difference in mortality or the combined outcome of mortality or recurrence. LDLT recipients had lower relative mortality risk than patients who did not undergo LDLT after the center had more experience (p = 0.03). Enthusiasm for LDLT as HCC treatment is dampened by higher HCC recurrence compared to DDLT.

Outcomes of liver transplant recipients with hepatitis C and human immunodeficiency virus coinfection

Hepatitis C virus (HCV) is a controversial indication for liver transplantation (LT) in human immunodeficiency virus (HIV)–infected patients because of reportedly poor outcomes. This prospective, multicenter US cohort study compared patient and graft survival for 89 HCV/HIV‐coinfected patients and 2 control groups: 235 HCV‐monoinfected LT controls and all US transplant recipients who were 65 years old or older. The 3‐year patient and graft survival rates were 60% [95% confidence interval (CI) = 47%‐71%] and 53% (95% CI = 40%‐64%) for the HCV/HIV patients and 79% (95% CI = 72%‐84%) and 74% (95% CI = 66%‐79%) for the HCV‐infected recipients (P < 0.001 for both), and HIV infection was the only factor significantly associated with reduced patient and graft survival. Among the HCV/HIV patients, older donor age [hazard ratio (HR) = 1.3 per decade], combined kidney‐liver transplantation (HR = 3.8), an anti‐HCV–positive donor (HR = 2.5), and a body mass index < 21 kg/m2 (HR = 3.2) were independent predictors of graft loss. For the patients without the last 3 factors, the patient and graft survival rates were similar to those for US LT recipients. The 3‐year incidence of treated acute rejection was 1.6‐fold higher for the HCV/HIV patients versus the HCV patients (39% versus 24%, log rank P = 0.02), but the cumulative rates of severe HCV disease at 3 years were not significantly different (29% versus 23%, P = 0.21). In conclusion, patient and graft survival rates are lower for HCV/HIV‐coinfected LT patients versus HCV‐monoinfected LT patients. Importantly, the rates of treated acute rejection (but not the rates of HCV disease severity) are significantly higher for HCV/HIV‐coinfected recipients versus HCV‐infected recipients. Our results indicate that HCV per se is not a contraindication to LT in HIV patients, but recipient and donor selection and the management of acute rejection strongly influence outcomes. Liver Transpl 18:716–726, 2012.

Hypercoagulation and thrombophilia in liver disease

Summary.  A complex balance exists between endogenous procoagulants and the anticoagulant system in liver disease patients. Hypercoagulable events occur in cirrhosis patients despite the well‐known bleeding diathesis of liver disease. These events may be clinically evident, such as in portal vein thrombosis or pulmonary embolism, but these conditions may also be a silent contributor to certain disease states, such as portopulmonary hypertension or parenchymal extinction with liver atrophy as well as thrombosis of extracorporeal circuits in dialysis or liver assist devices. Moreover, liver disease‐related hypercoagulability may contribute to vascular disease in the increasingly common condition of non‐alcoholic fatty liver disease. Despite the incidence of these problems, there are few widely accessible and practical laboratory tests to evaluate the risk of a hypercoagulable event in cirrhosis patients. Furthermore, there is little research on the use of commonly accepted anticoagulants in patients with liver disease. This article is a result of an international symposium on coagulation disorders in liver disease and addresses several areas of specific interest in hypercoagulation in liver disease. Critical areas lacking clinical information are highlighted and future areas of research interest are defined with an aim to foster clinical research in this field.

Unresectable Cholangiocarcinoma: Comparison of Survival in Biliary Stenting Alone Versus Stenting With Photodynamic Therapy

BACKGROUND & AIMS Photodynamic therapy (PDT) for unresectable cholangiocarcinoma is associated with improvement in cholestasis, quality of life, and potentially survival. We compared survival in patients with unresectable cholangiocarcinoma undergoing endoscopic retrograde cholangiopancreatography (ERCP) with PDT and stent placement with a group undergoing ERCP with stent placement alone. METHODS Forty-eight patients were palliated for unresectable cholangiocarcinoma during a 5-year period. Nineteen were treated with PDT and stents; 29 patients treated with biliary stents alone served as a control group. Multivariate analysis was performed by using Model for End-Stage Liver Disease score, age, treatment by chemotherapy or radiation, and number of ERCP procedures and PDT sessions to detect predictors of survival. RESULTS Kaplan-Meier analysis demonstrated improved survival in the PDT group compared with the stent only group (16.2 vs 7.4 months, P<.004). Mortality in the PDT group at 3, 6, and 12 months was 0%, 16%, and 56%, respectively. The corresponding mortality in the stent group was 28%, 52%, and 82%, respectively. The difference between the 2 groups was significant at 3 months and 6 months but not at 12 months. Only the number of ERCP procedures and number of PDT sessions were significant on multivariate analysis. Adverse events specific to PDT included 3 patients with skin phototoxicity requiring topical therapy only. CONCLUSIONS ERCP with PDT seems to increase survival in patients with unresectable cholangiocarcinoma when compared with ERCP alone. It remains to be proved whether this effect is attributable to PDT or the number of ERCP sessions. A prospective randomized multicenter study is required to confirm these data.

Liver transplant recipient survival benefit with living donation in the model for endstage liver disease allocation era

Receipt of a living donor liver transplant (LDLT) has been associated with improved survival compared with waiting for a deceased donor liver transplant (DDLT). However, the survival benefit of liver transplant has been questioned for candidates with Model for Endstage Liver Disease (MELD) scores <15, and the survival advantage of LDLT has not been demonstrated during the MELD allocation era, especially for low MELD patients. Transplant candidates enrolled in the Adult‐to‐Adult Living Donor Liver Transplantation Cohort Study after February 28, 2002 were followed for a median of 4.6 years. Starting at the time of presentation of the first potential living donor, mortality for LDLT recipients was compared to mortality for patients who remained on the waiting list or received DDLT (no LDLT group) according to categories of MELD score (<15 or ≥15) and diagnosis of hepatocellular carcinoma (HCC). Of 868 potential LDLT recipients (453 with MELD <15; 415 with MELD ≥15 at entry), 712 underwent transplantation (406 LDLT; 306 DDLT), 83 died without transplant, and 73 were alive without transplant at last follow‐up. Overall, LDLT recipients had 56% lower mortality (hazard ratio [HR] = 0.44, 95% confidence interval [CI] 0.32‐0.60; P < 0.0001). Among candidates without HCC, mortality benefit was seen both with MELD <15 (HR = 0.39; P = 0.0003) and MELD ≥15 (HR = 0.42; P = 0.0006). Among candidates with HCC, a benefit of LDLT was not seen for MELD <15 (HR = 0.82, P = 0.65) but was seen for MELD ≥15 (HR = 0.29, P = 0.043). Conclusion: Across the range of MELD scores, patients without HCC derived a significant survival benefit when undergoing LDLT rather than waiting for DDLT in the MELD liver allocation era. Low MELD candidates with HCC may not benefit from LDLT. (HEPATOLOGY 2011;54:1313–1321)

Excess mortality on the liver transplant waiting list: Unintended policy consequences and model for End‐Stage Liver Disease (MELD) inflation

The Model for End‐Stage Liver Disease (MELD) allocation system for liver transplantation provides “exceptions” for diseases such as hepatocellular carcinoma (HCC). It was the aim of this study to assess equipoise between exception candidates and nonexception candidates on the waiting list and to assess if the exception system contributes to steadily increasing regional MELD at transplant. In all, 78,595 adult liver transplant candidates between January 2005 and December 2012 were analyzed. Yearly trends in waiting list characteristics and transplantation rates were analyzed for statistical association with MELD exceptions. Regional variations in these associations and the effect of exceptions on regional MELD scores at transplant were also analyzed. 27.29% of the waiting list was occupied by candidates with exceptions. Candidates with exceptions fared much better on the waiting list compared to those without exceptions in mean days waiting (HCC 237 versus non‐HCC 426), transplantation rates (HCC 79.05% versus non‐HCC 40.60%), and waiting list death rates (HCC 4.49% versus non‐HCC 24.63%). Strong regional variation in exception use occurred but exceptions were highly correlated with waiting list death rates, transplantation rates, and MELD score at removal in all regions. In a multivariate model predicting MELD score at transplant within regions, the percentage of HCC MELD exceptions was the strongest independent predictor of regional MELD score at transplant. Conclusion: Liver transplant candidates with MELD exceptions have superior outcomes compared to nonexception candidates and the current MELD exception system is largely responsible for steadily increasing MELD scores at transplant independent of geography. (Hepatology 2015;61:285–291)