Alexandru I. Musat

The Significance of Donor-Specific HLA Antibodies in Rejection and Ductopenia Development in ABO Compatible Liver Transplantation

The role of humoral alloreactivity in ABO‐compatible liver transplantation remains unclear. To understand the significance of donor‐specific HLA alloantibodies (DSA) in liver rejection, we applied the currently used strategy for detection of antibody‐mediated rejection of other solid allografts. For this purpose we reviewed the data on 43 recipients of ABO identical/compatible donor livers who had indication liver biopsy stained for complement element C4d and contemporaneous circulating DSA determination. Seventeen (40%) patients had significant circulating DSA in association with diffuse portal C4d deposition (DSA+/diffuse C4d+). These DSA+/diffuse C4d+ subjects had higher frequency of acute cellular rejection (ACR) 15/17 versus 13/26 (88% vs. 50%), p = 0.02, and steroid resistant rejection 7/17 versus 5/26 (41% vs. 19%), p = 0.03. Based on detection of the combination DSA+/diffuse C4d+, 53.6% of cases of ACR had evidence of concurrent humoral alloreactivity. Six of the 10 patients with ductopenic rejection had circulating DSA and diffuse portal C4d, three of whom (2 early and 1 late posttransplantation) developed unrelenting cholestasis, necessitating specific antibody‐depleting therapy to salvage the allografts. Thus, in ABO‐compatible liver transplantation humoral alloreactivity mediated by antibodies against donor HLA molecules appears to be frequently intertwined with cellular mechanisms of rejection, and to play a role in ductopenia development.

Liver transplantation for HELLP syndrome

Hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome is a rare complication of pregnancy that is associated with preeclampsia and may result in rupture of the liver. Although there have been case reports of liver transplantation for HELLP syndrome, the outcomes of transplantation for this rare indication have not been reported. Furthermore, the optimal management of complicated HELLP syndrome and indications for liver transplantation are unclear. Our objective was to review the national experience with liver transplantation for HELLP syndrome and to develop a comprehensive algorithm for the management of liver complications of HELLP syndrome, including indications for transplantation. A recent case from our institution is reported and the literature is reviewed. The results of liver transplantation for HELLP syndrome were analyzed from the United Network for Organ Sharing database. Between October 1987 and November 2003 there have been 8 deceased donor liver transplants performed for complications related to HELLP syndrome. As of the most recent follow‐up, 6 of the 8 patients are alive, with both deaths occurring within 1 month of transplantation, and 2 patients have required retransplantation. This review supports that good results can be obtained with liver transplantation for patients with complicated HELLP syndrome that have either ongoing, uncontrolled hemorrhage or liver necrosis and failure. Patients with complicated HELLP syndrome are best managed at a center with expertise in liver transplantation. (Liver Transpl 2005;11:224‐228.)

COMPLICATIONS ASSOCIATED WITH LIVER TRANSPLANTATION IN THE OBESE RECIPIENT

The prevalence of the metabolic syndrome with attendant morbid obesity continues to increase nationwide. A concomitant increase in non‐alcoholic steatohepatitis (NASH) and associated end‐stage liver disease requiring transplantation is expected to parallel this trend. Between January 1, 1997 and December 31, 2008, our center performed 813 solitary adult deceased‐donor liver transplants. Patients were divided into groups based on the World Health Organization International Classification of obesity. Patients within each obesity class were compared to normal weight recipients. Preoperative demographics among all groups were similar. NASH was more common in higher BMI groups. Operative time, blood product usage, ICU length of stay, infectious complications, and biliary complications requiring intervention were all higher in obese recipients. Deep venous thrombosis occurred more commonly in patients with Class III obesity. Patients with Class II obesity had lower patient (HR 1.82, CI 1.09–3.01, p = 0.02) and allograft survival (HR 1.62, CI 1.02–2.65, p = 0.04). Obesity class did not reach statistical significance on multivariate analysis. Despite increased technical operative challenges and medical complexities associated with increasing recipient BMI, morbid obesity in and of itself should not be an absolute contraindication to liver transplantation as these patients have reasonable long‐term outcomes.

Treatment with sildenafil and treprostinil allows successful liver transplantation of patients with moderate to severe portopulmonary hypertension

Portopulmonary hypertension (PoPH) refers to pulmonary arterial hypertension associated with portal hypertension with or without evidence of an underlying liver disease. Despite the potential for curing PoPH with liver transplantation, the presence of moderate or severe PoPH is associated with increased morbidity and mortality and is, therefore, a contraindication to transplantation. Previous studies have predominantly used intravenous epoprostenol for treatment in order to qualify patients for liver transplantation. In this retrospective case series, we describe the clinical course of 11 patients whom we successfully treated (predominantly with oral sildenafil and subcutaneous treprostinil) in order to qualify them for liver transplantation. The mean pulmonary artery pressure significantly improved from 44 to 32.9 mm Hg, and the pulmonary vascular resistance decreased from 431 to 173 dyn second cm−5. There were significant improvements in the cardiac output and the transpulmonary gradient with these therapies as well. All 11 patients subsequently received liver transplants with a 0% mortality rate to date; the duration of follow‐up ranged from 7 to 60 months. After transplantation, 7 of the 11 patients (64%) were off all pulmonary vasodilators, and only 2 patients required transiently increased doses of prostacyclins. In conclusion, an aggressive approach to the treatment of PoPH with sildenafil and/or treprostinil and subsequent liver transplantation may be curative for PoPH in some patients. Liver Transpl 18:686–695, 2012.

Infected Bilomas in Liver Transplant Recipients, Incidence, Risk Factors and Implications for Prevention

Bilomas, infected hepatic fluid collections, are a frequent complication of liver transplantation. We report a case‐control cohort study to determine the incidence and microbiologic profile of bilomas and risk factors for biloma formation in 492 patients undergoing liver transplantation from 1994 to 2001. Fifty‐seven patients (11.5%) developed one or more bilomas; 95% in the first year post‐transplantation. The most common initial infecting pathogens were enterococci (37%), one‐half resistant to vancomycin (VRE); coagulase‐negative staphylococci (26%); and Candida species (26%). Infection by coagulase‐negative staphylococci was strongly associated with the presence of a T‐tube (OR 9.60, p = 0.02). In stepwise logistic regression multivariable analyses, hepatic artery thrombosis (OR 90.9, p < 0.0001), hepatic artery stenosis (OR 13.2, p < 0.0001) and Roux‐en‐Y choledochojejunostomy (OR 5.8, p = 0.03) were independent risk factors for biloma formation; ursodeoxycholic acid use was highly protective (OR 0.1, p = 0.002). Strategies to prevent biloma formation must focus on measures to prevent hepatic artery thrombosis and colonization of liver transplant patients by multiresistant nosocomial pathogens. T‐tube drainage post‐transplantation bears reassessment. The protective effect of ursodeoxycholic acid found in this study warrants confirmation in a prospective multicenter, randomized trial.

Infected Bilomas in Liver Transplant Recipients: Clinical Features, Optimal Management, and Risk Factors for Mortality

BACKGROUND Infected hepatic fluid collections (bilomas) are a major infectious complication of liver transplantation. Limited data exist on management and outcome of biloma. METHODS We report a cohort study of 57 liver transplant recipients with posttransplantation bilomas undertaken to identify the clinical features of biloma, management strategies, and outcome. RESULTS Fever (44%) and abdominal pain (40%) were the most common presenting symptoms, but one-third of patients were asymptomatic; 79% had elevated hepatic enzyme levels. Patients without hepatic artery thrombosis (HAT) had the highest rates of resolution with percutaneous drainage and anti-infective therapy (64%). Retransplantation was necessary in 64% of patients with HAT and biloma. Independent predictors of resolution with nonsurgical therapy were absence of HAT (odds ratio [OR] 7.69; P=.01) and absence of Candida (OR, 9.09; P=.02) or enterococcal infection (OR, 7.69; P=.03). Patients with bilomas had significantly greater mortality (Cox proportional hazard ratio [HR], 2.38; P=.008, by log rank test) and graft loss (HR, 4.31; P<.0001). Predictors of mortality by multivariable analysis included renal insufficiency (OR, 12.51; P=.02) or infection with Candida species (OR, 4.93; P=.03) or gram-negative bacilli (OR, 9.12; P=.01). CONCLUSION Posttransplantation biloma should be suspected in patients with fever or abdominal pain or abnormalities of hepatic enzymes, and it can be confirmed by computerized tomography and radiographically guided aspiration. Bilomas are most likely to be successfully treated nonsurgically in patients without HAT and without Candida or enterococcus infection.

Pretransplant donor‐specific anti‐HLA antibodies as predictors of early allograft rejection in ABO‐compatible liver transplantation

The significance of preexisting donor‐specific HLA antibodies (HLA‐DSAs) for liver allograft function is unclear. Our previous studies have shown that humoral alloreactivity frequently accompanies acute cellular rejection (ACR). In the present study, we set out to determine whether pretransplant HLA‐DSAs correlate with clinically significant ACR in the first 90 days after transplantation and, if so, to determine their predictive values. Class I HLA‐DSAs and class II HLA‐DSAs were determined by single‐antigen bead flow cytometry for 113 consecutive adult transplants. A statistical analysis was performed for data from 109 consecutive patients with graft survival greater than or equal to 90 days. All patients who developed biochemical graft dysfunction underwent liver biopsy for hematoxylin‐eosin and complement component 4d staining. Cox proportional hazards models and associated hazard ratios revealed a significant association of pretransplant HLA‐DSAs with clinically significant ACR: this association started with a mean fluorescence intensity (MFI) as low as 300 for both class I (hazard ratio = 2.7, P  < 0.01) and class II (hazard ratio = 6.0, P  < 0.01). Pretransplant HLA‐DSAs were associated with an increased risk of ACR: P  < 0.01 for class I (42% versus 18%), P  < 0.001 for class II (37% versus 7%), and P  < 0.001 for either class I or II (36% versus 3%). Class I or II HLA‐DSAs with an MFI ≥ 1000 had the best positive predictive value for clinically significant ACR at 46%, whereas class I or II HLA‐DSAs with an MFI ≥ 300 had the best negative predictive value at 97.1%. Although our study was based on consecutive patients, it was limited by the relatively low number of single‐center subjects. In conclusion, the present study indicates that pretransplant HLA‐DSAs, even at low levels of allosensitization, correlate with the risk of clinically significant ACR. Our findings suggest that anti–human leukocyte antigen antibodies could serve as donor‐specific markers of immunoreactivity to the liver graft. Liver Transpl 19:1132‐1141, 2013.

The Impact of Donor Variables on the Outcome of Orthotopic Liver Transplantation for Hepatitis C

Morphologic characteristics of the graft have been proposed as a major contributor to the long-term outcomes in orthotopic liver transplantation (OLT). Our objective was to determine the impact of donor variables, including donor age, donor-recipient HLA match, and type of donation (DCD vs donation after brain death [DBD]), on the outcome of OLT in 192 patients with hepatitis C virus (HCV). Fourteen patients underwent OLT from donation after cardiac death (DCD) donors and 188 from DBD donors. Mean donor age, warm ischemia time at recovery, and cold ischemia time were similar between the groups. Overall graft survival rate at 1 year (55% DCD vs 85% DBD) and 5 years (46% DCD vs 78% DBD) was significantly lower in the DCD group (P = .0003). Similarly, patient survival rate at 1 year (62% DCD vs 93% DBD) and 5 years (62% DCD vs 82% DBD) was significantly lower in the DCD group (P = .0295). Incidences of hepatic artery thrombosis, portal vein thrombosis, and primary nonfunction were similar between the DCD and DBD groups. The incidence of liver abscess with ischemic-type biliary stricture was higher in recipients from DCD as compared with DBD (42% vs 2%). A trend toward lower graft survival was noted in recipients from donors older than 60 years of age in the HCV population (P = .07), with statistically lower patient survival (P = .02). Donor- recipient HLA matching did not appear to correlate with OLT outcome in patients with HCV. DCD donors and donors older than 60 years of age significantly impact patient and graft survival. Lower graft and patient survival in recipients from DCD donors does not appear to be related to early disease recurrence.

The Prevalence of Alcohol-Induced Liver Disease and Hepatitis C and Their Interaction in a Tertiary Care Setting

BACKGROUND & AIMS We examined the prevalence and clinical characteristics of alcohol-induced liver disease (ALD) in patients referred to a tertiary care center and examined the interaction between ALD and hepatitis C virus (HCV) in a longitudinal survival model. METHODS A total of 1611 patients with chronic liver disease referred to a tertiary care center between 1994 and 2001 were analyzed. The survival of ALD, HCV, and the combination of the 2 (ALD + HCV) was compared in cirrhotic and precirrhotic patients by using Kaplan-Meier estimates. A Cox proportional hazards model was used to examine the independent effects of predictors on survival. RESULTS ALD comprised 31% of the cohort, ALD + HCV comprised 14%, HCV comprised 22%, and the rest comprised 33%. The survival of precirrhotic patients with HCV was significantly better than the survival of those with ALD (hazard ratio, 0.27; P = 0.0006) over long-term and 1-year (hazard ratio, 0.24; P = 0.016) follow-up periods. There was no difference in survival between patients with ALD and ALD + HCV ( P = 0.62). In patients with cirrhosis, survival did not differ by cause; decompensated liver disease (hazard ratio, 1.67; P = 0.004) and continued alcohol abuse (hazard ratio, 2.19; P = 0.002) predicted worse survival in this group. CONCLUSIONS ALD with HCV remains a prevalent cause of chronic liver disease in patients referred to a U.S. tertiary care center. In patients with ALD, the addition of HCV does not change survival, suggesting alcoholism is the driving force for mortality in patients coming to clinical attention. In patients with cirrhosis, ongoing excessive alcohol use and complications of end-stage liver disease drive mortality, irrespective of the underlying cause of chronic liver disease.

Surgical portosystemic shunts for treatment of portal hypertensive bleeding: outcome and effect on liver function.

BACKGROUND Since the advent of liver transplantation and transjugular intrahepatic portosystemic shunts (TIPS), the role of surgical portosystemic shunts in the treatment of portal hypertension has changed. However, we have continued to use portosystemic shunts in patients with noncirrhotic portal hypertension and in patients with Childs A cirrhosis. METHODS We performed 48 surgical portosystemic shunt procedures between 1988 and 1998. The outcomes of these patients were evaluated to assess the efficacy of this treatment. Data from 39 of 48 patients were available for analysis. The average follow-up was 42 months. RESULTS Liver function generally remained stable for the patients; only 2 patients had progressive liver failure and required transplant procedures. Gastrointestinal bleeding (3 patients), encephalopathy (3 patients), and shunt thrombosis (3 patients) were rare. Patient survival was 81% at 4 years, similar to survival with liver transplantation (P = .22). CONCLUSIONS Surgical shunts remain the treatment of choice for prevention of recurrent variceal bleeding in patients with good liver function and portal hypertension.