Rachel A. Pedersen

Frequency and Outcomes of Liver Transplantation for Nonalcoholic Steatohepatitis in the United States

BACKGROUND & AIMS The relative frequency of nonalcoholic steatohepatitis (NASH) as an indication for liver transplantation and comparative outcomes following transplantation are poorly understood. METHODS We analyzed the Scientific Registry of Transplant Recipients for primary adult liver transplant recipients from 2001 to 2009. RESULTS From 2001 to 2009, 35,781 patients underwent a primary liver transplant, including 1959 for who NASH was the primary or secondary indication. The percentage of patients undergoing a liver transplant for NASH increased from 1.2% in 2001 to 9.7% in 2009. NASH is now the third most common indication for liver transplantation in the United States. No other indication for liver transplantation increased in frequency during the study period. Compared with other indications for liver transplantation, recipients with NASH are older (58.5±8.0 vs 53.0±8.9 years; P<.001), have a larger body mass index (>30 kg/m2) (63% vs 32%; P<.001), are more likely to be female (47% vs 29%; P<.001), and have a lower frequency of hepatocellular carcinoma (12% vs 19%; P<.001). Survival at 1 and 3 years after liver transplantation for NASH was 84% and 78%, respectively, compared with 87% and 78% for other indications (P=.67). Patient and graft survival for liver recipients with NASH were similar to values for other indications after adjusting for level of creatinine, sex, age, and body mass index. CONCLUSIONS NASH is the third most common indication for liver transplantation in the United States and is on a trajectory to become the most common. Outcomes for patients undergoing a liver transplant for NASH are similar to those for other indications.

Evolution of Causes and Risk Factors for Mortality Post-Liver Transplant: Results of the NIDDK Long-Term Follow-Up Study

Although mortality rates following liver transplantation (LT) are well described, there is a lack of detailed, prospective studies determining patterns of and risk factors for long‐term mortality. We analyzed the multicenter, prospectively obtained The National Institute of Diabetes and Digestive and Kidney Diseases LT Database of 798 transplant recipients from 1990 to 1994 (follow‐up 2003). Overall, 327 recipients died. Causes of death >1 year: 28% hepatic, 22% malignancy, 11% cardiovascular, 9% infection, 6% renal failure. Renal‐related death increased dramatically over time. Risk factors for death >1 year (univariate): male gender, age/decade, pre‐LT diabetes, post‐LT diabetes, post‐LT hypertension, post‐LT renal insufficiency, retransplantation >1 year, pre‐LT malignancy, alcoholic disease (ALD) and metabolic liver disease, with similar risks noted for death >5 years. Hepatitis C, retransplantation, post‐LT diabetes, hypertension and renal insufficiency were significant risk factors for liver‐related death. Cardiac deaths associated with age, male gender, ALD, cryptogenic disease, pre‐LT hypertension and post‐LT renal insufficiency. In summary, the leading causes of late deaths after transplant were graft failure, malignancy, cardiovascular disease and renal failure. Older age, diabetes and renal insufficiency identified patients at highest risk of poor survival overall. Diligent management of modifiable post‐LT factors including diabetes, hypertension and renal insufficiency may impact long‐term mortality.

Delayed-Onset Primary Cytomegalovirus Disease and the Risk of Allograft Failure and Mortality after Kidney Transplantation

BACKGROUND During the contemporary era of antiviral prophylaxis, the impact of delayed-onset primary cytomegalovirus (CMV) disease on the outcome of kidney transplantation is not known. We evaluated the incidence, clinical features, risk factors, and outcomes of CMV disease among high-risk kidney transplant recipients. METHODS The medical records of CMV-seronegative recipients of kidney transplants from CMV-seropositive donors were reviewed. Cox proportional hazards regression was used to identify factors associated with CMV disease and to assess its impact on allograft loss and mortality. RESULTS None of the 176 CMV-seronegative recipients of kidney transplants from CMV-seropositive donors developed breakthrough CMV disease during a median of 92 days (interquartile range, 90-92 days) of oral ganciclovir or valganciclovir prophylaxis. Thereafter, 51 patients (29%) developed CMV disease at a median of 61 days (interquartile range, 40-143 days) after stopping antiviral prophylaxis. Early-onset bacterial and fungal infection (hazard ratio, 3.61; 95% confidence interval, 1.78-7.33; p < .001) and a Charlson comorbidity index > or =3 (hazard ratio, 2.21; 95% confidence interval, 1.15-4.22; p = .011) were associated with a higher risk of delayed-onset primary CMV disease, and postrejection antiviral prophylaxis (hazard ratio, 0.29; 95% confidence interval, 0.09-0.94; P = .039) was associated with a lower risk of such CMV disease. A time-dependent Cox regression analysis revealed a statistically significant association between tissue-invasive CMV disease and allograft loss or mortality (hazard ratio, 2.85; 95% confidence interval, 1.22-6.67; P = .016). CONCLUSION This study of a large cohort of CMV-seronegative recipients of kidney transplants from CMV-seropositive donors illustrates the ongoing challenge of delayed-onset primary CMV disease and its impact on transplantation outcomes despite antiviral prophylaxis. Better strategies for CMV disease prevention after kidney transplantation are warranted.

Predictors of early re-bleeding and mortality after acute variceal haemorrhage in patients with cirrhosis

Background and aims: Risk factors for mortality and re-bleeding following acute variceal haemorrhage (AVH) are incompletely understood. The aim of this study was to determine risk factors for 6-week mortality, and re-bleeding within 5 days in patients with cirrhosis and AVH. Methods: Kaplan–Meier and Cox proportional hazards regression analyses were used to determine risk factors among 256 patients with AVH entered into a randomised, prospective trial. Results: Thirty-five patients (14%) died within 6 weeks of AVH; 14 deaths (40%) occurred within 5 days. Only the Model for End-stage Liver Disease (MELD) score and units of packed red blood cells (PRBCs) transfused in the first 24 h were associated with 6-week mortality univariately (HR 1.11, p<0.001; HR 1.22, p<0.001) and bivariately (HR MELD = 1.10, p<0.001; HR per unit of PRBCs transfused = 1.15, p = 0.005). Re-bleeding within 5 days occurred in 37 patients (15%); MELD score (p = 0.01) and a clot on a varix (p = 0.05) predicted re-bleeding. Patients with a MELD score ⩾18; both MELD score ⩾18 and ⩾4 units of PRBCs transfused; both MELD score ⩾18 and active bleeding at index endoscopy; and variceal re-bleeding had increased risk of death 6 weeks post-AVH (HR = 7.4, p<0.001; 11.3, p<0.001; 9.9, p<0.001; 10.2, p<0.001 respectively). Conclusions: Patients with AVH and MELD score ⩾18, requiring ⩾4 units of PRBCs within the first 24 h or with active bleeding at endoscopy are at increased risk of dying within 6 weeks. MELD score ⩾18 is also a strong predictor of variceal re-bleeding within the first 5 days.

Predictors of Disease Recurrence Following Neoadjuvant Chemoradiotherapy and Liver Transplantation for Unresectable Perihilar Cholangiocarcinoma

Background. Sixty-five patients with unresectable hilar cholangiocarcinoma (CCA) have undergone orthotopic liver transplantation (OLT) after neoadjuvant chemoradiotherapy per a clinical care protocol developed in 1993. We reviewed our experience with the aim to identify clinicopathological predictors of disease recurrence. Methods. All patients with CCA that underwent OLT at our institution between 1993 and January 1, 2006 were treated in accord with our published protocol. We analyzed multiple clinical and explant pathologic factors using Cox regression analysis. Results. Sixty-five patients with CCA underwent OLT. Four patients died within six months due to postoperative complications. At last follow-up, 11 patients (17%) had developed recurrence seven to 64 months after OLT. Mean time to recurrence was 29 months, and eight patients had died from recurrent disease. Patient and disease-free survival were 76% and 60% five years after OLT. Predictors of recurrence were older age, pretransplant cancer antigen (CA) 19-9 >100 U/ml, prior cholecystectomy, mass on cross-sectional imaging, residual tumor in explant >2 cm, tumor grade and perineural invasion in explant. Underlying primary sclerosing cholangitis, percutaneous biliary intubation, gender, and other time points for CA 19-9 were not associated with recurrence. Prolonged staging-to-OLT intervals for patients transplanted after implementation of model for end-stage liver disease (MELD) showed a trend toward increased recurrence. Conclusions. Older patients and those with high CA-19.9 levels, and larger tumors are more likely to develop recurrent disease. Prolonged waiting time may emerge as a significant risk factor with longer follow-up. These findings may guide patient selection, applicability of live donor transplantation and MELD score exceptions for this aggressive protocol.

Trends in Waiting List Registration for Liver Transplantation for Viral Hepatitis in the United States

BACKGROUND & AIMS In the last decade, significant progress has been made in the treatment of liver disease associated with chronic hepatitis, especially in patients infected with the hepatitis B virus (HBV). To investigate whether the population-wide application of antiviral therapies has impacted liver transplant waiting list registration, we analyzed longitudinal trends in waiting list registration for patients with hepatitis B and C and those with nonviral liver disease. METHODS This study represented a retrospective analysis of registry data containing all US liver transplant centers. All adult, primary liver transplantation candidates registered to the Organ Procurement and Transplantation Network between 1985 and 2006 were included in the analysis. Standardized incidence rates were calculated for waiting list registration for liver transplantation by underlying disease (HBV and HCV infection and other) and by indication for transplantation (fulminant liver disease, hepatocellular carcinoma [HCC], and end-stage liver disease [ESLD]). RESULTS Of 113,927 unique waiting list registrants, 4793 (4.2%) had HBV, and 40,923 (35.9%) had HCV infections; the remaining 68,211 (59.9%) had neither. The incidence of waiting list registration for ESLD and fulminant liver disease decreased, whereas that for HCC increased. The decrease in ESLD registration was most pronounced, and the increase in HCC was least dramatic among registrants with hepatitis B. The decrease in registration for ESLD secondary to HCV infection was also significantly larger than that for ESLD patients with nonviral etiologies. CONCLUSIONS The pattern of liver transplantation waiting list registration among patients with hepatitis B suggests that the widespread application of oral antiviral therapy for HBV contributed to the decreased incidence of decompensated liver disease.

Delayed-onset primary cytomegalovirus disease after liver transplantation

Clinical practice guidelines recommend antiviral prophylaxis to cytomegalovirus (CMV) donor‐positive/recipient‐negative (D+/R−) liver transplant recipients. We assessed the outcome of this strategy by determining the incidence, clinical features, and risk factors of CMV disease among CMV D+/R− liver transplant recipients who received antiviral prophylaxis. Sixty‐seven CMV D+/R− liver transplant recipients (mean age ± standard deviation: 49.5 ± 11.4 years; 75% male) received oral ganciclovir [n = 9 (13%)] or valganciclovir [n = 58 (87%)] prophylaxis for a median duration of 92 days (interquartile range: 91‐100). No breakthrough CMV disease was observed during antiviral prophylaxis. However, primary CMV disease was observed in 2%, 25%, 27%, 27%, and 29% of patients at 1, 3, 6, 12, and 24 months, respectively, after antiviral prophylaxis was stopped. The incidence of delayed‐onset primary CMV disease was similar between those who received oral ganciclovir and valganciclovir. Nine (47%) patients had CMV syndrome, 8 (42%) had gastrointestinal CMV disease, and 2 (11%) had CMV hepatitis. Female patients (P = 0.01) and younger age at transplant (P = 0.03) were associated with an increased risk, whereas diabetes mellitus (P < 0.001) was significantly associated with a lower risk of delayed‐onset primary CMV disease. Allograft loss or mortality occurred in 8 (12%) patients during the median follow‐up period of 3.31 (range: 0.8‐5.9) years. No significant association was observed between CMV disease and patient and allograft survival. In conclusion, CMV disease remains a common complication in CMV D+/R− liver transplant patients during the contemporary era of antiviral prophylaxis. Female patients and younger patients are at increased risk of delayed‐onset primary CMV disease. Liver Transpl 13: 1703–1709, 2007.

Use of sirolimus in liver transplant recipients with renal insufficiency: A systematic review and meta‐analysis

Sirolimus is used in patients with renal insufficiency after liver transplantation (LT) and especially in those with calcineurin inhibitor (CNI)–associated nephrotoxicity. We conducted a systematic review of all randomized controlled trials and observational studies to test the hypothesis that the use of sirolimus is associated with an improvement in renal function at 1 year in LT recipients with renal insufficiency [glomerular filtration rate (GFR) < 60 mL/minute or creatinine level ≥ 1.5 mg/dL]. We performed a search of all major databases, conference proceedings, and relevant journals through December 2009 and contacted content experts, corresponding authors, and the pharmaceutical manufacturer. A random effects model was used to determine the pooled estimate of the change in renal function and pooled risk estimates of adverse events that may be associated with sirolimus‐based therapy at 1 year. Eleven studies (three randomized controlled trials and eight observational studies) met the final inclusion criteria. A nonsignificant improvement of 3.38 mL/minute [95% confidence interval (CI) = −2.93 to 9.69] was observed in methodologically sound observational studies and controlled trials reporting the primary outcome. In controlled trials, baseline GFR >50 mL/min sirolimus use was associated with an improvement of 10.35 mL/minute (95% CI = 3.98‐16.77) in GFR or creatinine clearance. Sirolimus was not significantly associated with death [relative risk (RR) = 1.12, 95% CI = 0.66‐1.88] or graft failure (RR = 0.80, 95% CI = 0.45‐1.41), although reporting was incomplete. It was associated with a statistically significant risk of infection (RR = 2.47, 95% CI = 1.14‐5.36), rash (RR = 7.57, 95% CI = 1.75‐32.70), ulcers (RR = 7.44, 95% CI = 2.03‐27.28), and discontinuation of therapy (RR = 3.61, 95% CI = 1.32‐9.89). Conclusion: Conversion to sirolimus from CNIs is associated with a nonsignificant improvement in renal function in LT recipients with renal insufficiency, although the results are limited by heterogeneity, a risk of bias, and a lack of standardized reporting. (HEPATOLOGY 2010;)

Alcoholic Liver Disease-Related Mortality in the United States: 1980-2003

OBJECTIVES:Data on temporal changes in alcoholic liver disease (ALD)-related mortality in the United States are lacking. This longitudinal assessment is important, given the divergent data on trends in worldwide ALD-related mortality, concerns for underestimation of mortality attributed to ALD in previous investigations, and shifting attention to hepatitis C virus (HCV)-related mortality.METHODS:We analyzed mortality data compiled in the multiple cause-of-death public-use data file from the National Vital Statistics System from 1980 to 2003 using categorization by both International Classification of Diseases (ICD)-9 and ICD-10 systems. The main outcome measure was age- and sex-adjusted death rates attributable to ALD, HCV, or both (ALD/HCV) listed as immediate or underlying cause of death.RESULTS:A total of 287,365 deaths were observed over the 24-year period. Age- and sex- adjusted incidence rates of ALD-related deaths decreased from 6.9/100,000 persons in 1980 to 4.4/100,000 persons by 2003. After introduction of HCV diagnostic testing, HCV-related liver mortality increased to 2.9/100,000 persons by 2003. Death rates for subjects with concomitant ALD/HCV rose to 0.2/100,000 persons by 1999 and then remained unchanged through 2003. Age-specific mortality related to ALD was highest in the ages of 45–64 years. Between 1980 and 2003, the age- and sex-adjusted ALD-related mortality (per 100,000 persons) decreased from 6.3 to 4.5 among Caucasians, 11.6 to 4.1 among African Americans, and 8.0 to 3.7 among the “other” race group.CONCLUSIONS:Despite a decline in ALD-related mortality, the proportion of alcohol-related liver deaths is still considerably large and comparable in scope to that of HCV.

Predictors of cardiovascular events after liver transplantation: A role for pretransplant serum troponin levels

Cardiovascular complications are major causes of morbidity and mortality after liver transplantation. Identifying candidates at highest risk of postoperative complications is a cornerstone of optimizing outcomes and utility. Using traditional cardiac risk factors in addition to C‐reactive protein (CRP) levels, troponin levels, and echocardiographic parameters before transplantation, we sought to define cardiac risk so that we could predict cardiovascular events after transplantation. From December 1998 to December 2001, 230 adult patients who underwent liver transplantation with a median follow‐up of 8.2 years were studied. The risk factors for cardiac disease were as follows: male gender with a mean age of approximately 50 years (57%), smoking history (60%), diabetes (23%), hypertension (19%), elevated troponin (25%), elevated CRP (25%), and preexisting cardiac disease (16%). Fifty‐nine cardiac events occurred over 8.2 years. Risk factors (univariate analysis) for first cardiac events included age in decades [hazard ratio (HR) = 1.31, P = 0.047], diabetes (HR = 2.20, P = 0.004), prior cardiovascular disease (HR = 4.77, P < 0.0001), a troponin I level > 0.07 ng/mL (HR = 2.00, P = 0.023), left ventricular hypertrophy (HR = 2.06, P = 0.047), stress wall abnormalities (HR = 2.25, P = 0.018), and ischemia on stress imaging (HR = 2.89, P = 0.015). Multivariate analysis confirmed age, diabetes, a troponin I level > 0.07, and prior cardiac disease as independent risk factors for posttransplant cardiac events. In conclusion, pretransplant elevated troponin levels, diabetes, and a history of cardiovascular disease, alone or in combination, are strongly associated with the occurrence of posttransplant cardiovascular events. Liver Transpl 17:23–31, 2011.