Meta-analysis and systematic review: Prevalence, graft failure, mortality, and post-operative thrombosis in liver transplant recipients with pre-operative portal vein thrombosis.

AIMS: This study seeks to evaluate the association between pre-transplant portal vein thrombosis (PVT) and overall survival, graft failure, waitlist mortality, and post-operative PVT after liver transplantation. METHODS: A conventional pairwise meta-analysis between patients with and without pre-transplant PVT was conducted using hazard ratios or odds ratios where appropriate. RESULTS: Prevalence of preoperative PVT was 11.6% (CI 9.70-13.7%). Pre-operative PVT was associated with increased overall mortality (HR 1.45, 95% CI 1.27-1.65) and graft loss (HR 1.58, 95% CI 1.34-1.85). In particular, grade 3 (HR 1.59, 95% CI 1.00-2.51) and 4 (HR 2.24, 95% CI 1.45-3.45) PVT significantly increased mortality, but not grade 1 or 2 PVT. Patients with PVT receiving living donor (HR 1.54, 95% CI 1.24-1.91) and deceased donor (HR 1.52, 95% CI 1.21-1.92) liver transplantation had increased mortality, with no significant difference between transplant types (P = .13). Furthermore, pre-transplant PVT was associated with higher occurrence of post-transplant PVT (OR 5.06, 95% CI 3.89-6.57). Waitlist mortality was not significantly increased in patients with pre-transplant PVT. CONCLUSION: Graft failure, mortality, and post-operative PVT are more common in pre-transplant PVT patients, especially in grade 3 or 4 PVT. Prophylactic anticoagulation can be considered to reduce re-thrombosis and improve survival.

Liver Transplantation for Alcoholic and Nonalcoholic Fatty Liver Disease: Pretransplant Selection and Posttransplant Management.

Alcoholic fatty liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are common causes of chronic liver disease throughout the world. Although they have similar histologic features, a diagnosis of NAFLD requires the absence of significant alcohol use. ALD is seen commonly in patients with a long-standing history of excessive alcohol use, whereas NAFLD is encountered commonly in patients who have developed complications of obesity, such as insulin resistance, hypertension, and dyslipidemia. Lifestyle contributes to the development and progression of both diseases. Although alcohol abstinence can cause regression of ALD, and weight loss can cause regression of NAFLD, many patients with these diseases develop cirrhosis. ALD and NAFLD account for nearly 30% of liver transplants performed in the United States. Patients receiving liver transplants for ALD or NAFLD have similar survival times as patients receiving transplants for other liver disorders. Although ALD and NAFLD recur frequently after liver transplantation, graft loss from disease recurrence after transplantation is uncommon. Cardiovascular disease and de novo malignancy are leading causes of long-term mortality in liver transplant recipients with ALD or NAFLD.

Diagnostic Accuracy of Laboratory Tests and Diagnostic Imaging in Detecting Biliary Strictures After Liver Transplantation.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is often required to diagnose post-liver transplant (LT) biliary strictures. We evaluated the diagnostic accuracy of noninvasive laboratory and imaging tests in detecting post-LT biliary strictures. METHODS: Adult LT recipients who underwent ERCP between 2008 and 2015 were evaluated. Biliary strictures were diagnosed after blinded review of cholangiograms by three interventional endoscopists. The accuracy of liver enzymes, ultrasound, and MRI was determined using cholangiography as the reference standard. To evaluate the accuracy of change in liver enzymes, the difference between baseline and liver enzymes prior to ERCP (Δlab) was utilized. RESULTS: Biliary strictures were present on cholangiogram in 48 (58%) of 82 LT recipients meeting inclusion criteria. Baseline liver enzyme values did not differ significantly between patients with and without strictures. The optimal cutoffs for ΔALT, ΔAST, Δbilirubin, and Δalkaline phosphatase (AP) were determined to be 174 IU/L, 75 IU/L, 3.1 mg/dL, and 225 IU/L, respectively. ΔALT had a sensitivity of 100%, specificity 43%, and negative predictive value 100%. ΔAP had the highest specificity (53%) but modest sensitivity (69%) with a positive predictive value of 67%. Ultrasound had sensitivity of 29% and specificity of 69%, while MRI had sensitivity of 78% and specificity of 56%. DISCUSSION: The diagnostic accuracy of liver enzymes and imaging modalities is modest in detecting post-LT biliary strictures and cannot be used solely to identify patients needing further workup.

Validation of noninvasive methods for detecting hepatic steatosis in patients with human immunodeficiency virus infection.

Nonalcoholic fatty liver disease (NAFLD) is common among patients with human immunodeficiency virus (HIV) infection; a reliable noninvasive method of detection is needed. We aimed to validate noninvasive means of identifying steatosis in HIV-positive patients. We performed a single-center retrospective study to validate the abilities of the liver fat score (LFS) and the lipid accumulation product (LAP) to detect hepatic steatosis in HIV-positive patients, compared with HIV-negative individuals (controls); NAFLD was confirmed by histology, and findings were compared with those from ultrasonography. These models then were validated in HIV-positive patients with NAFLD vs patients co-infected with HIV and hepatitis C virus (HCV) infection, without hepatic steatosis. LFS identified hepatic steatosis in HIV-positive subjects, compared with controls, with an area under the receiver operating curve value of 0.971 ± 0.027 (95% confidence interval, 0.91-1.000). At a cut-off value of -0.945, the LFS identified patients with steatosis with 100% sensitivity and 84% specificity. At a cut-off of value of -0.234, the LFS differentiated between HIV-positive subjects with NAFLD and patients co-infected with HIV and HCV with 100% sensitivity and 74% specificity. LAP scores ≥38 identified HIV-positive patients with steatosis with 89% sensitivity and 83% specificity. LAP scores ≥42 differentiated between HIV-positive subjects with steatosis and patients co-infected with HIV and HCV with 89% specificity and 70% sensitivity. We validated the accuracy of LFS and LAP in detecting hepatic steatosis in HIV-positive patients.

De novo hepatic steatosis drives atherogenic risk in liver transplantation recipients.

Nonalcoholic fatty liver disease is associated with cardiovascular disease (CVD) in the general population. Despite a high prevalence of de novo hepatic steatosis after liver transplantation (LT), there are no data exploring the association between hepatic steatosis after LT and atherogenic risk. The aim of the study was to explore the impact of hepatic steatosis on serum atherogenic markers in liver transplantation recipients (LTRs). Biomarkers of CVD risk were compared in 89 LTRs with no known history of dyslipidemia, ischemic heart disease, or graft cirrhosis. To avoid potential confounders, LTRs on oral hypoglycemic agents, exogenous insulin, corticosteroids, or lipid-lowering therapy were excluded. Only patients for whom histological assessment was available after LT were included in the study. Thirty-five LTRs had de novo hepatic steatosis after LT, whereas 54 did not. Both cohorts were similar with regards to age, sex, ethnicity, and follow-up from LT. Additionally, the traditional lipid profile was similar between the 2 cohorts. LTRs with hepatic steatosis had higher serum concentrations of small-dense low-density lipoprotein cholesterol (sdLDL-C; 34.8 ± 16.9 versus 22.7 ± 11.2 mg/dL; P < 0.001), sdLDL-C to low-density lipoprotein cholesterol ratio (32.6 ± 11.6 versus 24.6 ± 10.2; P < 0.01), small-dense low-density lipoprotein particle concentration (sdLDL-P; 770 ± 440 versus 486 ± 402 nmol/L; P < 0.01), very low density lipoprotein particle concentration (VLDL-P; 7.90 ± 7.91 versus 3.86 ± 3.18 nmol/L; P < 0.01), and very low density lipoprotein size (VLDL-size; 51.9 ± 6.4 versus 48.7 ± 6.3 nm; P = 0.06). LTRs with hepatic steatosis had higher serum insulin concentrations (27.8 ± 41.8 versus 11.7 ± 7.8 uU/mL; P < 0.01) but similar fasting glucose and hemoglobin A1c. Steatosis grade was directly related to sdLDL-C, sdLDL-P, insulin, VLDL-P, and VLDL-size. In multivariate analysis, the association between steatosis grade and sdLDL-C (ß = 0.03; P = 0.029), VLDL-size (ß = 0.316; P = 0.04), and low-density lipoprotein particle size (ß = -0.27; P = 0.05) was independent of sex, body mass index, age, diabetes mellitus, time from transplant, and indication for LT. In conclusion, de novo hepatic steatosis after LT is associated with atherogenic lipoproteins and independent of traditional CVD risk factors.

Evolution of serum atherogenic risk in liver transplant recipients: Role of lipoproteins and metabolic and inflammatory markers.

Although cardiovascular disease (CVD) is the leading cause of long-term mortality in liver transplant recipients (LTRs), the role of recently identified biomarkers of CVD risk in liver transplantation is unknown. We aimed to evaluate an extensive CVD risk profile in LTRs. Markers of CVD risk in 65 LTRs with no known history of diabetes mellitus (DM), dyslipidemia, or ischemic heart disease were compared to age-, sex-, and body mass index (BMI)-matched controls with no chronic medical disease. LTRs on corticosteroids or those with graft cirrhosis (GC) were excluded. The effect of calcineurin inhibitors on the CVD risk profile was separately analyzed in LTRs receiving either tacrolimus (Tac) or cyclosporine A (CsA). To evaluate the impact of GC, a comparison was made between LTRs with and without GC. Non-DM LTRs were matched to controls with respect to age, sex, and BMI. LTRs had similar serum high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), and total cholesterol in comparison with BMI-matched controls. Proatherogenic small-dense (sd) LDL-C (33.6 ± 14 versus 25.9 ± 9.9 mg/dL; P < 0.001) and %sdLDL-C (30% ± 10% versus 26.4% ± 9%; P = 0.02) were significantly higher in LTRs. In comparison with controls, LTRs had higher apolipoprotein B (apoB; 98 ± 37 versus 88 ± 24 mg/dL; P < 0.01), very low density lipoprotein-particle concentration (VLDL-P; 7.7 ± 6.7 nmol/L versus 3.2 ± 9.1 nmol/L; P < 0.001), and VLDL size (51.1 ± 6.6 versus 46.5 ± 6.9 nm; P < 0.001). In LTRs, VLDL size and VLDL-P were directly related to serum CsA levels (r = 0.53, P = 0.09, and r = 0.63, P < 0.01, respectively) but not to Tac levels. In comparison with controls, LTRs had significantly lower total serum high-density lipoprotein-particle concentration. In comparison with those with preserved graft function, LTRs with GC had lower levels of serum atherogenic markers characterized by low sdLDL-C, apoB, triglycerides, LDL-C, and total cholesterol. In conclusion, LTRs have a proatherogenic lipoprotein profile that is not captured with a traditional lipid panel, and this suggests that a detailed serum atherogenic profile is needed to truly assess CVD risk in LTRs.

Vascular Disease in Patients with Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is increasingly being diagnosed and is considered to be the most frequent chronic liver disorder in Western countries. It represents a histopathological spectrum ranging from simple hepatic steatosis to steatohepatitis and finally cirrhosis. NAFLD is considered as the hepatic manifestation of the metabolic syndrome and is associated with increased mortality. Increasing evidence now suggests that NAFLD is also associated with higher cardiovascular disease (CVD) morbidity and mortality independent of conventional cardiometabolic risk factors (such as obesity, insulin resistance, and diabetes mellitus). The exact mechanisms linking NAFLD to increased CVD risk are still incompletely understood and likely reflect multiple coexisting pathways. Recent evidence suggests a contributive effect of an altered hemostasis in patients with NAFLD. For example, patients with NAFLD have higher levels of prothrombotic factors (e.g., von Willebrand factor, fibrinogen, factor VII activity, and plasminogen activator inhibitor-1), which correlate with underlying histological severity of the disease. The current review focuses on these hemostatic abnormalities in NAFLD and the link with increased CVD risk.

Association between high-normal levels of alanine aminotransferase and risk factors for atherogenesis.

BACKGROUND & AIMS: Liver disease has been associated with cardiovascular disorders, but little is known about the relationship between serum levels of alanine aminotransferase (ALT) and markers of atherogenesis. We investigated the relationship between low-normal and high-normal levels of ALT and an extended panel of cardiovascular risk factors among individuals with no known diseases in a primary care setting. METHODS: We performed a retrospective analysis of data collected from 6442 asymptomatic patients at wellness visits to a primary care setting in central Virginia from 2010 through 2011. Serum levels of ALT were compared with levels of lipids and lipoproteins, as well as metabolic, inflammatory, and coagulation-related factors associated with risk for cardiovascular disease. RESULTS: Serum levels of ALT were higher than 40 IU/L in 12% of subjects, and in the high-normal range (19-40 IU/L in women and 31-40 IU/L in men) in 25% of subjects. ALT level was associated with the apolipoprotein B level, concentration and particle size of very-low-density lipoproteins, concentration of low-density lipoprotein (LDL) particles (LDL-P), and percentages of small dense LDL (sdLDL) and sdLDL-cholesterol (sdLDL-C) (P < .0001 for all). A high-normal level of ALT was associated with higher levels of LDL-C, LDL-P, sdLDL-C, and sdLDL particles (P < .001 for all). These effects were independent of age, body mass index, and hyperinsulinemia. Increasing levels of ALT and fasting hyperinsulinemia (>12 µU/mL) synergized with increasing levels of triglycerides, very-low-density lipoprotein particles, LDL-P, sdLDL-C, and percentage of sdLDL-C. Levels of APOA1, high-density lipoprotein-cholesterol, and high-density lipoprotein-class 2 were associated inversely with serum level of ALT (P < .0001 for all). CONCLUSIONS: In an analysis of asymptomatic individuals, increased serum levels of ALT (even high-normal levels) are associated with markers of cardiovascular disease.

Range of Normal Serum Aminotransferase Levels in Liver Transplant Recipients.

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are used to monitor liver transplant recipients (LTR) but the reference range and context of its use is not well defined. We aimed to determine the healthy ranges in LTR without chronic liver disease. METHODS: One hundred and three LTR without chronic liver disease based on serology, transient elastography with controlled attenuated parameter, and ultrasound were included. A healthy range of aminotransferases was set to 95th percentile. An updated normal aminotransferase range was used to detect recurrence in post-liver transplantation (LT) with hepatitis C virus (HCV) and nonalcoholic fatty liver disease (NAFLD). RESULTS: The normal ALT and AST range was 0 to 57 and 0 to 54 IU/L, respectively, in LTR and was not affected by age, sex, obesity, or choice of immunosuppressant. The diagnostic performance of serum ALT and AST to detect recurrence of NAFLD by a controlled attenuated parameter was poor with area under the receiver operating characteristic curve of 0.573 (95% confidence interval 0.493, 0.655; P = .08) and 0.537 (0.456, 0.618; P = .4), respectively. In contrast, the diagnostic performance of ALT and AST to detect recurrence of HCV after LT was 0.906 (0.868, 0.944; P < .001) and 0.925 (0.890, 0.959; P < .001), respectively. CONCLUSION: The updated aminotransferase range in LTR is higher than the general population and accurate for detecting recurrent HCV, but not NAFLD.

Significant infections in liver transplant recipients undergoing endoscopic retrograde cholangiography are few and unaffected by prophylactic antibiotics.

INTRODUCTION: Current practice guidelines recommend prophylactic antibiotics prior to endoscopic retrograde cholangiopancreatography (ERCP) in liver transplant recipients (LTR). This study evaluated the risk of clinically significant infections after ERCP in LTR who received antibiotic prophylaxis compared to those who did not. METHODS: This retrospective case-cohort study evaluated all LTR who underwent elective, outpatient ERCP from 2008 to 2015. Hospitalized patients, pediatric allograft recipients and patients with cholangitis or incomplete biliary drainage were excluded. The primary outcome was unanticipated hospitalization from procedure-related clinically significant infection occurring within 3 days of ERCP. RESULTS: Sixty-nine patients (48 males; mean age 60.5 ±â€¯7.4 years) underwent 191 ERCPs after liver transplantation. Prophylactic antibiotics were administered during 82 ERCPs and not administered for 109 ERCPs. Unscheduled admissions for fever within 3 days occurred in 4 patients. Only 2 patients had documented bacteremia, of which only 1 patient received prophylactic antibiotics and also met primary outcome. Interventions during ERCP, patient demographics, and time from transplantation were not associated with increased risk of hospitalization from infections or bacteremia. CONCLUSIONS: The risk of infectious complications after ERCP in LTR is low and not affected by administration of prophylactic antibiotics. A tailored approach to antibiotic prophylaxis may be more appropriate than universal prophylaxis in selected LTR at low risk of infections.

Intensive care unit management of patients with liver failure.

Acute liver failure (ALF) and acute-on-chronic liver failure (ACLF) usually mandate management within an intensive care unit (ICU). Even though the conditions bear some similarities, precipitating causes, and systemic complications management practices differ. Although early identification of ALF and ACLF, improvements in ICU management, and the widespread availability of liver transplantation have improved mortality, optimal management practices have not been defined. This article summarizes current ICU management practices and identifies areas of management that require further study.

Posttransplant metabolic syndrome.

Metabolic syndrome (MS) is a cluster of metabolic derangements associated with insulin resistance and an increased risk of cardiovascular mortality. MS has become a major health concern worldwide and is considered to be the etiology of the current epidemic of diabetes and cardiovascular disease. In addition to cardiovascular disease, the presence of MS is also closely associated with other comorbidities including nonalcoholic fatty liver disease (NAFLD). The prevalence of MS in patients with cirrhosis and end-stage liver disease is not well established and difficult to ascertain. Following liver transplant, the prevalence of MS is estimated to be 44-58%. The main factors associated with posttransplant MS are posttransplant diabetes, obesity, dyslipidemia, and hypertension. In addition to developing NAFLD, posttransplant MS is associated with increased cardiovascular mortality that is 2.5 times that of the age- and sex-matched individuals. Additionally, the presence of posttransplant MS has been associated with rapid progression to fibrosis in individuals transplanted for HCV cirrhosis. There is an urgent need for well-designed prospective studies to fully delineate the natural history and risk factors associated with posttransplant MS. Until then, early recognition, prevention, and treatment of its components are vital in improving outcomes in liver transplant recipients.