Lisa B. VanWagner

Patients transplanted for nonalcoholic steatohepatitis are at increased risk for postoperative cardiovascular events

Nonalcoholic steatohepatitis (NASH) is an independent predictor of coronary artery disease (CAD). Our aim was to compare the incidence of cardiovascular (CV) events between patients transplanted for NASH and alcohol (ETOH)‐induced cirrhosis. This is a retrospective cohort study (August 1993 to March 2010) of 242 patients (115 NASH and 127 ETOH) with ≥12 months follow‐up after liver transplantation (LT). Those with hepatocellular carcinoma or coexisting liver diseases were excluded. Kaplan‐Meiers and Coxs proportional hazard analyses were conducted to compare survival. Logistic regression was used to calculate the likelihood of CV events, defined as death from any cardiac cause, myocardial infarction, acute heart failure, cardiac arrest, arrhythmia, complete heart block, and/or stroke requiring hospitalization <1 year after LT. Patients in the NASH group were older (58.4 versus 53.3 years) and were more likely to be female (45% versus 18%; P < 0.001). They were more likely to be morbidly obese (32% versus 9%), have dyslipidemia (25% versus 6%), or have hypertension (53% versus 38%; P < 0.01). On multivariate analysis, NASH patients were more likely to have a CV event <1 year after LT, compared to ETOH patients, even after controlling for recipient age, sex, smoking status, pretransplant diabetes, CV disease, and the presence of metabolic syndrome (26% versus 8%; odds ratio = 4.12; 95% confidence interval = 1.91‐8.90). The majority (70%) of events occurred in the perioperative period, and the occurrence of a CV event was associated with a 50% overall mortality. However, there were no differences in patient, graft, or CV mortality between groups. Conclusions: CV complications are common after LT, and NASH patients are at increased risk independent of traditional cardiac risk factors, though this did not affect overall mortality. (HEPATOLOGY 2012;56:1741–1750)

Association of nonalcoholic fatty liver disease with subclinical myocardial remodeling and dysfunction: A population-based study

Nonalcoholic fatty liver disease (NAFLD) and heart failure (HF) are obesity‐related conditions with high cardiovascular mortality. Whether NAFLD is independently associated with subclinical myocardial remodeling or dysfunction among the general population is unknown. We performed a cross‐sectional analysis of 2,713 participants from the multicenter, community‐based Coronary Artery Risk Development in Young Adults (CARDIA) study who underwent concurrent computed tomography (CT) quantification of liver fat and comprehensive echocardiography with myocardial strain measured by speckle tracking during the Year‐25 examination (age, 43‐55 years; 58.8% female and 48.0% black). NAFLD was defined as liver attenuation ≤40 Hounsfield units after excluding other causes of liver fat. Subclinical left ventricular (LV) systolic dysfunction was defined using values of absolute peak global longitudinal strain (GLS). Diastolic dysfunction was defined using Doppler and tissue Doppler imaging markers. Prevalence of NAFLD was 10.0%. Participants with NAFLD had lower early diastolic relaxation (e’) velocity (10.8 ± 2.6 vs. 11.9 ± 2.8 cm/s), higher LV filling pressure (E/e’ ratio: 7.7 ± 2.6 vs. 7.0 ± 2.3), and worse absolute GLS (14.2 ± 2.4% vs. 15.2 ± 2.4%) than non‐NAFLD (P < 0.0001 for all). When adjusted for HF risk factors or body mass index, NAFLD remained associated with subclinical myocardial remodeling and dysfunction (P < 0.01). The association of NAFLD with e’ velocity (β = −0.36 [standard error = 0.15] cm/s; P = 0.02), E/e’ ratio (β = 0.35 [0.16]; P = 0.03), and GLS (β = −0.42 [0.18]%; P = 0.02) was attenuated after controlling for visceral adipose tissue. Effect modification by race and sex was not observed. Conclusions: NAFLD is independently associated with subclinical myocardial remodeling and dysfunction and provides further insight into a possible link between NAFLD and HF. (Hepatology 2015;62:773–783)

Activation of the insulin-like growth factor-1 receptor induces resistance to epidermal growth factor receptor antagonism in head and neck squamous carcinoma cells

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) have poor efficacy in head and neck squamous carcinoma cells (HNSCC). Because the IGF-1 receptor (IGF1R) generates potent prosurvival signals and has been implicated in therapeutic resistance, its ability to induce resistance to EGFR-TKIs was studied in vitro. Five HNSCC cell lines showed reduced sensitivity to the EGFR-TKI gefitinib when the IGF1R was activated. In SCC-25 and Cal27 cells, gefitinib inhibited basal and EGF-stimulated EGFR, extracellular signal–regulated kinase (Erk), and Akt phosphorylation and reduced cell number. This correlated with initiation of apoptosis based on a 4-fold increase in PARP cleavage and a 2.5-fold increase in Annexin V positivity. The apoptotic response and reduction in cell number were blocked by IGF1R activation, which resulted in phosphorylation of both Erk and Akt. In both the cell lines, IGF1R-induced Erk, but not Akt, activation was eliminated by gefitinib. IGF1R-induced gefitinib resistance was unaffected by MAP/Erk kinase inhibition with U0126 but was partially impaired by inhibition of phosphoinositide-3-kinase with LY294002. The IGF1R-TKI PQ401 inhibited growth of SCC-25 and Cal27 cells alone and also acted synergistically with gefitinib. Thus, the IGF1R can make HNSCC cells resistant to EGFR-TKI treatment via a prosurvival mechanism. Of the 8 HNSCC tumor samples studied, all samples expressed the IGF1R and 5 showed detectable IGF1R phosphorylation, suggesting that this receptor may be relevant in vivo, and thus, combined EGFR/IGF1R inhibition may be necessary in some patients for effective targeted molecular therapy. Mol Cancer Ther; 10(11); 2124–34. ©2011 AACR.

Hepatocellular Carcinoma Decreases the Chance of Successful Hepatitis C Virus Therapy with Direct-Acting Antivirals.

BACKGROUND & AIMS The approval of all-oral direct-acting antiviral (DAA) regimens for the treatment of hepatitis C virus (HCV) has led to the expansion of therapy to include patients with cirrhosis who have hepatocellular carcinoma (HCC). Data on the use of DAAs in HCV+ patients with HCC is limited. The aim of this study was to assess the efficacy of all-oral-DAA regimens in HCV+ cirrhotic patients who have or had HCC compared to those without HCC. METHODS A retrospective cohort study was conducted on all cirrhotic patients who were treated for HCV with DAAs at our institution between January 2014 and November 2015. RESULTS A total of 421 HCV+ patients with cirrhosis were identified, of whom 33% had active or a history of HCC. Failure to achieve sustained virologic response (SVR) occurred in 21% of patients with HCC compared to 12% of patients without HCC (p=0.009). Of the 29 patients with HCC who did not achieve SVR, 27 (93%) occurred when an active tumor was present. DAA therapy in the presence of an inactive tumor or after removal of tumor (resection/transplant) resulted in excellent SVR rates, similar to those without HCC (p<0.0001). In multivariable analysis, the primary predictor of DAA treatment failure was the presence of active HCC at the time of HCV treatment initiation (adjusted odds ratio=8.5, 95% confidence interval=3.90-18.49). CONCLUSIONS The presence of active HCC tumor at the initiation of HCV therapy is significantly associated with all-oral DAA treatment failure. HCV treatment after curative therapies for HCC resulted in excellent SVR. LAY SUMMARY The new medications for hepatitis C have excellent cure rates. However, our study shows that in patients with both liver cancer and hepatitis C, they do not achieve these cure rates. Patients with liver cancer are almost 8 times more likely to fail hepatitis C treatment than patients without liver cancer.

Factors associated with major adverse cardiovascular events after liver transplantation among a national sample

Assessment of major adverse cardiovascular events (MACE) after liver transplantation (LT) has been limited by the lack of a multicenter study with detailed clinical information. An integrated database linking information from the University HealthSystem Consortium and the Organ Procurement and Transplant Network was analyzed using multivariate Poisson regression to assess factors associated with 30‐ and 90‐day MACE after LT (February 2002 to December 2012). MACE was defined as myocardial infarction (MI), heart failure (HF), atrial fibrillation (AF), cardiac arrest, pulmonary embolism, and/or stroke. Of 32 810 recipients, MACE hospitalizations occurred in 8% and 11% of patients at 30 and 90 days, respectively. Recipients with MACE were older and more likely to have a history of nonalcoholic steatohepatitis (NASH), alcoholic cirrhosis, MI, HF, stroke, AF and pulmonary and chronic renal disease than those without MACE. In multivariable analysis, age >65 years (incidence rate ratio [IRR] 2.8, 95% confidence interval [95% CI] 1.8–4.4), alcoholic cirrhosis (IRR 1.6, 95% CI 1.2–2.2), NASH (IRR 1.6, 95% CI 1.1–2.4), pre‐LT creatinine (IRR 1.1, 95% CI 1.04–1.2), baseline AF (IRR 6.9, 95% CI 5.0–9.6) and stroke (IRR 6.3, 95% CI 1.6–25.4) were independently associated with MACE. MACE was associated with lower 1‐year survival after LT (79% vs. 88%, p < 0.0001). In a national database, MACE occurred in 11% of LT recipients and had a negative impact on survival. Pre‐LT AF and stroke substantially increase the risk of MACE, highlighting potentially high‐risk LT candidates.

High early cardiovascular mortality after liver transplantation

Cardiovascular disease (CVD) contributes to excessive long‐term mortality after liver transplantation (LT); however, little is known about early postoperative CVD mortality in the current era. In addition, there is no model for predicting early postoperative CVD mortality across centers. We analyzed adult recipients of primary LT in the Organ Procurement and Transplantation Network (OPTN) database between February 2002 and December 2012 to assess the prevalence and predictors of early (30‐day) CVD mortality, which was defined as death from arrhythmia, heart failure, myocardial infarction, cardiac arrest, thromboembolism, and/or stroke. We performed logistic regression with stepwise selection to develop a predictive model of early CVD mortality. Sex and center volume were forced into the final model, which was validated with bootstrapping techniques. Among 54,697 LT recipients, there were 1576 deaths (2.9%) within 30 days. CVD death was the leading cause of 30‐day mortality (40.2%), and it was followed by infection (27.9%) and graft failure (12.2%). In a multivariate analysis, 9 significant covariates (6 recipient covariates, 2 donor covariates, and 1 operative covariate) were identified: age, preoperative hospitalization, intensive care unit status, ventilator status, calculated Model for End‐Stage Liver Disease score, portal vein thrombosis, national organ sharing, donor body mass index, and cold ischemia time. The model showed moderate discrimination (C statistic = 0.66, 95% confidence interval = 0.63‐0.68). In conclusion, we provide the first multicenter prognostic model for the prediction of early post‐LT CVD death, the most common cause of early post‐LT mortality in the current transplant era. However, evaluations of additional CVD‐related variables not collected by the OPTN are needed in order to improve the models accuracy and potential clinical utility. Liver Transpl 20:1306–1316, 2014.

Physical activity as a treatment of non-alcoholic fatty liver disease: A systematic review

AIM To review the effectiveness of exercise as a therapy for nonalcoholic fatty liver disease (NAFLD) and potential benefits in treating insulin resistance and atherosclerosis. METHODS Medline (EBSCOhost) and PubMed were searched for English-language randomized controlled trials and prospective cohort studies in human adults aged ≥ 18 which investigated the various effects of exercise alone, a combination of exercise and diet, or exercise and diet coupled with behavioral modification on NAFLD from 2010 to Feburary 2015. RESULTS Eighteen of 2298 available studies were chosen for critical review, which included 6925 patients. Nine (50%) studies were randomized controlled trials. Five (27.8%) studies utilized biopsy to examine the effects of physical activity on hepatic histology. The most commonly employed imaging modality to determine change in hepatic steatosis was hydrogen-magnetic resonance spectroscopy. Only two studies examined the effects of low impact physical activity for patients with significant mobility limitations and one compared the efficacy of aerobic and resistance exercise. No studies examined the exact duration of exercise required for hepatic and metabolic improvement in NAFLD. CONCLUSION While exercise improved hepatic steatosis and underlying metabolic abnormalities in NAFLD, more studies are needed to define the most beneficial form and duration of exercise treatment.

Impact of renal impairment on cardiovascular disease mortality after liver transplantation for nonalcoholic steatohepatitis cirrhosis

Non‐alcoholic steatohepatitis (NASH) is an independent risk factor for cardiovascular disease (CVD) morbidity after liver transplantation, but its impact on CVD mortality is unknown. We sought to assess the impact of NASH on CVD mortality after liver transplantation and to predict which NASH recipients are at highest risk of a CVD‐related death following a liver transplant.

Program-specific reports: Implications and impact on program behavior

Purpose of reviewMeasuring and monitoring transplant center performance is vital to ongoing quality assessment and performance improvement initiatives geared toward ensuring optimal care for patients with end-stage organ failure. The impact of regulatory oversight on transplant center behavior and programmatic decision-making is complex. Recent findingsProgram-specific reports (PSRs) are published by the Scientific Registry for Transplant Recipients (SRTR) and are publically available for use by a variety of stakeholders, including patients, regulators, insurers, and care providers. PSRs have been both groundbreaking and controversial. The principal areas of concern relate to potential unintended consequences of PSRs, limitations in both the data collected by the registry and the currently used statistical methodology employed by the SRTR for risk adjustment, and the subsequent impact on transplant program behavior. SummaryPSRs, which serve the purposes of fueling ongoing performance improvement initiatives and informing consumers and payers by fostering transparency in the communication of risk, also involve trade-offs because of their unintended use for regulatory oversight and subsequent impact on transplant center behavior. Future research is necessary to improve data integrity and risk-adjustment methodologies which will enhance regulation and preserve access to transplantation among vulnerable patient populations.

Extrahepatic Manifestations of Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide with an increased prevalence of metabolic, macro-, and microvascular complications. The primary causes of mortality in NAFLD are cardiovascular disease (CVD), malignancy, and liver disease. NAFLD is a multisystem disease that affects a variety of extrahepatic organ systems. The main focus of this review is to summarize the reported extrahepatic associations, which include CVD, chronic kidney disease, obstructive sleep apnea, osteoporosis, psoriasis, colorectal cancer, iron overload, and various endocrinopathies (e.g., type 2 diabetes mellitus, thyroid dysfunction, and polycystic ovarian syndrome). Due to the systemic manifestations of NAFLD, patients require a multidisciplinary assessment and may benefit from more rigorous surveillance and early treatment interventions to decrease mortality related to malignancy or cardiometabolic diseases.