Objectives: Frequency of liver transplants because of nonalcoholic steatohepatitis is increasing. Data are conflicting on nonalcoholic steatohepatitis as a risk factor for cardiovascular events after transplant.

Materials and Methods: We reviewed medical records of liver transplant recipients (between years 2005 and 2010) for alcoholic cirrhosis or nonalcoholic steatohepatitis for cardiovascular events (arrhythmia, congestive heart failure, coronary disease, pulmonary hypertension, or stroke) and patient survival within 3 years.

Results: Compared with the 65 transplant recipients for alcoholic cirrhosis, the 78 transplant recipients for nonalcoholic steatohepatitis were significantly (P < .0001 for all) more likely to be female (46% vs 8%), have a larger mean body mass index (34 ± 7 vs 29 ± 5), more likely to have diabetes (58% vs 26%), less likely to be hepatitis C virus-positive (3% vs 29%), and less likely to smoke (29% vs 69%). Eleven patients with nonalcoholic steatohepatitis and 9 patients with nonalcoholic steatohepatitis had cardiovascular events; however, these groups were not significantly different 1 year (7.7% vs 6.1%; P = .45) or 3 years (14.1% vs 13.8%; P = .9) after liver transplant. The odds of having a cardiovascular event were about 9-fold greater for patients with concomitant hepatitis C virus and 3-fold greater for men. Eighteen patients died, with patients with cardiovascular events having greater than 4-fold increased mortality (mean 4.1-fold; range, 1.2-fold to 13.9-fold).

Conclusions: Cardiovascular events occurred with similar frequency in transplant recipients for nonalcoholic steatohepatitis or alcoholic cirrhosis. Patient survival was affected in both groups, but male patients with concomitant hepatitis C virus infection remained at higher risk for a cardiovascular event after liver transplant. Development of a cardiac evaluation protocol for liver transplant recipients could help monitor these patients.

Key words : Fatty liver, Nonalcoholic fatty liver disease, Alcoholic liver disease, Cardiac event

Introduction

Alcohol abuse and nonalcoholic steatohepatitis (NASH) are common causes of steatohepatitis-related cirrhosis requiring liver transplant.^1,2 Both diseases share similar pathogenesis and histology despite their different phenotypes and risk factors. Because in it was first established as a distinct category for liver transplant in 2000, the number of liver transplants for patients with NASH has increased, accounting for approximately 8% to 10% of all liver transplants in 2009,^2,3 especially among recipients > 65 years old and with more performed in Southeastern and Midwestern regions of the United States.⁴

Patients with metabolic syndrome because of concomitant comorbidities such as diabetes, hyper­tension, obesity, and dyslipidemia are more likely to present with atherosclerosis and its complications and have an increased risk for cardiovascular and all-cause mortality.^5,6 In addition, the use of potent immuno­suppressive agents among liver transplant recipients increases the risk of developing the metabolic syndrome.^7,8 Although the association between liver disease and cardiovascular disease is well recognized, it remains unclear whether NASH is a predictor of a cardiac event after transplant.^9-11 Because metabolic syndrome is more persistent and more frequent in patients who undergo transplant for NASH-related cirrhosis versus those with other liver diseases, we hypothesized that causes related to NASH are a risk factor for cardiovascular events after liver transplant. To test this hypothesis, we compared patients who received liver transplants for NASH cirrhosis with patients who received liver transplants for alcoholic cirrhosis.

Materials and Methods

Study population
The 598 patients who underwent deceased-donor liver transplant at our center between January 2005 and December 2010 were analyzed retrospectively. Using the United Network of Organ Sharing codes, we identified 147 patients who underwent liver transplant for steatohepatitis-related cirrhosis due to NASH (Code 4214) or alcohol abuse (Code 4215). Medical records were reviewed for accuracy of cause of liver disease. Two patients with confounded diagnosis of alcoholic cirrhosis (primary biliary cirrhosis in 1 and α1-antitrypsin deficiency ZZ phenotype in 1) were excluded. Two additional patients (1 with alcoholic cirrhosis) were excluded because 3-year posttransplant follow-up data were missing. The study was approved by the Ethical Review Committee of the Institute. All of the protocols conformed to the ethical guidelines of the 1975 Helsinki Declaration.

Definitions of clinical findings and diagnoses
Nonalcoholic steatohepatitis
We confirmed the diagnosis of NASH by reviewing liver biopsy or explant histology results and/or if other causes of liver disease (including alcohol abuse, hepatitis B or C virus infections, autoimmune hepatitis, hepatotoxin- or drug-induced liver disease, Wilson disease, hemochromatosis, α1-antitrypsin deficiency) could be excluded, as well as the presence of metabolic syndrome. Alcohol use of < 10 g/day was considered consistent with diagnosis of NASH-related liver disease.

Metabolic syndrome
Patients were diagnosed with metabolic syndrome if they had 3 or more of the following factors, which are based on the National Cholesterol Education Program Adult Treatment Panel III: obesity (body mass index > 29.9), hypertension (> 130/85 mm Hg or being on antihypertensive medications), diabetes mellitus (fasting blood glucose > 110 mg/dL or being on insulin or oral hypoglycemia agents), elevated triglycerides (> 150 mg/dL), and low levels of high-density lipoprotein cholesterol (< 40 mg/day in men and < 50 mg/dL in women).^12,13

Alcoholic cirrhosis
Patients were confirmed as having alcoholic cirrhosis based on histologic results and/or clinical diagnosis of cirrhosis and exclusion of other causes of liver disease except hepatitis C virus infection and on documentation of alcohol abuse (> 14 drinks/wk in men and > 7 drinks/wk in women for > 5 years).

Liver disease complications
Presence of ascites or fluid collection in the abdominal cavity was determined from the clinical notes or from imaging results. Hepatopulmonary syndrome was diagnosed based on presence of hypoxia (PO₂ < 60 mm Hg, echocardiographic findings of intrapulmonary shunt with shunt fraction of > 6% as evaluated by macroaggregated albumin scan). Diagnosis of hepatorenal syndrome was based on findings from the medical record, determined as renal failure in cirrhosis patients who did not improve with volume response, with clinical evaluation showing no intrarenal or obstructive causes.

Cardiovascular event
A cardiac event was defined as occurrence of sudden cardiac death, stable or unstable angina, myocardial infarction, need for cardiac stent or coronary artery bypass grafting, congestive heart failure, atrial fibrillation, other atrial or ventricular arrhythmia requiring intervention or treatment, valvular heart disease, peripheral artery disease, or cerebrovascular disease (brain disorders related to diseases of blood vessels of the brain). Patients with peripheral artery disease had reduced blood supply to the lower limbs because of narrowing and hardening of the arteries.

Cardiac evaluation findings
The QT interval was corrected to the heart rate or R-R interval as QT/√R-R; normal results were those below 440 ms. Ejection fraction, the fraction of blood pumped by the heart with each beat, was calculated as stroke volume divided by end-diastolic volume.

Data collection
Medical records were reviewed for patient demo­graphics (age, sex, race, and body mass index); Model for End-Stage Liver Disease score; liver disease complications (ascites, hydrothorax, hepatocellular carcinoma); comorbidities, including risk factors for cardiovascular disease (concomitant hepatitis C virus infection, diabetes mellitus, hypertension, dys­lipidemia, cardiac disease, smoking, family history of heart disease); medication use before liver transplant (statins, beta blockers, clopidogrel, and aspirin); occurrence of posttransplant cardiovascular event; and survival status at the time of last follow-up. Patients were defined as smokers if they had a history of smoking until 5 years before the transplant. Cardio­pulmonary evaluation details were recorded for electrocardiogram, echocardiogram, dobutamine stress echocardiography, right heart catheterization, left heart catheterization, and pulmonary function test. Dobutamine stress echocardiography was done in accordance with the American Association for Study of Liver Diseases guidelines for patients ≥ 50 years old who have a history of chronic smoking or risk factors for cardiac disease.^14,15 Patients with right ventricular systolic pressure > 35 mm Hg on echocardiogram at our center underwent right heart catheterization for measurement of mean pulmonary arterial pressure. Patients with established coronary artery disease or with abnormal dobutamine stress echocardiography underwent left heart catheterization for coronary arterial patency. Time intervals between cardiopulmonary evaluation and liver transplant were recorded and analyzed. At our center, all patients receive steroids as induction immunosuppressive therapy, which are then tapered over 4 to 6 weeks and followed by maintenance immunosuppressive therapy with tacrolimus or cyclosporine in combination with mycophenolate mofetil. In addition, short-term use of corticosteroids is administered to treat patients with severe acute cellular rejection.

Statistical analyses
We compared the baseline characteristics of liver transplant recipients from NASH cirrhosis or from alcoholic cirrhosis using chi-square tests for categorical and t tests for continuous variables. Cardiovascular events and patient survival status within 3 years of liver transplant were analyzed. Patients who had no events at 3 years of follow-up were censored for respective outcomes. Kaplan-Meier survival curves were generated for (1) occurrence of cardiovascular events in transplant recipients with NASH cirrhosis versus alcoholic cirrhosis, (2) survival after transplant in patients with NASH cirrhosis versus alcoholic cirrhosis, and (3) survival after transplant in patients with versus without a cardiovascular event. Significant baseline results and other clinically relevant variables even if not significant were entered in a Cox proportional hazards regression model to examine predictors (including cause of liver disease by NASH vs alcoholic cirrhosis) of development of a cardiovascular event and of patient survival. We used Statistical Analysis Software (SAS) Version 9.3 (SAS Institute Inc, Cary, NC) for all statistical analyses. P < .05 was considered significant.

Results

Baseline characteristics
Demographics
We analyzed the medical records of 143 patients (78 patients with NASH). Patients who received liver transplants for NASH cirrhosis were older, more likely to be female, and more likely to have diabetes, hypertension, and a higher body mass index. Patients who received liver transplants for alcoholic cirrhosis were more likely to be hepatitis C virus positive, to be smokers, and have hepatocellular carcinoma (Table 1). We recorded 55 patients (38%) who had a family history of heart disease, with no significant difference between patients with alcoholic cirrhosis and NASH cirrhosis (Table 1). Similarly, patient groups were not significantly different in regard to presence of ascites, hepatorenal syndrome, and hepatopulmonary syndrome.

Pretransplant cardiovascular evaluation
Of 143 patients, 75 had a personal history of heart disease, with no significant difference between transplant recipients for NASH (55%) and alcoholic cirrhosis (49%; P = .48). Frequency of history of specific heart disease was also similar in the 2 groups (Table 2). Pretransplant cardiopulmonary evaluation details were recorded for electrocardiogram (n = 128), echocardiogram (n = 140), dobutamine stress echocardiography (n = 125), right side of the heart catheterization (n = 20), left side of the heart catheterization (n = 9), and pulmonary function test (n = 112) and are shown in Table 1. Transplant patients for NASH cirrhosis were less likely to have abnormal left ventricular size (23% vs 40%; P = .03), right ventricular size (34% vs 53%, P = .02), and pulmonary shunting (45% vs 69%; P = .048) than transplant recipients for alcoholic cirrhosis. On cardiac catheterization, NASH patients had higher systemic vascular resistance (718 ± 243 dyn·s/cm⁵ vs 388 ± 251 dyn s/cm⁵; P = .03).

Development of cardiovascular events after liver transplant
A total of 29 cardiovascular events developed in 20 patients (11 NASH) during the 3-year follow-up after transplant. No significant differences were shown between NASH and alcoholic cirrhosis transplant patients, with 4 patients in each group having multiple cardiovascular events (Table 2). When we analyzed all of the variables listed in Table 1, a significant difference between patients with a cardiovascular event (n = 20) and those without a cardiac event (n = 123) was only found for pretransplant history of peripheral arterial disease (1/20 vs 0/123; P = .014). When we compared the NASH and alcoholic cirrhosis transplant recipients, the cumulative probability of developing a cardiovascular event was similar at 1 year (7.7% vs 6.1%; P = .45) and at 3 years (14.1% vs 13.8%; P = .9) of follow-up (Figure 1). Our Cox proportional hazards regression model showed that concomitant hepatitis C virus infection (9-fold increase) and male sex (3-fold increase) predicted occurrence of cardiovascular events (Table 3). If we excluded the 18 patients (16 with alcoholic cirrhosis) who were hepatitis C virus-positive, the cumulative cardio­vascular event probability remained similar in transplant recipients for alcoholic cirrhosis and for NASH cirrhosis (14.5% vs 10.2%; P = .5).

Posttransplant patient survival
Overall, 18 patients (10 NASH) died on follow-up, although the 3-year results were similar between transplant patients for NASH and transplant patients for alcoholic cirrhosis (87.2 vs 86.4%; P = .95 with log-rank test). At 3-year follow-up after transplant, patients who had died had shown a higher frequency of cardiovascular events than those who were alive (33.3% vs 11.2%; P = .0013). Survival results for other baseline characteristics listed in Table 1 were similar. Compared with patients without a cardiovascular event, the probability of survival at 3 years after liver transplant was lower in the presence of a cardio­vascular event (70% vs 90.1%; P = .008) (Figure 2).

Of the 10 NASH patients who died, 7 died from sepsis and 1 each from gastrointestinal bleeding, aspiration, and cardiovascular event. Deaths in the 8 transplant patients for alcoholic cirrhosis were similar: 2 died from cardiovascular event, 2 from malignancy, 2 from sepsis, 1 from graft failure due to hepatic artery thrombosis, and 1 from respiratory failure. The proportion of patients with biopsy-confirmed rejection episodes was similar for transplant recipients for NASH versus alcoholic cirrhosis (13% vs 8%; P = .32).

Discussion

In summary, our analyses of patients who received a liver transplant between 2005 and 2010 at our institution found no differences in frequency of cardiovascular events after liver transplant when we compared recipients for NASH and alcoholic cirrhosis. Concomitant hepatitis C virus infection and male gender predicted development of cardio­vascular events after liver transplant. Patients who had a cardiovascular event after transplant were at a higher risk of death on follow-up.

Although the risk of a cardiovascular event before transplant is well established in patients with metabolic syndrome and NASH, data remain conflicting on NASH and its causes as a predictor of cardiovascular events after liver transplant. It is known that transplant patients are more likely to develop a cardiovascular event, likely due in large part to development of posttransplant metabolic syndrome^7,8; however, we found that NASH and its causes as an indication for liver transplant is not an independent risk factor. Furthermore, we found no significant differences at 3 years in the type of events experienced between the 2 groups. Patients with alcoholic cirrhosis were more likely to have concomitant hepatitis C virus infection than patients with NASH cirrhosis. However, when we excluded patients with hepatitis C virus infection, the probability of a cardiovascular event remained similar between transplant recipients for NASH and alcoholic cirrhosis.

A recent study showed similar results that the cause of liver disease (from NASH or alcoholic cirrhosis) is not a predictor for cardiovascular events. However, on subgroup analysis, the authors concluded that trans­plant patients for NASH cirrhosis versus those for alcoholic cirrhosis remain at higher risk for early cardiovascular event within 1 year after liver transplant.

In our study, the probability of developing a cardiovascular event was similar between the NASH and alcoholic cirrhosis patients even at 1 year after liver transplant. The relatively smaller sample size in our study and the higher proportion of patients with a history of pretransplant cardiovascular disease among NASH transplants in the other reported study may partly explain the differences in findings.¹¹ In a recently meta-analysis of 9 studies on 4237 patients who received a liver transplant for various liver diseases (717 NASH), no differences in patient survival at 1, 3, and 5 years was shown when transplant patients with NASH and without NASH were compared. However, the authors concluded that NASH patients died more often from cardiovascular causes than the other groups. This meta-analysis included studies comparing NASH to all other causes of liver disease. Furthermore, death because of a cardiovascular event and the frequency of a cardiovascular event were analyzed.16 When we pooled the data from the 3 studies, which including ours and 2 other studies,^11,17 and compared NASH recipients versus alcoholic cirrhosis recipients, the probability of a cardiovascular event-related mortality remained similar between the groups (16 of 264 patients vs 7 of 275 patients; mean, 2.3; range, 0.7-8.2; P = .19).

In our study, concomitant hepatitis C virus infection and male gender predicted a cardiovascular event after liver transplant. In a previous study, patients who received transplants for hepatitis C virus cirrhosis had higher rates of developing metabolic syndrome than transplant patients for other liver diseases.⁷ Studies are needed to examine mechanisms for association of hepatitis C virus infection with occurrence of a cardiovascular event after transplant.

Patients who experience a postoperative cardio­vascular event are at significantly higher risk for overall mortality. This difference was more striking at 3 years after liver transplant, with greater than 4-fold increased mortality in patients with a cardiovascular event. Early deaths are more likely related to graft or technical operative factors. With the availability of potent immunosuppressive therapies, cardiovascular diseases and malignancy remain the primary causes of long-term patient mortality.¹⁰ Patients should remain closely observed after transplant with a high index of suspicion and low threshold for cardiovascular evaluation.

Our retrospective study design also may be limited by a potential selection bias of including only patients undergoing liver transplant. Larger prospective multicenter studies are suggested to develop a uniform protocol for cardiovascular evaluation, with the goal of improving outcomes of prospective liver transplant recipients. In summary, in an evenly matched group of NASH and alcoholic cirrhosis patients, there is no significant difference in the occurrence or type of cardiovascular event. Patients experiencing cardiac events after transplant remain at higher risk for mortality regardless of the cause for liver transplant.

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