Objectives: The incidence of hepatocellular carcinoma associated with nonalcoholic fatty liver disease is increasing. We sought to compare tumor characteristics and outcomes after a liver transplant according to the cause of liver disease and ethnicity.

Materials and Methods: We retrospectively evaluated patients with hepatocellular carcinoma (292, 23%) out of all the liver transplant recipients (N=1266) at the University of Miami between 2000 and 2010. Liver disease was caused by hepatitis C virus in 221 patients (76%), nonalcoholic fatty liver disease in 19 patients (6.5%), hepatitis B virus in 20 patients (7%), alcohol in 44 patients (15%), and other in 18 patients (6%). The median age was 57 years (range, 17 to 77 y), 218 were men (75%), 270 were white (92%), and 92 were Hispanic (31.5%).

Results: Patients with hepatocellular carcinoma and nonalcoholic fatty liver disease were more likely to be older (64 vs 57; P = .0006), Hispanic (58% vs 30%; P = .018); nonsmokers (89% vs 65%; P = .041), diabetic (84% vs 26% P < .0001), hypertensive (63% vs 27%; P = .003), and using statins (32% vs 4%; P = .0004) compared with hepatocellular carcinoma without nonalcoholic fatty liver disease. Diabetes, hypertension, and nonalcoholic fatty liver disease are significantly more common in Hispanics than in non-Hispanic persons with hepatocellular carcinoma. In persons without hepatocellular carcinoma, the proportion of Hispanics was similar between those with (n=84) and those without (n=1182) nonalcoholic fatty liver disease. Hispanic ethnicity was not associated with worse tumor behavior or overall survival.

Conclusions: Patients transplanted for hepatocellular carcinoma and nonalcoholic fatty liver disease were older, and were more frequently Hispanic than were persons with hepatocellular carcinoma and without nonalcoholic fatty liver disease. Hispanic ethnicity may be a risk factor for hepatocellular carcinoma.

Key words : Hepatoma, Hispanic, Steatosis, Nonalcoholic fatty liver disease, Metabolic syndrome

Introduction

Liver transplant (LT) is the definitive treatment for decompensated liver cirrhosis; it also is a well-established treatment option for hepatocellular carcinoma (HCC) in the setting of cirrhosis.¹ Hepatocellular carcinoma is the third leading cause of cancer mortality worldwide.² This increased incidence of HCC in developed countries parallels the epidemic of obesity³; both diabetes mellitus and obesity are established as independent risk factors for the development of HCC.⁴ In most cases, HCC develops on a background of cirrhosis, most frequently caused by hepatitis C virus in North America and Western Europe, or hepatitis B virus in areas of the world such as sub-Saharan Africa and South East Asia.^5-8 The most frequent cause of chronic liver disease in developed countries is now nonalcoholic fatty liver disease (NAFLD). It is anticipated that the prevalence of NAFLD in LT candidates also will increase.

Few studies have examined liver diseases in US minorities, but the Hispanic population presents a higher incidence and a more aggressive pattern of chronic liver diseases,⁹ and LTs are now performed more frequently in Hispanics.¹⁰ The Hispanic population now has surpassed other racial and ethnic groups, and is the largest and fastest growing US minority.¹¹ Moreover, an increased prevalence of the metabolic syndrome in Hispanics has been well documented.¹² Genetic markers of fat liver accumulation have been observed in Hispanic pediatric population.¹³ Additionally, significant racial and ethnic disparities in the outcomes of patients with HCC have been reported, with blacks having poorer graft and overall posttransplant survival.^14,15 We sought to compare outcomes after liver transplant according to cause of liver disease, with an emphasis on HCC and ethnicity.

Materials and Methods

Methods
Our transplant database of all adults (age ≥ 18 y) who underwent their first LT at the University of Miami between January 2000 and January 2011 was reviewed for liver diagnosis, ethnicity, and presence of HCC.

The following information was collected: age at LT, race/ethnicity, sex, diagnosis of liver disease, presence of HCC, body mass index, and patient and graft survival. Additionally, for patients with HCC and cryptogenic/NAFDL cirrhosis, clinical data including prior history or diagnosis of diabetes mellitus, hypertension, dyslipidemia or obesity, and laboratory data including serum creatinine, albumin, sodium, bilirubin, aminotransferases, gamma glutamyl transferase, alkaline phosphatase, cholesterol, triglycerides, uric acid, and alpha-fetoprotein as well as platelet count and international normalized ratio were obtained immediately before an LT. The following HCC characteristics also were collected: number and size of tumors, tumor differentiation, HCC incidentally found on explants, vascular invasion, and treatment received before the LT.

Follow-up was defined as the time from transplant to the last visit after an LT. Visits were conducted on an outpatient basis, and all patients received the same intraoperative, and postoperative care; main immunosuppressant regimen protocol was tacrolimus with a tapering dosage of prednisone within 6 months, with or without mycophenolate mofetil. Rapamycin was used in a few recipients, depending on the physician’s judgment.

In 1997, the US Office of Management and Budget published a document called, the Report and Recommendations on the Review of Directive No. 15, in which they addressed the important issues on how to report race/ethnicity. The report considers a person of “Hispanic or Latino” dissent as someone who comes from Cuban, Mexican, Puerto Rican, South or Central American, or other Spanish culture, or origin, regardless of race.¹⁶ Hispanic and non-Hispanic persons were viewed as having a heritage, nationality, lineage, or country of birth of the person, or the person’s parents, or ancestors before their arrival in the United States. Ethnicity was self-reported by the patients.

Consistent with the American Association for the Study of Liver Diseases Guidelines, patients with cirrhosis were referred for an LT when they had evidence of hepatic decompensation (Child-Turcotte-Pugh score ≥ 7 or model for end-stage liver disease score ≥ 10), or when they experienced an index complication (ascites, variceal bleeding, or hepatic encephalopathy) or a diagnosis of HCC.17 This study was approved by the local institutional review board. All protocols conformed with the ethical guidelines of the 1975 Helsinki Declaration.

Definitions
Hepatocellular carcinoma was confirmed either by radiologic criteria¹⁸ or by histologic documentation. Radiologic diagnosis was defined according to the American Association for the Study of Liver Diseases practice guidelines on managing HCC. According to these guidelines, radiologic diagnosis of HCC is defined as either (1) the presence of a hepatic lesion > 2 cm in diameter with typical vascular pattern for HCC on 1 dynamic imaging technique or alpha-fetoprotein > 200 μg/L, or (2) the presence of a lesion 1 to 2 cm in diameter, with a typical vascular pattern for HCC on 2 dynamic imaging techniques.¹⁸ We did not restrict the study to explant data, because we used pre-LT ablative therapy, leading to complete tumor necrosis in several patients.

The diagnosis of diabetes mellitus was made at the time of transplant using criteria recommended by the American Diabetes Association and Expert Committee on the Diagnosis and Classification of Diabetes Mellitus (fasting blood glucose value > 6.99 mmol/L [126 mg/dL] on 2 separate occasions in those persons not receiving hypoglycemic agents or corticosteroids). Patients who were taking insulin or oral hypoglycemic agents were assumed to have diabetes mellitus. Alcoholic liver disease was defined by the consumption of more than 2 drinks daily or more than 14 drinks per week for the past 5 years.¹⁹ Cryptogenic cirrhosis was diagnosed when no clear cause for liver disease was present, in the absence of the metabolic syndrome. For the purposes of this study, cryptogenic cirrhosis in the setting of the metabolic syndrome was considered NAFLD.

Nonalcoholic fatty liver disease was defined according to the clinical and histologic features of nonalcoholic steatohepatitis, before LT or on explanted liver, or cryptogenic cirrhosis in the presence of the metabolic syndrome without a history of significant alcohol intake. The metabolic syndrome was defined according to AHA/National Cholesterol Education Program Adult Treatment Plan III updated (2005),^20,21 except for minor modifications.^22,23 Because of incomplete data regarding waist circumference, body mass index ≥ 30 kg/m² was used instead. Thus, the metabolic syndrome was assumed if at least 3 of the following criteria were fulfilled:

1. Body mass index ≥ 30 kg/m²
2.  Elevated triglycerides > 1.7 mmol/L (150 mg/dL), or on drug treatment for elevated triglycerides
3. Elevated cholesterol level ≥ 5.18 mmol/L (200 mg/dL) or drug treatment for hyper­cholesterolemia
4. Elevated systolic blood pressure > 130 mm Hg, or diastolic blood pressure > 85 mm Hg, or on antihypertensive drug treatment in a patient with hypertension
5. Elevated fasting glucose > 5.55 mmol/L (100 mg/dL) or use of hypoglycemic therapy.

Statistical analyses
Statistical analyses were performed using JMP and SAS (SAS Institute v9.2, Cary, North Carolina, USA). Baseline characteristics were summarized using descriptive statistics. The chi-square test was used to compare the frequency of binary outcomes. Univariate statistics were calculated to examine the distribution of continuous variables relative to outcomes. The chi square and the t tests were used for statistical comparisons. A 2-tailed P value < .05 was considered statistically significant. Kaplan-Meier curves and survival estimates were generated in SAS.

Results

During the study, 1266 first LTs were performed in adults (>18 y) at the University of Miami. Table 1 shows the baseline and follow-up characteristics of the LT recipients according to ethnicity. Thirty-two percent (410) of LT recipients were of Hispanic descent. There were more female Hispanics than males (71% vs 59%; P < .0001), and they had a higher body mass index (26.1 vs 27.4; P = .003), and were more often white than black in origin. The prevalence of various causes of liver disease was similar between Hispanics and non-Hispanics, including that of NAFLD. Interestingly, at the end of the follow-up, the percentage of functioning grafts was higher in Hispanics compared with non-Hispanics (73% vs 66%; P = .023).

Characteristics of the LT recipients with (n=292) and without HCC (n=965) were different with respect to age and sex. Liver transplant recipients with HCC were more frequently of the male sex ([217/292, 74%] vs [619/965, 64%]; P = .0010 and older (58 ± 8 vs 52 ± 11; P < .0001). They died more frequently of liver-related disease ([59/103, 57%] vs [94/244, 38%]; P = .001) and follow-up was shorter (3.8 ± 2.8 vs 4.8 ± 3.8 y; P = .0003). The frequency of Hispanic ethnicity was similar between LT recipients with (33%) and without HCC (32%). Of the 292 patients with HCC, 52 had incidental tumors not identified before transplant (18%). Of 292 patients, 19 had NAFLD (6.5%), 221 had hepatitis C virus (76%), and 19 hepatitis B virus (6.5%). Alcohol consumption was identified as a risk factor for liver cirrhosis in 44 patients (15%), of whom 29 had viral hepatitis. Patients were predominantly male (n=218; 75%), white (n=270; 92%), with median age of 57 years (range, 17 to 77 y), and 92 were Hispanic (31.5%).

Treatment for HCC was performed in 151 patients before the LT as follows: microwave ablation (11; 3.4%), radiofrequency ablation (68; 23%), transarterial chemoembolization (52; 17%), resection (5; 2%), and combined treatment (14; 5%). For the remaining 141 patients (48%), the only intervention was the LT. After a median follow-up of 3.7 y (range, 0 to 11 y), tumor recurrence was diagnosed in 41 patients (14%).

Hepatocellular carcinoma and nonalcoholic fatty liver disease
Table 2 compares the characteristics of HCC recipients with and without NAFLD; the former group was more likely to be older (64 [range, 51 to 73 y] vs 57 [range, 29 to 77 y]; P = .0006), Hispanic (58% vs 30%, P = .018), a nonsmoker (89% vs 65%; P = .041), more frequently diabetic (81% vs 28%; P < .0001), hypertensive (63% vs 26%; P = .002), and using statins (32% vs 4%; P = .0004). Laboratory parameters were not significantly different between the groups except for serum aspartate aminotransferase (1.8 ± 3 vs 1.84 ± 1.4 μkat/L [108 ± 180 vs 110 ± 82 U/L]; P = .025), although this was not clinically significant.

Regarding tumor characteristics (Table 2), there were no significant differences in tumor grade, frequency of vascular invasion, size and number of lesions, total tumor burden before the LT, frequency of recurrence, or serum alpha-fetoprotein level between patients with and without NAFLD. The frequencies of incidental tumors and of pre-LT treatment of HCC also were similar between groups.

Effect of ethnicity
Table 3 shows recipient characteristics according to ethnicity. We found that diabetes (40% vs 24%; P = .009), hypertension (45% vs 22%; P = .001), and NAFLD (12% vs 4%; P = .018) were significantly more common in Hispanics with HCC than in non-Hispanics with HCC. No difference in the frequency of HCC according to ethnicity was seen in other liver disease causes. Hispanics were, on average, 2 years older than non-Hispanics (P = .008). Laboratory parameters were not different between Hispanics and non-Hispanics.

Regarding tumor characteristics, there were no differences between groups with respect to tumor grade moderate/poorly differentiated (63% vs 64%; P = .5), presence of vascular invasion (34% vs 25%; P = .15), prior ablative treatment (48% vs 53%; P = .2), total tumor burden (4.2 ± 1.9 vs 4.2 ± 1.9; P = .2), recurrence rates (20% vs 15%; P = .3), and serum alpha-fetoprotein levels (413 vs 345 μg/L (ng/dL); P= .12).

Outcomes
Hepatocellular carcinoma patients had a median follow-up of 3.7 years (range, 0 to 11 y). One hundred eight patients died during the study, 8 in the HCC/NAFLD group (42%), and 100 in the HCC/non-NAFLD group (37%; P = .6). Deaths were liver-related in 4/8 in HCC/NAFLD recipients (50%), and 55/97 in HCC/non-NAFLD recipients (57%; P = .72). Survival analyses showed no difference between HCC/NAFLD and HCC/non-NAFLD (P = .29). Similarly, Hispanics with HCC compared with non-Hispanics with HCC had no difference in survival (1-y survival 82%, and 5-y survival 67%) vs (1-y survival 87%, and 5-y survival 62%; P = .77) (Figure 1A).

Median follow-up of the 1266 LT recipients was 4.1 years (range, 0 to 11 y) and 72% of patients were alive at the end of follow-up. Causes of death were liver-related in 44%, infection (23%), and cardiovascular (12%). There was no difference in survival between Hispanics (1-y survival, 86%; and 5-y survival, 76%) and non-Hispanics (1-y survival, 86%; and 5-y survival, 73%; P = .43) (Figure 1B).

Patients with NAFLD had a median follow-up of 4.1 years (range, 0 to 11 y). Three hundred fifty-nine patients died during the study: 17 (20%) in the NAFLD group, and 342 (29%) in the non-NAFLD group (P = .10). Deaths were liver-related in 4/17 patients (24%) in the NAFLD group, and 149 patients (45%) in the non-NAFLD group (Table 4; P = .13). Patients with NAFLD died more often from infections (5 [28%]), while patients transplanted for other reasons died more frequently from liver-related conditions (149 [45%]). This was not statistically significant, and the analyses were limited by the small number of patients. Survival analyses showed no difference between Hispanic NAFLD and non-Hispanic NAFLD (P = .29).

Discussion

Our study shows that patients transplanted for HCC with NAFLD (HCC/NAFLD) were older and more frequently of Hispanic origin than were patients transplanted for HCC for other causes (HCC/non-NAFLD), despite the prevalence of Hispanics being the same across causes for non-HCC patients undergoing liver transplant. Tumor pathology characteristics, rates of HCC recurrence after LT, and patient survival in those transplanted for HCC/NAFLD were similar to patients transplanted for HCC/non-NAFLD. Hispanics undergoing an LT were more likely to be women, be older, and have a higher body mass index compared with non-Hispanics. Interestingly, frequency of baseline liver disease was the same including NAFLD between Hispanics and non-Hispanics. Hispanics with HCC had more diabetes mellitus and hypertension than did non-Hispanics. Yet, all those LT factors taken before baseline seemed not to influence patient survival after the LT. Our findings agree with Artinyan and associates, who found better survival among Hispanics with HCC after an LT when compared with blacks.¹⁴

Ethnicity is thought to be an independent risk factor for NAFLD. Hispanic patients seem to have a higher incidence of chronic liver diseases as well as a more aggressive clinical course.⁹ Recent data suggest that Hispanics have an increased incidence of metabolic risk factors^12,24 and may be more predisposed to nonalcoholic steatohepatitis, a more severe form of NAFLD, compared with whites.^25-28 In another study from the United States, investigators found a trend toward an increased risk of fibrosis progression in Hispanics with diabetes.²⁹ Moreover, Alterkruse and associates found an increased risk of HCC among Hispanics.² Our study adds to this body of literature, demonstrating that more Hispanics are transplanted for HCC in the setting of NAFLD. Liver transplant has become more frequent in Hispanics.¹⁰ In the past decade, 10% of all LT recipients in the United States have been Hispanic. At our transplant center in Miami, one third of all LT recipients are Hispanic.

The incidence of HCC has tripled in the United States from 1975 through 2005, mainly among middle-aged blacks, white males, and Hispanics.² Furthermore, the incidence of HCC was found to be higher among Hispanics born in the United States, compared with foreign-born Hispanics, implicating environmental, socioeconomic, and cultural factors.³ The authors propose that factors associated with life in the United States, perhaps including hepatitis C virus infection, alcohol abuse, or obesity, may adversely affect Hispanics. Bhamba and associates found that Hispanics with NAFLD performed less physical activity and had higher carbohydrate diets compared with non-Hispanic whites with NAFLD.²⁶ In this study, we found that Hispanics undergoing an LT for HCC were more likely to be diabetic than were non-Hispanics. We did not evaluate diabetes as a predictor of HCC, but diabetes has already been recognized as an independent risk factor for HCC.^4,30 Of note, the frequency of chronic hepatitis C virus was similar between Hispanics and non-Hispanics in our population with HCC. Thus, it is possible that the risk of HCC in Hispanics is increased because of (1) an increased rate of fibrosis progression, and
(2) an increased prevalence of diabetes, in addition to other potential genetic markers that are as of yet unknown. This combination of risk factors, if confirmed in further studies, could warrant specific preventive and screening strategies.

Finally, tumor characteristics, recurrence, and survival rates were not different between cases of HCC/NAFLD and HCC/non-NAFLD, although it is important to note that the number of deaths among HCC/NAFLD patients was small. Our results agree with those of Malik and associates who also verified similar tumor behavior after an LT in patients with and without NAFLD.⁸

In conclusion, our study shows a higher frequency of Hispanics were transplanted for HCC/NAFLD compared with patients transplanted for HCC/non-NAFLD, and also, Hispanics undergoing LT for HCC had a higher frequency of the metabolic syndrome. Importantly, being Hispanic did not confer a worse outcome after transplant. Our results apply to patients who actually underwent LT for HCC; therefore, larger studies are recommended to assess the effect of ethnicity, diabetes mellitus, and NAFLD on the risk of HCC and to further optimize HCC surveillance strategies in Hispanics with NAFLD.

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