Obesity Is an Independent Risk Factor for Hepatocellular Carcinoma Development in Chronic Hepatitis C Patients

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1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2008;6: Obesity Is an Independent Risk Factor for Hepatocellular Carcinoma Development in Chronic Hepatitis C Patients TAKAMASA OHKI, RYOSUKE TATEISHI, TAKAHISA SATO, RYOTA MASUZAKI, JUN IMAMURA, TADASHI GOTO, NORIYO YAMASHIKI, HIDEO YOSHIDA, FUMIHIKO KANAI, NAOYA KATO, SHUICHIRO SHIINA, HARUHIKO YOSHIDA, TAKAO KAWABE, and MASAO OMATA Department of Gastroenterology, University of Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan See Loomba R et al on page 953 for companion article in the April 2008 issue of Gastroenterology. Background & Aims: It is not fully elucidated whether obesity enhances hepatocarcinogenesis in patients with chronic hepatitis C. The aim of this study was to investigate the relationship between body weight and risk of hepatocarcinogenesis in chronic hepatitis C patients. Methods: We enrolled 1431 patients with chronic hepatitis C who visited our liver clinic between 1994 and 2004, excluding those with hepatocellular carcinoma (HCC) at their visit or with a previous history of HCC. They were divided into 4 groups according to body mass index (BMI): underweight (<18.5 kg/m 2,N 112); normal (18.5 to less than 25 kg/m 2, N 1023); overweight (25 to less than 30 kg/m 2,N 265); and obese (>30 kg/m 2,N 31). We assessed the impact of obesity on the hepatocarcinogenesis adjusted by multivariate Cox proportional hazard regression with other risk factors found significant in univariate analysis. Results: During the follow-up period (mean, 6.1 y), HCC developed in 340 patients, showing cumulative incidence rates of 10.5%, 19.7%, and 36.8% at 3, 5, and 10 years, respectively. The incidence differed significantly among the BMI groups (P.007). Adjusting for other significant factors, overweight and obesity were shown to be an independent risk factor of HCC, with a hazard ratio of 1.86 (95% confidence interval, ; P.022) and 3.10 (95% confidence interval, ; P.005) as compared with the underweight patients. Conclusions: The risk of HCC in patients with chronic hepatitis C increases in proportion to BMI in a wide range of its values, from underweight to obese. Chronic hepatitis C virus (HCV) infection affects more than 170 million people worldwide currently, posing a major health care problem. The prevalence is between 1% and 3% in the United States, 1 Southern European countries, 2,3 and Japan. 4 Although acute HCV infection usually is asymptomatic or accompanied by only mild nonspecific symptoms, chronic infection follows in as much as 80% of cases. 2 Once chronicity has been established, spontaneous clearance of viremia is rare, and cirrhosis may develop in 20 to 30 years. 2 According to a previous report, about one third of patients showed progression to cirrhosis in 20 years or less, whereas no progression in fibrosis was noted in another third for 30 years or longer. 5 Factors reported to accelerate fibrosis include old age, male sex, heavy alcohol intake, and immunosuppressive states such as co-infection with human immunodeficiency virus. 5 9 Once cirrhosis is established, the risk of hepatocellular carcinoma (HCC) development is increased to 1% to 4% per year. 2,10 Much higher incidence rates, 5% to 8% per year, are reported from Japan Thus, the risk factors that accelerate fibrosis are also risk factors for HCC development. Recently, various epidemiologic and other studies extensively have investigated possible risk factors of liver cancer caused by chronic hepatic diseases, identifying sex, age, severity of hepatic inflammation and fibrosis, and race. 4,14,15 In addition, interest in nonalcoholic fatty liver disease has prompted investigation of additional possible risk factors including comorbidity with diabetes mellitus, 4,15,16 obesity as indicated by body mass index (BMI), 14,17,18 and hyperinsulinemia. 19,20 Muto et al 21 and Ioannou et al 22 also reported that a BMI higher than 25 kg/m 2 was a risk factor for hepatocarcinogenesis. Although those previous reports did not evaluate hepatocarcinogenesis among HCVpositive patients in particular, it can be speculated that a higher BMI is an independent risk factor for hepatocarcinogenesis in chronic hepatitis C patients. Thus, we conducted this retrospective, follow-up study with consecutive patients to assess the potential effects of obesity on hepatocarcinogenesis among chronic hepatitis C patients. Patients and Methods Patients Between January 1994 and December 2004, a total of 1954 HCV RNA positive patients, excluding those with HCC or a past history of it, visited the liver clinic of the Department of Gastroenterology at the University of Tokyo Hospital. We analyzed 1431 of these patients, excluding 87 patients with concomitant hepatitis B virus surface antigen positivity and 423 patients who visited only for consultation purposes. Thirteen patients with intractable ascites also were excluded because this study was focused on the relationship between obesity and hepatocarcinogenesis and the amount of ascites affects body weight in these patients. These patients were all Japanese. All Abbreviations used in this paper: AFP, -fetoprotein; ALT, alanine aminotransferase; BMI, body mass index; CI, confidence interval; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; SVR, sustained virologic response by the AGA Institute /08/$34.00 doi: /j.cgh

2 460 OHKI ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 6, No. 4 blood tests were performed at the first visit of each patient. BMI was calculated as body weight in kilograms divided twice by body height in meters, which also was measured routinely at the first visit of each patient. Patients were divided into 4 groups by their BMI according to World Health Organization criteria 23 : underweight when the BMI is 18.5 kg/m 2 or less, normal when the BMI is 18.5 to 25 kg/m 2, overweight when the BMI is 25 to 30 kg/m 2, and obese when the BMI is greater than 30 kg/m 2.A diagnosis of diabetes mellitus was based on medical history or a 75-g oral glucose tolerance test. 24 Heavy alcohol consumption was defined as drinking alcohol equivalent to 100% ethanol of more than 80 g/day. 25,26 The amount of alcohol intake routinely was asked at the first visit in a questionnaire. Past history of blood transfusion before the diagnosis of chronic hepatitis also was examined. Human immunodeficiency virus antibody was not tested for routinely because the prevalence of human immunodeficiency virus co-infection among HCV-positive patients is very low in Japan. 27 We also examined the history of interferon therapies and responses during the follow-up period. A sustained virologic response (SVR) was defined as undetectable HCV RNA at least 24 weeks after the end of therapy. Patient Follow-Up Evaluations and Diagnosis of Hepatocellular Carcinoma Each patient was screened for HCC with ultrasonography at or immediately after the first visit and those in whom HCC was detected were not included in this study. Afterward, patients were followed up at the outpatient clinic with blood tests including tumor markers and ultrasonography every 3 to 6 months. Contrast-enhanced computerized tomography was performed when the serum -fetoprotein (AFP) level showed an abnormal increase and/or tumors were detected as possible HCC in ultrasonography. 28 HCC was diagnosed by dynamic computerized tomography, considering hyperattenuation in the arterial phase with washout in the late phase as the definite sign of HCC. 29 When diagnosis of HCC was not clear, ultrasound-guided tumor biopsy was performed and pathologic diagnosis was made based on Edmondson and Steiner 30 criteria. Observations were censored on June 30, Statistical Analysis Data were expressed as the median and range (25th 75th percentiles) unless otherwise indicated. Continuous variables were compared among groups by analysis of variance (parametric) or the Kruskal Wallis test (nonparametric). Trends in accordance with BMI were assessed with the exact trend test (proportion) or the Jonckheere Terpstra test (continuous variables). A P value of less than.05 on a 2-tailed test was considered significant. The annual incidence of hepatocarcinogenesis in each group was assessed by person-year method. The cumulative incidence of HCC was estimated using the Kaplan Meier method. In the analysis of risk factors for hepatocarcinogenesis, we tested the following variables obtained at the time of entry in univariate and multivariate Cox proportional hazard regression analyses: age, sex, BMI, heavy alcohol drinking, comorbidity with diabetes mellitus, serum albumin concentration, total bilirubin concentration, alanine aminotransferase (ALT) levels, prothrombin time activity, platelet counts, and -fetoprotein (AFP) concentration. We also performed sensitivity analysis among those who did not receive interferon therapies during the follow-up period. Multichotomous categoric variables were represented by corresponding binary dummy variables. Data processing and analysis were performed by using the S-PLUS 2000 (MathSoft Inc., Seattle, WA). Results Patient Profiles Baseline characteristics of patients, 727 men and 704 women, are shown in Table 1. There were 112 underweight patients, 1023 normal-range BMI patients, 265 overweight patients, and 31 obese patients. Heavy alcohol consumption was noted in 70 patients (4.9%) and diabetes mellitus was detected in 133 patients (9.3%). There were 271 patients whose AFP level exceeded 20 ng/ml ( 100 ng/ml in 46 patients and 400 ng/ml in 8 patients). We compared age, sex, heavy alcohol consumption, comorbidity with diabetes mellitus, serum albumin level, total biliru- Table 1. Baseline Characteristics Variable Total (n 1431) Underweight (n 112) Normal BMI (n 1023) Overweight (n 265) Obese (n 31) P Age, y a 60.1 ( ) 64.3 ( ) 60.3 ( ) 59.1 ( ) 55.9 ( ).009 b Male, n (%) 727 (50.8) 44 (39.3) 528 (51.2) 141 (53.2) 14 (45.2).15 c Drinking 80 g/day, n (%) 70 (4.9) 5 (4.5) 51 (5.0) 13 (4.9) 1 (3.2).92 c Diabetes mellitus, n (%) 133 (9.3) 11 (9.8) 88 (8.6) 27 (10.2) 7 (22.6).11 c Serum albumin level, g/dl a 4.0 ( ) 4.0 ( ) 4.1 ( ) 4.0 ( ) 3.9 ( ).99 d Total bilirubin level, mg/dl a 0.7 ( ) 0.6 ( ) 0.7 ( ) 0.8 ( ) 0.7 ( ).0001 d ALT level, IU/L a 61.0 ( ) 51.0 ( ) 61.0 ( ) 69.0 ( ) 80.0 ( ).04 b Prothrombin time activity (%) a 84.8 ( ) 88.9 ( ) 85.3 ( ) 80.6 ( ) 85.2 ( ).95 d Platelet count, 10 3 / L a 153 ( ) 153 ( ) 153 ( ) 149 (92 194) 153 ( ).95 b AFP level 20 ng/ml, n (%) 271 (18.9) 11 (9.8) 190 (18.6) 64 (24.1) 6 (19.4).0047 c Patients who received 209 (14.6) 8 (7.1) 151 (14.8) 48 (18.1) 2 (6.5).102 c interferon, n (%) Patients who achieved SVR, n (%) 69 (4.8) 1 (0.89) 55 (5.4) 13 (4.9) 0 (0).75 c a Expressed as median (25th 75th percentiles). b Analysis of variance test. c Exact trend test. d Jonckheere test.

3 April 2008 OBESITY AS A RISK FACTOR OF HCC 461 underweight group, 197 (19.3%) in the normal BMI group, 40 (15.1%) in the overweight group, and 6 (19.4%) in the obesity group (P.47 by the Fisher exact test). By the end of the follow-up period, HCC developed in 340 patients (3.9% per 1 person-year). The cumulative incidence rates of HCC at 3, 5, and 10 years estimated by the Kaplan Meier method were 10.5%, 19.7%, and 36.8%, respectively. Cumulative incidence rates at 3, 5, and 10 years in each group were 3.8%, 10.4%, and 29.6% (3.0% per 1 person-year) in the underweight group; 10.5%, 19.6%, and 36.0% (5.1% per 1 person-year) in the normal BMI group; 13.8%, 23.0%, and 42.7% (5.8% per 1 person-year) in the overweight group; and 6.7%, 29.2%, and 41.2 % (7.2% per 1 person-year) in the obese group, respectively (Figure 1). The incidence rates differed significantly among the 4 groups (P.007 by the log-rank test), increasing in accordance with BMI (Figure 1). Figure 1. Cumulative incidence of HCC divided by BMI. Dotted line, BMI of 18.5 kg/m 2 or less; small-dash line, BMI of 18.5 to less than 25 kg/m 2 ; long-dash line, BMI of 25 to less than 30 kg/m 2 ; solid line, BMI of greater 30 kg/m 2. Overweight and obese patients were revealed to be at significantly higher risk (P.022 and.005), respectively, as compared with underweight patients. P.007 by the log-rank test. bin level, ALT level, prothrombin time activity, platelet count, and AFP positivity ( 20 ng/ml) among the 4 groups (Table 1). A total of 15 patients were excluded from this analysis because of warfarin administration affecting prothrombin time activity (2 patients in the underweight group, 11 in the normal BMI group, and 2 in the overweight group). There was a significant difference in the mean age among the BMI groups (P.009 by analysis of variance), decreasing in the order of BMI, and the mean ALT level among the BMI groups (P.04 by analysis of variance), increasing in the order of BMI. The increasing trend in total bilirubin level over BMI also was statistically significant (P.0001 by Jonckheere test), whereas the trends in serum albumin level and prothrombin time activity were not. The proportion of patients positive for AFP ( 20 ng/ml) significantly increased with BMI (P.0047 by exact trend test). The number (proportion) of patients who had a history of blood transfusion before the diagnosis of chronic hepatitis was 61 (55%), 471 (46%), 106 (40%), and 17 (55%) in the underweight, normal, overweight, and obese patients, respectively. The median duration of infection estimated from the year of blood transfusion was 35, 34, 35, and 30 years in the underweight, normal, overweight, and obese patients, respectively. There was no statistical significance on the proportion of those with blood transfusion and the duration of infection. During the follow-up period, a total of 209 patients received interferon therapies and 69 patients achieved SVR (Table 1). The proportion of patients who received interferon therapies was the highest in the obese group but there was no significant trend over BMI (P.102 by exact trend test). There was no significant trend of the proportion of patients who achieved SVR rates over BMI (P.75 by exact trend test). Incidence of Hepatocellular Carcinoma The mean follow-up period was 6.1 years or 8729 personyears overall and 6.6 years, 6.0 years, 5.9 years, and 7.1 years for underweight, normal BMI, overweight, and obese groups, respectively. During the follow-up period, a total of 264 (18.4%) patients had been lost to follow-up evaluation: 21 (18.8%) patients in the Risk Analyses Univariate analyses showed that the normal, overweight, and obese patients had a higher risk of HCC, in this order of magnitude, than the underweight patients (Table 2). Other significant risk factors for HCC included older age, male sex, comorbidity with diabetes mellitus, heavy alcohol intake, lower serum albumin level, higher total bilirubin level, higher ALT level, lower prothrombin time activity, lower platelet counts, and AFP greater than 20 ng/ml. These factors were assessed by using a multivariate proportional hazard regression model (Table 3). The overweight and obese patients were revealed to be at significantly higher risk with a hazard ratio of 1.86 (95% confidence interval [CI], ; P.022) and 3.10 (95% CI, ; P.005), respectively, as compared with the underweight patients. Patients with a normal BMI also showed higher risk but did not reach statistical significance (relative risk, 1.52; P.094). Comorbidity with diabetes mellitus did not reach statistical significance either (relative risk, 1.26; P.15). The other risk factors indicated to be significant were older age, male sex, heavy alcohol intake, AFP level greater than 20 ng/ml, and laboratory parameters indicative of more advanced liver diseases, such as serum albumin level. The ALT level did not reach statistical significance (relative risk, 1.001; P.16). Table 2. Risk Factors for HCC Development: Univariate Analysis Variable Hazard ratio (95% CI) P Age (per 1 year old) 1.07 ( ).001 Male sex 1.95 ( ).001 Diabetes mellitus 1.58 ( ).005 Alcohol 80 g/day 2.04 ( ).001 BMI 18.5 kg/m kg/m 2 to 25 kg/m ( ) kg/m 2 to 30 kg/m ( ) kg/m ( ).045 Serum albumin level (per 1.0 g/dl) 0.20 ( ).001 Total bilirubin level (per 1.0 mg/dl) 1.90 ( ).001 ALT level (per 1 IU/L) ( ).001 Prothrombin time activity (per 1%) 0.94 ( ).001 Platelet count (per 10 3 / L) 0.98 ( ).001 AFP level 20 ng/ml 4.57 ( ).001

4 462 OHKI ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 6, No. 4 Table 3. Risk Factors for HCC Development: Multivariate Analysis Variable Hazard ratio (95% CI) P Age (per 1 year old) 1.07 ( ).001 Male sex 2.10 ( ).001 Diabetes mellitus 1.26 ( ).15 Alcohol 80 g/day 1.41 ( ).015 BMI 18.5 kg/m kg/m 2 to 25 kg/m ( ) kg/m 2 to 30 kg/m ( ) kg/m ( ).005 Serum albumin level (per 1.0 g/dl) 0.55 ( ).001 Total bilirubin level (per 1.0 mg/dl) 0.80 ( ).016 ALT level (per 1 IU/L) ( ).16 Prothrombin time activity (per 1%) 0.97 ( ).001 Platelet count (per 10 3 / L) 0.92 ( ).001 AFP level 20 ng/ml 1.77 ( ).001 The increasing risk of HCC development in proportion to BMI also was shown in the subgroup analysis in patients who did not have a history of interferon therapies during the follow-up period (n 1222). Among these interferon-untreated patients, overweight and obese patients were at significantly higher risk with a relative risk of 1.94 (95% CI, ; P.014) and 3.18 (95% CI, ; P.0043) as compared with the underweight patients, respectively. Discussion The increasing prevalence of obesity, which leads to various morbidities, is now a major concern in the health care system in developed countries. 16,17,31 34 It is well documented that obesity contributes to the development of various diseases including diabetes, hypertension, cardiovascular, and cerebrovascular with increased mortality. In addition, obesity is also known as a risk factor of cancers. Calle et al 17 reported that obesity was associated with increased mortality from various cancers including esophagus, colorectal, stomach, breast, ovary, and liver cancer. Our current study showed that obese patients with chronic hepatitis C were at a higher risk of HCC with an adjusted relative risk of 3.10 compared with underweight patients. N Kontchou et al 35 also reported overweight as an independent risk factor of hepatocarcinogenesis in chronic hepatitis C patients. In the current study, we also found a tendency of higher risk of HCC even in normal BMI patients than in underweight ones. Thus, the risk of HCC appears to increase in proportion to BMI in a wide range of its values, from underweight to obese. Because this study was observational, we cannot determine whether obesity directly enhances hepatocarcinogenesis. One possibility is that obesity affects hepatocarcinogenesis through changes in the levels of adipocytokines. Reportedly, the plasma level of adiponectin is correlated negatively with BMI and differs substantially even between underweight ( 18.5 kg/m 2 ) and normal-range ( kg/m 2 ) BMI, 36 and a lower level of adiponectin, a major adipose cytokine, is associated with the risk of several cancers. 37,38 Another possible hypothesis may be that obesity promotes hepatocarcinogenesis through steatosis in the liver. The association between liver steatosis and HCC has been reported recently among HCV-positive patients. 18,39 41 Hepatic steatosis, which also is associated closely with obesity, causes hepatic inflammation in the liver without hepatitis viruses 32,34,42 44 and the underlying mechanisms are well investigated in nonalcoholic steatohepatitis. Although we did not assess fatty changes in each patient, the fact that a higher BMI correlated with a higher ALT level suggests that steatosis-related hepatic inflammation may play a role also in hepatocarcinogenesis in chronic hepatitis C patients. The mechanisms by which steatosis promotes fibrosis in chronic hepatitis C currently are under investigation. Some piece of evidence implicates enhanced oxidative stress, activation of subsinusoidal stellate cells, and increased susceptibility to apoptosis. 45 There is obviously a strong relationship between diabetes and obesity. Several large-scale cohort studies reported that diabetes was a significant risk factor for primary liver cancer. 16,46 In the current study, however, the presence of diabetes mellitus was associated significantly with the risk of HCC in univariate analysis but did not retain significance in multivariate analysis controlling for BMI. The effect of insulin resistance on hepatocarcinogenesis is difficult to assess because HCV infection is reported to induce insulin resistance by itself. 47 Further studies with data on insulin resistance are required to elucidate the exact contribution of diabetes mellitus on hepatocarcinogenesis in chronic hepatitis C patients. One of the major concerns is that a higher BMI may merely indicate the presence of ascites or edema, the status that reflects advanced liver disease. Thus, we excluded those with ascites evident at enrollment. Another confounder to be considered was a history of antiviral therapy because it was reported that antiviral therapy reduced the risk of hepatocarcinogenesis 48,49 and BMI also closely was related to SVR rate. 50 The results may be biased if either the indication for interferon therapies or its virologic response varied among BMI groups. Thus, we performed a subgroup analysis excluding those who received interferon therapies after entry. The results also showed that the risk of HCC development increased in proportion to BMI. Cirrhosis is the most important risk factor for HCC. 15 However, because this study was based on outpatient care, liver biopsy rarely was performed. Thus, we cannot assess the relationship between BMI and fibrosis stage. Although it is not clear whether liver fibrosis plays a direct role in hepatocarcinogenesis, the degree of fibrosis may surrogate the accumulated DNA damages as a consequence of long-term necroinflammation and regeneration. Recently, it was reported that fibrosis in chronic hepatitis C correlates significantly with BMI. 51 BMI and steatosis probably are correlated because obesity may aggravate steatosis. Thus, even if accelerated fibrosis is a consequence of necroinflammation exacerbated by obesity-related liver steatosis, the relationship between BMI and HCC is not spurious, although possibly mediated by histology. In summary, the current study has shown an association between BMI and the risk of hepatocarcinogenesis in chronic hepatitis C patients in a wide range of BMIs. Although the mechanism of this phenomenon remains to be investigated, patients may practically be advised to avoid obesity. References 1. Alter MJ, Kruszon-Moran D, Nainan OV, et al. 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6 464 OHKI ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 6, No Angulo P, Keach JC, Batts KP, et al. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology 1999;30: Powell EE, Jonsson JR, Clouston AD. Steatosis: co-factor in other liver diseases. Hepatology 2005;42: Lai MS, Hsieh MS, Chiu YH, et al. Type 2 diabetes and hepatocellular carcinoma: a cohort study in high prevalence area of hepatitis virus infection. Hepatology 2006;43: Hui JM, Sud A, Farrell GC, et al. Insulin resistance is associated with chronic hepatitis C virus infection and fibrosis progression [corrected]. Gastroenterology 2003;125: Shiratori Y, Ito Y, Yokosuka O, et al. Antiviral therapy for cirrhotic hepatitis C: association with reduced hepatocellular carcinoma development and improved survival. Ann Intern Med 2005;142: Yoshida H, Tateishi R, Arakawa Y, et al. Benefit of interferon therapy in hepatocellular carcinoma prevention for individual patients with chronic hepatitis C. Gut 2004;53: McCullough AJ. Obesity and its nurturing effect on hepatitis C. Hepatology 2003;38: Ortiz V, Berenguer M, Rayon JM, et al. Contribution of obesity to hepatitis C-related fibrosis progression. Am J Gastroenterol 2002;97: Address requests for reprints to: Haruhiko Yoshida, MD, Department of Gastroenterology, University of Tokyo, Hongo, Bunkyo-ku, Tokyo ,Japan. yoshida-2im@h.u-tokyo.ac.jp;fax:(81)