Role of ethnicity in risk for hepatocellular carcinoma in patients with chronic hepatitis C and cirrhosis

CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2004;2:820 – 824

Role of Ethnicity in Risk for Hepatocellular Carcinoma in Patients With Chronic Hepatitis C and Cirrhosis MINDIE H. NGUYEN,*,‡ ALICE S. WHITTEMORE,§ RUEL T. GARCIA,储 SARAA A. TAWFEEK,* JING NING,* SUZANNA LAM,* TERESA L. WRIGHT,储,¶ and EMMET B. KEEFFE* *Division of Gastroenterology & Hepatology, and §Department of Epidemiology & Biostatistics, Stanford University, Stanford; ‡Department of Epidemiology & Biostatistics, and 储Division of Gastroenterology, University of California, San Francisco; and ¶Division of Gastroenterology, Veterans Administration Medical Center, San Francisco, California

Background & Aims: In the United States, hepatocellular carcinoma (HCC) is more common among Asians and African Americans than Caucasians, with chronic hepatitis C virus (HCV) infection accounting for up to half of the patients. Our study examined ethnicity as a potential risk factor for HCC among patients with chronic hepatitis C. Methods: We conducted a case-control study of 464 patients with chronic hepatitis C and cirrhosis (207 cancer patients and 257 controls) using medical records and pathology records at 4 medical centers. We estimated odds ratios with 95% confidence intervals by using conditional logistic regression on case-control sets, matched within study centers and study period on sex and age groups (<45, 46 –55, 56 – 65, >65 yr). To control for potential confounding caused by severity of cirrhosis and residual confounding caused by age, we also included Child–Turcotte–Pugh (CTP) scores and age (continuous variable) in all regression analyses. Results: Compared with Caucasians, the cancer risk was increased significantly among Asians (adjusted odds ratio, 4.3; 95% confidence interval, 2.1–9.0 for men, and 4.6; 1.2–18.5 for women) and somewhat increased among African-American men (adjusted odds ratio, 2.4; 95% confidence interval, 0.9 – 6.3). Conclusions: This study suggests that, among patients with chronic hepatitis C and cirrhosis, liver cancer risk is increased 4-fold in Asians and may be doubled in African-American men, compared with Caucasians. These results need confirmation in larger studies from racially diverse populations, but, if confirmed, these results point to high-risk populations that should be targeted for screening and preventive efforts.

nfection with hepatitis B virus (HBV) and hepatitis C virus (HCV) are the major risk factors for hepatocellular carcinoma (HCC).1– 4 In the United States, the overall age-adjusted HCC incidence has increased from 1.4 per 100,000 between 1975 and 1977 to 3.0 per 100,000 between 1996 and 1998, with the greatest rate of increase among patients between 45 and 49 years of age (1.9 per 100,000 in 1975–1977 to 6.5 per 100,000

I

in 1996 –1998), owing largely to the increasing rate of HCV-related HCC.5–9 Given the burden of HCV infection in the United States, HCV-related HCC is predicted to be a major health problem in the next few decades.7,10 Identification of high-risk patients among those infected with HCV may enhance our understanding of disease mechanisms and identify patients who may benefit the most from screening and chemopreventive efforts.11–14 Advanced age, more severe liver disease, and male gender are known to be associated with an increased risk for HCC in patients with various chronic liver diseases including chronic hepatitis C.15–18 On the other hand, results regarding HCV genotypes and alcohol and tobacco use as potential synergistic risk factors for HCC generally have been conflicting.16 –33 In the United States, higher overall HCC incidence and mortality also have been observed in African Americans and Asians,5,34,35 but few studies to date have examined ethnicity as a potential HCC risk factor in patients with chronic hepatitis C. Studies of Asians in the United States have suggested an association between excess HCC risk in Asians with chronic hepatitis B infection, but whether this excess risk also exists when Asian patients with chronic hepatitis C (without chronic hepatitis B) are compared with other racial/ethnic groups with chronic hepatitis C is unclear.36 –39

Materials and Methods Study Participants To examine ethnicity as a potential HCC risk factor in patients with chronic hepatitis C, we conducted a case-control study of patients with chronic hepatitis C and cirrhosis from 4 San Francisco Bay medical centers. Specifically, we reviewed medical and pathology records for diagnoses of chronic hepaAbbreviations used in this paper: AFP, ␣-fetoprotein; CTP, Child– Turcotte–Pugh score. © 2004 by the American Gastroenterological Association 1542-3565/04/$30.00 PII: 10.1053/S1542-3565(04)00353-2

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Table 1. Distribution of Patients’ Clinical Characteristics, by Sex Men

Women

Risk factors

HCC (N ⫽ 172)

Controls (N ⫽ 197)

HCC (N ⫽ 35)

Controls (N ⫽ 60)

Age (yr, mean ⫾ SD) CTP (1–15 points, mean ⫾ SD) AFP (ng/mL, median and range) Ethnicity, N (%) Caucasian Hispanic African American Asian

57.8 ⫾ 9.7 7.8 ⫾ 2.4 51.5 (1.9–669,000)

52.1 ⫾ 7.8 7.3 ⫾ 2.6 7.0 (0.25–137)

62.7 ⫾ 9.5 8.4 ⫾ 2.5 183.0 (2.0–11,490)

55.7 ⫾ 8.2 7.2 ⫾ 2.3 9.0 (2–128.6)

95 (55) 17 (10) 18 (11) 42 (24)

140 (71) 34 (17) 8 (4) 15 (8)

9 (26) 5 (14) 5 (14) 16 (46)

35 (58) 8 (13) 7 (12) 10 (17)

titis C, cirrhosis, and HCC at Stanford University Medical Center during the period from January 1998 to December 2002, at the San Francisco Veterans Administration Medical Center from January 1995 to January 2001, at the University of California in San Francisco from January 1995 to July 2001, and at the San Francisco General Hospital from January 1996 to June 2001. All patient characteristics including ethnicity were obtained by chart review. We evaluated patient characteristics (e.g., age, serum ␣-fetoprotein [AFP], Child–Turcotte–Pugh [CTP] score)40,41 at a reference date, defined as the date of diagnosis for patients and as the date of first available AFP and imaging studies for controls. Eligible patients and control patients had chronic hepatitis C and cirrhosis (as determined by liver histology, clinical, and/or radiographic evidence of portal hypertension such as varices, ascites, encephalopathy, thrombocytopenia, and splenomegaly), no history of prior malignancy, no evidence of metabolic or autoimmune hepatitis, and no evidence of infection with HBV or human immunodeficiency virus. For case patients, we verified HCC diagnosis by cytology, histology, or by noninvasive criteria.42– 49 For control patients, we verified the absence of HCC by either negative explants, negative imaging studies and AFP level of 20 ng/mL or less,50,51 or negative imaging studies with at least one biphasic computed tomography, magnetic resonance image, and/or angiogram at least 6 months after the reference date if AFP level was greater than 20 but 200 ng/mL or less. Those with negative imaging studies but AFP level greater than 200 ng/mL have a high likelihood of occult HCC and were excluded.44 We identified a total of 520 potentially eligible patients with chronic hepatitis C and cirrhosis. Of these, 48 (9.2%) could not be classified as patients or controls because of insufficient data and were excluded. Eight patients with ethnicity listed other than Caucasian, Hispanic, African American, and Asian also were excluded. The study included the remaining 464 patients with chronic hepatitis C and cirrhosis: 207 patients and 257 controls. The study protocol was approved by the institutional review boards at Stanford University and University of California, San Francisco.

Statistical Analysis We estimated odds ratios with 95% confidence intervals by using conditional logistic regression on case-control sets, matched within study centers and study period, and sex and age group (ⱕ45, 46 –55, 56 – 65, ⬎65 yr). To control for potential confounding caused by cirrhosis severity and residual confounding caused by age, we also included CTP scores and age (continuous variable) in all regressions. Statistical significance was defined as a 2-sided P value of less than 0.05. All statistical analyses were performed using STATA (version 7.0; STATA Corporation, College Station, TX).

Results Patient Characteristics Table 1 shows the distribution of patient characteristics by sex. Among both sexes, patients were more likely than controls to be older, have higher CTP scores, higher AFP levels, and to be identified as Asian. Among men, patients also were more likely than controls to be identified as African American. The mean tumor size was 4.2 ⫾ 3.3 cm (SD) among patients. African-American patients were more likely to have multilobar tumor involvement compared with Caucasians, Hispanics, and Asian Americans (57% vs. 27%, 43%, and 24%, respectively, P ⫽ 0.009) (Table 2). Although there were no statistically significant differences in other tumor characteristics between the different ethnic groups, there is a trend for having larger or diffuse tumors, tumor vascular invasion, and multifocal tumors in African Americans (Table 2). Risk Factors for Hepatocellular Carcinoma in Hepatitis C Virus Cirrhosis Table 3 shows odds ratios adjusted for study center, reference age, and CTP score. Within each sex, Asians were more likely than Caucasians to develop HCC (odds ratio, 4.3; 95% confidence interval, 2.1–9.0 for

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Table 2. Tumor Characteristics by Ethnicity Tumor characteristics Tumor size ⬍5 cm ⱖ5 cm or diffuse Tumor number 1 2–3 ⱖ4 or diffuse Lobar involvement Unilobar Multilobar Vascular invasion No Yes

Caucasian (N ⫽ 104)

Hispanic (N ⫽ 22)

African American (N ⫽ 23)

Asian (N ⫽ 58)

65.1% 34.9%

71.4% 28.6%

39.1% 60.9%

64.9% 35.1%

0.089

54.8% 22.1% 23.1%

68.2% 22.7% 9.1%

30.4% 21.8% 47.8%

52.6% 24.6% 22.8%

0.095

76.0% 24.0%

57.1% 42.9%

43.5% 56.5%

73.2% 26.8%

0.009

80.5% 19.5%

80.0% 20.0%

68.8% 31.2%

92.5% 7.5%

0.10

men; odds ratio, 4.6; 95% confidence interval, 1.2–18.5 for women). There was also a trend toward increased HCC risk in African-American men (odds ratio, 2.4; 95% confidence interval, 0.89 – 6.3).

Discussion The present study indicates that, among patients with cirrhosis secondary to chronic hepatitis C, Asians and possibly African Americans have a higher risk for HCC than do Caucasians. After adjustment was made for age, sex, and severity of liver disease, Asian Americans were approximately 4 times more likely to have HCC than Caucasians (P ⬍ 0.0001). Published literature from Japan does report a much higher 5-year cumulative HCC incidence than the literature from Western patients.52–54 A prospective study of Italian patients with HCV and compensated cirrhosis reported a 5-year cumulative HCC incidence of approximately 4% to 6%.52 On the other hand, prospective studies of Japanese patients with HCV Table 3. HCC Risk According to Ethnicity on Case-Control Sets Matched Within Study Centers, Study Period, and Age Groups, by Sex

Sex Predictors Men, N ⫽ 369 Caucasian Hispanic African American Asian Women, N ⫽ 95 Caucasian Hispanic African American Asian

HCC (N ⫽ 207) n (%)

Controls (N ⫽ 257) n (%)

Multivariate ORa (95% CI)

95 (55) 17 (10) 18 (11) 42 (24)

140 (71) 34 (17) 8 (4) 15 (8)

1.0 (referent) 0.9 (0.44–1.7) 2.4 (0.89–6.3) 4.3 (2.1–9.0)

9 (26) 5 (14) 5 (14) 16 (46)

35 (58) 8 (13) 7 (12) 10 (17)

1.0 (referent) 1.2 (0.18–7.5) 2.2 (0.43–12.1) 4.6 (1.2–18.5)

aAdjusted for severity of liver disease (CTP score) and age (continuous variable).

P value

and cirrhosis reported a 5-year cumulative HCC incidence of up to 21.5% to 41%, albeit many if not the majority of these Japanese patients also had decompensated end-stage liver disease in addition to cirrhosis.53,54 Besides ethnicity-related genetic factors, other explanations for the observed increased HCC risk in Asians may involve potentially higher prevalences of occult HBV infection, longer duration of HCV infection, or differences in access to care or health-care–seeking behavior. Although the current analysis excluded patients with obvious HBV infection, traces of HBV still can be detected by sensitive polymerase chain reactions in serum and/or liver tissues of such patients.2 Asian immigrants also may acquire HCV infection during childhood from unsanitary medical practices and living conditions.36 Thus, at the same reference age, Asian patients may have been infected with HCV for 2–3 decades longer than Caucasian patients, many of whom may not have acquired the infection until the second or third decade of life. In addition, when compared with the ethnic distribution of San Francisco and Santa Clara County where the 4 study centers are located,55 there were more Caucasians and less Asians in the study group. This observation may be related to poorer access to care and different health-care–seeking behavior in Asians, but also could be due to the fact that at least 3 of the study centers (University of California, San Francisco Medical Center, Veterans Administration Medical Center in San Francisco, and Stanford University Medical Center) also serve patients from other parts of California (especially Northern and Central California), where there may be more Caucasians and less Asians than in the San Francisco Bay area. We limited our study to patients with cirrhosis secondary to HCV infection to focus on the most common cause of HCC in the United States and to exclude the possibility of

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confounding by case-control differences in prevalences of HBV infection and cirrhosis, 2 of the strongest HCC risk factors. We did not have adequate data to evaluate potential confounding by cigarette and alcohol use. However, evidence for association between these 2 exposures and HCC that is independent of causes of primary liver disease, presence, and severity of cirrhosis is still inconclusive because many studies examining these exposures include patients without any primary liver diseases or patients with liver disease of mixed causes or mixed severity in the control groups.16 –18,23–25,33 Spuriously increased odds ratios associated with ethnicity could arise if controls were obtained largely from one center that treated a high proportion of Caucasians, while cases were obtained from another center that treated a racially diverse set of patients. To minimize this possible bias, we matched all case-control sets within study centers and study periods in addition to adjusting for severity of liver cirrhosis in all regressions. The present study indicates that, among patients with HCV-related cirrhosis, the HCC risk is 4-fold higher in Asians than Caucasians and also may be increased in African-American men. These results need confirmation in larger studies in racially diverse populations and, if confirmed, point to high-risk populations that could be targeted for screening and preventive efforts.

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Address requests for reprints to: Emmet B. Keeffe, M.D., Professor of Medicine, Co-Director, Liver Transplant Program, Chief of Hepatology, Stanford University Medical Center, 750 Welch Road, Suite 210, Palo Alto, California 94304-1509. e-mail: [email protected]; fax: (650) 498-5692. Supported in part by the American Association for the Study of Liver Diseases/Schering Hepatology Research Fellow Award and by grant T32DK07056-26 from the National Institutes of Health to Stanford University (to M.H.N., S.A.T., J.N., S.L., and E.B.K.).