Role of ethnicity in risk for hepatocellular carcinoma in patients with chronic hepatitis C and cirrhosis
Authors: Mindie H. Nguyen, Alice S. Whittemore, Ruel T. Garcia, Saraa A. Tawfeek, Jing Ning, Suzanna Lam, Teresa L. Wright, Emmet B. Keeffe
Journal: Clinical Gastroenterology and Hepatology (2004)

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. 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. Infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) are the major risk factors for hepatocellular carcinoma (HCC).1Szilagyi A. Alpert L. 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Specifically, we reviewed medical and pathology records for diagnoses of chronic hepatitis 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 α-fetoprotein [AFP], Child-Turcotte-Pugh [CTP] score)40Child III, C.G. Turcotte J.G. Surgery in portal hypertension.in: Child III, C.G. The liver and portal hypertension. WB Saunders, Philadelphia1964: 50Google Scholar, 41Pugh R.N.H. Murray-Lyon I.M. Dawson J.J. Pietroni N.C. Williams R. 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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 analysisWe 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 (≤45, 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).ResultsPatient characteristicsTable 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.Table 1Distribution of Patients' Clinical Characteristics, by SexRisk factorsMenWomenHCC (N = 172)Controls (N = 197)HCC (N = 35)Controls (N = 60)Age (yr, mean ± SD)57.8 ± 9.752.1 ± 7.862.7 ± 9.555.7 ± 8.2CTP (1–15 points, mean ± SD)7.8 ± 2.47.3 ± 2.68.4 ± 2.57.2 ± 2.3AFP (ng/mL, median and range)51.5 (1.9–669,000)7.0 (0.25–137)183.0 (2.0–11,490)9.0 (2–128.6)Ethnicity, N (%) Caucasian95 (55)140 (71)9 (26)35 (58) Hispanic17 (10)34 (17)5 (14)8 (13) African American18 (11)8 (4)5 (14)7 (12) Asian42 (24)15 (8)16 (46)10 (17) Open table in a new tab 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).Table 2Tumor Characteristics by EthnicityTumor characteristicsCaucasian (N = 104)Hispanic (N = 22)African American (N = 23)Asian (N = 58)P valueTumor size <5 cm65.1%71.4%39.1%64.9%0.089 ≥5 cm or diffuse34.9%28.6%60.9%35.1%Tumor number 154.8%68.2%30.4%52.6%0.095 2–322.1%22.7%21.8%24.6% ≥4 or diffuse23.1%9.1%47.8%22.8%Lobar involvement Unilobar76.0%57.1%43.5%73.2%0.009 Multilobar24.0%42.9%56.5%26.8%Vascular invasion No80.5%80.0%68.8%92.5%0.10 Yes19.5%20.0%31.2%7.5% Open table in a new tab Risk factors for hepatocellular carcinoma in hepatitis C virus cirrhosisTable 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 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).Table 3HCC Risk According to Ethnicity on Case-Control Sets Matched Within Study Centers, Study Period, and Age Groups, by SexSex PredictorsHCC (N = 207) n (%)Controls (N = 257) n (%)Multivariate ORaAdjusted for severity of liver disease (CTP score) and age (continuous variable). (95% CI)Men, N = 369 Caucasian95 (55)140 (71)1.0 (referent) Hispanic17 (10)34 (17)0.9 (0.44–1.7) African American18 (11)8 (4)2.4 (0.89–6.3) Asian42 (24)15 (8)4.3 (2.1–9.0)Women, N = 95 Caucasian9 (26)35 (58)1.0 (referent) Hispanic5 (14)8 (13)1.2 (0.18–7.5) African American5 (14)7 (12)2.2 (0.43–12.1) Asian16 (46)10 (17)4.6 (1.2–18.5)a Adjusted for severity of liver disease (CTP score) and age (continuous variable). Open table in a new tab DiscussionThe 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.52Fattovich G. Ribero M.L. Pantalena M. Diodati G. Almasio P. Nevens F. Tremolada F. Degos F. Rai J. Solinas A. Mura D. Tocco A. Zagni I. Fabris F. Lomonaco L. Noventa F. Realdi G. Schalm S.W. Tagger A. Hepatitis C virus genotypes: distribution and clinical significance in patients with cirrhosis type C seen at tertiary referral centres in Europe.J Viral Hepat. 2001; 8: 206-216Crossref PubMed Scopus (43) Google Scholar, 53Ikeda K. Saitoh S. Koida I. Arase Y. Tsubota A. Chayama K. Kumada H. Kawanishi M. A multivariate analysis of risk factors for hepatocellular carcinogenesis: a prospective observation of 795 patients with viral and alcoholic cirrhosis.Hepatology. 2003; 18: 47-53Crossref Scopus (698) Google Scholar, 54Tanaka K. Sakai H. Hashizume M. Hirohata T. A long-term follow-up study on risk factors for hepatocellular carcinoma among Japanese patients with liver cirrhosis.Jpn J Cancer Res. 1998; 89: 1241-1250Crossref PubMed Scopus (37) Google Scholar A prospective study of Italian patients with HCV and compensated cirrhosis reported a 5-year cumulative HCC incidence of approximately 4% to 6%.52Fattovich G. Ribero M.L. Pantalena M. Diodati G. Almasio P. Nevens F. Tremolada F. Degos F. Rai J. Solinas A. Mura D. Tocco A. Zagni I. Fabris F. Lomonaco L. Noventa F. Realdi G. Schalm S.W. Tagger A. Hepatitis C virus genotypes: distribution and clinical significance in patients with cirrhosis type C seen at tertiary referral centres in Europe.J Viral Hepat. 2001; 8: 206-216Crossref PubMed Scopus (43) Google Scholar On the other hand, prospective studies of Japanese patients with HCV 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.53Ikeda K. Saitoh S. Koida I. Arase Y. Tsubota A. Chayama K. Kumada H. Kawanishi M. A multivariate analysis of risk factors for hepatocellular carcinogenesis: a prospective observation of 795 patients with viral and alcoholic cirrhosis.Hepatology. 2003; 18: 47-53Crossref Scopus (698) Google Scholar, 54Tanaka K. Sakai H. Hashizume M. Hirohata T. 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Viral pathogenesis of hepatocellular carcinoma in the United States.Hepatology. 1993; 18: 1326-1333PubMed Google Scholar Asian immigrants also may acquire HCV infection during childhood from unsanitary medical practices and living conditions.36Do S. The natural history of hepatitis B in Asian Americans.Asian Am Pac Islander J Health. 2001; 9: 141-152PubMed Google Scholar 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 whe