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Volume 328:1797-1801 June 24, 1993 Number 25 Next

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ABSTRACT

Background and Methods To detect potentially curable cases of hepatocellular carcinoma, outpatients with chronic hepatitis or compensated liver cirrhosis who were seen at the Center for Adult Diseases (Osaka, Japan) were examined periodically by means of ultrasonography and measurement of serum alpha-fetoprotein. Risk factors for hepatocellular carcinoma were identified with a Cox proportional-hazards model.

Results A total of 917 patients, 40 to 69 years old, were registered from May 1987 to March 1991. By the end of September 1991, liver cancer had developed in 54. The three-year cumulative risk of liver cancer was 12.5 percent for 240 patients with liver cirrhosis at enrollment and 3.8 percent for 677 patients with chronic hepatitis. Cox regression analysis showed that the risk of liver cancer was increased almost sevenfold in patients with hepatitis B surface antigen (rate ratio, 6.92; 95 percent confidence interval, 2.92 to 16.39) and fourfold in patients with hepatitis C antibody (rate ratio, 4.09; 95 percent confidence interval, 1.30 to 12.85). A high alpha-fetoprotein value at enrollment was also a risk marker for liver cancer.

Conclusions Patients with hepatitis C virus infection have a greatly increased risk of liver cancer. Further studies are required to clarify the roles of other risk factors, including drinking and smoking habits.

Methods

Enrollment and Follow-up

Outpatients meeting the following criteria were enrolled in the study: (1) a clinical diagnosis of chronic hepatitis or compensated cirrhosis (without ascites or jaundice, or a history of bleeding esophageal varices) during the period May 1987 through March 1991; (2) a serum total bilirubin level of 2.0 mg per deciliter or less (34 µmol per liter) and a serum albumin level of 3.0 g per deciliter or more; (3) age of 40 to 69 years; (4) no history of liver cancer or evidence of this disease at enrollment (patients in whom liver cancer was detected at the initial examinations or diagnosed within three months after enrollment were excluded); (5) no serious diseases; and (6) consent from both the patient and physician.

Among the registered patients, those with chronic hepatitis and an elevated serum alpha-fetoprotein concentration ( 20 ng per milliliter) and those with liver cirrhosis were scheduled to undergo both ultrasonography and alpha-fetoprotein measurement at three-month intervals. Patients with chronic hepatitis and normal alpha-fetoprotein concentrations at enrollment were scheduled to undergo both tests at six-month intervals; the interval between examinations was reduced to three months if their alpha-fetoprotein concentrations increased to 20 ng per milliliter or more or if the clinical stage of the disease progressed to cirrhosis.

Serologic Evaluation

Routine serum biochemical tests were carried out with automated techniques (SMAC, Technitron, Tokyo, Japan). Hepatitis B surface antigen (HBsAg) was detected by reversed passive hemagglutination (Meguro Institute, Osaka), and hepatitis B core antibody (anti-HBc) by enzyme immunoassay (Abbott Laboratories, Tokyo). If a serum sample was positive for anti-HBc, a 200-fold dilution of the sample was retested for the antibody. If the percentage of inhibition in the diluted sample was 90 percent, the titer for anti-HBc was considered high. These tests were performed in all patients at enrollment. Hepatitis C antibody (anti-HCV, C100-3 antibody) was detected by enzyme-linked immunosorbent assay (ELISA, Ortho Diagnostics, Tokyo). This test became available in April 1990; in a majority of the patients, testing for anti-HCV was performed during the follow-up period, and before the date of diagnosis of liver cancer, although not at enrollment. Alpha-fetoprotein was periodically measured by latex photometric immunoassay (Daiayatoron, Tokyo) (normal, <20 ng per milliliter).

Lifestyle Habits and Medical History

Information about cigarette smoking, alcohol drinking, the medical history, and family history of liver cancer was obtained at the time of enrollment through interviews by experienced public health nurses using a structured questionnaire.

Diagnosis of Liver Cancer

Space-occupying lesions detected or suspected at the time of ultrasonography or alpha-fetoprotein measurement were further examined with computed tomography, hepatic arteriography, fine-needle aspiration biopsy,³ and other clinical diagnostic techniques such as hepatic scintigraphy, unless the ultrasonographic findings confirmed that the lesions were unquestionably benign (e.g., hemangiomas or cysts). A final diagnosis of hepatocellular carcinoma was based on histologic findings in resected hepatic tumors or biopsy specimens or on the radiologic findings of hepatic arteriography.

In spite of great efforts to prevent patients from dropping out of the study, some withdrew because they were transferred to other hospitals, declined to undergo the periodic examinations, or moved from the Osaka area. Their vital status as of the end of May 1991 was determined from their medical records or their resident offices. Copies of death certificates were also obtained from local government offices (Local Justice Bureau).

Statistical Analysis

The method of Kaplan and Meier⁴ was used to estimate the cumulative risk of liver cancer according to the clinical stage of liver disease at enrollment. Cox proportional-hazards regression analysis⁵ was performed to estimate rate ratios for possible risk factors for liver cancer. The period of observation used in calculating the risk of liver cancer began at the date of enrollment and ended at the date of diagnosis of liver cancer, the date of death, or the end of September 1991, whichever came first.

Data analysis was performed with the SAS/PC statistical package (SAS Institute, Cary, N.C.). All reported P values are two-tailed.

Results

Characteristics at Enrollment

Table 1 shows the basic characteristics of the patients at enrollment. A total of 917 patients met the study criteria and were registered: 240 had clinically diagnosed cirrhosis of the liver, and 677 had chronic hepatitis. Serum alpha-fetoprotein levels were elevated in 214 patients at initial examination ( 20 ng per milliliter). HBsAg was detected in 80 of the 917 patients (8.7 percent), and anti-HBc was present in high titers in 56 patients (6.1 percent). Anti-HCV was detected in 433 of the 731 patients (59.2 percent) tested for the antibody. The proportion of patients under the age of 50 years was much smaller among the women than the men (2.3 percent vs. 20.8 percent); otherwise, the distributions of age as well as the other factors listed in Table 1 were similar with respect to sex.

View this table: [in this window] [in a new window]   Table 1. Characteristics of Patients with Chronic Liver Disease at Base Line, According to Sex.

 
Table 2 shows distributions of patients according to their medical histories and lifestyle habits as recorded during interviews at enrollment. Two hundred eleven patients had a history of blood transfusions; 53 of these patients had a history of post-transfusion hepatitis. Fifty-six patients had a family history of liver cancer in parents, siblings, or children. The male patients differed from the female patients in their smoking and drinking habits: 48.2 percent of the men were current smokers and 39.0 percent were current daily drinkers, whereas 10.6 percent of the women were smokers and 6.2 percent were drinkers.

View this table: [in this window] [in a new window]   Table 2. Medical Histories and Lifestyle Habits of the Patients, According to Sex.

 
The base-line characteristics of the 917 patients, including their medical histories and lifestyle habits, were compared with those of 215 patients who dropped out of the study before the end of the follow-up period. No remarkable differences were observed between the groups except in the prevalence of a family history of liver cancer (2.3 percent vs. 6.1 percent).

Development of Liver Cancer

During the follow-up period (from enrollment to the end of September 1991, a mean [±SD] duration of 35.7 ±13.0 months; range, 5 to 52), liver cancer developed in 54 patients. Hepatocellular carcinoma was diagnosed during the study in 20 patients on the basis of findings at hepatic arteriography, with or without elevated serum alpha-fetoprotein levels, and in 29 patients on histologic examination. Liver cancer was diagnosed post mortem in 5 patients during a follow-up study of deaths among the 215 patients who had dropped out. Three of these five patients died of liver cancer with cirrhosis of the liver, and two died of liver cancer with chronic hepatitis, according to their death certificates.

Of the 54 patients with liver cancer, 28 were found to have liver cirrhosis at enrollment and the other 26 were found to have chronic hepatitis. Ten of the 26 patients with chronic hepatitis had elevated alpha-fetoprotein levels at enrollment.

Cumulative Risk of Liver Cancer

Figure 1 shows Kaplan-Meier estimates of the cumulative risk of liver cancer, according to the stage of liver disease and the serum alpha-fetoprotein level at enrollment. The three-year cumulative risk (±SE) of liver cancer was 12.5 ±2.5 percent among the 240 patients with liver cirrhosis diagnosed at enrollment, and 3.8 ±0.8 percent among the 677 with chronic hepatitis. A log-rank test of the two curves (Figure 1) showed a significant difference between these groups (P<0.001). Among the patients with chronic hepatitis, those who had an elevated alpha-fetoprotein level at enrollment were at significantly higher risk for liver cancer than those who had a normal level (P<0.001 by log-rank test); the three-year cumulative risk was 10.2 ±2.7 percent in the former and 2.9 ±0.8 percent in the latter.

View larger version (70K): [in this window] [in a new window]   Figure 1. Cumulative Risk of Liver Cancer in 917 Patients with Chronic Liver Disease, According to the Clinical Stage of Disease at Enrollment. AFP denotes the serum level of alpha-fetoprotein.

 
Hazard Rate Ratios for Liver Cancer

Table 3 shows the results of Cox proportional-hazards regression analyses in which age, sex, and other possible confounders (stage of disease, serum alpha-fetoprotein levels, hepatitis virus markers, and drinking and smoking habits) were adjusted for simultaneously to estimate hazard rate ratios for the development of liver cancer.

View this table: [in this window] [in a new window]   Table 3. Results of Cox Proportional-Hazards Regression, Adjusted for Age, Sex, and Other Potential Confounders.

 
The risk of liver cancer in men was 1.33 times that in women, but the difference was not significant. A positive association was observed between the risk of liver cancer and age at enrollment. Patients in their 60s had significantly higher rate ratios (6.46) than patients in their 40s. The chi-square value for the linear trend between age at enrollment and the risk of liver cancer was significant (P = 0.004).

The stage of disease constituted an independent risk factor for liver cancer after adjustment for possible confounders. Patients with liver cirrhosis diagnosed at enrollment had significantly higher rate ratios for liver cancer (1.93) than patients with chronic hepatitis. The serum alpha-fetoprotein level at enrollment was also confirmed as a significant marker for a high risk, regardless of the stage of disease (chronic hepatitis or liver cirrhosis).

Each of the serum markers for hepatitis virus -- HBsAg, anti-HBc (in high titer), and anti-HCV -- was significantly associated with the risk of liver cancer. The adjusted rate ratios for HBsAg, anti-HBc, and anti-HCV were estimated to be 6.92, 4.54, and 4.09, respectively. Patients whose status for anti-HCV was unknown appeared to have an elevated risk of liver cancer, but this finding was considered an artifact. Since 11 patients who had liver cancer before April 1990 left the study before the test for anti-HCV became available at our institutions, their status for anti-HCV necessarily remained unknown.

Smoking and drinking were also possible risk factors for liver cancer, since many case-control studies^6,7,8,9,10 and a few cohort studies^11,12 have indicated a relation between these lifestyle factors and the risk of liver cancer. The risks in current smokers and exsmokers were, respectively, 2.30 and 1.68 times the risk in nonsmokers, although these differences were not significant. The chi-square value for the linear trend between smoking and the risk of liver cancer approached significance (P = 0.07). Associations between drinking and the risk of liver cancer were not so evident, as shown by the adjusted rate ratios for drinking categories (Table 3).

Relations between smoking and drinking habits and the risk of liver cancer were further analyzed according to the clinical stage of liver disease at enrollment. Among the patients with liver cirrhosis, the adjusted rate ratios for current smokers and exsmokers increased to 7.96 and 3.44, respectively (chi-square for linear trend, 8.617; P = 0.003); the rate ratio was 1.32 for current heavy drinkers (P = 0.75) and 3.75 for former heavy drinkers (P = 0.04). Among the patients with chronic hepatitis, there were no significant associations between these lifestyle factors and the risk of liver cancer.

A medical history of blood transfusions, post-transfusion hepatitis, or surgical procedures was not significantly associated with the risk of liver cancer (rate ratios after adjustment for age and sex, 1.24, 1.18, and 1.26, respectively). A history of liver cancer in a parent, sibling, or child or in a spouse showed a tendency toward an association with the risk of liver cancer (rate ratios after adjustment for age and sex, 1.93 and 2.66, respectively), but was not a significant risk factor.

Discussion

Several case-control studies^13,14,15,16 have already reported that hepatitis C virus has an important role in the pathogenesis of liver cancer. In the only follow-up study of patients with hepatitis C virus and liver cancer, Colombo et al.¹⁷ followed 447 Italian patients with well-compensated liver cirrhosis (including 201 positive for anti-HCV) for a mean period of 33 months and found a yearly incidence rate of 3 percent for hepatocellular carcinoma. In their study, the cumulative hazard of hepatocellular carcinoma was higher among patients with elevated serum alpha-fetoprotein levels than among those with consistently normal levels, but the authors found no relation between the risk of liver cancer and specific causes of cirrhosis. By contrast, our study shows a close relation between the risk of liver cancer and hepatitis C virus. Our results also indicate that smoking may increase the risk of liver cancer among patients with chronic liver disease.

One limitation of our study was the use of a first-generation enzyme immunoassay for anti-HCV, since this test may be less sensitive and specific than second-generation assays^18,19,20,21. The rate ratio for patients positive for anti-HCV in our study might be underestimated because of random misclassification of their status for the antibody.

Another limitation was that in a majority of the study patients, the anti-HCV status was determined during follow-up, not at enrollment. This limitation may have also led to the underestimation of the rate ratio for liver cancer, since some carriers of hepatitis C virus may lose their reactivity to anti-HCV during the follow-up period^22,23. Besides, some of the patients who had liver cancer before April 1990, whose status for anti-HCV was necessarily unknown, may have been positive for the antibody.

The dropout rate in our study could be another problem: 215 patients dropped out before the end of the study period. If the patients with risk factors had dropped out at a higher or lower rate than those without risk factors, estimates of the rate ratios would have been biased. However, when we checked whether the observed risk factors for liver cancer would predict dropping out, by designating patients who dropped out as patients with liver cancer and designating patients who had hepatocellular carcinoma as "censored" patients in the proportional-hazards model, while still designating patients censored at the end of observation as "censored," the rate ratios for dropping out, which ranged from 0.71 to 1.31, were not significantly different from the referent value (1.00) for all variables listed in Table 3. Therefore, we do not consider the effect of dropping out to be sufficient to distort our results.

Although there were no significant associations between smoking and drinking habits and the risk of liver cancer among the patients with chronic hepatitis diagnosed at enrollment, among the patients with liver cirrhosis the risk was significantly increased in current smokers and former heavy drinkers but was small and insignificant in current heavy drinkers. On the basis of a large-scale cohort study in Japan, Hirayama²⁴ estimated the relative risk of liver cancer among the patients with cirrhosis to be 2.67 in daily cigarette smokers (as compared with nonsmokers) and 1.00 in daily alcohol drinkers (as compared with those who did not drink alcohol daily). Recently, Adami et al.²⁵ conducted a cohort study of Swedish patients with a diagnosis of alcoholism, liver cirrhosis, or both, and found that alcoholism alone carried a moderately increased risk of liver cancer and that alcoholism with liver cirrhosis did not increase the risk more than cirrhosis alone. These results are supported by our findings and suggest that alcohol may be a liver carcinogen only because it is causally involved in the development of liver cirrhosis,²⁵ whereas cigarette smoking may be involved in the development of liver cancer from liver cirrhosis²⁴. If so, intervention against drinking should be carried out as early as possible, before liver cirrhosis develops, and smoking-cessation programs should be offered even to patients who already have chronic liver disease, particularly those with liver cirrhosis.

Differences between Japan and the United States in types of hepatitis C virus have been reported^26,27,28,29. Different types of the virus may have different clinical outcomes,³⁰ and these differences may also explain some of the differences between Italy¹⁷ and Japan in the relation of anti-HCV to the risk of liver cancer. Comparative studies of the risks of liver cancer due to hepatitis C virus in other countries are needed.

Supported in part by a Grant-in-Aid for Cancer Research from the Ministry of Health and Welfare and by a Grant-in-Aid for International Scientific Research Program-Special Cancer Research from the Ministry of Education, Science and Culture, Japan.

Source Information

From the Department of Field Research (H.T., I.F.), Research Institute (T.H.), and Hospital (S.T., M.N., T.Y., T. Kitamura, K.N., A.I.), Center for Adult Diseases, and the Center for Cancer Detection and Prevention (H.Y., T. Kawashima), Osaka, Japan.

Address reprint requests to Dr. Tsukuma at the Department of Field Research, Center for Adult Diseases, Osaka, 3-3 Nakamichi 1-chome, Higashinari-ku, Osaka 537, Japan.

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