Medical History and Primary Liver Cancer1

The relationship between selected aspects of medical history and the risk of primary liver cancer was analyzed in a hospital-based case-control study conducted in Northern Italy on 242 patients with histologically or serologically confirmed hepatocellular carcinoma and 1169 controls in hospital for acute, nonneoplastic, or digestive diseases. Significant asso ciations were observed for clinical history of hepatitis (odds ratio (OR), 3.7; 95% confidence interval (CI), 2.3-5.9], cirrhosis (OR, 16.8; 95% CI, 9.8-28.8), and three or more episodes of transfusion in the past (OR, 2.2; 95% CI, 1.4-4.1). Among other diseases considered, there was a significant association with diabetes (OR, 2.5; 95% CI, 1.7-3.8), and a protection by history of drug allergies (OR, 0.5; 95% CI, 0.2-0.9). These associations were not appreciably modified by allowance for major iden tified potential confounding factors and were observed for diseases oc curring less than 5 or 5 or more years before liver cancer diagnosis, although for cirrhosis the risk was higher in the short term occurrences (OR, 50). For hepatitis, the association was more evident at older ages, confirming the long lead time between infection and cancer occurrence, while for diabetes it was stronger (or restricted) to cases aged less than 60, suggesting a possible specific role of type I diabetes. While for hepatitis, cirrhosis, and blood transfusion this study offers further quan titative estimates of risk in a European population, the possible direct association with diabetes and protection by drug allergy were unexpected, lacked plausible biological or previous epidemiological support, and should be simply regarded as working hypotheses for further work. INTRODUCTION Primary liver cancer is associated with several liver diseases, including hepatitis (1-9), cirrhosis (2, 10), as well as disturb ances of heme synthesis and hence porphyrin metabolism re lated to porphyrias (11). There is, however, still uncertainty about the strength of the association in different populations. With reference to hepatitis B virus infection, for instance, the relative risks reported from Taiwan are on the order of 100 (1, 7), with a range of variation between 20 and 200, while in European and Northern American populations the relative risks are on the order of 10 and range between 5 and 15 (2-5, 8). Only scanty information, moreover, is available on other as pects of past medical history and liver cancer. To shed further light on the issue, we consider in this article selected aspects of medical history in the risk of primary liver cancer, using data from a case-control study from Northern Italy. SUBJECTS AND METHODS The data considered were derived from an ongoing study of digestive tract neoplasms, based on a network of teaching and general hospitals in the Greater Milan area. Recruitment of cases of liver cancer started in January 1984, and the present article is based on data collected up to December 1989. Received 3/19/90; accepted 6/4/90. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1This work was conducted within the framework of the National Research Council (CNR) Applied Projects "Oncology" (Contract 87.01544.44) and "Risk Factors for Disease." and with the contributions of the Italian Association for Cancer Research and the Italian League Against Tumours. Milan. The general structure of this investigation has already been described (12). Briefly, trained interviewers identified and questioned cases and controls in the major teaching and general hospitals of the Greater Milan area. The structured questionnaire included information on sociodemographic characteristics, smoking habits, alcohol drinking, intake of coffee and 14 selected indicator foods, and a problem-oriented medical history including 12 selected diseases or interventions. By definition, the diseases or interventions considered had to anticipate by at least 1 year the onset of the symptoms of the disease which led to admission. Age at onset of each condition was recorded. On the average, less than 2% of cases and controls refused to be interviewed. The cases included in the present analysis were patients below the age of 75 years with histologically or serologically (elevated a-fetoprotein levels) confirmed hepatocellular carcinoma diagnosed within the year preceding the interview, after specific exclusion of all metastatic or undefined liver neoplasms, admitted to the National Cancer Institute, several university clinics (chiefly of surgery), and the Ospedale Mag giore of Milan. A total of 242 cases (180 males, 62 females) ages 22 to 74 years (median age, 57 years) were interviewed. The comparison group consisted of 1169 subjects (875 males, 294 females) admitted to the same network of hospitals for acute, nonneo plastic or digestive diseases, unrelated to alcohol or tobacco consump tion. The age range was 21 to 74 years, and the median age was 55 years. Thirty-two % were admitted for trauma, 15% were seen for nontraumatic orthopedic conditions, 39% had acute surgical diseases, and 14% had other miscellaneous disorders, including acute infections, skin, eye diseases, etc. The catchment area of cases and controls was comparable: 80% of the cases and 83% of the controls resided in the same region, Lombardy; 90% of the cases and 94% of the controls came from Northern Italy. ORs2 and the corresponding 95% CI ( 13) according to various aspects of medical history were first computed from data stratified for sex and decade of age using stratification and the Mantel-Haenszel procedure (14). Secondly, to account simultaneously for the potential confounding effect of various risk factors, unconditional multiple logistic regression, with multiple likelihood fitting, was used (13, 15). All the regression equations reported included terms for age, sex, area of residence, education, smoking, and alcohol consumption. RESULTS Table 1 gives the distribution of liver cancer cases and the comparison group according to sex, age group, education, and alcohol consumption. Cases were slightly older than controls, significantly less educated (x2i for trend, 12.71; P < 0.001), and more frequently heavy drinkers (OR for >6 drinks/day, 1.6; 95% CI, 1.1-2.2). In Table 2, the relationship between liver cancer and selected aspects of medical history is considered. Twelve % of cases versus 4% of the controls gave a clinical history of hepatitis; the corresponding odds ratio was 3.7, with 95% CI 2.3-5.9. Serological markers of hepatitis B virus were not determined in this study. Liver cirrhosis was reported by 15% of the cases versus 1% of the controls, for an OR of 16.8 (95% CI 9.8-28.8). Significantly more cases than controls (15% versus 6%) had a history of diabetes mellitus. The age-adjusted OR was 2.5, and the 95% CI was 1.7-3.8. No significant association was observed between thyroid disease, gastroduodenal ulcer, pan2The abbreviations used are: OR, odds ratio; CI. confidence interval. 6274 on July 23, 2017. © 1990 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from MEDICAL HISTORY AND PRIMARY LIVER CANCER Table I Distribution of 242 cases of liver cancer and 1169 controls according to sex, age group, education, and alcohol consumption, Milan, Italy, 1984-1989 Table 3 Relation of liver cancer with selected diseases according to time since diagnosis among 242 cases and 1169 controls, Milan, Italy, 1984-1989 Liver cancer No. % Controls No. % SexMalesFemalesAge (yr)<4545-5455-6465-74Education<77-11212Unknown18062364798611515237274.425.614.919.440.525.262.421.515.30.8875294235330353251552349260874.925.120.128.230.221.547.229.922.20.7 Total alcohol consumption (drinks/day) 0<44-6>6Unknown60764658224.831.419.024.00.8205525237198417.544.920.316.90.3 DiseaseHepatitisLiver cirrhosisDiabetesDrug allergyVr since diagnosis<525<525<525<525No. (%) of subjects with the diseaseLiver cancer6 (2.5)21