143 FACTORS INFLUENCINGTHE DEVELOPMENTOF HEPATOCELLULARCARCINOMA(HCC) IN CIRRHOSIS; A 5 YEARPROSPECTIVESTUDY OF 613 PATIENTS P.J. Johnson, S.N. Zaman, W.M. Melia, R.D. Johnson, R. Williams Liver Unit, King's College Hospital, Denmark Hill, London SE5, England. Although a recent prospective study involving over 20,000 apparently healthy Chinese men has clearly shown that HBsAg seropositivity is a risk factor for the subsequent development of HCC, the interrelationship between the HBsAg and underlying chronic liver disease could not be adequately assessed. We have followed-up 613 patients with cirrhosis (489 from the UK, 385 male), referred between 1978 and 1983, for up to 5 years. The influence of the following factors on HCC development was assessed: age, sex, aetiology and duration (from diagnosis) of cirrhosis and serum HBV markers (HBsAg, HBsAb, HBeAg and Anti HBe in all, and Anti HBc in 214. Patients were screened regularly by serum AFP estimation and clinical examination, and to date HCC development has been documented in 42 (17% of those dying from cirrhosis). Using multiple regression analysis the major independent factors associated with the development of HCC were, in decreasing order of significance, non-UK nationality, male sex and increasing age (all p 0.05). Whenonly UK patients were considered increasing age and male sex were again the only significant risk factors (p 0.05). HBsAgsero- positivity was not a significant risk factor for the development of HCC in UK or non-UK cirrhotic patients. In epidemiological studies showing association between HCC and HBsAg seropositivity, the latter may be acting as a marker of underlying cirrhosis, which is itself the important risk factor. 144 DIFFERENTIAL EFFECT OF LIVER DISEASE ON THE CYTOCHROME P-450 and P-448 SYSTEMS G. Jost~ U. v. Mandach, A. Wahll~nder, R. Preisi 9 Department of Clinical Pharmacology, University of Berne, Switzerland Based on circumstantial evidence only, chronic liver disease has hitherto been thought to result primarily in a loss of tell mass with the remaining hepatocytes function- inq normally. Since methods are now available to assess subcellular functions specifically, we have studied simultaneously the clearances of caffeine Ca P-448 probe) and antipyrine Ca P-450 probe). 14 normal volunteers (NV; mean age 37 years), 18 ambulatory patients with biop- sy documented cirrhosis (CI; mean age 50 years; 7 alcoholic, 11 nonalcoholic) and 16 subjects with noncirrhotic liver disease (LD; mean age 41 years; fatty liver, chronic persistent hepa- titis) were given a single p.o. dose of 10 mg/kg b.w. antipyrine with lunch. They were asked to abstain from caffeine intake after dinner and to collect a saliva sample before bedtime and upon arising. Saliva concentrations of caffeine (C) were measured with EMIT , those of anti pyrine (A) with HPLC, and clearances (Cl) calculated using a constant VD of 0.6 l/kg b.w. Although for the entire population, CCI and ACI were significantlycorrelated (r=O.8O, p< 0.001), in the disease groups there were notable differences in clearance ratios (CCI/ACI). Compared to CCI of 1.70+S.D.O.5ml/min/kg and ACI of 0.80+0.3 in NV (ratio 2.3+0.6), the re- spective, significantly~educed values were 0.90+0.4 and 651+0.2 in LD (ratio~.8+O.7), 0.49 +0.3 and 0.39+0.1 in CI (ratio 1.3+0.7). This Ttriking change in clearance ratios suggests preferential r-eduction of the cytoc~rome P-448 system in remaining and/or regenerated cells, thus arguing against the "intact hepatocyte hypothesis". Therefore, simultaneous measurement of CCI and ACI, besides being noninvasive and practical in quantifying hepatic function, may provide new insight into the pathophysiology of chronic liver disease. $72

Factors influencing the development of hepatocellular carcinoma (HCC) in cirrhosis; A 5 year prospective study of 613 patients

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Page 1: Factors influencing the development of hepatocellular carcinoma (HCC) in cirrhosis; A 5 year prospective study of 613 patients

143 FACTORS INFLUENCING THE DEVELOPMENT OF HEPATOCELLULAR CARCINOMA (HCC) IN CIRRHOSIS; A 5 YEAR PROSPECTIVE STUDY OF 613 PATIENTS

P.J. Johnson, S.N. Zaman, W.M. Melia, R.D. Johnson, R. Williams

Liver Unit, King's College Hospital, Denmark H i l l , London SE5, England.

Although a recent prospective study involving over 20,000 apparently healthy Chinese men has clearly shown that HBsAg seroposit ivity is a risk factor for the subsequent development of HCC, the interrelationship between the HBsAg and underlying chronic l i ver disease could not be adequately assessed. We have followed-up 613 patients with cirrhosis (489 from the UK, 385 male), referred between 1978 and 1983, for up to 5 years. The influence of the following factors on HCC development was assessed: age, sex, aetiology and duration (from diagnosis) of cirrhosis and serum HBV markers (HBsAg, HBsAb, HBeAg and Anti HBe in a l l , and Anti HBc in 214. Patients were screened regularly by serum AFP estimation and c l in ical examination, and to date HCC development has been documented in 42 (17% of those dying from cirrhosis). Using multiple regression analysis the major independent factors associated with the development of HCC were, in decreasing order of significance, non-UK nat ional i ty , male sex and increasing age (a l l p 0.05). When only UK patients were considered increasing age and male sex were again the only signif icant risk factors (p 0.05). HBsAg sero- pos i t iv i ty was not a signif icant risk factor for the development of HCC in UK or non-UK cirrhot ic patients. In epidemiological studies showing association between HCC and HBsAg seroposit ivity, the la t ter may be acting as a marker of underlying cirrhosis, which is i t se l f the important risk factor.

144 DIFFERENTIAL EFFECT OF LIVER DISEASE ON THE CYTOCHROME P-450 and P-448 SYSTEMS G. Jost~ U. v. Mandach, A. Wahll~nder, R. Preisi 9 Department of Clinical Pharmacology, University of Berne, Switzerland

Based on circumstantial evidence only, chronic l iver disease has hitherto been thought to result primarily in a loss of t e l l mass with the remaining hepatocytes function- inq normally. Since methods are now available to assess subcellular functions specif ical ly, we have studied simultaneously the clearances of caffeine Ca P-448 probe) and antipyrine Ca P-450 probe). 14 normal volunteers (NV; mean age 37 years), 18 ambulatory patients with biop- sy documented cirrhosis (CI; mean age 50 years; 7 alcoholic, 11 nonalcoholic) and 16 subjects with noncirrhotic l iver disease (LD; mean age 41 years; fat ty l iver , chronic persistent hepa- t i t i s ) were given a single p.o. dose of 10 mg/kg b.w. antipyrine with lunch. They were asked to abstain from caffeine intake after dinner and to collect a saliva sample before bedtime and upon arising. Saliva concentrations of caffeine (C) were measured with EMIT , those of anti pyrine (A) with HPLC, and clearances (Cl) calculated using a constant VD of 0.6 l/kg b.w. Although for the entire population, CCI and ACI were s ign i f icant lycorre lated (r=O.8O, p< 0.001), in the disease groups there were notable differences in clearance ratios (CCI/ACI). Compared to CCI of 1.70+S.D.O.5ml/min/kg and ACI of 0.80+0.3 in NV (ratio 2.3+0.6), the re- spective, significantly~educed values were 0.90+0.4 and 651+0.2 in LD (ratio~.8+O.7), 0.49 +0.3 and 0.39+0.1 in CI (rat io 1.3+0.7). This Ttr ik ing change in clearance ratios suggests preferential r-eduction of the cytoc~rome P-448 system in remaining and/or regenerated cells, thus arguing against the "intact hepatocyte hypothesis". Therefore, simultaneous measurement of CCI and ACI, besides being noninvasive and practical in quantifying hepatic function, may provide new insight into the pathophysiology of chronic l iver disease.

$72