April 1995 AASLD A1053 THE ROLE OF ETHNICITY AND OTHER RISK FACTORS FOR CHOLELITHIASIS IN A HIGHLY PREVALENT AREA: CROSS-SECTIONAL AND COHORT STUDIES IN CHILEANS AND AMERINDIAN ARAUCANOS. ¢ovarrnbias C., Miquel J.Fce., Puglielli L., Hofmann E., GianeasperoR., Ebensberger E. Migrone G., Greco A., Buoni C. & Nervi F.. Depto. de Gastroenterologiay Centro para la Prevenciony Tratamientodel C,Jmcer Digestivo,Pontificia UniversidadCat61ica, Chile. Universit,i Cattolica dell Sacro Cuore, Italia. Hispano-Americancountries have a high prevalence of cholelithiasis, One reason invoked for this condition is the Amerindian ancestry of these populations. This racial factor is also commonlyaccepted as the cause of the higher prevalenceof gallstones in Pima Indians and Mexican Americans as compared with Anglo-Americans and Spaniards. A/ms: 1. to investigatethe prevalenceand risk factors of cholelithiasis in an urban free-living population from Santiago. 2. to study the prevalence of cholelithiasis in a cohort study of native Indians-Araucanos in southern Clnle (Araneania)3. to evaluate if the Amerindian ancestry represented a risk factor for cholelithiasis. Methods: The study population (1037 women and 662 men; age2_20)was randomly selected from one urban neighborhood in Santiago, representing the most frequently socioeconomicstrata (Graffar 3 to 5) and European-American admixture index of our population. A cohort study in Native-Araucanos (n=182; age~_20) was performed in the Huapi island reservation, Ranco lake. Participants were screened for the presence of gallstones by ultrasonography, completed a questionnaire on family and personal history, socioeconomicstrata, and underwenta physical examination,blood chemistryand ABO blood group determination. Amerindian admixture index was determined from ABO genotypie frequency according to the Bernstein's method. Satistically significant association were established by univariate analysis of the age-standardizeddata and by step-wise multiple logistic regression. Res,/ts: The prevalence of eholelithiasis was 37,4% in women and 14,5% in men (9<0.0001). At univariate analysis age, Blvi/, total/HDL-cholesterol index, serum trigiycerides and glucose were associated with gallstones in men. In addition, total and LDL.-cholesterol,HI)L-cholesterol and parity were the conespondent association in women.By logistic regression,only age and lower HDL-chniesternishoweda significant independentassociation with gallstones in men. In women, gallstones were independently associated with age, BMI, serum glucose level, parity and with decreasing HDL-cholesterol. Amerindian admixture index of the study polmlatinn in Santiago and Huapi island was 0.4 and 0.9 respectively(p<0.0001). Ethnicity was not associated with a higher risk of gallstones as judge by logistic regression analysis. Furthermore,in a sex, age and BMI adjusted paired sample (n=146 each group) the prevalence of gallstones was similar in both, the racially mixed "Chilean" and uahve-Arancano populations (17 vs. 17% men; 42 vs. 42% women). Conclusions: In a highly prevalent area, risk factors for gallstones did not substamially differ from other comparablestudies done in USA and Europe. Remarkably,this study suggests that ethnicity per se may not explain the high prevalenceof gallstones in this area. The results more likely stress the relevance of complex genetic-environmental interactions in the pathogenesis of gallstone disease. [Supported byMinistero degli Affari Estefi d'Italia and lstitutoperla Cooperazione Universitaria, Italia.] CHRONIC VIRAL HEPATITIS B AND C IN AIDS. J~ Cowan and C.B. Leevy, UMD-NJMS Liver Center, Newark, NJ. Investigations were undertaken to determine the role of chronic viral hepatitis on clinical and laboratory findings in patients with AIDS. Each of 30 patients was an IV drug abuser and had hepatomegaly with abnormal liver function tests. HIV immune complexes prevented expression of HBsAg and HBeAg despite the pre sence of HBV-DNA in 13 patients. Liver biopsies showed necrosis and inflammation in each of the patients, with fibrosis in 12. PCR revealed HCV-RNA in 6, HBV-DNA in 7, and HCV-RNA and HBV- DNA in 17. Nine of I0 patients had HIV in CD 4 cells, macrophages and the portal area using a p Ben 6.5 HIV-c-DNA probe. Patients with combined HBV and HCV exhibited a significantly greater degree of liver dysfunction than those with HBV or HCV alone, except for 2 patients with HBV without HCV who had marked increases of ALT (1340 and 1965), reflecting a cytopathic effect of HBV. H3T incorporation into DNA and hepatic albumin mRNA production were also diminished in patients with multiviral infection: HIV NEO HIV POSITIVE HBV HCV HBV-HCV DNA Syn/10 ~ 150±30 25±5 35±5 15~5 Hepatocytes 32P mRNA 3±0.5 1.3±0.6 1.8±0.5 0.75~0.3 Absorbance Serial studies of patients with fulminant disease due to HBV or multiviral infected patients showed a progressive down hill course despite symptomatic and supportive measures. Conclusion: Hepatotrophic viruses and HIV potentiate each other in liver injury. The cytopathic effect of both HBV and HCV alone, or together contributes to observed immunologic and metabolic disarray in AIDS. • DOWN-REGULATION OF HEPATOCYTE CANALIC~ BILE SALT TRANSPORT BY BILIARY DIVERSION. James M. Crawford and Aleta R. Crawford. Brigham and Women's Hospital & Harvard Digestive Diseases Center, Boston, MA. The hepatic capacity for bile salt secretion appears to be regulated by the bile salt load, with evidence for a reduction in secretion capacity following biliary diversion (J.Lipid Res. 35:1738-1748, 1994). We exam- ined whether canalieular membrane bile salt transport, in particular, is down-regulated following bile salt depletion. Methods: Canalicular membrane vesicles (eLPM) were prepared from the pooled livers of 4 adult male rats subjected to 18h biliary diversion (depleted), or from 4 sham-operated (control) rats (n=16 paired preparations). [~H]Tauro- cholate ([aH]TC) transport was measured, and the protein content of an apical 100 kDa eeto-ATPase/putative bile salt transporter (Am.J.Physiol. 258:G728-G737, 1990) was evaluated by Western blotting. Steady-state levels of mRNA for this protein were measured in liver homogenate all- quote from these same animals. Results: ATP-dependent uptake of [~H]TC (1.0/~M) by cLPM at 250C was 16.4+-5.6 vs. 9.6+-3.3 pmol/mg prot/10s (+-SD) in control vs. depleted rate, respectively. On a pairwise basis, the decrease was 39+-2% (p<0.01). SiroSlarly, uptake of [aH]TC over a concentration range of 1 to 200/~M was reduced by an average of 43+-3% (p<0.01). ATP-dependent efflux of l~tM [aH]TC was 19.6_+ 1.2 vs. 12.2+-0.3 pmol/mg/10s, respectively, a reduction of 38-+4% (p<0.01). No differences in eleetrogenie uptake or effiux were identi- fied. By Western blotting, protein content of the 100 kDa ecto-ATPase decreased 34+-6% in depleted vs. control animals (p<0.01). Steady-state mRNA levels for this protein decreased by a similar amount. Conclusions: The decrease in transhepatic bile salt flux induced by 18h biliary diversion down-regulates eanalicular membrane bile salt transport capacity by about 40%. This down-regulation is correlated with similar decreases in the membrane content of a 100 kDa protein thought to play a role in canalicular bile salt transport, and in the steady-state hepatic levels of the mRNA for this protein. These data corroborate the in vivo observation that hepatic bile salt secretion capacity declines - 40% following 18h biliary diversion. Our findings implicate modulation of the content of bile salt transport protein system(s) in the canalieular membrane as a primary mechanism for reg- ulating hepatic bile salt secretion capacity. A decreased transhepatic bile salt flux rate leads to decreased canalicular bile salt transport. • THE EFFECT OF CHOLESTASIS ON MYOCARDIAL ISCHEMIA REPERFUSION INJURY. Juan A. Crestanello, Kim U. Kahng, Joseph Kamelgard, Ting Liu, David I,ingle, Glenn J. Whitman. The Medical College of Pennsylvania Philadelphia,PA Cholestasis is associated with hemodynamic disturbances that may be due to altered systemic vasomotor tone and myocardial dysfunction. Since bile duct ligation (BDL) has been slmwn to potentiate renal ischemic injury, we hypothesized that cholestasis would have similar effect on myocardial ischemia reperfusion injury (IR). The purpose of this study was to determine the effect of BDL on 1) myocardial function, 2) myocardial tolerance to IR, and 3) vasodilatory responses of the coronary vascular bed. Rats (n=5/group) were subjected to either bile duct ligation or sham operations (CTRL). Four days later, hearts were harvested and perfused in a Langendorff apparatus. After 15 minutes of Equilibration (EQ), hearts were subjected to 25 minutes of ischemia, and 15 minutes of reperfusion (RP). Developed pressure (DP). -+dp/di, coronary flow (CF), myocardial oxygen consumption (MVO2), and myocardial aerobic efficiency (DP/MVO2) were measured. In parallel groups of hearts, endothelial dependent and independent vasodilatation were tested respectively by measuring CF during a 5 minute infusion of bradykinin (BK, 5xl0-SM) and sodium nitroprusside (SNP, lxl0-5 M) at end EQ and at end RP. Values are expressed as Mean + SEM. Student's unpaired t test were used for stalistical analysis. EQUILIBRATION 15 :t soL°T"~ ............ ............. o.::o. ~7!!! ;7:, ':2£ ;:S ~ I REPERFUSION 15 i Dp ÷dPldt .dp/dt DPIMVO2 CF ~ P CFfusi I I I I I,,.,= ..... i ..... (mmHg) (mmHQ $-1) (mmHg m- ) H~ ( I/ I V) CTRL 18±5 4.£1 3±1 o. 19:~0.07 13~.9 *p < 0.0S vs CTRL BDL had no effect on basal myocardial function. DP/MVO2 at EQ did not differ between the two groups, suggesting that mitochondrial function was not altered after BDL. 1R resulted in severely compromised myocardial function and reduced myocardial aerobic efficiency in the CTRL hearts. The magnitude of this injury was similar in BDL hearts. Vasodilatory responses to BK and SNP at EQ were similar in the two groups. IR significantly diminished these responses in CTRL hearts, however the response to SNP was better preserved in the BDL group. We conclude that 1) myocardial function is not adversely affected after BI)L, 2) cholestasis does not potentiate myocardial IR injury, and 3) 1R related damage to vascular smooth muscle is attenuated in the presence of cholestasis.