HEPATOLOGY Vol. 22, No. 4, Pt. 2, 1995 AASLD ABSTRACTS 437A

1321 A TIIERAPEUTIC TRIAL OF ItlGIIER DOSING REGIMEN OF ALPHA (¢) IN- TERFERON (IFN) MONITORED BY SERUM HCV-RNA LEVELS FOR PATIENTS WITII CIIRONIC IIEPATITIS (CII) C, WHO FAILED THE TREATMENT WITH 3 MU STANDARD DOSE OF ~IFN. H. Kawanishi. Dept. of Med., Robert Wood Johnson Medical Seh0ol, New Brunswick, NJ

Several controlled and uncontrolled trials have shown that higher doses and longer treat- ment periods of ~II=N tend to produce higher long-term sustained response rates. In the present studies, we investigated the efficacy of 'SMU ~IFN (2b) Regimen' (5MU x daily for the first 2 weeks, then TIW up to 6 months, followed by tapering to 3MU TIW x 2 months and 1.5 MU TIW x the last 2 months) in CH C patients, who had failed to respond to the conventional cdFN treatment (3 MU TIW x 6 months). HCV RNA levels (bDNA assay and RNA-RT-PCR) were monitored during the ezlFN treatment. Complete responders were defined as those with normal ALT and non-detectable serum HCV RNA by RNA-RT-PCR. These responders continuously administered 5 MU cdFN TIW for additional 2 months (prior to tapering) al~er the complete response was obtained. When ALT did not decrease by more than 50% within 4 1/2 months and serum HCV RNA remained detectable, these patients were terminated as non-responders.

Results: A total of 3O patients with CH C were enrolled. Two patients were dropped out because of ~IFN side effects. Of the remaining 28 patients (21%) (43.6 + l0 y.o.a.; 18 M/10F), complete response was found in 6, breakthrough 3, partial response (ALT reduction >50% and positive serum HCV RNA) 9, and no response I0. Recur- fence of 6 months-follow up after cessation of cdFN in the complete responders (6 eases) was seen in 2 cases fpositive serum HCV RNA and normal ALT) (33%). Significant unfavorable factors in response to ~IFN in the patient population studied were albumin, iron, alpha fetoprotain, gammaglobulin, platelet count, preRx histopathology, and obesity. PreRx HCV RNA and ALT levels did not show any significant differences in the responsiveness. All complete responders had one of the unfavorable fael~rs or none.

In summary, the present higher dosing regimen in 3MU conventional dose-failure patients with CH C induced the complete response in ca 20% , but one third of the patients recurred within 6 months. The present studies indicate the clinical outcome of the current ~IFN treatment even with its higher tolerable dosage is not entirely encouraging in the Conventional dose-failure patients. Use of additional newer antl-viral agents is needed. However, the complete response to the present dose regimen could be expected only in a selected subset of the above patient group, which has one or none of the unfavorable factors. Thus, scoring of the unfavorable factors may provide a therapeutic guideline of the present higher dosing IFN regimen for selection of complete response-prone patients from conventional cdFN dose-failure ones.

1322 EFFECTS OF CIMETIDINE ON BLOOD ETHANOL LEVELS AFTER ALCOHOL INGESTION AND GENETIC POLYMORPHISMS OF cr-ALCOHOL DEHYDROGENASE IN JAPANESE. O. KAWASHIMA, M. YAMAUCHI, Y. MAEZAWA, G. TODA First Department of Internal Medicine, The Jikei University School of Medicine, Tokyo 105, Japan

First-pass ethanol metabolism by if-alcohol dehydrogenase (ADH) is thought to be an important determinant of blood ethanol levels as well as area under the blood ethanol curve (AUC) after oral intake of ethanol. Preteatment of cimetidine increases blood ethanol levels after acute ethanol administration. This has been attributed to decreased gastric first-pass metabolism of ethanol due to cimetidine's inhibitory effect on ff-ADH activity. Racial difference in If-ADH activity has been reported (Life Sci 49:1929, 1991). Recently, molecular studies on ~-ADH showed that a point mutation might occur at position 287 (G-*T) of ff-ADH gene in Japanese deficient type (FEBS Letters 351:411, 1994). In addition, five substitutions have been reported for key residues in the coenzyme binding site'. 230 (GAG), 251 (AGT), 259 (GGC), 260 (AAC) and 281 (AAC), which may contribute to the week coenzyme binding properties for human class IV ADH. In order to clarify the relationship between first-pass metabolism of ethanol and polymorphisms of ~-ADH, we analysed nucleotide sequence at these positions of If-ADH in ii individuals who were administered ethanol orally before and after treatment with cimetidine. Higher blood ethanol levels after cimetidine administration was found 4 out of ii Japanese subjects (group A), while high blood ethanol levels showed in 7 out of ll cases (group B), irrespective of cimetidine administration. Amplified 228 bases (position Z00-Z74) and 89 bases (position 279-301) as PCR-product were sequenced by Dye Primer method. Genetic polymorphisms at each position were not observed in all Japanese subjects. These results indicate polymorphisms of (r-ADH at position 230, 251,259,280,261, and Z87 are not associated with the difference in bioavallability of ethanol between A and B groups.

1323 DESF[IN EXPRESSING CRIJ~ DURING ~BR¥ONIC HEPATIC ~H~4ATOPOIF~IS IN RAT. A.P. Kiassov, i) P. Van Eyken~ J.F. van Pelt~ E. Depla, J. Fevery, l) V.J. Desmet and S.H. Yap. Dept. of Internal Medecine, Laboratory of Hepatology and l) Dept. of Pathology, Laboratory of Histo- and Cytochemistry, Univ. of Leuven, Belgium.

The expression and cellular distribution of desmin and cytokeratin no.8 (CK-8) in normaI adult, fetal and neonatal rat liver were examined im~onohistochemically on cryostat sections. At days 14 and 15 of gestation, nonhemtopoietic liver cells were strongly desmin- positive. A close association of desmin-positive Ito cell processes with hematopoietic cells was observed during fetal and early neonatal development. From day 16 of gestation the prehepatocytes became desmin negative, remained CK-8 positive. Desmin-expressing cells were numerous in the liver from the embryonic period to the neonatal age. However, their absolute number per unit area, as well as their number relative to parenchymal cells decreased with age. We suggest that desmin-positive liver cells may act as stromal cells in the hepatic hematopoietic microenvironment and Support hepatocyte development. In addition, desmin can be also considered as an early embryonic marker for liver epithelial lineage cells.

1324 TRANSIENT MYOCARDIAL DYSFUNCTION AFTER LIVER TRANSPLANTATION B Kim*, D Plevak, B Nan' , A Lerman, R Click, R Espinosa, J Poterneha, W Duma. Departments of Anesthesiology and Internal Medicine, Divisions of Critical Care Medicine, Cardiology, and Gastroenterology, Mayo Clinic, Rochester, MN, USA

Patients with end stage l iver disease usually have an elevated cardiac output (CO). This physiologic condition, known as the Hyperdynamic Circulatory State, tends to persist unti l weeks after successful l iver transplantation (OLT). However, it was our impression that some patients experience low CO and myocardial dysfunction (MD) after OLT. Methods: We reviewed data on 552 consecutive OLT performed at our institution between March 1987 until November 1994 for evidence of postoperative pulmonary edema and associated MD. We eliminated those patients with a diagnosis of myocardial infarction. With the patients identified, we attempted to prepare a clinical description, determine causative factors and ascertain prognosis. Results: Seven patients were identified. Four were female. Ages ranged 21-62 years. Two had alcoholic l iver disease. Pulmonary edema was identified between I and 26 (median 3) days after OLT. All patients required reintuhation. CO fell f rom 9.31(3.26 SD) L /min prior to MD, to 4.72 (1.03 SD) L/rain during MD (p<.008) . Four of 7 patients had preOLT echocardiograms with ejection fractions (EF) ranging between 57-75%. All 7 patients had echocardiograms (range 20-25% EF) at the time of MD. Six. of 7 patients experienced improvement in EF (range 35-56%) and all 6 were extuhated within 8 days. Two of the 7 patients had documented septicemia and 1 had hepatic dysfunction from hepatic artery thrombosis at the time of MD. One of the 7 patients had an intraoperative cardiac arrest and successful resuscitation. Conclusion: MD can occur after OLT and appears to be transient in most cases. More than one factor may be operative as the cause of MD.