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• EFFECT OF TOTAL PLASMA EXCHANGE ON CEREBRAL EDEMA OF FULMINANT HEPATITIS. D. Odiz, S. Westerberg, S.J. Munoz. Jefferson Medical College, Philadelphia, Pennsylvania.

Cerebral edema Is a leading cause of death in patients with fulminant hepatitis (FH), but its pathophysioiogy is poorly understood. Serum from FH patients has an inhibitory in-vitro effect on neuronal Na+K+-ATPase activity. Circulating neurotoxic substances, accumulation of osmotically active amino acids, and various mechanisms of blood brain barrier disruption have been postulated. For several years we have used exchange plasmapheresis (EP) as therapy for severe ccagulopathy of FH. AIM: Since EP isovolumetrically removes a large fraction of a patient's plasma volume, we studied the effects of EP on intracranial pressure (ICP), cerebral perfusion pressure (CPP) and outcome in patients with FH. METHODS: Mean artedal pressure (MAP) and ICP were continuously recorded in seven patients with FH (hepatic encephalopathy within 8 weeks of onset of symptoms) before, dudng, and after total EP. To detect delayed effects of EP, parameters were also assessed dudng the 24 hours following EP. CPP was estimated as MAP minus ICP. Clinical outcome, defined by the frequency of brain swelling, neurolog~c sequelae, and survival, was compared between the study group and 10 ccntemporary FH patients who did not undergo EP. RESULTS: Seven FH patients underwent eight EP procedures. Duration of EP was 2.3 + 0.6 hrs. Mean ICP, MAP, and CPP prior to EP were 16 :i: 8, 85 + 12, and 69 + 18 mmHg respectively. Dudng EP, the mean ICP was 23 + 15, MAP 81 + 25, and CPP 58 + 16 mmHg. After EP, ICP was 17 + 7, MAP 77 + 9, and CPP 61 + 9 mmHg. Dudng the 24 hr. period following EP, CPP significantly decreased to 50 + 26 mmHg (p < 0.025), primarily due to the development of intracranial hypertension (ICP: 34 + 23 mmHg; p < 0.05 vs. pre-EP). There was no difference in the frequencies of brain edema, neurological sequelae or survival between FH patients who underwent EP and FH patients who did not undergo EP. CONCLUSIONS: Exchange plasmapheresla in patients with FH i~as no immediate effects on intracranial pressure or systemic hemodycamics. However, this procedure was associated with a significant elevation of intracranial pressure (leading to diminished cerebral perfussion pressure) dudng the 24 hr. podod following EP. These observations de not support the concept of circulating substances causing intracranial hypertension in FH, but rather suggest that humoral compensatory factors present in plasma may have a Iowedng effect on ICP. Removal of these putative factors by EP may result in the increased ICP observed after EP in fulrnthant hepatitis.

SIGNIFICANT ROLE OF NEUTROPHILS IN HEPATIC ISCHEMIA AND REPERFUSION INJURY. Y. Oshiro, S. Marubayashi, T. Maeda, 1~ K. Yamada, S. Koyama, z) H. Ito, 3) M. Miyasaka, 4) K. Dohi, 1) Depts. of Surgery ~) and Biochemistry, z) Hiroshima University School of Medicine, Dept. of Pathology, Tottori University School of Medicine 3) , Dept. of Bioregulation, Biomedical Research Center, Osaka University School of Medicine 4), JAPAN

We have showed that cellar damage in hepatic ischemia followed by reperfusion(I/R) can be explained by free radical reaction processes during hepatic ischemia and especially reperfusion, (1) The source of reactive oxygen in the liver remains to be elucidated. The aim of present sturdy was to determine whether neutrophils (PMNs) could contribute to I/R injury, and pretreatment with monoclonal antibodies(mAbs) of anti-ICAM- 1 (IA29) and anti-LFA-1 (anti-CD11 a,WT-1 ) and anti-CD18(WT-3) could improve this injury. Male Wistar rats were used and blood vessels supplying median and left lateral hepatic lobes were occluded with arterial clip for 90 rain. After reperfusion , the infiltration of PMNs and the expression of ICAM-1 was examined histologically. IA29 mAb and WT-1 mAb or IA29 mAb and WT-3 mAb were injected i.v. 5 min before ischemia at a dose of 0.5 mg/kg each. To examine the effect of mAbs treatment, ATP and Malondialdehyde levels in hepatic tissue were determined as an index of liver cell injury and lipid peroxidation. The number of PMNs increased continuously up to 24 hours after reperfuion. The expression of ICAM-1 was enhanced in the liver 4 hours after reperfusion. With treatment of mAbs, PMNs infiltration was suppressed significantly 6 hours after reperfusion, ATP resynthesis was improved 6,1 2and 24 hours after reperfusion and MDA level was completely suppressed 12 hours after reperfusion. Then these mAbs were also effective on the rat survival rate of total hepatic ischemia model. These results suggest that PMNs contribute to I/R injury in the liver several hours later after reperfusion, and that these mAbs to adhesion molecule are useful for the prevention of ischemic liver cell injury. (1)Surgery 110:537-543,1991.

• PRETREATMENT SERUM HCV RNA LEVELS WITH A BRANCHED DNA ASSAY PREDICT THE EFFICACY OF INTERFERON TREATMENT IN GENOTYPE 1B PATIENTS WITH CHRONIC HEPATITIS C, BUT NOT IN 2A AND 2B. M. Oshita, N. Hayashi, A. Kasahara, H. Hagiwara, T. Hijioka, K. Katayama, H. Fusamoto, T. Kamada. First Department of Medicine, Osaka University School of Medicine, Osaka, JAPAN.

Interferon (IFN) therapy has been proved to be useful for chronic hepatitis C and serum HCV RNA levels before treatment is an important factor that influenced its efficacy (Gastroenterology 104:877,1993). Recently, a branched DNA probe (bDNA) assay was developed and the quantities of HCV RNA have been able to be measured easily. This study was aimed to examine the relationship between serum pretreatment HCV RNA levels and the efficacy of IFN therapy in patients with chronic hepatitis C. Subjects and Method: Three hundred and twenty-six patients with chronic hepatitis C were enrolled. Natural IFN-cc was given (human lymphoblattoid IFN; Sumitomo Pharmaceuticals Co., Osaka, Japan) at a dose of 6 MU/day every day for 2 weeks, and then 3 times a week for 14 or 22 weeks. Pretreatment HCV RNA levels in serum were measured with bDNA assay and HCV genotype was examined by the Okamoto's method. Sustained responder (SR) was defined as a patient whose ALT level remained within the normal range more than six months after treatment. Result: (1)The rate of SR in lb, 2a and 2b patients were 22%, 60% and 40%. (2)The rate of SR was higher in lb patients whose HCV RNA levels < 1.0x10 s eq/ml than in those whose HCV RNA levels > 1.0xlO s eq/ml [38% (30/78) vs. 13% (16/128), p<O.01]. Of genotype lb sustained responders with HCV RNA levels < 1.0xlO s eq/ml, 73% (22/30) were HCV RNA negative 3 months after the end of treatment, but of those with HCV RNA levels > 1.0x106 eq/ml, 13% (2/16) were HCV RNA negative. (3)The rate of SR in 2a and 2b patients with HCV RNA levels < 106 eq/ml was similar to in those with HCV RNA levels > 106 eq/ml [2a patients; 65%(26/40) vs. 47%(8/17), 2b patients; 44%(4/9) vs. 60%(3/5)]. Conclusion: In lb patients, pretreatment HCV RNA levels by bDNA assay predicted the response to IFN treatment, but in 2a and 2b patients it did not. IFN treatment is not effective in l b patients whose HCV RNA levels _> 1.0xl06 eq/ml.

• TWELVE-MONTHS TREATMENT EXHIBITS A HIGHER INTERFERON EFFICACY THAN SIX-MONTHS TREATMENT IN CHRONIC HEPATITIS C PATIENTS WITH ADVANCED LIVER FIBROSIS M. Oshita, N. Hayashi, A. Kasahara, N. Hiramatsu, H. Hagiwara, T. Hijioka, K. Katayamal), M. Kate, M. Masuzawa2), H. Yoshihara3), Y. Kishida4), Y. ShimizuS), A. Inoue6), H. Fusamoto, T. Kamadal). 1)First Department of Medicine, Osaka University School of Medicine, 2)National Osaka Hospital, 3)Osaka Rousai Hospital, 4)Osaka Kousei-Nenkin Hospital, s)Osaka Prefectural Hospital, S)The Center for Adult Diseases, Osaka, JAPAN.

Response to interferon (!FN) treatment in patients with chronic hepatitis C was reported to be associated with liver histology including fibrosis and periportal and Iobular inflammation before therapy. IFN therapy was not effective for patients with advanced liver fibrosis. In present study, we examined whether prolonged (12- months course of) IFN treatment improved its efficacy in chronic hepatitis C patients with bridging fibrosis. Subjects and Method: Eighty-eight patients who were proven to have chronic hepatitis C histologically were examined in this study. Natural IFN-e~ was given (Otsuka Pharmaceuticals Co., Osaka, Japan) at a dose of 5 MU/day 3 times a week for 28 weeks (28- week treated group, n=45) or 52 weeks (52-week treated group, n=43). HCV genotype was examined by the Okamoto's method. Sustained responder was defined as a patient whose ALT level remained within the normal range more than 6 months after the end of treatment. Result: (1)The rate of sustained responders in 28-week and 52- week treated group were 33%(15/45) and 54%(23/43). (2)Efficacy of IFN treatment in patients without bridging fibrosis was not different between the two therapeutic groups, but in patients with bridging fibrosis the efficacy of 52-week treated was higher than that of 28- week treated (Table). In genotype lb patients, same tendency was recognized. (3)Histologically, the hepatic fibrosis score improved after IFN treatment in sustained responders. Conclusion: These data suggests that prolonged IFN treatment increased its efficacy in patients with advanced liver fibrosis.

<Efficacy of IFN therapy in patients with/without bridging fibrosis> Without bridging fibrosis With bridging fibrosis

28-week treated 11/25(44%)1 4/20(20%)3 52-weektreated 9/20(45%)J n.s 11/23(48%)J p=0.055