Treatment of chronic hepatitis C with recombinant alfa interferon 2B

Treatment of chronic hepatitis C with recombinant alfa interferon 2B


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April 1995

• PREDICTORS OF OUTCOME OF LIVER TRANSPLANT FOR CHOLESTATIC LIVER DISEASE. P. Ricci-Blue. TM Themeau, JL Petz, J Benson, M Malinchoc, JS Crippin, GB Klintmalm, J. Steers, RH Wiesner, TE Starzl, K Abu-Elmagd, ER Dickson. Mayo Clinic, Rochester, MN; Baylor University Medical Center (BUMC), Dallas, TX; University of Pittsburgh, Pittsburgh, PA

Background: Optimization of patient selection and timing of orthotopic liver transplant (OLT) has become an important focus of research because of the increasing disparity between demand and donor availability. Aim: To define which preoperative variables are best at predicting morbidity in patients (pts) with cholestatic liver disease undergoing OLT. Methods: We studied 375 pts with PBC and PSC who underwent OLT between 1985 and 1994 at three medical centers: Baylor University Medical Center (BUMC), University of Pittsburgh, and Mayo Clinic. Data were collected from NIH Liver Transplant Database forms (University of Pittsburgh, Mayo Clinic) and similar forms mapped to NIH data forms (BUMC). Median follow-up time was 1.1 yrs post-OLT. Preoperative variables studied were: age, Kamofsky score, Child's grade, Mayo "r" score, UNOS status, ascites, encephalopathy, GI bleeding, nutrition, edema, renal failure, albumin, creatinine, bilirubin, INR, and therapy with ursodeoxycholic acid. Outcome studies included: intraoperative blood loss, days in intensive care unit, and major complications before and after 30 days from OLT. Univariate analysis was stratified by disease and institution. Results: Overall two-year survival was 90%. Several preoperative factors significantly predicted intraoperative blood loss and ICU stay: Karnofsky, Child, and Mayo "r" scores, UNOS, nutritional status, ascites, renal failure, INR (p<0.001), age, edema, total bilirubin, albumin (p<0.005), and encephaiopathy (p<0.01). Significant predictors of severe complicalions within a month of OLT includes Child and Mayo "r" scores, UNOS status, renal failure (p<0.001), Kamofsky score, total bilrubin (p<0.01), ascites, encephalopathy, and nutritional status (p<0.005). Severe complications more than a month after OLT were related to nulritional status and renal failure (i><0.05). Coneluslons: In patients with PBC and PSC, many preoperative variables predict inlraoperative blood loss, ICU stay, and morbidity in the first month post-OLT but do not predict complications which occur beyond the fh'st month POsI-OLT. The Mayo "r" score was a very significant predictor of intraopemtive blood loss, ICU stay, and morbidity in the first month post-OLT, while renal failure was the most powerful predictor of all four outcomes.

O OUTCOME OF ACETAMINOPHEN OVERDOSE IN PEDIATRIC PATIENTS AND FACTORS CONTRIBUTING TO LIVER TOXICITY. T. Rivera-Penera, R.Gugig, S. McDiarmid, J. Vargas, B. Berquist, M. Heyman, ME Ament. Depts. of Pediatric GI, UCLA, California-Pacific, UCSF Med. Ctrs. Forty nine pediatric patients with history of acetaminophen overdose were reviewed to determine outcome and factors contributing to liver toxicity. There were 11(22%) patients under 10 years of age, of which 9(81%) were multiple acetaminophen overdoses given by parents by mistake. Seven (63%) were females and 4(37%) were males. Thirty eight (77%) were above 11 years of age and were all suicide attempts with single massive overdoses. Thirty (79%) were females and 8(21%) were males. Overall, abnormal liver tests were found in 27(55%), 6(22%) of which were on the transplant list for progressive encephalopathy, rapid and persistent deterioration of liver tests and presence of cerebral edema refractory to medical management. All 6 underwent orthotopic liver transplantation (OLT), 4(67%) were under 10 years old and 2(33%) above I 1 years old. The remaining 21(78%) with abnormal liver tests recovered and started to improve 5.3 days (+/-7.4) postingestion except for one who died. The normal liver test group (NLTG) ingested 257 mg/kg (+/-206) vs. 378 mg/kg (+/228) (p=.07) for the abnormal liver test group (ALTG). The NLTG was symptomatic 7.5 hrs.(+/-9.6) postingestion vs. 40 hrs.(+/-31)(p<00l) for the ALTG and was admitted earlier. Twelve (55%) of the NLTG had toxic serum acetaminophen levels and were started on actetylcysteine 7.4 hrs.(+/-3.1) posfingestion while 21(80%) of the ALTG were given acetylcysteine 31 hrs.(+/29)(p=.012). Six (22%) of the ALTG were admitted >36 hours postingestion and not given the antidote. Nine (33%) of the ALTG received multiple overdoses within 48 hours of which 3(33%) underwent OLT and the NLTG were all single overdoses (p=.003). Six (22%) of the ALTG had increased intracranial pressure (ICP) and cerebral edema on CT scan except for one and all underwent OLT. Five (19%) of ALTG reached stage III encephalopathy while NLTG had only 2(9%) that reached stage II and reversed within 72 hours postingestion. CONCLUSION: Parental misguidance of acetaminophen dosing is the major cause of acetaminophen OD in patients under 10 years old; and suicide attempts for >l 1 years of age of whom majority are females. Contributing factors to liver toxicity include multiple overdoses, failure to recognize condition, late medical intervention and concomitant ingestion of hepatotoxic medications which may progress to irreversible liver failure.



O SUSTAINED CULTURES WITH COLLAGEN GEL BILAYERS WITH CREATION OF BILE DUCTULAR CELLS WITH STIMULATION OF HEPATOCYTES BY DEFINED MEDIA, HGF AND EGF, TR Riley, GD Block, W Bowen, B Petersen, GM Michalopoulos, Depts. Medicine and Pathology, University of Pittsburgh, PA. The recent development of a defined medium (HGM) has allowed long term support of hepatocytes (Hc) in tissue culture with sustained proliferation ( > l S days) and survival for >S0 days by HGF and EGF stimulation. The characteristics of these ceils in culture have been documented on collagen coated plates by light microscopy, Northern Blot analysis, and transcription factor assays. In this study, our aim was to evaluate the effect of EGF and HGF, stimulation on hepatocytes maintained in a collagen gel bilayer cultured with HGM. The hypothesis was that hepatocyte differentiation would be better maintained. Methods: Hc were obtained from normal male 1S0 gram Fischer 344 rats by collagenase perfusion and purified by differential centrifugation. Viability was assessed by Trypan blue exclusion and was always greater than 90%. Collagen gels were prepared using Type I collagen. Cells were plated at cellular concentrations of 200,000 cells/m]. A top layer of collagen was placed and the HGM media was added with or Without EGF/HGF. The wells were cultured at 37C in 5% CO2. The cells were studied using morphological descriptions with microscopic photographs and electron microscopy. RNA was prepared on days 0,3,5,10,15,20 and subjected to northern blot analysis and the gene expression for several markers is currently under study. Results: The morphological features showed normal hepatocyte proliferation with lining up into cords. Between Day 4 and Day 7, ductular structures formed with this becoming the predominant feature by Day 10-12 in the cells stimulated with EGF/HGF. In the HGM media alone, these ductular changes were not seen. By Northern blot analysis, cytokeratin 18 mRNA was induced in stimulated cells with HGF/EGF but not detected in cells in the control media. The electron microscopy images confirmed the bile ductular appearance of the structures formed, Conclusions : In a collagen bilayer, HGM media with EGF/HGF stimulation creates a novel ductular structure for which we have defined morphological characteristics. This model appears to be an in vitro system demonstrating a bi-directional expansion of mature cells from a hepatocyte pure culture, supporting the theory of a stem cell,

TREATMENT OF C H R O N I C HEPATITIS C WITH RECOMBINANT ALFA INTERFERON 2B.Tm_R~,F. Lopez,A. Perehes,J. Gonzales. Department of Gastroenterology,Hospital de E s p e o i a l i d a d e s Centro Medico La Raza. IMSS. Mexico D.F. Mexico. A I M : To e v a l u a t e the efficacy of recombinant alfa interferon 2B(IFNa) in patients with chronic hepa titis C (CHC). METHODS: Patients with CHC were included. Diagno sis was based on positive antibodies to h e p a t i t i s C ( a n t i V H C ) b y E L I S A II c o n f i r m e d with RIBA If;in creased alanine aminotrasnferase(ALT) value;histo logical features and exclusion of another causes of liver injury. All patients were treated with IFNa, S MU S times a week during 6 months and they were followed up for a further 6 months. Liver biop sy w a s p e r f o r m e d in all patients before'and after treatment(Tx).Activity histological was scored by Knodell index. Response to T x w a s d e f i n e d as fo flows:Complete Response(CR):return to n o r m a l A L T values at e n d o f T x ; P a r t i a l response(PR) decrease more than 50% ALT values at end of Tx;No Response (NR) w h e n A L T v a l u e s r e m a i n e d h i g h at e n d o f Tx. Relapse(R) in CR:return to a b n o r m a l values within 5 m o n t h s at t h e e n d o f Tx. RESULTS:!2 patients were treated,9 females,3 males mean age was 47 years(Si-57).All had the backgroud of transfusion or surgery. 4 patients had CR:35.3% 4 h a d P R a n d 3 NR. O n e p a t i e n t was excluded b y si de e f f e c t s . ALT values shown significant differen oe b e t w e e n initial a n d f i n a l v a l u e o f Tx. T h e r e w e re no histological improvement in all cases.During follow up a sustained CR was founded in S p a t i e n t s (75%) One patients(25%) relapsed. PR and NR had high ALT values. Side effects observed:fever,myal gins, asthaenia, all well tole~ed. CONCLUSIONS:We found a rate of relapse i n CR l o w e r than other reports,but rate of CR was similar to other reports. To date IFNa remains the only aocep ted Tx for CHC,but other regimens, different drugs and combinations n e e d to b e t e s t e d f o r N R p a t i e n t s .