HEPATOLOGY Vol. 22, No. 4, Pt. 2, 1995 AASLD ABSTRACTS 275A

673 CORRELATION BETWEEN TYPE I COLLAGEN mRNA LEVEL AND HISTOLOGICAL FEATURES IN LIVER BIOPSIES OF CHRONIC HEPATITIS C.. V Paradis. P Mathurin, M Vidaud; F Charlotte, P Opolon, T Povnard. and P Bedossa. Dept of Pathology, CNRS URA 1484, H6pital de Bic~tre, Groupe Hospitalier Piti6-Salp6tri~re, PARIS - FRANCE.

No criteria is presently available to determine which patients with chronic hepatitis C will develop liver fibrosis and cirrhosis. The aim of this study was to precise which pathological features are predictive of liver fibrogenesis. Since an increase of type I collagen (Col I) mRNA is required for liver fibrosis to develop, we compared the semi-quantitative scores of main neero-inflanunatory and fibrous lesions with the levels of type I collagen (Col I) and TGF~I mRNA (a major profibrogenie cytokine) in liver biopsies with chronic hepatitis C. Materials: 28 liver biopsies from patients with untreated chronic hepatitis C were studied. A part of each liver biopsy was used for RNA extraction and Col I and TGFI31 mRNA were quantified by a quantitative RT-PCR procedure including internal quantitative standards. The rest of the sample was processed for histological study. Portal inflammation, piecemeal necrosis, lobular necrosis, fibrosis and the degree of activity according to Metavir grade and Karodetl's index were semi-quantitatively assessed by txvo observers. Correlations between mRNA levels and histological scores, main clinical and biological data were performed using Pearson's test. Results: Col I mRNA level (mean=1.72, ranges:0-7.37) was correlated with the degree of fibrosis (p=0.01 ) but not with portal inflammation, piecemeal necrosis, lobular necrosis nor scores of activity. TGFI31 mRNA level (mean=0.49, ranges: 0-0.97) was correlated with lobular necrosis (p<0.01) and a score of activity (Metavir grade: p<0.01), but not with piecemeal necrosis, fibrosis nor Knodell's index. Among clinical and biological data, Col l mRNA was only correlated with bilimbin level (p=0.02) and TGF[31 mRNA with age (p=0.05). Furthernrore, there was a correlation between Col I and TGFI31 mRNA levels (p=0.04). conclusion: The only histological feature correlated with Col 1 mRNA level is fibrosis. Neither necro-inflammatory lesions nor scores of activity are predictive of fibrogenesis in chronic hep~/titis C, as assessed by liver Col I mRNA level. If confirmed in a larger group of patients, these data would have to be taken into account to treat chronic hepatitis C.

674 PRETREATMENT HISTOLOGY IN 2S8 PATIENTS IN THE BENELUX WITH CHRONIC HEPATITIS C: CORRELATION WITH CLINICAL PARAMETERS ANÙ PREDICTION OF RESPONSE TO INTERFERON. CM Bronkhorst, JT Brouwer, F Nevens, A Elewaut, M Adler. R Brenard, RAFM Chamuleau, P Michielsen, J Pirotte, ML Hautekeete, V Arendt, J Fevery, FJW ten Kate and SW Schalm. Univ. Hosp. Amsterdam, Rotterdam, Leuven, Gent, Brussels, Antwerp, Liege and Luxemburg.

The histological features of hepatitis C are well known, but less is known about their clinical relevance. Pretreatment fiver biopsies of 288 patients with a chronic HCV infection, participating in the multicenter randomized Benelux interferon trial, were analysed blindly by two pathologists. Biopsies were scored for features of the portal tract (PI - portal infiltrate, PMN - piecemeal necrosis, LA - lymphoid aggregates, CH - cholangiolitis), the Iobules (LI - Iobular infiltrate, FN - focal necrosis, ST - steetosis) and degree of fibrosis. An analysis was made for correlation with ALl- levels, duration of infection and later response to interferon, both for individual items and for the cumulative Knodell score. For the total group, mean ALT levels were 4.8 times the upper limit of normal (95% CI 4.4-5.2). ALT levels correlated with the degree of Iobular pathology (FN p=0.001, LI p=0.004, ST p=0.010) and PMN (p=0.001), but not with other portal events (PI, LA, CHI or fibrosis. In multivariate analysis, focal necrosis was the only factor correlating independently with ALl" (p=O.02). The duration of infection (mean 9.3 years, 8.1-10.4l correlated to the severity of fibrosis (p=0.0011, the degree of portal pathology (PI p=0.001, LI p=O.O05, PMN p=0.03) and steatosis (p=0.03), but not with other Iobular events (LI, FNL The mean sustained response rate (ALT and HCV-RNA) after interferon was 15% (11-20%). The only pretreatment histological factor correlating to therapy outcome was the presence or absence of cirrhosis (mean response rate 8%, 1-14%, versus 18%, 13-23%, p=0.04}. The cumulative Knodell score correlated with ALT (p=0.O002) and duration of infection (p- 0.001 }, but was not predictive for response to therapy. In eonclusion, ALT and Iobular activity are strongly correlated suggesting that both reflect disease activity. Steatosis, lymphoid aggrgates and ultimately cirrhosis apparently reflect the duration of infection. None of the histological features other than cirrhosis predict response to therapy.

675 IRON OVERLOAD IN CHRONIC HEPATITIS C : HOW COMMON IS IT? B Chandra . S Haoue*. MA Gerber*. ASF Lok. Dept o f Med a n d Path*, Tu lane Univ a n d VA Medical Center , New Orleans, IA.

Recent r epo r t s sugges t t ha t i ron over load is c o m m o n in pa t i en t s wi th ch ron ic hepa t i t i s C (CHC) a n d t ha t i nc reased s e r u m / h e p a t i c i ron is a s soc ia ted wi th p o o r r e sponse to i n t e r f e ron the rapy . A/ms : To d e t e r m i n e the p reva l ence of i r on over load in pa t i en t s wi th CHC a n d to d e t e r m i n e i f the re is a co r re l a t ion be tween increase in s e r u m / h e p a t i c i r on with ac t iv i ty / s t age o f HCV-liver disease. Patients : 67 anti-HCV posi t ive pa t i en t s w h o h a d l iver b iopsies showing ch ron ic hepat i t i s + c i r rhosis were s tud ied . Pat ients wi th o t h e r causes o f l iver disease inc lud ing HBV infec t ion a n d a lcohol abuse , a n d those wi th o t h e r causes of i r on ove r load s u c h as r e c u r r e n t t r ans fus ions were excluded. Methods : Hepat ic ac t iv i ty index (HAI) (0-18) & fibrosis (0-4), a n d hepa t i c i ron score (0-15) & g r a d e (0-4) were s co red a c c o r d i n g to Knodel l a n d Brissot, respect ively. Results : A h igh p r o p o r t i o n of pa t i en t s h a d s e r u m Fe indices (SH) above the u p p e r l imits o f n o r m a l ( se rum Fe > 1 6 0 u g / d l : 27%, t r ans f e r r i n s a tu r a t i on [TF sat] >50% : 31%, a n d fe r r i t in >180 u g / d l : 55%). A subs tan t ia l p r o p o r t i o n of pa t i en t s h a d SH tha t r e a c h e d h e m o c h r o m a t o t i c r a n g e (TF sat >629/0 : 17%, fer r i t in > 5 0 0 u g / d l : 36%, 15% h a d TF sat >62% & fe r r i t i n > 5 0 0 ug /d l ) . The p e r c e n t a g e of pa t i en t s wi th hepa t i c Fe g r a d e of O, 1, 2, 3, a n d 4 were respect ively, 33, 37, 27, 3, a n d 0. There was n o cor re la t ion be tween s e r u m i ron (TF sat o r ferr i t in) indices a n d hepa t i c i ron s c o r e / g r a d e wi th ac t iv i ty (HAI o r s e r u m ALT level) o r f ib ros i s / s t age of l iver disease. Conclusions : A ve ry h igh p r o p o r t i o n of pa t i en t s wi th CHC h a d inc reased s e r u m i ron levels. However, v e r y few (3%) h a d s ignif icant i nc reased hepa t i c i ron w h e n pa t i en t s wi th o t h e r causes of i ron ove r load were exc luded . The re was n o cor re la t ion be tween ac t iv i ty / s t age o f HCV l iver d isease a n d s e r u m / h e p a t i c i ron levels.

676 HEPATIC IRON CONCENTRATION (itIC) IN END STAGE LIVER DISEASE 0gSI.,D) 2 e TO CHRONIC ltEPATITIS C (rHCV) AND/OR ALCOHOLIC LIVER DISEASE (AID). KR Reddv. *BR Bacon. A Tzak/s. *BA N~Jschwand~-T~ai : L/Jeffm's. *AM Di B ~ e ~ DE Bem~*_in D Wmmler. M Webb. J Ne~. M de Medhm. A VieianL and ER Schiff. Urt/v. of Miami and VAMC, Miami FLand *St. Louis Univ. Health S c i ~ Ceater, St. Louis, Me. Increased HIC is foand in paticots (pts) with ALD and HCV, as well as in hereditary hemechmmatmis (HHC). The precise mech~ni~u of iron accamulation in ALD and HCV is unclear. It/s known that thea~ is a higher prevalence of HCV infection in AID. It is conceivable that HCV plays a role in iron accumelafion in ALD. Aim: To determine HIC and hepatic iron index (HII) in explanted livers and ascertain any differences in HCV, ALD, and ESLD dee to a dual etiology of alcohol and HCV. Methocb: 88 patients (pts) from 2 centers (66 UM and 22 St Louis Un/v.) were included. Paliants were randomly selec/ed based on the avaflabih'ty of cl/nical data, imraf~n blocks and/or flesh fimue. $2 mea and 36 women wexe selectecL Subject ages ranged from g to 65 yrs (mcon 47). The diasno~ at Uansplanmtion included cirrhosis 2° to HCV in 14 (Grmxp {Gr} 1), alcoholic c~rrhosis in 21 (Gr 2), and F, SLD 2 e to alcohol and HCV in 13 (Gr 3). 40 pts (Car 4) und=rgoing transpls,ntAtion four conditions other than HCV and/or AID were used as controls for comparative analyds. Pts with known HHC were excluded. HICs were determined on fresh and peraffan-embedded tissue by known methods. Bemlta: (Table)

I Mere, m c (~/Enm) [ Me.tu mI I HCV(C~d'I) [ 838 (ran~ 43-299'7) ] 0.41(ranAeO.02-2.34) I ALD(Gr2) t 1217(range54-8432) 0.49(range0.02-4.07) I

.HCV+ALD(Gr$) i 1350 (range SI-7568) 0.58(hinge0.02-3.38) [ OI~rESLD [ 713 (ran~ 81-2460) 0.31(ranl~ 0.03-1.22) ]

4/88 pts had HII of> L9 (2.18 to 4.07; Gt 1-1pt, Gr 2- 2 pts, Gr 3 -1 pt). There were no dsnificont differencm in mean HII and HIC betweea all groulm. Cenetm~,,,: Althoush net statistically significant, pus with ESLD due to a combination of HCV and ALD had the hlghest mcon HIC and m~n HII when compazed to ESLD due to either HCV or alcohol alone. In ESLD due to HCV and/or alcohol, a HII of> 1.9 represcots previously unrecognized HHC.