Does fluorodeoxyglucose positron-emission tomography (FDG-PET) of echinococcus multilocularis (EM) liver lesions reflect parasite vitality?

HEPATOLOGY VOI. 34, No. 4, Pt. 2, 2001

AASLD ABSTRACTS

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TRANSPLANTATION OF LIVERS FROM ANTI-HBC POSITIVE DONORS INTO ANTI-HBC NEGATIVE RECIPIENTS: MAINTENANCE LAMIVUDINE THERAPY PREVENTS DE NOVO HEPATITIS B. George E Loss Jr., Andrew L Mason, Satheesh Nair, Linsheng Guo, Jamie Blazek, Jeannie Lipscomb, Debbie Dick, Diana Kelly, Pare Raspino, S F Dodson, Robert P Perrillo, James D Eason, Ochsner Clinic, New Orleans, LA

ANTI-HBS AND HBSAG KINETICS DURING THE FIRST DAYS AFTER LIVER TRANSPLANTATION IN PATIENTS RECEIVING HEPATITIS B IMMUNE GLOBULIN FOR HBV REINFECTION PROPHYLAXIS: EVIDENCE FOR AN EARLY ACCELERATED ADMINISTRATION SCHEME. Jens Rosenau, Hans L Tillmann, Heiner Wedemeyer, Uwe J Tietge, Matthias J Bahr, Christian Trautwein, Klaus H Boeker, Bjoern Nashan, Ernst R Kuse, Juergen Klempnauer, Michael P Manns, Hannover Medical School, Hannover Germany

Transplantation of liver allografts from from hepatitis B core antibody (anti-HBc) positive donors into anti-HBc negative recipients has been associated with a high rate of viral transmission with 50% to 80% of umreated recipients developing de novo hepatitis B. Here we describe a strategy for transplanting livers from anti-HBc positive donors into anti-HBc negative recipients using a single dose of HBIG and maintenance lamivudine therapy. Methods: Liver biopsies from anti-HBc positive, HBsAg negative donors were performed at the time of procurement to rule out acute hepatitis or chronic donor liver disease. Donor serum and liver samples were collected for HBV DNA analysis by semi-nested polymerase chain reaction (PCR). Anti-HBc negative recipients were given a single dose of HBIG (10,000 units, i.v.) during the anhepatic phase of transplantation and placed on maintenance lamivudine monotherapy (150 rag/d) beginning on postoperative day 1. Surveillance consisted of analysis of serial recipient serum samples for HBsAg and HB¥ DNA by PCR. In addition, liver biopsies performed per protocol or for increased liver function tests (LFTs) were examined for histiologic or immunohistochemical evidence of HBV. Liver biopsies were also analyzed for HBV DNA by PCR. Results: Between February 1999 and June 200l, eleven anti-HBc negative recipients received liver transplants from anti-HBc positive donors. PCR analysis of serum from each donor was negative for HBV DNA. Liver PCR analysis for HBV DNA was positive in 6 of 11 (55%) donors, One patient, whose donor liver was initially negative for HBV DNA by PCR, had Iow levels of HBV DNA detected in a post-transplant liver biopsy. Thus 7 of 11 (64%) livers had evidence of HBV DNA by PCR. Follow-up periods ranged from 2 to 28 months (mean 13.1 ± 8.5 months). Actual patient and graft survival are both 100%. No case of d e n o v o hepatitis B occurred during the follow-up period. Serial serum HBsAg and HBV DNA assays have been negative to date. Twenty-four posttransplant liver biopsies were performed in 11 patients either per protocol or for elevated LFTs and none showed histologic or immunohistochemical evidence of hepatitis B. Interestingly, 5 of 6 (83%) patients whose donor livers were initially positive for HBV DNA by PCR now demonstrate decreased liver HBV DNA by PCR. Four of these 6 (67%) patients now have undetectable HBV DNA in their hepatic allograft biopsies by PCR analysis. Conclusions: Our PCR assay found evidence of HBV DNA in 64% of livers from anti-HBc positive donors, a rate consistent with published rates of hepatitis B transmission in untreated recipients of anti-HBc positive donor livers. Single dose HBIG followed by maintenance lamivudine monotherapy prevented d e novo hepatitis B during the follow-up period studied. Moreover, our data suggest residual hepatitis B virus may be reduced to below" detectable levels in most recipients of anti-HBc positive donor livers maintained on lamivudine monotherapy.

Hepatitis B immune globulin (HBIG) is considered essential for induction of HBsAgnegativity in hepatitis B patients after liver transplantation (OLT) to achieve a low long-term reinfection rate. In most protocols HBIG is administered during the anhepatic phase and the first postoperative days in fixed daily doses of 10000 IU. However, there are no data on the kinetics of anti-HBs and HBsAgduring the initialphase after OLT. In order to optimize HBIG administration we investigated the pharmacokinetics of 18 patients receiving combination prophylaxis with HB1G (10000 1U/day) and lamivudine. Daily HBIG administration was continued until HBsAgnegativity was achieved. Ami-HBs-titers were determined quantitatively, HBsAg-levelswere assessed semi-quantitatively by ELISA (Abbott Laboratories). In all patients anti-HBs-trough-titers and HBsAg-levelswere determined directly before HBIG infusions. In 9 patients levels of anti-HBs and HBsAgwere measured every hour during HBIG infusions (10000 IU/3 hours) and 1, 3, 6, 12 and 2I hours after each HBIG administration. In all 18 patients anti-HBs titers increased in a gradient stepwise fashion. Required HBIG doses to achieve certain anti-HBs titers and HBsAg negativity differed interiudividually(table 1). In the 9 patients with frequent Mood sampling anri-HBs and HBsAgkinetics showed distinct patterns. During HBIG infusion (administration over a period of 3 hours) anti-HBs-titers rose and HBsAg-levels fell continuously. Between infusions anti-HBs titers fell in a decelerating manner, while HBsAg-levelsshowed two patterns: A further decline after termination of the infusion followed by a reincrease before the next infusion was observed predominantly in patients with high total HBIG requirement (-->30000 units for HBsAg negativity, 6/9 patients). In contrast, a decelerating decrease without reincrease was seen predominantly in patients with low total HBIG requiremere (--<20000units for HBsAgnegativity, 3/9 patients). In conclusion, a slow decline of HBsAgand a reincrease of HBsAgbetween HBIG infusions indicate a suboptimal administration of HBIG in some individuals. An earlier elimination of HBsAgmay he achieved by an accelerated individualized HB1G administration during and immediately after liver transplantation. HBIGadmin,(IU) Days afterOLT Numberof patients Anti-HBs-titer_>100 Anti-HBs-titer->500 Anti-HBs-titer->1500 HBsAgpos, patients admin, = administered,

10000 20000 1 2 18 18 33% 72% 17% 56% 0% 39% 94% 67% pos, = positive

30000 3 18 94% 78% 56% 44%

40000 4 t3 92% 92% 69% 22%

50000 5 8 100% 88% 88% 17%

60000 6 3 100% 100% 66% 11%

70000 7 2 100% 100% 100% 6%

80000 8 I t00% t00% I00% 0%

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DOES FLUORODEOXYGLUCOSE POSITRON-EMISSION TOMOGRAPHY (FDG-PET) OF ECHINOCOCCUS MULTILOCULARIS (EM) LIVER LESIONS REFLECT PARASITE VITALITY?. Ec Renner-Schneiter, Ak Kuenzle, University Hospital Zurich, Zurich Switzerland; F Grimm, University of Zurich, Zurich Switzerland; L Kraebenbuehl, Gk Von Schulthess, University Hospital Zurich, Zurich Switzerland; P Deplazes, University of Zurich, Zurich Switzerland; Pa Clavien, Rw Ammann, E1 Renner, University Hospital Zurich, Zurich Switzerland

A STUDY OF BILE ACIDS AS OPIOID RECEPTOR LIGANDS. Nora V Bergasa, College of Physicians and Surgeons of Columbia University, New York, NY; Christine M Dersh, Addiction Research Ctr, Natl Inst of Drug Abuse, Baltimore, MD; Richard B Rothman, Addiction Research Ctr, Baltimore, MD

The fox tapeworm EM is prevalent in most countries of the Northern hemisphere. In Switzerland, up to >40% of foxes are infected and the incidence of EM infection in man, a false intermediate host, is estimated at 1-2 per Mio population. In infected people, EM's larval state develops as a slowly, but invasively and destructively growing liver mass which at the time of diagnosis is inoperable in 2/3 of cases. While long-term pharmacotherapy with benzimidazoles has proven to be effective in increasing survival (Ammann R. Schweiz Med Wschr 129: 323, 1999), it remains unclear whether it must be continued indefinitely or may finally be stopped after years. This is largely due to the difficulty of predicting the parasitds vitality in vivo. Recently, Reuter et al. reported that EM liver lesions may stain positive by FDG-PET (Clin Infect Dis 29: 1057, 1999). AIM: To explore whether FDG-PET reflects vitality of EM lesions in man. PATIENTS/METHODS: In an ongoing study, all EM cases newly diagnosed at our institution are subjected to FDG-PET. Diagnosis of EM is based on typical imaging (CT, MRI) and serology. Whenever technically feasible, radical surgery is attempted, inoperable/not radically operated cases being treated with benzimidazoles according to WHO guidelines. At surgery, EM material is collected and subjected to vitality testing using a mouse model. RESULTS: 6 patients (5 F, 1 M; median age 67.5 yrs. [range 53 -72]) have been studied solar. 4 of the 6 patients showed clear positivity of liver lesions in FDG-PET, in 2 patients FDG-PET was negative. At diagnosis, both of the latter showed extensively calcified lesions and serology was only weakly positive, suggesting inactive disease; one was nevertheless started on albendazole (10mg/kg per day), but developed drug-induced hepatitis 14 wks into treatment which rapidly resolved after discontinuation; in this patient FDG-PET was performed 14 wks after stop of treatment; the patient was then successfully operated; in vivo vitality tests of the resected parasite material in mice remained negative. CONCLUSION: FDG-PET of liver lesions was positive in 4/5 untreated, and negative in 2/2 extensively calcified, presumably inactive human EM cases, one of the latter being proven to be avital. These preliminary data support that FDG-PET may reflect parasite vitality. Wether negativation of FDG-PET during benzimidazole treatment may be used as indicator for safely stopping therapy remains to be seen.

Opiate drugs with agontst activity at opioid receptors induce pruritus. For example, the pharmacological increase in opioidergic neurotransmission by the central administration (e.g. intrathecally) of morphine is associated with pruritus in human beings, which can be effectively treated with opiate antagonists. In cholestasis, there is evidence to suggest that central opioidergic neurotransmission is increased, and that this altered neurotransmission contributes, at least in part, to the pruritus associated with this syndrome. In support of this idea is that opiate antagonists ameliorate the pruritus of cholestasis in a substantial number of patients. A role of bile acids in the mediation of this type of pruritus has been proposed. Theoretically, opioid-receptor mediated pruritus and scratching could result if bile acids bound to this type of receptor. To explore the idea of bile acids as opioid ligands, we studied the ability of some bile acids to displace specific ligands from the mu, delta and kappal opioid receptors in a series of binding assays. The bile acids tested, chenodeoxycholic, cholic, deoxycholic and hyocholic, accumulate in plasma in cholestasis, including that secondary to primary biliary cirrhosis. The methods used in these experiments have been extensively validated (Life Sci 1991: 48; PL111, Peptides 1990; 11: 311). Mu and delta binding sites on rat brain membranes were labeled with [3H] DAMGO (2 aM) and [3H] DADLE (2 nM), respectively; the nonspecific binding was determined with 20 nM levallorphan. The kappa1 binding sites on guinea pig brain membranes were labeled with k 1 [3H]U69,593. Nonspecific binding was determined with 1/~M U69,593. All membranes were prepared on the day of the experiments. The assays were conducted at 25°C. Each tritiated ligand was displaced two times by 10, 100, 1000 and 10,000 nM solutions of each bile acid tested. The experiments were conducted four times. None of the bile acids at any of the concentrations tested displaced significantly the opioid ligands from their receptors. These results suggest that bile acids in vitro are not opioid receptor ligands. Ahhough it is not known whether bile acids undergo conformational changes in cholestasis that allow for the binding of these substances to opioid receptors in vivo, the results of this study do not support a role of these bile acids as mediators of the pruritus of cholestasis by an opioid receptor-mediated mechanism.