Iron excess in the hepatic explant is associated with an increased risk of invasive fungal infection in liver transplant recipients

288A

AASLD ABSTRACTS

HEPATOLOGYOctober 2001

463

464

CONSERVATIVE MANAGEMENT OF HEMOLYTIC CRISIS A N D FULMIN A N T HEPATIC FAILURE IN WlLSON'S DISEASE. Leonid Vilenski, Anil

RECIPIENT VON WILLEBRAND FACTOR DEPENDANT PLATELET AGGREGATION A N D ITS FUNCTIONAL ANTIGEN PRE-OLTX DOES CORRELATE W I T H MARKERS OF HEPATOCELLULAR DAMAGE FOLLOWING OLTX. Jan Schuhe Am Esch II, Roy Tustas, Ayse Akyildiz, Dieter C

Potti, Department of Internal Medicine, University of North Dakota School of Medicine and Health Sciences, Fargo, ND; Donald L Zogg, Department of Gastroenterology, MeritCare Medical Group, Fargo, ND Wilson's disease less commonly presents as fulminant hepatic failure and hemolysis. This has been associated with near uniform mortality unless liver transplantation is performed. Plasma exchange has stabilized patients before transplantation. A. Matsumura et al reported success in avoiding transplantation in a 17-year-old male with early (day 6) initiation of plasma exchange(Ann Int Med,131(ll),866,1999). We present another success with early (day 4) plasma exchange, now stable at 6 months. Case report: A 19-year-old male presented with abdominal pain and jaundice. Laboratory work up revealed evidence of liver failure, severe hemolysis and acute renal failure. The diagnosis of Wilson's disease was made based on low alkaline phosphatase, low serum ceruloplasmin 5.5mg/dl (nl 23-43), elevated urinary copper 15,700mcg/24h (n115-60) and Kayser-Fleischer rings. Therapy was initiated on day 4 with plasma exchange for 6 consecutive days. Estimated copper removal was 780 lmcg. Stepwise addition of d-penicillamine over the next 48h was associated with a temporary increase in transaminases and worsening renal function. Transjugular liver biopsy on day 5 was consistent with Wilson's. Hemolysis resolved, renal function improved and hepatic function stabilized. He was discharged clinically stable on day 10. Follow-up over six months shows steady improvement in hepatic function. Renal function has normalized. Conclusion: Although the current treatment standard of hemolytic crisis in Wilson's disease is liver transplantation, early (day 4) plasma exchange with addition of dpenicillamine therapy achieved rapid reduction in serum copper levels. Hemolysis and renal failure resolved. Long term stabilization of hepatic function was achieved and hepatic transplantation was avoided.

Broering, Xavier Rogiers, University of Hamburg, Hamburg Germany INTRODUCTION: Early graft function and overall outcome of orthotopic liver transplantation (oLTX) is correlated with the extend of hepatocellular damage after reperfusion of the graft. Platelets and their functional status of the recipient seem to have an important role in ischemia/reperfiasion (I/R) injury of the liver. Von Wfllebrand Factor (vWF) serves as a major platelet adhesion and activation molecule at sites of endothelial injury as observed in I/R injury. This prospective study in 34 consecutive LTX-patients was conducted to correlate vWF-dependent platelet aggregation pre-oLTX as well as total and functional vWF-plasma levels with markers of I/R injury and early graft function following oLTX. METHODOLOGY:Whole-blood aggregometry as marker of platelet function was performed in the course of oLTX. Muhimeric analysis was per~ formed to evaluate functional plasma-vWF utilizing immunoblotting subsequent to plasma-SDS-aggarose gel electrophoreses. Serum-GPT levels served as markers of hepatocellular damage following graft reperfusion, PT as marker of early graft function. RESULTS: Patients were divided in a group with high I/R damage (hi/R) demonstrating serum-GPTqevel above 5001U on day 1 or 2 after oLTX and one with low I/R injury (II/R) staying below 500 IU postope> atively. Demographics were comparable between the two patient collectives. hI/R was characterized by significantly decreased PT levels on day 3 and 4 in comparison to the lI/R group, vWF-dependent platelet aggregation was significantly increased in the hI/R group if contrasted to the II/R group and did positively correlate with GPT levels on day 1 (r=0.55; p<0.002) and day 2 (r=0.54; p<0.002) after oLTX. This was in contrast to other stimuli of platelet aggregation like ADP and collagen. Recipients functional vWF-level pre-oLTX correlated positively with serum GPT-level on day 1 (r=0.42; p=0.023) and day 2 (r=0.5; p=0.006), as did differences of functional vWF between preoLTX and 20 rain. post-reperfusion with GPT levels (day 1: r=0.55; p=0.006; day 2 (r=0.67; p=0.0004). CONCLUSION: These data suggest vWF as important participant in the scenario of platelet recruitment and reperfusion injury in the graft after oLTX. This mechanism seems at least in part to be determined prior to grafting. Modulation of platelets in the course of oLTX may improve early outcome of oLTX.

465

466

A NOVEL MODEL OF ARTERIALIZED ORTHOTOPIC LIVER TRANSPLANTATION IN MICE. Yinghua Tian, Hannes A Rudiger, Nazia Sehner,

IRON EXCESS IN THE HEPATIC EXPLANT IS ASSOCIATED W I T H AN INCREASED RISK OF INVASIVE FUNGAL INFECTION IN LIVER TRANSPLANT RECIPIENTS. Ajit P Limaye, Mary P Bronner, Kris V Kowd-

Markus Sehner, Pierre-Alain Clavien, University hospital of Zurich, Zurich Switzerland Background: Recently, an increasing number of genetically aherated mice and monoclonal antibodies against murine proteins have been developed. The availability of a orthotopic liver transplantation (OLT) model in mice, would enable novel discoveries. Arterialization of the graft has been recommended in rat model of transplantation. Previous described OLT models in mouse have not included arterialization of the graft, and were associated with biliary stenosis. We develop and evaluate a novel technique of arterialized OLT in mice. Method: Isogenic orthotopic liver transplantation was performed in male Balb/c mice weighing 25-30 g. The mesenteric, aortic, celiac and hepatic arteries were dissected in the donor animal and removed en bloc with the graft. In the recipient animal, the anastomosis of the suprahepatic vena cava was performed by running suture (10-0 nylon). Then, the anastomosis of the portal vein and the infrahepatic vena cava was performed by cuff technique. Bile duct continuity was restored by placement of a stent interponate. The hepaticceliac-aorta-mesenteric artery segment was anastomozed end-to-side with the recipient aorta by running suture (10-0). Results: Patent anastomosis could be achieved in 90% of the transplanted mice. The re-warming time in all cases were between I5 to 18min. Total length of the operation was 80 to 85 rain. Serum levels of total bilirubin remained normal for 9 weeks. Normalization of AST levels was observed in all animals within 3 days after transplant. Longterm survival was excellent with 5/5 animals alive 9 weeks after transplant. Conclusions:We provide a new and reliable model of arterialized OLT in mice. This model offers unique opportunities to use genetically altered mice and numerous monoclonal antibodies to further study mechanisms of injury in liver transplantation.

ley, University of Washington, Seattle, WA Background: Several uncontrolled studies have suggested that patients with hepatic iron overload are at increased risk of developing serious infections after liver transplantation. The purpose of this study was to determine if hepatic iron overload was independently associated with invasive fungal infection (IF1) in this clinical setting. Methods:, We retrospectively examined the relationship between several pretransplant variables (including age, sex, diabetes, etiology and severity of underlying disease, serum albumin, platelet count, and presence of stainable iron in the hepatic explant) and the development of invasive fungal infection (IFI) in a consecutive series of patients undergoing a first liver transplant between 1/97 and 12/99 at a single transplant center using a multivariate model, All explanted livers underwent routine evaluation for stainable iron by a pathologist who was unaware of the patient's clinical status. IFI was defined as the demonstration of a fungal pathogen in a normally sterile site and/or a tissue specimen by either culture or pathologic examination. Results: IFI developed in 28 of 153 (18%) patients, and included Candida (n=19), Cryptococcus (n=2), Saccharomyces (n= 1), and Aspergillus (n=6). The following pretransplant variables were significantly associated with an increased hazard (HR) of developing IFI in a univariate analysis: fulminant hepatic failure (HR 9.9, p= .0002), ICU location at the time of transplant (HR 3.1, p=.03), pretransplant hemodiatysis (HR 3.6, p= .02), and stainable iron in the hepatic exptant (HR 3.1, p =.003). Furthermore, the hazard of developing IFI among patients with stainable hepatic iron remained higher than that among those without stainable hepatic iron even after controlling for all non-iron variables in a multivariate model (HR 2.8, 95% CI, 1.3 to 6, p=0.009). Conclusions: Stainable iron in the hepatic explant is significantly and independently associated with the development of invasive fungal infection among liver transplant recipients. Further studies are needed to define the mechanism(s) and explore the role of iron depletion in this clinical setting.