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Hepatocyte Transplantation in an Acute Liver Failure Due to Mushroom Poisoning

2006; Wolters Kluwer; Volume: 82; Issue: 8 Linguagem: Inglês

10.1097/01.tp.0000232451.93703.ab

1534-6080

Andrea L.C. Schneider, Masoumeh Attaran, Peter N. Meier, Christian P. Strassburg, Michael P. Manns, Michael Ott, Marc Barthold, Lubomir Arseniev, Thomas Becker, Bernd Panning,

Organ Transplantation Techniques and Outcomes

Acute liver failure (ALF) remains a condition with substantial mortality (1, 2). The only intervention of proven benefit for ALF is emergency liver transplantation (OLT) (3). The potential reversibility of ALF, the scarcity of donor organs, and the substantial mortality in patients, who have been transplanted in critical condition, have resulted in the development of techniques, which allow temporary support of liver function (4–6). In this report, we document intraportal transplantation of cryopreserved hepatocytes into the portal vein of a 64-year-old woman who accidentally ingested liver toxin-producing amanita phalloides mushrooms. The patient was admitted to our hospital and transferred to the intensive care unit in stable condition. The clinical workup for OLT revealed considerable obesity, hypertension, and chronic heart failure. During counseling in the absence of encephalopathy the patient repeatedly refused to consent to OLT. At day 3 after ingestion of the mushrooms, International Normalized Ratio (INR) and factor V levels reached 4.2 and 9%, respectively, with no adequate increase after substitution. We decided to treat the patient with intraportal hepatocyte transplantation (HcTx) as hepatic coma progressed to level III. Under general anesthesia, the patient was mechanically ventilated and substituted with fresh frozen plasma, prothrombin complex concentrate, and antithrombin III. Under ultrasound and radiographic guidance, a peripheral portal vein branch was punctured transcutaneously and a 6-F catheter was placed into the central part of the portal vein. The procedure did not result in bleeding complications. Immunosuppression was started by intravenous application of steroids and cyclosporine A. Blood group matched human hepatocytes were isolated from cadaveric livers according to Good Medical Practice guidelines as previously published and cryopreserved (7). Immediately prior to application, the cell suspensions were thawed rapidly and tested for viability by the trypan blue exclusion test. The average viability of the final transplant was 62%. The cells were infused through the portal vein catheter with continuous monitoring of the portal venous pressure. Altogether, 8×109 hepatocytes including ∼5×109 viable cells were infused over a period of 30 hr. The catheter was removed without complications thereafter. At the time of HcTx, the patient met the Clichy and King's College criteria for OLT (8, 9). Then 36 hr after HcTx, the coagulation parameters remained at noncritical levels without further substitution of plasma proteins. Ammonia levels reached peak concentrations of 126 μmol/L immediately before HcTx. Eight hours after the last infusion of hepatocytes ammonia levels dropped to 45 μmol/L and remained stable. Bilirubin levels peaked one day after completion of HcTx and decreased continuously during the following days (Figure 1, A–C). Seven days after HcTx, the patient was extubated and transferred from the intensive care unit to the regular ward. Eight weeks after HcTx, an abdominal ultrasound scan showed normal liver architecture and a normal portal blood flow. Twelve weeks after HcTx, immunosuppressive therapy was stopped without signs of relapse. The patient finally recovered without concomitant extrahepatic organ damage. We conclude that the repeated application of primary human hepatocytes is safe and results in measurable benefit for patients with acute liver failure. Randomized studies will now be necessary to demonstrate a survival benefit for these patients.FIGURE 1.: The time course of factor V plasma concentration, serum ammonia and total serum bilirubin concentrations. The time point of poisoning and HcTx as well as the time of substitution with plasma products are indicated. The circle in the gray box indicates the intravenous application of 1000 U antithrombin III each, the cross represents 100 U prothrombin complex concentrate (PCC) and the dashes (one dash equals 250 ml) indicate the application of fresh frozen plasma. The arrows indicate the time points of hepatocyte transplantation. 5×109 viable primary hepatocytes and 8×109 total number of cells were transplanted in three portions within a time period of 30 hr.Andrea Schneider Masoumeh Attaran Peter N. Meier Christian Strassburg Michael P. Manns Michael Ott Department of Gastroenterology, Hepatology and Endocrinology Center of Internal Medicine Hannover Medical School Hannover, Germany Marc Barthold Lubomir Arseniev Cytonet GmbH & Co. Branch Hannover Hannover, Germany Thomas Becker Department of Visceral and Transplant Surgery Hannover Medical School Hannover, Germany Bernd Panning Department of Anesthesiology Hannover Medical School Hannover, Germany