Allen L. Hoffman

A bioartificial liver to treat severe acute liver failure.

ObjectiveTo test the safety and efficacy of a bioartificial liver support system in patients with severe acute liver failure. Summary Background DataSummary Background Data authors developed a bioartificial liver using porcine hepatocytes. The system was tested in vitro and shown to have differentiated liver functions (cytochrome P450 activity, synthesis of liver-specific proteins, bilirubin synthesis, and conjugation). When tested in vivo in experimental animals with liver failure, it gave substantial metabolic and hemodynamic support. MethodsSeven patients with severe acute liver failure received a double lumen catheter in the saphenous vein; blood was removed, plasma was separated and perfused through a cartridge containing 4 to 6 X 109 porcine hepatocytes, and plasma and blood cells were reconstituted and reinfused. Each treatment lasted 6 to 7 hours. ResultsResults patients tolerated the procedure(s) well, with neurologic improvement, decreased intracranial pressure (23.0 ± 2.3 to 7.8 ± 1.7 mm Hg; p < 0.005) associated with an increase in cerebral perfusion pressure, decreased plasma ammonia (163.3 ± 21.3 to 112.2 ± 9.8 μMoles/L; p < 0.01), and increased encephalopathy index (0.60 ± 0.17 to 1.24 ± 0.22; p < 0.03). All patients survived, had a liver transplant, and were discharged from the hospital. ConclusionsConclusions bioartificial liver is safe and serves as an effective “bridge” to liver transplant in some patients.

The use of a pig liver xenograft for temporary support of a patient with fulminant hepatic failure

A 26-year-old female patient with fulminant hepatic failure and a history of autoimmune hepatitis was heterotopically transplanted with a pig hepatic xenograft to provide temporary metabolic support prior to transplantation with a human donor organ. Circulating natural antipig antibodies were removed prior to transplantation by plasmapheresis and ex vivo en bloc perfusion of the donor pig kidneys. The liver xenograft functioned after transplantation as measured by active bile production, stabilization of prothrombin levels, and reduction in the circulating levels of lactic acid and the enzymes AST and ALT. Despite the removal of greater than 90% of the recipients natural xenoantibodies prior to transplantation, the levels of antibody rapidly returned and were associated with antibody and complement-mediated rejection of the donor graft. Immunohistochemical evidence of graft rejection could be detected by the deposition of antibody, complement components including properdin, and endothelial swelling as early as 3 hr posttransplantation. These lesions progressed in severity and were accompanied by evidence of thrombosis and ischemic necrosis of the liver xenograft by 34 hrs posttransplantation. The main portal vein, hepatic artery, and vena cava were patent. The placement of the liver graft did not result in any improvement in the neurological status of the patient and she died 34 hr after xenografting due to irreversible brain damage. The information derived from this case has renewed interest in the clinical use of bioartificial devices and whole organ perfusion using xenogeneic tissue for temporary bridging of patients prior to allografting.

The use of FK-506 for small intestine allotransplantation : inhibition of acute rejection and prevention of fatal graft-versus-host disease

Small intestine allotransplantation in humans is not yet feasible due to the failure of the current methods of immunosuppression. FK-506, a powerful new immunosuppressive agent that is synergistic with cyclosporine, allows long-term survival of recipients of cardiac, renal, and hepatic allografts. This study compares the effects of FK-506 and cyclosporine on host survival, graft rejection, and graft-versus-host-disease in a rat small intestine transplantation model. Transplants between strongly histoincompatible ACI and Lewis (LEW) strain rats, and their F1 progeny are performed so that graft rejection alone is genetically permitted (F1----LEW) or GVHD alone permitted (LEW----F1) or that both immunologic processes are allowed to occur simultaneously (ACI----LEW). Specific doses of FK-506 result in prolonged graft and host survival in all genetic combinations tested. Furthermore, graft rejection is prevented (ACI----LEW model) or inhibited (rejection only model) and lethal acute GVHD is eliminated. Even at very high doses, cyclosporine did not prevent graft rejection or lethal GVHD, nor did it allow long-term survival of the intestinal graft or the host. Animals receiving low doses of cyclosporine have outcomes similar to the untreated control groups. No toxicity specific to FK-506 is noted, but earlier studies by other investigators suggest otherwise.

Enhanced Oral Cyclosporine Absorption With Water-Soluble Vitamin E Early After Liver Transplantation

We evaluated the effect of Liqui‐E, a water‐soluble vitamin E preparation, on cyclosporin A (CyA) whole blood concentration in liver transplant recipients, and its impact on the cost of CyA. Patients were 26 liver transplant recipients (19 adults, 7 children) who were unable to achieve and maintain therapeutic CyA whole blood concentrations with the standard recommended oral daily dose in the early post‐transplant period. Liqui‐E 6.25 IU/kg orally was administered with CyA every 12 hours (median time of starting Liqui‐E day 14.5). With Liqui‐E, the daily oral CyA requirements (mean ± SD) were decreased in adults from 22.6 ± 8.9 to 16.2 ± 7.3 mg/kg/day (p<0.001) and in children from 78.6 ± 34.1 to 53.7 ± 35.0 mg/kg/day (pl0.02); intravenous administration of CyA was unnecessary. The CyA trough concentrations (mean ± SD) before and after Liqui‐E were 670 ± 186 and 1012 ± 216 ng/ml, respectively, in adults (pl0.001) and 732 ± 187 and 1052 ± 166 ng/ml, respectively, in children (pl0.01). When given with Liqui‐E, the daily cost of CyA decreased by 26% in both adults and children. No clinical or biochemical evidence of Liqui‐E toxicity was observed. Thus its administration in the early post‐transplantation period can enhance CyA absorption in adults and children who are unable to achieve adequate whole blood concentrations with the usual recommended oral dosages. In addition, a significant cost saving can be realized by coadministration.

Neurological and psychological sequelae in transplant recipients after bridging with the bioartificial liver

Prior to the advent of the bioartificial liver there was little hope to offer the families of comatose patients unless an organ could be found immediately, or xenografting was attempted. The elevated intracranial pressure that develops is more life-threatening than prolonged bleeding times. Over a 2-year period, nine patients were bridged to transplantation using the BAL to keep them neurologically intact prior to surgery. The goal is to maintain the ICP less than 20 mmHg in adults and between 10 and 15 mmHg in children, so that the cerebral perfusion pressure remains above 50 mmHg. The first patients, a 35-year-old woman, arrived in stage II coma. The second patient, a 10-year-old boy in stage IV coma, had decerebrate posturing and anisocoria. The third patient, an 18-year-old girl, had an ICP of 28 mmHg with decerebrate posturing and disconjugate gaze. The fourth patient, a 34-year-old male, had an ICP of > 38 mmHg. The fifth patient, a 24-year-old male, had fixed dilated pupils. The sixth patient, a 50-year-old woman, had readings to 52 mmHg. The seventh patient, a 48-year-old male, had postoperative numbness in his fingertips that remitted. The eighth patient, a 31-year-old female, had decerebrate posturing and an ICP of 64 mmHg transiently. The ninth patient, a 52-year-old woman, had decerebrate posturing with a peak ICP of 50 mmHg. All nine patients survived.