Bilateral living donor lung transplantation in which two healthy donors donate their right or left lower lobes is an alternative to cadaveric transplantation. The most common procedure involves a right lower lobectomy from a larger donor and a left lower lobectomy from a smaller donor. Potential donors should be competent, willing to donate free of coercion, medically and psychosocially suitable, and fully informed of risks, benefits, and alternative treatment available to the recipient. All recipients should fulfill the criteria for conventional cadaveric transplantation. Due to possible serious complications in the donor lobectomy, living donor lobar lung transplantation (LDLLT) should be reserved for critically ill patients who are unlikely to survive the long wait for cadaveric lungs. Postoperative immunosuppression usually consists of triple-drug therapy with cyclosporine (CyA), azathioprine (AZA) and corticosteroids without induction. LDLLT may be associated with a lower incidence of Bronchiolitis obliterans syndrome (BOS), especially in pediatric patients.
479 An extra-corporeal perfusion model has been established in order to test the viability of hDAF transgenic pig livers when perfused with fresh, whole, human blood. Three groups have been studied: alloperfusions (pig blood), xenoperfusions of unmodified pig livers and xenoperfusions of hDAF transgenic pig livers. Liver function was measured using pH, base excess, potassium, bile production, oxygen consumption, ALT, bilirubin, urea synthesis, factor V synthesis and complement production. Hemolysis was assessed by serial hematocrit and free hemoglobin assessment. Histological appearances were assessed using light microscopy and immunohistochemistry staining for IgM, IgG, and complement deposition. In the alloperfusion control group function and structural integrity was demonstrated for at least 72 hours. Xenoperfusions were carried out for periods of up to 72 hours and, unlike alloperfusion, were limited by progressive hemolysis; histological appearances were of patchy necrosis with most lobules remaining normal. The cause of hemolysis has been investigated; porcine antibodies were demonstrated in the human blood perfusing both normal and transgenic pig livers. Peak antibody levels were reached within one minute of commencing perfusion and did not significantly change throughout the duration of perfusion. This implies elution of porcine antibodies rather than production of new antibodies by the porcine livers. We have further demonstrated by FACS analysis that a proportion of these antibodies are pig anti-human specific. In addition, porcine livers perfused with human blood have been shown to produce supraphysiologic levels of complement activity as assessed by CH50 analysis on sheep red blood cells (RBC). Interestingly, however, when serum from these xenoperfusions was incubated with fresh human RBC, it was not possible to demonstrate lysis. Thus, while there appear to be both pig anti-human antibodies and complement present, classical pathway complement hemolysis could not be demonstrated. Investigations of the hemolysis continues, in order to assess whether this would be a limitation in clinical studies. This research was funded by the Wellcome Trust and carried out in collaboration with Imutran (Novartis).
Sirolimus (rapamycin) is a new immunosuppressant that appears to be synergistic with cyclosporine in kidney transplantation, but with a different side-effect profile. This pilot study evaluated sirolimus in liver transplantation.Patients undergoing orthotopic liver transplantation for primary tumors (8), and later for nonmalignant disease (7), received one of three sirolimus-based immunosuppressive regimens. Protocol A comprised sirolimus, microemulsion cyclosporine (target whole blood concentration: 100 ng/ml), and prednisolone; protocol B omitted prednisolone; and protocol C was sirolimus alone. By 3 months after transplantation, all patients were receiving sirolimus as monotherapy.Fifteen patients were treated with a follow-up of 117-806 days. Rejection was more common on monotherapy than double therapy, and absent on triple therapy. The drug was generally well tolerated, with only three patients discontinuing sirolimus: one for hyperlipidemia, one for pneumocystis pneumonia, and one for inability to tolerate the taste of the drug. Two patients discontinued cyclosporine early, both as a result of neurological complications; they continued on sirolimus monotherapy. Five patients died; one suffered a cardiac arrest, and four died from sepsis in association with graft-versus-host disease, recurrent tumor, a paralyzed right hemidiaphragm, and primary nonfunction.Sirolimus combined with cyclosporine provided potent immunosuppression of liver allografts, and sirolimus monotherapy was adequate and well tolerated as maintenance therapy. Side effects of sirolimus over the short period of follow-up were uncommon and reversible with dose reduction or cessation of therapy.
Production of the antiviral cytokine, tumor necrosis factor-α is increased in chronic hepatitis B virus infection, and clinical studies of tumor necrosis factor-α have indicated a proviral effect at higher doses. To determine whether this might be related to abnormal cell surface tumor necrosis factor-α receptor expression, binding characteristics of cell surface tumor necrosis factor-α receptor on peripheral blood mononuclear cells in chronic hepatitis B virus carriers were studied using radioiodinated recombinant tumor necrosis factor-α. The specific binding curves generated were analyzed according to the method of Scatchard to determine cell surface receptor numbers and dissociation constants. A single class of cell surface tumor necrosis factor-α receptor was demonstrated on peripheral blood mononuclear cells and mononuclear subsets. The median number (range) of cell surface tumor necrosis factor-α receptors on peripheral blood mononuclear cells from controls (n = 11), chronic hepatitis B virus patients seropositive for hepatitis B virus DNA (n = 8) and seronegative for hepatitis B virus DNA (n = 8) were 2,329 (range = 1,538 to 3,133), 3,375 (range = 2,300 to 6,718) (p < 0.01) and 3,113 (range = 2,229 to 5,246) (p < 0.05) sites/cell, respectively. They all had similar dissociation constants of 8.4 × 10 −10 mol/L (range = 4.1 to 16.9), respectively. Further dissection of the peripheral blood mononuclear cells showed that this increase in cell surface receptor number was confined to the monocyte fraction (p < 0.01). Plasma tumor necrosis factor-α levels in five patients with increased monocyte cell surface tumor necrosis factor-α receptor numbers were also elevated. No correlation between cell surface tumor necrosis factor-α receptor number and serum AST, HBsAg, hepatitis B virus DNA or liver histology was observed. These data indicate that cell surface tumor necrosis factor-α receptor number is increased in monocytes but normal in lymphocytes and support previous observations that monocytes are activated in chronic hepatitis B virus infection. (HEPATOLOGY 1991;14:44-50.)
An ever increasing number of herbal remedies are recognized as potentially hepatotoxic. We report a case of fulminant hepatic failure requiring liver transplantation associated with the use of Ma huang, a traditional Chinese remedy containing ephedrine-type alkaloids. The literature surrounding the potential liver toxicities of Ma huang is reviewed and the proposed pathogenetic mechanisms are critically examined.
Serum tests of acute hepatocellular injury are commonly used to investigate the presence and monitor the progress of liver disease (1)(2). The release of cytoplasmic proteins from damaged hepatocytes into the vascular system follows tissue necrosis caused by, e.g., acetaminophen intoxication, ischemia and reperfusion injury, or rejection after liver transplantation. Although the hepatocytes are in direct contact with the vasculature and no interstitial barrier is between the two, smaller proteins appear earlier in the circulation than do larger ones (1) and would therefore increase earlier in serum above their upper reference value after an acute hepatocellular injury. α-Glutathione S -transferase (α-GST; 26 kDa) is a more sensitive and specific marker of hepatocellular damage (3)(4) than either alanine transaminase (ALT; 96 kDa) or aspartate transaminase. α-GST is present in liver, kidney, and intestine; is released rapidly from damaged hepatocytes; and has a relatively short in vivo plasma half-life (3)(4). The use of α-GST for the detection of hepatocellular injury secondary to acute rejection after liver transplantation improved the biochemical monitoring of patients and decreased mortality and morbidity (3). In search of even smaller and more specific cytoplasmic proteins for the detection of liver injury, we have studied the liver-type fatty acid-binding protein (L-FABP). FABPs are a family of 15-kDa proteins that are involved in the intracellular transport of long-chain fatty acids (5). To date, nine different FABPs have been identified and named according to the tissues in which they were first identified (5). L-FABP occurs mainly in the liver but, in small quantities, also in kidney and small intestine. In the hepatic lobule, L-FABP is expressed in hepatocytes in a declining portal-to-central gradient (5)(6). Extensive studies …
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