Luis Podesta

Primary nonfunction of hepatic allografts with preexisting fatty infiltration

One of the unresolved problems in liver transplantation is how to determine accurately the cause of the primary nonfunction that is seen in about 10% of hepatic grafts (1, 2). It is often assumed that ischemic injury has occurred when the new liver does not function. Acute immunologic injury comparable to the humorally mediated hyperacute rejection of kidneys probably occurs rarely, if at all (3), but an indolent version of hyperacute hepatic rejection that is not clearly associated with demonstrable preformed antibodies can cause hemorrhagic necrosis within 1 or 2 days (4). The other most common etiology of primary nonfunction probably is intraoperative injury of the transplant when a flawed operation is performed by the recipient team (1). Preexisting acute or chronic hepatic disease in the recipient will undoubtedly aggravate any of the foregoing factors, or may itself preclude success. Although hepatic injury may occur as part of the trauma that has led to brain death or may be an iatrogenic complication of the care that is provided, this may be difficult to prove even with biopsies of the homograft. Makowka et al. (5) have reported a surprising lack of correlation between so-called good- and bad-risk donor parameters and the clinical outcome of the recipient. We report here 2 examples of acute fatty infiltration of livers that had been procured from seemingly good donors who had been in good health until 1 and 2 ½ days previously. The grafts that were full of fat never functioned and were replaced immediately in 1 case and 3 days later in the other. This report suggests how to identify and avoid this lethal situation.

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.

Abdominal organ cluster transplantation for the treatment of upper abdominal malignancies

Ten patients with primary malignant tumors of the biliary tract, duodenum, or stomach and with secondary involvement of the liver underwent removal of most or all of the stomach, liver, pancreas, spleen, duodenum, proximal jejunum, terminal ileum, and ascending and transverse colon. The void in the upper abdomen was filled with an organ cluster graft consisting of the liver, pancreas, duodenum, and variable segments of proximal jejunum. Eight of the ten patients are alive after 3 to 9 months, all with good liver and pancreas function, and most with satisfactory function of the gastrointestinal tract. One of the surviving patients was in the hospital for 4 months because of multiple enteric fistulas and infections; the other seven survivors were discharged after an average of 43 +/- 17.61 (SD) days. Recurrent tumor has not been proved in any of the surviving recipients and is suspected in only one. The study of such cases should provide insight and guidelines applicable to other visceral transplantation procedures that may be attempted in the future.

Control of cerebral oedema by total hepatectomy and extracorporeal liver support in fulminant hepatic failure

Keeping a patient with fulminant hepatic failure (FHF) alive until a donor liver is available for transplantation can be a problem. We describe an 18-year-old woman with paracetamol-induced FHF, who was treated by total hepatectomy, hypothermia, plasma exchange, and extracorporeal liver support. The patient was anhepatic for 14 h. The liver-support system consisted of plasma separation and perfusion through a charcoal filter and a hollow-fibre module seeded with matrix-attached porcine hepatocytes. With artificial liver treatment there was reversal of severe neurological dysfunction, normalisation of intracranial pressure, and decreased serum ammonia. The patient underwent emergency transplantation with an ABO-incompatible liver, followed by transplantation with a compatible organ eight days later. The patient has fully recovered and is neurologically intact.

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.

Acute liver failure due to lymphoma

Lymphomatous involvement of the liver may present as acute liver failure but is an absolute contraindication for liver transplantation. Therefore it is imperative to diagnose such patients since survival in this group is poor and recurrence is high. We describe two patients with acute liver failure referred for liver transplantation whose diagnostic testing revealed hepatic lymphoma. These cases underscore the importance of considering lymphoma in the differential diagnosis of acute liver failure prior to liver transplant.

Prolongation of Pig-to-Dog Renal Xenograft Survival by Modification of the Inflammatory Mediator Response

The pathogenesis of hyperacute renal rejection consists of a nonspecific effector cascade that invokes most of the components of a typical acute inflammatory response. Platelet-activating factor (PAF) represents the most recent and perhaps the most significant mediator and promoting agent of this phenomenon. These studies evaluated SRI 63–441, a novel, synthetic, and the most potent PAF receptor antagonist available, alone and in combination with other prostanoids, for their ability to influence this response and to prolong renal xenograft survival and function in a model of pig-to-dog heterotransplantation. Inhibition of PAF by SRI 63–441 alone, at the dosage and schedule used in these experiments, did not significantly prolong xenograft survival or function. However, the combination of SRI 63–441 with either prostacyclin (PGI2) or prostaglandin E1 (PGE1) infusion demonstrated significant synergism, and resulted in a 6–9-fold increase in kidney survival and a 3–20-fold increase in urine output. Neither PGI2 nor PGE1 infusions alone significantly influenced this xenograft model. Electromagnetic flow studies demonstrated significantly delayed diminution in renal artery blood flow in the combination-treated animals. Serial and end-stage histologic examination of kidneys receiving combination therapy demonstrated a delayed onset of the pathologic deterioration and an overall amelioration of the entire process. These studies demonstrate that significant abrogation of a rapid and violent form of hyperacute rejection can be achieved solely by the pharmacologic manipulation of the inflammatory mediator response.

Detection of hepatitis C virus with RNA polymerase chain reaction in fulminant hepatic failure

The role of hepatitis C virus (HCV) infection in fulminant hepatic failure is controversial. The frequency of serum HCV RNA positivity in previously reported patients with fulminant hepatic failure (FHF) of indeterminate cause ranged from 0 to 12% in the United States and Europe and from 43% to 59% in Asia. We assessed serum HCV RNA using polymerase chain reaction (PCR) and oligoprimers from the 5′UTR of the HCV genome in 26 consecutive patients with FHF. Another laboratory independently performed PCR on 21 of the serum samples using different oligoprimers from the 5′UTR and NS3 region of the HCV genome. Serum HCV RNA was detected in two of seven (28%) patients with hepatitis B, 9 of 15 (60%) with an indeterminate cause, and in none with hepatitis A (n = 2) or drug‐induced hepatotoxicity (n = 2). HCV RNA PCR results were concordant between both laboratories in 17 of 21 (81%) of samples. In patients with an indeterminate cause, HCV RNA positivity was significantly associated with the transmission risk factor of low socioeconomic status and Hispanic ethnicity. Eighteen patients underwent liver transplantation (LT) and 15 (83%) survived. Among patients with FHF of indeterminate cause, recurrent or acquired HCV infection after transplantation occurred in three of five (60%) and one of four (25%) patients, respectively. Three of four (75%) patients with hepatitis C virus infection post‐LT also developed histologic hepatitis. HCV appears to be the causative agent of a substantial number of cases of FHF classified as indeterminate in the Los Angeles area. Differences in patient populations or risk factors may explain the discordant incidences of HCV infection in FHF observed among different programs. (Hepatology 1995; 22:1379–1386).

Epstein-Barr virus infection in liver transplantation patients: correlation of histopathology and semiquantitative Epstein-Barr virus-DNA recovery using polymerase chain reaction.

Epstein-Barr virus (EBV) infection may complicate orthotopic liver transplantation, and can lead to hepatitis with subsequent graft failure and to benign and malignant lymphoproliferative disorders. Early diagnosis allows for prevention or treatment of complications. Histopathologic features of EBV infection in the liver vary and may be difficult to recognize. To delineate the morphologic features that allow for recognition we studied 61 biopsy specimens from 37 patients, correlating the results of EBV-DNA demonstration after polymerase chain reaction with histopathology of formalin-fixed, hematoxylin-eosin-stained liver biopsy specimens. DNA was extracted from fresh liver biopsy samples, and polymerase chain reaction was carried out with EBV primers (capsid protein gp220) using standard techniques and 25-cycle amplification. Epstein-Barr virus-related sequences after polymerase chain reaction were detected by DNA blot assay. Histopathologic features were classified into three categories on the basis of the semiobjective determination of the number and distribution of immunoblasts and other immature lymphocytes in portal tracts and sinusoids: highly suggestive (three biopsy specimens), indeterminant (one biopsy specimen), and negative (57 biopsy specimens). Only the three highly suggestive biopsy specimens had high levels of EBV-DNA. We conclude that the histopathologic features of EBV infection after orthotopic liver transplantation can be relied on to establish the diagnosis.

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.