Successful liver transplantation following medical management of portopulmonary hypertension: a single-center series.

Severe portopulmonary hypertension (POPH) is an absolute contraindication to orthotopic liver transplantation (OLT). Vasodilators have been used, but the safety of subsequent transplantation and the reversibility of pulmonary hypertension after transplantation are uncertain. This study examined the feasibility and post-transplant effects of liver transplantation following medical control of POPH. Eight consecutive patients (three females and five males, ages 39-51) with POPH as their only contraindication to transplantation were treated with continuous intravenous epoprostenol. Liver transplantation was considered if the mean pulmonary artery pressure (PAM) was lowered to <35 mmHg. Epoprostenol 2-8 ng/kg/min successfully improved hemodynamics in seven of eight patients, usually within 6.5 months of initiating therapy. PAM declined from an average of 43-33 mmHg (p=0.03); mean pulmonary vascular resistance declined from 410 to 192 dyn s cm-5 (p=0.01) and cardiac output increased from 6.6 to 10 L/min (p=0.02). Six of the seven responders were actively listed for liver transplantation. Two died on the waiting list; the remaining four were transplanted and remain alive and well 9-18 months post-OLT-two without vasodilators, and two on oral medication. We conclude that pulmonary vasodilators permit safe liver transplantation in some cases, and that POPH may be reversible after transplantation.

In situ splitting of the cadaveric liver for two adult recipients.

BACKGROUND: Split-liver transplantation offers a unique opportunity to expand the existing donor pool. However, it has previously been stated that due to inadequate liver volume the advantages of split-liver transplantation would be lost when attempting to split the liver for two adult recipients. In this study, we sought to determine the safety, efficacy, and applicability of split-liver transplantation in select adult liver transplant recipients. METHODS: Liver allografts for eight adult recipients were procured by in situ splitting of four adult cadaveric livers. The donor ages were 17, 19, 22, and 25 years and weights were 72, 77, 78, and 87 kg, respectively. In situ splitting resulted in three right trisegmental grafts, one right lobe graft, one left lobe graft, and three left lateral segmental grafts. The median recipient age was 49 years (range 38-61 years), whereas the median recipient weight was 84 kg (range 78-98 kg) for the right-sided grafts and 52 kg (range 51-53 kg) for recipients of the left-sided grafts. The median graft-to-recipient body weight ratio for right trisegmental, right lobe, left lobe, and left lateral segmental grafts was 1.31%, 1.26%, 1.35%, and 0.70%, respectively. RESULTS: Overall patient and graft survival in this series is 100%. All prothrombin times were normalized within 4 days of transplantation. No evidence of ascites or prolonged hyperbilirubinemia was encountered in any right- or left-sided graft recipient. The incidence of hepatic artery, portal vein, and hepatic vein thrombosis is 0%, 0%, and 0%, respectively. Hepatic arterial anastomotic bleeding and a cut surface bile leak each occurred in one patient. Median United Network for Organ Sharing (UNOS) waiting time was 242 days (range 4-454 days) for the patients to which the donor liver was allocated. In contrast, the median waiting time for the four patients receiving the extra split-liver graft was reduced significantly to 37 days (range 21-101 days) (P<0.02). CONCLUSIONS: This study demonstrates that split-liver transplantation can expand the cadaveric donor liver pool available for select adult liver transplant recipients. When both the donor organ and the transplant recipient are chosen carefully, split-liver transplantation can be safely performed without a delay in allograft function, increase in technical complications, or compromise in graft or patient survival.

Etiology and outcome for 295 patients with acute liver failure in the United States.

Little information is available on acute liver failure (ALF) in the United States. We gathered demographic data retrospectively for a 2-year period from July 1994 to June 1996 on all cases of ALF from 13 hospitals (12 liver transplant centers). Data on the patients included age, hepatic coma grade on admission, presumed cause, transplantation, and outcome. Among 295 patients, 74 (25%) survived spontaneously, 121 (41%) underwent transplantation, and 99 (34%) died without undergoing transplantation. Ninety-two of 121 patients (76%) survived 1 year after transplantation. Acetaminophen overdose was the most frequent cause (60 patients; 20%), followed by cryptogenic/non A non B non C (NANBNC; 15%), idiosyncratic drug reactions (12%), hepatitis B (10%), and hepatitis A (7%). Spontaneous survival rates were highest for patients with acetaminophen overdose (57%) and hepatitis A (40%) and lowest for those with Wilson's disease (no survivors of 18 patients). The transplantation rate was highest for Wilson's disease (17 of 18 patients; 94%) and lowest for autoimmune hepatitis (29%) and acetaminophen overdose (12%). Age did not differ between survivors and nonsurvivors, perhaps reflecting a selection bias for patients transferred to liver transplant centers. Coma grade on admission was not a significant determinant of outcome, but showed a trend toward affecting both survival and transplantation rate. These findings on retrospectively studied patients from the United States differ from those previously gathered in the United Kingdom and France, highlighting the need for further study of trends in each country.

Prophylaxis against hepatitis B recurrence following liver transplantation using combination lamivudine and hepatitis B immune globulin.

Patients undergoing liver transplantation for hepatitis B-related liver disease are prone to recurrence. The mainstay of prophylaxis has been passive immunotherapy with hepatitis B immune globulin (HBIG). Antiviral therapy with lamivudine has proven effective in lowering hepatitis B virus (HBV) DNA and improving histology in patients with hepatitis B infection; its role in prophylaxis against hepatitis B recurrence following liver transplantation is under investigation. Viral breakthrough and resistance, however, are a significant problem with monotherapy with either HBIG or lamivudine. The efficacy of combination lamivudine/HBIG prophylaxis has not been reported. Fourteen patients underwent transplantation for decompensated liver disease owing to hepatitis B. Lamivudine (150 mg p.o./d) was begun before transplantation in 10 patients, including 4 who were HBV DNA-positive. In addition, 1 patient was HBV DNA-positive when transplanted. HBIG was given perioperatively and continued thereafter; treatment with lamivudine was maintained or initiated at the time of transplantation and continued indefinitely. The median follow-up was 387 days. Actuarial 1-year patient and graft survival was 93% (1 patient died of unrelated causes). At a median interval of 28 days following lamivudine treatment, all 5 HBV DNA-positive patients cleared HBV DNA from the serum; 1 went on to clear hepatitis B surface antigen (HBsAg), before transplantation, at day 148 of lamivudine treatment. By the highly sensitive polymerase chain reaction (PCR), at a median of 346 days (range, 130-525 days) following transplantation, all 13 surviving patients had no detectable serum HBV DNA. Lamivudine suppresses HBV replication in patients awaiting liver transplantation. At a median follow-up of 1.1 years, combination prophylaxis with lamivudine and HBIG prevented hepatitis B recurrence following liver transplantation.

Liver transplantation for decompensated cirrhosis after jejunoileal bypass: a strategy for management.

BACKGROUND: Although jejunoileal bypass results in end-stage liver disease in up to 100% of patients, little is known about outcome after liver transplantation. METHODS: The clinical courses of six patients who underwent liver transplantation at UCLA for decompensated cirrhosis owing to a jejunoileal bypass were reviewed. Liver function, allograft pathology, renal function, and nutritional status were assessed. RESULTS: Of the four patients with an intact jejunoileal bypass, two of the three who were biopsied had recurrent steatotic liver disease. The two patients whose jejunoileal bypass was reversed at the time of liver transplantation had lower alkaline phosphatase, lower creatinine, higher albumin, and higher cholesterol, and were more obese than their counterparts with intact bypasses. CONCLUSIONS: Patients undergoing liver transplantation for jejunoileal bypass-associated liver disease should, if possible, have their bypass reversed at the time of transplantation; otherwise, they must be followed closely and be biopsied routinely. Recurrent liver disease should prompt reversal of the jejunoileal bypass.

Adult liver transplantation for metabolic liver disease.

Liver replacement provides an effective method of replacing a failing liver, and corrects the underlying defect in many metabolic conditions. Results of liver transplantation for metabolic diseases have been encouraging, with the exception of hereditary hemochromatosis, in which infectious and for which cardiac complications appear to increase posttransplant mortality. An improved understanding of the underlying genetic and molecular defect will lead to advances in medical therapy and perhaps will decrease the need for liver replacement. The prospects of gene therapy are being pursued for many metabolic disorders, however until this research leads to direct clinical application, liver transplantation remains the only effective option for many patients with metabolic liver disease.

Long-term survival after retransplantation of the liver.

OBJECTIVE: The authors determined the long-term outcome of patients undergoing hepatic retransplantation at their institution. Donor, operative, and recipient factors impacting on outcome as well as parameters of patient resource utilization were examined. SUMMARY BACKGROUND DATA: Hepatic retransplantation provides the only available option for liver transplant recipients in whom an existing graft has failed. However, such patients are known to exhibit patient and graft survival after retransplantation that is inferior to that expected using the same organs in naiive recipients. The critical shortage of donor organs and resultant prolonged patient waiting periods before transplantation prompted the authors to evaluate the results of a liberal policy of retransplantation and to examine the factors contributing to the inferior outcome observed in retransplanted patients. METHODS: A total of 2053 liver transplants were performed at the UCLA Medical Center during a 13-year period from February 1, 1984, to October 1, 1996. A total of 356 retransplants were performed in 299 patients (retransplant rate = 17%). Multivariate regression analysis was performed to identify variables associated with survival. Additionally, a case-control comparison was performed between the last 150 retransplanted patients and 150 primarily transplanted patients who were matched for age and United Network of Organ Sharing (UNOS) status. Differences between these groups in donor, operative, and recipient variables were studied for their correlation with patient survival. Days of hospital and intensive care unit stay, and hospital charges incurred during the transplant admissions were compared for retransplanted patients and control patients. RESULTS: Survival of retransplanted patients at 1, 5, and 10 years was 62%, 47%, and 45%, respectively. This survival is significantly less than that seen in patients undergoing primary hepatic transplantation at the authors' center during the same period (83%, 74%, and 68%). A number of variables proved to have a significant impact on outcome including recipient age group, interval to retransplantation, total number of grafts, and recipient UNOS status. Recipient primary diagnosis, cause for retransplantation, and whether the patient was retransplanted before or after June 1, 1992, did not reach statistical significance as factors influencing survival. In the case-control comparison, the authors found that of the more than 25 variables studied, only preoperative ventilator status showed both a significant difference between control patients and retransplanted patients and also was a factor predictive of survival in retransplanted patients. Retransplant patients had significantly longer hospital and intensive care unit stays and accumulated total hospitalization charges more than 170% of those by control patients. CONCLUSIONS: Hepatic retransplantation, although life-saving in almost 50% of patients with a failing liver allograft, is costly and uses scarce donor organs inefficiently. The data presented define patient characteristics and preoperative variables that impact patient outcome and should assist in the rational application of retransplantation.

Aplastic anemia complicating orthotopic liver transplantation.

The clinical characteristics and outcome of posttransplantation aplastic anemia (AA) were determined in 12 of 1,736 patients (0.007%) undergoing orthotopic liver transplantation (OLT) that were afflicted with AA. None of the affected patients had a history of hematologic disease. Median patient age was 53 years (range, 2-61 years); 10 of the affected patients were men, and 2 were women. The etiologies of AA included non-A, non-B, non-C fulminant hepatic failure (FHF) (3 patients), graft-versus-host disease (4 patients), Parvovirus-induced (1 patient), and idiopathic (4 patients). The median duration between OLT and the onset of AA was 12 days (range, 11-14 days) in the 3 patients undergoing OLT for FHF; in contrast, AA developed in the other 9 patients at 37 days (range, 27-51 days) after OLT. Eleven patients were treated with reduction of their cyclosporine or tacrolimus dosage, granulocyte colony-stimulating factor, anti-thymocyte globulin, and Solumedrol. Two of the 3 patients developing AA following OLT for FHF achieved hematologic recovery 21 and 92 days after diagnosis. In contrast, all 9 non-FHF patients developing AA after OLT died, 5 due to infectious complications and 4 following intracranial bleeding. AA is an unusual complication of OLT. In the setting of FHF, it affects young males in the early posttransplantation period, and, when infectious complications can be avoided, remission and stable allograft function can be anticipated. However, in the non-FHF patient, AA occurs in older individuals later in the posttransplantation period and has a uniformly poor outcome.

Orthotopic liver transplantation for primary sclerosing cholangitis. A 12-year single center experience.

OBJECTIVE: The purpose of this study was to analyze a single center's 12-year experience with 127 orthotopic liver transplantations (OLT) for primary sclerosing cholangitis (PSC). SUMMARY BACKGROUND DATA: Primary sclerosing cholangitis is a chronic cholestatic liver disease of unknown origin that occurs most commonly in young men and is associated frequently (70-80%) with inflammatory bowel disease (IBD). Patients with PSC also are at risk for the development of cholangiocarcinoma (CCA) and those with IBD for colon carcinoma. Although the course of PSC is variable, it frequently is progressive, leading to cirrhosis and requirement for OLT. METHODS: The medical records of 127 consecutive patients undergoing OLT for PSC from July 1, 1984, to May 30, 1996, were reviewed. Actuarial patient and graft survival was determined at 1,2, and 5 years. The incidence and outcome of patients with CCA, recurrent sclerosing cholangitis, and post-transplant colon carcinoma was determined. Results were analyzed by way of stepwise Cox regression to determine the statistical strength of independent associations between pretransplant covariates and patient survival. The median follow-up period was 3.01 years. Incidental cholangiocarcinoma (ICCA) was defined as a tumor < 1 cm in size that was discovered at the time of pathologic sectioning of the explanted liver. RESULTS: Ninety-two patients (72%) had associated IBD. Seventy-nine (62%) had undergone previous biliary tract surgery. One hundred seven patients (84%) received a single graft, whereas 20 patients (16%) required 22 retransplants. Patients received either cyclosporine- (n = 76) or tacrolimus- (n = 51) based immunosuppression. The 1-, 2-, and 5-year actuarial patient survivals were 90%, 86%, and 85%, respectively, whereas graft survival was 82%, 77%, and 72%, respectively. The presence of previous biliary surgery had no effect on patient survival. Ten patients (8%) had ICCA and their survival was not significantly different from patients without ICCA (100%, 83%, and 83% at 1, 2, and 5 years, respectively). Four patients were known to have CCA at the time of OLT, all recurred within 6 months, and had a significantly worse outcome (p < 0.0001). Recurrent sclerosing cholangitis developed in 11 patients (8.6%). The patient and graft survival in this group was not different from those in whom recurrence did not develop (patient; 100%, 90%, and 90%; graft: 80%, 70%, and 52%). Thirty patients (23%) underwent colectomy after liver transplantation for dysplasia-carcinoma or symptomatic colitis. Of the nine covariates entered into the Cox multivariate regression analysis, only common bile duct frozen section biopsy specimen showing CCA was predictive of a survival disadvantage. CONCLUSIONS: Liver transplantation provides excellent patient and graft survival rates for patients affected with PSC independent of pretransplant biliary tract surgery. Incidental cholangiocarcinoma does not affect patient survival significantly. However, known CCA or common duct frozen section biopsy specimen or both showing CCA are associated with poor recipient survival, and OLT should be proscribed in these cases. Recurrent PSC occurs in approximately 9% of cases but does not affect patient survival. Post-transplant colectomy does not affect patient survival adversely.

Aerosol gene delivery in vivo.

The ability to express transgenes selectively within the lung will greatly facilitate the development of gene therapy for a variety of human diseases. We have demonstrated that aerosol administration of a chloramphenicol acetyltransferase (CAT) expression plasmid complexed to cationic liposomes produces high-level, lung-specific CAT gene expression in mice in vivo. Significant levels of CAT activity are seen in the lungs for at least 21 days following aerosolization. In situ immunostaining for intracellular CAT protein reveals that the majority of airway epithelial and alveolar lining cells are transfected in vivo. Histological analyses show no apparent treatment-related damage. These results have important implications for the development of human gene therapy.

Attempted nonenzymatic template-directed oligomerizations on a polyadenylic acid template: implications for the nature of the first genetic material.

Previous attempts to produce nonenzymatic template-directed oligomerizations of activated pyrimidines on polypurine templates have been unsuccessful. The only efficient reactions are those where the template is composed primarily of pyrimidines, especially cytosine. Because molecular evolution requires that a synthesized daughter polynucleotide be capable of acting as a template for the synthesis of the original polynucleotide, the one-way replication achieved thus far is inadequate to initiate an evolving system. Several uracil analogs were used in this investigation in order to search for possible replacements for uracil. The monomers used in this investigation were the imidazolides of UMP, xanthosine 5'-monophosphate, the bis-monophosphates of the acyclic nucleosides of uracil, and 2,4-quinazolinedione. The concentrations of various salts, buffers, pH, and temperature were among the different variables investigated in attempts to find conditions that would permit template-directed oligomerizations. Although the different monomers in this study demonstrated varying abilities to form very short oligomers, we were unable to detect any enhancement of this oligomerization that could be attributed to the poly(A) template. Although special conditions might be found that would allow purine-rich templates to work, these reactions cannot be considered robust. The results of our experiments suggest that pyrimidines were not part of the original replicating system on the primitive Earth. It has already been shown that ribose is an unlikely component of the first replicating systems, and we now suggest that phosphate was absent as well. This is due to the low solubility of phosphate in the present ocean (3 x 10(-6) M), as well as the difficulty of prebiotic activation of phosphates.

Template-directed synthesis of oligonucleotides under eutectic conditions.

One of the most important sets of model prebiotic experiments consists of reactions that synthesize complementary oligonucleotides from preformed templates under nonenzymatic conditions. Most of these experiments are conducted at 4 degrees C using 0.01-0.1 M concentrations of activated nucleotide monomer and template (monomer equivalent). In an attempt to extend the conditions under which this type of reaction can occur, we have concentrated the reactants by freezing at -18 degrees C, which is close to the NaCl-H2O eutectic at -21 degrees C. The results from this set of experiments suggest that successful syntheses can occur with poly(C) concentrations as low at 5 x 10(-4) M and 2MeImpG concentrations at 10(-3) M. It was also anticipated that this mechanism might allow the previously unsuccessful poly(A)-directed synthesis of oligo(U)s to occur. However, no template effect was seen with the poly(A) and ImpU system. The failure of these conditions to allow template-directed synthesis of oligo(U)s supports the previously proposed idea that pyrimidines may not have been part of the earliest genetic material. Because of the low concentrations of monomer and template that would be expected from prebiotic syntheses, this lower temperature could be considered a more plausible geologic setting for template-directed synthesis than the standard reaction conditions.

High-performance liquid chromatography of oligoguanylates at high pH.

Because of the stable self-structures formed by oligomers of guanosine, standard high-performance liquid chromatography techniques for oligonucleotide fractionation are not applicable. Previously, oligoguanylate separations have been carried out at pH 12 using RPC-5 as the packing material. While RPC-5 provides excellent separations, there are several limitations, including the lack of a commercially available source. This report describes a new anion-exchange high-performance liquid chromatography method using HEMA-IEC BIO Q, which successfully separates different forms of the guanosine monomer as well as longer oligoguanylates. The reproducibility and stability at high pH suggests a versatile role for this material.

Energy yields for hydrogen cyanide and formaldehyde syntheses: the HCN and amino acid concentrations in the primitive ocean.

Prebiotic electric discharge and ultraviolet light experiments are usually reported in terms of carbon yields and involve a large input of energy to maximize yields. Experiments using lower energy inputs are more realistic prebiotic models and give energy yields which can be used to estimate the relative importance of the different energy sources on the primitive earth. Simulated prebiotic atmospheres containing either CH4, CO or CO2 with N2, H2O and variable amounts of H2 were subjected to the spark from a high frequency Tesla coil. The energy yields for the synthesis of HCN and H2CO were estimated. CH4 mixtures give the highest yields of HCN while H2CO is most efficiently produced with the CO mixtures. These results are a model for atmospheric corona discharges, which are more abundant than lightning and different in character. Preliminary experiments using artificial lightning are also reported. The energy yields from these experiments combined with the corona discharge available on the earth, allows a yearly production rate to be estimated. These are compared with other experiments and model calculations. From these production rates of HCN (e.g. 100 nmoles cm-2 yr-1) and the experimental hydrolysis rates, the steady state concentration in the primitive ocean can be calculated (e.g., 4 X 10(-6) M at pH 8 and 0 degrees). A steady state amino acid concentration of 3 X 10(-4) M is estimated from the HCN production rate and the rate of decomposition of the amino acids by passage through the submarine vents.

Electric discharge synthesis of HCN in simulated Jovian atmospheres.

HCN has been detected in the Jovian atmosphere at a column density of about 2.2 x 10(-7) moles cm-2. While photochemical synthesis from methylamine and aziridine, upwelling, and lightning have been proposed as possible sources of this HCN, corona discharge has not been previously considered. HCN energy yields (moles J-1) were measured using corona discharge for gas mixtures containing H2, CH4, NH3, with H2/CH4 ratios from 4.4 to 1585. The yields are approximately proportional to the mole fraction of methane in the gas mixture. Assuming that the 3/1 ratio of corona discharge to lightning energy on the Earth applies to Jupiter, HCN column densities from corona discharge could account for approximately 10% of the observed HCN. These estimates are very dependent on the values used for the energy available as lightning on Jupiter and the eddy diffusion coefficients in the region of synthesis.