Biomedical subjects
Publications and source records attributed to M R Lucey.
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A multicenter, retrospective analysis of 623 liver transplant recipients was performed to define safe and effective cyclosporine doses and blood levels at various times after transplantation. Patient and graft survival were assessed as efficacy parameters, and serum creatinine and cholesterol levels as safety parameters. The mean daily cyclosporine dose was 12.1 mg/kg/d at 1 month posttransplantation and 5.5 mg/kg/d after 1 year. After 4 years, the mean cyclosporine dose was maintained at 4.0 mg/kg/d. Mean cyclosporine blood levels showed a similar trend. Patient and graft survival after 4 years of cyclosporine maintenance therapy were 72% and 67%, respectively. Both serum creatinine and cholesterol levels were stable over the study period, and neither correlated with cyclosporine dose. The cumulative incidence of biopsy-proven acute cellular rejection was 59% for early (< 6 months) episodes and 21% for late (> or = 6 months) episodes. Patient and graft survival did not differ significantly between patients experiencing early or late acute rejection episodes and those who did using univariate analysis. The high patient and graft survival, low rejection rates, and lack of significant renal dysfunction or hypercholesterolemia suggest that the cyclosporine doses and blood levels described are safe and therapeutically effective.
The purposes of this study were to determine among a cohort of long-term alcoholic survivors after liver transplantation (1) the incidence of alcohol use, (2) its effect on allograft integrity and extrahepatic health, and (3) the validity of the pretransplant alcohol prognosis screening process. Retrospective clinical cohort study of all alcoholic patients undergoing orthotopic liver transplantation at a single center from February 1987 until January 1991 with follow-up through December 1994, giving a median duration of follow-up of 63 months (range, 6-89 months). Multidisciplinary liver transplantation program at a tertiary-care academic medical center. Fifty alcoholic, long-term liver transplant recipients. The frequency of alcohol relapse, defined as any alcohol use in the period after transplantation, was determined by two questionnaire studies and by clinical follow-up. Allograft integrity was assessed by coded review of serial percutaneous allograft biopsies. Potential systemic effects of alcohol relapse were assessed by chart review. The alcohol prognosis screening process was evaluated by retrospectively comparing pretransplant estimates of putative indicators of alcoholism prognosis in posttransplant alcohol users and abstainers. Thirty-three recipients (66%) consistently denied any alcohol use throughout the duration of posttransplant follow-up, whereas 17 (34%) were identified as having consumed alcohol at least once since the transplant. There were no significant differences at the time of evaluation between abstainers and alcohol users in age, sex distribution, severity of liver dysfunction, median duration of abstinence, or University of Michigan alcoholism prognosis score. The median interval from transplantation to alcohol relapse was 17 months, with a range of 3 to 45 months. Recurrent alcohol use was associated with significant medical complications sufficient to require admission to the hospital in 6 patients. One patient died of graft dysfunction, noncompliance with immunosuppressant medications, and presumed graft rejection while drinking. Mild or progressive hepatitis, which was the most common abnormality in posttransplant liver biopsy findings, was equally distributed between both alcohol users and abstainers and sometimes occurred in the absence of antibody to hepatitis C virus antibodies. There was a similar frequency of biopsy-proven acute cellular rejection in alcohol users and abstainers. Typical histological features of alcoholic liver injury were present in posttransplant biopsies from 1 alcohol user only. Alcohol use by alcoholics is uncommon in the first 5 years after liver transplantation, and alcohol-associated liver injury is unusual. Mild nonspecific hepatitis is common in both alcohol users and nonusers alike. Among a small subset of alcoholic transplant recipients, drinking behavior after liver transplantation is associated with considerable morbidity, requiring hospital admissions and occasionally leading to graft loss and death.
Cytomegalovirus (CMV) is a significant cause of morbidity in immunosuppressed patients. It is characterized in the liver by parenchymal microabscesses, usually containing CMV-infected cells. However, not all hepatic microabscesses are due to CMV infection. In 1992, we described "mini" microabscess (MMA) syndrome, a distinct clinical syndrome that occurs in transplanted livers. This report analyzes the clinical and laboratory features of 57 cases of MMA syndrome occurring in 52 patients and compares these with 19 biopsy-proven cases of CMV infection. The diagnosis of MMA syndrome can only be made histologically. The microabscesses are smaller and more numerous than in CMV infection, and there are no viral inclusions present. CMV DNA could not be detected in liver biopsy specimens with MMAs by using "nested" polymerase chain reaction (PCR), indicating that MMA syndrome is not caused by CMV infection. The pattern of liver enzyme and bilirubin elevation is predominantly hepatocellular, with transaminase levels elevated, on average, six to eight times the upper limit of normal. The clinical features of MMA syndrome are that it predominantly affects female (40 of 52 patients) orthotopic liver transplant (OLT) recipients of all ages (range, 11 months to 66.9 years). MMA syndrome is unrelated to the indication for initial OLT and tends to occur later after transplantation than CMV infection (median, 91 days post-OLT vs. 32 days for CMV hepatitis). Although the etiology of MMA syndrome is not clear, it does not appear to adversely affect graft or patient survival.
Increased activation of the central benzodiazepine receptor (BZR) appears to play an important role in hepatic encephalopathy (HE). However, there is controversy regarding whether the density or affinity of BZRs is altered. A previous positron emission tomography (PET) study using the BZR antagonist [11C]flumazenil (FMZ) found two- to threefold greater cerebral cortical tracer uptake in recurrent HE, but did not account for impaired FMZ metabolism due to liver disease or assess the relative contributions of tracer delivery versus BZR binding. We hypothesized that correcting for these factors would affect estimations of BZR binding in HE. Nine patients with recurrent HE and 13 age-comparable controls were studied with [11C]FMZ PET. After intravenous administration of [11C]FMZ, arterial blood samples were collected, and PET images were acquired over 60 minutes. FMZ transport and binding maps were calculated for each subject by using a physiological tracer kinetic model. In agreement with the previous report, we found that FMZ reached a much higher level and was retained longer in the HE cerebral cortex despite similar total blood radioactivity levels in the two groups. However, the patients showed impaired hepatic metabolism of FMZ. After physiological modeling incorporating these data, significant increases in BZR binding were found in the thalamus (13%), cerebellum (20%), and pons (23%). There were minor, statistically insignificant increases in cerebral cortical (10%), putamen (12%), and whole brain (12%) BZR binding in patients with recurrent HE. These findings are in general agreement with results of autopsy studies, confirming a lack of major increases in cortical or basal ganglial BZR binding in HE. They emphasize that physiological tracer modeling should be used and altered peripheral radioligand metabolism considered in future PET studies of HE.
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This report summarizes a recent meeting cosponsored by the American Society of Transplant Physicians and the American Association for the Study of Liver Diseases to formulate minimal criteria by which patients with severe liver disease will be placed on the waiting list for liver transplantation. The participants agreed that only patients in immediate need of liver transplantation should be placed on the waiting list. Patients should not be placed in anticipation of some future need for such therapy. It was agreed that minimal criteria could assist but not replace the clinical judgment of the transplant professionals at individual centers. The criteria will be summarized below for adult patients with acute or chronic liver disease. The most important non-disease-specific criterion for placement on the transplant waiting list was an estimated 90% chance of surviving 1 year. This translated into a Child-Pugh score of > or = 7 for patients with cirrhosis which places the patient in Child-Pugh class B or C. Cirrhotic patients who have experienced gastrointestinal bleeding caused by portal hypertension or a single episode of spontaneous bacterial peritonitis would meet the minimal criteria irrespective of their Child-Pugh score. There were disease-specific criteria also. These include a sole minimal criterion for patients with fulminant hepatic failure regardless of etiology of the onset of stage 2 hepatic encephalopathy. A requirement for 6 months abstinence from alcohol before placement on the transplant waiting list was considered appropriate for most patients with alcoholic liver disease. Exceptional cases could get access to the waiting list through a regional review process. Chronic cholestatic diseases present difficulties because of a different natural history than that of chronic hepatocellular diseases. The use of specific risk scores for primary biliary cirrhosis and primary sclerosing cholangitis will likely replace Childs-Pugh classification as the scoring systems become refined. Minimal criteria for any patient with a primary hepatocellular cancer would admit any patient with a tumor confined to the liver irrespective of size or number of tumors, after careful investigation had failed to show spread to lymph nodes, the portal vein, or distant organs. Unusual or rare indications for liver transplantation, including Budd-Chiari syndrome, Wilson's disease, and other hereditary disorders, were also discussed. Finally, it was agreed that there should be no absolute contraindications to placement of patients on the liver transplant waiting list. These criteria should be open to regular review to accommodate advances in the field.
Liver transplantation has been demonstrated to be a successful therapeutic modality for patients with end-stage liver disease. The high rate of survival for an otherwise terminal condition has resulted in significant expansion of the indications and diseases treated by this procedure, and is hampered only by the limited numbers of organs available for transplantation. Efforts in clinical and laboratory medicine should be directed to identify candidates who would benefit most from this procedure, to provide better means for accurate assessment of liver reserve and the appropriate timing for transplantation, to identify quality liver grafts that would have the potential to tolerate cold preservation and reperfusion injury, and to assist in accurate monitoring of graft function immediately after transplantation. The aim of this manuscript is to describe the existing pathways for clinical and laboratory assessment of pretransplant residual liver function, the donor liver graft, and immediate posttransplantation function.
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Orthotopic liver transplantation is an established therapy for end-stage liver disease. This study evaluated the range of cardiovascular abnormalities in patients undergoing evaluation for orthotopic liver transplantation and determined the prognostic implications of abnormal echocardiographic features, including ischemia during dobutamine stress echocardiography, in predicting postoperative cardiac events. Two-dimensional echocardiography was performed in 190 patients for assessment of left ventricular function, valvular pathology, and pulmonary hypertension. Dobutamine stress echocardiography was performed in 165 patients for evaluation of inducible ischemia. Contrast echocardiography for detection of intrapulmonary shunting was performed in 125 patients at rest and in 99 during dobutamine stress. Left ventricular dysfunction, significant valvular regurgitation, and inducible ischemia were identified in <1O% of patients. Pulmonary hypertension, left ventricular hypertrophy and > or = moderate intrapulmonary shunting were present in 12%, 16%, and 26% of patients, respectively. Severe intrapulmonary shunting predicted death prior to transplantation (P=0.01). Of the 71 transplanted patients, major perioperative events included global left ventricular dysfunction in four patients and myocardial infarction in one patient with normal coronary arteries. No preoperative echocardiographic parameters, including ischemia on dobutamine echocardiography, predicted these perioperative events. No cardiac events related to obstructive coronary artery disease occurred in the 154 patients without ischemia on dobutamine stress echocardiography. The majority of patients with end-stage liver disease, including those with alcoholic cirrhosis, have normal cardiac function on two-dimensional echocardiography. Severe intrapulmonary shunting portends a poor prognosis in patients awaiting transplantation. A negative dobutamine stress echocardiogram appears useful in excluding patients at risk for perioperative cardiac events related to obstructive coronary artery disease.
Fulminant hepatic failure (FHF) in the absence of serum markers of hepatitis A (HAV) or B (HBV) infection or another cause is called non-A, non-B (NANB) FHF. The pathogenetic role of viral infection in NANB FHF remains controversial. To better define this relationship, we studied patients who underwent orthotopic liver transplantation (OLT) for FHF. Thirty-six patients with FHF underwent transplantation between 1987 and 1992. Pre-OLT serum was available for 24 patients, 14 with NANB FHF (all female; mean age, 32 years), and 10 (3 males, 7 females; mean age, 20 years) with a defined origin for FHF who formed the control group. Sera were tested using polymerase chain reaction for HAV, HCV, HDV, and HEV RNA and HBV DNA, and also serologically for antibodies to these viruses. In the NANB group, pre-OLT serum was negative for all viruses tested. Four patients in the control group had HBV serologically, 2 with HBV DNA in serum. One of these 4 also had hepatitis C and one hepatitis D infection. There was no difference in intensive care unit or hospital stay between the groups. The only significant difference in laboratory data was for peak creatinine pre-OLT (0.94 mg/dL in NANB v 1.62 mg/dL; P < .05). Two patients in the NANB groups and 3 in the control group required early retransplantation for graft primary nonfunction. One case of NANB FHF appeared to recur at 6 months but not after subsequent retransplantation. NANB FHF is not associated with hepatitis A, B, C, D, or E in plasma. It has a later age of onset but a similar clinical course to other forms of FHF and appears to preferentially affect women.
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The incidence of hemorrhagic complications from large volume paracentesis in patients with cirrhosis and portal hypertension is unknown. We have reviewed the cases of 179 outpatients undergoing large volume paracentesis at our institution during a 1-yr period. Of these 179 patients, four developed severe hemorrhagic complications requiring hospital admission and blood transfusion. Three of these patients developed intraperitoneal hemorrhage, one of which was localized to the paracentesis puncture site. One patient experienced an abdominal wall hematoma, localized by ultrasound. The symptoms and signs of hemorrhage became evident anywhere from hours up to 1 wk after completion of the paracentesis procedure. The mechanism of delayed hemorrhage is not known but may relate to the the rupture of large intra-abdominal venous collaterals in these patients. The literature does not support a correlation between degree of coagulopathy or thrombocytopenia and risk of bleeding in this setting. To promote early detection of this potentially life-threatening complications, a mechanism should exist for close outpatient follow-up of patients after large volume paracentesis.
Acute cellular rejection of the allograft is a potentially serious complication after liver transplantation, yet its true incidence is unknown. We therefore investigated the frequency of acute cellular rejection reported by transplant centers and its impact on morbidity and mortality. Morbidity was defined as duration of hospitalization. Of 200 articles screened, 18 were selected for inclusion in the study database, in which there was a total of 1,437 patients who received transplants. All contained more than 20 patients and invariably used histopathology for diagnosis of acute cellular rejection. These reports included all transplant patients within a fixed period and sufficient data to determine the incidence of acute cellular rejection. Morbidity data were obtained from our previous series. The mean incidence of acute cellular rejection in all centers was 49.8% (range between centers, 24% to 80%). Two immunosuppressive cohorts were identified: high-dose cyclosporine induction (> or = 5 mg/kg/d) and low-dose cyclosporine induction (< or = 4 mg/kg/d). Acute cellular rejection was reported in 27.0% of the high-dose group and 63.6% of the low-dose group, P = .0001. Strict adherence to Snover's histological criteria for acute cellular rejection did not alter the reported mean incidence. Frequency of acute cellular rejection was 45.2% (range between centers, 24% to 80%) in 8 studies that used Snover's criteria, and 51.6% (range between centers, 37% to 80%) in 10 studies that did not. There was no correlation between mortality and incidence of acute cellular rejection in the 9 studies that reported survival (R2 = .105). Morbidity data showed that the average length of initial hospitalization after transplantation for patients with acute cellular rejection was 52.4 +/- 8.3 (range, 14 to 124) days, in contrast to 28.3 +/- 2.3 (range, 9 to 87) days for patients with no rejection. P = .0008. The total number of hospital days in the first 6 months for patients with acute cellular rejection was 55.6 +/- 8.6 (range, 14 to 124) days and with no rejection, was 37.7 +/- 3.1 (range, 9 to 99) days. P = .0232. The incidence of acute cellular rejection varies widely among transplant centers, regardless of the use of Snover's criteria. Acute cellular rejection appeared to be less frequent in programs using high-dose cyclosporine induction regimens. The presence of acute cellular rejection seemed to have no correlation with mortality but significantly increased morbidity and therefore the cost of transplantation.
The hepatitis B virus (HBV) polymerase has no editing function and thus frequently transcribes its template incorrectly to result in viral variants that go under the name of "mutants." These mutants may be viewed as part of a continuing Darwinian evolution of HBV with some survival benefit. They also result in unusual extrahepatic manifestations of HBV infection, which will doubtless continue to divert the hepatologist.
A double-blind placebo-controlled trial of intravenous prostaglandin PGE1 (40 micrograms/h) was conducted in adult orthotopic liver transplant recipients. Infusion was started intraoperatively and continued for up to 21 days. Patients were followed up for 180 days postoperatively. Among 172 patients eligible for treatment in the study, 160 could be evaluated (78 PGE1; 82 placebo). Patient and graft survival were similar (PGE1: 16 deaths, 9 retransplantations [7 survivors]; controls: 15 deaths, 6 retransplantations [3 survivors]). In patients with surviving grafts, however, PGE1 administration resulted in a 23% shorter mean duration of hospitalization following transplantation (PGE1: 24.4 days; controls: 31.8 days; P = .02) and a 40% shorter length of time postoperatively in the intensive care unit (PGE1: 8.2 days; controls 13.7 days; P = .05). Reduced needs for renal support (P = .03) or surgical intervention other than retransplantation (P = .02) were also noted with PGE1 use. Further, PGE1 administration resulted in a trend toward improved survival rates in patients with mild renal impairment (preoperative serum creatinine 1.5 mg percent or greater; P = .08). Neither the incidence of acute cellular rejection nor of primary nonfunction was significantly different in the two groups. Phlebitis was the only complication that was more common during PGE1 administration, (PGE1: 9; controls: 4). These results suggest that PGE1 use in hepatic allograft recipients reduces morbidity and may result in sizable cost reductions.
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