Receiver operating characteristic analysis for biliary complications in liver transplantation.

Receiver operating characteristic (ROC) analysis was used to assess the use of the serum chemical markers, gamma-glutamyl transferase (GGT), alkaline phosphatase (AP), and total bilirubin (BR) as tests for biliary complications in patients who had undergone orthotopic liver transplantation. Our study consisted of 105 consecutive adult transplant patients at the University of Chicago from March 1985 to November 1988. Biliary complications were determined by cholangiogram. Maximum serum values for three postoperative time periods (days 0 to 30, days 31 to 90, and > 90 days) were obtained for each patient. ROC analysis showed that GGT was the best single test during the earliest and latest time periods, whereas BR was best during days 31 through 90. We also assessed the time periods, surgical biliary anastomosis, pretransplant diagnosis, and location of biliary lesions compared with the incidence of biliary pathology for the patients. We found that patients with a pretransplant diagnosis of acute parenchymal liver disease were more likely to have biliary complications, and patients with end-to-end anastomosis with T tube were also more likely to have biliary complications. We further conclude that GGT, BR, and AP are all useful in screening for biliary complications and should be used routinely in liver transplant patients.

Diagnosis of hepatic allograft rejection: role of liver biopsy.

The role of the liver biopsy for establishing a diagnosis of liver allograft rejection was investigated by examining under code 151 liver biopsies from 32 recipients and correlating the results with the clinical diagnosis determined by chart review. One-hundred-and-four biopsies were obtained to evaluate the cause of liver dysfunction and 47 were performed on a weekly protocol basis independent of the clinical status. A diagnosis of "definite histologic rejection" was made if a biopsy contained portal triaditis, bile duct injury, and endothelialitis, while biopsies were said to be suspicious for rejection if portal triaditis and bile duct injury were evident. A diagnosis of rejection using clinical and biochemical findings and response to therapy was made in association with 37 biopsies, of which 16 had definite histologic rejection and 13 were suspicious for rejection. Of the 114 biopsies performed in patients without clinical rejection, 71 had histology suspicious for rejection. Thus, biopsy was sensitive for the detection of rejection (78%), but was not very specific (33%). The positive predictive value was low (28%), while the negative predictive value was high (83%). These results indicate that liver biopsy is useful to evaluate graft dysfunction, to exclude rejection, to confirm clinically suspected rejection, and to diagnose other problems that can affect allograft function. Protocol biopsies appear to have little value.

OKT3 therapy for hepatic allograft rejection. Differential response in adults and children.

The clinical courses following OKT3 therapy for hepatic allograft rejection (HAR) in adults and children have not been individually defined. We have reviewed our experience with OKT3 therapy for HAR in adults and children to compare: (1) the initial response to OKT3 therapy, (2) the clinical course following OKT3 therapy, and (3) the antimurine antibody response and immunologic monitoring results. Children required OKT3 therapy more frequently than adults: fourteen courses of OKT3 therapy were required in 130 orthotopic liver transplants (OLT) in 108 adult patients, whereas nineteen courses of OKT3 therapy were required in 94 OLT in 78 children (P less than 0.02). Repeat OKT3 therapy was not required in adults--however, four of nineteen courses of OKT3 therapy in children were repeat OKT3 therapy for rejection. No differences existed between adult and pediatric treatment groups with respect to number of prior OLT procedures, previous graft loss to rejection, percentage of ABO-incompatible grafts, frequency of positive donor-recipient lymphocyte crossmatches, or time to first rejection. The initial response to OKT3 therapy (rapid reversal, delayed reversal, and failure) was remarkably similar in adults and children. However, nine of 13 (70%) children with clear evidence of response to OKT3 treatment experienced breakthrough rejection or early recurrent rejection, whereas none of 12 adults suffered breakthrough rejection or early recurrent rejection (P less than 0.01). Early recurrent rejection did not correlate with delayed reversal of rejection, early return of CD3+ cells by peripheral blood monitoring, or development of anti-OKT3 antibodies. All 4 courses of OKT3 retreatment in children were successful in reversing rejection, and breakthrough rejection and early recurrent rejection did not occur. Overall graft and patient survival in pediatric patients requiring OKT3 therapy (67% and 73%) was not different from that in adults (71% and 79%). Results obtained in one patient provide the first evidence that successful OKT3 retreatment of HAR can be achieved in the presence of preexisting idiotypic anti-OKT3 antibody. In conclusion, OKT3 therapy for HAR was required more frequently in children than in adults. The clinical outcome following OKT3 therapy for HAR also differs markedly, with early recurrent rejection and breakthrough rejection occurring more frequently in children.

Liver transplantation in the management of fulminant hepatic failure.

Liver transplantation is now performed for the treatment of fulminant hepatic failure, but the selection of patients for this procedure has been incompletely described. We used worsening hepatic encephalopathy, clinical evidence of brain edema, and prolongation of the prothrombin time after 24-48 h of intensive medical treatment as key factors influencing the decision to recommend liver transplantation. Thirty-seven patients (29 adult, 8 pediatric) were admitted with fulminant hepatic failure. Ten improved with medical treatment, so liver transplantation was not recommended. Twenty-seven deteriorated despite medical treatment. Eight of these, 7 with grade 4 hepatic encephalopathy and persistent coagulopathy, did not receive transplantation because of contraindications (n = 5), failure to find a donor (n = 1), or refusal of therapy (n = 2). None of these survived. Sixteen of the other 19 patients developed grade 4 hepatic encephalopathy, 5 had brain edema, and all had persistent coagulopathy, so liver transplantation was performed. One year actuarial survival was 58%. This retrospective analysis confirms that survival exceeding 50% can be obtained with liver transplantation in patients with fulminant hepatic failure. Additional studies of prognostic markers are needed to define the role of liver transplantation in the management of this disease.

Effect of ethanol on stimulus-induced insulin secretion and glucose tolerance. A study of mechanisms.

The effect of ethanol on stimulus-induced insulin secretion was studied, and possible mechanisms were examined in fasting unanesthetized and unrestrained rats with indwelling jugular and aortic catheters. Glucose (150 mg.) or tolbutamide (10 mg.) was given rapidly, i.v., one hour after agavage of ethanol or saline (control). Acutely, ethanol treatment caused marked inhibition of glucose-induced insulin secretion and impaired glucose disappearance rate. Tolbutamide-induced insulin secretion was also significantly inhibited, and decline in glucose was significantly less in ethanol-treated rats. In response to ethanol, serum calcium concentration significantly declined for two hours. In another study, an ethanol metabolite, acetate (0.4 micronmole/min.) or vehicle (control) was infused for 60 minutes prior to 150 mg. glucose pulse. Acetate priming significantly potentiated glucose-induced insulin secretion and also improved glucose tolerance. It is proposed that (1) ethanol in vivo acutely induces hypocalcemia, which inhibits glucose- and tolbutamide-induced insulin secretion--which, in turn, causes glucose intolerance and prevents tolbutamide-induced hypoglycemia. (2)Acetate might be the actual petentiating influence on glucose-induced insulin secretion observed several hours after ethanol treatment.

A method for studying acute insulin secretion and glucose tolerance in unanesthetized and unrestrained rats. The effect of mild stress on carbohydrate metabolism.

A technique is described for glucose infusions and for frequent sampling of small quantities of blood in unrestrained and unanesthetized small laboratory animals. Under pentobarbital anesthesia, polyethylene catheters were implanted into the jugular vein and the aorta, and distal ends were exteriorized on the back of the neck of 250-gm. rats. Five to seven days following surgery the rats regained weight and were in a normal anabolic state, despite indwelling catheters. On the day of the intravenous glucose tolerance test (ivGTT), the exterior ends of the indwelling jugular and aortic catheters were connected to specially prepared extension catheters, through which a glucose pulse was given and frequent blood samples in small quantities were collected, respectively. During the entire procedure, the animals were resting quietly, unrestrained and unanesthetized. In another group of similar rats with indwelling catheters, ivGTT was performed after they were restrained in plastic restrainers. During the ivGTT, serum glucose levels were significantly higher in the restrained rats than those observed in the control rats. The mean glucose disposal rate (K) of 2.2 +/- 0.2 was significantly slower in restrained rats than the K of 3.0 +/- 0.3 in unrestrained rats. Following the glucose pulse, insulin secretion was significantly lower in restrained rats than that observed in the unrestrained rats. These observations emphasize the importance of controlling the modifying effects of mild stress on glucose tolerance and insulin secretion.