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Ribavirin is a guanosine analogue that normalizes serum liver enzymes in most nontransplant patients with chronic hepatitis C virus (HCV) infection. We conducted an uncontrolled pilot study of ribavirin in 9 liver transplantation recipients that had persistently elevated liver enzymes, active hepatitis by liver biopsy, and HCV RNA in serum by polymerase chain reaction. Ribavirin was given orally at dosages of 800-1200 mg per day for 3 mo. All 9 patients promptly responded to ribavirin: mean (+/- SD) ALT decreased from 392 +/- 377 IU/L immediately before treatment to 199 +/- 185 and 68 +/- 37 IU/L after 1 and 12 weeks of treatment, respectively, complete normalization of enzymes occurred in 4 patients. None of the patients cleared the virus from their serum during therapy, and biochemical relapse occurred in all patients 4 +/- 4.2 weeks after cessation of therapy. The hepatitis activity index of liver biopsy specimens obtained before and at the cessation of therapy was similar. Ribavirin treatment was resumed in 4 patients because of increasing fatigue (2 patients), rising bilirubin (3), or increasing necroinflammation on liver biopsy (2); the biochemical response to the second course of therapy was similar to the first course in all 4 patients. Ribavirin caused reversible hemolysis in all patients, including symptomatic anemia in 3 patients that resolved after reduction of drug dosage. These results suggest that ribavirin may be of benefit in the treatment of HCV infection after liver transplantation. Further studies are needed to determine the optimal dosage and duration of therapy.

The University of Toronto liver transplant program began in 1985 at a time when the procedure had already evolved from an experimental form of surgery to an accepted treatment for many forms of liver failure. The program was established not only to provide clinical care for patients but also to address academically the barriers which impeded success. The program brought together experts in medicine, surgery, pathology, and the basic sciences of immunology, virology and molecular biology. Our group has had a special interest in transplantation for viral hepatitis. We demonstrated the role of HBV DNA as a prospective factor in both viral recurrence and survival. We further studied a number of agents to prevent re-infection including PGE, HBIG and more recently lamivudine. Although the short-term results of transplantation for HCV appear excellent, reinfection of the graft and development of chronic hepatitis and cirrhosis may make long-term results problematic. Therefore, we have directed attention to studies of pathogenesis and treatment of HCV in liver transplantation. Our studies have demonstrated a unique role for ribavirin as an immunomodulatory agent which can benefit the course of posttransplant HCV. Future studies will examine combination therapy in an attempt to eradicate the virus. Our group also has been interested in PNF and FHF and have demonstrated a positive effect of PGE in this setting. As we look to the future, the greatest challenges facing transplantation are the shortage of organ donors and the toxic effects of long-term immunosuppression. Our group now has established research efforts both in tolerance induction and xenotransplantation which we feel are necessary to make transplantation an effective, universal treatment for end stage organ failure.

The analyses presented in this chapter are a subset of the yearly audit of organ donation and transplantation in Canada published in the CORR Annual Report. They represent the collaborative efforts and the voluntary contributions of many of the transplant physicians, surgeons, nurses and coordinators in Canada. In Canada, organ donation has remained static at approximately 14 per million population. Despite many local and provincial as well as corporate initiatives, this rate is approximately half the current rate in many regions of the U.S.A. and Spain. The modest increases in transplant activity represent an increase in the use of living donors, reassessment of the traditional donor risk factors (including age) and expansion of the potential donors for each organ. Analysis of the renal transplant activity has determined that the likelihood of being transplanted during the first year on the list was less than 40%. A graft loss rate of 4% per year after the first year was observed for a cadaveric kidney, compared with graft loss rates of 3% and 2% per year for living-related and living-unrelated donor kidneys, respectively. Cox regressional analysis identified that the major determinants of patient survival were the transplant year, the region where the transplant was performed, the presence of diabetes, the recipient's age, and whether the kidney was from a living donor. Liver transplantation has increased each year at the transplant centers in Vancouver, Edmonton, London, Toronto, Montreal, and Halifax. Patient and graft survival rates have improved since 1985 and the most significant determinant of patient survival following transplantation was the patient's medical status at the time of transplantation. Living-related liver donor transplant programs have begun in London and Toronto. Pancreas transplantation remains limited across Canada, but with the development of new pancreas programs in Toronto and Halifax, an increase in the availability of this therapy for Type 1 diabetics is anticipated. Heart transplantation has recovered from a decline in 1991-1992 to approximately 6 hearts per million population. There has been a trend towards better one- and 3-year patient survival rates since 1985. With the development of a lung transplantation program in Winnipeg, lung transplantation has increased. This likely reflects increased utilization of the available donor lungs. A particular increase in double-lung transplants was noted.

Background: Acute pancreatitis (AP) has not been recognized as a frequent complication following orthotopic liver transplantation (OLT). Reports have suggested that this condition is associated with high morbidity and mortality rates., Study Design: A retrospective review of 354 patients who underwent OLT at the University of Toronto, with at least one-year follow-up, was done to identify the incidence, etiology, risk factors, and severity of pancreatitis following OLT, as well as to discuss its management. A possible correlation between AP and hepatitis B was also investigated. Prognostic score systems, including Ranson, Imrie, and APACHE II, were also evaluated., Results: Acute pancreatitis occurred in 5.9 percent of the OLT recipients. Based on clinical presentation and diagnostic tests, AP could be subdivided into three distinct categories: biochemical AP, significant increase of serum amylase or lipase levels in absence of objective radiologic or surgical evidence of the disease; clinical AP, pancreatitis with radiologic or surgical evidence of the disease; and AP in the critically ill patient. Biochemical AP occurred in the early postoperative period and was consistently a benign condition. Clinical AP occurred after a delay and was associated with a 40 percent mortality rate. Acute pancreatitis in the critically ill patient was only one component of multiorgan failure, which was lethal in each case. About one-half of the patients with biochemical and clinical AP were hepatitis surface antigen positive prior to OLT. The incidence of AP was significantly higher in patients with hepatitis B (17 percent) than in patients without hepatitis B (3 percent) (p < 0.01). APACHE II was the best prognostic score system in the clinical group with a positive and negative predictive value for a score equal to or greater than 10 points of 67 and 100 percent, respectively., Conclusions: Acute pancreatitis is not an uncommon complication of OLT. Clinical presentation and diagnostic tests have important prognostic values. In some patients, hepatitis B virus may play an important role. APACHE II scores appear to be useful in the evaluation of clinical AP following OLT. Treatment of AP should be similar in both the transplant and nontransplant setting.

Background: Prostaglandins are cytoprotective agents that have been shown to benefit patients with a variety of acute and chronic liver diseases. Few data exist on the frequency of adverse effects of prostaglandins in these patients., Methods: We retrospectively studied 105 patients with liver disease who were treated with either intravenous (i.v.) or oral prostaglandin E (PGE). Forty-four patients with primary nonfunction after liver transplantation and 36 patients with fulminant hepatic failure received i.v. PGE1 for 4.5 +/- 2.6 and 12.6 +/- 10.9 days, respectively. Twenty-five patients with recurrent hepatitis B viral infection after liver transplantation received oral PGE1 for 105 +/- 94 days or PGE2 for 464 +/- 399 days., Results: Twenty-six of 80 patients (33%) receiving i.v. PGE1 developed gastrointestinal and/or cardiovascular side effects and 8% developed arthritis. Twenty-three of 25 patients (92%) who received high-dose oral PGE1 or PGE2 incurred arthritis and/or gastrointestinal adverse effects. Twenty-five patients received prolonged PGE therapy (oral > 60 days; i.v. > 28 days). Of this group, 23 (92%) developed clubbing and cortical hyperostosis resembling hypertrophic osteoarthropathy. All adverse effects were dose related and resolved with reduction or cessation of therapy., Conclusion: PGE therapy resulted in a wide spectrum of multisystem adverse effects which were reversible with reduction or cessation of therapy. Although the administration of PGE was safe and generally well tolerated, close medical supervision is necessary to avoid serious side effects.

Objective: This study defined negative outcomes of solid organ transplantation, proposed a new classification of complications by severity, and applied the classification to evaluate the results of orthotopic liver transplantation (OLT)., Summary and Background Data: The lack of uniform reporting of negative outcomes has made reports of transplantation procedures difficult to interpret and compare. In fact, only mortality is well reported; morbidity rates and severity of complications have been poorly described., Methods: Based on previous definition and classification of complications for general surgery, a new classification for transplantation in four grades is proposed. Results including risk factors of the first 215 OLTs performed at the University of Toronto have been evaluated using the classification., Results: All but two patients (99%) had at least one complication of any kind, 92% of patients surviving more than 3 months had grade 1 (minor) complications, 74% had grade 2 (life-threatening) complications, and 30% had grade 3 (residual disability or cancer) complications. Twenty-nine per cent of patients had grade 4 complications (retransplantation or death). The most common grade 1 complications were steroid responsive rejection (69% of patients) and infection that did not require antibiotics or invasive procedures (23%). Grade 2 complications primarily were infection requiring antibiotics or invasive procedures (64%), postoperative bleeding requiring > 3 units of packed red cells (35%), primary dysfunction (26%), and biliary disease treated with antibiotics or requiring invasive procedures (18%). The most frequent grade 3 complication was renal failure, which is defined as a permanent rise in serum creatinine levels > or = twice the pretransplantation values (11%). Grade 4 complications (retransplantation or death) mainly were infection (14%) and primary dysfunction (11%). Comparison between the first and last 50 OLTs of the series indicates a significant decrease in the mean number of grade 1 and 2 complications. This was partially a result of better medical status of patients at the time of transplantation. Using univariate and multivariate analyses of risk factors, the best predictor of grade 1 complications was donor obesity; for grade 2 complications, the best predictor was a donor liver rewarming time of > 90 minutes, and for grade 3 and 4 complications, the best predictor was the APACHE II scoring system and donor cardiac arrest., Conclusions: Standardized definitions and classifications of complications of transplantation will allow us to better evaluate and compare results of transplantation among centers and over time, and better compare effectiveness of new therapies. Orthotopic liver transplantation still is a procedure with high morbidity that requires careful analysis of risk factors to optimize selection of patients and organ sharing.

While orthotopic liver transplantation (OLT) has become the treatment of choice for most irreversible end-stage liver diseases, its role in patients with hepatitis B (HBV) infection is controversial. A high risk of reinfection of the transplanted graft, associated with significant morbidity and mortality, has been reported. Although passive and active immunization can delay reappearance of the virus in the allograft, there is not yet an effective therapy for recurrent HBV infection in liver transplant recipients. Between October 1985 and March 25, 1991, 28 OLT in 25 patients with acute and chronic HBV infections were performed. Twelve of the patients were HBV DNA-negative, six were HBV DNA-positive, and seven were not tested prior to transplantation. Only the 19 patients surviving more than 100 days after transplantation were considered to have sufficient duration of follow-up (mean 734 days; range 500-1545) to include in analysis of recurrence. Five (26%) were free of recurrent disease at the time of last follow-up (mean 1031 days, range 526 to 1770 days. Recurrent HBV in the allograft, as defined by positive immunoperoxidase stains of biopsy sections for viral antigens, was detected in 74% (13 male, 1 female; 7 Asian, 7 white) at a mean of 134 days posttransplantation. Histological changes of viral hepatitis, first appearing an average of 157 days (range 95-326) posttransplantation, were evident in 13 of 14 with positive immunostaining. Twelve of the 14 patients were treated, on an open trial basis, with intravenous and oral prostaglandin E (PGE) because of deteriorating clinical condition. Eleven of the twelve responded to PGE with an initial drop in serum transaminases, improvement in coagulopathy and resolution of encephalopathy. One patient failed to respond and died of a myocardial infarction within 9 days of institution of therapy. Three of the eleven patients with an initial response relapsed and died in liver failure as a direct result of recurrent HBV after 13, 16, and 37 days of treatment in association with generalized sepsis. Eight of the 12 patients (67%) had a sustained favorable response to PGE therapy (mean follow-up 737 days, range 403-1545). All patients with a sustained response had accompanying improvement in histology and reduction in viral antigen staining in hepatocytes. Treatment with PGE appeared to be of benefit in recurrent HBV infection of the transplanted liver with an initial response rate of 92% and a sustained response rate of 67%.

Twenty-nine patients with hepatocellular carcinoma (HCC) underwent orthotopic liver transplantation (OLTx) at the University of Toronto. Four patients did not have cirrhosis. Of the 25 patients with cirrhosis, 19 had known or suspected HCC before OLTx. Eleven patients tested positive for the hepatitis B surface antigen (HBsAg). No patients received adjuvant chemotherapy. None of the patients have developed recurrent HCC in a follow-up of 9 to 87 months (mean: 33 months). The actuarial post-transplant survival of all patients at 3 months, 1 year and 3 years was 75%, 61%, and 46%, respectively. The survival of HBsAg-negative patients was 69% at 3 years, whereas HBsAg-negative patients had a 3-year survival of 18% (p = 0.045). These results suggest that OLTx for carefully selected patients with otherwise unresectable HCC is associated with a low risk of recurrence. HBsAg-positive patients with HCC have a high mortality, suggesting that they make poor candidates for OLTx.

The Sugiura operation has been reported to have low operative mortality, rebleeding, and encephalopathy rates when carried out in a predominantly nonalcoholic Japanese population with good liver function. A literature review of reports of the Sugiura procedure outside Japan reveals a high complication and mortality rate when it is used as an emergency procedure in patients with advanced liver disease, especially in those with alcoholic cirrhosis. Uncontrolled studies report results that differ little from the Japanese series when the operation is confined to good-risk patients in the elective situation. Our experience with the Sugiura operation supports its role in these circumstances, especially in patients with portal vein thrombosis and normal liver function. The only good prospective controlled trial has been carried out in patients with schistosomiasis and suggests that the Sugiura operation is far superior to total shunt and may have a slight advantage over the Warren shunt because of its low incidence of postoperative encephalopathy. More controlled trials are required to establish its role in good- to moderate-risk patients with alcoholic cirrhosis.

Early and accurate diagnosis and prognosis of patients with fulminant liver failure is of critical importance for optimum management. We investigated the role of transjugular liver biopsy in the management of patients with fulminant liver failure and assessed its value in comparison with the recently proposed King's College criteria. Sixty-one patients with fulminant liver failure, ages 2 to 82 yr, were retrospectively analyzed. The main outcome measures were survival vs. death or progression to orthotopic liver transplantation. Transjugular liver biopsy was successful in 60 of 61 patients, with a mean core tissue length of 2.1 cm. There were eight minor complications, all of which were managed conservatively. Biopsy specimens were evaluated for degree of fibrosis, percentage of hepatocellular necrosis and presence of bile duct proliferation, hepatocellular mitotic figures and binucleate hepatocytes for each of the 54 specimens available for analysis. In 34 of 54 patients (63%), the presumed clinical diagnosis was confirmed by transjugular liver biopsy. In 11 patients the procedure served to clarify clinical uncertainty, whereas in 9 of 54 (16.7%) the diagnosis was altered after transjugular liver biopsy. The percentage of necrosis was the only histological parameter that appeared to have significant discriminatory prognostic value, with only 2 of 19 survivors having greater than 70% necrosis. Twenty-one of these biopsy specimens were reviewed by two pathologists, and their degree of correlation for the various features was assessed. Almost perfect concordance was found between the two pathologists on the percentage of hepatocellular necrosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Background: Small hepatocellular carcinomas frequently were found incidentally during routine pathologic examinations of adult livers removed at liver transplant., Methods: Sixty-nine carcinomas of all sizes were found in 25 patients; 39 of the tumors were smaller than 1 cm in diameter, and 18 of the carcinomas in five patients were not clinically suspected. These small incidental carcinomas lend themselves to analysis of the morphologic basis of human hepatocellular carcinogenesis., Results: All of these tumors arose in cirrhotic livers. Most of the small carcinomas were multilobulated and subdivided by pre-existing fibrous septa. The surrounding capsule usually was not a true capsule. They were all well differentiated, most formed bile, Mallory bodies, or showed alpha-1-antitrypsin (A1AT) positivity. Transition from cirrhotic nodular parenchyma to areas of hyperplasia or atypical hyperplasia to well-differentiated carcinoma were common. Large cell dysplasia also was common., Conclusions: These morphologic transitions closely parallel changes seen in experimental chemical carcinogenesis. They also strongly suggest a multicentric origin of the tumors. In addition, in every instance, the lesions were multiple in the liver and involved both lobes. This latter finding has possible implications for recurrence after local surgical excision of small hepatocellular carcinomas.

We examined platelet adhesion in thirty human donor livers to determine if the degree of platelet adhesion could predict outcome of transplantation. Wedge liver biopsies were taken at the start of the donor operation (biopsy 1) and 1 hr after reperfusion in the recipient (biopsy 2). Biopsies were stained with a monoclonal antibody against platelet glycoprotein Ib and graded for platelet adhesion. Hematoxylin and eosin-stained sections were examined for polymorphonuclear leukocyte adhesion and necrosis. Platelet adhesion was much more frequent and extensive than expected in biopsy 1. Nine of 30 biopsies showed moderate or high-grade platelet adhesion. Thus in this study endothelial cell damage was present in about one-third of donors before the donor operation. The injury was not detectable by routine microscopic or clinical examination or biochemical tests. The degree of platelet adhesion in biopsy 1 predicted development of PMN adhesion and necrosis in biopsy 2 and postoperative transaminase concentrations and prothrombin times in recipients. During preservation and implantation some livers converted from low to either moderate or high grades of platelet adhesion. The grade of platelet adhesion in biopsy 2 predicted postoperative outcome as measured by transaminase and PT levels. Patients whose platelet grade converted to a higher level during preservation and implantation did not do as well as patients who remained at a low adhesion grade. These findings strongly suggest that the degree of platelet adhesion is an important determinant in assessing outcome and may provide a means of measuring the status of liver allografts prior to transplantation.

Background: Sodium retention in cirrhosis has been attributed to an imbalance between vasoconstrictive, antinatriuretic forces such as the renin aldosterone angiotensin system and the sympathetic nervous system, and vasodilatory, natriuretic agents such as atrial natriuretic factor (ANF). Patients with diuretic resistant refractory ascites may require peritoneovenous shunting (PVS) to control ascites., Methods: To study the factors responsible for the improvement in sodium homeostasis post-PVS, we compared the response to ANF infusion before and 1 month after PVS in 6 patients with massive ascites., Results: Before PVS, sodium excretion at baseline and in response to ANF infusion was blunted but became more normal post-PVS. ANF infusion post-PVS induced a significant increase in the glomerular filtration rate and filtration fraction and also in distal delivery of sodium. ANF's distal effect of increasing the fractional excretion of distally delivered sodium was present pre-PVS and was not significantly increased post-PVS. Changes in sodium handling were accompanied by a significant decrease in antinatriuretic forces (baseline aldosterone, 2079 +/- 507 vs. 647 +/- 17 nmol/L; P < 0.04) post-PVS., Conclusions: The improvement in sodium homeostasis and response to ANF infusion post-PVS appears to be associated with the decrease in antinatriuretic forces with the loss of massive refractory ascites. Thus, PVS restores the balance toward ANF responsiveness.

Organ donors are typically subject to acute hyponutrition that might affect postpreservation liver function. Livers from nutritionally supplemented rats function better after preservation than livers from fasted rats. We have developed a method to glycogenate the liver of large animals in the temporal context of a human donor liver operation and have studied the fate of glycogen stores during preservation. Starved anesthetized pigs were infused with a hexose solution (glucose, fructose or galactose) by way of the superior mesenteric vein for 3 hr. Regular porcine insulin was infused to maintain a hyperglycemic hyperinsulinemic arterial glucose clamp at 12 to 16 mmol/L. Liver biopsy specimens and blood samples were taken before infusion and hourly. At 3 hr the liver was excised, stored for 24 hr at 1 degrees C in University of Wisconsin solution and biopsied. It was then placed at 20 degrees C for 1 hr to simulate the reimplantation stage of transplantation. Glycogen and nucleotide levels were measured, and results were corrected for starch in the University of Wisconsin solution. A 20% glucose infusion produced rapid hepatic glycogenation without side effects. Greater glycogenation was obtained with 20% fructose but at the cost of lactic acidosis and a fall in pH. A combination of 15% glucose and 5% fructose produced intermediary glycogenation without significant side effects. Galactose (20%) was less efficient than glucose alone. The addition of alanine and glutamine (20 mmol/L) did not significantly improve glycogenation. Metabolism of glycogen at 1 degree C did occur. Glycogen content fell 0.15% +/- 0.05% dry weight liver per hour during cold preservation and 5.49% +/- 2.15% per hour during ischemic rewarming.(ABSTRACT TRUNCATED AT 250 WORDS)

Recent animal studies suggest that nutritional repletion may improve function of liver allografts, and the authors have found that intraportal glucose infusion in pigs produces rapid and substantial hepatic glycogenation. A controlled prospective randomized study in 32 patients was done to determine glycogen content and degradation in human livers during transplantation, and the effect of intraportal glucose-insulin infusions during the donor operation on these variables and on outcome of transplantation. Peripheral blood glucose concentrations were "clamped" at 14 mmol/L during the glucose-insulin infusion. Liver biopsies were taken at various stages of the procedure. Liver glycogen decreased 2.0 +/- 1.2 g/100 g dry weight liver (mean +/- standard error of the mean) in controls, but increased 6.8 +/- 1.8 g/100 g dry weight in glucose-infused donors. In both groups there was glycogen degradation during periods of cold preservation, anoxic rewarming, and after reperfusion with portal blood. Degradation rates were greater in the glucose-infused group than in controls in all three periods (p less than 0.05). Despite wide variation in postoperative aspartate aminotransferase (AST) levels among recipients in both groups, the difference in peak postoperative AST levels approached significance (p = 0.06). In addition, peak AST levels were closely correlated to anoxic rewarming time in both groups, but the slope of the relationship was much lower (3834 versus 734, p less than 0.01) in the glucose-infused group. Thus at anoxic rewarming times over 90 minutes, glycogenation was protective of liver function. Peak postoperative AST was significantly correlated to glycogen degradation in the cold preservation and rewarming periods in the glucose-infused group only. Intraoperative glucose infusions in humans can reglycogenate the liver, increase glycogen degradation, and improve certain outcome measures in liver transplantation.

Recurrence of hepatitis is a well-documented complication of hepatitis B liver disease, post-transplantation. It is well established also that the earliest hepatocellular change is the appearance of hepatitis B viral (HBV) markers and that the disease is rapidly progressive. In this article on 17 liver transplants in 16 HBV positive patients with long-term follow-ups (100-1234 days), the distinctive pathologic features of this disease are emphasized: the extreme viral load, the steatosis, and/or fibrosis. An attempt to quantitate the magnitude of the viral burden was made and the result was a staggering figure. In one patient, an estimated 10(18) HBV core particles were present in the liver. One of two patterns of progression were noted. In four patients in addition to the massive nuclear hepatitis B core antigen (HBcAg) and cytoplasmic hepatitis B surface antigen (HBsAg) positivity, superimposed hepatitic changes led to diffuse hepatic fibrosis (fibroviral hepatitis B); and in another six patients, extraordinary hepatocellular viral marker positivity and steatosis were the hallmarks (steatoviral hepatitis B). Steatosis is not usually considered a feature of HBV liver pathology. These results suggest that more than one type of posttransfusion recurrent hepatitis B liver disease exists pathologically.

The sonographic appearances of primary non-Hodgkin lymphoma developing in the porta hepatis in three patients soon after hepatic transplantation were reviewed. The lymphomas appeared as large hypoechoic masses encasing vital portal structures--the hepatic artery and the common bile duct--in all three cases and displacing the portal vein in two. The liver was only locally involved. All patients presented with jaundice soon after transplantation (average interval, 6.3 months). Rapid tumor progression caused hepatic infarction, necessitating retransplantation in two patients. The third patient died shortly after diagnosis. The authors believe this complication will be seen increasingly as liver transplantation becomes more common. Non-Hodgkin lymphoma should be considered when an obstructing mass is found in the porta hepatis, even when the time interval since transplantation is short.

Background and Methods: We describe a new form of hepatitis, occurring in 10 patients over a period of six years, characterized clinically by manifestations of severe hepatitis, histologically by large syncytial giant hepatocytes, and ultrastructurally by intracytoplasmic structures consistent with paramyxoviral nucleocapsids., Results: The patients ranged in age from 5 months to 41 years. The tentative clinical diagnosis before biopsy was non-A, non-B hepatitis in five patients and autoimmune chronic active hepatitis in the others. Five patients underwent liver transplantation; the others died. The diagnosis of syncytial giant-cell hepatitis was established pathologically. The liver cords were replaced in all 10 patients by syncytial giant cells with up to 30 nuclei. In 8 of the 10 the cytoplasm contained pleomorphic particles of 150 to 250 microns, filamentous strands, and particles of 14 to 17 nm with peripherally disposed spikes resembling paramyxoviral nucleocapsids. Structures resembling degenerated forms were found in the other two patients. One of two chimpanzees injected with a liver homogenate from the index patient had an increase in the titer of paramyxoviral antibodies, probably an anamnestic reaction to previous paramyxoviral infection, suggesting that a paramyxoviral antigen but not viable virus was present in the liver homogenate., Conclusions: Although further virologic studies will be required for precise classification, we believe that paramyxoviruses should be considered in patients with severe sporadic hepatitis.

Scarcity of small donors results in a high mortality rate for children on liver transplant waiting lists. To alleviate this problem, we have recently started to reduce the size of livers from older donors to use in children. In the last year, a total of 20 liver transplants were performed in 17 patients, including seven reduced-size liver transplants (RSLT) in six children. Mortality on the waiting list has been reduced to negligible amounts compared with a mortality rate of 25% before starting RSLT in patients with acute liver failure or those whose weight was less than 10 kg. Children undergoing RSLT weighed 10.8 +/- 8.5 kg compared with 20.9 +/- 20.3 for all others (NS). Cold ischemia time was significantly longer in the RSLT group (9.5 +/- 3.0 v 6.0 +/- 2.8 hours, P less than .05) as was intraoperative blood loss (9.4 +/- 9.4 v 3.0 +/- 3.5 blood volumes). There was no significant difference in postoperative aspartate aminotransferase and prothrombin time between the two groups. Four children received a RSLT as a primary procedure and three have survived with good liver function. Two patients were retransplanted with RSLT after a failed first transplant and both died of nonhepatic complications. This compares with 11 of 13 survivors in the whole liver transplant group. Causes of death in children who died after RSLT include cytomegalovirus sepsis (2) and myocardial infarction(1).(ABSTRACT TRUNCATED AT 250 WORDS)

Shunt surgery remains an important therapeutic option in the management of variceal bleeding, and both total and selective shunts have a role to play. The distal shunt is associated with a lower long-term encephalopathy rate and may yield better survival in the nonalcoholic patient; it is, therefore, the preferred shunt in the elective situation. The total shunt is technically easier to perform and more widely available; it is, therefore, preferred in the emergency situation. Ordinarily, the side-to-side and end-to-side shunts have similar outcomes; however, in patients with hepatic venous outflow obstruction and patients with intractable ascites, the side-to-side shunt should be used.

Emergency surgery should be considered one of the treatment options for the patient with acute variceal bleeding in whom the usual nonsurgical modes of therapy fail, and who is deemed fit to tolerate a major operation. A total shunt (portacaval or mesocaval) is recommended for most of these patients, although a distal splenorenal shunt might be considered for some very good risk, nonalcoholic patients who have only moderate bleeding. Devascularization procedures have a limited role in the emergency situation, but they may be useful in patients who are nonshuntable because of splanchnic venous thrombosis. The Sugiura type of operation is appropriate for the nonalcoholic patient, and esophageal transection is appropriate for the alcoholic patient with cirrhosis. Patients with end-stage nonalcoholic liver disease should also be considered for liver transplantation.

For 51 liver allograft recipients, we evaluated whether serum profiles of delta (Bd) and conjugated bilirubins (Bc) could be used to diagnose rejection during the first 30-50 postoperative days, in comparison with histology as the "gold standard." Daily measurements of aspartate aminotransferase, alkaline phosphatase, total bilirubin, Bd, and Bc were made, the last two by liquid chromatography. In 34 patients without any biochemical or histological evidence of rejection, within seven to 10 postoperative days Bd increased to greater than 40-50% of total bilirubin, while Bc decreased to less than 10%. In patients with severe rejections resulting in death, Bc increased rapidly to greater than 50%, while Bd remained less than 30%. In 24 histologically proven episodes of rejection in 17 patients there was either a rapid decrease in Bd or its persistence at 30%, plus either a steep increase in Bc, or its remaining at greater than 50% total bilirubin. Treatment of rejection resulted in a prompt reversal of these trends. Individually promising as prognostic adjuncts to existing liver-function markers, Bd and Bc also complemented each other, rendering the diagnosis of liver rejection much more incisive.

To define the relationship between portal hypertension and renal excretion of salt and water, two acute animal models of portal hypertension were investigated. In both models, it was necessary for systemic and renal hemodynamics to remain unchanged during the creation of portal hypertension so as to eliminate the effects of change in these parameters on renal excretion. In eight dogs, portal hypertension was induced by controlled tightening of a ligature around the superior hepatic vein and changes in hemodynamics were prevented by controlled i.v. titration with canine plasma. Rises in portal pressure 9.3 +/- 2.6 to 15.6 +/- 2.3 cm H2O were associated with significant decreases in urine volume 1.57 +/- 0.53 to 0.66 +/- 0.21 ml per min (p less than 0.05) and urinary sodium excretion [340 +/- 82 to 145 +/- 75 mEq per min (p less than 0.05)]. In contrast, similar experiments in five dogs in which the portal vein was partially ligated with increases in portal pressure from 8.3 +/- 0.6 to 18.6 +/- 0.5 cm H2O resulted in no change in urinary volume or sodium excretion. Acute reversible portal hypertension induced by hepatic vein constriction is associated with acute reversible retention of water and salt in the absence of changes in renal blood flow and creatinine clearance which only occur when the liver is involved and not with portal vein constriction.

The effect of PG on patients with fulminant and subfulminant viral hepatitis (FHF) was studied. 17 patients presented with FHF secondary to hepatitis A (n = 3), hepatitis B (n = 6), and non-A, non-B (NANB) hepatitis (n = 8). 14 of the 17 patients had stage III or IV hepatic encephalopathy (HE). At presentation the mean aspartate transaminase (AST) was 1,844 +/- 1,246 U/liter, bilirubin 232 +/- 135 mumol/liter, prothrombin time (PT) 34 +/- 18, partial thromboplastin time (PTT) 73 +/- 26 s, and coagulation Factors V and VII 8 +/- 4 and 9 +/- 5%, respectively. Intravenous PGE1 was initiated 24-48 h later after a rise in AST (2,195 +/- 1,810), bilirubin (341 +/- 148), PT (36 +/- 15), and PTT (75 +/- 18). 12 of 17 responded rapidly with a decrease in AST from 1,540 +/- 833 to 188 +/- 324 U/liter. Improvement in hepatic synthetic function was indicated by a decrease in PT from 27 +/- 7 to 12 +/- 1 s and PTT from 61 +/- 10 to 31 +/- 2 s, and an increase in Factor V from 9 +/- 4 to 69 +/- 18% and Factor VII from 11 +/- 5 to 71 +/- 20%. Five responders with NANB hepatitis relapsed upon discontinuation of therapy, with recurrence of HE and increases in AST and PT, and improvement was observed upon retreatment. After 4 wk of intravenous therapy oral PGE2 was substituted. Two patients with NANB hepatitis recovered completely and remained in remission 6 and 12 mo after cessation of therapy. Two additional patients continued in remission after 2 and 6 mo of PGE2. No relapses were seen in the patients with hepatitis A virus and hepatitis B virus infection. Liver biopsies in all 12 surviving patients returned to normal. In the five nonresponders an improvement in hepatic function was indicated by a fall in AST (3,767 +/- 2,611 to 2,142 +/- 2,040 U/liter), PT (52 +/- 25 to 33 +/- 18 s), and PTT (103 +/- 29 to 77 +/- 44 s), but all deteriorated and died of cerebral edema (n = 3) or underwent liver transplantation (n = 2). These results suggest efficacy of PGE for FHF, and further investigation is warranted.

The Hospital for Sick Children's initial 2-year experience with pediatric liver transplantation is reviewed. Patients are divided into high- and low-risk groups according to certain criteria. The high-risk group includes patients under 10 kg in weight, those with extrahepatic biliary atresia (EHBA), those with portal vein atresia or thrombosis, and those in hepatic coma. All others were considered low risk. Twenty-nine patients were assessed for transplantation: 18 were transplanted and 6 (21% of total referred) died while on the waiting list. Eighteen patients received 23 transplants. Of the 18 recipients, nine had EHBA, four had fulminant hepatic failure, two had tyrosinemia, one had glycogen storage disease, one had Indian childhood cirrhosis, and one had idiopathic cirrhosis. Seven of the 13 patients in the high-risk group survived (55% survival) with 1 to 23 month follow-up. Survival was significantly higher (80%) in the low-risk group (P less than 0.05). Four patients were retransplanted and two survived. Early deaths occurred from prolonged warm ischemia, recurrent portal vein thrombosis, and brain death in a patient who had been transplanted in hepatic coma. Late deaths occurred from cytomegalovirus (CMV) disease (2 patients), acute rejection (1 patient), and myocardial infarction (1 patient). The incidence of primary nonfunction was 4.3% (1 of 23) and of arterial thrombosis was 13% (3 of 23). Survival in patients transplanted for EHBA (67%) was slightly higher than it was for the rest of the group, although not as good as it was in the low-risk group.(ABSTRACT TRUNCATED AT 250 WORDS)

The use of 20- to 40-mg biopsies of rat skeletal muscle to measure protein synthesis and degradation rates in vitro was investigated and compared to that of the intact extensor digitorum longus (EDL) and soleus muscles. During incubations in oxygenated Krebs-Ringer bicarbonate buffer with glucose, insulin, 23 amino acids at 10 times rat plasma levels, and [14C]tyrosine, the specific activity of intracellular tyrosine approximated that of the incubation medium and was constant in the biopsy, the EDL, and the soleus. The rate of incorporation of tyrosine into the protein of the biopsy was constant for 3 hr and was 39 and 32% of the rates of the EDL and soleus, respectively. The rate of release of tyrosine from protein in the biopsy during incubations in buffer with glucose and cycloheximide was constant for 3 hr and was intermediate between the rates of the EDL and soleus. The effects of starvation on the in vitro protein metabolism of the biopsy were the same as on the intact muscles. The 42% decrease in synthesis and the 53% increase in degradation in the biopsy were intermediate between the changes measured in the EDL and soleus muscles. The ability of this technique to identify proportional changes in the in vitro protein synthesis and degradation rates makes this a valid technique suitable for the measurement of changes of in vitro protein metabolism using serial biopsies from larger animals, including man.

To investigate the acute effect of sustained volume expansion in patients with chronic hepatic ascites, renal and hemodynamic studies were performed on six patients receiving the peritoneovenous shunt. Within 1 hr of shunt insertion, the cardiac output rose by 20% to 60% above the preoperative level and the renal blood flow by 70% to 300%. At the same time both the plasma renin activity and serum aldosterone levels fell to a mean of 34% of the preoperative levels. The urine output increased from fourfold to 38-fold, but the sodium excretion increased in only two of the six patients. The data show that the acute effect of sustained volume expansion is predominantly on water rather than on sodium excretion. This manoeuver acutely suppressed circulating renin and aldosterone levels; however, the blunted natriuretic response suggests that other factors are involved in the sodium retention in these patients.

Vascular instability as defined by systemic hypotension and unresponsiveness to endogenous or exogenous vasoactive substances is a feature of both patients and experimental animals with obstructive jaundice. In this study, we have attempted to dissect the possible mechanisms for these abnormalities using both in vivo and in vitro methods. In vivo cumulative pressor responses (Rmax) to intravenous and intraarterial infusions of norepinephrine and angiotensin II and to intravenous infusion of angiotensin I were studied pre- and postoperatively in chronic bile duct-ligated dogs and compared to sham-operated dogs. Preoperatively, the pressor responses to the cumulative infusion of six doses of vasoactive substances in the pre-sham operated and pre-chronic bile duct-ligated dogs were not significantly different. Postoperatively, in the sham-operated dogs, there was no significant change in systemic blood pressure at 1 and 3 weeks, and only in isolated instances were significantly different pressor responses found compared to the preoperative result. In chronic bile duct-ligated dogs, the mean systemic blood pressure fell significantly from 117.2 +/- 3.1 to 107.2 +/- 3.0 mm Hg (p less than 0.01) at 1 week and remained significantly lower at 3 weeks [109.7 +/- 2.6 mm Hg (p less than 0.05)]. The Rmax to intravenous, but not intraarterial norepinephrine, was significantly decreased. In contrast, the Rmax to both intravenous and intraarterial angiotensin II infusions were significantly depressed at both 1 and 3 weeks. Similarly, the response to intravenous angiotensin I was significantly depressed. Cardiac output rose moderately in two sham-operated dogs from an average of 3.1 to 3.5 liters per min by 3 weeks associated with a decrease of 14.8% in peripheral vascular resistance.(ABSTRACT TRUNCATED AT 250 WORDS)

The results and complications in our first 23 consecutive patients receiving the peritoneovenous shunt for intractiable hepatic ascites are presented. A good initial diuretic effect was obtained in 20 of the 23 patients, with reversal of hepatorenal failure in 3 of 5 patients. The postoperative complication rate was high (74 percent). Infection, coagulopathy and complication of the underlying liver disease contributed to a mortality rate of 26 percent. Late complications were related to the primary liver disease. The 6 month survival rate was 58 percent and the 1 hear survival rate 52 percent with five patients followed up for more than 2 years. Because of the significant morbidity and mortality associated with the peritoneovenous shunt, we recommend it only for patients with massive intractable hepatic ascites whose condition is refractory to maximal medical therapy.

Biochemical data were studied in 18 patients with severe acute pancreatitis receiving lipid associated with total parenteral nutrition. The mean nonprotein energy intake was 30 kcal/kg/day, with 34-70% of the nonprotein calories as lipid. These parameters were no different between patients who survived and those who died. The mean sum of Ranson criteria was significantly higher in patients who died as compared with those who survived. Plasma triglycerides, glucose, albumin, and the amount of insulin supplementation were related to the severity of the disease and to the outcome. Persistent hypertriglyceridemia, hyperglycemia, hypoalbuminemia, and higher insulin requirements were observed in patients who died in comparison with those who survived and this appeared to be an index of fatal outcome. These abnormalities reflect in part an inability to utilize nonprotein energy, because the measured energy expenditure in relation to intake was lower in the patients who died, despite comparable intakes and expected energy expenditures.

In summary, PVS has potentially a wide variety of indications. However, it is important to remember, as described in detail in this review, that this technically rather simple procedure may result in major complications. Thus, the clinician considering to employ PVS must be fully cognizant of its limitations so that it is wisely used and not abused.

Variceal hemorrhage can be controlled by nonsurgical means in over 50% of patients. As a result, their general hepatic status can often be improved by preoperative preparation for the elective procedure. The major problem following elective end-to-side portacaval shunting is encephalopathy; it occurs in up to one half of patients who undergo this shunting procedure. Mesocaval shunting has been proposed as a better operation because of lower frequency of encephalopathy; however, the authors' experience has not confirmed this. Distal splenorenal shunting, as shown by the results of a prospective controlled trial, does have a lower frequency of encephalopathy, but the initial morbidity and mortality are higher and an improvement in the duration of survival is not yet evident.

The continent Koch ileostomy constitutes a major improvement in the quality of life for patients requiring an ileostomy. Complete continence is achieved in most patients, although the mechanisms underlying this control of fecal flow are poorly understood. Pressure studies on the pouch, the nipple valve and the outlet were preformed and results showed the presence of a high pressure zone in the nipple valve relative to the pouch. The high pressure zone maintained, even when the intra-abdominal pressure was raised or during contractions of the pouch, and most likely, contributes to continence. The pressure in the nipple valve and outlet was further intermittently increased by spontaneously occurring phasic and tonic contractions. Distention of the pouch with air caused a tonic contraction that was first recorded from the pouch and that traveled aborally along the intestinal layers of the intususcepted nipple valve and the outlet. By frequent emptying of the pouch, such contractions are avoided, and the risk of desusception of the nipple valve may be reduced.

Metabolic effects of increasing nitrogen intake during total parenteral nutrition (TPN) were studied in nine septic patients. The patients were given 5% dextrose (D5W) for 1 d. For the next 6 d they received total parenteral nutrition (TPN), at 1.35 times resting energy expenditure (REE), containing either 191 or 366 mg N/(kg.d) Non-protein calories were divided equally between glucose and lipid emulsion. Three patients were studied on both diets (n = 6 for each diet). On the high- but not the low-N diet were significant increases in protein oxidation, blood urea N, O2 consumption, and CO2 production. TPN normalized most plasma amino acid levels but intramuscular amino acids remained unchanged. Transient positive N balance occurred during days 1-3 on the high- but not the low-N intake; on days 5-6 N balance did not differ significantly from zero on either diet and the improvement (165 mg N/[kg.d]) was the same for both diets.