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Energy expenditure, whole body substrate oxidation rates and arterial substrate concentrations were measured in 14 patients with liver cirrhosis and 13 control subjects before and during sequential infusions of a long chain (LCT) or a medium chain triglyceride emulsion (MCT) without and with concomitant insulin plus glucose infusions. Resting energy expenditure, basal substrate oxidation rates and the arterial concentrations of glucose, lactate, triglycerides and ketones were normal, whereas plasma free fatty acids and glycerol were both increased in patients with liver cirrhosis. The arterial plasma triglyceride and free fatty acid concentrations as well as whole body lipid oxidation rate rose in response to LCT in both groups and the maximum lipid oxidation rate was 1.1 or 1.3 mg/kg fat free mass x min in controls and in cirrhotics, respectively (n.s.). Concomitantly, glucose oxidation rate fell to 65% of basal values in controls (p < 0.01), but remained nearly unchanged in the cirrhotic group (89% of the basal value; n.s.). The increase in plasma ketones was reduced to 67% of control values in liver cirrhosis (p < 0.01). Only a slight effect on energy expenditure was observed in both groups. When compared to controls, liver cirrhosis impaired insulin-induced increases in glucose disposal (-30%, p < 0.01) and in non oxidative glucose metabolism (-93%, p < 0.01). Concomitantly, normal increases in energy expenditure, glucose oxidation rate and the arterial plasma lactate concentrations and normal decreases in lipolysis, lipid oxidation and ketogenesis were observed in patients with liver cirrhosis. When lipids were given together with glucose, energy expenditure and lipid oxidation increased in controls, but glucose was the preferred fuel oxidised and lipid-induced thermogenesis was reduced in the cirrhotic group. Using a 50% MCT-emulsion, plasma free fatty acid concentrations further increased, but energy expenditure and lipid oxidation remained unchanged in both groups and further increases in plasma ketones were only observed in controls. Infusing glycerol in a subgroup of patients showed no thermogenic effect and a reduced glycerol clearance in liver cirrhosis.

Insulin-induced glucose metabolism was investigated in 26 patients with biopsy-proven liver cirrhosis and 10 control subjects. Two glucose clamp protocols together with continuous indirect calorimetry were performed to examine whether reduced rates of glucose oxidation and/or nonoxidative glucose metabolism explain insulin resistance in liver cirrhosis. Using a 4-hour, two-step protocol (0-2 hours, plasma glucose 5.2 mmol/L, plasma insulin 92 mU/L to test the half-maximum response; 2-4 hours, hyperglycemia 10.0 mmol/L, plasma insulin 442 mU/L to test the maximum cellular glucose disposal) liver cirrhosis reduced glucose disposal to 45% and 60% of control values, respectively. Simultaneously, insulin-induced increases in glucose oxidation, plasma lactate levels, and lipogenesis were normal, whereas nonoxidative glucose metabolism was reduced (-82% and -47% of controls, respectively). To determine whether reduced nonoxidative glucose metabolism was caused by reduced glucose disposal, glucose disposal was "matched" to normal values in a subgroup of cirrhotic patients. Nonoxidative glucose metabolism values were normal, but plasma lactate concentrations disproportionally increased (+96%) after "matching" glucose disposal. Insulin resistance was independent of the etiology of the cirrhosis, the biochemical parameters of parenchymal cell damage and liver function, and the clinical and nutritional state of the patients. It is concluded that liver cirrhosis impairs insulin sensitivity and maximum cellular glucose disposal. Reduced glucose disposal is caused by defective glucose storage. Insulin resistance is independent of the etiology of liver cirrhosis and of the clinical and nutritional state of the patient.

Many clinicians subjectively feel that cirrhotic patients frequently have clinical signs of hypermetabolism. However, it is unknown whether hypermetabolism is a constant feature of chronic liver disease, corresponds to liver destruction and repair or is of prognostic value. This article is about resting energy expenditure and substrate oxidation rates in 123 patients with biopsy-proven cirrhosis differing with respect to cause, duration of the disease, biochemical parameters of parenchymal cell damage, cholestasis, liver function, number of complications, clinical staging and nutritional state. Resting energy expenditure varied between 1,090 and 2,300 kcal/day and differed from the predicted values in 70% of the patients. Resting energy expenditure was closely related to fat-free mass, and 52% of the variability could be explained by fat-free mass, age and sex. Of all the patients, 18% were hypermetabolic and 31% were hypometabolic. Hypermetabolism showed no strict association with the cause of cirrhosis, the duration of the disease, liver function, cholestasis, cell damage, clinical staging, blood hemoglobin, plasma thyroid hormone levels or human leukocyte antigens. An increased resting energy expenditure was associated with significant losses of muscle, body cell mass and extracellular mass at unchanged body fat, whereas fat and fat-free mass were increased in hypometabolic patients when compared with normometabolic patients. Lipid oxidation was increased, but glucose oxidation was reduced in nearly all patients with cirrhosis. This was most pronounced at advanced stages of liver disease. Although similar with respect to liver function and clinical staging, 76.2% of hypermetabolic patients had transplants within the observation period, compared with only 16.7% and 8.1% in the normometabolic group and hypometabolic group, respectively. Posttransplantation mortality was independent of pretransplantation resting energy expenditure, but it increased significantly in patients with losses in body cell mass. In conclusion, hypermetabolism is not a constant feature of cirrhosis and results more from extrahepatic than from hepatic factors. It may cause malnutrition and contributes to the clinical outcome of patients with chronic liver disease.

The aim of this prospective study was to examine the usefulness of flow-dependent dynamic liver function tests and conventional methods of evaluating liver function as predictors of pretransplant survival in patients with advanced cirrhosis. Patients who underwent orthotopic liver transplantation within the follow-up period of 365 days were excluded. One hundred one patients with histologically confirmed cirrhosis were studied. Fifty-eight patients had post-hepatitic cirrhosis, 13 had cryptogenic cirrhosis and 30 had biliary cirrhosis. During follow-up, 28 patients died of their liver diseases. At entry, we recorded indocyanine green half-life, monoethylglycinexylidide formation from lidocaine, bilirubin and albumin serum concentrations, activities of cholinesterase and alkaline phosphatase, prothrombin time, clinical complications of ascites and encephalopathy and the Pugh score. These variables were subjected as covariates to a stepwise survival analysis by use of the Cox proportional-hazards model. At the final step, Pugh score, monoethylglycinexylidide formation and indocyanine green half-life were found to be the only independent variables significantly related to 1-yr survival. The parallel combination of Pugh score and monoethylglycinexylidide test yielded the highest prognostic sensitivity (82%). The series approach combining either the Pugh score and indocyanine green test or the monoethylglycinexylidide and indocyanine green tests was associated with the highest specificity (96%/97%) and high predictive values of a positive result (81%/82%). These findings suggest that appropriate combinations of the studied flow-dependent dynamic liver function tests and the Pugh score could be useful in improving transplant candidate selection and the timing of transplantation.

Liver transplantation in HBs-antigen (HBsAg) positive allograft recipients is associated with a high risk of HBV recurrence some time after surgery. So far, results of measures to prevent recurrent HBV-infection by means of treatment with interferon, hepatitis B vaccination and short-term passive immunization with hepatitis B immunoglobulin (HBIg) or monoclonal antibody to HBsAg (anti-HBs) have been disappointing. In the present study the results of long-term, anti-HBs monitored passive immunization with HBIg is reported. In 23 HBsAg-positive liver transplant recipients an anti-HBs level of greater than or equal to 100 IU/l was maintained for 6 or 12 months, respectively. The rate of recurrent infection was found to be less than 20% under HBIg substitution, whereas 11 graft recipients with no or only short-term HBIg prophylaxis were reinfected by month 15 after transplantation. HBV recurrence was associated with chronic liver disease and recurrent cirrhosis in the allograft.

The objective of this prospective study was to assess the prognostic value of dynamic liver function tests and traditional methods of evaluating liver function in potential candidates for hepatic transplantation. Patients who underwent orthotopic liver transplantation within the follow-up period of 120 days were excluded. The study included 107 adult and 57 pediatric patients with cirrhosis. Postnecrotic cirrhosis was present in 107 and biliary cirrhosis in 57 of 164 patients. During the follow-up period, 26 of 164 patients died of their liver disease. At the time of inclusion, we recorded monoethylglycinexylidide (MEGX) formation from lidocaine, indocyanine green (ICG) half-life, bilirubin and albumin serum concentration, activity of cholinesterase and alkaline phosphatase, prothrombin time, the clinical complication of ascites, and--in adults--the Pugh score also. These variables were subjected as covariates to a survival analysis (Cox proportional hazards regression model) using separately the data from adults, pediatric patients, all patients with postnecrotic cirrhosis, and all patients with biliary cirrhosis. In all of these four subgroups there was a significant relationship between MEGX and ICG test results and the 120-day survival. In the stepwise analysis, none of the remaining parameters contributed to a further relevant improvement of our predictive ability when added to the values of ICG and MEGX. Our results suggest that the ICG and the MEGX test are superior to conventional liver function tests and the Pugh score in assessing short-term prognosis in cirrhotics independently from the etiology of the underlying liver disease. These findings may have important implications for determining the optimum timing of transplantation.

A method for rapid assessment of hepatic function in cirrhotics based on the formation of the lidocaine metabolite, monoethylglycinexylidide (MEGX), was evaluated. The formation kinetics and urinary excretion patterns of MEGX clearly distinguished cirrhotics (n = 12) from healthy volunteers (n = 16). In a prospective study, we compared the prognostic value of the MEGX test with that of traditional parameters in transplant candidates. Patients who underwent transplantation during follow-up were excluded. The study included 58 adult patients with biopsy-proven posthepatitic or biliary cirrhosis. During the follow-up period of 120 days, 10 of 58 patients died of their liver disease. At the time of inclusion, we recorded MEGX formation, indocyanine green (ICG) half-life, caffeine clearance, and the Child-Pugh score. These variables were subjected as covariates to a survival analysis (Cox proportional hazards regression model). The results of the MEGX and the ICG test were significantly related to the 120-day survival. In the stepwise analysis, none of the parameters evaluated contributed to a further significant improvement of our predictive ability when added to the values of ICG (improvement: p less than 0.0005) and MEGX (improvement: p less than 0.0005). These findings suggest that the ICG and MEGX tests were the best short-term prognostic indicators. The easy handling favors the MEGX test over the ICG test as a tool for assessment of hepatic function and short-term prognosis in transplant candidates with cirrhosis.

For the evaluation of certain differences in the diminution of export proteins of the liver we examined some exactly defined groups of liver diseases with the aim of further differentiation of the pathogenetic mechanisms. We measured the activity of glutamate-oxalacetate transaminase, glutamate-pyruvate transaminase, glutamate dehydrogenase, lactate dehydrogenase, alkaline phosphatase, cholinesterase and lecithin-cholesterol acyltransferase, the Quick value, the coagulation factors I, II, V, VII, VIII, IX and X. Clotting factors were determined by a Schnitger-Gross Coagulometer. Prothrombin, antithrombin III, plasminogen, factor VIII associated antigen and activated factor XIII were measured by immunoelectrophoresis according to Laurell. Lipoprotein electrophoresis in agarose gel was performed to evaluate changes in lecithin-cholesterol acyltransferase activity. Except of the rising diminution of export proteins in the course of liver disease from acute hepatitis to cirrhosis we found also specific changes of the patterns of the plasma specific enzymes. These proteins were diminished dependent on their half life time and the inflammatory activity--measured as the height of the transaminases. Lecithin cholesterol acyltransferase and factor VIII did not participate in the general diminution of the most export proteins; some details were found to explain this differing behaviour. Results are critically discussed with regard to new aspects in the biochemistry of the damaged liver cell.

The introduction of liver transplantation as a therapeutic procedure in the treatment of chronic liver disease has accelerated efforts to establish objective criteria in the evaluation of the prognosis of chronic liver disease. Evaluation of the optimum time for liver replacement involves the estimation of the spontaneous prognosis and the possible prognosis after transplantation. Because both items develop dynamically in different directions, criteria for the best time for the indication of liver transplantation are controversial; clinical deterioration of the patient seems to mark the beginning of this time even if the dynamic process of the evolution of clinical complications are taken into account. The change in biochemical parameters is more likely to define the end-point of this period when transplantation could be performed with reasonable success. The development of scores from multivariate statistical analyses has to include the aetiology of the underlying liver disease, but also the specific dynamics of the course of the disease. If these presumptions are fulfilled, the use of such scores seems to be a great step forward to the goal of objective criteria to define the optimum time for liver transplantation.