Alfred L. Baker

Application of reduced-size liver transplants as split grafts, auxiliary orthotopic grafts, and living related segmental transplants.

The University of Chicago program in pediatric liver transplantation continues actively to seek innovative surgical solutions to problems related to the management of children with end-stage liver disease. Among the most important problems facing these children is a shortage of donor organs, which results from three factors in addition to the actual supply of pediatric donors: the concentration of pediatric liver disease in the population younger than 2 years; the necessity for a graft that is small enough; and the epidemiology of accidents and other events that lead to organ donation. Transplantation using a liver lobe as a graft overcomes size disparity and shifts the available supply of organs from older donors to younger recipients. This work describes the technical aspects of recent innovations in the use of liver lobes in pediatric transplantation, simple reduced-size liver transplantation (RLT), split-liver transplantation (SLT), orthotopic auxiliary liver grafting (ALT), and transplantation using a living related donor (LRLT), and compares their results. Since November 1986 a total of 61 procedures have been performed in which a liver lobe was used as a graft: 26 RLT; 30 SLT, 25 in children and 5 in adults; 5 LRLT; and 1 ALT. Overall 62% of transplants performed in children have involved using a liver lobe as a graft. The rates of complications are somewhat higher than with whole-liver transplantation, but this may not be entirely the result of the complex procedures. Split liver transplantation is associated with the highest mortality and complication rates. Living related liver transplantation has been associated with complications in donors and recipients, but to date survival is 100%. Orthotopic auxiliary liver transplantation effectively corrected the metabolic defect in one patient with ornithine transcarbamylase deficiency. Overall the various modalities of using graft reduction have resulted in postoperative results similar to those achieved with full-size grafts, while pretransplantation mortality has been limited to less than 2%. Thus the use of grafts as liver lobes accomplishes the goal of reducing global mortality among children with end-stage liver disease, but at the cost of increased surgical complexity and more postoperative complications.

Liver transplantation, including the concept of reduced-size liver transplants in children.

Since the establishment of a clinical program in liver transplantation in 1984, 162 liver transplants have been performed in 131 patients (78 adults, 53 children). The patient mortality rate while waiting for a suitable organ has been 8% for adults and only 4% for children (25–46% reported in the literature). The low pcdiatric mortality is a result of the use of reduced-size liver transplants. A total of 14 procedures have been performed in recipients whose clinical condition was deteriorating and for whom no full-size graft could be located. Of 14 children, 13 were less than 3 years of age. Patient survival is 50%, comparable to survival of highrisk recipients of full-size livers. Using reduced-size liver grafting in a transplant program can lower mortality for children awaiting a transplant by overcoming size disparity. Reduced-size liver grafting will allow more effective use of donor resources and provide a potential avenue of research for organ splitting and living related donation.

Hepatic effects of long-term methotrexate use in the treatment of inflammatory bowel disease

Hepatic effects of long-term methotrexate use in the treatment of inflammatory bowel disease

Chaparral Ingestion: The Broadening Spectrum of Liver Injury Caused by Herbal Medications

Unconventional medical practices, including the use of herbal remedies, are prevalent in the United States. Chaparral is an herbal preparation made from a desert shrub and used for its antioxidant properties. We report the case of a 60-year-old woman who took chaparral for 10 months and developed severe hepatitis for which no other cause could be found. Despite aggressive supportive therapy, the patient deteriorated and required orthotopic liver transplantation. She is now well, more than 1 year after her transplant. This case suggests that chaparral can cause serious liver injury and fulminant hepatic failure. Herbal medications should be considered as potential causes of liver toxicity.

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.

Hepatic complications of total parenteral nutrition

Total parenteral nutrition is now widely used in the treatment of nutritional depletion. Among problems that persist in the use of this technique, the development of hepatic abnormalities has received increasing attention. In this review, the current understanding of the pathogenesis and management of liver injury during short-term total parenteral nutrition is summarized. These complications include fatty liver, cholestasis, and nonspecific triaditis. The experience with hepatic complications during long-term total parenteral nutrition is also reviewed. Evidence that progressive liver injury develops in some patients requiring lifelong total parenteral nutrition raises a serious dilemma for both patients and physicians. Better understanding of the pathogenesis is required before appropriate treatment can be prescribed.

The caffeine CO2 breath test: Dose response and route of N‐demethylation in smokers and nonsmokers

The optimal conditions for performing the caffeine CO2 breath test (CBT) were investigated in smokers and nonsmokers. Caffeine labeled with13C or 14C in all three (1, 3, and 7) methyl groups or specifically in the 1‐, 3‐, or 7‐methyl groups were orally administered to healthy adults and the expiration of labeled CO2 was measured for 8 or 24 hr. The absolute rate of labeled CO2 excretion from trilabeled caffeine was proportional to the dose up to 3 mg/kg in all subjects. In smokers, the rate of labeled CO2 excretion averaged twice that in nonsmokers at all doses. A correlation was observed between the 2‐hr cumulative CO2 excretion from trilabeled caffeine and the apparent oral metabolic clearance rate (MCR) of caffeine (r = 0.90). Monolabeled CBTs in smokers and nonsmokers demonstrated that 80% ± 4% of labeled CO2 expired in the breath during the first 2 hr of a trilabeled CBT was derived from the 3 position; at 6 to 8 hr equal amounts were derived from the 3 and 7 positions. Little N‐demethylation was observed from the 1 position at any time during the 8‐hr test. The results indicate that the 2‐hr cumulative excretion of labeled CO2 could be used to accurately predict the metabolic clearance rate of caffeine and is the best CBT parameter for detecting the effect of smoking on caffeine N‐demethylation. The data suggest that the primary routes of caffeine metabolism are 3‐N‐demethylation and ring hydroxylation and confirm that caffeine metabolites are N‐demethylated primarily in the 3 and 7 positions.

Small-bowel length and the dose of cyclosporine in children after liver transplantation

Children, particularly infants, require large oral doses of cyclosporine to achieve immunosuppression after liver transplantation. In 53 children who had received liver transplants, we examined the relation of height, weight, residual small-bowel length, and (in 17 children) the terminal plasma clearance rate of cyclosporine to the dose of cyclosporine required to achieve blood levels of 200 ng per milliliter. The required intravenous dose of cyclosporine (expressed as milligrams per day) increased steeply as body size and bowel length increased, whereas the required oral dose declined with increasing bowel length. When expressed as milligrams per square meter of body-surface area per day, the required intravenous dose did not change with body size, but the required oral dose declined with increasing body size. Small-bowel length correlated closely and inversely with the log of the oral dose of cyclosporine (r = -0.77, P = 0.0001). The rate of clearance was also related to the log of the oral dose (r = 0.57, P = 0.017) but was independent of age and size. Multiple regression analyses that included height and weight showed that only small-bowel length and the rate of clearance from plasma were independently related to the required oral dose of cyclosporine. We concluded that the length of the small bowel is the chief determinant of the required dose of orally administered cyclosporine in children after liver transplantation. Children and infants require large oral doses of cyclosporine because of the limited absorptive surface area of their intestines.

Nonalcoholic liver disease: Overlooked causes of liver injury in patients with heavy alcohol consumption

Alcoholic subjects with abnormal liver chemistry studies are often assumed to have alcoholic liver disease, even though the diagnosis is not established by liver biopsy. To determine the magnitude of nonalcoholic liver disease in patients with heavy alcohol consumption, the data on 145 consecutive patients judged to consume at least 80 g of alcohol daily for prolonged periods, and who underwent liver biopsy at the University of Chicago, were reviewed. Nonalcoholic liver disease was suspected clinically and confirmed by liver biopsy in 40 (28 per cent), whereas alcoholic liver disease was suspected in 105 but confirmed in only 83 (80 per cent). The remaining 22 patients had liver disorders, including cholangitis or pericholangitis, acute hepatitis or some form of chronic hepatitis, for which they required appropriate therapy. Neither clinical features, hepatitis B surface antigen (HBsAg), anti-HBsAg nor serum glutamic oxaloacetic transaminase to serum glutamic pyruvic transaminase (SGOT:SGPT) ratios distinguished these 22 patients from those with alcoholic liver disease. Thus, liver biopsy is necessary for the identification of nonalcoholic liver disease in patients suspected of harboring alcoholic liver disease, since other clinical features do not allow identification of these patients.

Sodium Taurocholate Modifies the Bile Acid-Independent Fraction of Canalicular Bile Flow in the Rhesus Monkey

Bile acid-independent secretion and the choleretic response to taurocholate were determined in rhesus monkeys fitted with indwelling silastic cannulas in the common bile ducts. Bile acids were infused intravenously in random order at 3.5, 7.0, or 10.5 mumol/min for 1.5 h each. When data were analyzed with a single regression line, bile flow increased in proportion to the level of bile acid secretion, although the y-intercepts (the conventional measurement of bile acid-independent secretion) varied widely (77.9+/-40.9 ml/24 h). The variation in y-intercepts was observed between animals and with repeated studies in the same animal and could not be explained by sex differences or the effects of the indwelling silastic cannulas, but seemed to be related to the order of bile acid infusion. With only two taurocholic acid infusion rates (7.0 and 3.5 mumol/min), [(14)C]erythritol clearance was greater per mole of secreted bile acid when the initial bile acid infusion was at the high level, but approached zero at low bile acid secretion rates, which suggests that so-called bile acid-independent canalicular flow is closely related to bile acid secretion or is small in size. The augmentation in [(14)C]erythritol clearance when the high infusion rate was given first was also associated with an increase in biliary clearance of [(3)H]inulin, which indicates that the premeability to inulin was also enhanced. Identical experiments which substituted equimolar infusions of a nonmicelle-forming bile acid (taurodehydrocholate) for taurocholate failed to demonstrate any difference in choleretic response or biliary clearance of [(3)H]inulin with the order of bile acid infusion. These experiments demonstrate that a micelleforming bile acid, taurocholate, can increase the permeability of the biliary system to large molecular weight solutes and simultaneously modify the y-intercept and the volume of bile secreted in response to the transported bile acid. Taurocholate may, therefore, modify its own choleretic response, perhaps by altering the structure or function of bile secretory membranes, and appears to be a major determinant of so-called bile acid-independent flow in rhesus monkeys.