Paul G. Killenberg

Acetaminophen hepatotoxicity. An alternative mechanism.

Alcohol-fed hamsters were used to study the mechanism by which acetaminophen initiates hepatotoxicity. Animals maintained on an ethanol-containing diet (Group B) exhibited an increased mortality rate after administration of acetaminophen (400 mg/kg) as compared to control hamsters (Group A). However, in those animals in which the ethanol-containing diet had been replaced by the control diet 24 hr before receiving acetaminophen (Group C), significant protection against acetaminophen toxicity was observed as compared to control animals (Group A). This observation correlates well with the finding that Group C hamsters had higher levels of glutathione and catalase than was found in either Group A or Group B animals. It was also demonstrated that acetaminophen was oxidized by cytochrome P-450, producing acetaminophen free radical and hydrogen peroxide. The free radical in the presence of oxygen was found to generate superoxide and presumably N-acetyl-p-benzoquinone imine. Microsomal lipid peroxidation was found to be stimulated markedly in the presence of acetaminophen. The role of glutathione in protecting hamsters from acetaminophen-mediated hepatotoxicity is discussed.

Peribiliary vascular plexus in primary sclerosing cholangitis and primary biliary cirrhosis

The peribiliary vascular plexus plays an important role in physiology of bile flow. Disturbance of the microcirculation may contribute to ductal injury, but little is known about alterations in the vascular supply of small bile ducts in liver disease. Immunoperoxidase stains for vascular endothelium (Ulex europaeus, factor VIII-related antigen, CD34) were used to study the peribiliary vascular plexus in 20 cases of primary sclerosing cholangitis (PSC) and 27 cases of primary biliary cirrhosis (PBC), two diseases characterized by bile duct destruction. Normal liver from 10 autopsy cases of sudden cardiac death was used as a control. Interlobular bile ducts (20- to 80-microm diameter) were identified on AE1/AE3 immunostain; vessels adjacent to the basement membrane of these ducts were counted. Normal interlobular bile ducts had an average of 2.15 vessels per duct (range, 1.68 to 2.71). Few PBC or PSC cases had a normal number of peribiliary vessels. There was a trend toward vasopenia at higher stage, although vascular loss was noted in early stages as well. The pattern of vascular loss was different for the two diseases; in PSC, the periductal capillaries were often preserved but were pushed away from the basement membrane by concentric deposits of collagen. Small residual vessels could be identified within fibrous scars of obliterated bile ducts in PSC. In 4 stage 3 or 4 PSC cases with little bile duct injury, vessel/duct ratio approached normal levels. In PBC, vessels were obliterated in areas of granulomatous inflammation and heavy lymphocytic infiltrate around bile ducts. In conclusion, loss of peribiliary vessels is common in PSC and PBC. Vessel loss is seen in early stages and may contribute an element of ischemia to continued small bile duct loss but is probably secondary to the inflammatory process.

Alterations of chemosensory function in end-stage liver disease.

Taste and smell dysfunction has been documented in patients with both acute and chronic liver disease. The purpose of this study was to determine if chemosensory function is improved after restoration of hepatic function with liver transplantation. Nine subjects (seven women and two men) with end-stage liver disease participated in the study. Taste and smell detection and recognition thresholds were determined before and after transplantation. A significant improvement in detection of the taste of sodium chloride and the odor of phenethyl alcohol was found after transplantation. These findings may have clinical significance in food choices and nutritional status of these patients.

Medical care of the liver transplant patient

Chapter 1: Selection of Patients and Timing of Liver Transplantation Don C. Rockey Chapter 2: Evaluation of Potential Liver Transplant Recipients Mark W. Swaim Chapter 3: Fulminant Hepatic Failure Michael A. Heneghan Chapter 4: Management of Portal Hypertension and Biliary Disease Prior to Transplantation Nazia Malekkiani, Janet E. Tuttle-Newhall, and Pierre-Alain Clavien Chapter 5: Transplantation in Patients with Alcoholic Liver Disease Jeff M. Georgi Chapter 6: Psychiatric Evaluation and Care of the Liver Transplant Patient Valerie F. Holmes Chapter 7: Financial Considerations in Liver Transplantation Syvil S. Burke and Donald W. Witten, Jr. Chapter 8: Procurement and Allocation of Donor Livers R. Randal Bollinger and Michael Heneghan Chapter 9: The Transplant Operation Pierre-Alain Clavien Chapter 10: Adult-to-Adult Living Related Liver Transplantation Markus Selzner, Zakiyah Kadry, Pierre-Alain Clavien Chapter 11: Anesthesia for the Liver Transplant Patient Kerri Robertson Chapter 12: Recovery Following Liver Transplant Julie S. Tart and Judith W. Gentile Chapter 13: Rejection of the Liver Graft Bradley H. Collins Chapter 14: Vascular Aspects of Liver Transplantation Paul Suhocki, Ravi Chari, Richard McCann, and Pierre A. Clavien Chapter 15: Biliary Complications Following Liver TransplantationM. Stanley Branch Chapter 16: The Role of Histopathology in the Evaluation of the Liver Transplant Recipient Mary K. Washington and David N. Howell Chapter 17: Research in Liver Transplantation: A Cooperative Endeavor Pierre-Alain Clavien Chapter 18: Medical Problems after Liver Transplantation Paul G. Killenberg Chapter 19: Recurrence of the Original Liver Disease After Transplantation Jeffrey D. Bornstein Chapter 20: Infectious Complications and Considerations in the Liver Transplant Recipeint Barbara M. Alexander Chapter 21: Renal Function in the Liver Transplant Patient Stephen R. Smith Chapter 22: Cutaneous Problems in Liver Transplant Patients Sarah A. Myers Chapter 23: Social Rehabilitation of the Liver Transplant Patient Z. Elaine Dowdy and R. Scott Pollard Chapter 24: Pharmacology of the Immunosuppressive Drugs Used in Liver Transplantation Andrew Muir Chapter 25: Drug Interactions with Commonly Used Immunosuppressive Agents Paul G. Killenberg Chapter 26: Liver Transplantation in Children William Treem

Diurnal variation of rat liver enzymes catalyzing bile acid conjugation and sulfation

This study investigated the diurnal variation in the activity of the hepatic enzymes catalyzing conjugation and sulfation of bile acids. A circadian rhythm was noted in cholic acid : CoA ligase and glycolithocholate sulfotransferase activity. There was no diurnal variation in lithocholate sulfotransferase activity raising the possibility of multiple bile acid sulfotransferases in liver.