Hyperbilirubinemia in an Animal Model

Cornelius, Charles

Abstract

Bolivian squirrel monkeys (Saimiri scuireus) and human patiens with Gilbert's syndrome both exhibit a mild nonhemolytic hyperbilirubinemia, marked fasting hyperbilirubinemia, reduced hepatic clearance of unconjugated bilirubin, reduced hepatic bilirubin UDP-glucuronyl transferase (UDPGT) activities, and decreased bilirubin diglucuronide to bilirubin monoglucuronide ratio in bile. This new nonhuman primate model will be studied in regards to its associated fasting hyperbilirubinemia and reduced bilirubin clearance. Any overproduction of bilirubin will be measured. Livers will be perfused simultaneously with 125I-albumin and 3H-bilirubin to determine the rates of bilirubin influx which are independent of liver mass and intracellular events such as protein binding and conjugation. Overproduction of bilirubin, if present during fasting, will be assessed through the measurement of the bilirubin daily production, heme oxygenase activities in the spleen and liver before and after Sn-heme treatment, the measurement of endogenous bilirubin excretion into bile and the quantities of the early-labeled bilirubin peaks in bile samples following the injection of H-aminolevulinic acid and H-glycine. Hepatic UDPGT enzyme kinetic studies will be perfomed in fed and fasted monkeys to determine whether a differing Vmax and Km is present in Bolivian monkeys as compared to the uneffected control strain of Brazilian squirrel monkeys. The effects of fasted serum and fatty acids on the hepatic uptake of bilirubin will also be studied in the perfused monkey liver. A variety of hypocaloric diets containing differing amounts of lipid, protein, and carbohydrates will be fed to Bolivian monkeys and compared to the results of similar studies in fasting hyperbilirubinemia previously performed in human cases of Gilbert's syndrome.