Thyroid hormones and the hepatic handling of bilirubin. II. Effects of hypothyroidism and hyperthyroidism on the apparent maximal biliary secretion of bilirubin in the Wistar rat.
This study was undertaken in the Wistar R/A Pfd rat to investigate the effects of hypothyroidism and of hyperthyroidism on the maximal biliary excretion (Tm) of bilirubin and on the concentration and composition of bilirubin in liver and plasma at the end of a bilirubin load. Hypothyroidism caused a cholestatic condition with a 50% decrease in bile flow and in bilirubin Tm, and with an increased proportion of conjugated bilirubin in liver and plasma. This was associated with an increased ratio of bilirubin diconjugates to monoconjugates in bile, liver, and plasma, which can be ascribed to the increased hepatic conjugation activity towards bilirubin and/or to the prolonged retention of bile pigments in the hepatocytes with increased conversion of monoconjugates to diconjugates. Cholestasis induced by hypothyroidism was further characterized by a decreased biliary output of unconjugated bilirubin. The latter phenomenon might represent an indirect effect related to a decreased output of bilirubin monoconjugates with impaired hydrolysis to unconjugated bilirubin; it might also reflect the cholestatic condition with decreased excretion of the unesterified bile pigment as such. Hyperthyroidism resulted in a 1.3-1.4-fold increase in bile flow. The maximal bilirubin concentration in bile decreased 1.3-1.4-fold, so that the apparent maximal bilirubin excretion rate remained unchanged at 115 nmol.min-1.100 g-1, as observed in untreated rats. Hyperthyroidism lowered the bilirubin UDP-glucuronosyltransferase activity, produced a decreased ratio of bilirubin di- to monoconjugates in bile and plasma, and a decreased ratio of conjugated to total bile pigment concentration in liver and in plasma. Similar findings are present in the heterozygous Gunn rat strain and in patients with hepatic bilirubin UDP-glucuronosyltransferase deficiency. We therefore propose the hyperthyroid rat as an experimental animal model of Gilbert's syndrome.
Van Steenbergen
W
W
Department of Medical Research, U.Z. Gasthuisberg, Leuven, Belgium.
Fevery
J
J
De Groote
J
J
D000818:Animals; D001652:Bile Ducts / Q000378:metabolism*; D001663:Bilirubin / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D006980:Hyperthyroidism / Q000503:physiopathology*; D007037:Hypothyroidism / Q000503:physiopathology*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013965:Thyroidectomy; D013974:Thyroxine / Q000494:pharmacology*
D013974:Thyroxine; D001663:Bilirubin