Characterization of Gilbert-like syndrome in squirrel monkeys (Saimiri sciureus).

Bolivian squirrel monkeys, unlike those of Brazilian origin, exhibit a marked fasting hyperbilirubinemia (FH) similar to that observed in Gilbert's syndrome in man. Since no delays in the hepatic clearance of sulfobromophthalein or indocyanine green are present, the Bolivian monkey appears to be similar to Gilbert's type I syndrome. FH can be significantly decreased by either phenobarbital or tin-protoporphyrin pretreatment. Nicotinic acid-induced hyperbilirubinemia and delayed tolbutamide clearance were not observed as in the human syndrome.

Bile acid clearance in sheep with hereditary hyperbilirubinemia.

The disappearance of IV injected [24-14C]cholic acid from plasma was studied in normal and mutant Corriedale and Southdown sheep exhibiting hereditary defects in hepatic organic anion transport. Hepatic cholic acid clearance was determined from the integral of the 40-minute disappearance curves fit to the sums of two exponential functions. Cholic acid clearance among Corriedale sheep was significantly less (P less than 0.05) for mutant sheep (8.44 +/- 0.86 SEM ml/minute/kg of body weight) than for normal sheep (12.7 +/- 0.58 ml/minute/kg). Cholic acid clearance in the Southdown mutant (1.97 +/- 0.59 ml/minute/kg) was less than 15% of normal clearance rate (13.3 +/- 2.2 ml/minute/kg). Clearance of [14C]taurocholic acid (curves fit to three exponential function) in the Southdown mutant (10.8 +/- 0.4 ml/minute/kg) was significantly greater (P less than 0.01) than cholic acid clearance, yet was not significantly different (P greater than 0.05) from normal taurocholate clearance (17.8 +/- 2.5 ml/minute/kg). Hepatic regurgitation of conjugated bile acid was not detected after [14C]cholic acid injection. Both the mutant Corriedale and Southdown sheep, which exhibited inherited defects in hepatic bilirubin transport similar to Dubin-Johnson syndrome and Gilbert's disease in man, exhibited defects in hepatic bile acid clearance.

Renal radial fibrosis in mutant Southdown sheep with congenital hyperbilirubinemia.

Kidneys from 7 mutant Southdown sheep with congenital hyperbilirubinemia, aged from 1 to 5 years were examined. Renal biopsies were taken from another mutant at 3 months and 12 months of age. At 3 months, lesions consisted of thin radial bands of myxomatous tissue in the medullary rays and atrophy of the adjacent collecting tubules. By 1 year collagen had replaced myxomatous tissue. Grossly, the kidneys were normal until 2 years when they became red and gray mottled and stained with bilirubin. The capsules stripped readily to reveal fine granular surfaces in sheep over 2 years of age. On the cut surface of the cortex were 0.5 mm wide radial gray streaks of fibrous tissue. Progressive fibrosis in sheep 2 to 5 years old resulted in a thinning of the cortex. With increasing fibrosis, the number of cystic tubules increased progressively. Protein casts and hyaline droplet degeneration were numerous in sheep over 2 years of age. Plasma cells and lymphocytes were frequently seen in the fibrous bands, and bile pigment was visible in the macrophages in the fibrous tissue and in the epithelium of the proximal tubule cells. Polyuria, low specific gravity urine and reduced effective renal plasma flow and glomerular filtration rates resulted from the replacement of specialized proximal tubule cells by low cuboidal cells, fibrous tissue separating the capillaries from the loops of Henle, destruction of glomeruli and segregation of glomeruli in fibrous bands. The kidney lesions may be determined by the same gene responsible for the hepatic excretion defect for bilirubin.