Reversible Cholestasis Research Articles

Interleukin-2 induces profound reversible cholestasis: a detailed analysis in treated cancer patients.

Interleukin-2 (IL-2)-based immunotherapy is associated with profound reversible cholestasis and hyperbilirubinemia. We performed a nonrandomized retrospective and prospective analysis to determine the incidence, characteristics, clinical course, and nature of the IL-2-induced liver dysfunction in patients with cancer. Patients received IL-2 at a dose of 20,000 to 100,000 units (U)/kg thrice daily for up to 5 days. Fifty-one patients on adjuvant treatment protocols received a mean of 10.18 +/- 2.38 IL-2 doses and 11.67 +/- 4.16 doses were delivered to 210 patients with advanced disease during this period. Retrospective analysis of all patients receiving this therapy revealed increases in the following liver function tests expressed as median, 25th percentile, and 75th percentile (range): bilirubin (mg/dL) 4.5, 2.6, 6.5 (.4 to 38.5); alkaline phosphatase (U/L) 256, 179, 378 (56-1680); SGOT (U/L) 80, 52, 117 (18 to 483); SGPT (U/L) 91, 64, 132 (20-540); prothrombin time 13.4, 12.8, 14.5 (10.8 to 35.4); and albumin (g/dL) values decreased (trough) slightly 3.0, 2.8, 3.2 (2.3 to 3.8). Multiple regression analysis revealed several factors that were significantly associated with the increase in bilirubin when jointly considered (model P2 less than or equal to .001) including total IL-2 dosage, increase in creatinine, alkaline phosphatase, weight, and SGOT. Similar increases were noted in a prospectively evaluated group of 10 patients. A return to normal levels of bilirubin was noted within 5.6 days of stopping IL-2. Fasting serum cholylglycine increased from a mean of 32.3 +/- 1.6 to a peak of 1556.0 +/- 625.0 mg/mL. Although conventional ultrasound examinations were unrevealing, tissue ultrasound examinations revealed a mean scatterer spacing (MSS) increase compared to baseline of .10 +/- .04 (P less than .02) suggesting hepatic edema or an infiltrative process. Further, computerized hepatobiliary nuclear medicine scans revealed a delay in uptake (2.2 +/- 0.5 fold greater) and excretion (8.0 +/- 5.9 fold greater) of technetium-99m labeled disofenin. These findings support the development of profound reversible cholestasis as the primary basis for the elevated bilirubin in patients undergoing IL-2 treatment and may have implications for understanding the jaundice observed in some patients postoperatively as well as that associated with sepsis and other inflammatory disorders. Specifically, the release of IL-2 or the induction of other factors similarly induced by IL-2 may be responsible for these findings. Tissue ultrasound and computerized hepatobiliary scans provide additional noninvasive assessments of liver function and physiology.

Effect of chlorpromazine on hepatic transport of indocyanine green in rats

The effect of chlorpromazine hydrochloride (CPZ) on the hepatic transport of indocyanine green (ICG) was studied in the rat, in an attempt to elucidate the mechanisms of hepatotoxicity of CPZ in vivo, by comparing the pharmacokinetic parameters of ICG after bolus and chronic administration of CPZ. Delays were shown in both plasma disappearance and biliary excretion of ICG in the CPZ-treated rats (10 and 15 mg/kg intraportal bolus administration). Significant decreases were observed in the pharmacokinetic parameters, V 2 and total body clearance ( CL tot) in CPZ 10 mg/kg treated rats and k 34, V 2 and CL tot in CPZ 15 mg/kg treated rats, while a significant increase was observed in k 21 in both CPZ-treated groups; V 1 was not altered. The apparent liver-to-plasma concentration ratio ( K p,app ) of ICG at 50 min after i.v. administration was decreased significantly in CPZ 15 mg/kg treated rats when compared to control rats, suggesting an alteration in the distribution of ICG to the liver by CPZ. Bile flow rates decreased immediately after bolus intraportal administration of CPZ in both CPZ-treated groups, and they then returned progressively to the basal levels. The output of bile acids was also inhibited by CPZ in a time-dependent and reversible manner and the bile acid independent fraction of bile flow was decreased significantly in both CPZ-treated groups. Chronic treatment with CPZ (10 or 20 mg/kg, i.p., per day for 3 weeks) did not alter either the pharmacokinetic parameters or the bile secretion profile of ICG, although there were significant decreases in body and liver weights in CPZ-treated groups. This may have been due to the rapid metabolism and excretion of CPZ in the rat when compared to humans. It is proposed that the acute toxic effect of CPZ on hepatic transport of ICG in the rat may be due mainly to the time-dependent and reversible cholestasis induced by CPZ, and that chronic treatment with CPZ may not alter the hepatic transport of ICG in the rat.

Ethynylestradiol-induced impairment of bile secretion in the rat: Protective effects of S-Adenosyl-l-methionine and its implication in estrogen metabolism

Previous investigations demonstrated that S-adenosyl-l-methionine suppresses the cholestatic effect of ethynylestradiol and reduces the irreversible binding of the estrogen to rat liver microsomes, probably favoring ethynylestradiol transformation into its methyl-derivatives. Since it is not known whether SAMe also prevents the changes of bile lipid composition induced by EE and how methylation interferes with estrogen metabolism and biliary excretion, female rats have been treated with ethynylestradiol (5 mg/kg body wt, orally for 3 days) or with ethynylestradiol plus S-adenosyl-l-methionine (25 mg/kg body wt, i.m., t.i.d.). After bile duct cannulation, 5 μCi of [6,7-3H]ethynylestradiol were injected i.v., and an 8-h bile collection was started. Bile flow in ethynylestradiol + S-adenosyl-l-methionine treated rats was similar to controls, but significantly higher than in ethynylestradiol-treated animals (1.44 ± 0.11; 1.66 ± 0.30; 0.97 ± 0.17 μl/min/g liver, respectively as mean ± SE). Cholesterol molar percentage was significantly higher in ethynylestradiol (3.46 ± 0.25) than in ethynylestradiol + S-adenosyl-l-methionine treated (2.16 ± 0.41) or control rats (1.90 ± 0.30). Total radioactivity excretion was similar in all groups, ranging from 74% to 76% of the administered dose, but radiogaschromatography showed a significant increase of methylated ethynylestradiol metabolites in S-adenosyl-l-methionine treated rats. These data indicate that in ethynylestradiol treated rats S-adenosyl-l-methionine can: (a) reverse both cholestasis and related abnormalities of biliary lipids; (b) modify the pattern but not the total amount of biliary ethynylestradiol excretion.