title: Interleukin-2 induces profound reversible cholestasis: a detailed analysis in treated cancer patients.
abstract: 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.
authors.affiliation: Surgery Branch, National Cancer Institute, Bethesda, MD 20892.
authors.forename: B
authors.initials: B
authors.lastname: Fisher
authors.forename: A M
authors.initials: AM
authors.lastname: Keenan
authors.forename: B S
authors.initials: BS
authors.lastname: Garra
authors.forename: S M
authors.initials: SM
authors.lastname: Steinberg
authors.forename: D E
authors.initials: DE
authors.lastname: White
authors.forename: A M
authors.initials: AM
authors.lastname: DiBisceglie
authors.forename: J H
authors.initials: JH
authors.lastname: Hoofnagle
authors.forename: P
authors.initials: P
authors.lastname: Yolles
authors.forename: S A
authors.initials: SA
authors.lastname: Rosenberg
authors.forename: M T
authors.initials: MT
authors.lastname: Lotze
mesh_terms: D001663:Bilirubin / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury; D002779:Cholestasis / Q000139:chemically induced*; D006000:Glycocholic Acid / Q000097:blood; D006801:Humans; D007376:Interleukin-2 / Q000009:adverse effects*; D008107:Liver Diseases / Q000000981:diagnostic imaging; D008111:Liver Function Tests; D009369:Neoplasms / Q000188:drug therapy; D011446:Prospective Studies; D011877:Radionuclide Imaging; D012044:Regression Analysis; D012189:Retrospective Studies
chemical_list: D007376:Interleukin-2; D006000:Glycocholic Acid; D001663:Bilirubin