Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0008370 (cholestasis)
 9,378 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Interleukin-2 induces profound reversible cholestasis: a detailed analysis in treated cancer patients. 258 24

Basal plasma cholecystokinin levels were measured by a bioassay using dispersed rat pancreatic acini in various digestive diseases and compared with corresponding values by CCK-8 specific radioimmunoassay. The mean basal level in healthy volunteers was 0.40 +/- 0.06 pM. The basal level in liver cirrhosis was significantly elevated to 0.92 +/- 0.14 pM. The patients with cholestasis, that is, primary biliary cirrhosis and obstructive jaundice due to choledocholithiasis, bile duct cancer or lymph node metastasis , had markedly increased basal plasma CCK-8 like bioactivities from 1.88 pM to more than 25 pM. These CCK bioactivities were not correlative with CCK immunoreactivities. It was concluded not only that basal plasma CCK in patients with bile flow disturbance were truly increased, but also that interfering substances of the bioassay might appear in the plasma of these patients.
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PMID:[Basal plasma cholecystokinin levels in digestive diseases--comparison between CCK-8 like bioactivity by bioassay and CCK immunoreactivity by radioimmunoassay]. 260 Nov 19

Patients with pancreatic cancer usually lack signs and symptoms in the early course of the disease. Even when malignancy is suspected, differential diagnosis between benign and malignant pancreatic disorders may be difficult with current methods. An increasing interest has been focused on the utility of immunological tumour markers. CEA has been widely used since the early seventies, but the results in diagnosis of pancreatic cancer have been disappointing. Tumour marker tests for CA 19-9 and CA 50 are based on monoclonal antibodies to colonic carcinoma cell lines. CA 19-9 and CA 50 are strongly expressed in most tissue specimens from pancreatic carcinomas, but are also found in normal pancreas and benign pancreatic diseases. The CA 19-9 and CA 50 antigens are shed or released into the circulation, and are found in increased concentrations in 70-80% of patients with pancreatic cancer. Also 50-65% of patients with small resectable carcinomas have elevated CA 19-9 and CA 50 levels, although very high serum concentrations usually indicate advanced disease. Slightly elevated serum CA 19-9 and CA 50 levels are seen in some patients with benign pancreatic diseases, more often in acute than in chronic pancreatitis. Elevated values are often observed in patients with benign obstruction of the common bile duct, particularly in patients with cholangitis. In patients with jaundice of hepatocellular origin, the CA 19-9 and CA 50 levels are lower than in extrahepatic cholestasis. CA 19-9 and CA 50 have better diagnostic accuracy for pancreatic cancer than CEA, CA 125, DU-PAN-2, TPA and PSTI/TATI. However, the sensitivities and specificities of CA 19-9 and CA 50 are too low for screening of an asymptomatic population. Nevertheless, CA 19-9 and CA 50 have in our experience shown to be useful complements to other diagnostic methods in symptomatic patients with suspicion of pancreatic cancer. Combinations of different markers improve the sensitivity only slightly compared to the use of CA 19-9 or CA 50 alone. Follow-up using CA 19-9 and CA 50 is a simple and sensitive way of monitoring the postoperative course of patients with pancreatic cancer, and may give a lead time of several months for a recurrence compared to conventional methods.
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PMID:Tumour markers in pancreatic cancer. 266 48

Pharmacokinetics of ornidazole, a nitroimidazole derivative, was investigated after intravenous injection in 3 groups of 10 patients with different hepatic diseases: hepatitis, noncholestatic cirrhosis and extrahepatic cholestasis. Plasma concentrations of ornidazole and its two major hydroxylated metabolites, M1 [alpha-(chloromethyl)-2-hydroxymethyl-5-nitroimidazole-1-ethanol] and M4 [3-(2-methyl-5-nitroimidazole 1-yl)-1,2-propane diol] were measured by HPLC assay. As a consequence of a decreased clearance (26% to 48%), the half-life and MRT are increased in all patients by 19% to 38% when compared with healthy volunteers. No clear difference could be established between the different groups. The volume of distribution remains the same in all patients and controls except those suffering from cancer. As previously shown in patients with severe liver cirrhosis, both metabolites accumulate in plasma as a result of decreased elimination; formation is no longer the rate-limiting step of their kinetics. This metabolite accumulation is in part due to decreased biliary excretion and to hepatocellular failure.
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PMID:Pharmacokinetics of ornidazole in patients with acute viral hepatitis, alcoholic cirrhosis, and extrahepatic cholestasis. 270 94

Immunotherapy with recombinant interleukin-2 (rIL-2) and lymphokine-activated killer cells (LAK) has become a new form of therapy that has been shown to induce remissions in patients with renal cell carcinoma and melanoma. Despite encouraging results, this form of therapy has been associated with increasing toxicity, often requiring therapy in an intensive-care unit. In this report severe intrahepatic cholestasis occurred in two patients receiving rIL-2 and LAK cells. This form of cholestasis appeared to be directly related to rIL-2 administration at a doses of 2 x 10(6) U/m2 and 3 x 10(6) U/m2 t.i.d. A liver biopsy showed moderate hepatocellular bile stasis, with lobular and portal inflammation. All other studies for potential cause of this cholestasis were negative, including studies for metastatic disease. When therapy was discontinued, evidence for cholestasis and bile stasis resolved. We conclude that rIL-2 is a drug with a potential to induce severe hepatic injury that is reversible upon cessation of therapy with rIL-2. Further care should be exercised when rIL-2 is administered to patients with abnormal liver function.
J Cancer Res Clin Oncol 1989
PMID:Severe intrahepatic cholestasis in patients treated with recombinant interleukin-2 and lymphokine-activated killer cells. 278 19

The pharmacokinetics of methotrexate (MTX) and 7-hydroxymethotrexate (7-OH-MTX) in bile, urine, and serum was studied in rats in vivo after short-time infusions of 10, 50, 250, and 1000 mg/kg MTX. All animals were anesthetized and drained of bile during experiments. The biliary secretion rate of MTX approached saturation when serum MTX levels surpassed 700-800 microM, causing a significant reduction in biliary recovery as the parent compound (49 to 32%) at MTX doses exceeding 50 mg/kg. The hepatic metabolism of MTX to the 7-hydroxy metabolite was not saturated at the doses used. Serum MTX pharmacokinetics demonstrated dose dependency, inasmuch as doses exceeding 10 mg/kg were accompanied by a reduced total body clearance (Clr) and biliary clearance (ClB). A significant finding in relation to acute hepatotoxicity reported after high-dose MTX in humans was the occurrence of cholestasis 30-90 min after drug infusion and the observation of macroscopic precipitations in the bile duct in five of six animals treated with 1000 mg/kg MTX. In these five animals, cessation of bile secretion occurred at similar bile 7-OH-MTX levels [9800 +/- 1100 (SD) microM], while the single rat that secreted bile throughout the experiment had a 5-fold lower peak 7-OH-MTX concentration in bile. Analysis of biliary precipitates formed in vivo and in vitro found 7-OH-MTX to constitute 97% and MTX 3% of the drug content of the precipitated material.
Cancer Res 1989 Nov 15
PMID:Dose-dependent pharmacokinetics of methotrexate and 7-hydroxymethotrexate in the rat in vivo. 280 82

Eighteen patients with hepatic metastases primarily from colorectal carcinoma were treated on a phase I protocol employing hepatic artery infusion (HAI) of 5-fluorouracil (FUra) and 5-iodo-2'-deoxyuridine (IdUrd) via implantable infusion pump. Patients received a 14-day continuous HAI of 300 mg/day FUra. During days 8-14 of therapy, patients received IdUrd as a separate 3-h HAI daily x 7. Treatment cycles were repeated every 28 days. IdUrd was escalated from 0.1 to 2.86 mg/kg/day x 7. Myelosuppression and stomatitis were mild and not dose limiting. Hepatotoxicity was dose limiting and similar to that reported for 5-fluoro-2'deoxyuridine alone administered as a 14-day infusion every month. One patient developed a clinical picture consistent with sclerosing cholangitis and another had biopsy-proven cholestasis and triaditis. Catheter complications occurred in 7 of 18 patients. Plasma concentrations of FUra during the 7-day continuous HAI of FUra alone were consistently either undetectable or very low (less than or equal to 0.1 microM). At level 3 (1.0 mg/kg/day IdUrd) and beyond, measurable plasma concentrations of FUra, iodouracil, and IdUrd were found at the end of the daily 3-h infusion of IdUrd. The maximum tolerated dose of IdUrd as administered in this trial is 2.2 mg/kg/day x 7 and the recommended starting dose for further clinical investigation is 1.7 mg/kg/day x 7.
Cancer Res 1989 Nov 15
PMID:Phase I trial of hepatic artery infusion of 5-iodo-2'-deoxyuridine and 5-fluorouracil in patients with advanced hepatic malignancy: biochemically based combination chemotherapy. 280 87

Serum 5-nucleotidase enzyme activity and serum sialic acid concentrations were measured in 219 pregnant women to establish the incidence of cholestasis of pregnancy and the effect of rapid fetoplacental growth on serum sialic acid level. Serum 5-nucleotidase activity increases in diseases of the liver and obstruction of the biliary tract, whereas the level of serum sialic acid, a carbohydrate component of plasma membrane and cellular glycoproteins, rises in the presence of rapidly proliferating cells such as tumors. Serum 5-nucleotidase activity did not change between the first and the third trimesters of pregnancy. The elevation of serum 5-nucleotidase activity and of alkaline phosphatase in one case most likely indicated a cholestatic effect of pregnancy, and represented an incidence of 0.45% in the women studied. Among 201 cases, we found a graded and significant increase in the mean (+/- SD) serum sialic acid concentration with progressing pregnancy, from 1.63 +/- 0.3 mmol/L at the onset of pregnancy (five to eight weeks) to 2.06 +/- 0.49 at term; in the last stages of pregnancy, some of the values may overlap with those of cancer patients. We could not find any earlier report in the literature regarding the increase in serum sialic acid level in pregnancy.
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PMID:Serum 5-nucleotidase and serum sialic acid in pregnancy. 283 8

High-dose megestrol acetate, a synthetic progestin, has been advocated recently in treating patients with metastatic breast carcinoma; no significant increase in adverse effects has been reported. This report describes a patient with jaundice and intrahepatic cholestasis after high-dose megestrol acetate therapy. This cholestatic lesion may have a pathogenesis similar to that observed with estrogens and oral contraceptives.
Cancer 1989 Feb 01
PMID:Jaundice and intrahepatic cholestasis following high-dose megestrol acetate for breast cancer. 291 22

The authors reviewed the liver histopathology and the clinical features of eight patients with liver metastases from colorectal cancer who were treated by hepatic arterial infusion chemotherapy (HAIC) via an implantable pump (Infusaid). Before HAIC, these patients had no evidence of hepatitis, and results of liver biopsies performed on three patients showed only minor morphologic alterations. All the liver tumors responded to HAIC, but all patients developed hepatitis. Clinical findings included nausea, vomiting, abdominal pain and jaundice. Serum transaminases, alkaline phosphatase and bilirubin levels were increased. Clinical observations suggested that 5-fluoro-2'-deoxyuridine (FUDR), the predominant drug given, was the hepatotoxic agent. Toxic effects were hepatocyte necrosis, steatosis, cholestasis, central vein sclerosis, and alterations in the portal triad. In addition, central vein lesions like those in veno-occlusive disease, and micronodular cirrhosis resembling that induced by alcohol, were encountered. Although individual susceptibility to FUDR appeared to vary, portal triad fibrosis was present in all eight cases and, together with central vein sclerosis and cirrhosis, appeared to be related to the dose and duration of HAIC.
Cancer 1986 Aug 15
PMID:Liver pathology following hepatic arterial infusion chemotherapy. Hepatic toxicity with FUDR. 294 Nov 40


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