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)

The effects of postoperative infusion of a hypertonic glucose solution on the blood glucose level, blood ketone body ratio (acetoacetate/beta-hydroxybutyrate), and plasma alanine and proline levels were studied in 70% hepatectomized rabbits (group A) and in rabbits 70% hepatectomized and, in addition, subjected to bile duct obstruction at 12 h after hepatectomy (group B). Glucose infusion was started at the end of hepatectomy and continued for 20 h. The blood glucose level in group A remained at approximately 300 mg/dl throughout the study; however, it reached 789 mg/dl in group B at 20 h. The blood ketone body ratio, which reflects hepatic mitochondrial redox potential, decreased from 0.90 +/- 0.09 in untreated rabbits to 0.38 +/- 0.05 in group A, and to 0.19 +/- 0.03 in group B at 20 h. As the blood ketone body ratio decreased, plasma proline and alanine levels increased rapidly (proline, r = -0.601, p less than 0.02; alanine, r = -0.640, p less than 0.001). In addition, the blood ketone body ratio was positively correlated with the hepatic energy charge level [(ATP + 0.5 ADP)/(ATP + ADP + AMP)] (r = 0.57, p less than 0.001). It is suggested that the entry of glucose and amino acids into the Krebs cycle is inhibited as the blood ketone body ratio decreases, and under such conditions the infused glucose tends to accumulate, resulting in severe hyperglycemia.
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PMID:Changes in blood glucose levels in relation to blood ketone body ratio following hypertonic glucose infusion in 70% hepatectomized rabbits. 646 65

Numerous factors are known to increase or decrease drug-induced liver injury. The aim of this study was to test the effect of cholestyramine. Cholestyramine, and anion exchange resin binding in the gut substances taken up and metabolized by the liver such as bile salts, vitamins, endotoxins, etc., could indirectly modify drug-induced toxicity. Two groups of animals were studied: cholestyramine-fed and pair-fed controls. Five days after feeding, carbon tetrachloride or corn oil was injected intraperitoneally. Liver function and histology were normal after corn oil injection in both groups. One day after carbon tetrachloride injection liver weight/body weight ratio was lower in the cholestyramine-fed than in the pair-fed group (4.0 +/- 0.4 mean +/- SD vs. 4.4 +/- 0.3, p less than 0.05). Alanine and aspartate aminotransferases were lower (618 +/- 782 IU and 242 +/- 147 IU vs. 8245 +/- 8189 and 1966 +/- 1524 IU, p less than 0.001), as was necrosis (p less than 0.05). Steatosis and inflammatory reaction were similar in both groups. Two and four days later there were no significant differences between the two groups, because necrosis was no longer a major feature in the pair-fed group. Similar experiments were performed with bromobenzene. Here too cholestyramine prevents necrosis but to a much lesser extent. These results confirm that steatosis and necrosis are independent toxic effects of carbon tetrachloride. Cholestyramine, a widely used drug in cholestasis, could provide a potentially clinically important hepatocellular resistance to toxicity from environmental agents.
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PMID:Decreased acute hepatotoxicity of carbon tetrachloride and bromobenzene by cholestyramine in the rat. 725 Jun 39

The clinical and pathological features of 14 cases of acute drug-induced liver disease (DILD) were analyzed using the French group method for drug reaction assessment. Among them, 8 were of the cytotoxic type, 4 were of the cholestatic type and 2 were of the mixed type. Serum alkaline phosphatase (ALP) levels of the cytotoxic type DILD were all < 1.8 times the normal value, while those of the cholestatic type DILD > 1.8 times (P < 0.05). The alanine aminotransaminase and aspartate aminotransaminase (ALT and AST) levels of the cholestatic type were all < 13.1 times the normal value, while those of the cytotoxic type varied from 2.2 to 118 times the normal value. We found that steatosis was the major feature in the cytotoxic type with ALT and AST < 2.5 times the normal value. Piecemeal necrosis was noted only in all the cases with ALT and AST > 20 times the normal value. In the cholestatic type, the pathological features of the oral contraceptive-related DILD showed mainly cholestasis, whereas chlorpromazine-related DILD revealed additional portal inflammation. Meticulous taking of patient history and clinical assessment are mandatory for the diagnosis of DILD. The ALP levels were helpful in distinguishing different types of DILD. There are some correlations between biochemical changes and pathological features, and both are helpful in distinguishing different etiologies of DILD when the inciting drug is in doubt.
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PMID:Drug-induced liver disease--a review of 14 cases. 760 56

Receiver operating characteristic (ROC) analysis was used to determine the strength of the serum chemical parameters alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase (GGT), total bilirubin, conjugated bilirubin, and the ratio of delta bilirubin to conjugated bilirubin as tests of acute cellular rejection in liver transplant patients. The study consisted of 70 liver biopsies performed between February 1989 and January 1992 on 37 transplant patients who were classified as showing either no rejection (35 biopsies) or moderate to severe rejection (35 biopsies); mild cellular rejection biopsies were not included in this study to highlight any differences between rejectors and nonrejectors. Corresponding serum values for liver enzymes, alkaline phosphatase, GGT, and bilirubin fractions were obtained on the morning of the biopsy. ROC analysis demonstrated that there is no single chemical parameter or combination thereof that can statistically or clinically distinguish patients with acute rejection from those with other etiologies of allograft dysfunction. We also assessed by regression analysis the correlation between histologic features in the biopsies and corresponding serum parameters. The degree of histologic cholestasis was compared with the same-day serum value for total bilirubin, alkaline phosphatase, and GGT. The degree of centrilobular necrosis and the number of apoptotic cells were compared with values for aspartate aminotransferase and alanine amino-transferase. There was no correlation between the serum values and histologic abnormalities. We conclude that serum chemistry values are not good tests for rejection or histologic abnormalities in the liver transplant population; liver biopsy should therefore be performed on a scheduled basis.
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PMID:Receiver operating characteristic analysis of serum chemical parameters as tests of liver transplant rejection and correlation with histology. 788 3

A distinct clinical syndrome of cholestasis and hepatitis occurred during early infancy in seven infants with perinatally acquired human immunodeficiency virus 1 infection. In five infants hepatitis was the first manifestation of human immunodeficiency virus 1 infection. The median age of onset of hepatitis was 7 months (range, 5 to 10 months). The mean total bilirubin concentration at presentation was 7.4 mg/dl (range, 3.9 to 11 mg/dl), the mean aspartate aminotransferase was 1512 IU/liter (range, 782 to 2960 IU/liter) and the mean alanine amino-transferase 512 IU/liter (range, 92 to 1247 IU/liter). The absolute CD4 count at the time of onset of hepatitis ranged from 191 to 2298 cells/mm3 (mean, 766 cells/mm3). Six of the seven children died within 12 weeks of onset of hepatitis, three as a result of complications of Pneumocystis carinii pneumonia, and two died of complications secondary to cytomegalovirus. In only one infant was the cause of death the direct consequence of liver failure. The seventh infant died 17 months after the onset of hepatitis of dilated cardiomyopathy. No specific etiologic agent has been identified as the cause of cholestatic hepatitis in these infants. In situ hybridization studies to detect human immunodeficiency virus 1 messenger RNA was negative in the liver tissue obtained at biopsy and autopsy in five of the samples tested.
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PMID:Cholestatic hepatitis in children infected with the human immunodeficiency virus. 810 98

Aluminium accumulates in the livers of patients receiving either parenteral nutrition or haemodialysis. When given parenterally to rats, aluminium causes cholestasis. However, the mechanism of hepatic aluminium uptake and the fate of aluminum in the liver are poorly understood. We examined the effect of parenteral aluminium administration on biliary excretion of transferrin, the major circulating aluminum-binding protein. Male Wistar rats were given parenterally aluminum 5 mg/kg/day for 1-14 days. Bile was collected for 3 hr at the end of the study period. Biliary total protein concentration and IgA/total protein were unaffected by up to 14 days of parenteral aluminium administration. However, biliary transferrin excretion increased with duration of aluminum administration up to five-fold by day 14. Biliary transferrin concentration and transferrin/total protein was higher in aluminum treated rats than controls after 7 and 14 days of study. Hepatic aluminum concentration reached a maximum after 4 days of parenteral aluminum administration, at which time serum bile acid and alanine amino transferase values were not different from controls. Since biliary transferrin is normally derived from the serum, it is likely that aluminum promotes hepatocellular uptake of transferrin and that aluminum enters the hepatocyte bound to transferrin. We postulate that transferrin may direct aluminum to intracellular sites where its toxic effects would be minimized.
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PMID:Increased biliary transferrin excretion following parenteral aluminium administration to rats. 836 48

Two siblings presented with neonatal cholestasis and early liver insufficiency. The older was admitted for end-stage cirrhosis with severe hypoglycemia and had long-term successful liver transplant at the age of 15 months. The second child presented a similar neonatal history of cholestasis, hypoglycemia, hyperlactacidemia, liver insufficiency and progressive cirrhosis. Extensive work-up excluded all known causes of neonatal cholestasis. Gluconeogenesis was found normal following alanine and fructose infusion. Repeated hypoglycemia with early post-prandial hyperlactacidemia led us to investigate the mitochondrial respiratory chain enzyme activities. Selective defects of complexes I, III and IV, coded by mitochondrial DNA, were detected in liver tissue of this patient and on preserved frozen tissue from his sibling, whilst normal activities were found in liver tissue samples from control patients with end-stage liver diseases. No extrahepatic manifestations were found. We conclude that liver deficiency of mitochondrial respiratory chain enzymes may cause liver disease in neonates, associated with hypoglycemia and post-prandial hyperlactacidemia. The disease is cured by liver transplantation.
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PMID:Mitochondrial respiratory chain defect: a new etiology for neonatal cholestasis and early liver insufficiency. 855 Sep 93

Clinical observations indicate an increased number of post-operative complications and deaths in jaundiced patients. The patient may require some simultaneous treatment of concomitant ailments, among which cardiovascular diseases occur rather frequently. Some of the drugs administered then, like digoxin, are, in spite of being predominantly eliminated via the kidneys, metabolized in the liver, secreted into the bile or participating in the enterohepatic circulation. The changed pharmacokinetics of such drugs, in the case of mechanical jaundice, may be due to an altered liver status which can affect the function of the kidneys. The aim of the study was to evaluate the pharmacokinetics of digoxin administered both intravenously and into the stomach, in the state of mechanical, extrahepatic cholestasis. The study was carried out on male rabbits, divided randomly into four groups: the first two (experimental and control) were administered digoxin intragastrically and the next two groups (experimental and control)-intravenously (Tab. 1). The animals of the experimental groups had the bile ducts ligated, whereas the controls were sham-operated on. Digoxin was given to all the animals 4 days before the operation and 6 days after the surgery, in a dose of 0.02 mg/kg. Blood samples were collected ten times for 24 hours after the drug administration. Digoxin concentrations were determined by FPIA method, and pharmacokinetic parameters were calculated by the two compartment open model for intragastric drug administration, and by the noncompartmental analysis for intravenous route. The levels of serum total bilirubin, creatinine, urea, glucose, albumin and activities of alanine, aspartate aminotransferases and alkaline phosphatase were estimated in all of the animals. The rabbits were sacrificed at the end of the study i.e. on the 7th day after the operation. The kidneys and the livers were weighed and examined macro- and microscopically. The laboratory tests as well as the anatomopathological investigations showed the symptoms of cholestasis and the hepatorenal syndrome (Tab. 2, 3). The blood serum concentrations of digoxin, both after intragastric and intravenous administration, were statistically higher during the whole observation period in the animals with obstructive cholestasis versus the controls (Tab. 4, 6). There were no significant alterations of digoxin parameters in the animals of the control groups, measured prior to and after the surgery. In the jaundiced animals, however, most of the pharmacokinetic parameters were markedly changed as compared with the preoperative values. In the rabbits which were given digoxin intragastrically, an increase in area under the plasma concentration-time curve (AUC) and in the peak concentration of the drug (Cmax) was noted (Tab. 5). Besides, the prolongation of mean residence time (MRT) and decrease in total body clearance (Cl) as well as apparent volume of distribution (Vz), were observed, as compared to the sham-operated controls. After the intravenous administration the following changes took place (Tab. 7): an increase in AUC, the prolongation of elimination half-life (t1/2 lambda z) and decrease in the total body clearance. All the above differences were statistically significant. Thus, digoxin, a drug predominantly eliminated via the kidney undergoes an impaired elimination in obstructive cholestasis. Basing on the results of the present study, the following statements could be expressed: (1) experimental, extrahepatic jaundice alters the pharmacokinetics of digoxin given intragastrically as well as intravenously; (2) the administration of therapeutic dose of digoxin in the state of mechanical jaundice may lead to its overdose; (3) obstruction of the common bile duct should indicate the necessity of monitoring the serum concentration of digoxin; (4) extrahepatic cholestasis may induce hepatorenal syndrome.
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PMID:[The effect of experimental extrahepatic cholestasis on absorption, distribution and elimination of digoxin]. 919 26

Lipopolysaccharide (LPS) initiates cholestasis. Whether this process is mediated by tumor necrosis factor-alpha (TNF-alpha) and whether the cholestatic response to LPS is associated with intrahepatic accumulation of possibly toxic substances are under debate. To study these questions the hepatic uptake and biliary excretion of indocyanine green (ICG) was examined in the isolated perfused rat liver 18 h after intravenous treatment of rats with either saline, 1 mg/kg body wt LPS, or LPS and intraperitoneal pentoxifylline (POF) (n = 6 in each group). POF inhibits TNF-alpha release after LPS administration. LPS induced a typical acute-phase response with increased mRNA for acute-phase proteins, reduced albumin mRNA, and increased hepatic uptake of alanine. Intrinsic hepatic clearance of ICG in controls (1.01 +/- 0.05 ml. min(-1). g liver(-1)) was similarly decreased by LPS alone (0.62 +/- 0.04 ml. min(-1). g(-1); P = 0.002 vs. control) or combined with POF (0.66 +/- 0.06 ml. min(-1). g(-1)). A kinetic analysis indicated that LPS reduced both uptake and excretion processes in a balanced manner, so that intrahepatic ICG content was unaffected or even slightly reduced, as confirmed by measurement of ICG contents in the perfused livers. In livers from parallel-treated nonperfused rats, mRNA for the organic anion transporting protein-1 (Oatp1, which is likely to mediate ICG uptake) was unaffected by LPS, whereas the concentration of Oatp1 protein was reduced. Thus LPS induced an acute-phase response that included downregulation of ICG uptake by reduction of Oatp1 protein concentration, possibly at a posttranscriptional level. TNF-alpha appears not to be the mediator because POF did not modify these LPS effects.
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PMID:Effects of LPS on transport of indocyanine green and alanine uptake in perfused rat liver. 1040 55

Seventeen patients with established fasciolosis and ten normal controls were enrolled in the study. The Fasciola patients were divided according to infection intensity into two groups (four patients with high intensity and thirteen patients with low intensity) as assessed by egg counts coupled with ultrasonography for detection of worms in the biliary system. Aspartate and alanine aminotransferases (AST and ALT) levels were similar to those of the controls, within the accepted normal limits, before and after treatment denoting absence of hepatocellular injury. Total serum bile acids, individual bile acids: cholic acid (CA) and chenodeoxycholic acid (CDCA), gamma glutamyl transpeptidase (GGT) and serum alkaline phosphatase (SAP) were significantly higher among all patients as compared to the controls denoting a degree of cholestatic lesion in those patients. Patients with high infection intensity revealed higher parameters than those with low intensity. The difference was not significant. One month after treatment, there was a significant improvement in the cholestasis indicating parameters in all Fasciola cases compared to the pretreatment ones. This indicates the effective role of the drug on the hepatobiliary function. However, the levels were still different from the controls. In Fasciola infection, total and individual serum bile acids in conjunction with GGT and SAP evaluate the hepatobiliary status and detect any minor abnormalities especially in anicteric subjects. Studied after treatment, they can be useful indices for assessment of the improvement.
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PMID:Human fasciolosis: a study on the relation of infection intensity and treatment to hepatobiliary affection. 1060 89


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