Pathophysiology of cholestasis
TL;DR: This nonmechanical theory excludes from the category of cholestatasis other types of direct reacting hyperbilirubinemia, such as early primary biliary cirrhosis and chronic idiopathic jaundice, but includes thecholestatic component found in many liver diseases of established cause.
About: This article is published in Human Pathology.The article was published on 1970-03-01. It has received 155 citations till now. The article focuses on the topics: Cholestasis & Primary biliary cirrhosis.
Citations
More filters
TL;DR: Data provide evidence that SPGP is the human bile salt export pump (BSEP), and the product of the orthologous rat gene has been shown to be an effective bile acid transporter in vitro.
Abstract: The progressive familial intrahepatic cholestases (PFIC) are a group of inherited disorders with severe cholestatic liver disease from early infancy. A subgroup characterized by normal serum cholesterol and gamma-glutamyltranspeptidase (gammaGT) levels is genetically heterogeneous with loci on chromosomes 2q (PFIC2) and 18q. The phenotype of the PFIC2-linked group is consistent with defective bile acid transport at the hepatocyte canalicular membrane. The PFIC2 gene has now been identified by mutations in a positional candidate, BSEP, which encodes a liver-specific ATP-binding cassette (ABC) transporter, sister of p-glycoprotein (SPGP). The product of the orthologous rat gene has been shown to be an effective bile acid transporter in vitro. These data provide evidence that SPGP is the human bile salt export pump (BSEP).
908 citations
TL;DR: This review summarizes their variable clinical presentations, examines the role of transport proteins in hepatic drug clearance and toxicity, and addresses the increasing importance of genetic determinants, as well as practical aspects of diagnosis and management.
347 citations
01 Jan 1985
276 citations
TL;DR: In this paper, the concentrations and qualitative distribution of bile acids in rat livers were determined before, and 3 and 10 days after, bile duct ligation, using a method modified to detect ursodeoxycholic acid and β-muricholic acid.
263 citations
TL;DR: The high but transient elevation of transaminase activity soon after bile duct ligation was not associated with morphological signs of injury and the changes in the endoplasmic reticulum with hypertrophy of the smooth form may be adaptive in nature.
137 citations
References
More filters
Journal Article•
TL;DR: It is of considerable interest that certain inducers of liver microsomal enzymes have recently been used therapeutically for the treatment of hyperbilirubinemia in jaundiced children and for thetreatment of Cushing's syndrome.
Abstract: In increasingly large numbers, drugs, pesticides, herbicides, food additives, and environmental carcinogenic hydrocarbons are being found to stimulate their own metabolism or the metabolism of other compounds. The evidence suggests that foreign chemicals exert this action by increasing the amount of drug-metabolizing enzymes in liver microsomes.Treatment of animals or man with suitable inducers of liver microsomal enzymes accelerates drug metabolism in vivo and alters the duration and intensity of drug action. For instance, barbiturates decrease the anticoagulant activity of coumarin anticoagulants by accelerating their metabolism. This effect requires that the dosage of coumarins be raised to obtain an adequate anticoagulant response, and serious toxicity can result after combined therapy with a coumarin anticoagulant and a stimulator of drug metabolism when the enzyme stimulator is withdrawn and the anticoagulant is continued without an appropriate decrease in dose.
The stimulatory effect of drugs on their own metabolism often allows the organism to detoxify drugs more rapidly. This effect has considerable importance when it causes drugs to become less toxic and less effective during prolonged administration. However, if a metabolite has more activity than the parent drug, enzyme induction can enhance the drug's action. Enzyme induction may also be important during chronic exposure to environmental carcinogens, such as 3, 4-benzpyrene. The ability of 3, 4-benzpyrene to stimulate its own metabolism in liver, lung, gastrointestinal tract and skin represents an important mechanism for the detoxification of this substance.
Inducers of microsomal enzymes stimulate the metabolism or synthesis of several normal body substrates such as steroid hormones, pyridine nucleotides, cytochromes, and bilirubin. Evidence has accumulated that steroids are normal body substrates of drug-metabolizing enzymes in liver microsomes. Accordingly, treatment of rats with phenobarbital enhances the hydroxylation of androgens, estrogens, glucocorticoids, and progestational steroids by liver microsomes. This effect is paralleled in vivo by enhanced metabolism of steroids to polar metabolites and by a decreased action of steroids such as estradiol, estrone, and progesterone.
Recent studies suggest that inducers of liver microsomal enzymes enhance the hydroxylation of steroids in man. Phenobarbital, diphenylhydantoin, and phenylbutazone are examples of drugs that stimulate cortisol hydroxylase activity in guinea pig liver microsomes and enhance the urinary excretion of 6 β-hydroxycortisol in man. Further research is needed to learn whether the stimulatory action of drugs on the metabolism of normal body constituents is harmful or whether it restores a homeostasis that was upset by drug administration. It is of considerable interest that certain inducers of liver microsomal enzymes have recently been used therapeutically for the treatment of hyperbilirubinemia in jaundiced children and for the treatment of Cushing's syndrome. Considerable further work is required to evaluate more completely the effects of liver microsomal enzyme inducers on the metabolism of bilirubin, cortisol, and other normal body constituents in experimental animals and man.
2,869 citations
1,713 citations
TL;DR: Structural homogeneity is found in over 80% of normal rat liver parenchymal cells, with most of the significant differences being confined to those cells immediately surrounding the central veins.
Abstract: The principles of stereology have been applied to a morphometric analysis of parenchymal cells from the peripheral, midzonal, and central regions of normal rat liver lobules. The fractional volumes of cytoplasm occupied by mitochondria, peroxisomes, lysosomes, lipid, and glycogen have been determined. The surface densities of smooth- and rough-surfaced endoplasmic reticulum and of mitochondrial envelope and cristae have also been measured. The average number and dimensions of mitochondria and peroxisomes have been evaluated. By the use of an independent measurement of the average cytoplasmic volume, these data have been expressed as the actual volumes, areas, and numbers per cell in the different parts of the hepatic lobule. Similarly, the volumes of the envelope, cristae, and matrix compartments and the area of cristae membranes have been calculated for the average-sized mitochondrion in each lobular zone. Structural homogeneity is found in over 80% of normal rat liver parenchymal cells, with most of the significant differences being confined to those cells immediately surrounding the central veins.
676 citations
TL;DR: This review summarizes the authors' views of information presently available on the physical properties of bile salts in solution and at interfaces, both of which are relevant to their physiological function.
Abstract: The aphorism, "To study the phenomena of disease without books is to sail an uncharted sea, while to study books without patients is not to go to sea at all" (210), applies aptly to bile salts:6 for to consider the function of bile salts in ignorance of their physical properties is to be deprived of many helpful concepts; conversely, studies of the physical properties of bile salts which have been carried out in ignorance of their physiological functions have overlooked many of their distinctive properties. l �.This review summarizes the authors' views of information presently available o n the physical properties of bile salts in solution and at interfaces, both of which are relevant to their physiological function. The detergent
577 citations
TL;DR: The agreement between photochemical action spectrum and spectrophotometric difference spectrum supports the conclusion that the CO-binding pigment is the terminal oxidase of mixed function oxidase systems of mammals.
Abstract: The reversal of the carbon monoxide inhibition by bands of monochromatic light was determined for the oxidative demethylation of codeine and monomethyl-4-aminopyrine and the hydroxylation of acetanilide by rat liver microsomes and for the hydroxylation of 17-hydroxyprogesterone at carbon-21 by bovine adrenocortical microsomes. Maximum reversal occurred at 450 millimicrons, the light absorption maximum of the CO compound of the CO-binding pigment of microsomes. The agreement between photochemical action spectrum and spectrophotometric difference spectrum supports the conclusion that the CO-binding pigment is the terminal oxidase of mixed function oxidase systems of mammals.
509 citations