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)

Homozygosity for alpha 1-antitrypsin deficiency, usually of the genotype PIZZ, is one of the more common single gene defects in infants of European origin, occurring in about 1 in 2000 to 1 in 7000 of the newborn population. About 17% of such infants present with neonatal hepatitis and a small number with intracranial haemorrhage thought to be caused by vitamin K deficiency associated with cholestasis. At least 3% of PIZZ infants will die of cirrhosis in later childhood unless successfully treated by liver transplant. The pathogenesis of the liver disease is not understood and this is unsatisfactory both for treatment and for genetic counselling. The locus coding for alpha 1-antitrypsin (alpha 1AT) is designated PI for proteinase inhibitor. Careful study of the genotypes at this locus in neonatal disease shows that the only certain association is with the homozygous PIZZ genotype. The mutation results in a normal rate of synthesis of a polypeptide that becomes entrapped in the endoplasmic reticulum of the hepatocyte. Some other factor (or factors), as yet unidentified, determines whether severe liver damage results. The low level of alpha 1AT in the plasma seems unlikely to be the primary cause of damage but may play a secondary role. There is some evidence that the other factor(s) may be familial since in one study, though not in all, a high correlation for severity of liver disease was found between PIZZ siblings. The heterogeneity of the clinical course does not result from heterogeneity of PIZ alleles and there is no evidence that it is determined by variation in other related genes on chromosome 14. Only two possible clues have emerged so far. There is some evidence of a protective effect of breast-feeding, and a recent study has found the HLA class II DR3 antigen to be more common than expected in children with alpha 1-antitrypsin deficiency and liver disease. Accumulation of alpha 1AT protein in the hepatocytes may predispose them to some unidentified alteration of the immune response. It is possible that lack of antiprotease activity in the plasma might exacerbate the original damage, so the possibility of useful therapy with alpha 1AT cannot be ruled out entirely. At present, there is no valid way of predicting the severity of disease in a PIZZ child; hence, it is common for parents of a severely affected child to wish to terminate any future PIZZ pregnancy. The most direct method to diagnose the PIZZ genotype of a chorion villus sample is by allele-specific hybridization or sequencing of amplified DNA.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Genetics of alpha 1-antitrypsin deficiency in relation to neonatal liver disease. 218 61

Progress has recently been made in the understanding of normal bile secretion mechanisms. The membrane carriers for bile acids have been identified and new insights into intracellular transport mechanisms have been obtained. In particular, characterization of a vesicular pathway involving the Golgi apparatus is well under way. Hypercholeretic bile acids, such as ursodeoxycholic acid, have been discovered. Their choleretic effect is far greater than that of physiological bile acids and they stimulate bicarbonate secretion. Testable hypotheses to explain their hypercholeretic effect have been proposed, in particular the chole-hepatic shunt hypothesis. Several mechanisms capable of inducing cholestasis have been identified: a) inhibition of Na+, K(+)-ATPase; b) increased permeability of the paracellular pathway leading to leakage of bile constituents back into plasma; c) microtubule or microfilament dysfunction; d) increased cytosolic free calcium concentration due to permeabilization of the endoplasmic reticulum calcium stores. It is not yet possible, in a given case, to establish which of these mechanisms is predominant. Several may operate. A better knowledge of the mechanisms involved may lead to improved treatment.
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PMID:Recent concepts in bile formation and cholestasis. 225 45

The hypothesis that monohydroxy bile acids exert their cholestatic and hepatotoxic effects via a sustained elevation of cytosolic [Ca2+] was tested in the isolated perfused rat liver. Infusion of the specific inhibitor of microsomal Ca2+ sequestration, 2,5-di(tert-butyl)-1,4-benzohydroquinone (tBuBHQ) (25 microM for 10 min) produced efflux of Ca2+ from the liver and a sustained (20 min) increase in cytosolic [Ca2+] as indicated by the threefold increase in hepatic glucose output. Release of the endoplasmic reticular Ca2+ pool was demonstrated by the complete abolition of vasopressin- and phenylephrine-induced Ca2+ exchange between the liver and perfusate. Despite the profound perturbation of intracellular Ca2+ homeostasis produced by tBuBHQ, there was no decrease in bile flow and no evidence of hepatocellular injury (for 60 min), as indicated by lactate dehydrogenase release. In contrast, lithocholic acid (25 microM for 10 or 30 min) or taurolithocholic acid (5 microM for 10 or 30 min) produced an 80-90% inhibition of bile flow and a progressive increase in perfusate lactate dehydrogenase activity. During and after bile acid infusion, there was no change in Ca2+ fluxes between liver and perfusate, no stimulation of glucose output from the liver, and hormone-stimulated Ca2+ responses were preserved. It is concluded that the mechanisms for bile acid-induced cholestasis and hepatotoxicity in the intact liver are not attributable to changes in intracellular Ca2+ homeostasis, and especially not to prolonged release or depletion of Ca2+ sequestered in the endoplasmic reticulum.
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PMID:Release of Ca2+ from the endoplasmic reticulum is not the mechanism for bile acid-induced cholestasis and hepatotoxicity in the intact rat liver. 231 79

Primidone, phenytoin, or phenytoin and primidone in combination were given to healthy Beagle dogs for 6 months. Serum biochemical changes in dogs given primidone alone or phenytoin and primidone in combination for the entire 6-month test period included increased activities of alanine aminotransferase, alkaline phosphatase (AP), and gamma-glutamyltransferase, and decreased concentrations of albumin and cholesterol. Changes in dogs given phenytoin alone were limited to increased AP activity and decreased albumin concentration. Sulfobromophthalein excretion and conjugated bile acid concentration were within normal limits. All dogs given primidone alone or phenytoin alone remained clinically healthy throughout the treatment period. Three of 8 dogs given both drugs in combination became clinically ill after 9, 14, and 15 weeks of treatment, and were euthanatized. Two of the dogs developed clinical jaundice. In addition to the serum biochemical abnormalities observed in clinically healthy dogs, these dogs developed hyperbilirubinemia, delayed sulfobromophthalein excretion, and increased conjugated bile acid concentrations. Histologic examination of the liver showed intracanalicular casts of bile pigment typical of intrahepatic cholestasis in all 3 dogs. Histologic findings characteristic of treated dogs included hepatocellular hypertrophy attributable to hyperplasia of the smooth endoplasmic reticulum. Single-cell necrosis and multifocal lipidosis were observed in individuals of all treatment groups. Electron microscopy of the liver showed dilated bile canaliculi and damaged sinusoidal epithelium in dogs given both drugs. The elevated serum AP activity, associated with anticonvulsant drug therapy, was found to be exclusively the liver isoenzyme by cellulose acetate electrophoresis. The hepatic AP was localized to primarily the canalicular membranes by enzyme histochemistry. There was a statistically significant positive correlation between the AP activities of liver and serum. The results of this study indicate that long-term administration of anticonvulsant drugs to dogs is associated with clinical, serum biochemical, and histologic evidence of hepatic dysfunction. High drug dosage contributed most to abnormal serum biochemical test results, and combining phenytoin with primidone was responsible for more severe electron microscopic lesions of the liver of surviving dogs and for the death of 3 dogs.
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PMID:Effects of long-term primidone and phenytoin administration on canine hepatic function and morphology. 285 43

Liver tissue from five children with cystic fibrosis, obtained through percutaneous liver biopsies, have been investigated via light and electron microscopy. None of the patients had clinical evidence of liver disorder, and their blood chemistry was mainly normal. Light microscopy showed slight fibrosis in three cases, more advanced fibrosis in one case and focal cirrhotic changes in one case. All patients had fatty infiltration in the hepatocytes and glycogen in the nuclei of these cells. Electron microscopy showed an increase in the number of Ito cells around the portal tracts and also fibrosis in all patients. In the majority of hepatocytes, no evident necrosis was seen. Hypertrophy of the smooth endoplasmic reticulum and the Golgi apparatus were noted. Large lysosomes containing lipofuscin and lipids were also present. No direct evidence of cholestasis could be seen in the hepatocytes. The bile canaliculi were not dilated and did not contain bile plugs. No bile pigment was seen in the cells, and direct evidence of cholestasis was thus not found in the hepatocytes. Other organelles, such as the rough endoplasmic reticulum, peroxisomes and mitochondria, had a normal appearance. Bile ducts, even when seen in fibrotic portal tracts, were not dilated. The ultrastructural findings cannot explain the basis for the liver cell damage. Cholestasis does not seem to be a presumable etiological factor as judged from the findings in the present study.
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PMID:Morphological findings in the liver of children with cystic fibrosis: a light and electron microscopical study. 287 28

Prolyl hydroxylase was purified from human placentae, specific antiserum against it was prepared, and a new radioimmunoassay system employing 125I-labelled enzyme preparation was established. The molecular weight of the placental enzyme was shown to be 320,000 by gel filtration. SDS-polyacrylamide gel electrophoresis showed two bands of unequal intensity having molecular weights of 60,000 and 130,000. Their amino acid compositions were identical to each other, suggesting the polypeptide with a molecular weight of 130,000 might be a dimer of the polypeptide with a molecular weight of 60,000. The new radioimmunoassay established had a sensitivity of the order of 10 ng/ml, indicating it was more sensitive than previous radioimmunoassay employing 3H-labelling method. Clinical studies on patients with liver diseases disclosed that the concentrations of serum immunoreactive prolyl hydroxylase were elevated both in cases of hepatocellular damage and in cases of cholestasis. In cases of hepatocellular damage the enzyme behaved like cytoplasmic enzymes such as glutamic oxaloacetic transaminase, glutamic pyruvic transaminase and lactic dehydrogenase, but in cases of cholestasis it resembled biliary enzymes such as alkaline phosphatase and gamma-glutamyl transpeptidase. This result might be associated with the peculiar location of the enzyme within the cell, in the membrane of rough endoplasmic reticulum.
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PMID:Human prolyl hydroxylase. Purification, radioimmunoassay and clinical studies in liver diseases. 299 Oct 66

Hepatocytes are considered to be the predominant source of alpha 1-antitrypsin (AAT), the major antiprotease in human plasma. The development of emphysema in the hereditary PiZ AAT deficiency state suggests that inhibition of leukocyte elastase in the lung is a major function of this protein. In addition, patients with AAT deficiency are at increased risk for developing cholestasis in infancy and chronic liver disease as adults. The mechanism for hepatic cell injury, however, is not understood. Transgenic mice that express the normal human AAT gene demonstrate abundant AAT in hepatocytes and specific cell types of numerous nonhepatic tissues. Immunoperoxidase techniques have previously disclosed AAT in many of the cell types seen in transgenic mice; however, the issue of local synthesis vs. endocytosis in these cell types has remained unresolved. In this study, AAT mRNA was seen in a variety of tissues in the transgenic mouse. Immunoelectron microscopy of renal tubular and small intestinal epithelial cells in the transgenic mice demonstrated AAT within the cisternae of the rough endoplasmic reticulum, as in hepatocytes. These findings support the possibility of local synthesis in the various cell types. The results suggest that in addition to maintaining tissue integrity in the lung, the protease/antiprotease balance may have physiological functions in other organs as well.
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PMID:Multiple tissues express alpha 1-antitrypsin in transgenic mice and man. 326 Jun 5

Indomethacin was parenterally administered (6 mg/Kg/day) for 30 days to rabbits, to evaluate changes in serum biochemical parameters and any ultrastructural alterations induced by the drug at the hepatic level. An analysis of the results demonstrated that when the group of rabbits, a statistically significant increase in the serum ALT was found in the treated rabbits. Ultrastructural observations showed the following hepatocyte alterations: 1) minimum mitochondrial alterations 2) mild signs of cholestasis (pericanalicular osmophilic bodies) 3) Smooth endoplasmic reticulum hyperplasia. These findings suggest that indomethacin has the capacity to induce hepatic lesions in the rabbit and this is probably due to the surfactant mechanism.
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PMID:Hepatic alterations in indomethacin-treated rabbits. 340 44

Light microscopic and transmission electron microscopic changes were studied in the livers of 6 cats at 25 to 54 days after their extrahepatic bile ducts were experimentally obstructed. Histologic findings included various degrees of bile duct dilatation, ductular proliferation, and peribiliary fibrosis. Concentric layers of dense, birefringent connective tissue surrounded midsized bile ducts. The degrees of bile duct proliferation, hepatocellular degeneration, and bile retention were similar in each cat, but the amount of periductular connective tissue increased with chronicity of bile duct obstruction. Ultrastructural changes included marked swelling of endoplasmic reticulum and mitochondrial inner compartments, marked dilatation and distention of the canaliculi by bile casts, and numerical reduction of canalicular microvilli. Microvilli were often swollen and blunt. Mitochondria were swollen and long, and the cristae lacked normal distribution and density. Cytoplasmic accumulations of granular, electron-dense material and concentrically laminated arrays of material indicative of bile substances were also observed.
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PMID:Light microscopic and electron microscopic changes in the livers of cats with extrahepatic bile duct obstruction. 372 28

Major histocompatibility complex products Class I (HLA Class I) antigens are not expressed on the surface of normal human hepatocytes but become so in pathological conditions. The purpose of this study was to specify the ultrastructural topography of HLA Class I antigens expression. Nine human liver specimens, known from light microscopic investigation to display membranous positivity for HLA Class I antigens, were processed for immunoelectronmicroscopy using monoclonal anti-HLA Class I in an indirect immunoperoxidase procedure. HLA Class I antigens were detected on the basolateral membrane of hepatocytes and bile duct cells; some cisternae of the endoplasmic reticulum were also positive. The membranes of normal bile canaliculi of hepatocytes and the apical border of bile duct cells were negative. In one case of presumably drug-induced cholestasis, abnormal cholestatic canaliculi displayed HLA Class I antigens. These results indicate that HLA Class I antigens are synthesized by the hepatocytes and bile duct cells and incorporated into the plasma membrane; the basolateral expression follows the pattern as in other polarized cells. The expression in cholestatic canaliculi suggests a disturbed polarity of the hepatocyte.
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PMID:Ultrastructural immunocytochemical demonstration of HLA class I antigens in human pathological liver tissue. 390 57


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