Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018133 (graft-versus-host disease)
 18,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The morbidity and mortality from chronic biliary diseases (i.e., the cholangiopathies) remains substantial. End-stage liver disease from biliary causes of cirrhosis (e.g., primary biliary cirrhosis [PBC], and primary sclerosing cholangitis) account for approximately one third of patients referred for liver transplantation. A single-topic conference sponsored by the American Association for the Studies of Liver Diseases entitled "The Pathobiology of Biliary Epithelia" brought together investigators to review the status of the field of cholangiocyte pathobiology, identify new areas of interest, and propose future directions. This information was presented in 6 sessions: "Structural and Functional Characteristics of the Bile Duct System," "Biological Topics from Nonbiliary Epithelia," "Malignant Transformation of Cholangiocytes," "Cholangiocyte Proliferation and Death," "Transport Mechanisms in Bile Duct Epithelia," and "Pathobiology of Biliary Epithelia." In the 7 years since the first symposium on this topic, major advances have been made in our understanding of ductal bile formation, including, greater insight into the hormones, intracellular signaling mechanisms, and effector proteins responsible for bile secretion and absorption. More sophisticated imaging technologies have increased our understanding of the polarity of cholangiocytes, their embryology and ultrastructural anatomy, and in vivo human secretory responses to current medical therapy. Information on mediators of inflammation permeated many sessions, having potentially important roles in malignant transformation of cholangiocytes, cholangiocyte apoptosis, fluid and electrolyte transport, and have begun to be specifically characterized for certain biliary diseases, e.g., acquired immunodeficiency syndrome (AIDS) cholangiopathy and graft-versus-host disease (GVHD).
 ...
PMID:The pathobiology of biliary epithelia. 1198 76

Ursodeoxycholic acid (UCDA) is increasingly used for the treatment of cholestatic liver diseases. Experimental evidence suggests three major mechanisms of action: (1) protection of cholangiocytes against cytotoxicity of hydrophobic bile acids, resulting from modulation of the composition of mixed phospholipid-rich micelles, reduction of bile acid cytotoxicity of bile and, possibly, decrease of the concentration of hydrophobic bile acids in the cholangiocytes; (2) stimulation of hepatobiliary secretion, putatively via Ca(2+)- and protein kinase C-alpha-dependent mechanisms and/or activation of p38(MAPK) and extracellular signal-regulated kinases (Erk) resulting in insertion of transporter molecules (e.g., bile salt export pump, BSEP, and conjugate export pump, MRP2) into the canalicular membrane of the hepatocyte and, possibly, activation of inserted carriers; (3) protection of hepatocytes against bile acid-induced apoptosis, involving inhibition of mitochondrial membrane permeability transition (MMPT), and possibly, stimulation of a survival pathway. In primary biliary cirrhosis, UDCA (13-15 mg/kg/d) improves serum liver chemistries, may delay disease progression to severe fibrosis or cirrhosis, and may prolong transplant-free survival. In primary sclerosing cholangitis, UDCA (13-20 mg/kg/d) improves serum liver chemistries and surrogate markers of prognosis, but effects on disease progression must be further evaluated. Anticholestatic effects of UDCA have also been reported in intrahepatic cholestasis of pregnancy, liver disease of cystic fibrosis, progressive familial intrahepatic cholestasis, and chronic graft-versus-host disease. Future efforts will focus on definition of additional clinical uses of UDCA, on optimized dosage regimens, as well as on further elucidation of mechanisms of action of UDCA at the molecular level.
 ...
PMID:Ursodeoxycholic acid in cholestatic liver disease: mechanisms of action and therapeutic use revisited. 1219 43

Hepatic formation of bile is critical to survival and is one of the most easily disrupted liver functions. Liver biopsy is performed to obtain a definitive diagnosis of cause, to exclude potential etiologies, or simply to assist in development of a differential diagnosis. Parenchymal changes of cholestasis (feathery degeneration of hepatocytes, dilated bile canaliculi with retained bile, Kupffer cell phagocytosis of bile that has leaked into the sinusoidal space) are nonspecific and may be seen with both nonobstructive and obstructive cholestasis. The portal tract changes of obstruction are characteristic: bile ductular proliferation, inspissated bile in bile ducts, portal tract edema, neutrophilic inflammation, and cholate stasis of periportal hepatocytes. Uncorrected obstruction incites robust fibrogenesis by portal tract myofibroblasts, engendering a characteristic jigsaw pattern of fibrous septa. Diseases with specific histological features include primary biliary cirrhosis, primary sclerosing cholangitis, biliary atresia, and graft-versus-host disease. However, the pathologist is cautioned not to overinterpret the cholestatic liver biopsy and to apply rigorous criteria for specific causal diagnoses. Most of the histological features of cholestasis are nonspecific. Hence, both practicing physician and pathologist should have sound knowledge of the pathology of cholestasis.
 ...
PMID:The pathology of cholestasis. 1508 84

Our understanding of biliary epithelial cells (BEC) in physiobiology and immunology has steadily expanded. BEC transports IgA as well as IgM into bile, synthesizes and secretes various chemokines, cytokines, and expresses adhesion molecules involved in cell interaction and signal transduction. These then suggest a myriad of potential roles for BEC in defense from invading microorganisms as well as the pathogenesis of diverse immunologically driven diseases such as primary biliary cirrhosis (PBC), graft-versus-host disease, and primary sclerosing cholangitis (PSC). Despite the progress, there still remain many areas of BEC biology that require further investigation. Most importantly, it remains to be clarified that the extent to which the immunologic activities observed in BEC represent a BEC response to tissue injury or whether BEC themselves are the active participants in the pathogenesis of various cholestatic immunological diseases, including PBC and PSC.
 ...
PMID:A review of the physiological and immunological functions of biliary epithelial cells: targets for primary biliary cirrhosis, primary sclerosing cholangitis and drug-induced ductopenias. 1555 65

The cholangiopathies represent diseases and syndromes affecting the biliary system at any site between the canals of Hering and the ampulla of Vater. Hepato-canalicular cholestasis reflects biliary secretory failure of the hepatocyte caused by disturbances of intracellular organelles or damage to the bile canalicular excretory functions. Drug reactions are related especially to antibiotics, phenothiazine derivates and carbamazepine. Immune-mediated cholangiopathies cause destruction and reduction of interlobular bile ducts, and are sometimes called vanishing bile duct diseases. They include primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune cholangitis, chronic hepatic allograft rejection, graft-versus-host disease and chronic cholestatic sarcoidosis. Ischemic (vascular) cholangiopathies include traumatic, hepatic arteritis and mechanical causes. Infectious cholangiopathies usually are associated with the immunosuppressed patient.
 ...
PMID:Overview of chronic cholestatic conditions in adults: terminology and definitions. 1556 29

Lymphocytic destructive cholangitis is a histological pattern associating bile duct intraepithelial lymphocytic infiltration and bile duct epithelial damage. Lymphocytic destructive cholangitis is an important diagnostic feature of primary biliary cirrhosis, but it can also be seen in primary sclerosing cholangitis, autoimmune hepatitis, the so-called overlap syndrome, acute or chronic viral hepatitis C, drug-induced hepatitis, and acute rejection or graft-versus-host disease in liver or bone marrow transplantation. In the present paper we report a case of acute hepatitis with lymphocytic destructive cholangitis on liver biopsy. Clinical and biological examinations showed that the patient had hepatitis E with no other cause of liver disease. Therefore, hepatitis E should be considered as a diagnostic possibility when liver biopsy shows acute hepatitis and lymphocytic destructive cholangitis. The mechanism of bile duct damage in hepatitis E remains unknown.
 ...
PMID:Acute hepatitis E: a cause of lymphocytic destructive cholangitis. 1589 7

Autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) all nestle within the umbrella term of autoimmune liver disease, in which the end result is immune-mediated hepatocellular or hepatobiliary injury. All three conditions are associated with gut inflammation; PSC and AIH being strongly linked to inflammatory bowel disease (IBD) and PBC to coeliac disease. This clinical observation has stimulated several intriguing pathogenic concepts in which gut commensals, pathogens and intestinal antigens are all implicated in causing liver injury. Th17-cells have also been linked to AIH, PBC and more recently PSC. Given that the intestine is a key regulator of immunopathogenic Th17 responses, this may underpin a common disease mechanism and open up novel treatment avenues based on rational targeting of immune pathways. Moreover, the discovery of long-lived mucosal memory T-cells being recruited to the liver in response to aberrantly expressed endothelial-cell adhesion molecules and chemokines, which are normally 'gut-restricted,' could plausibly explain why these diseases are associated with site-restricted tissue distributions and pave the way for therapeutic strategies based on modulating tissue specific lymphocyte homing. That particular gene-polymorphisms have been found which confer combined PSC/IBD susceptibility underscores the fundamental role of mucosal immunogenicity in disease pathogenesis. Mucosal lymphocytes may also play a pivotal role in graft versus host disease affecting the liver, and there is increasing evidence to support dysregulated mucosal immunity as being responsible for the hepatic manifestations of gluten-sensitive enteropathy, graft versus host disease, as wells as the pancreatobiliary manifestations of IgG4-related disease.
...
PMID:Mucosal immunity in liver autoimmunity: a comprehensive review. 2389 Nov 69


<< Previous 1 2