GI Tract and Liver

Cards (157)

  • Shift, 2nd Sem
    2nd
  • Cholestasis
    Either a decrease in the volume of bile formed or an impaired secretion of specific solutes into bile, which results in elevated serum levels of bile salts and bilirubin
  • Liver
    The main organ where exogenous chemicals are metabolized and eventually excreted
  • Liver
    • It facilitates the performance of its enormous task of maintaining the metabolic homeostasis of the body
    • It is the first organ to encounter ingested nutrients, vitamins, metals, drugs, and environmental toxicants as well as waste products of bacteria that enter portal blood
    • Efficient scavenging or uptake processes extract these absorbed materials from the blood for catabolism, storage, and/or excretion into bile
  • Lobule
    Classically, the liver is divided into hexagonal lobules oriented around terminal hepatic venules (also known as central veins)
  • Portal triad
    At the corners of the lobule, containing a branch of the portal vein, a hepatic arteriole, and a bile duct
  • Acinus
    The preferred concept of a functional hepatic unit, divided into three zones: Zone 1 (closest to the entry of blood), Zone 2 (intermediate), and Zone 3 (abuts the terminal hepatic vein)
  • Blood entering the acinus consists of oxygen depleted blood from the portal vein (60% to 70% of hepatic blood flow) plus oxygenated blood from the hepatic artery (30% to 40%)
  • Hepatocytes in zone 3 are exposed to substantially lower concentrations of oxygen than hepatocytes in zone 1, and zone 3 is hypoxic compared to other tissues
  • Heterogeneities in protein levels of hepatocytes along the acinus generate gradients of metabolic functions
  • Hepatocytes in the mitochondria rich zone 1 are predominant in fatty acid oxidation, gluconeogenesis, and ammonia detoxification to urea
  • There are higher levels of glutathione in zone 1 and greater amounts of cytochrome P450 proteins, particularly CYP2E1, in zone 3
  • Sinusoids
    The channels between cords of hepatocytes where blood percolates on its way to the terminal hepatic vein
  • Sinusoidal cells
    • Endothelial cells (lined with fenestrae), Kupffer cells (resident macrophages), and stellate (Ito) cells (synthesize collagen and store vitamin A)
  • Bile
    Contains bile acids, cholesterol, glutathione, bilirubin, phospholipids, and other organic anions, proteins, metals, ions, and xenobiotics
  • Canalicular lumen

    The space formed by specialized regions of the plasma membrane between adjacent hepatocytes
  • Canaliculi
    Channels between hepatocytes that connect to a series of larger and larger channels or ducts within the liver
  • Bile salts and other osmolytes
    The major driving force of bile formation, actively transported into the canalicular lumen
  • Influx transporters in hepatocytes and cholangiocytes
    • Apical sodium-dependent bile salt transporter (ASBT)
    • Sodium taurocholate cotransporting polypeptide (NTCP)
    • Organic anion transporting polypeptide (OATP)
    • Organic cation transporter (OCT)
    • Organic anion transporter (OAT)
  • Efflux transporters in hepatocytes and cholangiocytes
    • Bile salt export pump (BSEP)
    • Heterodimeric ATP binding cassette transporter G5/G8 (ABCG5/G8)
    • Multidrug resistance protein (MRP)
    • Breast cancer resistance protein (BCRP)
    • Multidrug resistance associated protein (MRP)
    • Heterodimeric organic solute transporter alpha and beta
  • Canalicular multiple organic anion transporter (MOAT) system and multiple drug resistant (MDR) P-glycoproteins
    Exporters of particular relevance to canalicular secretion of toxic chemicals and their metabolites
  • Biliary excretion is important in the homeostasis of metals, notably copper, manganese, cadmium, selenium, gold, silver, and arsenic
  • Inability to export Cu into bile is a central problem in Wilson's disease, a rare genetic disorder characterized by accumulation of Cu in the liver and then in other tissues
  • Bile ducts modify bile by absorption and secretion of solutes, and biliary epithelial cells express phase I and phase II enzymes that may contribute to the biotransformation of toxicants present in bile
  • Toxicant related impairments of bile formation are more likely to have detrimental consequences in populations with other conditions where biliary secretion is marginal, such as neonates
  • Types of hepatobiliary injury
    • Hepatocyte/cell death
    • Canalicular cholestasis
    • Bile duct damage
    • Sinusoidal disorders
    • Disruption of the cytoskeleton
    • Immune-mediated response
  • Immune-mediated response
    • Diclofenac
    • Ethanol
    • Halothane
  • Neonates
    Infants in the first 28 days after birth
  • Neonates are more prone to develop jaundice
    When treated with drugs that compete with bilirubin for biliary clearance
  • Types of Hepatobiliary Injury
    • Hepatocyte/Cell Death
    • Canalicular cholestasis
    • Bile duct damage
    • Sinusoidal disorders
    • Immune-mediated response
    • Fatty Liver
    • Fibrosis and cirrhosis
    • Tumors
  • Hepatocyte/Cell Death
    Most common type of response when exposed to toxicant
  • Toxins causing Hepatocyte/Cell Death
    • Acetaminophen (most common)
    • Allyl alcohol
    • Copper
    • Dimethylformamide
    • Ethanol (most common)
  • Canalicular cholestasis
    Decrease in the volume of bile formed or an impaired secretion of specific solutes into bile
  • Toxins causing Bile duct damage
    • Alpha-naphthylisothiocyanate
    • Amoxicillin
    • Methylene dianiline
    • Sporidesmin
  • Toxins causing Immune-mediated response
    • Diclofenac
    • Ethanol
    • Halothane
    • Tienillic acid
  • Toxins causing Fatty Liver
    • Amiodarone (drug for HTN)
    • CCl4
    • Ethanol
    • Fialuridine
    • Tamoxifen
    • Valproic acid
  • Toxins causing Fibrosis and cirrhosis
    • CCI4
    • Ethanol
    • Thioacetamide
    • Vitamin A
    • Vinyl chloride
  • Necrosis
    Cell swelling, Leakage, Nuclear disintegration (karyolysis), Influx of inflammatory cells
  • Apoptosis
    Cell shrinkage, Formation of apoptotic bodies, Nuclear fragmentation, Lack of inflammation
  • Hepatocyte death can occur in a focal, zonal, or panacinar (widespread) pattern