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    by: Vadivel Kumaran

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    2 : Definition Cholestasis: Interruption of bile flow or formation anywhere between the basolateral (sinusoidal) membrane of the hepatocyte and the ampulla of Vater.
    3 : Liver Functions Synthesis – Defective synthesis of bile acids Secretory – Bile, Bile acids-Salt & pigments Excretory – Bilirubin, drugs, toxins- Obstructed or diseased secretory system
    4 : What cholestasis does to liver? High levels of toxic bile acids- Lithocholic and chenodeoxycholic acids- hydrophobic Direct damage to hepatocytes and bile duct cells Lead to immune activation Degree of liver damage related to bile acid level Damage to cell membranes, necrosis Bile duct loss and failure to transport bile acids
    5 : Obstruction of the biliary tree-backpressure Proliferation of the duct epithelial cells Looping Reduplication of ducts and ductules Labyrinthine ductules reabsorb secreted bile salts Focal detergent dissolution of hepatocytes-bile lakes Unrelieved-portal tract fibrosis, with relative preservation of hepatic architecture Compensatory function of Liver
    6 : Classification Intrahepatic or extrahepatic. Mechanical or functional (hepatocellular ,decreased hepatic secretion of H2O and/or organic anions; bil.and bile acids). Acute or chronic.
    7 : Etiology:
    8 : Adult Cholestatic Liver Disease Intrahepatic cholestasis Pregnancy induced PBC PSC TPN induced cholestasis GVHD liver Sarcoidosis Idipathic ductopenia Liver transplant rejection Cystic fibrosis AIDS cholangiopathy Extra hepatic Drug induced cholestasis Anabolic steroids Oral contraceptives Cyclosporine Antibiotics Neuroleptics
    9 : COMMON PEDIATRIC ETIOLOGIES Premature infants Sepsis/Acidosis TPN-associated Drug-induced Idiopathic neonatal hepatitis~50% Extrahepatic biliary atresia-20% Alpha-1-antitrypsin deficiency-15% Intrahepatic cholestasis syndromes Cystic fibrosis, Alagille’s syndrome, Byler’s disease
    10 : Medical cholestasis
    11 : Hepatitis Hepatitis: Inflammation of Liver Viral, Alcohol, immune, Drugs & Toxins Acute, Chronic & Fulminant - types Viral Hepatitis – Specific – Heptitis A, B, C, D, E, & other Systemic - CMV, EBV. Swelling, canalicular obstruction
    12 : Bacterial infections and sepsis Kupffer cell response to endotoxin Staph.aureus,S.typhi, syphilis TNF alpha ? ?MRP2 and ? bile flow. IL 6 ? ? bile acid transport. Acute inflammation of the wall of the bile ducts with entry of neutrophils into the luminal space
    13 : TB Sarcoidosis Amyloidosis (late) Hodgkin’s lymphoma Malignancy Infiltrative disease
    14 : Drug induced hepatotoxicity Diseases involving bile duct PBC Destruction of medium-sized IHBD HLA class II on BD Ab against-nuclear pore proteins, centromeric proteins E2 subunit of PDC-E2 Infiltration of Terminal&conducting BD with CTL. ?? Cytokines ? liver cell damage. PSC Destruction of IHBD/EHBD Unknown. Genetic Immunologic Infections Vascular Toxins (subluminal portogenous bacterial or endotoxin damage) Graft versus host disease
    15 : A single drug can produce cholestasis by several ways
    16 :
    17 : Last trimester. Multifactorial - altered hormonal state - secretion defects of bile salts-MDR-3 - sulfated progesterone metabolites Jaundice is rarely deep(5 mg/dL) & disappears after delivery. Cholestasis with pregnancy
    18 : TPN associated cholestasis Altered enterohepatic circulation and ?neuroendocrinal stimuli
    19 : Inherited Cholestatic Conditions Dubin-Johnson Syndrome ABCC2 10q24 FIC 1 PFIC 1/BRIC ATP8B1 18q21-22 PFIC 2 ABCB11 2q24 PFIC 3 ABCB4 7q21 CYSTIC FIBROSIS ABCC7 7q31-2 PBAM SLC10A2 13q33
    20 :
    21 : Defects in bile acid synthesis 3ß-hydroxysteroid dehydrogenase Severe cholestasis Normal serum GGT Absence of pruritus PFIC-4
    22 : NONSYNDROMIC PAUCITY OF THE INTERLOBULAR BILE DUCTS Interlobular bile ducts:No.of portal tracts< 0.4 Arise from true biliary dysgenesis, active injury and loss of bile ducts -Congenital infections- rubella,cytomegalovirus -a1-antitrypsin deficiency -Williams and Noonan syndromes
    23 : Due to mutation in one of transmembrane receptor proteins called the Jagged 1 gene. Autosomal dominant Paucity apparent after 3 months Alagille’s syndrome (Syndromic paucity of intra-hepatic bile ducts)
    24 : Surgical cholestasis Outside : Diverticulum. Pancreatic tumour. Pancreatitis. LNs or Hepatoma Inside the lumen: Stone. Blood (haemobilia) Parasites Ascaris Hydatid Fasciola Papillary stenosis. Wall: Choledochal cyst. Congenital atresia. Stricture. Sclerosing cholangitis. Cholangiocarcinoma.
    25 : BILIARY ATRESIA Complete obstruction of bile flow-destruction or absence of all or a portion of the EHBD Concomitant injury and fibrosis of IHBR-variable extent Conception during the spring Low dietary-vitamin E, copper, phosphorus, and beta tocopherol Cytomegalovirus, rubella virus, human herpesvirus 6,papillomavirus,Reovirus type 3 HLA-B12, A9, B5, A28, and B35
    26 : SPONTANEOUS PERFORATION OF THE BILE DUCT Rare but distinct disorder Perforation at the junction of the cystic and bile ducts Obstruction- stenosis or inspissated bile at the distal end of the bile duct
    27 : BILE PLUG SYNDROME A plug of thick, inspissated bile and mucus Commonly in sick, premature infants who cannot be fed and require prolonged parenteral nutrition
    28 : Summary
    29 : Thank you

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