new presentation Intra hepatic cholestasis 1.pptx

new presentation Intra hepatic cholestasis 1.pptx

1. ETIOLOGY AND PATHOGENESIS OF INTRAHEPATIC CHOLESTASIS Dr.Vijula MGE resident

2. BILE Complex lipid rich micellar solution that is isosmotic with plasma production :500-600ml/d Direction of bile flow – opposite to that of blood flow (Blood: sinusoids to central veins Bile : central hepatocytes to the periphery) Water : 85%

3. SOLUTES IN BILE Bile acids: 67% Phospholipid(phosphatidyl choline) : 22% Cholesterol : 4% Bilirubin : 0.3% Protein : 4.5%

4. BILE FLOW

5. BILIARY ANATOMY: EXTRA AND INTRAHEPATIC Biliary Tree Extrahepatic Intrahepatic Hepatic duct - >800 µm (left and right) Common hepatic duct Common bile duct Cystic duct Gall Bladder Ampulla of Vater Duodenum small bile ducts(<400 µm ) septal ducts ( 100- 400 µm) interlobular ducts ( 15–100 µm) Medium sized 40–100 µm Small sized 15–40 µm Ductules ( <20 µm ) canal of Hering ( 0.5 to 1.0 μm ) Large bile ducts (>400µm) segmental ducts 400–800µm area ducts 300–400µm (sectorial ducts)

6. PHYSIOLOGY OF BILIARY SYSTEM The biliary secretion apparatus comprises of canalicular membrane with its carrier proteins, the intracellular organelles and the cytoskeleton of the hepatocyte. Tight junctions- seal the biliary space from the blood compartment NTCP- conjugated bile acids OATP- organic anions, bilirubin MDR1- drugs MRP2- sulphated and glucuronidated bile acids BSEP-glycine and taurine conjugated bile acids MRP 3-Phospholipids (phosphatidyl choline) MRP4- export glutathione and bile acids

7. HEPATIC BILE ACID TRANSPORT AND BILE SECRETION PRIMARY- ATP dependent SECONDARY- Na dependent TERTIARY- OH-, HCO3- dependent AE

8. BILE ACID DEPENDENT BILE FLOW 225ml/d bile flow relating to bile acid secretion Contributes to 40% bile acid flow ATP- dependent Choleretic activity : it is the volume of bile flow induced per amount of the solute secreted 1µmol bile acid secretion= 8-30µlt of bile flow

9. BILE ACID INDEPENDENT BILE FLOW 225ml/d d/t active secretion of inorganic electrolytes and other solutes like reduced glutathione, bicarbonate 1. GSH ATP dependent canalicular secretion via MRP2 raises the solute concentration Contributes to osmotic driving force for canalicular bile formation 2. hepatic and biliary secretion of HCO3- via the HCO3−/Cl− anion exchanger AE2 ATP-independent- hormones and neuropeptides, such as secretin and VIP dependent secretion

10. HEPATIC SINUSOIDAL( BASOLATERAL) NA+-DEPENDENT CONJUGATED BILE ACID UPTAKE >80% conjugated, < 50% unconjugated bile acid uptake Na+,K +-ATPase ( maintains Na+ gradient) Na+taurocholate cotransporting polypeptide (NTCP; gene symbol SLC10A1) is responsible for the hepatocytic Na+-coupled uptake of bile acids as well as certain drugs such as rosuvastatin- no inherited defects in NTCP ASBT- Apical Sodium Dependent Bile Acid Transporter- Na+-coupled uptake cholangiocytes , ileocytes , PCT

11. HEPATIC SINUSOIDAL NA+-INDEPENDENT BILE ACID UPTAKE Driving force not well understood passive diffusion electroneutral exchange that couple solute uptake to bicarbonate or GSH efflux 1. organic anion transporting polypeptide (OATP) gene family : OATP1B1 and OATP1B3 Unconjugated bile acids, organic anions, BSP, bilirubin glucuronides, steroid metabolites, drugs (e.g., rifampin, statins, digoxin, fexofenadine ) 2. MRP2: transport of glucuronide, glutathione, sulfated conjugates

12. HEPATIC SINUSOIDAL BILE ACID EFFLUX PROTECTIVE MECHANISM IN CHOLESTATIC CONDTIONS- reduce bile acid overload OST α- OST β , MRP3 (gene symbol ABCC3) and MRP4 (gene symbol ABCC4)- efflux of bile acids at the sinusoidal surface down-regulation of NTCP, OATP family

13. DEFINITION Cholestasis is impaired formation or flow of bile. Morphologically , cholestasis is recognized from accumulation of biliary constituents in liver cells and biliary passages. Clinically , cholestasis results in retention in blood of substances normally excreted in bile typically with elevated levels of serum alkaline phosphatase (biliary isoenzyme), γ- gt and cholesterol.

14. CLASSIFICATION Intra- or extrahepatic Acute or chronic (>6months)

15. Intrahepatic cholestatic disorders Hepatocellular injury or biliary obstruction. Categorized histologically into three types Infiltrative Injury to cholangiocytes within intrahepatic bile ductules Those in which major histologic changes are not evident

16. INTRAHEPATIC CHOLESTASIS

17. HEPATOCELLULAR CHOLESTASIS Primary injury to intracellular membranes Leakage of bile salts through defective canaliculi, impaired hydroxylation of cholesterol to bile acids in ER -- Reduced bile- salt dependent bile flow Inhibition of canalicular ATPase- interferes with bile salt independent secretion

18. HEPATOCELLULAR CHOLESTASIS Sepsis, endotoxemia- induced cholestasis decreased Na+ K+ ATPase activity- decreased membrane fluidity Cholestatic variety of viral hepatitis especially in OCP users Alcoholic hepatitis tender hepatomegaly, cutaneous spider naevi Non-alcoholic steatohepatitis total parenteral nutrition altered EHC, decreased neuroendocrine stimulation of bile flow, and by bacterial 7alpha dehydroxylation in the intestinal tract

19. HEPATOCELLULAR CHOLESTASIS Benign infiltrating disorders: amyloidosis Protein deposition in the space of Disse , portal tracts, and vessel walls causing architectural distortion and cholestasis sarcoidosis Other granulomatoses storage diseases Paraneoplastic syndromes: e.g., Hodgkin disease (unknown cause) renal carcinoma ( Stauffer’s Syndrome )- tumor derived cytokines that interfere with NTCP, MRP2, BSEP function

20. HEPATOCELLULAR CHOLESTASIS Ductal plate malformations: e.g., congenital hepatic fibrosis (small interlobular bile ducts) Nodular regenerative hyperplasia Vascular disorders: e.g., Budd–Chiari syndrome, veno -occlusive disease, congestive hepatopathy ( Elevated right atrial pressure and central venous pressure result in backward congestion of hepatic venules and sinusoids leading to hepatocellular dysfunction) Cirrhosis (any cause) The cholestasis of intrahepatic atresia ( infantile cholangiopathy )- related to viral injury to intrahepatic bile ducts

21. HEPATOCELLULAR CHOLESTASIS ZELLWEGER’S SYNDROME: Cerebrohepatorenal syndrome rare presents before 6 months of age with progressive cholestasis and hepatomegaly. There is associated mental retardation, a characteristic facies with high forehead, midface hypoplasia, hypotonia and renal cysts. defect in hepatic peroxisomes and bile acid oxidation is abnormal with the appearance of C27 bile acids in serum and bile. Affected individuals have a short survival of only a few years. Oral bile acid therapy should be considered

22. HEPATOCELLULAR CHOLESTASIS Genetic disorders: e.g., BRIC, PFIC, ABCB4 deficiency, intrahepatic cholestasis of pregnancy (ICP), erythropoietic protoporphyria Malignant infiltrating disorders: e.g., hematologic diseases, metastatic cancer Drug induced cholestasis

23. Drugs causing cholestatic hepatitis Immunosuppressive – Azathioprine , Cyclosporin A Antihypertensive- Nifedipine Antifungal- Terbinafine Tricyclic Antidepressants Hypoglycemic agent- Chlorpropamide, Troglitazone Benzodiazepines Antithyroid - Methimazole Antiepileptic- Carbamazepine NSAID's : Nimesulide , Sulindac , Diclofenac Psychotropic – Chlorpromazine, Risperidone Serotonin antagonist- Pizotyline (anti-migraine) Hormone- Danazol (modified testosterone) Antinflammatory - Mesalamine Narcotic analgesic- Propoxyphene Antimicrobial- Loracarbef ( carbacephem ) Miscellaneous- Gold Xenobiotics – Amoxicillin/clavulanic acid, dapsone, erythromycin, trimethroprim /sulfamethoxazole, flucloxacillin, nitrofurantoin, azithromycin, roxithromycin, clarithromycin

24. CHOLANGIOCELLULAR CHOLESTASIS Retained hydrophobic bile salts are incorporated into the membrane- altered membrane fluidity and function Ducts<0.1mm - chronic graft rejection, GVHD, Alagille , drugs, toxins small interlobular bile duct- PBC, CHF, VMC, Alagille med sized interlobular bile duct- ADPCKD Large interlobular bile duct- PSC, Caroli’s disease, 2-fluoro 2-deoxyuridine septal ducts -PBC Segmental duct- PSC

25. CAUSES

26. CHOLANGIOCELLULAR CHOLESTASIS Ductal plate malformations: Biliary hamartoma / Von Mayenberg complexes <1.5cm nodular cystic lesions Associated pancreatitis, cholangitis, cholelithiasis, malignancy small i nterlobular bile ducts affected ADPCKD ( medium sized interlobular bile ducts), Caroli syndrome ( large interlobular bile ducts) , Cystic fibrosis ( large interlobular bile ducts), biliary atresia Drug-induced cholangiopathy

27. CHOLANGIOCELLULAR CHOLESTASIS Graft vs. host disease endothelialitis , Lymphocytic infiltration of the portal areas,Immune cholangitis, Bile duct destruction, and Portal fibrosis- later secondary sclerosing cholangitis Secondary sclerosing cholangitis : e.g., due to various forms of cholangiolithiasis , ischemic choangiopathies (hereditary hemorrhagic telangiectasia, polyarteritis nodosa and other forms of vasculitis), infectious cholangitis related to AIDS and other forms of immunodepression, etc.

28. Classification of choledochal malformations according to Todani Ia - Common type; Ib - segmental dilatation; Ic - diffuse dilatation; II- diverticulum; III- choledochocele ; Iva-multiple cysts (intra and extrahepatic); IVb , multiple cysts (extrahepatic); V, single or multiple dilatations of the intrahepatic ducts

29. CANALICULAR MEMBRANE CHANGES

30. Bland cholestasis: Absence of any cellular infiltrate or other evidence of liver injury. Oral contraceptives- Within 2 months Ethinyl estradiol causes downregulation of sinusoidal bile salt uptake by ntcp , competitive inhibition of bsep , interference with mrp2 function-- decreased fluidity of sinusoidal plasma membrane, decreased bile secretion Anabolic steroids- similar to estrogen Pregnancy

31. Drugs causing bland cholestasis Promazine group (affects polymerization of actin) Long-acting sulphonamides , Antithyroid drugs Azathioprine Cyclosporin A Cytosine-arabinoside Fosinopril Infliximab Tamoxifen

32. DRUG INDUCED Integrity of canalicular membrane- altered either by disruption of canalicular tone and contraction or the tight junction Phalloidin(mushroom) - depolymerization of the actin of microfilaments Cytochalsin b (mycotoxin) and androgens- disrupt microfilaments and canaliculi become less contractile Phalloidin and estrogen disrupt tight junctions- loss of normal permeable barrier with passage of larger molecules directly into the canaliculus from the blood, and regurgitation of solutes from bile to blood Colchicine, chlorpromazine(anti psychotic)- disrupted integrity of microtubules, vesicular transport affected

33. GENETIC DEFECTS IN TRANSPORTERS

34. PFIC

35. HERITABLE DISORDERS OF CONJUGATED BILIRUBIN EXCRETION Dubin – johnson and rotor syndromes are uncommon, In dubin – johnson syndrome, mutations in mrp2 result in deficient canalicular transport of bilirubin conjugates Rotor syndrome has deficiency of the plasma membrane transporters oatp1b1 and oatp1b3 Reduced reuptake of conjugated bilirubin that has been pumped out of hepatocytes into the portal blood by MRP3 In both disorders, general hepatocellular function is preserved and liver chemistries are normal. Bilirubin values 2 and 5 mg/dl, although values of <25 mg/dl for prolonged periods have been described. No significant adverse consequences, even if prolonged for months at levels of up to 35–40 mg/dl.

36. AR CONJUGATED HYPERBILIRUBINEMIAS- ORGANIC ANION CONJUGATE TRANSPORTER DEFECT DUBIN JOHNSON SYNDROME D ark liver D onot visualize GB on oral cholecystogram (HIDA) BSP: D ouble peak(45 and 90min) D oesnot have raised urine coproporhyrin (isomer 1(80%)>isomer 3) MRP2 R O T O R SYNDROME Normal appearance GB visualized on oral cholecystogram Single peak Raised urine coproporphyrin (isomer 1 <70%) O ATP1B1/1B3

37. Disorder Transporter defect Defective protein (gene) Characteristic features PFIC 1 (RARE AR) Aminophospholipids ( Susceptible to damage from hydrophobic bile acids ) FIC1(ATP8B1) P- type ATPase Chr 18 (Non-sense, frame shift, large deletion mutation) Progressive cholestasis, elevated bile acids, pruritus, normal GGTP, pancreatitis, resp. symptoms, intestinal malabsorption and diarrhoea , hearing loss PFIC 2 Bile acids BSEP( ABCB11) Chr 2 Progressive cholestasis, jaundice, lobular and portal fibrosis, hepatobiliary malignancy, gall stones, normal GGTP PFIC 3 (MAY OCCUR IN ADULTHOOD) Phophatidylcholine (reduced mixed micelle formation with bile acid to buffer cytotoxic detergent effect) MDR3 (ABCB4) Progressive cholestasis, extensive bile duct proliferation, periportal fibrosis, hepatomegaly, elevated GGTP

38. PFIC 4 TJP 2- tight junction protein 2 mutation Severe cholestasis Normal GGT Disruption of tight junctions at the biliary canaliculus

39. BRIC Similar genes as PFIC affected, AR Missense mutations, milder forms Intermittent attacks First pruritus, then jaundice No progression to CLD BRIC 1- FIC1- extrahepatic manifestations BRIC 2- BSEP- hepatosplenomegaly LPAC( BRIC 3)- MDR3- intrahepatic stones, biliary cirrhosis, cholelithiasis, elevated GGTP Itching, influenza type illness, vomiting, 25% pain, fatigue, anorexia, wt loss Jaundice may persist for 3-4mths, starts in 1 st decade

40. Hepatic histology : shows cholestasis with bile plugs, portal zone expansion, mononuclear cells and some liver cell degeneration, mainly in zone 1. Hepatic histology and liver function are normal in remission. The condition may recur at particular times of the year. TREATMENT The attacks are self- limiting and vary in duration. Corticosteroid treatment is probably of little benefit. S- adenosylmethionine is ineffective. Results with UDCA are conflicting. Rifampicin has been highly effective in some

41. INTRAHEPATIC CHOLESTASIS OF PREGNANCY Fasting serum bile acids have also been noted to be an early marker of intrahepatic cholestasis of pregnancy.

42. OBSTRUCTION TO THE LUMEN OF CANALICULI AND DUCTULES

43. Sickle Cell Crisis : Following Massive Haemolytic Episodes , The Lumen Of Bile Canaliculi May Be Expanded And Occluded By Solid Biliary Precipitate. Hereditary Protoporphyria : Protoporphyrin Precipitation In The Canalicular Ducts( Maltese Cross ) Benoxaprofen , An Antirheumatoid Drug Withdrawn From The Market Because Of Fatalities Due To Its Hepatotoxicity : Canalicular Concretions And Inspissated Casts In Ductules Severe Bacterial Infections , Particularly In Childhood Or Postoperatively. :Cytokine Dependent Downregulation Transporters Ntcp , Mrp2, Bsep - Bile Plugs In Dilated Periportal Cholangioles CYSTIC fibrosis : INSPISSATED BILE - CHOLESTASIS

44. DUCTOPENIA

45. Alagille syndrome AD Syndromic paucity of bile ducts small interlobular Bile ducts affected NOTCH2 mutation broad, prominent forehead, deep-set eyes, and a small pointed chin CVS: Tetralogy of Fallot, Pulmonary stenosis is common amongst Alagille patients and other defects ; overriding aorta, ventricular septal defect; and right ventricular hypertrophy Skeleton- butterfly vertebrae Kidney and CNS may be affected

46. VANISHING BILE DUCT SYNDROME Inspection of portal tracts in some patients with cholestasis reveals the triad is incomplete and that in more than 50%, the portal vein and hepatic artery have no accompanying interlobular bile duct. atypical ductular proliferation, cholestasis, biliary fibrosis and progression to liver cirrhosis This ductopenia is termed either paucity of intrahepatic bile ducts or the vanishing bile duct syndrome. Adults and adolescents with paucity of intrahepatic bile ducts are being increasingly described. Familial, drug–induced, late -onset form of the non-syndromic type seen in children

47. Other causes of ductopenia Extreme irreversible ductopenia may occur as part of chronic allograft rejection following liver transplantation flucloxacillin, co- amoxyclavulanic acid Hodgkin’s disease In severe cases all trace of interlobular bile ducts is lost and bile has the appearance of clear water. Lesser degrees of ductopenia are seen in sarcoid, primary sclerosing cholangitis and primary biliary cirrhosis

48. Primary Biliary Cirrhosis Antimitochondrial antibody- AMA-M2, against pyruvate dehydrogenase complex (PDC E2) Loss of tolerance to mitochondrial antigens ductulopenia - small and medium interlobular bile ducts, septal ducts

49. Fatigue, pruritus, jaundice(30-64yr female) AMA >1:40, elevated IgM Anti-Sp100 and anti-gp210 - high specificity for PBC (>95%). liver biopsy is not essential unless absent antbody or high ALT,ASTor IgG Annual reassessment of biochemical markers of cholestasis UDCA (13– 15 mg/kg/d) Liver transplantation - Bil >6 mg/ dL,Decompensated cirrhosis with an unacceptable quality of life PRIMARY BILIARY CIRRHOSIS

50. PBC criteria 1. AP >2 ULN or cGT >5 ULN 2. AMA 1:40 3. Liver biopsy specimen showing florid bile duct lesions AIH criteria 1. ALT >5 ULN 2. IgG >2 ULN or a positive test for anti-smooth muscle antibodies 3. Liver biopsy showing moderate or severe periportal or periseptal lymphocytic piecemeal necrosis Diagnostic criteria of PBC–AIH overlap syndrome of which at least 2 of 3 accepted criteria for PBC and AIH, respectively, should be present (proposed by Chazouilleres et al. ). Histological evidence of moderate to severe lymphocytic piecemeal necrosis (interface hepatitis) is mandatory for the diagnosis PBC-AIH OVERLAP

51. Primary Sclerosing Cholangitis Unknown etiology Resulting from inflammation, fibrosis and destruction of the intra and extrahepatic bile ducts and eventually progressing to biliary cirrhosis Bile ducts of all sizes can be affected, usually upto 0.3mm bile ducts are destroyed- extra, large interlobular bile ducts Peribiliary ischemia, loss of biliary bicarbonate protection, bile toxicity, paracellular leakage of bile, ductopenia, strictures PRIMARY SCLEROSING CHOLANGITIS (PSC)

52. LARGE BILE DUCT DISEASE WITH UNDILATED BD Choledocholithiasis with recently migrated stone from Gall bladder Small duct PSC Secondary sclerosing cholangitis complicating severe biliary infections, sarcoidosis, histiocytosis x

53. ASSESSMENT OF BILE DUCTS IN THE PORTAL TRACT An adequate biopsy size is 3 cm in length and 16 gauge in caliber to yield a sufficient number of portal tracts Diagnostic accuracy declines with specimen size, especially when smaller than 2 cm in length At least 11 portal tracts are required for accurate semiquantitative assessment, although 20 or more is ideal

54. Specific Bile Duct Changes Cholestatic Disorder Non-suppurative destructive cholangitis Primary biliary cirrhosis Fibrous obliterative cholangitis Primary sclerosing cholangitis Malignant cholangitis Lymphoma (Hodgkin’s or non-Hodgkin’s) Granulomatous cholangitis Portal Tract changes

55. DARK LIVER- MELANIN/ EPINEPHRINE METABOLITE DEPOSITION

56. DIAGNOSTIC APPROACH TO CHOLESTASIS IN ADULT PATIENTS.

57. EXTRA HEPATIC CHOLESTASIS INTRA HEPATIC CHOLESTASIS History Abdominal pain, Fever, rigors, Prior biliary surgery, Older age Anorexia, malaise, myalgias (viral prodrome) Known viral exposure History of blood product receipt or of injection drug use, Exposure to known hepatotoxin , Family history of liver disease Physical examination Fever, Abdominal tenderness, Palpable abdominal mass, Abdominal surgical scar Spider angiomata , Stigmata of portal hypertension, Asterixis Laboratory studies   Predominant elevation of serum alkaline phosphatase relative to aminotransferases Prothrombin time (INR) normal or normalizes with vitamin K administration Leukocytosis Elevated serum amylase or lipase level Predominant elevation of serum aminotransferase levels relative to alkaline phosphatase Prolonged prothrombin time that does not normalize with vitamin K administration Thrombocytopenia Serologies indicative of specific liver disease

58. PRURITIS MANAGEMENT Cholestyramine 4 g up to four times daily or other resins are regarded as first-line treatment of pruritus Resins should be spaced away from UDCA and other drugs by at least 4 hours Rifampicin : second-line treatment 150 mg max: 600 mg/daily Naltrexone(opiate antagonist):3rd line : 50 mg/d starting at a low dose of 25 mg /d Sertralin – 4th Line

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