Hyperbilirubinemia

These slides describe in short about the conditions in which Hyperbilirubinemia can occur.

1. hyperbilirubinemia

2. introduction Hyperbilirubinemia :- An elevated level of the pigment bilirubin in the blood. Occurs when ,serum bilirubin >2 mg/dl Yellowing of the skin, scleras (white of the eye), and mucous membranes (jaundice) A sufficient elevation of bilirubin produces  jaundice. Hyperbilirubinemia is a biochemical finding but jaundice is a clinical finding for increased bilirubin levels in the blood.

3. Bilirubin metabolism

4. Bilirubin formation

5. Hepatocellular bilirubin transport Transfer of bilirubin from blood to bile involves four distinct but interrelated steps, as follows: Hepatocellular Uptake Intracellular Binding Conjugation Biliary Excretion

6. Bilirubin and its breakdown

7. Enterohepatic circulation

8. Hepatocellular Conditions that May Produce Jaundice Viral hepatitis Hepatitis A, B, C, D, and E Epstein-Barr virus Cytomegalovirus Herpes simplex Alcohol Drug toxicity Predictable, dose-dependent (e.g., acetaminophen) Unpredictable, idiosyncratic (e.g., isoniazid ) Environmental toxins Vinyl chloride Jamaica bush tea— pyrrolizidine alkaloids Kava Kava Wild mushrooms— Amanita phalloides or A. verna Wilson's disease Autoimmune hepatitis

9. Cholestatic Conditions that May Produce Jaundice 1. Intrahepatic Viral hepatitis 1. Fibrosing cholestatic hepatitis—hepatitis B and C 2. Hepatitis A, Epstein-Barr virus, cytomegalovirus Alcoholic hepatitis Drug toxicity 1. Pure cholestasis —anabolic and contraceptive steroids 2. Cholestatic hepatitis—chlorpromazine, erythromycin estolate 3. Chronic cholestasis —chlorpromazine and prochlorperazine Primary biliary cirrhosis Primary sclerosing cholangitis Vanishing bile duct syndrome 1. Chronic rejection of liver transplants 2. Sarcoidosis 3. Drugs Inherited 1. Progressive familial intrahepatic cholestasis 2. Benign recurrent cholestasis Cholestasis of pregnancy

10. Cholestatic Conditions that May Produce Jaundice 1. Intrahepatic Total parenteral nutrition Nonhepatobiliary sepsis Benign postoperative cholestasis Paraneoplastic syndrome Venoocclusive disease Graft-versus-host disease Infiltrative disease 1. TB 2. Lymphoma 3. Amyloid Infections 1. Malaria 2. Leptospirosis

11. Cholestatic Conditions that May Produce Jaundice 2 . Extrahepatic A. Malignant 1. Cholangiocarcinoma 2. Pancreatic cancer 3. Gallbladder cancer 4. Ampullary cancer 5. Malignant involvement of the porta hepatis lymph nodes B. Benign 1. Choledocholithiasis 2. Postoperative biliary structures 3. Primary sclerosing cholangitis 4. Chronic pancreatitis 5. AIDS cholangiopathy 6. Mirizzi's syndrome 7. Parasitic disease ( ascariasis )

12. INCREASED BILIRUBIN PRODUCTION Hemolysis Increased destruction of RBCs eg sickle cell anemia, thalassemia Drastic increase in the amount of bilirubin produced Unconj . bilirubin levels rise due to liver’s inability to catch up to the increased rate of RBC destruction Prolonged hemolysis may lead to precipitation of bilirubin salts in the gall bladder and biliary network result in formation of gallstones and conditions such as cholecystitis and biliary obstruction UNCONJUGATED HYPERBILIRUBINEMIA

13. Clinical manifestation Unconjugated hyperbilirubinemia Normal serum level of transaminases,alkaline phosphatase,proteins Acholuric jaundice (bile pigment absent in urine) Dark brown color in stool Increased urinary excretion of urobilinogen

14. Ineffective erythropoiesis develoing erythroid cells destroyed in bone marrow fraction of total bilirubin production increased unconjugated hyperbilirubinemia Occurs in thalassemia major Megaloblastic anemia Congenital erythropoietic porphyria Lead poisoning Other Degradation of Hb originating from areas of tissue infarctions and hematomas

15. DECREASED HEPATIC UPTAKE ( unconj . Hyperbilirubinemia ) Several drugs have been reported to inhibit bilirubin uptake by the liver e.g. novobiocin , flavopiridol , Rifampicin Bile MRP2 B + GST CB Plasma Hepatic cell Alb B Alb :GST B sER B + UDPGA UGT1A1 Impairment in dissociation of bilirubin from albumin Dearrangement of binding to cytoplasmic protein –GST

16. due to defect or deficiency in the enzyme bilirubin-UDP glucurunosyl transferase P hysiological jaundice of Newborn incompletely developed hepatic physiologic processes decreased UGT1A1 in neonates,alternate excretory pathway unconjugated bilirubin in the gut (intestinal flora under-developed;bilirubin urobilinogen ) enterohepatic circulation of unconjugated bilirubin unconjugated hyperbilirubinemia (5-10mg/dl) in 2-5 days In pre-term infants,profound hepatic dysfunction can lead to higher levels of unconjugated hyperbilirubinemia (>20mg/dl) Complication:kernicterus t/ t:Phototherapy,exchange transfusion 3) DISRUPTED INTRACELLULAR CONJUGATION ( unconj . Hyperbilirubinemia )

17. Impaired bilirubin conjugation Acquired conjugation defects Breast milk jaundice bilirubin conjugation inhibited by certain fatty acid present in breast milk EGF in breast milk is also associated Diffuse hepatocellular disease Hepatitis cirrhosis Drugs inhibiting UGT1A1 activity pregnanediol Novobiocin Chloramphenicol Gentamicin

18. HEREDITARY DEFECTS IN BILIRUBIN CONJUGATION Three familial disorders characterized by differing degrees of unconjugated hyperbilirubinemia have long been recognized. D iffering degrees of deficiency in the ability to conjugate bilirubin. Some of the disorders are as follows :- Crigler Najjar Syndrome Gilbert’s Syndrome

19. Crigler-najjar syndrome This syndrome is of two types:- Crigler Najjar Syndrome Type 1 Crigler Najjar Syndrome Type 2

20. Crigler Najjar Syndrome Type 1 Characterised by unconjugated hyperbilirubinemia of about 20-45 mg/ dL . Rare disorder – Shows Autosomal Recessive Inheritence . Usually appears in Neonatal period and persists for life. Mutation in UGT1 gene. Conventional hepatic function tests are normal. Hepatic histology is normal but sometimes bile plugs can develop in canaliculi. Bilirubin glucuronides – Absent in the bile. N o detectable constitutive expression of UGT1A1 activity in hepatic tissue. Unconjugated bilirubin accumulation (but can be excreted via alternative pathways) No response to Phenobarbital or other enzyme inducers. E arly liver transplantation remains the best hope to prevent brain injury and death.

21. Crigler Najjar Syndrome Type 2 Similar presentation to Crigler Najjar Syndrome Type 1 Differences: Average bilirubin concentrations are lower in CN-II CN-II is only infrequently associated with kernicterus B ile is deeply colored Bilirubin glucuronides are present (Characteristic increase in the proportion of monoglucuronides ) UGT1A1 in liver is usually present at reduced levels (typically ≤10% of normal ) Reduction of serum bilirubin concentrations by >25% in response to enzyme inducers such as phenobarbital distinguishes CN-II from CN-I. Incidence of kernicterus in CN-II is low

22. Gilbert Syndrome Mild unconjugated hyperbilirubinemia. Serum bilirubin concentrations are most often < 3 mg/ dL M>F N ormal values for standard hepatic biochemical tests N ormal hepatic histology but modest increase in lipofuscin . Association with other conditions like stress, fatigue, alcohol use, etc. can aggrevate the bilirubin levels Relieving factors :- enzyme inducing agents UGT1A1 activity is reduced to about 10-35% of normal. Phenobarbital normalizes serum bilirubin concentration and hepatic bilirubin clearance D efect in bilirubin uptake as well as in conjugation

23. DISORDERS OF BILIRUBIN METABOLISM LEADING TO MIXED OR PREDOMINANTLY CONJUGATED HYPERBILIRUBINEMIA

24. DISRUPTED SECRETION OF BILIRUBIN INTO BILE CANALICULI Dubin –Johnson Syndrome mild conj. hyperbilirubinemia , but can increase with concurrent illness, pregnancy, and use of oral contraceptives; otherwise asymptomatic Inability of hepatocytes to secrete CB after it has formed Due to mutation in the MRP2 gene ( autosomal recessive trait) Liver histology shows black pigmentation Bile MRP2 B + GST CB Plasma Hepatic cell Alb B Alb :GST B sER B + UDPGA UGT1A1

25. Rotor Syndrome Autosomal recessive condition Characterized by increased total bilirubin levels due to a rise in CB Caused by a defect in transport of bilirubin into bile Similar to Dubin – johnson , but no pigmentation in liver histology T otal urinary coproporphyrin excretion is substantially increased in Rotor syndrome

26. BENIGN RECURRENT INTRAHEPATIC CHOLESTASIS(BRIC) Autosomal recessive FIC1 gene mutated Characterised by recurrent attacks of pruritis and jaundice Typical episode malaise elevation in serum aminotransferase rise in alkaline phosphatase and conjugated bilirubin onset of jaundice and itching Benign because it does not lead to cirrhosis or end-stage liver disease

27. Cholestatic conditions

28. Cholestatic Diseases : Cholestasis Cholestasis is caused by: impaired bile formation and bile flow G ives rise to accumulation of bile pigment in the hepatic parenchyma. C an be caused by: extrahepatic or intrahepatic obstruction of bile channels or defects in hepatocyte bile secretion.

29. Cholestatic Diseases : Cholestasis Morphologic features of cholestasis : Cholestatic hepatocytes are enlarged W ith dilated canalicular spaces Apoptotic cells may be seen Kupffer cells frequently contain regurgitated bile pigments

30. Cholestatic Diseases : Cholestasis Morphologic features of cholestasis : 5. Bile plug ( arrow) showing the expansion of bile canaliculus by bile. 6. FEATHERY DEGENERATION: Droplets of bile pigment also accumulate within hepatocytes , which can take on a fine, foamy appearance .

31. Cholestatic Diseases : Large Bile Duct Obstruction Most common cause of bile duct obstruction in adults: Extrahepatic cholelithiasis (gallstones) followed by Malignancies of the biliary tree or head of the pancreas, and Strictures resulting from previous surgical procedures. Obstructive conditions in children include: biliary atresia cystic fibrosis choledochal cysts syndromes in which there are insufficient intrahepatic bile ducts.

32. Cholestatic Diseases : Large Bile Duct Obstruction Acute biliary obstruction, either intrahepatic or extrahepatic , causes D istention of upstream bile ducts  become dilated . B ile ductules proliferate at the portalparenchymal interface , accompanied by stromal edema and infiltrating neutrophils . These labyrinthine ductules reabsorb secreted bile salts, serving to protect the downstream obstructed bile ducts from their toxic detergent action. H istologic hallmark of ascending cholangitis is the influx of these periductular neutrophils directly into the bile duct epithelium and lumen

33. Cholestatic Diseases : Large Bile Duct Obstruction C hronic biliary obstruction and ductular reactions: S econdary inflammation initiate Periportal fibrosis, eventually leading to hepatic scarring and N odule formation, generating secondary or obstructive biliary cirrhosis.

34. Cholestatic Diseases : Large Bile Duct Obstruction Chronic biliary obstruction and ductular reactions:Cholestatic features in the parenchyma may be severe with: Extensive feathery degeneration of periportal hepatocytes Cytoplasmic swelling often with Mallory- Denk bodies ( periportal predominance) Formation of bile infarcts from detergent effects of extravasated bile. Ascending cholangitis may be superimposed on this chronic process as well, sometimes triggering acute on-chronic liver failure.

35. Cholestatic Diseases : Cholestasis of Sepsis Sepsis may affect the liver by several mechanisms: Through direct effects of intrahepatic bacterial infection ( e.G. , Abscess formation or bacterial cholangitis ), Ischemia relating to hypotension caused by sepsis (particularly when the liver is cirrhotic), or In response to circulating microbial products (LPS).

36. Cholestatic Diseases : Cholestasis of Sepsis Two forms: Canalicular cholestasis : Bile plugs within predominantly centrilobular canaliculi . Associated with activated kupffer cells and mild portal inflammation, But hepatocyte necrosis is scant or absent

37. Cholestatic Diseases : Cholestasis of Sepsis 2. Ductular cholestasis : More ominous finding Dilated canals of hering and bile ductules at the interface of portal tracts and parenchyma become dilated and contain obvious bile plugs Often accompanies or even precedes the development of septic shock.

38. Cholestatic Diseases : Primary Hepatolithiasis Hepatolithiasis is a disorder of intrahepatic gallstone formation that leads to Repeated bouts of ascending cholangitis Progressive inflammatory destruction of hepatic parenchyma Predisposes to biliary neoplasia .

39. Cholestatic Diseases : Primary Hepatolithiasis Hepatolithiasis has pigmented calcium bilirubinate stones in distended intrahepatic bile ducts. The ducts show chronic inflammation, mural fibrosis, and peribiliary gland hyperplasia , all in the absence of extrahepatic duct obstruction. Biliary dysplasia may be seen and may evolve to invasive cholangiocarcinoma .

40. Cholestatic Diseases : Neonatal Cholestasis Prolonged conjugated hyperbilirubinemia in the neonate beyond 14-21 days after birth. Major causes: Neonatal Hepatitis Biliary Atresia Differentiation between two must: surgical correction for Biliary A tresia

41. Cholestatic Diseases : Neonatal Cholestasis Neonatal hepatitis is not a specific entity Nor are the disorders necessarily inflammatory. Morphologic findings Lobular disarray with focal liver cell apoptosis and necrosis Panlobular giant-cell transformation of hepatocytes Prominent hepatocellular and canalicular cholestasis

42. Cholestatic Diseases : Neonatal Cholestasis Morphologic findings Mild mononuclear infiltration of the portal areas; Reactivechanges in kupffer cells; and Extramedullary hematopoiesis . Parenchymal pattern of injury may blend into a ductal pattern of injury: With ductular reaction And fibrosis of portal tracts In these cases distinction froman obstructive biliary atresia may therefore be difficult.

43. Cholestatic Diseases : Neonatal Cholestasis Biliary Atresia : Biliary atresia is defined as a complete or partial obstruction of the lumen of the extrahepatic biliary tree within the first 3 months of life. Two forms: Fetal form: aberrant intrauterine development of the extrahepatic biliary tree Perinatal form: presumed normally developed biliary tree is destroyed following birth. Etiology unknown  viral infection ( Reovirus , rotavirus,and cytomegalovirus) and autoimmunereactions are leading suspects.

44. Cholestatic Diseases : Neonatal Cholestasis Variability in the anatomy of biliary atresia : Common duct (type I) Right and/or left hepatic bile ducts (type II) Obstruction of bile ducts at or above the porta hepatis (type III) Salient features of biliary atresia : Inflammation and fibrosing stricture of the hepatic or common bile ducts Periductular inflammation may progress into the intrahepatic bile ducts  progressive destruction of the intrahepatic biliary tree

45. Primary Biliary Cirrhosis PBC is an autoimmune disease characterized by nonsuppurative , inflammatory destruction of small and medium sized intrahepatic bile ducts. Large intrahepatic ducts and the extrahepatic biliary tree are not involved . Pathogenesis AMA : recognize the E2 component of the pyruvate dehydrogenase complex (PDC-E2 ) PDC-E2–specific T cells Aberrant expression of MHC class II molecules on bile duct epithelial cells, accumulation of autoreactive T cells around bile ducts, and antibodies against other cellular components Cholestatic Diseases : Autoimmune Cholangiopathies

46. Primary Biliary Cirrhosis: Sagittal section: liver enlargement , nodularity indicative of cirrhosis, and green discoloration due to cholestasis . Cholestatic Diseases : Autoimmune Cholangiopathies

47. Primary Biliary Cirrhosis: Ductular reactions follow duct injury, and these in turn participate in the development of portal-portal septal fibrosis Cholestatic Diseases : Autoimmune Cholangiopathies

48. Primary Biliary Cirrhosis: THE FLORID DUCT LESION: Interlobular bile ducts are actively destroyed by lymphoplasmacytic inflammation with or without granulomas Cholestatic Diseases : Autoimmune Cholangiopathies

49. Primary Sclerosing Cholangitis (PSC) PSC is characterized by inflammation and obliterative fibrosis of intrahepatic and extrahepatic bile ducts with dilation of preserved segments. Pathogenesis: Immunologically mediated injury to bile ducts: T cells in the periductal stroma P resence of circulating autoantibodies A ssociation with HLA-B8 and other MHC antigens L inkage to ulcerative colitis It has been proposed that T cells activated in the damaged mucosa of patients with ulcerative colitis migrate to the liver where they recognize a cross-reacting bile duct antigen. Autoantibody profiles in PSC are not as characteristic as they are in PBC Cholestatic Diseases : Autoimmune Cholangiopathies

50. Primary Sclerosing Cholangitis (PSC): Large duct inflammation: Similar to ulcerative colitis Acute, neutrophilic infiltration of the epithelium superimposed on a chronic inflammatory background. Inflamed areas develop strictures because edema and inflammation narrows the lumen or because of subsequent scarring. Smaller ducts: Little inflammation Striking circumferential “onion skin” fibrosis around an increasingly atrophic duct lumen eventually leading to obliteration by a “tombstone” scar. Cholestatic Diseases : Autoimmune Cholangiopathies

51. Primary Sclerosing Cholangitis (PSC): Because the likelihood of sampling smaller duct lesions on a random needle biopsy is miniscule, diagnosis depends on radiologic imaging of the extrahepatic and larger intrahepatic ducts. Cholestatic Diseases : Autoimmune Cholangiopathies