5 Normal Physiology Bilirubin is from breakdown of hemoglobin Unconjugated bilirubin transported to liverBound to albumin because insoluble in waterTransported into hepatocyte & conjugatedWith glucuronic acid → now water solubleSecreted into bileIn ileum & colon, converted to urobilinogen10-20% reabsorbed into portal circulation and re-excreted into bile or into urine by kidneys
6 PathophysiologyJaundice = bilirubin staining of lvl greater than ~2Mechanisms:↑ production of bilirubin↓ hepatocyte transport or conjugationImpaired excretion of bilirubinImpaired delivery of bilirubin into intestine“surgically relevant jaundice” or obstructive jaundice“Cholestasis” refers to the latter two, impaired excretion and obstructive jaundice
7 What causes jaundice? Category Definition Pre-hepatic Pathology occurs prior to the liverHepaticPathology locatedwithin the liverPost-hepaticPathology located afterthe conjugation of bilirubin in the liver
9 Prehepatic JaundicePrehepatic jaundice is caused by increased destruction of erythrocytes either:- mature cells or- precursors (ineffective erythropoiesis).The breakdown of mature cells can be caused by:- haemolysis, or- as a result of the metabolism of bloodfollowing internal haemorrhage, e.g. intoa soft tissue injury or fracture.
10 Prehepatic JaundiceIneffective erythropoiesis occurs in conditions such as:- pernicious anaemia, where thematuration of red cells is impaired, or- thalassaemia, where the structureof haemoglobin is abnormal.Hyperbilirubinaemia in prehepatic jaundice results fromthe accumulation of unconjugated bilirubin; this is not excreted by the kidney.
11 Prehepatic JaundiceJaundice occurs because the conjugating capacity of the liver is saturated,- the capacity of the liver for conjugation isgreater than the normal rate of bilirubin production.Increased fluxes of bilirubin through the liver into the gutGreater amounts of urobilinogen are produced, with- increased urobilinogen excretion in urine.
12 KEY POINTS Prehepatic jaundice is most commonly Caused by haemolytic diseaseBilirubin (unconjugated) is not excreted in urineUrinary urobilinogen concentration is increased
13 Hepatic JaundiceCongenital disorders of bilirubin transport lead to jaundice because of:- defective uptake, reduced conjugationor impaired excretion of bilirubin.Generalized hepatocellular dysfunction may occur in hepatitis and hepatic cirrhosis.Drugs may cause hepatocellular damage, either due to dose-dependent hepatoxicity (e.g. paracetamol).
14 Hepatic JaundiceThe pathogenesis of jaundice in these conditions is complex,- reduced hepatic uptake,- decreased conjugation and,- impaired intracellular transportof bilirubin, all contributing.
15 Hepatic JaundiceWhen hyperbilirubinaemia is caused by impaired conjugation of bilirubin;- unconjugated bilirubin, and noincreased fluxes of bilirubin through the liver,- bilirubinuria does not occur and- urinary urobilinogen is not increased.
16 Hepatic JaundiceSerum bilirubin may be unconjugated or conjugated, as glucuronyl transferase and intracellular transport may be defective.If the rate of conjugation exceeds excretory capacity;- conjugated hyperbilirubinaemia willoccur and bilirubin may be excreted,in urine,- this is sometimes seen in recovery from acuteviral hepatitis.
17 KEY POINTS Jaundice due to hepatocyte dysfunction may be caused by selective transport defectsof generalized cell dysfunctionBoth conjugated and unconjugated hyperbilrubinaemiamay occur in hepatocellular jaundiceBilirubin and excess urobilinogen may befound in urine
18 Cholestatic JaundiceCholestatic jaundice results from interference to biliary flow between the sites of secretion by the hepatocyte and drainage into the duodenum.It may be caused by lesions;- within the liver (intrahepatic cholestasis),or in the biliary tree or head of thepancreas (extrahepatic cholestasis);- the term cholestatic is preferable to post-hepaticto describe this pattern of jaundice.
19 Cholestatic JaundiceIntra- and extra-hepatic cholestasis can be differentiated by;- ultrasound examination or- liver biopsy, but not by liver function tests.Intrahepatic cholestasis may result from generalized hepatocellular dysfunction, such as occurs in;- Hepatitis,- Hepatic cirrhosisHepatic malignancies may block branches of the biliary tree.
20 Cholestatic JaundiceSome drugs may cause intrahepatic cholestasis such as:- anabolic steroids, and- phenothiazinesExtrahepatic obstruction may be due to tumours in:- major branches of the biliary tract,- head of pancreas.Gallstones may obstruct biliary flow.
21 Cholestatic JaundiceJaundice is due to impaired excretion and accumulation of conjugated bilirubin which can be filtered by the kidney and appear in urine.If obstruction is complete bilirubin does not reach the gut, therefore urobilinogen:- is not produced, and- is absent in urine.Under such circumstances the stools are pale.
22 KEY POINTS Cholestasis may be caused by lesions within or outside the liverJaundice is due to conjugated bilirubinBilirubin is found in urine
23 Obstructive Jaundice Common Infrequent Rare Common bile duct stones Carcinoma of the head of pancreasMalignant lymph nodes at the porta hepatisInfrequentAmpullary carcinomaPancreatitisLiver secondariesRareBenign strictures - iatrogenic, traumaRecurrent cholangitisMirrizi's syndromeSclerosing cholangitisCholangiocarcinomaBilary atresiaCholedochal cysts
25 DDx: Unconjugated bilirubinemia ↑productionExtravascular hemolysisExtravasation of blood into tissuesIntravascular hemolysisErrors in production of red blood cellsImpaired hepatic bilirubin uptake(trnsport)CHFPortosystemic shuntsDrug inhibition: rifampin, probenecid
31 Laboratory Tests Bilirubin level in serum (total and direct) Complete blood countProthrombin timeOther laboratory tests pertinent to historyCoombs testElectrophoresis of hemoglobinViral hepatitis panelBilirubin level in serum (total and direct)AminotransferaseAlkaline phosphataseU/A for bilirubin and urobilogen
32 TreatmentTreatment requires a precise diagnosis of the specific cause and should be directed to the specific problem
33 Summary in liver function tests in the differential diagnosis of jaundice Test Prehepatic Hepatic CholestaticSerum bilirubin Uncojugated Mixed ConjugatedUrine bilirubin Absent//Present Present PresentUrine Urobilinogen Increased Increased DecreasedALT & AST Normal Marked Slightincrease increaseALP Normal Slight Marked increase increase
34 Clinical Case 1 50 year old female Acute, severe pain in RUQ Nausea and vomitingCalls GP – pethidine pain reliefNext few days notices dark urine and pale stoolsHer husband comments she has a pale yellow tinge
35 Emergency admission What investigations would you do ? What results would you expect?
36 Abdominal Ultrasound showing multiple gallstones in gallbladder
41 Case 1 Obstructive jaundice due to gallstone in common bile duct Blood tests show high bilirubin and high alkaline phosphataseUrine contains bilirubinTreatment includes ERCP to remove stone and then plan Cholecystectomy