Jaundice
•Definition•Causes•History• Investigation-Imaging•Clinical Cases
Definition
• Jaundice is a yellowing of the skin, conjunctiva and mucous membranes caused by hyperbilirubinaemia.
Jaundice
Normal Physiology
• Bilirubin is from breakdown of hemoglobin• Unconjugated bilirubin transported to liver
– Bound to albumin because insoluble in water• Transported into hepatocyte & conjugated
– With glucuronic acid → now water soluble• Secreted into bile• In ileum & colon, converted to urobilinogen
– 10-20% reabsorbed into portal circulation and re-excreted into bile or into urine by kidneys
Jaundice
Pathophysiology• Jaundice = bilirubin staining of tissue @ lvl
greater than ~2• Mechanisms:
– ↑ production of bilirubin– ↓ hepatocyte transport or conjugation– Impaired excretion of bilirubin– Impaired delivery of bilirubin into intestine
• “surgically relevant jaundice” or obstructive jaundice
– “Cholestasis” refers to the latter two, impaired excretion and obstructive jaundice
Category Definition
Pre-hepaticPathology occurs prior to the liver
Hepatic Pathology located within the liver
Post-hepatic
Pathology located after the conjugation of bilirubin in the liver
What causes jaundice?
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Prehepatic Jaundice • Prehepatic 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 blood
following internal haemorrhage, e.g. into a soft tissue injury or fracture.
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Prehepatic Jaundice
• Ineffective erythropoiesis occurs in conditions such as:
- pernicious anaemia, where the maturation of red cells is impaired, or
- thalassaemia, where the structure of haemoglobin is abnormal.
• Hyperbilirubinaemia in prehepatic jaundice results from the accumulation of unconjugated bilirubin; this is not
excreted by the kidney.
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Prehepatic Jaundice
• Jaundice occurs because the conjugating capacity of the liver is saturated,
- the capacity of the liver for conjugation is greater than the normal rate of bilirubin production.
• Increased fluxes of bilirubin through the liver into the gut
• Greater amounts of urobilinogen are produced, with
- increased urobilinogen excretion in urine.
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KEY POINTS
Prehepatic jaundice is most commonly Caused by haemolytic disease
Bilirubin (unconjugated) is not excreted in urine
Urinary urobilinogen concentration is increased
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Hepatic Jaundice • Congenital disorders of bilirubin transport lead to
jaundice because of: - defective uptake, reduced conjugation
or 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).
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Hepatic Jaundice
• The pathogenesis of jaundice in these conditions is complex,
- reduced hepatic uptake,
- decreased conjugation and,
- impaired intracellular transport
of bilirubin, all contributing.
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Hepatic Jaundice
• When hyperbilirubinaemia is caused by impaired conjugation of bilirubin;
- unconjugated bilirubin, and no increased fluxes of bilirubin through the liver,
- bilirubinuria does not occur and
- urinary urobilinogen is not increased.
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Hepatic Jaundice
• Serum 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 will occur and bilirubin may be excreted,in urine,
- this is sometimes seen in recovery from acute viral hepatitis.
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KEY POINTS
Jaundice due to hepatocyte dysfunction may be caused by selective transport defects
of generalized cell dysfunction
Both conjugated and unconjugated hyperbilrubinaemiamay occur in hepatocellular jaundice
Bilirubin and excess urobilinogen may be found in urine
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Cholestatic Jaundice • Cholestatic 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 the pancreas (extrahepatic cholestasis);
- the term cholestatic is preferable to post-hepatic to describe this pattern of jaundice.
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Cholestatic Jaundice
• Intra- 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 cirrhosis
• Hepatic malignancies may block branches of the biliary tree.
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Cholestatic Jaundice
• Some drugs may cause intrahepatic cholestasis such as: - anabolic steroids, and
- phenothiazines
• Extrahepatic obstruction may be due to tumours in:
- major branches of the biliary tract, - head of pancreas.
• Gallstones may obstruct biliary flow.
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Cholestatic Jaundice
• Jaundice 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.
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KEY POINTS
Cholestasis may be caused by lesions within or outside the liver
Jaundice is due to conjugated bilirubin
Bilirubin is found in urine
Obstructive Jaundice• Common
– Common bile duct stones– Carcinoma of the head of pancreas– Malignant lymph nodes at the porta hepatis
• Infrequent– Ampullary carcinoma– Pancreatitis– Liver secondaries
• Rare– Benign strictures - iatrogenic, trauma– Recurrent cholangitis– Mirrizi's syndrome– Sclerosing cholangitis– Cholangiocarcinoma– Bilary atresia– Choledochal cysts
Jaundice
Broad Differential Diagnosis↑production ↓transport or
↓conjugationImpaired excretion
Biliary obstruction
↑ Unconjugate ↑ Unconjugate ↑ Conjugated ↑ Conjugated
Hemolysis Gilbert’s Rotor’s CH/CBD stone
Transfusions Crigler-Najarr DubinJohnson Stricture
Sepsis Cirrhosis Cirrhosis Chronic pancreatitis
Burns Hepatitis Hepatitis PSC
Hgb-opathies Drug inhibition Amyloidosis
Pregnancy
Jaundice
DDx: Unconjugated bilirubinemia
• ↑production– Extravascular hemolysis– Extravasation of blood into tissues– Intravascular hemolysis– Errors in production of red blood cells
• Impaired hepatic bilirubin uptake(trnsport)– CHF– Portosystemic shunts– Drug inhibition: rifampin, probenecid
Jaundice
DDx: Unconjugated bilirubinemia
• Impaired bilirubin conjugation– Gilbert’s disease– Crigler-Najarr syndrome– Neonatal jaundice (this is physiologic)– Hyperthyroidism– Estrogens– Liver diseases
• chronic hepatitis, cirrhosis, Wilson’s disease
Jaundice
DDx: Conjugated Bilirubinemia• Intrahepatic cholestasis/impaired excretion
– Hepatitis (viral, alcoholic, and non-alcoholic)• Any cause of hepatocellular injury
– Primary biliary cirrhosis or end-stage liver dz– Sepsis and hypoperfusion states– TPN– Pregnancy– Infiltrative dz: TB, amyloid, sarcoid, lymphoma– Drugs/toxins i.e. chlorpromazine, arsenic– Post-op patient or post-organ transplantation– Hepatic crisis in sickle cell disease
Jaundice
DDx: Obstructive Jaundice• Obstructive Jaundice– extrahepatic
cholestasis– Choledocholithiasis (CBD or CHD stone)– Cancer (peri-ampullary or cholangioCA)– Strictures after invasive procedures– Acute and chronic pancreatitis– Primary sclerosing cholangitis (PSC)– Parasitic infections
• Ascaris lumbricoides, liver flukes
Jaundice
History Physical examination Blood tests - laboratory Ultrasonography CT MRI Liver biopsy ERCP Endoscopic ultrasound
Diagnosis
Laboratory Tests
Bilirubin level in serum (total and direct)
Aminotransferase Alkaline
phosphatase U/A for bilirubin and
urobilogen
Complete blood count
Prothrombin time Other laboratory
tests pertinent to history
Coombs test Electrophoresis of
hemoglobin Viral hepatitis panel
Treatment
Treatment requires a precise diagnosis of the specific cause and should be directed to the specific problem
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Summary in liver function tests in the differential diagnosis of jaundice
Test Prehepatic Hepatic Cholestatic
Serum bilirubin Uncojugated MixedConjugated
Urine bilirubin Absent//PresentPresent Present
Urine Urobilinogen Increased Increased Decreased
ALT & AST Normal Marked Slight increase increase
ALP Normal Slight Marked increase increase
•Clinical Case 1
• 50 year old female• Acute, severe pain in RUQ• Nausea and vomiting• Calls GP – pethidine pain relief• Next few days notices dark urine and
pale stools• Her husband comments she has a pale
yellow tinge
Emergency admission
• What investigations would you do ?
• What results would you expect?
Abdominal Ultrasound showing multiple gallstones in gallbladder
US shows stone in Common Bile Duct
MRCP showing stone in Common Bile Duct
ERCP showing stone in Common Bile Duct
Case 1
• Obstructive jaundice due to gallstone in common bile duct
• Blood tests show high bilirubin and high alkaline phosphatase
• Urine contains bilirubin• Treatment includes ERCP to
remove stone and then plan Cholecystectomy
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