Clinical Presentation and Management of Liver / Gallbladder Disease Flashcards Preview

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What is jaundice?

  • Jaundice is a clinical sign due to the accumulation of bilirubin in the bloodstream and deposition in the skin, sclera and mucous membranes. 


What is the normal range for total bilirubin?

  • 3.4-20µmol/L = normal range. 
  • Jaundice may not be clinically evident until >50µmol/L.


What is bilirubin used for?

  • Bilirubin is the main component in bile. It is responsible for bruises being yellow. 
  • After bilirubin metabolism, is it responsible for the yellow tinge of urine and brown colour of faeces (stercobilinogen).


Describe the role of bilirubin in the reticuloendothelial system.

  • When RBCs come to the end of their ~120 day life, macrophages phagocytose and digest them in the spleen; Hb is broken down into:
    • Globin chains → further broken down into amino acids. 
    • Haem groups → split into Fe and protoporphyrin. 
  • Protoporphyrin is then converted to → UNCONJUGATED biliirubin (lipid soluble; not water soluble). 
  • Albumin in the plasma binds this unconjugated bilirubin→ this enables the unconjugated bilirubin to be transported in the blood stream to the liver. 


Describe what happens to bilirubin in the liver.

  • Albumin transports unconjugated bilirubin (UCB) to the hepatocytes. 
  • Hepatocytes CONJUGATE the UCB vie uridine glucuronly transferase (UGT) → this produces conjugated bilirubin that is WATER-SOLUBLE. 


What happens to bilirubin after it has been conjugated in the liver?

  • The conjugated (water-soluble) bilirubin is then transported out of the liver via the bile canaliculi → for storage in the gall bladder as bile.
  • When you next eat, the gallbladder contracts (cholecystokinin) and secretes the bile that contains the conjugated bilirubin. 
    • The bile passes through the common bile duct into the duodenum.


What happens to bile after it has been passed into the duodenum?

  • The bile is de-conjugated to urobilinogen by intestinal microbes in the gut. 
    • 90% ofthe urobilinogen is reduced into stercobilinogen and stercobilin - excreted into the faeces and makes it brown. 
    • 10% of the urobilinogen (colourless) is reabsorbed into the blood via the hepatic portal vein and spontaneously oxidises into urobilin. 
      • Most of the urobilin is sent to the liver and some is sent to the kidneys = makes urine yellow. 


Describe the basic physiology of jaundice.

  • Jaundice arises when there are disruptions along the metabolic pathway. 
    • Increased RBC destruction (haemolysis) or impaired bilirubin conjugation (e.g. secondary to hepatocyte damage or hepatitis, where hepatocytes die and release their bilirubin) → leads to an increase in unconjugated bilirubin.
    • Conjugated bilirubin increases from hepatocellular damage (intra-hepatic cause) or biliary obstruction (post-hepatic cause).
    • Overall → increased bilirubin in the blood can be :
      • Conjugated (water-soluble) or unconjugated (lipid-soluble) = yellowing of sclera and skin. 


Give the changes in the following as a result of pre-hepatic jaundice:

  • Colour of stool
  • Unconjugated bilirubin (lipid-soluble)
  • Conjugated bilirubin (water-soluble)
  • Bilirubin in urine 
  • Urinary urobilinogen (colourless)
  • Other significant findings

  • Colour of stool - dark
  • Unconjugated bilirubin (lipid-soluble) - ++
  • Conjugated bilirubin (water-soluble) - Normal
  • Bilirubin in urine - Normal
  • Urinary urobilinogen (colourless) - ++ but may be dark with haemoglobinuria. 
  • Other significant findings - Haemolytic markers, anaemia.


Give the changes in the following as a result of intrahepatic jaundice:

  • Colour of stool
  • Unconjugated bilirubin (lipid-soluble)
  • Conjugated bilirubin (water-soluble)
  • Bilirubin in urine 
  • Urinary urobilinogen (colourless)
  • Other significant findings

  • Colour of stool - Pale
  • Unconjugated bilirubin (lipid-soluble) - +
  • Conjugated bilirubin (water-soluble) - +
  • Bilirubin in urine - + Dark
  • Urinary urobilinogen (colourless) - Normal or +
  • Other significant findings - + transaminases + cholestatic enzymes.


Give the changes in the following as a result of intrahepatic jaundice:

  • Colour of stool
  • Unconjugated bilirubin (lipid-soluble)
  • Conjugated bilirubin (water-soluble)
  • Bilirubin in urine 
  • Urinary urobilinogen (colourless)
  • Other significant findings

  • Colour of stool - Pale
  • Unconjugated bilirubin (lipid-soluble) - Normal
  • Conjugated bilirubin (water-soluble) - ++
  • Bilirubin in urine - ++ Coke
  • Urinary urobilinogen (colourless) - Low
  • Other significant findings - Dilated bile ducts; + cholestatic enzymes. 


What are the 2 principal mechanisms which bilirubin metabolism goes wrong?

  • Increased production or bilirubin = pre-hepatic cause. 
  • Failure of excretion 
    • Defective conjugation within the hepatocytes = intra-hepatic cause. 
    • Defective delivery to the canaliculi = intra-hepatic cause. 
    • Blockage of the bile ducts - intra and / or extra-hepatic biliary tree = post-hepatic cause. 


Describe the mechanisms of unconjugated hyperbilirubinaemia.

  • Increased haemoglobin breakdown
    • Haemolysis e.g. G6PD deficiency, sickle cell anaemia. 
    • Dys-erythropoiesis: thalassaemia, pernicious anaemia, sideroblastic anaemia. 
    • Internal haemorrhage.
  • Impaired hepatic uptake of bilirubin e.g. patient on sulphonamides. 
  • Defective conjugation of bilirubin = intra-hepatic.
    • Inherited hyperbilirubinaemia: Gilbert's and Crigler-Najjar syndrome.
    • Neonatal jaundice (immature UDP-glucuronyl transferase).
    • Liver disease: hepatitis, cirrhosis.


What are the mechanisms of conjugated hyperbilirubinaemia?

  • Due to intrahepatic cholestasis (hepatocellular injury through infection, cirrhosis, inflammation), or extrahepatic outflow obstruction (biliary obstruction by calculi, malignancies, strictures).
    • Extrahepatic cholestasis


Why would a patient suffer from decreased excretion / reuptake of bilirubin?

What does this cause?

  • Causes conjugated hyperbilirubinaemia.
  • Caused by​ inherited disorders - Dubin-Johnson syndrome, Rotor syndrome.


What are the causes of intrahepatic cholestasis? 

What does it cause?

  • Causes conjugated hyperbilirubinaemia. 


  • Intrahepatic cholestasis (cholestasis = reduction or stoppage of bile flow).
    • Liver disease - hepatitis (autoimmune or viral) and cirrhosis.
    • Primary biliary cholangitis.
    • Drugs - oestrogens, methotrexate (can cause cirrhosis). 
    • Post-operative cholestasis - precipitated by hypotension / massive blood loss with subsequent hepatic ischaemia requiring transfusions. 
    • Sepsis
    • Pregnancy - reversal 


What are the causes of extrahepatic cholestasis? 

What does it cause?

  • Causes conjugated hyperbilirubinaemia. 
  • Extrahepatic cholestasis (biliary obstruction):
    • Choledocholithiasis - presence of gallstones in the common bile duct. Conditions include: 
      • Cholangitis
      • Gallstone pancreatitis 
      • Obstructive jaundice 
    • Tumours - pancreatic cancer, gallbladder cancer.
    • Inflammatory process - primary sclerosing cholangitis (autoimmune aetiology, strong association with ulcerative colitis), acute and chronic pancreatitis and abscesses. 
    • Malformations of the bile-ducts: post-operative / inflammatory strictures. 
    • Parasitic infection such as flukes. 
    • Post-operative bile leaks from biliary duct strictures. 


What is Gilbert's syndrome?

Inherited metabolic disease, impairing the intrahepatic conjugation of unconjugated bilirubin. 


What is Crigler-Najjar syndrome?

A rare autosomal recessive condition, resulting in the absence (type 1) or reduced activity (type 2) of UDP-glucuronoyl transferase.


What are the congenital causes of increased unconjugated bilirubin?

  • Gilbert's syndrome
  • Crigler-Najjar syndrome


What are the congenital causes of increased conjugated bilirubin?

  • Dubin-Johnson syndrome
  • Rotor's syndrome


What is Dubin-Johnson syndrome?

  • A rare autosomal recessive disorder of bilirubin excretion - there is an absence of biliary transport protein, resulting in the inability to excrete bilirubin glucuronides from hepaticytes into the bile canaliculi.
    • A black liver is often identified on the posrt-mortem (one does not die of the condition; secondary to adrenaline metabolism dysfunction). 


What are the prehepatic causes of jaundice?

  • Haemolysis. Example:
    • Glucose-6-phosphate dehydrogenase deficiency, sperocytosis. 
  • Ineffective erythropoiesis. Examles:
    • Thalassaemia
    • Pernicious anaemia (vitamin B12 deficiency)


What are the intrahepatic causes of jaundice?

  • Non-obstructive biliary disease. Examples:
    • ​Hepatitis
    • Cirrhosis of the liver
    • Congestive hepatopathy
    • Primary biliary cirrhosis (PBC)
    • Cystic fibrosis
  • Mechanical biliary obstruction. Examples:
    • ​Tumours of the liver
    • Intrahepatic gallstones
    • Primary sclerosing cholangitis (PSC)


What are the post-hepatic causes of jaundice?

  • Choledocholithiasis
  • Inflammation (e.g. primary sclerosing cholangitis)
  • Malformations of the biliary tract
  • Tumours (e.g. carcinoma of th pancreas)
  • Bile duct strictures


Describe the pathophysiology of pre-hepatic jaundice. 

  • Haemolysis due to:
    • Glucose-6-phosphate dehydrogenase deficiency
    • Sickle cell anaemia
    • Spherocytosis
    • Blood transfusions
  • Ineffective haematopoiesis (dys-erythropoiesis) due to increased degradation by macrophages. 


  • Increased unconjugated bilirubin occurs - the hepatocyte capacity to conjugate UCB has been reached. 
    • This increases conjugated bilirubin in the bile = increases the risk of pigmented gallstones
    • Stool is dark - an increased conjugated bilirubin in the bile - this is deconjugated by intestinal microbes in the duodenum, leading to increased production of stercobilinogen and stercobilin = darker faeces


Describe the pathophysiology of intra-hepatic jaundice.

  • Can be due to both increased unconjugated and conjugated bilirubin. 
  • Increased unconjugated bilirubin
    • Defective conjugation of bilirubin e.g. inherited defects or liver disease. 
  • Increased conjugated bilirubin
    • Leads to darkened urine (water-soluble bilirubin).


Describe the pathophysiology of extra-hepatic jaundice.

  • Due to increased conjugated bilirubin. 
  • Leads to very dark urine (coka cola).


What is tested in an LFT?

What are the normal ranges?

  • Alanine aminotransferase (ALT) → Normal = 0.45 IU/L.
  • Alkaline phosphatase → Normal = 30-120 IU/L.
  • Bilirubin → Normal = 2-17 µmol/L.
  • Albumin → Normal = 40-60 g/L.
  • Other liver enzyme tests = aspartate aminotransferase (AST) and gamma glutamyltransferase (gGT).


What are the true liver function tests?

  • Bilirubin
  • Albumin (constitutively produced by the hepatocytes; indicative of liver function). 
  • Prothrombin time - measures how quickly blood clots. 
    • Prothrombin is a constitutively producd protein in the liver - liver disease will INCREASE the prothrombin time = the blood takes longer to clot.