Clinical Presentation and Management of Liver / Gallbladder Disease

Question 1

What is jaundice?

Answer 1

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

Question 2

What is the normal range for total bilirubin?

Answer 2

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

Question 3

What is bilirubin used for?

Answer 3

• 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).

Question 4

Describe the role of bilirubin in the reticuloendothelial system.

Answer 4

• 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.

Question 5

Describe what happens to bilirubin in the liver.

Answer 5

• 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.

Question 6

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

Answer 6

• 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.

Question 7

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

Answer 7

• 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.

Question 8

Describe the basic physiology of jaundice.

Answer 8

• 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.

Question 9

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

Answer 9

• 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.

Question 10

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

Answer 10

• 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.

Question 11

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

Answer 11

• 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.

Question 12

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

Answer 12

• 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.

Question 13

Describe the mechanisms of unconjugated hyperbilirubinaemia.

Answer 13

• 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.

Question 14

What are the mechanisms of conjugated hyperbilirubinaemia?

Answer 14

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

Question 15

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

What does this cause?

Answer 15

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

Question 16

What are the causes of intrahepatic cholestasis?

What does it cause?

Answer 16

• 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

Question 17

What are the causes of extrahepatic cholestasis?

What does it cause?

Answer 17

• 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.

Question 18

What is Gilbert’s syndrome?

Answer 18

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

Question 19

What is Crigler-Najjar syndrome?

Answer 19

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

Question 20

What are the congenital causes of increased unconjugated bilirubin?

Answer 20

• Gilbert’s syndrome
• Crigler-Najjar syndrome

Question 21

What are the congenital causes of increased conjugated bilirubin?

Answer 21

• Dubin-Johnson syndrome
• Rotor’s syndrome

Question 22

What is Dubin-Johnson syndrome?

Answer 22

• 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).

Question 23

What are the prehepatic causes of jaundice?

Answer 23

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

Question 24

What are the intrahepatic causes of jaundice?

Answer 24

• 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)

Question 25

What are the post-hepatic causes of jaundice?

Answer 25

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

Question 26

Describe the pathophysiology of pre-hepatic jaundice.

Answer 26

* **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**.

Question 27

Describe the pathophysiology of intra-hepatic jaundice.

Answer 27

* 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).

Question 28

Describe the pathophysiology of extra-hepatic jaundice.

Answer 28

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

Question 29

What is tested in an LFT? What are the normal ranges?

Answer 29

* 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).

Question 30

What are the true liver function tests?

Answer 30

* 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.

Question 31

What are the normal functions of the liver?

Answer 31

* Protein, carbohydrate and lipid metabolism. * Bile acid metabolism. * Bilirubin metabolism. * Hormone and drug metabolism e.g. breaking down of endogenous oestrogens - impairment can lead to gynaecomastia in males. * Immunological defence.

Question 32

* What are the patterns shown on LFTs of liver damage caused by: * Hepatic / hepatocellular cause? * Cholestatic (bile duct) cause?

Answer 32

* **Hepatic / hepatocellular cause**: * ALT / AST → predominantly elevated. * Alkaline phosphatase / gGt → near normal. * **Cholestatic (bile ducts) cause**: * ALT / AST → near normal. * **Alkaline phophatase /** gamma-GT → predominantly **elevated.** * Mixed - particularly common with viral hepatitis' (A&E) * ALT and alkaline phosphatase / gamma GT → BOTH HIGH.

Question 33

Which investigations would be appropriate for a patient who is jaundice?

Answer 33

* FBC and blood film * Haemolysis → indicative via reduced Hb and on the film. * U&E * Clotting - prothrombin time * LFTs * Liver immunology * Viral serology * **Alpha-1 antitrypsin** → a protease inhibitor = deficiency associated with hepatic scarring and COPD. * **Cearuloplasmin** → a glycoprotein produced in the liver that transports \>95% of the copper in the plasma. * **Ferritin** (intracellular protein that stores iron and releases it in a controlled fashion).

Question 34

What is painless jaundice a red flag for?

Answer 34

* If a patient has lost weight and has NO abdominal pain = painless jaundice. * Red flag for **pancreatic carcinoma.**

Question 35

What is acetylcysteine used to treat?

Answer 35

Paracetamol overdose.

Question 36

Describe the characteristics of chronic liver disease.

Answer 36

* Duration \>6 months. * Can present acutely. * Duration → may be sub-clinical. * Outcome → initially fibrosis, then progression to cirrhosis. * **Signs and symptoms:** * **​**Dependent on the underlying disease or features of cirrhosis. * **Pathology:** * **​**Recurrent inflamation and repair with fibrosis and regeneration.

Question 37

What are the commonest causes of liver cirrhosis?

Answer 37

* Alcohol * Hepatitis C infection * Non-alcoholic steatohepatitis (a type of NAFLD)