11. Jaundice and Liver Failure Flashcards
What does jaundice/icterus describe?
- Yellow discolouration of sclerae and skin
- Raised bilirubin
- Detectable clinically - serum bilirubin >50µmol/litre
Outline bilirubin metabolism
- Free bilirubin enters hepatocyte, binds to cytoplasmic proteins
- Unconjugated bilirubin => bilirubin glucuronide [glucuronyl transferase]
- => diglucoronide BR
- Conjugation makes bile water soluble
- Transported across concentration gradient into bile canaliculi
- Bilirubin glucuronide => mixture of compounds/urobilinogen/stercobilinogen (in the gut)
- Most of the stercobilinogen is oxidised to stercobilin (brown colour of faeces)
- 10% of sterconbilinogen is reabsorbed and returned to the liver
What is haemolytic jaundice?
- Pre-hepatic (spleen)
- Haemolytic anaemias e.g. SCD
- Higher breakdown of erythrocytes, higher production of bilirubin
- Unconjugated bilirubin - insoluble, doesn’t pass into urine
- Increase serum urobilinogen
- Normal liver biochemistry
- Hb drop without overt bleeding
Describe bile flow/formation through hepatocytes/cholangiocytes
• Excretion of bile salts and toxins by transporters on the apical surface • Transporters govern the rate of flow • Dysfunction - cholestasis • Main transporters: - Bile Salt Excretory Pump (BSEP) - MDR related proteins (MRP1 & MRP3)
How does BESP work?
- Active transport of bile acids
- Across hepatocyte canalicular membranes
- Determines bile flow
How does MDR 1 and 3 work?
- MDR1 - mediates canalicular excretion of xenobiotics, cytotoxins
- MDR 3 - encodes a phospholipids transporter protein that translocates phosphatidylcholine from inner to outer part of canalicular membrane
What effect does terminal ileal resection/disease have on bile?
- Less reabsorption
- More bile in stool
- More fat in stool - liver can’t increase rate of bile production enough
- Malabsorption of fat soluble vitamins (ADEK)
What is a cholecystectomy and what are the effects of this?
- Removal of gall bladder
- Normal health and nutrition
- Slow bile discharge into duodenum
- Avoid food with high fat content
Where does bilirubin come from?
- Haemoglobin breakdown
- Catabolism of other haem proteins
- Ineffective bone marrow erythropoeisis
What form of metabolised bilirubin can be reabsorbed by the GIT mucosa?
• Unconjugated bilirubin
• Urobilinogens
(- urine excretion)
What is hepatic jaundice?
- Defective uptake => high unconjugated
- Defective conjugation => high unconjugated
- Defective excretion => high conjugated
- Liver failure => high conjugated
- Intrahepatic cholestasis
What is post-hepatic jaundice?
- Defective transport by biliary duct system
- bile duct stones, HepPancBil malignancy, lymphadenopathy
- Build up of serum bilirubin
- Could cause cholangitis - sepsis
What is the most common hereditary cause of increased bilirubin?
- Gilbert’s Syndrome
- Up to 5% of the population
- Autosomal recessive
- Reduction in glucurodination activity of UDPGT-1A1 (uridine-diphosphate-glucuronosyltansferase isoform 1A1)
- Elevated unconjugated bilirubin
- Mild jaundice may appear under: infections, stress, exertion, fasting
- Usually asymptomatic
What are the most common causes of liver disease?
- Developed world - alcohol and non-alcoholic fatty liver disease (genetic predisposition, immunological mechanisms, 10-20% of heavy drinkers => cirrhosis)
- Developing world - chronic viral hepatitis B or C
What is Cirrhosis?
- Final common pathway for liver disease
- Response to chronic liver injury
- Necrosis of liver cells
- Progressive fibrosis and nodule formation
- Impairment of liver cell function
- Distortion of architecture
- Portal hypertension
What is Acute Liver Failure?
- Massive loss of hepatocytes
- Severe hepatic dysfunction - occuring within 6 months within 6 months of onset of symptoms
- Clinical manifestation of hepatic encephalopathy or coagulopathy
What are the clinical features of Acute Liver Failure?
• Jaundice • CNS complicaitons • Coagulopathy (prolonged bleeding) • Renal failure • Sepsis - bacterial 90%, fungal 32% of cases - normal features of fever and leucocytosis are absent • CVS complications - hypotension - reflex to increase CO • Metabolic complications - hypoglycaemia and hypoxia
Summarise the pathophysiology of Acute Liver Failure
• Apoptosis - e.g. from paracetamol - activation of caspase (by cytokines) - nuclear shrinkage - no cell membrane rupture - no release of intracellular content • Necrosis (ischaemia) - ATP exhaustion resulting in swollen cell - eventually lyses - release of intracellular content
What is the difference between fulminant and sub-fulminant hepatic failure?
• Fulminant
- rapid development (<8 weeks) of severe acute liver injury with impaired synthetic function + encephalopathy
- previously normal/well-compensated liver
- cerebral oedema is common
• Sub-fulminant
- < 6 months
- renal failure & portal hypertension is more frequent
How can Fulminant Acute Liver Failure be classified?
- Hyperacute - encephalopathy occurs within 7 days of onset of jaundice
- Acute - encephalopathy occurs after 8-28 days of jaundice
- Subacute - encephalopathy occurs 5-12 weeks after onset of jaundice
How common is Acute Liver Failure in the UK, and what is the most common cause (in the USA)?
• Relatively uncommon (< 500 deaths/year)
• < 15% of liver transplants/year
• Paracetamol is the most common cause
(• other causes include Amanita phalloides (fungus) and Bacillus cereus)
What doses of paracetamol can pose a danger in a 70kg patient?
• Toxicity possible > 10g • Sever toxicity certain > 25g • Lower doses can be hepatoxic in: - chronic alcoholics - malnutrition or fasting - tegretol, phenobarbital, rifampacin
The synthesis of which major proteins are reduced in liver failure?
- Albumin => ascites and oedema
- Clotting factors => bruising and bleeding
- Complement => infection and sepsis
