Jaundice and Liver Failure Flashcards
State three roles of bile.
Cholesterol homeostasis
Dietary lipid/vitamin absorption
Removal of xenobiotics, drugs and endogenous waste products (e.g. steroid hormones)
List the major components of bile.
Bile salts, cholesterol, bilirubin, phospholipids, bicarbonate, WATER
How much bile is produced daily?
500 mL
The capacity of the gallbladder = 15-60 mL
Which cell types produce bile? State the relative proportions of bile produced by each cell type.
Hepatocytes - 60%
Cholangiocytes - 40%
What does bile flow depend on?
The concentration of the bile
What regulates bile concentration?
The transporters in the cholangiocytes - therefore, these transporters govern the rate of bile flow and dysfunction can cause CHOLESTASIS.
What channel transports bicarbonate and chloride ions into the bile?
CFTR
State some of the main transporters that regulate bile concentration.
Bile Salt Excretory Protein (BSEP)
MDR related proteins
Multidrug Resistance Genes
Familial Intrahepatic Cholestasis gene
What are the primary bile acids and their respective secondary bile acids? What is the difference between primary and secondary bile acids?
Primary bile acids are produced by the liver. They are converted to secondary bile acids by the action of colonic bacteria. Deoxycholate is reabsorbed but 99% of lithocholic acid is excreted in the stool.
Primary = Cholic Acid + Chenodeoxycholic Acid
Secondary = Deoxycholic Acid + Lithocholic Acid
What percentage of bile is water?
97%
Describe the effect of cholecystokinin on bile release.
Cholecystokinin causes contraction of the gallbladder and relaxation of the sphincter of Oddi
What percentage of bile salts are reabsorbed in the terminal ileum?
95%
Describe how terminal ileal disease can cause steatorrhoea.
Terminal ileal disease will mean that less bile salts are reabsorbed so less bile salts are released in the bile into the duodenum so there is less fat emulsification, digestion and absorption so more fat passes through the small intestines and enters the colon and leaves the body.
What is another important consequence of fat digestion and absorption is reduced?
They also absorb fewer fat soluble vitamins - ADEK
State three important roles of the gallbladder.
Store bile
Acidify bile
Concentrate the bile
What are the effects of cholecystectomy?
The bile drips into the duodenum and you can function perfectly fine. However, you will not be able to produce a large release of bile due to gallbladder contraction so there may be some discomfort after eating a fatty meal.
What are the main sources of bilirubin?
75% Breakdown of haem group in haemoglobin
22% Breakdown of other haem proteins
3% from ineffective erythropoiesis
What plasma protein carries bilirubin to the liver?
Albumin
What happens to bilirubin when it reaches the liver?
Bilirubin is conjugated with glucuronic acid to make it more water soluble by the action of UDPGA from smooth ER.
Bilirubin diglucoronide is transported into the bile canaliculi and then it enters the GIT.
What two substances can bilirubin be converted to in the intestines and how are they excreted?
Bilirubin can be converted to urobilinogen and excreted via the kidneys. Urobilinogen is formed mainly in the intestines by bacterial action. GIT mucosa is impermeable to conjugated bilirubin but is permeable to unconjugated bilirubin and urobilinogens. So some unconjugated BR enters the enterohepatic circulation, and some forms urobilinogens.
Half of urobilinogens formed are reabsorbed and taken up via the portal vein to the liver, enters circulation and is excreted by the kidneys. 20% of urobilinogens are reabsorbed into the general circulation.
It can be converted to stercobilinogen and then to stercobilin and excreted with the stools - stercobilin is brown.
What concentration of bilirubin is considered jaundice?
> 34 mcmol/L
What are the three types of jaundice?
Pre-hepatic
Hepatic
Post-hepatic
State some causes of pre-hepatic jaundice. What would be the expected conjugated: unconjugated ratio?
Increased unconjugated bilirubin because there is too much bilirubin being produced for the liver to conjugate it all.
It is caused by haemolysis (could be autoimmune), haematoma resorption, massive transfusion, ineffective erythropoiesis.
*If RBCs are lasting less than 120 days, too much BR is produced for the liver to handle.
What causes hepatic jaundice?
Caused by ineffective uptake, conjugation and bilirubin excretion.
Issues with the liver.
What can cause post-hepatic jaundice?
An obstruction to the biliary system e.g. pancreatic carcinoma or common bile duct stones.
What are some simple clinical features of post-hepatic/obstructive jaundice?
Pale stools - because bile isn’t entering the intestines so there is less stercobilin being produced
Dark urine - the body is trying to excrete some of the bilirubin via the urine, which would contain a lot of urobilinogen, which is dark
What is Gilbert’s Syndrome?
The most common hereditary cause of increased bilirubin.
Caused by a 70-80% decrease in the glucuronidation activity of UDPGA.
Leads to elevated unconjugated bilirubin.
Autosomal recessive.
ONLY ISSUE IS EPISODIC JAUNDICE.
Anatomy of the Biliary System
Each hepatocyte is apposed to several bile canaliculi -> intralobular bile ducts -> interlobular bile ducts -> right and left hepatic ducts -> common hepatic duct.
Hepatic duct from liver and cystic duct from gall bladder join to form the common bile duct which joins the pancreatic duct at the AMPULLA - controlled by the Sphincter of Oddi.
Effect of enterohepatic circulation on drugs
Liver cells transfer substances including drugs from plasma to bile.
Hydrophilic drug conjugates (glucoronide) are concentrated in bile -> GUT -> glucoronide hydrolysed -> active drug re-released -> reabsorbed -> cycle repeated.
This creates a reservoir of re-circulating drug which can prolong its action e.g. morphine.
What is acute liver failure?
Rapid development of severe acute liver injury with impaired synthetic function and encephalopathy in a person with a previously normal liver or well-compensated liver disease.
RATE OF HEPATOCYTE DEATH > REGENERATION
Pathophysiology of ALF
Apoptosis and necrosis.
Caspase cascade in apoptosis activated by cytokines like TNF alpha.
Insults which cause apoptosis may also cause necrosis.
Classification of liver failure
Fulminant hepatic failure:
Hyperacute = 0-7 days.
Acute = 8-28 days.
Subacute = 29 days to 12 weeks.
Sub-fulminant = less than 6 months - cerebral oedema is rarer but renal failure and portal hypertension is more frequent.
Causes of ALF
Uncommon in western world - PARACETAMOL, Bacillus cereus and Amanita phalloides.
Eastern world - VIRAL HEPATITIS.
Consequences of hepatocyte failure
Encephalopathy (accumulated neurotoxic substances in the brain) and cerebral oedema Hypoglycaemia Coagulopathy and bleeding Increased susceptibility to infection Circulatory collapse and renal failure
Symptoms of ALF
Initially non-specific: malaise, nausea, lethargy.
Jaundice.
After a time period, encephalopathy.
ALF treatment?
Emergency liver transplant - chance of mortality from the transplant itself.
