An Introduction to the Liver

Question 1

What is the anatomy of the liver like?

Answer 1

Largest gland and 2nd largest organ in body
Numerous functions- impact on all body systems
Major aspects of structure which influence function:
Vascular system
Biliary tree
3D arrangement of liver cells with the vascular and biliary systems
Liver is traditionally divided into 2 primary lobes by the falciform ligament
Underneath the liver is the gall bladder
The right lobe is much larger than the left lobe

Question 2

What is blood supply to the liver like?

Answer 2

75% of blood supply from portal vein i.e. blood returning from GI tract
25% from hepatic artery
Central veins of liver lobules drain into hepatic vein and back to the vena cava

Question 3

What are the types of cells that make up the liver?

Answer 3

The cells of the liver are:
Hepatocytes (60%)- perform most metabolic functions
Kupffer cells (30%)- type of tissue macrophage
Others are liver endothelial cells and stellate cells
Functional unit is the hepatic lobule
Hexagonal plates of hepatocytes around central hepatic vein
At each of 6 corners is triad of branches of portal vein, hepatic artery and bile duct

Question 4

How does the liver’s microstructure support its role?

Answer 4

How doe the liver’s microstructure support its role?
Massive surface area for exchange of molecules
Sophisticated separation of blood from bile
Blood flows in the opposite direction to the bile

Question 5

What does the liver’s protective barrier do?

Answer 5

Kupffer cells- found in sinusoids:
Represent approx. 80% of all fixed tissue macrophages
Function as mononuclear phagocyte system (MPS)
Exposed to blood from gut that contain pathogenic substances
Clear gut-derived endotoxin from portal blood

Question 6

What is bile and. where does it come from?

Answer 6

Complex fluid- water, electrolytes, mix of organic molecules
Organic molecules- bile acids, cholesterol, bilirubin and phospholipids
Where does it come from?
Bile secreted in 2 stages:
By hepatocytes- synthesise bile salts, cholesterol and other organic constituents
By epithelial cells lining bile ducts- produce large quantity of watery solution of Na+ and HCO3- stimulated by hormone secretin in response to acid in duodenum

Question 7

What is the biliary system?

Answer 7

Bile from hepatic ducts 
↓
common bile duct 
↓
duodenum 
OR 
diverted via cystic duct (if the bile is not needed for digestion)
↓
GALL BLADDER
↓  
concentrated
 & stored (30-50ml) in gall bladder
↓
Released by cholecystokinin in response to presence of fat in duodenum

Question 8

How are bile acids formed?

Answer 8

The liver synthesises bile acids from cholesterol to primary bile acids- cholic acid and chenodeoxycholic acid
This synthesis is regulated by the enzyme 7 alpha-hydroxylase which requires oxygen and cytochrome P450
The presence of the COOHO and OH makes it much more water soluble than cholesterol
Then conjugated with the amino acid glycine or taurine to form bile salt
These bile salts are then transported against the concentration gradient into the bile canaliculi via the help of an ATP dependent carrier called human bile salt export protein
Within the intestine there are intestinal bacteria that break down the primary bile acid turning them to secondary bile acid- deoxycholic acid or lithocholic acid

Question 9

What is the enterohepatic circulation of bile acids like?

Answer 9

Liver synthesises primary bile acids then bile salts
Bile salts get transported to bile canaliculi via an ATP dependent carrier
Goes into the duodenum where they are deconjugated to form the primary bile acid then broken down into secondary bile acid
Within the small intestine the majority of bile acids are reabsorbed (95%)
As bile acids get transported back to liver via the portal vein there is a higher concentration of bile acids which inhibits bile synthesis from cholesterol
This is called cholestasis?

Question 10

What does bile do?

Answer 10

Essential for fat digestion and absorption via emulsification
Bile + pancreatic juice neutralises gastric juice as it enters the small intestine ->
Aids digestive enzymes
Elimination of waste products from blood in particular bilirubin and cholesterol
500mg of cholesterol converted to bile acids per day

Question 11

What are gallstones?

Answer 11

Imbalance in the chemical make-up of bile inside the gallbladder leads to gallstones
2 types of stones:
Cholesterol stones (80%) and pigment stones (20%)
Risk factors cholesterol stones:
High fat diet
Increased synthesis of cholesterol
Inflammation of gall bladder epithelium changes absorptive characteristic of mucosa
Excessive absorption of H2O and bile salts-> cholesterol concentrates
More common in women than men
Risk factors- obesity, excess oestrogen (e.g. during pregnancy, HRT
Gallstones can form anywhere along the biliary tract
Pigment stones come from the breakdown of red blood cells to form bilirubin

Question 12

What is bilirubin?

Answer 12

Liver metabolises and excretes many compounds sand toxins into bile
The most important of these is bilirubin
A yellow pigment formed from breakdown of haemoglobin
Useless and toxic but made in large quantities ( around 6g/day) -> must be eliminated

Question 13

How is bilirubin formed and eliminated?

Answer 13

Mature red blood cells are broken down by the reticular endothelium system for example the spleen
The haemoglobin is broken down to haem and globin
Haem is broken down further to biliverdin (green pigment)
Biliverdin converted to bilirubin by biliverdin reductase
Unconjugated bilirubin is bound to albumin and transported to the liver
Unconjugated bilirubin is not soluble in water, so is conjugated with glucuronic acid to form a conjugated bilirubin
It is then secreted into bile and then into the intestine where there is an intestinal bacteria that converts the bilirubin to urobilinogen
This goes back into the circulation, to the kidney where it will be excreted
Or the urobilinogen can be converted to stercobilin (brown) to be excreted in faeces

Question 14

What is the pathophysiology of jaundice?

Answer 14

When plasma bilirubin concentration exceeds 1.5mg/dL so free bilirubin in extracellular fluid
Pre-hepatic (haemolytic):
Excessive breakdown RBC e.g. neonatal jaundice
Excess unconjugated bilirubin
Hepatic:
Hepatocyte damage (>80%) e.g. cirrhosis, drugs, hepatitis A, B, C, E, Gilberts syndrome
Excess conjugated and/or unconjugated bilirubin
Post-hepatic (obstructive)
Excess conjugated bilirubin
Obstruction to passage into duodenum
Enters circulation and into urine (very dark) e.g. gallstones, carcinoma of pancreas/bile ducts

Question 15

What is the use of sunlight canopies for jaundice?

Answer 15

Development of sunlight canopies for use in low-resource countries
Sunlight includes blue light
Filters out most of the ray (UVA, UVB, UVC, IR etc.) but allows therapeutic blue light to pass through which decreases risk of over-heating or sunburn

Question 16

What substances are used in coagulation factor synthesis?

Answer 16

Blood clotting factors:
Fibrinogen
Prothrombin
Nearly all the other factors e.g. V, VI, IX, X, XII
Vitamin K is essential for formation of pro-thrombin and factors II, VII, IX and X

Question 17

What does the liver store?

Answer 17

Hepatocytes (stellate cells in particular are important depots for storage of fat-soluble vitamins A, D, E, and K
Liver dysfunction-> fat malabsorption-> vitamin deficiency
Stores vitamin B12 and enough stored to last 2-3 years
Vit B12 deficiency-> pernicious anaemia
Stores folate, which is required in early pregnancy
Iron is stored as ferritin (blood-Fe buffer)

Question 18

What substances does the liver biotransform or detoxify?

Answer 18

Liver is vital in metabolism and excretion of various substances that can be toxic to body:
Bilirubin
Ammonia
Hormones e.g. all steroid hormones (androgens, oestrogens, cortisol, aldosterone, thyroxine) inactivated by conjugation and excretion
Drugs and exogenous toxins e.g. aspirin, paracetamol, ethanol
Spider angioma in women due to excess oestrogen- more than 5 is indicative of liver damage

Question 19

What are the effects of impaired detoxification by the liver?

Answer 19

Gynaecomastia (enlargement of the breasts) due to alcoholic cirrhosis
A 32 year old male patient with normal secondary sex characteristics, no testicular mass, no history of drug ingestion, no other endocrine abnormalities and a normal neurological examination
Nevertheless, he had a history of more than 15 years of large amounts of alcohol intake and a liver biopsy confirm alcoholic cirrhosis

Question 20

Under what conditions does the liver regenerate?

Answer 20

Adult hepatocytes are long lived and normally do not undergo cell division i.e. they are in G0 phase of the cell cycle
After partial hepatectomy (removal of 70% of liver) or in response to toxic injury, they rapidly re-enter cell cycle and proliferate
This regeneration is rapid and proliferation stops once the original mass of the liver is established; allows for use of partial livers from living donors for transplantation
Does NOT involve liver stem cell or progenitor cells, but replication of mature functioning liver

Question 21

What are the two pathways hypothesised to be the way the liver regenerates?

Answer 21

Still not understood fully but 2 pathways involved (hypothesised):
Growth-factor mediated pathway -> most important HGF (hepatocyte growth factor) and TGFa (transforming growth factor alpha)
Cytokine signalling pathway sing IL-6 via TNFa binding to its receptor on Kupffer cells
Prolonged alcohol misuse can reduce regenerative ability of liver
After a patrial hepatectomy there are several signals which are initiated simultaneously in the liver
The LPS reach the liver through the portal blood flow and within the liver and activate cells like Kupffer and stellate cells
With the Kupffer cells they will then stimulate the increase in tumour necrosis factor alpha production and also interleukin- 6 production
Other factors are also released that come from other parts such as insulin, EGF and T3
These all help move the hepatocyte from the G0 to G1 and then S phase
Stellate cells also produce the hepatocyte group factor that will act on the hepatocyte on the G0 stage and move it to G1 and S phase

Question 22

What can liver function tests do?

Answer 22

Liver function tests check the levels of certain enzymes and proteins in the blood and can be used to indicate various condition:
Screen for liver infections, such as hepatitis
Monitor the progression of a disease, such as viral of alcoholic hepatitis, and determine how well a treatment is working
Measure the severity of a disease, particularly scarring of the liver (cirrhosis)
Monitor possible side effects of the medications