29) The liver - An introduction to its function

Question 1

What is the liver?

Answer 1

• The liver is the largest gland and second largest organ in the body
• It is divided into 2 primary lobes (left lobe and right lobe) which is separated by the falciform ligament
• Each lobe has its own blood supply
• The right lobe is larger and consists of a quadrate lobe (below the portal vein) and caudate lobe (above the portal vein) on the posterior surface
• The caudate lobe is the only part of the liver that comes in contact with the vena cava

Question 2

What is the gall bladder?

Answer 2

• A little green sac located underneath the inferior vena cava
• It secretes bile into the duodenum vie the common bile duct

Question 3

How is the liver perfused?

Answer 3

• The liver has a double blood supply
• 75% of the blood comes from the portal vein (i.e. blood returning from the GI tract)
• 25% from hepatic artery
• The central vein of the liver lobes drain into the hepatic vein and back to the vena cava

Question 4

What cells make up the liver?

Answer 4

• Hepatocytes (most common) perform metabolic functions
• Kupffer cells are a type of tissue macrophage which remove any bacteria and pathogens in the blood before it reaches the heart
• There are also liver sinusoidal endothelial cells and stellate cells (for storage of fats)

Question 5

What are the hepatic lobes?

Answer 5

• The liver consists of two hepatic lobes.
• These are the functional unit consisting of hexagonal plates of hepatocytes around the central hepatic vein
• At each corner of the hexagonal plate we find triads which contains branches of the portal vein, hepatic artery and bile duct
• The bile duct flows in the opposite direction to the blood flowing in the portal vein and hepatic artery
• The blood flows in the same direction in the portal venule and hepatic arteriole. These join together to form the central hepatic vein leaving the kidney

Question 6

What are the different zones of the hepatic acinus?

Answer 6

• Zone 1 (closest to the middle): The periportal hepatocytes which have the highest oxygen pressure and receive most of the nutrients. They are most specialised in oxidative metabolism and other functions. They are found closest to the portal tract (between the two lobes)
• Zone 2 (found in between zone 1 and 3)
• Zone 3 (furthest from the middle): The pericentral hepatocytes which are closest to the central vein. They are mainly involved in the biotransformation and blood detoxification. They are found furthest from the portal tract (between the two lobes)

Question 7

How does the liver’s microstructure support its role?

Answer 7

• They have a massive surface area for exchange of molecules

- It is highly sophisticated when separating blood from bile

Question 8

How is the protective function of the liver achieved?

Answer 8

• It is achieved by Kupffer cells found n the sinusoids which function as mononuclear phagocyte system (MPS)
• They are exposed to blood from the gut that can contain pathogenic substances and help clear gut-derived endotoxin from portal blood
• They are found closer to the lumen above hepatocytes

Question 9

What is bile?

Answer 9

• Bile is a complex fluid consisting of water, electrolytes (e.g. Sodium) and a mix of organic molecules (such as bile acids, cholesterol, bilirubin and phospholipids)

Question 10

Where can bile be created?

Answer 10

• First by hepatocytes as they synthesise bile salts, cholesterol and other organic constituents which will make up the bile and secrete it
• Second by epithelial cells lining the bile ducts as they produce large quantities of watery solution of Na+ and HCO3- stimulated by the hormone secretin (which is produced in response to the acid in the duodenum)

Question 11

What is the mechanism of bile secretion?

Answer 11

• Bile is initially secreted from hepatocytes and drains from both lobes of the liver into the right and left hepatic ducts
• These hepatic ducts join together to form the common hepatic duct
• The common hepatic duct joins with the cystic duct to form the common bile duct
• The common bile duct connects with the duodenum near the Sphincter of Oddi
• The bile duct is able to open when the Sphincter of Oddi is open allowing the bile to enter the duodenum
• When bile is not required then the bile is directed from the common hepatic duct into the cystic duct and to the gall bladder for storage
• When food containing fatty material enters the duodenum Cholecystokinin (CCK) is released which will stimulate the contraction of the gall bladder to release the concentrated bile into the duodenum

Question 12

How are bile salts synthesised?

Answer 12

• Bile acids are derivatives of cholesterol and are made in the hepatocytes
• Cholesterol is first converted into primary bile acids by the enzyme 7α-hydrolase in the presence of O2, NADH and Cytochrome P450
• The primary bile acids (cholic and chenodeoxycholic acids) are then conjugated by Glycine and Taurine to bile salts (this increases solubility of the bile and minimises passive absorption of bile)

Question 13

What happens to bile salts in the small intestines?

Answer 13

• The bile salts then enters the small intestines, via bile ducts, where it is broken down/deconjugated by intestinal bacteria to primary bile acids
• These primary bile acids are further broken down by intestinal bacteria to secondary bile acids
• Most of the bile acids are reabsorbed from the small intestines and goes back into the liver where the cycle begins again (starting with conjugation)
• Only a very tiny amount is excreted in faeces

Question 14

What is the circulation of bile called?

Answer 14

• The enterohepatic circulation

Question 15

How is synthesis of primary bile salts from cholesterol regulated?

Answer 15

• As more bile acids enter the liver to be reused there is a negative feedback system which stops cholesterol from being used to synthesise primary bile slats

Question 16

What does bile do?

Answer 16

• Bile is essential for fat digestion and absorption via emulsification
• Bile and pancreatic juice neutralises gastric juices as it enters the small intestines which aids the digestive enzymes
• Elimination of waste products from the blood (in particular bilirubin and cholesterol)

Question 17

What are gall stones?

Answer 17

• Stone that form as a result of imbalance in the chemical make up of bile inside the gall bladder
• They form at any point in the biliary tract
• Some stones can be a mixture of bilirubin nucleus with clear cholesterol crystals

Question 18

What are the different type of gall stones?

Answer 18

• There are cholesterol stones (most common) and pigment stones (least common)
• Pigment stones contain bilirubin due to an increased breakdown of red blood cells

Question 19

What are the risk factors of cholesterol stones?

Answer 19

• High fat diet
• Increased synthesis of cholesterol
• Inflammation of the gall bladder epithelium which changes absorptive characteristic of the mucosa. Excessive absorption of H2O and bile salts leads to increased concentration of cholesterol in the gall bladder
• Cholesterol stones are more common in women than in men as their risk factors is due to obesity, excess oestrogen (e.g. during pregnancy) and use of hormone replacement therapy (HRT)

Question 20

How is unconjugated bilirubin formed from the breakdown of RBCs?

Answer 20

• When red blood cells are broken down it releases haem and globin. The haem group is then converted to bilivirdin by the action of the enzyme haem oxygenase
• Bilivirdin is then converted to unconjugated bilirubin through bilivirdin reductase

Question 21

How is conjugated bilirubin formed from unconjugated bilirubin?

Answer 21

• Unconjugated bilirubin is insoluble and so is carried through the body bound to albumin
• In the liver the unconjugated bilirubin is then conjugated by glucuronic acid with the help of the enzyme glucuronic transferase to form conjugated bilirubin which is water soluble
• This means it can be secreted into bile and then into the duodenum

Question 22

How is conjugated bilirubin excreted in faeces?

Answer 22

• In the intestines conjugated bilirubin is acted on by intestinal bacteria to convert it into urobilinogen
• Urobilinogen can be acted on by colonic bacteria to form stercoblin which is excreted in the faeces.
• It is the stercoblin which gives faeces their colour and is the way in which majority of the bilirubin is excreted

Question 23

What happens to left over urobilinogen that is not excreted in faeces?

Answer 23

• The leftover urobilinogen is reabsorbed into the liver by the enterohepatic circulation
• From here it enters into blood circulation where it can get into the kidney and be excreted by urine in the form of urobilinogen

Question 24

What is jaundice?

Answer 24

• Yellowing of the skin, mucosal membrane or the sclera of the eye due to accumulation of bilirubin in the plasma

Question 25

What are the different classifications of jaundice?

Answer 25

• Pre-hepatic (haemolytic)
• Hepatic
• Post-hepatic (obstructive):

Question 26

How does pre-hepatic jaundice occur?

Answer 26

• This is due to an increase in haemolysis which can lead to excess bilirubin in the liver and so has no capacity to process unconjugated bilirubin.
• As a result there is an excess of bilirubin in the body

Question 27

How does hepatic jaundice occur?

Answer 27

• Occurs when there is damage of hepatocytes (e.g. cirrhosis, drugs, hepatitis, Gilberts Syndrome).
• This means the liver is not able to conjugate bilirubin at an appropriate level and so unconjugated bilirubin as well as conjugated bilirubin accumulate in the blood

Question 28

How does post-hepatic jaundice occur?

Answer 28

• Caused by an obstruction in the passage of conjugated bilirubin into the duodenum.
• As a result this conjugated bilirubin cannot be secreted into the duodenum (either due to gall stones, carcinoma of the pancreas/ bile ducts).
• There is excess conjugated bilirubin which is reabsorbed into the blood and is excreted in the urine by the kidneys
• This means extra urobilinogen is made to be secreted in the urine making the urine appear very dark

Question 29

How are sunlight canopies used in medicine?

Answer 29

• Neonatal jaundice is caused by a build of bilirubin in the blood
• Sunlight canopies are being developed for use in low-income countries
• The canopies filter out most of the rays of the sun but allows therapeutic blue light to pass through
• This blue light converts non conjugated bilirubin into harmless substances and in doing so decreases bilirubin levels in the plasma
• They also decrease the risk of overheating and sunburn

Question 30

How does the liver produce clotting factors?

Answer 30

• The kidney plays a key role in the synthesis of Fibrinogen, Prothrombin and nearly all other clotting factors
• Vitamin K is essential for the formation of pro-thrombin and some factors. It converts them (with the help of enzyme carboxylase) from the inactive form to the active form
• Warfarin, which helps prevent clotting, does so by blocking the oxidised Vitamin K

Question 31

How does the liver achieve its storage function?

Answer 31

• The liver plays an important role in the storage of fat soluble vitamins (A, D, E and K) through the stellate cells
• The liver also stores enough Vitamin B12 to last 2-3 years
• Stores folate which is required in early pregnancy
• Iron is stored as ferritin

Question 32

How can vitamin deficiency occur?

Answer 32

• A liver dysfunction can lead to bile not being synthesised and secreted efficiently.
• This will reduce the ability of lipid digestion.
• Hence this can cause fat malabsorption leading to vitamin deficiency

Question 33

What causes Vitamin B12 deficiency?

Answer 33

• Pernicious anaemia can lead to Vitamin B12 deficiency
• Pernicious anaemia happens when there is a deficiency in an intrinsic factor in the stomach
• These intrinsic factors aid the transport and storage of Vitamin B12
• So without these intrinsic factors they transport and storage of Vitamin B12 is hindered leading to Vitamin B12 deficiency

Question 34

What function does the liver serve in biotransformation and detoxification?

Answer 34

• The liver plays a vital role in the metabolism and excretion of various substances which can be toxic to the body.
• Bilirubin (accumulation can lead to jaundice)
• Ammonia
• Hormones (e.g. steroid hormones become inactivated by conjugation then excretion)
• Drugs and exogenous toxins (e.g. aspirin, paracetamol and ethanol) are bio transformed and excreted so they do not accumulate

Question 35

What is Spider Angioma?

Answer 35

• A condition that occurs in women due to excess oestrogen
• It is enlarged blood vessels in the skin which resembles a spider
• When more than 5 Spider Angiomas are found it is indicative of liver damage

Question 36

What is gynaecomastia?

Answer 36

• A benign (harmless) proliferation (rapid increase) of male breast granular tissue caused by increased oestrogen activity and a decrease in testosterone activity
• A damage of the liver (e.g. alcoholic cirrhosis) means it is unable to catabolise oestrogen leading to increased activity of oestrogen and enlargement of the breasts

Question 37

What enables the liver to have a regenerative function?

Answer 37

• Adult hepatocytes are long lived and do not undergo cell division as they are in the G0 phase of the cell cycle
• After partial hepatectomy (removal of 70% of the liver) of in response to toxic injury they can rapidly re-enter the cell cycle and proliferate
• This regeneration is rapid and proliferation stops when the original mass of the liver is obtained
• This allows for the use of partial livers from living donors during transplantation

Question 38

How does regeneration of the liver occur?

Answer 38

• There are two hypothesised pathways.
• Growth-factor mediated pathway: It involves the Hepatocyte Growth Factor (HGF) and Transforming Growth Factor alpha (TGFα)
• Cytokine signalling pathway: It involves Interleukin 6 (IL-6) via TNFα binding to its receptor on Kupffer cells
• Prolonged alcohol misuse can reduce regenerative ability of the liver

Question 39

How do gut derived factors initiate liver regeneration?

Answer 39

• When partial hepatectomy/liver injury occurs it initiates several signals simultaneously in the liver.
• Gut derived factors (e.g. Lipopolysaccharide, LPS) are upregulated and reaches the liver in the portal blood where they activate non-parenchymal cells (cells not involved in the kidneys functions) such as the Kupffer cells and the Stellate cells

Question 40

What do stimulated Kupffer cells secrete?

Answer 40

• Stimulated Kupffer cells release TNFα (Tumour Necrosis Factor α) and IL-6 (Interleukin 6)

Question 41

What does stimulated Stellate cells release that aids regeneration?

Answer 41

• Stellate cells release HGF (Hepatocyte Growth Factor)

Question 42

How do other molecules aid liver regeneration?

Answer 42

• The thyroid releases T3, the pancreas releases insulin, the adrenal gland releases norepinephrine and the duodenum releases EGF
• These molecule incorporate signalling on the hepatocytes in the G0 allowing them to over come the checkpoint control
• By doing so they move from G0 to G1 and then to S phase for proliferation

Question 43

How is liver regeneration regulated?

Answer 43

• The Stellate cells also releases TGFβ (Transforming Growth Factor β ) whihc inhibits furhter proliferation fo the cell from G1 to the S phase
• In doing so it allows proliferation to stop at a stage

Question 44

What are liver function tests?

Answer 44

• Tests which investigate the levels of certain enzymes and proteins in the blood.
• These levels of certain enzymes may indicate various conditions
• It is used to screen for liver infections such as hepatitis
• It monitors the progression of a disease (e.g. viral or alcoholic hepatitis and to determine how well a treatment is going
• It also measures the severity of a disease and particularly scarring of the liver cirrhosis

Question 45

What are the most common sections of the liver function test?

Answer 45

• Alanine aminotransferase (ALT): Found in hepatocytes and leak in to blood when the hepatocytes are damaged
• Aspartate aminotransferase (AST): Found in hepatocytes and leak in to blood when the hepatocytes are damaged
• Alkaline phosphate (ALP) : They are enzymes found in the bile ducts and so will indicate any obstruction in the bile flow
• Gamma glutamyl Transferase (GGT): Also indicates obstruction on the liver
• Bilirubin: An increase of bilirubin can cause jaundice
• Albumin: A damage in liver can cause decrease in albumin
• Clotting studies: If low levels of clotting factors are present then the prothrombin time is longer