The Liver: An Introduction to its Function

Question 1

Describe the liver’s anatomy and structure.

Answer 1

• It is the largest gland and the second largest organ in the body.
• It has numerous functions that have impact on all the body systems.
• The major aspects of its structure which influence its function are: -
  
  • Vascular system.
  • Biliary tree - (Refers to the liver, gall bladder and bile ducts, and how they work together to make, store and secrete bile).
  • 3D arrangement of liver cells with the vascular and biliary systems.
• The liver is divided into two lobes (Left and right lobe) by the falciform ligament. Each lobe receives its own blood supply.
• At the bottom of the liver there is a gall bladder (not all species have a gall bladder such as horses and bats. Yoy can still live if you have your gall bladder removed).

Question 2

Describe the blood supply to the liver.

Answer 2

• The majority (75%) of the liver’s blood supply is venous blood from the portal vein, i.e. carrying blood returning from the GI tract full of digested products. (This is related to its functions to remove toxins and harmfuls substances before it goes back out into the system again).
• The remaining 25% is from the hepatic artery.
• Blood from the central veins in the liver lobules drain into the hepatic vein and then into the vena cava.

Question 3

Describe the functional anatomy of the liver (ie. its different cells and its functional unit).

Answer 3

• The two primary cells of the liver are:
  
  • HEPATOCYTES (60%) - they perform the most metabolic functions.
  • KUPFFER CELLS (30%) - a type of tissue macrophage that get rid of all the bacteria, virus and antigens.
  • LIVER ENDOTHELIAL CELLS.
  • STELLATE CELLS.
• The functional unit is the hepatic lobule.
  
  • It consists of hexagonal plates of hepatocytes around the central hepatic vein.
  • At each of the 6 corners is a triad of branches of the portal vein, hepatic artery and bile duct.
  • The blood enters the lobules through branches of the portal vein and hepatic artery, then flows through small channels called sinusoids that are lined with primary liver cells (hepatocytes).
  • The hepatocytes remove toxic substances, including alcohol, from the blood, which the exits the lobule through the central vein (ie. the hepatic venule).
  • The flow of blood is in the opposite direction to the flow of bile.
  • The blood entering the lobule (at the hepatic artery) is relatively oxygen-rich, but the blood leaving the lobule contains low levels of oxygen (at the terminal hepatic venule) because hepatocytes along the sinusoids have used up much of the available oxygen.

Question 4

How does the biliary system go (in terms of structures)?

Answer 4

1. Bile is secreted by hepatocytes.
2. It goes through series of channels between cells (canalinculi).
3. Goes to small ducts.
4. Goes to large ducts (hepatic ducts).
5. All the hepatic ducts from throughout the liver anastamose onto a common bile duct.
6. This bile can then go to the duodenum or to the gallbladder.

Question 5

How does the liver’s microstructure support its roles?

Answer 5

• It has a massive surface area for exchange of molecules (as it is a big organ and has all the lobules are stacked on top of one another giving high surface area).
• Sophisticated separation of blood from bile (its able to do two different functions).
• Specific positioning of pumps to achieve specific localisation of materials (at a cellular level).

Question 6

How do Kupffer cells act as a protective barrier?

Answer 6

• Kupffer cells are phagocytic macrophages.
• As blood flows through intestinal capillaries (sinusoids), the kupffer cells pick up many bacteria from the intestine.
• When a bacterium comes in contact with Kupffer cells, in <0.01 seconds, the bacterium passes inwards through the wall of the Kupffer cells to become permanently lodged there till digested.
• A sample of blood taken from the portal veins before it enters the liver is almost always going to grow colon bacilli when cultured, wheras growth of colon bacilli from systemic blood is rare.
• Probably <1% of the bacteria entering the portal blood from the intestines succeeds in passing through the liver into the systemic circulation.
• The Kupffer cells efficiently cleanse the blood as it passes through the sinusoids.

Question 7

What is bile?

Answer 7

• It is a greenish-yellow liquid consisting of a complex mix of water, electrolytes and organic molecules (such as bile acids, cholesterol, bilirubin and phospholipds).
• Adults humans produce 400-800ml of bile every day.
• Initially, the hepatocytes secrete bile into the canaliculi, which flows into the bile ducts and contains a large amount of bile salts, cholesterol and other organic constituents.
• It is then modified by water and bicarbonate-rich secretion from epithelal ductal cells.

Question 8

What does bile do?

Answer 8

• It is essential for fat digestion and absorption via emulsification.
• Bile and pancreatic juice neutralises gastric juice as it enters the small intestine and aids digestive enzymes (as enzymes need a particular pH to work efficiently).
• It helps in the elimination of waste products from the blood, in particular bilirubin and cholesterol.
  
  • 500mg of cholesterol is converted to bile acids per day.

Question 9

How does bile enter the duodenum?

Answer 9

• All the bile from the hepatic ducts will either pass down to the common bile duct and enter the duodenum along with the pancreatic juice (from the pancreatic duct).
• The entry of bile and pancreatic juice into the duodenum is regulated by the sphincter of Oddi.

OR

• The bile is diverted to the gallbladder via the cystic duct where it is stored and concentrated (it can store about 30 - 50ml).

it enters via the major duodenal paillae (the Sphincter of Odii; it controls bile’s entry). Bile can also be diverted into the gall blader via the cystic duct where it is stored and concentrated 5-fold.

Question 10

What is bilirubin?

Answer 10

• It is a yellow pigment formed from the breakdown of haemoglobin; it is what gives bile its colour.
• The life of a RBC is ~ 180 days. At the end of this time period all the RBCs that have reach the end of their life span will be broken down including all its components (including haemoglobin).
• It is useless and toxic, but it’s made in large quantities (~6g/day), so it has to be eliminated.

Question 11

Describe the destruction of aged RBCs.

Answer 11

• Dead or damaged RBCs are digested by macrophages throughout the body (traditionally this happens in the spleen, but can also occur elsewhere such as liver, bone marrow, etc.).
• Part of the haemoglobin is just protein so it can be catabolised (broken down into its constituent amino acids and reused).
• The Fe is recycled (The haem part will release the iron, which is taken up into the iron store and can be stored).
• The Haem part that contains the porphyrin (that gives blood its characteristic colour and does all the binding) cannot be recycled, so it has to be eliminated.
• Thus, haem is converted in a series of steps into bilirubin.

Question 12

Describe the formation and elimination of bilirubin.

Answer 12

1. As the senescent (old) red cell is broken down (into globin, haem and iron), the haem is converted into biliverdin which is then converted into free bilirubin in a series of steps.
2. This free bilirubin is released into the plasma and carried around the body bound to albumin.
3. Albumin-bound bilirubin is then stripped of the albumin and absorbed into hepatocytes, where it is conjugated with glucuronic acid inorder to make it soluble.
4. The conjugated bilirubin is then secreted into the bile, where it is metabolised by the bacteria of the intestinal lumen.
5. Bacteria in the intestinal lumen metabolise bilirubin to a series of other compounds which are ultimately eliminated either in faeces or, after reabsortion, in urine.
6. The major metabolite of bilirubin in faeces is stercobilin, which gives feces their characteristic brown color.
7. In the urine, we have yellow urobilin and urobilinogen.
8. The renal excretion of urobilin and stercobilinogen is increased in cases of hepatitis and other damage to hepatocytes.

Question 13

What is jaundice and what can cause it?

Answer 13

• Jaundice comes from the French word ‘jaune’, which means yellow.
• It is when excessive quantities of either free or conjugated bilirubin accumulate in the extracellular fluid a yellow discolouration of the skin, sclera (the opaque, usually white, fibrous outer layer of the eye) and mucous membranes is observed.
• The normal plasma bilirubin concentration is < 17μmol/L (1.0mg/dl).
• When the bilirubin concentration goes > 34-51μmol/L (2-3mg/dl) you start to see discolourations.

Question 14

What was the rare case of ‘green’ jaundice reported?

Answer 14

A very rare case of ‘green’ jaundice was reported, caused by a mutation of the biliverdin reductase gene, hence biliverdin was not converted to bilirubin and instead built up in the serum, giving it the green colour (aggravated by alcohol cirrhosis).

Question 15

What are the three types of jaundice?

Answer 15

The formation of bilirubin is quite complex and if you can work out where in the steps it has gone wrong you can work out the type of jaundice. There are 3 types of jaundice:-

1. Prehepatic jaundice (haemolytic)
2. Hepatic jaundice.
3. Post hepatic jaundice (obstructive).

Question 16

What are the causes of pre-hepatic jaundice?

Answer 16

• It occurs when there is an increased haemolysis, causing excess bilirubin and the liver has no capacity to process/conjugate it.
• Unconjugated bilirubin cannot be excreted in the urine and remains in the circulation.
• This is commonly seen in neonatial jaundice.
• Neonates have increased red cell mass for their survival in utero.
• At birth and during the first few days of life, the increased rate of RBC destruction as foetal Hb is replaces with adult Hb results in normal physiological jaundice.
• In addition, the liver is still a bit immature, so there is a delay in processing this excess amount of bilirubin.
• Phototherapy is used to treat cases of neonatal jaundice through the isomerisation of bilirubin, and consequently, to transformation into water-soluble compounds that the newborn can excrete via urine and stools.
• All newborns have raised unconjugated bilirubin, and in 50-60% of full-term healthy neonates, levels rise sufficiently to cause jaundice.

Question 17

What are the causes of hepatic jaundice?

Answer 17

• Problems with hepatocytes [eg. damage to the hepatocytes (> 80% damage) and biliary tree due to cirrhosis, drugs, viral infections like hepatitis A,B,C,E] results in an increase in unconjugated and conjugated serum bilirubin.
• Gilbert’s Syndrome is a congenital disorder where patients have decreased levels of an enzyme that conjugated bilirubin with glucoronic acid, leading to an increase in unconjugated bilirubin.

Question 18

What are the post-hepatic causes of jaundice?

Answer 18

• The passage of conjugated bilirubin into the duodenum is blocked and leaks into the circulation and urine, making it very dark.
• You also get pruritus (severe itching).

Question 19

Describe the liver’s role in biotransformation / detoxification.

Answer 19

• The liver is vital in the metabolism and excretion of various substances that can be toxic to the body, such as:
  
  • Bilirubin.
  • Ammonia.
  • Hormones - eg. all steroid hormones (androgens, oestrogens, cortisol, aldosterone, thyroxine) are inactivated by conjugation and excretion.
  • Drugs and exogenous toxins (E.g. asprin, paracetamol, ethanol, etc.)
• Most steroids are excreted as glucuronide/sulphate conjugates.

Exogenous meaning - originating outside the body.

Question 20

Describe the three phases of the metabolism of drugs.

Answer 20

1. PHASE 1: (primarily oxidation and reduction)
   
   • It occurs in the smooth ER.
   • The primary mechanism is oxidation via cytochrome P₄₅₀ enzymes, although other enzymes/mechanisms do occur.
   • Usually, the common feature of all these reactions it to make a substrate a more polar compound, which sometimes makes it more active/toxic.
2. PHASE 2: (conjugation)
   
   • Then, conjugation occurs in order to make the drug water-soluble to be eliminated.
   • It’s usually conjugated with different groups, such as glucuronyl (the most important), acetyl, methyl, glycyl, sulphate and slutamate.
   • This is the true detoxification step.
3. PHASE 3: [Some textbooks dont have a stage 3]
   
   • The conjugate substance is eliminated into the blood or bile using ATPase pumps.

Question 21

Give information about paracetamol.

Answer 21

• Paracetamol (aka acetaminophen) has a narrow therapeutic index, and accidental / deliberate overdose is common.
• Paracetamol overdose has 3 phase effects.
• The maximum dose is 4g/day or 1g/dose.
• It is not to be taken after alcohol consumption.

Question 22

Describe the detoxification of paracetamol.

Answer 22

Paracetamol is metabolised by 3 pathways: -

1. Glucoronidation pathway - (45-55% of paracetamol is gotten rid off)
   
   • A phase 2 biotransformation reaction in which glucuronide residue is conjugated onto the paracetamol.
2. Sulfation pathway - (20-30% water is gotten rid off)
   
   • A sulphate residue is conjugated onto the paracetamol.
3. The remainder is gotten rid of by the phase 1 and phase 2 reactions.
   
   • Phase 1 uses the N-hydroxylation and rearrangement.
   • The intermediate product is toxic and is quickly gotten rid of in the second phase 2 reaction, which is the conjuagtion to glutathione (GSH).

• Paracetamol overdose liver enzymes become saturated and glutathione stores become quickly depleted.
• This leads to the build up of NAPQI (which is a toxic intermediate). This can cause liver necrosis and kidney damage.
• Paracetamol overdose has this phase 2 effect, so damage is not immediate and patients can wake up feelin fine and do not seek help till it’s too late for effective treatment.

Question 23

Describe ethanol metabolism.

Answer 23

• Alcohol is readily absorbed in the gastrointestinal tract; however, alcohol cannot be stored, and therefore, the body must oxidise it to get rid of it.
• Alcohol can only be oxidised in the liver, where enzymes are found to initiate the process and then it enters into normal metabolic pathways and gets metabolised as if it were fat.
• The first step in the metabolism of alcohol is the oxidation of ethanol to acetaldehyde catalysed by the enzyme alcohol dehydrogenase, containing the coenzyme NAD+.
• Excess NADH produced by the oxidation of alcohol must be got rid of (as it hijacks other metabolic processes):
  
  1. The conversion of pyruvic acid to lactic acid requires NADH.
     
     • Pyruvic Acid + NADH + H⁺ –> Lactic Acid + NAD⁺
     • This pyruvic acid is intended for conversion into glucose by gluconeogenesis, but since most of it gets converted to lactic acid, this pathway is inhibited, which could result in hypoglycaemia from the lack of glucose synthesis.
     • Also, the excess NADH produced by alcohol metabolism can result in acidosis from lactic acid build-up.
  2. Excess NADH may be used as a reducing agent in two pathways involved in lipogenesis.
     
     • one to synthesise glycerol and the other to synthesise fatty acids.
     • As a result, heavy drinkers may be initially overweight.
  3. The NADH may be used directly in the ETC to synthesis ATP as a source of energy.
     
     • This reaction has the direct effect of inhibiting the normal oxidation of fats in the fatty acid spiral and citric acid cycle.
     • Fats or Acetyl CoA may accumulate, with the resulting production of ketone bodies.
     • Accumulation of fat in the liver can be alleviated by secreting lipids into the blood stream.
     • The higher lipid levels in the blood may be responsible for heart attacks.
     • The excess acetaldehyde itself is toxic to the liver, leading to hepatitis and cirrhosis.

Question 24

Describe the alcohol flush reaction.

Answer 24

• Alcohol flush reaction is a condition in which the face and/or body experiences flushes or blotches, due to an accumulation of acetaldehyde.
• The acetaldehyde accumulation can be caused by a missense polymorphism that encodes the enzyme, acetaldehyde dehydrogenase (ALDH2), normally responsible for breaking down acetaldehyde, a product of metabolism by alcohol.
• 50% of asians have one normal copy of the ALDH2 gene, and one mutant copy that encodes for the inactive mitochondrial isoenzyme.
• A remarkably higher frequency of acute alcohol intoxication among Asians than among Caucasians has been repeatedly shown to be related to this very much reduced activity of the mutant ALDH2-2 isoenzyme.

Question 25

What are some liver problems caused by alcohol?

Answer 25

• Alcoholic liver disease occurs after prolonged heavy drinking, typically for at least 10 years and particularly among those who are physically dependant on alcohol.
• Liver problems caused by alcohol include: -
  
  • FATTY LIVER: alcohol abuse can lead to the accumulation of fat within the liver cells.
  • ALCOHOL HEPATITIS: the excessive use of alcohol can cause acute and chronic hepatitis (inflammation of the liver).
  • ALCOHOLIC CIRRHOSIS: Anything which results in severe liver injury can cause cirrhosis. Common causes include excessive alcohol intake, chronic hepatitis B and C infections, iintake of certain chemicals and poisons, too much iron or copper, severe reaction to drugs, and the obstruction of the bile duct. Cirrhosis of the liver is a degenerative disease where liver cells are damaged and replaced by scar formation.

Question 26

How does severe liver disease affect coagulation?

Answer 26

• The liver activates several factors that are essential in the coagulation cascade, such as fibrinogen, prothrombin, and nearly all the other factors (eg. V, VI, IX, X, XII).
• Vitamin K is also essential for the formation of prothrombin and factors II, VII, IX and X.
• Hence, in severe liver disease, excessive bleeding may result due to a lack of these factors.

Question 27

Describe the storage in the liver.

Answer 27

• Hepatocytes (stellate cells in particular) are important depots for storage of fat-soluble Vitamin D, K, E and A.
• With liver dysfunction, we will end up with fat malabsorption, which would lead to a vitamin deficiency.
• The liver stores Vitamin B12; enough is stored for the next 3 years.
• A Vitamin B12 deficiency eventually leads to pernicious anaemia.
• It also stores folate, which is required in early pregnancy.
• Iron is stored as ferritin, which can be released when needed (blood-Fe buffer).