The Liver - An Introduction to Its Function Flashcards
What are the 3 major aspects of the liver’s structure that influence its function?
- vascular system
- biliary tree
- 3D arrangement of liver cells with the vascular and biliary systems
What accounts for a majority of blood supply to the liver?
Venous blood from the portal vein
Where does the blood in the portal vein come from?
Blood returning from the GI, full of digested products
What accounts for a minority of blood supply to the liver?
Hepatic artery
How does blood from the liver return to the vena cava?
- Blood from the central veins in the liver lobules drain into the hepatic vein
- This drains into the vena cava.
What are the four types of liver cells?
HEPATOCYTES
KUPFFER CELLS
LIVER ENDOTHELIAL CELLS and STELLATE CELLS.
What are the purpose of hepatocytes?
Metabolic functions in liver
What is the functional unit of the liver?
Hepatic lobule
Describe the structure of the hepatic lobule.
- Hexagonal plates of hepatocytes around the central hepatic vein.
- At each of the corners are branches from the portal vein, hepatic artery and bile duct.
Describe blood flow through the liver.
- Enters the lobules through branches of the portal vein and hepatic artery
- Flows through small channels called sinusoids that are lined with hepatocytes.
- Blood exits lobule through central vein (hepatic venule)
- Blood flow is in the opposite direction to the flow of bile.
What do hepatocytes do to blood flowing through the lobule?
Remove toxic substances, including alcohol, from the blood
Compare and contrast the oxygen content of blood entering the lobule to blood leaving the lobule.
- Blood entering (at the hepatic artery) is relatively oxygen-rich
- Blood leaving contains low levels of oxygen (at the terminal hepatic venule)
Why does blood leaving the lobule have low levels of oxygen?
- Hepatocytes along the sinusoids use up much of the available oxygen
How does the biliary system go (in terms of structures)?
- bile is secreted by hepatocytes
- goes through canalinculi
- goes to small ducts
- goes to large ducts
- anastamose onto common bile duct
How does the liver’s microstructure support its roles?
- massive surface area for exchange of molecules
- sophisticated separation of blood from bile
- specific positioning of pumps to achieve specific localisation of materials
What happens to blood as it passes through the intestinal capillaries?
- Picks up bacteria
What are the purpose of Kupffer cells?
Cleanse the blood as it passes through the sinusoid
What happens as bacteria come into contact with Kupffer cells?
- Bacterium passes inwards through the wall of the Kupffer cells
- Permanently lodged in wall till digested.
What is bile?
Liquid consisting of a complex mix of water, electrolytes and organic molecules
Give examples of the organic molecules found in bile.
- Cholesterol
- Bilirubin
- Phospholipids
Outline what occurs during bile secretion.
- Hepatocytes secrete bile into the canaliculi
- Bile flows into the bile ducts
- Modified by water and bicarbonate-rich secretion from epithelial ductal cells.
What does bile do?
- Fat digestion and absorption via emulsification
- Neutralises gastric juice as it enters the small intestine and aids digestive enzymes.
- Aids elimination of waste products from the blood
What waste products does bile aid the elimination of?
- Bilirubin
- Cholesterol
How does bile enter the duodenum?
Via the major duodenal papillae (the Sphincter of Odii)
What is the purpose of the Sphincter of Odii?
Controls bile entry
How can bile be transported to the gall bladder?
Via the cystic duct where it is stored and concentrated
What is bilirubin?
- Yellow pigment formed from the breakdown of haemoglobin
- Gives bile its colour.
- Toxic and made in large quantities so has to be eliminated.
Describe the destruction of aged RBCs. PART 1
- Digested by macrophages throughout the body.
- Fe is recycled.
- Globin chains are catabolised to various amino acids and then reused.
Describe the destruction of aged RBCs. PART 2
- Haem cannot be recycled so has to be eliminated
- Haem converted to bilirubin
Describe the formation and elimination of bilirubin. PART 1
- Senescent red cell is broken down into globin, haem and iron
- Haem is converted into free bilirubin.
- Bilirubin is released into the plasma and carried around bound to albumin.
Describe the formation and elimination of bilirubin. PART 2
- Albumin-bound bilirubin is then stripped of the albumin and absorbed into hepatocytes, where it is conjugated with glucuronic acid.
- Conjugated bilirubin then secreted into the bile, where it is metabolised by bacteria of the intestinal lumen.
Describe the formation and elimination of bilirubin. PART 3
- Bacteria in the intestinal lumen metabolise bilirubin to other compounds which are eliminated either in faeces or in urine (following reabsorption).
- Major metabolite of bilirubin in faeces is stercobilin.
- In the urine, yellow urobilin and urobilinogen.
What is increased during hepatocyte damage/hepatitis?
Renal excretion of urobilin and stercobilinogen
What is jaundice?
Excessive quantities of free or conjugated bilirubin accumulate in the ECF
What are the symptoms of jaundice?
Yellow discolouration of the skin, sclera and mucous membranes is observed
What was the rare case of ‘green’ jaundice caused by?
- Mutation of the biliverdin reductase gene
- Biliverdin not converted to bilirubin and instead built up in the serum
What are the consequences of increased haemolysis in neonates?
Excess bilirubin that the liver has no capacity to conjugate
What cannot be done with unconjugated bilirubin in neonates?
Cannot be excreted in the urine and remains in circulation
What causes neonatal jaundice?
- Neonates have increased red cell mass for survival in utero.
- Increased rate of RBC destruction as foetal Hb replaced with adult Hb after birth
- Liver still immature, so delay in processing.
How can light therapy be used to treat neonatal jaundice?
- Isomerisation of bilirubin
- Transformation into water-soluble compounds that can be excreted via urine and stools.
Describe the hepatic causes of jaundice. PART 1
Problems with hepatocytes - increase in unconjugated and conjugated serum bilirubin.
Describe the hepatic causes of jaundice. PART 2
Gilbert’s Syndrome
- Congenital disorder where patients have decreased levels of an enzyme that conjugates bilirubin with glucuronic acid
- Accumulation of unconjugated bilirubin.
What hepatocyte problems can cause jaundice?
- Damage to the hepatocytes and biliary tree from cirrhosis
- Drugs
- Viral infections like Hep A, B, C,E
Describe the post-hepatic causes of jaundice.
- Passage of conjugated bilirubin into the duodenum is blocked and leaks into the circulation and urine
- Causes itching (pruritus)
Describe the liver’s role in biotransformation/detoxification.
Metabolises and excretes toxic substances:
- bilirubin
- ammonia
- hormones (eg. all steroid hormones (androgens, cortisol, aldosterone, thyroxine) are inactivated by conjugation and excretion
- drugs and exogenous toxins (such as asprin, paracetamol, ethanol, etc.)
In what form are most steroids excreted as?
Glucuronide/sulphate conjugates.
RECAP TO FPP: Describe Phase 1 of drug metabolism.
- Oxidation via cytochrome P450 enzymes.
- Substrate becomes more polar which sometimes makes it more active/toxic.
RECAP TO FPP: Describe Phase 2 of drug metabolism.
- Conjugation occurs in order to make the drug water-soluble to be eliminated.
- Conjugated with different groups, such as glucuronyl (the most important), acetyl, methyl, sulphate, etc.
RECAP TO FPP: Describe Phase 3 of drug metabolism.
Conjugate substance eliminated into the blood or bile using ATPase pumps.
Describe what happens during paracetamol overdose.
- Liver enzymes are saturated and glutathione stores are rapidly depleted
- Leads to liver necrosis and damage to the kidney by toxic metabolites.
What is the main treatment for paracetamol overdose?
Giving N-acetylcysteine, the precursor to glutathione, which increases its levels.
Describe why ethanol metabolism and oxidation is important.
- Alcohol is readily absorbed in GI tract
- Alcohol cannot be stored, and therefore, must be oxidised, which only happens in liver.
What occurs during ethanol metabolism?
- Oxidation of ethanol to acetaldehyde
- Catalysed by the enzyme alcohol dehydrogenase, containing the coenzyme NAD+.
Alcohol oxidation produces high amounts of NADH, which has many uses. Describe some of these uses. PART 1
Conversion of pyruvic acid to lactic acid requires NADH.
- Pyruvic Acid + NADH + H+ = Lactic Acid + NAD+
How can pyruvic acid conversion lead to hypoglycaemia?
- Pyruvic acid used for conversion into glucose by gluconeogenesis
- Most get converted to lactic acid
- Pathway is inhibited from the lack of glucose synthesis.
How can pyruvic acid conversion lead to acidosis?
Lactic acid accumulation
Alcohol oxidation produces high amounts of NADH, which has many uses. Describe some of these uses. PART 2
Used as a reducing agent in two pathways involved in lipogenesis - one to synthesise glycerol and the other to synthesise fatty acids.
Alcohol oxidation produces high amounts of NADH, which has many uses. Describe some of these uses. PART 3
May be used directly in the ETC to synthesis ATP as a source of energy
What is the consequence of increased NADH consumption within the ETC? PART 1
- Inhibits normal oxidation of fats in the fatty acid spiral and citric acid cycle.
- Fats or Acetyl CoA may accumulate, with resulting production of ketone bodies.
What is the consequence of increased NADH consumption within the ETC? PART 2
- Accumulation of fat in the liver can be alleviated by secreting lipids into the blood stream.
- Higher lipid levels in the blood may be responsible for heart attacks.
What is the result of excess acetaldehyde?
- Toxic to liver
- Can cause hepatitis and cirrhosis
Describe the alcohol flush reaction.
- Face and/or body experiences flushes or blotches, due to an accumulation of acetaldehyde.
What is the alcohol flush reaction caused by?
- Missense polymorphism that encodes acetaldehyde dehydrogenase (ALDH2), normally responsible for breaking down acetaldehyde
What are some liver problems caused by alcohol? PART 1
FATTY LIVER - alcohol abuse can lead to the accumulation of fat within the liver cells
What are some liver problems caused by alcohol? PART 2
ALCOHOL HEPATITIS: the excessive use of alcohol can cause acute and chronic hepatitis (inflammation of the liver)
What are some liver problems caused by alcohol? PART 3
ALCOHOLIC CIRRHOSIS: Degenerative disease where liver cells are damaged and replaced by scar formation.
What can cause cirrhosis?
- Excessive alcohol intake
- Chronic hepatitis B and C infections
- Intake of certain chemicals and poisons
- Too much iron or copper
How does severe liver disease affect coagulation? PART 1
- Liver activates several factors that are essential in the coagulation cascade, such as fibrinogen, prothrombin, and other factors (eg. V, VI, IX, X, XII).
How does severe liver disease affect coagulation? PART 2
- Vitamin K is also essential for the formation of prothrombin and factors II, VII, IX and X.
- In severe liver disease, excessive bleeding may result due to a lack of these factors.
Describe the vitamin storage in the liver.
- Hepatocytes (stellate cells in particular) are involved in storage 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.
Describe Vitamin B12 storage in the liver.
- Liver stores Vitamin B12
- Vitamin B12 deficiency leads to anaemia.
Why does the liver store folate?
Required in early pregnancy
Describe iron storage in the liver.
- Stored as ferritin
- Released when needed (blood-iron buffer).
What divides the liver into 2 lobes?
Falciform ligament
Why is accidental overdose common with paracetamol?
Narrow therapeutic index
When should paracetamol not be taken?
Following alcohol consumption
What are the 3 pathways that paracetamol is metabolized by?
→ Glucuronidation
→ Sulfation
→ N-hydroxylation & dehydration
