Liver metabolic functions

Question 1

What are the two vascular sources of the liver?

Answer 1

• portal vein - brings large volume of metabolite-loaded blood to the liver for processing
• Hepatic artery – provides oxygenated blood

Question 2

Describe the blood supply to the liver

Answer 2

 Hepatic artery
o Supplies O 2 rich blood from heart to liver
o Provides 20-30% of blood supply to liver

 Portal vein
o Supplies nutrient rich blood from the digestive tract
o Provides 70-80% of blood supply to the liver

Question 3

What are the cell types of the liver?

Answer 3

• hepatocytes (Regenerative capacity (if no longer exposure to toxin or in partial hepatectomy), Perform major functions of liver)
• kupffer cells (macrophages acting as phagocytes)

Question 4

What is the acinus?

Answer 4

micro-circulatory unit that divides the liver micro structure into 3 metabolically distinct zones

Question 5

Describe zone 1 of the acinus

Answer 5

closer to afferent arteriole.
o Respiratory chain
o Citric acid cycle
o Fatty acid oxidation
o Gluconeogenesis
o Urea synthesis
o Production and bile excretion

Question 6

Describe zone 2 of the acinus

Answer 6

ill-defined intermediate area, transition zone

Question 7

Describe zone 3 of the acinus

Answer 7

closer to the terminal hepatic veins
o Glycolysis
o Glutamine synthesis
o Xenobiotic metabolism (drug metabolism)

Question 8

Where are oxidative functions performed in the acinus?

Answer 8

zone 1

Question 9

where are low-oxygen requiring functions performed in the acinus?

Answer 9

zone 3

Question 10

What is the livers role in carbohydrate metabolism?

Answer 10

Storage (as glycogen) and release (glycogenolysis) of carbohydrates

Gluconeogenesis (synthesis of glucose from other sources, e.g. lactate, pyruvate, glycerol and alanine)
 Glucose as energy substrate (glycolysis, citric acid cycle, synthesis of FA and TG)
 Conversion of fructose and galactose to glucose phosphates

Question 11

Describe the livers role in lipid metabolism

Answer 11

 Mitochondrial beta oxidation of short chain fatty acids

 Leads to synthesis of FA, TAG, CHOLESTEROL, phospholipids and lipoproteins

Question 12

Describe Systemic primary carnitine deficiency

Answer 12

genetic defect in carnitine transporter
 inborn error of fatty acidtransportcaused by
adefectin thetransporterresponsible for
movingcarnitineacross the plasma membrane.
 leads to a variety of symptoms: chronic muscle
weakness, cardiomyopathy, hypoglycemia and liver
dysfunction

Question 13

What is the role of the liver in protein metabolism

Answer 13

 Most circulating proteins are synthesised wholly or largely by the liver and used as measure` of hepatic
synthetic function
 Albumin, glycoproteins
 Glycation of protein

Question 14

Describe the metabolism of amino acids and diposal of urea in the liver

Answer 14

 Nitrogen is converted into urea in the liver and excreted by the kidneys
 Ammonia production and clearance
o If ammonia accumulates in the body, it crosses the BBB and causes confusion in patients
 NB: hepatorenal syndrome – accumulation of toxic metabolites in the body

Question 15

What is the role of the liver in biotransformation and excretion?

Answer 15

Usually for detoxification, but can generate toxic or carcinogenic metabolites

Question 16

What are the phase 1 reactions of biotransformation?

Answer 16

o Occur in the smooth endoplasmic reticulum
o Mediated by cytochrome P450 to produce hydroxylated or carboxylated compounds
o Many drugs are metabolised at this level
o Statins interfere with cytochrome P450

Question 17

What are the phase 2 reactions in biotransformation

Answer 17

Subsequent conjugation with glucuronic acid, acetyl or methyl radicals or glycine, taurine or
sulphate

Question 18

Describe the metabolism of bilirubin

Answer 18

By-product of RBC destruction

Around 126 days, RBCs are phagocytized and Hb is released

Hb broken down into:
o Haeme, which is converted to bilirubin
o Globins are broken into amino acids and recycled
o Iron is bound by transferrin and returned to iron stores in the liver or bone marrow

Question 19

What is the fate of conjugated bilirubin?

Answer 19

80% of urobilinogen formed is oxidized to stercobilin and excreted in faeces, giving stool the
brown colour
o 20% of urobilinogen formed is absorbed by extra-hepatic circulation to be recycled through liver
and re-excreted
 Enters systemic circulation to be filtered by kidneys and excreted in urine

Question 20

Why s bilirubin protein bound and taken to the liver?

Answer 20

Bilirubin is normally bound by albumin and taken to liver (unconjugated or indirect bilirubin)
o Water insoluble
o Cannot be removed from body

Question 21

What does the liver do to bilirubin?

Answer 21

unconjugated bilirubin flows into sinusoidal tissue and albumin releases it
 Ligandin picks up the unconjugated bilirubin and presents it to glucuronic acid
 In the liver it becomes conjugated with the help of UDP glucuronyl transferase
 Conjugated bilirubin is water soluble
 Combines with gallbladder secretions and expelled into intestines

Question 22

What inherited disease can disturb liver metabolism

Answer 22

 Essential product deficit e.g. G-6- P deficiency (Glycogen storage I)
 Precursor accumulation e.g. OTC deficiency (Hyperammonaemia)
o Rare X-linked genetic disorder characterized by complete or partial lack of the enzymeornithine
transcarbamylase(OTC).
o OTCis essential for the urea cycle
 Alternative pathway activation e.g. Amino-acidopathy
o Any disorder caused by a defect in an enzymatic step in the metabolic pathway of one or more
amino acids or in a protein mediator necessary for transport of an amino acid in/out of a cell.

Question 23

What are the outcomes of mitochondrial damage?

Answer 23

 Inhibition of beta oxygenation of fatty acids leads to micro-vesicular steatosis
 Interference with oxidative phosphorylation leads to insufficient ATP generation
 Impairment of the respiratory chain leads to excess ROS with lipid peroxidation
 Increase in permeability transition leads to cell death (apoptosis)

Question 24

What can cause mitochondrial dysfunction?

Answer 24

Inborn enzyme deficiencies involving:
o fatty acid oxygenation
o organic acids
o lactate metabolism
o oxidative phosphorylation
o urea cycle
 Episodic de-compensation precipitated by inter-current stress

Question 25

What can cause toxic damage to the mitochondria?

Answer 25

o Drugs (antivirals, salicylate, valproate, tetracycline)
o Toxins (hypoglycin, atractyloside)

Question 26

What can cause toxic damage to the endothelium?

Answer 26

o Drugs (cytotoxic drugs)
o Toxins (Senecio, aflatoxin, pyrrolizidine)

Question 27

What toxic damage can cause Glutathione depletion and cell death?

Answer 27

o Glutathione is an antioxidant
o Drugs (paracetamol)
o Hypoxic ischaemia

Question 28

What is centrilobular necrosis?

Answer 28

necrosis of the centrilobular tissue of the hepatic lobule.

o Centrilobular zone is most prone to metabolic toxins, e.g. those generated in alcoholic hepatitis.

Question 29

What can cause centrilobular necrosis?

Answer 29

 Sepsis
 Shock induced ischaemia
 Congestive heart failure
 Toxicity from drugs and poisons

Made worse by:
o Malnutrition
o Infection
o Fasting
o Exercise

Question 30

What are the Pathologic manifestations of metabolic disease of the liver

Answer 30

 No structural abnormalities evident but severe functional disturbance
 Hepatocyte injury leading to apoptosis, necrosis, cirrhosis or tumours
 Storage of lipid, glycogen or other products manifesting as hepatomegaly

Question 31

Describe Clinical patterns of metabolic disease involving the liver

Answer 31

 New-born acute metabolic crisis - mimics sepsis
o serious health condition caused by low blood sugar and the build-up of toxic substances in the
blood.
o Symptoms of a metabolic crisis are poor appetite, nausea, vomiting, diarrhoea, extreme
sleepiness, irritable mood and behaviour changes.
o If not treated, can cause breathing problems, seizures, coma, and death.
 Severe vomiting and failure to thrive
 Recurrent episodes of vomiting and encephalopathy with acidosis
 Progressive retardation or seizures with hepatomegaly
 Hepatomegaly with/without jaundice and failure to thrive/grow normally