Liver metabolic functions Flashcards
What are the two vascular sources of the liver?
- portal vein - brings large volume of metabolite-loaded blood to the liver for processing
- Hepatic artery – provides oxygenated blood
Describe the blood supply to the liver
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
What are the cell types of the liver?
- hepatocytes (Regenerative capacity (if no longer exposure to toxin or in partial hepatectomy), Perform major functions of liver)
- kupffer cells (macrophages acting as phagocytes)
What is the acinus?
micro-circulatory unit that divides the liver micro structure into 3 metabolically distinct zones
Describe zone 1 of the acinus
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
Describe zone 2 of the acinus
ill-defined intermediate area, transition zone
Describe zone 3 of the acinus
closer to the terminal hepatic veins
o Glycolysis
o Glutamine synthesis
o Xenobiotic metabolism (drug metabolism)
Where are oxidative functions performed in the acinus?
zone 1
where are low-oxygen requiring functions performed in the acinus?
zone 3
What is the livers role in carbohydrate metabolism?
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
Describe the livers role in lipid metabolism
Mitochondrial beta oxidation of short chain fatty acids
Leads to synthesis of FA, TAG, CHOLESTEROL, phospholipids and lipoproteins
Describe Systemic primary carnitine deficiency
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
What is the role of the liver in protein metabolism
Most circulating proteins are synthesised wholly or largely by the liver and used as measure` of hepatic
synthetic function
Albumin, glycoproteins
Glycation of protein
Describe the metabolism of amino acids and diposal of urea in the liver
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
What is the role of the liver in biotransformation and excretion?
Usually for detoxification, but can generate toxic or carcinogenic metabolites
What are the phase 1 reactions of biotransformation?
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
What are the phase 2 reactions in biotransformation
Subsequent conjugation with glucuronic acid, acetyl or methyl radicals or glycine, taurine or
sulphate
Describe the metabolism of bilirubin
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
What is the fate of conjugated bilirubin?
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
Why s bilirubin protein bound and taken to the liver?
Bilirubin is normally bound by albumin and taken to liver (unconjugated or indirect bilirubin)
o Water insoluble
o Cannot be removed from body
What does the liver do to bilirubin?
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
What inherited disease can disturb liver metabolism
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.
What are the outcomes of mitochondrial damage?
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)
What can cause mitochondrial dysfunction?
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
What can cause toxic damage to the mitochondria?
o Drugs (antivirals, salicylate, valproate, tetracycline) o Toxins (hypoglycin, atractyloside)
What can cause toxic damage to the endothelium?
o Drugs (cytotoxic drugs) o Toxins (Senecio, aflatoxin, pyrrolizidine)
What toxic damage can cause Glutathione depletion and cell death?
o Glutathione is an antioxidant
o Drugs (paracetamol)
o Hypoxic ischaemia
What is centrilobular necrosis?
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.
What can cause centrilobular necrosis?
Sepsis
Shock induced ischaemia
Congestive heart failure
Toxicity from drugs and poisons
Made worse by: o Malnutrition o Infection o Fasting o Exercise
What are the Pathologic manifestations of metabolic disease of the liver
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
Describe Clinical patterns of metabolic disease involving the liver
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
