the liver - intro to function Flashcards
what is the importance of the location of the liver ?
- The largest visceral organ (1.5kg), about 2-3% total body’s mass; O2 consumption is 25-30%
- Dual blood supply: Portal vein & Hepatic artery.
- Hepatic vein empties directly into major vessel entering the heart.
- Bile ducts empty directly into gut.
what are the cells of the liver ?
- Hepatocytes (80%) – perform most metabolic functions
- Kupffer cells (30% of NPC) – type of tissue macrophage
- Others are: LSEC, Stellate cells.
what is the hepatic lobule ?
- functional unit
- hexagonal plates of hepatocytes around central hepatic vein
describe the protective barrier functions of the liver
- Kupffer cells - found in sinusoids;
- Represent approx 80% of all fixed tissue macrophages - and function as mononuclear phagocyte system (MPS)
- exposed to blood from gut that contain pathogenic substances.
- clear gut-derived endotoxin from portal blood
- LSECs form an intact sinusoidal wall separating blood flow from hepatocytes
- it is the first in contact with portal-delivered gut-derived pathogens,
- has important physiological and immunological functions including filtration, endocytosis, antigen presentation
- it is equipped with abundant scavenger receptors and specific organelles including endosomes, lysosomes, and micropinocytic vesicles.
- LSEC can mediate immune tolerance in response to pathogenic factors such as PAMPs, to prevent inflammatory injuries.
- Capable of eliminating blood-borne microorganisms and molecules, including viruses
describe coagulation factor synthesis
- Hepatocytes synthesises most blood clotting factors;
- Fibrinogen
- Prothrombin
- Nearly all the other factors e.g. V, VII, IX, X, XII, C
- Vitamin K is essential for activating prothrombin, factors VII, IX & X
- Liver sinusoidal endothelial cells produce VIII, vWF
- Liver diseases can lead to coagulation defects
- commonly vit K-dependent factors decrease; starting with VII and protein C due to short half-life.
- decreased factor V levels seen in acute/chronic
- L/T antibiotic treatment may also cause deficiency of vit K-dependent factors.
describe the storage function of the liver
- Hepatocytes (stellate cells in particular) are important depots for storage of fat-soluble vit A, D, E and K Vit
- Liver dysfunction ⇒fat malabsorption ⇒vitamin deficiency
- Stores Vit B12 and enough stored to last 2-3 years
- Vit B12 deficiency ⇒ pernicious anaemia
- Stores folate, which is required in early pregnancy.
- Iron is stored as ferritin (blood-Fe buffer)
what is bile and where does it come from ?
- Complex fluid = water, electrolytes + mix of organic molecules
- 1st secretion by hepatocytes into bile canaliculi; this contains bile acids, cholesterol, bilirubin & phospholipids.
- 2nd stage secretion is made of water, bicarbonate, NaCl by ductal epithelial cells are stimulated by Ach & Secretin in response to acid in duodenum.
describe bile synthesis
Cholesterol is converted into bile acids cholic & chenodeoxycholic acids.
- Liver synthesises bile acids from cholesterol to primary bile acids, a) Cholic acid; 3-OH groups, b) Chenodeoxycholic acid; 2-OH groups
- Synthesis regulated by the enzyme 7 α- hydroxylase which requires O2, NADH and cytochrome P-450
- Presence of -COOH and -OH groups makes bile acids water soluble than cholesterol
- Primary acids conjugate with glycine or taurine, prior to secretion into bile canalicular. (ratio of glycine to taurine 3:1)
- Conjugated bile salts in sinusoidal blood actively taken up and transported against conc gradient into bile canaliculi.
describe gallbladder function and gallstone synthesis
*GB is small, pear-shaped pouch under liver.
* It holds about 30-50 ml of bile.
* Sphincter of Oddi between common bile duct and duodenum diverts hepatic bile to gall bladder,
* smooth muscle of GB relaxes under the influence of NO/VIP from vagal innervation.
- Abnormal conditions caused by an imbalance in the chemical make-up of bile inside the gallbladder, forming gallstones.
- 2 types of stones: Cholesterol (80%) & Pigment (20%)
Risk factors for cholesterol stones:
* High fat diet
* increased synthesis of cholesterol
* Inflammation of GB epithelium changes absorptive characteristic of mucosa
* excessive absorption of H2O & bile salts, cholesterol concentrates
* More common in women than men
* risk factors = obesity, excess oestrogen (e.g. during pregnancy), HRT
describe biotransformation and detoxification
- Biotransformation is a metabolic process mainly in the liver, to facilitate the excretion of both exogenous and endogenous substances.
- Exogenous substances: Drugs (e.g. Paracetamol) and Ethanol
- Endogenous substances like Bilirubin, Ammonia, Hormones:
- all steroid hormones (androgens, oestrogens, cortisol, thyroxine) inactivated by conjugation & excretion
Biotransformation may occur 2 phases:
* Phase 1 occurs in smooth ER, catalysed by Cyt. P450 enzymes
* Phase 2 to make it more water soluble
* Not all drugs use both phases
what is jaundice
- a manifestation of yellow discoloration of the skin and sclera of the eye, due to accumulation of excess free (unconjugated) or conjugated bilirubin’ in ECF.
- Bilirubin is a yellow pigment formed from breakdown of haemoglobin
what are the different classifications of jaundice
Pre-hepatic (haemolytic):
Excessive breakdown RBC e.g. neonatal jaundice
Excess unconjugated bilirubin
Hepatic:
Hepatocyte damage (>80%)
e.g. cirrhosis; drugs; hepatitis A,B,C,E;
Excess conjugated &/or unconjugated bilirubin
Post-hepatic (obstructive):
Excess conjugated bilirubin
Obstruction to passage into duodenum
Enters circulation & into urine (very dark)
e.g. gallstones, carcinoma of pancreas/bile ducts
describe liver regeneration
- Adult hepatocytes are long lived and normally do not undergo cell division i.e. they are in G0 phase.
- but rapidly re-enter cell cycle and proliferate after partial hepatectomy or in response to toxic injury.
- The proliferation stops once the original mass is established.
- allows for use of partial livers from living donors for transplantation.
- Does NOT involve liver stem cells or progenitor cells, but replication of mature functioning liver cells.
- Mechanism still not understood fully but 2 pathways may be involved:
- Growth-factor mediated pathway → most important HGF (hepatocyte growth factor) and TGFα (transforming growth factor alpha)
- Cytokine signalling pathway using IL-6 via TNFα binding to its receptor on Kuppfer cells
- Prolonged alcohol misuse can reduce regenerative ability of liver.
what are the mechanisms of liver regeneration ?
Hepatocyte Proliferation – Mature liver cells (hepatocytes) re-enter the cell cycle and rapidly divide to replace lost tissue. This is the primary mechanism for regeneration.
Activation of Liver Progenitor Cells – When hepatocyte proliferation is impaired (e.g., in severe injury or chronic disease), liver progenitor cells (also called oval cells) are activated to differentiate into hepatocytes or bile duct cells.
Growth Factor Signaling – Various growth factors, such as hepatocyte growth factor (HGF), epidermal growth factor (EGF), and vascular endothelial growth factor (VEGF), stimulate cell division, tissue repair, and blood vessel formation.
Cytokine Signaling – Cytokines like tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) prime hepatocytes for regeneration by promoting cell cycle entry and enhancing survival.
Angiogenesis (Blood Vessel Formation) – New blood vessels form to supply oxygen and nutrients to the regenerating liver, facilitated by VEGF and other angiogenic factors.
Extracellular Matrix (ECM) Remodeling – The liver’s structural framework is dynamically remodeled by enzymes like matrix metalloproteinases (MMPs) to support new cell growth and tissue reorganization.
