Liver physiology Flashcards
What are the main types of cells in the liver?
Hepatocytes, Kupffer cells, endothelial cells, stellate (Ito) cells
What is the function of the stellate cells and where are they located?
Perisinusoidal cells, located specifically in the Space of Disse.
Functions: store vitamin A, fat and collagen
What is the functional unit of the liver?
The hepatic lobule: hexagonal plates around a central hepatic portal vein
What does a portal triad contain?
Portal vein, hepatic artery, bile duct
What are Kupffer cells?
fixed tissue macrophages, which filter blood coming from the small intestine via the hepatic portal vein
In which direction does bile flow in the liver? In what?
Bile flows in canniculae (sit between hepatocytes). Flows in a retrograde manner from the common vein to the portal triad.
What are the main components of bile?
cholesterol, phospholipids, bilirubin, bile acids, water, electrolytes
What do hepatocytes do in bile secretion?
secrete bile acids, cholesterol and other organic components into the cannaliculae
What is the second stage of bile acid secretion facilitated by endothelial cells in bile ducts?
Addition of water to the bile salts etc, plus electrolytes (inc: Na+ and HCO3-)
What is the hormonal control of bile acid synthesis and release from the liver?
Secretin is released from S cells in response to gastric acid in the duodenum
How much bile does the gall bladder store on average?
30-50ml
What is the hormonal control for release of bile from the gall bladder?
Release of cholecystokinin (CCK) from I cells in response to fat in the duodenum.
Cholesterol is immediately broken into which 2 acids?
cholic acid + chenodeoxycholic acid
Why are bile salts conjugated with amino acids (e.g. taurine or glycine)?
AA-conjugation makes the bile salts water-soluble
What are primary bile salts?
Refers to the species occurring as Na+-salts, secreted from the liver
What are secondary bile salts?
Formation of deoxycholic acid and Lithocholic acid following bacterial fermentation in the small intestine
How are secondary bile salts transported back to the liver?
Transported from the terminal ileum via enterohepatic circulation back to the liver
What are 2 main types of gall stones?
Cholesterol (80%), pigment (20%)
What are the main risk factors for gall stones?
HFD, gall bladder mucosal inflammation, F>M, excess oestrogen
What is the function of bile?
To emulsify fats, enabling lipase-mediated digestion and aiding absorption
What is bilirubin?
Breakdown product of RBC degradation, yellow pigment
What helps to neutralise the HCL in gastric acid?
Bile + pancreatic juices
What reaction is bilirubin generated from?
Haem -> (iron +) porphyrin -> bilirubin
What is the intermediate formed before bilirubin that can cause a greenish jaundice
biliverdin
Which cell type catalyses the breakdown of haem into bilirubin? Where does this occur?
Kupffer cells (macrophages) in the sinusoids of lobules
How is unconjugated bilirubin carried in the blood (during physiology)?
It is conjugated to albumin, thus making it water-soluble?
What are the 3 methods of paracetamol conjugation in the liver?
Sulfonation, n-hydroxylation, glucoronidation
What is free bilirubin conjugated to in the liver?
Glucuronic acid
How is conjugated bilirubin then excreted?
It leaves the liver with bile, and is then either excreted renally (as urobilin) or in faeces (as stercobilin)
What is jaundice? Why does it happen?
yellowish tinge to skin, mucosa or sclera (eyes).
Caused by accumulation of unconjugated/free bilirubin in the plasma
At what [bilirubin] is jaundice likely to be present?
> 1.5mg/dL
How does conjugated bilirubin in the bile get excreted in faeces?
conjugated bilirubin is metabolised by intestinal microbiota, redox reactions promote the formation of stercobilin. This colours and is excreted in faeces
A mutation in what causes the rare green jaundice (biliverdin)?
What can exacerbate this?
mutation in biliverdin reductase
prevents conversion of biliverdin to bilirubin
Can be aggravated by EtOH cirrhosis
What can be used to treat jaundice in low-income countries, particularly in infants?
How do they work?
Sunlight canopies
Filters so that only blue light gets through
Therefore reduced UV-mediated damage
What are the 2 main processes by which glucose is generated in the liver?
gluconeogenesis
glycogenolysis
Through which process is Glucose-6-phosphate converted to pyruvate?
Glycolysis
Which enzyme catalyses the breakdown of glycogen to glu-1-P?
What is the name of this reaction?
Glycogen phosphorylase
Glycogenolysis
Which transporter is used for uptake of Glu into the hepatocyte?
Glut2
Which hormones stimulate glycogenolysis?
Glucagon (GCG)
Adrenaline
Which hormones stimulate glycogenesis?
insulin
What are the 4 methods of fat metabolism in the liver?
Adipose storage
Oxidation of TGs to ATP (OXPHOS)
Lipoprotein synthesis
cholesterol and phospholipid synthesis
What are the 4 methods of protein metabolism in the liver?
transamination/deamination of AAs
synthesis of non-essential AAs
synthesis of plasma proteins (e.g. albumin)
urea synthesis (excretion of ammonia)
How is glutamine (AA) removed by the liver?
Conversion to NH3 and then excretion via the urea cycle
Why is glutamine (accumulation) toxic?
Glutamine interferes with GABA and dopamine receptors and can cause hepatic encephalopathy
What clinical feature is indicative of excess/toxic oestrogen? How many is considered to be concerning?
Spider angiomas
>5
What are the broad phases of liver metabolism/detoxification? What do they involve?
Phase 1 (redox) Phase 2 (conjugation) Phase 3 (excretion)
Why is an OD more likely with paracetamol?
It has a narrow therapeutic window
What is the toxic metabolite generated through breakdown of paracetamol? Through which phase I reaction does it occur?
NAPQI
Generated through n-hydroxylation and dehydration of paracetetamol
What are the toxic effects of NAPQI?
Liver necrosis and renal failure
Why is there an accumulation of NAPQI in paracetamol during OD?
NAPQI should be conjugated to GSH, but this gets depleted and it is then left to circulate a free species in the plasma
What is the antidote for paracetamol OD? How does it work?
N-acetyl cysteine (NAC), IV infusion
NAC is the precursor to GSH, it enables restoration of the GSH stores and therefore allows conjugation and excretion of NAPQI
How is EtOH metabolised?
EtOH -> acetaldehyde -> conjugate acid
Which enzymes catalyse the metabolism of EtoH?
alcohol dehydrogenase (EtOH -> acetylaldehyde) acetylaldehyde dehydrogenase (-> conjugate acid)
Consequences of chronic EtOH abuse (>10yr)
fatty liver disease
cirrhosis
alcoholic hepatitis
What kind of cells are hepatocytes?
stable cells: will only regenerate in response to injury or trauma. Otherwise cells are quiescent (G0)
What is an example of a labile cell?
Skin
What are the 2 main pathways of liver generation?
growth factor mediated
cytokine dependent
How does chronic EtOH dependence affect liver regeneration?
reduced ability for liver to regenerate
Activation of liver regeneration can occur via non-parenchymal cells. Which cells are these?
stellate (Ito)
Kupffer
Which LFT is an indicator of bile flow obstruction? Which other marker may be indicated?
elevated ALP
elevated GGT
Hypoalbuminaemia indicates:
malnutrition or chronic liver disease
