The two roles of the liver are:
- Processing of absorbed materials
- Excretion of unwanted products and secretion of stuff to help with fat digestion
- The liver is divided into many thousands of ‘lobules’ – each of which is about 1mm across. These are the functional units of the liver.
- A lobule has a central canal, into which drain many sinusoids. The sinusoids contain a mixture of oxygenated blood (~ 20% – from hepatic arteries) and deoxygenated blood (~80% from the portal venous system)
- Bile flows the opposite way to the blood, away from the central canal, in small canaliculi. These canaliculi drain into bile ducts.
- The sinusoids and canaliculi do not have an endothelial lining – they are in direct contact with hepatocytes. The sinusoids do have some sort of sparse lining make up of a collagenous substance, and a few small endothelial cells, and some specialised cells called Kupfer cells. These cells are phagocytotic, and will pick up and old RBCs as well as performing other general cleaning jobs.
- There are tight junctions between hepatocytes that separate the canaliculi and sinusoids; however, these are not totally impermeable, and allow the flow of stuff between these two spaces.
- Conjugation is basically just a process by which molecules have another molecule (usually glycine or taurine) added to them, which then makes them water soluble, and thus easy to secrete. The main thing that the liver conjugates is Bile salt. Bile salts are the conjugated form of bile acid, and thus, bile acids are what we have circulating in our blood, and bile salts are what we secrete in bile.
- The main constituents of bile are lipids, cholesterol, bile salts and lecithin. These are basically all secreted together in micelles.
- Bile salts are taken up by hepatocytes against their concentration gradient. A hepatocyte will pump out Na+, then Na+ will want to travel down its concentration gradient back into the cell, and as it does this, it brings a bile salt with it. Bile salts are quickly bound to receptors within the cell to keep the concentration of free bile salts low. Bile acids are pumped out into bile by a separate mechanism.
- Initially, the micelles are composed entirely of bile acids. These are called primary micelles. These can’t incorporate much cholesterol, but are able to incorporate phospholipid. As the micelle takes up more phospholipid it will become a mixed micelle. Generally, the micelles will grow in size as they absorb more phospholipid.
- Cholesterol is held at the core of a micelle.
- Micelles are negatively charged and so will repel each other.
- Micelle formation determines the volume of bile secreted – a micelle counts as only one osmotic particle – so if micelles don’t form, then the number of osmotic particles will be greatly increased, even though the actual number of particles present is less than if there were enough present to form micelles. This will mean that as bile is isotonic with plasma, the volume of bile will be greatly increased.
- Bile contains conjugates of loads of waste products, as well as bile salts! These toxins will be at much higher concentrations than in plasma, and so are actively secreted into the bile.
- Conjugation occurs inside hepatocytes. The whole point of conjugation is to give the molecule a negative charge which will make it hydrophilic. Conjugation usually occurs in two steps – in the first (usually oxidation, and involving cytochrome p450) the molecule is polarised. Then in the second it is fully conjugated and given an overall negative charge.
- Usually conjugates are less toxic than their precursors.
- Many substances are conjugated by the liver, but then excreted by the kidneys. Generally, smaller molecules are secreted by the kidney, and larger ones by the liver. Conjugation makes molecules larger, and thus usually conjugated substances are excreted in bile, and unconjugated ones are more likely to be excreted by the kidney.
- Bacteria in the colon can metabolise conjugated products and thus make them less hydrophilic, and then they are more likely to be reabsorbed again by the gut.
- The inside of a hepatocyte is negatively charged relative to the canniculi (about 40mV) and thus this helps to ‘push’ things into the canniculi. However, most things are also actively secreted into the bile against their concentration gradient anyway.
- Bilirubin is normally bound to albumin in the circulation – as are just about all organic molecules!
- Bilirubin is red/orange, but it may degrade in the presence of oxygen to become a green colour. Unconjugated bilirubin cannot be excreted at all. Once bilirubin has been conjugated in hepatocyctes, some may escape (possibly from the calliculi into the sinusoid) into the blood, and be excreted in the urine – giving urine its colour!
- Conjugated bilirubin cannot be absorbed in the gut, but unconjugated can be. Some bilirubin becomes unconjugated by the action of bacteria, and thus is absorbed. Urobillogen is a colourless compound that is absorbed by the gut, having been metabolised by bacteria. Urobillogen that isn’t absorbed will oxidise to stercobillogen and this is a brown colour and it is excreted in faeces; giving the faeces its colour.
- Bile salts are rarely actually excreted in the faeces – they just go round and round in a cycle of excretion and absorption – their role being to help absorb fat.
- Proteins are also present in the bile. These are generally plasma proteins, the main one being IgA, which helps prevent the gut from getting infected. This is actively secreted into the bile.
- The gallbladder ‘concentrates’ bile – i.e. it absorbs stuff out of it! The gallbladder will absorb bicarbonate, sodium and chloride ions, and thus the bile becomes less alkaline. The sodium ions are actively pumped out of the bile – and this also causes water to passively flow out of the bile. Other stuff present in the bile will become more concentrated as water leaves the bile – thus potassium, calcium and organic molecules all become more concentrated in gallbladder bile.
- Hepatic bile is a brown colour, but after concentration in the gallbladder, bile will become almost black.