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Liver
Written by Tim Sheppard MBBS BSc. Created 24/6/09; last updated 28/12/09

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What is the liver?

The liver is the biggest solid organ in the body - a reddy brown organ that can usually be found in the upper-right part of the abdomen. Although it is in the right, it's so big that the left lobe stretches across the abdomen to the left side. It sits right on top of the main vein in the body, the inferior vena cava, into which blood can easily flow in order to get back to the heart. The arterial blood supply to the liver (to deliver oxygen) comes from the hepatic artery; but the liver also gets blood coming from the gut through the portal circulation.

The liver has a long list of very important jobs to do. One of the most important (although many of them are essential jobs) is producing a lot of things for the blood (e.g. proteins). The proteins that the liver produces include the clotting factors, a protein that encourages growth called inuslin-like growth factor, and angiotensinogen (a precursor to angiotensin). One of the most important proteins that the liver produces is albumin. It is important because it makes up about 60% of the protein that you find in blood, and prevents water leaving the blood by osmosis.

Proteins aren't the only thing that the liver produces. In fact, the liver is important in making the building blocks of proteins, amino acids. It also makes cholesterol and fats, and helps to manufacture new glucose out of old amino acids. As well as all these chemicals involved in metabolism, the liver produces bile, which is needed to help absorb fats.

Another of the important processes that the liver needs to do is to clean the blood. It's not the same as the kidney, which acts as a filter. The liver is more like a drive-through car wash for the blood. When your blood is coming from the gut, having picked up all the nutrients from your food, it passes through the liver to make sure that any dangerous chemicals are either destroyed, removed or inactivated by a large number of enzymes. There's also a number of immune cells that hang around waiting for any foreign antigens that might need to be picked up.

One of the other things that the liver is involved in is storage. It's a pretty big organ, as already mentioned, so it's well placed to store a number of different things. It's particularly important for storing glucose (sugar), in the form of glycogen, but it also stores certain vitamins (A, D, B12) and minerals (iron, copper).


What is the anatomy of the liver?

If you're thinking about it from a bigger perspective, the liver is basically made up of four lobes. The left and right lobes can be seen from the front, divided by the falciform ligament. The other two are best seen if you turn the liver over and look from the back; you'll still have the left and right lobes, but between them you have two others - the caudate lobe on top, and the quadrate lobe underneath. The ligamentum teres and ligamentum venosum run across the back of the liver, separating the left lobe from the others. The inferior vena cava runs over the right sagittal fossa.

Knowing about the lobes is very important. If the liver is healthy, it can regrow very well, so you could remove up to half the liver and an individual could still survive. The healthy remains of the liver cope until the rest of the liver has regrown. Sometimes people are able to donate a lobe to help people who don't have any healthy liver.

The liver itself sits just below the diaphragm, so it is pushed down during breathing. It is (usually) on the right of the stomach, and the gall bladder sits just underneath it.

The blood supply to the liver comes from two blood vessels, the hepatic artery and the portal vein. The blood going to the gut picks up its nutrients and then passes through a special vein that goes on to the liver. These two blood vessels then feed into the liver as described below. When the blood wants to leave the liver, it finds its way through to a number of veins that leave the lobes of the liver (the hepatic veins) and on to the inferior vena cava.

The liver is important in producing bile, a solution that helps to digest fats and get rid of the haemoglobin from old red blood cells. The bile needs to get into the gut, so it travels through bile ducts - firstly in the liver (intrahepatic) and then outside the liver (extrahepatic). Bile is made continuously so it can be stored in the gall bladder. These ducts ultimately travel through the pancreas to meet the small intestine at the duodenum.


What is the structure of the liver?

As already mentioned, the liver is split up into four lobes: left, right, caudate and quadrate. However, in order to do it's job, the liver needs to work on a much smaller scale. In fact, each lobe is divided up into much smaller subunits. At the very basic level, you've got what is called a lobule, which is a hexagonal shape with a central vein running through the middle. This vein carries blood away from the liver cells and up towards one of the hepatic veins. At each corner of the hexagon is a portal triad, made up of a branch of the hepatic artery, a branch of the portal vein, and a bile duct leading eventually to the common hepatic duct.

In every lobule, then, there are two directions of flow. Bile, which is produced by the liver and is destined for the gut, travels away from the portal vein through a bile canal and into a bile duct, which takes the bile away and eventually into the duodenum. Blood, travelling from the heart (in the hepatic artery) and the gut (in the portal vein), travels through branches of these blood vessels through hepatic sinusoids and into the central vein.

Each lobe of the liver is made up of many of these lobules, and each one of these is like the factory of the liver. Between these vessels of blood and bile you'll find the hepatocytes, the cells of the liver which do all the hard work. Blood travelling through hepatic sinusoids to reach the central vein can be cleaned, and the liver can throw into it all the proteins and other chemicals which the hepatocytes are producing.

The sinusoids are also lined by cells known as Kupffer cells or Browicz-Kupffer cells. These cells are involved helping the liver with it's job of cleaning the blood, as detailed below.


How does the liver clean the blood?

Since the liver has a number of important jobs to do, it needs a well organised system of getting things done. Part of this is achieved because of its structure. However, the liver is also filled with enzymes to help with the various things that need doing. Enzymes are special proteins found all around the body for helping to get things done, a bit like the workers in a factory. And the cells in the liver - the hepatocytes - are like loads of tiny factories which contain these workers to make sure everything runs smoothly.

With all of these mini hepatocyte factories working furiously, the first major task is to clean the blood coming through. This basically means that anything which is extra in the blood needs to be checked and then destroyed, inactivated or removed if necessary. Recognising absolutely anything which could come through is hard, however, so there's two particular ways of handling this.

The first is that there are loads of enzymes in the liver working toward Phase 1 metabolism. This is the first step of metabolism designed to deal with substances coming through. In fact, Phase 1 metabolism is often something which activates a substances as it comes through, to make sure that it's going to do its job. This could be by adding or removing an oxygen atom, splitting molecules, or changing the shape of a molecule to make it work differently. There is one particular family of enzymes in the liver called the cytochrome p450 (or CYP) enzymes. This family of enzymes is actually found all around the body, but in the liver they're extremely useful for making changes to chemicals that come floating through. The main change that they do is called a monooxygenase reaction, where a molecule of oxygen is added to a chemical to give it a 'hydroxy-' group (-OH). Like other phase 1 metabolic reactions, this can make a previously innocent or inert substance more dangerous. However, that's not the end of the story.

Phase 2 metabolism then comes along with other enzymes that usually add more atoms onto a molecule. Again, there are a number of enzymes in the liver which are set up to add an extra load onto the end of a molecule (e.g. adding glucoronic acid, a process known as glucuronidation, or sulphonates, known as sulphonation). This has two helpful effects - suddenly the molecule is much heavier, so it's much less likely to be a danger to the body (it is often 'inactivated'). Also, it's often much easier to get rid of, through the kidney or elsewhere. Even though the enzyme might not have been able to recognise exactly what the original chemical was, the series of reactions has been able to inactivate a random chemical to prevent it doing damage. I often find it helpful to think of this process as adding a handle to the end of the molecule to make it easier for other things to grab hold of it and get rid of it.

Now, I said there were two ways of handling absolutely anything which could come through. The first is this special metabolism that goes on, performing standard reactions which can activate or inactivate random chemicals. The second is a rather sly immune response.

In many places in the body, including the liver, there is a specialised immune system called the reticuloendothelial system. This contains cells that basically gobble up many things coming through. There are several cells which do this, but in the liver there are Kupffer cells (or Browicz-Kupffer cells) which are made from monocytes. These will eat up old red blood cells, and also anything which has been coated in complement.

By the time you've used enzymes to inactivate chemicals and gobbled up invaders with your Kupffer cells, you blood should be pretty clean. But the liver's always got other work to do...


What does the liver produce?

The body is constantly renewing itself; new cells are made all the time, at an extremely fast rate. In addition to that, the body is constantly using up chemicals in all of the processes which are going on - you can see that many chemicals are involved just by looking at the sections on metabolism or DNA. But a lot of these chemicals are used up or worn out, so the body needs to make more.

The liver is one of many parts of the body that is involved in all this. However, it's a particularly important part because it is involved in making so many things. In fact, one of the reasons why it's so hard to make an artificial liver machine is that it's hard to make something that is able to produce all of the things the liver is involved in making.

One of the things the liver is most famous for making is bile. This is a liquid which is made up mainly of water, salts, bile pigment and fats, and it is released into the intestines to help digest fat and to make your poo look brown. The pigment is made up of old red blood cells, where the haemoglobin in them has been turned into bilirubin and biliverdin. If you don't get rid of this pigment because of a problem around the liver, it deposits in the skin and you turn yellow - or jaundiced. Bile is also important to help digest fats, as it makes them easier to digest and absorb.

As already mentioned, one of the most important proteins that the liver produces is albumin. Albumin is a protein which makes up about 60% of the protein that you can find in the blood, and is made up of almost 600 amino acids. It acts a bit like a courier, transporting things like ions and hormones around the body. However, because it is so abundant, it is really important in maintaining the oncotic pressure of blood (i.e. controlling how much osmosis is going on).

When the body has a problem, such as an injury or an infection, the liver produces what are known as acute phase proteins, which are in some way related to the body's response to these events. When an injury or infection happens, immune cells such as neutrophils recognise the event and send off chemical messengers called cytokines to alert the body to the fact that it's happened. The liver effectively sees these cytokines and will produce more of some proteins (such as those involved in the immune response, e.g. C-reative protein) and less of others (e.g. albumin). Proteins like C-reactive protein (or CRP) then act as a marker that something is going on.

The liver is also responsible for making the clotting factors which enable blood to clot. Looking at how well the blood is clotting is actually really good way of seeing how well the liver is functioning - "liver function tests" are blood tests which can show if there is a bit of damage to the liver, but it can sometimes be much quicker and sensitive to see whether there is a problem with clotting factor production.

The other main group of chemicals which the liver produces is protein or peptide hormones. Most of the main, exciting hormones are produced elsewhere (e.g. the pituitary gland, pancreas or adrenal glands). However, angiotensinogen is important in the renin-angiotensin system. Insulin-like growth factor (IGF) is a key protein produced when growth hormone is released into the blood, and it helps cells to grow a bit more - and can reduce their death. This doesn't mean that you can inject yourself with IGF to stay alive forever, but it does mean that when the body produces it, it's helpful for controlling how cells grow and change.


What else does the liver do?

As well as producing lots of things and cleaning the blood, the liver is responsible for storing lots of important things that we get from our diet. Along with muscles, the liver is responsible for storing sugar in the form of glycogen. It's also need in order to make sure that there's a store of certain fat-soluble vitamins (namely A, D and B12) so that if you don't get enough in the diet (and you have had enough in the past to store it!), you can still have enough to work.

Perhaps the most exciting and complicated thing that the liver does is its role in metabolism - not just carbohydrate and fat metabolism, but helping to actually make fats and amino acids, and make and break down vitamins. Unfortunately discussion of these is way beyond the scope of this article, but it's an important area of liver function because without it, the body would not be able to perform cellular functions.


Further Reading