Tuesday, 17 June 2014

basic liver biology - why things go wrong when it's infected

Being a virologist is hard. Not only do you have to know molecular biology but you also have to know cell biology and if you are interested in how viruses cause disease, you have to know anatomy and physiology. As you can imagine, while being extremely interesting, it is very time consuming This is why I have spent the last few days (weeks now) trying to come to terms with my liver. 

Your liver is pretty amazing. Chances are you take it's special role for granted but you really shouldn't. This is something that I have been thinking about over the last few months after starting a postdoc into hepatitis C virus (HCV) biology, while I pondered on what it must feel like to lose the function of your liver. To appreciate what is happening during a disease like viral hepatitis, you have to understand how the liver does it job when it's not sick. This post will hopefully be the beginning of a series of blog posts aimed at trying to understand HCV infection and pathogenesis and how my research fits into it. FYI - I have not included any references in this post because what I am writing is established understanding in basic textbooks. This post will act as background as I continue my exploration of the liver and HCV.

You probably won't have seen your liver and your only experience of its metabolic work will have been after you've had a few drinks and you don't remain inebriated for too long. But it also does much, much more. Your liver carries out a complex array of functions, very difficult to summarise in a post like this (but I'll give it a go). Your liver operates a central role in keeping you alive by carrying out a 'biotransformative' role, lying between absorption (your intestines do this) and excretion (your kidneys do this). Biotransformation exists as two major metabolic functions: altering and breaking down molecules (catabolism) and synthesising them and releasing them into your blood stream to feed the rest of your body (anabolism). Another variation in this role is to break down toxins that can damage your body and it can even release hormones and bile, allowing it to function as a gland (again, variations of catabolism and anabolism). It can also store glycogen, an important carbohydrate storage vessel. What did I say, it is a complicated organ, so no wonder things go bad when it gets infected. The most important feature of your liver that allows it to function as a biotransformative organ is its close association with your blood stream and to do this, your liver employs some interesting physiological tricks. But it is these tricks that open it up to infections and disease
your liver, in relation to stomach and pancreas. Note the lobes and blood supply. (integrated.ca.com) 

Anatomically, your liver is a large (1.5 kg), triangular organ in the top right hand side of your chest, beside your stomach and your intestines.  It is divided into four sections, referred to as lobes. Allowing it to carry the job of breaking down and releasing important molecules into your bloodstream, is it's intimate relationship with your circulatory system, which is composed of blood and lymph fluids. Testament to this relationship is its reported blood flow of 1.5 litres per minute. Unlike other organs it has a dual blood supply made up of two major blood vessels run through your liver, the hepatic artery, which brings in oxygen-rich blood, and the the hepatic portal vein that brings in absorbed nutrients and toxins from your small intestine and allows the blood to flow back into circulation. What makes this dual supply even more impressive is the dense network of smaller blood-circulating endothelial cells that are in near-direct contact with your liver cells throughout your liver tissue. This anatomic arrangement allows maximisation of the surface area to volume ratio of you liver for optimal biotransformation.

hepatic lobules centred around a central vein (dnwalker.com)
The liver is a honeycomb mesh of four major cell types, which for ease of understanding are referred to either as parenchymal (hepatocytes) or non-parenchymal (endothelial, macrophage and fibroblast). Your liver parenchymal cells are largely made up of a single cell type, the hepatocyte, which are arranged into single-cell thick epithelial sheets. These cells are the business end of the liver and the one that is responsible for the majority of its metabolic activity (and mass). The main aim of the liver is to maximise the interaction between the hepatocyte and the blood. To do this, your liver employs endothelial cells to form the aforementioned dense network of blood supply between hepatocytes. These endothelial cells form hollow tracts, known as sinusoids, which line sheets of hepatocytes. Two other cell types, the macrophage-like 'kupfer' cells and the fibroblastic 'stellate' cells sit in close proximity to the liver sinusoids and serve immunological, filtering and healing roles, which I won't discuss here. But have covered elsewhere before. 

If you threw these four cell types into a pile together, very little would happen, but when arranged in the way that they are in your liver, they can efficiently interact with your blood. The patterns that these cell types are arranged in come in three flavours: classical hepatitic lobules, portal lobules and acini. Each pattern describes a different spatial interaction of hepatocytes with endothelial cells. The major structural unit of the liver is the classical hepatitic lobule. Within a single lobe of your liver there are many classical hepatitic lobules, each lobule is composed of a hexagonal arrangement of hepatocytes and endothelial cells. Both the hepatoyctes and endothelial cells are organised around a central vein with five-fold symmetry. At each point of the hexagon lies a 'portal triad' of hepatic arterioles, venules and bile ducts. The oxygen-rich blood coming from the hepatic artery and then moving through the liver lobules into the hepatic portal vein. Other patterns can be observed in your liver, and the lobules can also be divided into acini (with two-fold symmetry between portal triads and the other is the portal lobules, which is relevant for bile drainage. 
cells in the hepatic lobules: not hepatocytes, sinosoidal endothelial cell and kupfer cells

And so we come to the business end of the liver. Each cell has it's own role but it is the interactions between each of them allow the liver to carry out its important job. Importantly, the hepatocytes are the metabolic workhorses of the liver, and rightly, they make up the vast majority of the liver's mass. But in order to absorb and secrete, they must be in close contact with the blood supply and it is this interaction that is facilitated by the non-parenchymal cells, which essentially bridge the liver and the circulation. Most importantly, the endothelial cells form what are known as 'sinusoids', single-cell thick vessels with 'leaky' (fenestrated with no basement membrane) walls allowing extremely easy transport of blood fluid over the hepatocytes. But what happens inside the hepatocytes? I will explore this cell type in more detail in the next post.
the hepatocyte in relation to endothelial cells (hakeem-sy.com)

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