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The liver ~ Medical student education

THE LIVER:

Aim

  • To understand the basic anatomy and function of the liver
  • To understand some of the common disease processes of the liver

Discussion

The liver is the highly complex metabolic engine of our body. It shares this duty with several other organs but is relatively unique in its ability to rapidly regenerate. Can you think of any other organs capable of regeneration? (See below for answer). The regenerative ability of the liver allows recovery from some diseases but ironically is the cause of others.

Anatomy

As with most critical organs, the liver is tucked away from probing fingers, in this case in the protected by ribs in the right upper quadrant. It is connected to both the systemic vascular system (hepatic artery and hepatic vein) and the portal vascular system (portal vein). Why are both systemic and portal connections necessary?

Function

Table 1

The liver has numerous functions best grouped into Metabolic, storage and immunological functions.

The main function of the liver is as a metabolic filter, analogous to a desalination plant….albeit far more successful than our equivalent down at Wonthaggi (the local reference is for you Toby). Much like the desalination plant, the liver requires a large amount of energy to drive the filtration process. Blood from the portal vein is the ‘sea-water’ and contains large amounts of digestion products and toxins from the gastrointestinal tract. The liver also makes serum proteins and it also storage organ. One of the best ways to understand liver function is to see a patient with liver failure. Their big concerns are encephalopathy (toxins), bleeding problems (loss of clotting factors and platelets), ascites (decreased albumin), chronic jaundice (build up of bilirubin), and systemic illness (various causes).

Fig 1. Hepatic lobule with central hepatic vein (often termed centri-lobular) and surrounding portal tracts forming a hexagon.

The filtration unit of the liver is the lobule (Fig 1.). The starting point is the portal triad (branch of the hepatic artery and portal vein and bile duct) surrounded by fibrous stroma, all together referred to as a ‘portal tract’. This fibrous structure is the only significant support for the liver; the liver is in fact a very soft organ and this is why it is so prone to trauma. The portal tracts can expand and this is the site in which lymphocytes first enter the liver (portal inflammation).

From these portal triad vessels, blood enters the liver sinusoids (Fig 2.); these are low pressure vascular channels lined on either side by a single layer of hepatocytes. They carry a mixture of oxygenated Hepatic artery blood and nutrient/toxin laden portal vein blood. At the opposite end of the sinusoid is the central hepatic vein which will carry blood out of the liver back into the systemic circulation. The hepatic sinusoids also contain specialised macrophages (Kupffer cells) and cells that store vitamin A and potentially stimulate fibrosis (Ito cells).

Fig 2. Diagram showing mixing of arterial and portal blood into a sinusoid with flow into a central hepatic vein branch and flow of bile back to the portal tract

Disease

Hepatocytes along the length of a sinusoid are exposed to blood with different composition with proximal hepatocytes exposed to higher O2 levels, but also higher levels of toxins. This critical concept accounts for the concept of  zonation in the liver and explains some of the disease processes we see. The higher O2 levels means hepatocytes closest to the portal tracts (periportal) are more resistant to hypoxia so ischaemic damage in the liver is usually greatest in the zone around the hepatic (central) vein (centrilobular necrosis – Fig 4.). At the same time, the hepatocytes are also exposed to higher levels of toxin and are often where we first see toxic damage or toxin accumulation (iron and copper overload are first seen in the proximal hepatocytes adjacent to the portal tracts (periportal accumulation – Fig 3.).

Histology showing centri-lobular necrosis

Fig 4. Liver showing a zone of centri-lobular necrosis - the necrotic zone is between two portal tracts, where we would usually see a central hepatic vein (dotted circle)

Histology of iron overload (Perls stain)

Fig 3. Perls stain for iron showing haemosiderosis (iron overload) - the blue iron deposits are most prominent in the periportal hepatocytes.

The sinusoidal system is analogous to a production line where the conveyor belt is the sinusoid containing blood with workers (hepatocytes) on either side. Hepatocytes have one surface exposed to the flowing blood where they add/remove substances according to need, both as active (energy consuming) and passive processes. The opposite surface faces into a bile canaliculus where bile (containing the waste the hepatocytes have removed) flows back to the portal tract for excretion into the gastro-intestinal lumen.

Microscopically speaking, the hepatocyte is a big cell, mainly due to it’s abundant eosinophilic cytoplasm (eosino-philic means there is prominent staining with Eosin – this is the orangey/pink in the pink and purple world of histology – Fig 5.).

Histology of liver

Fig 5. Real life histology is never as perfect as Fig 2. above but this histo-micrograph gives a good impression of how the hepatocytes are arranged to create sinusoids (the clear canals between hepatocytes). The sinusoids drain into a hepatic vein (upper left corner).

The cytoplasm is full of machinery (organelles) responsible for the metabolic process of the liver, as well as those responsible for producing all the energy to run the ‘machines’. When the hepatocyte is insulted by a toxin, cell function is impaired and one of the first things we see under the microscope is accumulation of fat in the cytoplasm (fatty change or steatosis). This can be an acute event (heavy night out on the turps) or a more chronic process. Histologically we describe steatosis as microvesicular (many small vacuoles in each cell), macrovesicular (a single large vacuole per cell) or mixed, as the pattern of steatosis may help diagnose a cause. If the hepatocyte is unable to survive the insult, it undergoes death stimulating a local acute immune response, resulting in steatohepatitis; the most common causes of steatohepatitis are alcohol abuse and the ‘metabolic syndrome’; the latter is referred to as ‘non-alcoholic steatohepatitis’ or NASH. If inflammation is ongoing, both conditions can result in cirrhosis. Can you think of any other causes of cirrhosis?

The liver is extremely good at regenerating. The stem cells of the liver are found at the border of the portal tract and the hepatocytes. These cells can differentiate into bile ducts or hepatocytes. At the time of liver damage there is a large amount of activity occurring at this junction. If the liver undergoes enough insult so that the hepatocytes cannot regenerate fast enough, the body tries to deal with this by replacing the hepatocytes with fibrous tissue; this is a form of organisation. This usually starts at this junctional site and spreads out in a stellate manner from the portal tract (described as fibrous spurs), progressing to bridging fibrosis between portal tracts and to central veins. This destruction of the normal architecture destroys the normal flow mechanism. The liver requires a higher pressure to pass the blood through the remaining functional units causing raised portal pressure. This alters the flow of blood at points where the portal venous system interfaces with the systemic venous system; these are primarily at the lower end of the oesophagus (oesophageal varices), anus (haemorrhoids) and various cutaneous sites.

Histology of liver cirrohosis

Fig 6. Histology showing cirrhosis with thick bands of fibrous tissue replacing the tissue between portal tracts (dotted circles). These fibrous tissue bands surrounding surviving hepatocytes and as these attempt to regenerate they form parenchymal nodules.

The hepatocytes also regenerate but are now trapped by fibrous tissue and form nodules. As the fibrous tissue increases in amount the normal architecture is destroyed, with extensive bridging of fibrous tissue obliterating the normal portal tract to central vein architecture of the lobule (Fig 6.). This pattern is termed cirrhosis. It is important to remember that the early stages of cellular fibrosis (anywhere in the body) is reversible but as a fibrous tissue becomes more mature and less cellular, fibrous tissue is permanent and irreversible.

Sometimes cirrhosis is further defined by the size of the nodules (micronodular, macronodular and mixed nodularity); the size of the nodules is partly determined by the toxin, the chronicity of the process and the ability of cells to regenerate. In acute toxic attack the cirrhosis is more likely to be macronodular as the hepatocytes are not constantly being damaged.

You should look up the diseases that can result in cirrhosis. The common ones that we see include chronic alcohol abuse (toxic), hepatitis viruses (infective), iron overload (metabolic), obesity (greed) and idiopathic. These causes indicate the wide range of potential toxins that can damage the liver. Interestingly, despite the varied causes, the end point of all these chronic insults is the same…..cirrhosis.

Each individual will respond differently to the same toxin, partly related to the HLA status, which defines the immune response. In hepatitis B infection, only a small proportion of people are unable to clear the virus. In these cases, the virus becomes incorporated into the hepatocyte genome. Replication involves the virus budding from the hepatocyte cell surface. Viral replication occurs in waves. As the virus is expressed on the surface an immune response is mounted (cell mediated). If you look at these patients you often see fluctuating liver enzyme profiles reflecting this immune response.

In patients with haemochromatosis, there is an inability to manage iron. The metal gets deposited in hepatocytes where it slowly becomes toxic. The metal is also deposited in other organs. Do you know what other organs are effected by haemochromatosis? Haemochromatosis is important because it is carried by those with Celtic origins and is therefore common in Australia

As in any situation where there is chronic inflammation and damage, the liver can undergo malignant change. The primary carcinoma of the liver is called a hepatocellular carcinoma (HCC). These are more common in patients with chronic viral infections, and any chronic toxic situation. Primary tumours of the bile duct radicals are called cholangiocarcinomasMetastasis to the liver is common, particularly from the gastrointestinal tract. This is due to the fact that it ‘filters’ much of the blood from the gastrointestinal system.

Some things to think about

To make sure you understand the functions of the liver think about a few of these things;

  • Revise the symptoms and signs of chronic liver failure. Try to group them into functional groups (ie those related to decreased excretion, those related to decreased synthesis etc.).
  • Appreciate the benefits and problems with alcohol intake.
  • Understand the different sorts of infection that can occur in the liver.  Ask yourself why viral infections are more common.
  • Find out which metals can be toxic.  Wilson’s disease is a fascinating condition.
  • It is important to understand the different mechanisms for jaundice (pre-hepatic, hepatic and posthepatic). This becomes very important in the diagnostic process for jaundice.
  • Find out how paracetamol damages the liver…and how overdose is treated.
Answers to above questions

Can you think of any other organs capable of regeneration?

  • The adrenal glands are capable of regeneration.
  • Some consider the skin to be an organ, and this undergoes constant regeneration.

Why are both systemic and portal connections necessary?

  • The hepatic artery delivers oxygenated blood.
  • The portal vein delivers all nutrients/vitamins and minerals/fluid/toxins absorbed from the gastro-intestinal tract.
  • The hepatic vein drains blood from the hepatic parenchyma – this contains all waste products from the gastro-intestinal tract along with various metabolites, some of which have been activated for delivery back into the systemic circulation.
  • Nb – There is no portal artery.

Can you think of any other causes of cirrhosis?

  • As discussed above, the most common causes are alcohol, NASH and chronic viral infection. Comprehensive lists can be found in any basic textbooks or quick google search.

Do you know what other organs are effected by haemochromatosis?

  • Liver – cirrhosis.
  • Pancreas – diabetes.
  • Heart – cardiomyopathy.
  • Joints – arthropathy.
  • Skin – pigmentation of the skin….in fact an old name for the disease was ‘bronze diabetes’.

A/Prof John Pedersen and Dr Andrew Ryan


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