The liver is a remarkable organ with a wide array of functions. It helps detoxify harmful substances in our blood such as medicines and alcohol, synthesises clotting factors, plays important roles in the metabolism of carbohydrates, fat and protein and has a large number of Kupffer cells, resident macrophages that defend the body against potential pathogens in our bloodstream. It is therefore not surprising that diseases affecting the liver can be incredibly detrimental to a person’s health.

Liver disease as a whole is a major health issue in the UK, with mortality rates increasing by 400% since 1970 (1). Prolonged liver disease can lead to cirrhosis, a non-reversible condition in which the liver becomes permanently scarred and can no longer function properly. Repeated episodes of damage and inflammation of hepatocytes, the cells that make up the liver, can also increase the risk of liver cancer and ultimately, death. Therefore it is important that health professionals understand the importance of addressing the causes of these conditions and help patients who may be at risk of developing them.

ETHANOL METABOLISM

Ethanol is a highly toxic substance. Its lipophilic properties enable it to disrupt cell membranes, perturbing their integrity and function. For these reasons, hepatocytes metabolise ethanol in an attempt to convert it into something less harmful.

Within the hepatocyte cytosol, ethanol is first metabolised to acetaldehyde by the enzyme alcohol dehydrogenase (ADH).

Reaction 1

Acetaldehyde is yet another toxic substance, so is shuttled into the mitochondria where it is metabolised into acetate, by the enzyme aldehyde dehydrogenase. Acetate is much less harmful and can be converted into other biomolecules such as acetyl CoA which is involved in fatty acid synthesis.

Reaction 2

Ethanol can also be processed by two other pathways in the liver, the microsomal ethanol oxidising system (MEOS) and the catalase pathway. These pathways are generally more active in individuals who regularly consume alcohol. The microsomal ethanol oxidising system is found in the smooth endoplasmic reticulum, in which a cytochrome P450 enzyme oxidises ethanol to acetaldehyde and water, but this reaction also generates reactive oxygen species which are harmful to cells. The catalase pathway occurs in the peroxisome and involves oxidation of ethanol by the enzyme catalase, once again into acetaldehyde and water.

Reaction 4Reaction 4

So we can see that when a small amount of alcohol is consumed, the liver’s hepatocytes are able to convert it into less harmful products. However, if a large amount of alcohol is consumed, this can overwhelm the usual metabolic pathways, leading to a rise in ethanol and subsequently acetaldehyde within the cells. In chronic consumers of alcohol whose alternative metabolic pathways are more active, an even higher amount of acetaldehyde is produced, along with reactive oxygen species which are extremely damaging to hepatocytes. With time, these processes can result in a number of liver diseases, including fatty liver disease (steatosis), hepatitis and cirrhosis of the liver.

FATTY LIVER DISEASE (STEATOSIS)

The metabolic pathways which convert ethanol into acetaldehyde and acetaldehyde into acetate, both require NAD+ as a cofactor, to enable them to take place. At low levels of alcohol consumption this doesn’t cause a problem, but again, when alcohol consumption is high, the increased metabolism of ethanol leads to an increase in the production of NADH that occurs as a result.

The NADH produced reacts with gluconeogenic precursors, such as pyruvate and oxaloacetate. This is dangerous, because it results in a reduced amount of gluconeogenic precursors, biomolecules which can be converted back into glucose should blood glucose levels fall. This can result in what is known as ethanol-induced hypoglycaemia.

Reaction 5

To overcome this problem, the excess NADH produced can be reacted with dihydroxyacetone phosphate (DHAP) instead and this reaction produces glycerol-3-phosphate.

Reaction 6

This may appear less harmful, but remember that during alcohol metabolism, acetaldehyde is converted into acetate within the mitochondria and that this acetate is converted into acetyl CoA which can be converted into fatty acids. When fatty acids and glycerol-3-phosphate are produced at a high enough number, they can combine to form triacylglycerol (TAG). The formation of TAG within hepatocytes is known as fatty liver, or steatosis. With excessive TAG production, metabolic processes within the liver become impaired, eventually leading to cell death and subsequent inflammation. This causes steatohepatitis, fatty liver disease along with inflammation.

CIRRHOSIS OF THE LIVER

As we mentioned earlier, ethanol itself is toxic and disrupts cell membranes, disrupting the integrity and function of hepatocytes, affecting their ability to perform their usual metabolic processes. Acetaldehyde is involved in lipid peroxidation, which allows it to disrupt cell membranes and it forms protein adducts, disrupting the cell cytoskeleton and impairing the transport of biomolecules within hepatocytes. All these processes reduce the function of hepatocytes, so they are less able to carry out all of the important roles the liver plays in the body.

As hepatocytes become increasingly dysfunctional, they begin to apoptose and necrose as the damage becomes irreversible. Hepatocytes are known as “stable” cells because they have the ability to regenerate if they become damaged. This enables the liver to retain its function, but repeated regeneration of cells affects the sinusoids and bile canaliculi and subsequently the flow of blood and bile through the liver. With time, blood flow is impaired to such an extent, that it begins to flow backwards into the portal system, thereby increasing the pressure within this system. This causes portal hypertension and also reduces blood flow to the liver itself, causing ischaemia of hepatocytes which further impairs the function of the liver.

Liver Lobule
The structural unit of the liver is the liver lobule which is shown here. Rows of hepatocytes form a channel between adjacent rows, which are called sinusoids. Blood from the portal system flows through these sinusoids towards the centre of each lobule (purple arrow), where the filtered blood flows back into the venous system. Bile flows from the central canal into bile ducts, which are found in the portal triads.
Liver Histology
Hepatocytes (yellow) form rows within the liver lobules. Blood flows through sinusoids and bile flows through bile canaliculi. Ordinarily, the highly ordered structure of these cells enables blood and bile to flow through the liver interrupted.
Liver Histology - Disease
When hepatocytes are damaged and regenerate, the flow of blood through sinusoids becomes disturbed. If the damage becomes extensive, sinusoids become so disrupted that blood cannot flow through them at all and instead begins to flow backwards into the veins that supply the liver with portal blood. This can lead to portal hypetension.

As well as the structural implications of hepatocyte damage and regeneration, necrosis of these cells triggers an inflammatory response within the liver. Kupffer cells and hepatocytes begin to release growth factors and cytokines such as epidermal growth factor (EGF), tumor necrosis factor alpha (TNF-a), transforming growth factor beta (TGF-b) and interleukin 1 beta (IL-1b). These activate stellate cells (also known as Ito cells or perisinusoidal cells) within the liver, which play a role in vitamin A storage. Activated stellate cells act like myofibroblasts, which contract to further increase the pressure within the liver sinusoids, but they also secrete collagen, causing fibrosis of the liver.

If alcohol continues to be consumed, these processes will continue and the ongoing inflammation and collagen deposition will continue to cause fibrosis of the liver. With time, hepatocytes lose their ability to regenerate and the once functioning liver cells become replaced with scar tissue. This is known as cirrhosis of the liver, an irreversible condition in which liver function is reduced. This leads to reduced protein synthesis, impaired metabolism, an increased risk of bruising and bleeding and eventually death if left untreated.

“An older Miss Muffett

Decided to rough it

And lived upon whisky and gin.

Red hands and a spider

Developed outside her –

Such are the wages of sin.”

[1] Williams R, Aspinall R, Bellis M et al. Addressing liver disease in the UK: a blueprint for attaining excellence in health care and reducing premature mortality from lifestyle issues of excess consumption of alcohol, obesity and viral hepatitis. The Lancet. 2014; 384 no. 9958: 1953-1997.

 

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