Purple Queens and Orange Llamas

Alcoholic Liver Disease

It starts with ethanol.

Alcoholism is a vastly common cause of cirrhosis. Cirrhosis is defined as “nodular regeneration surrounded by scarring and fibrosis”, which is a highly scientific way of saying “your liver is fucked, and there’s nothing we can do about it”.

The normal metabolism of alcohol is as such:

Ethanol is metabolised to acetaldehyde, via the alcohol dehydrogenase enzyme (ADH) and CYP2E1, which is one of the cytochrome P450 enzymes (that is also involved in paracetamol metabolism, hence why a paracetamol overside combined with alcohol is bad news. Additionally, if you drink a lot/take a lot of paracetamol, you start to upregulate this enzyme, which is why a chronic alcoholic can drink a bottle of wine and still seem sober, while a fourteen year old is throwing up on a single alcopop). Acetaldehyde, which is toxic, is then swiftly metabolised to acetic acid via aldehyde dehydrogenase (ALDH). ADH and ALDH require the reduction of the NAD carrier protein to NADH to work properly.

Lots of alcohol means that the ALDH, which is the only enzyme that can convert acetaldehyde, gets used up, and acetaldehyde builds up in the body. This is what causes that wicked hangover the next morning. It is also directly toxic to liver cells.

The other thing that happens is that all the alcohol will eventually be metabolised. This is usually when you start craving bacon. For alcohol to be metabolised, NAD has to be converted to NADH, that’s jsut how the enzymes work. More alcohol means more metabolism means less NAD and more NADH.

This change in NAD/NADH ration has an effect on fat absorption. It isn’t absorbed as well into the bloodstream, and with nowhere else to go, ends up being deposited in the liver. The liver isn’t supposed to have fat in it, and alarmed by its sudden presence, it amounts an immune response against it. Specialised liver macrophages called Kupffer cells are the masterminds behind this. One of the other thing that these Kupffer cells do is activate another type of cell in the liver called a stellate cell.

Stellate cells are pretty boring normally, they produce the extra cellular matrix that hold everything in place. It’s a vital role, but kind of boring. When they are activated by Kupffer cells they go into overdrive, and start producing and depositing collagen. This is what causes the “surrounded by scarring and fibrosis” bit from earlier.

At an early stage, when there is just a bit of fat infiltrate, itis known as fatty liver, which is reversible. Our livers have a remarkable ability to heal themselves, which is why we don’t all develop cirrhosis after a heavy night out. If someone stops drinking at the fatty liver stage, they probably won’t progress to cirrhosis, which is why it’s important to encourage those patients to quit alcohol sooner rather than later.

If the patient continues to drink, they will progress to perivenular fibrosis, which is an early stage of cirrhosis. This is followed by alcoholic liver fibrosis and subsequently the end stage of alcoholic liver cirrhosis. After this point there is no going back. The only definitive treatment is a liver transplant, and it’s not like you can pick a liver up in Boots next time you’re in town.

Cirrhosis goes on to cause a bunch of other problems, I’m going to talk about the three most important ones.

1. Liver failure. The iflammation, infiltration, scar tissue and the toxic effects of the acetaldehyde all contribute to a liver that doesn’t work properly any more.
2. Bleeding varisces. Portal hypertension caused by the inflammation and failure of the liver means that blood in the portal venous system is under higher pressure. There are three key points where the portal system anastomose with the normal venous circulation, and these are weak points where varisces are likely to occur. They are in the oesophagus (oesophageal varisces), in the anus (anorectal varisces) and around the umbilicus (caput medusae). If pressure gets too high they can bleed profusely, and can be very alarming.
3. Increased risk of hepatocellular carcinoma. The repeated onslaught of toxins and cytokines makes for cells that are more likely to mutate.

Happy drinking people!