Liver: Introduction

Last updated: Tuesday, September 27, 2022

NB: See learning outcomes for this tutorial mapped to competencies, a PDF of the whole text, and a one-page summary.

☞ Why this subject matters...

It is likely you will see patients with liver disease in your practice (e.g. cirrhosis due to alcoholism). You will also encounter patients with liver dysfunction, who may not have liver disease but the function of their liver is affected in some way (e.g. secondary to sepsis).

In this tutorial we will cover the normal functioning of the liver, how this can change when a patient has liver dysfunction, and how you can tell. Above all, we will provide pointers on how to use medicines safely and effectively in this patient group.

Role of the liver

The liver is an important organ for many functions of the body. It is where a wide variety of compounds are synthesised, including bile, clotting factors, hormones, cholesterol and triglycerides, albumin, glycogen to store glucose, and many more. It also has important metabolic functions, breaking down hormones such as insulin and oestrogen, as well as many waste products such as ammonia and bilirubin to allow their excretion.

Many of these actions determine the absorption, distribution, metabolism and excretion of medicines. As a result, changes in liver function can have significant implications for how we use drugs. Some of these are reviewed briefly below.

1.  Absorption  
Lipophilic drugs often need bile salts for absorption from the gut (e.g. fat-soluble vitamins), so any impairment in bile excretion may reduce drug absorption. This may happen in patients with cholestasis, for example.

2. Distribution
Many drugs are bound to plasma proteins produced by the liver such as albumin. These proteins are important for transporting drug molecules around the body in blood. The portion of a drug dose bound to plasma proteins is not free to bind to receptors and exert a pharmacological effect and cannot be eliminated from the body.

If the liver’s ability to make proteins (its 'synthetic function') is impaired, there will be reduced amounts in the systemic circulation. This may lead to an increase in the pharmacologically active unbound or 'free' fraction of drug in the blood. In this situation, highly protein bound medicines (e.g. phenytoin) may appear more potent in liver dysfunction causing increased side effects: so you may consider reducing the dose or using a different drug. Sometimes, highly protein bound drugs can be displaced from albumin in patients with high bilirubin levels which also gives higher levels of free drug. 

3. Metabolism 
The liver is the main site of drug metabolism in the body, and the principal location for cytochrome p450 and other metabolic enzymes. Liver metabolism often alters molecules so that they become more water soluble, enabling elimination by the kidney.

First-pass metabolism
Courtesy of Simon Wills
If the liver isn’t working effectively, the levels of hepatically metabolised drugs may be increased. However, some medicines are inactive when taken and need to be metabolised to active compounds in order to work. Pro-drugs of this kind include cyclophosphamide. Liver dysfunction may decrease activity of these medicines because they don’t get activated to the same extent.

The metabolic role of the liver is important for drugs administered orally. Blood from the gut passes through the liver first before entering the systemic circulation, and this gives an opportunity for the organ to remove a proportion of a dose. This ‘first-pass metabolism’ significantly reduces the bioavailability of many oral drugs (e.g. opioids), and in some cases is so efficient that administration by the oral route is not possible (e.g. buprenorphine).

4. Excretion
The liver excretes some medicines into the gut via bile (e.g. rifampicin, leflunomide). Impairment of bile production and excretion may therefore affect drug clearance. Many of these drugs are excreted in the bile conjugated to bile salts. The flora of the bowel can digest these conjugates, releasing free drug into the gut, which then enables it to be re-absorbed. This is called enterohepatic recycling and is an important mechanism by which blood levels of some drugs are maintained (e.g. oestrogens).