Liver 2: Introduction

Last updated: Thursday, June 13, 2019

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. However, much more relevant to your practice will be patients with liver dysfunction, where they may not have liver disease but the function of their liver is affected in some way. Through this tutorial the aim is to give you background information on the functioning of the liver, how this can change when a patient has liver dysfunction, how you can tell, and what this may mean for your patient’s medicines.

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 and other products to aid digestion, 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.

Because of these roles, the liver is important in the absorption, metabolism and excretion of medicines, and changes in its function can have significant implications for how we use drugs. Some of these are reviewed briefly below.

1. Metabolism 

The liver is the main site of drug metabolism in the body, but not the only one. However, it is the principal location for cytochrome p450 metabolism. Liver’s metabolism often alters molecules so that they become more water soluble, enabling elimination by the kidney.

Many drugs are metabolised by the liver. If the liver isn’t working effectively, this may increase drug levels in the body. Conversely, some medicines are inactive when taken and need to be metabolised to active compounds in order to work. Pro-drugs of this kind include e.g. cyclophosphamide. Liver dysfunction may decrease activity of these medicines because they don’t get metabolically activated to the same extent.

The metabolic role of the liver is particularly 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 high 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).

                     First pass metabolism  

2. Excretion

The liver excretes some medicines into the gut in bile (e.g. rifampicin, leflunomide). Impairment of bile production and excretion may therefore affect drug excretion. 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 entero-hepatic recycling and is an important mechanism by which blood levels of some drugs are maintained (e.g. oestrogens).

3. Absorption 

Certain drugs rely on substances in bile to aid absorption (e.g. fat-soluble vitamins), so impairment in bile excretion may affect their absorption.

4. Plasma proteins 

Many drugs are bound to plasma proteins produced by the liver (e.g. albumin), which are important for transporting drug molecules around the body. 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 synthetic function is impaired, there may be reduced plasma proteins. This may increase the free fraction of drug in the blood, which is the pharmacologically active fraction, so these medicines may appear more potent in liver dysfunction.