Metabolic;

Exocrine;

Endocrine;

Immunological;

Synthetic;

Hepatic clearance of drugs;

A number of additional miscellaneous functions.

Carbohydrate metabolism. Many metabolic processes occur in the liver in order to maintain a normal plasma glucose concentration:

1. 
   

   – Glycolysis. Like all other cells, the liver produces energy by transforming glucose into pyruvate.

   
   
2. 
   

   – Glycogenesis. Following a meal, plasma glucose concentration rises, which causes insulin to be released from the pancreas. In the liver, insulin stimulates the polymerisation of excess glucose into its storage form, glycogen. Up to 100 g of glucose can be stored in this way.

   
   
3. 
   

   – Glycogenolysis. When plasma glucose concentration falls between meals, insulin secretion is reduced and glucagon is released from the pancreas. In response to glucagon secretion, the liver releases glucose by breaking down its glycogen store.

   
   
4. 
   

   – Gluconeogenesis. When plasma glucose concentration is low, glucagon also simulates the liver to synthesise glucose from non-carbohydrate precursors (e.g. amino acids, lactate and glycerol).

Fat metabolism. Lipid is the body’s most efficient method of energy storage. The liver is involved in lipid metabolism in a number of ways:

1. 
   

   – Lipid breakdown. Energy is extracted from free fatty acids as they are metabolised in a process called ‘β-oxidation’ within the hepatocyte mitochondria.

   
   
2. 
   

   – Lipid synthesis. The liver synthesises triglyceride from excess glucose. Cholesterol is also synthesised in the liver. Cholesterol is used as a structural component of cell membranes and as a precursor for steroid hormone and bile salt synthesis.

   
   
3. 
   

   – Lipid processing. Apolipoproteins are synthesised in the liver. These are involved in the packaging of cholesterol and triglyceride as low-density lipoprotein, very-low-density lipoprotein and high-density lipoprotein.

Protein metabolism:

1. 
   

   – Deamination. Individual amino acids have their amino groups removed by the liver. The resulting carbon skeleton (a keto acid) can be used for energy in the citric acid cycle (see Chapter 77), transformed into another amino acid or used as a substrate for gluconeogenesis.

   
   
2. 
   

   – Urea formation. The other product of deamination is ammonia (NH₃). This is detoxified in the liver through conversion to urea or glutamine.

   
   
3. 
   

   – Amino acid synthesis. Keto acids can be transformed into non-essential amino acids by transamination, taking an amino group from one amino acid and transferring it to a keto acid, forming a new amino acid. Essential amino acids cannot be synthesised within the body and are only found in the diet.

   
   
4. 
   

   – Protein synthesis. The liver synthesises most plasma proteins, with the exception of immunoglobulins and some hormones (see below).

Around 1000 mL of bile is produced by the hepatocytes per day. This is then concentrated to a fifth of its volume within the gallbladder.

The main constituents of bile are water, electrolytes, bile salts, bile pigment, cholesterol and phospholipids.

Bile acids are produced through the oxidation of cholesterol. Bile salts – the Na⁺ and K⁺ salts of bile acids – have an essential role in the emulsification of dietary lipid:

1. 
   

   – Bile salts are amphipathic: they are hydrophobic at one end and hydrophilic at the other.

   
   
2. 
   

   – Bile salts surround the dietary lipid, breaking up large fat droplets into a suspension of small fat droplets.

   
   
3. 
   

   – Formation of these micelles is essential; without them, pancreatic lipase is unable to act on the dietary lipid in their core.

   
   
4. 
   

   – The micelles then make contact with enterocytes, which absorb the lipid contents. The fat-soluble vitamins (vitamins A, D, E and K) are also absorbed by this micelle-mediated mechanism.

Bile is the main route of excretion of bilirubin metabolites, also known as bile pigment. The metabolism of bilirubin is complex (Figure 66.1):

1. 
   

   – Red blood cells (RBCs) are taken up by the spleen when they get old or damaged.

   
   
2. 
   

   – In the spleen, haemoglobin (Hb) is broken down (1) and its useful components recycled: the globin chain is broken down into its constituent amino acids and the Fe²⁺ ion is bound to transferrin and transported to the bone marrow for use in erythropoiesis (see Chapter 74). However, the body cannot make further use of the porphyrin ring.

   
   
3. 
   

   – Within the macrophages of the spleen, the porphyrin ring is oxidised to biliverdin and then reduced to bilirubin (2).

   
   
4. 
   

   – This unconjugated bilirubin is not water soluble, so is bound to albumin and transported to the liver for further processing (3).

   
   
5. 
   

   – In the liver, the hepatocytes take up bilirubin and conjugate it to glucuronic acid, making it water soluble (4). The enzyme responsible for this process is glucuronosyltransferase.

   
   
6. 
   

   – This conjugated bilirubin is excreted with the bile into the small intestine (5). Almost all of the conjugated bilirubin in the small intestine ends up being reabsorbed (6), transported to the liver in the portal vein and re-secreted into the small intestine; this is known as ‘enterohepatic circulation’. However, some conjugated bilirubin inevitably passes into the large intestine.

   
   
7. 
   

   – In the large intestine, conjugated bilirubin is converted into urobilinogen by colonic bacteria (7). Urobilinogen has two fates: it may be oxidised further to urobilin and stercobilin (8) and excreted with faeces (stercobilin gives faeces its brown colour). Alternatively, urobilinogen may be reabsorbed by the gut (9) and transported via the portal vein to the liver (i.e. enterohepatic circulation). Hepatic uptake of urobilinogen is incomplete, so some reaches the systemic circulation (10) and is excreted by the kidney (11), giving urine its yellow colour.