The liver is the principal site of synthesis of all circulating proteins apart from y-globulins, which are produced in the reticuloendothelial system. It receives amino acids from the intestine and muscles and, by controlling the rate of gluconeogenesis and transamination, regulates levels in the plasma. Plasma contains 60-80 g litre-I of protein, mainly in the form of albumin, globulin and fibrinogen.
Albumin has a half-life of 16-24 days and 10-12 g are synthesized daily. Its main functions are first to maintain the intravascular oncotic (colloid osmotic) pressure, and second to transport water-insoluble substances, e.g. bilirubin, hormones, fatty acids and drugs. Reduced synthesis of albumin over prolonged periods produces hypoalbuminaemia and is seen in chronic liver disease and malnutrition. Hypoalbuminaemia is also found in hypercatabolic states, e.g. trauma with sepsis, and in diseases where there is an excessive loss, e.g. nephrotic syndrome, protein-losing enteropathy.
Transport or carrier proteins such as transferrin and caeruloplasmin, and other proteins, e.g. ai-antitrypsin and o-fetoprotein, are also produced in the liver. The liver also synthesizes all coagulation factors (apart from factor VIII) i.e. fibrinogen, prothrombin, factors V, VII, IX, X, XIII, and components of the complement system Degradation (nitrogen excretion) Amino acids are degraded by transamination and oxidative deamination to produce ammonia, which is then converted to urea and excreted by the kidneys. This is a major pathway for the elimination of nitrogenous waste. Failure of this process occurs in severe liver disease.
Glucose homeostasis and the maintenance of the blood sugar is an important function of the liver. It stores approximately 80 g of glycogen. In the immediate fasting state, blood glucose is maintained either by glucose released from the breakdown of glycogen (glycogenolysis) or by newly synthesized glucose (gluconeogenesis). Sources for gluconeogenesis are lactate, pyruvate, amino acids from muscles (mainly alanine and glutamine) and glycerol from lipolysis of fat stores. In prolonged starvation, ketone bodies and fatty acids are used as alternative sources of fuel and the body tissues adapt to a lower glucose requirement.
Fats are insoluble in water and are transported in the plasma as protein/lipid complexes (lipoproteins). These are discussed in detail. The liver plays a major role in the metabolism of lipoproteins.
It synthesizes very low-density lipoproteins (VLDLs) and high-density lipoproteins (HDLs). HDLs are the substrate for lecithin-cholesterol acyltransferase (LCAT), which catalyses the conversion of free cholesterol to cholesterol ester (see below). Hepatic lipase removes triglyceride from intermediate-density lipoproteins (IDLs) to produce low-density lipoproteins (LDLs) rhich are degraded by the liver after uptake by specific cell-surface receptors.
Triglycerides may be of dietary origin but are also formed in the liver from circulating free fatty acids (FFA) and glycerod glycerol and incorporated into VLDLs. Oxidation or de novo synthesis of FFA also occurs in the liver, depending on the availability of dietary fat. Cholesterol may also be of dietary origin but most is synthesized from acetyl-CoA mainly in the liver, intestine, adrenal cortex and skin. It occurs either as free cholesterol or esterified with fatty acids, this reaction being catalysed by LCAT. This enzyme is reduced in severe liver disease, increasing the ratio of free cholesterol to ester, which alters memebrane structures. One result of this is the red cell abnormalities, e.g. target cells, seen in chronic liver disease. phospholipids, e.g. lecithin, are also synthesized in the liver.
The complex interrelationships between protein, carbohydrate and fat metabolism are shown.
Formation of bile
Bole consists of water, electrolytes, bile acids, cholesterol, phospholipids and bilirubin. Two processes are involved in bile secretion across the canalicular membrane of the hepatocyte:
1 In the bile salt-dependent process there is active secretion of bile salts; water and electrolytes follow down an osmotic and electrical gradient.
2 In the bile salt-independent process, bile flow is linked to sodium transport, which is dependent on Na”, K+ ATPase activity. One-third of the bile flow emanates from the epithelial cells of the bile ductules. Secretion, particularly of bicarbonate, is stimulated mainly by secretin. The average total bile flow is approximately 1 litre per day. In the fasted state half of the bile flows directly into the duodenum, half being diverted into the gallbladder. The mucosa of the gallbladder absorbs 80-90% of the water and electrolytes, but is impermeable to bile acids and cholesterol. Following a meal, cholecystokinin is secreted by the duodenal mucosa and stimulates contraction of the gallbladder and relaxation of the sphincter of Oddi, so that bile enters the duodenum. An adequate bile flow is dependent on bile salts being returned to the liver by the enterohepatic circulation.
Bile acid metabolism
Bile acids are synthesized in hepatocytes from cholesterol. The rate-limiting step in their production is that catalysed by cholesterol-7a-hydroxylase. They are excreted into the bile and then pass into the duodenum. The two primary bile acids-cholic acid and chenodeoxycholic acid are conjugated with glycine or taurine (in a ratio of 3 : 1 in humans) and this process increases their solubility.
Intestinal bacteria convert these acids into secondary bile acids-deoxycholic acid and lithocholic acid. shows the enterohepatic circulation of bile acids. Bile acids act as detergents; their main function is lipid solubilization. Bile acid molecules contain both a hydrophilic and a hydrophobic end. In aqueous solutions they aggregate to form micelles, with their hydrophobic (lipidsoluble) ends in the centre. Micelles are expanded by cholesterol and phospholipids (mainly lecithin), forming mixed micelles.
Bilirubin is produced mainly from the breakdown of mature red cells in the Kupffer cells of the liver and in the reticuloendothelial system; 15% of bilirubin comes from the catabolism of other haem-containing proteins,such as myoglobin, cytochromes and catalases.
Normally, 250-300 mg of biliru bin are produced daily . The iron and globin are removed from the haem and are reutilized. Biliverdin is formed from the haem and this is reduced to form bilirubin. The bilirubin produced is unconjugated and water insoluble, and is transported to the liver attached to albumin. Bilirubin dissociates from albumin and is taken up by the hepatic cell membrane and transported to the endoplasmic reticulum by cytoplasmic proteins, where it is conjugated with glucuronic acid and excreted into bile. The microsomal enzyme uridine diphosphoglucuronyl transferase catalyses the formation of bilirubin mono glucuronide and then diglucuron ide. This conjugated bilirubin is water soluble and is actively secreted into the bile canaliculi and excreted into the intestine with the bile. It is not absorbed from the small intestine because of its large molecular size. In the terminal ileum, bacterial enzymes hydrolyse the molecule, releasing free bilirubin, which is then reduced to urobilinogen. Some of this is excreted in the stools as stercobilinogen. The remainder is absorbed by the terminal ileum, passes to the liver via the enterohepatic circulation, and is re-excreted into the bile. Urobilinogen bound to albumin enters the circulation and is excreted in the urine via the kidneys. When hepatic excretion of conjugated bilirubin is impaired, a small amount of conjugated bilirubin is found strongly bound to serum albumin. It is not excreted by the kidney and accounts for the continuing hyperbilirubinaemia for a short time after cholestasis has resolved.
Hormone and drug inactivation
The liver catabolizes hormones such as insulin, glucagon, oestrogens, growth hormone, glucocorticoids and parathyroid hormone. It is also the prime target organ for many hormones, e.g. insulin. It is the most important site for the metabolism of drugs and alcohol . Fat-soluble drugs are converted to water-soluble substances that facilitate their excretion in the bile or urine.
The reticuloendothelial system of the liver contains many immunologically active cells. The liver acts as a ‘sieve’ for the bacterial and other antigens carried to it via the portal tract from the gastrointestinal tract. These antigens are phagocytosed and degraded by Kupffer cells, which are macrophages attached to the endothelium. Kupffer cells have specific membrane receptors for ligands and are activated by several factors, e.g. infection. They secrete interleukins, tumour necrosis factor (TN F), collagenase and lysosomal hydrolases. Antigens are degraded without the production of antibody as there is very little lymphoid tissue. They are thus prevented from reaching other antibody- producing sites in the body and thereby prevent generalized adverse immunological reactions. The reticuloendothelial system is also thought to play a role in tissue repair, T and B lymphocyte interaction, and cytotoxic activity in disease processes. Thus in patients with liver disease immune response to infection is impaired. Furthermore immune-mediated damage can occur possibly initiated by antigens expressed on the hepatocyte surface itself.