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The liver plays a major role in metabolism, maintaining within narrow limits the supply of carbohydrates, proteins, lipids and macromolecules to other tissues, in spite of wide variations in dietary intake and in metabolic demands. It is involved in the chemical transformation of many endogenous and exogenous substances, thereby changing their metabolic, therapeutic or toxic effects and facilitating their biliary excretion. By forming bile it contributes to digestion and absorption. It serves as a store for carbohydrates in the form of glycogen, and also for the fat-soluble vitamins, A, D, E and K and vitamin B12.
Bilirubin metabolism
Bilirubin has a limited aqueous solubility at physiological pH. It is carried from the reticulo-endothelial system to the liver in the circulation firmly bound to albumin. Within the liver a poorly-understood but very efficient mechanism dissociates bilirubin from albumin and the bilirubin passes into the hepatocyte. What determines hepatic selectivity of bilirubin uptake is not clear. It appears that the process requires no energy but is a carrier-mediated membrane transport system. Within the hepatocytes bilirubin is transported to the endoplasmic reticulum, possibly carried by cytoplasmic proteins, such as ligandin and Z protein. In the endoplasmic reticulum an enzymatic process converts bilirubin to a water-soluble form, mainly bilirubin diglucuronide, but also to the monoglucuronide and possibly to conjugates with glucose, xylose and sulphate. The bilirubin conjugates are excreted into the biliary system by an energy-dependent process. The bilirubin is then carried in the bile to the bowel where it is converted to stercobilin and excreted in the stools. There is little or no enteric reabsorption. Enzymatic defects of bilirubin conjugation lead to massive increase in circulating unconjugated bilirubin which crosses the brain barrier with the risk of kernicterus.
Carbohydrate metabolism
Monosacccharides, glucose, galactose and fructose absorbed from the gut are avidly taken up by the liver, where they may be utilised for immediately required energy, being incorporated in the citric acid cycle, or they may be used to form glycogen. During fasting, hepatic glycogen is an invaluable source of carbohydrate, releasing glucose to other tissues and preventing hypoglycaemia. Gluconeogenesis in the liver increases with prolonged fasting utilising amino acids released from peripheral tissues. Large amounts of glycogen appear in the liver towards the end of gestation and glycogen is rapidly mobilised immediately after birth. It is thought that post-natal hypoglycaemia arises because of ineffective gluconeogenesis which does not replenish hepatic glycogen. Liver glycogen stores are lower in premature or light-for gestational age infants. Hypoglycaemia occurs in inborn errors of carbohydrate, amino acid and lipid metabolism, fulminant hepatic failure, Reye’s syndrome and with poisoning by drugs such as ethanol or hypoglycin.
Lipids and bile salts
The liver has a key role in the synthesis, catabolism and biliary excretion of lipids, lipoproteins, phospholipids, sphingolipids, cholesterol derived steroids and enzymes involved in their metabolism. Neutral fats absorbed from the small intestine are oxidised within the liver into glycerol and free fatty acids. Fatty acids may be further oxidized to acetyl coenzyme A (CoA) which enters the Kreb’s tricarboxylic acid cycle. Hepatic fat is usually triglyceride synthesised from fatty acids and glycerol-3-phosphate. There is continuous recycling of fatty acids between the liver and the adipose tissue. Hepatic uptake increases with serum fatty acid concentrations. The liver has a limited ability to oxidise fatty acids and to secrete triglycerides as very low density lipoproteins. Fat accumulation in the liver may thus occur because of increased lipolysis in adipose tissue or from hepatic derangement limiting fatty acid oxidation or triglyceride excretion. Cholesterol is synthesised in the liver, intestinal mucosa, adrenal cortex and arterial walls. It is excreted in the bile as a neutral steroid. As well as providing the basic structure for sex hormones, cholesterol is the precursor of bile salts. These are synthesised only within the liver, which also has a key role in the uptake, reabsorption and conjugation of free bile acids arriving with the portal blood . These are rapidly conjugated with glycine or taurine, prior to biliary excretion. In the newborn infant serum bile acid and cholesterol concentrations are lower than in older children or in adults. Bile acid synthesis and pool are reduced and bile acid secretion is low although there is no defect in bile acid transport. Malabsorption of fats results. All forms of hepatocellular injury and cholestasis cause mild hypertriglyceridaemia, decreased serum cholesterol esters, reduced alpha-lipoprotein and increased beta-lipoprotein concentrations. With cholestasis there is also a rise in free cholesterol and unusual lipoproteins, particularly lipoprotein X and a deficiency of cholesterol acyltransferase.
Protein and amino acid metabolism
The liver, with muscle, plays a key role in amino acid metabolism. Amino acids absorbed from the intestine are rapidly taken up by the liver, where they are utilised in protein synthesis, gluconeogenesis or ketogenesis following deamination or transamination. Ammonia produced by the deamination of amino acids is rapidly converted to urea. Most of the proteins in plasma, apart from the immunoglobulins, are synthesised by the rough endoplasmic reticulum of the hepatocytes. Quantitatively, albumin is the most important of these, but haptoglobulin, transferrin, caeruloplasmin, C reactive protein, alpha 1 anti-trypsin, alpha 2 globulin, ferritin and alpha and beta lipoproteins are also formed in the liver. Other important proteins synthesised in the liver are fibrinogen, prothrombin and coagulation factors V, VII, IX, X and, to some extent, VIII. Factors II, VII, IX and X synthesis is dependent on the presence of vitamin K. Inhibitors of the coagulation system, such as anti-thrombin III and components of the fibrinolythic system, e.g. plasminogen, are also synthesised within hepatocytes. The liver binds avidly desialyted glycoproteins clearing them from the circulation. Protein synthesis is very active in foetal life and in the newborn period. The main serum protein in foetal life is alpha fetoprotein. It first appears in the serum at 6 weeks gestation, rising to a peak concentration at 13 weeks, and then declining linearly. Albumin synthesis starts at approximately 3 to 4 months gestation, the serum concentration being at the adult value at birth. Low levels are common in premature infants. Proteins involved in coagulation are frequently low around the time of delivery, but increase to normal levels within a few days. Caeruloplasmin is low at birth and reaches its highest concentration at about the age of 3 months, thereafter falling slowly to the adult level by the age of 2 years. Although amino acids, except cysteine, are in higher concentrations in foetal blood than in the adult, the enzymes involved in metabolism or degradation of amino acids are at low activity around the time of birth. Premature infants given a high protein intake may be unable to metabolise amino acids and have dangerously elevated serum concentration as a result. If liver function is impaired significantly, serum concentrations of amino acids increase, except for branched chain amino acids which are preferentially taken up by muscle. Protein synthesis decreases as shown clinically by low concentrations of clotting factors and by low serum albumin concentration. During hepatic regeneration alpha fetoprotein production increases. Alpha fetoprotein production is prolonged and increased in neonatal obstructive liver diseases: it is also produced by 70-90% of hepatocellular tumours.
Drugs, toxin and xenobiotic metabolism
The metabolism of drugs, toxins and xenobiotics within the liver occurs in two stages in most instances. The first step (phase I) is a biochemical transformation resulting in oxidation, reduction, hydrolysis, hydration or isomerization. This is followed by conjugation (phase 2) which renders the compound more water-soluble, making it more readily excreted in the urine or bile. Continuos administration of drugs such as phenobarbitone, phenytoin or rifampicin, which are metabolised by the endoplasmic reticulum, has the effect of increasing the concentration and activity of enzymes involved in drug metabolism. This process is known as ‘enzyme induction’. The outcome may not be to the patient’s advantage: adverse effects include e.g. increased vitamin D or cyclosporin requirements during phenobarbitone treatment. In the first 2-4 weeks of life, drug metabolism is different from that in adults because of differences in the binding of drugs by serum proteins, inefficient renal function, and differences in hepatic metabolism. Phase 2 reactions are usually normal in early infancy but it is 3 months of age before phase 1 drug metabolising enzyme activity levels are similar to those in adult life. As a result, both the pharmacological action of drugs and their half-life are often different. It is generally necessary to give neonates lower doses less frequently. In childhood, hepatic metabolism of drugs such as teophylline is twofold higher than in adults. In hepatic insufficiency the effects on drug metabolism are complex and depend on the degree of biotransformation in other tissues, changes in binding protein concentrations in addition to changes in liver function. In general the pharmacological half-life is prolonged.
Vitamins
The liver has a critical role in the uptake, storage, metabolism and transport of both water- and fat-soluble vitamins, frequently being the main organ of synthesis of specific transport proteins. Hepatocytes and Ito cells are involved in vitamin A metabolism. Thiamine, riboflavin, niacin, vitamin B12, B6, folic acid, biotin, and pantothenic acid are metabolised in the liver and are essential for other aspects of hepatic metabolism. The liver produces essential active metabolites of vitamin D and E. Vitamin K is necessary for the synthesis of clotting factors II, VII, IX, X and proteins C and S. Normal bile production is essential for absorption of fat-soluble vitamins. Hepatic insufficiency is associated to deficiency of fat-soluble vitamins, which affects all other tissues.
Hormones
The liver has an important role in the metabolism of glucocorticoids, mineralocorticoids, thyroxine, parathyroid hormone, insulin, glucagon, growth hormone, oestrogens, aldosterone and gut hormones. The main step is usually production of an active metabolite which is then conjugated to either glucuronic acid or sulphate and is then excreted by the kidney. Many of the binding proteins and somatomedin are synthesised in the liver. The liver is a major target organ for many hormones, frequently producing secondary messengers which are essential for the full effects of a particular hormone. Feedback control mechanisms minimise the effects of liver disease on most hormonal derangements in childhood.
Reticulo-endothelial function
In foetal life, the liver is an important site of haematopoiesis, activity being maximal at 7 months gestation. Within 6 weeks from birth haematopoiesis is normally confined to the bone marrow, but in the presence of haemolythic anaemia, or where the bone marrow space has been destroyed, the reticulo-endothelial cells of the liver are again involved in haem formation. Kupffer cells are phagocytic and have an important function in removing a variety of bacterial products, such as endotoxin, and other antigens which have been absorbed into the portal blood. They produce many cytokines with antiviral effects and others including leucotrienes which influence metabolism in hepatocytes and Ito cells. The Kupffer cells may have an important role in conjunction with the rest of the reticulo-endothelial system in producing antibodies.
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