1. Gross Anatomy and Connecting Vessels
1.1 Location
The liver is a large organ – weighing about 1.5 kg – located in the abdomen immediately below the diaphragm. It overlaps the stomach and is attached to the diaphragm above by the falciform ligament. The gal bladder, which stores the bile secreted by the liver, lies below it and is connected to the duodenum by the bile duct.
1.2 Structure
The liver has 2 lobes – left and right – that are separated by the falciform ligament. The right lobe is larger than the left and the left lobe lies over the stomach. The liver itself is immediately covered by a thin, fibrous connective tissue – the Glisson’s capsule – that becomes thicker at the hilum, where the hepatic portal vein and the hepatic artery enter the liver and the left and right hepatic ducts and lymphatics exit. These vessels and ducts are surrounded by the Glisson’s capsule all the way to their termination (or origin)) in the portal spaces between classic liver lobules. Surrounding the Glisson’s capsule is a smooth, moist peritoneum. The right lobe is 6 times larger than the left lobe.
1.3 Main Vessels and Ducts
1.3.1 Hepatic Artery
Its final destination is the liver and goes from the heart through the aorta and to the liver. It supplies oxygen rich blood to the liver and supplies an adequate amount of oxygen to the liver cells. It may contain toxins or waste products and is accounted for 20% of the hepatic blood supply.
1.3.2 Hepatic Portal Vein
It supplies blood rich in digested food materials from the small intestines to the liver. Nutrients are accumulated and transformed in the liver. It may contain toxins aor waste products. This is accounted for 80% of the hepatic blood supply.
1.3.3 Hepatic Vein
It carries deoxygenated blood from the liver back to the heart. Digested food materials would have been metabolized already. Blood would have been detoxified and wastes have been removed. It drains blood from the liver to the inferior vena cava.
1.3.4 Bile Ducts
It transports bile synthesized by the liver cells to the gall bladder. It is formed by bile capillaries that unite after collecting bile from the liver cells.
2. Microscopic Anatomy
2.1 Concept of a Lobule
In light microscope sections, structural units called liver lobules can be observed. Each liver lobule is formed of a polygonal mass of tissue about 1mm in diameter. A branch of the hepatic vein lies in the centre of each lobule. In certain animals (e.g. the pig), lobules are separated from each other by a layer of connective tissue. This does not occur in humans, where the lobules are in close contact along lost of their extent, making it difficult to establish the exact limits between different lobules.
At corners, the lobules are demarcated by connective tissue containing blood vessels (i.e. branches of the hepatic artery and the hepatic portal vein), lymphatics, bile ducts and nerves, This region is called the portal area / portal tract.
2.2 Hepatocytes – How do they make up the liver?
The basic structural component of the liver is the liver cell or hepatocyte. Each of them is polygonal, with 6 or more surfaces and has a diameter of 20 to 30 microns. Each hepatocyte has a prominent nucleus and Golgi apparatus, numerous mitochondria and is rich in lysosomes, glycogen granules and fat droplets.
The hepatocytes are structurally undifferentiated and are all identical. They are arranged in 1-cell thick plate-like layers, sometimes referred to as acini (singular, acinus). The acini are directed from the periphery of the lobule towards the centre. They anastomose freely, forming a labyrinthine and sponge-like structure.
2.3 What are sinusoids?
The space between the acini contains capillaries known as the sinusoids. These sinusoids are open channels through which blood flows in direct contact with the hepatocytes, from the periphery of the lobule towards the centre.
Branches of the hepatic artery and the hepatic portal vein are situated at the periphery of the lobule in the portal area. Blood coming into the liver from these 2 vessels is mixed as it flows into the sinusoids. Thus, hepatocytes receive a double supply of blood: oxygenated blood from the hepatic artery and blood containing newly absorbed nutrients from the gut.
Sinusoidal capillaries are irregularly dilated vessels composed of a thin layer of endothelial cells bearing pores. The area of the surfaces of the hepatocytes facing the blood is increased by multiple in-folding of the cell membranes (microvilli). As the blood flow past, hepatocytes extract oxygen and food substances, as well as various metabolites and any poisons present. They also secrete into the blood, products manufactured for use elsewhere in the body.
2.4 What are Kupffer Cells?
In addition to the endothelial cells, the sinusoids contain phagocytic cells known as Kupffer cells. The cells are found on the luminal surface of the endothelial cells and they function to metabolize aged RBCs, digest Hb and secrete proteins related to the immunological processes.
2.5 What are bile canaliculi?
Each bile canaliculus forms a blind tube between 2 rows of hepatocytes. The bile produced by the hepatocytes flows through the bile canaliculi to the bile ductules before merging to form the bile ducts in which the bile is drained from the lover to be stored in the gall bladder.
3. Homeostatic Functions of the Liver
It has been estimated that the liver carries out several hundred separate functions involving thousands of different chemical reactions. The liver and the kidneys are the major organs responsible for regulating the steady state of blood metabolites and the composition of blood tissues.
The functions of the liver fall into 2 main categories: firstly, the storage of food materials and the synthesis of their derivatives and secondly, the breakdown of substances not required by the body prior to their excretion. Finally, as a result of the number of metabolic activities occurring within the liver, it may be a main source of heat production for animals living in cold climates.
3.1 Carbohydrate Metabolism
Hexose sugars enter the liver from the gut via the hepatic portal vein, which is the only blood vessel in the body having an extremely variable sugar content – this gives a clue to the role of the liver in carbohydrate metabolism as the organ that maintains the blood glucose level at approximately 90mg of glucose per 100cm3 of blood. The liver prevents blood glucose from fluctuating according to feeding patterns, thus preventing damage to tissues that cannot store glucose, such as the brain.
3.1.1 Glycogenesis
The stimulus is an increase in hexose content and the response is to store hexose as glycogen so as to decrease hexose content. All hexose sugars, including fructose and galactose are converted to glucose by the liver and stored as glycogen. Up to 100g of glycogen are stored in the liver but more are stored in the muscle. This conversion of glucose to glycogen is termed as glycogenesis and is stimulated by the presence of the hormone insulin. Glucose is converted to glucose-6-phosphate by insulin and then to glucose-1-phosphate and finally to glycogen by glycogen synthase, all of which are reversible reactions.
3.1.2 Glycogenolysis
The stimulus is a decrease in hexose content and the response is an increase in conversion of glycogen to glucose. Glycogen is broken down to glucose to prevent the blood glucose level from falling below 60mg per 100cm3 of blood. This process is called glycogenolysis and involves stimulation of a phosphorylase enzyme by the pancreatic hormone glucagon. In times of danger, stress of cold, glucagon activity is also stimulated by adrenaline (released by the adrenal medulla) and noradrenaline (released by endings of sympathetic neurons). Glycogen is converted to glucose-1-phosphate by a phosphorylase and then to glucose-6-phosphate by phosphoglucomutase and then to glucose by glucose-6-phosphatase. All reactions are reversible.
3.1.3 Lactate Metabolism – Cori Cycle
Muscle lacks the enzyme glucose-6-phosphatase and cannot convert glycogen directly to glucose via glucose-6-phosphate, as in the liver. Instead, glucose-6-phosphate is concerted to pyruvate which is used to produce ATP during aerobic and anaerobic respiration. Lactate produced by anaerobic respiration in skeletal muscle can be converted later into glucose and hence glycogen in the liver by a biochemical pathway known as the Cori cycle.
3.1.4 Gluconeogenesis
When demand for glucose has exhausted the glycogen store in the liver, glucose can be synthesized form non-carbohydrate sources, such as amino acids, glycerol and fatty acids. This is called gluconeogenesis. Glucocorticoid hormones stimulate the release of amino acids, glycerol and fatty acids into the blood and increase the rate of synthesis of enzymes in the liver that convert amino acids and glycerol into glucose. Fatty acids are converted I into acetyl CoA and are utilized directly in the Krebs cycle.
3.2 Protein Metabolism
The liver plays an important role in protein metabolism and may be considered under the headings of deamination, urea-formation, transamination and plasma protein synthesis.
3.2.1 Deamination
The body is unable to store absorbed amino acids – those that are not immediately required for protein synthesis or gluconeogenesis and are deaminated in the liver.
Deamination involves the enzymatic removal of the amino group from the amino acid with simultaneous oxidation of the remainder of the molecule to form a carbohydrate. The amino group is removed along with a hydrogen atom so that the nitrogenous product of deamination is ammonia, NH3. The ammonia may be used for the synthesis of certain amino acids or nitrogenous bases such as adenine and guanine. Deamination is the process by which excess amino acids are broken down in the liver (removal of the amino group of an amino acid).
3.2.2 Urea Formation – Ornithine Cycle
Ammonia produced by deamination is converted in the liver into the soluble secretory product, urea. This occurs by a cyclic reaction known as the ornithine cycle.
3.2.3 Transamination
Transamination is the synthesis of amino acids by the enzymatic transfer of the amino group from an amino acid to a carbohydrate in the form of a keto acid. All non-essential amino acids are synthesized this way, should they be temporarily deficient in the diet. The general principle underlying these reactions is the mutual exchange of characteristic radicals between the amino acid and the keto acid.
3.2.4 Plasma Protein Production
The liver is responsible for the production of vital proteins found in the blood plasma. These include albumins and globulins as well as the clotting factors prothrombin and fibrinogen. These proteins are synthesized on polyribosomes attached to the rough ER. Contrary to what is observed in other glandular cells, the hepatocytes do not store proteins in its cytoplasm as secretory granules but continuously releases then into the bloodstream, thus functioning as an endocrine gland. The depletion of plasma protein can cause rapid mitotic division of hepatocytes and actual growth of the liver, which will be coupled with an increase in the synthesis of plasma proteins until plasma protein levels in the blood are normal again.
3.3 Lipid Metabolism
Lipids entering the liver may either be broken down or modified for transport to storage areas elsewhere in the body.
Once the glycogen store in the liver is full, excess carbohydrate will be converted to fat by the liver. Fats are insoluble, so lipoproteins are formed from triglycerides and protein molecules to be transported with ease.
Excess cholesterol in the blood is excreted into bile by the liver, which conversely can synthesize cholesterol when that absorbed by the intestine is inadequate for the body’s need. The removal of cholesterol is essential as its accumulation may cause arteriosclerosis, leading to thrombosis. If in considerable excess, its presence in the bile may lead to the formation of gallstones that can block the bile duct.
3.3.1 Beta Oxidation of Fats
Fats can be used in respiration to provide energy, Cardiac muscles uses fatty acids as its preferred respiratory substrate. If no carbohydrate has been eaten during a period of one day, or exercise levels are so high that the carbohydrate stores are used up, then fats are increasingly used by other body tissues as well.
The liver can use fats as a respiratory substrate. The liver absorbs fatty acids and glycerol from blood. Glycerol is converted to glucose. Fatty acids are broken down through bets oxidation to provide large amounts of acetyl CoA.
However, because the enzymatic reaction that converts pyruvate to acetyl CoA cannot be reversed, acetyl CoA cannot be used to synthesize glucose. Instead some acetyl CoA molecules deliver their 2 carbon fragments t the TCA cycle, where they are broken down. The ATP generated can then be used to support gluconeogenesis. Some of the acetyl CoA is converted to ketone bodies which can be utilized by peripheral tissues. Ketone bodies are also produced during the catabolism of amino acids. Liver cells cannot metabolize any of the ketone bodies and these compounds diffuse through the cytoplasm into the general circulation. Cells in the peripheral tissues then reabsorb the ketone bodies and reconvert them to acetyl CoA for introduction to the TCA cycle.
3.3.2 Conversion of Excess Carbohydrates into Fats
Acetyl CoA is derived from fat break down and carbohydrate break down and is a major fat precursor.
3.3.3 Storage of Fat
When circulating lipid levels are high, the lipids are removed for storage. However, because most lipids absorbed by the digestive tract bypass the hepatic portal circulation, this regulation occurs only after lipid levels have risen within the general circulation
3.3.4 Synthesis of Lipoproteins for transport of fatty acids, fats and cholesterol
As fats are insoluble in water, they cannot be transported just as they are. Triglycerides are combined with protein molecules to form lipoproteins.
3.3.5 Synthesis of Cholesterol and Phospholipids
Cholesterol is an important constituent of the plasma membrane and is the pre-cursor molecule in the synthesis of other steroid molecules. Cholesterol is derived from the diet but the majority however is synthesized in the liver.
Thyroxine both stimulates cholesterol formation in the liver and increases the rate of excretion in the bile. Excess amounts of cholesterol in the blood can lead to its deposition in artery walls thus causing atherosclerosis and increase rick of formation of blood clots which may block blood vessels thus causing thrombosis.
Cholesterol is esterified in the liver. Severe liver disease results in a decrease in esterification of cholesterol with an alteration in the cholesterol to ester ratio thus altering membrane structures.
3.3.6 Excess Cholesterol in blood is excreted into the bile by liver
Liver catabolizes cholesterol to bile salts which are secreted in the bile. Cholesterol may be one of the components of bile as an excretory waste.
3.4 Storage of Vitamins
The main vitamins stored in the liver are fat-soluble vitamins A, D, E, and K. The liver of certain fishes, such as cod and halibut, contains high levels of vitamins A and D. Vitamin K is a vital factor in blood clotting.
The liver stores some of the water-soluble vitamins B and C especially those of the B group such as nicotinic acid, vitamin B12 and folic acid. Vitamin B12 and folic acid are required by the bone marrow for the formation of erythrocytes and a deficiency of these vitamins leads to various degrees of anemia.
These vitamins are absorbed from the blood and stored in the liver where these reserves are called on when your diet contains inadequate amounts of these vitamins.
3.5 Storage of Minerals
Trace elements such as copper, zinc, cobalt and molybdenum are stored in the liver together with iron and potassium. Iron is stored primarily as ferritin, which is a complex of iron and beta globulin. Approximately 1 mg per gram dry mass of the liver tissue in humans is iron. Most of this iron in the liver is temporary and comes from the break down of old erythrocytes. It is stored here for later use in the manufacture of new erythrocytes in the bone marrow.
3.6 Storage of Blood
The hepatic portal vein, together with the blood vessels of the liver, contains a large volume of blood that acts as a reservoir though this is not a static store. Sympathetic neurons and adrenaline from the adrenal medulla can constrict many of these hepatic vessels and make blood more available to the general circulation. Likewise, if the blood volume increases, as for example during blood transfusion, the hepatic veins together with the other veins can dilate to accommodate the excess volume.
3.7 Formation of Erythrocytes
The liver of the foetus is responsible for RBC production (erythropoiesis) but this function is gradually taken over by the cells of the bone marrow. Once this process is established, the liver takes on an opposite role and assists in the breaking down of RBCs and haemoglobin.
3.8 Break down of Haemoglobin
RBCs have a life span of about 120 days. Those that have reached the end of their useful lives are engulfed by the phagocytic cells of the reticulo-endothelial system of the liver, spleen and bone marrow. In the case of the liver, the Kupffer cells in the liver sinusoids engulf the aged RBCs. Haemoglobin from these RBCs are released and dissolved in the plasma.
Haemoglobin is broken down as haem and globin. The globin is reduced to its constituent amino acids and enters the liver’s amino acid pool to be used according to demand. The iron is removed from haem and the remaining pyrrole rings form a green pigment called biliverdin. This then converted to bilirubin which is yellow and is a component of bile. Bilirubin also gives the faeces its characteristic colour.
The accumulation of bilirubin in the blood is symptomatic of liver disease and produces a yellowing of the skin, a condition known as jaundice.
3.9 Bile Production
Bile is a viscous, greenish yellow fluid secreted by the hepatocytes and contains both secretory and excretory products such as bile salts, bile pigments, inorganic salts cholesterol and water. It flows through the bile canaliculi, bile ductules and bile ducts, which gradually merge to form the hepatic duct that continues into the duodenum as the common bile duct. In the duodenum, bile salts are involved in fat digestion. When the stomach is empty of food, bile will be channelled to the gall bladder for storage.
3.9.1 Functions of Bile Salts
Bile salts are derivatives of the steroid cholesterol, which is synthesized in the hepatocytes. The most common ones are sodium glycolate and sodium taurocholate.
Bile salts are secreted with cholesterol and phospholipids as large particles called micelles. The cholesterol and phospholipids hold the polar bile salt molecules together so that all the hydrophobic ends of the latter are orientated in the same way. The hydrophobic ends attach to the lipid droplets whilst the other ends are attached to water. This decreases the surface tension of the lipid droplets and enables the lipids to separate, forming an emulsion. The smaller droplets have an increased surface area for attack by pancreatic lipase. Products of lipid digestion, fatty acids and glycerol, can then be absorbed from the gut.
Bile salts also facilitate transport of sterols and unsaturated fatty acids towards the intestinal wall. Too little bile salts in the bile increases the concentration of cholesterol, which may precipitate out in the gall bladder or bile duct as gallstones. The gallstones can block the bile duct and cause severe discomfort.
3.10 Hormone Production and Break Down
Whilst the liver is not generally considered as an endocrine gland, it synthesizes and releases growth-promoting factors called somatomedins under the influence of somatotrophin, released from the pituitary gland.
The liver destroys almost all hormones to various extents. Testosterone and aldosterone are rapidly destroyed, whereas insulin, glucagon and gut hormones, female sex hormones, ADH and tyroxine are destroyed less rapidly. In this way, the liver has a homeostatic effect o the activities of these hormones.
3.11 Detoxification
Toxins / poisons are usually naturally occurring compounds which can be toxic if allowed to build up in the body. Detoxification is part of homeostasis and helps to maintain the composition of blood in a steady state. Liver is ideally suited to remove or render harmless, toxic material absorbed by the intestines. Liver contains immunological cells in the form of Kupffer cells and a small amount of lymphoid cells in the portal tracts. The liver acts as a sieve, removing toxins and antigens form the intestinal absorption without the production of a systemic immune response. Foreign material or organisms are ingested by Kupffer cells; while toxic chemicals released by them are made safe by chemical conversions within hepatocytes.
Alcohol and nicotine are also removed through detoxification. Alcohol taken in excess over a period of time can result in liver break down such as cirrhosis of liver in alcoholics. It is removed by the enzyme alcohol dehydrogenase. Drugs, dyes, food additives and insecticides are inactivated by the liver. Detoxification / inactivation and removal of toxins are the functions of the liver and this can limit their effects on the body.
3.12 Heat Production
Under conditions of extreme cold, the hypothalamus will increase the exothermic activities of the liver by its influence on the release of adrenaline by the sympathetic nervous system and the release of thyroxine. This high metabolic rate, coupled with the liver’s large size and excellent blood supply, makes the liver ideal for the steady transfer of heat energy.
In normal
body temperatures, however, the liver has been shown to be thermally neutral.
This is because many of the liver’s metabolic activities are endothermic and
therefore require heat energy rather than release it. The liver is about 1.2oC
hotter than the rest of the body core.
