I.

Liver Functions
The liver has a wide variety of functions, among these are: A. Endocrine functions
Endocrine System

1. In response to growth hormone, secretes insulin-like growth factor ( (IGF-I), which promotes growth by stimulating mitosis in various tissues, including bone 2. Contributes to the activation of vitamin D 3. Forms triiodothyronine (T3) from thyroxine (T4) 4. Secretes angiotensinogen, which is acted upon by renin to form angiotensin. 5. Metabolizes hormones

B. Clotting functions

1. Produces many of the plasma clotting factors, including prothrombin and fibrinogen 2. Produces bile salts, which are essential for the gastrointestinal absorption of vitamin K, which is, in turn, needed for production of the clotting factors

C. Plasma proteins:

Synthesizes and secretes plasma albumin, acute phase proteins, binding proteins for steroid hormones, lipoproteins, and other proteins mentioned later on this page

D. Digestive functions
Digestive Functions

1. Synthesizes and secretes bile acids, which are necessary for adequated digestion and absorption of fats 2. Secretes into the bile a bicarbonate-rich solution of inorganic ions, which helps neutralize acid in the duodenum
Bile Circulation

E. Organic metabolism 1. Converts plasma glucose into glycogen and triacylglycerols during absorptive period

2. Converts plasma amino acids to fatty acids, which can be incorporated into triacylglycerols, during absorptive period 3. Synthesizes triacylglycerols and secretes them as lipoproteins during absorptive period 4. Produces glucose from glycogen (glycogenolysis) and other sources (gluconeogenesis) during postabsorptive period and releases the glucose into the blood 5. Converts fatty acids into ketones furing fasting 6. Produces urea, the major end product of amino acid (protein) catabolism, and releases it into the blood

F. Cholesterol metabolism 1. Synthesizes cholesterol and releases it into the blood 2. Secretes plasma cholesterol into the bile 3. Converts plasma cholesterol into bile acids

G. Excretory and degradative functions

1. Secretes bilirubin and other bile pigments into the bile 2. Excretes, via the bile, many endogenous and foreign organic molecules as well as trace metals 3. Biotransforms many endogenous and foreign organic molecules 4. Destroys old erythrocytes

Anatomy The liver is the largest organ in the abdominal cavity and the most complex (Figure 7). It consists of a myriad of individual microscopic functional units called lobules. The liver performs a variety of functions including the removal of endogenous andexogenous materials from the blood, complex metabolic processes including bile production, carbohydrate homeostasis, lipidmetabolism, urea formation, and immune functions. The liver is located in the right upper quadrant, between the fifth intercostal space in the midclavicular line down and the rightcostal margin. It weighs approximately 1800 grams in men and 1400 grams in women. The surfaces of the liver are smooth and convex in the superior, anterior and right lateral regions. Indentations from the colon, right kidney, duodenum and stomach are apparent on the posterior surface.

1 Anatomy of the liver; A, gross view; B, histological (microscopic) view.

The line between the vena cava and gallbladder divides the liver into right and left lobes. Each lobe has an independentvascular and duct supply. The lobes are divided into eight segments each containing a pedicle of portal vessels, ducts, andhepatic veins. The portal venous system extends from the intestinal capillaries to the hepatic sinusoids (Figure 8). This system carries blood from the abdominal gastrointestinal tract, the pancreas, the gallbladder and

the spleen back to the heart (coursing through theliver). The largest vessel in this system is the portal vein, which is formed by the union of the splenic vein and superiormesenteric veins. The left gastric and right gastric veins and the posterior superior pancreaticoduodenal vein drain directly into the portal vein. The portal vein runs posterior to the pancreas and its extrahepatic length is anywhere from 5 to 9 centimeters. At the porta hepatis, it divides into the right and left portal veins within the liver, and the cystic vein typically drains into the righthepatic branch.

1 Anatomy of the portal venous system.

The portal vein supplies 70% of the blood flow to the normal liver, but only 40% of the liver oxygen supply. The remainder of the blood comes from the hepatic artery, and blood from both vessels mixes in the sinusoids. The liver receives a tremendous volume of blood, on the order of 1.5 liters per minute. This dual blood supplyfrom the portalvein and hepatic arteryallows the liver to be relatively resistant to hypoxemia. Unlike the systemic vasculature, the hepaticvascular system is less influenced by vasodilation and vasoconstriction. This is due to the fact that sinusoidal pressures remain relatively constant in spite of changes in blood flow. A classic example is hepatic vein occlusion resulting in high sinusoidal pressure and extracellular extravasation of fluid. To maintain a constant inflow of blood, hepatic artery blood flow is inversely related to portal vein flow. This appears to be hormonally mediated rather than neurally mediated, since it persists even in the transplanted liver.

Anatomy and Physiology of the liver

Human liver development begins during the third week of gestation and does not acheive mature architecture until about 15 years of age. It reaches its largest relative size, 10% of fetal weight, around the ninth week. It is about 5% of body weight in the healthy neonate. The liver is about 2% of body weight in the adult. It weighs around 1400g in an adult female and about 1800g in the male.* The liver is located in the right upper quadrant of the abdomen, just below the diaphragm. It is almost completely behind the rib cage but the lower edge may be palpated along the right costal margin during inspiration. A connective tissue layer called Glisson's capsule covers the surface of the liver. The capsule extends to invest all but the smallest the vessels within the liver. * The falciform ligament attaches the liver to the abdominal wall and diaphragm and divides the liver into a larger right lobe and a smaller left lobe. In 1957, the french surgeon Claude Couinaud described 8 liver segments. Since then, radiographic studies describe an average of twenty segments based on distribution of blood supply*. Each segment has its own independent vascular and biliary branches. Surgeons utilize these independent segments when performing liver resection for tumor or transplantation. There are at least three reasons why segmental resection is superior to simple wedge resection. First, segmental resection minimizes blood loss because vascular density is reduced at the borders between segments. Second, it

results in improved tumor removal for those cancers which are disseminated via intrasegmental branches of the portal vein. Third, segmental resection spares normal liver allowing for repeat partial hepatectomy*. Each segment of the liver is further divided into lobules. Lobules are usually represented as discrete hexagonal aggregations of hepatocytes. The hepatocytes assemble as plates which radiate from a central vein. Lobules are served by arterial, venous and biliary vessels at their periphery. This model is useful for teaching purposes but more closely resembles the adult pig lobule than the human. Human lobules have little connective tissue separating one lobule from another. The paucity of connective tissue makes it more difficult to identify the portal triads and the boundaries of individual lobules. Central veins are easier to identify due to their large lumen and because they lack connective tissue that invests the portal triad vessels. Lobules consist of hepatocytes and the spaces between them. Sinusoids are the spaces between the plates of hepatocytes.

Sinusoids receive blood from the portal triads. About 25% of total cardiac output enters the sinusoids via terminal portal and arterial vessels. Seventy-five percent of the blood flowing into the liver comes through the portal vein; the remaining 25% is oxygenated blood that is carried by the hepatic artery. The blood mixes, passes through the sinusoids, bathes the hepatocytes and drains into the central vein. About 1.5 liters of blood exit the liver every minute. The liver is central to a multitude of physiologic functions, including:

Clearance of damaged red blood cells & bacteria by phagocytosis Nutrient management Synthesis of plasma proteins such as albumin, globulin, protein C, insulin-like growth factor, clotting factors etc. Biotransformation of toxins, hormones, and drugs Vitamin & mineral storage

Phagocytosis

Red blood cell (RBC) lifespan is about 120 days. Reticuloendothelial (macrophage) cells in the spleen, liver and bone marrow are primarily responsible for clearing pathogens and debris. Kupffer cells are reticuloendothelial cells resident in the liver sinusoids that scavange damaged RBCs and bacteria as they pass through. Hundreds of millions of RBCs are removed by the reticuloendothelial system every minute. Kupffer cells, like other reticuloendothelial macrophages, lyse RBCs into heme and globin. Globin is further catabolized into polypeptide components for reuse. Heme is broken into biliverdin and iron. Biliverdin is converted to bilirubin. Iron is transported by transferrin to the liver and spleen for storage and to the bone for hematopoiesis. About 85% of bilirubin is derived from lysis of RBCs, the rest comes from the breakdown of other hemoproteins like myoglobin, cytochromes and peroxidases. Kupffer cells like other reticuloendothelial macrophages release bilirubin into the blood. In the blood, bilirubin binds to albumin. The albumin/bilirubin compound is small enough to pass through the

endothelial fenestrae and into the space of Disse where it contacts the hepatocyte. Hepatocytes cleave bilirubin from albumin and absorb the bilirubin. In the hepatocyte cytoplasm, bilirubin is conjugated to glucouronic acid. Bilirubin uridine diphosphate glucuronyl transferase (UDPGT) catalyzes the bonding of glucuronic acid and bilirubin to produce water-soluble bilirubin. Water soluble conjugated bilirubin is secreted into canaliculi along with water, electrolytes, bicarbonate, bile acids, salts, cholesterol and phospholipids. This combination is called bile and serves as a detergent to keep bile soluble in the biliary tract. Bile drains from the canaliculi>canal of Hering>bile ducts>common hepatic duct>gallbladder>common bile duct>ampulla of vater>duodenum.* In the duodenum, bile salts attach to fat globules forming smaller micelles that collect fatty acids and glycerol. The micelles travel to the jejunum where they deliver their cargo to the intestinal epithelium. Inside the epithelial cells glycerol and fatty acids are rejoined to form triglycerides. Finally triglycerides are joined to cholesterol and proteins are added to the surface; creating a chylomicron. Lipid management* The liver receives a variety of lipid forms including: chylomicrons remnants, very low density lipoproteins (VLDL), low density lipoproteins (LDL), high density lipoproteins (HDL) and fatty acids. Large lipoprotein molecules are broken into smaller units by the lytic action of lipoprotein lipase (LPL) expressed on endothelium of vessels. Circulating lipoproteins small enough to enter the space of Disse attach to receptors on the hepatocyte. These lipoprotein remnants are held near the heptocyte surface and exposed to hepatic lipase compounds. Low Density Lipoprotein receptors transfer the lipoprotein fragments into the hepatocyte by the process of endocytosis.

Chylomicrons are the product of intestinal packaging of dietary fats. Chylomicrons are produced in the duodenal villi and secreted into the lymph lacteals for delivery to the thoracic duct>subclavian vein>superior vena cava>right ventricle>lungs>Left ventricle>aorta>hepatic artery>sinusoid.Chylomicrons range from 75-1200nm in diameter. They contain 98% lipids and 2% protein. Chylomicrons are degraded in the blood by contact with LPL. Chylomicrons become smaller and more dense as fatty acids are stripped off. Loss of fatty acids results in chylomicron remnants of various sizes and density when they finally reach the liver. Hepatic lipase expressed by the hepatic sinusoidal endothelium and hepatocytes continues the remnant degradation. Very low density lipoproteins (VLDL) are synthesized primarily in the hepatocyte. VLDLs range from 30-80nm. They contain 90% lipids and 10% protein.Their purpose is to transport triglycerides made in the liver into plasma for use or storage outside the liver. Low density lipoprotein (LDL) is formed from VLDLs in the plasma by the action of lipase. LDL diameter is about 20nm. They contain 70% lipids and 30% protein. LDLs distribute cholesterol throughout the body. Cholesterol is an important constituent of: VLDL, cell membranes, hormones, bile etc. High density lipoprotein (HDL) are small lipoprotein particles (5-15nm) formed in the liver and intestine. They range from 5-15nm in diameter.They contain 50% lipids and 50% protein. HDLs collect cholesterol & lipoprotein fragments from the blood and blood vessel plaques and return them to the liver for repurposing. Fatty acids are linear hydrocarbon chains that are the major constituents of dietary lipoproteins (triglycerides). The liver degrades lipoproteins with hepatic lipase or synthesizes fatty acids from carbohydrate sources. When carbohydrate energy sources are low fatty acids are oxidized for energy.

Carbohydrate management: When energy intake exceeds energy output the body stores the surplus glucose as glycogen or triglyceride. When energy output exceeds energy intake the body reacts by releasing stored energy as glucose and fatty acids. Glucose is the preferred energy source for most tissues but the body maintains very limited supplies of free circulating glucose. Certain tissues like the brain, RBCs, lens and cornea use glucose almost exclusively. To supply these tissues when blood glucose drops the liver lyses glycogen. Glycogen is a complex molecule composed of thousands of glucose units. Hepatocytes and myocytes store glucose as intracellular glycogen granules. The liver is central to blood glucose management because the liver is the only organ that can store and release glucose into the blood for use by other organs. After a meal the liver removes excess blood glucose and stores up to 8% of its weight as glycogen. Myocytes can store about 1-2% of total muscle mass as glycogen but once glucose enters a myocyte it must be used or stored by that myocyte. Myocytes lack the enzyme necessary to release glucose into the circulation. The liver uses three metabolic processes to manage carbohydrates and insure adequate blood glucose:

Glycogenesis - excess glucose, fructose, and galactose are converted to glycogen and stored in the liver. Glycogenolysis - when blood glucose falls, the liver breaks down stored glycogen to raise blood glucose levels Gluconeogenesis - the liver can synthesize glucose from lactic acid, some amino acids and glycerol. When glucose is low the liver can derive energy from the metabolism of fatty acids which can conserve available glucose.

Protein management: Dietary protein is denatured by stomach acids and digested into amino acids in the small intestine. Amino acids are absorbed by

the small intestine and delivered to the liver via the portal circulation. Up to 50% of the livers' energy requirements can be supplied by amino acid oxidation. Oxidative deamination breaks amino acids into keto acid and an ammonia molecule. The keto acid is used in the Kreb's cycle to produce ATP. The liver combines ammonia with CO2 to form urea and H2O. The liver also uses dietary amino acids and those released during normal tissue breakdown to produce its own proteins and enzymes as well as plasma proteins. Plasma proteins produced by hepatocytes include: albumin, fibrinogen, prothrombin, afetoprotein, a2-macroglobin, hemopexin, transferrin, complenent components C3,C6 andC1, a1-antitrypsin, caeruloplasmin.*

Albumin is only produced by the liver and equals about 50% its total protein synthesis. About 12 grams of albumin are synthesized by the normal liver daily.* Patients with decompensated cirrhosis produce only about 4 g per day. About 40% of total albumin is intrascular. a-fetoprotein peaks about 16 weeks gestation and disappears a few weeks after birth. It may reappear in association with chronic hepatitis and a number of carcinomas a1-antitrysin deficiency is inherited a2-macroglobin functions as a protease inhibitor. It is active in the inhibition of thrombin and plasmin. hemopexin transports heme in the plasma protecting tissues from the actions of heme. transferrin is globulin that transports heme to bone marrow for incorporation into erythroid precursors. complement components assist the immune system to raise an immune response. caeruloplasmin is the major copper carrying plasma protein.

Biotransformation Hepatocytes protect the body from injury by biotransforming toxins and drugs and by deactivating hormones. The liver

employs enzymes to make substances more water soluble, so they can be excreted from the body in the urine and feces. In Phase 1 biotransformations the cytochrome P450 enzymes alter the target molecule by adding or exposing functional groups such as -OH or -COOH. Phase 2 biotransformation enzymes add sugars, amino acids, sulfates or acetyl groups to the functional group which makes them more water soluble. Vitamins The liver also plays an important role in vitamin and mineral (iron & copper) storage. About 80% of the body's vitamin A stores are concentrated in fat droplets within the stellate cells of the liver. In pathological conditions like hepatic fibrosis or liver cirrhosis the stellate cells lose vitamin A, transform into fibroblasts or myofibroblasts and begin producing large amounts of collagen and adhesive glycoproteins.* Normal vitamin A reserves are enough to prevent a deficiency for about 10 months. The liver also contains about a year supply of B12. Vitamin D stores equal about 3-4 months. Small amounts of Vitamins E and K and Vitamin C are stored in the liver to facilitate liver functions.
Anatomy
The liver is a reddish brown organ with four lobes of unequal size and shape. A human liver normally weighs 1.441.66 kg (3.23.7 lb),[3] and is a soft, pinkishbrown, triangular organ. It is both the largest internal organ (the skin being the largest organ overall) and the largest gland in the human body. It is located in the right upper quadrant of the abdominal cavity, resting just below the diaphragm. The liver lies to the right of the stomach and overlies the gallbladder. It is connected to two largeblood vessels, one called the hepatic artery and one called the portal vein. The hepatic artery carries blood from the aorta, whereas the portal vein carries blood containing digested nutrients from the entire gastrointestinal tract and also from the spleen and pancreas. These blood vessels subdivide into capillaries, which then lead to a lobule. Each lobule is made up of millions of hepatic cells which are the basic metabolic cells. [edit]Blood

flow

The liver receives a dual blood supply from the hepatic portal vein and hepatic arteries. Supplying approximately 75% of the liver's blood supply, the hepatic portal vein carries venous blood drained from the spleen,gastrointestinal tract, and its associated organs. The hepatic arteries supply arterial blood to the liver, accounting for the remainder of its blood flow. Oxygen is provided from both sources; approximately half of the liver's oxygen demand is met by the hepatic portal vein, and half is met by the hepatic arteries.[4] Blood flows through the liver sinusoids and empties into the central vein of each lobule. The central veins coalesce into hepatic veins, which leave the liver.

[edit]Biliary

flow

The biliary tree

The term biliary tree is derived from the arboreal branches of the bile ducts. The bile produced in the liver is collected in bile canaliculi, which merge to form bile ducts. Within the liver, these ducts are called intrahepatic (within the liver) bile ducts, and once they exit the liver they are considered extrahepatic (outside the liver). The intrahepatic ducts eventually drain into the right and left hepatic ducts, which merge to form the common hepatic duct. The cystic duct from the gallbladder joins with the common hepatic ductto form the common bile duct.

Bile can either drain directly into the duodenum via the common bile duct, or be temporarily stored in the gallbladder via the cystic duct. The common bile duct and thepancreatic duct enter the second part of the duodenum together at the ampulla of Vater. [edit]Surface

anatomy

[edit]Peritoneal ligaments

Apart from a patch where it connects to the diaphragm (the so-called "bare area"), the liver is covered entirely by visceral peritoneum, a thin, doublelayered membrane that reduces friction against other organs. The peritoneum folds back on itself to form the falciform ligament and the right and left triangular ligaments.

These "lits" are in no way related to the true anatomic ligaments in joints, and have essentially no known functional importance, but they are easily recognizable surface landmarks. An exception to this is the falciform ligament, which attaches the liver to the posterior portion of the anterior body wall. [edit]Lobes

Traditional gross anatomy divided the liver into four lobes based on surface features. The falciform ligament is visible on the front (anterior side) of the liver. This divides the liver into a left anatomical lobe, and a right anatomical lobe.

If the liver is flipped over, to look at it from behind (the visceral surface), there are two additional lobes between the right and left. These are the caudate lobe (the more superior) and the quadrate lobe (the more inferior).

From behind, the lobes are divided up by the ligamentum venosum and ligamentum teres (anything left of these is the left lobe), the transverse fissure (or porta hepatis) divides the caudate from the quadrate lobe, and the right sagittal fossa, which the inferior vena cava runs over, separates these two lobes from the right lobe.

Each of the lobes is made up of lobules; a vein goes from the centre, which then joins to the hepatic vein to carry blood out from the liver.

On the surface of the lobules, there are ducts, veins and arteries that carry fluids to and from them.

[edit]Functional

anatomy

Correspondence between anatomic lobes and Couinaud segments

Segment*

Couinaud segments

Caudate

Lateral

2, 3

Medial

4a, 4b

Right

5, 6, 7, 8

* or lobe, in the case of the caudate lobe Each number in the list corresponds to one in the table. 1. Caudate 2. Superior subsegment of the lateral segment 3. Inferior subsegment of the lateral segment 4a. Superior subsegment of the medial segment 4b. Inferior subsegment of the medial segment 5. Inferior subsegment of the anterior segment 6. Inferior subsegment of the posterior segment 7. Superior subsegment of the posterior segment 8. Superior subsegment of the anterior segment

The central area where the common bile duct, hepatic portal vein, and hepatic artery proper enter is the hilum or "porta hepatis". The duct, vein, and artery divide into left and right branches, and the portions of the liver supplied by these branches constitute the functional left and right lobes.

The functional lobes are separated by an imaginary plane joining the gallbladder fossa to the inferior vena cava. The plane separates the liver into the true right and left lobes. The middle hepatic vein also demarcates the true right and left lobes. The right lobe is further divided into an anterior and posteriorsegment by the right hepatic vein. The left lobe is divided into the medial and lateral segments by the left hepatic vein. The fissure for the ligamentum teres also separates the medial and lateral segments. The medial segment is also called the quadrate lobe. In the widely used Couinaud (or "French") system, the functional lobes are further divided into a total of eight subsegments based on a transverse plane through the bifurcation of the main portal vein. The caudate lobe is a separate structure which receives blood flow from both the right- and left-sided vascular branches.[5][6] [edit]In

other animals

The liver is found in all vertebrates, and is typically the largest visceral organ. Its form varies considerably in different species, and is largely determined by the shape and arrangement of the surrounding organs. Nonetheless, in most species it is divided into right and left lobes; exceptions to this general rule include snakes, where the shape of the body necessitates a simple cigar-like form. The internal structure of the liver is broadly similar in all vertebrates.[7]

An organ sometimes referred to as a liver is found associated with the digestive tract of the primitive chordate Amphioxus. However, this is an enzyme secreting gland, not a metabolic organ, and it is unclear how truly homologous it is to the vertebrate liver.[7] [edit]Physiology

The various functions of the liver are carried out by the liver cells or hepatocytes. Currently, there is no artificial organ or device capable of emulating all the functions of the liver. Some functions can be emulated byliver dialysis, an experimental treatment for liver failure. The liver is thought to be responsible for up to 500 separate functions, usually in combination with other systems and organs. [edit]Synthesis Further information: Proteins produced and secreted by the liver

A large part of amino acid synthesis The liver performs several roles in carbohydrate metabolism:

Gluconeogenesis (the synthesis of glucose from certain amino acids, lactate or glycerol) Glycogenolysis (the breakdown of glycogen into glucose) Glycogenesis (the formation of glycogen from glucose)(muscle tissues can also do this)

The liver is responsible for the mainstay of protein metabolism, synthesis as well as degradation The liver also performs several roles in lipid metabolism:

Cholesterol synthesis Lipogenesis, the production of triglycerides (fats).

The liver produces coagulation factors I (fibrinogen), II (prothrombin), V, VII, IX, X and XI, as well as protein C, protein S and antithrombin. In the first trimester fetus, the liver is the main site of red blood cell production. By the 32nd week of gestation, the bone marrow has almost

completely taken over that task.

The liver produces and excretes bile (a yellowish liquid) required for emulsifying fats. Some of the bile drains directly into the duodenum, and some is

stored in the gallbladder.

The liver also produces insulin-like growth factor 1 (IGF-1), a polypeptide protein hormone that plays an important role in childhood growth and

continues to have anabolic effects in adults.

The liver is a major site of thrombopoietin production. Thrombopoietin is a glycoprotein hormone that regulates the production of platelets by

the bone marrow. [edit]Breakdown

The breakdown of insulin and other hormones The liver glucoronidates bilirubin, facilitating its excretion into bile. The liver breaks down or modifies toxic substances (e.g., methylation) and most medicinal products in a process called drug metabolism. This

sometimes results in toxication, when the metabolite is more toxic than its precursor. Preferably, the toxins are conjugated to avail excretion in bile or urine.

The liver converts ammonia to urea (urea cycle)

[edit]Other

functions

The liver stores a multitude of substances, including glucose (in the form of glycogen), vitamin A (12 years' supply), vitamin D (14 months'

supply), vitamin B12 (1-3 years' supply), iron, and copper.

The liver is responsible for immunological effects- the reticuloendothelial system of the liver contains many immunologically active cells, acting as a

'sieve' for antigens carried to it via the portal system.

The liver produces albumin, the major osmolar component of blood serum. The liver synthesizes angiotensinogen, a hormone that is responsible for raising the blood pressure when activated by renin, an enzyme that is

released when the kidney senses low blood pressure.