Liver

The liver is an organ of the digestive system. It is the largest gland in the human body and has a variety of functions that contribute to nutrient homeostasis and detoxification.

Embryology
The liver develops around 3 to 4 weeks of gestation. This process begins as a growing bud from ventral foregut endoderm, responding to signals from the developing heart. The earliest stage of hepatic development is the formation of the hepatic diverticulum, adjacent to the developing heart. The anterior portion develops into the liver and intrahepatic biliary tree, while the posterior portion develops into the gallbladder and extrahepatic bile ducts. The cells delaminate from the growing bud around 9.5 weeks, invading the septum transversarum. At this stage, they are hepatoblasts. These cells will soon differentiate into hepatocytes and cholangiocytes, forming the liver parenchyma and bile duct system, respectively. As the hepatoblasts invade the mesenchyme of the septum transversarum, they communicate with endothelial cells allowing hepatic morphogenesis to occur. Between 10 and 15 weeks, the liver bud grows and develops quickly, eventually giving rise to the fetal hematopoietic organ.

Hepatocyte differentiation produces an apical-basal bipolarity around 7 weeks. Cellular differentiation is dependent upon signals from the growing cardiac mesoderm, including fibroblast growth factor (FGF) and bone morphogenic protein (BMP).

Biliary development begins at six weeks. The hepatocytes that are in close proximity to the portal mesenchyme express biliary-specific antigens, forming a solitary ring around the portal mesenchyme. This is called the ductal plate. Subsequently, the ductal plate becomes bilayered and the development of lumens begins. The cells that do not form ducts undergo apoptosis. Around the time of birth, the remaining ducts become part of the portal mesenchyme. The process by which hepatocytes differentiate into biliary cells is poorly understood but it is believed to involve various cellular signaling pathways, such as the Notch pathway.

Gross Anatomy
The liver is the largest gland in the body. It occupies the right upper quadrant, just beneath the diaphragm. It has a parietal peritoneum covering it. There is a bare area where the liver comes into contact with the diaphragm. Here, the liver is suspended by fibrous tissue and hepatic veins. The liver is attached to the diaphragm via the superior and inferior coronary ligaments and the right and left triangular ligaments.

The liver has four anatomic lobes: right, left, caudate and quadrate. The large right and small left anatomic lobes are separated by the falciform ligament, which is a broad thin peritoneal fold. It attaches the superior surface of the liver to the diaphragm and the anterior abdominal wall. The ligamentum teres hepatis, also known as the round ligament of the liver, is a degenerative piece of tissue formed from the free edge of the falciform ligament. It divides the left lobe into medial and lateral sections. The caudate lobe lies between the ligamentum venosum fissure and the inferior vena cava. It is connected to the right lobe by the caudate process. The quadrate lobe lies between the ligamentum teres fissure and the gallbladder fossa. Functionally, the caudate and quadrate lobes are part of the left lobe, receiving their blood supply from the left hepatic artery and portal vein, and delivering their bile to the left hepatic duct.

The liver has a dual blood supply, the hepatic artery and the portal vein. These structures enter the liver at the hilum, also known as the porta hepatis. The porta hepatis is located on the inferior surface of the liver and separates the caudate and quadrate lobes. The hepatic artery carries fully oxygenated arterial blood to the liver. It divides into right and left branches at the porta hepatis. The portal vein supplies the liver with deoxygenated venous blood as well as digestive products and toxins from the intestinal tract.

The nerve supply to the liver consists of branches of the sympathetic system and vagus nerve. Sympathetic chain fibers form a plexus around the blood vessels in the liver, and derive from the celiac ganglia. Vagus nerve (parasympathetic) fibers reach the porta hepatis via the lesser omentum located on the lesser curvature of the stomach. Their branches innervate the hepatic artery, hepatic vein, and portal vein. These nerves collectively regulate liver metabolism, the biliary system, and blood flow through the liver.

The extrahepatic biliary tree is formed by the common hepatic duct, right and left hepatic ducts, cystic duct and gallbladder. The right and left hepatic ducts drain their respective lobes of the liver. They fuse to form the common hepatic duct.

Histology
Histologically, the liver is divided into hexagonal lobules. These lobules have a portal triad (bile duct, hepatic artery, and portal vein) at the six corners and a central vein in the middle. The central vein is a branch of the hepatic vein and serves as the drainage point for each lobule. This architecture can be divided into functional zones based on oxygen supply. These functional areas are known as acini. Zone 1 (periportal zone) encircles the portal tracts. Here, hepatic artery blood feeds this area directly. Zone 3 (perivenular zone) is located around the central vein and has poor oxygenation due to its distance from the hepatic arterial supply. Zone 2 (intermediate zone) lies between zone 1 and zone 3.

Hepatocytes comprise the bulk of the lobule, and are arranged in cords that are separated by vascular sinusoids. The vascular sinusoids are lined by fenestrated endothelium that lacks a basement membrane. There is a space between the endothelium and the hepatocytes known as the space of Disse. The interstitial fluid in this space is blood plasma and this architecture allows blood plasma to wash freely over hepatocytes. Bile canaliculi are formed by the apical surfaces of adjacent hepatocytes. These form a network of canals contained within each cord.

Physiology
The liver is responsible for a number of important functions in the body. It controls blood levels of nutrients during periods of food ingestion and starvation. It is the primary site of intermediary metabolism, utilizing several versatile and massive biochemical pathways to transform molecules. It also detoxifies substances in the body that may be harmful.

Protein metabolism
The liver is involved in the breakdown and production of proteins into peptides and amino acids. Utilizing oxidative deamination and transamination reactions, the liver metabolizes amino acids to glutamine, keto-acids and ammonia. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are two enzymes involved in these reactions. They can be detected in the serum when liver damage occurs, a useful clinical tool. The Krebs-Henseleit cycle functions in the liver to remove ammonia and other nitrogenous wastes from the body. If liver function becomes compromised, these wastes build up and are toxic to the body.

The liver creates proteins as well. These proteins include hormones, cytokines, chemokines, coagulation pathway proteins, transport proteins, and acute phase reactants. Albumin is the chief protein produced by the liver. It binds to and transports a variety of substances in the body, affecting their activity and clearance.

Carbohydrate metabolism
The liver functions to help maintain glucose within a normal, narrow range in the body. It is at the center of carbohydrate metabolism. It performs this function through three processes: glycogenesis, glycogenolysis, and gluconeogenesis. When glucose is plentiful, the liver stores excess glucose as glycogen, a long carbohydrate polymer, in a process known as glycogenesis. In the fasting state, the liver depolymerizes the stored glycogen during glycogenolysis, supplying the body with needed glucose. Both of these processes require multiple steps and utilize a series of enzymes. The rate-limiting enzyme in glycogenesis is glycogen synthase. The rate-limiting enzyme in glycogenolysis is glycogen phosphorylase. After prolonged activity, liver glycogen stores can become depleted. In this case, the liver forms glucose in a process known as gluconeogenesis.

Lipid metabolism
Dietary fat reaches the liver through the blood and lymphatics. Once at the liver, these fats can be esterified to triglcyerides, the major storage form of free fatty acids. The liver may then either retain the triglycerides or package them into lipoproteins for transport to other tissues in the body.

Beta-oxidation is the process by which fatty acids are broken down to acetyl coenzyme A for energy. Acetyl CoA is oxidized by cellular mitochondria to form energy (adenosine triphosphate) in the tricarboxylic acid cycle (TCA cycle). If the TCA cycle is overwhelmed with substrate, the excess acetyl CoA is metabolized to ketone bodies (acetoacetate, acetone, and beta-hydroxybutyrate). All other tissues except the liver can utilize ketone bodies for energy during periods of starvation. These tissues have the enzyme ketoacyl CoA transferase, allowing them to break down ketone bodies.

Bile Metabolism/Enterohepatic Circulation
Bile is formed from many different substances, including electrolytes, lipids, organic anions, and bile salts (bile acids). Bile salts serve very important functions: they activate lipases, allow for micelle formation, and facilitate the uptake of cholesterol, lipids, and fat-soluble vitamins in the intestinal tract. They also enable the excretion of many lipophilic wastes from the body. The body recycles bile salts through enterohepatic circulation.

Coagulation
The liver is responsible for the production of the majority of pro-coagulation factors involved in the coagulation cascade.

Erythropoiesis and Erythrocytosis
The liver is the primary site of erythropoiesis during fetal development and early infancy. As the bone marrow matures, it takes over this function and hematopoietic cells in the liver decrease in number. In healthy adulthood, roughly 20% of heme production occurs in the liver and the rest occurs in the bone marrow. Heme synthesis is a complex biochemical pathway that involves several important enzymes. The rate-liming enzyme is ALA synthase.

Endocrine physiology
Being the largest gland in the body, the liver is involved in the metabolism of numerous hormones and hormone-binding proteins: angiotensinogen, insulin-like growth factor I, and thrombopoietin, to name a few. The liver also inactivates many hormones.

Immune system functions
The liver has immunologic cells known as kupffer cells that help defend the body against invading bacteria and viruses. Kupffer cells degrade toxins and destroy bacteria before blood from the splanchnic circulation enters the central circulation. These cells are also involved in the inflammatory process, and may promote or attenuate it through the production or destruction of proinflammatory mediators, respectively.

Drug metabolism and excretion
The liver also functions to metabolize drugs and excrete them. Greater then 90% of drug biotransformations utilize the CYP system or microsomal oxidases.