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A large gland found in all vertebrates. It consists of a continuous parenchymal mass arranged to form a system of walls through which venous blood emanating from the gut must pass. This strategic localization between nutrient-laden capillary beds and the general circulation is associated with hepatic regulation of metabolite levels in the blood through storage and mobilization mechanisms controlled by liver enzymes.
The large size of the liver is matched by its functional complexity and involvement in a diverse array of regulatory mechanisms. The liver plays a key role in assuring carbohydrate homeostasis (dynamic steady-state conditions) by removing simple sugars from the general circulation after ingestion of food and storing them as glycogen. In the intervals between ingestion of food, liver glycogen is broken down. This process tends to maintain blood sugar levels between 80 and 100 mg per 100 ml of blood. Under conditions of prolonged fast, where glycogen stores are exhausted, the liver is capable of converting noncarbohydrate metabolites such as amino acids and fats into glucose to maintain blood sugar levels. The complex steps involved in maintaining carbohydrate metabolism are subject to endocrine control, with the liver serving as a particularly sensitive target organ of hormone regulators such as insulin. See Carbohydrate metabolism, Glucose, Glycogen, Insulin
The liver is key in the interconversion of many metabolites. It is a major site of production of fatty acids, triglycerides, phospholipids, ketone bodies, and cholesterol. Steroid hormones are degraded in the liver. See Cholesterol, Ketone, Lipid, Steroid
The liver is the sole source of such necessary constituents of the blood as fibrinogen, serum albumin, and cholinesterase. In the embryonic stage of most vertebrates the liver serves as the major manufacturing site of erythrocytes, a process known as erythropoiesis. The liver also removes toxins from the systemic circulation and degrades them, as well as excess hormones. Particulate material may be removed through a phagocytic action of specialized cells (Kupffer cells) lining the lumen of the hepatic “capillary spaces,” or sinusoids. In addition to the products which the liver delivers directly to the general circulation (endocrine function), it secretes bile through a duct system which, involving the gallbladder as a storage chamber, eventually passes into the duodenum (exocrine function). Bile functions as an emulsifier of fats to facilitate their digestion by fat-splitting lipases, and may also activate the lipase directly. See Gallbladder
The human liver is a massive wedge-shaped organ divided into a large right lobe and a smaller left lobe. Its anterior surface underlies the diaphragm. The upper portion of the liver is partially covered ventrally by the lungs, whereas the lower portion overhangs the stomach and intestine. The entire liver is covered by Glisson's capsule, an adherent membranous sheet of collagenous and elastic fibers.
Venous blood from the intestine, and to a lesser extent from spleen and stomach, converges upon a short broad vessel, called the hepatic portal vein, which enters the liver through a depression in the dorsocaudal surface termed the porta hepatis. There the hepatic portal vein divides into a short right branch and a longer left branch. These vessels then ramify into the small branches which actually penetrate the functional parenchymal mass as the inner tubes of the portal canals.
The hepatic artery also enters at the porta hepatis and ramifies into smaller branches, which flank the portal venules within the portal canals. The branches of the portal vein and hepatic artery then empty into sinusoids, which are major regions of hepatovascular exchange. They communicate with small branches of the hepatic veins and, through the hepatic vein, the blood is returned to the heart by way of the vena cava.
The tiny bile canaliculi, which lie between grooves in adjacent parenchymal cells, communicate with tiny intralobular bile ducts. These intralobular bile ducts empty into increasingly larger interlobular bile ducts which lie within the portal canals and make up the third element of the so-called portal triad.
a large gland that participates in digestion, metabolism, and blood circulation and maintains homeostasis by performing specific protective, detoxifying, enzymatic, and excretory functions.
Comparative morphology. The invertebrate liver is a midgut outpouching that takes part in the digestion and assimilation of food and serves as a reservoir for nutrients, fats, and carbohydrates. In many invertebrates, the liver is often called the hepato-pancreas. In most mollusks, the liver is a massive, lobulated organ, usually paired, that opens into the stomach through a single duct or through several ducts. Molluscan liver cells are phagocytic. Among arthropods, livers are found in crustaceans, members of the order Xiphosura, and most arachnids. The crustacean liver, which consists of sacciform outpouchings of the anterior portion of the midgut, produces an enzyme that splits cellulose. The arachnid liver consists of paired outpouchings of the abdominal midgut. Among echinoderms, only crinoids and starfishes have large hepatic outpouchings of the stomach.
In chordates and man, the liver is the site of major metabolic activity; it also secretes bile, a substance that participates in digestion. The liver of tunicates is usually an arborescent outpouching of the stomach that presses against the gastric wall and opens into the stomach through a single duct. In the lancelet, the liver is a sacciform outpouching of the intestine.
In vertebrates, the liver originates as an arborescent outpouching of the abdominal midgut and eventually assumes the structure of a tubular gland. The lumina of the terminal tubules of the liver form biliary canaliculi, through which bile flows into the larger hepatic ducts. The individual hepatic ducts are usually combined into the common bile duct, which opens into the duodenum. The gallbladder is usually formed from part of the common bile duct. The tubular structure of the liver persists throughout life only in hagfishes. In lampreys, fish, and amphibians, the tubular structure is partly modified by the transverse anastomosing trabeculae that arise between the tubules of the liver; the trabeculae are vascularized and innervated.
In reptiles, birds, and mammals the abundant anastomoses transform the tubular gland into a reticular one. In lampreys and certain fish the liver consists of one solid mass, but in most animals it has a right and left lobe; the gallbladder is always attached to the right lobe. In some animals, especially mammals, both lobes may be divided into lobules. The liver is relatively larger in predators than in herbivores and larger in fish and amphibians than in reptiles, birds, and mammals. The shape of the liver varies with the shape of the animal’s body. In certain amphibians, fish, and mammals the liver is in close contact with the pancreas, whose ducts open into the common bile duct.
In man the liver is the largest digestive gland. It develops in the third week of intrauterine life from an epithelial outpouching of the duodenal mucosa. The liver of an adult human weighs 1.5–2 kg—about one-fiftieth of the body weight—and is firm, although functional loads and the weight of the surrounding organs change its shape and size. The diaphragm lies between the liver below and the heart and lungs above. Below the liver are the stomach, duodenum, part of the transverse colon, and the right kidney with the adrenal gland. Behind are the esophagus and vertebral column, and in front is the anterior wall of the abdominal cavity.
The surfaces of the liver are designated anterosuperior, or diaphragmatic, and inferior, or visceral; the anterior border has a sharp edge, while the posterior border’s edge is rounded. The convex, anterosuperior surface is divided by the falciform ligament into a larger right lobe and a smaller left one. The inferior surface is somewhat concave. It is split by right and left longitudinal fissures and a transverse fissure—the hepatic porta— that divide the liver into four lobes: right, left, caudate, and quadrate. The gallbladder lies in the anterior part of the right longitudinal fissure, and the vena cava inferior in the posterior part. The left longitudinal fissure contains the round ligament anteriorly, which is the remnant of the unbilical vein, and the venous ligament posteriorly, which arose by the embryonic union of the umbilical vein and the vena cava inferior. The porta is the entrance for the portal vein, the hepatic artery, and nerves, while the lymphatics and hepatic ducts exit from it. The hepatic duct joins the cystic duct to form the biliferous duct, which empties into the duodenum.
Most of the liver is covered by a serous membrane, part of the peritoneum; the portion of the liver that lies adjacent to and is fused with the diaphragm remains uncovered. The serous membrane stretches from the liver to the adjacent organs and forms the falciform ligament, the right and left venous coronary ligaments (which connect the liver to the diaphragm), and several ligaments that proceed from the porta, for example, the hepatogastric ligament. The ligaments hold the liver in place. The following factors are also very important in fixing the liver’s position: intra-abdominal pressure, which pushes the mutually supportive abdominal organs firmly against each other; the vena cava inferior, which together with its branchings, the hepatic veins, grows into the liver tissue; cohesive contact between the serous membrane of the liver and the diaphragm; and the connective tissue that joins the liver to the diaphragm in the places not covered by the peritoneum.
The liver is predominantly situated in the right hypochondriac region and extends to the left hypochondriac region through the epigastrium. The lower boundary of the liver in an adult human normally does not emerge on the right side from under the margin of the right costal arch. In newborns the liver occupies the entire upper portion of the abdominal cavity, and the left lobe touches the spleen; the lower border of the liver often reaches the umbilicus. The liver in infants protrudes 2–3 cm from under the costal margin, by which it is not obscured until age 4.
The liver is a complex tubular gland. Under the serous membrane is Glisson’s capsule, a connective-tissue structure containing elastic fibers. The capsule thickens in the porta and together with the blood vessels penetrates the liver, which is thus divided into prismatic hepatic lobules 0.5–2.0 mm in size. A central vein passes through the middle of each lobule. Columns of hepatic cells radiate from the central vein; collectively, they constitute the glandular parenchyma of the liver. The lobules are formed from thin, wide columns that anastomose and consist of a single layer of hepatic cells. Between the columns are bile capillaries that coalesce to form the intralobular and interlobular bile ducts, which in turn constitute the hepatic duct.
The liver is supplied with blood by the hepatic artery, which brings oxygen-rich blood, and by the portal vein. The blood that reaches the liver by way of the portal vein from the stomach, spleen, intestine, pancreas, and other abdominal organs contains some products of protein, carbohydrate, and, in part, fat digestion; the venous blood also contains a variety of chemical substances that sustain the physiological functions of the liver.
The terminal branches of the hepatic artery and portal vein within the lobules pass into the sinusoids, where the rate of blood flow is comparatively low. After exchanging substances with the hepatic cells in the sinusoids, the blood enters the central lobular veins, which combine into three or four hepatic veins that empty into the vena cava inferior. The branched capillary network covers a surface of 400 m2 and carries about 2,000 liters of blood daily through the liver; about 80 percent of the blood travels by way of the portal system, and 20 percent of the blood travels through the hepatic artery. All capillaries are lined with endothelium; the intralobular capillaries, or sinusoids, like ordinary capillaries, are additionally provided with highly phagocytic, reticular, stellate cells that belong to the reticuloendothelial system. The liver is innervated by the vagus nerves and branches of the celiac plexus.
Physiology and biochemistry. Substances that are absorbed in the intestine enter the blood and are carried to the liver, where they are chemically altered. The liver helps maintain the dynamic equilibrium between many substances in plasma, including sugar, cholesterol, proteins, iron, vitamin A, and water. About 1½ liters of blood pass through the liver per minute, and one-seventh of the body’s entire energy is released in the liver. The temperature of blood flowing from the liver rises 1°–2°C during digestion.
The liver inactivates many hormones, including thyroxine, estrogens, gonadotropic hormones, adrenocortical steroids, and serotonin. Some substances become more toxic after passing through the liver, for example, the alkaloid colchicine is converted to a more toxic substance, hydroxycolchicine, and sulfanilamides become less soluble after acetylation in the liver and are consequently precipitated in the urinary tract. The liver is capable of forming bile, which is synthesized in the hepatic cells from precursors that arrive with blood and which is important for digestion and fat metabolism.
The storage of blood is an equally important function of the liver. Hepatic blood vessels can hold 20 percent of the entire volume of blood in the body, and retention of blood in a normal healthy liver is not due to venous congestion. The activity of the other organs that store blood—the spleen and intestine—depends on liver function. All the blood that leaves the spleen and intestine must pass through the liver, where excess water is removed to produce lymph and bile. One-third to one-half of all the lymph, which has a fairly high protein content—6 percent—is formed in the liver.
The liver consists of 70-75 percent water, 12–24 percent simple and complex proteins and their degradation products, 2-6 percent lipids, and 2-8 percent carbohydrates and their breakdown products, as well as coenzymes, vitamins, hormones, various low-molecular organic substances, and mineral cations and anions. The liver performs very important functions. It is the synthesis site of many essential substances—nucleic acids (DNA and RNA), various dinucleotides and mononucleotides, and purine and pyrimidine bases. In addition, the liver contains enzymes that are responsible for deamination, for the breakdown of nucleic acids and nucleotides, and for the oxidation of free purine bases. It also participates to some extent in protein, carbohydrate, lipid, vitamin, mineral, and water metabolism. The breakdown products of all the nutrients in the liver form the body’s main metabolic reserve, from which the body draws essential substances when needed.
Protein metabolism. The liver accounts for about one-half of the 80–100 g of protein that are degraded and newly synthesized per day in man. Proteins are renewed in the liver in seven days, while in other organs, in 17 days or more; this is an indication of the intensity of hepatic protein metabolism. The liver is the site of protein synthesis, which starts with activation of amino acids in the hyaloplasm and formation of compounds with messenger RNA, which is specific for each amino acid. The culminating stage of synthesis is the emergence of long peptide chains from their site of production in the ribosomes.
The liver produces not only its own characteristic proteins but also plasma proteins—albumins as well as many globulins, and fibrinogen and other factors that participate in blood coagulation. Catheptic proteases and peptidases in the liver help degrade proteins and form amino acids, which undergo transamination, deamination—a process that is practically confined to the liver —and decarboxylation—which gives rise to biogenic amines. Such methylated compounds as choline, creatine, and epinephrine are formed by the transfer of a methyl group from adenosyl-methionine.
The conversion pathways of some amino acids, for example, tryptophan, phenylalanine, histidine, and lysine, are unusual and occur only in the liver. Tryptophan is the starting material for the biosynthesis of such biologically active substances as trypta-mine; hydroxytryptophan and its decarboxylation product, serotinin; and quinolinic acid and its two decarboxylation products, nicotinic and picolinic acids. Formiminoglutamic acid, glutamic acid, and histamine are formed from histidine, and ornithine and urea are formed from arginine. Ornithine enters a cycle of reactions whose end product is the final metabolic product of simple proteins—urea; the ornithine cycle involves carbon dioxide, ammonia, magnesium ions, adenosine triphosphate (ATP), and several amino acids. The liver synthesizes substances that neutralize such toxic metabolic products as phenols and aromatic hydrocarbons; the products of these neutralizations include many compounds, for example, paired glucuronic thioether acids, mercapto acids, and hippuric and phenaceturic acids, whose formation requires glycine.
Carbohydrate metabolism. The liver maintains the blood sugar concentration at a level sufficient to continuously provide all the tissues with glucose. This is done by regulating the interaction between the synthesis and breakdown of glycogen, which is stored in the liver. On the average, the human liver contains 30 to 100 g of glycogen, an amount sufficient to serve as a reservoir for regulating blood sugar levels. When sugar is absorbed from the intestine, the level of glucose in the portal vein blood may rise to 400 mg percent, while the level in the peripheral blood does not exceed 200 mg percent. Glucose is converted to glycogen and stored in the liver, or it is used to obtain energy. The excess ingested glucose that can remain after glycogen and other syntheses is converted to fat. Under conditions of starvation, the liver keeps the blood sugar level constant chiefly by splitting glycogen; if this is not sufficient, an additional mechanism is glyconeogenesis—conversion of amino acids and glycerin into sugar.
Insulin, which is formed by the beta cells of the islands of Langerhans in the pancreas, acts on the liver by influencing blood sugar levels and the formation and breakdown of glycogen. Under the influence of phosphorylase, the end glucose residues of the glycogen molecule are split off to form glucose-1-phosphate, which takes part in the formation of uridine diphosphate glucose, the transport form of glucose and the main form from which glucose undergoes glycogen synthesis. Interference with the enzymatic conversion of galactose-1-phosphate to glucose-1-phosphate results in the severe pathological phenomena associated with the hereditary disease galactosemia.
The usual pathway for the conversion of glucose-1-phosphate to glucose-6-phosphate is of great biological significance, since glucose-1-phosphate plays a central role in the conversion of carbohydrates and in the regulation of carbohydrate metabolism. Glucose-6-phosphate markedly inhibits the phosphorolative splitting of glycogen in the liver, stimulates the enzymatic transport of glucose from uridine phosphoglucose to the glycogen molecule that is being formed, and is the substrate for the oxidative conversion of glucose by the pentose phosphate pathway.
A reduced form of nicotinamide-adenine dinucleotide phosphate (NADP) is created during the oxidation of glucose-6-phosphate. NADP is an essential coenzyme in the reductive syntheses of fatty acids and cholesterol and in the conversion of glucose-6-phosphate to pentose phosphates; it is also an essential component in the formation of nucleotides and nucleic acids. Glucose-6-phosphate can undergo further glycolytic conversions on a pathway that leads through fructose-6-phosphate and fruc-tose-6-diphosphate to the triose phosphates and pyruvic and lactic acids. This further conversion provides the body with biosynthetically needed compounds and plays an important role in energy metabolism, since the formation of each lactic acid molecule is energetically equivalent to the formation of one high-energy phosphate bond in the ATP molecule. Finally, the splitting of glucose-6-phosphate by phosphatase ensures the entry into the blood of free glucose, which can then be supplied to all the organs and tissues.
Fat metabolism. The liver is able to store a significantly larger amount of lipids than glycogen; about 20–30 percent of the liver’s dry weight is lipids. The composition of phosphatides and cholesterol, which constitute 10–15 percent of all lipids, is fairly constant, while that of neutral fats varies. Fat is stored in fatty tissue and not in the liver. On the whole, the liver does not play as vital a role in lipid metabolism as it does in carbohydrate and protein metabolism. The splitting of fatty acids is not confined to the liver alone. The degradation of fat and the oxidation of fatty acids take place in the liver, which also contains the enzyme systems for the biosynthesis of high-molecular fatty acids, neutral fats, and complex lipids. The intermediate product of these syntheses is phosphatate.
Cholesterol is also synthesized in the liver. The fatty acids that are formed during fat degradation are oxidized to form acetyl coenzyme A, which reacts in the presence of a condensing enzyme with oxalacetic acid, to form citric acid, the main substrate of the oxidative conversions in the tricarboxylic acid cycle. In hepatic cells, as in the cells of other organs, oxidative conversions are concentrated chiefly in the mitochondria; they are associated with the formation of high-energy coumpounds, such as ATP, and their end products are CO2 and H2O. The synthesis of macromolecular fatty acids occurs outside the mitochondria in the cytosol and is therefore physically separated from the site of macromolecular fatty acid oxidation. The second NADP-dependent system for the oxidation of hydrocarbons, steroids, and cholesterol is nonmitochondrial and is concentrated in the microsomal fraction of the liver. This system is found exclusively in the endoplasmatic reticulum and carries out hydroxylation reactions.
Pigment metabolism. The liver is the degradation site for hemoglobin and the synthesis site for bilirubin, which is subsequently converted to a soluble form, diglucuronide bilirubin. Pigment metabolism in the liver is closely related to bilirubin and porphyrin metabolism and plays an important role in iron metabolism.
Mineral metabolism. The liver is directly involved in mineral metabolism and in the maintenance of pH. Mineral components, including Mg, Mn, Fe, Cu, and Zn, are found in the liver both in free form and as part of such complex organic compounds as enzymes. The cations of these components, for example, Na+, Ca2+, K+, Ni2+, Co2+, and Cr3+, function as activators of enzymes. The ferroprotein ferritin and the copper-containing protein hepatocuprein are also present in the liver, where they participate in hematopoiesis.
Vitamin metabolism. The liver is also involved in vitamin metabolism. It contains the B-complex vitamins, the D-complex vitamins, vitamin C, and the fat-soluble vitamins E and K. Vitamin A is formed from carotenoids in the liver, where it is also stored; it is absorbed from the intestine only in the presence of bile. Ascorbic acid promotes glycogenesis, and vitamin K is essential for prothrombin synthesis.
Bile formation and the metabolic processes in the liver are regulated by neural and hormonal mechanisms. The regulatory hormones are epinephrine, insulin, glucagon, corticosteroids, pituitary hormones, and intestinal hormones, especially secretin, cholecystokinin, and pancreozymin. The activity of many hormones in the liver is dependent on the cyclic mononucleotides —cyclic adenosine monophosphate (cAMP) and cyclic guano-sine monophosphate (cGMP). These are formed by splitting the nucleoside triphosphates ATP and GTP, a reaction that is catalyzed by cyclase, an enzyme which is mainly found in the plasma membrane. The cyclic mononucleotides function as regulators of many enzymes by activating protein kinases, which transfer a phosphate group from ATP to other enzymes. Phosphorylation intensifies the activity of phosphorylases and lipases and suppresses the activity of glycogen synthetase and pyruvate decarboxylase.
The biochemical processes that occur in the liver influence the central nervous system through interoceptors. The variety and interdependence of the factors that affect hepatic cells account for both the intensity and directivity of the metabolic processes within the liver.
Diseases. In man and animals the hepatic parenchyma, or cells, and the interstitial tissue of the liver are most susceptible to disease. Acute hepatitides, which may cause chronic lesions, constitute a substantial part of all liver diseases. Among infectious hepatitides, a distinction is made between a primary hepatitis, for example, viral hepatitis, and a secondary one, as arises with brucellosis, leptospirosis, and syphilis. Toxipathic hepatitides develop after direct exposure of the liver to chemicals, including medicines. Cirrhosis may be an outcome of hepatitis. Degenerative changes of the liver arise from many types of nutritional and metabolic disorders, including alcoholism, vitamin deficiency, pathological starvation, diabetes mellitus, hepatocerebral dystrophy, and obesity. Circulatory disturbances also cause degenerative changes, especially when accompanied by high pressure in the vena cava inferior and in the hepatic veins. The human and animal liver may be the habitat of many parasites: protozoans, worms, and, less commonly, arthropods. Giard lamblia and leishmania may penetrate from the intestine into the biliary tract. The extraerythrocytic development of the causative agent of malaria occurs in the human liver, which is also the site for the development of the causative agent of echinococcosis. The hepatic ducts and the gallbladder can be infected by a variety of trematodes that cause cholangitis and cholecystitis. Finally, the liver is susceptible to such neoplasms as carcinoma and sarcoma.
REFERENCESDogel’, V. A. Sravnitel’naia amtomiia bespozvonochnykh, part 1. Leningrad, 1938.
Shmal’gauzen, I. I. Osnovy sravnitel’noi anatomii pozvonochnykh zhivotnykh, 4th ed. Moscow, 1947.
Pavlov, I. P. “Lektsii po fiziologii.” Poln. sobr. soch., 2nd ed., vol. 5. Moscow-Leningrad, 1952.
Fischer A. Fiziologiia i eksperimental’naia patologiia pecheni. Budapest, • 1961. (Translated from English.)
Rapoport, S. M. Meditsinskaia biokhimiia. Moscow, 1966. (Translated from German.)
Vvedenie v klinicheskuiu biokhimiiu (osnovy patobiokhimii). Leningrad, 1969.
Bondar’, Z. A. Klinicheskaia gepatologiia. Moscow, 1970.
Blūger, A. F., and A. B. Rajcis. “Serotonin i pechen’.” Uspekhi gepatologii, fasc. 3. Riga, 1971.
Zbarskii, B. I., I. I. Ivanov, and S. R. Mardashev. Biologicheskaia khimiia, 5th ed. Leningrad, 1972.
S. E. SEVERIN, A. N. DRUZHININ, and A. A. GLADYSHEVA
What does it mean when you dream about a liver?
Dreaming about liver can be a dream about one’s health: either we need a diet change or perhaps we are hurting our liver with alcohol or prescription drugs. Also note the expression “lily-livered,” which refers to cowardice.