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LIVER AND ZHELCHEVYDELITELNY SYSTEM EMBRYONIC DEVELOPMENT OF STRUCTURE AND FUNCTION OF THE LIVER
Anatomic and cellular morphogenesis. The knowledge of embryology and anatomy of a liver and bilious ways allows to understand physiology and a pathophysiology of this body, and also the inborn damages to bilious channels caused by disturbances of an organogenesis.
The liver, bilious channels and gall bladder come from group of the cells forming a ventral bag in primary front gut. On 18 — the 22nd day of pre-natal development this bag is divided into 2 rudiments (fig. 12-20, an embryo 3 mm long): solid cranial from which the liver, and hollow caudal from which form a gall bladder, vesical and the general bilious channels forms.
Epithelial tyazh and tubules from a cranial rudiment contact to blood vessels in an adjacent mesenchymal cross partition (fig. 12-20, an embryo 5 mm long). The network of primitive hepatocytes, sinusoid and mesenchymal partitions already on 5 — the 6th week of pre-natal development forms the structure corresponding to very tectonics of a segment of a mature liver (fig. 12-20, an embryo 7 mm long). Holangiola are formed of vesicles which appear in hepatocytes around the smallest branches of a portal vein. Tubules — special sites of a surface of hepatic cells on which bile cosecretes appear in the form of small vesicles between hepatocytes on the 6th week of development.
The gall bladder and the general bilious channel form from a caudal rudiment of a hepatic bag. Puzyrny Canal is formed on the 4th week (fig. 12-20, an embryo 12 mm long). In the beginning a gall bladder and hepatic channels hollow, but then the proliferating epithelial vystilka closes a gleam. This epithelium is exposed to vacuolation on the 7th week owing to what there is a rekanalization of the general bilious channel, and then vesical which extends in the distal direction, finally forming a gall bladder.
Fig. 12-20. Stages of embryonic development of a liver, bilious channels and gall bladder. (With the permission of Dr. N. Linder.)
Fig. 12-21. Structure of system of vnutripecheiochny bilious channels.
In completely created organism the hepatic end of biliary system is provided by intercellular tubules. They open in bilious ductules. The interlobular bilious channels going parallel to terminal branches of a portal vein (fig. 12-21) are formed of the last. Interlobular channels merge in the courses of the bigger size which in portal fissures depart from a portal vein and proceed in the extrahepatic bilious courses. The right and left lobar channels go out of a liver; they are called hepatic channels, at their merge the general hepatic channel lying kpered from a portal vein is formed. The last unites to a vesical channel, forming the general bilious channel. It goes distally on the right edge of an omentulum, coming to an end in the field of an intramural big duodenal (faterov) nipple on the left wall of a duodenum. Here the general bilious channel integrates with the main pancreatic channel, creating a hepatopancreatic (faterova) ampoule. Oddi's sphincter covers intra duodenal part of the general bilious canal, pancreatic channel (at 80% of people) and an ampoule. This sphincter consisting of smooth muscle fibers regulates intake of bile in intestines, interferes with throwing of bile to the pancreatic canal and intestinal contents to canals.
Division of a liver into shares happens at early stages of pre-natal development when bilious channels and branches of a hepatic artery and a portal vein going with them begin to branch. The hepatic tyazh formed by ranks of hepatocytes and divided into sinusoids converge with branches of the hepatic vein located in the center of a segment; bile through tubules and holangiola comes to interlobular canals. The products cosecreted by a liver, such as proteins of plasma, are transported from afferent vessels (a portal vein and a hepatic artery) through sinusoids in the general system of circulation (the central vein). Components of bile move on system of the extending channels from tubules to the general bilious channel and stream in intestines.
Functional development. A mature liver — the main body maintaining constancy of internal environment of an organism. The liver absorbs the soaked-up nutrients and turns them into the components participating in metabolic processes, or into the end not used products; the first come to blood or bile, and the last — only to bile. This function is provided that hepatocytes are located ranks between which there are channels with the blood and bile circulating in them, and the directions of the movement of these liquids are perpendicular each other.
The maternal liver through a placenta provides a fruit with energy and nutrients, it removes slags. Processes of a glycogenolysis, formation of bile acids and elimination of slags in a liver of a fruit proceed rather poorly. The main function of a liver during the pre-natal period consists in formation of proteins of plasma according to requirements of the developing vascular system and quickly proliferating fabrics. Later the liver synthesizes and accumulates irreplaceable nutrients which are necessary during the early post-natal period. Till the birth portal circulation goes, passing a liver, via the shunt (a venous channel). After the birth nutrients from intestines come to portal system; venous the channel is closed, and nutrients are delivered to a hepatic parenchyma where they stimulate synthesis of bile acids and reaction of biotransformation in microsomes, and also strengthen bile outflow.
Regulation of power processes. The liver of a fruit accumulates a glycogen — the polymer of the carbohydrate nature which is easily breaking up to monomeric glucose. The newborn's life completely depends on glycogen stocks in a liver as it provides an organism with glucose which intake suddenly stops at the time of the birth. The liver begins to synthesize a glycogen on the 9th week, however its fast accumulation happens only before childbirth and reaches 20 mg/g of a liver a day. By the time of the birth the liver of a fruit contains 2 — 3 times more glycogen, than the adult's liver. About 90% of the saved-up glycogen are spent in the first 2 — 3 h after the birth when placental blood supply suddenly stops. Other glycogen is gradually spent during the subsequent 48 h, and its accumulation begins only on the 2nd week of post-natal life again. Concentration it reaches the level inherent to an adult organism, on the 3rd week at the child who was born in time (on condition of normal food). The liver of a fruit begins to accumulate also fat at early stages of development, and this process considerably accelerates before the birth. The saved-up fat gradually is spent in the first days of life.
Protein synthesis. A liver — the main source of the proteins coming to blood, including proteins of plasma, enzymes and blood-coagulation factors. In an organism of a fruit of squirrels goes for forming of fabrics and plasma; besides, rapid growth of a liver before the birth demands that processes of formation of nuclear and cytoplasmatic structures of a cell proceeded with the maximum intensity. Albumine is present at plasma at the 8th week of pre-natal development, by the time of the birth its concentration increases from 20 g/l almost up to the level characteristic of adults while the level of the alpha globulins containing alpha-fetoprotein considerably decreases. In liver cuts 3-4 monthly fruits of amino acid join in all fractions of serum proteins, and also in fibrinogen, transferrin and lipoproteins of low density. Since 11th week plasma of a fruit contains all main proteins, but their concentration is much lower, than in an adult organism (in particular, it concerns ceruloplasmin, lipoproteins of low density and a gaptoglobin). At mammals the fruit liver, as well as a mature liver, is capable to synthesize additional proteins-reaktanty in response to stressful influences.
In post-natal life the content of one proteins reaches the level characteristic of adults, during several dyy, and others — during 1 — 2 flying. In the first 3 — 4 days after the birth concentration of lipoproteins of all types increases up to sizes which then do not change up to the period of prlovy maturing. At the same time the level of albumine increases gradually, within several months. The amount of ceruloplasmin and factors of a complement increases slowly, from very low level to almost adult, within the first year of life. Contrary to it the content of transferrin in blood by the time of the birth corresponds to its level at adults; in the next 3 — 5 months it decreases and only then again begins to increase up to initial level.
Biotransformation and allocation of metabolites. Monooksigenazny system. The oxidizing, recovery, hydrolytic reactions and conjugation tests participating in biotransformation happen in microsomes, i.e. in the smooth endoplasmic reticulum (SER) of hepatocytes. Though the maintenance of GER in a liver of the newborn is very small, and activity of microsomal enzymes is not defined at all or is extremely low, the main substrates which are carrying out transfer of electrons and entering into monooksigenazny system (R-450 cytochrome, cytochrome b, cytochrome with reductase, NADF-tsitokhry R-450 reductase), are found in microsomal fraction on the 7th week of pre-natal development. Activity of R-450 cytochrome and NADF-tsitokhr from reductase at a fruit makes 25 and 50% of activity at adults respectively. Definition in urine of metabolites of widely applied medicinal substances (diazepam, caffeine, phenobarbital, diphenylhydantoin) shows that ability to oxidation of these substances at the children who were born in time is very low and is practically absent at premature. Similarly an elimination half-life of drugs (the process catalyzed by the monooksigenazny system dependent on R-450 cytochrome) at children of chest age much more, than at adults; in particular, an elimination half-life of Tolbutamidum, diphenylhydantoin and an amobarbital at children in 2 — 5 times more, than at their mothers.
Monooksigenazny activity of a liver of a fruit allows to turn drugs into potentially dangerous metabolites already in the first trimester; it is possible that the medicine taken by mother at early stages of pregnancy influences development of a liver and other bodies. On the other hand, relative inefficiency of reactions of biotransformation at the birth can lead to the fact that the drugs appointed to the newborn will work excessively strongly or too long. Maturing of monooksigenazny system after the birth happens quickly enough.
Conjugation tests. Conjugation tests turn metabolites or end products into substances which can eliminirovatsya with bile; these reactions are catalyzed by microsomal enzymes of a liver. The fetalis liver is almost completely deprived of the glyukuroniltransferazny activity responsible for transformation of toxic free bilirubin into the excreted connected bilirubin. The amount of transferase after the birth increases, but nevertheless an opportunity to conjugate bilirubin during this period is very limited. The mechanisms inducing bilirubin conjugation are studied insufficiently fully. In the first week after the birth the tranzitorny hyperbilirubinemia, mainly owing to relative insufficiency of a glyukuroniltransferaza is observed. In the blood taken from an umbilical cord there is no connected bilirubin. Monoconjugates of bilirubin appear in the first 24 — 48 h in a certain sequence, and the dekonjyugirovaniye occurs for the 3rd day. Unlike umbilical blood of healthy newborns umbilical blood of children with a prenatal hyperbilirubinemia owing to group incompatibility contains both mono - and bilirubin diglucuronides. Thus, activity of a glyukuroniltransferaza can be induced during the pre-natal period if concentration of bilirubin in fruit blood a long time is increased.
Activity of a microsomal glyukuroniltransferaza concerning bilirubin and other substrates can be stimulated with such drugs as barbiturates which also induce production of R-450 cytochrome and other components of monooksigenazny system. The mechanism of action of such drugs on activity of microsomal enzymes consists in change of properties of membranes on which these enzymes are localized.
Metabolism of bile acids. Bile acids belong to steroids; they facilitate process of education in the water environment of the mixed micelles containing cholesterol and phospholipids. The hydrophobic core and hydrophilic outside part of a micelle provide dissolution and absorption in intestines of such hydrophobic substances as lipids, fatty acids and fat-soluble vitamins. Two primary bile acids, cholic and chenodesoxycholic, are synthesized in a liver, conjugated with amino acids glycine and tuariny, and then excreted with bile. Conjugation of bile acids influences their absorption in a jejunum thanks to what their concentration in upper part of a small bowel is maintained above the critical level necessary for formation of micelles. After absorption of food fats the conjugated bile acids reabsorbirutsya in terminal part of an ileal gut, get back into a liver and reekskretirutsya with bile. Such enterohepatic circulation happens after each meal, at the same time 90 — 95% of the bile acids which are emitted during each cycle reabsorbirutsya.
Those bile acids which were not soaked up in an ileal gut are exposed to dehydroxylation under the influence of colibacilli, at the same time secondary bile acids are formed. Cholic acid turns in dezoksikhoyevy, and chenodesoxycholic — in lithocholic. Content of various acids in normal bile approximately following: horevy — 50%, chenodesoxycholic — 30%, deoxycholic — 15% / and lithocholic — 5%. At mammals newborns differ in relative insufficiency of processes of education, an intestinal reabsorption and excretion of bile acids. As at newborns concentration of bile acids in intestines it is frequent below, than it is required for formation of micelles (1 — 2 mmol), food fats are soaked up not completely. The liver of a fruit develops a significant amount 31-gidroksi-D5-holenoyevoy acids that can become the cholestasia reason. In the course of pre-natal development concentration of this bile acid gradually falls.
At the newborn products of bile acids are approximately twice lower, than at the adult, and respectively below their concentration in intestines. As a result big loss of bile acids with a stake is followed by their insufficient reabsorption in intestines. At premature children concentration of bile acids in intestines is much lower than the critical level necessary for formation of micelles.
Inferiority of kishechnopechenochny circulation is confirmed by test with food loading (concentration of the conjugated cholic acid in plasma remains high during 2 h after food).
Inferiority of processes of education and circulation of bile at newborns is shown by considerable losses of bile acids with a stake, malabsorption of food fats and fat-soluble substances, and also tendency to a cholestasia.