Liver

The liver consists of two lobes: right and left. In the right lobe there are two more secondary lobes: square and caudate. According to the modern segmental scheme proposed by Claude Quino (1957), the liver is divided into eight segments , forming the right and left lobes. The liver segment is a pyramidal segment of the hepatic parenchyma, which has a sufficiently isolated blood supply , innervation and outflow of bile . Tailed and square lobes, located behind and in front of the gates of the liver, according to this scheme correspond to S _I and S _{IV of the} left lobe. In addition, S _II and S _{III of the} liver are isolated in the left lobe, the right lobe is divided into S _V - S _VIII , numbered around the gate of the liver clockwise.

Histological structure of the liver

Parenchyma - lobed. The hepatic lobule is a structural and functional unit of the liver. The main structural components of the hepatic lobule are:

• hepatic plates (radial rows of hepatocytes );
• intralobular sinusoidal hemocapillaries (between the hepatic beams);
• bile capillaries ( lat. ductuli beliferi ) inside the hepatic beams, between two layers of hepatocytes; (expansion of the bile capillaries when they exit the lobules);
• Disse perisinusoid space (slit-like space between the hepatic beams and sinusoidal hemocapillaries);
• central vein (formed by fusion of intralobular sinusoidal hemocapillaries).

The stroma consists of the outer connective tissue capsule, interlobular interlayers RVST (loose fibrous connective tissue), blood vessels, nervous system.

• neutralization of various foreign substances ( xenobiotics ), in particular, allergens , poisons and toxins , by transforming them into harmless, less toxic or easier to remove compounds from the body; detoxification of the liver of the fetus is negligible, since it is performed by the placenta ;
• neutralization and removal from the body of excess hormones , mediators , vitamins , as well as toxic intermediate and end products of metabolism, for example, ammonia , phenol , ethanol , acetone and ketonic acids;
• providing the body's energy needs with glucose and converting various energy sources (free fatty acids, amino acids , glycerol , lactic acid , etc.) into glucose (the so-called gluconeogenesis );
• replenishment and storage of rapidly mobilized energy reserves in the form of glycogen and regulation of carbohydrate metabolism ;
• replenishment and storage of some vitamins depot (especially rich in liver stocks of fat-soluble vitamins A, D, water-soluble vitamin B ₁₂ ), as well as depot cations of a number of microelements - metals , in particular, iron , copper and cobalt cations. Also, the liver is directly involved in the metabolism of vitamins A, B, C, D, E, K, PP and folic acid;
• participation in blood formation processes (only in the fetus), in particular, the synthesis of many plasma proteins - albumin , alpha and beta globulins , transport proteins for various hormones and vitamins, blood coagulation and anticoagulant systems, and many others; the liver is one of the important organs of hemopoiesis in prenatal development;
• synthesis of cholesterol and its esters, lipids and phospholipids , lipoproteins and regulation of lipid metabolism;
• synthesis of bile acids and bilirubin , production and secretion of bile ;
• it also serves as a depot for a fairly significant amount of blood, which can be thrown into the general bloodstream in case of blood loss or shock due to narrowing of the vessels supplying the liver;
• hormone synthesis (for example, insulin-like growth factors).

The characteristics of the blood supply to the liver reflect its important biological detoxification function: blood from the intestines containing toxic substances consumed from the outside, as well as the metabolic products of microorganisms ( skatole , indole , etc.) are delivered to the liver via the portal vein (v. Portae). Next, the portal vein is divided into smaller interlobular veins. Arterial blood enters the liver through its own hepatic artery (a. Hepatica propria), branching to the interlobular arteries. The interlobular arteries and veins emit blood into the sinusoids, where, therefore, mixed blood flows, the drainage of which occurs in the central vein. The central veins are collected in the hepatic veins and further into the inferior vena cava. In embryogenesis to the liver approaches the so-called. Arancia duct carrying blood to the liver for effective prenatal hematopoiesis.

Neutralization of substances in the liver lies in their chemical modification, which usually involves two phases. In the first phase, the substance undergoes oxidation (detachment of electrons), reduction (attachment of electrons), or hydrolysis. In the second phase, a substance is added to the newly formed active chemical groups. Such reactions are called conjugation reactions, and the addition process is called conjugation. Also, when toxic substances enter the liver, the area of ​​agranular EPS in the cells of the latter increases, which allows them to be neutralized.

Liver cirrhosis is a chronic progressive liver disease characterized by a violation of its lobular structure due to the growth of connective tissue and the pathological regeneration of the parenchyma ; manifested by functional liver failure and portal hypertension.

The most common causes of the disease are chronic alcoholism (the proportion of alcoholic cirrhosis in different countries ranges from 20 to 95%), viral hepatitis (10-40% of all cirrhosis of the liver), the presence of helminths in the liver (most often opistorhis, fasciola, clonorchis , toksokara, notokotilus), as well as the simplest, including Trichomonas .

Liver cancer is a serious illness. Among the tumors that affect humans, this disease is in seventh place. Most researchers identify a number of factors that are associated with an increased risk of liver cancer. These include: cirrhosis of the liver, viral hepatitis B and C, parasitic liver invasions, alcohol abuse, contact with certain carcinogens (mycotoxins) and others.

The emergence of benign adenomas, liver angiosarcomas, and hepatocellular carcinomas are associated with human exposure to androgenic steroid contraceptive and anabolic drugs.

Main symptoms of liver cancer:

• weakness and decreased performance;
• weight loss, weight loss, and then severe cachexia , anorexia .
• nausea, vomiting, earthy skin color and spider veins;
• complaints of a feeling of heaviness and pressure, dull pains;
• fever and tachycardia ;
• jaundice, ascites and abdominal surface veins;
• gastroesophageal bleeding from varicose veins;
• pruritus;
• gynecomastia;
• flatulence, intestinal dysfunction.

Aflatoxicosis

Aflatoxicosis - acute or chronic intoxication with aflatoxins , the strongest hepatotoxins and hepatocarcinogens , arises exclusively by alimentary means , that is, through food. Aflatoxins are secondary metabolites that produce microscopic mold fungi of the genus Aspergillus , in particular Aspergillus flavus and Aspergillus parasiticus .

Aspergillus affects almost all food products, but the basis consists of plant products made from grains, legumes and oilseeds such as peanuts , rice , corn , peas , sunflower seeds , etc. With a single use of contaminated (contaminated) foods with aspergillus, acute aflatoxosis - the strongest intoxication, accompanied by acute toxic hepatitis . With a sufficiently long use of contaminated foods, chronic aflatoxosis develops, in which hepatocellular carcinoma develops in almost 100% of cases.

Hemangiomas of the liver are abnormalities in the development of liver vessels.
The main symptoms of hemangioma :

• heaviness and feeling of spreading in the right hypochondrium;
• gastrointestinal dysfunctions (loss of appetite, nausea, heartburn, belching, flatulence).

Nonparasitic liver cysts. Complaints in patients appear when the cyst reaches a large size, causes atrophic changes in the liver tissue, squeezes the anatomical structures, but they are not specific.
Main symptoms:

• constant pain in the right hypochondrium;
• fast-on satiety and abdominal discomfort after eating;
• weakness;
• excessive sweating;
• loss of appetite, nausea at times;
• shortness of breath, dyspeptic symptoms;
• jaundice.

Parasitic cysts of the liver. Hydatid echinococcosis of the liver is a parasitic disease caused by the introduction and development of Echinococcus granulosus larvae in the liver. The appearance of various symptoms of the disease may occur several years after infection with a parasite.
Main symptoms:

• soreness;
• feeling of heaviness, pressure in the right hypochondrium, sometimes in the chest;
• weakness, malaise, shortness of breath;
• recurring urticaria, diarrhea, nausea, vomiting.

Other liver infections : clonorchosis , opisthorchiasis , fascioliasis .

The liver is one of the few organs that can restore its original size, even if only 25% of its normal tissue remains. In fact, regeneration occurs, but very slowly, and the rapid return of the liver to its original size is more likely due to an increase in the volume of the remaining cells. ^[one]

Four types of stem / progenitor cells of the liver — so-called oval cells, small hepatocytes, epithelial cells of the liver, and mesenchymal-like cells are found in the mature liver of humans and other mammals.

Oval cells in the rat liver were discovered in the mid-1980s. ^[2] The origin of oval cells is unclear. They may come from bone marrow cell populations ^[3] , but this fact is being questioned. ^[4] Mass production of oval cells occurs with various lesions of the liver. For example, a significant increase in the number of oval cells was observed in patients with chronic hepatitis C , hemochromatosis , and alcohol poisoning of the liver and directly correlated with the severity of liver damage. ^[5] In adult rodents, oval cells are activated for reproduction in the case when replication of the hepatocytes themselves is blocked. The ability of oval cells to differentiate into hepatocytes and cholangiocytes (bipotential differentiation) has been shown in several studies. ^[3] It is also shown the ability to maintain the reproduction of these cells in vitro. ^[3] Recently, oval cells have been isolated from the liver of adult mice, capable of bipotential differentiation and clonal expansion in vitro and in vivo. ^[6] These cells expressed cytokeratin-19 and other surface markers of liver precursor cells and, when transplanted into an immunodeficient strain of mice, induced regeneration of the organ.

Small hepatocytes were first described and isolated by Mitaka et al. ^[7] from the non-parenchymal fraction of rat liver in 1995. Small hepatocytes from the liver of rats with artificial (chemically induced) damage to the liver or with partial removal of the liver (hepatotectomy) can be isolated by differential centrifugation. ^[8] These cells are smaller than normal hepatocytes, can multiply and transform into mature hepatocytes in vitro. ^[9] It has been shown that small hepatocytes express typical markers of hepatic progenitor cells - alpha-fetoprotein and cytokeratins (CK7, CK8 and CK18), which indicates their theoretical ability to bipotential differentiation. ^{[10] The} regenerative potential of small rat hepatocytes was tested in animal models with artificially induced liver damage: the introduction of these cells into the portal vein of animals caused induction of repair in various parts of the liver with the appearance of mature hepatocytes. ^[eleven]

A population of liver epithelial cells was first found in adult rats in 1984 ^[12] These cells have a repertoire of surface markers that overlap, but still differ from the phenotype of hepatocytes and ductal cells. ^[13] Transplantation of epithelial cells into rat liver led to the formation of hepatocytes expressing typical hepatocyte markers - albumin, alpha-1-antitrypsin, tyrosine transaminase and transferrin. Recently, this population of progenitor cells was also found in an adult. ^[14] Epithelial cells are phenotypically different from oval cells and can differentiate in vitro into hepatocyte-like cells. Experiments on the transplantation of epithelial cells into the liver of SCID mice (with congenital immunodeficiency) showed the ability of these cells to differentiate into hepatocytes expressing albumin one month after transplantation. ^[14]

Mesenchymal cells were also obtained from a mature human liver. ^[15] Like mesenchymal stem cells (MSCs), these cells have high proliferative potential. Along with mesenchymal markers (vimentin, smooth muscle alpha actin) and stem cell markers (Thy-1, CD34), these cells express hepatocyte markers (albumin, CYP3A4, glutathione transferase, CK18) and ductal markers (CK19). ^[16] Once transplanted into the liver of immunodeficient mice, they form mesenchymal functional islets of human liver tissue, producing human albumin, prealbumin and alpha-fetoprotein. ^[17]

Further research is needed on the properties, culture conditions, and specific markers of the precursor cells of the mature liver to evaluate their regenerative potential and clinical use.

Recently, biologically active substances have been discovered that contribute to the regeneration of the liver in injuries and toxic injuries. There are various approaches to stimulating the regeneration of the liver in its injuries or massive resections. Attempts have been made to stimulate regeneration through the introduction of amino acids, tissue hydrolysates, vitamins, hormones, growth factors ^[18] , such as, for example, hepatocyte growth factor (HGF), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), as well as stimulating substance from the liver (hepatic stimulator substance, HSS). ^{[19] [20]}

Liver stimulant

A liver stimulating substance ( hepatic stimulator substance, HSS ) is an extract obtained from the liver after 30% of its resection. The substance, known as the hepatic stimulator substance (HSS), was first described in the mid-1970s. ALR ( augmenter of liver regeneration , a product of the gene ) discovered in 1980–1990 is considered the main active ingredient in HSS. In addition to ALR, tumor necrosis factor , insulin-like growth factor 1 , hepatocyte growth factor, epidermal growth factor and other already known and possibly not yet identified humoral factors contained in such preparations may also affect liver regeneration. ^[21] There are various ways of obtaining HSS ^[22] , differing in the options for purification of extracts of regenerating liver of animals.

The first liver transplant in the world was performed by an American transplantologist Thomas Starls in 1963 in Dallas. ^[23] Later, Starls organized the first transplant center in the world in Pittsburgh (USA), which now bears his name. By the end of the 1980s, over 500 liver transplants were performed in Pittsburgh under the direction of T. Starsla. The first in Europe (and the second in the world) medical center for liver transplantation was established in 1967 in Cambridge (UK). He was headed by Roy Caln. ^[24]

With the improvement of surgical transplantation methods, the opening of new transplant centers and conditions for the storage and transportation of transplanted liver, the number of liver transplants has steadily increased. If in 1997 in the world, up to 8,000 liver transplants were performed annually, now this number has risen to 11,000, with the United States accounting for more than 6,000 transplants and up to 4,000 - for Western European countries. Among European countries, Germany, Great Britain, France, Spain and Italy play a leading role in liver transplantation. ^[25]

Currently, 106 liver transplant centers operate in the United States ^[26] . In Europe, 141 centers were organized, including 27 in France, 25 in Spain, 22 in Germany and Italy, and 7 in the UK ^[27] .

Despite the fact that the first experimental liver transplantation in the world was performed in the Soviet Union by V. P. Demikhov, the founder of world transplantology in 1948 ^[28] , this operation was introduced into clinical practice in the country only in 1990. In 1990 in the USSR, no more than 70 liver transplants were performed. Now in Russia, regular liver transplants are performed in four medical centers, including three in Moscow (Moscow’s Liver Transplant Center, Scientific Research Institute of Emergency Care named after N. V. Sklifosovsky, Scientific Research Institute of Transplantology and artificial organs named after Academician V. I. Shumakov, Russian Scientific Center for Surgery Academician B. V. Petrovsky) and the Central Research Institute of Roszdrav in St. Petersburg. Recently, a liver transplant was started in Yekaterinburg (Regional Clinical Hospital No. 1), Nizhny Novgorod, Belgorod and Samara. ^[29]

Despite the constant increase in the number of liver transplants, the annual need for transplantation of this vital organ is satisfied on average by 50%. The frequency of liver transplants in leading countries ranges from 7.1 to 18.2 operations per 1 million population. The true need for such operations is now estimated at 50 per 1 million population. ^[25]

The first human liver transplants did not bring much success, as the recipients usually died within the first year after the operation due to transplant rejection and the development of severe complications. The use of new surgical techniques (cavalial shunting and others) and the emergence of a new immunosuppressant, cyclosporin A, have contributed to an exponential increase in the number of liver transplants. Cyclosporin A was first successfully used for liver transplantation by T. Starszl in 1980 ^[30] , and its widespread clinical use was permitted in 1983. Thanks to various innovations, the postoperative lifespan was significantly increased. According to the Unified Organ Transplant System (UNOS - United Network for Organ Sharing), modern survival of patients with a transplanted liver is 85–90% a year after surgery and 75–85% five years later. ^[31] According to forecasts, 58% of recipients have a chance to live up to 15 years. ^[32]

Liver transplantation is the only radical method of treating patients with irreversible, progressive liver damage, when there are no other alternative therapies. The main indication for liver transplantation is the presence of chronic diffuse liver disease with a life expectancy of less than 12 months, subject to the ineffectiveness of conservative therapy and palliative surgical treatment methods. The most common cause of liver transplantation is liver cirrhosis caused by chronic alcoholism, viral hepatitis C and autoimmune hepatitis (primary biliary cirrhosis). Less common indications for transplantation include irreversible liver damage due to viral hepatitis B and D, drug and toxic poisoning, secondary biliary cirrhosis, congenital liver fibrosis, cystic liver fibrosis, and inherited metabolic diseases (Wilson-Konovalov disease, Reye's syndrome, alpha-1 deficiency antitrypsin, tyrosinemia, type 1 and type 4 glycogenoses, Neumann-Pick disease, Crigler-Nayar syndrome, familial hypercholesterolemia, etc.). ^[33]

A liver transplant is a very expensive medical procedure. According to UNOS, the necessary costs for inpatient care and preparation of the patient for the operation, payment for medical staff, removal and transportation of donor liver, carrying out the operation and post-operative procedures for the first year amount to $ 314,600, and for follow-up and therapy up to $ 21,900 per year . ^[34] For comparison, in the US, the cost of similar costs for a single heart transplant in 2007 was $ 65,8,800, a lung cost was $ 399,000, and a kidney cost was $ 246,000. ^[35]

Thus, the chronic shortage of donor organs available for transplantation, the operation waiting time (in the USA, the waiting period in 2006 was an average of 321 days ^[36] ), the urgency of the operation (the donor liver must be transplanted within 12 hours) and an exceptional high cost Traditional liver transplants create the necessary prerequisites for finding alternative, more economical and effective liver transplant strategies.

Currently, the most promising method of liver transplantation is liver transplantation from a living donor (TPR) . It is more efficient, simpler, safer, and much cheaper than the classic transplantation of a cadaveric liver, both whole and split. The essence of the method is that the donor is removed, today often and endoscopically, that is, low-impact, the left lobe (2, 3, sometimes 4 segments) of the liver. TPRW has given a very important opportunity for kinship donation - when the donor is a relative of the recipient, which greatly simplifies both administrative problems and the selection of tissue compatibility. At the same time, thanks to a powerful regeneration system, in 4-6 months the donor’s liver completely restores its mass. The donor liver lobe is transplanted to the recipient either orthotopically, with the removal of its own liver, or, more rarely, heterotopically, leaving the liver of the recipient. At the same time, naturally, the donor organ is practically not subjected to hypoxia, since the operations of the donor and recipient go in the same operating room and at the same time.

A bioengineering liver, similar in structure and properties to a natural organ, has yet to be created, but active work in this direction is already underway.

For example, in October 2010, a bioengineering liver organoid was grown by a American bio-framework from natural VKM from cultures of precursor cells of the liver and endothelial cells, developed by American researchers from the Institute of Regenerative Medicine at the Medical Center of Wake Forest University (Winston-Salem, North Carolina). human cells ^[37] . The liver bio-framework with the system of blood vessels preserved after decellularization was populated by progenitor and endothelial cell populations through the portal vein. After incubation of the biocase for a week in a special bioreactor, with the continuous circulation of the nutrient medium, the formation of liver tissue with the phenotype and metabolic characteristics of human liver was noted. In 2013, the Ministry of Defense of Russia developed a technical assignment for a prototype bioengineered liver. ^[38]

In March 2016, scientists at Yokohama University managed to create a liver that can replace a human organ. Clinical trials are expected to be conducted in 2019. ^[39]

In Homer's ideas, the liver personified the focus of life in the human body ^[40] . In ancient Greek mythology, the immortal Prometheus for conferring fire on people was chained to the Caucasus Mountains, where the neck (or eagle) flew in and pecked his liver, which was restored over the next night. Many ancient peoples of the Mediterranean and the Middle East practiced divination on the livers of sheep and other animals.

In Plato, the liver is considered a source of negative emotions (first of all, anger, envy and greed). In the Talmud, the liver is considered a source of anger, and the gallbladder is a source of resistance to this anger.

In Farsi , Urdu and Hindi, the liver (جگر or जिगर or jigar ) is an image of courage or strong feelings. The expression jan e jigar (literally: the power of my liver ) in urdu is one of the expressions of tenderness. In Persian slang, a jigar can denote a beautiful person or a subject of desires. In Zulu language, the concepts of "liver" and "courage" are expressed in one word ( isibindi ).

In the language of Gbaya ( Ubangian languages ), the liver (sèè) is the source of human feelings. The expression “happiness” (dí sèè) is literally translated as “good liver”, and “discontent” (dáng sèè) - as “bad liver”; the verb “envy” (áá sèè) is literally translated as “placed in the liver”. Also, the liver in this language expresses the concept of the center.

In the Kazakh language, the liver is denoted by the word " bauyr ." The same word ( word-homonyms ) is often called a relative and close person ^[41] . The “Bauyrym” ( my own ) address is very common, as a rule, in relation to a person of the youngest age. And in this way can appeal not only to a relative, but also to a stranger male. Such treatment is often used when Kazakhs communicate with each other, as well as to emphasize the degree of closeness (in relation to a countryman, a representative of his clan, etc.). The Kazakhs have the male name "Bauyrzhan" ( native soul , in the Russian version sometimes they write "Baurzhan"). In particular, it was the name of the Hero of the Soviet Union , the National Hero of Kazakhstan ( Khalyk Kakharmany ) Bauyrzhan Momyshuly , Panfilov , the heroic commander of the battalion during the Defense of Moscow in 1941 .

In Russian, there is an expression “to sit in the livers ^[42] ”, which means to disturb or annoy someone very much.

In the Lezgin language , one word is used to designate an eagle and a liver - “lek”. This is due to the long-standing custom of the Highlanders to expose the bodies of the dead to be devoured by predatory eagles, who primarily tried to reach the liver of the deceased. Therefore, Lezgins believed that it was in the liver that the human soul was contained, which now passed into the body of the bird. There is a hypothesis that the ancient Greek myth of Prometheus, whom the gods chained to the rock, and the eagle pecked his liver daily, is an allegorical description of such a rite of burial of the highlanders ^[43] .

• Metabolism
• Regenerative Surgery
• Regeneration