The liver is a vital organ with a variety of functions aimed at maintaining homeostasis in the body. The liver is a "large chemical laboratory" (K. Ludwig), the central organ of the metabolism of proteins, carbohydrates, fats, and medicines. The structural and functional unit of the liver is the hepatic acinus. In the liver occur:
1. The formation of bile pigments, the synthesis of cholesterol, the synthesis and secretion of bile.
2. Neutralization of toxic products coming from the gastrointestinal tract.
3. Synthesis of proteins, including blood plasma proteins, their deposition, reamination and deamination of amino acids, urea formation and the synthesis of creatine.
4. Synthesis of glycogen from monosaccharides and non-carbohydrate products.
5. Oxidation of fatty acids, the formation of ketone bodies.
6. Depositing and exchanging many vitamins (A, PP, B, D, K), depositing ions of iron, copper, zinc, manganese, molybdenum, etc.
7. Synthesis of most enzymes that provide metabolic processes.
8. Regulation of the balance between coagulation and anticoagulation systems of blood, the formation of heparin.
9. Destruction of some microorganisms, bacterial and other toxins.
10. Depositing of blood plasma and shaped elements, regulation of the blood system.
11. Hood formation in the fetus.
General etiology and pathogenesis of liver function disorders
Among the numerous etiological factors, the most important are:
1. Infectious agents, primarily hepatotropic viruses (A, B, C, D, E, F, G, TTV, etc.). Identification of these viruses became possible due to the method of enzyme immunoassay with determination of antigens and antibodies, polymerase chain reaction with the determination of RNA or DNA viruses. Epstein-Barr viruses, cytomegalovirus, herpes simplex virus, Coxsackie virus, etc. play a smaller role. Some infections (brucellosis, leptospirosis, salmonellosis, etc.) can also cause impaired liver function, but this is already seen as a secondary syndrome.
Damage to the liver can be primary (for example, with viral hepatitis) or secondary (due to generalized diseases - tuberculosis, alcoholic illness, sepsis, etc.).
Pathogenesis of hepatocyte damage. Despite the constantly expanding volume of knowledge about the causes of liver diseases, many questions about the mechanism of the onset and progression of this pathology remain open.
Nevertheless, in the pathogenesis of viral liver damage, the following mechanisms can be distinguished:
1. Direct damage, consisting of:
- in cytolytic action (due to the replication of viral particles within the cell and its complete destruction);
- in cytopathic action (damage to cellular organelles while maintaining the cell itself).
2. Immune mediated damage to hepatocytes:
- activation of resident liver macrophages (Kupffer cells, hepatic sinusoid endotheliocytes) and induction of a specific T- and / or B-immune response;
- activation of cytotoxic lymphocytes (CTL-CB8 +) and T-CD4 + lymphocytes, which results in the destruction of hepatocytes containing viral antigenic determinants;
- activation of the humoral immune response with the synthesis of specific antibodies (M- and G-classes) mediating complement-dependent lysis of immune complexes or antibody-dependent cellular cytotoxicity.
3. Induction of hepatocyte apoptosis:
- cytotoxic lymphocytes cause apoptosis of infected cells (via attachment to Fas-receptors of infected hepatocytes, which are expressed in a pre-infection);
- activation of apoptosis by viral proteins formed during viral replication (hepatitis B virus X-protein and co-protein of hepatitis C virus);
- Increased sensitivity of infected hepatocytes to cytokines (eg, TNF-α) secreted by immunocompetent cells during specific effector (CTL-CB8 +, T-CD4 +, normal killer) immune or autoimmune reactions.
4. Autoimmune mechanism: when exposed to pathogenic factors, the hepatocyte acquires new antigenic determinants and becomes an autoantigen. The virus, damaging the membrane of the hepatocyte, releases membrane lipoprotein, which is part of the structure of a specific hepatic antigen. In some cases, there may be a genetic defect in the immune system ("weakness" of T suppressors). The lack of suppressors increases the production of antibodies and the formation of immune complexes, which causes autoimmune lesions, accompanied by the death of hepatocytes and the involvement of other organs and systems in the pathological process (autoantibodies IgM and G markers of autoimmune hepatitis are formed). Perhaps in the development of autoimmune lesions, the existence of molecular mimicry between the AH of the virus and epitopes of host cells plays a significant role, which causes the lymphocytes to be sensitized to the lipoprotein of liver membranes, mitochondrial and other autoantigens.
In addition, in the pathogenesis of viral defeat, it is necessary to take into account the relationship between host and virus factors. The host factors (genetic, age, initial state of antiviral immunity) determine one or another response to infection, the possibility of elimination or persistence of the virus, the nature of the immune response.
Mechanism of damage to hepatocytes by toxic agents. Toxic agents can have a direct damaging effect on the liver, resulting in the development of dystrophic changes up to irreversible necrosis (poison pale toadstool). A number of xenobiotics do not themselves induce necrosis of hepatocytes, but in the body they can undergo biotransformation with the formation of metabolites that have a damaging effect (tetracycline, salicylates, ethanol). Thus, the main metabolite of ethanol is acetaldehyde (85% of ethanol is converted to acetaldehyde under the influence of the cytosolic enzyme alcohol dehydrogenase).
Acetaldehyde is a chemically active molecule capable of binding to albumin, hemoglobin, tubulin, actin, etc., thus forming compounds that are capable of remaining in the liver tissue for a long period even after the completion of the metabolism of ethanol. The association of acetaldehyde with cytoskeleton proteins can lead to irreversible cell damage, disrupting the secretion of the protein and contributing to the formation of balloon dystrophy of hepatocytes (protein and water retention).
In addition, in the mechanism of damage to hepatocytes under the influence of ethanol, the following main effects are distinguished:
1. Enhancement of lipid peroxidation causes damage to cell membranes, leading to an increase in their permeability and, as a consequence, disruption of transmembrane transport, cellular receptors, membrane-bound enzymes.
2. Disturbance of mitochondrial functions (chronic alcohol consumption reduces the activity of mitochondrial enzymes, there is an uncoupling of oxidation and phosphorylation, which is accompanied by a decrease in the synthesis of ATP).
3. Suppression of DNA repair in cells and activation of apoptosis.
4. Activation of the complement system and stimulation of products superoxide by neutrophils, etc.
In a number of cases, immune mechanisms play a role, which are included when drugs or metabolites, acting as haptens, transform hepatocyte proteins into immunogens.
The main liver diseases are hepatitis and cirrhosis.
Hepatitis is characterized by diffuse inflammation of the liver tissue. Among the hepatitis distinguish primary (independent nosological forms) and secondary (develop with other diseases).
Primary hepatitis for etiology are more often viral, alcoholic, medicinal, autoimmune. Downstream they are divided into acute and chronic.
Acute hepatitis is characterized by dystrophic and necrobiotic changes in hepatocytes, reactive changes in interstitial tissue with the formation of inflammatory infiltrates in the stroma, as well as a vascular reaction characteristic of inflammation.
Viral hepatitis A and E are related to diseases with a fecal-oral mechanism of infection transmission and a reversible course. Carrier and transition to a chronic form, as a rule, are not noted. Infection with virus A is realized by water, food and contact-household transmission routes. Among the sick, about 80% are children under the age of 15. Viral hepatitis A (Botkin's disease) has a seasonal increase in morbidity in the summer-autumn period. After the transferred disease remains lifelong immunity, caused by antibodies antHAV-IgG.
Hepatitis B, C, D have a parenteral mechanism for the transmission of the pathogen. Viral hepatitis B can occur in the form of a mono-or mixed infection. According to WHO, hepatitis B affects more than 2 million people worldwide, the number of carriers - more than 350 million.
The transmission paths can be natural and artificial. Natural ways of transmission of infection:
1) sexual - during sexual intercourse, especially homo- and bisexual;
2) vertical - from the mother to the fetus;
3) household infection through shaving, manicure devices, toothbrushes, etc.
The artificial way of transmission is the penetration of the virus through the damaged skin, mucous membranes under various manipulations (operations, injections, endoscopic procedures, tattooing, etc.).
A group of people at risk for hepatitis B are drug addicts; Medical workers who have contact with the blood of patients (dentists, lab technicians, obstetrician-gynecologists, surgeons, etc.); People leading a promiscuous sex life, homosexuals, as well as persons who are addicted to tattooing, piercing, etc.
Sources of infection, the mechanism and ways of transmission of hepatitis C are largely similar to the hepatitis B virus. Most often, infection occurs when blood and its transfusions are transfused. The most numerous at risk are drug addicts with parenteral use of drugs. Transmission of the pathogen in everyday life with heterosexual and homosexual contacts, from an infected mother to a newborn can take place, but is less likely to be realized than in viral hepatitis B.
All viral hepatitis under the manifest course are four periods:
1. Incubation (from 2 to 26 weeks).
2. Prodromal (pre-jaundiced) - the detection of nonspecific symptoms.
3. Jaundice - the period of the unfolded clinical picture.
4. The period of convalescence.
The following clinical and morphological forms of acute viral hepatitis are distinguished:
1. Cyclic icteric (classical manifestation of viral hepatitis).
2. Without jaundice (80% of viral hepatitis C and 70% of viral hepatitis B).
3. Subclinical (inpatient).
4. Lightning or fulminant (with massive progressive necrosis of hepatocytes).
5. Cholestatic (involving small bile ducts in the process).
Outcomes of acute hepatitis:
1. Complete recovery.
2. Recovering with residual effects (post-hepatitis syndrome, dyskinesia of the biliary tract, hepatophybrosis).
3. Transition to chronic hepatitis.
4. Development of cirrhosis of the liver.
5. Risk of hepatocellular carcinoma.
Chronic hepatitis. About chronic hepatitis speak in the event that acute hepatitis lasts more than 6 months without noticeable improvement. The duration of its flow - months, years, tens of years.
Chronic hepatitis - diffuse inflammatory-dystrophic chronic liver damage of various etiologies, morphologically characterized by dystrophy of hepatic cells, histiolymphoplasmocytic infiltration and moderate portal fibrosis, hyperplasia of stellate endotheliocytes while maintaining the lobular structure of the liver.
Chronic hepatitis is an independent nosological unit, but it can be part of some other disease, for example systemic lupus erythematosus (in this case it is considered a syndrome).
In addition, it is necessary to distinguish chronic hepatitis and nonspecific reactive hepatitis, which is a syndrome of various pathological processes, in particular diseases of the gastrointestinal tract (peptic ulcer of stomach and duodenum, stomach cancer, pancreatitis, etc.). The course of nonspecific reactive hepatitis depends on the underlying disease. The outlook is usually favorable.
The International Congress of Gastroenterologists, held in Los Angeles in 1994, proposed the classification of chronic hepatitis, taking into account the etiology, the degree of activity and the stage of chronicization of the process.
Taking into account the peculiarities of etiology, it is suggested to isolate 4 types of chronic hepatitis: viral, autoimmune, medicinal, cryptogenic (of unknown etiology, idiopathic). But, as can be seen from the cited classification, among the etiological forms of chronic hepatitis there are no such species as alcoholic, hereditary, mixed. The classification proposed in 1993 by S.D. Podymova, which distinguishes 8 types of chronic hepatitis:
1. Viral hepatitis (B, C, D).
2. Medicinal hepatitis.
3. Toxic hepatitis.
4. Alcoholic hepatitis.
5. Genetically determined or metabolic hepatitis (with Wilson-Konovalov disease, hemochromatosis).
6. Idiopathic (autoimmune, etc.).
7. Nonspecific reactive hepatitis.
8. Secondary biliary hepatitis with extrahepatic cholestasis.
The degree of activity of the process is established on the basis of laboratory enzyme tests and a morphological study of liver biopsy. Among the laboratory tests, the most informative is the determination of the activity of alanine aminotransferase (ALT) and aspartate aminotransferase (ASAT). In addition, the index of histological activity (IHA) is also known, known as the Knodell index, which takes into account the morphological components of chronic hepatitis-necrosis intralobular or periportal, dystrophy, inflammatory infiltrates, fibrosis.
Proceeding from this, 4 levels of activity are distinguished: 1) minimal (IHA - 1-3 points); 2) weak (IHA - 4-8 points); 3) moderate (IHA - 9-12 points); 4) severe, severe degree (IHA - 13-18 points).
In determining the degree of activity of the process, extrahepatic manifestations must be considered. Patients may have glomerulonephritis, nodular periarteritis, arthralgia, etc. This can mask the presence of liver pathology.
The stage of chronicization is determined by the severity and nature of fibrosis:
0) without fibrosis;
1) mild portal and periportal fibrosis;
2) mild fibrosis with portoportal septa;
3) severe fibrosis with port-central septa;
4) cirrhosis of the liver (considered as an irreversible stage of chronic hepatitis):
A) with manifestations of portal hypertension;
B) with signs of hepatic insufficiency.
Cirrhosis of the liver
Cirrhosis of the liver is a chronic, progressive polyhepatic disease of the liver characterized by a significant decrease in the number of functioning hepatocytes, increasing fibrosis, restructuring of the normal structure of the parenchyma and the vascular system of the liver, the appearance of regeneration sites and the subsequent development of hepatic insufficiency and portal hypertension.
Pathogenesis. As a result of the direct action of the etiological factor and the developing immune response, hepatocyte death occurs, massive parenchyma necrosis may occur. On the site of the dead cells the reticulin frame collapses and a scar forms. Vessels of the portal tract approach the central vein and conditions are created for the transfer of blood from the hepatic artery and portal vein into the central one, bypassing the sinusoids. The current of blood bypassing the sinusoid vessels of intact sites leads to their ischemia followed by necrosis. As a result of necrosis, substances that stimulate liver regeneration are released, regeneration nodes are formed, which compress the vessels and contribute to an even greater violation of blood flow. In addition, the decay products of hepatocytes stimulate the inflammatory response, the spread of inflammatory infiltrates, resulting in intense fibrosis. Vascular anastomoses are formed, due to which the blood, bypassing the parenchyma of the lobules, immediately enters the hepatic vein system, which leads to the development of ischemia and necrosis. This is also facilitated by compression of the venous vessels of the liver with a connective tissue.
Classification of cirrhosis of the liver. The first classification of liver cirrhosis was adopted by the V Pan American Congress of Gastroenterologists in 1956. According to this classification, postnecrotic, portal, biliary (with or without extrahepatic biliary tract obstruction) and mixed cirrhosis were identified. In 1978, WHO recommended a morphological classification: small-node (micronodular), coarse nodular (macronodular), incomplete septal and mixed (macro-microiodular).
Depending on the role of the genetic factor, hereditary and acquired cirrhosis is distinguished. Among the acquired cirrhoses of the liver with established etiology, toxic (more often alcoholic cirrhosis of the liver), infectious (more often viral cirrhosis), biliary (with lesion of intra- and extrahepatic bile ducts), exchange-alimentary, dyscirculatory (with congestive heart failure) and mixed origin. Hereditary include cirrhosis in hemochromatosis, Wilson-Konovalov's disease, insufficiency of a1-antitrypsin.
Classification of cirrhosis of the liver (according to AS Loginov, Yu.E. Blok, 1987):
- On etiology: viral, alcoholic, autoimmune, toxic, genetically conditioned, cardiac, due to intrahepatic cholestasis, cryptogenic;
- by morphology: micronodular, macronodular, mixed, incomplete septal, biliary;
- depending on the stage of hepatic insufficiency: compensated, subcompensated, decompensated.
In addition, activity (minimal, moderate, severe) and phase (active and inactive) of the process are taken into account.
The main clinical and laboratory syndromes of cirrhosis:
1. Jaundice (jaundice forms can be diagnosed, but with biliary cirrhosis jaundice is always observed).
2. Portal hypertension. Syndrome of portal hypertension arises from the violation of blood flow in the portal vein.
There are 3 types of portal hypertension: subhepatic, intrahepatic, superhepatic.
Superhepatic portal hypertension occurs due to compression or thrombosis of the hepatic veins, right ventricular failure, pericarditis and is characterized by difficulty in venous outflow from the liver.
Intrahepatic portal hypertension develops with cirrhosis, tumors, echinococcosis and other liver lesions.
Sub-hepatic portal hypertension is associated with thrombosis or compression of the portal vein (scars, compression with ascitic fluid, tumor) or with abnormalities of its development.
The main link in the pathogenesis of portal hypertension is the stagnation of blood in the portal vein system.
Portal hypertension is accompanied by compensatory shunting of blood through portocaval anastomoses (the lower third of the esophagus and the cardiac part of the stomach, the anterior abdominal wall in the navel - the head of Medusa, the hemorrhoidal veins system) followed by varicose vasodilation. This makes the walls of the vessels vulnerable to mechanical damage, the outcome of which can be gastrointestinal bleeding, often ending lethal.
As a result of portal hypertension, splenomegaly develops (enlarged spleen), hypersplenism (increased spleen function), resulting in pancytopenia (thrombocytopenia, anemia, leukopenia) and ascites (accumulation of fluid in the abdominal cavity).
In the mechanism of development of ascites, the following pathogenetic factors play a role:
- increased pressure in the portal vein;
- decrease in oncotic blood pressure due to a violation of the protein-synthesizing function of the liver;
- impaired lymph circulation;
- secondary aldosteronism (due to decreased metabolism in the liver), which is accompanied by hypernatremia, hypokalemia, hypervolemia.
4. Hemorrhagic syndrome - with hepatic diseases, deficiency of I, II, V, VII, IX, X and other factors of coagulation hemostasis due to impaired hepatic synthesis and inadequate absorption of vitamin K. In liver lesions, the activity of the fibrinolytic system increases (insufficient inhibition of hepatic Activators of plasmin), the DIC-syndrome can develop. Due to splenomegaly and hypersplenism, there is a disruption of vascular-platelet hemostasis (thrombocytopenia), which is accompanied by the formation of bruises and petechial hemorrhages in the skin, nasal and uterine bleeding, patients have increased prothrombin time, clotting time and bleeding time.
In clinical practice, a prothrombin ratio is determined that characterizes the total activity of clotting factors - prothrombin, proconvertin, acclerin, and the Stewart-Prower factor. A distinct decrease in prothrombin ratio is noted in acute and chronic liver diseases, when there is a significant necrosis of hepatocytes. A sudden and sharp decrease in prothrombin ratio in patients with liver disease always indicates a marked hepatic-cell insufficiency and an impending hepatic coma. If coagulopathy accrues in connection with cholestasis or intestinal dysfunction (due to the use of broad-spectrum antibiotics), then it is possible to improve the indices against intramuscular injection of vitamin K (10 mg). However, if hypoprothrombinemia is associated with hepatic insufficiency, then the coagulation with exogenous administration of vitamin K can not be corrected.
5. Skin itching is the earliest and permanent, and sometimes the only manifestation of cirrhosis. The nature of pruritus is not fully understood, but it has been established that the mediators of pruritus are proteases released in the skin under the action of bile acids.
Hepatic-cell failure is a violation of one, several or many liver functions that result from damage to hepatocytes. Isolate acute and chronic hepatic insufficiency.
Acute liver failure is a syndrome that is associated with massive necrosis of hepatocytes, leading to severe severe impairment of liver function. The most frequent causes of acute hepatic insufficiency are fulminant forms of acute viral or toxic hepatitis, more rare are cytomegalovirus, infectious mononucleosis virus, rickettsiosis, mycoplasmosis and mixed fungal infections leading to severe liver necrosis. In addition, the causes of acute hepatic insufficiency can be acute fatty hepatosis in pregnant women, Reye's syndrome, postoperative state, as well as liver abscesses, purulent cholangitis, sepsis. Reye syndrome - acute encephalopathy with cerebral edema and fatty liver infiltration, occurs in newborns, children, adolescents (usually aged 4-12 years), is associated with a viral infection (chicken pox, influenza) and the intake of drugs containing acetylsalicylic acid. The most common cause of its occurrence is illiterate prescription of aspirin in acute viral infection, which is contraindicated, especially in children.
Chronic hepatic insufficiency develops in chronic liver diseases of infectious and non-infectious etiology, in the late stage of liver cirrhosis, and also after surgical interventions on portocaval shunting.
Isolate small hepatic insufficiency (hepatodepressive syndrome) and major hepatic insufficiency (hepatarga). In hepatarga, in contrast to small liver failure, there are signs of hepatic encephalopathy.
With true hepatic-cell insufficiency, the following syndromes develop:
1) the syndrome of impaired nutrition (worsening of appetite, nausea, abdominal pain, unstable stool, weight loss, the appearance of anemia). The basis of this syndrome is the violation of metabolic processes;
2) fever syndrome (up to 38 ° C and even up to 40 ° C) with a nuclear shift of the leukocyte formula to the left. This syndrome is associated with necrosis of hepatocytes, the intake of toxic products into the blood, bacteremia (possibly the entry of microorganisms into the blood from the intestine);
3) jaundice syndrome;
4) the syndrome of endocrine disorders. There is a decrease in libido, testicular atrophy, infertility, gynecomastia, mammary atrophy, uterus, menstrual cycle disorders. Possible development of diabetes mellitus and secondary aldosteronism;
5) syndrome of impaired hemodynamics - the accumulation of histamine-like and other vasoactive substances, leading to vasodilation (compensatory increase in cardiac output in combination with hypotension). Reduction of albumin synthesis and a decrease in oncotic pressure, as well as the development of secondary hyperaldosteronism, cause edematous-ascitic syndrome;
6) a specific hepatic odor (fetor hepatitis) is associated with the release of methyl mercaptan. This substance is formed from methionine, which accumulates in connection with a violation in the liver of the processes of demethylation and can be contained in the exhaled air;
7) "liver signs" - telangiectasia and palmar erythema;
8) syndrome of hemorrhagic diathesis - a decrease in the synthesis of clotting factors and frequent bleeding causes the possibility of developing DIC syndrome.
Hepatic insufficiency is characterized by the following laboratory parameters: in the blood serum, the albumin content (an extremely important indicator!) And clotting factors decreases, cholesterol level decreases, bilirubin content increases, phenol accumulation, ammonia accumulation and aminotransferase activity increase.
Hepatic insufficiency can lead to the development of hepatic encephalopathy and hepatic coma.
Hepatic encephalopathy (hepatocerebral syndrome) - a neuropsychic disorder with a violation of intelligence, consciousness, reflex activity and the functions of vital organs. Isolate acute and chronic hepatic encephalopathy (the latter can last for years with periodic episodes of precoma).
There are 4 stages of hepatic encephalopathy in accordance with the criteria adopted by the International Association for the Study of the liver.
Stage I - prodromal. There are initial changes in the psyche - slowing of thinking, behavior disorders, disorientation of the patient in the surrounding reality, sleep disorders (drowsiness during the day, sleeplessness at night), tearfulness, weak-willedness. Patients may fall into periods of stupor with a fixation of the glance. A characteristic and rather early symptom is a change in handwriting (dysgraphia). EEG, as a rule, is not changed.
Stage II - beginning coma. The symptoms of stage I are aggravated. Part of the patients have convulsions and psychomotor agitation, during which they try to escape from the ward. Stereotypic movements are formed, for example, clapping tremor of hands (asterixis), deafening. Patients can become untidy, familiar. Often the body temperature rises, liver odor from the mouth appears. On the EEG, minor initial changes are found.
Stage III - stupor. Patients are in a prolonged sleep, interrupted by rare awakenings. In the neurological status, the rigidity of the musculature, the masklike face, the slowing down of voluntary movements, gross speech disorders (dysarthria), hyperreflexia, the clonus of the patella, etc. are noted. EEGs reveal deep disturbances, the shape of the curve approaches the isoline.
Stage IV - coma. The consciousness is lost, there is no reaction to the pain stimulus, in the initial phase pathological reflexes are noted. In the future, the pupils dilate, reflexes fade, blood pressure drops, the breath of Kussmaul or Cheyne-Stokes may appear, and death occurs.
Consequently, the hepatic coma is the terminal stage of hepatic encephalopathy, characterized by loss of consciousness, lack of reflexes and a violation of the basic functions of the organs.
Factors that provoke the rapid development of coma: protein food, the intake of diuretics (not saving potassium), sedatives / Mortality of patients in stage IV, reaches 80-90%.
According to the etiology, 4 types of coma are distinguished: 1) endogenous; 2) exogenous; 3) mixed; 4) Electrolyte.
Endogenous (true) coma develops with massive necrosis of hepatocytes in cases of acute hepatic insufficiency, which is characterized by a disruption of many liver functions, marked bleeding, increased free bilirubin level in the blood, hepatic hyperaemiaemia, liver odor from the mouth. The treatment lends itself hardly.
Exogenous (shunt, by-pass) coma often occurs with cirrhosis in the case of the development of powerful collaterals between the portal and lower vena cava systems. It can also occur with artificial application of portocaval anastomoses, in which blood from the intestine, rich in biologically active substances (BAS - ammonia, cadaverine, putrescine, etc.), bypasses the liver, pours into the total bloodstream and has a toxic effect on the brain. This form is easier to treat (blood dialysis, intestinal cleansing, broad-spectrum antibiotics), has a more favorable prognosis.
Mixed coma is more common, which develops with far-reaching cirrhosis of the liver with the death of a large number of hepatocytes and the presence of portocaval anastomoses.
Electrolyte coma is associated with the development of hypokalemia. In the pathogenesis, secondary aldosteronism plays a role, the use of diuretic drugs that do not conserve potassium, frequent vomiting, diarrhea, which leads to a violation of the electrolyte balance (hypokalemia, alkalosis). Is manifested by severe weakness, decreased muscle tone, adynamia, convulsive twitching of the calf muscles, a violation of cardiac activity (tachycardia, the rhythm of the "woodpecker"), a violation of breathing. Treatment of electrolyte coma - the use of potassium preparations.
Pathogenesis of hepatic encephalopathy and coma. The mechanism of development of hepatic encephalopathy is not fully understood. There are three most common theories:
1. Theory of toxic effects of ammonia. Ammonia is formed in all tissues where proteins and amino acids are exchanged. However, the greatest amount of it enters the bloodstream from the gastrointestinal tract. The source of ammonia in the intestine is any substance that contains nitrogen: decaying food proteins, some polypeptides, amino acids and urea, which came from the blood. The release of ammonia occurs with the help of enzymes - urease and aminoacid oxidase of intestinal microflora and intestinal mucosa. 80% of ammonia coming from the intestine through the portal vein into the liver, is converted to urea (ornithine cycle). Ammonia not included in the ornithine cycle, as well as various amino and keto acids (glutamate, a-ketoglutarate, etc.) under the influence of glutamate synthetase, glutamine is formed. Both mechanisms prevent the entry of toxic ammonia into the total bloodstream. But with liver failure, an increase in the concentration of ammonia is observed not only in the blood, but also in the cerebral fluid. The entry of ammonium cations through the blood-brain barrier into the neurons of the brain causes their energy starvation (ammonia combines with a-ketoglutaric acid to form glutamine, as a result, an outflow of a-ketoglutarate from the CTA is observed, which leads to a decrease in the synthesis of ATP) and, as a consequence, CNS.
Theory of false neurotransmitters (transmitto - transmit). Dysfunction of the liver helps to reduce the concentration of amino acids with branched chain - valine, leucine, isoleucine, which are used as a source of energy, and increase the level of aromatic amino acids - phenylalanine, tyrosine, tryptophan (their metabolism is normally carried out in the liver, with liver diseases, the concentration of these amino acids increases Not only in the blood, but also in the urine - aminoaciduria).
Normally the ratio between branched chain amino acids and aromatic amino acids is 3-3.5. With pathology, this indicator decreases. For these amino acids, there is a single transport system, and aromatic acids use a liberated transport system to penetrate the GEB into the brain, where the enzyme system involved in the synthesis of normal mediators is inhibited. The synthesis of dopamine and norepinephrine decreases and false neutrotransmiters (octopamine, β-phenylethylamine, etc.) are formed.
The theory of strengthened GABAergic transmission. The essence of this theory is that in pathology, the clearance of GABA in the liver is violated (GABA is formed in the reaction of decarboxylation of glutamic acid). GABA accumulates in brain tissue, exerting an inhibitory effect on neurons, disrupting their function, leading to the development of hepatic encephalopathy.
In addition, an important role in the mechanism of the development of hepatic encephalopathy and coma is played by other disorders: intoxication, acid-base, water-electrolyte (hypokalemia, hypernatremia) and hemodynamic disorders.
Violation of the detoxification and clearance functions of the liver
The liver is involved in the neutralization of toxic products endo - and exogenous origin. Detoxication is carried out by oxidative processes, reducing reactions, and also by hydrolysis. Oxidation is the most important reaction, which requires the presence of reduced NADP-2H and molecular oxygen. An important role is played by the transport system component - cytochrome P450. Some compounds are rendered harmless by including them in the synthesis of substances used in metabolism (for example, the inclusion of ammonia in the synthesis of urea).
The reaction of detoxification is conjugation, in which neutralization occurs due to a compound with glucuronic or sulfuric acids. So steroid hormones, bilirubin, bile acids, aromatic hydrocarbons, etc. are inactivated. Neutralization can also occur by binding with glycerol, taurine, cysteine, when binary compounds of bile, benzoic and nicotinic acids are formed. A number of substances are absorbed from the blood and excreted with bile in unchanged form.
In the liver, fixation and phagocytosis of various microbes occur due to the active activity of the cells of the reticuloendothelial system. Kupffer cells of the liver have not only pronounced phagocytic activity in relation to microbes, but also provide purification of blood from endotoxins of the intestinal microflora. The ability of the liver to metabolize foreign compounds can be enhanced by the introduction of inductor substances into the body. Some of them, for example phenobarbital, stimulate the metabolism of a number of xenobiotics in hepatocytes by inducing the synthesis of cytochrome P450 and NADP-2H-cytochrome C reductase and increase the activity of the enzyme glucuronyltransferase.
In a number of liver diseases, especially with cirrhosis, its detoxification function is usually inhibited. The function of the reticuloendothelial system ("blockade" of phagocytosis by the products of cell decay) falls out, hemodynamic changes appear (portocaval anastomoses, decreased blood supply to the liver). The results of these disorders are compared with the consequences of portocaval shunting, when the systemic blood flow is filled with products coming from the intestine through the portal vein. This leads to endotoxemia - fever, leukocytosis, erythrocyte hemolysis, renal failure, which is especially pronounced in hepatic coma.
The role of the liver in metabolic disorders
Violation of carbohydrate metabolism. The liver is involved in maintaining a normal level of glucose in the blood serum by glycogenogenesis, glycogenolysis and gluconeogenesis.
The homeostasis of glucose is often disturbed by cirrhosis of the liver. As a rule, at the same time, hyperglycemia and a decrease in glucose tolerance are determined. The level of insulin in the plasma or in the norm, or increased, which is associated with resistance to it. Insulin resistance is explained by the absolute decrease in the ability of the liver to metabolize glucose after a load due to a decrease in the mass of functioning hepatocytes. In patients with cirrhosis, a decrease in the response to insulin may be due to receptor and postreceptor anomalies in hepatocytes.
With cirrhosis of the liver, the level of lactate in the serum can also increase due to the reduced ability of the liver to utilize it for gluconeogenesis.
In severe acute hepatitis, as a rule, there is hypoglycemia, and with cirrhosis of the liver it occurs in the final stage - with hepatic insufficiency. In patients with liver cirrhosis, the role of carbohydrates as an energy source decreases (2% for cirrhosis and 38% for healthy ones) and the role of fats (respectively 86 and 45%) increases with fasting. This is accompanied by the mobilization of triacylglycerols as an energy source. In the final stage of cirrhosis, hypoglycaemia is due to a decrease in the ability of the liver (due to extensive damage to its parenchyma) to synthesize glycogen and a decrease in the production of insulinase (an enzyme that destroys insulin).
Normally, galactose, which enters the body as a part of milk sugar, turns into glucose, but in violation of the functional state of the liver (in acute and chronic diseases), the ability to use galactose is reduced.
Violation of protein and enzyme metabolism in liver diseases manifests itself in a change: the breakdown of proteins (up to amino acids), the synthesis of proteins, deamination, transamination, decarboxylation of amino acids, the formation of urea, uric acid, ammonia, creatine.
As a consequence, the following violations occur:
1. Hypoproteinemia - a decrease in protein level usually reflects a violation of the protein-synthetic function of the liver. Hepatocytes synthesize almost all albumin, up to 85% of globulins. In severe chronic liver diseases, albumin production decreases by more than 2-3 times, but its level decreases slowly due to a prolonged half-life. Therefore, in acute liver failure, the albumin concentration may turn out to be normal, and the violation of the albumin-synthesizing function of the liver will manifest itself only after two to three weeks.
2. Changes in the composition of globulins (high levels of α2 and especially β-globulins) can occur with biliary cirrhosis and serve as a differential sign of the difference between this type of cirrhosis and others. The α2 fraction includes ceruloplasmin proteins, α2-antithrombin, haptoglobin, and α2-macroglobulin. Ceruloplasmin is the main copper-containing plasma protein, which determines its antioxidant activity. A low concentration of this protein can be observed with Wilson-Konovalov's disease and with decompensated liver cirrhosis of any etiology. The level of haptoglobin decreases with chronic liver diseases, with haemolytic crisis. The content of transferrin (a part of β-globulin) decreases with hemochromatosis (a violation of iron metabolism) and with cirrhosis of the liver. In diffuse diseases of the liver, the content of γ-globulins increases significantly, which is associated with an increase in the antigenic stimulation of the immune system. So, with autoimmune hepatitis and cryptogenic cirrhosis, the level of IgG significantly increases. In a healthy person, α-fetoprotein is not detected, since after birth it disappears from the blood, but can appear in it in patients with primary liver cancer (hepatoma) and serves as a marker for this disease in the differential diagnosis of hepatomegaly.
3. Dysproteinemia develops in the synthesis of qualitatively altered globulins in the liver (paraproteins of macroglobulins, cryoglobulins).
4. Violation of the metabolism of amino acids occurs with severe liver damage and leads to an increase in the level of free amino acids in the blood and urine (aminoacidemia, aminoaciduria). In fulminant hepatitis, generalized aminoaciduria with predominant excretion of cystine and tyrosine is noted, which is a prognostically unfavorable feature.
5. Hemorrhagic syndrome develops due to a violation of the synthesis of coagulation factors and inhibitors of coagulation and fibrinolysis.
6. The increase in residual nitrogen and ammonia in the blood is detected when the synthesis of urea is violated (the index of severe hepatic insufficiency).
7. Increase in blood levels of a number of enzymes (aminotransferases, γ-glutamyltranspeptidase, etc.) The most important diagnostic value is the determination of the activity of aminotransferases - ALAT and ASAT in the blood serum. Their activity is the most reliable indicator of the cytolytic process in liver damage. The cytolysis syndrome is most pronounced in acute liver diseases of any genesis, but it acquires special significance for the diagnosis of acute viral hepatitis occurring in anicteric and latent forms. This test is informative even with small damage to the liver cells, which is of great importance for the early diagnosis of diseases. The cytolysis syndrome in liver pathology is characterized by a more pronounced increase in ALT activity compared to ASAT, and the de Ritis coefficient (the ratio of ASAT / ALAT) allows one to judge the severity of liver damage. Normally, this factor is 1.33; With acute viral hepatitis it becomes less than 1.
Of the markers of cholestasis (excretory enzymes) the greatest clinical significance is the determination of the activity of alkaline phosphatase in the blood. Sources of this enzyme, besides the liver, are bone tissue, intestine, placenta, but the main excretory organ is the liver. Therefore, an increase in the activity of alkaline phosphatase is an important indicator of violations of cholestatic (cholestasis). The highest hyperfermentemia is recorded with subhepatic jaundice and biliary cirrhosis. In acute viral hepatitis, the serum alkaline phosphatase level is usually either normal or increases to moderate levels. The diagnostic value of the determination of isoenzyme activity of this enzyme increases due to the fact that a high level of its activity may indicate the possibility of tumors of different localization.
Disturbance of fat metabolism. Fat metabolism in liver pathology is characterized by:
1) violation of the cleavage and absorption of food fats in the intestines, which is associated with a deficiency of bile acids in the pathology of bile formation and bile secretion;
2) a violation of the synthesis and oxidation of triacylglycerols, phospholipids, lipoproteins, cholesterol;
3) an increase in the formation of ketone bodies.
Damage to hepatocytes causes a decrease in the content of cholesterol, its esters and leads to a decrease in the production of bile acids. With a number of liver diseases, the synthesis of lipoproteins decreases, which leads to the accumulation of triacylglycerides followed by infiltration and fatty liver dystrophy. The causes of this condition, in particular, is the lack of food lipotropic substances (choline - an integral part of lecithin, methionine or participating in their synthesis of vitamin B12, folic acid). In the pathogenesis of fatty liver disease, the following main mechanisms can be distinguished: a) fat intake into the liver; B) reduced synthesis of phospholipids and increased production of triacylglycerols from fatty acids; C) reduction of oxidation of fatty acids and lipolysis;
4) a violation of the fat yield from the liver due to the decreased formation of very low density lipoproteins (VLDL is the main transport form of removing triacylglycerols from the liver) or the lack of lipocaine production by the pancreas.
Hepatitis and cirrhosis are often accompanied by a decrease in the formation of esterified cholesterol or a decrease in its total amount in the blood, a violation of the synthesis and oxidation of cholesterol, its excretion with bile. Hypercholesterolemia with mechanical jaundice occurs as a result of cholesterol entering the bile into the bloodstream, and also due to a violation of the synthesis of bile acids from cholesterol.
Disturbance of hormone exchange. The violation of the metabolism of hormones and biologically active substances in liver pathology is manifested in a change in: a) the synthesis of hormones (tyrosine is the precursor of thyroxine, triiodothyronine, catecholamines), transport proteins (transcortin binding 90% glucocorticoids); B) inactivation of hormones (conjugation of steroid hormones with glucuronic and sulfuric acids, enzymatic oxidation of catecholamines under the influence of aminoxidases, insulin cleavage by insulinase); C) inactivation of biologically active substances (oxidative deamination of serotonin and histamine). The defeat of the liver and the violation of inactivation of hormones such as insulin, thyroxine, corticosteroids, androgens, estrogens leads to a change in their content in the blood and the development of the corresponding endocrine pathology. Reduction of deamination of BAS can aggravate the clinical manifestations of allergy in liver pathology.
Violation of the exchange of vitamins. Violation of vitamin metabolism in liver pathology is characterized by: a) a decrease in the absorption of fat-soluble vitamins (retinol, ergocalciferol, tocopherol, etc.) as a result of a violation of bile excretory liver function; B) a violation of the synthesis of vitamins and the formation of active forms (retinol from carotene, active forms of vitamin B6, etc.); C) violation of the deposition of vitamins (cyanocobalamin, folic, nicotinic acids, etc.) and their excretion. As a result of the violation of the exchange of vitamins, many pathological processes in the liver may be accompanied by hypovitaminosis.
VIOLATION OF LIVER-BORN AND SPECIFIED (EXCRETER) FUNCTION OF THE LIVER
Hepatocytes secrete bile, which includes bile acids, cholesterol, phospholipids, fatty acids, bile pigments, mucin, water and other substances.
The liver takes part in the synthesis, metabolism and excretion of bile pigments. In stellate endotheliocytes of the liver, macrophages of the bone marrow, spleen from the hem of the destroyed erythrocytes is formed under the influence of the enzyme biliverdin hemoxygenase, which, with the participation of the biliverdin reductase enzyme, turns into bilirubin (unconjugated, free, indirect), it binds to albumin in the blood, forming a water-insoluble complex, Which does not pass through the renal filter, is toxic, lipophilic. Indirect bilirubin with the participation of proteins (Y-ligandine and Z-glutathione transferase) is transferred to hepatocytes, where it is conjugated with uridine-diphospho-glucuronic acid under the influence of the microsomal enzyme UDP-glucuronyltransferase. A bilirubin that is bound or straight, which is soluble in water, is non-toxic, enters the intestine in the bile, where it is converted into urobilinogen (mesobilinogen) by the action of the enzymes of the intestinal microflora, while bilirubin cleaves glucuronic acid and restores it. From the small intestine, part of the urobilinogen is absorbed into the bloodstream and enters the liver via the portal vein, where it is split into dipyrrole compounds and does not penetrate into the general bloodstream. Unabsorbed in the blood urobilinogen in the large intestine is restored to sterocilinogen, and in the lower parts of the colon is oxidized, turning into stericilin. The main part of the sterocilin is excreted with feces, giving it a natural color. Only a very small amount of sterkobilinogen comes through the intestinal wall into the hemorrhoidal veins, and from there to the total blood flow and is excreted in the urine. Thus, normal urine contains traces of sterocilinogen.
Properties of direct and indirect bilirubin
Gives an indirect reaction to Ehrlich's diazo reaction
Reacts directly with Ehrlich's diazo-reagent
Normally, the serum content does not exceed 3.4-22.2 μmol / l
It is found only in bile
Does not appear in the urine
Appears in the urine
Soluble in fats
Soluble in water
Not bound to glucuronic acid
Coupled with glucuronic acid
Etiology and pathogenesis of jaundice
Jaundice (icterus) is a symptom complex characterized by a yellow color of the skin, a sclera, more deeply located tissues and accompanied by an increased concentration of bile components in the blood serum and in some biological fluids.
Jaundice should be distinguished from the yellow pigmentation of the skin due to caroteneemia (when consuming a large amount of carrots), due to the presence of carotene pigments in the blood and the appearance of yellow staining in the palms, rather than the sclera. Jaundice is associated with diseases of the liver and biliary tract or with increased destruction (hemolysis) of erythrocytes. Visible jaundice appears with hyperbilirubinemia more than 35 μmol / l. It is customary to distinguish between bilirubinophilic and bilirubinophobic tissues. Skin, mucous membranes and the inner wall of blood vessels are most dyed. The cornea of the eye, cartilage, nervous tissue usually stain little. Saliva, gastric juice, tear fluid, as a rule, are not yellow.
There are three types of jaundice: superhepatic, hepatic and subhepatic. Hyperbilirubinemia is noted in all cases.
Superhepatic (hemolytic) jaundice, not associated with liver damage, occurs due to increased hemolysis of erythrocytes and a violation of bilirubin metabolism. The causes of superhepatic jaundice are different. There are a number of hereditarily caused enzymes and hemoglobinopathies, accompanied by hemolytic jaundice, for example hereditary microspherocytic hemolytic and sickle-cell anemia. There are also autoimmune, infectious (for malaria, sepsis), toxic (poisoning with arsenic, lead, hydrogen sulphide, snake venom) and other acquired forms of hemolytic anemia. With increased destruction of circulating erythrocytes, increased production of indirect bilirubin is noted.
Classification scheme of pathogenetic types of jaundice (according to AF Bluger)
Type of jaundice
Characteristics of the main pathological process
Leading mechanism of jaundice development
Nosological forms and syndromes
Increased decay of erythrocytes
Increased formation of indirect bilirubin, insufficiency of the function of bilirubin capture by the liver
Hemolytic jaundice, hematomas, infarcts
The defeat of hepatocytes (and cholangiol)
Violation of the capture and excretion of bilirubin, regurgitation of bilirubin
Hepatic-cell jaundice in acute and chronic hepatitis, hepatosis, cirrhosis
Disturbance of excretion and regurgitation of bilirubin
Cholestatic jaundice with cholestatic hepatosis, primary biliary cirrhosis, with hepatic-cell lesions
Disturbance of conjugation and capture of bilirubin by hepatocytes
Enzimopathic jaundice with Gilbert and Kriegler-Nayar syndromes, physiological jaundice of newborns
Disturbance of bilirubin excretion
With the syndromes of Dabin-Johnson and Rotor
Disturbance of conduction of bile ducts
Disturbance of excretion and regurgitation of bilirubin
Intracanalicular occlusion with stone, tumor, parasites, inflammatory exudate. Extracanalicular obstruction of the tumor, echinococcus, etc.
The liver is able to metabolize and release into bile the amount of bilirubin, 3-4 times higher than its normal physiological level. With the increased hemolysis of red blood cells, the liver can not cope with either the conjugation process or the transport of excess bilirubin, which can lead to at least a 4-fold increase in its concentration in the blood. With this variant of jaundice, bilirubin, it would seem, should only be unconjugated, since it is an accumulation of indirect bilirubin. However, it is necessary to take into account that an excess amount of bilirubin enters the hepatic cell, it is conjugated, and the transport system of removing it from the cell may be insufficient, and then in the blood, along with indirect bilirubin, the increased content of which will necessarily prevail, Bilirubin.
The main signs of this jaundice are an increase in the level of bilirubin mainly due to the unconjugated fraction, the absence of bilirubin in the urine. In addition, with hemolytic jaundice in the liver, bile ducts and intestines, excess amounts of bilirubin glucuronides, urobilinogen, strobobilinogen (hypercholia-increased secretion of bile in the intestine) are synthesized, which leads to an increase in the amount of urobilinogen and sterocilinogen in urine and feces in the absence of clinical and Laboratory evidence of liver disease. The liver metabolizes more than normal, the amount of pigment, and therefore bilirubin is stronely secreted through the bile and further into the intestine. Accumulation in the blood of bile acids and cholesterol does not occur, since the outflow of bile is free. In some cases (cirrhosis, tumors, infections) simultaneously can be defined as increased hemolysis of erythrocytes, as well as violations of the liver. As a rule, with uncomplicated hemolysis, serum bilirubin level increases only 2-3 times (40-60 μmol / l) and rarely reaches 100 μmol / l.
Unconjugated hyperbilirubinemia also occurs as a result of bilirubin conjugation disorders with a decrease in UDP-glucuronyl transferase activity. Almost every newborn on the 3-5th day of life has a slight, transient, unconjugated hyperbilirubinemia (up to 50 μmol / l), associated with immature during this period glucuronyl transferase. Within a few days (up to 2 weeks) of life, the activity of glucuronyltransferase increases and the level of bilirubin normalizes.
Hepatic jaundice (parenchymal or hepatocellular) develops in acute and chronic liver diseases of any etiology (viral, alcoholic, autoimmune), as well as in severe infections (typhus, malaria, acute pneumonia), sepsis, poisoning with fungi, phosphorus, chloroform and other poisons . As a result of the defeat of hepatocytes, lysosomes of liver cells secrete bile in the lymphatic and blood vessels. It is also possible to reverse the absorption of bile from the bile ducts into the blood. Hyperbilirubinemia is noted in the blood due to direct and indirect bilirubin, which is associated with a decrease in the activity of glucuronyltransferase in damaged cells and a violation of the formation of bilirubin glucuronides. Developed cholomic syndrome, which is due to the intake of bile acids in the blood. It is characterized by bradycardia and a decrease in blood pressure due to the influence of bile acids on the receptors and the center of the vagus nerve, the sinus node of the heart and blood vessels. The toxic effect of bile acids on the central nervous system is manifested in the form of asthenia, irritability, disturbance in the rhythm of sleep, headache and increased fatigue. Irritation of sensitive nerve endings of the skin with bile acids leads to skin itch. Urine has a dark color due to bilirubinuria (direct bilirubin) and urobilinuria (disrupted the transformation of urobilinogen, absorbed into the blood from the small intestine and entering the liver). In the urine, bile acids and traces of sterocilinogen are determined due to a decrease in its formation in the intestine, where little glucuronide bilirubin is supplied.
In the group of hepatic jaundice, hepatic-cellular, cholestatic and enzymatic jaundice are distinguished.
With hepatocellular jaundice, there is a complex disturbance of liver function, relating to both metabolism and transport of bilirubin. It is based on damage to the function and structure of hepatocytes - a cytolytic syndrome, leading to hepatic-cell failure.
Cholestatic jaundice (intrahepatic cholestasis) can be observed as an independent phenomenon or more often complicates the cytolytic syndrome. Cholestasis can occur both at the level of the hepatocyte, when the metabolism of bile components is disrupted, and at the level of the bile ducts, with bilirubinemia present, and the excretion of urobilin compounds with urine and feces is reduced.
Etymopathic jaundice is caused by a disturbance in the metabolism of bilirubin in hepatocytes. This is a partial form of liver failure, associated with a decrease or inability to synthesize enzymes involved in pigment metabolism. By origin these jaundices are, as a rule, hereditary.
Depending on the mechanism of development, the following forms of jaundice are distinguished:
Gilbert's syndrome is of a family nature and is characterized by benign chronically occurring unconjugated hyperbilirubinemia associated with a partial deficiency of UDP-glucuronyltransferase. Usually this syndrome manifests itself at the age not earlier than 20 years. As a rule, the level of bilirubin increases only to 30 μmol / l and rarely exceeds 50 μmol / l (only 20% of total bilirubin will be conjugated). Clinically, this pathology is often not manifested and is established in a laboratory study. The intensity of jaundice is transient, it disappears, then intensifies. The latter is observed after prolonged starvation or compliance with a low-calorie diet, after intercurrent infection, surgical interventions, alcohol intake. The intake of phenobarbital, increasing the activity of the enzyme, leads to a normalization of the level of bilirubin.
Syndrome Kriegler-Nayyar. Two forms of this disease are known: type I - a clinically severe form associated with complete absence of glucuronyl transferase, and type II, associated with partial deficiency. I type is rare. Characterized by the appearance of jaundice from the first days of life, a sharp increase in the content of indirect bilirubin in the blood, a lesion of the central nervous system. The level of unconjugated bilirubin in children reaches high figures - 200-450 μmol / l. The functional state of the liver does not suffer, but it does not contain a conjugating enzyme. In connection with the fact that the liver does not synthesize bound bilirubin, bile in such children is colorless. Treatment with phenobarbital is ineffectual. Sick children usually; Die in the first year of life due to brain damage (bilirubin encephalopathy). Patients with type II syndrome have only partial deficit of glucuronyltransferase, which is expressed in an increased level of unconjugated bilirubin up to 60-200 μmol / l. Treatment with phenobarbital gives a temporary effect. The disease refers to the proceeding relatively favorably in cases where the level of bilirubin does not exceed 200 μmol / l. The acquired glucuronyl transferase deficiency that occurs in newborns due to the inhibition of this enzyme by a number of drugs (levomycetin, novobiocin or vitamin K) is possible.
With Kriegler-Nayyar syndrome and hemolytic disease of newborns (Rh-incompatibility of erythrocytes of the mother and fetus), bilirubin encephalopathy can result from a so-called nuclear jaundice.
"Nuclear" jaundice is a severe form of jaundice of newborns, in which bile pigments and degenerative changes are found in the nuclei of the cerebral hemispheres and the brainstem (free bilirubin, not included in the bond with albumin, penetrates the blood-brain barrier and stains the nuclei of the brain - hence the term " Nuclear "jaundice). This jaundice is characterized by the following: in newborns on the 3rd-6th day of life spinal reflexes disappear, hypertone of the muscles of the trunk, sharp crying, drowsiness, restless limb movements, convulsions, respiratory failure, it may stop and die. If the child survives, then deafness, paralysis, mental retardation may develop.
Dabin-Johnson syndrome. This variant of jaundice arises from the defect of enzymes involved in the excretion of bilirubin-diglucuronide through the membrane of the hepatic cells into the bile capillaries. As a result, direct bilirubin enters not only the bile capillaries but also partially into the blood. Clinically, jaundice with a moderate increase in the blood content of direct bilirubin and its appearance in the urine. With liver biopsy in hepatocytes, a dark, brown-orange pigment (lipochrom) is detected.
Rotor Syndrome (conjugated hyperbilirubinemia). Clinically similar to the previous syndrome, but unlike it, in the syndrome of Rotor there is no accumulation of pathological pigment in the cells of the liver. The syndrome has a benign course, is inherited by an autosomal recessive type.
Subhepatic jaundice (mechanical or obstructive) develops when there is an obstruction to the flow of bile through the extrahepatic bile ducts. The causes are: a) obturation of the hepatic and common bile duct with stone, parasites, tumor; B) compression of the bile ducts by a tumor of nearby organs, cysts; C) narrowing of the bile ducts with postoperative scars, spikes; D) dyskinesia of the gallbladder as a result of disturbance of innervation. With subhepatic jaundice, pain syndrome, nausea, vomiting, and upset of the stool are observed. Prolonged cholestasis is accompanied by an increase in the liver, which depends on the overflow of its stagnant bile and increase in the mass of the hepatic tissue. At the beginning of the development of mechanical jaundice, the hepatic cells still continue to produce bile, but the outflow of it in the usual ways is disturbed, and it pours out into the lymphatic fissures, getting from there into the blood. In the blood, the amount of bilirubin bound increases. Isolation of urobilin with urine is absent, the isolation of stercobilin with feces is reduced or insignificant. The blood contains all the components of bile, including bile acids, leading to the development of cholemia. In addition, this type of jaundice is characterized by achiolia, which is caused by a persistent violation of bile excretion through the bile capillaries (which leads to intrahepatic cholestasis), ducts and from the gallbladder.
Acholia syndrome is a condition characterized by a significant decrease or cessation of bile flow into the intestine, combined with a violation of cavitary and membrane digestion. In this syndrome, there are: a) steatorrhea (loss of body fat with feces as a result of a violation of emulsification and assimilation of fat in the intestine due to a deficiency of bile); B) dysbacteriosis; C) intestinal autoinfection and intoxication due to loss of bactericidal action of bile, which promotes the activation of processes of putrefaction and fermentation in the intestine and the development of flatulence; D) deficiency of fat-soluble vitamins (A, D, E, K), leading to impairment of twilight vision, demineralization of bones with the development of osteomalacia and fractures, a decrease in the effectiveness of the antioxidant tissue protection system, development of hemorrhagic syndrome; E) decolorized feces due to a decrease or absence of bile in the intestine.
Gallstone disease is one of the most common diseases, occupying the third place after cardiovascular pathology and diabetes. In Russia, the prevalence of this disease varies between 3-12%.
According to the chemical composition, three types of gallstones are distinguished: cholesterol (cholesterol content 79% and higher), black pigment and brown pigment. Cholesterol and black pigmented stones are formed mainly in the gall bladder, brown - in the bile ducts. In Russia, with cholelithiasis, cholesterol stones are more common (80-90%).
There are 4 main groups of factors that take part in the formation of cholesterol stones: 1) promoting the saturation of the bile with cholesterol; 2) contributing to precipitation of cholesterol; 3) causing a violation of the gallbladder; 4) leading to disruption of enterohepatic circulation of bile acids.
Factors contributing to the saturation of bile with cholesterol:
- age (with the increase in the content of cholesterol in bile);
- Sex (women have cholelithiasis 3-4 times more often than men). Sexual differences are associated with the hormonal background. Chololithiasis is common in women who have repeatedly given birth. During pregnancy, the evacuation function of the gallbladder suffers, which subsequently leads to the formation of gallstones;
- heredity (risk of gallstones formation is 2-4 times higher in people whose relatives suffer from cholelithiasis);
- obesity (increased synthesis and excretion of cholesterol);
- food (high cholesterol foods, refined carbohydrates). It is believed that drinking coffee 2-3 cups a day reduces the risk of gallstones;
- liver disease. It is suggested that people with HbsAg have the risk of gallstones.
Factors contributing to the precipitation of cholesterol:
- Bile proteins (the most important is mucinglicoprotein gel - N-aminopeptidase, immunoglobulins, phospholipase C, etc.);
Calcium bilirubinate. In the center of cholesterol stones is bilirubin, and, apparently, cholesterol crystals are deposited in the gall bladder on protein-pigment complexes.
Factors leading to a violation of the basic functions of the gallbladder (contraction, absorption, secretion). Disturbance of gallbladder emptying, which is observed with flatulence, pregnancy, decreased sensitivity and the number of receptors for cholecystokinin, methionine, etc., which are stimulants of motor activity. It is established that with age, the sensitivity of the gallbladder receptors to stimulants (cholecystokinin) decreases. The contractile function of the gallbladder is reduced by somatostatin, atropine, bile acids and other agents.
Factors leading to disruption of enterohepatic circulation of bile acids.
- diseases of the terminal section of the small intestine;
- resection of the ileum;
- diseases of the small intestine with severe impairment of absorption (eg, gluten enteropathy), as well as resection of the small intestine with violation of all major types of metabolism and absorption of bile acids;
- bile fistula (contribute to a massive loss of bile acids).
Pathogenesis of the formation of cholesterol stones
The main pathogenetic factors: a) glut of bile with cholesterol; B) violation of the colloidal properties of bile, increased mucus formation, precipitation of cholesterol crystals; C) a decrease in the evacuation function of the gallbladder.
Pathogenesis of formation of pigmented stones
Pigmented are stones containing less than 30% cholesterol. Isolate black and brown pigmented stones.
Black pigmented stones account for 20-30% of the total number of gallstones, more common in old age. They consist mainly of calcium bilirubinate, phosphate and calcium carbonate without an admixture of cholesterol. The formation of such stones is characteristic for chronic hemolysis (hereditary spherocytic or sickle cell anemia), implantation of artificial heart valves, liver cirrhosis.
Brown stones are localized mainly in the bile ducts. These stones contain calcium bilirubin, palmitate and calcium stearate and cholesterol. Their formation is associated with infection (E. coli, opisthorchiasis, giardiasis, etc.). Under the influence of bacteria glucuronidase, deconjugation of direct bilirubin occurs, which leads to precipitation of insoluble unconjugated bilirubin. Brown pigmented stones are usually formed above the strictures or in the areas of dilatation of the biliary tract.
Gallstone disease, as a rule, does not have specific symptoms. The exception is biliary colic, which attacks are usually associated with an error in the diet and develop after a plentiful intake of fried, spicy food. The cause of the disease is mechanical irritation of the gallbladder wall and bile ducts with a stone, their hyperextension.
The main method of diagnosis of cholelithiasis is ultrasound.
Experimental modeling of liver pathology
A number of experimental methods used to study liver functions in physiological and pathological conditions are known.
The imposition of fistula Ecka is a method applied in 1877 by the Russian researcher Eck in the laboratory of N.V. Tarkhanov. It consists in the following: an anastomosis is created between the lower hollow and portal veins in dogs. The portal vein above the anastomosis is bandaged, and all blood flowing from the organs of the abdominal cavity enters directly into the lower vena cava, bypassing the liver. This experiment made it possible to study the detoxifying, as well as urea, formation of the liver.
After Eck's operation in animals, ataxia, maneuvers, periodically clonic and tonic convulsions appeared in animals 3-4 days later when feeding with meat food or 10-12 days after using the milk-plant diet. The blood increased ammonia, which is normally disinfected in the liver, protein synthesis was reduced, cholesterol metabolism and bile formation were disturbed.
Back fistula Ekka-Pavlova. In 1893, I.P. Pavlov proposed after dressing the anvil on the gates and in the lower vena cava to tie up the anus not the gates but the lower vena cava. In this case, the blood rushed blood not only from the digestive tract through the portal vein, but also from the posterior half of the trunk. Animals with such a fistula live for years. This experimental model is used to study the functional state of the liver under different conditions of the food load.
Complete removal of the liver. Produced in two stages. In the beginning, the back fistula Ekka-Pavlova is reproduced. The consequence of this operation is the development of collateral circulation. As a result, a part of the venous blood from the back of the body through v. Azygos and internal thoracic veins are diverted to the upper vena cava, bypassing the liver. 3-4 weeks after the first operation, the second is performed: the portal vein is bandaged and the liver is removed. In the next few hours after liver removal, the muscular weakness, adynamia, abruptly decreases the sugar content in the blood and at a decrease of less than 2.5 mmol / l, hypoglycemic coma may develop, followed by the death of the animal. The introduction of glucose can prolong the life of the animal. At the same time, the amount of ammonium compounds increases in the blood and the urea content decreases. Dogs after such surgery live no more than 12-15 hours. Removal of the liver is, in fact, an experimental model of the hepatic coma. After partial removal of the liver (up to 3/4 of the body), very severe disturbances of metabolism do not occur because the rest of the liver retains its functions and implements compensatory possibilities.
When studying the functional role of the liver in normal and pathological conditions, the angiostomian method of ES is also used. London, proposed in 1919. Metal cannulas (stainless or silver) are attached to the walls of large blood vessels (portal and hepatic veins), the free ends of which are removed through the covers of the abdominal wall to the outside. Cannulas make it possible to systematically draw blood from vessels and introduce various substances into them. The method of angiostomy has given much valuable in the study of the role of the liver in bilirubin formation, carbohydrate, protein, fat and salt metabolism.
An experimental model is the method of perfusion of an isolated liver. Liver donors are mainly laboratory animals: rats, rabbits, cats. Now for these purposes the liver of large animals is used: dogs, pigs and calves. This experimental model is applicable for studying the role of the liver in metabolic processes, as well as in solving organ transplant problems.
For the experimental reproduction of liver diseases, infectious and toxic agents are introduced into the body. A strong hepatotropic poison is CC14 (four-carbon chloride). Parenteral administration of 0.2 ml / 100 g of an 80% oily solution of this substance causes alteration and necrobiosis of hepatocytes in the central zones of the hepatic lobules. Chloroform, heliotrope seeds are also used for these purposes. Fat hepatitis is reproduced by the introduction of hydrazine sulphate and alcohol. The toxic effect of alcohol on the liver is expressed in vascular disorders and focal dystrophic-destructive changes in the parenchyma.