PATHOPHYSIOLOGY OF A LIVER

PATHOPHYSIOLOGY OF LIVER

 

The main liver functions are as follows: metabolic, disintoxicative, bile forming and bile excretory. Besides that, liver participates in digestion, blood coagulation, thermoregulation, hemodynamics, phagocytosis and other processes.

Ethiology of liver functions violation

In the prevailing majority of cases, liver pathology is presented by two processes:

1)    Hepatitis – liver inflammation;

2)    Cirrhosis – the intensified diffuse growth of the new connective liver tissue (stroma) on the background of dystrophic and necrotic hepatocytes (parenchyma) damage.

Liver diseases are caused by the great number of factors:

1) Infectious agents – hepatitis virus, Koch’s bacillus, pale Spirochaeta, Actynomyces, Echinococcuses, Ascarises;

2) Hepatotropic poisons, including medicines – tetracycline, PASA (paraaminosalycil acid), sulphanilamides, industrial poisons (CCl₄, arsenic, chloroform); plants poisons (aphlatoxine, muscarine);

3) Physical influences – ionizing radiation;

4) Biological substancies – vaccines, serums;

5) Blood flow violations – thrombosis, embolism, venous hyperemia;

6) Endocrine pathology – diabetes mellitus, hyperthyroidism;

7) Tumors;

8) Hereditary enzymes pathology.

 Liver diseases pathogenesis is characterized by two main mechanisms:

– the direct hepatocytes affection – dystrophy, necrosis;

– autoimmune injury  of hepacytes by autoantibodies, which are formed in response to hepacytes antigens structure changed.

Liver affection by any of the above described etiologic factors may lead to such state, when the liver becomes not capable to execute its functions and to provide the homeostasis. That state is called the liver insufficiency. It may be total, when all functions are suppressed; or partial, when only some functions suffer, e.g., the bile-forming one.

Metabolic function failure

Liver is the central organ of the chemical homeostasis. It is placed between the collar vein from one side, and the systemic circulation from the other. Its placement should be recognized as the optimal one for the execution of the metabolic function. All substances coming with food, excluding only those, which are transported via mesentery lymphatic vessels into the breast blood stream, must go through the liver. Only in such way, with liver participation, food is either decomposed, or expelled, or deposited.

The metabolic liver function means liver participation in the chemical elements metabolism of almost all classes – carbons, fats, proteins, enzymes, vitamins. Hepatocytes affectioegatively influences each of those metabolisms.

Carbohydrate  metabolism disorder

Glycogen synthesis and its splitting are the main regulatory processes, with the help of which liver keeps glucose homeostasis, particularly its level in blood. The slowing-down of glycogen synthesis may happen at any hepatocytes affection. That leads to the simultaneous limitation of glucuronic acid formation, which is indispensable in disintoxication of many exogenic poisons (industrial toxins) and final metabolites (cadaverine, putrescine) and unconjugated bilirubin.

The slowing-down of glycogen splitting in liver is conditioned by corresponding enzymes defect or their total absence. The diseases belonging to that group are called glycogenosises, all being of inheritable origin. They are manifested by glycogen accumulation in liver, by hepatomegalia and hypoglycemia. Several forms are distinguished among them, depending which enzymes is not synthesized.

Glycogenosis of type I is caused by the defect of glucose-6-phosphatase (Hirke disease). This enzymes provides the formation of 90 % of glucose, which is released in liver from glycogen, thus it plays the central role in glucose homeostasis. Glucose, which is formed at glycosis or gluconeogenesis, undergoes phosphorilation to glucose-6-phosphate (G-6-Ph). Before entering the blood stream, it should get rid of the phosphate group. If that does not take place (G-6-Ph deficit), then glucose does not come into blood and hypoglycemia appears. Then the majority of G-6-Ph is used for glycolysis with the formation of lactate with hyperlactatemia development (metabolic acidosis). A part of G-6-Ph participates in the pentosophosphatic cycle and is turned into 5-ribosilpirophosphate – the predecessor of the lithic acid. The urates production increases, the urates being badly removed through kidneys at hyperlactatemia. The combined hyperuricemia takes place – productive + retentive.

Glycogenosis of type III (Korri disease, Forbs disease, so called debrancher enzyme defect) is the deficit of amilo-1,6-glucosidase, the enzymes, which breaks the connections in the places of glycogen molecule branching. That is why the branched molecule does not turn into a direct chain of glucose monomers. In response to the decrease of glucosa level in blood, glycogen is rended only to the branching areas. In the result of that, a lot of unsplitted glycogen accumulates in hepatocytes. Hepatomegalia, hypoglycemia and cramps take place. However, some part of glucose does come into blood.

Glycogenosis of type VI (Gers’s disease) is conditioned by the deficit of liver phosphorilasis complex – proteinkinasa, phosphorilasa kinasa and phosphorilasa. Glycogen mobilization in response to glucagone action becomes not possible, as the result liver is enlarged. However, hypoglycemia is not characteristic for that state.

The galactose-I-phosphaturidiltranspherasa deficit causes galactozemia and hepatomegalia.

 

Fat metabolism disorder. Liver fatty infiltration

One of the most striking liver functions is the critical evaluation of the correlation among food substances, which come to it from the stomach via the collar vein. If there is no balance in food ingredients, the liver reacts very peculiarly – it takes for a temporal depositing the surplus substances and stores them until the necessary product appears to construct macromolecules and to expel them into blood.  At pathologic conditions, liver stores mainly fats. That phenomenon is called the fats liver infiltration.

Exogenic triglycerides are hydrolyzed in the intestines, and in enterocytes they are resynthesized and come into the liver as a part of hylomicrones. They come into hepatocytes and are decomposed to fatty acids and glycerin. Fatty acids are partly oxidized and partly participate in the formation of triglycerides, phospholipids and cholesterin ethers. The formed triglycerides are expelled by the liver into blood in the form of lipoproteides of very low and of low density.

The production of lipoproteides by the liver demands the close linkage of the processes of lipidic and albumin synthesizes. The availability of the starting products is also indispensable, but in the balance amount. The reason of fats infiltration can be any agent, which violates this balance in such way, that lipids amount become higher in the correlation to albumins amount. In the result of that it is impossible to involve the liver lipids into the synthesis of lipoproteides and to excret them into blood. A part of lipids deposits in liver.

Liver fats infiltration becomes possible in such cases:

a) The increased lipolysis in the fat tissue, most often – at the decompensated diabetes mellitus. The lipidic predecessors of lipoproteides (fatty acids) are so high at diabetes patients, that they have no time to start to participate in triglycerides synthesis and the last – in lipoproteides synthesis.

b) Hypoglycemia (at starvation or glycogenosis) can provoke the liver fats infiltration. In the conditions of glucose deficit, the insulin production secondarily decreases and lipolysis is activated. The excess of free fat acids, which come into the liver, can exceed the abilities to join triglycerides into lipoproteides. The incompatibility between the delivery and synthesis processes provokes the fats infiltration.

c) Lipoproteides production and fats expelling from the liver decrease in the conditions, when sources of aminoacids are restricted (e.g., at albumin starvation), thus apoproteines synthesis is decreased. Lipides, as raw material for lipoproteides synthesis, remain unused because the deficit of protein component.

d) The fatty infiltration can be caused by the lipotropic aminoacids deficit (choline and metionine) in food.

e) The same picture can be caused by B₁₂ – hypovitaminosis and folic acid deficit, because it is caused by endogenic choline deficit.

f) The fatty infiltration can be also conditioned by toxins influences, for example amanitotoxine, which blockes ß-oxidixation of fatty acids in mitochondrias.

g) Hypoxia is believed to be one of the important pathogenic links of fatty infiltration. All factors, which cause the lasting hypoxia or suppress mitochondrias, the limit of hepatocytes energy synthezise, lead to the fatty distrophy of the liver.

Protein metabolism infringement

The main consequences of albumin metabolism infringement at the liver affection are as follows:

a)     Hypoproteinemia is the result of blood level decrease of albumins, α- and β-globulins, which are synthesized by hepatocytes. It leads to hypooncia and as the result edema develops.

b) Hyper-gamma-globulinemiais the result of   gamma-globulines synthesize increase by Kuffer’s cells and plasmocytes.

c) Dysproteinemia is the result of macroglobulins and crioglobulins accumulation.

d) Hemorrhagic syndrome in the result of the decreased synthesis of blood coagulation factors (besides УШ factor).

e) The increase of blood RN (retarded nitrogen) in the result of the decreased urea synthesis and ammonia accumulation. That happens at 80% parenchyma affection.

f) Increase of enxymes level in blood (aminotranspherases).

Microelements metabolism disorder

The well-known example is Wilson’s disease, when copper deposits in hepatocytes. Normally, the copper, which comes into a hepatocyte, is distributed among the cytoplasm and the subcellular organals. There is a special albumin in the liver – metall-thionein, which binds copper. It functions as a temporal copper depositor. In some time, the deposited copper enters the metal-containing enzymes, or is withdrawn with bile. Some persons have got metall-thionein with very high relation to copper, which is determined hereditary. That shifts of copper liver pool balance in such a way that leads to the drop of its secretion with bile and to the decrease of its joining the ceruloplasmin, an albumin that transports copper in blood. At the long-term copper accumulation by abnormal metall-thionein, the binding centres satiate, and copper excess is absorbed by liver lysosomes. The metal is accumulated in hepatocytes and leads to hepatomegalia.

 Cirrhosis

In the final result, the metabolism violation in the liver may lead to cirrhosis. This is a complicated process, which results in abnormal connective tissue growth. The clue of understanding of this matter lies in anatomic connection of the liver lobe with the microcirculation unit – a blood capillary, a billary duct and a lymphatic vessel. The more stable to demage and capable to regenerate are the hepatocyte of 1-st zone, and the less stable to demage and capable to regenerate are the hepatocyte of 3-d zonemore sensible, wich are localised afar to the microcirculation unit.

The cirrhosis development depends on the nature, the level and the duration of the unfavourable influence onto the liver parenchyma. The liver has got a wonderful ability to regenerate. If a rat is ablated of 50-70 % of the liver, this organ regenerates its initial mass within quite a short period of time. In that case, however, the damage has only the quantitative and local character, and not the difuse one, when damage captures more sensible cells in the whole organ simultaneously. E.g., at Wilson’s disease hepatocytes are liable to chronic influence of the unphisiologically high copper concentrations. That damage is not local any more, it spreads over the whole liver. Hepatocytes of zone 3, which are the least capable to withstand a damage, die and are replaced with the more resistant hepatocytes of zones 2-nd and 1-st. That leads to the unorganized parenchyma regeneration that is characteristic for cirrhosis. Parallel, fibroblasts are activated, and the additional connective tissue starts to be synthesized. Its growth is a determinant process in the cirrhosis formation.

Fibroblasts activation leads to the excess synthesis by them of glucosaminoglycanes, glycoproteides and collagen. Normally, collagen is adjusted to cellular surface, and its synthesis is restricted by the cellular surface. However, in the process of fibrosis, collagen is formed behind its connection with a cell, and is located chaotically. Anatomic correlations in a liver lobe alter. The lobe structure is distorted by the regenerating parenchyma nodules and the nodules of the fibrous connective tissue. The blood stream through the lobes is violated (portal hypertension arises), and that leads to further death of hepatocytes, fibrosis spreading and the loss of hepatocytes ability to regenerate. The cell amount decreases. The decreased parenchyma does not correspond to the metabolism demands. The liver insufficiency takes place.

Antitoxic function disorder

 The antitoxic liver function aggravation is connected to the violation of certain reactions directed to rendering harmless the toxic substances, which are formed in an organism or come from outside:

a) Urea synthesis disorder resulting in ammonia accumulations.

b) Conjugation disorder, i.e. the formation of pair compounds with glucuronic acid, glycin, cystine, taurine. In such way unconjugated bilirubin, scatol, indol, phenol, kadaverin, thyramin, etc. become harmless.

c) Acetylization disorder leading to sulphamides accumulation at their long-term usage.

d) Oxidization disorder leading to the accumulation of aromatic carbons.

Deep disorders of the antitoxic liver function bring forward liver encephalopathy and liver coma.

Hepatocerebral coma

The Hepatocerebral coma is a syndrome developing in the result of the liver insufficiency. It is characterized by the deep affection of the central nervous system (consciousness loss, reflexes loss, cramps, blood flowand breathing disorders).

The most frequent liver coma reasons are as follows: viral hepatitis, toxic liver dystrophy, cirrhosis, portal hypertensia. The main mechanism of the central nervous system damage is the accumulation of toxic neurotropic substances:

a) Ammonia. In liver mytochondria urea is synthesized from ammonia. At liver affection, ammonia does not join the urea cycle (ornitative cycle). Ammonia binds with α-ketoglutaric acid and forms glutaminic acid. Exclusion of α-ketoglutaric acid from Krebs cycle slows down ATP and decreases energy outcome ieurons, decreases their repolarization and function.

b) Rotting products, which are absorbed from the large intestine – phenol, indol, skatol, kadaverine, thyramine.

c) Low-molecular fatty acids – oleic, capronic, valeric. They interact with lipids of neurons membranes and slow down the excitement transfer.

d) Pyroracemic acid derivatives – acetoine, butylenglicol.

Other pathogenic links:

a) Aminoacid disbalance in blood – the decrease of valine, leucine, isoleucine: the increase of phenylalanine, thyrosine, thryptophane, metionine. In the result of that, false mediators are synthesized – oktopamine, β-phenilethyramine, which displace noradrenaline and dophamine from synaptosomes and block synaptic transfer to the central nervous system.

b) Hypoglycemia resulting from gluconeogenesis or glycogenolysis weakening in hepatocytes that additionally restricts ATP synthesis in the brain.

c) Hypoxia of hemic type in connection with the blockage of the breathing surface of erythrocytes by toxic substances.

d) Hypopotassiumia as the result of the secondary aldosteronism.

e) Disorder of the acid-basic balance ieurones and in intercellular liquid.

 

Disorders of bile formation and secretion. Jaundices

Liver cells secret bile. It consists of water, bile acids, bile pigments, cholesterine, phospholipids, fat acids, mucin and other ingredients. The main indicator of bile formation and bile secretion is the secretion of bile pigments, i.e. bilirubin and its derivatives. Bilirubin is formed in SMP cells (liver, spleen, red bone marrow) from the gem by chipping-off iron by means of hemoxygenase (biliverdin) and further renovation by biliverdin-reductase (unconjugated bilirubin). Its paradoxical, but the transformation of biliverdin into bilirubin decreases the substance solutability, and its secretion becomes problematic. Unmconjugated bilirubin is not soluble in water. In blood, 75 % of it binds with albumin and circulates in such form. Unconjugated bilirubin approaches the hepatocyte and binds with lipandin, the albumin placed on its surface, or with γ-albumin, which might be identical to glutation-5-transpherasa. Ligandin transports unconjugated bilirubin to microsomes, where it binds with glucuronic acid (conjugation). The reaction is catalized by microsomic UDP-glucuroniltranspherasa (uridine-dyphosphate- glucuroniltranspherasa). Monoglucuronide and bilirubin dyglucuronide are formed. The conjugated bilirubin is secreted into the duodenum and is removed from the organism as stercobilin with feces and urine. A part of the conjugated bilirubin is restored up to urobilinogen in liver ducts, gallbladder and small intestines under the influence of microflora enzymes. Urobilinogen does not enter the general blood flow and normally is not excreted. It is absorbed into the liver vein and is splitted by the liver to pirolites (figure).

The violation of bile formation and bile excretion is manifested by characteristic syndromes: jaundice, cholemia and steatorrhea.

Jaundice (icterus)

This means yellowishing of skin, mucous membranes and sclera in the result of bile pigments depositing in them. There are three types of jaundice:

A.   Hemolytic jaundice, conditioned by the surplus formation of unconjugated bilirubin or by the violation of its transportation.

B.   Parenchimatous jaundice, conditioned by hepatocytes pathology.

C.   Obstructive jaundice, which takes place on the basis of the insufficient bile outflow.

 

Hemolytic jaundice appears, as a rule, in the result of the excess erythrocytes hemolysis. Its reasons are the same as for the haemolytic anemia. The special features of bile pigments exchange at this jaundice are as follows: in the blood – high level of unconjugated bilirubin; in the feces – stercobilin concentration is increased; in the urine – stercobilin concentration is increased too, and no cholemia.

Parenchimatous jaundice is conditioned by endogenic (inheritable) and outside influences.

The basis of inheritable hepatic jaundice is the violations of the unconjugated bilirubin capture by hepatocytes, its insufficient conjugation or its insufficient isolation of the conjugated bilirubin from the hepatocyte.

The insufficient capture of the unconjugated bilirubin brings forward Jilbert’s syndrome. The genetic defect means the blockage of ligandin (γ-albumin) synthesis, which transports unconjugated bilirubin through the membrane to the inside of the hepatocyte.

The low intensity of conjugation depends on the defecit of UDP-glucuroniltranspherasa of hepatocytes. Krigler-Nayar syndrome takes place. At the total absence of the enzymes (type I), the classic bilirubinous encephalopathy develops; at autopsy the nucleus jaundice is found out. The majority of sick children die, and those, who don’t, suffer with choreoathetosis. Child’s brain is especially disposed to the development of bilirubinous encephalopathy within the first weeks or months of life. At type II the conjugative ability of hepatocytes increases after phenobarbital introduction. The introduction this substance within 2-3 weeks normalizes bilirubin level in blood.

The laboured discard of the conjugated bilirubin from the hepatocyte into the bile is clinically displayed by two syndromes: Dubin-Johnson and Rotor.

The acquired liver jaundice is connected with the hepatocytes affection by virous, toxic and other agents. Its pathogenetic mechanism is the decrease of conjugation processes.

Parenchimatous jaundice is characterized by the following violations of bile pigments metabolism: in the blood – the unconjugated bilirubin concentration is increased and the conjugated bilirub appears; in the feces – stercobilin drops; in the urine – stercobilin drops, the appearance of urobilin and conjugated bilirubin.

Obstructive jaundice is connected with the obstruction for bile outflow (tumour, cholelithiasis).

Peculiarities of bile pigments metabolism at this type of jaundice are as follows: in the blood – the increase of the unconjugated bilirubin and the appearance of the conjugated bilirubin; in the feces – the absence or the drop of stercobilin; in the urine –  the absence or the drop of stercobilin, the appearance of the conjugated bilirubin.

Cholemic syndrome appears at obstructive and parenchimatous jaundices, when bile comes into blood. It is caused by bile acids and the main symptoms are the next: bradycardia, hypotension, excitability, skin itch.

Steatorea is a syndrome, which is based on the violation of digestion and fats absorption. Fats are excreted with feces. The fat-like vitamins are being lost together with fats.