MINISTRY OF PUBLIC HEALTH OF UKRAINE
BUKOVINIAN STATE MEDICAL UNIVERSITY
Approval on methodological meeting
of the department of pathophisiology
Protocol №
Chief of department of the pathophysiology,
professor
Yu.Ye.Rohovyy
“___” ___________ 2008 year.
Methodological Instruction
to Practical Lesson
Мodule 2 : PATHOPHYSIOLOGY OF THE ORGANS AND SYSTEMS.
Contenting module 6. Pathophysiology of digestion, liver and kidney.
Theme 14: PATHOPHYSIOLOGY OF THE LIVER-1
Chernivtsi – 2008
1.Actuality of the theme. The diseases of liver and bile exretory
system take considerable specific weight in a general morbidity of the
population, and last decade the further growth of them was increased.
Technological revolution and associated with it the negative ecological shifts
have resulted in useful increase of frequency and spread spectrum of diseases of
liver and cholic tracts. In connection with urbanisation of life, hypokinesia, and
also such negative phenomenon as alcoholism, morbidity the hepatitises and
cirrhosis of liver, cholelithiasis and cholecystitis considerably has increased.
The chemicalization of effecting, agriculture, mode of life activities and
medicine promoted growth of frequency of toxic and medicamental damages of
liver. Sharp increase of medical manipulations, blood transfusion have
stimulated useful increase of morbidity by serumal hepatitis.
The main morphological types of damages of liver is hepatitis, cirrhosis,
cancer. Etiological value in formation of the majority of acute and chronic
diseases of liver have the agents many zymotic and infection diseases (viruses,
bacteria, spirochetes, pathogenic fungi, elementary, helminths) and toxic
substances - hepatotoxins, including alcohol and medicin drugs. Therefore
preventive maintenance encompasses them the broad audience of problems. The
pathogenetic treatment of diseases of liver bases on knowledge of their
mechanisms of disturbance of structure and function of liver, which one are
revealed with the help biochemical, cyto-chemical, radio-isotope and other
method of testings.
2.Length of the employment – 2 hours.
3.Aim:
To khow: the pathogenesis of the liver fatty infiltration.
To be able: to analyse the mechanisms of the complications of liver
dysfunction.
To perform practical work: to analyse the mechanisms of the liver fibrosis.
4. Basic level.
The name of the previous
disciplines
1.
histology
2.
biochemistry
3.
physiology
The receiving of the skills
Structure of liver and bile excretory.
Features of blood supply of liver.
Functions of liver.
Participation of liver in metabolism of
carbohydrates, fat and proteins.
Mechanism of detoxical function of liver.
Metabolism of cholic pigments.
5. The advices for students.
1. Microscopic architecture of the liver parenchyma. Both a lobule and an
acinus are represented. The classic hexagonal lobule is centered around a central
vein (CV), also known as terminal hepatic venule, and has portal tracts at three of
its apices. The portal tracts contain branches of the portal vein (PV), hepatic artery
(HA), and the bile duct (BD) system. Regions of the lobule are generally referred
to as "periportal," "midzonal," and "centrilobular," according to their proximity to
portal spaces and central vein. Another way of defining the architecture of the liver
parenchyma is to use the blood supply as a source of reference. Using this
approach, triangular acini can be recognized. Acini have at their base branches of
portal vessels that penetrate the parenchyma ("penetrating vessels"). On the basis
of the distance from the blood supply, the acinus is divided into zones 1 (closest to
blood source), 2, and 3 (farthest from blood source).
2. The liver is a big chemical laboratory. The liver is the most important
glandular organ providing the constancy of the medium of the organism ("a big
chemical laboratory" by Ludwing). The following processes take place in the
liver: 1. The creation of bile pigments synthesis of cholesterol, synthesis and
secretion of bile. 2. The detoxication of toxic products, coming from
gastrointestinal tract. 3. The synthesis of proteins (proteins of plasma of blood
among them), their deposition, transamination and desamination of aminoacids,
the formation of urea, the synthesis of creatinine. 4.
The synthesis of
glycogene from monosaccharides. 5.
The oxidation of fatty acids, the
formation of acetone ami ketone bodies. 6. The deposition and exchange of
vitamins (А,ВД), the deposition of iron, copper, zinc ions. 7. The regulation
of the balance between coagulant ami anticoagulant blood system, the formation
of heparine. 8. The destruction of some microorganisms, bacterial and other
toxins. 9. The deposition of plasma of blood, the regulation of a total amount
of blood. 10. Hemopoiesis in the fetus.
3. The cases of 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 (CCl 4, 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.
4. Carbohydrate metabolism disorder in liver.
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.
5. 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 link 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.
6. 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).
7. Microelements metabolism disorder in liver.
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.
8. Cirrhosis of the liver.
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, and
that leads to further death of hepatocytes, fibrosis spreading and the loss of
hepatocytes ability to regenerate. The cell mass decreases. The decreased
parenchyma does not correspond to the metabolism demands. The liver
insufficiency takes place.
9. Antitoxic liver 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.
10. 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 flow and 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 αketoglutaric acid from Krebs cycle slows down ATP and decreases energy
outcome in neurons, 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, βphenilethyramine, 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 in neurones and in intercellular liquid.
5.1. Content of the theme. Microscopic architecture of the liver
parenchyma. The liver is a big chemical laboratory. The cases of liver pathology.
Carbohydrate metabolism disorder in liver. Fat metabolism disorder. Liver fatty
infiltration. Protein metabolism infringement. Microelements metabolism disorder
in liver. Cirrhosis of the liver. Antitoxic liver function disorder. Hepatocerebral
coma.
5.2. Control questions of the theme:
1. Microscopic architecture of the liver parenchyma.
2. The liver is a big chemical laboratory.
3. The cases of liver pathology.
4. Carbohydrate metabolism disorder in liver.
5. Fat metabolism disorder. Liver fatty infiltration.
6. Protein metabolism infringement.
7. Microelements metabolism disorder in liver.
8. Cirrhosis of the liver.
9. Antitoxic liver function disorder.
10. Hepatocerebral coma.
5.3. Practice Examination.
Task 1. The patient which one has transferred hepatitis and still use alcohol, the
signs of cirrhosis of liver with an ascites and edemas on the lower
extremitus have appeared. What change of blood structure has become
determining in development of edemas?
A. Hypoalbuminemia B. Hypoglobulinemia C. Hypocholesterinemia
D. Hypopotassiemia E. Hypoglycogenemia
Task 2. The inflammatory processes in cholic bladder arise in change of colloidal
properties of bile. As a result of it the components of bile crystallize,
precipitate and originate formation of gallstones. Crystallization of what
substans have principal value?
A . Sodium phosphates B. Urates C. Sodium oxalates D. Proteins
E. Cholesterol
Task 3. The man 38 years old working on chemical manufactury, has noted icteric
staining of skin. The examination of given following results: an anemia,
increase nondirect bilirubin in blood, increase of stercobilin in feces and
urine. Splenomegalia. It’s:
A. Hemolytic icterus B. Mechanical icterus C. Parenchymatous icterus
D. Inheritable icterus of Dgilbert Е. Inheritable icterus of Kriglers-Nahjar
Task 4. The patient with cirrhosis of liver and ascites. The main role in its
development belongs to:
A. Increased production of аldosteronum B. Hyperproduction of
antidiuretic hormone C. Decrease of protein in a blood
D. Hypertension in portal vein E. Increased permeability of vessels
Task 5. The patient, long time suffering from cholecystitis, has come in polyclinic
with complains to sharpening of illness. The headache, disorders of sleep ,
irritability, dermal itch, icteric tint of skin have appeared. The feces is
decolorized. A pulse rate - 64 in 1 minutes, arterial pressure – 105/75 mm
Hg. These information testify delay of outflow of bile and development of
cholemic syndrome. Its pathogeny is conditioned by accumulation in
blood
A. Aethers of cholesterol B. Nondirect bilirubin C. Direct bilirubin
D. Cholic acids E. Fatty acids
Task 6. The patient with a cholecystitis, which one has become complicated with
mechanical icterus, the hemorrhagic syndrome was advanced. It is
connected with
A. Accumulation of cholic acids in the blood B. Increase of bilirubin in
blood C. Delayed absorption of fatty acids D. Lack absorption of
vitaminum K E. Lack absorption of calcium
Task 7. To experimental dog the liver is completely removed. In some hours she
will die from
A. Hypoalbuminemia B. Hypoglycogenemia C. Acidosis
D. Hemorrhage E. Hyperamoniemia
Real-life situations to be solved:
The patient complain on dermal itch , irritebleness, disorders of sleep, fast
weakening. A skin and mucous icteric colour. A pulse rate - 56/mines, arterial
pressure - 100/75 mm Hg. A feces acholic. A urine darkcolour.
.
What type of an icterus?
.
What it can be caused by?
.
Why patient has the irritability of skin?
.
What stained skin and mucous by?
.
.
.
What components of bile cause low pulse and low arterial pressure?
What the decolorization of feces is connected?
Why the urine has dark colour?
Literature:
1.Gozhenko A.I., Makulkin R.F., Gurcalova I.P. at al. General and clinical
pathophysiology/ Workbook for medical students and practitioners.-Odessa, 2001.P.216-222.
2.Gozhenko A.I., Gurcalova I.P. General and clinical pathophysiology/ Study
guide for medical students and practitioners.-Odessa, 2003.- P.277-290.
3. Robbins Pathologic basis of disease.-6th ed./Ramzi S.Cotnar, Vinay Kumar,
Tucker Collins.-Philadelphia, London, Toronto, Montreal, Sydney, Tokyo.-1999.