Pathology of the cell: cell injury, intracellular accumulations.

Extracellular accumulation of substances.

All the diseases, in some way, morphologically are represented as organ

insufficiency, the cause of which is tissue injury. All forms of tissue injury start with
molecular or structural alterations in cells. It is necessary then to begin our consideration
of pathology with an examination of disease at the cellular and subcellular levels.
The cell injury begins at cellular alteration.
Alteration (change) is the pathological changes of cells structure, intercellular
material, tissue and organs which are accompanied by violation of their vital functions.
Cell injury is reversible up to a certain point, but with severe or persistent stress,
the cell suffers irreversible injury and is fated to die.

Reasons of development of alteration:

1. hypoxia
2. chemicals and drugs
3. physical agents
4. microbiological agents (bacteria, viruses, mushrooms)
5. immune mechanisms
6. genetic defects (apoptozis)
7. nutritional imbalances
8. aging

Mechanisms of the development of dystrophies (dystrophy morphogenesis):

There are 4 mechanisms - infiltration, decomposition, perverted synthesis,
transformation.
1. Iinfiltration – redundant accumulation (deposition) of metabolites into the
cells and intercellular matix. Infiltration is a surplus penetration of products of exchange
from a blood and lymph in cells or intercellular substances with subsequent their
accumulation in connection with insufficiency of the enzymic systems, metabolysing these
products.
2. Decomposition (phanerosis) – disintegration of membranous structures of
the cells and intercellular matrix. Decomposition in cells and disorganization in tissue is
destruction of cellular membranes and intercellular substances.
3. Perverted synthesis - synthesis of abnormal substances in the cells and
tissues. It is the synthesis of matters that are not meeting in a norm (synthesis of amyloid,
alcoholic gyalin in hepatocytes, glykogen in the epithelium of nefron).
4. Transformation – formation of one type of metabolism’s products from
common initial substances for proteins, fats and carbohydrates. Transformation is the
change of ways of metabolism typical for cells (for the synthesis of albumen fats and
carbohydrates in place of amino acid that are used in hepatocytes).

The cellular morphologic alteration can be divided into:

1) patterns of acute cell injury — reversible and irreversible cell injury leading to
necrosis or apoptosis,
2) subcellular alterations that occur largely as a response to more chronic or
persistent injurious stimuli,
3) intracellular accumulations of a number of substances — lipids, carbohydrates,
proteins—as a result of derangements in cell metabolism or excessive storage.

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 PATTERNS OF ACUTE CELL INJURY
1. Cellular swelling appears if cells are incapable of maintaining ionic and fluid
homeostasis. Macroscopically, organ is pallor, increased turgor, and increase in weight.
Microscopically, small clear vacuoles may be seen within the cytoplasm.
The ultrastructural changes:
(1) plasma membrane - blebbing, blunting, and distortion of microvilli; creation of
myelin figures;
(2) mitochondrial changes - swelling, rarefaction, and the арpearance of
phospholipid-rich amorphous densities;
(3) dilatation of the endoplasmic reticulum with detachment and disaggregation of
polysomes;
(4) nucleolar alterations.
2. Fatty change is appearance of small or large lipid vacuoles in the cytoplasm and occurs
in hypoxic and various forms of toxic injury.

INTRACELLULAR ACCUMULATIONS
Cellular dystrophy is the morphological display of the broken exchange of cell’s
organelles, attended with the change of cell’s structure.

The stockpiled substances fall into three categories:

(1) A normal endogenous substance is produced at a normal or increased rate, but
the rate of metabolism is inadequate to remove it. An example of this type of process is
fatty change in the liver.
(2) A normal or abnormal endogenous substance accumulates because it cannot be
metabolized. The most common cause is lack of an enzyme that blocks a specific
metabolic pathway, so that some particular metabolite cannot be used. When the enzyme
lack is due to a genetically determined inborn error of metabolism, the disorders are
referred to as storage diseases;
(3) An abnormal exogenous substance is deposited and accumulates because the cell
has. neither the enzymic machinery to degrade the substance nor the ability to transport it
to other sites. Accumulations of carbon particles and such non-metabolizable chemicals as
silica particles are examples of this type of alterationa pigment or an infectious product.

INTRACELLULAR ACCUMULATIONS Can represented by accumulation of:

 __ Lipids (fatty changers)
 __ Cholesterol and cholesterol esters
 __ Proteins
 __ Glycogen
 __ Complex Lipids and Carbohydrates
 __ Pigments
Intracellular Lipid accumulation
In the cytoplasm of cells lipids forms moveable lipoprotein complexes, lipids with
proteins – lipoproteids. They make basis of cell membranes.

Reasons:
1. anoxaemia at:
а) diseases of the cardio-vascular system
b) chronic diseases of lungs

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 c) anemia’s
2. diabetes mellitus
3. obesity
4. protein malnutrition
5. hepatotoxins (alcohol abuse)
The most frequent localization: myocardium, liver, kidney

Liver: organ enlarges and becomes yellow, soft and greasy. It is called “goose liver”.
Microscopically there are small fat vacuoles in the cytoplasm of hepatocytes around the
nucleus.

Heart. Lipid is found in heart muscle in the form of small droplets. It occurs in two
patterns:
1. prolonged moderate hypoxia, which create grossly apparent bands of yellow myocardium
alternating with bands of darker, red-brown, uninvolved myocardium “tiger’s heart”.
2. fatty change produced some forms of myocarditis

Kidneys are enlarged, flabby, the cortical substances is grey with yellow drops

Intracellular accumulations of proteins

Any disorder producing proteinuria leads to pinocytotic reabsorption of the protein in
kidney tubules. When these pinocytotic vesicles in the epithelial cells fuse with lysosomes,
hyaline cytoplasmic droplets, which appear pink in hematoxylin and eosin stains, are
formed.
Mechanism: infiltration.
Accumulations of immunoglobulins synthesized in the cisternae of the RER of
plasma cells may create rounded, acidophilic Russell bodies.

Intracellular accumulations of pigments

Pigments can be:
1. exogenous, coming from outside the body,
2. endogenous, synthesized within the body itself.

Exogenous pigment is carbon or coal dust, which is a ubiquitous air pollutant of

urban life. When inhaled, it is picked up by alveolar macrophages and transported through
lymphatic channels to the regional tracheobronchial lymph nodes (anthracosis).

Endogenous pigments are:

1. hemoglobin-derived – derivative of hemoglobin;
2. protein-derived – derivative of amino acid;
3. lipopigments – lipofuscin.

Violations of pigments exchanging consist of:

1. increase of its quantity
2. stopping of pigment’s synthesis
3. violation of further metabolism
4. the appearance of pigments that are not meeting in the norm.

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 Hemoglobin-derived pigments

From fragments of hemoglobin the following pigments are appeared :

in norm - ferritin , hemosiderin, billirubin
in pathology – gematin, gematoidin, porfirin

Hemosiderin is a hemoglobin-derived, golden-yellow granular pigment, in such form

iron is stored in cells.

Hemosiderin accumulate in cells as:

1. a localized process - result from hemorrhages
2. a systemic hemosiderosis – it is deposited in many organs and tissues. It is seen at
(1) increased absorption of dietary iron,
(2) impaired utilization of iron,
(3) hemolytic anemias,
(4) transfusions. (5) intoxications (6) infection

Melanin it is an endogenous, brown-black tyrosin-derived pigment formed in

melanocytes.

Classification of pathology:
1. system increasing –general hyperpigmentation of skin (sunburn), in pathology:
a) vices of ectoderm development
b) destruction of cortex or all adrenal gland
2. local increase of melanin:
a) pigmental nevus – innate vice of development of skin in which pigmental
cells are increased in quantity
3. depigmentation:
а) general – at albinism (genetic pathology) – white skin and hairs, red eyes
b) local – autoimmune local destruction of melanogenic cells of skin – white
spots (vitiligo), or destruction of nerves, which innervate melanocytes – at Syphilis
(leykoderma).

Billirubin: — it is the normal major pigment found in bile.

It is derived from hemoglobin but contains no iron. Its normal formation and excretion are vital
to health, and jaundice is a common clinical disorder due to excesses of this pigment within cells
and tissues.
Bilirubin formed outside the liver is bound principally to serum albumin and transported to the
liver.
Bilirubin pigment within cells and tissues is visible morphologically only when the patient is
rather severely jaundiced for some period of time. Even though this pigment is distributed
throughout all tissues and fluids of the body, the accumulations are most evident in the liver and
kidneys In the liver, particularly with diseases caused by obstruction of the outflow of bile (e.g.,
cancers of the common bile duct and head of the pancreas), bilirubin is encountered within bile
sinusoids, Kupfier's cells, and hepatocytes. In all these sites, it appears as a mucoid, green-brown to
black, amorphous, globular deposit. In advanced cases of such obstructive jaundice, the aggregates
of pigment may be quite large, creating so-called bile lakes.
Hepatic processing of bilirubin involves
1) carrier-mediated uptake at the sinusoidal membrane;
2) intracellular binding, especially to ligandin;
3) delivery to endoplasmatic reticulum, possibly by rapid membrane-membrane transfer;

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 4) conjugation with one or two molecules of glucuronic acid by bilirubin
glucuronosyltransferase;
5) excretion of the water-soluble, nontoxic bilirubin glucuronides into bile.
Most bilirubin glucoronides are deconjugated by bacterial beta-glucuronidases and degraded to
colorless urobilinogens. The urobilinogens and the residue of intact pigment are largely excreted in
feces. Approximately 20% of the urobilinigens formed are reabsorbed in the ileum and colon,
returned to the liver, and promptly re-excreted into bile. The small amount that escapes this
enterohepatic circulation is excreted in urine.
Normal blood levels of bilirubin are less than 1.2 mg/dl.
Jaundice becomes evident when bilirubin levels rise above 2.0 to 2.5 mg/dl; levels as high as 30 to
40 mg/dl can occur in severe disease.
Bilirubin is presented like the yellow-red crystals. It does not contain Fe. For the exposure of it use
the reactions, based on power of pigment it is easily to oxidize with formation it is different painted
products - reaction Gmelina, at which under act of the concentrated aquafortis of bilirubin gives at
first green, and then dark blue or purple painting.
The violation of exchange of bilirubin is related to disorder of its formation and selection. This
conduces to the promoted maintenance of bilirubin in blood plasma and to the yellow painting by it
skins, skler, mucous and serosis shells and inlying organs — to the icterus.

On the mechanism of development jaundice is divided into three kinds:

1. before-hepatic (hemolytic)
2. hepatic (parenhimatosis)
3. sub-hepatic (mechanical).
They are differentiate on the billirubin concentration, on the tint of skin, on the color of urine
and excrement.

JAUNDICE AND CHOLESTASIS.

Clinical jaundice appears when bilirubin is elevated in blood and is deposited in tissues.
Cholestasis refers to bile secretory failure per se, which is accompanied by the accumulation in the
blood of substances normally excreted in bile ( bilirubin, bile salts, and cholesterol).
Unconjugated bilirubin is not soluble in aqueous solution and is tightly complexed to albumin:
As such, it can not be excreted in urine even when the blood levels are high. The small amount of
unbound pigment, when present in excess, may cause toxic damage to the neonatal brain
(kernicterus) owing to immaturity of the blood-brain barrier. In contrast, conjugated bilirubin is
water-soluble, nontoxic, and weakly associated with albumin. When present in excess, it is readily
excreted in urine (bilirubinuria). With both unconjugated and conjugated hyperbilirubinemia,
pigmentation of the skin and sclerae is readily visible.
Jaundice occurs when bilirubin production exceeds hepatic clearance capacity: excessive
production of bilirubin, reduced hepatic uptake, and impaired hepatic conjugation produce
unconjugated hyperbilirubinemia. Decreased hepatic exceretion of bilirubin conjugates and
impaired extrahepatic bile -flow produce conjugated hyperbilirubinemia.
Cholestatic conditions, which may result from hepatocellular dysfunction or intrahepatic
biliary obstruction, may also present with jaundice.
MORPHOLOGY. Common to both obstructive and hepatocellular cholestasis is the
accumulation of bile pigment within the hepatic parenchyma. Elongated green-brown plugs of bile
are visible in dilated canaliculi, most prominent toward the centers of lobules; this may become
panlobular in the most severe cases. Rupture of canaliculi leads to extravasation of bile, which is
quickly phagocyotsed by Kupffer cells. Droplets of the bile pigment also accumulate within
hepatocytes, causing the cells to take on a wispy appearance (feathery or foamy degeneration).

The Before-hepatic (hemolytic) icterus.

It is characterized by the promoted formation of bilirubin (the promoted level of indirect bilirubin is
determined in blood) because of increasing red cells breakdown. It is shows up as lemon-yellow
color of skin and organs, at the ordinary color of urine and excrements.

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Reasons of development of hemolytic icterus:
Inter-vessel hemolysis at:
1. bacterial toxinemia (at infections - sepsis, malaria, recurrent typhus)
2. poisoning by the hemolytical poisons
3. isoimmune reactions – during transfusion of inno-group blood or incompatible on Rh-
factor
4. hemolytical illness of new-born.
The hemolytical icterus can be conditioned by the bug of red ccells. Such are inherited
fermentopathie (mikrosferocytosis, ovalocytosis), hemoglobinopathie, or hemoglobinosis
(talassemia, or hemoglobinosis F; serpovid-cells anaemia, or hemoglobinosis S), paroksismal
nightly hemoglobinuriya, so-called shuntov icteruss (at the deficit of vitamin B12, some
hypoplastical anemia’s and other).
Thanatogenesis: (processes)
1. the concentration of free Hb rises in blood, which destroys an epithelium of kidneys canals
2. the concentration of potassium rises in blood, which went out from the blasted red cells,
that conduces to the stop of the heart
3. sharp anaemia develops, which requires correction.
At the newborn with concentration of billirubina more than 300 mmol/l develops billirubin
entsefalopathia (cramps, arefleksiya, increasing respiratory insufficiency), that is a reason of
damage of neurons of NS by billirubin penetration through the hematoentcefalic barrier. Basal
nucleus are painted by billirubin in yellow color (nuclear icterus).
Prophylaxis of icterus is the exchange of blood.

Hepatic (parenhimatosis) icterus.

It begins at the defeat of hepatocytes, as a result violated seizure of bilirubin by them are appeared,
conjugation of it with the glucuron acid and its ekskretion. The concentration of direct and indirect
billirubin in blood is rises. An icterus shows up as greenish tint of skin and mucous, by
billirubinuriey and by poorly painted excrements.
Reasons:
1. viral hepatitis
2. necrosis of liver
3. festering hepatitis
4. poisoning by the mushroom poisons
5. action of medicinal substances with the holestatical effect
6. fermentopathical hepatic icterus - at inherited pigmental hepatosis, at which one of the
phases of hepatical exchange of bilirubin is broken.

Outcomes:
1. death from the hepatic-cellular insufficiency
а) violated of blood rolling up
б) endogenous insufficiency
в) holalemiya
г) rise of concentration of amiak > hepatic coma > loss of consciousness and arefleksiya
2. damage of epithelium of kidney canals > kidney-hepatic insufficiency.

Sub-hepatic (mechanical) icterus.

It is related to violation of bilious channels, that hampers of exkretion and determines regurgitation
of biles. This icterus develops at presence of obstacles to the outflow of bile from liver, lying
inwardly or out the bilious channels, that is observed at:
1. bile-stone illnesses
2. the cancer of bilious paths
3. the cancer of the head of pancreas and papilla of duodenum
4. atrezia (gipoplazia) of bilious paths
5. metastases of cancer in the periportal lymphatic nodules and liver.

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 The stagnation of bile in liver leads to fireside of necrosis with the subsequent substitution by
their connecting tissue and development of cirrhosis (the second biliar cirrhosis). Stagnation of
bile leads to the expansion of bilious channels and to the break of bilious capillaries. Holemiya
develops, which causes the intensive colouring of skin and became the reason of general
intoxication. Because of intoxication the rolling up of blood falls down, appear plural
hemorrhage (hemorragical syndrome). The development of hepatic-kidney insufficiency began
because of autointoxication and defeats of kidneys.
The concentration of the direct faction of billirubin increase in blood. An icterus shows up the
dark and yellow coloring of skin covers, and by the aholical excrement (argil).
Surgical tactic is needed of conduct of patient and detoxication.
Outcomes:
1. hepatic-cellular insufficiency
2. hemorrhagic syndrome
3. kidney-hepatic insufficiency.

Hyaline change.
The term "hyaline" is widely used as a descriptive histologic term rather than a
specific marker for cell injury. It usually refers to an alteration within cells or in the
extracellular space, which gives a homogenous, glassy, pink appearance in routine
histologic sections stained with hematoxilin and eosin.
Exracellular hyaline has been somewhat more difficulty to analyze. Collagenous
fibers tissue in old scars may appear hyalinized, but the physicochemical mechanism
underlying this change is not clear.
In long-standing hypertension and diabetes mellitus, the walls of arterioles,
especially in the kidney, become hyalinized, owing to extravasated plasma's protein and
deposition of basement membrane material.
It is characterized by accumulation in tissue of pathological albumens of dense
consistency, reminding a hyaline cartilage. Hyaline consists of plasma albumens, lipids,
carbohydrates and AT.

Forms hyaline changers according to mechanisms of forming:

1. hyaline in the finale of fibrinoid necrosis – arises up in damaged perivascular
strome of organs or in the wall of the damaged arteries or arterioles
2. hyaline in the finale of plasmatic impregnation of vascular wall – in the wall
of vessels after protracted angiospasm at patients with hyperglycemia and hyperlipidaemia
> vascular permeability rises > hyalin appears in the wall of vessels.
3. local hyalinosis in the finale of inflammation – after calming down of process
in the hearth of inflammation appears local hyalinosis.
Outcomes: A process is irreversible, is completed by structural deformation of organs
(heart-disease at rheumatism).

Muсoid swelling.
It is superficial, reversible disorganization and swelling of connecting tissue.
Microscopic research: there is the phenomenon of metaxromazia. That is basophyl
color of basic substances. Collagen fibers save the structure, but swell and undergo to
fibrillar de-structure. A process is often accompanied by the cellular reactions - there are
lymphocytes, plazmocytes and hystyocytes.
Macroscopic research: tissue or organ is stored.
Process is reversible at the removal of reason.

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 Fibrine changes.
It is deep and irreversible disorganization of connecting tissue, destruction of main
substances and fibers lies in basis it. It is accompanied by the acute increase of permeability
of vessels and formation of fibrinoid.
It is characterized by swelling of intercellular matrix and collagen fibers, their
destruction with formation of fibrinoid in place of the blasted fibers.
Morphogenesis: large amount of water + EIDERS of intercellular matrix > swelling
of fibers > destruction of fibers > the area of destruction is saturated with plasma squirrel
with plenty of fibrinogen > fibrinoid > fibrinoid necrosis.
A process arises up round vessels.
Fibrinoid insudation – arises up in the walls of vessels (arterioles) after the protracted
spasm during hypertensive kris (sympathoadrenal kris is violation of the endocrine
adjusting, that is a results of feed violation of vascular wall > permeability of wall of vessel
for plasma albumens rises > plazmacytical impregnation of wall of vessel > compression of
wall > forming of fibrinoid).
Microscopic research: the bunches of collagen fibers are saturated with the squirrel
of plasma and become homogeneous, forming insoluble durable connections with a fibrin;
they eozynophyl, SHYK-“+” is acute.
Macroscopic research: tissue or organ is stored.
Outcomes: 1. fibrinoid necrosis,
2. hyalinosis,
3. sclerosis is substitution of the blasted tissue by connective tissue.