AlterationAlteration DegenerationsDegenerations

NekrosisNekrosis

Lecture on pathological anatomy for Lecture on pathological anatomy for the 3-rd year students the 3-rd year students

V. M. VASYLYKV. M. VASYLYK

Alteration. Cell injury.Alteration. Cell injury.AlterationAlteration is the pathological changes of cellular structure, is the pathological changes of cellular structure,

extracellular matrix, tissue and organs which are extracellular matrix, tissue and organs which are accompanied by violation of their vital functions. accompanied by violation of their vital functions.

The cellular morphologic changes induced by various The cellular morphologic changes induced by various stimuli can be divided into:stimuli can be divided into:

1.1. Patterns of acute cell injury — reversible and irreversible Patterns of acute cell injury — reversible and irreversible cell injury leading to necrosis or apoptosiscell injury leading to necrosis or apoptosis

2.2. Subcellular alterations that occur largely as a response to Subcellular alterations that occur largely as a response to more chronic or persistent injurious stimulimore chronic or persistent injurious stimuli

3.3. Intracellular accumulations of a number of substances — Intracellular accumulations of a number of substances — lipids, carbohydrates, proteins—as a result of lipids, carbohydrates, proteins—as a result of derangements in cell metabolism or excessive storage.derangements in cell metabolism or excessive storage.

Reasons of development of Reasons of development of alterationalteration

1.1. hypoxia hypoxia 2.2. chemical agents and drugs chemical agents and drugs 3.3. physical agents physical agents 4.4. microbiological agents (bacteria, viruses, microbiological agents (bacteria, viruses,

fungies)fungies)5.5. immune mechanismsimmune mechanisms6.6. genetic defects (apoptosis)genetic defects (apoptosis)7.7. nutritional imbalancesnutritional imbalances8.8. agingaging

Classification of degenerationsClassification of degenerations1. 1. ССlassification in depending on localization of metabolism:lassification in depending on localization of metabolism: parenchymalparenchymal stromally - vascularstromally - vascular mixedmixed2. Classification in depending on deposition of protein, lipids, 2. Classification in depending on deposition of protein, lipids,

carbohydrate , mineral (on predominance of the broken carbohydrate , mineral (on predominance of the broken exchange):exchange):

Proteinous (Dysproteinoses)Proteinous (Dysproteinoses) Fatty (lipidoses)Fatty (lipidoses) CarbohydrateCarbohydrate MineralMineral PigmentalPigmental3. Classification in depending on prevalence of process:3. Classification in depending on prevalence of process: LocalLocal SystemSystem4. Classification in depending on an origin:4. Classification in depending on an origin: AcquiredAcquired HereditaryHereditary

CategoriesCategories of intracellularof intracellular accumulationsaccumulations

1.1. a normal cellular constituent accumulated a normal cellular constituent accumulated in excess, such as water, lipid, protein, in excess, such as water, lipid, protein, and carbohydrates; and carbohydrates;

2.2. an abnormal substance, either exogenous, an abnormal substance, either exogenous, such as a mineral, or a product of such as a mineral, or a product of abnormal metabolism; abnormal metabolism;

3.3. a pigment or an infectious product. a pigment or an infectious product.

Parenchymal dysproteinoses, Parenchymal dysproteinoses, mechanisms.mechanisms.

CellCellDenaturation and Denaturation and

coagulation of coagulation of cytoplasmic proteinscytoplasmic proteins

Hyaline-drop dystrophyHyaline-drop dystrophy

Focal coagulativeFocal coagulativenecrosis of cellnecrosis of cell

Total coagulativeNecrosis Total coagulativeNecrosis of cellof cell

Hydratation and Hydratation and colliquation of cell’s colliquation of cell’s

cytoplasmcytoplasm

Hydropic dystrophyHydropic dystrophy

Focal colliquative necrosis of cell

(balloon dystrophy)Total colliquative

necrosis of cell

The most frequent localization of intracellular accumulations of proteins, lipids and carbohydrates ismyocardium (cardiomyocytes), liver (hepatocytes),kidneys (nephrocytes).

Types of intracellular Types of intracellular parenhymatous parenhymatous degenerationsdegenerations

Granular Granular Hyaline-dropHyaline-dropHydropic (vacuolar, balloon)Hydropic (vacuolar, balloon)Keratoid (horney) Keratoid (horney)

Here are Mallory bodies

ParenhymatousParenhymatous fatty degenerations fatty degenerationsThis liver is enlarged and has a pale yellow appearance. It is greasy to touch. It is called “Goose liver”.

Microscopically: there are numerous lipid vacuoles in the cytoplasm of hepatocytes.             

Extracellular proteinous Extracellular proteinous degenerationsdegenerations

1.1. MukoMukoiidd swelling swelling2.2. FFiibrbriinonoiidd changes changes3.3. HHyalynoyalynosissis4.4. AmyloydoAmyloydosissis

Mucoid swellingMucoid swellingIt is disorganization and swelling of It is disorganization and swelling of perivascular extracellular matrix perivascular extracellular matrix (disorganization of connective tissue) (disorganization of connective tissue) due to increased vascular permeability, due to increased vascular permeability, plasmorrhagia and deposition of plasmorrhagia and deposition of glucosaminoglycans (GAG).glucosaminoglycans (GAG).

Microscopically:Microscopically: there is the phenomenon of metachromasia. there is the phenomenon of metachromasia. That is basophylic color of basic substances. Collagen fibers That is basophylic color of basic substances. Collagen fibers save the structure, but swell and undergo to fibrillar save the structure, but swell and undergo to fibrillar destructure. destructure. Gross appearanceGross appearance:: tissue or organ is saved. tissue or organ is saved.Process is convertible.Process is convertible.

Fibrinoid changesFibrinoid changes It is deep and irreversible disorganization of It is deep and irreversible disorganization of connective tissue, in basis of which destruction of connective tissue, in basis of which destruction of basic substances and fibers. It is accompanied basic substances and fibers. It is accompanied by the sharp increase of permeability of vessels by the sharp increase of permeability of vessels and formation of fibrinoid and formation of fibrinoid masses.masses.

Microscopically: the bands of collagen fibers are homogenous, impregnated with plasma proteins.

Outcomes: fibrinoid necrosis, hyalinosis, sclerosis.

Hyaline changeHyaline change It is an alteration within cells or in the extracellular

space, which gives a homogenous, glassy, pink appearance in routine histologic sections stained with H&E.H&E.

Hyalinosis is classified according to its localization:Vascular hyalinosis (arteries are thickened with sharply narrowed or obliterated lumen)Hyalinosis of connective tissue is usually localized; it develops in scars, adhesions, in the areas of chronic inflammation (e.g. “glazed spleen”).

The outcome of hyalinosis is irreversible.

Functional significance of hyalinosis is different:• Vascular hyalinosis may lead to atrophy or sclerosis, infarction of organs.

• Local hyalinosis in the cardiac valves results in heart defects.

AmyloidosisAmyloidosisAmyloidosisAmyloidosis is the term used for a group of diseases is the term used for a group of diseases characterized by extracellular deposition of febrillar characterized by extracellular deposition of febrillar proteinaceous substance called amyloid.proteinaceous substance called amyloid.Nature and etiologyNature and etiologyAmyloid is composed of 2 main types of complex proteins:Amyloid is composed of 2 main types of complex proteins:Fibril proteins Fibril proteins comprising about 90% of amyloid.comprising about 90% of amyloid.P-component P-component comprising about 10% of amyloid.comprising about 10% of amyloid.

Of the 15 biochemically distinct forms of amyloid Of the 15 biochemically distinct forms of amyloid proteins that have been identified, two are the most proteins that have been identified, two are the most common: common:

One, called One, called AL (amyloid light chain)AL (amyloid light chain) is derived from is derived from plasma cells (immunocytes) and contains immunoglobulin plasma cells (immunocytes) and contains immunoglobulin light chains.light chains.

The other, designated The other, designated AA (amyloid-associated),AA (amyloid-associated), is a is a unique nonimmunoglobulin protein synthesized by the unique nonimmunoglobulin protein synthesized by the liver.liver.

Classification of amyloidosisClassification of amyloidosis A. Systemic AmyloidosisA. Systemic Amyloidosis1. Primary amyloidosis1. Primary amyloidosis (idiopathic) is the defect (idiopathic) is the defect of primary mesodermal tissueof primary mesodermal tissue2. 2. Secondary amyloidosis Secondary amyloidosis ((acquired, reactive)acquired, reactive) is is complication of chronic diseases (chronic complication of chronic diseases (chronic infections, malignant tumors) infections, malignant tumors) 3. Familial amyloidosis 3. Familial amyloidosis (inherited, genetic) is (inherited, genetic) is predisposition of certain ethnic groups (periodic predisposition of certain ethnic groups (periodic illness).illness).B. Localized AmyloidosisB. Localized Amyloidosis

1. Senile amyloidosis 1. Senile amyloidosis 2. Endocrine amyloidosis2. Endocrine amyloidosis

Diagnosis of amyloidosisDiagnosis of amyloidosis

Histologic examination of biopsy material Histologic examination of biopsy material is the commonest and confirmatory is the commonest and confirmatory method for diagnosis in a suspected case method for diagnosis in a suspected case of amyloidosis.of amyloidosis. If renal manifestations are present, kidney If renal manifestations are present, kidney is the preferred site for biopsy. is the preferred site for biopsy. Other sites such as rectum, gingiva, and Other sites such as rectum, gingiva, and more recently abdominal fat, are biopsied more recently abdominal fat, are biopsied and are followed by and are followed by Congo red stainingCongo red staining for for confirmation.confirmation.

Pathology Pathology Systemic amyloidosis (AA) related to chronic inflammation Systemic amyloidosis (AA) related to chronic inflammation tends to involve parenchymatous organs, such astends to involve parenchymatous organs, such as kidneys, kidneys, spleen, liver, and adrenals.spleen, liver, and adrenals.While amyloidosis (AL) related to myeloma tends to affect While amyloidosis (AL) related to myeloma tends to affect mesodermal or other tissues, such as heart, gastrointestinal mesodermal or other tissues, such as heart, gastrointestinal tract, peripheral nerves, skin, and tongue.tract, peripheral nerves, skin, and tongue.

Grossly:Grossly:Organs extensively infiltrated by amyloid are usually enlarged Organs extensively infiltrated by amyloid are usually enlarged and have a pale, waxy ("lardaceous") or varnished appearance and have a pale, waxy ("lardaceous") or varnished appearance and firm consistency.and firm consistency.The iodine test for amyloid is done by applying iodine solution The iodine test for amyloid is done by applying iodine solution to the washed cut surface of the organ: amyloid typically stains to the washed cut surface of the organ: amyloid typically stains mahogany-brown, and this color reaction changes to blue ( a mahogany-brown, and this color reaction changes to blue ( a "starch-like" reaction) after the application of dilute sulfuric acid"starch-like" reaction) after the application of dilute sulfuric acid

Primary amyloidosis of Primary amyloidosis of kidneys.kidneys.

Grossly, amyloid kidneys Grossly, amyloid kidneys are usually enlarged, are usually enlarged, pale, and smooth pale, and smooth surfaced and have a firm surfaced and have a firm consistency. On cortical consistency. On cortical transaction, the glomeruli transaction, the glomeruli (visible as pink dots in the (visible as pink dots in the normal kidney) may be normal kidney) may be seen as enlarged, waxy, seen as enlarged, waxy, gray dots. gray dots.

Microscopically: the amorphous pink deposition of amyloid may be found in and around arteries, in interstitium, or in glomeruli. A Congo red stain will demonstrate the red material to be amyloid.

This section of myocardium demonstrates amorphous deposits of pale pink (H&E ) or red (Congo red) material between myocardial fibers. Amyloidosis is a cause for "infiltrative" or "restrictive" cardiomyopathy.

H&E

Congo red

Amyloidosis of myocardium

Amyloidosis of the spleen Amyloidosis of the spleen Amyloidosis of the spleen has two different anatomical patterns. Most commonly, the amyloid deposits is limited to the splenic follicles, resulting in the gross appearance of a moderately enlarged spleen dotted with gray nodules (so called "sago" spleen). Alternatively, the amyloid deposits may spare the follicles and mainly infiltrate the red pulp sinuses, producing a large, firm spleen mottled with waxy discolorations ("lardaceous" spleen).

Amyloidosis of adrenal gland Amyloidosis of adrenal gland Amyloid deposits Amyloid deposits surround, compress, surround, compress, and replace some and replace some cortical cells and cortical cells and infiltrate the wall of infiltrate the wall of a small blood vessel. a small blood vessel. Congo redCongo red. .

Amyloidosis of the Amyloidosis of the tonguetongue

Amyloid infiltrates the Amyloid infiltrates the capillary walls and capillary walls and narrows the lumens of narrows the lumens of some of them. H&E. some of them. H&E.

Amyloidosis of the liverAmyloidosis of the liverThe hepatic parenchyma The hepatic parenchyma is infiltrated and replaced is infiltrated and replaced by nodular accumulations by nodular accumulations of amyloid (pink). H&E.of amyloid (pink). H&E.

Clinical manifestations of amyloidosis Clinical manifestations of amyloidosis

Stromal vascular fatty degenerations•Stromal fatty infiltration is the deposition of mature adipose cells in the

stromal connective tissue.•The condition occurs most often in patients with obesity.

Classifications of Obesity1. According to the etiology : Primary (idiopathic) and

Secondary.2. There are several types of secondary obesity: Alimentary,

Cerebral, Endocrine, Hereditary in Gierke’s disease.3. According to the patient's appearance: symmetrical,

upper, medial, and lower.4. According to morphological peculiarities of adipose

tissue: •In hypertrophic type adipose tissue enlarges due to

increased volume of fatty cells•In hyperplastic due to increase in their number.

PATHOLOGY OF PIGMENTSPATHOLOGY OF PIGMENTSPigmentsPigments are colored substances, some of which are are colored substances, some of which are normal constituents of cells where as others are abnormal normal constituents of cells where as others are abnormal and collect in cells only under special circumstances.and collect in cells only under special circumstances.Pigments are generally classified into two broad categories:Pigments are generally classified into two broad categories:

1.1. Endogenous pigments, which are normal constituents of Endogenous pigments, which are normal constituents of cells and tissues;cells and tissues;

2.2. Exogenous pigments introduced into the body from Exogenous pigments introduced into the body from environment.environment.

Classification of endogenous pigmentsClassification of endogenous pigments1.1. Hemoglobinogenic pigments:Hemoglobinogenic pigments: Physiologic pigments: Physiologic pigments: Ferritin, Hemosiderin,Ferritin, Hemosiderin, BilirubinBilirubin Pathologic pigments:Pathologic pigments: Hematoidin,Hematoidin, Hematin, PorfirinHematin, Porfirin 2.2. Proteinogenic (melanin).Proteinogenic (melanin).3.3. Lipidogenic (lipofuscin).Lipidogenic (lipofuscin).

HemosiderosisHemosiderosisLocal hemosiderosisLocal hemosiderosis is is characterized by local characterized by local breakdown of red cells in breakdown of red cells in tissues, e.g. in internal tissues, e.g. in internal hemorrhage.hemorrhage.Mechanism of local Mechanism of local hemosiderosis is hemosiderosis is extravascular hemolysis.extravascular hemolysis.It occurs regularly around It occurs regularly around areas of bruising and areas of bruising and hemorrhage.hemorrhage.

In the lungs hemosiderin-laden In the lungs hemosiderin-laden macrophages (siderophages) macrophages (siderophages) are appropriately referred to as are appropriately referred to as “heart failure cells”.“heart failure cells”.

Visceral siderosis (systemic hemosiderosis).Visceral siderosis (systemic hemosiderosis).

Mechanism of systemic Mechanism of systemic hemosiderosis is intravascular hemosiderosis is intravascular hemolysis.hemolysis.It is seen in the liver, spleen It is seen in the liver, spleen and sometimes in kidneys in and sometimes in kidneys in cases of hemolytic anemia, in cases of hemolytic anemia, in patients requiring repeated patients requiring repeated blood transfusion, in patients blood transfusion, in patients with chronic ineffective with chronic ineffective erythropoiesis. The pigment erythropoiesis. The pigment imparts a deep brown color to imparts a deep brown color to tissues and organs when it is tissues and organs when it is present in high present in high concentrations.concentrations.

A Prussian blue reaction is seen in this iron stain of the liver to demonstrate large amounts of hemosiderin that are present in hepatocytes and Kupffer cells.

                       

Pathology of bilirubin’s metabolism.

Jaundice.Types of jaundice:1. Prehepatic jaundice (Hemolytic jaundice) is

characterized by lysis of the red blood cells in a variety of conditions.

2. Intrahepatic jaundice (Hepatocellular jaundice) - results from failure both of hepatocytes to conjugate bilirubin and of bilirubin to pass through the liver into the intestine. Both of conjugated bilirubin and unconjugated bilirubin increase its amount in blood. The liver is light yellowish-green color of saffron (“saffron liver”).

3. Posthepatic jaundice (Obstructive jaundice) - results from an obstruction of the passage of conjugated bilirubin from hepatocytes to the intestine. Conjugated bilirubin is water-soluble and is excreted in the urine. The liver is dark green.

In the liver, bile pigments may appear:• As bile pigment droplets in the hepatocytes.• As bile impregnations in necrotic areas.• As bile casts (bile capillaries, cholangioles, or bile canaliculi).• In Kupffer’s cells.

The yellow-green globular material seen in small bile ductules in the liver here is bilirubin pigment.

                           

This is dystrophic calcification in the wall of the stomach. At the far left is an artery with calcification in its wall. There are also irregular bluish-purple deposits of calcium in the submucosa. Calcium is more likely to be deposited in tissues that are damaged.

Here is so-called "metastatic calcification" in the lung of a patient with a very high serum calcium level (hypercalcemia).

Calcium metabolism disturbances

Cells DeathCells DeathIt is the premature death and destruction of It is the premature death and destruction of cell in the living organism under action of cell in the living organism under action of factors of critical damage factors of critical damage

Classification of Cells Death, based on the Classification of Cells Death, based on the mechanism of development:mechanism of development:necrosisnecrosispathogenic inducted apoptosispathogenic inducted apoptosisimmunological elimination of cells.immunological elimination of cells.

NECROSISNECROSIS

If the acute or chronic injury to which If the acute or chronic injury to which a cell must react is too great, the a cell must react is too great, the resulting changes in structure and resulting changes in structure and function lead to the death of cells.function lead to the death of cells. Death of the cells and tissues in a Death of the cells and tissues in a living organism is called Necrosis.living organism is called Necrosis.

According to the cause of According to the cause of necrosis there are the following necrosis there are the following

types of necrosis:types of necrosis:

traumatic necrosis;traumatic necrosis;toxic necrosis;toxic necrosis;trophoneurotic necrosis;trophoneurotic necrosis;allergic necrosis;allergic necrosis;vascular or ischemic necrosis.vascular or ischemic necrosis.

Two essential changes bring about irreversible cell Two essential changes bring about irreversible cell injury in necrosis - cell digestion by denaturation of injury in necrosis - cell digestion by denaturation of proteins and lytic enzymes.proteins and lytic enzymes.coagulative necrosis coagulative necrosis develops (during denaturation of develops (during denaturation of proteins ). proteins ).

liquefactive necrosis liquefactive necrosis is a progressive catalysis of cell is a progressive catalysis of cell structures (during enzymic digestion)structures (during enzymic digestion). . Liquefactive necrosis is typical of organs in which the tissues have a lot of lipid (such as brain) or when there is an abscess with lots of acute inflammatory cells whose release of proteolytic

Both of these processes require hours to developBoth of these processes require hours to develop

Main types of necrosisMain types of necrosis

Clinic-morphological forms of Clinic-morphological forms of necrosis of organs: necrosis of organs:

1) 1) Gangrene Gangrene – total necrosis of the organ, reported with the – total necrosis of the organ, reported with the external environment:external environment:dry dry – at the thrombosis of arteries, an organ acquires the black coloring– at the thrombosis of arteries, an organ acquires the black coloringmoist (wet) –moist (wet) – at the thrombosis of arteries and veins + influencing of putrid at the thrombosis of arteries and veins + influencing of putrid bacteria.bacteria.gas gangrenegas gangrene bedsorebedsore is a type of gangrene, death of the tissue under the influence of is a type of gangrene, death of the tissue under the influence of pressure (sacral area, buttocks, great trochanter). It is trophoneurotic pressure (sacral area, buttocks, great trochanter). It is trophoneurotic necrosis of the bed- patientsnecrosis of the bed- patientsnomanoma – widespread necrosis of soft tissue of person. – widespread necrosis of soft tissue of person.

2) 2) SequesterSequester – fragment of dead tissue, which can’t be autolysed, – fragment of dead tissue, which can’t be autolysed, replaced by connective tissue and which is localized among replaced by connective tissue and which is localized among alive tissuealive tissue

3) 3) InfarctionInfarction – vascular or ischemic necrosis; – vascular or ischemic necrosis;4) 4) Fat necrosisFat necrosis5) 5) Caseous necrosisCaseous necrosis6) 6) Fibrinoid necrosisFibrinoid necrosis. .

This is an example of coagulative necrosis. This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia). Here, there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney.

The contrast between normal adrenal cortex and the small pale infarct is good. The area just under the capsule is spared because of blood supply from capsular arterial branches. This picture illustrates the shape and appearance of an ischemic (pale) infarct well.

               

Infarction

At high magnification, liquefactive necrosis of the brain demonstrates many macrophages at the right which are cleaning up the necrotic cellular debris.

Grossly, the cerebral infarction at the upper left here demonstrates liquefactive necrosis. Eventually, the removal of the dead tissue leaves behind a cavity

Liquefactive necrosisLiquefactive necrosis

This is gangrene. In this case, the toes were involved in a frostbite injury. This is an example of "dry" gangrene in which there is mainly coagulative necrosis from the anoxic injury.

This is gangrene of the lower extremity. In this case the term "wet" gangrene is more applicable because of the liquefactive component from superimposed infection in addition to the coagulative necrosis from loss of blood supply. This patient had diabetes mellitus.

Gangrene

This is fat necrosis of the pancreas. Cellular injury to the pancreatic acini leads to release of powerful enzymes which damage fat by the production of soaps, and these appear grossly as the soft, chalky white areas seen here on the cut surfaces.

Microscopically, fat necrosis is seen here. Though the cellular outlines vaguely remain, the fat cells have lost their peripheral nuclei and their cytoplasm has become a pink amorphous mass of necrotic material.

Fat necrosis

This is more extensive caseous necrosis, with confluent cheesy tan granulomas in the upper portion of this lung in a patient with tuberculosis. The tissue destruction is so extensive that there are areas of cavitation (cystic spaces) being formed as the necrotic (mainly liquefied) debris drains out via the bronchi.

Microscopically, caseous necrosis is characterized by acellular pink areas of necrosis, as seen here at the upper right, surrounded by a granulomatous inflammatory process.

Caseous necrosis

Sometimes the small arteries and arterioles can be damaged so severely in malignant hypertension that they demonstrate necrosis with a pink fibrin-like quality that gives this process its name - fibrinoid necrosis.

Fibrinoid necrosis

Phase of necrosisPhase of necrosisMany nuclei have become pyknotic (shrunken and dark). It It process is called process is called karyopicnosiskaryopicnosis..

After that After that karyorrhexis karyorrhexis (fragmentation) develops. develops. Nucleus is decomposed into Nucleus is decomposed into small granules.small granules.

Also mayAlso may be be developsdevelops karyolysiskaryolysis, , when the nucleus when the nucleus dissolves.dissolves.The cytoplasm and cell borders are not recognizable.

Regeneration of tissues – replacement of the dead tissue with a new one;Incapsulation – formation of the connective tissue capsula around necrotic area;Organization – replacement of the dead tissue with connective tissue;Petrification – replacement of the dead tissue with calcium salts;Incrustation – replacement of the dead tissue with any other salts exept calcium;Ossification – the formation of the bone tissue in the necrotic area;Hyaline change – the appearance of the hyaline-like substance in the necrotic area;Sequestration – formation of sequester;Mutilation – spontaneous tearing away of the dead tissue;Cystic formation.Suppuration fusion of necrotic tissues

The outcomes of necrosis