1_cellular Injury Calcification Pathology presentation

7/23/2019 1_cellular Injury Calcification Pathology presentation

http://slidepdf.com/reader/full/1cellular-injury-calcification-pathology-presentation 1/91

What is disease?

• A condition in which the presence of an abnormalitycauses a loss of normal health

• Manifests in signs and symptoms

subjective: e.g., painobjective: confirmed by diagnostic tests

• Duration of disease: short lasting - acutelong lasting - chronic

• Outcome: varies; may be lethal



What is pathology?

• The study (logos) of suffering (pathos)

• Devoted to the study of- the cause of the disease (etiology )- the mechanism(s) of disease development( pathogenesis)

- the structural alteration induced in cells and tissuesby the disease (morphologic change)

- the functional consequences of the morphologicchanges (clinical significance)

• The morphologic change may be focal (localizedabnormality) or diffuse



Teaching program of pathology formedical students

General pathologyBasic reactions of cells and tissues toabnormal stimuli, i.e. common features of

various disease processes in various cellsand tissues

Systematic pathology

The descriptions of specific diseases as theyaffect given organs or organ systems



Pathology of cellular injury and death

Cells react to adverse influences by1) Reversible cell injuryChanges that can be reversed when the stimulus isremoved

2) Irreversible cell injuryChanges that cause cell death

3) Cellular adaptationStimuli result in new but altered state that maintainsthe viability of the cell



Intracellular mechanisms vulnerable tocellular injury

• Maintenance of membrane integrityCritical for cell and organellar ionic and osmotichomeostasis

• Aerobic respiration, involving mitochondrial oxidativephosphorilation and ATP production

• Synthesis of enzymes and structural proteins

• Preservation of the integrity of the genetic apparatus



Common cellular injuries

1.Hypoxic injury2.Injury induced by O2-derived free radicals

3.Chemical injury



Hypoxia

Reduction in available oxygen

Common causes1. Upper airway obstruction (eg., sudden swelling of

laryngeal mucosa)

2. Inadequate oxygenation of blood in lung diseases

3. Inadequate O2 transport in blood because ofdecreased number of RBCs (anemia)

4. Inadequate perfusion of blood in the tissues in heartfailure



Ischemia: inadequate blood supply to an organ or part of itdue to impeded arterial flow or reduced venousdrainage



Reversible hypoxic injury 1.Hydropic change

2.Fatty change

1. Hydropic change (synonym: cell swelling)Example: in the kidneys

ATP depletion malfunction of Na+/K+ ATPase influx of sodium and water from the extracellularspace

Grossly, the kidneys are enlargedElectron microscopy (EM)....Light microscopy (LM)....



Hydropic change in the proximal tubule by EM: accumulationof water in the cytoplasm, in the invaginations of the surface

plasma membrane (hydropic vacuoles), in the cisterns of theRER, and in the mitochondria; loss of microvilli.



Hydropic change by LM: the cells are vacuolated,

and the brush border is lost.



Hydropic change

Clinical consequence: acute renal failure



2. Fatty change

Accumulation of lipid vacuoles in the cytoplasm ofcells involved in or dependent on fat metabolism,e.g., hepatocytes and myocardial cells



Fatty change of liver. The hepatocytes are vacuolated;

representing accumulations of neutral lipids that have

been removed by lipid solvents during tissue processing



2. Fatty change

Clinical consequence:- liver function tests may be abnormal- decrease in myocardial contractility



Irreversible hypoxic injury

• The transition from reversible to irreversiblestate is gradual and occurs when adaptivemechanisms have been exhausted

• Depletion of ATP, influx of Ca

2+

, activation ofmultiple cellular enzymes, such as

phospholipases degradation of membrane

phospholipidsproteases degradation of membrane andcytoskeletal protein

ATPases enhance ATP depletion

endonucleases chromatin fragmentation



EM features of irreversible injury

• Rupture of cell and plasma membranes

• Lysis of cell and nuclear components

(leakage of lysosomal enzymes result indigestion of organelles and other cytosoliccomponents)

• Amorphous densities in swollen mitochondria

Th it h d i ll th i b



The mitochondria are swollen, their membranes areruptured, and amorphous densities are in their matrix



Irreversible hypoxic injury: rupture of cellmembranes and lysis of chromatinReversible hypoxic injury



Dead cells show typical nuclear changesby LM

• Pyknosis (pyknos, dense) - condensation ofchromatin

• Karyorrhexis - (rhexis, tearing apart) –

fragmentation of nuclear material• Karyolysis - lysis of chromatin due to the action

of endonucleases

Full-blown picture: loss of nuclear staining, the

cytoplasm is eosinophilic (pink)

LM features of irreversible hypoxic injury: loss of



LM features of irreversible hypoxic injury: loss ofnuclear staining, the cytoplasm is eosinophilic (pink)



Injury induced by O2-derived free radicals

• Inflammation, radiation, chemicals, reperfusionlead to the formation of O2 –derived free radicals:superoxide anion radical (O2.

-),hydrogen peroxide (H2O2),

hydroxyl radical (OH

.

),nitric oxide (NO.)

• These molecules cause

lipid peroxidation membrane damagecross-link proteins inactivation of enzymescause DNA breaks blockade of DNA

transcription,

termed collectively as oxidative stress of cells



Injury induced by O2-derived free radicals

Insidiously ongoing oxidative stress of cells plays arole in the process of aging



Chemical injury

2 mechanisms

Direct damage, by binding to some criticalmolecular component of cell membrane proteins,

causing permeability

Indirect damage, by conversion to reactive toxicmetabolites, which cause cell injury by

- direct binding to membrane proteins and lipids- formation of free radicals



Laboratory markers of irreversible cell injury

Cytoplasmic enzymes are released throughdamaged cell membranes into the blood

• Creatine kinase (CK) - cardiac or skeletal muscle

injury

• Aspartate aminotransferase (AST) and alanineaminotransferase (ALT) - liver cell injury

• Lactate dehydrogenase (LDH) is released fromruptured RBCs



Necrosis – morphology of irreversibleinjury

Necrosis (necros, dead): death of cells, tissues, ororgans in a living organism

Necrotic area is always surrounded by livingtissues – reactive changes

Histological signs: loss of nuclear staining

Outcome: may result in death; in survivors, repairby fibrous scarring occurs



Main types of necrosis

1. Coagulative necrosis2. Liquefactive necrosis3. Caseation4. Fat necrosis5. Gangrene

6. Fibrinoid necrosis

Grosslyvisible



Coagulative necrosis

Most common form of necrosis, predominatedby protein denaturation with preservation of thecell and tissue framework

Arterial occlusion distally: hypoxic (anoxic)death in tissues (exception: brain)

Types:anemic infarcthemorrhagic infarct



Anemic infarct

Cause: occlusion of an end arteryIn the heart, spleen, kidney

Gross:circumscribed yellowish lesion, the marginsare hyperemic

Ci ib d ll i h l i th i h i



Circumscribed yellowish lesion, the margins are hyperemic



Anemic infarct

Cause: occlusion of an end artery

In the heart, spleen, kidney

Gross:yellowish lesion, the margins are hyperemic

LM:

dead cells become eosinophilic with loss ofnuclear staining, the border of necrotic tissueis hyperemic and infiltrated by neutrophils

LM of myocardial infarction: eosinophilia of necrotic fibers



LM of myocardial infarction: eosinophilia of necrotic fibers,disappearance of nuclear staining. Neutrophils in the

interstitium



Hemorrhagic infarct

In the lungs, due to occlusion of a segmental

pulmonary artery; sec. hemorrhage viabronchial arteries

Hemorrhagic infarct of lung: wedge shaped, raised, dark-red



Hemorrhagic infarct of lung: wedge shaped, raised, dark redarea



Hemorrhagic infarct

In the small bowels, due to occlusion of the

mesenteric superior artery;sec. hemorrhage via anastomosing arcades

H h i i f f ll b l



36

Hemorrhagic infarct of small bowels

i f i i



Liquefactive necrosis

The necrotic tissue undergoes softening due to

action of hydrolytic enzymes

Examples1. Brain infarct

2. Abscess

1.Brain infarctOcclusion of cerebral artery leads to anemic

infarct; then enzymes released from dead cellsliquefy the necrotized area

Brain infarct: the necrotic area is softened and pale



Brain infarct: the necrotic area is softened and pale

Internal capsule

Infarcted area

Caudate nucleus

Brain infarct Macrophages scavenge necrotic lipid rich debris



Brain infarct. Macrophages scavenge necrotic, lipid-rich debris.

Li f ti i



Liquefactive necrosis

2. Abscess - localized purulent inflammation.

Hydrolytic enzymes derived from neutrophilgranulocytes induce necrosis of infected area

Liquefactive necrosis: abscess



Liquefactive necrosis: abscess

Caseous necrosis



Caseous necrosis • Distinctive form of coag. necrosis in foci of

tuberculous infection of the lung• Grossly, caseous necrosis is white and

cheesy

LM features: the necrotic area is eosinophilic



LM features: the necrotic area is eosinophilic,amorphous, and is surrounded by activated

macrophages (epitheloid cells) which mediate thenecrosis and kill the bacteria



Enzymatic fat necrosis

• Occurs in pancreatitis, induced by the actionof lipases derived from injured pancreatic cells

• Lipases catalyse decomposition oftriglycerides to fatty acids, which complex withcalcium to create calcium soaps

The swollen pancreas displays several



The swollen pancreas displays severalyellowish foci of necrosis



Gangrene

• This (mostly) clinical term refers to theseveremost forms of necrosis

• Total destruction of all tissue components

• Often putrefactive bacteria invade the necrotictissue

•Three types (detailed in Inflammation chapter)



One subtype: dry gangrene

• In the leg of patients suffering from

atherosclerosis-related occlusion of the tibialarteries

• The affected tissues appear black because of

the deposition of iron sulphide from degradedhemoglobin

Dry gangrene of the great toe



Dry gangrene of the great toe



Fibrinoid necrosis

• Limited to medium-sized and small arteries,arterioles, and glomeruli affected byautoimmune disoders (e.g., SLE, arteritis) ormalignant hypertension

• The wall of these vessels undergo necrosisand is impregnated with fibrinogen and otherplasma proteins

• It can be recognized only in histologic slides

Fibrinoid necrosis of small arteries. The necrotized



smooth muscle cells are eosinophilic. Inflammatorycells have infiltrated the periarterial space

Apoptosis: programmed cell death



Apoptosis: programmed cell death

• A form of energy-dependent process for

selective deletion of unwanted individual cells

• An internal suicide program becomes activated

• The dead cell’s membrane remain intact

• The dead cell is rapidly cleared by phagocytosisbefore its content have leaked out; therefore,apoptosis does not induce an inflammatory reaction

Remember! Features of necrosis: loss of membraneintegrity, enzymatic digestion of cells, and frequentlyan inflammatory reaction



Apoptosis

• Prevented or induced by a variety of stimuli

• Apo contributes to cell accumulation, e.g.neoplasia

•

Apo results in extensive loss, e.g. atrophy

Extrinsic (death receptor) pathway of



Extrinsic (death receptor) pathway of

apoptosis

Mitochondrion

Bcl-2 , Bax

Executioncaspases

Death receptors CytotoxicT-cells

If death receptors on the cell surface (TNF-R, FAS-R)cross-link with the ligand, activation of execution

caspases occurs.



Intrinsic (mitochondrial) pathway ofapoptosis

Mitochondrion

Bcl-2 inhibitsBax activates Executioncaspases

When cells are deprived of survival signals or subjected

stress,anti-apoptotic Bcl-2 protein is replaced by pro-apoptoticBax protein in the mitochondrial membraneand in turn, the execution caspases become activated



Execution pathway of apoptosis

Bax Execution caspases:cascade of proteolytic

enzymes

• Breakdown of cytoskeleton

• Cell shrinkage• Chromatin condensation

and fragmentation• Formation of apoptotic

bodies

Death receptors(TNF, FAS)

CytotoxicT-cells

Apoptosis of tubular epithelial cells (cell shrinkage, andd ti f l ) i d d b t t i T l h t



condensation of nucleus) induced by cytotoxic T- lymphocytesin acute T-cell-mediated rejection of transplanted kidney



Adaptations

Changes that occur in cells and tissues inresponse to prolonged stimulation orchronic injury

• Atrophy

• Hypertrophy• Hyperplasia• Metaplasia

• Dysplasia (to be lectured later)• Intracellular accumulation of varioussubstances

Atrophy



Atrophy

• Decreased cell mass: reduction in size of

cells (nucleus and cytoplasm), tissue, ororgans.

• Atrophied organs are smaller than normal.

• Normal weight (g) of parenchymal organs:- spleen 150- kidneys 150-150

- heart 300 to 350- lungs 400-400- brain 1300- liver 1500



Physiologic atrophy

- Involution of the thymus in adolescence

- Senile atrophy in aging- Atrophy of female genitalia in menopause

Pathologic atrophy



g y

1.Disuse. Atrophy of skeletal muscles in people whodo not use them (prolonged bed rest, immobilization

of limb for healing of bone fracture)

2. Loss of innervation of skeletal muscle

3. Lack of trophic hormones in pituitary disease

4. Ischemia. Slow but progressive reduction of bloodsupply leads to renal atrophy or atrophy of the brain

5. Malnutrition cause marasmus: atrophy of skeletalmuscles, parenchymal organs, and general wasting

6. Increased pressure, e.g., hydrocephalus or

hydronephrosis

Obstruction of the CSF flow leads to pressure atrophyof the brain ith the enlargement of entricles



of the brain, with the enlargement of ventricles:hydrocephalus

Hydronephrosis: obstruction of the ureter leads to



y psac-like dilation of renal pelvis and calyces, and

pressure atrophy of parenchyma

Hypertrophy



• An increased cell mass leading to an increasedsize of organs

• Physiologic:hypertrophy of uterus in pregnancy,compensatory hypertrophy of the remnant kidney

after unilateral nephrectomy,exercise

Increased exercise leads



Increased exercise leadsto hypertrophy of muscles

Hypertrophy



• An increased cell mass leading to an increasedsize of organs

• Physiologic: ...

• Pathologic: in the muscles

• Muscles are not able to divide, therefore anincreased demand for action can be met only byenlarging the size of cells

• Examples: hypertrophy of the myocardium,hypertrophy of the detrusor muscles of urinarybladder

Hypertrophy of heart, triggered by action of mechanicalstimuli ( workload) and vasoactive substances (e g



stimuli ( workload) and vasoactive substances (e.g.,angiotensin II). Free wall thickness: above 15 mm

Hypertrophy of the muscles of urinary bladder due to urethralobstruction



obstruction



Hyperplasia

• Hormonal stimulation results in an increase inthe size of a tissue or organ due to anincreased number of constituent cells. Thecells may have an increased volume.

• Physiologic:- proliferation of the glandular epithelium of the

breast during lactation

Pathologic hyperplasias



Pathologic hyperplasias

- Endometrial hyperplasia, induced by estrogens;clinical feature: bleeding from the uterus betweenmenstrual periods (metrorrhagia)

- Hyperplasia of prostate, induced bydihydrotestosterone, estrogens and peptide growthfactors; clinical consequence: urinary tract obstruction

- Bilateral adrenal cortex hyperplasia, induced by

increased ACTH secretion; clinical consequence:increased production of corticosteroids leading to theCushing’s sy- etc.

Metaplasia



• Replacement of one adult cell type by anotheradult cell type; reversible.

• Squamous metaplasia of the bronchus: chronicirritation-induced replacement of bronchialstratified columnar epithelium by squamous

epithelium in smokers• Gastric metaplasia of the oesophagus: chronic

irritation induced by gastric juices in gastrooeso-phageal reflux leads to the replacement of

squamous epithelium by gastric epithelium

• If the adverse circumstances persist, metaplasiamay progress to dysplasia (precancerous)

Bronchus: squamous metaplasia (right)



Intracellular accumulations

• Lipids - triglycerides, cholesterol• Proteins

• Pigments



Accumulation of triglycerides

• Most common in the liver, but also occurs inthe heart; reversible

• Fatty change/steatosis of liver : due to- alcohol abuse

- morbid obesity- diabetes- protein-energy malnutrition- hypoxia

- hepatotoxins• Biochemical pathways of uptake and metabolism of fatty acids bythe liver, formation of triglycerides, and secretions of lipoproteins:not detailed here

Steatosis: the liver is enlarged, yellow and greasy,resembles to goose liver



resembles to goose liver

Courtesy of E. Kemény, SZTE Patholo

The lipid molecules accumulate in large vacuoles



p g

Frozen section, Oil Red O



• In atherosclerosis, cholesterols andcholesterol esters accumulate extra- andintracellularly in the intima of aorta and largearteries and form atheromatous plaques.

Atheromatous plaque: the lipids are dissolved duringnormal histologic processing



normal histologic processing

The dissolved cholesterol crystals appear ascleftlike cavities



Accumulation of lipids in macrophages

In cerebral infarction, macrophagesphagocytose membrane lipids derived from

dead oligodendrocytes and transform intofoamy macrophages



Accumulation of proteins

Hyaline change: any alteration within cells thatimparts a homogeneous, glassy pinkappearance in H&E-stained histologic sections

- Hyaline droplets in proximal tubular cells inheavy proteinuria

- Mallory-hyaline in hepatocytes in alcoholicliver injury

Hyaline droplets in proximal tubular epithelial cell



Hyaline droplets in proximal tubular epithelial cell

Mallory-hyalin



Accumulation of pigments



Exogeneous- Inhaled coal dust (black) - leading to anthracosis

of lungs; stored in pulmonary macrophages- Pigments of tattooing, taken up by macrophages

Endogeneous

- Lipofuscin (brown), associated with tissueatrophy, in the myocardium of elderly people- Hemosiderin (brown), hemoglobin-derivedintracellular pigment composed of aggregatedferritin, indicates previous hemorrhage.Systemic accumulation: termed hemosiderosis

- Melanin (brown): product of nevus cells- Jaundice (icterus): systemic bilirubin retention;yellow skin and sclera discoloration

Pathologic calcification



Abnormal deposition of Ca-salts in soft tissues

DystrophicIn nonviable or dying tissues;the serum Ca++ level is normal.

Precipitation of a crystalline Ca-phosphate starts with

nucleation (initiation) on membrane fragments, followed bypropagation of crystal formation.

Very common, with serious clinical consequences

Examples• Arteries in atherosclerosis• Damaged heart valves• Areas of various necrosis

Dystrophic calcification of aortic valves(calcifying aortic stenosis)



(calcifying aortic stenosis)



Metastatic calcification

Results from hypercalcemia

• Destruction of bones by myeloma, metastases,• Increased secretion of parathormone in

hyperparathyroidism• Etc.

Deposits in the arteries, and at sites of acidification:kidneys, lungs, and stomach

Metastatic calcification of arteries in end-stage renal disease



Radial art.

Ulnar art.

Bereczki Csaba, SZTE Pediatrics

Jaundice: yellowish discoloration of skin



Jaundice (should be learned in the 2nd semester)



The bilirubin metabolism should be reviewed first

• 200-300 mg bilirubin is produced daily in the body, and stems predominantly fromsenescent RBCs

• Transformation of heme into biliverdin in the mononuclear phagocytic cells(including the spleen)

• Biliverdin is reduced to bilirubin released into the blood

• Binding of bilirubin to albumin (the complex is not water soluble; unconjugated or

indirect bilirubin)

• Uptake of albumin-bound bilirubin by hepatocytes, and conjugation of bilirubin to glucuronic acid (water-soluble; conjugated or direct bilirubin)

• Excretion of bilirubin glucuronides in bile

• Deconjugation of most bilirubin glucuronides by bacteria in the intestineformation of colorless urobilinogen (UBG)

• Conjugated bilirubin and UBG are excreted in feces

• Some UBG and bile acids are reabsorbed in the gut and are

returned to the liver (enterohepatic circulation)

Jaundice (icterus)f



Yellow discoloration of the skin, sclerae, and mucousmembranes due to increased levels of bilirubin in circulation (>40 umol/L)

Normally, blood contains < 20 umol/L of bilirubin, most of it in anunconjugated form

Laboratory classification of hyperbilirubinemia

• Predominantly unconjugated• Mixed• Predominantly conjugated

Pathogenetic forms of jaundice•

Prehepatic jaundice resulting from hemolysis increased biru is predominantly in an unconjugated form

• Hepatic jaundice resulting from liver cell injury increased biru is partially in a conjugated and partially in an unconjugated form

• Posthepatic jaundice resulting from the obstruction of majorextrahepatic biliary ducts increased biru is predominantly in a conjugated

form

Main causes of predominantly unconjugated hyperbilirubinemiaA i h l i i



• Autoimmune hemolytic anemias• Malaria• Erythroblastosis fetalis• Mismatched transfusion (should not happen)

Main causes of mixed hyperbilirubinemia• Hepatitis (viral, drug-induced, alcoholic)• Cirrhosis (usually mild)

Main causes of predominantly conjugated hyperbilirubinemia Associated with an elevation of alkaline phosphatase in the blood; progressively worsening jaundice and pale ( ‘ acholic’ ) stool

•

Gallstone in the common bile duct• Carcinoma (head of pancreas, common bile duct, ampulla ofVater)

• Stenosis (sclerosis) of ampulla of Vater• Primary biliary cirrhosis and primary sclerosing cholangitis

1_cellular Injury Calcification Pathology presentation

Documents

Transcript of 1_cellular Injury Calcification Pathology presentation