MT1 - NECROSIS/CELL DEATH

GNPATH

Necrosis

• gross and histologic correlate of cell death

• results when:
  - damage to membranes is severe
  - enzymes leak out of lysosomes
  - enter the cytoplasm
  - digest the cell

• may elicit host reaction ( inflammation)

• major pathway of cell death

• always pathologic

morphology of necrosis

1. increased eosinophilia
       - RNA + increased binding of eosin to denatured cytoplasmic
         proteins

2. glassy homogeneous appearance

3. myelin figures

4. calcification

5. nuclear changes

eosinophilia

denatured proteins and whorls of cytoplasm (myelin figures) stain strongly with eosin. Also, loss of ribosomes decreases overall basophilia

karyolysis

nucleus becomes pale and eventually disappears

pyknosis

nucleus shrinks, chromatin condenses, becomes deeply basophilic

karyorrhexis

nucleus undergoes fragmentation

Coagulative Necrosis

• Develops with the presence of denaturation

• Preservation of basic outline of the cell

• Characteristic of hypoxic death in all tissues except the brain

• Affected tissue- firm texture"
  1. Injury or increasing intracellular acidosis
  2. denatures structural proteins and enzymes
  3. blocking the proteolysis of the cell

Liquefactive Necrosis

• a.k.a. suppurative necrosis

• charateristic of focal bacterial or fungal

• Microbes stimulate accumulation of inlammatory cells

• Hypoxic death - CNS

• Liquefaction digests dead cells

• Tissue transformation into liquid viscous mass

• Creamy yellow - pus

kidney

one organ in the body that can undergo either coagulative and liquefactive necrosis

Caseous Necrosis

• Cheesy white gross appearance

• Distinctive form of coagulative necrosis

• Most often in tuberculous infection

Fat necrosis

• Does not denote pattern of necrosis

• Descriptive of focal areas of fat destruction

• Result of pancreatic lipases
  - Release in substance of the pancreas and peritoneal cavity
  - Enzymes liquefy fat cell membranes
  - Released fatty acids combine with Calcium

• Chalky white areas (fat saponification)

• Shadowy outlines of necrotic fat cells with basophilic calcium deposits, surrounded by an inflammatory reaction

coagulative necrosis, liquefactive necrosis, caseous necrosis, fat necrosis

4 MORPHOLOGIC PATTERNS OF NECROSIS

necrosis, apoptosis

2 types of cell death

Apoptosis

• Induced by a tightly regulated intracellular program

• Characterized by nuclear dissolution without complete loss of membrane integrity

• Cells destined to die activate enzymes that degrade own nuclear DNA and cytoplasmic proteins

• Often physiologic, means of eliminating unwanted cells

• Maybe pathologic

Apoptosis in Physiologic Situations

(Apoptosis in Physiologic Situations):

• Programmed destruction of cells during embryogenesis
  - Death of specific cell types at defined times during development

• Hormone- dependent involution in the adult
  - Cell breakdown – menstrual cycle

• Cell deletion in proliferating cell population
  - Intestinal epithelia to maintain constant number

• Death of host cells that have served their useful purpose
  - Neutrophils and lymphocytes

• Cell death induced by cytotoxic T-cells
  - Virus – infected and neoplastic cells

Apoptosis in Pathologic Conditions

(Apoptosis in Pathologic Conditions):

• Cell death produced by a variety of injurious stimuli
  - Radiation and cytotoxic drugs

• Cell injury in viral diseases
  - Viral hepatitis

• Pathologic atrophy in parenchymal organs after duct obstruction

• Cell death in tumors

Morphology of Apoptosis - Electron Microscope

(Morphology of Apoptosis - Electron Microscope):

• Cell shrinkage

• Chromatin condensation

• Formation of cytoplasmic blebs and apoptotic bodies

• Phagocytosis of apoptotic cells or cell bodies by phagocytes

Morphology of Apoptosis - Hematoxylin & Eosin Stain (H&E)

(Morphology of Apoptosis - Hematoxylin & Eosin Stain (H&E)):

• Single cells or small clusters of cells

• Round or oval

• Intensely eosinophilic cytoplasm

• Dense nuclear chromatin fragments

• Difficult to detect histologically
  - Rapid phagocytosis
  - No inflammation

Intracellular Accumulations

• Manifestations of metabolic derangements in cells

• Transient or permanent

• Harmless or severely toxic

• Nucleus or cytoplasm

Abnormal amounts of various substances

• INTRACELLULAR ACCUMULATIONS

• (Abnormal amounts of various substances):
  - normal cellular constituents
  - abnormal substance
  - pigment

Most accumulations are attributable to three types of abnormalities

(Most accumulations are attributable to three types of abnormalities):

1. Endogenous substance
   - Produced at normal rate
   - Inadequate rate of metabolism to remove

2. Normal or abnormal endogenous substance

   - Genetic or acquired defects in metabolism, packaging,
      transport or secretion

3. Abnormal exogenous substance
   - Deposited and accumulates
   - Lack enzymes to degrade

Lipids

• INTRACELLULAR ACCUMULATIONS

• Triglycerides

• Cholesterol / cholesterol esters

• Phospholipids

• Steatosis (Fatty change)

  • abnormal accumulations of triglycerides

  • Occurs in :hypoxia

• Possible Mechanism:

  • Defects in either uptake, catabolism or secretion of fatty acids

Steatosis (Fatty change)

• abnormal accumulations of triglycerides

• Occurs in :hypoxia

• Possible Mechanism:

  • Defects in either uptake, catabolism or secretion of fatty acids

Cholesterol and cholesterol esters

• Lipids

• Used by most cells in the synthesis of cell membrane

• Intracellular vacuoles in pathologic process:

  1. atherosclerosis

  2. xanthomas

  3. inflammation and necrosis

  4. cholesterolosis

xanthoma

Intracellular lipid accumulation

PROTEIN

• INTRACELLULAR ACCUMULATIONS

• Rounded,eosinophilic droplets,vacuoles or aggregates in the cytoplasm

• Causes:

  1. kidney diseases
     - Reabsorption droplets in proximal renal tubules

  2. Excessive synthesis of normal secretory proteins
     - ER-hugely distended producing large, homogenous, eosinophilic inclusions (Russell bodies)

  3. Defects in protein folding

Russell bodies

• proteins

• ER-hugely distended producing large, homogenous, eosinophilic inclusions

Hyaline Change

• alteration within cells or extracellular space

• homogenous, glassy,pink appearance

• descriptive histologic term

• i.e. Mallory alcoholic hyalin

Glycogen

• INTRACELLULAR ACCUMULATIONS

• Abnormality in glucose or glycogen metabolism

• Clear vacuoles within the cytoplasm

• i.e Diabetes Mellitus

  • Epithelial cells of renal tubules

  • Liver cells

  • Β cells of the Islets of Langerhans

  • Heart muscles

Pigments

• Colored substances

• Normal cell constituents (i.e.melanin)

• Abnormal
  - Collects in cells under special circumstances

Carbon or coal dust

• INTRACELLULAR ACCUMULATIONS: PIGMENTS

• Exogenous

• most common exogenous pigment

anthracosis

accumulation of coal in lungs

Lipofuscin

• INTRACELLULAR ACCUMULATIONS: PIGMENTS

• Endogenous

• Insoluble pigment

• wear and tear or aging pigment

• Lipids complexed with protein

• Not injurious to the cell

• Latin (fuscus= brown) → brown lipid

• Heart or liver of aging patients

• Patients with severe malnutrition or cachexia

• Tissues - yellow brown, finely granular perinuclear pigment

melanin

• INTRACELLULAR ACCUMULATIONS: PIGMENTS

• Endogenous

• Greek (melas= black)

• Brown- black pigment

• Endogenous

• Non-hemoglobin derived pigment

• Tyrosine to dihydroxyphenylalanine

  • Tyrosine catalase

  • melanocytes

homogentisic acid

• INTRACELLULAR ACCUMULATIONS: PIGMENTS

• Endogenous

• Black pigment

• Alkaptonuria

• ochronosis
  - Skin
  - Connective tissue
  - Cartilage

alkaptonuria

accumulation of homogentisic acid in the urine

ochronosis

accumulation of homogentisic acid in skin, connective tissue, and cartilage

hemosiderin

• INTRACELLULAR ACCUMULATIONS: PIGMENTS

• Endogenous

• Hemoglobin-derived

• Golden yellow to brown, granular crystalline pigment

• Local or systemic excess of iron, ferritin forms hemosiderin granules

• Can be seen in macrophages in organs engaged in red cell break down

Accumulates within cells by:
- A. Local excesses of iron
        - Common bruise
        - Erythrocytes-lyse
        - hemoglobin-hemosiderin
- B.Systemic Overload of Iron
        - 1. increased absorption of dietary iron
        - 2.Impaired use of iron
        - 3.Hemolytic anemias
        - 4.transfusions

• Hemochromatosis: liver, heart and pancreatic damage

Hemochromatosis

accumulation of hemosiderin in liver, heart and pancreatic damage

Bilirubin

• INTRACELLULAR ACCUMULATIONS: PIGMENTS

• Endogenous

• Normal major pigment in bile

• Derived from hemoglobin

• No iron

• jaundice

iron, magnesium

• PATHOLOGIC CALCIFICATION

• Abnormal tissue deposition

• Calcium salts (binds with):
  - _________
  - _________

Dystrophic calcification

• Deposition in dying tissues

• Normal levels of calcium

• happens in:
  - Areas of necrosis
  - Aging or damaged heart valves
  - Cell injury

• Pathogenesis

  • Formation of crystalline calcium phosphate mineral in the form of an appatite

• Two major phases

  1. initiation

  2. Propagation

DYSTROPHIC CALCIFICATION: Pathogenesis

(DYSTROPHIIC CALCIFICATION: Pathogenesis):

• INITIATION

  • Intracellular - mitochondria of dead cells or dying cells that accumulate calcium

  • Extracellular
    - Initiators: phospholipids found in membrane bound
      vesicles

               - Matrix vesicles- bones and cartilage
               - Pathologic conditions – degenerating or aging cells

• Calcium is concentrated by Membrane facilitated calcification
  1. Calcium ion + Phospholipids in the vesicle membrane
  2. Phosphate + Calcium
  3. Binding is repeated
         - raise local concentrations
         - producing deposit near the membrane
  4. Structural changes → microcrystals → propagate and 
      perforate the membrane

Metastatic calcification

• Normal tissues

• Hypercalcemia

• causes:
  1. increased PTH secretion with bone resorption
         a. parathyroid tumors
         b. ectopic secreton of PTH-related protein by malignant
             tumors.

  2. destruction of bone tissue
  3. vitamin D related disorder
  4. renal failure.

• may occur widely throughout the body

• Resemble dystrophic calcification.

calcitonin

hormone that lowers calcium in blood

parathyroid hormone (PTH)

hormone that increases calcium in blood