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Pathology

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Pathology Powered By Docstoc
					  “No doubt knowledge is
        valuable..”,
  but above it are power,
goodness & most important
        Character”
Dr. T. Krishna
           MBBS., MD
Course Director
         Pathology

Bridging science

Explain the whys?
    (signs and symptoms )

Basic foundation
      Divisions-Pathology

General - basic reactions of cells
  and tissues to abnormal stimuli
  that underlie all diseases

Special / Systemic - specific
  responses of specialized organs
  and tissues to well-defined stimuli
Aspects of disease process

Cause (etiology)

Mechanisms of development
   (pathogenesis)

Functional changes (clinical
    significance)

Structural alterations (morphologic
    changes)
        Cause (Etiology)

Two classes

   Intrinsic or genetic

   Acquired
       Infectious
       Nutritional
       Physical
       Chemical
           Pathogenesis

sequence of events in the response
of cells or tissues to the etiologic
agent
 Structural alterations
(morphologic changes)


structural alterations
characteristic or diagnostic
     Functional changes
(clinical significance)

Clinical features
   (symptoms and signs)
Course
Prognosis
        Cellular Responses
   (Stress and Noxious Stimuli )
                                        steady state to normal
                                        physiologic demands




Hyperplasia
                                                       Apoptosis
Hypertrophy
                                                       Necrosis
Atrophy

              Stages in cell response
                       Cell death
                   (Ischemic necrosis)

Adaptation
(hypertrophy)

                Cell death
  Sub-cellular alterations

Changes other than adaptations
Exposed to sub-lethal or chronic
stimuli

1. Intracellular accumulations
2. Pathologic calcification
3. Cell aging
                        Cellular Responses to Injury
                                                                       Cellular Response

Altered physiologic stimuli:                                     Cellular adaptations:
• Increased demand, increased trophic stimulation (e.g. growth   • Hyperplasia, hypertrophy
factors, hormones)
• Decreased nutrients, stimulation                               • Atrophy
• Chronic irritation (chemical or physical)                      • Metaplasia
Reduced oxygen supply; chemical injury; microbial                Cell injury:
infection
• Acute and self-limited                                         • Acute reversible injury
• Progressive and severe (including DNA damage)                  • Irreversible injury → cell
                                                                 death
                                                                   Necrosis
                                                                  Apoptosis
• Mild chronic injury                                            • Sub cellular alterations in
                                                                 various organelles
Metabolic alterations, genetic or acquired                       Intracellular accumulations;
                                                                 calcifications
Prolonged life span with cumulative sub lethal                   Cellular aging
injury
                     HYPERPLASIA
        “Increase in the number of cells in an
                   organ or tissue”
        “ cells capable of synthesizing DNA
                  & mitotic division”

    Physiologic                  Pathologic
                            cancerous proliferation
Hormonal                    Hormonal
 pregnant uterus             Endometrium
 female breast at puberty
                             Benign prostatic hyperplasia
Compensatory                Growth factors
 after damage
                             wound healing
 partial resection
                             viral infections
Mechanisms of Hyperplasia


caused by
   Growth factors
   Growth factor receptors
   Intracellular signaling pathways
             HYPERTROPHY
   “Increase in the in the size of cells in
               an organ or tissue”
       “ larger but no new cells”
  “nondividing cells & higher DNA content”
   Physiologic                    Pathologic
Hormonal                      Hormonal
 pregnant uterus
                              Functional Over-load
 female breast at Lactation
Functional Over-load
 Heart – Hemodynamic load
 (HTN & Defective valves)
          Physiologic hypertrophy
         (uterus during pregnancy)




             normal
gravid                normal         gravid

                               Microscopy
   Mechanisms of Hypertrophy
         Signal transduction
              path ways



          Induction of genes


Stimulate synthesis of cellular proteins
Expression of selected genes and proteins during myocardial hypertrophy
Genes induced during hypertrophy

  Transcription factors
             (c-fos, c-jun)


  Growth factors
            (TGF-β, IGF-1, FGF)


  Vaso-active agents
            (α-adrenergic agonists
  endothelin-1,angiotensin II)
Re-expression of fetal or neonatal
            proteins

  β form replacing α-myosin heavy chain
       Decreased ATPase
       Slower, more energetically
           economical contraction

  Atrial natriuretic factor (ANF)
       secretion by atrium & ventricle
 Triggers for hypertrophy
             Heart

Mechanical-stretch

Trophic

Polypeptide growth factors (IGF-1)
Vasoactive agents (angiotensin II,
        α-adrenergic agonists)
  Limiting factors of hypertrophy
                 Cardiac hypertrophy

                   De-compensated

                     Cardiac failure

Not well known
     Vascular supply
     Oxidative capabilities of mitochondria
     Alterations in protein synthesis ,
     degradation & cytoskeleton


Lysis and loss of myo-fibrillar contractile elements
     (apoptosis or necrosis)
                 ATROPHY
  “Shrinkage in the size of the cell by loss of
               cell substance”
    “Adaptive response and may lead to cell
                    death”
  Physiologic                     Pathologic
Early development      Decreased workload (atrophy of disuse)
                       Loss of innervation (denervation atrophy)
  Notochord            Diminished blood supply
  Thyro-glossal duct   Inadequate nutrition
                       Loss of endocrine stimulation
  Uterus               Aging (senile atrophy)
                       Pressure
          ATROPHY



             Gyri




            Sulci




36-year             82-year
    Mechanisms of Atrophy

Not clear

Increased protein degradation

proteolytic systems
    Lysosomes
    Ubiquitin-proteasome pathway
    Ubiquitin - Proteasome pathway

Proteins    ubiquitin


              Proteasome (degradation)
                (cancer cachexia)
Hormones

    Glucocorticoids     Insulin

    Thyroid hormone
         ATROPHY        contd..
“ Reduction in the structural
    components of the cell ”

Reduced number of
    Mitochondria
    Myofilaments
    Endoplasmic reticulum

Diminished function but not dead

Apoptosis also induced by the same
   signals (atrophy )
               METAPLASIA


“ Reversible change in which one adult cell
 type is replaced by another adult cell type ”

  “ Metaplastic cells survive but protective
            mechanism is lost ”

             persistent stimulus


           Malignant transformation
          METAPLASIA
             ( contd… )

Types
    Epithelial
    Mesenchymal

a) Epithelial
    1.columnar to squamous
         Respiratory tract
              cigarette smoking
              vitamin A deficiency

        Stones in the excretory ducts
    METAPLASIA – Types
             ( contd… )


    2. Squamous to columnar type
         Barrett esophagus

b) Mesenchymal
        Myositis ossificans
            METAPLASIA




columnar to squamous
                       squamous to columnar type
METAPLASIA – Mechanisms

         Reprogramming

Stem cells in          Undifferentiated
normal tissues         mesenchymal
                           cells

“ Not because of change in the
  phenotype of a differentiated cell ”
METAPLASIA – Mechanisms
       contd…

    “precursor cells differentiate
        along a new pathway”

Signals
    cytokines
    growth factors
    extracellular matrix components
METAPLASIA – Mechanisms
                      contd…


“Tissue-specific and differentiation
    genes are involved”

      Bone morphogenetic proteins
      TGF-β super family

stem cells expression of
  Cartilage & Bone
suppressing the differentiation
 into muscle or fat
METAPLASIA – Mechanisms
               contd…


“Drugs causing metaplasia ”

Disruption of DNA methylation patterns
         (Cytostatic drugs)


              Fibroblast

         Muscle            Cartilage
Cell Injury and Cell Death
Cell Injury and Cell Death
Cellular and biochemical sites
   of damage in cell injury
Reversible cell injury
    reduced oxidative phosphorylation
    ATP depletion
    cellular swelling

Irreversible injury
    no clear answer

In Myocardium
    Structural -amorphous densities in
          mitochondria,
    Functional- loss of membrane permeability
            Cell death

Necrosis - always pathological
     lysosomal enzymes leak into cytoplasm
     digestion of the cell
     leak out of cellular contents

Apoptosis – also normal
     Some noxious stimuli damage DNA
     Nuclear dissolution
     No complete loss of membrane integrity
            Stimuli

Apoptosis                  Necrosis
              intensity
              duration
       biochemical derangements
      rapidity of the death process
Features of Necrosis and Apoptosis
Feature                     Necrosis                    Apoptosis
Cell size                   Enlarged (swelling)         Reduced (shrinkage)
Nucleus                     Pyknosis → karyorrhexis     Fragmentation into
                            → karyolysis                nucleosome size
                                                        fragments
Plasma membrane             Disrupted                   Intact; altered structure,
                                                        especially orientation of
                                                        lipids

Cellular contents           Enzymatic digestion; may    Intact; may be released in
                            leak out of cell            apoptotic bodies
Adjacent inflammation       Frequent                    No


Physiologic or pathologic   Invariably pathologic       Often physiologic, means
role                        (culmination of             of eliminating unwanted
                            irreversible cell injury)   cells; may be pathologic
                                                        after some forms of cell
                                                        injury, especially DNA
                                                        damage
Ultra structural changes seen in cell death
Causes of Cell Injury

Oxygen Deprivation
Physical Agents
Chemical Agents and Drugs
Infectious Agents
Immunologic Reactions
Genetic Derangements
Nutritional Imbalances
Oxygen Deprivation

Hypoxia
   anemia
   carbon monoxide poisoning


Ischemia
   Physical Agents

Mechanical trauma
Temperature (burns & deep cold)
Changes in atmospheric Pressure
Radiation
Electric shock
Chemical Agents and Drugs
Simple chemicals
     Glucose, Salt ,Oxygen

Poisons
      Trace amounts of agents can destroy
sufficient numbers of cells within minutes to
hours to cause death

Social stimuli
Therapeutic drugs
Pollutants
     Infectious Agents
Viruses
Rickettsiae
Bacteria, Fungi, Parasites

Immunologic Reactions
Mainly defensive function but also
     cause cell injury

Anaphylactic reaction
Autoimmune diseases
   Genetic Derangements

Congenital malformations

Chromosomal abnormality - Down syndrome

single amino acid substitution -
    Hemoglobin S in sickle cell anemia

Inborn errors of metabolism
Nutritional Imbalances
Deficiencies
    Protein-calorie
    Specific vitamins
    Self-imposed, as in anorexia nervosa

Excesses
    Atherosclerosis
    Obesity
    Metabolic diseases- diabetes
Mechanisms of Cell Injury

          Principles applicable to most
           forms of cell injury
            cellular response depends on the
             type of injury, its duration, and its
             severity
            consequences depend on the type,
             state, and adaptability of the injured
             cell
            It from functional and biochemical
             abnormalities in one or more of
             several essential cellular
             components
Mechanisms of Cell Injury
   Most important targets of
    injurious stimuli
     aerobic respiration involving
      mitochondrial oxidative
      phosphorylation & depletion of
      ATP
     integrity of cell membranes
     protein synthesis
     Cytoskeleton
     integrity of the genetic apparatus
      of the cell
A. DEPLETION OF ATP
             DEPLETION OF ATP

   ATP depletion and decreased synthesis
     frequently associated with both hypoxic and
      chemical (toxic) injury
     required for many synthetic and degradative
      processes within the cell (Membrane transport,
      protein synthesis, lipogenesis, and the
      deacylation-reacylation reactions)
     produced in two ways
         major pathway- Aerobic (oxidative
          phosphorylation of ADP)
         second is the glycolytic pathway (in the absence
          of oxygen)
                DEPLETION OF ATP
   ↓ ATP to <5% to 10% of normal levels
       activity of the plasma membrane energy-dependent
        sodium pump (ouabain-sensitive Na+, K+-ATPase) is
        reduced
       sodium to accumulate intracellularly and potassium to
        diffuse out of the cell causing cell swelling
       dilation of the endoplasmic reticulum
   Cellular energy metabolism is altered
       switch to increase in glycolytic enzymes (adenosine
        monophosphate stimulate phosphofructokinase and
        phosphorylase activities) & rapidly depleted glycogen
        stores
   Accumulation of lactic acid and inorganic
    phosphates (reduces the intracellular pH, resulting
    in decreased activity of many cellular enzymes)
             DEPLETION OF ATP
   Failure of the Ca2+ pump leads to influx of Ca2
    damaging numerous cellular components
   Structural disruption of the protein synthetic
    apparatus
       detachment of ribosomes from the rough endoplasmic
        reticulum and dissociation of polysomes into
        monosomes (reduction in protein synthesis)
   Proteins become misfolded-unfolded protein
    response
   Irreversible damage to mitochondrial and lysosomal
    membranes lead to cell injury and even death( by
    necrosis)
B. MITOCHONDRIAL
DAMAGE
              MITOCHONDRIAL DAMAGE

   Mitochondria
       important targets for virtually all types of
        injurious stimuli (hypoxia and toxins)
   Damaged by
     increases of cytosolic Ca2+
     oxidative stress

     breakdown of phospholipids

     lipid breakdown products
          MITOCHONDRIAL DAMAGE
   Formation of a high-conductance channel-
    called mitochondrial permeability transition
    (in the inner mitochondrial membrane)
   Reversible in its early stages, becomes
    permanent if the inciting stimuli per
   Leakage of Cytochrome c (component of the
    electron transport chain) into the cytosol
   Deathblow to the cell (trigger apoptotic
    death pathways
C. INFLUX OF INTRACELLULAR
CALCIUM & LOSS OF CALCIUM
HOMEOSTASIS
               INFLUX OF INTRACELLULAR
               CALCIUM
   Normal Cytosolic free calcium -<0.1 μmol
    (extracellular levels of 1.3 mmol) &
    Sequestered in mitochondria and
    endoplasmic reticulum
   Ischemia and certain toxins
       Early increase in cytosolic calcium
        concentration
                of Ca2+ across the plasma membrane
          influx
          (by energy-dependent Ca2+, Mg2+-ATPases)
          and the release of Ca2+ from mitochondria
          and endoplasmic reticulum
INFLUX OF INTRACELLULAR
CALCIUM
   Activates   a number of enzymes
     • ATPases (thereby hastening ATP
       depletion),
     • phospholipases (which cause
       membrane damage),
     • proteases (which break down both
       membrane and cytoskeletal
       proteins),
     • endonucleases (which are
       responsible for DNA and
       chromatin fragmentation).
D. ACCUMULATION OF OXYGEN-
DERIVED FREE RADICALS
(OXIDATIVE STRESS)
   Cells generate energy by reducing molecular
    oxygen to water
   Small amounts of partially reduced reactive
    oxygen forms are produced as byproduct of
    mitochondrial respiration- Reactive oxygen
    species
   Some of these are free radicals that can
    damage lipids, proteins, and nucleic acids.
   Defense systems are present to prevent
    injury caused by these products
             ACCUMULATION OF OXYGEN-
             DERIVED FREE RADICALS
             (OXIDATIVE STRESS)
   Imbalance results in oxidative stress
    associated with cell injury seen in many
    pathologic conditions (Radiation injury,
    ischemia-reperfusion injury (induced by
    restoration of blood flow in ischemic tissue),
    cellular aging, and microbial killing by
    phagocytes)
   Chemical species that have a single unpaired
    electron in an outer orbit
   Energy is released through reactions with adjacent
    molecules (inorganic or organic chemicals-proteins,
    lipids, carbohydrates in membranes and nucleic
    acids)
ACCUMULATION OF OXYGEN-
DERIVED FREE RADICALS
(OXIDATIVE STRESS)
                   ACCUMULATION OF OXYGEN-
                   DERIVED FREE RADICALS
                   (OXIDATIVE STRESS)
Free radical formation is Initiated within cells in several ways,
  later initiate autocatalytic reactions,
    Absorption of radiant energy (e.g., ultraviolet light, x-rays).
     ionizing radiation hydrolyzes water into hydroxyl (OH) and
     hydrogen (H) free radicals
    Enzymatic metabolism of exogenous chemicals or drug
     (CCl4-generate CCl3)
    reduction-oxidation reactions that occur during normal
     metabolic processes (normal respiration), small amounts of
     toxic superoxide anion radical (O2-), hydrogen peroxide
     (H2O2), and hydroxyl ions (OH).
 Transition metals -iron and copper donate or accept free
  electrons during intracellular reactions during Fenton reaction
  (H2O2 + Fe2+ → Fe3+ + OH + OH-).
 Nitric oxide (NO) act as a free radical and can also be
  converted to highly reactive peroxynitrite (ONOO-) as well as
  NO2 and NO3-.
   ACCUMULATION OF OXYGEN-DERIVED FREE
   RADICALS (OXIDATIVE STRESS)
Effects of these reactive species
 Lipid peroxidation of membranes within plasma and
  organellar membranes
    double bonds in unsaturated fatty acids of membrane
     lipids are attacked particularly by OH
    autocatalytic reaction ensues (called propagation
    implicated in cell aging and in malignant transformation
     of cells
    result in extensive membrane, organellar, and cellular
     damage
 Oxidative modification of proteins.

    formation of protein-protein cross-linkages (e.g., disulfide
     bonds),
    oxidation of the protein backbone & protein fragmentatio
 Lesions in DNA-Reactions with thymine produce single
  stranded breaks in DNA.
            ACCUMULATION OF OXYGEN-
            DERIVED FREE RADICALS
            (OXIDATIVE STRESS)
   Mechanisms to remove free radicals and
    thereby minimize injury
     1. Inherently unstable and generally decay
      spontaneously- Superoxide (dismutates) into
      oxygen and hydrogen peroxide in the
      presence of water
     2. Antioxidants-block the initiation of free
      radical formation or inactivate (vitamins E and
      A as well as ascorbic acid and glutathione
     3. Iron and copper levels are minimized by
      binding of the ions to storage and transport
      proteins (e.g., transferrin, ferritin, lactoferrin,
      and ceruloplasmin)
          ACCUMULATION OF OXYGEN-
          DERIVED FREE RADICALS
          (OXIDATIVE STRESS)
 4.   Series of Enzymes
    A. Catalase, present in peroxisomes, break
     down hydrogen peroxide and superoxide anion
    B. Superoxide dismutases

      • manganese-superoxide dismutase, which is
        localized in mitochondria, and copper-zinc-
        superoxide dismutase, which is found in the
        cytosol.
    C. Glutathione peroxidase
E. DEFECTS IN MEMBRANE
PERMEABILITY
                    DEFECTS IN MEMBRANE
                    PERMEABILITY
   Consistent feature of most forms of cell injury
   affect the mitochondria, the plasma membrane, and other
    cellular membranes
   Ischemia result in series of events involving ATP depletion and
    calcium-modulated activation of phospholipases (also be
    damaged directly by certain bacterial toxins, viral proteins, lytic
    complement components, and a variety of physical and
    chemical agents)
      Mitochondrial dysfunction
      Loss of membrane phospholipids –
      Cytoskeletal abnormalities- anchors connecting the
       plasma membrane to the cell interior.
      Reactive oxygen species
      Lipid breakdown products- include unesterified free fatty
       acids, acyl carnitine, and lysophospholipids, causing
       changes in permeability and electrophysiologic alterations,
       detergent effect on membranes
DEFECTS IN MEMBRANE
PERMEABILITY
   Injury to lysosomal membranes
    results in leakage of their enzymes
    into the cytoplasm and activation of
    these enzymes (RNases, DNases,
    proteases, phosphatases,
    glucosidases, and cathepsins)
   digestion of cell components & cell
    death by necrosis