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PATHO 1: RESPONSE TO CELLULAR INJURY - Coggle Diagram

- - - - Hypoxia @ oxygen deficiency
        • Extremely important and common causes of cell injury & death
        
        EG:
        
        pneumonia à difficult to breath à inadequate oxygen inhalation à inadequate oxygenation in the blood à target organs received less oxygen
        
        Blood loss anemia à reduction in the oxygen-carrying capacity of the blood à inadequate oxygenation in the blood à target organs received less oxygen
    - - • Drugs produce their therapeutic effects by modifying the function (and morphology) of specific populations of cells.
        • Insecticide, pesticide pose low risks to humans if used with cautious
        
        EG: poisons, occupational exposure,
        environmental pollutants, drugs.
      - HOW IT INDUCE CELL- INJURY
        
        • block or stimulate cell membrane receptors,
        • alter specific enzyme systems,
        • produce toxic free radicals,
        • alter cell permeability,
        • damage chromosomes,
        • modify metabolic pathways, and
        • damage structural components of cells.
    - - VIRUS
        
        obligate intracellular microorganism that redirect host cell enzyme systems toward synthesis of viral proteins and genetmaterials to the detriment of host cells.
        • Cell changes induced by viral agents vary from little effect todeath or neoplastic transformation.
      - BACTERIAL
        
        • As result from the action of potent toxins on specific host cells (clostridial infections, enterotoxigenic Escherichia coli infection)
        • overwhelming or ineffective inflammatory response to uncontrolled bacterial replication in tissue.
        • Some bacteria, such as Lawsonia intracellularis, can result in excessive intestinal epithelial cell replication.
    - - • The immune response misdirected against antigens of host cells (autoimmune disease,
        eg: SLE).
        • It also can cause cell injuries and death although the main function of immune system is to defend the body against pathogenic microbes
        • An inappropriate or exaggerated response to certain antigens results in immunologic disease referred to as hypersensitivity (allergy).
        Eg: allergy dermatitis.
        • The activity of the immune system is greatly amplified by its effect on serum complement and inflammation. These reactions often lead to serious injury to the kidney, skin, and joints.
    - - Genetic defect --> LOW functional proteins --> DNA damage --> cell die
        
        Genetic variations --> development of many complex diseases --> influence the susceptibility of cells to injury
    - - Protein-calorie, insufficiency among under privileged population
        
        These deficiencies require metabolic adaptation by large populations of cells.
        Lipolysis, catabolism of muscle protein, and glycogenolysis enable short-term survival
        
        Specific vitamin/mineral insufficiency
      - PHYSICAL AGENT
        
        TRAUMA - may cause direct rupture and death of large numbers of cells, or it may damage the blood supply to cells.
        
        EXTREME
        
        COLD - impairs the blood flow, and intracellular ice crystals rupture cell membranes.
        
        HEAT
        
        denatures essential cell enzymes and other proteins.
        
        can increase the rate of metabolic reactions so that substrates,
        water, and pH changes reach lethal levels.
        
        ELECTRICITY- generates great heat as it passes through tissue. It also alters conduction of nerves and muscle.
        
        IONISING RADIATION - causes ionization of cellular water with production of highly reactive “free radicals” that injure cell components.
      - AGING
        
        diminished ability to respond to damage à alteration in replicative and repair ability of individual cells
        
        Some of the lesions commonly found include nodular hyperplasia of parenchymal cells in the liver, pancreas, adrenal, spleen, and thyroid.
        
        Aged cells may suffer a lifetime of damage to their DNA, or there may be accumulation of cellular debris that interferes with normal cell functions.
  - - - = deterioration of live cells following injury (stimuli), but with possibility of the injured cells to reverse to its normal stage/function
        • Manifested as some abnormality of biochemical function, structural changes, biochemical changes, or combination
        • May progress to necrosis if injury persist
        
        Deterioration of cells is evaluated in terms of morphological changes that occur inside or outside the cells
        • Morphological changes that occur inside the cells following injury involve accumulation of metabolites in the ER
        • Eg: accumulation of water following hypoxia
        • Other metabolite: protein, carbohydrate, lipids
        
        accumulation
        
        WATER
        
        = cell swelling
        • The earliest morphological change that occur whenever the plasma membrane is injured.
        • Cell swelling occurs in response to loss of the cell’s homeostasis secondary to mechanical, hypoxic, toxic, free radical, cellular energy production depletion, etc
        • It is characterized by swelling of the cell due to distention of the ER with water
        • Can be observed by light microscope
        
        PROTEIN
        
        = hyaline droplet degeneration • Accumulation of excess normal protein droplets inside the cells • Affected cells are replaced by homogenous translucent/glassy material that become homogenous acidophilic substances
        
        Hyaline droplets can be seen in the following cells:
        
        Intestinal epithelial cells of neonates following excessive absorption of colostrums immunoglobulins
        
        Epithelial cells in the renal tubules following absorption of protein leaking from damaged glomeruli
        
        CARBOHYDRATE
        
        = glycogen degeneration
        • Excess glucose in blood becomes stored in hepatocytes in the form of glycogen
        • Long standing hyperglycemia leads to accumulation of glycogen in hepatocytes that brings cell morphological changes
        • Use PAS special staining
        
        LIPID
        
        = fatty changes
        
        Define as accumulation of excess normal lipids inside the cells
        
        Lipid vacuoles in the cytoplasm
        
        Due to interference in any of the metabolic pathways of lipid metabolism
        
        Occur mostly in the liver, and occasionally in the kidney and heart
    - - NECROSIS
        
        Due to severe, persistent stimuli
        
        Loss of membrane integrity --> leakage of cellular contents due to degradation action of enzymes --> induce local host reaction (inflammation) --> eliminate dead cells and start repair process
        
        CHARACTERISTICS:
        
        NUCLEAR CHANGE
        
        KARYOLYSIS = nuclei dissolved, the basophilia of the chromatin fades which appear to reflect DNA loss
        
        PYKNOSIS =DNA condensation, nuclear shrinkage & increased basophilia
        
        KARYORRHEXIS = the pyknotic nucleus undergoes fragmentation.
        
        ○ Cytoplasmic changes: eosinophilic stain
        ○ Calcification (+/-)
        
        Loss of the outline of cell membrane
        
        GROSS FINDINGS
        
        ○ paleness of the area, corresponding to a white infarct caused by occlusion of arterial blood supply (ischemic)
        ○ red circumscribed area, corresponding to a red infarct caused by occlusion of arterial blood supply in organs with collateral blood supply, eg: spleen
        ○ Softening of the area due to rupture lysosomes and induce autolysis
        ○ Demarcation of the area by hyperemic zone, corresponding to vascular response of the viable tissue adjacent to the dead area
        
        TYPE
        
        COAGULATIVE
        
        Commonest pattern
        ● Characteristic: denaturation of cytoplasmic proteins with preservation of the cellular outline, loss of nuclei
        ● Characteristic of infarction
        ● Affected tissue: firm texture
        
        FAT NECROSIS
        
        Focal area of fat destruction, typically due to activated pancreatic lipase released into the substance of the pancreas and the peritoneal cavity
        ● Occur in acute pancreatitis ( white chalky deposition represent fat necrosis with calcium soap formation/saponification)
        ● microscopic examination: the foci of necrosis contain shadowy outlines of necrotic fat cells
        
        LIQUEFACTIVE
        
        Seen in focal bacterial or occasionally fungal infections
        ● Microbes stimulate the accumulation of inflammatory cells and the enzymes from leukocytes (=inflammatory cells) digest/liquefy the tissues
        ● Complete digested dead cells will transform the tissues into liquid viscous mass/liquid substance
        ● If the process was initiated by acute inflammation, (eg: bacterial infection), the material is creamy yellow (=pus/abscess)
        
        “Why liquefactive necrosis is always linked to brain necrosis?
        
        Brain has a very high concentration of lysosomes.
        
        Lysosomes will digest dead cells in the brain, increasing the chance of liquefactive necrosis occurring.
        
        CASEOUS
        
        Characteristic of tuberculosis
        ● Caseous = cheese-like, derived from the friable yellowwhite appearance of the area of necrosis, in the centre of foci of tuberculous infection
        ● Aggregation/accumulation of inflammatory cells, eg: macrophages
        ● Microscopic examination: the necrotic focal appear as a collection of fragmented @ lysed cells with completely obliterated tissue architecture. Often enclosed within distinctive inflammatory border, known as granuloma.
        
        FIBRINOID
        
        Complex of antigen-antibody reaction deposited in the wall of arteries
        ● Deposits of these immune complex, coupled with fibrin that leaked from arteries forms a bright pink, amorphous appearance in H&E stain
        ● Eg: immune vasculitis, (immune system attacks blood vessels)
        
        GANGRENOUS
        
        DRY
        
        DEFINITION
        
        gangrene that develops in the presence of arterial obstruction, is sharply localized, and is characterized by dryness of the dead tissue which is sharply demarcated from adjacent tissue by a line of inflammation
        
        ETIOLOGY
        
        Due to ischemia without involvement of bacterial infection.
        
        Loss of blood supply to the body part lead to necrosis of tissue due to lack of oxygen.
        
        MORPHO PRESENT'
        
        Affected area is dry, shrunken and dark black or brown
        
        Clear line of demarcation between dead and viable tissue
        
        EXAMPLE
        
        Frostbite
        
        Artherosclerotic peripheral vascular disease in lower limb of diabetic patient
        
        WET
        
        DEFINITION
        
        gangrene that develops in the presence of combined arterial and venous obstruction, is usually accompanied by an infection, and is characterized by a watery discharge usually of foul odor
        
        ETIOLOGY
        
        Sudden arterial or venous obstruction
        
        Embolism
        
        Crush injury
        
        Caused by infection and physical injuries (wound,cut) leading to death of tissues and results in settling of wet substance.
        
        MORPHO PRESENT'
        
        Wet,soft,swollen, Pus formation, Dark, No line of demarcation
        
        EXAMPLE
        
        people with diabetes who unknowingly injure a toe or foot
        
        GAS
        
        DEFINITION
        
        progressive gangrene marked by impregnation of the dead and dying tissue with gas and caused by one or more toxin-producing clostridia
        
        ETIOLOGY
        
        Caused by gas-forming clostridia (gram-positive anaerobic bacteria) which enters the body through wounds
        
        Bacteria can also enter due to complication in colon surgery because clostridia is normally present in intestines
        
        MORPHO PRESENT'
        
        Affected area is swollen, painful, oedematous and crepitant due to accumulation of gas bubbles within tissues
        
        Subsequently, the area becomes dark black and has a foul smell
        
        EXAMPLE
        
        GI abnormalities (colon cancer)
        
        Clostridial myonecrosis
        
        Subcutaneous emphysema
      - APOPTOSIS
        
        A normal physiological process, balanced by cell renewal
        ○ when a cell is deprived of growth factors, cell kills itself and does not elicit an inflammatory response.
        ○ Program cell death, eg:
        i) during fetal development;
        ii) in response to hormonal cycle and
        iii) normal turnover of highly proliferating tissues
        ○ Cells shrink, not swell
        ○ Nuclei condense and DNA fragments
        ○ Cells fragment into membrane-bound bits
        ○ Bits are phagocytosed by macrophages
  - - - Hyperplasia
        
        =cell population, may occur concurrently with hypertrophy
        ● Due to physiological & pathological factor
        
        PHYSIOLOGICAL
        
        Hormonal hyperplasia: proliferation of glandular epithelium of female breast during puberty/pregnancy
        ■ Compensatory hyperplasia: residual tissues grows after removal/loss.
        
        PATHOLOGICAL
        
        Excessive hormonal, growth factor stimulation
        ■ Eg: hyperplastic epithelium in skin wart caused by papilomaviruses
        
        Focal epithelial hyperplasia (also known as Heck's disease)
      - Hypertrophy
        
        ● = HIGH in the size of cells resulting in the size of the organ.
        ● no new cells, only BIGGER CELLS with HIGH amount of structural proteins & organelles, cells have limited capacity to divide
        ● Due to: HIGH functional/physiological demand, HIGH growth factor, HIGH hormonal stimuli, pathological factor
        ● Eg: enlargement of the uterus during pregnancy, weightlifter, cardiac enlargement
      - Atrophy
        
        Shrinkage in size of the cell by loss of cell substances
        ● Due to: decreased workload (bedridden patient), inadequate nutrition, aging
      - Metaplasia
        
        = Reversible changes in which one cell type is replaced by other cell type
        ● Often in response to chronic irritation, that makes cells adapt & withstand the stress
        ● Eg: habitual cigarette smoker (normal ciliated columnar epi of trachea & bronchi ® stratified squamous epi)
      - DYSPLASIA
        
        Development of abnormal types of cells within a tissue, which
        may signify a stage proceeding the development of cancer
      - APLASIA
        
        Part of the organ does not develop.
        ● Aplasia is obvious at birth.
      - HYPOPLASIA
        
        Underdevelopment or incomplete development
        ● it properly refers to an inadequate or below-normal number of cells.
    - - Occurs when cells break down
        ● =destruction of cells/tissues by their own enzymes especially those released by lysosomes
        ● When the cell membrane dissolves. Enzymes and other cell contents spill out and digest surrounding tissue
        ● Morphologically, autolysis is identified by homegenous & eosinophilic cytoplasm with loss of cellular details & remains of cells as debris.
- - - - VASCULAR CHANGE
        
        VASODILATION
        
        One of the earliest reactions of acute inflammation
        • Induced by mediators notably histamine
        • First involves arterioles and then leads opening of new capillary beds
        • Results in increased blood flow
        • Responsible for the externally visible redness (erythema) and warmth (heat) at the site of inflammation
        
        Vasodilation quickly followed by increased permeability – outpouring of protein-rich fluid (EXUDATE) into extravascular tissue (causing swelling).
        • The escape of fluid, proteins, and blood cells from the vascular system is known as EXUDATION.
        
        Loss of fluid and increased vessel diameter lead to:
        
        ✓ Slower blood flow
        
        ✓ HIGH red cells concentration in small cells & viscosity
        --> Results in stasis of the blood flow, engorgement of small vessels (histology) with slowly moving red cells
        
        Vasodilate → Hyperemia → Stasis
        
        As stasis develops, blood leukocytes (neutrophils) accumulate along the vascular endothelium - a process called margination.
        • Endothelial cells are activated by mediators produced at sites of infection and tissue damage, and express HIGH level of adhesion molecules
        
        EXUDATION
        
        The escape of fluid, proteins and blood cells from vascular system into interstitial tissues or body cavities
        
        • Dilutes bacterial toxins & chemical irritants
        • Brings antibodies to inflammation area
        • Brings the chemical mediators derived from plasma to the area
        
        MARGINATION
        
        blood leukocytes (neutrophils) accumulate along
        the vascular endothelium
        
        Leads to the accumulation of inflammatory cells
        • Neutrophils stick to the vascular endothelium
        • Moves and migrates through endothelial gaps (emigration/extravasation)
      - CELLULAR EVENT
        
        Leukocyte recruitment to site of injury from the vascular lumen to the extravascular space
        
        ROLLING & ADHESION
        
        Leukocytes tumble slowly along the endothelium and adhere transiently, detach and bind again.
        • 4 type of distinct adhesion molecule – selectins, addresins, integrins, immunoglobulin family adhesion molecule.
        
        DIAPEDESIS
        
        After arresting on the endothelial surface, leukocytes migrate through the vessel wall, primarily by squeezing between inter-endothelial junctions
        • This extravasation of leukocytes is called transmigration or diapedesis
        • After adhesion, neutrophils throw out their cytoplasmic pseudopods and escapes out into extravascular space.
        
        CHEMOTAXIS
        
        After exiting the circulation, leukocytes move in the tissues toward the site of injury → a process called chemotaxis
        • Chemotactic factors mediated the migration of leukocytes
        • Both exogenous & endogenous substances can be chemotactic for leukocytes (chemoattractants)
        
        MIGRATION
        
        Slowly move along the endothelium and adhere transiently (process called rolling) finally they come to rest at some point – adhere firmly.
        ➢ After adhesion, they insert the pseudopods into endothelial cell junction and squeeze through this layer into the extravascular space.
        ➢ The process of adhesion and transmigration is determined by binding of adhesion molecules on leukocytes and endothelial cells
        
        Leukocyte activation at the site of injury
        
        ✓ Phagocytosis
        
        ✓ Intracellular destruction
        
        ✓ Liberation of substances that destroy extracellular microbes and
        
        dead tissues
        
        ✓ Production of mediators
        
        Phagocytosis of particles (engulfment process)
        
        II. Engulfment with subsequent formation of phagocytic vacuole (phagolysosome)
        
        I. Recognition & attachment to the ingesting leukocyte
        
        III. Killing & degradation of the ingested material
        
        The process of engulfment of solid particulate material
        by the leukocytes (neutrophils and monocytes)/cell-eating.
    - - VASODILATION - prostaglandin, nitric oxide, histamine
      - VASCULAR PERMEABILITY- vasoactive amines, bradykinin, leukotrienes, PAF, subs P, VEGF
      - CHEMOTAXIS - chemokine, IL-8, TNF
      - PAIN - prostaglandin, bradykinin, subs p
      - TISSUE DAMAGE- neutrophils, macrophage, lysosomal enz, nitric oxide
    - - tissue edema, neutrophils margination, neutrophils emigration
    - - COMPLETE RESOLUTION
        
        uncomplicated acute inflammation
        • Return to normal tissue
        • Exudate and cellular debris are liquefied and removed by macrophages
      - REPAIR/HEALING
        
        • Healing by regeneration in case of superficial tissue loss
        • Healing by fibrosis in case of extensive tissue loss
      - PROGRESSION TO CHRONIC INFLAMM'
        
        When the acute inflammatory response cannot be resolved
        • Because of either the persistence of the injurious agent
  - - - PERSISTENCE INFECTION
        
        i. Microorganism that are difficult to eradicate
        (eg: Mycobacterium tuberculosis)
        ii. Unresolved acute inflammation evolves into chronic inflammation (eg. acute bacterial infection of the lung progresses to a chronic lung abscess)
      - HYPERSESITIVITY
        
        Excessive and uncontrolled activation of immune system.
        
        i. In autoimmune diseases → self antigen mistakenly reacts against person’s own tissues (eg. rheumatoid arthritis, multiple sclerosis).
        
        ii. In allergic diseases → excessive immune responses against common environmental substances (bronchial asthma)
      - PROLOGED EXPOSURE
        
        to toxic agent (exogenous/endogenous)
        
        i. Exogenous: silica inhalation for prolonged period → cause chronic inflammation in lungs (silicosis)
        
        ii. Endogenous : cholesterol (products of normal fat metabolism). In excess cause → atherosclerosis
    - - PRIMARY - No initial phase of acute inflammation
      - PROGRESSION FROM ACUTE INFLAMM'
        
        Usually the suppurative type
        
        Fails to vanquish the agent in acute phase
        ❑ Eg; osteomyelitis – abscess in bone marrow cavity
    - - INFLAMMATION
        
        Infiltration with mononuclear cells
        • Macrophages • Lymphocytes • Plasma cells
      - TISSUE INJURY
        
        Tissue destruction induced by
        • Persistent offending agent • Inflammatory cells
      - ATTEMPTS AT REPAIR
        
        By connective tissue replacement of damaged tissue
        • Angiogenesis (proliferation of small blood vessels)
        • Fibrosis
    - - DOMINANT CELLS
        
        MACROPHAGES
        
        Contribute to the chronic inflammatory reaction by secreting cytokines (TNF, IL-1, chemokines) and growth factors that act on various cells, activating other cells (T lymphocytes)
        → destroying foreign invaders and tissues
        
        In certain organs – different name
        (resident tissue macrophage):
        
        ➢ Liver: Kupffer cells
        
        ➢ Spleen & lymph nodes: histiocytes
        
        ➢ CNS: microglial cells
        
        ➢ Lungs: alveolar macrophages
        
        ROLE
        
        Eliminate injurious agents (eg. phagocytize microbes) and initiate tissue repair, but also responsible for much of tissue injury.
        
        Secrete mediators of inflammation (eg: IL-1, chemokines) – induce more inflammatory reaction.
        
        Display antigen to T-lymphocytes and respond to signal from T-cells : essential for defense against many microbes
        
        Activation Pathway
        
        Classical activation (M1)
        
        Produced NO (nitric oxide) (fx: microbicidal), ROS and upregulate lysosomal enzymes
        
        Main role: enhance killing activity (destroy microbes), secrete cytokine to promote inflammatory response
        
        Induced by microbial products (endotoxin), foreign substance (crystals, particulate matter)
        • Which engage TLRs and other sensors; Cytokine IFN-gamma (T cell - derived signal)
        
        important to eradicate infections and dominate many inflammatory reaction → capable of injuring normal tissues
        
        Alternative activation (M2)
        
        Not actively microbicidal
        
        Principal function → Inhibit inflammation and promote TISSUE REPAIR
        
        Secrete growth factor – promote angiogenesis
        
        Activate fibroblast and stimulate collagen synthesis
        
        Induced by mediators OTHER THAN IFN-gamma (eg: IL -4, -13) produced by T lymphocytes & other cells.
      - LYMPHOCYTES
        
        Microbes & other environmental antigens activate T and B lymphocytes → Amplify & propagate chronic inflammation
        
        When activated, inflammation tends to be persistent and severe.
        
        May be the dominant cells in autoimmune and other hypersensitivity diseases.
        
        Macrophages & lymphocytes continuously stimulate each other until antigen is removed.
        
        Macrophage-lymphocyte interactions
        
        Activated T cells produce cytokines (TNF, IL-17) that recruit macrophages and others that activate macrophages (IFN-GAMMA)
        
        Activated macrophages in turn stimulate T cells by presenting antigens and via cytokines (IL12).
        
        Prolonged reactions involving T cells and macrophages may result in granuloma formation
        
        NEUTROPHILS - → Induced by persistent microbes or mediators produced by activated macrophages & T lymphocytes
      - EOSINOPHILS
        
        have granules, mono-lobed to bi-lobed nuclei, contain major basic protein, (highly cationic protein) → toxic to parasites but also injures host epithelial cells
        ➢ Control parasitic infections
        ➢ Contribute to tissue damage (in immune reaction eg. allergies)
      - CELLS
        
        PLASMA
        
        • Derived from activated B cells, produce antibodies
        • “clock face” nuclear chromatin appearance
        
        MAST
        
        Participate in both acute & chronic inflammatory rx (immediate hypersensitivity)
    - - ANTIGENIC (microbe/self - take several days)
        
        GRANULOMATOUS inflam'
        
        aggregation of activated macrophages & T lymphocytes.
        • FX: Cellular attempt to contain an offending agent that is difficult to eradicate
        
        NON-GRANULOMATOUS- accumulation of sensitized lymphocytes, plasma cells, macrophages – SCATTERED
      - NON-ANTIGENIC
        
        FORIEGN BODY GRANULOMA
        
        When foreign material that is LARGE, inert and non-antigenic (incites no immune response) enters tissue and persist there → form foreign body granuloma
        ➢ Non-antigenic material : sutures, inert fibres, talc.
        ➢ Macrophages aggregate around (non-immune phagocytosis) forming foreign body giant granuloma
        
        Numerous nuclei dispersed throughout the cells
      - MIXED - as in chronic suppurative inflammation and recurring acute inflammation
    - - ✓ Fever - Usually low-grade and insidious onset
        ✓ Weight loss & loss of apetite
        ✓ Changes in plasma protein (C-reactive protein, fibrinogen, serum amyloid A protein)
        
        Elevated levels of plasma immunoglobulin
        
        Associated with secondary amyloidosis
        
        HIGH ESR
        
        ✓ Peripheral white blood cell counts
        
        Leukocytosis: High WBC count → sign of inflammatory rx (commonly infection)
        
        Lymphocytosis, monocytosis, eosinophilia
  - - - infection, trauma, tissue necrosis, foreign bodies, immune (hypersensitivity rxn)
    - - heat, redness, swelling/edem, pain, loss of ofunction [all due to Increased blood flow, stasis, increased vascular permeability, chem mediators]
- - - - Chronic granulomatous inflammation
        
        Distinctive pattern of chronic inflammation (Type IV hypersensitivity immune response)
        
        Abundant cell: epitheloid cells (activated macrophages)
        
        Why it is important? Few diseases associated with this type of lesion and are clinically important
      - Non granulomatous chronic inflammation
        
        Characterized by lymphocytes and plasma cells infiltrate the tissues, with presence of cell necrosis and fibrosis
        
        Eg: chronic viral infection, autoimmune disease (eg: Chronic ulcerative colitis, Hashimoto’s thyroiditis), chronic alcoholic liver disease.
        
        Histology: structure-less unorganized diffuse infiltration of inflammatory cells
    - - INFECTIOUS
        
        CAUSES
        
        BACTERIA- M. tuberculosis, M. leprae, B. henselae
        
        FUNGI- C. neoformans, S. schenckii
        
        PARASITE - Schistosoma mansoni
        
        UNKNOWN - Sarcoidosis
        
        Usually associated with hardy microorganism that resist killing process by host immune system
        
        Macrophage -> epithelioid cells -> multinucleated giant cells
      - NON-INFECTIOUS
        
        Do not provoke inflammatory response, but multinucleated giant cells are present
        
        Eg: Foreign body granuloma. usually found in the centre of granuloma
        
        Causes: metal (silicosis), suture material, hair
      - CASEATING
        
        With CENTER that has undergone caseous necrosis
        ○ Occur typically in TB
        ○ Cheese-like appearance
        ○ Histology: the center appear as mass of formless debris with no nuclei present.
      - NON-CASEATING
        
        ○ DO NOT HAVE a center that undergone caseating necrosis
        ○ Found in diseases, eg: Crohn’s disease, leprosy
    - - MORPHO
        
        Primary pulmonary tuberculosis (Ghon complex)
        • The gray-white multiple foci, caseation in nature, at the parenchymal area of the upper lobe
      - HISTO
        
        MICROSCOPIC
        
        Hallmark is necrotizing granulomatous inflammation, composed of central necrotic zone surrounded by epithelioid histiocytes with varied number of multinucleated giant cells and lymphocytes
        
        Multinucleated giant cells may contain Langhans type giant cells (nuclei arranged in a horseshoe shaped pattern at the periphery of the cell) but Langhans type giant cells are not specific for TB infection
        
        Organisms are usually present within the central zone of necrosis, seen on special stains (in some cases)
        
        Nonnecrotizing granulomas can be present as well
    - - Tuberculoid leprosy (TT)
        
        Among individual with good cellular immunity response
        • Peripheral nerve involvement: usually limited to one nerve that enlarged and palpable
        • Clinical manifestation: sensory loss (ulnar, peroneal, facial nerve) -> easily to get injuries -> chronic skin ulcer/inflammation -> autoamputation of the affected parts
        • Lesions: well defined, hypopigmented, anesthetic skin lesion, dry patch, distinct delineated raised border
      - Borderline leprosy
      - Lepromatous leprosy (LL)
        
        Among individual with poor cellular immunity response
        • Lesions: poor demarcated, nodular lesions on all part of body, disfigurement occurs: Leonine facies, claw-shaped hands, pendulous ear lobes, saddle nose
        • Histology: sheets of foamy macrophages in the dermis which contain the antigen
    - - Aetiology agent: Treponema pallidum
        ● Transmission: Sexually transmitted /Transplacenta
        ● 4 different stages: primary, secondary, latent, tertiary & congenital syphilis
      - STAGE
        
        PRIMARY
        
        • Typically acquired by direct sexual contact with infectious lesions of another individual
        • After incubation period (up to 90 days), chancre (skin lesion) appears on the site of contact
        • Site: cervix (44%), penis (99%), anal & rectum (34%), other site (7%)
        • Lesion: single, firm, painless, non-itchy ulcer -> macule -> papule -> erosion & ulcer
        • Highly infectious stage
        
        SECONDARY
        
        10 w after primary infection
        • Involve skin, MM, LN
        • Lesion: symmetrical, reddish-pink, non itchy rash, condyloma lata (wart like lesion) on MM
        • Symptom: fever, sore throat, malaise, weight loss, headache
        • Lesion resolved after 6w
        • Certain people do not develop primary syphilis, but directly demonstrate secondary symptoms
        • Infectious stage
        
        LATENT
        
        EARLY
        
        <1y after secondary stage- relapse symptoms, contagious
        • A reactive serologic test for syphilis in an asymptomatic individual who has had a negative serologic test within the preceding year
        
        LATE
        
        1y after secondary stage – asymptomatic
        • Not infectious, BUT for the pregnant woman, it may be transmitted to the fetus
        
        TERTIARY
        
        Gummatous syphilis (granulomatous nodular lesions in various organs, commonly skin and bone)
        
        Cardiovascular syphilis (common: aortitis -> aortic valve insufficiency and aneurysms of proximal aorta)
        
        Neurosyphilis (include chronic meningiovascular disease, general paresis)
        
        CONGENITAL
        
        Transmitted during pregnancy @ during birth
        • Late abortion / stillbirth • Early syphilis: during 2 years of life. • Symptoms: nasal discharge, bullous rash of hands, feet, mouth & anus, hepatomegaly, skeletal abnormalities • Late syphilis: after 2 years of life • Distinctive trial of interstitial keratitis, Hutchinson teeth (small, widely spaced, central notches on biting surface, pegshaped incisor), nerve deafness
  - - - AL amyloidosis (immunoglobulin light chain amyloidosis). The most common type/primary amyloidosis.
      - ○ AA amyloidosis. Also known as secondary amyloidosis, this variety is usually triggered by an inflammatory disease, such as rheumatoid arthritis.
      - ○ Hereditary amyloidosis (familial amyloidosis). It most commonly happens when a protein made by your liver is abnormal. This protein is called transthyretin (TTR).
      - ○ Wild-type amyloidosis/senile systemic amyloidosis, affect men over age 70 and typically targets the heart. It can also cause carpal tunnel syndrome.
      - ○ Localized amyloidosis. This type of amyloidosis often has a better prognosis than the varieties that affect multiple organ systems.
    - - GROSS- organs contained large amount of amyloid have a pale, grayish waxy appearance on cut surface
      - HISTO - homogenous, eosinophilic, acellular substances in the interstitial area and walls of blood vessels
      - CONFIRM' - Congo red stain -> apple green birefringence under
        polarized light
    - - PRIMARY
        
        AL type amyloid
        ○ Occurs in 5-10% patients with multiple myeloma
        ○ The neoplastic plasma cells synthesize abnormal quantities of a single Ig or Ig light chain
        ○ Involve heart, GIT, peripheral nerves, skin, tongue, etc
      - SECONDARY
        
        AA type amyloid (synthesized in liver & elevated in inflammatory states)
        ○ Associated with chronic inflammatory states. Eg: rheumatoid arthritis, scleroderma, chronic osteomyelitis
        ○ Typically involve kidney, spleen LN, adrenal, thyroid
    - - INVOLVE
        
        RENAL
        
        Proteinuria -> nephritic syndrome
        ■ Progressive demolition of glomeruli -> renal failure
        
        CARDIAC
        
        Insidious congestive heart failure
        ■ Amyloid deposition -> arrhythmias -> fatal
        
        GIT
        
        Usually, asymptomatic
        ■ Eg: in tongue -> enlarged -> disturb speech & swallowing
        ■ Eg: in stomach/intestine -> malabsorption -> disturbances in digestion
      - Asymptomatic -> death
        ● Depending on the number of deposition & organs involved
    - - Depends on subtypes of amyloidosis
        ● General: poor
        ● Better prognosis in reactive systemic amyloidosis & its prognosis depends on the control of the underlying factor
  - - - MELANIN
        
        Produced by melanocytes
        ○ Brown-black pigment formed when the enzyme tryosinase catalyzes the oxidation of tyrosinase to dihydroxyphenyalanine in melanocytes
        ○ Pigment that give color to human skin, hair, eyes ○ >melanin =dark skin
        ○ Provide some protection from sun light
      - BILIRUBIN
        
        End product of heme degradation
        ○ Normal major pigment found in bile
        ○ Clinical manifestation: jaundice, due to excess accumulation of this pigment in cell and tissues
      - HEMOSIDERIN
        
        Hemoglobin-derived granular pigment
        ○ Color: golden yellow to brown
        ○ Accumulate in tissues when there is excess of iron
      - LIPOFUSCIN
        
        Insoluble brown lipid pigment
        ○ = aging pigment
        ○ Not harmful to the cell
        ○ Seen in cells undergoing slow, regressive changes and is particularly in the liver and heart of aging patients @ patient with severe malnutrition
    - - CARBON
        
        Most common exogenous pigment
        ○ Air pollutant of urban life
        ○ Inhale -> phagocytosed by the macrophages in the alveoli -> trasported to LN -> accumulate -> blackish -> = anthracosis
      - COPPER
        
        Accumulation found within the liver is characteristic of Wilson's disease.
        ○ Pigment in liver tissue may be deposited from intravenous (IV) gold (used to treat rheumatoid arthritis) or illicit drug use.
      - TATTOO, ASBESTOS, LEAD
  - - - Dystrophic
        
        Occurs in area of necrosis
        ● Associated with intimal injury in the aorta and large arteries
        ● Develop in aging/damage heart valve
        ● Induce aortic stenosis (severely compromised valve motion)
        
        Initiation + propagation à intra & extra cellular à formation of
        crystalline calcium phosphate à deposition in organs
        
        MACROSCOPIC
        
        : calcium salt appear as fine, white granules & gritty
        
        MICROSCOPIC
        
        Basophilic, granular/clumped
        
        Location: intracellular, extracellular
        
        Resemble to grains of sand
        
        Psammoma bodies (round, concentric lamellated calcified structure)
      - Metastatic
        
        Occur in normal tissue
        ● Morphology: ○ Occur in any part of body (esp in stomach, kidney, lungs, arteries, veins) , Calcium salt = dystrophic calcification
        ● Clinical significance ○ No clinical dysfunction , Massive involvement in lungs -> seen in x-ray films , Massive deposition in kidney -> renal damage
        ● Hypercalcemia, which is due to increased secretion of PTH hormone, destruction of bone tissue, Vit. D related disorders, renal failure