Posted in Pathology

Cellular injury

Autophagy 

  • Autophagy involves sequestration of cellular organelles into cytoplasmic autophagic vacuoles. (autophagosomes) that fuse with lysosomes and digest the enclosed material. 
  • Autophagy is an adaptive response that is enhanced during nutrient deprivation, allowing the cell to cannibalize itself to survive. 
  • Autophagosome formation is regulated by more than a dozen proteins that act in a coordinated, and sequential manner. 
  • Dysregulation of autophagy occurs in many disease states including cancers, inflammatory bowel diseases, and new rodegenerative disorders. Autophagy plays a role in host defense against certain microbes. 

Abnormal Intracellular Depositions and Calcifications 

    • Abnormal deposits of materials in cells and tissues are the result of excessive intake or defective transport or catabolism. 
    • Deposition of lipids :
    1. Fatty change: Accumulation of free triglycerides in cells, resulting from excessive intake or defective transport (often because of defects in synthesis of transport proteins); manifestation of reversible cell injury 
    2. Cholesterol deposition: Result of defective catabolism and excessive intake; in macrophages and smooth muscle cells of vessel walls in atherosclerosis 
    • Deposition of proteins: Reabsorbed proteins in kidney tubules; immunoglobulins in plasma cells 
    • Deposition of glycogen: In macrophages of patients with defects in lysosomal enzymes that break down glycogen (glycogen storage diseases) 
    • Deposition of pigments: Typically indigestible pigments, such as carbon, lipofuscin (breakdown product of lipid peroxidation), or iron (usually due to overload, as in hemosiderosis) 
    • Pathologic calcifications :
    1. Dystrophic calcification: Deposition of calcium at sites of cell injury and necrosis 
    2. Metastatic calcification: Deposition of calcium in normal tissues, caused by hypercalcemia (usually a consequence of parathyroid hormone excess) 

    Cellular Aging 

      • Cellular aging results from a combination of accumulating cellular damage (e.g., by free radicals), reduced capacity to divide (replicative senescence), reduced ability to repair damaged DNA, and defective protein homeostasis 
      • Accumulation of DNA damage: Defective DNA repair mechanisms; conversely, caloric restriction activates DNA repair and is known to prolong aging in model organisms 
      • Replicative senescence: Reduced capacity of cells to divide secondary to progressive shortening of chromosomal ends (telomeres) 
      • Defective protein homeostasis: Resulting from impaired chaperone and proteasome functions. 
      • Nutrient sensing system: Caloric restriction increases longevity. Mediators may be reduced lGF-1 signaling and increases in sirtuins. 

        ©Robbins Basic Pathology, Ninth edition

        Posted in Pathology

        Mechanism of cell injury

        • ATP depletion: failure of energy-dependent functions –> reversible injury –> necrosis 
        • Mitochondrial damage: ATP depletion –> failure of energy-dependent cellular functions –> ultimately, necrosis; under some conditions, leakage of mitochondrial proteins that cause apoptosis 
        • Influx of calcium: activation of enzymes that damage cellular components and may also trigger apoptosis 
        •  Accumulation of reactive oxygen species: covalent modification of cellular proteins, lipids, nucleic acids
        •  Increased permeability of cellular membranes: may affect plasma membrane, lysosomal membranes, mitochondrial membranes; typically culminates in necrosis 
        • Accumulation of damaged DNA and misfolded proteins: triggers apoptosis 

        Ischemic and Toxic Injury 

        • Mild ischemia: Reduced oxidative phosphorylation –>. reduced ATP generation -> failure of Na pump –> influx of sodium and water -> organelle and cellular swelling (reversible) 
        • Severe/prolonged ischemia: severe swelling of mitochondria, calcium influx into mitochondria and into the cell with rupture of lysosomes and plasma membrane. Death by necrosis and apoptosis due the release of cytochrome c from mitochondria 
        • Reperfusions injury follows blood flow into ischemic area is caused by oxidative stress due to release of free radicals from leukocytes and endothelial cells. Blood brings calcium that overloads reversibly injured cells with consequent mitochondrial injury. Influx of leukocytes generates free radicals and cytokines. Local activation of complement by lgM antibodies deposited in ischemic tissues. 
        • Chemicals may cause injury directly or by conversion into toxic metabolites. The organs chiefly affected are those involved in absorption or excretion of chemicals or others such as liver where the chemicals are converted to toxic metabolites. Direct injury to critical organelles such as mitochondria or indirect injury from free radicals generated from the chemicals/toxins is involved. 

        Apoptosis :

        • Regulated mechanism of cell death that serves to eliminate unwanted and irreparably damaged cells, with the least possible host reaction 
        • Characterized by enzymatic degradation of proteins and DNA, initiated by caspases; and by recognition and removal of dead cells by phagocytes 
        • Initiated by two major pathways: 
        1. Mitochondrial (intrinsic) pathway is triggered by loss of survival signals, DNA damage, and accumulation of misfolded proteins (ER stress); associated with leakage of pro-apoptotic proteins from mitochondrial membrane into the cytoplasm, where they activate caspases; inhibited by anti-apoptotic members of the BCL2 family, which are induced by survival signals including growth factors 
        2. Death receptor (extrinsic) pathway is responsible for elimination of self-reactive lymphocytes and damage by cytotoxic T lymphocytes; is initiated by engagement of death receptors (members of the TNF receptor family) by ligands on adjacent cells. 

        Necroptosis and Pyroptosis:

        • Necroptosis resembles necrosis morphologically and apoptosis mechanistically as a form of programmed cell death. 
        • Necroptosis is triggered by ligation of TNFR1, and viral proteins of RNA and DNA viruses. 
        • Necroptosis is caspase-independent but dependent on signaling by the RlP1 and RlP3 complex. 
        • RlP1 -RlP3 signaling reduces mitochondrial ATP generation, causes production of ROS, and permeabilizes lysosomal membranes, thereby causing cellular swelling and membrane damage as occurs in necrosis. 
        •  Release of cellular contents evokes an inflammatory reaction as in necrosis. 

        • Pyroptosis occurs in cells infected by microbeslt involves activation of caspase-1 which cleaves the precursor form of lL-1 to generate biologically active lL-1. Caspase-1 along with closely related caspase-11 also cause death of the infected cell. 

        ©Robbins Basic Pathology, Ninth edition

        Posted in Pathology

        Causes of cell injury

        Cellular adaptation to Stress:

        Hypertrophy: increased cell and organ size, often in response to increased workload; induced by growth factors produced in response to mechanical stress or other stimuli; occurs in tissues incapable of cell division 

        Hyperplasia: increased cell numbers in response to hormones and other growth factors; occurs in tissues whose cells are able to divide or contain abundant tissue stem cells 

        Atrophy: decreased cell and organ size, as a result of decreased nutrient supply or disuse; associated with decreased synthesis of cellular building blocks and increased breakdown of cellular organelles 

        Metaplasia: change in phenotype of differentiated cells, often in response to chronic irritation, that makes cells better able to withstand the stress; usually induced by altered differentiation pathway of tissue stem cells; may result in reduced functions or increased propensity for malignant transformation 


        Morphology of reversible injury:

        • Cellular swelling is the first manifestation of almost all forms of injury to cells. It is a difficult morphologic change to appreciate with the light microscope; it may be more apparent at the level of the whole organ. When it affects many cells, it causes some pallor, increased turgor, and increase in weight of the organ. On microscopic examination, small clear vacuoles may be seen within the cytoplasm; these represent distended and pinched-off segments of the ER. This pattern of nonlethal injury is sometimes called hydropic change or vacuolar degeneration. Swelling of cells is reversible. Cells may also show increased eosinophilic staining, which becomes much more pronounced with progression to necrosis. 
        • The ultrastructural changes of reversible cell injury include: 

        1. Plasma membrane alterations, such as blebbing, blunting, and loss of microvilli 

        2. Mitochondrial changes, including swelling and the appearance of small amorphous densities 

        3. Dilation of the ER, with detachment of polysomes; intracytoplasmic myelln figures may be present 

        4. Nuclear alteration, with disaggregation of granular fibrillar elements.


        ©Robbins Basic Pathology, Ninth edition

        Posted in Pathology

        Mechanism of Helicobacter Pylori induced injury-Summary

        Helical gram-negative rod.

        Enzyme produced is urease, which splits urea. Resulting bicarbonate creates alkaline environment. Another enzyme mucinase degrades mucus. 

        Lives only in gastric epithelium.
        Injury is due to: 

        • Toxins such as vacuolating cytotoxin increased gastrin levels 
        • Phospholipases 
        • Platelet-activating factor 
        • Increased immunoglobulin response (host response) 

        Cytotoxins 

        Other factors 

        • Local tissue injury 
        • Local ischaemia 

        Remember as HELlCO 

        © Manipal manual of surgery, fourth edition

        Posted in surgery

        Most common for Oesophagus

        1. Most common among the oesophageal diverticula is Zenker’s diverticulum.
        2. Most common benign oesophageal tumour is leiomyoma or stromal tumour (GIST).
        3. Most common upper GI disorder of the Western world is gastro-oesophageal reflux disease.
        4. Most common histological type of carcinoma oesophagus in the world is squamous cell carcinoma.
        5. Most common histological type of carcinoma oesophagus among whites is adenocarcinoma.
        6. Most commonly adenocarcinoma affects lower oesophagus. Most common presenting feature of Barrett’s oesophagus is dysphagia.
        7. Most common site of gastrointestinal involvement in scleroderma is smooth muscle of oesophagus.
        8. Most common cause of oesophageal perforation is instrumentation.
        9. Most serious but rare type of perforation is Boerhaave syndrome-barotrauma, seen in gluttons.

        © Manipal manual of surgery, fourth edition

        Posted in surgery

        Investigation of choice

        Oesophagus & Diaphragm

        • Investigation of choice for diagnosis with histological proof is endoscopic biopsy. 
        • Investigation of choice to identify haematogenous metastasis is CT scan
        • Investigation of choice to detect tracheal/bronchial involvement is bronchoscopy
        • Investigation of choice to know the depth of invasion is endosonography
        • Investigation of choice to detect enlarged nodes which are malignant or nonmalignant is PET scan. 

        © Manipal manual of surgery, fourth edition

        Posted in surgery

        Clinical note 

        A 60-year-old agriculturist was referred to the department of ENT for dysphagia of 3-4 days duration. A Registrar who saw the case did rigid oesophagoscopy under GA. The findings were normal. Later in the evening he was called to see this patient who had rigid abdomen. A general surgeon was consulted. He suspected a perforation. An X-ray abdomen (erect) however, was normal. A senior faculty surgeon was consulted who examined the case properly and gave a correct diagnosis. It was a case of tetanus with mild trismus. The patient had injured his left thumb a few days back. The anaesthesiologist acknowledged later that there was some difficulty in opening the patients mouth during endotracheal intuabtion. 

        Occasionally, patients undergo gastroscopy for dysphagia which will be normal only to realise later that what he is having is a stroke! ! l. 

        © Manipal manual of surgery, fourth edition,