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Intracellular Accumulation


A. Lipids

  1. Triglycerides (eg. Fatty change in liver cells, heart kidney)
  2. Cholesterol (eg. Atherosclerosis, xanthomas)
  3. Complex lipids (eg. Sphingolipids accumulation)

B. Proteins

  1. Protein accumulates in proximal renal tubules in proteinuria
  2. Russell bodies: intracytoplasmic accumulation of immunoglobulins in plasma cells.
  3. Defective protein folding can also result in protein accumulation.
  4. Normal protein synthesis and folding
    1. Proteins synthesized as polypeptide chains on ribosomes
    2. Chains arranged into a helices/beta sheets and folded property.
    3. Protein folding and transportation across E.R., golgi and beyond is aided by protein called
    4. chaperones.

C. Chaperones:

  1. Synthesized constitutively, affect normal intracellular protein trafficking
  2. Induced by stress c.a heat shock protein~ eg hsp 70, hsp 90Q
  3. Rescue' shock stressed proteins from mis folding: Q
  4. If folding is not successful, ubiquitin (a type of chaperones) facilitate degradation of damaged
  5. proteins
  6. There are two mechanism

a. Defect in intracellular transport and secretion of critical proteins.

  1. Anti-trypsin-1 deficiency-Mutations in protein slow the folding. Partially folded protein
  2. accumulates in ER of liver and is not secreted – seen in emphysema.
  3. Cystic fibrosis
  4. Familial hyper cholesterolemia

b. ER stress induced by mis folded/unfolded protein

  1. MIS folded protein in ER → unfolded protein response.
  2. Unfolded protein → Initially cytoprotective – increase chaperones and decrease protein translation response → Later, activated caspase’s 12 in ER – cell death by apoptosis
  3. Eg Neurodegenerative diseases- Alzheimer's disease, Huntington, Parkinson's disease,
  4. Abnormal / mis folded protein may accumulate in tissues and cause damage - seen in amyloidosis.

D. Glycogens storage diseases. Diabetes mellitus.

  1. Stain - Best Carmine or PAS with diastase sensitivityQ.
  2. Best fixative to demonstrate glycogen is absolute alcohol

E. Exogenous pigments

  1. Anthracotic pigment of lung is secondary to inhalation of carbon
  2. Tattoos- Cinnabar, India ink dyes used
F. Endogenous pigments

1. Lipofuscin:

  1. Wear and tear pigment
  2. Tell tail sign of free radical injury
  3. Perinuclear yellow brown pigment
  4. Indigestible material within lysosomes
  5. Common in liver and heart
  6. Brown atrophy, a trophy of organ with lipofuscin pigment

2. Melanin:         

  1. Brown black pigment (only endogenous black pigment)*
  2. Found in melanocytes & substantia nigra

3. Hemosiderin  

  1. Golden yellow brown pigment
  2. Found in area of haemorrhage / bruises
  3. Systemic iron overload
  4. Prussian blue positive – Perls reactionQ
Hyaline Change
Specific term used to describe any intracellular or extracellular alteration that has pink homogenous appearance on H & E.
  1. Eg of intracellular hyaline
    1. Resorption droplets in PCT           
    2. Russel bodiesQ                      
    3. Alcoholic hyalineQ
  2. Eg of extracellular hyaline
  1. Hyaline arteriolosclerosis       
  2. Amyloid         
  3. Hyaline membrane disease of newborn
Pathological Calcification
It is defined as abnormal deposition of calcium salts, together with smaller amounts of iron,
magnesium and other salts.
  1. Dystrophic calcification:
    1. Precipitation of calcium phosphate in dying or necrotic tissue
    2. S. Calcium level is normal with normal calcium metabolism
  1. Calcification in areas of fat necrosis
  2. Calcification in area of coagulative and caseous necrosis
  3. Psammoma bodiesQ- laminated concretions that occur in meningiomas, papillary carcinoma of thyroid & ovary
  4. Monckeberg’s medial Q calcific stenosis
  5. Atherosclerotic plaques Q
  1. Metastatic calcification
    1. Precipitation of calcium phosphate in normal tissues due to hypercalcemia
    2. CausesQ:
      1. Hyperparathyroidism,Parathyroid adenomas, Real failure, Paraneoplastic syndrome
      2. Vitamin D intoxication, Milk-alkali syndrome, Sarcoidosis, Pagets disease, Multiple myeloma
      3. Metastatic cancer to the bone
    3. Location of calcification
      1. Begins in mitochondria in all the organs except kidney where it begins in the basement membrane of the tubules. Q
    4. Stains used for demonstration of calcium:
      1. Von Kossa & Alzarine Red–S
Cellular Aging
Represents progressive accumulation over the years of sublethal injury which leads to cell death

Structural and biochemical changes.
  1. Decreased oxidative phosphorylation
  2. Decreased synthesis of nucleic acids and structural and enzymatic proteins
  3. Decreased uptake of nutrients.
  4. Decreased repair of chromosomal damage
  5. Lipofuscin deposition implicating the role of free radical injury.
  6. Advanced glycosylation end products eg. in lens protein leading to senile cataract
  7. Abnormally folded proteins in senile neurodegenerative diseases like Alzheimer’s     ­
  8. Cells have abnormally bilobed nuclei, pleomorphic vacuolated mitochondria, decreased E.R and            distorted golgi. ­
  9. Werner syndrome, a rare syndrome, is characterized by premature aging. Defect in enzyme DNA Helicase (required for DNA replication & repair) results in accumulation of chromosomal damage.
  10. Timing of aging.  
  • After a fixed number of division, normal cells become arrested in a terminally non-dividing state known as replicative senescence. With each cell division there is some shortening of specialized structure, called telomeres, at the ends of chromosomes. Once the telomeres are shortened beyond a certain point, the loss of telomere function leads to activation of p53-dependent cell-cycle checkpoints, causing proliferative arrest or apoptosis. Thus, telomere shortening functions as a clock that counts cell divisions.
  • In germ cells, telomere shortening is prevented by the sustained function of the enzyme telomerase, thus explaining the ability of these cells to self-replicate extensively.  This enzyme is absent in most somatic cells,  and hence they suffer progressive loss of telomeres.
  • Cancer cells prevent telomere shortening by the reactivation of telomerase activity. Telomerase activity has been detected in more than 90% of human tumors. Telomerase activity and maintenance of telomere length are essential for the maintenance of replicative potential in cancer cells.  

Telomere shortening with age due to decreased telomerase activity. Q
Telomerase activity is maximum in actively dividing cells, germ cells and cancer cells.
  1. Fixatives
Target Fixative of Choice Fixative to Avoid
Proteins Neutral Buffered Formalin,
Osmium Tetroxide
Enzymes Frozen Sections Chemical Fixatives
Lipids Frozen Sections*,
Glutaraldehyde/Osmium Tetroxide
Alcoholic fixatives, Neutral Buffered Formalin
Nucleic Acids Alcoholic fixatives, HOPE Aldehyde fixatives
Mucopolysaccharides Frozen Sections Chemical fixatives
Biogenic Amines Bouin's~, Neutral Buffered Formalin  
Glycogen Alcoholic based fixatives Osmium Tetroxide

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