Pathologic Calcification and Intracellular Accumulation Notes

Pathologic Calcification and Intracellular Accumulation

Intended Learning Outcomes

  • Define pathologic calcification.
  • Identify types of pathologic calcification.
  • Discuss intracellular accumulation of lipid, proteins, and glycogen.
  • Outline an abnormal accumulation of pigments.
  • Discuss free radicals.
  • Discuss cellular aging.

Pathologic Calcification

  • Definition: Abnormal deposition of calcium salts, along with smaller amounts of iron, magnesium, and other mineral salts, in areas other than bone or teeth.
  • Types:
    • Dystrophic calcification
    • Metastatic calcification

1) Dystrophic Calcification

  • Definition: Deposition of calcium salts in dead or dying tissue, despite normal serum levels of calcium and in the absence of derangements in calcium metabolism.
  • Often a cause of organ dysfunction.
  • Common Sites (mostly in areas of necrosis):
    1. Areas of coagulation (coagulative necrosis).
    2. Caseous and liquifactive necrosis.
    3. Foci of enzymatic fat necrosis.
    4. Damaged heart valves.
    5. Thrombosis.
    6. Atheromas of advanced atherosclerosis.
    7. Psammoma bodies in some tumors (e.g., meningiomas, papillary carcinoma of thyroid and ovary).
      • Psammoma bodies: Outer layers may create lamellated configurations

2) Metastatic Calcification

  • Definition: Deposition of calcium salts in normal tissues due to some derangements in calcium metabolism, leading to hypercalcemia.
  • Common Sites: Interstitial tissues of kidneys, systemic arteries, pulmonary veins, lungs, and gastric mucosa.
  • Causes of Hypercalcemia:
    1. Hyperparathyroidism
    2. Hyperthyroidism
    3. Idiopathic hypercalcemia
    4. Vitamin D intoxication
    5. Addison’s disease (adrenocortical insufficiency)
    6. Increased bone catabolism (e.g., multiple myeloma, metastatic cancer & leukemia).
    7. Decreased bone formation (e.g., immobilization).
    8. Systemic sarcoidosis (in which macrophages activate a vitamin D precursor).
    9. Milk-alkali syndrome
    10. Renal failure.

Intracellular Accumulations

  • Definition: Accumulation of abnormal amounts of various substances within the cytoplasm, within organelles (typically lysosomes), and in the nucleus of the cell.
  • These accumulated substances may be harmless or may cause varying degrees of cell injury.

Accumulation of Lipid

  1. Fatty Change (Steatosis): Any abnormal accumulation of triglycerides within parenchymal cells.
    • Organ involved:
      • Liver is the most common site (as the liver is the major organ involved in fat metabolism).
      • It may also occur in the heart, skeletal muscle, kidney, and other organs.
    • Causes of Fatty Change:
      1. Toxins: Alcohol abuse.
      2. Diabetes mellitus
      3. Obesity
      4. Protein malnutrition (starvation)
      5. Corticosteroids use
      • Note That The first Three causes are the most common.
  2. Cholesterol and Cholesterol Esters:
    • Most cells use cholesterol for the synthesis of cell membranes without intracellular accumulation.
    • Several pathologic conditions are associated with cholesterol and cholesteryl ester accumulation:
      1. Foam cells
      2. Atheromas
      3. Xanthomas
      • Foam Cells: Macrophages in contact with lipid debris may become stuffed with lipid because of their phagocytic activities; these are called foam cells (Lipid-laden macrophages).
      • Atheromas: In atherosclerosis, smooth muscle cells and macrophages within the intimal layer of the aorta & large arteries become filled with lipid and produce masses that narrow the lumen of blood vessels.
      • Xanthomas: In hereditary and acquired Hyperlipidemias, macrophages become filled with lipid and produce masses in the subepithelial connective tissue of skin and tendons, are called Xanthomas.

Accumulations of Proteins

  • Morphologically, visible protein accumulations are much less common than lipid accumulations.
  • Intracellular accumulations of proteins usually appear as rounded, eosinophilic droplets, or aggregates.
  • Examples:
    1. In Nephrotic syndrome: Protein accumulation in the proximal convoluted tubules of the kidney with heavy protein leakage (proteinuria).
    2. In multiple myeloma: Marked accumulation of newly synthesized immunoglobulins in plasma cells (Russel bodies).
    3. In alcoholic liver disease: Accumulation of aggregates of denatured keratin filaments which appears as eosinophilic cytoplasmic inclusions in the hepatocytes called Mallory’s body or alcoholic hyaline.
    4. In Alzheimer disease: Accumulation of protein inclusion that contains microtubule-associated proteins in the brain. These inclusions are called neurofibrillary tangles.
      • Mallory body Inclusions are composed predominantly of aggregated intermediate cytokeratin filaments
      • Russel bodies: Eosinophilic uniformly staining membrane-bound bodies which contain immunoglobulin.

Accumulation of Glycogen

  • Excessive intracellular deposits of glycogen are associated with abnormalities in the metabolism of either glucose or glycogen
  • Examples:
    1. In poorly controlled diabetes mellitus, glycogen accumulates in renal tubular epithelium, cardiac myocytes, and β cells of the islets of Langerhans.
    2. In glycogen storage diseases, or glycogenoses: A group of closely related genetic disorders, glycogen accumulates within cells.

Accumulation of Pigments

  • Pigments are colored substances that are either exogenous, coming from outside the body, or are endogenous, synthesized within the body itself
    • Exogenous Pigments: Carbon, Iron, Silicon, Tattooing
    • Endogenous Pigments: Lipofuscin, Melanin, Hemosiderin
  • Exogenous pigment
    1. Carbon (Coal dust):
      • Carbon is the most common exogenous pigment. It has two forms:
        1. In Anthracosis (blackening of the lung): Inhaled carbon is picked up by alveolar macrophages and transported through lymphatic channels to the regional tracheobronchial lymph nodes
        2. In coal workers' pneumoconiosis: Heavy accumulations of coal dust induce fibroplastic reaction or even emphysema.
    2. Tattooing:
      • It is a form of localized, exogenous pigment.
      • Pigments like India ink, cinnabar, and carbon are introduced into the dermis in the process of tattooing where the pigment is taken up by macrophages and lies permanently in the connective tissue (do not usually evoke any inflammatory response).
    3. Iron: in siderosis, accumulation of excess iron causes rust-like discoloration of the lung.
    4. Silicon: In silicosis, accumulation of silicon causes fibrosis of the lung
  • Endogenous Pigments
    1. Lipofuscin: or “wear-and-tear pigment,”
      • Lipofuscin is an insoluble brownish-yellow granular intracellular material that accumulates in a variety of tissues (particularly the heart, liver, and brain) with aging or atrophy
      • It is not injurious to the cell
      • The brown pigment, when present in large amounts, imparts an appearance to the tissue that is called brown atrophy.
    2. Melanin:
      • Melanin is an endogenous, brown-black pigment that is synthesized by melanocytes
      • Located in the epidermis and acts as a screen against harmful UV radiation
    3. Hemosiderin:
      • It is a hemoglobin-derived, golden-yellow to brown pigment, consists of aggregates of ferritin micelles, and represents stored iron.
      • Hemosiderosis: It is excess hemosiderin accumulation within tissue macrophages without associated tissue or organ damage. It is of two types:
        • A. Localized Hemosiderosis: It occurs as a result of local hemorrhage in a tissue. Example: bruise
        • B. Systemic Hemosiderosis:
          1. Increased absorption of dietary iron
          2. Impaired utilization of iron
          3. Hemolytic anemia
          4. Repeated transfusions
  • Hemosiderin pigment
  • Hemochromatosis: It refers to extreme accumulation of iron in the liver, pancreas, and skin, causing:
    1. Liver cirrhosis
    2. Diabetes mellitus (Bronze diabetes)
    3. Skin pigmentation
    4. Heart failure

Cellular Aging

  • Cellular aging is the result of a progressive decline in cellular function and viability.
  • Several mechanisms are known or suspected:
    1. Accumulation of DNA damage and defects in DNA repair enzymes
    2. Decreased Cellular Replication: reduced capacity of cells to divide secondary to progressive shortening of chromosomal ends (telomeres)
    3. Loss of normal proteins and accumulation of misfolded proteins.
  • Aging is exacerbated by chronic diseases, stress, and is slowed down by calorie restriction and exercise
  • Decreased Cellular Replication:
    • All normal cells have a limited capacity for replication and changed to a non-dividing state
    • Telomere is a short, repeated sequence of DNA present at the linear ends of chromosomes – ensures complete replication of chromosomes and protects chromosome endings from fusion and destruction.
    • Telomeres shorten each time the DNA replicates at chromosome ends and no longer divide, leading to aging.
    • Telomerase maintains the normal length of telomeres in immortal cells.
    • Telomerase activity is increased in the vast majority of cancer cells.
    • In humans, telomerase is active in germ cells.

Free Radical –Mediated Cell Injury

  • Definition: Free radical refers to "a chemical species that has a single unpaired electron in their outermost orbit".
  • Mechanism of cell death:
    • Lipid peroxidation
    • Cytoskeletal damage
    • Protein oxidation
    • DNA damage
  • Conditions with free radical injury:
    • Free radicals are emerging as the final common pathway of cell injury in the following processes:
      1. Oxygen and other gaseous toxicity
      2. Chemical and radiation injury
      3. Killing of microorganisms by phagocytic cells (neutrophils and macrophages)
      4. Hyperoxia (toxicity due to oxygen therapy)
      5. Cellular ageing
      6. Inflammatory damage
      7. Tumour destruction cells
      8. Atherosclerosis.
  • Effects of Free Radicals
    1. Lipid peroxidation of membranes: It refers to "the process by which double bonds present in polyunsaturated lipids of membranes are attacked by oxygen-derived free radicals with the formation of peroxides".
      • Lipid peroxides are unstable and reactive, giving rise to an autocatalytic reaction that causes extensive damage to plasma and organellar membranes.
    2. Non-peroxidative Mitochondrial Damage: Free radicals cause loss of Mitochondrial function
    3. DNA damage (Nuclear and mitochondrial DNA): Formation of single-stranded breaks in DNA which leads to cell killing (cellular aging) or mutation and malignant transformation.
    4. Protein oxidation: Cross-Linking of labile amino acids (like methionine, histidine, cystine, and lysine) causes inactivation of enzymes, especially sulfhydryl enzymes
  • Termination of free radicals
    1. Spontaneous decay: (superoxide decays into oxygen and hydrogen)
    2. Enzymatic degradation:
      • Catalase: Present in peroxisomes
      • Superoxide dismutase: decomposes superoxide into hydrogen peroxide and oxygen
      • Glutathione peroxidase: decomposes OH into H_2O
    3. Antioxidants are endogenous or exogenous substances that inactivate the free radicals. These substances include the following:
      • Vitamins E, A, and C (ascorbic acid)
      • Sulfhydryl-containing compounds e.g., cysteine and glutathione.
      • Serum proteins e.g., ceruloplasmin and transferrin.