1. INTRACELLULAR ACCUMULATIONS Dr (Prof) Vishal Saxena MBBS, MD (Path)
Definition: abnormal accumulation of some products within the cell.

2. Accumulation of abnormal amounts of various substances within cells:
Is a manifestation of metabolic derangement of cells.
Three categories of substances:
Normal cellular constituent
Water, lipids, proteins, carbohydrates.
Abnormal substance
Exogenous: e.g. Mineral
Endogenous: product of abnormal metabolism
Pigments

3. Mechanism of intracellular accumulation

4. Mechanism of intracellular accumulation

5. Lipid Accumulations ACCUMULATIONS OF : Triglycerides Fatty change
Cholesterol
Atherosclerosis
Xanthomas
Cholesterolosis
Niemann Pick disease, type C

6. Fatty Change (Steatosis)
It is abnormal accumulation of triglycerides in parenchymal cells.
Organs affected
Liver (most common)
Heart, muscles and kidneys
Fatty change: mechanism:
Results from imbalance among the uptake, utilization and secretion of fat.

7. Fatty Change Also known as fatty metamorphosis. Fatty Change in Heart:
Causes:
Prolonged hypoxia (severe anemia)
Diphtheria toxin (decreased beta oxidation of FA).
Morphology
Moderate hypoxia
yellow bands alternating with normal tissue.
= (“tigered effect” or “tabby cat heart”)
Severe hypoxia and diphtheria
diffusely yellow myocardium.

8. FFA FA TG Lipoproteins 1 2 Oxidation to ketone Acetate bodies 3 4
α Glycero-
phosphate
Phospholipids
Cholesterol esters TG 5
Apoprotein
Lipoproteins
Mechanism of fatty change:
FFA from diet and adipose tissue transported into hepatocytes.
Esterified to Triglycerides.
Converted into cholesterol or phospholipids or
Oxidized to ketone bodies.
Some fatty acids synthesized from acetate as well.
Triglycerides combine with apoprotein to form lipoproteins.
Lipoprotein then egress from hepatocyte and enter circulation.
Accumulation of triglyceride may result from:
Defect in any step from FA entry to lipoprotein exit 6

9. Causes of fatty change : liver
Alcohol is the MCC of fatty change in the liver: 3 reasons
Increased glycerol 3 phosphate synthesis
Due to increased reduced NADH
Increased acetyl CoA due to increased acetate Increased FA synthesis
Decreased beta oxidation of FA
Other causes include:
Kwashiorkor (Decreased Protein intake)
Decreased synthesis of apolipoproteins
Starvation
Increased mobilization of FA from adipose tissue
CCL4 and
Reye’s syndrome
Alcohol:
Metabolism of alcohol causes production of three substrates that contribute to the synthesis of triglycerides in the liver.
These substances are:
NADH + H+ (causes buildup of dihydroxyacetone phosphate  glycerol 3 phosphate (carbohydrate backbone of TG)
acetate (form acetyl CoA)
acetyl CoA (used to make up FA)
Alcohol also interferes with the synthesis of apolipoproteins (therefore VLDL) cannot be excreted and hence gets accumulated.
Increased reduced NADH inhibits beta oxidation of fatty acids in mitochondria.

10. Reye’s syndrome
An acquired encephalopathy of young children that follows an acute febrile illness, usually influenza or varicella infection.
Recurrent vomiting, agitation, and lethargy, which may lead to coma with intracranial hypertension; ammonia and serum transaminases are elevated.
Death may result from edema of the brain
and resulting cerebral herniation.

11. Morphology : Fatty Liver
Gross: normal or enlarged liver with a yellowish discoloration.
MICRO:
Clear spaces pushing the nucleus of the hepatocytes to the periphery.
Single or multiple
May fuse to form fatty cysts.
R/o water and glycogen accumulation
Sudan IV and Oil Red O (orange red color to lipid).
PAS (magenta color to glycogen)

12. Normal
liver
Liver showing
fatty change

13. Fatty change: liver Oil Red O stain for fat
Intracellular accumulations of a variety of materials can occur in response to cellular injury.
Here is fatty metamorphosis (fatty change) of the liver.
Most common cause for fatty change is alcoholism.
Lipids , water and glycogen, all appear as clear spaces within cells.
Stain for lipid : Oil red O and Sudan IV
Stain for glycogen : PAS
Water does not stain with any stain.

14. Cholesterol and Cholesterol Esters
Cells use cholesterol for synthesis of cell membrane.
Metabolism is tightly regulated.
Accumulation of cholesterol seen in many pathological conditions:
Atherosclerosis
Xanthomas
Cholesterolosis
Niemann Pick disease, type C
Atherosclerosis:
Cholesterol gets accumulated within smooth muscle cells and macrophages in the intima of arteries leading to formation of a lesion known as Atheroma or atheromatous plaque (decreases the size of the lumen of blood vessels and may rupture leading to formation of thrombus  cuts off the blood supply).
Niemann Pick disease, type C
Lysosomal storage disease
An enzyme involved in cholesterol trafficking is mutated.
Cholesterol accumulates in multiple organs.

15. Xanthomas Xanthomas Tumor like masses composed of
clusters of macrophages (foamy cells) containing cholesterol.
Occur in the
sub epithelial connective tissue of skin & in tendons.
Seen in hereditary hyperlipidemic states.
Xanthomas

16. GB with cholesterolosis (strawberry gall bladder)
Refers to
focal accumulation of cholesterol laden macrophages in the
lamina propria of gall bladder
Cholesterolosis. Cholesterol-laden macrophages (foam cells) from a focus of gallbladder cholesterolosis (arrow).
Cholesterol-laden macrophages

17. Hyaline change
Nonspecific term used to describe any intracellular or extra-cellular accumulation that has a pink homogenous appearance.
Most commonly occurs due to accumulation of proteinaceous material (protein accumulation).
Accumulation can be:
Within cells (intracellular)
Outside the cells (extracellular)
Intracellular hyaline:
Russell bodies – seen in plasma cells
Mallory Alcoholic hyaline – alcoholic liver disease
Extracellular hyaline:
Hyaline arteriolosclerosis – benign hypertension, DM
Amyloid – multiple organs
Hyaline membrane disease of newborn - lungs

18. Russell Body Excess immunoglobulin accumulation in RER of plasma cells
Fuse to form eosinophilic globules k/a Russell bodies.
Plasma cell with one Russell body.
Bright red globules of immunoglobulins in the cytoplasm of plasma cells.
Seen in chronic inflammation and multiple myeloma.

19. Mallory bodies (=Alcoholic Hyaline)
Are masses of prekeratin intermediate filaments within hepatocytes.
Seen in patients with alcoholic liver disease.
Here are Mallory bodies (the red globular material) composed of cytoskeletal filaments in liver cells chronically damaged from alcoholism.
These are a type of "intermediate" filament between the size of actin (thin) and myosin (thick).
Mallory bodies

20. Hyaline arteriolosclerosis
Refers to arterioles that have a pink, glassy, amorphous appearing eosinophilic material in the vessel wall that often causes arterial wall thickening narrowing lumen
Seen in small vessels in
DM and Hypertension. DM: nonenzymatic glycosylation of protein in the BM renders them permeable to protein.
Hypertension: increased intraluminal pressure pushes plasma proteins into the wall of the arteriole.
Hyaline arteriolosclerosis, is demonstrated by the markedly thickened arteriole to the lower right of this glomerulus with PAS stain. Hyaline arteriolosclerosis is seen in the elderly, but more advanced lesions are seen in persons with diabetes mellitus and/or with hypertension.

21. Hyaline membrane disease
This is hyaline membrane disease due to prematurity and lack of surfactant production from the immature lung. Note the thick pink membranes lining the alveolar spaces.
B: Microscopic appearance of amyloidosis of kidney:
The amorphous pink deposits of amyloid may be found in and around arteries, in interstitium, or in glomeruli.
Congo red stain will demonstrate the pink material to be amyloid. Such collections of amyloid add to renal bulk, but diminish renal function.
Amyloid

22. Pigment Accumulations
Pigments are Colored substances.
Exogenous: from outside the body
Carbon / coal dust
Tattoo ink
Endogenous: synthesized within the body
Lipofuscin
Melanin
Bilirubin
Hemosiderin

23. Carbon or coal dust = Anthracotic pigment Air pollution
Inhalation  alveolar macrophages  accumulation in lymphatics, regional lymph nodes and lungs  black coloration = anthracosis.
Coal dust:
In Coal miners accumulation of carbon dust  induces fibroblastic reaction  lung disease = coal worker’s pneumoconiosis.
Tattooing
Localized pigmentation of skin
Pigments  phagocytosed by dermal macrophages.

24. Lung anthracosis Anthracosis
The black streaks seen between lobules of lung beneath the pleural surface are due to anthracotic pigment.
This anthracosis of the lung is not harmful and comes from the carbonaceous material breathed in from dirty air typical of industrialized regions of the planet.
Lung microscopy showing collection of anthracotic pigment
Anthracosis

25. Tattoo Pigment Here is a tattoo.
Tattooing is a practice that is thousands of years old.
In many cultures, tattoos have great significance.
The pigment in tattoos is transferred to the dermis with a needle, so there can be a risk for infection.
The tattoo itself over time tends to lose sharpness and intensity of color.
This is the microscopic appearance of tattoo pigment (black) in the dermis.
Note that this pigment is well within the dermis and, therefore, difficult to remove.
Therefore, removing or changing a tattoo is difficult.
Cosmetic surgery is not covered by insurance, either.

26. Endogenous pigments Lipofuscin: (Latin: fuscus= brown)
also known as Lipochrome, wear and tear or aging pigment.
Is un-digestible residue of subcellular membrane.
Not injurious to cell.
Sign of free radical injury and lipid peroxidation.
Appearance: yellow brown, finely granular, intracytoplasmic, often perinuclear.
Seen in liver and heart of
aging patients.
Patients with malnutrition or cancer cachexia.
Lipofuscin becomes more abundant during normal aging, or following atrophy.
"Brown atrophy" is simply atrophy where the lipofuscin is visible grossly.
A good place to find lipofuscin is at the poles of the nuclei of cardiac muscle cells from elderly people. By age 90, the heart may contain 30% lipofuscin by weight.

27. Lipofuscin granules in a cardiac myocyte
Lipofuscin granules in a cardiac myocyte as shown by A, light microscopy (deposits indicated by arrows), and
B, electron microscopy (note the perinuclear, intralysosomal location).
Light microscopy
Electron microscopy

28. Dihydroxyphenylalanine
Melanin
A brown black pigment.
Synthesized in melanocytes within the epidermis.
Sunlight and ACTH stimulate melanin synthesis in the skin.
Tyrosine
tyrosinase
Dihydroxyphenylalanine
(DOPA)
Melanin is synthesized in the melanocytes within epidermis.
Enzyme tyrosinase converts tyrosine into Dihydroxyphenylalanine (DOPA).
DOPA is polymerized in the Golgi apparatus into membrane bound organelles called melanosomes
Golgi apparatus
Melanosomes

29. Melanocytes with melanin pigment
This is normal skin from a person with a dark complexion.
The amount of skin pigmentation varies among races and individuals.
Melanin is made in melanosomes in melanocytes that are interspersed with basal cells of the epidermis.
The number of melanocytes is relatively constant, so the degree of pigmentation and darkness of skin in different persons is determined by the number of melanosomes and the amount of melanin pigment produced.
Ultraviolet light exposure is the signal for melanosomes to use their tyrosinase enzyme to manufacture melanin.

30. Melanin excess Conditions associated with an increase in ACTH:
Functioning pituitary adenoma
Ectopic ACTH
Addison’s disease (destruction of adrenal gland)
Adrenogenital syndrome (enzyme deficiency in cortisol synthesis).
All associated with increased skin pigmentation.
Nevocellular nevi or moles:
benign proliferation of nevus cells which are modified melanocytes.
Malignant melanoma:
A malignant tumor of melanocytes
Ectopic ACTH: Small cell cancer of lung and Medullary carcinoma of thyroid
Addison’s disease: destruction of adrenal glands.
Adrenogenital syndrome: enzyme deficiencies in cortisol synthesis.

31. Malignant melanoma: microscopy
Benign nevi or moles B
Malignant melanoma A
A: These are benign nevi.
Small brown flat to slightly raised nevi are quite common in Caucasians.
They are usually less than a centimeter in diameter.
B: Malignant melanoma of the skin is shown here.
Sun exposure in light-skinned persons leads to melanoma formation.
C: This is the microscopic appearance of a malignant melanoma.
Large polygonal cells (or spindle cells in some cases); have very pleomorphic nuclei which contain prominent nucleoli.
The neoplasm is making brown melanin pigment.
A Fontana-Masson stain for melanin may help to detect small amounts of cytoplasmic melanin.
Most (not all) melanomas contain at least a little melanin, and finding melanin production by tumor cells proves a cancer is a melanoma.
To prove a pigment is melanin, the pathologist applies a little hydrogen peroxide (hair bleach) to the section. If it's melanin, it bleaches. C
Malignant melanoma: microscopy

32. Absence of Melanin Albinism Characterized by absence of tyrosinase.
Melanocytes are present but do not contain melanin within melanosomes.
Vitiligo
Autoimmune destruction of melanocytes produces patchy areas of depigmentation.
Phenylketonuria (PKU)
Missing enzyme :phenylalanine hydroxylase.
Normally converts phenylanaline into tyrosine.
Therefore, deficiency of tyrosine  blond hair.

33. ALBINISM
Vitiligo

34. Melanin “Look Alikes” Anthracotic pigment= Coal dust Alkaptonuria
Characterized by absence of homogentisate oxidase.
Resulting in accumulation of black homogentisate pigment in joints, cartilage, and urine (turns black on exposure to sunlight).
Pigmentation is k/a OCHRONOSIS.
Melanosis coli (black bowel syndrome)
Refers to deposition of black anthracene pigment in macrophages within lamina propria of large intestine.
Associated with laxative abuse from which the pigment is derived.

35. Melanosis coli Melanosis coli.
This uncommon colonic lesion has been known for many years, and, in fact, used to be more common than it is today.
The lesion is associated with chronic constipation and use of laxatives of the anthracene group.
In most instances pigment is only seen on microscopic sections, as in the photo on the RIGHT.
Brown granular pigment accumulates within phagocytic histiocytes in the lamina propria of the colon.
In some cases, sufficient pigment accumulates so that the gross appearance of the mucosal surface is brown to black.
Although the pigment is called "melanosis pigment" it is not melanin.
The endoscopic or histologic finding of melanosis coli suggests the possibility of long term laxative use, but has no other known significance.

36. Accumulation of hemosiderin and bilirubin
Bilirubin and hemosiderin:
Derived from breakdown of hemoglobin by macrophages that have phagocytosed RBCs.
Hb = heme (iron+protoporphyrin) + globin (α,β,γ,and δ chains).
Bilirubin: derived from protoporphyrin.
Hemosiderin: composed of packets of ferritin (storage form of iron).

37. Hemosiderin Accumulation
Iron containing pigment, consists of aggregates of ferritin.
Normally found within macrophages in bone marrow, spleen and liver.
Appears Golden yellow to brown in color on H&E stain
Identification: Prussian blue (Perl’s) stain.
P.S. Hematin: Prussian blue negative, blackish pigment, derived from oxidation of heme.
Hematin excess: associated with malaria and autoimmune hemolytic anemias. Deposited in spleen after RBCs are destroyed by macrophages.

38. Hemosiderin Excess
Hemosiderosis: accumulation of hemosiderin, primarily within tissue macrophages, without associated tissue or organ damage.
Local Hemosiderosis:
Local deposition of hemosiderin.
Results from hemorrhage into tissues
Ex: Pulmonary congestion (left heart failure)
Systemic hemosiderosis:
Generalized hemosiderin deposition without tissue damage.
Results from multiple blood transfusions, excessive Fe intake, hemolysis.

39. Hemosiderin Excess
Hemochromatosis: extensive accumulation of hemosiderin, often within parenchymal cells, with accompanying tissue damage and organ dysfunction.
Occurs in two forms:
Hereditary hemochromatosis:
Most often caused by mutation in HFE gene.
Characterized by hemosiderin deposition and organ damage in the liver, pancreas, myocardium and multiple endocrine glands.
These result in triad of findings: cirrhosis, Diabetes mellitus and dark skin pigmentation. (Ferric ion blocks breakdown of melanin).
This set of findings = BRONZE DIABETES
Secondary hemochromatosis:
Is most often caused by multiple blood transfusions as in beta thalassemia major.
HFE gene: regulates iron absorption.
Ferric ion blocks breakdown of melanin, a fact that explains the dark pigmentation in the skin of hemochromatosis patients.

40. Hemosiderin granules in liver cells.
Heart failure cells 1
Hemosiderin granules in liver cells.
1: The brown coarsely granular material in macrophages in this alveolus is hemosiderin that has accumulated as a result of the breakdown of RBC's and release of the iron in heme.
The macrophages clear up this debris, which is eventually recycled.
Pulmonary congestion (left heart failure)
Causes pulmonary hemorrhage and phagocytosis of RBC by alveolar macrophages.
Hemosiderin is breakdown product in these cells = heart failure cells.
Responsible for rust colored sputum.
2 and 3 Hemosiderin granules in liver cells.
2: H&E section showing golden-brown, finely granular pigment.
3: Prussian blue reaction, specific for iron. 3 2

41. Bilirubin Derived from
the breakdown of hemoglobin by macrophages in the spleen and bone marrow.
Released from macrophages as lipid soluble , unconjugated bilirubin (UCB).
Bound in plasma to albumin.
Delivered to hepatocytes for conjugation into conjugated bilirubin (CB)
An increase in CB or UCB (or both) produces jaundice = yellow discoloration
First noted in sclera when conc > 2mg/dL (why??)
Hyperbilirubinemia: increased bilirubin in the blood.
Answer: Elastic tissue has high affinity for bilirubin.

42. UCB increase:
Hemolytic anemias (hereditary spherocytosis)
Problem with uptake and conjugation of bilirubin (physiologic jaundice of newborn).
Newborns with Rh disease of newborns may develop kernicterus
Due to entry and dissolution of UCB in brain tissue.
CB increase:
Hepatitis and
Obstructive jaundice (gallstone in CBD)

43. Yellow sclera: jaundice
The sclera of the eye is yellow because the patient has jaundice, or icterus.
The normally white sclerae of the eyes is a good place on physical examination to look for icterus.
The yellow-green globular material seen in small bile ductules in the liver here is bilirubin pigment.
Bilirubin pigment

44. Pathologic Calcification
Abnormal deposition of calcium in tissues.
Two forms:
Dystrophic calcification
Metastatic calcification

45. Dystrophic (Dystrophic means : “seeking out the bad”) calcification
Occurs in dead ,dying and necrotic tissues.
In the presence of normal serum calcium and phosphorus levels.
Examples:
Calcification associated with
Enzymatic fat necrosis: visible on X rays
Damaged heart valves:
Mitral valve calcific mitral stenosis
Bicuspid aortic valve  aortic stenosis
Atheroclerotic plaques
Periventricular calcification in Congenital CMV infection
Granulomas (tuberculosis, histoplasmosis).
Dead fetus  lithopedion (stone child).
Breast cancer  visible on mammograph
Psammoma bodies  thyroid cancer, ovarian cancer
Remember: in dystrophic calcification:
calcium is deposited in damaged tissue and there is
normal serum calcium/phosphate levels.
Dystrophic means : “seeking out the bad”

46. Morphology Gross: Calcium deposits have
White (chalky white) granular appearance
Gritty sensation while cutting.
Microscopy:
H & E stain: calcium salts have basophilic appearance.
A single calcified cell may progressively acquire outer layers of calcium giving rise to lamellated calcified structures k/a psammoma bodies.
PSAMMOMA BODIES :
Seen in
papillary carcinoma thyroid,
meningioma and
paillary cystadenocarcinoma of ovaries

47. dystrophic calcification
Ghon tubercle
with
dystrophic calcification
Trachea, bronchi, and lung, Ghon tubercle with dystrophic calcification - Gross, cut surface  The white nodule in the lung represents calcification of tissue damaged by a primary tuberculosis infection. The serum calcium in this patient was normal.    

48. Nodular masses of deposited calcium
Dystrophic Calcification: Aortic Valve
This image is looking down at the aortic valve.
Nodular masses of deposited calcium are prominent here.
Dystrophic calcification commonly develops in aging or damaged heart valves.

49. Dystrophic Calcification Atherosclerotic Plaque
Dystrophic calcification in
the wall of the stomach
A: This is dystrophic calcification in the wall of the stomach.
At the far left is an artery with calcification in its wall.
There are also irregular bluish-purple deposits of calcium in the submucosa.
Calcium is more likely to be deposited in tissues that are damaged.
B:Atherosclerosis of an artery with nearly complete occlusion and calcification in the wall. B

50. Dystrophic calcifications: Breast Carcinoma Mammograph

51. Psammoma body Papillary carcinoma of thyroid.
Note the small psammoma body in the center.
Psammoma body

52. Metastatic calcification
Deposition of calcium in normal and undamaged (healthy) tissue.
Due to increase in serum calcium (hypercalcemia).
Examples of metastatic calcification:
Nephrocalcinosis: in hyperparathyroidism
Calcification of tubular basement membrane.
Calcification of basal ganglia: due to high phosphorous levels.
Calcification of
alveolar wall
Gastric epithelium
Metastatic means “another place”
Tissue with predilection for metastatic calcification:
Interstitial tissue of
kidney (nephrocalcinosis) in primary hyperparathyroidism: calcification of tubular BM.,
gastric mucosa,
lungs ,systemic arteries and pulmonary veins. (WHY???)
Answer: all have an internal alkaline compartment.

53. Cause for hypercalcemia
Increased secretion of PTH
Primary hyperparathyroidism (most common).
Parathyroid hyperplasia or adenoma
Ectopic PTH related protein secretion (SCC of lung).
Destruction of bone tissue
Multiple myeloma, breast cancer, Paget’s dis.
Vitamin D related disorders
Vitamin D intoxication
Milk and Antacid abuse
Cause for hyperphosphatemia:
Renal failure
Parathyroid adenoma: a benign tumor of parathyroid gland. May secrete parathyroid hormone.
SCC= squamous cell carcinoma
Other causes of hypercalcemia:
Metastasis to bone (breast carcinoma)
Sarcoidosis (macrophages activate a vitamin D receptor)
Idiopathic hypercalcemia of infancy (Williams syndrome) characterized by abnormal sensitivity to vitamin D.
Milk alkali syndrome : due to excessive ingestion of calcium (milk and antacids )

54. Metastatic Calcification: Kidney
Metastatic Calcification: Lung
A: Note amorphous calcium deposits within intact, non-necrotic, alveolar septa (arrow).
B:Dark blue deposits of calcium salts within kidney tubules

55. Sub-cellular responses to injury

56. Sub-cellular responses to injury
Changes that occur in
cell organelles or the cytoskeleton in response to
Certain conditions/stimuli.
The important ones are:
Cytoskeletal abnormalities.
Mitochondrial alterations

57. Cytoskletal abnormalities
Cytoskeleton: Network of protein filaments in cytosol.
Maintains cell structure (shape) and helps in motility.
Composed of: Microtubules, actin filaments and intermediate filaments.
Microtubules: Composed of protein tubulin.
Actin thin filaments:
Present in muscle and non-muscle tissue.
Involved in contractile process.
Intermediate filaments:
Ex: keratin, vimentin, desmin, neuro and, glial filaments.
Cytoskeleton: network of protein filaments in the cytosol that maintains the shape of cells. Also responsible for motility in some cells.
Actin filaments present in muscle and non-muscle cell.
Thin filaments: required for cell movement.
Clinical significance:
Phalloidin, toxin of mushroom Amanita phalloides binds to actin filament.
Intermediate filaments: important in integration of cell organelles.

58. Cytoskletal abnormalities may be reflected by:
Defects in cell function:
Cell locomotion and intracellular organelle movement.
Intracellular accumulation of fibrillar material.

59. Conditions associated with defect in microtubule organization
Chediak-Higashi syndrome: characterized by defective neutrophil movement.
Immobilization of the cilia of respiratory tract  Bronchiectasis (Kartagener’s syndrome).
Inhibition of leukocyte migration
Clinical Use: colchicine given for gout.
Inhibition of cell division
Clinical Use: vinca alkaloids used as anticancer drug.

60. Chediak-Higashi syndrome
Autosomal recessive disease
Defect in microtubule polymerization
Defective phagocytosis : increased susceptibility to infections
Giant red inclusions in peripheral blood leukocytes : represent giant lysosomes filled with enzymes that have never been released.

61. Intermediate filaments
Provide structural support to cells.
Divided into five classes
Keratin (epithelial cells)
Neurofilaments (neurons)
Desmin (muscle cells)
Vimentin (connective tissue cells)
Glial filaments (astrocytes)
Clinical application: Immunohistochemical stains utilizing monoclonal antibodies against individual intermediate filaments are useful in identifying the origin of neoplasms.

62. Let’s first learn what CHAPERONS are?
Chaperons: aid in proper folding of proteins.
Misfolded proteins are degraded.
Important chaperons include:
Heat shock protein (ex ubiquitin): marks abnormal proteins for degradation.
Damaging stimuli to cell  release of ubiquitin  binds to damaged protein (ubiquination= marked for destruction)  delivers it to proteases  degradation.
Accumulation of misfolded protein
promotes apoptosis and associated with
Alzheimer’s disease,
Huntington’s Chorea and
Parkinson’s disease.

63. Examples of intermediate filament defects:
Mallory body: ubiquinated (marked for destruction) masses of prekeratin filaments
Seen in hepatocytes of alcoholics
Microscopic feature of alcoholic hepatitis.
Lewy body: ubiquinated neurofilaments from degenerated substantia nigra neurons in Parkinson’s disease.
Neurofibrillary tangle
Ubiquinated neurofilaments in brain.
Seen in old age / Alzheimer’s disease.

64. Aging

65. Cellular Aging Aging: not a disease
Represents progressive accumulation of sublethal injury that
Compromises cell function and
Leads to cell death.
Aged persons more susceptible to diseases.

66. A number of functional and morphological changes occur in aging cells:
Reduced
Oxidative phosphorylation
Synthesis of nucleic acids, structural proteins and enzymes
Repair of chromosomal damage

67. Accumulation of
Lipofuscin
Abnormally folded proteins
Advanced glycosylation end products (AGEs)

68. Morphologic Changes Associated with Cell Aging
Irregular nuclei
Vacuolated mitochondria
Diminished endoplasmic reticulum
Distorted Golgi apparatus

69. Theories of cell aging Cellular changes:
Cellular aging is due to cumulative injury to cells.
Genetics:
Another theory states that aging is programmed
Individual cells die (apoptosis) after completing life span.
Environmental stress: increased glucocorticoids
Neuroendocrine dysfunction: decreased hormone
Nutrition: high calorie increased free radicals

71. Replicative Senescence
Cells have limited capacity for replication.
Cellular Senescence: is the non dividing state after fixed number of divisions.
Telomere:
Short repeated sequences of DNA (TTAGGG).
Present at the ends of chromosomes.
Ensure complete replication of chromosome ends.
How dividing cells count divisions?
With each replication telomere length becomes short.
= Telomere shortening: due to incomplete replication of chromosome ends.
Werner Syndrome: a disorder characterized by premature aging.

72. Telomerase: enzyme that maintains the length of telomeres.
Telomerase activity:
Maximum in germ cells, least in somatic cells.
In cancer cells telomerase activity  high.

73. Premature Aging Progeria (Werner syndrome):
Characterized by premature aging.
Due to defects in DNA repair.
Defective enzyme: DNA helicase (Werner)
involved in DNA replication and repair
“The balance between cumulative metabolic damage and the response to that damage could determine the rate at which we age”.

74. Progeria - (Werner syndrome)

75. I FINALLY GOT IT RIGHT THAT’S BECAUSE I STUDY PATH
I GOT THE DIAGNOSIS
I FINALLY GOT IT RIGHT
THAT’S BECAUSE I STUDY
PATH
TILL 12 O’ CLOCK AT NIGHT !!!

76. Give a man a fish and he will eat for a day
Give a man a fish and he will eat for a day. Teach him how to fish, and he will sit in a boat and drink beer all day.

77. Thank You !