The document discusses intracellular accumulations, highlighting the abnormal buildup of various endogenous and exogenous substances in tissues, which can have either harmless or toxic effects. It outlines four pathways of such accumulations, including inadequate removal of normal substances, accumulation due to defects in metabolism, and the failure to degrade metabolites. The document also covers various types of accumulations like fatty change in the liver, protein accumulation, pigments, and pathologic calcification, detailing their morphology, causes, and potential consequences.

1. Intracellular Accumulations

3. Intracellular Accumulations
L Os
• To identify abnormal accumulations of various
endogenous or exogenous substances in
tissues e.g. pigments
• To explain their causes
• To understand and describe the consequences
of accumulations

4. Intracellular Accumulations
• Substances within Cytoplasm, organelles (Lysosomes),
Nucleus. May accumulate Transiently or Permanently
• Harmless or toxic.
• Endogenous or exogenous. Produced by cell or elsewhere
• 4 Pathways of abnormal accumulations
1. Inadequate removal of Normal substances due to defects
in packaging and transport. Fatty liver
2. Accumulation of abnormal endogenous substances due
to genetic or acquired defects in folding, packaging
transport and secretion
3. Failure to degrade metabolite due to inherited enzyme
deficiencies. Storage diseases
4. Accumulation of abnormal exogenous substances due to
absence of enzymatic machinery to degrade or transport
e.g. carbon, silicon

5. Intracellular Accumulations
1. Excessive Normal cellular constituents:
Exogenous or Endogenous substances produced at
increased rate or normal rate but rate of metabolism
is inadequate to remove it. example: fatty change in
liver
water, Lipid, Proteins, carbohydrates
2. Abnormal substances
Exogenous: minerals, products of infectious agents
(viral inclusion bodies)
Endogenous: products of abnormal synthesis or
metabolism

6. Intracellular Accumulations
3. Pigments
Exogenous:
inhalation - Carbon
injection - Tattooing
ingestion - Beta carotene
Endogenous:
Hemoglobin derivative
Non Hemoglobin derivative

7. Fatty change (Steatosis)
• Abnormal accumulation of triglycerides within
parenchymal cells.
• May be mild and reversible or Severe producing
irreversible cell injury
• Common sites: liver, Heart, Skeletal muscle, Kidney
• Causes:
• General Hypoxia
• Fat diet – Obesity, Diabetes mellitus, Alcohol abuse
• Starvation, Protein Malnutrition
• Hepatotoxins, Chemicals. drugs, Carbon tetrachloride
• Chronic illnesses like TB
• Late pregnancy
• Reye’s syndrome

8. Fat Metabolism in liver

9. Fatty change in liver`
• Decreased processing within the liver: ischemia, toxins
e.g. CCl4
• Decreased removal from liver: hypoproteinemic states
• Significance: Reversible usually, no cell dysfunction
• Morphology
• Gross: Enlarged, yellow and greasy liver
• Microscopic:
– early change: fat accumulation as clear vacuoles in
cytoplasm (microvesicular) in centrilobular
hepatocytes, extending outward
– late stage: vacuoles coalesce to form a single large
vacuole (macrovesicular) or signet ring appearance;
rupture of vesicles (fatty cysts)

10. Microscopic features

11. Morphology
• Gross:

12. Accumulation of Cholesterol and
Cholesteryl esters
• As membrane bound Cholestrol vacuoles in
macrophages – Foam cells
• Fibrofatty plaques of atherosclerosis
• Xanthomas. Cholestrol rich yellow patch /nodule on
skin
• Inflammation / Necrosis

13. Protein accumulation
• Excessive presentation to cell or excessive formation
by cells
• Improper formation /folding cell injuries
• Proteinuria in nephrotic syndrome, as Pink hyaline
cytoplasmic droplets/vesicles in renal tubular cells.
• Amyloid
• Excess Immunoglobulins formation in RER of Plasma
cells as eosinophilic Russell bodies
• α1-antitrypsin deficiency
• Mallory-Denk body (keratin) – Alcoholic hyaline in
liver
• Neurofibrillary tangles in neurons - Alzheimer
disease - brain

15. Carbohydrate accumulation
• Glycogen deposits due to abnormal glucose or
glycogen metabolism in
– Diabetes mellitus (renal tubule, cardiac myocytes
and islets cell
– Glycogen storage disorders

16. Pigments
• Pigments are normal/abnormal colored substances that
accumulate within the cells either due to increased
production/decreased removal/lack of metabolic
enzymes
• Classification of pigments: Endogenous and Exogenous
• Endogenous
– Hemoglobin derivative
• Hemosiderin: Localised or Generalised:
• Acid heamatin
• Bilirubin and Porphyrins
– Non hemoglobin derivative: Melanin and Lipofuscin
• Exogenous: carbon

17. Hemoglobin derived pigments
• Hemolysis or red cell destruction in macrophages.
Hb released, Hemoglobinuria
• globin – to protein pool,
• Porphyrin ring yields bilirubin & iron gives
hemosiderin.
• Hemochromatosis (hemosiderin + heme free
pigment in liver cirhosis, heart failure, diabetes –
bronze skin
• Cyanosis increased reduced Hb,

18. Hemosiderin
• granular, golden-yellow to
brown pigment, accumulates
in tissues in case of local or
systemic iron excess.
• It represents large aggregates of ferritin micelles
• Causes: excessive dietary iron absorption, transfusion,
hemolytic anemias, local deposits at sites of hemorrhage
e.g. bruise
• Hemosiderosis: accumulation in organs & tissues.
• Macrophages of liver, bone marrow, spleen & lymph
nodes Siderophage. Later parenchymal cells involved
• Perl’s stain: special stain used for detection
• Prussian blue reaction: used to stain iron deposits in
tissues
Bruise

19. Hemosiderin brown
coarsely granular
material in macrophages
in alveolus.
Accumulated as a result
of RBC's breakdown.
Macrophages clear up
debris to be recycled.
Hemosiderin in
alveoli

20. A Prussian blue iron
staining of liver
demonstrate large
amounts of hemosiderin
in hepatocytes and
Kupffer cells
Hemosiderin in renal
tubules
demonstrated by
iron stain.

21. Bilirubin
• Accumulation of Bilirubin in the interstitial tissues gives
yellow green discoloration
• Accumulation in parenchymal cells leads to dysfunction
Increased amounts of circulating
Bilirubin in the blood lead to physical
examination finding of "icterus" or
jaundice as seen here as yellowish hue
of the skin..
The normally white sclerae of eyes
is an easiest place on physical
examination, is yellow

22. Bilirubin pigment yellow-green globular material seen
in small bile ductules in liver

23. Non Hemoglobin derivative
• Melanin, Lipofuscin
• Melanin: An endogenous brown-black pigment
synthesized by melanocytes & injected by them into
adjacent macrophages. Protect from UV radiation
• Increased Pigment
– Freckles accumulation in adjacent keratinocytes
– Lentigo (small pigmented lesion due to increased
number of melanocytes) juvenilis, senilis
– Ephelides (increases pigment production)
– Neoplasms (nevus, malignant melanoma)
• Chloasma gravidarum, Addisons disease
• Melanosis coli, Ochronosis
• Decreased pigment; Vitiligo (loss of pigmentation)
Albinism (absence of pigment)

25. Melanin

26. Non Hb derived
• Lipofuscin: ‘wear & tear pigment’. An insoluble,
brownish-yellow, granular intracellular pigment.
• Protein-lipid complexes derived from free radical
catalyzed peroxidation of polyunsaturated lipids of
subcellular membranes. Aging & atrophy in heart, liver,
brain etc. Brown Atrophy. Not injurious to cell. indicates
free radical induced injury. Appearance by E/M, seen as
perinuclear granules

27. Lipofuscin

28. Exogenous pigments
• Tattooing
• Coal workers Pneumoconiosis
• Anthracosis: Aggregates of of carbon or coal dust as black
pigment in lymph nodes and lung parenchyma due either
to atmospheric pollution or smoking or occupational
exposure. Inhaled, Injected, Ingested. Most common
• Morphology in lung :
• Gross: blackening of parenchyma
• Microscopic: macrophages full of black pigment
• Outcome:
– Mild to moderate depositions - without any effects
– Heavy depositions - occupational exposure lead to
serious lung disease

29. Carbon
Anthracotic pigment in
macrophages in a hilar
lymph node. most
pronounced in Smokers . It
looks bad, causes no major
organ dysfunction.

30. Anthracotic pigment seen asblack streaks between lobules
of lung beneath the pleural surface. Anthracosis not
harmful, occurs due to inhalation of carbonaceous
material in dirty air typical of industrialized regions

31. Tattooing
• Intentional
introduction of
pigment into skin for
cosmetic reasons.
• The pigment is taken
up by dermal
macrophages and
remains there

32. Pathologic Calcification
• Abnormal deposition of calcium salts together with small
amount of Iron, magnesium and other minerals in
soft tissues of body, other than osteoid or enamel.
Types: (i) Dystrophic (ii) Metastatic
Metastatic calcification: occurs in normal tissues secondary to
derangement in calcium metabolism (hypercalcemia)
• Causes:
• Hyperparathyroidism: Parathyroid hyperplasia, adenoma,
carcinoma
• Bone destruction due to increase turn over. Pagets disease,
immobilization, bone tumors and metastasis Multiple
myeloma, Leukemia
• Vitamin D related disorders intoxication, Sarcoidosis
• Milk alkali syndrome and Renal failure→ PO4 retention →
secondary hyperparathyroidism

33. Metastatic Calcification
• Sites: normal tissues, acid secreting areas, having
background alkalinity. Gastric mucosa, walls of major blood
vessels, kidney, lungs
• Morphology: Gross: white, gritty to feel, fine granules or
clumps
• Microscopic: intensely basophilic structureless deposits
• Stainnig: red with Alizarin,
blue with Von Kossa
• Extensive, shadows on X rays
• Outcome: generally no
cell/organ dysfunction.
May cause respiratory
deficit or Renal damage.
lung

34. Dystrophic Calcification
• occurs at dead or degenerate tissues
• Pathogenesis
• Two Steps: Initiation & Propagation – extra or intra-cellular
• Initiation: at extra-cellular occurs as matrix vesicles of
200nm size derived from cartilage, bone and degenerated
cells. Calcium affinity to phospholipids, phosphate
accumulate due to action of phosphatases. intra-cellular
calcification occurs in mitochondria of dead or dying cell.
• Propagation: progressively Calcium Phosphate crystals
formation, which depends on
– Calcium and Phosphate conc. in extracellular space
– Degree of collagenization
– Osteopontin (ca binding phosphoprotein)
– mineral inhibitors.
• outcome: cell/organ dysfunction

35. Dystrophic Calcification
• Morphology:
• Gross: fine white granules or
clumps, gritty to feel. s/t as stone
• Microscopic: intracellular or
extracellular intensely basophilic
structure less deposits. s/t as bone
in necrotic areas.
• Conditions
• fat and caseous necrosis,
dead parasites , infarcts
• CVS: Atheromas, thrombi,
damaged valves
• Tissue damage :
medium sized arteries, muscles,
tendons, hematomas
• Neoplasms, Scars
• Senile: costal cartilages, aorta
dystrophic calcification in wall of
stomach. At far left - artery with
calcification. Irregular bluish-purple
calcium deposits in submucosa.

36. Cellular aging
• It is the result of progressive decline in the life span and
functional capacity of cells and accumulation of cellular
damage.
• One of the strongest risk factor for many chronic diseases
• Mechanisms:
• DNA damage: accumulation of metabolic insults lead to
nuclear and mitochondrial DNA damage. Defects in DNA
repair.
• Decreased cellular replication – limited replication capacity
of cells. Fixed number of divisions- arrest – replicative
senescence - telomere shortening –cell cycle arrest. Role of
telomerase in maintaining length by adding nucleotides.
(activity present in germ, stem and cancer cells. Absent in
somatic cells)

37. Cellular aging
• Defective protein homeostasis. Due to decreased
synthesis and increased turnover. Accumulation of
misfolded proteins triggering apoptosis
• Factors effecting aging
• Environmental stresses like calorie restriction
• Reduced signaling by insulin like growth factor
receptors, reduced activation of kinases and altered
transcriptional activity. Counteract aging by
improving DNA repair, protein homeostasis and
enhanced immunity.
• Environmental stresses activate proteins of Sirtuin
family Sir2 - protein deacytalase – activate DNA
repair and stabilization