Various substances can accumulate inside cells through endogenous or exogenous means. Common intracellular accumulations include fatty change, pigmentation, calcification, amyloid, and mucoid substances. Fatty change occurs when fat accumulates in cells due to metabolic disturbances interrupting lipid metabolism. Pigmentation results from the deposition of substances like iron, melanin, or carbon particles that cells cannot degrade. Calcification involves the abnormal accumulation of calcium salts in dead or damaged tissues. Amyloid involves the deposition of abnormal protein fibrils that cells cannot break down. Mucoid substances resemble mucus and accumulate when connective tissues secrete too much mucopolysaccharide material.

1. INTRACELLULAR
ACCUMULATIONS
Dr. Mohammad Abdullah Sadiq

2. • Various substances can get accumulated – abnormal amounts
• Can be produced inside cell OR may be produced else where
• a normal endogenous substance present in normal amount, but
its degeneration and removal might not be appropriate (e.g.
Fatty change in liver)
• Mutated form of a normal endogenous substance accumulating
due to error in its secretion, packaging, transport. E.g. Alpha-1
antitrypsin (protease inhibitor –inflammation)
• Failure to degrade a metabolite due to inherited enzyme
deficiency e.g. Storage diseases? (GSD, LSD)

3. • An abnormal exogenous substance accumulates because
the cell cannot degrade or remove it e.g. carbon particles
in lungs (coal workers)
TWO accumulations of concern
1. Fatty change
2. Pigmentation

4. Fatty Change
Accumulation of Fats???
•Any excess accumulation of fat in parenchymal cells of tissue
(Fatty degeneration / fatty infiltration)
Fatty Degeneration
•Cell injury  cell’s metabolic activity disturbed  impaired
mobilization & utilization of fats in cell accumulation of fat
in cell
•Fat sourced from inside the cell. Neucleus can remain central

6. Fatty Infiltration
•Accumulation of fat in completely normal cells
•Fat sourced not from within cell but from excess of fat
in body
•Injury to cell happens after fat accumulation
•Fat present in large fat globules in cell & neucleus can
be pushed to one side – indication that fat came from
outside the cell

8. Etiology
•Metabolic disturbances – common in Obese
•Absence of lipotropic factors in food (choline – B complex)
•All that can cause Hypoxia can lead to fatty change
•Toxins (bacteria, viruses, organic / inorganic, parasites)
•Infective diseases

9. Organs involved
• Liver, heart, kidneys & muscles – common
• Lipids are large source of energy in such organs
Causes in Liver
•Alcohol
•Protein malnutrition
•Diabetes mellitus
•Obesity / fat rich food
•Hepatotoxins
•Acute fatty liver in pregnancy (familial – enzyme def)
•Endocrine factors (insulin deficiency, hyperthyroidism etc)

10. Pathogenesis of fatty liver
• Already discussed (Apolipoprotein dysfunction / fat repackaging
problem)
Heart
• Second most common organ – fatty change
• Two patterns for fatty change
1. Prolonged moderate hypoxia (anemia)  Grossly  bands of
yellowed myocardium + normal red / brown myocardium
2. Severe Hypoxia (myocarditis e.g. diphtheria)  uniform
involvement of whole myocardial tissue
• E.g. diphtheria exotoxin alters metabolism of Carnitine (amino acid)
disrupting the oxidation of fatty acids

12. Pigmentation
Deposition of coloring material in diff. parts of body
Classification
1. Exogenous Pigmentation (from outside)
•Inhalation – Coal dust (Anthracosis), Silica (Silicosis),
Asbestos (Asbestosis), Iron dust (Siderosis)
•Ingestion – Lead (Plumbism), Silver (Argyria)
•Injection – Tattoo making

13. Classification
2. Endogenous Pigmentation (from inside – metabolic source)
A) Hemoglobin derived
• Intracarpuscular Pigments – Met-hemoglobin – chololate brown
(metaloprotein with ferric) , Sulf haemoglobin – Sulfur atom
(greenish – cyanosis) , Carboxy haemoglobin (COHb)
• Haemoglobin breakdown pigments – Bilirubin, Iron pigments
(Haemosiderin – brown color - Perls' Prussian-blue stain)
• Non-Haemoglobin derived pigments – Melanin, Lipofuscins
(wear and tear pigment – yellow brown)

15. A) Melanin Pigmentation
Normal pigment – brown granules in skin, hair, eyes etc.
Melanin synthesis
• Formed from tyrosine by action of tyrosinase in the presence of
Copper
• Melanin Stimulating Hormone (MSH – Pituitary)  increases
serum levels of copper  increased production of Melanin
• Subepithelial layer has melanocytes
• More UV exposure to skin  more production of melanin (racial
differences)
• Hydrocortisone (adrenal cortex) inhibits release of MSH

17. Pathological Excess of Pigmentation
•Addison’s Disease – pigmentation incr. due to destruction of
adrenal cortex (Hydrocortisone inhibition MSH release)
•Haemochromatosis – partly pigmentation of skin due to
deposition of iron (Hemosiderin)
•Chloasma – localized facial pigmentation during pregnancy
(incr. copper levels in serum + MSH in urine) (uterine /
ovarian disorders)

18. ADDISON’S DISEASE

19. CHOLASMA

20. Pathological Excess of Pigmentation
• Albrights Syndrome – localized pigmented spots in association with
multiple neurofibromatosis
• Pigmented Nevus – a mole, due to excess of melanin pigment
• Malignant melanoma – excess of melanin in skin
• Melanosis Coli – dark pigmentation of intestines in obstruction /
constipation. Stasis  absorption of products which can destroy
proteins  converted to pigments by enzymes

21. NEUROFIBROMATOSIS

22. Pathological Excess of Pigmentation
•Ochronosis – melanin like colored pigment deposition in
cartilages
•Congenital metabolic disturbance  faulty proteins /
enzymes  accumulation of haemogentisic acid  excretion
through urine  development of degenerative arthritis in old
age
•Melasma – third trimester – incr. in serum copper – incr.
MSH in urine – pigmentation in exposed parts of body

23. Pathological Decrease in Pigmentation
• Leukoderma – white depigmented patches on skin (Leprosy) –
nerve supply is interrupted
• Albinism – congenital absence of melanin (autosomal recessive
lack of Tyrosine)
B) Haemochromatosis (Primary / Heriditary)
• Abnormal gene at chromosome 6  excessive absorption of iron
in body (2-6mg / day)
• Male > Female (9:1) – Menstruation provides protection
• Patients with multiple transfusions can develop
• Pigmentation of liver, pancreas, endocrine glands, heart etc.
• Liver Cirrhosis, diabetes mellitus (Bronze diabetes)

24. Pathological Excess of Pigmentation
Liver morphology in haemochromatosis
•Fibrous tissue in liver due to constant irritation by
Hemosiderin  known as Pigmentary Cirrhosis
•Grossly
•Chocolate in color, cuts with difficulty due to fibrosis.
•Nodular / granular outer surface (compensatory hyperplasia)
•Depressions between nodules – fibrosis
•Cut surface interlacing fibers of fibrous tissue

26. •Microscopic morphology haemochromatosis
•Golden brown granules of hemosiderin
•Excessive fibrous tissue
•Same pigment seen in and around blood vessels
•Another pigment Hemofuschin (pale yellow granular) seen in
fibroblasts and smooth cells of blood vessels / bile ducts.

28. Pathological Calcification
•Deposition of calcium in tissues other than osteoid or enamel
Types  Dystrophic & Metastatic Calcification
Dystrophic Calcification
•Deposition of calcium in a degenerated / dead tissue with
normal levels of calcium in body (localized)
Sites for dystrophic calcification
•In Dead Tissue – Caseous material, Dead parasites, Fat
necrosis, infarction, Thrombi, Hematomas
•In Degenerating tissue – Scars, chronic inflammation /
granulation tissue, Atheroma, cysts, Degenerative tumors

29. Gross Morphology Calcification
•Fine white granular deposition in dead / degenerated tissue
•Calcium deposition – radiopaque on X-ray examination
•E.g. old T.B scars OR calcified lymph nodes
Microscopically  intra / extracellular basophilic
accumulations (Dark blue to black in color)
Pathogenesis:

30. Metastatic Calcification
•Deposition of calcium in normal tissue with increased serum
calcium levels (metabolic derangement / hypercalcemia)
•Hypercalcemia  generalized calcification
•Plasma phosphates  occasionally renal osteodystrophy
Causes of Metastatic calcification
•Endocrine disorders, Neoplasia, excessive absorption,
Hypervitamin D state, compulsive milk drinking, Renal
tubular acidosis, systemic sarcoidosis, thyroid disorders, bone
hypercatabolism, Decreased bone formation (immobilization)
Morphology same as in dystrophic

31. Pathogenesis

32. Amyloid Degeneration
•Amyloid  Abnormal proteinaceous substance which cannot
be degraded by usual body mechanisms
•Deposition of Amyloid in various body tissues / organs
Physical Nature of Amyloid – Electron microscopy
Appears to be made of 2 components
•Non branching fibrils with indefinite length (w 7.5 to 10 nm)
•Fibers can be individually paired in a filament OR in a Beta-
Pleated sheet structure

35. Chemical Nature of Amyloid
• 2 major classes of amyloid (AL & AA) and several other
biochemically distinct proteins
1. Amyloid light chain (AL) immunoglobulin light chains –
mostly it is Lambda (λ) light chain giving rise to AL (B-cell
dyscrasias (abnormal mixture) in multiple myeloma)
2. Amyloid Associated (AA) protein – gives rise to HDL (high
density lipoproteins) (Amyloidosis in chronic inflammation)
3. Transthyretin – normal protein which binds to thyroxine &
retinol (form of vit A). It’s mutant forms found in amyloidosis in
aging and familial amyloid polyneuropathies

36. Chemical Nature of Amyloid
4. Beta 2 (β2) Microglobulin – normal serum protein –
component of MHC class 1 antigens – found in patients
receiving long term Hemodialysis
5. Beta 2 (β2) Amyloid Protein (A β2) – derived from a
transmembrane glycoprotein precursor – present in
Alzheimer’s disease, walls of cerebral blood vessels cerebral
plaques
6. Others – e.g. Keratin, Procalcitonin and Proinsulin

37. Classification of Amyloidosis
•Based on clinical setting, anatomic distribution & chemical
composition
A. Systemic Amyloidosis (Generalized)
1. Primary Amyloidosis – Immunocyte dyscariasis –
common in multiple myeloma – lambda light chain
precursor leading to formation & deposition of Amyloid
light chain (AL)
2. Secondary Amyloidosis – reactive systemic amyloidosis –
Chronic Inflammation – major protein fibril is AA
(Amyloid associated protein)

38. Classification of Amyloidosis
3. Hemodialysis Associated Amyloidosis – precursor fibril is
beta 2 macroglobulin – major fibril is beta 2 macroglobulin –
seen in chronic renal failure
4. Hereditary Amyloidosis
i) Transthyretin precursor protein  major protein
Transtyretin – present in Familial Amyloidotic
Neuropathies
ii) Protein precursor SAA – major fibril is AA – present in
Familial Mediterranean fever

39. Classification of Amyloidosis
B. Locallized Amyloidosis
1. Senile Cardiac Amyloidosis – Precursor and major fibril
protein is Transthyretin
2. Senile Cerebral Amyloidosis – precursor and major fibril
protein is Transthyretin – Alzheimer’s
3. Endocrine Amyloidosis – precursor is calcitonin – major
fibril protein is procalcitonin – medullary carcinoma of
thyroid

40. Pathogenesis of Amyloidosis
•Inability of enzymes in the body responsible for dissolution /
destruction of precursor proteins
•End result is build up of the various types major fibers of
Amyloid protein which are not degradable
•E.g. SAA not degraded  insoluble AA deposition
•E.g. Immunoglobulin light chains not degraded properly 
insoluble AL deposition

41. Gross & Microscopic Morphology of Amyloidosis
•Grossly the tissue usually becomes pallor (less pinkish / less
reddish), Swollen & Waxy on physical examination (tissue
biopsy / Postmortem)

44. CONGO RED STAIN USED IN KIDNEY TISSUE SAMPLE

45. Mucoid Degeneration
•Mucoid  material produced by connective tissue cells –
similar in structure to Mucin but differs in solubility
•Common change in epithelial cell tumors capable of
producing mucin  cells produce excessive mucoid and gain
a signet ring appearance / get dissolved in mucoid
•Example  inflammation of stomach, intestine and mucinous
tumors
•Connective tissue occasionally secretes mucin 
mucopolysacharide filled spaced between connective tissue
fibers (Myxoedema / mucoid production happens in
myxomas)