MEDICAL COUNCIL OF INDIA CURRICULUM BASED UNDERGRADUATE CURRICULUMFOR THE INDIAN MEDICAL GRADUATE, 2018

1. PA 2.3
INTRACELLULAR ACCUMULATIONS OF
FATS,PROTEINS,CARBOHYDRATES,PIGMENTS
Dr IRA BHARADWAJ
MCI TEACHER ID: PAT 2300569
KUHS FACULTY ID: M21512

2. TEXTBOOK REFRENCES
• ROBBINS BASIC PATHOLOGY
• HARSH MOHAN TEXTBOOK OF PATHOLOGY
• OTHER STANDARD REFRENCES

3. SLO
• Definition of accumulations
• Etiopathogenesis of accumulations
• Types of accumulations
• Accumulations of fats
• Accumulation of proteins
• Accumulation of glycogen
• Accumulation of endogenous pigments
• Accumulation of exogenous pigments

4. INTRACELLULAR ACCUMULATIONS
DEFINITION
Intracellular accumulation, implies the
storage of some product by individual cells,
of diverse nature and origin

5. INTRACELLULAR ACCUMULATIONS
ETIOPATHOGENESIS
• Chronic mild cell injury eg, fatty liver
• Derangement of cellular metabolism eg,
genetic deficiency of alpha -1- antitrypsin,
lysosomal & glycogen storage disorders

6. INTRACELLULAR ACCUMULATIONS
ETIOPATHOGENESIS
• An abnormal exogenous substance is deposited
and accumulates, as body cannot metabolize it
Eg, carbon
• A normal endogenous substance is produced at a
normal rate, but the rate of metabolism to
remove it is decreased eg lysosomal storage
disorders
• A normal endogenous substance is produced at
an increased rate & the normal rate of
metabolism is inadequate to remove it, eg,
amyloid

7. INTRACELLULAR ACCUMULATIONS
ETIOPATHOGENESIS
A normal or abnormal endogenous substance
accumulates because of genetic or acquired
defects in the metabolism of
• Packaging & transport & secretion eg, A-1-AT
deficiency
• Deficiency of enzymes eg, storage disorders

8. INTRACELLULAR ACCUMULATIONS: ETIOPATHOGENESIS
:
1. Abnormal metabolism as in fatty change in the liver
2. Mutations causing alterations in protein folding and transport, as
in alpha1 – anti trypsin deficiency

9. 3) deficiency of critical enzymes that prevent breakdown of substrates
that accumulate in lysosomes, as in lysosomal storage diseases; and
(4) inability to degrade phagocytosed particles, as in hemosiderosis
and carbon pigment accumulation.

10. INTRACELLULAR ACCUMULATIONS
TYPES [nature of substance]
• FATS - triglyceride, cholesterol and many
other types of lipids in lysosomal storage
disorders
• PROTEINS – hyaline, mucin & others
• CARBOHYDRATES - glycogen
• PIGMENTS – endogenous & exogenous

11. INTRACELLULAR ACCUMULATIONS
FATS: CHOLESTEROL & ESTERS
• TRIGLYERIDES: FATTY LIVER [already discussed]
• ATHEROSCLEROSIS – accumulation of
cholesterol in intima of arteries leading to
narrowing of lumen
• XANTHOMAS – deposits of cholesterol &
esters in subcutaneous tissues, seen in
hyperlipidemia

12. INTRACELLULAR ACCUMULATIONS FATS:
ATHEROCLEROSIS [cholesterol appears as empty, clear
space in intima of vessel wall]

13. INTRACELLULAR ACCUMULATIONS
FATS: lysosomal storage disorders
Lysosomal storage disorders occur due to
deficiency of lysosomal enzymes that metabolize
complex substrates containing lipids into soluble
end products, eg:
• Gangliosides [glycosphingolipids] accumulate
in CNS in Tay-Sachs disease
• Sphingolipids [sphingomyelin] accumulates in
in phagocytic cells & neurons in Nieman-Pick
disease

14. INTRACELLULAR ACCUMULATIONS: FATS:
LYSOSOMAL STORAGE DISORDERS
• Glycolipid [glucocerebroside] accumulates in
phagocytic cells in Gaucher disease
• Mucopolysaccharides [lipids & glycoprotein
complex] accumulates in various tissues in
Hurler & Hunter syndromes
This topic shall be taken up in detail during
discussion of genetic diseases

15. INTRACELLULAR ACCUMULATIONS
PROTEIN
• PROTEINURIA, due to any cause, leads to
accumulation of proteins in proximal renal
tubules
• RUSSEL BODIES are plasma cells full of
immunoglobulin secretions in ER
• AMYLOID is an abnormal protein deposited in
certain conditions [to be studied in detail later]

16. INTRACELLULAR ACCUMULATIONS
PROTEIN: proteinuria

17. INTRACELLULAR ACCUMULATIONS
PROTEIN
• HYALINE is any protein which appears glassy &
eosinophilic in H&E stain
• MUCIN is any protein which appears
basophilic in H&E
• A1 ANTITRYPSIN DEFICIENCY is caused by lack
of normal A-1-AT, the mutant A-1-AT
accumulates in the hepatocytes

18. INTRACELLULAR ACCUMULATIONS: PROTEIN:
extra cellular hyaline; leiomyoma showing
hyaline change

19. INTRACELLULAR ACCUMULATIONS: PROTEIN:
intracellular hyaline; hepatocytes showing hyaline
change ka Mallory body in alcoholic liver disease

20. INTRACELLULAR ACCUMULATIONS
PROTEIN: mucin; Ca breast showing
extracellular mucin pools

21. ALPHA-1-ANTITRYPSIN DEFICIENCY
AAT
• AR, mutation of AAT gene on chr 14, several
subtypes exist, most variants are asymptomatic,
PiZZ variant has only 10% of normal circulating
AAT
• AAT is produced in the hepatocytes
• The mutant AAT is misfolded & causes ER stress
leading to apoptosis of hepatocytes
• 10-20% of affected persons develop liver
disease
• Some other symptoms may also occur due to
deficiency of AAT, eg, emphysema

22. INTRACELLULAR ACCUMULATIONS PROTEIN:
mutant A-1-AT in hepatocytes in A-1-AT
deficiency [red globules in PAS stain]

23. INTRACELLULAR ACCUMULATIONS
GLYCOGEN
ETIOLOGY
• Glycogen storage diseases
• Diabetes mellitus
• Appears as clear area as it is washes off during
tissue processing
• Special stain is PAS with diastase digestion for
confirmation

24. INTRACELLULAR ACCUMULATIONS
GLYCOGEN:GLYCOGEN STORAGE DISEASES
• Many types (at least 10), mostly AR
• There is deficiency in enzymes involved in
glycogen synthesis or degradation,
• Resulting in storage of normal/abnormal forms
of glycogen in
• Liver ka von Gierke disease or
• Muscle ka McArdle syndrome
• Generalized ka Pompe disease [overlaps with
lysosomal diseases]
• To be studied in detail later

25. INTRACELLULAR ACCUMULATIONS
PIGMENTS: ENDOGENOUS PIGMENTS
• Melanin
• Melanin like – alkaptonuria
- - ochronosis - increased
homogentisic acid
- Dubin-Jhonson syndrome – darkly
pigmented liver due to metabolized epinephrine
metabolites
• Hemoprotein derived
• Lipofuscin [lipochrome]
• Copper

26. INTRACELLULAR ACCUMULATIONS
PIGMENTS: MELANIN
NORMAL METABOLISM
• Produced in melanocytes & dendritic cells,
• Seen in skin, hair, eye, meninges, adrenal
medulla, substantia nigra of brain
• Tyrosine is converted to DOPA (dihydroxy
phenyl alanine) &DPOA is converted to
melanin
• It is taken up by macrophages, when in excess

27. INTRACELLULAR ACCUMULATIONS
PIGMENTS: MELANIN
GENERALISED HYPERPIGMENTATION
• Due to increase in ACTH – increase
production from pituitary (Cushing's
syndrome) or decrease feedback from adrenal
cortex (Addison's disease)
• Increase in estrogen – pregnancy, therapy
(chloasma)
• Chronic liver disease
• Chronic arsenic poisoning

28. Addison's Disease

29. CHLOASMA

30. INTRACELLULAR ACCUMULATIONS
PIGMENTS: MELANIN
LOCALISED HYPERPIGMENTATION
• Freckles
• Tumors of melanocytes -nevus & melanoma
• Genetic diseases – Peutz - Jeghers syndrome

31. PEUTZ-JEGHERS SYNDROME

32. MELANOMA

33. MELANOMA SKIN INVADING MUSCLE

34. INTRACELLULAR ACCUMULATIONS
PIGMENTS: MELANIN
GENERALISED HYPOPIGMENTATION
Genetic defect of melanin metabolism
leading to total absence of pigment ka
albinism, associated with
• No pigment in skin, hair, iris , etc
• Photophobia,
• Increased risk of skin cancers

35. INTRACELLULAR ACCUMULATIONS
PIGMENTS: MELANIN
LOCALISED HYPOPIGMENTATION
• Genetic - leukoderma / vitiligo,
• Acquired – leprosy, wound healing, old
age

36. VITILIGO

37. INTRACELLULAR ACCUMULATIONS: PIGMENTS:
HEMOPROTEIN DERIVED: HEMOSIDERIN
• HEMOSIDERIN- blue black brown
aggregates of ferritin, stained by
Prussian blue stain
• Localized - following internal
hemorrhage

38. BLACK EYE

39. INTRACELLULAR ACCUMULATIONS: PIGMENTS:
HEMOPROTEIN DERIVED: HEMOSIDERIN
SYSTEMIC
• liver, spleen ,pancreas, kidney, heart resulting
• hemosiderosis (no parenchymal damage) or
• hemochromatosis (parenchymal damage
present )
• Due to increased hemolysis (hemolytic
anemia),also increase iron intake- repeated
blood transfusions, diet, inc iron absorption

40. The brown coarsely granular material is
hemosiderin that has accumulated as a result of
the breakdown of RBC's and release of the iron in
heme. The macrophages remove it eventually

41. PRUSSIAN BLUE STAIN FOR IRON

42. INTRACELLULAR ACCUMULATIONS:
PIGMENTS: HEMOPROTEIN DERIVED
• ACID HEMATIN (HAEMOZOIN ) seen in
malaria , mismatched Blood Transfusion
• BILIRUBIN - yellow brown pigment seen
in jaundice, which may be prehepatic,
hepatic & post hepatic

43. JAUNDICE

44. THE YELLOW-GREEN BILIRUBIN PIGMENT

45. INTRACELLULAR ACCUMULATIONS:
PIGMENTS: HEMOPROTEIN DERIVED
PORPHYRINS-
• Genetic defect in iron metabolism so
that it is converted to porphyrin instead
of heme
• Disease is precipitated by certain drugs
& chemicals
• Occurs in two common variants
erythropoietic & hepatic

46. INTRACELLULAR ACCUMULATIONS:
PIGMENTS: LIPOFUSCIN [LIPOCHROME]
• Also known as WEAR & TEAR PIGMENT (
yellow to brownish black in color)
• END RESULT OF FREE RADICAL INJURY –
lipid-protein complex are present in
lysosomes- PERINUCLEAR location
• Leads to atrophy of cells ka BROWN
ATROPHY

47. BROWN ATROPHY OF THE HEART

48. PERINUCLEAR LIPOFUSCIN PIGMENT

49. INTRACELLULAR ACCUMULATIONS:
PIGMENTS: COPPER: WILSON DISEASE
ETIOPATHOGENESIS
• AR
• Mutations in ATP7B gene on chr 13 leading to
accumulation of copper
• Absorption & transport of Cu are normal
• Excretion of Cu through bile is decreased due
to low levels of apoceruloplasmin, leading to
low levels of ceruloplasmin

50. INTRACELLULAR ACCUMULATIONS:
PIGMENTS: COPPER: WILSON DISEASE
CELL INJURY OCCURS DUE TO
• Increasing free radical formation
• Binding to sulfhydryl groups of proteins
• Displacing other metals in metalloenzymes
FREE CU ESCAPES FROM DAMAGED HEPATOCYTES
[presents with liver disease] by age 5, leading to
• Hemolysis of RBC

51. INTRACELLULAR ACCUMULATIONS:
PIGMENTS: COPPER: WILSON DISEASE
• Copper accumulates in other tissues like brain,
cornea [Green to brown Cu pigment is
deposited in Descemet membrane in the
corneal limbus, ka Kayser-Fleischer ring],
kidney, bones, joints causing cellular injury
• Special stains for Cu are rhodamine & orcein

52. INTRACELLULAR ACCUMULATIONS:
EXOGENOUS PIGMENTS
• Inhaled pigments accumulate in the
respiratory tract
• Ingested pigments in gastrointestinal tract
• Injected pigments at local at site of injection ,
as in tattoo

53. INTRACELLULAR ACCUMULATIONS:
EXOGENOUS PIGMENTS: INHALED
• ANTHRACOSIS – carbon deposition in lungs of
urban population - asymptomatic
• COALMINERS PNEUMOCONIOSIS – coal dust
deposition in lungs of persons in & around
coal mines – disease & death
• SILICOSIS – in silica industry
• ASBESTOSIS – in asbestos industry

54. INTRACELLULAR ACCUMULATIONS:
EXOGENOUS PIGMENTS: INGESTED
• ARGYRIA—brown pigment in skin, bowel, kidney
due silver ingestion
• LEAD POISONING—blue gum line
• CAROTENEMIA---yellow-red skin due to excessive
ingestion of carotenes
• MELANOSIS COLI—black colon due to laxative
abuse

55. MELANOSIS COLI

56. MELANOSIS COLI