AMYLOIDOSIS

1. AMYLOIDOSIS DEFINITION- AMYLOID IS AN ABNORMAL PROTEINACEOUS SUBSTANCE THAT IS DEPOSITED BETWEEN CELLS IN MANY TISSUES & ORGANS OF THE BODY IN A VARIETY OF CLINICAL DISORDERS.

2. AMYLOIDOSIS AMYLOID APPEARS AS AN INTERCELLULAR PINK TRANSLUCENT MATERIAL

3. AMYLOIDOSIS WORD MEANING IS -STARCH LIKE. IT IS A GROUP OF DISEASES THAT SHARE IN COMMON THE DEPOSITION OF SIMILAR APPEARING PROTEINS.

4. PHYSICAL NATURE OF AMYLOID E M – 1 .PROTEIN COMPONENT(95%) - NONBRANCHING FIBRILS OF WIDTH 7.5 -10 nm X RAY CRYSTALLOGRAPHY, INFRARED SPECTROSCOPY-CROSSED β PLEATED SHEET CONFORMATION SECOND COMPONENT – ( 5%) MINOR NONFIBRILLAR PENTAGONAL P COMPONENT-A GLYCOPROTEIN

5. PHYSICAL NATURE OF AMYLOID 2.P COMPONENT & OTHER GLYCOPROTEINS - 5% OF AMYLOID – NONFIBRILLAR PENTAGONAL

6. AMYLOID PROTEIN-NONBRANCHING FIBRILS HAVING CROSSEDβPLEATED PATTERN

7. CHEMICAL NATURE OF AMYLOID 2 MAJOR CHEMICAL CLASSES 1. IMMUNOGLOBULIN LIGHT CHAIN AL (AMYLOID LIGHT CHAIN)- IS MADE UP OF COMPLETE Ig LIGHT CHAIN

8. CHEMICAL NATURE OF AMYLOID OR N TERMINAL FRAGMENT OF LIGHT CHAINS OR BOTH. MOST FREQUENTLY AL IS LAMDA LIGHT CHAIN 2 . NONIMMUNOGLOBULIN PROTEIN- AA (AMYLOID ASSOCIATED PROTEIN)

9. CHEMICAL NATURE AL AMYLOID PROTEIN IS ASSOCIATED WITH B- CELL DYSCRASIAS & IS PRODUCED BY IMMUNOGLOBULIN SECRETING CELLS.

10. CHEMICAL NATURE AA IS A NONIMMUNOGLOBULIN PROTEIN WITH MOLECULAR WEIGHT 8500 DALTONS DERIVED FROM PRECURSOR PROTEIN SAA WHICH IS AN ACUTE PHASE REACTANT.

12. OTHER PROTEINS FOUND IN AMYLOID 1 . TRANSTHYRETIN- NORMAL SERUM PROTEIN – TRANSPORTS THYROXIN & RETINOL- MUTANT FORM OF TRANSTHYRETIN – AMY LOID TRANSTHYRETIN (ATTR) IS DEPOSITED IN A GROUP OF GENETIC DISORDERS KNOWN AS FAMILIAL AMYLOID POLYNEUROPATHIES.

13. OTHER PROTEINS FOUND IN AMYLOID TRANSTHYRETIN IS DEPOSITED AS AMYLOID WITH AGING IN THE HEART.AMYLOID IN SUCH CASES IS STRUCTURALLY NORMAL(SENILE SYSTEMIC AMYLOIDOSIS)

14. OTHER PROTEINS FOUND IN AMYLOID 2 .β2 MICROGLOBULIN- A COMPONENT OF MHC CLASS 1 MOLECULE- A NORMAL SERUM PROTEIN- AS AMYLOID FIBRIL SUBUNIT (Aβ2m) ( INCREASED IN RENAL DISEASES) SEEN IN AMYLOIDOSIS ASSOCIATED WITH LONG TERM HAEMODIALYSIS.

15. CHEMICAL NATURE 3 . β AMYLOID PROTEIN( Aβ ) - A 4kD PEPTIDE SEEN IN CEREBRAL PLAQUE & WALLS OF CEREBRAL BLOOD VESSELS IN ALZHEIMER DISEASE- DERIVED FROM AMYLOID PRECURSOR PROTEIN (APP).

16. CHEMICAL NATURE 4. HORMONE PRECURSORS (PROCALCITONIN) & KERATIN

17. CLASSIFICATION OF AMYLOIDOSIS 1. SYSTEMIC 2.LOCALISED SYSTEMIC IS SUBCLASSIFIED INTO A.PRIMARY B.SECONDARY AMYLOIDOSIS C. HEREDITARY OR FAMILIAL AMYLOIDOSIS

18. CLASSIFICATION OF AMYLOIDOSIS a. FAMILIAL MEDITERANEAN FEVER b.FAMILIAL AMYLOIDOTIC NEUROPATHIES(SEVERAL TYPES) c.SYSTEMIC SENILE AMYLOIDOSIS

19. CLASSIFICATION OF AMYLOIDOSIS D.HAEMODIALYSIS – ASSOCIATED AMYLOIDOSIS

20. CLASSIFICATION OF AMYLOIDOSIS LOCALIZED AMYLOIDOSIS A. SENILE CEREBRAL –ALZHEIMER DISEASE B.ENDOCRINE a. MEDULLARY CARCINOMA THYROID b. ISLET OF LANGERHANS IN TYPE 2 DIABETES

21. PRIMARY SYSTEMIC AMYLOIDOSISIMMUNOCYTE DYSCRASIAS WITH AMYLOIDOSIS MOST COMMON – 1.MULTIPLE MYELOMA- MALIGNANT B CELLS SECRETE MYELOMA PROTEIN(M PROTEIN) & LAMDA & KAPPA LIGHT CHAINS (BENCE JONES PROTEINS –SERUM & URINE).

22. PRIMARY AMYLOIDOSIS(IMMUNOCYTE DYSCRASIAS WITH AMYLOIDOSIS) 6 – 15 % OF MYELOMA PATIENTS WHO HAVE FREE LIGHT CHAINS DEVELOP AMYLOIDOSIS.

23. PRIMARY AMYLOIDOSIS 2. OTHER β CELL DYSCRASIAS WITHOUT TUMOUR MASSES

24. SECONDARY AMYLOIDOSIS(REACTIVE SYSTEMIC AMYLOIDOSIS) 1. PROTRACTED CELL INJURY DUE TO INFECTIOUS & NONINFECTIOUS CHRONIC INFLAMMATORY CONDITIONS. 2. TUMOURS LIKE RENAL CELL CARCINOMA, HODGKIN DISEASE.

25. HEREDOFAMILIAL AMYLOIDOSIS RARE, OCCUR IN LIMITED GEOGRAPHIC AREAS, • MEDITARRANEAN FEVER- AUTOSOMAL RECESSIVE FEVER WITH SEROSAL INFLAMMATION- IN ARMANIAN SEPHERDIC JEWISH & ARABIC ORIGINS- AMYLOID DEPOSITED IS AA PROTEIN

26. HEREDOFAMILIAL AMYLOIDOSIS 2 . FAMILIAL AMYLOIDOTIC POLYNEUROPATHIES AUTOSOMAL DOMINANT. AMYLOID DEPOSITION IN PERIPHERAL & AUTONOMIC NERVES PORTUGAL, JAPAN ,SWEDEN & U S – MUTANT TRANSTHYRETINS(ATTR)

27. LOCALISED AMYLOIDOSIS SINGLE ORGAN OR TISSUE MAY PRODUCE NODULAR MASSES OR MAY BE MICROSCOPIC

28. LOCALISED AMYLOIDOSIS LUNG, LARYNX,SKIN ,URINARY BLADDER,TONGUE & ABOUT THE EYE LYMPHOCYTES & PLASMA CELLS ARE SEEN ABOUT THE MASSES. IN SOME CASES AMYLOID CONSIST OF AL PROTEIN

29. ENDOCRINE AMYLOID 1.MEDULLARY CARCINOMA OF THYROID 2.ISLET TUMOURS OF PANCREAS, 3. PHEOCHROMOCYTOMA 4. UNDIFFERENTIATED CARCINOMA OF STOMACH

30. ENDOCRINE AMYLOID 5. ISLETS OF LANGERHANS IN TYPE 2 DIABETES IN THESE SETTINGS AMYLOIDOGENIC PROTEINS ARE DERIVED FROM POLYPEPTIDE HORMONES OR ISLET AMYLOID POLYPEPTIDE (IAPP)

31. AMYLOID OF AGING SENILE SYSTEMIC AMYLOIDOSIS 70 -80 YEAR OLD.PRESENT AS RESTRICTIVE CARDIOMYOPATHY HENCE THE NAME SENILE CARDIAC AMYLOIDOSIS – TRANSTHYRETIN & MUTANT FORM OF TRANSTHYRETIN

32. REACTIVE SYSTEMIC AMYLOIDOSIS LONG STANDING TISSUE INJURY & INFLAMMATION- ELEVATED LEVELS OF SAA PROTEIN SYNTHESIZED BY THE LIVER UNDER THE INFLUENCE OF CYTOKINES –IL-1 &IL- 6.

33. REACTIVE SYSTEMIC AMYLOIDOSIS SAA IS DEGRADED TO SOLUBLE END PRODUCTS BY THE ACTION OF MONOCYTE –DERIVED ENZYMES

34. PATHOGENESIS IN INDIVIDUALS WITH ENZYME DEFECT – INCOMPLETE BREAKDOWN OF SAA- INSOLUBLE AA MOLECULES PRIMARY AMYLOIDOSIS- AMYLOID MATERIAL IS DERIVED FROM DEFECTIVE PROTEOLYSIS OF IMMUNOGLOBULIN LIGHT CHAINS

35. PATHOGENESIS ALZHEIMER DISEASE- BREAKDOWN PRODUCT OF AMYLOID PRECURSOR PROTEIN (APP) CODED BY LOCUS ON 21 CHROMOSOME. BREAKDOWN PRODUCT OF APP IS β AMYLOID(Aβ)

36. MORPHOLOGY ORGAN DISTRIBUTION IS DIFFERENT IN DIFFERENT TYPES SECONDARY AMYLOIDOSIS- KIDNEY ,LIVER, SPLEEN,LYMPH NODES, ADRENALS, THYROID & MANY OTHER TISSUES.

37. MORPHOLOGY IMMUNOCYTE ASSOCIATED AMYLOIDOSIS- THE ORGANS INVOLVED ARE HEART, GIT,R S, PERIPHERAL NERVES, SKIN ,TONGUE

38. MORPHOLOGY CONTI- HEREDOFAMILIAL AMYLODOSIS – DISTRIBUTION MAY BE WIDE SPREAD OR LOCALISED

39. MORPHOLOGY CONTI- AMYLOID DEPOSITS MAY OR MAY NOT BE APPARENT GROSSLY SMALL AMOUNTS CAN BE RECOGNISED BY PAINTING THE CUT SURFACE WITH IODINE & SULFURIC ACID- MAHOGANY BROWN COLOUR

40. MORPHOLOGY WHEN LARGE AMOUNT IS DEPOSITED- ORGAN IS ENLARGED- TISSUE APPEARS GREY WITH A WAXY FIRM CONSISTANCY

41. MORPHOLOGY MICROSCOPY – DEPOSITION IS BETWEEN THE CELLS OFTEN CLOSELY ADJACENT TO THE BASEMENT MEMBRANE. IN COURSE OF TIME AMYLOID ENCROACHES ON THE CELLS- ATROPHIC AND DISAPPEAR

42. MORPHOLOGY IN IMMUNOCYTE -ASSOCIATED AMYLOIDOSIS - PERIVASCULAR & VASCULAR LOCALISATION IS COMMON.

43. MORPHOLOGY THE HISTOLOGIC DIAGNOSIS OF AMYLOIDOSIS IS BASED ENTIRELY ON ITS STAINING CHARACTERISTICS

44. STAINING OF AMYLOID GROSS STAINING- SLICE OF THE TISSUE IS DIPPED IN LUGOL’S IODINE FOLLOWED BY DIPPING IN DILUTE SULFURIC ACID – AMYLOID GIVES DARK BLUE COLOUR WITH IODINE & IT BECOMES BROWN WITH DILUTE SULFURIC ACID.

45. MICROSCOPIC STAINING 1.H & E- AMYLOID IS PINK,EOSINOPHILIC 2.PAS – PINK COLOUR

46. MICROSCOPIC STAINING 3. WITH METACHROMATIC STAINS – A COLOUR MAY EMERGE THAT IS NOT VISIBLE IN THE ORIGINAL DYE OR IN IT’S COMBINATION – THE PROPERTY IS KNOWN AS METACHROMASIA & SUCH DYES ARE KNOWN AS METACHROMATIC DYES

47. METACHROMATIC STAINS THE TWO MOST COMMONLY USED METACHROMATIC DYES ARE A. . METHYL VIOLET – AMYLOID GIVES BRIGHT PINK COLOUR B. CRYSTAL VIOLET –BRIGHT PINK COLOUR

48. MICROSCOPIC STAINING 4. OTHER STAINS ARE CONGO RED- PINK COLOUR- WHEN SEEN UNDER POLARIZING MICROSCOPE - AMYLOID GIVES APPLE GREEN BIREFRINGENCE (MOST DEPENDABLE STAIN)

49. CONGO RED ,CONGO RED WITH POLARIZING MICROSCOPY-APPLE GREEN BIREFRINGENCE

50. STAINING OF AMYLOID 5.FLUORESCENT STAINS- A.THIOFLAVIN T-YELLOW FLUORESCENCE, B THIOFLAVIN S – RED FLUORESCENCE,