Amyloidosis (4noarhonpathology study amyloidosis immin

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1. Amyloidosis

2. T erm ‘ amyloid’ coined by Virchow (1854) meaning starch like. Starch gives deep blue colour when iodine is applied Amyloid affected organ show ‘waxy texture’ described as ‘ waxy degeneration’ or lardaceous disease’ (von Rokitansky 1842) INTRODUCTION

3. Fig. Waxy appearance of kidney

4. A ggregates of   proteins   characterised by a  fibrillar  morphology of 7–13  nm  in  diameter , monomer assemble to form a  beta sheet  (β-sheet)  secondary structure . Has an ability to be  stained  by particular dyes, such as  Congo red . AMYLOID

5. It is a condition associated with a number of inherited and inflammatory disorders in which extracellular deposits of fibrillar proteins are responsible for tissue damage and functional compromise. These abnormal fibrils are produced by aggregation of misfolded proteins . Amyloidosis

6. Amyloid is not a single entity. More than 20 different protein can aggregate and form fibril with appearance of amyloid. Amyloidosis is a group of disease having deposition of similar appearing proteins. Properties of AMYLOID:

7. Physical Property of Amyloid Electron microscope: Consists of continuous, nonbranching fibrils with diameter approx 7.5 to 10 nm X-ray crystallography and infrared spectroscopy: cross β - sheet conformation

8. Chemical Nature: Composed of fibrillary protein and non – fibrillary glycoprotein. Defines 3 major forms of amyloid protein and more than 20 different minor form. Chemical analysis reveals heterogenous nature of amyloid.

9. Composition Fibrillary protein 95% Eg. Most common amyloid: AL protein, AA protein, β -amyloid protein Other less common are : Transthyretin (TTR), β₂ - microglobulin , prion proteins Non- fibrillary Glycoprotein 5% Eg . Serum amyloid P component, proteoglycan, highly sulfated glycosaminoglycan, apolipoprotein E

10. AL Amyloid (Amyloid Light Chain) Made up of complete immunoglobulin light chain, the amino terminal fragments of light chain, or both Composed of λ light chain mostly and some κ chain Associated with certain form of plasma cell tumor Protein

11. 2. AA type protein: This type of Amyloid is made from SAA (Serum amyloid associated protein) synthesized by liver. Production of SAA protein is increased in Inflammatory condition. This form of amyloidosis is associated with chronic inflammation and is often called as secondary amyloidosis

12. 3 . β -amyloid protein “A beta” is 4000 dalton peptide; derived from large transmembrane precursor glycoprotein. Constitutes core of cerebral plaques found in Alzheimer disease

13. Amyloid deposits in extracellular space, occurs gradually. On light microscope and H/E stained: Amorphous; Eosinophilic; Hyaline extracellular substance and progressive accumulation produces pressure atrophy on adjacent cells. Morhology

14. Amyloid on Normal microscope light Polarising Microscopy Pink/Red Deposits Green Bire fringence

15. Normal glomeruli H AND E stained

16. Polarizing microscopy

17. Classification: APP: Amyloid precursors protein

18. Gold standard: Congo red histology of abdominal fat aspirate EM aid in diagnosis Biopsies taken from organ involved eg . Kidney in nephrotic pt sural nerve in familial polyneuropathies In rectal biopsies, full thickness of muscularis taken since amyloid deposited in wall of submucosal vessels. Serum and urine protein electrophoresis and immunoelectrophoresis Diagnosis

19. Haematoxylin and Eosin: Appears amorphous, eosinophillic , extracellular, faintly refractive substance displaying green birefringence under polarized light DEMONSTRATION OF AMYLOID

20. 2 . Congo Red: Two factors imp for Congo-red-amyloid reaction: Linearity of dye molecule Cross β -pleated structure of amyloid

21. Fig. linearity of congo red

22. Kidney Spleen Liver Heart Amyloid Deposition

23. OTHER ORGANS: 1. Tongue Macroglossia 2. Respiratory tract 3. Brain: Alzheimer disease 4. Nerves: Familial amyloidotic neuropathy 5. Carpal ligaments of wrist: long term hemodialysis patient

24. Transthyretin is a transport protein in the plasma and cerebrospinal fluid that transports the thyroid hormone thyroxine and retinol to the liver

25. KIDNEY: Occurs in two group of population: Those with plasma cell disorder Long standing chronic inflammatory disease or neoplasm ( Nodular glomerulosclerosis and diabetic glomerulosclerosis may mimic amylodosis ) GROSS: Normal sized or enlarged C/S: pale, waxy and translucent Morphology of amyloid

26. Glomerulosclerosis Amyloidosis

27. M/E: Primarily occurs in glomeruli, peritubular interstitial tissue and wall of arterioles Appear on BM- later extend to produce luminal narrowing and distortion of glomerular capillary tuft Subtle thickening of mesangial matrix, uneven widening of BM. Later: C apillary narrowing and distortion of glomerular vascular tuft Capillary lumen obliteration

28. Fig. Amyloid of kidney

29. Spleen: May be inapparent grossly or moderate to marked spleenomegaly ( 800gm) Two pattern of deposit seen Sago spleen lardaceous spleen 2. Deposits limited to 2. Deposit in wall of sinus , splenic follicles connective tissue in red 3.Tapoica like granules on pulp gross inspection 3. Resemble pig fat

30. Fig. Lardaceous spleen

31. fig. Microscopic image

32. 3. liver: Inapparent grossly or produce hepatomegaly Initial: Amyloid appear in space of disse , progress to adjacent hepatic parenchymal cells and sinusoids Later: Deformity, pressure atrophy and disappearance of hepatocytes Total replacement of liver parenchyma Vascular involvement and deposits in kupffer cells

33. Fig. gross picture of amyloid deposit in liver Fig. Microscopic picture

34. Heart: Major organ involved in senile amyloidosis Heart enlarged, firm but shows no significant changes on gross inspection Initial: Focal subendocardial accumulation and within myocardium between muscle fibres Later: Expansion of myocardial deposit causes pressure atrophy of myocardial fibres Conduction system may be damaged

35. contd Fig. Gross picture of amyloid deposit in heart Fig. Microscopic picture