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- 1. AMYLOIDOSIS
- 2. OUTLINES Definition Physical Nature of Amyloid Chemical Nature of Amyloid Classification Pathogenesis Clinical Correlations Stainings Morphology In Organs
- 3. Disease characterized by deposition of amyloid in the tissue. Amyloid = starch like Amylum – Starch (Latin) + Oid (resembling) Definition
- 4. Amyloid, a pathologic proteinaceous substance, deposited between cells in various tissues and organs of the body in a wide variety of clinical settings (inherited and inflammatory disorders). Amyloid refers to an extracellular abnormal deposit of insoluble polymeric protein fibrils in tissues and responsible for tissue damage and functional compromise. These abnormal fibrils are produced by the aggregation of misfolded proteins (which are soluble in their normal folded configuration). Definition
- 5. Amyloidosis is not a single disease; rather it is a group of diseases having in common the deposition of similar-appearing proteins. Amyloid refers to a group of diverse extracellular protein deposits that have (1) common morphologic properties. (2) affinities for specific dyes. (3) when stained, a characteristic appearance under polarized light. Definition
- 6. These fibrils are continous, nonbranching, insoluble, linear, rigid and measures 7.5 - 10 µm in diameter . Physical Nature of Amyloid
- 7. Physical Nature of Amyloid By electron microscopy, amyloid is seen to be made up largely of nonbranching fibrils of indefinite length. This structure is identical in all types of amyloidosis. The fibers have characteristic cross-β-pleated sheets and are responsible for the distinctive staining and birefringence of Congo red-stained amyloid.
- 9. Chemical Nature of Amyloid A fibrillary protein (95%) which is characteristic for each different type of disease. Amyloid P component (5%) consists of stacks of doughnut- shaped proteins. All different types of amyloid possess this protein. A glycosoamynoglycan. This is the part of the molecule responsible for the positive reaction with iodine.
- 10. The most common forms of amyloid fibril proteins are: 1. Amyloid light chain(AL)-made up of complete immunoglobulin light chain, derived from the lambda light chain. 2. Amyloid associated(AA)-derived from a unique non-Ig protein made by the liver, derived from larger precursor protein SAA(serum amyloid associated protein) Chemical Nature of Amyloid
- 11. others 3. Aβ2 Microglobulin(AβM)-seen in patients on long term hemodialysis 4. Transthyretin(TTR) - serum protein synthesized in liver & transports thyroxine and retinol. 5. Amyloid β-peptide(Aβ)- seen in Alzheimers disease. 6. Prion proteins(APrP) 7. Precursor of AA=SAA(Serum Amyloid Associated Protein) Chemical Nature of Amyloid
- 12. Classification Location Classificatio n Causes SYSTEMIC Effect >1 organ or system LOCALISED Effect 1 organ or 1 tissue PRIMARY Arises from a disease with disordered immune cell function SECONDARY Complication of some other chronic inflammatory or tissue destructive disease
- 14. Pathogenesis
- 15. Pathogenesis
- 16. • Variable presentation: no clinical manifestations, or it may cause death. • At first nonspecific symptoms such as weakness, weight loss, light-headedness, or syncope. • Specific findings appear later and most often relate to renal, cardiac, and gastrointestinal involvement. • The symptoms depend on the magnitude of the deposits and on the organs affected. Clinical Correlations
- 17. Clinical Correlations Kidney Nephrotic syndrome, protenuria, renal failure Tongue , GIT Macroglossia, malabsorption Heart Cardiomegaly, heart failure Bone marrow involvement in Multiple Myeloma. Fracture/ Multiple myeloma
- 18. Clinical Correlations Liver Hepatomegaly, Alkaline phosphatase elevation, Hepatic rupture Endocrine organs Hypothyroidismdue to infiltration, development of Diabetes Mellitus Neurology Peripheral neuropathy, autonomic dysfunction, Dementia (Alzheimers disease), Hemorrhagic strokes Soft tissue/ENT Carpal tunnel syndrome, voice changes, nail changes
- 19. Stainings 1. Stain on Gross- oldest method used by Virchow on cut section of gross specimen is Lugols Iodine which imparts mahogany brown colour to the amyloid deposit which on addition of sulfuric acid turns blue.
- 20. 2. In routine histological sections (hematoxylin and eosin stains)amyloid appears amorphous, eosinophilic, hyaline, extracellular substance. * However all proteins are stained pink by eosin and thus this stain is not specific. Stainings
- 21. 3. All amyloids stain pink-red with the Congo Red stain. Stainings
- 22. But when these sections are viewed with polarized light they exhibit a apple green birefrigence. This feature of amyloid can be used to identify it in tissue sections. Stainings
- 23. OTHER SPECIAL STAINS Methyl & Cresyl Violet - Metachromatic stains, pink color ThioFlavin T & S - Exhibits Flouroscence Alcian Blue - Stains blue, due to presence of glycosaminoglycans Periodic Acid Schiff (PAS) - Stains Pink Immunohistochemistry - To distinguish AL, AA & ATTR types
- 24. Morphology In Organs Primary amyloidosis cannot reliably be distinguished from the secondary amyloidosis but more often it involves the heart, kidney, gastrointestinal tract, skin and tongue. Secondary amyloidosis usually involves kidneys, liver, spleen and lymph nodes as well as many other tissues. Macroscopically the affected organs are often enlarged and firm and have a waxy appearance.
- 25. Morphology in Kidney Most common organ involved. Grossly, the organ is swollen, mottled, pale and yellow to orange in colour Histologically the amyloid is deposited in the 1) Glomeruli, with progression there is hyalinization of the glomeruli. 2) Peritubular region extending into interstitium. 3) Blood vessels: hyaline thickening of the arteriolar wall and narrowing of lumen, eventually causing ischemia with tubular atrophy and interstitial fibrosis.
- 28. Morphology in Spleen May cause splenomegaly. The organ is waxy in consistency and the cut surface is grayish. Splenic corpuscles become large, gray and translucent. There are two patterns of deposition. 1) Sago spleen. 2) Lardaceous spleen.
- 32. Morphology in Liver May cause hepatomegaly. Grossly, Liver is enlarged with rounded edges, doughy in consistency, pits on pressure and ruptures easily because of its friable nature. The amyloid appears first in the space of Disse and then progressively encroaches on adjacent hepatic parenchymal cells and sinusoids. In time due to pressure atrophy disappearance of hepatocytes replacement of large areas of liver by amyloid. Vascular involvement & deposits in Kupffer cells are frequent.
- 36. Morphology in Heart Grossly, heart is enlarged and firm. • Epi/endocardium and valves show tiny nodular deposits. Microscopically-focal subendocardial accumulations; in primary form, deposits are seen around myocardial fibres in ring forms also known as ring fibres. In localized, deposits seen in left atrium.
- 39. REFERENCES Immunopathology including Amyloidosis . In: Mohan H ed. Text book of pathology. 6th ed. Jaypee publication: India, 2010:82-92 Amyloid. In Vowles G H, Bancroft J D eds. Theory and Practice of Histological Techniques. 6th ed. Churchill Livingstone Elsevier; 2002: 261-281 Robbinson's basic pathology 8 ed Harsh Mohan -Textbook of Pathology 6th Ed. Color atlas of pathology https://www.sciencedirect.com/science/article/pii/S105488071500085X#s0030 http://ilovepathology.com/amyloidosis-part-2-pathogenesis-classification/ www.unckidneycenter.org http://webpathology.com
- 40. THANK YOU
Notas do Editor
- Amyloid is a starch-like substance which stains brown/blue/black with Iodine
- Amyloidosis refer to variety of condition where in normally soluble proteins become insoluble and are deposited in the extracellular space of various organs or tissues, disrupting their normal function.
- Birefringence = double refraction of light Amyloid is specially stained with Congo Red. Under polarized light, red-green dichroism (birefringence) is noticed because of alignment of fibrils. β-pleated sheet configuration is seen in X-ray diffraction.
- The amyloid forms a β-pleated sheet despite their chemical heterogeneity. β-pleated sheet are extremely hydrophobic do not dissolve in proteolysis This makes the fibril resistant to digestion by macrophages and phagocytic cells and hence accumulates in tissues (aggregation). Amyloid is specially stained with Congo Red. Under polarized light, red-green dichroism (birefringence) is noticed because of alignment of fibrils. Meanwhile β-pleated sheet configuration is seen in X-ray diffraction.
- AP & GAG are non fibrillary proteins Another non fibrillar amyloid protein is Apolipoprotein-E (apoE), alpha-1-anti chymotrypsin, Protein X P component = a type of glycoprotein, a 25kDa molecular weight, inhibits the differentiation of monocyte-derived fibroblast-like cells called fibrocytes, promotes the formation of immuno-regulatory macrophages, and inhibits neutrophil adhesion to extracellular matrix proteins. The P-component which is a glycosa-amino-glycan (GAG) facilitates polymerization of amyloid. The GAG makes the amyloid to stain with iodine. The amyloid is resistant to enzymatic digestion and progressively accumulate in tissues until the underlying disease process persists.
- Amyloid light chain(AL), Amyloid associated(AA), Aβ2 Microglobulin(AβM), Transthyretin(TTR) - serum protein synthesized in liver & transports thyroxine and retinol, Amyloid β-peptide(Aβ), Prion proteins(APrP), Precursor of AA=SAA(Serum Amyloid Associated Protein), AApoAl (Apolipoprotein A1), AGel (Gelsolin), ALys (Lysozyme), Afib (Fibrinogen alpha chain), Acys (Cystasin C) Plasma cell dyscrasias = plasma cell proliferative disease, including Multiple Myeloma, Waldenstrom’s macroglobulinemia Familial Mediterranean fever - Autosomal recessive, Autoinflammatory syndrome, Excessive production of IL1 in response to inflammation, Characterized by attacks of fever with serosal inflammation, Wide spread amyloidosis, AA protein
- Amyloidosis results from abnormal folding of proteins, which are deposited as fibrils in extracellular tissues and disrupt normal function. Under normal circumstances, these abnormal or misfolded proteins are degraded by proteasome pathway intracellularly and by the macrophages extracellularly. In Amyloidosis, these control mechanisms fail or there may be mutations which favor misfolding which further leads to accumulation and aggregation to form fibrils. Non-fibrillary proteins (Amyloid P component (5%) & A glycosoamynoglycan) facilitate aggregation and protection against solubilisation. So all these factors result in deposition of misfolded protein outside the cells.
- Amyloid light chain(AL), Amyloid associated(AA), Precursor of AA=SAA(Serum Amyloid Associated Protein),
- Renal involvement: proteinuria, can cause of the nephrotic syndrome. Progressive obliteration of glomeruli in advanced cases leads to renal failure and uremia The enlargement and ischaemic anoxia leads to tubular epithelial degeneration and necrosis, marked proteinuria, nephrotic syndrome, uremia and death Macroglossia – enlargement of tongue drooling, speech impairment, difficulty eating, stridor, snoring, airway obstruction GI: Dysphagia, malabsorption, GI bleeding, constipation, nausea Cardiac: Heart failure, arrhythmias, hypotension, constrictive pericarditis & amyloid deposits in valves. Cardiac amyloidosis: insidious congestive heart failure. The most serious complications are conduction disturbances and arrhythmias, which may prove fatal.
- Hypovolumic or haemorrhagic shock may occur following hepatic rupture. Hepatocellular atrophy occurs from pressure and nutritional deficiency alkaline phosphatase elevation DM : In pancreatic amyloidosis, leads to islet cell destruction and development of Diabetes mellitus. Neurologic: Peripheral neuropathy, autonomic dysfunction Soft tissue/ENT: carpal tunnel syndrome, voice changes, nail changes
- History • First described by Rokitansky in 1842. • Term first used by Rudolf Virchow in 1854 based on the color after staining it with crude iodine staining techniques. • Later recognized as Protein by Friedreich and Kekule 5 years later.
- Light microscope: amyloid appears as amorphous, eosinophilic, hyaline, extracellular substance that gradually encroaches on and produces pressure atrophy of adjacent cells.
- On congo red stain: amyloid gives a pink or red color under ordinary light and an apple green birefringence under polarizing light.
- Grossly, the organ is swollen, mottled, pale and yellow to orange in colour
- Deposit is in the splenic follicles, producing tapioca-like granules on gross inspection, called sago spleen. Deposit in splenic sinuses and connective tissue of the red pulp. Fusion of deposits gives rise to large, areas of amyloidosis, designated the lardaceous spleen.
- Lard = pig fat
- A, The pink acellular amyloid material is seen in the red pulp causing atrophy of while pulp. B, Congo red staining shows Congo philia as seen by red-pink colour. C, When viewed under polarising microscopy the corresponding area shows apple-green birefringence.
- Space of Disse (space between the hepatocytes & sinusoidal endothelial cells)
- May cause hepatomegaly. Grossly, Liver is enlarged with rounded edges, doughy in consistency, pits on pressure and ruptures easily because of its friable nature.
- Histologically the deposits are subendocardial and within the myocardium between the muscle fibers. Expansion of these myocardial deposits eventually causes pressure atrophy of myocardial fibers. When they are subendocardial, the conduction system may be damaged, causing electrocardiographic abnormalities.
- Fig. 4. Gross pathologic features of cardiac amyloidosis. (A) Pale myocardial mottling (arrowhead) can sometimes be seen in the setting of extensive amyloid deposition; (B) Amyloid can preferentially deposit in the ventricular septum, leading to disproportionate septal thickening and an increased ventricular septal-to-free wall ratio; (C–D) Endocardial deposition of amyloid can produce a mottled appearance or a roughened texture to the endocardial surface (C), which can sometimes also involve the atrioventricular valves (D).