Amyloidosis

Amyloidosis

1. Amyloidosis Lecture - 45

2. Learning Objectives Know about composition of amyloid material Describe pathogenesis of amyloid deposition Classify amyloidosis Explain systemic and localized types of amyloidosis Demonstrate how to diagnose amyloid in a biopsy tissue

3. Amyloidosis Is a condition in which extracellular deposition of proteins aggregate occurs forming insoluble fibrils called amyloid Approximately 95% of the amyloid material consists of fibril proteins, the remaining 5% non- fibrillar components being various glycoproteins

4. Amyloidosis - Pathogenesis At least 30 different proteins can aggregate to form non branching fibrils , each formed of intertwined polypeptides in a β pleated sheet conformation D eposition of these proteins may result from: E xcessive production of proteins that are prone to aggregation Mutations that produce proteins that cannot fold properly and tend to aggregate Defective or incomplete proteolytic degradation of extracellular proteins Amyloid deposits cause tissue injury and impair normal function by causing pressure on cells and tissues without initiating inflammatory reaction Amyloid fibril showing four fibrils wound around one another with regularly spaced binding of the Congo red dye

5. The three most common forms of amyloid are; AL (amyloid light chain) amyloid is made up of complete immunoglobulin light chains AA (amyloid-associated) amyloid derived by proteolysis from a larger precursor in the blood called SAA (serum amyloid associated) protein, which is synthesized in the liver β-amyloid protein (Aβ) derived by proteolysis from a much larger transmembrane glycoprotein, called amyloid precursor protein

6. Classification of Amyloidosis Clinicopathologic Category Associated Diseases Major Fibril Protein Chemically Related Precursor Protein Organs Commonly Involved SYSTEMIC (GENERALIZED) AMYLOIDOSIS Primary Amyloidosis Multiple myeloma & monoclonal plasma cell proliferations AL Immunoglobulin light chains, chiefly λ type Heart, bowel, skin, nerves and kidney Secondary (Reactive) Amyloidosis -Chronic inflammation e.g TB, RA -Cancers AA SAA Liver, spleen, kidneys, adrenals Hemodialysis-associated amyloidosis Chronic renal failure A β2 m β2- microglobulin Synovium, joints, tendon sheaths HEREDITARY AMYLOIDOSIS Familial Mediterranean fever AA SAA Liver, spleen, kidneys, adrenals Familial amyloidotic neuropathies ATTR Transthyretin Peripheral & autonomic nerves, Heart Systemic senile amyloidosis ATTR Transthyretin Systemic amyloidosis LOCALIZED AMYLOIDOSIS Senile cerebral Alzheimer disease A β APP Cerebral vessels, plaques, neurofibrillary tangles Endocrine Type 2 diabetes Proinsulin Islets of Langerhans Medullary carcinoma of thyroid A Cal Calcitonin Thyroid Islets of Langerhans AIAPP Islet amyloid peptide Senile cardiac -Asymptomatic type -Restrictive cardiomyopathy AANF ATTR -Atrial natriuretic factor -Transthyretin -Isolated atrial amyloidosis -Atrium and ventricle Nodular mass forming amyloid Lungs, larynx, skin, urinary bladder, tongue, eye AL Respective anatomic location

7. Diagnosis of Amyloid Based on histopathological evidence of amyloid in a biopsy tissue and appears as an amorphous, eosinophilic, hyaline, extracellular substance with H&E stain Congo red stain; gives a pink or red color to amyloid in tissue and specific apple green birefringence under polarizing microscopy; thus differentiating amyloid from other hyaline materials (e.g., collagen, fibrin) Most common sites of biopsies ; kidney , when renal manifestations present, rectal or gingival tissues in patients suspected of having systemic amyloidosis and aspiration cytology of abdominal fat stained with Congo red for diagnosis of systemic amyloidosis Confirmation by electron microscopy , which reveals amorphous non oriented thin fibrils

8. Amyloidosis - Spleen Amyloidosis spleen is seen in two forms; Sago spleen in which amyloid deposit are limited to the follicles Lardaceous spleen in which amyloid is deposited in the walls of the splenic sinusoids and spares the follicles

9. Amyloidosis kidney Congo red stain; the amyloid deposits are seen mainly in the glomerular capillary tuft stained red pink Viewing the same under polarising microscopy, the congophilic areas show apple-green birefringence

10. Amyloidosis Liver A section of liver stained with Congo red reveals pink-red deposits of amyloid in the walls of blood vessels and along sinusoids Gives apple-green birefringence under polarizing microscope

11. Cerebral Amyloidosis S mall cerebral artery branch in the cortex shows extensive orange-red Congo red staining indicative of amyloid deposition Adrenal Amyloidosis Congo red stained deposits of amyloid in the adrenal cortex

12. Cardiac Amyloidosis Myocardium stained with Congo red stain in a case of amyloidosis under polarized light, has an "apple-green" birefringence

13. Clinical Manifestations W eight loss, fatigue, renal failure, congestive heart failure, carpal tunnel syndrome, and peripheral neuropathy Organs most commonly affected are heart , liver and kidney where as GIT and lung involvement are usually asymptomatic Prognosis: poor for generalized amyloidosis and individuals with myeloma-associated amyloidosis even poorer, where as; individuals with reactive systemic amyloidosis have better out come depending upon the control of underlying condition

14. Case Scenario A 46-years-old male is admitted to medical ward with history of shortness of breath, loss of weight and appetite, and low grade fever , all for the last one month. He has been smoking bidis for 25 years, and gives history of having productive cough with foul smelling expectoration for 15 years, interspersed with haemoptysis off and on. During these years, he had two episodes of bronchopneumonia. On examination, he is poorly built and poorly nourished. His pulse rate is 90 per minute, respiratory rate 45 per minute, and blood pressure 130/90 mmHg. He has pallor ++, icterus +, pedal oedema +, and grade II clubbing of fingers . On auscultation of chest , rhonchi and crepts are heard. 1. Discuss the clinical correlation with pathogenesis of the features . 2. What is the probable diagnosis? 3. How will you investigate and confirm the diagnosis?

15. References Robbins Basic Pathology 10 th edition 2018 Page 182-187 www.webpath.com