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A Powerpoint presentation on the epidemiology, etiology, pathogenesis, clinical features, diagnostic work up and treatment of the common types of amyloid.

Published in: Health & Medicine
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  1. 1. AMYLOIDOSIS A presentation by Dr Charles C. Ntima Department of Internal Medicine BSUTH
  2. 2. AMYLOIDOSIS: OUTLINE  Introduction  Classification  Epidemiology  Risk Factors  Aetiology  Pathophysiology  Clinical features/ Complications  Investigations  Treatment  Prognosis  Conclusion
  3. 3. AMYLOIDOSIS: INTRODUCTION • Amyloidosis is the term used for diseases caused by the deposition of insoluble polymeric protein (amyloid) fibrils in tissues and organs. • Deposition of amyloid fibrils is usually extracellular. • These deposits alter the normal function of the tissues in which they accumulate.
  4. 4. AMYLOIDOSIS: CLASSIFICATION • Various classification methods have evolved over time. • Earlier classification models were based on organ distribution of amyloid deposits as well as clinical findings. • Later classification models are based on the type of amyloid protein implicated in the disease process.
  5. 5. AMYLOIDOSIS: CLASSIFICATION HISTORICAL CLASSIFICATION • Classification based on organ distribution: - Systemic amyloidosis (affecting ˃ 1 organ or tissue type) - Localised amyloidosis (affects only one organ or tissue type)
  6. 6. AMYLOIDOSIS: CLASSIFICATION HISTORICAL CLASSIFICATION • Classification based on associated clinical findings: - Primary (Idiopathic) amyloidoses: in which no associated clinical condition is identified with the disease process. - Secondary (Reactive) amyloidoses: usually associated with chronic inflammatory conditions.
  7. 7. AMYLOIDOSIS: CLASSIFICATION MODERN CLASSIFICATION • Based on the chemical composition of the deposited amyloid protein and not neccesarily on the clinical phenotype. • This method employs the use of an abbreviative system whereby the amyloidoses are referred to with a capital “A” (for amyloid) followed by an abbreviation for the fibril protein eg AL, AA
  8. 8. AMYLOIDOSIS: MODERN CLASSIFICATION OFFICIAL ABBREVIATION AMYLOID TYPE/GENE DESCRIPTION AL Amyloid light chain (λ) AL amyloidosis/ Multiple myeloma AA Serum amyloid A protein AA amyloidosis Aβ β amyloid Alzheimer’s disease Aβ2M β2 amyloid microglobulin Hemodialysis related amyloid ALect2 LECT2 protein LECT2 amyloidosis ATTR Transthyretin Familial amyloid polyneuropathies, Wild type transthyretin amyloidosis, leptomeningeal amyloidosis AIAPP amylin Type II diabetes APrP prion protein CJD, BSE ACys CST3 Cerebral Amyloid Angiopathy AGel GSN Finnish type amyloidosis AApoA1¹/ Afib²/ Alys³ APOA1¹/ FGA²/LYZ³ Familial visceral amyloidosis APro prolactin Prolactinoma AKer keratoepithilin Familial corneal amyloidosis AANF Atrial natriuretic factor Senile amyloid of the heart ACal Calcitonin Medullary carcinoma of the thyroid
  9. 9. AMYLOIDOSIS: EPIDEMIOLOGY • A rare disease (...and thus epidemiological studies are also rare) • Worldwide incidence not known • Limited data from developing countries • Estimated annual incidence in the USA is about 8.9 new cases/ million inhabitants/yr. • Studies in Europe have shown incidence rates of 5.2 to 11.9 new cases/million inhabitants/yr
  10. 10. AMYLOIDOSIS: EPIDEMIOLOGY • Data from the NIH (UK) showed that in 2002- 2003: - amyloidosis accounted for 0.008% of hospital consultations - 86% of these consultations required hospital admission - 23% of these presented as emergencies - mean length of hospital stay = 9.4 days
  11. 11. AMYLOIDOSIS: EPIDEMIOLOGY • More common in the middle aged/ elderly - median age at time of diagnosis = 64 yrs • More common in males than in females (˃ ⅔ of cases) • Most common types are AL amyloidosis, AA amyloidosis, and ATTR
  12. 12. AMYLOIDOSIS: EPIDEMIOLOGY • AL amyloidosis is the most common variation particularly in Western countries (accounting for about 90% of cases). • AA amyloidosis is the second most common type worldwide but prevalence rates are presumed to be higher in developing countries.
  13. 13. AMYLOIDOSIS: RISK FACTORS • Age (˃ 50 years) • Family history (hereditary types) • Race ( ATTR common among the Hispanic population) • Male sex (70% of cases) • Chronic inflammatory conditions • Associated history of multiple myeloma (10-15% of cases) • Long term haemodialysis • Ingestion of amyloid fibres in meat of animals affected with the disease
  14. 14. AMYLOIDOSIS: AETIOLOGY • The aetiological agent involved in amyloidosis is the pathological proteinaceous substance known as amyloid. • Characteristics - Fibrillar appearance on electron microscopy - Amorphous eosinophilic appearance on heamatoxylin & eosin staining - β-pleated structure seen by x-ray diffraction pattern - Apple green birefringence on Congo red histological staining - Solubility in H2O and buffers of low ionic strength
  15. 15. AMYLOIDOSIS: AETIOLOGY • Largely made up of continuous non-branching fibrils • Electron microscopic structure is identical in all types of amyloid (cross-β- sheet conformation). • Serum amyloid P component and glycoproteins make up 10- 15% of mass of the amyloid protein molecule
  16. 16. AMYLOIDOSIS: PATHOPHYSIOLOGY • The amyloidogenic precursors may trigger amyloid formation when their concentration ↑es in serum or because a mutation favors misfolding • Interaction with the extracellular environment may result in incomplete proteolytic cleavage and binding to matrix components such as glycosaminoglycans (GAGs) and collagen that facilitate aggregation • Serum amyloid P (SAP) binds to amyloid fibrils and protects them from reabsorption via normal protein scavenging mechanisms
  17. 17. AMYLOIDOSIS: PATHOPHYSIOLOGY • Organ damage is thought to be caused by both the oligomers as well as the amyloid fibrils themselves. • This damage is caused by physical / mechanical replacement of parenchymal tissue as well as direct cytotoxicity of the oligomers
  18. 18. AMYLOIDOSIS: CLINICAL FEATURES / COMPLICATIONS • Presentation is broad and depends on the site and type of amyloid accumulation. • In some tissues amyloid accumulation causes organ enlargement. • However, in certain other tissues amyloid deposits cause progressive decline in organ function and ultimatley organ failure.
  19. 19. AMYLOIDOSIS: CLINICAL FEATURES / COMPLICATIONS • Clinical suspicion: unexplained nephropathy, cardiomyopathy, neuropathy, enteropathy, arthropathy or macroglossia. • The kidneys and the heart are the most commonly involved organs
  20. 20. AMYLOIDOSIS: CLINICAL FEATURES / COMPLICATIONS • Renal (33-40%): - proteinuria ± ↑ Urea/↑SCr - renal insufficiency a rare complication • Cardiovascular (20-40%) Heart: - may present with either diastolic or systolic heart failure. RV dysfunction more common than LV dysfunction. - may also cause conduction abnormalities eg atrioventricular block, sinus node dysfunction, low voltage complexes on the ECG.
  21. 21. AMYLOIDOSIS: CLINICAL FEATURES / COMPLICATIONS • Cardiovascular Blood vessels: - ↑ed susceptibility to bruising/bleeding around the eyes (Raccoon eyes) - caused by deposition of amyloid in vessels around the eyes + ↓ed activity of Factor X and Thrombin.
  22. 22. AMYLOIDOSIS: CLINICAL FEATURES / COMPLICATIONS • Macroglossia (˂ 15%) due to accumulation of amyloid in the tongue - dyspnoea - obstructive sleep apnoea - dysphagia/dysphonia - Sialorrhea - Angular chelitis - Crenated tongue - Orthodontic abnormalities
  23. 23. AMYLOIDOSIS: CLINICAL FEATURES / COMPLICATIONS • Nervous System: Central Nervous System - Dementia (Alzheimer’s disease, Down’s Syndrome) - Haemorrhagic strokes (2° to Cerebral amyloid angiopathy) Peripheral Nervous System - Peripheral neuropathy - Autonomic neuropathy eg postural hypotension, GIT symptoms
  24. 24. AMYLOIDOSIS: CLINICAL FEATURES / COMPLICATIONS • Liver: - liver enlargement - ↑alkaline phosphatases ± ↑ transaminases • Spleen: - splenic enlargement (˂ 5% of cases) - splenic dysfunction (˃ 25% of cases) • GIT (amyloid deposits seen in 80-90% of cases, only 1% are symptomatic): - malabsorption
  25. 25. AMYLOIDOSIS: CLINICAL FEATURES / COMPLICATIONS • Musculoskeletal: - “Shoulder pad sign”: enlargement of the anterior shoulder due amyloid deposition in periarticular soft tissue - Involvement of the synovial space may result in chronic synovitis (Carpal tunnel syndrome in the wrist)
  26. 26. AMYLOIDOSIS: CLINICAL FEATURES / COMPLICATIONS • Endocrine organs: - Hypothyroidism 2° to infiltration of the thyroid gland - Hypoadrenalism - Type II Diabetes mellitus
  27. 27. AMYLOIDOSIS: CLINICAL FEATURES • Skin: - macular rash on the interscapular region of the back (Macular amyloidosis) - lichenoid papules appearing bilaterally on the shins ( Lichenoid amyloidosis) - nodules involving the acral area (nodular amyloidosis....a rare presentation)
  28. 28. AMYLOIDOSIS: INVESTIGATIONS • Tissue biopsy provides definitive diagnosis. • Diagnosis rests upon the identification of pathologic amyloid deposits as well as immunohistochemical or biochemical identification of amyloid type. • In the systemic amyloidoses, the involved organs can be biopsied, but amyloid deposits may be found in any tissue of the body.
  29. 29. AMYLOIDOSIS: INVESTIGATIONS • Fat Pad Biopsy: Fat, aspirated from the abdominal wall, is the most easily accessible tissue and biopsy is positive in ˃ 80% of patients with systemic amyloidosis (rectum → salivary gland/gingiva → internal organs). • Staining of the tissue specimen with Congo Red reveals an apple-green birefringence when viewed by polarized light microscopy.
  30. 30. AMYLOIDOSIS: INVESTIGATIONS • Other tests, although not diagnostic, which may be carried out include: - Peripheral blood film → Howell Jolly bodies seen in hyposlenism 2° to splenic involvement - Acute phase reactants (ESR, CRP) → ↑↑ in AA
  31. 31. AMYLOIDOSIS: INVESTIGATIONS - Urinalysis → proteinuria in renal amyloidosis. - Serum protein → ↓ed in renal amyloidosis. - Serum/urine protein electrophoresis → presence of monoclonal light (λ) chains in AL amyloidosis. - Bone marrow biopsy → identification of dominant plasma cell in AL amyloidosis.
  32. 32. AMYLOIDOSIS: INVESTIGATIONS - BNP, pro-BNP, Troponin → ↑ed in cardiac amyloidosis. - ECG → Low voltage QRS complexes, conduction blocks. - Echocardiography → restrictive filling pattern. Often a “ speckled” pattern can also be seen with an ↑ed echo signal.
  33. 33. AMYLOIDOSIS: INVESTIGATIONS - Serum alkaline phosphatase → ↑ed with liver involvement. Liver transaminases are often normal or slightly ↑ed. Serum bilirubin may also be ↑ed. - Thyroid function test → 1° hypothyoidism
  34. 34. AMYLOIDOSIS: TREATMENT • Amyloidosis has no cure • Initial management should include an assessment of the degree of organ involvement. • Treatment goals are two-fold: - supportive therapy - measures targeted at limiting further production of amyloid protein (...where this is possible)
  35. 35. AMYLOIDOSIS: TREATMENT • Supportive therapy - Patient counselling - Pain medication - Diuretics - Low salt diet - Dietary modifications especially in those with GIT amyloid
  36. 36. AMYLOIDOSIS: TREATMENT • Limiting further amyloid production: Treatment approach depends on the type of amyloidosis that is present - treatment of the underlying disease in AA amyloidosis - Compounds that interfere with the binding of glycosaminoglycans to the amyloid proteins (eg Eprodisate) have been successful in secondary amyloidosis
  37. 37. AMYLOIDOSIS: TREATMENT - use of cytotoxic agents (Melphalan or Bortezomib) + Stem cell transplantation OR steroids in cases of AL amyloidosis - use of immunomodulatory drugs (eg Thalidomide, Lenalidomide) + steroids in the treatment of some cases of AL amyloidosis.
  38. 38. AMYLOIDOSIS: TREATMENT - use of β2-macroglobulin adsorbing columns, changing the mode of dialysis or renal tranplants in patients with dialysis related amyloidosis. -Liver transplants may be an option in ATTR amyloidosis, - use of PO doxycycline (100mg od )in amyloid arthropathy
  39. 39. AMYLOIDOSIS: TREATMENT - Small molecules capable of stabilizing the amyloid precursor and preventing its misfolding and aggregation (diflunisal, tafamidis) are being tested in ATTR amyloidosis. - Serum amyloid P component can be cleared from amyloid deposits by using small palindromic drugs (eg, CPHPC).
  40. 40. AMYLOIDOSIS: PROGNOSIS • Prognosis varies with the type of amyloidosis. • AL amyloidosis carries the worst prognosis if left untreated with median survival of two years (↓es with ↑ing severity). • Outcomes in patients with AA amyloidosis depends on the underlying disease and symptoms may improve if the underlying condition is treated. • People with ATTR have the best prognosis and may survive over a decade. • Cause of death in most cases of amyloidosis is cardiac failure or sudden death from a fatal arrhythmia.
  41. 41. AMYLOIDOSIS: CONCLUSION • Amyloidosis is a chronic disorder affecting several organs with significant associated morbidity and mortality. • Although it is incurable, certain types of amyloidosis have a better prognosis than others. • Advances in the understanding of the molecular mechanisms involved in amyloid formation and tissue damage have stimulated ongoing research in novel treatment strategies. • Diagnosis and early initiation of treatment in some cases may improve the outcome.
  43. 43. References • Harrison’s Textbook of Internal Medicine, 19th Edition • Amyloidosis Treatment and Research Program, Boston University School of Medicine • JOURNAL OF CLINICAL ONCOLOGY 29, American Society of Clinical Oncology • 2010 recommendations from the nomenclature committee of the International Society of Amyloidosis