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Internal Medicine

Amyloidosis

Heterogeneous group of diseases caused by the extracellular deposition of autologous fibrillar proteins, which aggregate into a three-dimensional ß-lamina disposition that impairs normal organ function.

Heterogeneous group of diseases caused by the extracellular deposition of autologous fibrillar proteins, which aggregate into a three-dimensional ß-lamina disposition that impairs normal organ function.


Classification

About 60 amyloid proteins have been identified so far. Of those, at least 36 have been associated with human diseases.

A. Systemic amyloidosis:

  • Primary amyloidosis: AL (Amyloid light chain) protein
    • Seen in plasma cell disorders and multiple myeloma
  • Secondary amyloidosis: AA (Amyloid-associated) protein (M/C worldwide)
    • Complication of other chronic inflammatory conditions (eg, rheumatoid arthritis, IBD, familial Mediterranean fever, protracted infection)
  • Aβ amyloid

B. Localised amyloidosis:

  • Alzheimer’s disease: β-amyloid protein
    • Cleaved from amyloid precursor protein (APP)
  • Type 2 diabetes mellitus: Islet amyloid polypeptide (IAPP)
    • Caused by deposition of amylin in pancreatic islets
  • Medullary thyroid cancer: Calcitonin (A Cal)
  • Isolated atrial amyloidosis: ANP
    • Common in normal ageing ↑ risk of atrial fibrillation
  • Systemic senile (age-related) amyloidosis: Normal (wild-type) transthyretin (TTR)
    • Seen predominantly in cardiac ventricles (cardiac dysfunction more insidious than in AL amyloidosis)

C. Hereditary amyloidosis: Mutated transthyretin (ATTR)

  • Familial amyloid cardiomyopathy: Ventricular endomyocardium deposition → restrictive cardiomyopathy, arrhythmias
  • Familial amyloid polyneuropathiesDue to transthyretin gene mutation

Pathophysiology

Abnormal aggregation of proteins (or their fragments) into β-pleated linear sheets

Insoluble fibrils

Cellular damage and apoptosis

Molecular events leading to AL amyloidosis
Molecular events leading to AL amyloidosis and possible targeted therapies: The usually small and indolent B-cell clone may produce a light chain (λ in ∼80% of patients) with mutations in the variable region, causing low folding stability and high protein dynamics, favoring improper aggregation. Interactions with the microenvironment, such as extracellular chaperones, matrix components including glycosaminoglycans (GAGs) and collagen, shear forces, endoproteases, and metals modulate aggregation and oligomer formation. Cells may be transiently required in the amyloidogenic cascade and promote the initial nucleation of the deposits. The oligomers and, probably, the misfolded protein may exert toxic effects, impairing cell function and reducing cell viability in target organs. A propensity for certain germline genes to target specific organs has been reported, for instance, LV1-44 for heart, LV6-57 for kidney, and KV1-33 for liver. Oligomers are on the pathway to forming highly organized fibrils displaying an X-ray cross-β fiber diffraction pattern. SAP is ubiquitously present in amyloid deposits. The formation of soluble amyloid oligomers can be catalyzed by amyloid fibrils. As seen by electron microscopy, the amyloid deposits are formed by rigid, nonbranching 10- to 12-nm width fibrils and exhibit a characteristic affinity for Congo red staining with birefringence under polarized light. Physical and mechanical replacement of parenchymal tissue by amyloid deposits cause dysfunction of vital organs. In addition, amyloid fibrils may contribute to cell toxicity. The frequencies of involvement of main target organs are derived from 1065 patients with AL amyloidosis diagnosed at our center between 2004 and 2015. The callouts indicate therapeutic targets. (A) The synthesis of amyloid light chain can be effectively suppressed by high-dose chemotherapy and conventional chemotherapy using drugs that target critical plasma cell functions and, more recently, by antiplasma cell immunotherapy. (B) Small molecules able to stabilize the light chain variable regions, thus inhibiting proteolysis, aggregation, and proteotoxicity, are under development. (C) Counteracting proteotoxicity caused by the misfolded light chains and aggregates is a challenging task that might be pursued with molecules modulating the mitochondria-mediated production of reactive oxygen species, as well as with metal-binding compounds. (D) Inhibitors of fibril formation have been tested in vitro, and compounds, such as epigallocatechin gallate, redirecting the oligomer off-pathway, are in clinical trials. (E) Immunotherapies, using different antibodies targeting diverse epitopes on amyloid fibrils, aiming at promoting the clearance of amyloid deposits are now being actively tested in the clinic. | ANS, autonomous nervous system; PNS, peripheral nervous system. | Merlini, G. (2017). AL amyloidosis: from molecular mechanisms to targeted therapies. Hematology. American Society of Hematology. Education Program, 2017(1), 1–12. https://doi.org/10.1182/asheducation-2017.1.1

Presentation

Renal manifestations:

M/C affected system, 70-80% cases
  • Proteinuria (95%) → Nephrotic syndrome → Renal insufficiency (earliest and M/C clinical manifestation)

Cardiac manifestations ():

2nd M/C affected system with 50-60% cases and the leading cause of death
  • Restrictive myocardiopathy → heart failure
Pathophysiology of amyloid light chain (AL) amyloidosis
Pathophysiology of amyloid light chain (AL) amyloidosis illustrating three key mechanisms: (1) amyloid fibril infiltration, depicted as green, results in wall thickening and diastolic dysfunction. (2) Local effects of fibril infiltration contribute to myocyte dysfunction and apoptosis. (3) Circulating free light chains contribute to myocardial dysfunction. | Falk, R. H., Alexander, K. M., Liao, R., & Dorbala, S. (2016). AL (Light-Chain) Cardiac Amyloidosis. Journal of the American College of Cardiology, 68(12), 1323 LP – 1341. https://doi.org/10.1016/j.jacc.2016.06.053

GI manifestations:

  • Malabsorption, intestinal pseudo-obstruction, diarrhoea, or bleeding

Mucocutaneous manifestations:

  • Macroglossia (10%) (PATHOGNOMIC)
  • Raccoon eyes (cutaneous ecchymoses around the eyes)
Mucocutaneous manifestations of AL Amyloidosis
Mucocutaneous manifestations of AL Amyloidosis: (Left) Small periorbital spontaneous bruise in a man with cardiomyopathy due to AL amyloidosis. He had had recurrent spontaneous bruising of the eyes for >1 year and dyspnea for 6 months before the diagnosis was recognized. The combination of spontaneous periorbital bruising and heart failure is virtually pathognomonic of AL amyloidosis cardiomyopathy. (Right) Macroglossia in a 65-year-old woman with AL amyloidosis of the heart and soft tissues. Note the prominent tooth indentations on the tongue. She had seen 2 ear, nose, and throat specialists because of her large tongue. Despite the fact that the differential diagnosis is small, neither was aware of the association with amyloidosis, and both failed to recognize the cause. This is unfortunate, because early diagnosis would have allowed her to tolerate treatment better. | Falk, R. H., Alexander, K. M., Liao, R., & Dorbala, S. (2016). AL (Light-Chain) Cardiac Amyloidosis. Journal of the American College of Cardiology, 68(12), 1323 LP – 1341. https://doi.org/10.1016/j.jacc.2016.06.053

Neurologic manifestations:

  • Peripheral polyneuropathy

Musculoskeletal manifestations:

  • Carpal tunnel syndrome

Amyloid deposition in organs:

  • Hepatosplenomegaly and adrenal insufficiency
Radiology assessment of pulmonary amyloidosis
Radiology assessment of pulmonary amyloidosis. a) Computed tomography (CT) scan of the chest of a patient with nodular pulmonary amyloidosis; b) diffuse interstitial pulmonary amyloidosis in a patient with light-chain amyloidosis: high-resolution CT of the chest shows diffuse subpleural septal thickening. | Milani, P., Basset, M., Russo, F., Foli, A., Palladini, G., & Merlini, G. (2017). The lung in amyloidosis. European Respiratory Review, 26(145), 170046. https://doi.org/10.1183/16000617.0046-2017

Diagnosis

Diagnostic algorithm in patients with suspected amyloidosis
Diagnostic algorithm in patients with suspected amyloidosis | Abbreviations: ECG, electrocardiogram; EMG, electromyogram; MRI, magnetic resonance imaging; NT-proBNP, N-terminal probrain natriuretic peptide. | Gertz MA, Comenzo R, Falk RH, et al. Definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL): a consensus opinion from the 10th International Symposium on Amyloid and Amyloidosis, Tours, France, April 18–22, 2004. Am J Hematol. 2005;79(4):319–328

Tissue biopsy:

  • Sites:
    • Subcutaneous abdominal fat tissue aspiration
    • Rectal mucosa biopsy
    • Minor salivary gland biopsy
  • Findings:
    • Congo red dye (GOLD STANDARD): Classic apple-green birefringence under polarized light
    • H&E stain: Homogeneous and eosinophilic amyloid deposits

Management

  • Stage I and II AL amyloidosis: Stem cell transplantation
  • Ineligible subjects: High-dose melphalan + dexamethasone
  • ATTR: Liver transplantation (as mutated transthyretin which forms amyloids is produced in the liver)

Summary:

Amyloidosis
Merlini, G., Dispenzieri, A., Sanchorawala, V., Schönland, S. O., Palladini, G., Hawkins, P. N., & Gertz, M. A. (2018). Systemic immunoglobulin light chain amyloidosis. Nature Reviews Disease Primers, 4(1), 38. https://doi.org/10.1038/s41572-018-0034-3

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