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Pathophysiology and treatment of systemic amyloidosis

Abstract

Amyloid is an abnormal extracellular fibrillar protein deposit in the tissues. In humans, more than 25 different proteins can adopt a fibrillar conformation in vivo that results in the pathognomonic tinctorial property of amyloid (that is, green birefringence when an affected tissue specimen is stained with Congo red dye and viewed by microscopy under cross-polarized light). Amyloid deposition is associated with disturbance of organ function and causes a wide variety of clinical syndromes that are classified according to the respective fibril protein precursor. Systemic amyloidosis, in which amyloid deposits are widespread and typically accumulate gradually, continues to be fatal and is responsible for about one in 1,500 deaths per year in the UK. Advances in our understanding of the pathogenesis of systemic amyloidosis have resulted in the identification of new therapeutic targets, and several drugs with novel mechanisms of action are currently under development. Meanwhile, an increased awareness of amyloidosis coupled with enhancements to existing diagnostic techniques and therapeutic strategies have already resulted in better outcomes for patients with the disease.

Key Points

  • More than 25 different human proteins can misfold to form amyloid fibrils in vivo; 15 of these misfolded proteins cause systemic amyloidosis, which is usually fatal

  • Diagnosis of amyloidosis relies on a high index of clinical suspicion and requires histological confirmation by staining of tissue specimens with Congo red dye

  • Identification of amyloid should prompt a series of investigations to identify the amyloid fibril protein and associated organ involvement and dysfunction

  • Therapies to enhance clearance of amyloid are in development; current treatment involves reducing the supply of the amyloid fibril precursor protein to slow or halt new amyloid formation

  • Amyloidotic organ dysfunction may gradually improve when amyloid formation is slowed or halted, and supporting organ function while waiting for clinical improvement is a crucial aspect of management

  • Advances in understanding of the molecular mechanisms involved in amyloid formation have led to the identification of several new therapeutic targets, and new therapeutic approaches are now in development

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Figure 1: New approaches to amyloidosis therapy.
Figure 2: Amyloid deposits in a renal biopsy sample.

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Acknowledgements

The work of the Centre for Amyloidosis and Acute Phase Proteins is supported by grants from the Medical Research Council (UK), The Wellcome Trust, the Wolfson Foundation, and NHS Research and Development Funds.

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J. D. Gillmore researched the data for the article. The authors contributed equally to writing the article, to discussions of the content, and to reviewing and/or editing of the manuscript before submission.

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Correspondence to Julian D. Gillmore.

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Gillmore, J., Hawkins, P. Pathophysiology and treatment of systemic amyloidosis. Nat Rev Nephrol 9, 574–586 (2013). https://doi.org/10.1038/nrneph.2013.171

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