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Systemic Amyloidosis Recognition, Prognosis, and TherapyA Systematic Review

Educational Objective
To review the diagnosis and management of systemic amyloidosis.
1 Credit CME
Key Points

Question  When should clinicians suspect and how should they diagnose systemic amyloidosis?

Findings  Systemic amyloidosis should be suspected in patients with nondiabetic proteinuria, heart failure with preserved ejection fraction, unexplained peripheral neuropathy, or atypical monoclonal gammopathy of undetermined significance.

Meaning  Late diagnosis of amyloidosis is a barrier to improved outcomes. Early recognition by primary care clinicians is vital for effective therapy to have a meaningful effect on survival.

Abstract

Importance  Many patients with systemic amyloidosis are underdiagnosed. Overall, 25% of patients with immunoglobulin light chain (AL) amyloidosis die within 6 months of diagnosis and 25% of patients with amyloid transthyretin (ATTR) amyloidosis die within 24 months of diagnosis. Effective therapy exists but is ineffective if end-organ damage is severe.

Objective  To provide evidence-based recommendations that could allow clinicians to diagnose this rare set of diseases earlier and enable accurate staging and counseling about prognosis.

Evidence Review  A comprehensive literature search was conducted by a reference librarian with publication dates from January 1, 2000, to December 31, 2019. Key search terms included amyloid, amyloidosis, nephrotic syndrome, heart failure preserved ejection fraction, and peripheral neuropathy. Exclusion criteria included case reports, non–English-language text, and case series of fewer than 10 patients. The authors independently selected and appraised relevant literature.

Findings  There was a total of 1769 studies in the final data set. Eighty-one articles were included in this review, of which 12 were randomized clinical trials of therapy that included 3074 patients, 9 were case series, and 3 were cohort studies. The incidence of AL amyloidosis is approximately 12 cases per million persons per year and there is an estimated prevalence of 30 000 to 45 000 cases in the US and European Union. The incidence of variant ATTR amyloidosis is estimated to be 0.3 cases per year per million persons with a prevalence estimate of 5.2 cases per million persons. Wild-type ATTR is estimated to have a prevalence of 155 to 191 cases per million persons. Amyloidosis should be considered in the differential diagnosis of adult nondiabetic nephrotic syndrome; heart failure with preserved ejection fraction, particularly if restrictive features are present; unexplained hepatomegaly without imaging abnormalities; peripheral neuropathy with distal sensory symptoms, such as numbness, paresthesia, and dysesthesias (although the autonomic manifestations occasionally may be the presenting feature); and monoclonal gammopathy of undetermined significance with atypical clinical features. Staging can be performed using blood testing only. Therapeutic decision-making for AL amyloidosis involves choosing between high-dose chemotherapy and stem cell transplant or bortezomib-based chemotherapy. There are 3 therapies approved by the US Food and Drug Administration for managing ATTR amyloidosis, depending on clinical phenotype.

Conclusions and Relevance  All forms of amyloidosis are underdiagnosed. All forms now have approved therapies that have been demonstrated to improve either survival or disability and quality of life. The diagnosis should be considered in patients that have a multisystem disorder involving the heart, kidney, liver, or nervous system.

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Article Information

Accepted for Publication: March 30, 2020.

Corresponding Author: Morie A. Gertz, MD, Division of Hematology, Department of Medicine, Mayo Clinic, 200 First St SW, Mayo West 10, Rochester, MN 55905 (gertm@mayo.edu).

Author Contributions: Drs Gertz and Dispenzieri had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: All authors.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: All authors.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Dispenzieri.

Administrative, technical, or material support: All authors.

Supervision: Gertz.

Conflict of Interest Disclosures: Dr Gertz reported receiving personal fees from Akccea, Alnylym, Prothena, Janssen, Spectrum, Apellis, Amgen, Physicans Education Resource, Research to Practice, Johnson and Johnson, Proclara, and i3Health outside the submitted work and serving on data and safety monitoring boards for AbbVie and Celgene and receiving royalties from Springer Publishing, grant funding to the institution from the Amyloidosis Foundation and the Macroglobulinemia Foundation (NCI SPORE MM SPORE 5P50 CA186781-04), and personal fees from Sanofi. Dr Dispenzieri reported receiving grants from Celgene, Takeda, Alnylam, Prothena, and Pfizer and personal fees from Intellia and Akcea outside the submitted work.

Additional Contributions: We would like to recognize Patricia Erwin, MLS (Mayo Alix School of Medicine), for expert search services. Ms Erwin was not compensated for her contribution.

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