Abstract
Amyloidosis is an increasingly recognized group of disorders, characterized by the deposition of misfolded protein aggregates in various tissues and organs. For over 50 years, the Amyloidosis Center at Boston University Medical Center (BUMC) has taken lead in the comprehensive evaluation and treatment of patients with this disease. The center serves as a tertiary referral site both nationally and globally, with patients visiting from 18 countries in recent years. Historically, immunoglobulin light chain (AL) amyloidosis associated with a plasma cell dyscrasia has had the greatest prevalence at our center. Other forms of amyloidosis, such as the hereditary mutant transthyretin (ATTRm) and age-related wild type transthyretin (ATTRwt) amyloidoses, have been seen less commonly due in part to underdiagnosis and a perceived paucity of effective treatments.
We report here the spectrum of referrals at the Amyloidosis Center at BUMC from 1990 to 2017. We used data from a prospectively maintained database of consented patients. Of the 3084 patients seen for an initial evaluation at our center during this period, patients with AL amyloidosis decreased from 86% to 79% to 65% in the first, second and third decade, respectively. In the same time intervals, ATTRm amyloidosis cases increased from 12% to 14% to 19% of the total patients; an even steeper increase, from 2% to 7% to 16%, was seen in patients with ATTRwt amyloidosis.
There is a marked trend towards more referrals of ATTR amyloidosis at BUMC. We believe this reflects increasing awareness and advancements in the diagnostic and therapeutic landscape of ATTR amyloidosis. In the early 2000s, the potential for misdiagnosis of hereditary ATTR as AL amyloidosis was recognized (Lachmann, et al. N Engl J Med. 2002). Accordingly, biochemical analysis by immunogold electron microscopy or laser capture tandem mass spectrometry has become a standard for more accurate typing of amyloid protein. Availability and utilization of these specific pathological modalities may in part explain the growing proportion of ATTR amyloidosis seen at our center.
Perhaps an even more significant factor is the development of nuclear cardiac imaging techniques, which accurately diagnose ATTR cardiac amyloidosis without the need for endomyocardial biopsy. In the last decade, technetium associated bone-avid tracers, such as pyrophosphate (PYP), have been found to be highly sensitive and specific in identifying ATTR cardiac amyloidosis among patients with heart failure (Gillmore, et al. Circulation. 2016). Ease of performance and interpretation, availability and standardization have spurred widespread adaptation of this imaging modality, thereby allowing for recognition of ATTR cases that were undiagnosed in prior decades.
A recent surge in diagnosis of ATTR amyloidosis is coincident with an evolving therapeutic landscape. There have been a number of clinical trials for ATTR amyloidosis, investigating transthyretin protein suppression and stabilization, as well as fibril clearance. Three therapies have completed phase III trials and are pending US regulatory review and registration. Publicity surrounding these trials has led physicians and patients to seek referral to tertiary centers for evaluation for novel treatments. The rise in new ATTR referrals at BUMC is countered by a decline in AL amyloidosis referrals, from a former average of 102 new cases per year to 91 per year in the last decade. We believe this to be largely owed to increasing experience with and adoption by community hematologists of the therapeutic options for AL amyloidosis, which are derived from treatments for multiple myeloma.
In conclusion, once thought to be exceedingly rare, ATTR is becoming an increasingly prevalent form of amyloidosis at tertiary centers, comprising nearly 1 of every 3 new referrals at BUMC in the past decade. We anticipate that this proportion will rise further as PYP nuclear imaging becomes incorporated into screening algorithms for heart failure and awareness spreads about the anticipated approval of new pharmaceuticals for ATTR amyloidosis.
Disclosures
Berk: Ionis: Honoraria, Other: Investigator; Alnylam: Honoraria, Other: Investigator; Pfizer: Other: Investigator.
Pathophysiology and Therapeutic Approaches to Cardiac Amyloidosis