Diagnostic Delays in Light Chain Amyloidosis May Be Caused by Missed Early Signs and Comorbidities

Light chain amyloidosis (AL)-related cardiomyopathy is caused by direct proteotoxicity of amyloidogenic immunoglobulin light chains to cardiac myocytes, and by disruption of cardiac tissue due to the formation of amyloid fibrils. Diagnostic delays can cause cardiac damage that accumulates, and may be irreversible with currently available therapeutic options. Because diagnostic delays impact disease progression and outcomes, it may be critical to look for opportunities for early detection, prior to irreversible organ damage.

Most patients have signs and symptoms of AL cardiomyopathy well before being diagnosed with AL. In this study, Laura Hester, PhD, and colleagues investigated clinical prodromes and diagnostic delays, of patients with AL cardiomyopathy and related cardiac signs and signals. The intent of this study was to develop an overview of the overall prevalence, overlap, and timing of coexisting noncardiac signs and symptoms, before and after cardiomyopathy, as well as to assist with the identification of potential patterns that will serve as warning signs of AL in the future. Furthermore, the investigators were interested in clinical patterns of visits among patients with signs and signals of AL cardiomyopathy that may be associated with delays in diagnosis. They were also interested in confirming the importance of monoclonal gammopathy testing in patients with AL cardiomyopathy, possibly earlier in the disease progression.

Patients in a deidentified commercial healthcare claims database were identified as having AL cardiomyopathy if they had ≥1 of 9 codes associated with AL/cardiomyopathy signs and symptoms prior to index diagnosis with AL. A total of 1173 patients diagnosed between 2001 and 2018 were included in the analysis. Examples of signs and signals included cardiomyopathy and heart failure, as well as arrhythmia, cardiomegaly, pericarditis, pleural effusion, edema, dizziness, and dyspnea. Noncardiac signs and signals that were also identified included, but were not limited to, nephrotic syndrome, proteinuria, erectile dysfunction, neuralgia, peripheral neuropathy, dysphagia, abdominal pain, and monoclonal gammopathy. Cardiac signs and symptoms were the most prevalent preceding AL diagnosis, followed by renal, nervous, gastrointestinal/hepatic, other, and protein markers.

Monoclonal gammopathy testing was administered to 33% of patients with AL cardiomyopathy, prior to diagnosis of AL. Based on the unadjusted risk curves, it was suggested that receiving a diagnosis at or before the first cardiomyopathy sign leads to a higher likelihood of AL than not receiving monoclonal gammopathy of unknown significance.

Of the patients included in the study, the median age was 70 years and 88% had ≥1 cardiomyopathy signs/signals, which appeared at a median of 1.7 years prior to AL diagnosis. Most patients with AL cardiomyopathy signs and symptoms also had a sign or symptom indicating that another organ system was involved (97%) with 25% of these patients indicating the involvement of ≥4 systems (nervous, renal, hepatic, etc). Patients with monoclonal gammopathy detected before diagnosis of AL may have strongly benefited from a high degree of clinical suspicion of AL. The observed delay in seeing a cardiologist when experiencing AL cardiomyopathy signs and symptoms was 2 months; this was true even among patients who were seeing a cardiologist at their first visit for cardiomyopathy signals. In 50% of patients, AL diagnosis was still delayed by a full year; this highlights the need for a higher level of clinical suspicion and greater awareness of prodromes that may assist in early diagnosis.

The authors are currently developing a model that uses machine learning to make predictions and aims to provide the best methods for identifying patients earlier in the evolution of the disease continuum, based on the frequency of overlapping conditions and the complex signs and signals.

Reference

Hester L, Gifkins D, Bellew K, et al. Diagnostic delay and characterization of the clinical prodrome in AL amyloidosis-related cardiomyopathy among 1,173 patients diagnosed between 2001-2018. Presented at: American College of Cardiology 2020/World Congress of Cardiology Virtual Meeting. Abstract 1089-07.

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