Ethnic/racial differences in risk factors and clinical outcomes among patients with amyloidosis

Introduction

Amyloidosis is a rare and life-threatening disease that results from pathologic protein aggregation and abnormal extracellular deposition of insoluble fibrils causing multi-organ dysfunction due to disruption of tissue architecture by amyloid deposits.

Cardiac amyloidosis (CA) is due to an abnormal extracellular deposition of insoluble amyloid fibrils in the myocardium, stiffening the heart and leading to myocardial restriction and dysfunction. CA is an increasingly recognized form of infiltrative cardiomyopathies leading to heart failure. ^, Although the exact prevalence of CA remains unknown, there is recognition that this condition is more common than previously believed due to an increased number of referrals for suspicion of CA and autopsy findings. ^, A study looking at geographic disparities in amyloidosis mortality reported in the United States observed that non-Hispanic blacks were overrepresented in amyloidosis mortality, while simultaneously finding a lack of higher reported mortality rates in those states with a greater proportion of black residents, suggesting possible underdiagnoses of amyloidosis, including CA, in many areas of the United States (US).

However, there is no recent estimate available for amyloidosis in the US by ethnic/racial groups.

There are more than 30 human amyloid proteins that have been identified, of which amyloid light-chain immunoglobulins (AL) and hepatic-derived transthyretin (ATTR) are two of the most common subtypes worldwide. The AL subtype is associated with plasma cell dyscrasia and recognized as the most common form of systemic amyloidosis whereas the ATTR subtype is associated with normal or mutated transthyretin and older age and recognized as the most common hereditary amyloidosis worldwide.

^{, ,} Around 2,000 new cases of AL amyloidosis occur in the US per year with approximately half having significant cardiac involvement. Cardiac infiltration with AL or ATTR subtypes typically manifests with symptoms of heart failure and/or arrhythmias with some patients presenting with atrioventricular (AV) block, restrictive cardiomyopathy, and heart failure. ^{, ,} The burden of cardiac involvement is the main prognostic factor in patients with AL amyloidosis, being the most important predictor of the treatment outcome and overall survival. ^, Untreated CA is fatal with a reported median survival of less than 1 year for AL involvement and 4 years for ATTR, with an even lower median survival of around 6 months from onset of heart failure. ^{, ,} One study using healthcare claims databases found a significant increase in AL amyloidosis prevalence between 2007 and 2015.

Although the incidences of cardiac events and related mortality greatly differ by ethnicity/race, the ethnic/racial differences of amyloidosis have not been systemically studied in the US population.

While the factors that determine the organ distribution of amyloid deposits are not well understood, there is continued evidence that CA is part of a systemic disease rather than an isolated condition.

^, In addition to cardiac involvement, amyloid most commonly affects the kidneys, nerves, vasculature, the liver and gastrointestinal tract, and soft tissues. ^{, , ,} Systemic amyloidosis can also present with carpal tunnel syndrome, orthostatic hypotension, and periorbital purpura. ^{, ,} It has been suggested that small periorbital bruises in the setting of heart failure (HF) are pathognomonic for AL amyloidosis. Without treatment, amyloidosis-associated kidney disease usually progresses to end-stage renal disease (ESRD). Additionally, upper and lower gastrointestinal (GI) bleeding can occur due to gastric amyloidosis pathophysiology such as ischemia, infarction and lesions caused by amyloid infiltration. Improved responses to appropriate amyloidosis therapy initiation have been shown to depend on early diagnosis and accurate typing of amyloid deposits, which is often delayed due to these varied presentations.

Given the fatal outcomes associated with amyloidosis if untreated, and with advancements in the therapeutic management of amyloidosis, particularly the ATTR subtype, it is critical to better understand the epidemiological differences in amyloidosis and associated outcomes for timely identification and appropriate therapy. Specifically, understanding factors associated with GI bleeding and renal failure (RF) in amyloidosis is necessary for developing individualized care. Moreover, ethnic/racial differences may persist in outcomes of amyloidosis due to differences in clinical presentation. However, the distribution of GI bleeding, RF, and ESRD has not been studied according to ethnicity/race and amyloidosis subtypes.

Because amyloidosis is relatively a rare disease, National Inpatient Sample (NIS) data may be a powerful tool to study the ethnic/racial epidemiology of amyloidosis. We aimed to determine the prevalence of amyloidosis in US hospitalizations and sought to determine the differences in risk factors and outcomes according to ethnicity/race and amyloidosis subtypes among US hospitalizations.