The diagnosis of amyloidosis can be challenging for several reasons.
- First and foremost, presenting symptoms are often nonspecific and common to other conditions that can send clinicians in multiple directions.
- Second, due to the variability of presenting symptoms, rarely are two patient presentations identical.
- Third, the diagnostic process requires (a) the confirmation of amyloidosis, and (b) the typing of amyloidosis, only after which can an appropriate treatment regimen be developed.
The perceived rarity of the disease itself gives providers pause to consider. Collectively, as a result of these reasons, diagnosis is often delayed and/or misdiagnosed, leading to devastating consequences for patients. Often, the key to diagnosis begins with developing a clinical suspicion.
DEVELOPING A CLINICAL SUSPICION FROM SYMPTOMS
The first step in diagnosing AL amyloidosis is to develop a clinical suspicion, done through connecting the seemingly random presenting symptoms.
As seen in the figure above, multiple pathologies are often present with AL amyloidosis1. The most common is cardiac involvement, which also brings the highest mortality. Other common presentations range from nephropathy, including proteinuria (> 60% of patients), hepatomegaly (>50% of patients), neuropathy, whether autonomic (20% of patients) or peripheral (10-20% of patients), macroglossia (17% of patients), periorbital purpura (15% of patients) and GI manifestations (approximately 7% of patients).
Symptoms do not develop at the same time, nor in the same sequence from patient to patient. As a result, patients and providers often play “whack-a-mole,” going from specialist to specialist for specific symptoms. Misdiagnoses along the way are common, leading patients down paths that prove unproductive and, in some cases, counterproductive. This takes time, which is exactly what patients do not realize they do not have.
Suspicion of amyloidosis should be very high when a patient presents with heart failure combined with a constellation of unexplained extracardiac symptoms such as neuropathy, bleeding, carpal tunnel syndrome, nephrotic syndrome, proteinuria, diarrhea, hepatomegaly, peripheral and autonomic neuropathy, macroglossia, and periorbital purpura.1
ALGORITHM FOR DIAGNOSING AL AMYLOIDOSIS1
The figure below illustrates the current systematic, stepwise process for diagnosing amyloid light chain (AL) amyloidosis and differentiating it from other cardiomyopathies. It identifies each type of test that is essential for suspicion of AL amyloidosis, diagnosing the disease and typing of the amyloidogenic free light chains (FLCs).
ACR = albumin/creatinine ratio
DPD = 99mTc-3-diphosphono-1,2-propanodicarboxylic acid
Echo = echocardiography
EKG = electrocardiography
LFT = liver function test
MRI = magnetic resonance imaging
NT-proBNP = N-terminal pro–brain natriuretic peptide
PYP = 99mTc-pyrophosphate
SIFE = serum immunofixation electrophoresis
UIFE = urine immunofixation electrophoresis
TYPING AND CONFIRMING DIAGNOSIS1
Once the presence of amyloid has been confirmed, it is imperative to next identify the type of amyloid fibril in order to avoid misdiagnosis and initiation of incorrect or inappropriate treatment, which could have disastrous consequences for a patient.
The most common methods of amyloid fibril typing include immunohistochemistry or laser capture, followed by mass spectrometry. As the accuracy of immunohistochemistry is dependent on the expertise of the laboratory and needs an extensive panel of antibodies for accurate reporting, laser capture with mass spectrometry has become the method of choice for amyloid fibril typing.
Despite advances in noninvasive imaging, tissue biopsy remains a common and important confirmational step in most cases.
Once a diagnosis of amyloidosis has been confirmed, along with the specific type, an appropriate treatment regime can then be determined.
CONCLUSION – WHY EARLY DIAGNOSIS MATTERS
With AL amyloidosis, time is of the essence for patients. This is an aggressive disease where early treatment intervention can truly extend lives and improve QoL. As recently as the 1990s, this was considered a terminal disease with a high mortality rate, often offering patients months to a few years to live. With earlier diagnosis and advancements in treatments, survival is extending and QoL is improving.
IN CLOSING
The key take-aways are two-fold: (1) when confronted with multiple unexplained symptoms, suspect multi-system diseases like amyloidosis, and (2) remember that early diagnosis is key for patient survival.
For more detail on diagnosing and treating AL amyloidosis, please see the paper referenced below.
Source:
(1) Wechalekar, A, Fontana, M, Quarta, C. et al. AL Amyloidosis for Cardiologists: Awareness, Diagnosis, and Future Prospects: JACC: CardioOncology State-of-the-Art Review. J Am Coll Cardiol CardioOnc. 2022 Nov, 4 (4) 427–441.
