For most physicians, amyloidosis was a footnote in medical training – rare, untreatable and not worth looking for.
That model is now overdue for revision.
“When we went to medical school and residency, there was no treatment for ATTR amyloidosis,” says Marshall Hyden, MD, advanced heart failure and transplant cardiologist. “We thought it was super rare, so we didn’t look for it. It turns out it’s not as rare as we thought – because now we’re looking for it.”
The data bears that out. Registry studies suggest that up to 10% of patients with HFpEF – particularly those over 60 – may have underlying cardiac amyloidosis. That figure alone should prompt a reassessment of how often this diagnosis is on your differential.
HIDDEN: A clinical framework for suspicion
The challenge with ATTR amyloidosis isn’t diagnosis. It’s suspicion. By the time most patients are referred, the disease has been progressing for years. Dr. Hyden uses the HIDDEN mnemonic to help providers recognize the constellation of findings that should prompt evaluation:
- Heart failure with preserved ejection fraction, especially in patients age 60 and older.
- Intolerance to standard HFpEF therapies. Patients with amyloid infiltration have stiff, thickened myocardium and often cannot tolerate ACE inhibitors, ARBs or beta-blockers at standard doses.
- Discordance between LV wall thickness on echo and low voltage on EKG. The amyloid protein – not hypertrophied muscle – accounts for the wall thickness, attenuating the electrical signal.
- Diagnoses suggestive of systemic amyloid deposition: Bilateral carpal tunnel syndrome, spinal stenosis, spontaneous biceps tendon rupture, rotator cuff tears without significant injury and increased need for large joint replacements.
- Echocardiographic findings of increased wall thickness, often with a characteristic granular sparkling pattern.
- Nervous system involvement, including autonomic dysfunction and peripheral neuropathy.
“By the time I see these patients and go through their history, it’s very obvious that it was amyloid,” Dr. Hyden says. “We see them very late after those diagnoses.”
The average interval between the onset of bilateral carpal tunnel syndrome and an amyloidosis diagnosis is approximately seven years. That delay is not inevitable – it’s a function of the index of suspicion.
A new screening pathway through orthopaedics
The Nebraska Medicine advanced heart failure team has partnered with the orthopaedic hand and wrist team to create a proactive screening pathway. Patients undergoing bilateral carpal tunnel release can now undergo tissue biopsy during the procedure. When amyloid is identified histologically, those patients are referred directly for cardiac evaluation.
This collaboration is particularly valuable for identifying hereditary ATTR cases, which can present in younger patients and carry implications for cascade family screening. All patients diagnosed with ATTR amyloidosis with Nebraska Medicine undergo genetic testing at initial evaluation – a critical step given that 5% to 8% of cases are hereditary.
Diagnosis and the importance of early referral
The recommended first-line diagnostic test is a technetium pyrophosphate scan, which is both sensitive and specific for ATTR amyloidosis. Cardiac MRI with gadolinium contrast provides complementary information and can identify amyloid involvement even when the etiology is unclear. In cases identified through biopsy, tissue confirmation is already established.
The window for maximum treatment benefit is early.
“This is a progressive disease,” Dr. Hyden says. “The treatment slows down the disease process – it doesn’t fix it. If you wait longer until you’re sicker, that’s as good as you’re going to get. We’re not going to get you back to where you are today.”
Treatment and removing the cost barrier
Two classes of therapy are currently available for ATTR amyloidosis:
- Transthyretin stabilizers (tafamidis, acoramidis), administered orally once or twice daily.
- Silencer therapies (vutrisiran and patisiran), which reduce hepatic production of transthyretin protein and are administered by injection four to 12 times annually, depending on the agent.
Amyloid-depleter therapy is currently under investigation and represents a promising next frontier.
Both drug classes have demonstrated improvement in symptoms and survival compared to no treatment. Medication cost, which can reach $200,000 annually, should not be a barrier to referral. Manufacturer financial assistance programs make these therapies accessible for most patients.
“Many of my patients pay little to no cost for these drugs,” Dr. Hyden says.
Nebraska Medicine specialty pharmacy and nursing teams are experienced in navigating access programs and can support providers and patients through that process.
When to refer
If your patient is over 60 with HFpEF – particularly with intolerance to standard therapies, an EKG-echo voltage discordance, bilateral carpal tunnel syndrome or a history of spontaneous tendon rupture – amyloidosis warrants evaluation.
For referrals or additional information, email physicianoutreach@nebraskamed.com or call 402.559.2500.