Transthyretin amyloidosis
The anchor question: is this heart failure, neuropathy, carpal tunnel or spinal stenosis the first sign of transthyretin amyloid, and if so, is it hereditary? ATTR is treatable, the diagnostic pathway no longer needs a biopsy, and the first signs can surface in primary care, as carpal tunnel or neuropathy, before anyone thinks of the heart.
Status: Forming. Page and channel are up; the cohort needs a lead, ideally a cardiologist or neurologist from the specialist roster. The map below is a first draft to argue with.
Who this cohort covers
Adults with any recognized precursor or presentation of ATTR amyloidosis: bilateral carpal tunnel syndrome, lumbar spinal stenosis or biceps tendon rupture over age 50; unexplained LV thickening, HFpEF, or intolerance of standard heart-failure drugs; a length-dependent sensorimotor polyneuropathy with autonomic features; and anyone with a family history of amyloidosis or a known TTR variant. The cohort covers both hereditary ATTR (a TTR variant, with cascade testing of relatives) and wild-type, because the screening pathway is the same and only the genetics role differs.
Two findings make this a primary care cohort. In patients having carpal tunnel release, 10% had amyloid in the tenosynovium, and two of those had hereditary ATTR.1 And cardiac ATTR can now be diagnosed without a biopsy: grade 2 or 3 myocardial uptake on bone scintigraphy with no monoclonal protein in serum or urine was 100% specific for cardiac ATTR in 1,217 patients.2 Primary care can order both the scan and the paraprotein studies.
The treatments are real: tafamidis reduced all-cause mortality and cardiovascular hospitalization in ATTR cardiomyopathy,3 and patisiran halted or reversed polyneuropathy progression in hereditary ATTR.4 The inherited lipid disorders that share this cohort's infusion and specialty pathway (homozygous FH, familial chylomicronemia, lipodystrophy) go on this map or get their own, as the cohort decides.
Care map
| Role | Year 1, Establish | Year 2, Treat | Year 3, Sustain |
|---|---|---|---|
| Anchor | Recognize the red flags and act on them. History of carpal tunnel, spinal stenosis, tendon rupture, neuropathy, orthostasis, GI symptoms, heart failure. Three-generation pedigree with heart failure, neuropathy and "amyloid" asked about by name. Order the first-line tests. | Coordinate the therapy start, the infusion or specialty pharmacy arrangements, and the cash-price or coverage conversation. Hold the organ-by-organ monitoring calendar. | Annual review of cardiac, neurologic, renal and ocular status. Reassess therapy against the current approvals each year. |
| Genetics | TTR gene sequencing in every patient with confirmed ATTR, because hereditary and wild-type look alike and the family depends on the answer. Counseling before and after. | Cascade testing for first-degree relatives of a variant carrier, with a plan for monitoring asymptomatic carriers from an age set by the variant. | Carrier surveillance per protocol. Reclassification check on any variant of uncertain significance. |
| Specialists | Cardiology with amyloid experience for cardiac involvement; neurology for polyneuropathy; hematology to exclude AL amyloidosis whenever a paraprotein is present.2 | The prescribing specialist for the stabilizer or silencer, chosen by phenotype. Ophthalmology and nephrology per involvement. | Follow per organ involvement. Hepatology if a hereditary carrier is considered for liver-directed therapy. |
| Diagnostics | Technetium bone scintigraphy with serum and urine immunofixation and free light chains, ordered together.2 ECG, echocardiogram with strain, NT-proBNP, troponin. Nerve conduction studies for neuropathy. Cardiac MRI when scintigraphy is equivocal. | Biomarkers and echocardiography at six to twelve months to track response. Nerve conduction and functional scores for neuropathy. | Annual biomarkers, echocardiography and functional assessment. |
| Therapies | Physical therapy baseline for neuropathy and gait. Occupational therapy for hand function after carpal tunnel. | Ongoing program. Cardiac rehabilitation where tolerated. | Maintenance; equipment review. |
| Behavioral health and nutrition | Screen for depression. Dietitian for GI involvement and weight loss, which track prognosis. | Counseling for carriers and families facing a hereditary diagnosis. | As needed. |
| Community | Amyloidosis patient organizations; registry enrollment. | Trial referral where approved therapy does not fit. |
Visit one
| Ask | Carpal tunnel (which side, when, surgery), spinal stenosis, tendon rupture, numbness and burning in the feet, lightheadedness on standing, diarrhea or constipation, erectile dysfunction, breathlessness, intolerance of beta-blockers or ACE inhibitors. Family: heart failure, neuropathy, pacemakers, "amyloid," early deaths. |
| Examine | Postural vital signs. Distal sensation. Signs of heart failure. Thenar wasting and scars from carpal tunnel surgery. |
| Order | Technetium bone scintigraphy and serum and urine immunofixation with free light chains, together, so the result is interpretable.2 ECG, echocardiogram with strain, NT-proBNP. Nerve conduction studies if neuropathy. TTR sequencing once ATTR is confirmed, or earlier with a family history. |
| Refer | Cardiology with amyloid experience or neurology, with the scan and paraprotein results in hand; hematology if any paraprotein is present. Where: the imaging, procedural studies and specialist rosters. |
| Tell the patient | That this is a treatable condition if it is what it looks like; that the scan is the key test and the blood tests decide how to read it; that a hereditary result matters for relatives. |
| Document | The red flags present, the pedigree, the tests ordered as a set, and the referral question. |
Roster for this cohort
Drawn from the advanced imaging roster (nuclear medicine with amyloid scintigraphy protocols, cardiac MRI), the procedural studies roster (echo with strain, nerve conduction), and the specialist roster (cardiology with amyloid experience, neurology, hematology). Infusion and specialty pharmacy entries come from the empiric therapies cohort once it opens.
Readings
- Gillmore JD, Maurer MS, Falk RH, et al. Nonbiopsy diagnosis of cardiac transthyretin amyloidosis. Circulation. 2016;133(24):2404-2412. doi:10.1161/CIRCULATIONAHA.116.021612
- Sperry BW, Reyes BA, Ikram A, et al. Tenosynovial and cardiac amyloidosis in patients undergoing carpal tunnel release. J Am Coll Cardiol. 2018;72(17):2040-2050. doi:10.1016/j.jacc.2018.07.092
References
- Sperry BW, Reyes BA, Ikram A, et al. Tenosynovial and cardiac amyloidosis in patients undergoing carpal tunnel release. J Am Coll Cardiol. 2018;72(17):2040-2050. doi:10.1016/j.jacc.2018.07.092
- Gillmore JD, Maurer MS, Falk RH, et al. Nonbiopsy diagnosis of cardiac transthyretin amyloidosis. Circulation. 2016;133(24):2404-2412. doi:10.1161/CIRCULATIONAHA.116.021612
- Maurer MS, Schwartz JH, Gundapaneni B, et al. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. N Engl J Med. 2018;379(11):1007-1016. doi:10.1056/NEJMoa1805689
- Adams D, Gonzalez-Duarte A, O'Riordan WD, et al. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N Engl J Med. 2018;379(1):11-21. doi:10.1056/NEJMoa1716153