Introduction-Wild-Type ATTR Amyloidosis
The progressive, age-related disease wild-type ATTR amyloidosis (wtATTR) is a less common, yet increasingly diagnosed, condition, particularly in older adults. It is an age-related disease with the deposition of amyloid fibrils made of normal (wild-type) transthyretin (TTR) protein. It affects primarily the heart and causes a disorder called transthyretin amyloid cardiomyopathy (ATTR-CM).
Though the name might sound intimidating, it is possible to grasp its mechanism, symptoms, and treatment options, which would aid caregivers and patients in coping with this difficult diagnosis. In this blog entry, we discuss the finer points of wild-type ATTR amyloidosis—its etiology, symptoms, diagnosis, treatment, and living with the disease.
1. Understanding Amyloidosis
What is Amyloidosis?
Amyloidosis is a collection of illnesses brought on by the abnormal accumulation of misfolded proteins—amyloid fibrils—into organs and tissues. These deposits disrupt normal organ function and, if left untreated, can be fatal.
Amyloidosis has a number of different forms, which are as follows:
- AL (light-chain) amyloidosis
- AA (serum amyloid A protein) amyloidosis
- ATTR (transthyretin) amyloidosis
The ATTR form is subdivided into: - Hereditary (variant) ATTR amyloidosis
- Wild-type ATTR amyloidosis
2. What is Wild-Type ATTR Amyloidosis?
Definition
Wild-type ATTR amyloidosis, previously referred to as senile systemic amyloidosis, is when normal (wild-type) transthyretin protein gets misfolded and deposits as amyloid fibrils, mainly in the heart. It is not brought about by a genetic mutation, unlike hereditary ATTR.
Who Gets It?
- Affects men aged over 65 years most often
- The incidence increases with age
- Can be underdiagnosed because of overlap with symptoms of other conditions of aging
3. The Role of Transthyretin (TTR)
What is Transthyretin?
Transthyretin is a transport protein that is mainly produced in the liver. It transports:
- Thyroxine (T4) – thyroid hormone
- Retinol-binding protein – which transports vitamin A
Under healthy circumstances, TTR exists in the bloodstream as a stable tetramer. However, in elderly persons, the stability of the protein is lost, and it can dissociate into monomers. These unstable monomers have a tendency to misfold and form amyloid fibrils.
4. Pathophysiology of wtATTR Amyloidosis
- With time, wild-type TTR misfolds and accumulates in tissues.
- The heart is most frequently involved.
- Amyloid deposits harden the myocardium, making it unable to relax and contract.
- This results in restrictive cardiomyopathy and heart failure with preserved ejection fraction (HFpEF).
Amyloid can sometimes also deposit in the tendons, ligaments, and carpal tunnel, resulting in related orthopedic symptoms.
5. Common Signs and Symptoms
Symptoms of wild-type ATTR amyloidosis evolve over a period of time and can mimic those of other prevalent cardiac or musculoskeletal diseases:
Cardiac Symptoms
- Shortness of breath, particularly with exertion
- Fatigue
- Swelling of legs (edema)
- Irregular heartbeat (arrhythmias)
- Chest pain
- Dizziness or fainting (syncope)
Orthopedic Symptoms
- Bilateral carpal tunnel syndrome
- Lumbar spinal stenosis
- Biceps tendon rupture
These prodromal orthopedic symptoms can predate heart symptoms by years and be early warning signs.
6. Diagnosis of wtATTR Amyloidosis
Diagnosis needs a high index of suspicion, particularly in older patients with unexplained heart failure.
Diagnostic Steps:
- Medical History and Physical Exam
- Assess symptoms and family history
- Imaging Tests
- Echocardiography: Reveals thickened heart walls
- Cardiac MRI: Identifies amyloid deposits
- Blood and Urine Tests
- Exclude AL amyloidosis by checking for light chains
- Check NT-proBNP and troponin levels (indicators of heart failure)
- Nuclear Scintigraphy
- Technetium-99m-labeled bone scintigraphy (e.g., DPD or PYP scans)
- High uptake suggests ATTR amyloidosis
- Genetic Testing
- Excludes hereditary mutations
- Biopsy (if necessary)
- Cardiac or abdominal fat pad biopsy
- Congo red staining demonstrates apple-green birefringence under polarized light
Early diagnosis is critical to allow timely treatment.
7. How Is It Different from Hereditary ATTR?
| Feature | Wild-Type ATTR | Hereditary ATTR |
| ————— | ———————————— | ————————————-
| Cause | Age-related misfolding of normal TTR | Mutation in the TTR gene |
| Inheritance | Not inherited | Autosomal dominant inheritance |
| Age at Onset | > 60 years | Often earlier (30–70 years) |
| Typical Symptoms | Cardiac, carpal tunnel | Neuropathy, cardiac or combined symptoms |
8. Treatment Options
Treatment of wild-type ATTR amyloidosis was until recently limited to supportive care alone. With the advent of new therapies, however, disease management has been revolutionized.
1. TTR Stabilizers
- Tafamidis (Vyndaqel®)
- Sequesters TTR and inhibits misfolding
- FDA-approved for ATTR-CM
- Proven to decrease mortality and hospitalizations
2. Investigational Therapies
- RNA interference therapies (such as patisiran)
- Antisense oligonucleotides (such as inotersen)
- Not yet extensively approved for wild-type ATTR, primarily used in hereditary ATTR
3. Supportive Treatments
- Diuretics to manage fluid buildup
- Pacemakers for arrhythmias
- Heart failure medications (used cautiously)
- Carpal tunnel and orthopedic treatment
9. Prognosis and Disease Progression
Wild-type ATTR amyloidosis is a progressive disease, but its progression depends on age, severity, and response to treatment.
Without Treatment:
- Average survival from diagnosis: 3–5 years
- Heightened risk of heart failure and sudden cardiac death
With Tafamidis:
- Enhanced quality of life
- Longer survival
- Delayed progression of the disease
10. Living with wtATTR Amyloidosis
Living with wild-type ATTR demands a multidisciplinary strategy:
Lifestyle Changes:
- Low-sodium diet
- Gentle, regular exercise
- Fluid monitoring
Regular Medical Follow-Up:
- Cardiologist experienced with amyloidosis
- Cardiac biomarkers and symptom monitoring
Support Systems:
- Emotional support and counseling
- Amyloidosis support groups
- Patient education and awareness
11. Raising Awareness
Although wtATTR amyloidosis remains underdiagnosed, partly because of symptom overlap with many other prevalent geriatric diseases.
Who Should Be Screened?
- Older patients with heart failure but preserved ejection fraction
- Patients with bilateral carpal tunnel syndrome or spinal stenosis
- Unexplained cardiac symptoms in men over 65
Early detection can enhance outcomes and enable specific therapy.
12. Key Takeaways
- Wild-type ATTR amyloidosis is an age-related, non-genetic amyloid disease
- Resulting from misfolding of normal TTR protein, mainly involving the heart
- Initial signs are fatigue, carpal tunnel syndrome, and symptoms of heart failure
- Diagnosis includes imaging, laboratory tests, and genetic testing
- Tafamidis is a good therapy that stabilizes the TTR protein
- Early diagnosis and treatment enhance prognosis
Frequently Asked Questions (FAQs)
1. Is wild-type ATTR amyloidosis inherited?
No. It is not due to a gene mutation and is not hereditary.
2. What is the main difference between wild-type and hereditary ATTR?
Wild-type is a result of the normal TTR protein misfolding with age. Hereditary ATTR is due to a genetic mutation in the TTR gene.
3. Is wild-type ATTR curable?
A cure does not exist yet, but drugs such as tafamidis can delay disease progression.
4. Who has the highest risk?
Men over the age of 65 years with unexplained heart failure or carpal tunnel syndrome are at increased risk.
5. How is wtATTR amyloidosis treated?
Predominantly with TTR stabilizers such as tafamidis and supportive heart failure therapy.
Conclusion
Wild-type ATTR amyloidosis, while previously underappreciated, is increasingly being recognized as a major cause of heart failure in older adults. In the wake of increasing awareness and with the advent of targeted therapies, early identification is more vital than ever.
If you or a loved one are having sudden onset of cardiac symptoms without an obvious cause, particularly later in life, see a specialist who can screen for wtATTR. Being proactive can make a significant impact on treating this treatable and complex condition.