ATTR amyloidosis cases on the rise in the US as diagnostics improve
Study shows 26% jump in people living with the rare protein-misfolding disease
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The number of people diagnosed with transthyretin amyloidosis (ATTR) in the U.S. is climbing, a surge researchers attribute to better medical awareness and more advanced diagnostic tools. This increase spans both new diagnoses and the total number of people living with the condition, which includes hereditary ATTR with polyneuropathy (hATTR-PN).
A new study reveals that while ATTR is still officially classified as a rare disease, the heart-affecting form — known as ATTR with cardiomyopathy (ATTR-CM) — is the most prevalent. The data also show that most patients diagnosed with nerve damage (polyneuropathy) also have heart involvement, suggesting that “mixed” forms of the disease are more common than previously recognized.
The study, “Prevalence and incidence of amyloid transthyretin amyloidosis in the USA: insights from claims databases and electronic health records,” was published in the journal Open Heart, and conducted by researchers mostly from Alexion, AstraZeneca Rare Disease, the rare disease unit of AstraZeneca, which markets several ATTR treatments. Their findings suggest that as diagnostic coding improves and management strategies evolve, the documented burden of this once-hidden disease will likely continue to grow.
Understanding the different forms of ATTR amyloidosis
ATTR amyloidosis occurs when misfolded TTR protein builds up as toxic clumps, called amyloid deposits, that damage organs over time. The disease can be hereditary, meaning it results from mutations in the TTR gene, or wild-type, where the TTR protein becomes misfolded due to aging.
When amyloid deposits accumulate in the peripheral nerves, the disease is referred to as ATTR-PN; this form is most often hereditary. When they build up in the heart, it is called ATTR-CM, which is most often wild-type. Some patients have a mixed form of the disease, with damage to both the peripheral nerves and the heart.
Because there is a “lack of specific diagnostic codes for all ATTR amyloidosis [forms],” it is difficult to estimate how common it is, the researchers wrote. “ATTR amyloidosis is currently classified as a rare disease, but its prevalence is likely to be underestimated.”
To address this, the researchers retrospectively reviewed medical records and insurance claims in the U.S., using both strict (narrow) and looser (broad) definitions of ATTR amyloidosis overall, ATTR-PN, ATTR-PN only, ATTR-CM, ATTR-CM only, and ATTR-mixed.
They assessed the incidence and prevalence of ATTR amyloidosis, overall and specific forms, in 2022, as well as changes from 2019 to 2022. Incidence measures new diagnoses per year, while prevalence counts everyone who has the disease, new or existing.
According to the study’s narrow definition, the breakdown of new ATTR amyloidosis cases per million people in 2022 was:
- Total new cases: 16.6 per million
- ATTR-CM (heart involvement): 12.7 per million
- Heart involvement only: 10.8 per million
- ATTR-PN (nerve involvement): 3.5 per million
- Nerve involvement only: 1.7 per million
- Mixed form (both heart and nerve involvement): 1.9 per million
When using a broader definition for diagnosis, the number of new cases identified per million people in 2022 increased significantly:
- Total new cases: 81.1 per million
- ATTR-CM (heart involvement): 75.1 per million
- ATTR-PN (nerve involvement): 12.0 per million
- Mixed form (both heart and nerve): 4.7 per million
In terms of prevalence, nearly 60 people per million were living with ATTR amyloidosis in 2022, using the narrow definition. Again, ATTR-CM was the most common form (41.1 cases per million people), followed by ATTR-CM only (31.9 cases per million) and ATTR-PN (15.1 cases per million).
ATTR amyloidosis prevalence was much higher with the broad definition (250.8 cases per million people), suggesting many cases may be missed or coded differently in medical records and insurance claims.
Demographics and the prevalence of mixed symptoms
Most patients were older adults. More than two-thirds were 65 or older, and most were men. An exception was ATTR-PN only, where men and women were affected more equally. Most patients also had other health conditions, known as comorbidities. The proportion of patients with comorbidities was especially high in those with the mixed form of the disease.
In addition, people with ATTR-PN alone accounted for 39.1%-48.6% of the total new cases of ATTR-PN, meaning that most patients had a mixed form. In contrast, most people newly diagnosed with ATTR-CM (85.1%-89.1%) had heart involvement alone.
When the researchers examined trends from 2019 to 2022, they found that both the incidence and prevalence of ATTR amyloidosis increased (by 6.9% and 26.1%, respectively) using the narrow definition. These increases may reflect better awareness, improved testing, and longer survival, rather than a change in risk, the team noted.
The observed rise in the number of new and existing cases of ATTR amyloidosis was mainly driven by an increase in ATTR-CM cases and ATTR-CM-only cases. Still, the number of new cases of ATTR-PN only showed the greatest increase, by 15.6%, followed by ATTR-CM only (13.9%) and ATTR-CM (10.5%) with the narrow definitions.
While the study did not compare hereditary and wild-type ATTR amyloidosis, the findings suggest the disease is overall more common in the U.S. than previously thought, especially the form that affects the heart. This highlights the need for clearer diagnostic coding, which could improve research, diagnosis, and patient care.
“Given the increasing incidence and prevalence of the disease, as well as the [variable] approaches to diagnosis reported in the literature, there is a pressing need for a widely accepted and validated definition of ATTR amyloidosis,” the researchers wrote, “not only to get a better picture of the actual burden, but, more importantly, to facilitate appropriate patient management.”
