Transthyretin-Mediated Amyloidosis: Teasing Out the Diagnosis
—Recognizing musculoskeletal manifestations as potential early clues for transthyretin-mediated amyloidosis may be important for earlier diagnosis and initiation of appropriate management.
Transthyretin-mediated (ATTR) amyloidosis is a multisystem disease caused by the abnormal deposition of misfolded transthyretin protein as amyloid fibrils in various tissues. ATTR amyloidosis presents as 2 main subtypes that share similar clinical features. The hereditary (ATTRv) subtype is linked to mutations in the transthyretin gene, whereas wild-type (ATTRwt) occurs due to age-related changes in the transthyretin protein.1,2 Due in part to symptom overlap with other diseases, diagnosis of ATTR amyloidosis is often delayed until advanced stages, increasing morbidity and decreasing patients’ overall quality of life.
The good news, however, is that earlier detection and treatment of ATTR amyloidosis can mitigate disease progression and improve prognosis. According to a new systematic review published in BMC Musculoskeletal Disorders, musculoskeletal (MSK) manifestations may serve as an early indicator of disease. The data reported by Aldinc and colleagues suggest that MSK changes may be among the earliest signs of ATTR amyloidosis, preceding definitive diagnosis by years.3
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As the authors noted, “This systematic review was conducted to investigate the association between ATTR amyloidosis and MSK manifestations, and to investigate the temporal association between MSK manifestation onset and ATTR amyloidosis diagnosis, in order to potentially aid clinicians in identifying and diagnosing the disease earlier.”3
A systematic review of the literature
Aldinc and colleagues searched Ovid MEDLINE and Embase, with no restriction on the year of publication.3 Inclusion and exclusion criteria were determined using prespecified patient, intervention, comparator, outcome, time, study (PICOTS) criteria and included amyloidosis, ATTR, and MSK manifestations. “PICOTS criteria led to the inclusion of epidemiology, clinical burden and practice, pathophysiology, and temporality of MSK manifestations associated with ATTR amyloidosis,” the authors clarified.3
The search initially identified 7139 publications. Studies excluded from the final analysis were those reporting data only from patients diagnosed with amyloidoses other than those associated with ATTR; those focused only on outcomes related to MSK changes outside of the context of ATTR amyloidosis; and those that didn’t report on both MSK manifestations and ATTR amyloidosis. After applying all exclusion criteria, 164 studies were assessed in the review.
What the investigators discovered
The authors’ analysis found that ATTR amyloidosis can lead to a range of MSK manifestations. Carpal tunnel syndrome (CTS) was most frequently associated with ATTR amyloidosis, and often reported as bilateral, but spinal stenosis (SS) and osteoarthritis (OA) were also identified.3
“Some authors investigated CTS in patients with a confirmed diagnosis of ATTR amyloidosis, whereas other authors investigated the presence of ATTR amyloidosis in patients who had undergone treatment for CTS,” Aldinc and colleagues wrote.3 Consequently, the use of different methodologies prevented direct comparison of the associations among individual MSK manifestations.
Among patients with ATTR amyloidosis of either subtype, ATTRv or ATTRwt, CTS ranged between 0.5% and 80%. In patients with CTS and/or a history of carpal tunnel release (CTR) surgery, ATTR amyloidosis ranged between 0.9% and 38.0%, with a much higher prevalence of ATTRv amyloidosis in patients with a history of CTR surgery (87.5%). Aldinc and colleagues noted that 2 separate studies, which examined the same group of patients with CTS for ATTRv and ATTRwt amyloidoses, revealed that ATTRwt amyloidosis was more prevalent.
Several other significant findings emerge
In patients with any ATTR amyloidosis subtype, the prevalence for SS ranged between 8.4% and 22.0%. Similar to the prevalence of CTS, the range of prevalence of ATTR amyloidosis in patients with SS was broader than the range of SS prevalence in patients with ATTR amyloidosis. In studies investigating the prevalence of both CTS and SS in the same cohort of patients with ATTR amyloidosis, CTS was more prevalent than SS in patients with either subtype.
Aldinc and colleagues also suggested that OA may be more prevalent in patients who underwent surgery. In 3 studies, the presence of amyloid deposits led to a diagnosis of ATTR amyloidosis. For those studies which investigated ATTR amyloidosis in patients with OA, the association between the 2 conditions was confirmed through the staining of hip or knee biopsy samples, a standard method used to identify amyloid. “In patients biopsied during total hip arthroplasty, the prevalence of amyloid deposits in the synovial membrane was 22.0%, leading to a diagnosis of ATTRwt amyloidosis in these patients,” the authors stated. “In patients biopsied during total knee arthroplasty, the prevalence of amyloid deposits ranged from 8.1% to 33.0%.”3
Two database/registry studies—of 29 and 156 patients, respectively—focused on OA in patients with ATTR amyloidosis. In the first study, the prevalence of total hip arthroplasty was 59%, versus 41% for total knee arthroplasty. In the second study, the percentages were 12.8% and 14.1% for each surgery, respectively.
Other MSK manifestations identified included biceps tendon rupture, rotator cuff injury, and trigger finger, but studies reporting on the temporal associations between MSK manifestation onset and a diagnosis of ATTR amyloidosis were limited to CTS, SS, and OA.
Tracking the timing of symptoms
In this systematic review, symptoms of CTS preceded a diagnosis of ATTR amyloidosis by up to 12 years. Time to diagnosis of ATTRv amyloidosis after CTS symptom onset was broader compared to time to diagnosis of ATTRwt amyloidosis (range: 2 to 12 years versus 1.3 to 1.9 years, respectively).
One study reported that SS symptom onset occurred about 2 years before a diagnosis of ATTRv amyloidosis, while another reported a 7.4-year delay before a diagnosis of ATTRwt amyloidosis. In the same cohort of patients with ATTRwt amyloidosis, symptoms of CTS came on even earlier than those associated with SS, preceding the diagnosis of ATTR amyloidosis by 9.5 years.
Only 1 publication reported on the temporal association for OA, noting an average delay of 7.6 years before a diagnosis of ATTR amyloidosis with cardiomyopathy.
The exact length of time that MSK manifestations precede a diagnosis of ATTR amyloidosis is unclear. However, the data that Aldinc and colleagues reported suggest the delay between the time of onset of CTS symptoms to a diagnosis of ATTR amyloidosis is longer for hereditary ATTR amyloidosis compared to wild type.
A few cautionary notes
Despite its multisystem involvement, ATTR amyloidosis often presents with nonspecific symptoms, leading to delayed diagnosis. While the current systematic review supports that MSK changes can be among the earliest signs of the disease, Aldinc and colleagues noted several limitations to their analysis.
“This systematic review is not all-encompassing, and caution should be exercised when drawing conclusions from such a heterogenous evidence base, including many studies reporting on a small number of patients,” the authors stated.3 They also mentioned that the detection of amyloid in MSK tissues alone is not a definitive indicator of an impending diagnosis of ATTR amyloidosis. Additionally, an association between MSK manifestations and ATTR amyloidosis in a review of the literature does not always validate a clinical relationship, as some cases of ATTR amyloidosis may not be caused by early amyloid deposits.
Nonetheless, there’s a “potential benefit of utilizing MSK manifestations associated with ATTR amyloidosis to reduce the delay in diagnosis,” the authors concluded.3 Therefore, recognizing these MSK signs may be crucial for timely diagnosis and treatment initiation, potentially improving patient outcomes.
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