Musculoskeletal Manifestations of Transthyretin Cardiac Amyloidosis

Syed Bukhari

doi:10.37871/jbres1789

ISSN: 2766-2276

Medicine Group . 2023 August 19;4(8):1233-1235. doi: 10.37871/jbres1789.

Subject area(s)

Cardiovascular Diseases

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Mini Review

Musculoskeletal Manifestations of Transthyretin Cardiac Amyloidosis

Syed Bukhari*

Department of Medicine, Temple University Hospital, Jeanes Campus, USA

*Corresponding author: Syed Bukhari, Department of Medicine, Temple University Hospital, Jeanes Campus, USA E-mail:

Received: 09 August 2023 | Accepted: 17 August 2023 | Published: 19 August 2023

How to cite this article: Bukhari S. Musculoskeletal Manifestations of Transthyretin Cardiac Amyloidosis. 2023 Aug 19; 4(8): 1233-1235. doi: 10.37871/jbres1757, Article ID: jbres1757

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Abstract

Transthyretin Cardiac Amyloidosis (ATTR-CA) is caused by the deposition of misfolded transthyretin fibrils, leading to restrictive cardiomyopathy and eventually death if untreated. ATTR-CA is associated with certain musculoskeletal conditions, notably carpal tunnel syndrome, lumbar spinal stenosis, nontraumatic biceps tendon rupture, trigger finger and hip, knee and shoulder arthropathies. These musculoskeletal manifestations could provide a clue and potentially help in the timely diagnosis of ATTR-CA.

Introduction

Transthyretin amyloidosis results from the misfolding of transthyretin tetramer, which is a carrier protein formed in the liver, and transports retinol binding protein and thyroxine in the blood [1,2]. This misfolding results in the formation of amyloid fibrils, which are insoluble proteins that deposit in multiple organs, leading to organ dysfunction [3,4]. Deposition in the heart is known as Transthyretin Cardiac Amyloidosis (ATTR-CA), which causes stiffening of the heart, restrictive cardiomyopathy and eventually death if untreated. ATTR-CA is often preceded by deposition of amyloid fibrils in the musculoskeletal tissue [5]. These musculoskeletal manifestations include carpal tunnel syndrome, lumbar spinal stenosis, nontraumatic biceps tendon rupture, trigger finger and hip, knee and shoulder arthropathies [6-9]. In this minireview, we will briefly discuss each of these manifestations and review the existing literature.

Carpal Tunnel Syndrome

Carpal tunnel syndrome is the most common musculoskeletal manifestation of ATTR-CA [10]. Studies have found ATTR-CA prevalence of 8.3% in a population of age and gender-selected patients with a recent history of carpal tunnel syndrome [11]. Carpal tunnel syndrome usually precedes ATTR-CA by several years. In a study of 538 subjects (166 hereditary ATTR-CA, 107 wild-type ATTR-CA, 196 light chain amyloidosis; 64% male, median age 62.4 years), the adjusted prevalence of carpal tunnel syndrome was higher among elderly men with ATTR-CA compared with the general population [12]. CTS was a prognostic marker in ATTR-CA, independently of cardiac involvement, and preceded CA diagnosis by 5-9 years [12]. In a prospective, cross-sectional, multidisciplinary study of consecutive men age ≥50 years and women ≥60 years undergoing carpal tunnel release surgery, Congo red staining of tenosynovial tissue detected amyloid deposits in 10.2% of patients [13]. Concomitant cardiac evaluation identified patients with involvement of the myocardium, allowing for implementation of disease-modifying therapy. Hence, the awareness of association of carpal tunnel syndrome with ATTR-CA and the time delay offers an avenue for research into early pre-clinical ATTR-CA diagnosis.

Lumbar Spinal Stenosis

Lumbar spinal stenosis is another important association, and is a common occurrence in patients with ATTR-CA [10]. In a study comprising 250 patients to investigate the prevalence of ATTR deposits in ligament tissue in patients undergoing surgery for lumbar spinal stenosis, ATTR appeared in 93 samples (37%) [14]. Importantly, while the prevalence of ATTR deposits in ligamentum flavum in patients with lumbar spinal stenosis was high, it was not associated with manifest ATTR-CA, indicating that amyloid deposits in ligamentum flavum may be an early manifestation of systemic ATTR disease. In another prospective study of 47 patients undergoing clinically indicated lumbar spinal decompression, amyloid was detected in more than a third of older adults, and was more common with advancing age particularly those >75 years old [15]. There was no demographic, clinical, biochemical, or cardiac parameter that differentiated those with and without amyloid.

Spontaneous Biceps Tendon Rupture

Spontaneous biceps tendon rupture is particularly associated with ATTR-CA. In a study of 111 patients with ATTR-CA (mean age, 74.9 years; women, 3), spontaneous biceps tendon rupture was observed in 37 patients (33.3% [95% CI, 24.7-42.9]), occurring in the dominant arm in 35 patients (95% [95% CI, 82-99]) and bilaterally in 9 patients (24.3% [95% CI, 11.8-41.2]) [16]). Hence, presence spontaneous biceps rupture in a patient with congestive heart failure may raise suspicion for ATTR-CA, and potentially trigger further diagnostic workup.

Trigger Finger

Trigger finger is another commonly observed orthopedic manifestation in ATTR-CA and involves the same tendon sheath as carpal tunnel syndrome. Many case reports have shown the association of trigger finger with ATTR-CA [17]. In a prospective cross-sectional study enrolling 100 patients aged ≥50 years at the time of surgery for idiopathic trigger finger, only 2 out of 100 patients (mean age 65.5 ± 8.1 years) demonstrated amyloid deposits on Congo red staining; neither patient had cardiac involvement [18]. The authors concluded that this observation has important implications for the development of diagnostic algorithms to screen patients for amyloidosis during orthopedic operations.

Joint Arthropathies

Hip, knee and shoulder arthritis are more common in ATTR-CA than in general population. ATTR-CA patients are five times more likely to undergo total hip arthroplasty than the general population [19]. In a study of 313 patients with CA, compared to the general population, both Total Hip Arthroplasty (THA) and Total Knee Arthroplasty (TKA) were significantly more common among patients with ATTR-CA (THA: RR 5.61, 95% CI 2.25-4.64; TKA: RR 3.32, 95% CI 2.25-4.64). On average, arthroplasty occurred 7.2 years before ATTR-CA diagnosis. A systematic review demonstrated the presence of amyloid deposition detected at the time of common orthopedic surgeries, most commonly in patients ≥70 years old [20]. It further suggested that orthopedic surgeons may consider the potential need for amyloid biopsy in patients with other concomitant orthopedic manifestations including carpal tunnel syndrome, trigger finger and/or spontaneous biceps tendon rupture.

Conclusion

ATTR-CA is associated with musculoskeletal manifestations, notably carpal tunnel syndrome, lumbar spinal stenosis, nontraumatic biceps tendon rupture, trigger finger and hip, knee and shoulder arthropathies. These manifestations could provide clues for the presence of amyloid cardiomyopathy, and may be helpful in the early detection of ATTR-CA.