Ligamentous Changes as a Harbinger of Cardiac Amyloidosis – Histopathological and Clinical Study

Hypertrophy of Connective Tissue Compresses Passing Nerves

In lumbar spinal stenosis (LSS), there is a narrowing of the spinal canal or vertebral root canal in the lumbar section of the spine, leading to compression of the cauda equina spinal nerves. The pathology is either congenital or arises from changes in bones, joint connections, and connective tissue. LSS does not include narrowing caused by herniated intervertebral discs. LSS affects both sexes, and the prevalence increases with age, with clinical issues most often starting after the age of 60.

A common finding in LSS is thickening of the ligamentum flavum. Due to ligament hypertrophy, similar nerve compression occurs in carpal tunnel syndrome. Typical ligamentous changes in this diagnosis can be associated with local deposition of amyloid. It has recently been shown that carpal tunnel syndrome precedes other symptoms of systemic transthyretin amyloidosis (ATTR) by several years. ATTR is one of the most common systemic amyloidoses in developed countries and causes progressive restrictive cardiomyopathy.

Amyloid deposits have also been identified in the ligamentum flavum. Experts from Uppsala, Sweden, therefore, attempted in their study to detect the occurrence of deposits formed by transthyretin (TTR) in patients undergoing surgery for LSS. Additionally, the doctors wanted to know if these patients already had any signs of cardiac involvement.

Clinical Study

The study included 250 patients aged 50‒89 years. Women made up 57% of the study population. None of the participants had significant cardiovascular disease at the time of the study entry - surgery was performed only on patients falling into class 1‒2 according to the ASA (American Society of Anesthesiologists) classification.

The excised ligament tissue was histologically examined for the presence of amyloid, the type of protein was determined immunohistochemically and using molecular biology methods. The amount of amyloid in the examined sample was evaluated on a scale of 0‒4. Patients with a high amount of deposits in the ligament tissue (value 3‒4) were invited for a cardiological examination: echocardiography, cardiac magnetic resonance imaging (CMR), and determination of plasma NT-proBNP (N-terminal pro-brain natriuretic peptide) concentration. EKG records taken during pre-operative examinations or post-operative care were also analyzed.

Histopathological Examination of Tissues

Amyloid deposits were identified in 88.4% of the samples. Of these, TTR deposits accounted for 37.2% of the samples (93 patients) and high amounts of these deposits were found in 42 patients, significantly more often in men (17 women and 25 men; p < 0.03). The finding was significantly more frequent in the 7th-decade age group compared to younger patients in both genders (p < 0.0001 for comparison in women; p < 0.002 for comparison in men).

Most samples showed a typical birefringence after staining with Congo red. In several cases, the dye's affinity to the structure was weak. Other types of amyloid deposits were also evidently present in the preparations, as sites were identified that stained with Congo red but did not stain with the antibody against TTR amyloid. The presence of TTR deposits was also detected in the fat tissue and blood vessels present in the excised tissue samples. In all patients, the character of the identified amyloid fibrils corresponded to type A, a mixture of fragmented protein and full-length protein.

Clinical Examination of Patients

Twenty-nine out of 42 patients with a high number of TTR deposits came for detailed cardiological examination. All underwent echocardiography, 26 underwent magnetic resonance imaging, and NT-proBNP levels were measured in 28 patients.

Sonography showed septal thickness ≥ 12 mm in 11 patients, and CMR identified small localized areas of late gadolinium enhancement in 6 patients (only in men). Plasma NT-proBNP concentration > 125 ng/l was found in 13 patients. However, no clear signs of cardiac amyloidosis were found in any of the examined participants. Abnormal EKG was described in 7 people, more often in men. The amount of TTR deposits did not correlate with EKG abnormalities.

Five men from the group of patients with a high number of TTR deposits had a surgical history of carpal tunnel syndrome intervention, with 4 of them having bilateral involvement.

Conclusion

The prevalence of TTR amyloid deposits in the ligamentum flavum was high in patients undergoing surgery for LSS. However, it was not associated with manifest cardiac ATTR.

It is possible that the occurrence of amyloid deposits in connective tissue may be one of the early manifestations of systemic amyloidosis. This can be inferred from the presence of TTR deposits in other structures in the examined samples (fat tissue, blood vessel wall), a positive history of carpal tunnel syndrome, which is demonstrably associated with systemic amyloidoses, and the presence of type A TTR amyloid fibrils.

Although the presented study did not aim to determine this, it would be very interesting to follow up long-term on whether cardiomyopathy based on ATTR develops in its participants in the future.

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Sources:
1. Adamová B., Voháňka S., Bednařík J. Lumbar Spinal Stenosis – Clinical Picture, Diagnosis, Treatment. Neurology for Practice 2002; 1: 17‒20.
2. Eldhagen P., Berg S., Lund L. H. et al. Transthyretin Amyloid Deposits in Lumbar Spinal Stenosis and Assessment of Signs of Systemic Amyloidosis. J Intern Med 2021; 289 (6): 895‒905, doi: 10.1111/joim.13222.