Transthyretin amyloid deposits in lumbar spinal stenosis and assessment of signs of systemic amyloidosis

Abstract

Background: Wild-type transthyretin (ATTRwt) amyloidosis is the most common systemic amyloidosis in Western countries and manifests mainly as progressive restrictive cardiomyopathy.

Objective: To study the prevalence of ATTR deposits in ligament tissue in patients undergoing surgery for lumbar spinal stenosis and to assess whether these deposits are associated with cardiac amyloidosis.

Materials and methods: A total of 250 patients, aged 50-89 (57% women), none with known cardiovascular disease, were included. Ligaments were investigated microscopically for amyloid. ATTR type was determined by immunohistochemistry and fibril type by Western blot. The amount of amyloid was graded 0-4. All patients with grade 3-4 ATTR deposits were offered cardiac investigation including ECG, cardiac ultrasound, plasma NT-proBNP and cardiac magnetic resonance (CMR), including modern tissue characterization.

Results: Amyloid was identified in 221 of the samples (88.4%). ATTR appeared in 93 samples (37%) of whom 42 (17 women and 25 men) were graded 3-4; all had fibril type A (mixture of full-length TTR and fragmented TTR). Twenty-nine of 42 patients with grade 3-4 ATTR deposits accepted cardiovascular investigations; none of them had definite signs of cardiac amyloidosis, but five men had a history of carpal tunnel syndrome.

Conclusions: The prevalence of ATTR deposits in ligamentum flavum in patients with lumbar spinal stenosis was high but not associated with manifest ATTR cardiac amyloidosis. However, the findings of fibril type A, the prevalence of previous carpal tunnel syndrome and ATTR amyloid in surrounding adipose and vascular tissue indicate that amyloid deposits in ligamentum flavum may be an early manifestation of systemic ATTR disease.

Keywords: ATTR amyloidosis; Lumbar spinal stenosis; cardiac amyloidosis; magnetic resonance imaging; systemic amyloidosis.

Fig. 1

Visualization of the grading system of transthyretin amyloid deposits: (a), grade 1; (b), grade 2; (c), grade 3; and (d), grade 4. Amyloid deposits labelled with monoclonal antibody 7×. Bar = 50 µm.

Fig. 2

Flow chart.

Fig. 3

All patients with and without transthyretin amyloid deposits in lumbar ligament tissue. The y‐axis represents age.

Fig. 4

Ligament transthyretin amyloid stained with Congo Red, (a) without crossed polars and (b) between crossed polars. The typical birefringence is seen in (b). Bar = 50 µm.

Fig. 5

Ligament tissue double‐stained for amyloid with Congo red and for immunohistochemical detection of transthyretin amyloid (ATTR) by monoclonal antibody 7×. ATTR is stained brown (arrows), but in this case an additional type of amyloid of unknown composition is abundant (A). Bar = 50 µm.

Fig. 6

Adipose tissue in association with ligament tissue, in (a and d) stained with Congo red and examined with partially crossed polars, a method that enhances the red colour. (a) is from a section of ligament tissue, whilst (d) is from fat tissue particle. In panels (b and c), amyloid in adipose tissue from two different patients is visualized immunohistochemically with monoclonal antibody 7×. Brown colour demonstrates the transthyretin amyloid. Bar = 50 µm.

Fig. 7

Western blot analysis of extract of three degree 3 + ATTR ligament materials with the aid of in‐house rabbit antiserum 1898. Typical transthyretin amyloid bands, including fragments, are denoted. The heavy smear at higher molecular weight species is due to aggregates.