Hereditary transthyretin cardiac amyloidosis with Glu109Lys mutation presenting with low sensitivity to ^99mTc pyrophosphate in scintigraphy: a case description

Introduction

Transthyretin amyloidosis (ATTR) is a rare systemic disease characterized by the extracellular deposition of misfolded transthyretin (TTR) protein. The accumulation of misfolded amyloid deposits in the myocardial interstitium can lead to cardiac amyloidosis (CA), resulting in heart failure and even death (1). Diagnosing ATTR cardiac amyloidosis (ATTR-CA) remains challenging, and bone scintigraphy employed with tracers such as ^99mTc pyrophosphate (^99mTc-PYP) is commonly employed as a noninvasive means to diagnose ATTR-CA (2). In this report, we present a case of hereditary ATTR-CA caused by the TTR gene mutation p.Glu109Lys, which resulted in a mild uptake of ^99mTc-PYP in scintigraphy. This case underscores the importance of myocardial biopsy in patients with a high clinical suspicion of ATTR-CA.

Case presentation

A 51-year-old male was admitted to Peking Union Medical College Hospital with a 10-month history of abdominal pain and reduced exercise tolerance. On admission, his blood pressure was 123/95 mmHg, and the heart rate was 84 bpm. Physical examination revealed diffuse tenderness in the upper abdomen, but there were no signs of jugular venous distension, enlarged cardiac borders on percussion, or sensory abnormalities in the lower extremities. Laboratory examinations showed an elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) level of 4,325 pg/mL and a cardiac troponin I (cTnI) level of 190 pg/mL. Echocardiography indicated biventricular hypertrophy with a left ventricular posterior wall thickness of 16 mm, a right ventricular wall thickness of 7 mm, a septal thickness of 17 mm, and a left ventricular ejection fraction (LVEF) of 59%. However, the electrocardiogram did not show any high-voltage QRS complexes (Figure 1). Cardiac magnetic resonance imaging revealed increased left and right ventricular wall thickness, diffuse biventricular late gadolinium enhancement (LGE), and an increase in extracellular volume of 56% (Figure 2). CA was suspected. Serum and urine protein immunofixation, along with the level of serum-free light chains, was checked and considered normal. Subsequently, ^99mTc-PYP scintigraphy was performed and indicated grade 1 myocardial uptake, with a heart-to-contralateral (H/CL) ratio of 1.13 at 1 hour and 1.11 at 3 hours (Figure 3). Single-photon emission computed tomography (SPECT)-^99mTc-PYP scintigraphy showed mild myocardial uptake, with the radioactivity of the cardiac muscle being equivalent to that of the blood pool (Figure 4). Given the ambiguous scintigraphy findings, a definitive diagnosis of ATTR-CA could not be established, and so an endomyocardial biopsy was performed. Histological examination revealed amorphous, transparent deposits between myocardial fibers, and Congo red staining exhibited typical apple-green birefringence under polarized light microscopy (Figure 5). Mass spectrometry confirmed the presence of TTR in the biopsy tissue (Table 1). Further gene sequencing identified a c.325G>A (p.Glu109Lys) mutation in the TTR gene, leading to a final diagnosis of hereditary ATTR-CA. Following the diagnosis, the patient was treated with tafamidis. At the 6-month follow-up, the patient reported improved exercise tolerance, being able to walk continuously for over 1 hour. His NT-proBNP levels had decreased to 678 pg/mL, and echocardiography showed improvement in biventricular hypertrophy, with the septal thickness reducing to 13 mm.

Figure 1 Echocardiography and electrocardiography findings. (A) Apical four-chamber view from transthoracic echocardiography showed left and right ventricular hypertrophy (indicated by yellow arrows) and interventricular septal thickening (17 mm, indicated by red arrows). The inner diameter of both ventricles was normal. (B) The electrocardiogram showed sinus rhythm with a heart rate of 94 beats/min. No high-voltage QRS complexes were observed.

Figure 2 Cardiac magnetic resonance imaging. The LGE images showed diffuse delayed enhancement of the left and right ventricles (upper panel). The ECV map results indicated an ECV value of 56% (lower panel). ECV, extracellular volume; LGE, late gadolinium enhancement.

Figure 3 Planar-^99mTc pyrophosphate scintigraphy. The visual scoring of myocardial uptake indicated grade 1. The heart-to-contralateral ratios were 1.13 at 1 hour and 1.11 at 3 hours.

Figure 4 SPECT-^99mTc pyrophosphate scintigraphy showed no clear diffuse increased radioactive uptake in the myocardium. SPECT, single-photon emission computed tomography.

Figure 5 Congo red staining results of the biopsy myocardium. (A) Light microscopy revealed bright red amyloid material. (B) Polarized light microscopy displayed classic apple-green birefringence. Magnification: 150×.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for publication of this article and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

The two most common forms of CA are ATTR-CA and light-chain CA (AL-CA). Both are characterized by unexplained left ventricular hypertrophy (≥12 mm) with low or mismatched QRS voltage on electrocardiography (ECG) (3). Most patients also present with persistently elevated blood cTnI and natriuretic peptide levels. Some patients may present with polyneuropathy, manifesting as peripheral sensorimotor neuropathy, or symptoms of autonomic dysfunction such as abdominal pain, constipation, orthostatic hypotension, and urinary incontinence (4). For patients meeting these clinical criteria, a negative monoclonal immunoglobulin test strongly suggests ATTR-CA (5).

Patients with ATTR-CA have a poor prognosis and, if not treated promptly, can experience severe complications such as heart failure and arrhythmia. Once ATTR-CA is confirmed, treatment should be initiated as early as possible. The management of ATTR-CA includes supportive care and disease-modifying therapies, with commonly used drugs including TTR stabilizers, such as tafamidis, and small interfering RNA drugs, such as patisiran. However, even with aggressive treatment, patients with advanced ATTR-CA still face high rates of hospitalization and mortality. Early diagnosis and timely intervention are crucial for improving outcomes in these patients (6).

Traditionally, myocardial biopsy was required to confirm ATTR-CA (7). The discovery of ^99mTc-labeled phosphate derivatives, which bind tightly to TTR in cardiac tissue, enabled noninvasive diagnosis (8). Grade 2 or 3 myocardial uptake on ^99mTc-PYP scintigraphy is now widely accepted as a diagnostic standard (9,10). This method has a sensitivity exceeding 99% and a specificity of 86%, although false positives can occur in AL-CA (11). When this measure is combined with the absence of monoclonal proteins in serum or urine, the specificity and positive predictive value for the ATTR-CA approach 100% (2).

However, certain TTR mutations may cause false negatives in bone scintigraphy, reducing its sensitivity for hereditary ATTR-CA. For example, Phe64Leu-related hereditary ATTR-CA has a sensitivity of only 10.5% in ^99mTc-diphosphonate or ^99mTc-hydroxyl-methylene-diphosphonate bone scintigraphy (12). Other mutations associated with reduced sensitivity include Glu112Lys, Val30Met, Glu54Leu, Ala45Ser, His88Arg, Ala97Ser, Tyr60Ala, Ala45Gly, and Val122Ile (13,14). One hypothesis suggests that the reduced sensitivity may be related to amyloid fibril structure. The majority of patients with ATTR-CA may exhibit type A fibrils, comprising both full-length TTR and C-terminal fragments. In contrast, certain mutations, such as early-onset Val30Met, produce type B fibrils composed solely of full-length TTR, which may reduce tracer binding affinity (14,15). However, an alternative hypothesis proposes that the binding of bone scintigraphy tracers, such as ^99mTc-PYP, to amyloid proteins in patients with ATTR-CA may be associated with the presence of microcalcifications within TTR fibrils, suggesting that differences in tracer sensitivity cannot be fully explained by fibril structure alone. For instance, wild-type ATTR, Tyr60Ala, and Val122Ile, despite sharing identical fibril structures, demonstrate varying degrees of tracer uptake. Further research is necessary to fully elucidate the underlying mechanisms influencing the sensitivity of bone scintigraphy in ATTR-CA. As false negatives may occur in bone scintigraphy, the consensus guidelines recommend endomyocardial biopsy in cases of high clinical suspicion despite negative scintigraphy results (16).

It is worth noting that a significant proportion of patients with ATTR-CA present with polyneuropathy. The identification of neurological alterations represents a pivotal aspect of the comprehensive management strategy for ATTR. In patients with hereditary ATTR associated with the Phe64Leu mutation, prominent neurological involvement is frequently observed despite the limited sensitivity of bone scintigraphy in these cases. Neurological evaluation, particularly in cases where the scintigraphy results are inconclusive, is essential for timely diagnosis and ultimately improving clinical outcomes (12,17).

Conclusions

This is the first report of a patient with ATTR-CA and a Glu109Lys mutation who also had low myocardial uptake on ^99mTc-PYP scintigraphy, even with obvious ventricular hypertrophy. In such patients, endomyocardial biopsy is ultimately required to arrive at a definitive diagnosis if there is strong clinical suspicion of ATTR-CA but a lack or low grade of myocardial uptake of technetium-labeled radiotracers.

Acknowledgments

None.

Footnote

Funding: This work was supported by the National High Level Hospital Clinical Research Funding (No. 2022-PUMCH-D-002 to Z.T.) and the Xiong’an New Area Science and Technology Innovation Special Project (No. 2023XAGG0069 to Z.T.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2024-2928/coif). Z.T. received funding support from the National High Level Hospital Clinical Research Funding (No. 2022-PUMCH-D-002) and the Xiong’an New Area Science and Technology Innovation Special Project (No. 2023XAGG0069). The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional research committee and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for publication of this article and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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