Systemic amyloidosis is a group of diseases characterized by the deposition of amyloid fibrils in the extracellular space due to the misfolding of precursor proteins. These deposits impair organ function either through mechanical disruption or direct toxic effects on cells [1]. The accumulation of amyloid proteins can lead to multi-organ dysfunction, with the heart and kidneys being the most commonly affected organs across all types of amyloidosis. In particular, the expansion of the extracellular space in the heart ultimately results in restrictive cardiomyopathy. Cardiac involvement is a key determinant of prognosis, often leading to adverse outcomes [2, 3]. Early diagnosis is crucial as delayed treatment can result in severe adverse consequences. To date, 42 amyloid fibril proteins have been identified, of which 14 appear exclusively as systemic deposits, 24 are seen only in local amyloid deposits, and 4 can appear as both types. The two most common forms of systemic amyloidosis are transthyretin amyloidosis (ATTR) and light chain amyloidosis (AL) [3, 4]. The presence of amyloid proteins is typically confirmed by biopsy of affected organs or tissue samples containing amyloid deposits. Currently, subcutaneous fat tissue biopsy is widely used in clinical practice due to its minimal invasiveness and ease of operation, and these tissue samples can also be used for biochemical typing of amyloid proteins [5]. However, biopsies have notable limitations, including relatively high invasiveness, high technical demand on operators, and the potential for serious complications. Additionally, biopsies can only assess amyloid deposits in limited areas of local organs [6].

The focus has always been on cardiac imaging examinations, as death in patients with heart involvement is the primary cause. Non-invasive imaging plays a key role in the diagnosis of cardiac amyloidosis (CA). Echocardiography and cardiac magnetic resonance imaging (MRI) can detect structural changes and functional impairments in the heart caused by amyloidosis [7]. Additionally, serological markers such as cardiac troponin and N-terminal pro-B-type natriuretic peptide (NT-proBNP), have certain significance in the diagnosis of amyloidosis [8]. At present, the most widely recognized molecular imaging technique for diagnosing ATTR-CA is scintigraphy using ^99mTc-labeled bone-seeking tracers that are derivatives of bisphosphonates, namely ^99mTc pyrophosphate (PYP), ^99mTc 3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) [9], and ^99mTc hydroxymethylene diphosphonate (HMDP) [10]. However, these methods have corresponding limitations and can only evaluate amyloid deposits in a single organ. Nonetheless, the disease burden of amyloidosis is systemic. Therefore, whole-body amyloid imaging has emerged as a new, visual, noninvasive approach to assess systemic amyloidosis. ¹²³I-labeled serum amyloid P component (SAP) scintigraphy can detect amyloid deposits in visceral organs but is unreliable for detecting cardiac involvement and is available in only a few centers globally [11]. Based on alterations in regional calcium homeostasis, sodium fluoride (NaF)-positron emission tomography (PET)/computed tomography (CT) may serve as a feasible non-invasive approach for differentiating between ATTR and AL amyloidosis [12].

With advancements in other radiotracers, tracers for diagnosing Alzheimer’s disease such as ¹¹C-Pittsburgh Compound-B (¹¹C-PIB) [6, 13, 14], ¹⁸F-Florbetapir [15, 16, 17, 18, 19], and ¹⁸F-Florbetaben [20] have been applied to detect systemic amyloid deposits, making whole-body imaging of amyloidosis increasingly feasible. These tracers can detect and assess amyloid deposits in most organs, especially the heart. ¹²⁴I-Evuzamitide (¹²⁴I-labeled peptide p5+14) [21] also offers an opportunity for noninvasive detection of systemic amyloidosis through PET imaging.

Based on the existing literature, this meta-analysis aims to conduct a comprehensive review of current research on the use of PET imaging techniques in detecting organ involvement in systemic amyloidosis, with a particular focus on the diagnostic performance of cardiac involvement. This will provide further evidence to support future clinical applications and help optimize early diagnosis and management of amyloidosis patients.

This study, through a meta-analysis of published literature, found that PET imaging has high diagnostic value in detecting amyloid deposition in various organs affected by systemic amyloidosis, particularly in the detection of cardiac involvement, showing high sensitivity and good predictive ability.

In the 10 studies included, PET demonstrated statistically significant results in detecting amyloid deposition in multiple organs, including the bone marrow, CNS, heart, lungs, muscles, pancreas, salivary glands, spleen, thyroid, and tongue. Compared to traditional clinical diagnostic methods, PET showed higher detection rates for organ involvement. This provides strong support for the widespread use of PET in the evaluation of systemic amyloidosis.

PET imaging is particularly advantageous in assessing cardiac, pulmonary, splenic, bone marrow, glandular, and soft tissue involvement, while it has certain limitations in evaluating the peripheral nervous system and kidneys. The kidney, as one of the most commonly affected organs with 50% to 80% of systemic amyloidosis patients exhibiting renal involvement [22], often presents as nephrotic syndrome [23, 24], and in severe cases, can progress to end-stage kidney disease (ESKD), requiring renal replacement therapies such as dialysis or kidney transplantation [25]. However, PET imaging is less effective in detecting kidney involvement. This limitation may be due to the high metabolic activity of the kidneys as excretory organs, which could obscure the pathological changes caused by amyloidosis, thereby affecting PET’s sensitivity in detecting renal involvement.

Cardiac involvement is one of the most critical prognostic factors in patients with systemic amyloidosis [26], with approximately 61% of these patients dying from CA [27]. The seven studies included in this meta-analysis regarding cardiac involvement indicated that PET has high sensitivity (0.98) and moderate specificity (0.61) in diagnosing CA, with an AUC of 0.8954. These findings suggest that PET has significant potential in screening for CA. Specifically, ¹²⁴I-Evuzamitide exhibited high sensitivity (0.98), while ¹¹C-PIB showed high specificity (0.84). These results indicate that different radiotracers have varying performances in detecting CA, and clinicians can choose the best tracer based on specific circumstances. ¹¹C-PIB, a derivative of the amyloid-binding dye thioflavin-T, binds to $\beta$-amyloid plaques, allowing clear visualization of amyloid deposition in the brain on PET scans. It is believed to bind with various types of amyloid fibrils, making it highly promising for imaging organ involvement in systemic amyloidosis [28]. However, the short half-life of ¹¹C (20 minutes) limits its practical use in routine clinical applications [29]. In contrast, ¹⁸F-labeled amyloid PET radiotracers, such as ¹⁸F-Florbetapir, have longer half-lives and offer significant clinical advantages. A study by Clerc et al. [30] evaluated the prognostic value of ¹⁸F-Florbetapir PET imaging quantifying left ventricular amyloid load in systemic light chain amyloidosis. They found that left ventricular amyloid burden was closely associated with the occurrence of major adverse cardiac events, further emphasizing the potential of ¹⁸F-Florbetapir in assessing patient prognosis. Additionally, ¹²⁴I-Evuzamitide, a novel broad-spectrum amyloid radiotracer, has also shown substantial potential in imaging CA. Research has shown that ¹²⁴I-Evuzamitide can accurately differentiate CA from controls, with performance similar to ¹⁸F-Florbetapir in AL-CA and possibly more advantageous in wild-type transthyretin CA. Moreover, ¹²⁴I-Evuzamitide correlates strongly with cardiac structural and functional indices, further confirming its potential in detecting and quantifying cardiac amyloid deposits [31]. CA often presents as restrictive cardiomyopathy, and its early symptoms are subtle, often going unnoticed. As a non-invasive imaging technique, PET can detect cardiac involvement through whole-body scans, which is crucial for early diagnosis and the formulation of personalized treatment plans.

In subgroup analysis, we compared the effectiveness of PET in detecting cardiac involvement in AL and ATTR amyloidosis patients. The results showed that the RR in AL patients was significantly higher than in ATTR patients (p = 0.004), indicating that PET is more sensitive in diagnosing cardiac involvement in AL amyloidosis. This difference may be related to the heterogeneity of amyloid deposition in AL and ATTR types and their differing invasiveness in the heart. Despite the statistical significance of the subgroup analysis, there was considerable heterogeneity in the data (I² = 95.2%), suggesting that results varied widely across studies. Therefore, further research is needed to explore the differences in PET diagnostic performance between different subtypes of amyloidosis.

Previous studies have conducted meta-analyses to assess the diagnostic accuracy of detecting CA. A meta-analysis of six studies involving bone scintigraphy in ATTR-CA patients (529 patients) showed high sensitivity (92.2%, 95% CI = (89%, 95%)) and specificity (95.4%, 95% CI = (77%, 99%)), with an LR+ of 7.02 (95% CI = (3.42, 14.4)), an LR– of 0.09 (95% CI = (0.06, 0.14)), and a DOR of 81.6 (95% CI = (44, 153)) [32]. Kim et al. [33] conducted a meta-analysis of six PET imaging studies for CA (98 patients) and found a pooled sensitivity of 0.95, specificity of 0.98, LR+ of 10.130, LR– of 0.1, and DOR of 148.83. Additionally, semi-quantitative parameters of amyloid proteins in PET imaging demonstrated a diagnostic advantage for AL amyloidosis over ATTR amyloidosis. Another meta-analysis of 13 studies (90 patients) showed a pooled sensitivity of 0.97 and specificity of 0.98 for amyloid PET. The pooled sensitivity of F-18 labeled NaF PET was 0.63, with specificity of 1.00. Combining amyloid PET with F-18 labeled NaF PET showed a sensitivity of 0.88 and specificity of 0.98 [34]. A meta-analysis of non-invasive myocardial imaging for CA, including cardiac magnetic resonance (CMR), single photon emission computed tomography (SPECT), and PET, reported sensitivities of 0.84, 0.98, and 0.78, respectively, with specificities of 0.87, 0.92, and 0.95. SPECT demonstrated better diagnostic performance than the other two techniques in detecting CA [35].

Although this meta-analysis comprehensively assessed the diagnostic performance of PET in systemic amyloidosis, several limitations remain. First, the number of studies included was relatively small (only 10 studies), and many had small sample sizes, which may affect the robustness and external validity of the results. Second, the use of different radiotracers and the heterogeneity of amyloidosis subtypes increased the complexity of interpreting the results. High statistical heterogeneity in some pooled estimates introduces uncertainty and warrants cautious interpretation of these results. Therefore, future high-quality, large-scale prospective studies are needed to further validate the diagnostic efficacy of PET in different subtypes of systemic amyloidosis. While PET can detect amyloid deposits in multiple organs, how to integrate it with other imaging modalities (such as echocardiography, MRI, etc.) and biomarkers to form a more accurate diagnostic strategy remains an unresolved issue in clinical practice.

In conclusion, PET imaging has significant clinical value in diagnosing systemic amyloidosis, particularly in the early detection of cardiac involvement. By using different radiotracers, PET provides a more comprehensive and accurate whole-body evaluation for patients with amyloidosis, helping clinicians make more informed diagnostic and treatment decisions in the early stages of the disease. With the continuous emergence of novel radiotracers and the advancement of high-quality studies, the clinical applications of PET in systemic amyloidosis are expected to become even more promising.

ATTR, transthyretin amyloidosis; AL, light chain amyloidosis; CA, cardiac amyloidosis; MRI, magnetic resonance imaging; NT-proBNP, N-terminal pro-B-type natriuretic peptide; PYP, pyrophosphate; DPD, 3,3-diphospho-1,2-propanodicarboxylic acid; HMDP, hydroxymethylene diphosphonate; SAP, serum amyloid P component; PET, positron emission tomography; ¹¹C-PIB, ¹¹C-Pittsburgh Compound-B; QUADAS-2, Quality Assessment of Diagnostic Accuracy Studies; RR, relative risk; LR+, positive likelihood ratio; LR–, negative likelihood ratio; DOR, diagnostic odds ratio; CIs, confidence intervals; SROC, summary receiver operating characteristic; AUC, area under the curve; I², I-squared; CNS, central nervous system; ESKD, end-stage kidney disease; NaF, sodium fluoride; SPECT, single photon emission computed tomography.

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

TZ was responsible for data analysis, data curation, and writing the original draft. LX was responsible for manuscript review and supervision. HP was responsible for supervision and administrative support. All authors contributed to the conception and editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

Not applicable.

This work was supported by grants from the 2024 Graduate Teaching Reform Project: Integration of Radiopharmaceutical Diagnosis and Therapy Based on Novel Molecular Targeting Probes, Graduate Supervisor Team (CYYY-DSTDXM-202420).

The authors declare no conflict of interest.

Supplementary material associated with this article can be found, in the online version, at https://doi.org/10.31083/RCM37731.