Diagnostic Sensitivity of Abdominal Fat Aspiration Biopsy for Cardiac Amyloidosis: A Systematic Review and Meta-Analysis

Abstract

Introduction. Cardiac amyloidosis is a lethal disease, the incidence of which is increasing every year. Early diagnosis and treatment are the keys to reducing the mortality of this disease. Methods. Relevant English literature published in Embase, PubMed, Cochrane Library, and Web of Science were searched until December 1, 2022. Meta-analysis was performed with Stata 17.0 software. Results. A total of 1060 patients with 5 articles were included in this study. The sensitivity of abdominal fat aspiration biopsy for the diagnosis of cardiac amyloidosis was 0.66 (0.48–0.84) and the sensitivity for light chain amyloidosis cardiomyopathy and transthyretin amyloidosis cardiomyopathy was 0.90 (0.80–0.97) and 0.39 (0.18–0.60), respectively. Conclusion. Abdominal fat aspiration biopsy has high sensitivity and clinical value in the diagnosis of light chain amyloidosis cardiomyopathy, whereas there are limitations in the diagnosis of transthyretin amyloidosis cardiomyopathy.

Keywords

abdominal fat aspiration biopsy cardiac amyloidosis

Introduction

Amyloidosis is the formation of amyloid fibrils of misfolded proteins in beta-folded sheet structures that are deposited in multiple organs throughout the body, resulting in organ dysfunction. Cardiac amyloidosis (CA) is caused by the infiltration of amyloidogenic proteins into the interstitium of the heart, resulting in myocardial sclerosis and progressive cardiac dysfunction.^1–3 The classification of CA is based on the type of precursor protein,⁴ of which the two most common types are immunoglobulin light chain amyloidosis cardiomyopathy (AL) and transthyretin amyloidosis cardiomyopathy (ATTR). The latter is further divided into mutant ATTR (mATTR) and wild-type ATTR (ATTRwt).^1,2,5,6 CA is a lethal disease, the incidence of which is increasing every year, and this disease is often easily misdiagnosed as other heart diseases.⁷ Early diagnosis and treatment are the keys to reducing the mortality of this disease.⁸

Currently, the gold standard for the diagnosis of CA still relies on endomyocardial biopsy (EMB). However, an EMB is an invasive procedure that may lead to serious acute complications, in addition to many absolute and relative contraindications.⁹ CA is a systemic disease with many options for biopsy sites. Among them, abdominal fat aspiration biopsy has several unique advantages, such as minimally invasive, lower cost, and lower risk of complications.¹⁰ In general, abdominal fat aspiration biopsy was performed by a cytopathologist on the abdominal wall fat pad using a 22-gauge, 1.5-inch needle, which is the most commonly employed method for the detection of amyloid deposits.¹¹ Meanwhile, an increasing number of institutions are attempting to isolate amyloid from abdominal subcutaneous fat aspirates, which can then be used for the diagnosis of CA.

In the last 2 decades, the sensitivity of abdominal fat aspiration biopsy for the diagnosis of amyloidosis has been confirmed by many studies.¹² However, a high sensitivity of abdominal fat aspiration biopsy for the diagnosis of AL was reported, but for ATTR, the diagnostic sensitivity varied widely between articles.^12–15 What's more, the accuracy and completeness of the findings of some of these studies are limited by the insufficient number of patients included. In addition, until December 1, 2022, there is no systematic review summarizing the diagnostic sensitivity of abdominal fat aspiration biopsy for CA. We performed a systematic clinical review of the available literature to assess the diagnostic value of abdominal fat aspiration biopsy for CA and to summarize its sensitivity for the diagnosis of AL and ATTR, respectively.

Materials and Methods

Search Methods

A search was conducted on the following English databases: Embase (2000–December 2022), PubMed (2000–December 2022), Cochrane Library (2000–December 2022), and Web of Science (2000–December 2022). The search terms incorporated the following: (((((“Abdominal Fat”[Mesh]) OR (((((Abdominal Fats) OR (Fats, Abdominal)) OR (Fat, Abdominal)) OR (Abdominal Adipose Tissue)) OR (Adipose Tissue, Abdominal))) AND (“Biopsy, Needle”[Mesh])) OR (((((((((((Biopsies, Needle) OR (Needle Biopsies)) OR (Needle Biopsy)) OR (Aspiration Biopsy)) OR (Aspiration Biopsies)) OR (Biopsies, Aspiration)) OR (Biopsy, Aspiration)) OR (Puncture Biopsy)) OR (Biopsies, Puncture)) OR (Biopsy, Puncture)) OR (Puncture Biopsies))) AND ((cardiac) OR (cardiomyopathy))) AND (((((amyloid) OR (amyloidosis)) OR (AL)) OR (ATTR)) OR (TTR)). To expand the search results, we reviewed all references in the included articles.

Eligibility Criteria

Eligibility criteria were described according to the PICOS principles (population, intervention, comparators, outcomes, and study design). The inclusion criteria were as follows: (a) patients accepted the biopsy with CA, regardless of age, race, and gender; (b) diagnosis is made by abdominal fat aspiration biopsy; (c) endpoint indicators are diagnostic sensitivity; and (d) The design is a clinical trial and relevant data are available. The exclusion criteria were as follows: (a) animal and in vitro experiments, basic research; (b) conference abstracts, overviews, reviews, and case reports; (c) literature on diagnosis using abdominal lipectomy biopsy, abdominal skin biopsy, and so on, and (d) literature for which valid data cannot be extracted.

Study Selection and Data Extraction

The data extraction was independently performed, in duplicate, by two investigators, ensuring the accuracy of the data extracted. Any differences of opinion are resolved through joint discussion by the third investigator. An Excel-based, standardized data collection form was used to extract the information: study title, first author, year of publication, country/countries where the study was conducted, study population, number of cases, the subtype of CA, histopathological techniques, and sensitivity.

Study Registration

A predefined review protocol was registered at the PROSPERO international prospective registry of systematic reviews under registration number CRD42023390162.

Quality Assessment

We used the Agency for Healthcare Research and Quality (AHRQ) assessment scale to evaluate the quality of the included studies.¹⁶ Two reviewers assessed the quality of eligible studies independently. The AHRQ quality assessment tool involved 11 aspects: define the source of information, list inclusion and exclusion criteria for exposed and unexposed subjects or refer to previous publications, indicate the period used for identifying patients, indicate whether or not subjects were consecutive if not population-based, indicate if evaluators of subjective components of the study were masked to other aspects of the status of the participants, describe any assessments undertaken for quality assurance purposes, explain any patient exclusions from analysis, describe how confounding was assessed and/or controlled, if applicable, explain how missing data were handled in the analysis, summarize patient response rates and completeness of data collection, clarify what follow-up, if any, was expected and the percentage of patients for which incomplete data or follow-up was obtained.

Statistical Analysis

We used STATA 17.0 data analysis software to perform the meta-analysis. The effective size of the results was expressed as a 95% confidence interval (CI) containing the upper and lower limits. Heterogeneity was tested using the homogeneity test (Q test). P ≥ .10 and I² ≤ 50% were considered homogeneous, and the fixed effect model was selected; conversely, heterogeneity was suggested, and the random effect model was used. A subgroup analysis was performed for factors that may contribute to heterogeneity (type of CA). The Egger test was performed to determine the magnitude of publication bias. A difference was considered statistically significant at P < .05.

Results

Studies Characteristics and Quality Assessment

The study selection process was carried out using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline (Figure 1). Of 115 citations retrieved, 5 articles qualified for inclusion in this meta-analysis with a total of 1060 patients.^14,17–20 Based on the AHRQ quality assessment scale, the methodological quality of included studies was moderate to high quality with a mean score of 5.8 (range: 5–7). However, the inherent bias of observational study design should be considered while interpreting the result. The characteristics of the 5 studies that met the inclusion criteria and a detailed quality assessment are shown in Table 1.

Table 1.

Basic Characteristics and Quality scores of Included Studies.

Authors	Year	Country	Age （mean ± SD）	Sex		Histopathological Techniques	Subtype of CA	Number of Cases	Sensitivity （%）	Quality Score
Authors	Year	Country	Age （mean ± SD）	M	F	Histopathological Techniques	Subtype of CA	Number of Cases	Sensitivity （%）	Quality Score
Arbustini et al.¹⁷	2002	Italy	60 ± 6	10	5	EM, IEM	AL, ATTR, apolipoprotein A1	15	14（93）	6
Cohen et al.¹⁴	2020	Britain	—	—	—	IHC, MS	AL	221	170（76.9）	5
Fine et al.¹⁸	2014	The US	66 ± 11	244	42	IHC, MS, genetic testing	mATTR, ATTRwt	225	106（47）	7
Hasegawa et al.¹⁹	2022	Japan	77 ± 8	6	1	IHC, genetic testing	AL, ATTRwt	7	5（71.4）	6
Quarta et al.²⁰	2017	Britain	—	—	—	IHC, genetic testing	AL, mATTR, ATTRwt	600	274（45.7）	5

Abbreviations: CA, cardiac amyloidosis; AL, light chain amyloidosis cardiomyopathy; ATTR, transthyretin amyloidosis cardiomyopathy; mATTR, mutant ATTR; ATTRwt, wild-type ATTR; EM, electron microscopy, IEM, immunoelectron microscopy; IHC, immunohistochemistry, MS, mass spectrometry.

Pooled Analysis

Diagnostic Sensitivity of CA

All pooled results are shown in Figure 2. After pooling 5 studies, the sensitivity of abdominal fat aspiration biopsy in detecting CA was 0.66 (95% CI 0.48–0.84). There was statistically significant heterogeneity (P = .000, I² = 96.7%). Hence, the random effects model was used to pool and analyze the data.

Diagnostic Sensitivity of AL

Four articles were included. The sensitivity of abdominal fat aspiration biopsy in detecting AL was 0.90 (95% CI 0.80–0.97) (Figure 3), which suggested a strong diagnostic value. There was statistically mild heterogeneity (P = .07, I² = 57.94％). Hence, the random effects model was used to pool and analyze the data.

Diagnostic Sensitivity of ATTR

Three included studies measured and recorded the diagnostic sensitivity of ATTR. Pooled sensitivity was 0.39 (95% CI 0.18–0.60) (Figure 4). The analysis of data obtained from 3 studies indicated significant heterogeneity (P = .00, I² = 94.2％). These were pooled and analyzed using the random effects model. Subgroup analysis on the type of ATTR was performed.

Three included studies measured and recorded the diagnostic sensitivity of ATTRwt. Pooled sensitivity was 0.16 (95％ CI 0.09–0.24) (Figure 4). There was statistically mild heterogeneity (P = .121, I² = 52.7％). Hence, the random effects model was used to pool and analyze the data. All the 2 studies of mATTR had a pooled sensitivity of 0.58 (95％ CI 0.52–0.64) (Figure 4), which suggested a moderate diagnostic value. The analysis of data obtained from 3 studies indicated significant heterogeneity (P = .000, I² = 91.9％). These were pooled and analyzed using the random effects model. Furthermore, there were significant differences between the 2 subgroups.

Sensitivity Analysis

There was no evidence of change in the significance level of effect size as confirmed through sensitivity analysis by omitting each study 1 by 1 (leave one out) from the pooled analysis.

Publication Bias

For publication bias analysis of the included studies, the Egger test (t = 0.91, P = .428) of the abdominal fat aspiration biopsy study for the diagnosis of CA did not reveal a statistically significant publication bias.

Discussion

In recent years, CA has received more and more attention. However, in most clinical practices, the clinical manifestations of CA lack specificity, which is relatively vague and confusing, and the diagnostic process is much more complicated. Therefore, the final diagnosis can only be based on histopathological examination.²¹ Selection of the correct tissue or site for biopsy is essential to avoid false negatives and delayed diagnosis.²² EMB is a high-risk operation while it is generally accepted that abdominal fat aspiration biopsy provides a less invasive diagnostic modality, and it is necessary for us to further explore its diagnostic performance.²³ In addition, the prognosis of amyloidosis is closely related to the degree of heart failure.^1,2 Therefore, the meta-analysis focused on amyloidosis occurring in cardiac sites, intending to provide some theoretical basis for early screening, early diagnosis, early treatment, and improving the prognosis of CA.

In 1973, the first sensitivity assessment of abdominal fat aspiration biopsy was performed by a scholar, who showed that the technique was able to detect 9 abnormal deposits of protein in 28 patients with suspected systemic AA amyloidosis.²⁴ Since then, many similar experimental studies have been conducted by scholars in the field of clinical pathology, all of which have shown that abdominal fat biopsy can be used to assist in the diagnosis of CA.²⁵ This meta-analysis pooled data from 5 studies and the sensitivity of abdominal fat aspiration biopsy for the diagnosis of CA was 0.66 (0.48–0.84). Overall, abdominal fat aspiration biopsy is useful for the diagnosis of CA. The biopsy results in fewer complications and can be performed by 1 person in <5 min, which is not only safe but also convenient.¹⁹ To some extent, abdominal fat aspiration biopsy can replace organ biopsy as an initial screening modality, minimizing the risk of potential complications.²⁶

Due to treatment options for CA varying widely depending on its type, we subsequently performed a subgroup analysis based on the type of CA. The results showed that the sensitivity of abdominal fat aspiration biopsy for the diagnosis of AL and ATTR was 0.90 (0.80–0.97) and 0.39 (0.18–0.60), respectively, while the sensitivity for the diagnosis of mATTR and ATTRwt was 0.58 (0.52–0.64) and 0.16 (0.09–0.24), respectively. It can be seen that abdominal fat aspiration biopsy is a powerful test for the diagnosis of AL with a high diagnostic value. Therefore, when developing the diagnostic process for CA, many institutions prioritize biopsies from less invasive sites such as abdominal fat for patients with high suspicion of AL.^1,2 An EMB is not necessary. Nevertheless, there are limitations in the diagnosis of ATTR, especially in the diagnosis of ATTRwt. It is important to emphasize that with the development and innovation of the level of noninvasive diagnostic technology, radiographic bone tracing technology can effectively diagnose ATTR,^27,28 and sometimes tissue biopsy is not required. However, in special cases, such as patients with monoclonal gammopathy, the diagnosis of ATTR still requires the combination of radiographic bone tracing techniques with biopsy. In such cases, abdominal fat aspiration biopsy can be attempted as a priority. It should be noted, however, that abdominal fat aspiration biopsy lacks specificity and sensitivity in diagnosing both AL and ATTR in patients.²⁹

In summary, abdominal fat aspiration biopsy as an initial screening modality has a unique clinical translational value and significance. Abdominal fat aspiration biopsy is also a safe, simple procedure that is relatively inexpensive³⁰ and allows obtaining sufficient quantity and quality of tissue for diagnosis and accurate typing.³¹ It is suitable for application in daily clinical practice while providing new possibilities and ideas for minimally invasive clinical diagnosis of CA.

To the best of our knowledge, this meta-analysis was the first and most comprehensive one for the diagnostic value of abdominal fat aspiration biopsy. However, it still had several limitations requiring attention. First of all, due to the relatively limited number of institutions performing abdominal fat aspiration biopsy and the even smaller number of studies performed on cardiac sites, the final included literature was limited. Hence, more comprehensive research on CA and abdominal fat aspiration biopsy is warranted. In addition, the disparity in the number of patients is too large and we lack studies on other specific types of CA. Eventually, retrospective studies are often a source of inherent bias, reducing the certainty of the evidence.

This meta-analysis showed that abdominal fat aspiration biopsy is useful and helpful in the minimally invasive diagnosis of CA. Future studies should focus on the sensitivity of abdominal fat aspiration biopsy for the diagnosis of specific types of CA and conduct in-depth studies with large multicenter samples. This will provide a better basis for the diagnosis of CA by abdominal fat aspiration biopsy and will enable a greater degree of generalization of the findings to daily practice and guide clinical diagnosis and treatment.

Conclusion

After a comprehensive analysis of the diagnostic value of abdominal fat aspiration biopsy for detecting CA, we found that abdominal fat aspiration biopsy had a certain diagnostic value, which was valuable to clinical practice as an initial screening modality. In these subtypes of CA, abdominal fat aspiration biopsy had the highest sensitivity for diagnosing AL, while it has some limitations in helping to diagnose ATTR, especially for the diagnosis of ATTRwt.

Supplemental Material

sj-tiff-1-ijs-10.1177_10668969231177603 - Supplemental material for Diagnostic Sensitivity of Abdominal Fat Aspiration Biopsy for Cardiac Amyloidosis: A Systematic Review and Meta-Analysis

Supplemental material, sj-tiff-1-ijs-10.1177_10668969231177603 for Diagnostic Sensitivity of Abdominal Fat Aspiration Biopsy for Cardiac Amyloidosis: A Systematic Review and Meta-Analysis by Jiaqi Wang, Dong Chen, Fang Dong and Haochen Chi in International Journal of Surgical Pathology

Supplemental Material

sj-docx-2-ijs-10.1177_10668969231177603 - Supplemental material for Diagnostic Sensitivity of Abdominal Fat Aspiration Biopsy for Cardiac Amyloidosis: A Systematic Review and Meta-Analysis

Supplemental material, sj-docx-2-ijs-10.1177_10668969231177603 for Diagnostic Sensitivity of Abdominal Fat Aspiration Biopsy for Cardiac Amyloidosis: A Systematic Review and Meta-Analysis by Jiaqi Wang, Dong Chen, Fang Dong and Haochen Chi in International Journal of Surgical Pathology

Footnotes

Acknowledgements

We are indebted to the authors of the primary studies included in this meta-analysis.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Beijing Hospitals Authority Innovation Studio of Young Staff Funding (grant number 202114).

Ethical Approval

Not applicable, because this article does not contain any studies with human or animal subjects.

Informed Consent

Not applicable, because this article does not contain any studies with human or animal subjects.

Trial Registration

Not applicable, because this article does not contain any clinical trials.

ORCID iD

Jiaqi Wang

Supplemental Material

Supplemental material for this article is available online.

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