Diagnosis for Chinese patients with light chain amyloidosis: a scoping review

Abstract

Background

Amyloid light chain (AL) amyloidosis is the most common systemic amyloidosis. The objective of this scoping review was to map the available literature on the diagnosis of AL amyloidosis in China.

Materials and Methods

The published academic papers related to the diagnosis of AL amyloidosis were screened from 1 January 2000 to 15 September 2021. Chinese patients who have suspected AL amyloidosis were included. The included studies were categorized into accuracy studies and descriptive studies based on if the studies supplied the diagnostic accuracy data or not. The information on the diagnostic methods reported by included studies was synthesized.

Results

Forty-three articles were included for the final scoping review, with 31 belonging to descriptive studies and 12 having information on diagnostic accuracy. Although cardiac involvement was second top in Chinese patients with AL amyloidosis, a cardiac biopsy was rare. Next, we found light chain classification and monoclonal (M-) protein identification were essential methods for the diagnosis of AL amyloidosis in China. In addition, some combined tests (e.g. immunohistochemistry and serum free light chain, immunohistochemistry and immunofixation electrophoresis, and serum free light chain and immunofixation electrophoresis) can increase the sensitivity of the diagnosis. Finally, several adjuvant methods (e.g. Imaging, N-terminal-pro hormone BNP, and brain natriuretic peptide test) were important for AL amyloidosis diagnosis.

Conclusion

This scoping review details the characteristics and results of the recently published studies on diagnosing AL Amyloidosis in China. Biopsy is the most important method for AL Amyloidosis diagnosis in China. In addition, combined tests and some adjuvant methods played essential roles in the diagnosis. Further research is required to determine an acceptable and feasible diagnostic algorithm after symptom onset. REGISTRATION: INPLASY2022100096

KEY MESSAGES

1. This scoping review details the characteristics and results of the recently published studies on diagnosing Amyloid light chain (AL) Amyloidosis in China.

2. Biopsy is the most important method for AL Amyloidosis diagnosis in China.

3. Combined tests and some adjuvant methods played essential roles in the diagnosis.

Keywords:

• Diagnosis
• light chain amyloidosis
• biomarker
• China
• scoping review

Introduction

Amyloid light chain (AL) amyloidosis is the most common systemic amyloidosis with transthyretin amyloidosis being the next most common. The disease usually presents with impairment of multiorgan function due to extracellular aggregates generated through the deposition of misfolded light chains produced by an indolent plasma cell clone [1]. The estimated incidence of AL amyloidosis was between 5.73 to 12.80 per million persons per year [2–4]. Furthermore, the prevalence of amyloidosis has a geographical distribution difference, and an increasing trend was observed during the last decades [5,6]. Although AL amyloidosis is rare, its prognosis can be poor: the median survival after diagnosis is reported to be between six months to three years after diagnosis [6]. The current treatments of AL amyloidosis focus on eliminating the clonal plasma cell that produces amyloid [7]. Recently, several clinical trials suggested that CD38 monoclonal antibodies (e.g. Daratumumab) appeared to be well tolerated and could improve clinical response to this disease [8–11]. However, although the prognosis of AL amyloidosis improved due to the optimized treatment during the past forty years, the overall survival remains poor [12,13].

Early diagnosis is another strategy to improve the prognosis for AL amyloidosis besides optimal treatment [14]. It was reported that patients with diagnostic delays were found to have a significantly worse prognosis than those without a delay [15]. AL amyloidosis could be involved in almost all organs other than the brain, and the clinical manifestations are diverse, with common symptoms such as feeling fainting, numbness feeling in the hands and feet (peripheral neuropathy), nausea, diarrhea, or constipation, tingling and pain in the wrist, hand and fingers (carpal tunnel syndrome), and easy bruising [16,17]. In addition, as the clinical features of AL amyloidosis are mainly nonspecific, the disease is easily overlooked or misdiagnosed [18,19]. According to an observational study in the USA, a median delay from symptom onset to AL amyloidosis diagnosis was 2.7 years [20]. Hence, most of the patients with AL amyloidosis were advanced when the diagnosis was made [21,22]. Cardiac involvement is the most important prognosis factor in AL amyloidosis patients, Mayo staging system, combining cardiac biomarkers, troponin T and NT-proBNP, is commonly used to evaluate the severity of cardiac dysfunction and the prognosis of patients with AL amyloidosis [23]. Therefore, early diagnosis is the most important factor in avoiding irreversible organ damage and prolonging survival [20,24].

Both Chinese and International guidelines stipulate that three conditions must be met for a proper diagnosis of AL amyloidosis. These include 1. A combination of clinical signs, lab values and imaging that confirm organ involvement. 2. Identification of amyloid tissue by biopsy of involved tissue followed by Congo red staining. It should also be confirmed that the amyloid deposits are composed of light chains by immunohistochemical methods, electron microscopy, or mass spectrometry. 3. Evidence of monoclonal antibodies or identification of light chains in the serum or urine, or bone marrow examination which reveals monoclonal plasma cells or B cells [25]. However, diagnosing AL amyloidosis is difficult due to the lack of solid pathognomonic blood test or imaging test for it [26]. The definite diagnosis now depends on the tissue biopsy of involved organs stained with Congo red dye and immunoassays for further typing remain indispensable to establish the diagnosis [17]. Some clinical characteristics, such as symptoms, serum biomarkers, immunohistochemistry (IHC), and methods for M-protein identification, may raise the clinical suspicion of the disease and improve its diagnostic dilemma [19]. However, to our best knowledge, there is a lack of systematic synthesis on the diagnosis of AL amyloidosis in China. A scoping review is appropriate for this purpose [27].

The objective of this scoping review was to map the available literature on the diagnosis of AL amyloidosis and to consolidate recommendations for practice and future research in China. With this review, we also aimed to provide insights into AL amyloidosis that is specific to the current state of the Chinese medical system. This will both give medical professionals a frame of reference when testing patients, as well as allow policymakers to make better decisions when creating and updating relevant regulations.

Methods

The protocol of the present review was provided in Supplementary Appendix I. Besides, this scoping review was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines [28].

Eligibility criteria

The published academic papers related to the diagnosis of AL amyloidosis were screened from 1 January 2000 to 15 September 2021. The inclusion criteria were 1) Chinese patients who have suspected AL amyloidosis without age restriction, 2) published in English or Chinese, 3) having a sample size of at least 25 patients, 4) original studies included both experimental studies and observational studies, and 5) having information on the diagnosis of AL amyloidosis. Exclusion criteria were as follows: case reports, review, consensus, thesis, questionnaire, and correspondence.

Literature search

References were searched through MEDLINE, EMBASE, and CNKI databases from 1 January 2000 to September 15 September 2021. The key search terms included ‘amyloidosis’, ‘amyloidos*’ ‘amyloido*’, ‘AL amyloidosis’ and ‘China’. The details of the search strategies can be found in the protocol (Supplementary Appendix I).

Grey literature search of Google Scholar was also included in the search. We also explored sources identified by searching the reference list of all the included full-text papers. Where more information related to a potentially included literature is lacking, we contacted the literature authors and request further information.

Study selection

Search results were entered to Endnote version X9 and duplicates were removed before screening for relevance. Two authors (PJ & LW) reviewed the titles and abstracts of publications retrieved by the search to identify potentially eligible papers. All potentially relevant citations were requested and inspected in detail using the full-text version. In case of doubt on whether a study could be eligible, a third author (XL) reviewed the publication to make a collegial decision.

Data extraction

Data items were reviewed as follows: 1) clinical characteristics, such as age, sex, stage, type, organ involvement (as defined by the studies), and diagnostic delay; 2) diagnostic yield of Congo red staining, using different kinds of tissues; 3) light chains classification method; 4) radiological tools, flow cytometry, genetic tests, and other routine biomarkers, such as 24 h urinary protein, NT-proBNP or BNP and alkaline phosphatase. The data extraction form can be found in the protocol (Supplementary Appendix I).

A pretested data extraction form based on the PICOT (population, intervention, control, outcome, and time) structure was used to perform the data extraction. Data from each literature review were extracted by one reviewer and double-checked by another using a standard data extraction form. Any disagreements were resolved by discussion, with assistance from a third party if necessary. Data were extracted as follows: first author, title, year of publication, publication journal, country of study, study design, diagnostic delay, Congo red staining (biopsies, performance, and others), amyloid typing method (proportion and performance), AL Amyloidosis typing method (proportion and performance), organ involvement (diagnostic methods and corresponding performance).

Synthesis of results

The included studies were categorized into accuracy studies and descriptive studies based on if the studies supplied the diagnostic accuracy data or not. The information on the diagnostic methods reported in included studies was synthesized according to different organ involvement and expressed using the count and proportion of the studies. For each diagnostic method, the sample size of related patients was summed up and expressed as count and percentage. For the available accuracy data for any diagnostic method, a descriptive analysis was performed.

Results

Characteristics of the included studies and patients

A total of 891 papers were identified via reference searching. After removing duplicate articles and screening, 43 articles were included in the final scoping review [29–71]. A PRISMA flow diagram was constructed to show the whole literature selection process with reasons for exclusions at each stage (Figure 1). Of all included studies, 31 belong to descriptive studies [29,30,32–39,43,46–51,53–58,60,62,63,65,66,69–71], and 12 have information of diagnostic accuracy [31,40–42,44,45,52,59,61,64,67,68] (the characteristics of each included study can be found in Supplementary Appendix II).

Figure 1. PRISMA flow diagram for article selection for analysis.

A total of 2447 AL patients with amyloidosis were included in the final analysis. Among patients with amyloidosis, AL amyloidosis comprised a majority proportion, which depends on the kind of organ involved. The classification of AL amyloidosis was reported in 686 patients, most of whom were primary AL amyloidosis (656/686, 95.6%; 13 studies). The mean age of the included patients ranged from 49 to 61 years. In 2060 patients who reported gender, 63.1% (1299) were male. In terms of Mayo stage categorization, 170 patients were categorized according to Mayo 2004 cardiac staging system, and 537 patients were categorized according to Mayo 2012 cardiac staging system. In addition, there were 5% (32/695) patients who reported clonal plasma cells in bone marrow ≥ 10%. The details of the characteristics of patients collected from the 43 included studies can be found in Table 1.

Table 1. Summary of patients’ characteristics based on 43 included studies.

Characteristics	No. of reported patients (Percentage)	No. of studies
Age	1904	27
Reported mean of the age 49 to 61 years	1494 (78.5%)	22
Reported median of age 43 to 63 years	545 (28.6%)	8
Gender	2060	31
Female	761 (36.9%)	32
Male	1299 (63.1%)	30
Primary or secondary	686	13
Primary	656 (95.6%)	13
Secondary	30 (4.4%)	3
Type of light chains	1366	25
Lambda	1106 (81.0%)	25
Kappa	260 (19.0%)	24
Mayo 2004 cardiac staging system	170	2
I	35 (20.6%)	2
II	57 (33.5%)	2
III	62 (36.5%)	2
Mayo 2012 cardiac staging system	537	5
I	171 (31.8%)	5
II	135 (25.1%)	5
III	121 (22.5%)	5
IV	61 (11.4%)	5
Clonal plasma cell in bone marrow	695	10
≥10%	32 (5.0%)	2

AL amyloidosis diagnosis in China

Biopsy sites

The most common organ involvement reported in the 43 papers was the kidney (1979/2143, 92.3%), followed by the heart (899/1566, 57.4%), and the skin & soft tissue (150/300, 50.0%). The details of the organ involved in the included studies can be found in Supplementary Appendix III. Meanwhile, forty studies (40/43, 93.0%) reported the sites of biopsy in total 2101 patients with the top three of the kidneys (27/40, 67.5%) in 1367 (65.1%) patients, bone marrow (16/40, 40.0%) in 656 (31.2%) patients, and rectal mucosa (5/40, 12.5%) in 334 (15.9%) patients (Table 2).

Table 2. Summary of biopsy sites and related sample size of the patients based on 40 included studies (n = 2101).

Biopsy sites	Study		Sample size
	Number	Proportion	Number	Proportion
Renal	27	67.5%	1367	65.1%
Bone marrow	16	40.0%	656	31.2%
Tongue	7	17.5%	78	3.7%
Cardiac	6	15.0%	63	3.0%
Liver	6	15.0%	67	3.2%
Abdominal wall fat	5	12.5%	136	6.5%
Rectal mucosa	5	12.5%	334	15.9%
Fat	4	10.0%	76	3.6%
Skin and fat	3	7.5%	262	12.5%
Skin	2	5.0%	17	0.8%
Labial gland	2	5.0%	64	3.0%
Lung	1	2.5%	1	0.0%
Skin or fat	1	2.5%	15	0.7%

Spleen, gingiva, gastrointestinal tract, rectum, sural nerve, buccal mucosa, lymph gland and muscle were also reported in a small number of the literatures.

Light chain classification and monoclonal (M-) protein identification

A total of 23 studies supplied the details of the methods of classification of light chains. The most popular diagnostic method for light chain classification reported in China was IHC (15/43, 34.9%), immunofluorescence (IF) (12/43, 27.9%), and electron microscopy (10/43, 23.3%). Meanwhile, a total of 29 studies described the methods of detection of M-protein with the top three reported tests being serum-free light chain (20/43, 46.5%), blood immunofixation electrophoresis (8/43, 18.6%), urine-free light chain (8/43, 18.6%). The number of studies and patients that reported light chain classification methods and M protein identification tests in the 43 papers were described in Table 3.

Table 3. Summary of diagnostic methods for light chains classification and different M protein identification in 43 included studies.

Measurement	Study		Sample size
	Number	Proportion	Number	Proportion
Types of light chains classification method	39		2450
Immunohistochemistry	15	34.9%	593	24.2%
Immunofluorescence	12	27.9%	897	36.7%
Electron microscopy	10	23.3%	836	34.2%
Immunoelectron microscopy (SEM)	2	4.7%	282	11.5%
Mass Spectrometry	0	0.0%	0	0.0%
M protein identification	51		2447
Serum free light chain	19	44.2%	1402	57.3%
Blood immunofixation electrophoresis	8	18.6%	723	29.5%
Urine free light chain	7	16.27%	265	10.8%
Blood and urine immunofixation electrophoresis	6	14.0%	167	6.8%
Blood or urine immunofixation electrophoresis	3	7.0%	100	4.1%
Serum or urine free light chain	2	4.7%	60	2.5%
Blood serum protein electrophoresis	1	2.3%	59	2.4%
Urine serum protein electrophoresis	1	2.3%	7	0.3%
Urine immunofixation electrophoresis	1	2.3%	87	3.6%
Blood/urine SPE	0	0.0%	0	0.0%
Urine Bence-Jone protein (urine)	3	7.0%	152	6.2%

SEM: the scanning electron microscopy; SPE: serum protein electrophoresis.

Adjuvant diagnostic methods

As an important adjuvant diagnostic method for cardiac involvement, imaging has been reported in 19 (44.2%) studies, including echocardiogram (15/19, 78.9%), electrocardiogram (14/19, 73.7%), and cardiac MRI (10/19, 52.6%). In addition, N-terminal (NT)-pro hormone BNP (NT-proBNP) and brain natriuretic peptide (BNP) test were reported in 12 (12/43, 27.9%) and 3 (3/43, 7.0%) studies, respectively. Next, for renal involvement, 24 h urinary protein test was reported in 22 (51.2%) studies. Third, for bone marrow involvement, the flow cytometry (FCM) and genetic tests (CD138 MACS-FISH magnetic bead sorting combined with interphase fluorescence in situ hybridization) were stated valuable for the diagnosis of AL in 4 (4/43, 9.3%) and 3 (3/43, 7.0%) studies, respectively. Finally, for liver involvement, the liver percussion and alkaline phosphatase test were reported in 2 (2/43, 4.7%) and 1 (1/43, 2.3%) study, respectively (Supplementary Appendix II).

Diagnostic delay

Diagnostic delay was reported in two studies [44,55] (Citations), the median and mean delays were reported as 9.5 months (median) and 11.3 ± 10.4 months (mean ± SD), respectively.

Accuracy of the AL amyloidosis diagnosis in China

Amyloidosis testing accuracy

When stained with Congo red, the amyloidosis tissue will demonstrate apple-green birefringence under a polarizing microscope [72]. In the forty studies having information on biopsy, Congo red stain was the most popular method for detecting amyloid (32/40, 80%). The details of the sensitivity of Congo red staining ranged from 15.0% to 100.0%, as calculated using data reported by the studies. The lowest sensitivity (15.0%) was found in the marrow biopsy and the highest sensitivity (100%) was found in lung, renal, and rectal mucosal tissue. One of the included studies Li et al. [61] supplied the sensitivity of the deposit sites of amyloid and the IF. According to Li et al. combining skin fat biopsy with rectal mucosal biopsy can significantly increase the test sensitivity [61] (Table 4).

Table 4. The performance of diagnostic methods for detecting amyloidosis in China.

Measurement	Study ID	Positive events	Sample size	Sensitivity (%, 95% CI)	Specificity (%)	AUC (95% CI)
Biopsy
Congo red
Abdominal wall fat	Xu et al. [67]	37	54	68.5
	Xu et al. [31]	16	21	76.2
Abdominal wall fat and labial gland	Xu et al. [67]	35	41	85.4
Bone marrow	Xu et al. [67]	19	57	33.3
	Xu et al. [31]	10	21	47.6
	Wang et al. [64]	3	20	15
Labial gland	Xu et al. [67]	27	43	62.8
	Xu et al. [31]	13	21	61.9
Liver	Xu et al. [67]	1		50
Lung	Xu et al. [67]	1	1	100
Rectal mucosal	Li et al. [41]	167	176	94.9 (92–98)
	Li et al. [61] (Test Cohort)	127	134	94.8 (91.0–98.5)
	Li et al. [61] (Validation Cohort)	51	54	94.4 (87–100.0)
Renal	Zhang et al. [42]	14	14	100
	Xu et al. [67]	9	12	75
	Wang et al.2020b	5	6	83.3
	Xu et al. [31]	2	2	100
Skin	Wang et al. [64]	6	11	54.5
Skin and fat	Li et al. [41]	124	134	92.5 (88–97)
	Li et al. [61] (Test Cohort)	108	121	89.3 (83.5–94.2)
	Li et al. [61] (Validation Cohort)	47	51	92.2 (84.3–98.0)
Skin and fat and rectal mucosal	Li et al. [41]	105	124	84.7
Skin and fat or rectal mucosal	Li et al. [61] (Test Cohort)	89	90	98.9 (96.7–100.0)
	Li et al. [61] (Validation Cohort)	46	46	100
Spleen	Xu et al. [67]	1	1	100
Tongue	Wang et al. [64]	1	3	33.3
Deposit sites of amyloid
Skin and fat − Dermis	Li et al. [61]	−	155	45.8 (38.1–53.5)
Skin/fat − Subcutaneous tissue	Li et al. [61]	−	155	58.7 (50.3–66.5)
Skin and fat − Blood vessel	Li et al. [61]	−	155	36.1 (28.4–43.2)
Rectal mucosa − Mucosal layer	Li et al. [61]	−	178	42.7 (34.8–50.0)
Rectal mucosa − Submucosa layer	Li et al. [61]	−	178	40.5 (33.7–47.8)
Rectal mucosa − Blood vessel	Li et al. [61]	−	178	62.9 (55.1–70.2)
Immunofluorescence
Skin and fat	Li et al. [61] (Test Cohort)	30	37	81.1 (67.6–91.9)
	Li et al. [61] (Validation Cohort)	8	10	80
Rectal mucosal	Li et al. [61] (Test Cohort)	50	59	84.7 (74.6–93.2)
	Li et al. [61] (Validation Cohort)	34	37	91.9 (83.8–100)
Skin and fat or Rectal mucosal	Li et al. [61] (Test Cohort)	13	15	86.7
	Li et al. [61] (Validation Cohort)	7	7	100
Classification and identification methods
Types of light chains classification method
Immunohistochemistry	Zhai et al. [68]	21	25	84	−	−
Immunohistochemistry and serum free light chain or immunofixation electrophoresis	Zhai et al. [68]	24	25	96	−	−
Serum free light chain	Li et al. [41]	98	186	52.7	−	−
	Zhai et al. [68]	19	25	76	−	−
Serum free light chain and immunofixation electrophoresis	Zhai et al. [68]	22	25	88	−	−
	Zhou et al. [44]	−	625	65.6	98	0.659
	Yao et al. [45]	63	87	72.4	−	−
	Zhou et al. [44] (40–60 yr)	−	402	50	98	0.689
	Zhou et al. [44] (older than 60 yr)	−	223	81.3	98	0.585
M protein identification
Blood and urine immunofixation electrophoresis	Zhou et al. [44]	−	625	75	97.6	0.863 (0.832–0.894)
	Yao et al. [45]	105	157	66.9	−	−
	Zhou et al. [44] (40–60 yr)	−	402	68.8	97.7	0.832
	Zhou et al. [44] (older than 60 yr)	−	223	81.3	97.6	0.894
Blood immunofixation electrophoresis	Fan et al. [40]	66	112	58.9	−	−
	Li et al. [41]	83	161	51.6	−	−
	Zhou et al. [44]	−	625	56.3	98.6	0.653
	Yao et al. [45]	89	156	57.1	−	−
	Sa et al. [59]	71	119	59.7	−	−
	Zhou et al. [44] (40–60 yr)	−	402	43.8	98.6	0.684
	Zhou et al. [44] (older than 60 yr)	−	223	68.6	98.5	0.578
Immunofixation electrophoresis	Xu et al. [31]	18	21	85.7	−	−
	Zhai et al. [68]	17	25	68	−	−
Serum free light chain	Li et al. [41]	98	186	52.7	−	−
	Zhai et al. [68]	19	25	76	−	−
Serum free light chain and immunofixation electrophoresis	Zhai et al. [68]	22	25	88	−	−
	Zhou et al. [44]	−	625	65.6	98	0.659
	Yao et al. [45]	63	87	72.4	−	−
	Zhou et al. [44] (40–60 yr)	−	402	50	98	0.689
	Zhou et al. [44] (older than 60 yr)	−	223	81.3	98	0.585
Urine Bence−Jone protein
Urine Bence−Jone protein	Fan et al. [40]	73	114	64	−	−
Urine Bence−Jone protein and blood M protein	Fan et al. [40]	93	117	79.5	−	−
Radiological method
3D-STI diagnosis global circumferential strain
For GCS (Cut-off value = 16.09%)	Lei et al. [43]	49	52	94.23	87.5	0.927 (0.854–0.971)
For GAS (Cut-off value = 36.54%)	Lei et al. [43]	45	52	86.54	80	0.847 (0.757–0.914)
For GRS (Cut-off value = 31.90%)	Lei et al. [43]	42	52	80.8	47.5	0.664 (0.558–0.760)
Flow cytometry
Multiparametric flow cytometry (MFC) to measure the light chain restriction	Sa et al. [59]	96	119	80.70%

Light chain classification

Only four studies reported the accuracy of data on the light chain classification (Table 4). The top method for light classification was IHC, which was reported in 15 (34.9%) studies. However, the high sensitivity was more likely related to the combined method of immunofixation electrophoresis and serum light chain (88%) or IHC and serum free light chain (96%).

M Protein identification

For M protein identification, the reported sensitivity of different methods varied in a wide range. However, the highest sensitivity (88%) was reported for the Serum free light chain and immunofixation electrophoresis by Zhai et al. On the contrary, using blood immunofixation electrophoresis was reported the lowest (43.8%) sensitivity by Zhou et al. One study by Fan et al. reported the sensitivity of urine immunofixation electrophoresis (Bence-Jones protein). The sensitivity of the M protein identification was 64.0% by Bence-Jones protein and 79.5% by Bence-Jones protein and blood M protein, respectively (Table 4).

Three-dimensional speckle tracking imaging (3D-STI)

One of the studies [43] reported the accuracy of the 3D-STI assessed global circumferential strains (see details data in Table 2). The highest sensitivity (94.2%) and specificity (87.5%) were found in the 3D-STI diagnosis of GCS.

Multiparametric flow cytometry (MFC)

One study [59] reported that the positive rate of MFC to measure the light chain restriction was 80.7% (Table 4).

Discussion

In the present study, we studied the condition of AL amyloidosis diagnosis in China. According to our findings, although cardiac involvement was second top in Chinese patients with AL amyloidosis, cardiac biopsy was rare. Next, we found light chain classification and monoclonal (M-) protein identification were essential methods for the diagnosis of AL amyloidosis in China. In addition, some combined tests can increase the sensitivity of the diagnosis. Finally, some adjuvant methods were essential for AL amyloidosis diagnosis.

Congo red staining is the gold standard method for amyloid diagnosis and has been used for decades [73]. However, using Congo red also has several disadvantages. For instance, false-positive or false-negative results can occur due to inexperienced examiners [74]. In addition, the usual site of choice for biopsy is the involved organ. However, there are sometimes alternative sites chosen for biopsy due to the organ or technical limitations. In this study, we observed that the most biopsied sites in Chinese hospitals were for kidney, bone marrow, and skin/fat in that order, with varying favorable rates. In addition, we found that cardiac biopsy reports were rare, which may be due to the low acceptance of biopsy itself and the small number of healthcare providers with the relevant skills. Besides, we found that only 31.2% related patients were performed bone marrow biopsy. The reason may be due to the low percentage of bone marrow involvement and the percentage of myeloma plasma cells. Therefore, bone marrow biopsy may not be a good method for AL amyloidosis detection [75]. Hence, besides Congo Red staining, IF, IHC, electron microscope, mass spectrometry, and potassium permanganate staining are also recommended to improve the diagnostic accuracy of pathological examinations [29,36,76].

IF and IHC can distinguish multiple amyloid types but are prone to false negatives with a sensitivity of about 60% [77]. Therefore, IF or other sensitive immunoassays in combination with immunofixation electrophoresis of serum and urine are required to check serum k and λ light chain to determine the presence of monoclonal free light chains in serum or urine [78].

As nonquantitative techniques, serum and urine IFE (SIFE/UIFE) are routinely performed for the detection of monoclonal Ig among patients with plasma cell dyscrasia. As shown in the previous studies [40,41,44,45,59], blood IFE has a moderate sensitivity of 50–60% for AL Amyloidosis. However, the sensitivity could be improved if blood IFE is combined with urine IFE [44]. Recently, sFLC showed the sensitivities for diagnosis of AL Amyloidosis were 52.7% [41] and 76.0% [68], respectively. Prokaeva et al. found that the combination of each method (SIFE/UIFE and HLC, SIFE/UIFE and sFLC, and HLC and sFLC) have a sensitivity of 94%, 100%, and 93.5% for the AL amyloidosis diagnosis [79]. Similar findings were also observed in other reports. The sensitivity of combined sFLC and SIFE/UIFE testing for the diagnosis of AL amyloidosis ranges from 97 to 100% [80,81]. Therefore, baseline sFLC measurements and SIFE/UIFE are recommended by consensus guidelines for screening underlying clonal disease in suspected AL amyloidosis cases [79,82–84].

Two of the included studies reported on diagnosis delay. The reported diagnosis delay was considerably shorter than the delay reported by other international studies [20]. There are two possible hypotheses that may explain this disparity: 1. The Chinese studies that we included were conducted in relatively large medical institutions with amyloidosis subspeciality, which may have had access to a lot of healthcare resources to allocate to the patients, thus allowing the diagnosis to be conducted faster. 2. The staff at these institutions are experienced and familiar with the process of AL amyloidosis diagnosis and were able to make use of multi-disciplinary teams to speed up the process of diagnosis. It is important to keep in mind that the data we have obtained on this specific topic is limited and likely not representative of the situation in China as a whole.

In this article, we found that the knowledge gap as follows: (1) the lack of awareness of AL amyloidosis, which leads to delayed diagnosis of patients, and it takes nearly a year from the appearance of symptoms to the diagnosis [85], and it is a problem to raise the awareness of early suspicion of amyloidosis among doctors in related departments; (2) There is a lack of research on practical and applicable tests unless some hospitals are experienced in AL diagnosis, AL patients are easily misdiagnosed as other diseases in the clinic for treatment; (3) there is an urgent need to study other detection techniques that can identify AL amyloidosis as a disease at an early stage, including imaging assessment of the affected organs, early detection of abnormal biochemical indicators such as NT-proBNP, cardiac troponin T, and proteinuria.

This is the first attempt to systematize existing evidence on diagnosing AL Amyloidosis in China. The study has well addressed recent findings of AL Amyloidosis in China, which may improve the current diagnostic dilemma of AL Amyloidosis. However, some limitations should be considered when interpreting and applying those results. First, as known, the assessment of individual literature methodological quality is not required for scoping reviews. The authors could not identify gaps in the literature related to low-quality research. Second, this review is descriptive and would be limited by the low quality and heterogeneity of the included studies. Third, the rare nature of AL amyloidosis resulted in many studies with small sample sizes, limiting definitive conclusions. Fourth, this review was based exclusively on information from published reports. There has been no registered study and no data from the ClinicalTrials.gov website. Therefore, the accuracy and completeness of the data depend upon these previously reported studies. In the future, further research is required to draw more reliable conclusions.

Conclusions

This scoping review details the characteristics and results of the recently published studies on diagnosing AL Amyloidosis in China. Biopsy was still the most critical method for AL Amyloidosis diagnosis in China. In addition, combined tests and some adjuvant methods played essential roles in the diagnosis. However, further research and deliberation are required to amend the current Chinese guidelines in order to make them more practical and feasible.

Author contributions

Search strategy, X.C. and X.W.; draft protocol, M.C. and J.R.L.; study selection, J.R.L. and X.W.; data extraction, L.X., J.P. and W.L.; data analysis, M.C. and X.G.; writing review and editing, J.L. and J.R.L.; All authors have read and agreed to the published version of the manuscript.

Acknowledgments

We thank Medjaden Inc. for the editorial assistance and language editing and all other contributors who provided assistance and support but have not been mentioned. The collection and assembly of data and statistical expertise were provided by Yang Zhang and Sai Zhao, from Systematic Review Solutions, Ltd.

Disclosure statement

The authors declared that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors are responsible for all content and editorial decisions and received no honoraria related to the development of this publication.

Data availability statement

The original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding author.

Additional information

Funding

This research received no external funding.