Ultrasound-guided microwave ablation for secondary hyperparathyroidism: a systematic review and meta-analysis

Abstract

Objectives

Microwave ablation (MWA) is used for the treatment of severe secondary hyperparathyroidism (SHPT), but its efficacy and safety still remained unclear. This study aimed to investigate the efficacy and safety of ultrasound (US)-guided MWA in patients with SHPT.

Methods

The PubMed, Cochrane library, Embase, China national knowledge infrastructure (CNKI) and Wanfang databases were searched to identify published studies that evaluated the efficacy and safety of US-guided MWA in patients with SHPT. The primary outcomes were parathyroid hormone (PTH), serum calcium and phosphorus levels.

Results

A total of 26 studies with 932 patients were identified. The PTH levels showed significant reduction at 1 month [weighted mean difference (WMD) = 945.33, 95% CI: 797.15∼1093.52] and 6 months (WMD = 1,151.91, 95% CI: 990.93∼1312.89) after MWA of SHPT patients. The serum calcium (WMD = 0.39, 95% CI: 0.30 ∼ 0.48) and phosphorus levels (WMD = 0.64, 95% CI: 0.43 ∼ 0.85) showed significant reduction at 6 months after MWA of SHPT patients. The most common complications observed were hypocalcemia (35.2%) and transient hoarseness (9.2%). No other major complications or death occurred in our study patients.

Conclusion

These findings suggest MWA as a safe and effective minimally invasive technique for the management of SHPT. PTH, calcium, and phosphorus levels were significantly reduced at 1 and 6 months after MWA.

Keywords:

• Microwave ablation
• secondary hyperparathyroidism
• parathyroid hormone
• meta-analysis
• systematic review

Introduction

Secondary hyperparathyroidism (SHPT) is a frequently encountered problem in patients with end-stage renal disease (ESRD) [1,2], and about one-third of the patients undergoing long-term dialysis are affected [3,4]. The patients with uncontrolled SHPT have increased risk of fractures and mortality [5,6]. Although disease development can be controlled clinically by using intravenous vitamin D analogs [7], orally active vitamin D sterols [8] and cinacalcet [9], parathyroidectomy in patients with severe SHPT is still considered necessary [10]. Surgical parathyroidectomy exposes patients to anesthesia risks and permanent parathyroid function reduction [11]. A minimally invasive alternative treatment with potential advantages of reduced risk, faster recovery, fewer side effects and lower costs when compared to traditional surgical treatment is warranted.

Recently, image-guided thermal ablation has been used for the treatment of hyperparathyroidism (HPT) [12,13]. As a method of ablation, ultrasound-guided percutaneous microwave ablation (MWA) has achieved good clinical results [14,15].

This technique has the advantages of least damage and effectively reduction of the levels of intact parathyroid hormone (iPTH), gradually becoming clinically acceptable. However, the results of existing studies on microwave ablation for SHPT are not completely consistent. Therefore, a systematic review and meta-analysis of published literature to evaluate the efficacy and safety of US-guided microwave ablation for SHPT was conducted. Although a previous meta-analysis has been constructed by Cao et al, the number of literatures included in the current study is more than triple that of it.

Materials and methods

The present meta-analysis study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines [16].

Literature searches

The PubMed, EMBASE, Cochrane Library, China national knowledge infrastructure (CNKI) and Wanfang database were comprehensively searched from inception to March 2021 without any language restriction. The keywords used to search included “secondary hyperparathyroidism” plus “SHPT” and “microwave ablation” plus “MWA.” The reference lists of the relevant studies identified were manually scanned using these search terms.

Study selection

Relevant studies were included based on the following criteria: (1) observational cohorts including prospective and retrospective studies comparing pre-ablative and post-ablative clinical results; (2) patients with SHPT who underwent US-guided microwave ablation for therapy; (3) outcomes such as serum iPTH levels, serum calcium, serum phosphorus and complications; and (4) studies including a follow-up duration of at least 30 days. Studies were excluded if they met the following criteria: (1) studies published as case reports, conference abstracts, letters to editor, or reviews; (2) studies including patients with primary hyperparathyroidism; and (3) experimental studies of animal models or cell lines.

Data extraction and quality assessment

Data extraction was done using a standardized data collection form, which included author, year of publication, country, study design, number of patients, MWA power, number of lesion, age, gender, study duration, follow-up period and outcomes. The Newcastle-Ottawa Scale (NOS) [17] was used to evaluate the quality of included studies, in which studies with scores ≥ 6 represents high quality. Data extraction and quality assessment was independently done by two authors, and any disagreements between them were resolved by discussion.

Data synthesis and statistical analysis

Pooled estimates of proportions with corresponding 95% confidence intervals were calculated on the base of the Freeman Tukey double arcsine transformation [18,19]. Weighted mean difference (WMD) with 95% CIs were calculated as the difference between pre and post-treatment using random-effects model [20,21], in which I²>50% or p < 0.1 represents notable heterogeneity. To detect robustness of the results, sensitivity analysis was conducted by sequential elimination of each study from the pool [21,22]. Potential publication bias was assessed using visual inspection of funnel plots, Begg’s and Egger’s tests [23,24]. Statistical analyses were performed using STATA software (version14, Statacorp, College Station, Texas, USA). P < 0.05 indicates statistically significant difference.

Results

Literature search and study characteristics

A total of 122 studies were screened, and 41 full-texts of these were assessed for eligibility. Finally, 26 studies [14,25–49] were included in the current systematic review. A flowchart depicting the study selection process was presented in Figure 1. The eligible articles were published between 2015 and 2021, and included a total sample size of 932. Among these studies, seven were prospective studies and 19 were retrospective studies. The mean age of participants ranged from 38.67 to 69.1. Both male and female patients were included in the studies. The main characteristics of the included studies are presented in Table 1. The quality of included studies was shown in Table 2. The quality assessment scores ranged from 7 to 8, with an average score of 7.5 points, which represent satisfactory quality of the studies.

Figure 1. Flow diagram of study selection process.

Table 1. Characteristics of studies included in this meta-analysis.

Author/ year of publication	Country	Gender (Female %)	Mean age (Y)	Number of patients	MWA power (w)	Number of lesion	Conducted period	Follow-up	Study design
Luo/2015 [18]	China	56.3%	50.5 ± 10.7	16	NA	57	NA	6M	Retrospective
Diao/2016 [19]	China	63.3%	57.06 ± 9.14	30	25–35	NA	2009–2014	23M	Retrospective
Gao/2016 [20]	China	50%	56.6 ± 14.1	10	NA	32	2016	3M	Retrospective
Yu/2016 [21]	China	72.7%	51.3 ± 11	11	25	16	2014–2015	6.8M	Retrospective
Zhao/2016 [22]	China	53.6%	55.02 ± 10.01	56	30	138	2012–2013	6M	Prospective
Diao/2017 [23]	China	61.5%	55.1 ± 9.6	26	32.9 ± 5.13	60	2013–2014	16M	Prospective
Ding/2017 [24]	China	64.5	53 ± 6.75	40	25–35	NA	2014–2015	6M	Retrospective
Liao/2017 [25]	China	22.2%	38.67 ± 8.32	18	NA	56	2015–2016	12M	Prospective
Liu/2017 [26]	China	41.2	43.05 ± 7.71	34	25–35	NA	2014–2016	6M	Prospective
Zhuo/2017 [14]	China	51%	53.1 ± 12.9	51	25	96	2014–2015	11.1M	Prospective
Jiang/2019 [27]	China	45.4%	53.2 ± 14.2	33	25–35	115	2015–2017	24M	Retrospective
Li-a/2019 [28]	China	33.3%	49.7 ± 9.6	9	30	14	2016–2017	17.2M	Retrospective
Li-b/2019 [41]	China	40%	53.2 ± 10.3	20	30	22	2014–2016	15.3M	Retrospective
Zhuo/2019 [29]	China	45.7%	49.8 ± 12.9	35	25	63	2015-2017	15.9M	Prospective
Cao/2020 [30]	China	49%	50.8 ± 11.2	51	NA	83	2015–2018	6M	Retrospective
Fang/2020 [33]	China	35.7%	53.5 ± 12.44	14	30	42	2016–2018	6M	Retrospective
Kong/2020 [34]	China	46.7%	52.3 ± 8.74	60	NA	164	2017–2018	6M	Prospective
Ma/2020 [31]	China	56.3%	55.38 ± 15.17	16	25–45	52	2014–2016	6M	Retrospective
Pan/2020 [35]	China	35.7%	52.46 ± 8.19	28	30–50	NA	2017–2019	6M	Retrospective
Song/2020 [36]	China	58.6%	69.1 ± 9.4	29	35	NA	2017–2019	6M	Retrospective
Xiao/2020 [32]	China	48.8%	49.5 ± 14.9	41	30	NA	2014–2019	6M	Retrospective
Wei/2020 [37]	China	48.5	50.35 ± 13.12	171	30	NA	2018–2019	6M	Retrospective
Yu/2020 [42]	China	40%	48.9 ± 9.1	20	30	34	2016–1018	3M	Retrospective
Diao/2021 [38]	China	51.1	53.3 ± 10.8	47	25–35	94	2010–2019	60M	Retrospective
Li/2021 [39]	China	61.5	54.23 ± 10.96	13	25–35	26	2015	58M	Retrospective
Wang/2021 [40]	China	37.7	50.1 ± 10.3	53	25–35	NA	2016–2020	41M	Retrospective

Abbreviations: MWA: microwave ablation; Y: years; M: months; NA: not available.

Table 2. Quality assessment of included studies by NOS.

Author	Year	Selection	Comparability	Outcome
Luo [18]	2015	★★★	★★	★★
Diao [19]	2016	★★★	★★	★★★
Gao [20]	2016	★★★	★★	★★
Yu [21]	2016	★★★	★★	★★★
Zhao [22]	2016	★★★	★★	★★
Diao [23]	2017	★★★	★★	★★★
Ding [24]	2017	★★★	★★	★★
Liao [25]	2017	★★★	★★	★★★
Liu [26]	2017	★★★	★★	★★
Zhuo [14]	2017	★★★	★★	★★★
Jiang [27]	2019	★★★	★★	★★★
Li-a [28]	2019	★★★	★★	★★★
Li-b [41]	2019	★★★	★★	★★★
Zhuo [29]	2019	★★★	★★	★★★
Cao [30]	2020	★★★	★★	★★
Fang [33]	2020	★★★	★★	★★
Kong [34]	2020	★★★	★★	★★
Ma [31]	2020	★★★	★★	★★
Pan [35]	2020	★★★	★★	★★
Song [36]	2020	★★★	★★	★★
Xiao [32]	2020	★★★	★★	★★
Yu [42]	2020	★★★	★★	★★
Wei [37]	2020	★★★	★★	★★★
Diao [38]	2021	★★★	★★	★★★
Li [39]	2021	★★★	★★	★★★
Wang [40]	2021	★★★	★★	★★★

Quantitative synthesis

Parathyoid hormone (PTH) levels

Data regarding PTH levels were reported in 23 studies. The results showed that the PTH levels were significantly reduced at week 1 (WMD = 901.1, 95% CI: 762.1 ∼ 1,040.09, p< 0.001, I²=88.8%) (Figure 2(A)), 1 month (WMD = 945.33, 95% CI: 797.15 ∼ 1,093.52, p< 0.001, I²=85%) (Figure 2(B)), 6 months (WMD = 1,151.91, 95% CI: 990.93 ∼ 1312.89, p< 0.001, I²=93.7%) (Figure 2(C)) and end of the follow-up period (WMD = 856.25, 95% CI: 680.8 ∼ 1,031.71, p< 0.001, I = 89.7%) (Figure 2(D)) after microwave ablation of SHPT patients.

Figure 2. Forest plots showing PTH levels in SHPT patients before and after MWA. A) Week 1; B) 1 month; C) at 6 months; and D) end of follow-up period.

Calcium levels

Data regarding calcium levels were reported in 22 articles. The results revealed that the calcium levels were significantly reduced at week 1 (WMD = 0.36, 95% CI: 0.25 ∼ 0.47, p< 0.001, I²= 87.9%) (Figure 3(A)), 1 month (WMD = 0.40, 95% CI: 0.28 ∼ 0.51, p< 0.001, I²=86.3%) (Figure 3(B)), 6 months (WMD = 0.39, 95% CI: 0.30 ∼ 0.48, p< 0.001, I²= 85.1%) (Figure 3(C)) and end of the follow-up period (WMD = 0.29, 95% CI: 0.23 ∼ 0.36, p= 0.001, I²=67.5%) (Figure 3(D)) after microwave ablation of SHPT patients.

Figure 3. Forest plots showing calcium levels in SHPT patients before and after MWA. A) Week 1; B) 1 month; C) 6 months; and D) end of follow-up period.

Phosphorus levels

Data regarding the phosphorus levels were reported in 19 articles. The results showed that the phosphorus levels were significantly reduced at week 1 (WMD = 0.42, 95% CI: 0.27 ∼ 0.58, p< 0.001, I²=78.2%) (Figure 4(A)), 1 month (WMD = 0.52, 95% CI: 0.35 ∼ 0.69, p< 0.001, I²=81.4%) (Figure 4(B)), 6 months (WMD = 0.64, 95% CI: 0.43 ∼ 0.85, p< 0.001, I²=90.6%) (Figure 4(C)) and end of the follow-up period (WMD = 0.35, 95% CI: 0.20 ∼ 0.49, p< 0.001, I²= 72.7%) (Figure 4(D)) after microwave ablation of SHPT patients.

Figure 4. Forest plots showing phosphorus levels in SHPT patients before and after MWA. A) Week 1; B) 1 month; C) 6 months; and D) end of follow-up period.

Alkaline phosphatase (ALP) levels

Data regarding the ALP levels were reported in five articles. The ALP measurements obtained on day 1 after microwave ablation showed no significant differences (WMD = 17.67, 95% CI: −14.06 ∼ 49.41, p= 0.999, I²=0%) (Figure 5(A)) from those obtained before microwave ablation. However, the ALP levels were significantly reduced at the end of the follow-up period (WMD = 133.88, 95% CI: 9.93 ∼ 257.82, p= 0.002, I²=77.2%) (Figure 5(B)) after microwave ablation of SHPT patients.

Figure 5. Forest plots showing ALP levels in SHPT patients before and after MWA. A) one day; B) end of follow-up period.

Adverse events

Hypocalcemia

Data regarding the incidence of hypocalcemia were reported in 13 articles. The incidence of hypocalcemia after microwave ablation of SHPT patients was shown to be 35.2% (136/386; ES = 0.35, 95% CI: 0.21 ∼ 0.49, p< 0.001, I²=93.7%) (Figure 6(A)).

Figure 6. Forest plots showing complications in SHPT patients after MWA. A) Hypocalcemia; B) hoarseness; C) nerve injury; D) hematoma; E) subcutaneous edema; and F) swallowing water.

Hoarseness

Data regarding the incidence of hoarseness were reported in 13 articles. The incidence of hoarseness after microwave ablation of SHPT patients was shown to be 9.2% (41/447; ES = 0.07, 95% CI: 0.04 ∼ 0.11, p = 0.097, I²=35.8%) (Figure 6(B)).

Nerve injury

Data regarding the incidence of nerve injury were reported in 7 articles. The incidence of nerve injury after microwave ablation of SHPT patients was found to be 7.2% (18/251; ES = 0.04, 95% CI: 0.02 ∼ 0.07, p= 0.189, I²=31.3%) (Figure 6(C)).

Hematoma

Data regarding the incidence of hematoma were reported in 7 articles. The results showed that the incidence of hematoma after microwave ablation of SHPT patients was 3.6% (8/222; ES = 0.03, 95% CI: 0.01 ∼ 0.05, p= 0.913, I²=0%) (Figure 6(D)).

Subcutaneous edema

Data on the incidence of subcutaneous edema were reported in 3 articles. The incidence of subcutaneous edema after microwave ablation of SHPT patients was shown to be 9.5% (13/137; ES = 0.09, 95% CI: 0.04 ∼ 0.14, p= 0.79, I²=0%) (Figure 6(E)).

Swallowing water

Data regarding the incidence of swallowing water has been reported in 4 articles. It was shown that the incidence of swallowing water after microwave ablation of SHPT patients was 10% (19/190; ES = 0.08, 95% CI: 0.04 ∼ 0.12, p= 0.199, I²=35.6%) (Figure 6(F)).

Sensitivity analysis

Sensitivity analyses were performed to examine the influence of exclusion of each study on the combined results, and assess the robustness of all results. Each study was excluded at a time, and the pooled results of the remaining studies showed no significant differences (Supplementary Figure 1).

Publication bias

The funnel plots for meta-analysis of US-guided microwave ablation for SHPT are shown in Supplementary Figure 2. The results of Begg’s and Egger’s tests (PTH levels: Begg’s test p= 0.276, Egger’s test p= 0.637; Calcium levels: Begg’s test p= 0.858, Egger’s test p= 0.916; Phosphorus levels: Begg’s test p= 0.251, Egger’s test p= 0.355) indicated no evidence of publication bias.

Discussion

Despite potential complications associated with parathyroidectomy, such as transient or permanent hypocalcemia and laryngeal nerve injury, SHPT patients still obtained many benefits from this surgery. These include improvements in serum phosphorus and calcium levels, bone density, survival and relief from symptoms. Therefore, the Kidney Disease Improving Global Outcomes (KDIGO) currently recommends parathyroidectomy for patients with severe SHPT who are ineffective to drug treatment [50]. However, parathyroidectomy is not suitable for all patients with severe SHPT due to various reasons, such as preoperative hypocalcemia, the elderly with multiple comorbidities. Therefore, treatment strategies remain challenging in these patients and for clinicians. Several recent preliminary studies have confirmed that the destruction of parathyroid tissue in SHPT patients by ultrasound-guided MWA is considered as a safe and effective approach [14,28,30]. In this study, the efficacy and safety of US-guided MWA of SHPT patients were evaluated by systematic review and meta-analysis. Eighteen studies consisting of 932 patients were included. Our meta-analysis results revealed that PTH, serum calcium and phosphorus levels were significantly reduced at week 1, 1 month, 6 months and end of the follow-up period after MWA of SHPT patients.

Different from the results of previous meta-analysis study [51], the current meta-analysis study has fully gathered the data from a wide range of results and provided more in-depth insights on important clinical results. Also, due to the inclusion of additional studies and larger amounts of pooling, the results are different from that of the previous meta-analysis. A previous meta-analysis conducted by Cao et al. [51] has been limited due to inclusion of only eight studies that compared pre-ablative and post-ablative clinical results. The present study included 18 additional eligible studies. In addition, the results of this meta-analysis are not exactly the same as those of Cao et al. on the primary outcomes assessed. Cao et al. found no significant differences in terms of calcium levels at 6 months after MWA of SHPT patients, which were inconsistent with that of the previous meta-analysis. However, the present results indicated that calcium levels were significantly reduced at 6 months after MWA in patients with SHPT. The difference in these results might again be due to the larger sample size of this study as compared to the previous studies.

The side effects and minor complications reported in the present study included subcutaneous edema (9.5%), swallowing water (10%), transient hoarseness (9.2%) and hypocalcemia (35.2%). In contrast, recurrent or persistent SHPT patients after percutaneous ethanol injection therapy (PEIT) experienced transient hoarseness (5–30.6%) and hypocalcemia (40.8%) [52,53], and transient hoarseness (16.7%) after laser ablation [54]. Minor complications or side effects after high-intensity focused ultrasound (HIFU) treatment of SHPT patients included mild subcutaneous edema (60%), prolonged vocal cord dysfunction (40%), difficulty in swallowing water (20%), and prolonged bitonal voice (20%) [55]. However, the main complications and mortality rates associated with surgery are 6–21.6% and 1.7% respectively. The major complications included permanent mono- or double-sided laryngeal nerve injury, permanent parathyroid dysfunction, wound infection, postoperative hemorrhage and pneumonia [56,57].

However, there are some limitations in this study that should be acknowledged. Firstly, the heterogeneity included in this study was significant and observed throughout the analysis. Despite the heterogeneity observed in the study, the results of sensitivity analysis were considered reliable and robust. Secondly, most of the samples included in this trial were small. Thirdly, although published bias and sensitivity analyses confirmed the credibility of our analysis, this meta-analysis still showed heterogeneity due to several factors such as patient characteristics, sample size and treatment procedures that were not included in our analysis. Finally, most of the articles included were retrospective studies, and not randomized controlled trials. This limitation leaves a large gap in the existing evidence, and so further analysis of randomized controlled trials should be conducted. These factors should be clarified in the future research.

In summary, this meta-analysis indicated that MWA significantly reduced PTH, serum calcium and phosphorus levels in SHPT patients without increasing overall complications. Therefore, MWA is considered as a minimally invasive technique that is safe and effective for the management of SHPT. In addition, large-scale studies, such as randomized controlled trials, should be designed in the future to obtain more results.

Abbreviations
MWA	=	Microwave ablation
SHPT	=	secondary hyperparathyroidism
PTH	=	parathyroid hormone
HPT	=	hyperparathyroidism
ESRD	=	end-stage renal disease
iPTH	=	intact parathyroid hormone
PRISMA	=	Preferred Reporting Items for Systematic Reviews and Meta-analysis
CNKI	=	China national knowledge infrastructure
NOS	=	Newcastle-Ottawa Scale
ES	=	effect size
CIs	=	confidence intervals
ALP	=	Alkaline phosphatase
HIFU	=	high-intensity focused ultrasound

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The study was supported by the Science and Technology Bureau of Changshu City, Jiangsu Province in 2019[CS201911].