Introduction

Primary hyperparathyroidism (PHPT) is a condition characterised by an elevation in serum calcium associated with high or non-suppressed levels of parathyroid hormone (PTH). Well-recognized complications associated with PHPT include kidney stones, peptic ulcers and osteoporosis. Parathyroidectomy (PTx) in PHPT leads to overall improvement in bone health, and a reduction in peptic ulcers and prevents deterioration in renal function [1,2]. One of the most significant implications of PHPT is an increased risk of cardiovascular disease (CVD) [3]. Despite much research in recent years, there is conflicting evidence on the benefits of PTx in reducing the incidence of CVD in this cohort of patients.

The presence of cardiovascular risk factors is not included in endocrine or surgical guidelines as an indication for PTx. This is due to the lack of conclusive evidence of the benefits of PTx on CVD. There are several ways to assess CVD and studies use different endpoints. The outcomes include blood pressure, cholesterol levels, echocardiographic findings, cardiovascular events and mortality. Due to the multiple endpoints, there is very little high-quality evidence to determine whether there is a cardiovascular benefit to surgery in PHPT.

The outcomes which have been shown to have a potential benefit include blood pressure [4,5] and cholesterol levels [6]. Some studies have also shown an improvement in echocardiographic findings [7] and mortality rates [1]. However, there were limitations in all these studies and there are also contradictory results in the literature. Therefore, the results of these studies must be interpreted with caution.

This demonstrates the potential for PTx to reduce the risk of CVD in PHPT and highlight the necessity for further analysis to attain conclusive evidence of this potential benefit. The aim of this study is to perform a systematic review and meta-analysis to investigate the impact of PTx in PHPT on cardiovascular outcomes.

Methods

This systematic review and meta-analysis was performed in accordance to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and MOOSE guidelines [8,9]. The study was registered on PROSPERO (registration number: CRD42022376563). Each author contributed to formulating the study protocol. Local institutional ethical review and approval was not required.

PICO

Using the PICO framework, the aspects the authors wished to address were:

Population – Patients with a confirmed diagnosis of PHPT.

Intervention – Any patients in the selected group who were treated with PTx.

Comparison – Post-operative values were compared with pre-operative values.

Outcomes – Primary outcomes included: Blood pressure, cholesterol levels, fasting serum glucose levels and echocardiogram findings.

Search strategy

An electronic search was performed of the PubMed Medline, EMBASE and Scopus databases for relevant studies. This search was performed by two independent reviewers (G.G.C. and D.V.W.), using a predetermined search strategy that was designed by the senior author (A.D.K.H.). This search included the search terms: (primary hyperparathyroidism), (parathyroidectomy), and (cardiovascular outcomes), with ‘AND’ as a Boolean operator. Included studies were limited to the English language. The search was not restricted by year of publication. All duplicate studies were manually removed before titles were screened, and studies considered appropriate had their abstracts and full text reviewed. Retrieved studies were reviewed to ensure inclusion criteria were met for one primary outcome at a minimum. In cases of discrepancies of opinion, a third author was asked to arbitrate (J.B.). The final search was performed on 11 October 2022.

Inclusion and exclusion criteria

Clinical studies which provided pre- and post-operative values of cardiovascular outcomes in patients with PHPT treated by PTx were included. The pre- and post-operative values were compared. Outcomes of interest included SBP, DBP, total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides, fasting serum glucose levels, left ventricular ejection fraction percentage (LVEF%) and left ventricular mass index (LVMI). Studies including patients with secondary or tertiary hyperparathyroidism were excluded. Review articles, case reports, case series reporting outcomes in five patients or less, and editorial articles were all excluded.

Data extraction and quality assessment

The following data was extracted and collated from retrieved studies meeting inclusion criteria: [10] first author name [2], year of publication [3], study design [4], country of origin [5], number of patients who underwent PTx [6], mean age [7], how long after surgery the post-operative values were recorded [8] pre- and post-operative values of the outcomes of interest. In studies that provided post-operative values of the primary outcomes at multiple timepoints, we extracted the 6-month value as this was the most commonly used timepoint across all studies. In studies that did not have data at the 6-month timepoint, we extracted the data closest to this timepoint. This was in an attempt to improve the consistency of our results and limit the risk of bias. Risk of bias and methodology quality assessment was performed in accordance with the Newcastle-Ottawa Scale [11].

Statistical analysis

Pre- and post-operative data were expressed as continuous outcomes, reported as mean differences (MDs), and expressed with 95% confidence intervals (CIs) following estimation using the Mantel-Haenszel method. Statistical heterogeneity was determined using I2 statistics. Either fixed or random effects models were applied on the basis of whether significant heterogeneity (I2 > 50%) existed between studies included in the analysis. All tests of significance were two-tailed with P < 0.050 indicating statistical significance. Meta-analysis was performed using Review Manager, Version 5.4 (Nordic Cochrane Centre, Copenhagen, Denmark).

Results Literature search

Overall, 1741 studies were identified in the database search, of which, 130 were duplicates and 96 were not in the English language. Following screening of titles, 1471 studies were excluded. Of the remaining 44 articles, 13 were excluded after abstract screening. Finally, 31 full texts were screened and 15 were excluded as they did not meet the inclusion criteria leaving 16 studies for review. The search strategy and study identification are summarised in the PRISMA flow diagram (Fig. 1).

Fig. 1:

PRISMA flow diagram of study identification.

Study characteristics

There were 16 studies included in this systematic review and meta-analysis [12–27]. Overall, 87.5% of the included studies were prospective in design (14/16). One was a retrospective study and one was a randomised control trial (RCT). Publication dates ranged from 1998 to 2022. Data relating to the studies included in the meta-analysis are outlined in Table 1.

Table 1 - Data from the studies included in the meta-analysis Author Year Country Journal Study type Number of patients Beysel 2019 Turkey BMC Cardiovasc Disord Retrospective 60 Agarwal 2013 India Surgery Prospective 56 Farahnak 2010 Sweden Eur J Endocrinol Prospective 51 Luigi 2012 Italy Int J Endocrinol Prospective 30 Kepez 2017 Turkey Wien Klin Wochenschr Prospective 22 Piovesan 1999 Italy Clin Endocrinol (Oxf) Prospective 21 Valdemarsson 1998 Sweden J Intern Med Prospective 117 Frey 2022 France J Clin Med Prospective 139 Atasever 2020 Turkey Echocardiography Prospective 29 Storvall 2017 Finland Horm Metab Res Prospective 104 Cansu 2016 Turkey Clin Endocrinol (Oxf) Prospective 17 Tuna 2015 Turkey Clin Endocrinol (Oxf) Prospective 20 Walker 2012 USA Eur J Endocrinol Prospective 44 Rudman 2010 UK Endocr Res Prospective 12 Almqvist 2002 Sweden Surgery RCT 25 Hagström 2002 Sweden Clin Endocrinol (Oxf) Prospective 49

Risk of bias assessment highlighted the prevalence of performance bias and allocation concealment bias across the included studies. There was a low risk of selection, attrition and reporting bias. Risk of bias is outlined in Figs. 2 and 3.

Fig. 2:

Overall risk of bias assessment.

Fig. 3:

Risk of bias assessment by study.

Patient characteristics

In total, there was data from 796 patients included in the 16 studies. The mean age at surgery was 60.4 years (range 29–90 years) and BMI was 26.6 kg/m2. The mean pre- and post-operative calcium levels were 2.74 mmol/L and 2.31 mmol/L, respectively.

Primary outcomes Blood pressure

There were 9 studies that assessed SBP pre- and post-operatively in a combined total of 495 patients. Eight of these were prospective and one study (Beysel 2019) was retrospective. This analysis found a significant reduction in SBP in patients post-operatively [MD: 8.07, 95% CI: 2.80–13.33, P = 0.003, I2 = 92% (Fig. 4a)].

Fig. 4:

(a) Effect on SBP (mmHg). (b) Effect on diastolic blood pressure (mmHg).

The same 9 studies reported DBP values pre- and post-operatively. There was a reduction in DBP values in patients post-operatively but this reduction is on the cusp of significance [MD: 2.88, 95% CI: –0.05–5.80, P = 0.050, I2 = 91% (Fig. 4b)].

Cholesterol levels

There were 7 studies that assessed total cholesterol levels pre- and post-operatively in a combined total of 438 patients. Six of these studies were prospective and one was retrospective. There was no difference found in this analysis [MD: −0.05, 95% CI: −0.14 to 0.04, P = 0.320, I2 = 59% (Fig. 5a)].

Fig. 5:

(a) Effect on total cholesterol levels (mmol/L). (b) Effect on high-density lipoprotein levels (mmol/L). (c) Effect on low-density lipoprotein levels (mmol/L). (d) Effect on triglyceride levels (mmol/L).

Seven different studies investigated the impact of PTx on HDL levels. This analysis included 354 patients. There was no significant change in HDL levels post-operatively (MD: 0.02, 95% CI: −0.01 to 0.04, I2 = 36% (Fig. 5b)].

Again, 7 different studies with a combined total of 359 patients reported LDL levels before and after surgery. This analysis found no significant difference [MD: 0.08, 95% CI: −0.14 to 0.30, P = 0.480, I2 = 83% (Fig. 5c)).

Finally, 6 studies reported the effect of PTx on triglyceride levels in 439 patients. Again, there was no difference between the pre- and post-operative levels [MD: 0.03, 95% CI: −0.15 to 0.22, P = 0.730, I2 = 94% (Fig. 5d)].

Fasting blood glucose levels

Nine studies reported on fasting blood glucose levels in patients with PHPT who underwent PTx. Eight of these were prospective and one was retrospective. There were 499 patients included in this analysis. This found a significant reduction post-operatively [MD: 0.18, 95% CI: 0.09–0.26, P < 0.0001, I2 = 75% (Fig. 6a)].

Fig. 6:

(a) Effect on fasting blood glucose levels (mmol/L).

Echocardiographic outcomes

There were 7 studies including 234 patients which reported on LVEF% pre- and post-operatively. Six of these were of prospective design and one was a RCT. There was no significant difference found in LVEF% post-operatively [MD: −0.57, 95% CI: −3.27 to 2.13, P = 0.680, I2 = 0.680 (Fig. 7a)].

Fig. 7:

(a) Effect on left ventricular ejection fraction percentage. (b) Effect on left ventricular mass index (g/m2).

Seven different studies reported on LVMI in patients with PHPT pre- and post-PTx. Again, one of these was an RCT and the other six were prospective. This analysis included 249 patients and while the LVMI was reduced post-operatively, this finding fell short of statistical significance [MD: 7.85, 95% CI: −0.64 to 16.34, P = 0.070, I2 = 86% (Fig. 7b)].

Discussion

PHPT is a common disorder with a prevalence between 1 and 7 cases per 1000 adults [28–31] and is the most common cause of hypercalcaemia outside of the hospital setting [32]. It is two to three times more common in women than men [32]. Management of PHPT comprises medical surveillance and/or surgery. Medical management is the typical approach in asymptomatic PHPT [33]. Indications for surgery as per the National Institute for Health and Care Excellence guidelines include serum calcium >0.25 mmol/L above the normal limit, reduced T-score on bone density scan, vertebral fracture, impaired renal clearance, nephrolithiasis, or age less than 50 years.

Among patients with symptomatic PHPT, there is an increase in the presence of CVD including myocardial and vascular calcification as well as cardiovascular mortality [34]. The opposite is true in mild or asymptomatic PHPT. However, CVD is not included as an indication for surgery. The American Association of Endocrine Surgeons (AAES) outlined a list of evidence-based recommendations for intervention in PHPT [35]. As observational studies in mild (asymptomatic) PHPT have reported conflicting data about the impact of PTx on cardiac parameters, it is advised to weigh the possibility of improving cardiovascular morbidity and mortality on a case-by-case basis. Given that CVD, and particularly hypertension, is commonly seen in those with symptomatic PHPT [34] and the NICE guidelines recommend surgery in these cases, we sought to analyse the impact of PTx on cardiovascular risk factors.

This study found a significant reduction in SBP (P = 0.003) and a reduction in DBP falling just short of significance (P = 0.050), associated with surgery in PHPT. In 2020, Nelson et al. found a statistically significant improvement in both blood pressure and the incidence of metabolic syndrome in patients 1-year post-PTx [4]. Similarly, Graff-Baker et al. demonstrated a significantly lower mean arterial pressure and number of medications in patients 6 months, 1 year and 2 years after PTx than in those who had no surgery [5]. An important limitation of this study was the mean age of those who underwent surgery was significantly lower than those who did not. However, our analysis shows that PTx possibly improves blood pressure irrespective of age and suggests there may be a benefit to surgery in patients with PHPT who have hypertension. High blood pressure is a well-known risk factor for CVD and lowering blood pressure significantly reduces cardiovascular morbidity and mortality [36–38].

The results of this meta-analysis confirm that surgery does not improve cholesterol levels. Ejlsmark-Svensson et al. illustrated a benefit of PTx on total cholesterol levels 3 months after surgery compared with those who were managed conservatively [6]. The findings of this RCT were limited as patients with severe hypercalcemia were excluded. Furthermore, the difference in cholesterol levels between the two groups was due to total cholesterol levels in the control group disimproving rather than PTx leading to an improvement in cholesterol values. As our analysis only compares pre- and post-operative values, we are unable to comment on the impact of alternate treatment approaches on cholesterol levels. However, the findings of this RCT raise the point that it could be worth further investigating if PTx is a superior approach compared to pharmacological treatment of PHPT in terms of preventing cholesterol levels from getting worse.

In terms of fasting blood glucose levels, a significant reduction was found in patients post-operatively at meta-analysis (P < 0.0001). This was unsurprising as an unfavourable glycaemic profile in this patient cohort has been reported in the literature [39]. It is suggested that there is a direct adverse effect of PHPT on glucose homeostasis. PTx has been shown to decrease insulin resistance in patients with PHPT [40] and therefore, leads to improved glucose metabolism. Insulin resistance causes damage to the myocardium by signal transduction alteration, impaired regulation of substrate metabolism, and altered delivery of substrates to the myocardium [41]. Moreover, there is a significant correlation between atherosclerosis and glucose metabolism and higher glucose levels are associated with more severe disease [42]. Elevated glucose levels have also long been associated with heart failure [43]. The negative cardiovascular implications of increased blood glucose and insulin resistance are clear. In keeping with the association of PHPT and glucose levels along with the results of this study, PTx likely has a role in reducing glucose levels.

A recent meta-analysis revealed that PTx improved LVMI and that higher pre-operative PTH values were associated with the best improvements [7]. Our meta-analysis found that the difference in LVMI post-operatively fell short of significance (P = 0.070) and that LVEF was not affected (P = 0.680). The previous meta-analysis solely focussed on LVMI and therefore, had more focused search terms and included 15 studies. Our analysis did not reach statistical significance. However, the follow-up time was perhaps too short to elicit any significant change in LVMI. Considering the findings by McMahon et al [7]., the authors feel that there is a potential benefit to surgery in terms of improving LVMI and this should be investigated further.

This systematic review and meta-analysis is subject to a number of limitations. First, many of the included studies are prospective in design, and although there is only one retrospective study included, the results are inherently prone to bias. There was only one RCT included in our analysis indicating ascertainment, selection, and confounding biases. The studies included in the analysis have significant bias within them, and with small numbers of patients over a wide time range. This means there is heterogeneity between studies, which of course has ramifications upon the reliability of the results. Second, as we only evaluated pre- and post-operative values, many of the trials were not blinded in terms of treatment approach, predisposing to a potential for performance bias. Furthermore, we did not compare the outcomes of surgery with medical surveillance or pharmacological treatment. Thirdly, there was a big variety in the mean pre-operative calcium levels between some studies. For example, Piovesan 1999 reported levels of 2.94 while both Almqvist 2002 and Walker 2012 reported mean levels of 2.62. This likely has implications upon the results of our meta-analysis. Additionally, each sub-group analysis had less than the 16 total studies included in this review. Finally, it is worth noting that PTx is more likely to be indicated in those with advanced disease and symptoms at which stage, structural and physiological changes (causing hypertension and metabolic syndrome) due to chronically raised PTH may have become irreversible [4]. Another important consideration is that cardiovascular risk factors in patients could be due to underlying conditions not related to PHPT [44]. It is also worth mentioning that despite finding a significant reduction in SBP and fasting blood glucose levels, this analysis does not confirm whether this, in fact, improves cardiovascular outcomes.

Despite the aforementioned limitations, this study has many strengths. To our knowledge, it is the first meta-analysis that investigates the impact of surgery in PHPT on a wide range of cardiovascular parameters. The current recommendations for surgery as outlined by the AAES are unclear regarding the benefit in terms of cardiovascular outcomes. Moreover, CVD is not included in the NICE guidelines as an indication for PTx. Our study, however, demonstrates that there may be a benefit in some cases. It also highlights the necessity for further investigation in the form of an RCT to attain conclusive evidence and best advise the guidelines for surgery for PHPT in patients who have CVD.

Conclusion

This meta-analysis shows that PTx likely has a positive impact on SBP and blood glucose levels in patients with PHPT. Surgery also potentially improves DBP and LVMI. It is unclear if this in turn has any impact on long-term outcomes. These outcomes should be further investigated in the next generation of prospective, randomised studies to provide recommendations for intervention in PHPT patients with CVD.

Acknowledgements Conflicts of interest

There are no conflicts of interest.

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