Description of the condition
Primary hyperparathyroidism (PHP) is a common disorder of bone metabolism and hypercalcemia, occurring in 28 per 100,000 individuals yearly in the United States (Ning 2009), and in up to 2% of postmenopausal women. The most common etiology for the disease is a single gland adenoma in 80% to 85% of cases, with the rest of the cases constituting multiple gland hyperplasia (10% to 15%), double adenomas (2% to 5%) and carcinoma (1%). The molecular basis for sporadic hyperparathyroidism remains largely unknown. In some cases, it includes mutations in several proto-oncogenes and tumor suppressor genes, such as cyclin D1 and MEN1, that stimulate parathyroid gland growth, and as a result increase parathyroid hormone (PTH) secretion (Pyram 2011).
Since the development of adequate screening techniques, the disorder has evolved in developed countries into a mostly asymptomatic disease, often picked up as a laboratory abnormality, hypercalcemia, incidentally discovered via routine examinations. Conversely, in developing countries, classical presentations prevail including bone pain, nephrolithiasis, nephrocalcinosis, bone loss, increased fractures, and osteitis fibrosa cystica (Bilezikian 2000; Parfitt 1991). Skeletal effects seen through changes in bone mineral density (BMD) and histomorphic analysis were originally thought to be most prominent at cortical bony sites. However, newer studies have noted volumetric BMD loss at both sites (Chen 2003) and an increased fracture risk in both traditional cortical bony areas, such as the distal radius, as well as trabecular bony areas like the vertebrae (Khosla 2002). Renal calcification or stones appear to be increased up to four-fold in patients with PHP compared to controls (Starup-Linde 2012; Suh 2008). Non-classical manifestations of PHP include impaired concentration, decreased non-verbal learning process, difficulties in using direct memory, verbal fluency and visual constructive abilities (Babinska 2012).
Description of the intervention
In general, while surgery for hyperparathyroidism in the setting of chronic kidney disease often involves subtotal parathyroidectomy or total parathyroidectomy with autotransplantation (Al-Rawashdeh 2012), surgery for primary hyperparathyroidism aims to resect the diseased gland(s) and, therefore, remove the source for excess PTH production; the ultimate goal is to thus decrease the incidence of nephrolithiasis, improve bone mineral density, decrease fractures, and improve quality of life. Even in asymptomatic individuals, there is evidence that surgery improves BMD, functional capacity and quality of life (Ramakant 2012). Therefore, surgery is indicated for all patients with symptomatic PHP, and some patients with asymptomatic PHP presenting with either a serum calcium concentration of 1.0 mg/dl or more above upper limit of normal, creatinine clearance equal to or less than 60 ml/min, a bone density at any site with a T-score less than -2.5, or age less than 50 years (Bilezikian 2009). The T-score is a person's bone density compared with what is normally expected in a healthy young adult of the same sex. The T-score is the number of units (standard deviations) that this person's bone density is above or below the average.
Biateral neck exploration
Bilateral neck exploration is the traditional approach to primary sporadic hyperparathyroidism. While minimally invasive parathyroidectomy has largely replaced such an approach, bilateral neck exploration remains the mainstay treatment for patients with unlocalized pathology, familial or hereditary cases, or concomitant thyroid disease. The exploration is done via direct visualization of all parathyroid glands, and may be performed under local or general anesthesia, through an open traditional incision, minimally invasive incision, or even via a videoscopic approach (Alesina 2011; Allendorf 2007; Lo 1999; Lowney 2000).
Minimally invasive parathyroidectomy (MIP)
We will use the 2002 summary statement on asymptomatic hyperparathyroidism definition for MIP, mainly that it is a set of techniques employing preoperative imaging and intraoperative parathyroid hormone assays (IOPTH) to limit surgical visualization only to the suspected gland (Bilezikian 2002). There are currently several variations for techniques satisfying these criteria. In general, focused parathyroidectomy aims towards visualization of just the suspected gland, whereas unilateral exploration visualizes the entire side suspected to have a pathology. Exploration is either open or endoscopic. Two common endoscopic techniques are described in the literature, and offer advantages of magnified vision and tactile control over the procedure (Gracie 2012; Henry 1999; Miccoli 1999). The technique suggested by Henry et al uses a more lateral approach avoiding dissection of the strap muscles and allowing possible direct visualization of the adenoma but compromises through the frequent requirement of carbon dioxide insufflation in order to maintain an adequate working space. The technique suggested by Miccoli et al on the other hand suggests a more medial approach wherein gas insufflation is only maintained for a few minutes in order to allow for dissection of the strap muscles, after which a working space is maintained simply by the use of external retraction. This 'gasless approach' promised to avoid emphysema, pneumomediastinum, and neck swelling (Henry 1999; Miccoli 1999). Despite the nuances of slight differences in technique, the fundamental methods of all MIP are the same. Single gland disease is identified and localized by use of either preoperative ultrasound, Sestamibi scan (technetium (99mTc) nuclear medicine imaging), or both. A limited exploration then targets the suspicious side or gland in an attempt to avoid a cumbersome full neck exploration (Irvin 1991; Irvin 1994; Udelsman 2004). Intraoperative PTH (IOPTH) monitoring is carried out generally through peripheral venous measurements, with pre-incision, pre-gland ligation, and 5,10, and 20 minutes post-gland ligation measurements being drawn. Criteria used for evidence of adequate incision, and thus termination of surgery, vary widely. The most accepted, the Miami criterion, considers a decrease in PTH measurement by more than 50% from the highest baseline to the 10 minutes value post-gland ligation as evidence for adequate gland excision (Barczynski 2009; Carneiro-pla 2009; Irvin 1993). In the event of inadequate decline using this criterion, surgery is then converted to a bilateral conventional technique, possibly due to location of abnormal gland on the opposite side or due to suspicion of multiglandular disease. MIP techniques are usually offered to patients with preoperative localization studies suggestive of single gland disease, in the absence of thyroid pathology, familial or hereditary hyperparathyroidism, and of lithium intake.
Adverse effects of the intervention
Apart from a theoretical concern for possibilities of subcutaneous emphysema following gas insufflation in the endoscopic technique described by Henry et al (Henry 1999), both bilateral neck exploration and MIP have essentially similar adverse events, which are rare for both. These include anesthesia-related or postoperative complications, or both, such as hypocalcemia, vocal cord paralysis, hematomas, and infections. A retrospective review of 656 parathyroid operations showed a 3% complication rate for bilateral neck exploration and a 1.2% complication rate for MIP (Udelsman 2002). Hematomas are potentially life threatening complications arising in 0.3% of surgeries, and may present with a variety of symptoms including neck pain, respiratory distress, dysphagia and wound drainage (Burkey 2001; Carty 2004). Hypoparathyroidism is commonly transient and presents with decreased calcium concentration in association with either mild symptoms of tingling or numbness, or more severe symptoms like profound fatigue or carpopedal spasm. Severe hypocalcemia is rare unless after subtotal parathyroidectomy (Carty 2004). Such presentations are only transient and permanent hypoparathyroidism occurred in only 0.3% of 380 operations reviewed by Carty et al (Carty 2002). Similarly, permanent recurrent laryngeal nerve injury is very rare. In recent reports, 0.2% of 1112 patients, and 3 of 401 bilaterally explored patients had permanent recurrent laryngeal nerve injury (Allendorf 2007; Udelsman 2002) whereas 0.3% of 380 patients and 1 of 255 patients receiving a minimally invasive surgery had similar injury (Carty 2002; Udelsman 2002). Differences in the incidence of adverse effects between MIP and bilateral neck exploration are controversial and randomized controlled trials (RCT) have differing findings. Apart from scar length differences, Slepavicius et al did not report any significant differences in adverse events between intervention groups, Miccoli et al noted insignificant differences in one study and did not have any adverse events in either group in another, while Bergenfelz et al noted a greater incidence of severe hypocalcemia in the bilateral group (10% versus 0%) (Bergenfelz 2005; Miccoli 1999; Miccoli 2008; Rulli 2007; Slepavicius 2008).
How the intervention might work
The theoretical basis behind MIP is that most cases are caused by single gland pathology, and that modern tools can identify such pathology with acceptable accuracy, rendering the need for complete visualization of both sides of the neck almost obsolete. This may also decrease operative time and cost, although this has been debatable (Bergenfelz 2002; Miccoli 1999). Indeed, more than 80% of spontaneous primary hyperparathyroidism is caused by a single solitary adenoma (Kunstman 2012). Improvements in imaging techniques have reached sensitivities between 71% to 80% for ultrasound imaging and a sensitivity greater than 90% for Sestamibi scanning (Dijkstra 2002). The advent of intraoperative PTH monitoring assays have optimized the accuracy of adequate resection, reaching accuracy greater than 96% for the Miami criterion (Barczynski 2009; Carneiro 2003), and ensured the success of MIP for most surgeons. Indeed, by 2008, 68% of American surgeons were found to be practicing limited exploration techniques and only 10% practiced bilateral neck exploration exclusively (Greene 2009).
Why it is important to do this review
The importance of our review stems from the large number of patients undergoing these procedures yearly, without a definitive answer about the long-term success of MIP. The greatest uncertainty in this subject stems from concerns about increased long-term recurrence or missed multi-glandular disease in patients undergoing MIP. We are aware of only one RCT that had an extended follow-up for five years postoperatively. The investigators noted 4/47 recurrent cases in the MIP group compared to 2/44 in the conventional exploration group, with these results being statistically nonsignificant (Westerdahl 2007). Notably, 75% of patients in the MIP group who recurred had converted from MIP to bilateral neck exploration. A recent retrospective analysis by a high volume group found that the long-term failure rate of the unilateral approach was 11 times higher than that of conventional bilateral surgery. However, that group is known for not using IOPTH monitoring (Norman 2012). Another group noted a higher than 8% recurrence rate after eight years of follow-up in patients undergoing MIP as opposed to 0% in the open parathyroidectomy group (Schneider 2012). The differences were not significant because of the small number of patients followed up for this duration. Identifying further publications with long-term follow-up may either quell concerns, re-ignite them, or highlight the urgent need for long-term outcome studies.
The review will help characterize the respective risks and benefits of each type of surgery more clearly, both in the short term and longer term. Few RCTs have been published on this topic, often with differing conclusions, as was demonstrated in the adverse events section. A properly conducted systematic review and meta-analysis will provide an objective risk-benefit assessment for both techniques, on prespecified patient outcomes, in the short term as well as at long-term follow-up. This will serve to empower patients and doctors alike in making better educated choices.
Furthermore, we only identified one recent systematic review comparing both approaches on the topic (Gracie 2012). The above mentioned review had several limitations: amongst other things it excluded unilateral exploration. We also find the above-mentioned review to be deficient in key criteria reflecting methodological quality. On AMSTAR (Shea 2007), a validated tool used for assessing methodological quality of systematic reviews, the previous review scored only two out of a possible 11 queries positively. Inclusion and exclusion criteria were provided in a table format but the type of studies, languages, and publication status (grey literature) were not discussed. The methods of study selection and data abstraction were also not entirely clear and there was no indication of whether these processes occurred in duplicate. While the search study was presented in the paper, the initial results, excluded studies, and reasons for exclusions were not presented. There was no meta-analysis done for any of the outcomes of interest. There was also no attempt made to assess risk of bias in included studies.
The review also did not address what we feel is the greatest source of uncertainty in the topic, that is, long-term success rate. We believe that inclusion of this outcome is extremely important in order to truly gauge the long-term impact of potentially leaving residual enlarged tissue in patients who undergo minimally invasive techniques relying on localization studies and IOPTH monitoring. Our discussion will aim to highlight such long-term studies for specific analysis and discussion of the level of evidence we have about long-term outcomes.