Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.
Recommendations 1.1.1 to 1.1.10
Although no evidence was available, the committee are confident, based on their knowledge and experience, that albumin-adjusted serum calcium measurement produces an accurate indication of the amount of calcium that is active in the body. Calcium that is bound to albumin is not active and does not have clinical effects. Adjusting for albumin compensates for this, and allows better identification of the active calcium that may be causing symptoms or signs.
Limited evidence, and the committee's experience, suggest that hypercalcaemia in primary hyperparathyroidism is associated with particular symptoms, notably thirst, frequent or excessive urination, or constipation, and with conditions such as osteoporosis, fragility fractures or renal stones. Diagnostic testing is therefore indicated for people with these symptoms or conditions. However, the committee noted that hypercalcaemia is often asymptomatic and agreed that an incidental finding of elevated albumin-adjusted serum calcium in a person without symptoms should also trigger diagnostic testing.
Noting that people with primary hyperparathyroidism sometimes have chronic non-differentiated symptoms, the committee agreed that diagnostic testing could be considered for people with these symptoms. Examples include fatigue, depression, mild confusion, anxiety, irritability, insomnia or digestive problems. The committee acknowledged that there could be multiple causes for these symptoms and that their association with primary hyperparathyroidism is uncertain.
The committee agreed that ionised calcium should not be measured because point-of-care testing is not subject to the stringency of laboratory testing and the sample has to be handled very quickly, making ionised calcium measurement unreliable.
Because serum calcium levels can vary with changes in blood pH or serum albumin, and the cost of measurement is relatively low, the committee agreed that albumin-adjusted serum calcium should be measured at least twice before moving on to more expensive measurement of parathyroid hormone (PTH).
No evidence was available on measurement of PTH in the diagnosis or assessment of primary hyperparathyroidism. The committee based their recommendations on the normal reference range for albumin-adjusted serum calcium as defined by the Association of Clinical Biochemistry, which is 2.2 to 2.6 mmol/litre, and their own experience.
The committee noted that most people with primary hyperparathyroidism have an albumin-adjusted serum calcium level above 2.6 mmol/litre. However, they also discussed a type of primary hyperparathyroidism that affects a smaller number of people, in which the albumin-adjusted serum calcium level is within the normal range. This is known as 'normocalcaemic primary hyperparathyroidism' and it often goes unrecognised. To address this, the committee added a lower criterion of 2.5 mmol/litre (with clinical suspicion of primary hyperparathyroidism) for PTH measurement.
The committee were in agreement that PTH measurement can be done at any time of day. Although there is a marginal diurnal difference, it is not enough to need adjusting for. They agreed that the PTH measurement needs to be interpreted in the context of a concurrent albumin-adjusted serum calcium measurement. They also agreed that there is no benefit in repeating the PTH measurement in primary care.
The committee noted that PTH levels can vary widely from one individual to another, and that there is uncertainty about the level of PTH at which primary hyperparathyroidism can be ruled out. The reference range for PTH differs between laboratories so the committee were unable to specify numerical PTH thresholds.
The committee agreed, based on their experience, that advice from a specialist with expertise in primary hyperparathyroidism should be sought if:
PTH is above the midpoint of the reference range and primary hyperparathyroidism is suspected, because these features indicate that primary hyperparathyroidism is likely
PTH is below the midpoint of the reference range but albumin-adjusted serum calcium is raised, because this indicates that primary hyperparathyroidism cannot be ruled out.
If PTH is below the midpoint of the reference range and albumin-adjusted serum calcium is not raised, the committee agreed that primary hyperparathyroidism is unlikely.
The committee expects that these recommendations could lead to a change in practice for some providers. There may be an increased demand for primary care services (such as appointments or blood tests) as a result of increased awareness of symptoms such as thirst, frequent or excessive urination, or constipation. Repeating albumin-adjusted serum calcium measurements will increase the number of such tests but can be expected to reduce the number of PTH tests.
Implementing a standardised sequence of diagnostic tests should lead to more rapid diagnosis, and reduce the need to manage complications of undiagnosed primary hyperparathyroidism such as fractures, renal stones and chronic long-term symptoms.
Full details of the evidence and the committee's discussions are in evidence review A: indications for diagnostic testing and evidence review B: diagnostic tests.
Recommendations 1.2.1 to 1.2.3
No evidence was available on measuring vitamin D to assess primary hyperparathyroidism, so the recommendation is based on the committee's knowledge and experience.
The committee noted that vitamin D deficiency can lead to a rise in PTH level, exacerbate bone disease and increase postoperative risk. It is therefore important to assess and correct vitamin D for people with primary hyperparathyroidism. However, the committee were aware that vitamin D testing is not available to all primary care providers, and that waiting for vitamin D to be measured, and corrected if necessary, before seeking specialist advice could delay diagnosis. They therefore concluded that vitamin D measurement and correction are best carried out in secondary care.
The committee agreed that it is important to exclude familial hypocalciuric hypercalcaemia (FHH) because it needs no operative treatment. Evidence showed that the 3 tests recommended are equally accurate in the diagnosis of FHH. The committee were not able to recommend thresholds for these measurements because the evidence is inconsistent.
The committee agreed that baseline assessment will help to determine optimal management in secondary care. They did not recommend phosphate measurement because improvements in PTH assays have reduced its usefulness.
The committee acknowledged the potential of bone turnover markers to enable earlier and more accurate diagnosis of primary hyperparathyroidism but were unable to make a recommendation because of a lack of evidence. They therefore made a research recommendation on bone turnover markers.
Measuring vitamin D in secondary care is expected to be a change in practice for some services. Current practice varies, partly because of the varying availability of vitamin D measurement in primary care. In primary care services where vitamin D measurement is available, vitamin D is being measured and deficiencies corrected before PTH is measured. By standardising practice and reducing delays in diagnostic testing, the committee expects improvements in the diagnosis of primary hyperparathyroidism and more prompt treatment for people with the condition.
Measuring urine calcium excretion in secondary care is current practice.
Full details of the evidence and the committee's discussions are in evidence review A: indications for diagnostic testing and evidence review B: diagnostic tests.
Recommendations 1.3.1 and 1.3.2
There was no evidence available on surgery compared with non-surgical treatment for people with a confirmed diagnosis of primary hyperparathyroidism and symptoms or other indications for surgery. However, the committee reasoned that the lack of evidence is likely to reflect the broad consensus that surgery is beneficial for these people. The committee also agreed that surgery is cost effective because, although the initial cost is high, it can be expected to result in a cure and eliminate the need for further treatment. It relieves symptoms of hypercalcaemia such as thirst, polyuria and constipation, and can prevent future adverse events such as renal stones and fragility fractures. Non-surgical treatment, such as calcimimetics, is an ongoing cost with no curative benefit.
For people with a confirmed diagnosis of primary hyperparathyroidism but no symptoms or indications for surgery, the committee based their recommendation on limited evidence together with their clinical experience. They noted that surgery has shown benefits for this group. Although specific symptoms of primary hyperparathyroidism are absent, people in this group can experience non-specific symptoms such as fatigue, depression or muscle weakness that affect their quality of life. Furthermore, future decrements in quality of life and events associated with end‑organ damage may occur. Therefore surgery can be considered as a means of resolving non-specific symptoms and avoiding further deterioration in health.
The committee acknowledged the potential of bone turnover markers to help identify people who could benefit from surgery but were unable to make a recommendation because of a lack of evidence. They therefore made a research recommendation on bone turnover markers.
The recommendations are broadly in line with current practice. It is uncertain how many additional surgeries will be performed as a result of the recommendation to consider surgery for people without symptoms or signs, but the committee do not anticipate a significant increase in the number of referrals for surgery.
Full details of the evidence and the committee's discussions are in evidence review C: indications for surgery and evidence review B: diagnostic tests (for the research recommendation on bone turnover markers).
Recommendations 1.4.1 to 1.4.14
There was limited evidence on preoperative imaging so the committee also used their clinical knowledge and experience to make the recommendations. They agreed that the purpose of preoperative imaging is to help guide the surgical approach. It is not essential in all circumstances (for example, if a decision has already been made to perform 4‑gland exploration).
Evidence suggested that ultrasound scanning is accurate in identifying abnormal parathyroid tissue. Ultrasound scanning is widely available, safe and does not involve any exposure to radiation. However, the committee noted that the accuracy of ultrasound depends on the expertise of the person performing it. They therefore recommended sestamibi as an alternative.
Although dual scanning using 2 different imaging modalities has the advantage of providing both anatomical and functional information, the committee agreed that a second imaging modality is only needed if it will further inform the surgical approach. Evidence suggests that sestamibi scanning is accurate in detecting single-gland disease. The committee did not make a recommendation on 4D CT scanning because there was no evidence available.
The committee agreed that if dual scanning fails to identify an adenoma or is discordant, further imaging will not add useful information and will expose the person to unnecessary radiation. They acknowledged that preoperative imaging does not detect all adenomas, so 4‑gland exploration should be offered if preoperative imaging does not identify an adenoma.
The committee agreed that, based on their experience, people whose preoperative imaging does not identify a single adenoma will more frequently have multigland disease and will benefit from 4‑gland exploration. If the first-modality and second-modality scans are discordant, 4‑gland exploration can be considered because the specific anatomical location of the adenoma cannot be assured.
For people with a single adenoma, a small amount of evidence shows that both focused parathyroidectomy and 4‑gland exploration are safe and effective. The committee agreed that focused parathyroidectomy offers the potential advantages of lower temporary hypocalcaemia, a shorter surgery time and minor cosmetic benefit. However, it also carries a marginally (around 5%) higher chance of recurrence or persistent disease. They therefore agreed that people with a single adenoma should be offered a choice of focused parathyroidectomy or 4‑gland exploration, and that the possible benefits and risks of each type of surgery should be discussed with them.
There was limited evidence on intraoperative PTH (IOPTH) monitoring. The committee noted that in their experience, there is a marginal benefit with the use of IOPTH, but this could be partially attributed to surgical expertise.
IOPTH monitoring is costly and its effectiveness in improving surgical outcomes is uncertain. The committee agreed that their experience together with the limited evidence did not support IOPTH monitoring as part of standard practice.
Based on their knowledge and experience, the committee agreed that people who have had parathyroid surgery can be considered biochemically cured if their albumin-adjusted serum calcium and PTH levels are within the reference range before discharge after surgery and their albumin-adjusted serum calcium level is within the reference range 3 to 6 months after surgery.
The committee acknowledged the potential of bone turnover markers to check bone health after surgery for primary hyperparathyroidism but were unable to make a recommendation because of a lack of evidence. They therefore made a research recommendation on bone turnover markers.
There was no evidence on further surgical management for people who have had unsuccessful first surgery, and very limited evidence on drug therapy with cinacalcet compared with placebo. The committee agreed that input from a multidisciplinary team at a specialist centre should be sought, noting that repeat parathyroid surgery is relatively uncommon, failure rates are higher than in first surgery and it carries a higher risk. They also made a research recommendation on management after unsuccessful first surgery.
The recommendations for preoperative imaging largely reflect current practice. However, there is variation in the number and type of preoperative tests carried out and the resulting course of action. The committee thought that the recommendations will necessitate changes in practice for some providers. They noted that using a maximum of 2 imaging modalities before surgery would change practice in centres that currently use more than 2 imaging modalities.
Although not widely used, IOPTH testing is most likely to be found in larger centres that are undertaking parathyroidectomies most frequently. The recommendation is expected to lead to changes in practice in these centres.
The recommendations on type of surgery are considered to generally reflect current practice. However, in some centres, current practice is not to offer surgery to people if no adenoma is identified on imaging. These recommendations will therefore necessitate changes in practice for some providers.
The recommendations on follow‑up after surgery reflect current practice in most NHS centres, so the committee thought that there would be little change in practice.
The recommendations on unsuccessful surgery are current practice in many areas.
Full details of the evidence and the committee's discussion are in:
evidence review B: diagnostic tests (for the research recommendation on bone turnover markers)
evidence review D: surgical localisation (for the recommendations on preoperative imaging)
evidence review E: surgical interventions (for the recommendations on type of surgery)
evidence review F: management options in failed primary surgery (for the recommendations on unsuccessful surgery)
evidence review I: monitoring (for the recommendations on follow‑up after surgery).
Recommendations 1.5.1 to 1.5.5
Cinacalcet is the only calcimimetic for which evidence was available. The committee noted that cinacalcet does not directly stop kidney problems or bone loss caused by primary hyperparathyroidism, and that surgery is the only definitive treatment for primary hyperparathyroidism.
Based on the evidence and their experience, the committee agreed that treatment with cinacalcet could be considered for the purpose of reducing symptoms and lowering the risk of a hypercalcaemic crisis for people who have not had surgery and those for whom surgery has not been successful. The committee agreed that, in their experience, cinacalcet can improve quality of life for people with symptoms of hypercalcaemia and an albumin-adjusted serum calcium level of 2.85 mmol/litre or above. For people with an albumin-adjusted serum calcium level of 3.0 mmol/litre or above, who are more at risk of hypercalcaemic crises, cinacalcet can both improve quality of life and help to prevent hypercalcaemic crises.
The committee agreed that treatment-related changes in serum calcium should be managed by basing initiation and continuation of treatment on albumin-adjusted serum calcium level and symptoms. They also agreed that treatment with cinacalcet should be continued if it produces a decrease in albumin-adjusted serum calcium or an improvement in symptoms, because discontinuation is likely to reverse these improvements. The committee noted that there is no evidence for and little likelihood of benefit from cinacalcet for people with normal calcium levels and no symptoms.
There was evidence showing that bisphosphonate treatment improves lumbar spine bone mineral density for people with primary hyperparathyroidism. The committee based the recommendation on the NICE technology appraisal guidance on bisphosphonates for treating osteoporosis.
Based on the evidence and their clinical experience, the committee agreed that bisphosphonates should not be offered to reduce hypercalcaemia in the long term.
These recommendations are considered to be current practice in many areas, and are not expected to lead to major changes in practice.
Full details of the evidence and the committee's discussion are in:
Recommendation 1.6.1 and table 1
Based on their knowledge and experience, the committee agreed that the risk of recurrent disease after successful parathyroid surgery is very low and therefore it is sufficient to monitor albumin-adjusted serum calcium levels once a year.
For people who have osteoporosis, although bone density improves after surgery, skeletal recovery can take some time and needs specialist monitoring. The risk of renal stones decreases after successful surgery, but the residual risk persists and the committee agreed that specialist opinion on monitoring should be sought.
Based on their clinical experience, the committee agreed that monitoring for people who have had unsuccessful surgery should be the same as for people who have had no previous surgery. Monitoring bridges the gap between first surgery and multidisciplinary review and reassessment in a specialist centre.
The committee noted the increased risk of renal stones and fractures in people who have had unsuccessful or no parathyroid surgery. Evidence suggests that around one‑third of people who do not have symptoms or indications for surgery will go on to develop these. The committee agreed that monitoring will ensure that surgery, including repeat surgery, can be offered when needed.
People who have had parathyroid surgery for multigland disease, or have disease that recurs after successful surgery
The committee agreed that people with multigland disease, or disease that has recurred after successful surgery, have a slightly increased risk of future recurrence and will benefit from specialist endocrine opinion on monitoring.
For all people with primary hyperparathyroidism, the committee agreed that there was no evidence to suggest that surgery modifies cardiovascular disease risk or fracture risk, so these should be assessed in line with NICE guidance.
The committee noted the limited evidence on long-term outcomes and made a research recommendation.
The recommendations reflect current practice in most NHS centres, so the committee expects little change in practice.
Full details of the evidence and the committee's discussion are in evidence review F: management options in failed primary surgery and evidence review I: monitoring.
Recommendations 1.7.1 to 1.7.6
The committee noted that having surgery for primary hyperparathyroidism before becoming pregnant allows women to start their pregnancy with a normal serum calcium level, which reduces their risk of pregnancy-associated complications of primary hyperparathyroidism. They noted that the risk of stillbirth and neonatal tetany increases with a serum calcium level above 2.85 mmol/litre.
Based on their experience, the committee agreed that management of primary hyperparathyroidism during pregnancy should be discussed with a multidisciplinary team (MDT) because of the high risk of maternal and neonatal complications.
The safety and efficacy of cinacalcet for pregnant women is largely unknown, so the committee agreed that cinacalcet should not be offered during pregnancy. They also agreed that bisphosphonates are potentially harmful for the mother and the fetus.
There was no evidence on monitoring for pregnant women. The committee agreed that monitoring should be guided by a specialist centre MDT because of the risk of maternal or fetal complications. They also highlighted primary hyperparathyroidism as a risk factor for pre‑eclampsia and hypertension.
There was little overall evidence on managing primary hyperparathyroidism during pregnancy so the committee made a research recommendation.
The recommendations made for women who are pregnant or considering pregnancy might change practice in some areas. However, this is a small population so they are not expected to have a substantial impact on practice.
Full details of the evidence and the committee's discussion are in evidence review J: pregnancy.
Recommendations 1.8.1 to 1.8.5
No evidence was found so the committee based the recommendations on their knowledge and experience. The committee agreed that primary hyperparathyroidism is an under-recognised condition among both the general population and healthcare professionals. They emphasised the importance of accurate, balanced and up-to-date information so that people with the condition can understand it and make informed choices, particularly with regard to surgery.
The recommendations broadly reflect current practice. They focus on the information and support that should be given rather than on specific interventions and therefore are not expected to change practice.
Full details of the evidence and the committee's discussion are in evidence review K: patient information.