Fig. 28.1
HRpQCT image of the distal radius; separated according to cortical vs. trabecular components [48]
Fig. 28.2
Representative HRpQCT images of the distal radius of PHPT (a) and control (b) subjects [49]
HRpQCT findings, which document that the trabecular compartment is involved in the skeletal disease of PHPT, have been further substantiated by trabecular bone score (TBS). TBS estimates trabecular microstructure through analysis of pixel gray-level variations derived directly from the DXA image of the lumbar spine. A lower TBS value reflects a more porous, heterogeneous trabecular network and reduced bone strength. TBS values for microarchitecture are described in tertiles: normal, partially degraded, and degraded [25]. TBS was degraded or partially degraded in the majority of PHPT patients in one cohort despite the majority of subjects demonstrating normal spine bone mineral density (BMD) by DXA [26]. Similarly, in a case-control study, despite no difference in spine BMD by DXA, TBS was lower among patients with PHPT [27]. Furthermore, in this patient population, TBS was significantly correlated with many trabecular and cortical HRpQCT parameters at both the distal radius and tibia [26].
As a result of this more recent appreciation that in PHPT, skeletal involvement is likely more generalized and not restricted to the cortical compartment, the revised guidelines suggest a more proactive approach with systematic screening for complications within the trabecular compartment, namely vertebral compression fracture detection, in addition to DXA testing.
Natural History Without Surgery
The longest observational study of patients with asymptomatic PHPT was conducted over 15 years, detailing the natural history of 49 patients who did not meet surgical criteria or refused parathyroidectomy [19]. PTH, renal function, and urinary calcium excretion remained stable for 13 years, but serum calcium subsequently started to rise slightly. Despite the slight increase in the average serum calcium concentration at these later time points, no patient developed kidney stones during the follow up period. During the first 8 years of observation, BMD by DXA did not change at any site in this cohort. Thereafter, while lumbar spine BMD remained stable, both femoral neck and distal 1/3 radius sites declined by 10 % or more in the majority of patients. Overall, of these 49 subjects, 18 patients (37 %) progressed to develop new surgical criteria during the study period.
Guidelines on the Management of Asymptomatic PHPT
There is no controversy over the recommendation that symptomatic patients should all be considered for parathyroid surgery if there are no medical contraindications. The point of guidelines is to provide assistance on the management of patients with asymptomatic PHPT. Since 1991, these guidelines have been revised three times, most recently in 2013, to take into account the latest advances in knowledge about this predominant form of the disease [3, 6, 8, 9].
Initial Evaluation of Asymptomatic PHPT
The initial approach to patients with asymptomatic PHPT should focus on identifying patients at risk for fragility fractures and kidney stones (Table 28.1). These points have been noted above but are presented here along with other aspects of the evaluation that may lead to the recommendation for surgery. Consistent with previous guideline recommendations, all patients should have BMD measured by DXA at the lumbar spine, hip, and distal 1/3 radius. It should be emphasized that three-site densitometry is always recommended in this disease, compared to DXA evaluation in osteoporosis where many centers perform only lumbar spine and hip BMD. The distal 1/3 site is important to examine in PHPT because classically bone disease in PHPT seems to be seen at this site first by DXA. The newest guidelines go beyond DXA and now recommend that all patients should also be screened for vertebral fractures, with either thoracolumbar spine X-rays or vertebral fracture assessment (VFA) . VFA is lateral spine imaging performed at the time of DXA specifically for the purpose of fracture assessment and can reliably identify vertebral fractures [18]. Vertebral fractures are the most common fragility fractures, even in PHPT patients, and increase the risk of future fragility fractures [28]. However, because these fractures can occur without significant trauma, they are often unrecognized unless documented radiographically. Additional imaging with HRpQCT or TBS is optional, if available, but not routinely advocated.
Table 28.1
Recommended evaluation of patients with asymptomatic PHPT
Recommended evaluation of patients with asymptomatic PHPT | |
|---|---|
Category of work up | Recommended investigation |
Serum biochemistry | Serum calcium, albumin, phosphate, PTH, 25(OH)D, BUN, creatinine, alkaline phosphatase activity |
Urine biochemistry | 24-h urine calcium, creatinine, creatinine clearance, stone risk profile (if urine calcium >400 mg/day; >10 mmol/day) |
BMD | DXA of lumbar spine, hip, and distal 1/3 radius |
Spine imaging | X-ray or VFA by DXA |
Abdominal imaging | X-ray, ultrasound, or CT |
Genetic evaluation | If genetic cause of PHPT is suspected |
Another modification to the most recent guidelines is the recommendation for routine abdominal imaging with X-ray, ultrasound, or CT to assess for asymptomatic nephrocalcinosis or kidney stones. In addition, a 24-h urine collection for calcium and creatinine is recommended to identify either significant hypercalciuria (>400 mg/day) or hypocalciuria (see FHH below). If significant hypercalciuria is found, a complete calcium-stone urinary biochemical profile should be obtained to see if an additional risk factor(s) for the development of kidney stones is present. If they are present, parathyroidectomy should be considered.
Selection of Surgical Candidates
With the most recent guidelines, surgical criteria for asymptomatic patients with PHPT have been expanded to actively screen patients for asymptomatic kidney stones, nephrocalcinosis, or those at risk for stones as evidenced by marked hypercalciuria and additional abnormalities as detected by a urinary biochemical stone profile (Table 28.2). Although a history of fragility fracture has previously been a surgical indication, the addition of routine screening for morphometric vertebral fractures is likely to identify more patients.
Table 28.2
Patients with asymptomatic PHPT for whom surgery is indicated and comparison with previous guideline recommendations
Parameter | 2008 Indication | 2013 Indication |
|---|---|---|
Serum calciuma | >1.0 mg/dL (>0.25 mmol/L) upper limit of normal | >1.0 mg/dL (>0.25 mmol/L) upper limit of normal |
Skeletalb | BMD T-score < -2.5 at any site, or history of previous fragility fracture | BMD T-score <−2.5 at any site, or history of previous fragility fracture; including morphometric vertebral fractures discovered on spine imaging during initial assessment |
Renal | eGFR <60 cc/min | Creatinine clearance <60 cc/min, or hypercalciuria (>400 mg/day; > 10 mmol/day) with increased urine stone risk profile, or kidney stone/nephrocalcinosis documented by abdominal X-ray, US, or CT during initial assessment |
Age | <50 | <50 |
The remaining criteria have not changed from the prior guidelines. These criteria include age <50 years, impaired renal function (creatinine clearance <60 cc/min), or BMD in the osteoporotic range (T-score <−2.5) at any of lumbar spine, hip, or distal 1/3 radius site. Age <50 years is a guideline for surgery because younger patients with PHPT develop disease progression and surgical indications more frequently than older patients during the same follow up period (23 % vs. 62 %; [29]). An important point is that patients who do not meet any guideline indications for surgery can still undergo parathyroid surgery, if this is their preference, as long as there are no medical contraindications to surgery.
Monitoring of Nonsurgical Patients
Asymptomatic patients who do not meet any surgical criteria, and chose not to have surgery, can be safely followed but require monitoring [3, 30]. Annual testing of serum calcium and creatinine clearance, as well as 3-site DXA every 1–2 years is recommended. Spine imaging should be repeated if vertebral fracture is suspected because of back pain or height loss. Similarly, symptoms of renal colic should prompt renal imaging and repeat 24-h urine collection for stone profile.
Additional Considerations
Familial Hypocalciuric Hypercalcemia (FHH)
FHH is a rare autosomal dominant condition caused by a loss-of-function mutation in the calcium-sensing receptor (CaSR) gene. The condition also presents with hypercalcemia and inappropriately normal or mildly elevated PTH. However, FHH is characterized by very low urinary calcium excretion (calcium clearance/creatinine clearance ratio <0.01) as a result of defective calcium sensing by the kidney [6]. Diagnosing FHH is important because the condition does not resolve with surgery [31]. Furthermore, no specific therapy is necessary because FHH is not usually associated with any complications in adulthood [31]. A family history of mild hypercalcemia, especially if noted in childhood, or hypercalcemia that failed to correct with parathyroidectomy, suggests FHH. A 24-h urine calcium excretion should be measured in all patients to rule out FHH [6]. However, the fractional calcium excretion between FHH and PHPT can overlap, in which case genetic testing, which is now commercially available, is advised ([6]; Fig. 28.3).
Fig. 28.3
Recommended algorithm to differentiate FHH from asymptomatic PHPT. *UCCR: urinary calcium:creatinine clearance ratio. †Vitamin D insufficiency or renal impairment may artificially lower UCCR. Figure adapted from Eastell R, Brandi ML, Costa AG, D’Amour P, Shoback DM, and Thakker RV. Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the fourth international workshop. JCEM. 2014:99(10):3570–9
Genetic Forms of PHPT
It is important to recognize that PHPT can occur as part of a genetic syndrome. These syndromes include multiple endocrine neoplasia (MEN) type 1 (Menin gene mutation), type 2A (RET gene mutation), and familial isolated hyperparathyroidism (FIHPT; multiple gene mutations possible) [32, 33]. Almost all patients with MEN 1 develop PHPT, generally in their 20s, and usually as the first manifestation of the syndrome [32, 33]. Subsequently patients with MEN 1 may develop functioning or nonfunctioning tumors of the pancreas and anterior pituitary, adrenal adenomas, and rarely foregut carcinoid tumors [33, 34]. Approximately 90 % of patients with MEN 2A develop medullary thyroid cancer (MTC) , and this tends to be the initial presentation of the disorder [33, 34]. PHPT is found either concurrently or subsequently in 20–30 % of patients, usually after age 30 [33, 35]. Of particular significance perioperatively, half of MEN 2A patients develop pheochromocytoma [33, 34]. FIHPT is an inherited disorder of PHPT without evidence of other endocrinopathies or tumors [32]. Other genetic syndromes more rarely associated with PHPT include MEN 2B, MEN 4, and hyperparathyroidism-jaw tumor (HPT-JT) syndrome [32, 33]. Despite the great interest in genetic etiologies of PHPT and the different genetic forms identified, all the familial hyperparathyroid syndromes together, including FHH, account for only approximately 5–10 % of all PHPT cases [9].
Since all familial hyperparathyroid syndromes have an autosomal dominant pattern of inheritance, an accurate family history is important. However, sporadic mutations can also occur making patient identification challenging [6, 33]. In addition to screening and identifying other endocrinopathies and tumors in affected patients and their family members, confirmation of a familial hyperparathyroid syndrome also influences surgical management. Many of these patients have multiglandular disease and increased rates of disease recurrence, making more extensive surgical exploration often necessary [9]. When assessing a patient with PHPT, genetic testing is indicated when: (1) the patient has a first-degree relative with known or suspected familial hyperparathyroid syndrome; (2) the patient has PHPT and another typical manifestations of a familial hyperparathyroid syndrome (ex. PHPT and MTC); (3) PHPT is diagnosed before age 45; (4) PHPT is caused by multigland disease; (5) parathyroid carcinoma or atypical adenoma is diagnosed [6, 33].
Normocalcemic PHPT (NPHPT)
NPHPT is a variant of PHPT characterized by elevated PTH concentrations with consistently normal total and ionized serum calcium, in the absence of secondary causes for an elevated PTH such as vitamin D deficiency or renal dysfunction [36]. Diagnostic criteria for NPHPT were added to the most recent guidelines and require: (1) normal serum albumin-adjusted total calcium and normal ionized calcium on several occasions; (2) confirmation of elevated PTH on at least two other occasions over 3–6 months; (3) vitamin D sufficiency (25(OH)D level at least >20 ng/mL and preferably >30 ng/mL); (4) no malabsorption syndromes such as Celiac disease; (5) normal renal function (eGFR >60 mL/min); (6) no hypercalciuria; (7) no use of medications which can raise PTH (bisphosphonates, denosumab, thiazide or loop diuretics, or lithium [6].
The natural history of NPHPT has not been fully elucidated, but it appears that some of these patients are prone to skeletal complications, kidney stones, and development of hypercalcemia [37]. Annual serum calcium and PTH monitoring and DXA every 1–2 years are recommended. There are currently no prospective studies regarding the optimal management of these patients but surgery is recommended according to the asymptomatic PHPT guidelines if hypercalcemia develops or if patients demonstrate complications of PHPT such as progressive worsening of BMD, fragility fractures, or kidney stones [3].
Nonclassical Features
Cardiovascular disease in patients with asymptomatic PHPT should not be considered an indication for parathyroid surgery, because there are limited data on effects of mild PHPT on the cardiovascular system [8]. What data are available do not clearly implicate the disease nor is it clear what aspects of subtle abnormalities discovered are reversible after successful surgery. Similarly, surgery is not routinely recommended in otherwise asymptomatic PHPT patients for nonspecific complaints such as fatigue, mood disorders, or neurocognitive complaints, because randomized controlled trials of surgery vs. observation have failed to show a consistent benefit of surgery on quality of life and psychological outcomes [8]. Further research into these areas is necessary.
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