Recent advances in the understanding and management of primary hyperparathyroidism

Introduction

Primary hyperparathyroidism (PHPT) is a hormonal disorder whose prevalence is approximately 1–2% in the United States of America and is less prevalent in countries where biochemical screening is less common. It is most often diagnosed in postmenopausal women, though prevalence has been reported to be as high as 0.5–1% in older men. Recognition of this problem more than 90 years ago was originally in patients with severe symptomatology, such as impaired cognition, peptic ulcers, constipation, muscle weakness, and arthralgias, with the first parathyroidectomy carried out by Sir John Bland-Sutton before 1917¹. Previously, Felix Mandl of Germany had long been credited with performing the first parathyroidectomy in 1926². Over the years, as biochemical, pathological, and radiological technology has evolved, the clinical state of patients has changed radically. Initially, serum calcium and parathyroid hormone (PTH) levels were markedly elevated with kidney stones and fractures prominent. Over time, PHPT became more recognizable to clinicians in an earlier phase as routine chemistry became widely used and osteoporosis diagnosis increased with the advent of bone densitometry³. At present, a significant number of patients have “no symptoms”, although bone density may be decreased and occult nephrolithiasis may be present^4–6. Older adults are frequently underdiagnosed and undertreated, perhaps because of a lack of understanding of the consequences of the disorder⁷. A large survey of primary care patients has concluded that health cost savings associated with fracture risk could be achieved by appropriate screening and treatment of patients with a life expectancy of 16 years⁸.

Classification of primary hyperparathyroidism

PHPT is not a single entity. In most normal subjects, four glands are present and one or more may become pathologic. Other endocrine disorders may be present depending upon genetic abnormalities, which may be inherited. Table 1 summarizes the types of PHPT that have been reported. A single parathyroid adenoma is found in about 80% of cases. Double adenomas and sporadic hyperplasia account for the majority of the remaining cases, and all the other multi-gland cases account for the rest. Parathyroid carcinomas are rare.

Unlike classical PHPT, some patients are normocalcemic despite elevated serum PTH and others are hypercalcemic with serum PTH levels in the normal range⁹. In a 573-patient study of patients with PHPT, 405 patients were classic (70.7%), 96 were normohormonal (16.8%), and 72 were normocalcemic (12.5%)¹⁰. Normocalcemic hyperparathyroidism was associated with multi-gland disease (MGD) in 45% of patients, but only 10% in the normohormonal group and 9% in classic PHPT. Twelve months after surgery, the biochemistry was normal in >98% in all three groups.

It is important to distinguish PHPT from the rare disorder familial hypocalciuric hypercalcemia, of which there are three subtypes: FHH1, FHH2, and FHH3¹¹. Generally, these require no treatment. The diagnosis can be achieved by measuring 24-hour urinary calcium excretion. A calcium/creatinine level of less than 0.01 is found in most patients. Serum PTH levels are usually normal but may be elevated, and serum magnesium is usually elevated. These autosomal dominant disorders are caused by a loss-of-function mutation in the calcium-sensing receptor gene (CaSR) in the case of FHH1, loss of function in G-protein subunit alpha-1 (GNA11) in FHH2, and loss of function in adaptor protein-2 sigma 1 subunit (GNA11) in FHH3.

Indications for parathyroidectomy

Today, parathyroidectomy is recommended for the majority of patients diagnosed with PHPT. National and international guidelines recommend the minimum indications for surgical treatment of PHPT, but ultimately it is a decision reached by the patient, surgeon, and endocrinologist^12,13. Surgery remains the most cost-effective long-term strategy, even in mild, asymptomatic patients, when incorporating fracture risk, in addition to decreasing cardiovascular risk factors and kidney stone formation and producing sustained benefits in quality of life (QOL) and neurocognition^14–19. Frailty, based on either co-morbid conditions or an actual frailty score, not age itself, appears to be the main contra-indication for surgery, since parathyroidectomy can be beneficial even in the very elderly^20,21. For patients who refuse, cannot medically have surgery, or who are not cured by surgery, cinacalcet, an inhibitor of the calcium-sensing receptor, can produce long-term normocalcemia²². A bisphosphonate can also be added to prevent bone loss.

Recent QOL studies using either older scoring measures or a new PHPT-specific health-related QOL questionnaire, PHPQoL, have demonstrated decreased symptomatology and recovery not only for patients with classical PHPT but also in patients with normocalcemic and mild PHPT^23–27. Improvements in QOL factors were measured as early as the first week after surgery and were sustained long term in areas of mental health, sleep quality, somatic and cognitive depression domains, and neurocognition. The updated AAES management guidelines cite neurocognitive symptoms as another surgical indication in addition to kidney stones, osteoporosis, decreased kidney function, and hypercalcemia that are dictated in the NIH guidelines.

Pre-operative imaging

Imaging for parathyroid localization should be performed only after the diagnosis of PHPT has been confirmed and the decision has been made to proceed with surgery. Localization is not to be used for diagnosis and should not be used to decide if a patient should proceed with surgery. Moreover, the old adage still holds true: the best localization is an experienced parathyroid surgeon. With that said, the primary role of pre-operative imaging is to decide if a patient is a candidate for a focused, minimally invasive parathyroidectomy.

Ultrasound (US) is the most cost-effective and a fairly sensitive localization technique and should be the first imaging test ordered for a patient. Surgeon-performed US has the greatest sensitivity and should be standard for any surgeon performing parathyroidectomies, in both the clinic and the operating room. US is best at detecting enlarged inferior glands, and understandably less so for superior glands owing to their location behind the thyroid gland or ectopic glands. If the US is negative or equivocal, in the United States, a CT scan is the most sensitive and cost-effective first- or second-line localization test^28,29.Sestamibi remains inferior because of the false positive rates with nodules and especially thyroiditis, which are present in many individuals³⁰. Although some centers report almost equivalent efficacy with a two-phase compared to four-phase CT scans, the most common technique is a three-phase scan³¹. No imaging, including CT scans, has a high accuracy in patients with MGD^32–34. In the re-operative setting, multimodal imaging with at least two of Sestamibi, CT, MRI, and US has improved successful localization to 91.6% in one study of almost 350 patients³⁵.

Parathyroid surgery

Parathyroidectomy, regardless of the surgical technique (minimal access, video-assisted, robotic, or transoral) and whether it is a focused or a bilateral neck exploration (BNE), can be performed as an outpatient procedure. If the abnormal parathyroid gland(s) can be localized pre-operatively, a focused approach can be performed, resulting in decreased operative and anesthesia time, incision size (usually), and the amount of dissection, and therefore scar tissue, in the patient. In both the primary and the re-operative setting, parathyroidectomies should be performed by a high-volume surgeon and a multidisciplinary team engaged for complicated cases^12,40,41. When parathyroidectomy is performed by high-volume surgeons, rates of nerve injury are low, but post-operative hypercalcemia and hypocalcemia rates are reported to be 5% for index parathyroidectomies and 10% for re-operative parathyroidectomies⁴².

Summary

PHPT is prevalent, although older adults are frequently underdiagnosed and undertreated, perhaps owing to a lack of understanding of the consequences of the disorder. We now recognize multiple phenotypes of the disease that do not all include significantly high calcium and PTH levels. Advances in pre-operative imaging and surgical adjuncts continue to advance our ability to cure the disease, but more research into the genetic and molecular landscape of the disease is needed to improve our understanding and disease cure rates.