Primary and secondary hyperparathyroidism: from etiology to treatment

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Background

Significant advancements have been made in understanding pathophysiology and treatment of primary and secondary hyperparathyroidism. Parathyroidectomy, the surgical removal of the diseased parathyroid gland(s), is the primary treatment for PHPT. It is well-established that surgery provides a cure for most patients with PHPT, alleviating symptoms, normalizing calcium levels, and improving bone health. However, research continues to focus on refining surgical techniques, such as minimally invasive approaches, to optimize outcomes, reduce complications, and improve patients’ selection criteria. While surgery is generally curative, long-term follow-up studies are needed to assess the durability of cure and the impact on bone health, cardiovascular risk, and quality of life. Understanding the long-term outcomes of surgical treatment in different patient populations, including those with multiglandular disease or atypical presentations, can help guide management strategies. Non-Surgical Approaches: While surgery is the definitive treatment, there is ongoing research on non-surgical approaches for select cases of PHPT. These may include the use of calcimimetics to manage mild or asymptomatic PHPT, or medical management for patients who are not suitable candidates for surgery.

In SHPT, addressing the underlying cause (e.g., chronic kidney disease) is crucial. In some cases of severe and refractory SHPT, parathyroidectomy may be necessary. However, the indications, timing, and long-term outcomes of surgery in SHPT are areas of ongoing research. Biomarkers and Monitoring: Research is underway to identify and validate novel biomarkers for early detection, monitoring disease progression, and predicting treatment response in both PHPT and SHPT. Biomarkers such as fibroblast growth factor 23 (FGF23) and sclerostin are being studied to better understand their role in the pathogenesis and management of hyperparathyroidism.

Evaluating patient-reported outcomes and quality of life in PHPT and SHPT is an area of active research.

Potential areas of research for the future are represented by further research on long-term outcomes, including bone health, cardiovascular risk, and quality of life; optimal timing and selection criteria for surgical intervention in both PHPT and SHPT; enhanced understanding of the underlying pathophysiological mechanisms and molecular targets for potential targeted therapies.

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While significant progress has been made in the surgical treatment of hyperparathyroidism, there are still areas where knowledge gaps exist. Some aspects that are not yet fully understood in the surgical management of primary hyperparathyroidism include:

- Preoperative localization techniques like ultrasound, sestamibi scanning, and more recently, 4D-CT scans, are commonly used to localize parathyroid adenomas. Nevertheless, there is ongoing research to improve the accuracy and reliability of these methods including other more recent modalities like Choline-PET

- Minimally invasive surgical approaches: Minimally invasive parathyroidectomy (MIP) has become the standard of care for most cases of PHPT. However, there is ongoing research on refining the techniques and identifying patient selection criteria for successful MIP. Further studies could explore the long-term outcomes, complication rates, and comparative effectiveness of different MIP approaches, such as focused parathyroidectomy, video-assisted parathyroidectomy, or robotic-assisted surgery.

- Intraoperative parathyroid hormone (PTH) monitoring: Intraoperative PTH monitoring is commonly used to assess the success of parathyroid surgery and guide surgical decision-making. However, there are debates regarding the optimal timing and criteria for interpreting PTH levels intraoperatively. Research is needed to standardize the interpretation guidelines, especially for secondary hyperparathyroidism.

- Parathyroid autofluorescence: Near-autofluorescence devices seems to help surgeon not only to identify parathyroid glands but also to differentiate pathological glands from normal glands

- Postoperative outcomes and long-term cure rates: While parathyroid surgery is considered curative for most cases of PHPT, there is still a need for long-term follow-up studies to assess the durability of cure and evaluate postoperative outcomes.

- Surgical management in special populations: Certain patient populations, such as those with familial PHPT, multiple endocrine neoplasia syndromes, or geriatric patients, may present unique challenges in the surgical management of PHPT. Further research is needed to determine optimal treatment strategies, timing of surgery, and long-term outcomes in these special populations.

- Patient-reported outcomes and quality of life: While surgery effectively corrects the biochemical abnormalities associated with PHPT, the impact on patients' quality of life, mental well-being, and overall satisfaction with surgical outcomes is an area that requires further investigation.

- The actual role of cinacalcet in the treatment of patients with secondary and tertiary hyperparathyroidism as an established alternative to surgery

Keywords: Primary hyperparathyroidism, secondary hyperparathyroidism, tertiary hyperparathyroidism, parathyroidectomy, treatment

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