Primary hyperparathyroidism : genetics, comorbidities and environmental risk factors

<p dir="ltr">Context Primary hyperparathyroidism (PHPT) is a common endocrine disorder with a reported prevalence of approximately 1% in the adult population, rising with age to over 3% in postmenopausal women. Parathyroidectomy is the only curative treatment, with well-established benefits for classical end organ complications. Despite clear clinical guidelines, substantial geographical and demographic disparities in both clinical recognition and surgical management have been reported across different healthcare systems. The true biochemical incidence and prevalence of PHPT in Sweden, the extent of underdiagnosis at the population-level, factors influencing referral to surgery, the different regional access to parathyroidectomy and the role of familial predisposition beyond known syndromic pathways remain incompletely characterised.</p><p dir="ltr">Objective The overall aim of this thesis was to investigate the epidemiology and clinical management of PHPT in Sweden. The specific objectives were to (I) analyse regional variation in parathyroidectomy incidence with respect to disease burden and socioeconomic status, (II) assess familial clustering of PHPT and malignancies among first- degree relatives of affected patients, (III) determine the annual incidence rate and point prevalence of biochemically confirmed PHPT in the Stockholm Region, and (IV) quantify the gap between biochemical disease presence and clinical recognition and identify predictors of diagnosis and parathyroidectomy.</p><p dir="ltr">Design and setting Four population-based register studies were conducted using Swedish national and regional registries. Study I was a nationwide case-control study including all patients who underwent parathyroidectomy for PHPT between 2008 and 2017, identified through the Scandinavian Quality Register for Thyroid, Parathyroid, and Adrenal Surgery and the Swedish National Cancer Register, with matched population controls. Data on comorbidities, drug prescriptions, and socioeconomic variables were obtained from the National Patient Register, the National Prescribed Drug Register, and the Longitudinal Integrated Database for Health Insurance and Labour Market Research. Study II extended this dataset by linking it to the Swedish Multi-Generation Register, enabling identification of first-degree relatives of 6 693 patients born in Sweden after 1932 and 33 393 matched controls, in a combined case-control and prospective cohort design. Studies III and IV used the Stockholm CREAtinine Measurements healthcare database, a population-based repository covering approximately two-thirds of the adult Stockholm population (290% coverage in individuals >65 years), with linked laboratory data from three regional providers, administrative healthcare data, and national registries. Study III was a cohort study applying prespecified biochemical diagnostic algorithms based on paired calcium and parathyroid hormone measurements to determine incidence and prevalence of primary hyperparathyroidism between 2006-2020. Study IV was a cohort study of 7 342 adults with biochemically confirmed PHPT, employing time- to-event analyses with competing risks to identify predictors of clinical diagnosis and parathyroidectomy.</p><p dir="ltr">Results In Study I, a total of 8 626 patients underwent parathyroidectomy during the study interval, with an overall annual incidence of 9.0 operations per 100 000 persons. The age-adjusted regional incidence varied from 3.3 to 16.9 per 100 000 inhabitants. Socioeconomic factors had minimal influence on surgical rates. Patients in low-incidence regions had significantly higher prevalences of kidney stones, osteoporosis, and hypertension, as well as higher calcium levels and larger adenomas at the time of surgery compared with patients in high incidence regions.</p><p dir="ltr">In Study II, 218 729 first-degree relatives were identified. Relatives of patients with PHPT had significantly higher odds of PHPT, with the strongest association observed in patients diagnosed at age 45 years or younger (odds ratio 7.7; 95% CI, 5.23-11.34). A total of 6% of patients had one or more first-degree relatives with PHPT without a known syndromic form compared with 2% of controls. Relatives with concurrent PHPT and neuroendocrine neoplasia were substantially overrepresented among patients, consistent with known syndromic pathways. A modest overrepresentation of malignancy was observed (odds ratio 1.07; 95% CI, 1.01-1.13), attributable to prostate cancer, non-medullary thyroid cancer, and haematologic malignancies; however, no overall increased risk of malignancy in relatives was observed in the prospective cohort analysis, and no single-site associations remained statistically significant after correction for multiple testing.</p><p dir="ltr">In Study III, among 176 780 individuals contributing 578 227 PTH measurements, 10 190 patients fulfilling biochemical criteria for PHPT were identified. The age-and sex-adjusted incidence rate increased from 2.81 (95% CI, 2.55-3.09) to 4.28 (95% CI, 3.98-4.59) per 10 000 person-years between 2009-2020, with the steepest increase among women 270 years. Point prevalence increased from 0.35 to 4.76 per 1 000 individuals. Median ionised calcium was 1.39 mmol/L, indicating a predominantly mild biochemical phenotype. Only 52% of patients received a clinical PHPT diagnosis, and of those, 52% underwent parathyroidectomy.</p><p dir="ltr">In Study IV, among 7 342 patients with biochemically confirmed PHPT, the five-year cumulative incidence of clinical diagnosis was 34.9% and of parathyroidectomy 18.1%; among diagnosed patients, 50.0% underwent surgery within five years. PTH above the upper reference limit was the strongest predictor of both clinical recognition (HR 4.30; 95% CI, 3.89-4.76) and parathyroidectomy (HR 5.06; 95% CI, 4.31-5.94), indicating that inappropriately normal PTH in the context of hypercalcaemia fails to trigger established diagnostic criteria. PHPT-related bone disease predicted surgery but not clinical recognition. The calcium to surgery gradient was progressively attenuated with declining renal function and was absent at GFR G3b. Age 270 years, male sex, and higher comorbidity burden were independently associated with lower rates of both diagnosis and surgery. University education and higher income predicted parathyroidectomy but not diagnosis. African and Asian born individuals had lower diagnostic rates.</p><p dir="ltr">Conclusions The studies revealed a large regional variation in parathyroidectomy rates that probably reflects differences in clinical detection and referral thresholds rather than socioeconomic disparities or variation in disease prevalence. PHPT exhibits significant familial aggregation beyond known syndromic forms, supporting a genetic counselling threshold at 40 years, while the association between PHPT and malignancy in first-degree relatives is weak and likely influenced by surveillance bias. Both incidence and prevalence of biochemically confirmed PHPT are rising, predominantly in elderly women, with most patients presenting with mild biochemical disease. There is substantial underdiagnosis and undertreatment of PHPT in the Stockholm Region, despite high regional rates of parathyroidectomy. Clinical recognition depends heavily on PTH elevation above the reference limit, which is inconsistent with established diagnostic criteria where PHPT is defined as having inappropriately normal or high PTH and raised PTH is not a specific criterion for diagnosis. Age, renal function, and socioeconomic factors independently influence access to surgical treatment. Systematic efforts are needed to improve PHPT recognition in primary care, integrate calcium and PTH screening into osteoporosis care pathways, and address demographic and socioeconomic disparities in referral to curative surgery.</p><h3 dir="ltr">List of scientific papers</h3><p dir="ltr">I. <b>Thorsteinsson D,</b> Granath F, Branstrom R, Koman A, Zedenius J, Nilsson IL. Regional variations in the management of primary hyperparathyroidism in Sweden: population-based case-control study. BJS Open. 2024;8(1). <a href="https://doi.org/10.1093/bjsopen/zrad154" target="_blank">https://doi.org/10.1093/bjsopen/zrad154</a></p><p dir="ltr">II. <b>Thorsteinsson D,</b> Granath F, Branstrom R, Zedenius J, Nilsson IL. Familial aggregation of primary hyperparathyroidism and malignancy: nationwide case-control and cohort study. J Endocr Soc. 2025;9(11):bvaf152. <br><a href="https://doi.org/10.1210/jendso/bvaf152">https://doi.org/10.1210/jendso/bvaf152</a></p><p dir="ltr"><br></p><p dir="ltr">III. <b>Thorsteinsson D,</b> Granath F, Branstrom R, Zedenius J, Carrero JJ, Nilsson IL. Increasing incidence and prevalence of biochemically confirmed primary hyperparathyroidism in Stockholm, 2006-2020. J Clin Endocrinol Metab. 2026. <a href="https://doi.org/10.1210/clinem/dgag162">https://doi.org/10.1210/clinem/dgag162</a></p><p dir="ltr">IV. <b>Thorsteinsson D,</b> Nylen C, Granath F, Branstrom R, Zedenius J, Nilsson IL. Underdiagnosis and undertreatment of primary hyperparathyroidism in Stockholm - a cohort study. [Manuscript]</p>