Highlights
This population-based study of 176,780 adults in Stockholm reveals concerning trends in primary hyperparathyroidism epidemiology. Between 2009 and 2020, age- and sex-adjusted incidence rose from 2.81 to 4.28 per 10,000 person-years, representing a 52% increase. Prevalence surged dramatically from 0.35 to 4.76 per 1,000 individuals. Alarmingly, only 52% of biochemically confirmed cases received clinical diagnosis, while surgical treatment remained stable at 4-5% annually after 2013. Women aged 70 years and older exhibited the steepest increase in incidence, suggesting demographic shifts are driving this epidemic.
Background: The Unrecognized Burden of Primary Hyperparathyroidism
Primary hyperparathyroidism (PHPT) represents one of the most common endocrine disorders, yet it remains substantially underdiagnosed in clinical practice. The condition results from inappropriate parathyroid hormone (PTH) secretion, leading to hypercalcemia and potentially causing skeletal complications, renal manifestations, neuropsychiatric symptoms, and cardiovascular consequences. Historically considered a disease predominantly affecting postmenopausal women, PHPT’s epidemiology has evolved alongside demographic changes and improved laboratory testing.
The clinical significance of PHPT extends beyond biochemical abnormalities. Untreated disease can lead to osteoporosis, fractures, kidney stones, chronic kidney disease, and impaired quality of life. Paradoxically, while PHPT is potentially curable through parathyroidectomy, many patients remain undiagnosed or inadequately managed for years, accumulating preventable morbidity.
Accurate epidemiological data have been lacking, primarily because most previous studies relied on clinically diagnosed cases, potentially missing substantial proportions of individuals with biochemically confirmed disease. This diagnostic gap has hindered healthcare planning, resource allocation, and our understanding of the true disease burden. The current study addresses this critical knowledge deficit by applying strict biochemical criteria to a large population-based dataset.
Study Design
Researchers conducted a population-based healthcare cohort study in the Stockholm Region of Sweden, spanning 2006 to 2020. The investigation utilized the Stockholm CREAtinine Measurements (SCREAM) database, which captures laboratory measurements from both primary and secondary healthcare settings. This comprehensive database covers approximately two-thirds of the adult population in Stockholm, including over 90% of individuals aged 65 years and older.
The study cohort comprised adults aged 20 years and older with paired calcium and PTH measurements meeting predefined biochemical criteria for PHPT. Key exclusion criteria included estimated glomerular filtration rate (eGFR) of 30 mL/min/1.73 m² or lower, which could indicate secondary hyperparathyroidism or chronic kidney disease-related mineral bone disorder, and prior parathyroid surgery history.
The primary outcomes were annual incidence rate and point prevalence of biochemically confirmed PHPT. Secondary analyses examined clinical recognition rates, defined as documented PHPT diagnosis in medical records, and surgical management patterns, specifically parathyroidectomy utilization. The study employed rigorous statistical methods including age- and sex-adjustment using the European standard population, with 95% confidence intervals calculated throughout.
Key Findings
Demographics and Biochemical Characteristics
Among 176,780 individuals contributing 578,227 PTH measurements, the investigators identified 10,190 patients fulfilling biochemical criteria for primary hyperparathyroidism. The cohort demonstrated expected demographic patterns, with female predominance reflecting the known epidemiology of PHPT. The median ionized calcium level was 1.39 mmol/L, consistent with mild to moderate hypercalcemia typical of contemporary PHPT presentations.
Incidence Trends
The age- and sex-adjusted incidence rate demonstrated a striking upward trajectory over the study period. From 2.81 per 10,000 person-years in 2009, incidence rose to 4.28 per 10,000 person-years by 2020, representing a 52% increase. This trend was consistent across multiple sensitivity analyses, confirming the robustness of the findings.
The steepest increase occurred among women aged 70 years and older, suggesting that population aging substantially contributes to the rising disease burden. This demographic pattern aligns with known physiological changes in calcium homeostasis among elderly women, including decreased intestinal calcium absorption and declining renal function, which may unmask or exacerbate underlying parathyroid dysfunction.
Prevalence Dynamics
Point prevalence increased more than thirteen-fold during the study period, rising from 0.35 per 1,000 individuals in the earliest assessment to 4.76 per 1,000 by study completion. This remarkable increase substantially exceeds previously reported prevalence estimates, likely reflecting both true epidemiological changes and improved laboratory detection through routine PTH and calcium testing.
The cumulative prevalence of 4.76 per 1,000 translates to approximately 1 in 210 adults in the studied population, highlighting that PHPT affects a substantial proportion of the general population. This figure likely underestimates true disease burden given the exclusion of individuals without paired laboratory measurements.
Clinical Recognition Gap
Perhaps the most concerning finding concerned clinical recognition. Of the 10,190 patients meeting biochemical PHPT criteria, only 5,346 (52%) had documented clinical diagnosis in their medical records. This finding indicates that nearly half of individuals with biochemically confirmed disease remained undiagnosed despite interacting with healthcare systems where appropriate laboratory testing had occurred.
The diagnostic gap has profound implications. These individuals potentially experienced ongoing effects of hypercalcemia and elevated PTH, including subclinical bone loss, renal calcium handling abnormalities, and neurocognitive symptoms that may have been attributed to aging or other conditions. Without diagnosis, these patients could not access potentially curative surgical treatment or appropriate medical management.
Surgical Management Patterns
Among clinically diagnosed patients, 2,800 (52%) underwent parathyroidectomy, representing the definitive treatment for PHPT. Surgery rates demonstrated relative stability after 2013, fluctuating between 4% and 5% annually. This pattern suggests that clinical guidelines recommending surgical intervention for appropriate candidates were being followed, though the absolute proportion undergoing surgery among all biochemically confirmed cases remained low at approximately 27%.
Several factors may explain why more diagnosed patients did not undergo surgery. These include patient preferences, surgical risk assessment in elderly or comorbid populations, uncertainty about symptom attribution, and access to specialized surgical centers. Additionally, some patients may have been managed conservatively with surveillance, particularly those with mild asymptomatic disease.
Expert Commentary
The findings from this Stockholm cohort represent a paradigm shift in our understanding of PHPT epidemiology. While previous estimates suggested prevalence of approximately 1-2 per 1,000, this study demonstrates rates more than double those figures, challenging assumptions about disease rarity.
The 52% clinical recognition rate deserves particular attention from clinicians and health systems. Several factors likely contribute to this diagnostic gap. First, PHPT symptoms are often nonspecific, including fatigue, cognitive difficulties, and mood changes, which commonly receive alternative explanations. Second, the classic presentation of “stones, bones, groans, and psychiatric overtones” may manifest incompletely in contemporary practice, where milder biochemical abnormalities predominate.
The concentration of increasing incidence among elderly women raises important questions about screening strategies. Current guidelines generally recommend against universal screening for PHPT, instead targeting symptomatic individuals or those with specific complications. However, the data suggest that laboratory-based case finding during routine healthcare encounters may capture substantial undiagnosed disease burden.
Study limitations warrant acknowledgment. The SCREAM database, while comprehensive, includes only individuals who underwent PTH and calcium testing, potentially introducing selection bias toward healthier individuals or those with clinical indications for testing. Additionally, the Swedish healthcare context may limit generalizability to systems with different laboratory ordering patterns or population demographics.
Nevertheless, the study’s strengths are considerable. The population-based design, large sample size, and rigorous biochemical case definition provide confidence in the findings. The 15-year timespan enables robust trend analysis, and the use of clinical records for diagnosis verification allows meaningful assessment of recognition gaps.
Conclusion
This landmark investigation reveals that primary hyperparathyroidism represents a substantially larger public health burden than previously recognized. The 52% increase in incidence over 12 years, combined with a thirteen-fold rise in prevalence, demands attention from clinicians, health systems, and policymakers. The finding that nearly half of biochemically confirmed cases lack clinical diagnosis suggests urgent need for improved detection strategies.
For clinical practice, several implications emerge. First, maintaining awareness of PHPT as a common cause of hypercalcemia remains essential, particularly among elderly women. Second, clinicians should consider that nonspecific symptoms such as fatigue, depression, and cognitive changes may represent manifestations of undiagnosed hyperparathyroidism. Third, appropriate laboratory testing including calcium and PTH measurement in at-risk populations could identify substantial previously unrecognized disease.
Future research should examine long-term outcomes among undiagnosed PHPT populations, evaluate cost-effectiveness of screening strategies in high-risk groups, and investigate whether earlier diagnosis and treatment improve patient-centered outcomes. The rising tide of primary hyperparathyroidism presents both challenges and opportunities for improving endocrine care delivery.
References
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