Analysis of Comorbidities, Clinical Outcomes, and Parathyroidectomy in Adults With Primary Hyperparathyroidism

Axelsson, Kristian F; Wallander, Märit; Johansson, Helena; Harvey, Nicholas C.; Vandenput, Liesbeth; McCloskey, Eugene; Liu, Enwu; Kanis, John А.; Litsne, Henrik; Lorentzon, Mattias

doi:10.1001/jamanetworkopen.2022.15396

Cited by 25 publications

(10 citation statements)

References 42 publications

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“…A longitudinal cohort study of 3213 Danish patients with PHPT diagnosed from 1989 to 1999 with a median 6.1 years follow-up found no difference in the hazard of MI, hypertension, heart failure, arrhythmia, or stroke between patients treated with parathyroidectomy versus those managed nonoperatively after adjusting for age, sex, and history of each event prior to PHPT diagnosis 36 . A recently published population-based study of 16,374 patients with PHPT in Sweden showed a reduced risk of CV events in patients with PHPT who were treated with parathyroidectomy (HR: 0.84, 95% CI: 0.73–0.97), similar to our findings 37 . Long-term follow-up data from the 191-patient Scandinavian Investigation of Primary Hyperparathyroidism (SIPH) randomized controlled trial showed no statistically significant difference in the secondary outcome of CV events (HR: 0.81, 95% CI: 0.33–1.99) among adults with asymptomatic PHPT managed with parathyroidectomy versus nonoperatively, but this study was underpowered to detect differences in CV outcomes 38 .…”

Section: Discussionsupporting

confidence: 89%

“…These prior studies suggested that surgical cure with parathyroidectomy would alter the CV risk profile of patients with PHPT and lead to improved CV outcomes, consistent with our findings. However, it is important to note that the CV benefits of parathyroidectomy in our study and the recent Swedish cohort study 37 were modest and most likely to be clinically meaningful on long-term follow-up (ie, 5–10 years following surgery), which may not be relevant to patients with limited life expectancy. It is possible that more nuanced, short-term CV benefits are experienced by patients with PHPT treated operatively but that these are not as evident in the current analysis.…”

Section: Discussionmentioning

confidence: 60%

“…36 A recently published population-based study of 16,374 patients with PHPT in Sweden showed a reduced risk of CV events in patients with PHPT who were treated with parathyroidectomy (HR: 0.84, 95% CI: 0.73-0.97), similar to our findings. 37 Long-term follow-up data from the 191-patient Scandinavian Investigation of Primary Hyperparathyroidism (SIPH) randomized controlled trial showed no statistically significant difference in the secondary outcome of CV events (HR: 0.81, 95% CI: 0.33-1.99) among adults with asymptomatic PHPT managed with parathyroidectomy versus nonoperatively, but this study was underpowered to detect differences in CV outcomes. 38 Small, predominantly single-center studies have shown a beneficial effect of parathyroidectomy on surrogate CV endpoints, including arterial stiffness, endothelial dysfunction, and left ventricular mass.…”

Section: Discussionmentioning

confidence: 80%

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Adverse Cardiovascular Outcomes Among Older Adults With Primary Hyperparathyroidism Treated With Parathyroidectomy Versus Nonoperative Management

Seib¹,

Meng²,

Cisco³

et al. 2022

Annals of Surgery

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Objective: The authors sought to compare the incidence of adverse cardiovascular (CV) events in older adults with primary hyperparathyroidism (PHPT) treated with parathyroidectomy versus nonoperative management. Background: PHPT is a common endocrine disorder that is associated with increased CV mortality, but it is not known whether parathyroidectomy reduces the incidence of adverse CV events. Methods: The authors conducted a population-based, longitudinal cohort study of Medicare beneficiaries diagnosed with PHPT (2006–2017). Multivariable, inverse probability weighted Cox proportional hazards regression was used to determine the associations of parathyroidectomy with major adverse cardiovascular events (MACEs), CV disease-related hospitalization, and CV hospitalization-associated mortality. Results: The authors identified 210,206 beneficiaries diagnosed with PHPT from 2006 to 2017. Among 63,136 (30.0%) treated with parathyroidectomy and 147,070 (70.0%) managed nonoperatively within 1 year of diagnosis, the unadjusted incidence of MACE was 10.0% [mean follow-up 59.1 (SD 35.6) months] and 11.5% [mean follow-up 54.1 (SD 34.0) months], respectively. In multivariable analysis, parathyroidectomy was associated with a lower incidence of MACE [hazard ratio (HR): 0.92; 95% confidence interval (95% CI): 0.90–0.94], CV disease-related hospitalization (HR: 0.89; 95% CI: 0.87–0.91), and CV hospitalization-associated mortality (HR: 0.76; 95% CI: 0.71–0.81) compared to nonoperative management. At 10 years, parathyroidectomy was associated with adjusted absolute risk reduction for MACE of 1.7% (95% CI: 1.3%–2.1%), for CV disease-related hospitalization of 2.5% (95% CI: 2.1%–2.9%), and for CV hospitalization-associated mortality of 1.4% (95% CI: 1.2%–1.6%). Conclusions: In this large, population-based cohort study, parathyroidectomy was associated with a lower long-term incidence of adverse CV outcomes when compared with nonoperative management for older adults with PHPT, which is relevant to surgical decision making for patients with a long life expectancy.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 80%

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Adverse Cardiovascular Outcomes Among Older Adults With Primary Hyperparathyroidism Treated With Parathyroidectomy Versus Nonoperative Management

Seib¹,

Meng²,

Cisco³

et al. 2022

Annals of Surgery

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“…Moreover, the risk was reduced significantly for patients who had undergone a parathyroidectomy. This study brings to light the effect of PHPT on cardiovascular health and the benefit of parathyroidectomy [ 11 ].…”

Section: Discussionmentioning

confidence: 99%

A Delicate Balance: Challenges in the Management of Primary Hyperparathyroidism and Congestive Heart Failure

Mohan¹,

Bahniwal²,

Shah³

2023

Cureus

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Primary hyperparathyroidism (PHPT) is an excessive parathyroid hormone (PTH) production disorder, causing increased calcium levels. Commonly, these cases are asymptomatic and detected incidentally on routine labs. These patients are usually conservatively managed and monitored periodically, including bone and kidney health evaluation. Medical management of severe hypercalcemia secondary to PHPT includes IV fluids, cinacalcet, bisphosphonates, and dialysis, while the surgical treatment is parathyroidectomy. Patients suffering from heart failure with reduced ejection fraction (HFrEF) on diuretics and PHPT require a delicate balance of their volume status to prevent exacerbation of either condition. In patients with these two comorbidities on the opposite ends of the volume spectrum, it can lead to challenges in managing these patients. We present a case of a woman with repeated hospitalizations due to poor volume status control. An 82-year-old female with primary hyperparathyroidism (diagnosed 17 years ago), HFrEF due to non-ischemic cardiomyopathy, sick sinus syndrome with a pacemaker, and persistent atrial fibrillation presented to the emergency department with worsening bilateral lower limb swelling for several months. The remaining review of systems was largely negative. Her home medication regimen included carvedilol, losartan, and furosemide. Vitals were stable, and the physical exam revealed bilateral lower extremity pitting edema. Chest x-ray revealed cardiomegaly with mild pulmonary vascular congestion. Relevant labs were NT pro-BNP at 2190 pg/mL, calcium at 11.2 mg/dL, creatinine at 1.0 mg/dL, PTH at 143 pg/mL, and Vitamin D, 25-hydroxy at 48.6 ng/mL. The echocardiogram showed an ejection fraction (EF) of 39%, grade III diastolic dysfunction, severe pulmonary hypertension, and mitral and tricuspid regurgitation. The patient received IV diuretics and guideline-directed treatment for congestive heart failure exacerbation. She was managed conservatively for her hypercalcemia and advised to maintain hydration at home. Spironolactone and Dapagliflozin were added to her regimen, and the Furosemide dose was increased at discharge. The patient was re-admitted three weeks later with fatigue and decreased fluid intake. Vitals were stable; however, the physical exam revealed dehydration. Pertinent labs were calcium at 13.4 mg/dL, potassium at 5.7 mmol/L, creatinine at 1.7 mg/dL (baseline 1.0), PTH at 204 pg/mL, and Vitamin D, 25-hydroxy at 54.1 ng/mL. Repeat ECHO showed an ejection fraction (EF) of 15%. She was started on gentle IV fluids to correct the hypercalcemia while preventing volume overload. Hypercalcemia and acute kidney injury improved with hydration. She was put on Cinacalcet 30 mg, and home medications were adjusted for better volume control at discharge. This case highlights the complications of balancing the volume status with primary hyperparathyroidism and CHF. Worsening HFrEF resulted in a higher diuretic requirement, thereby worsening her hypercalcemia. With ...

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“…Some studies indicated increased mortality in severe PHPT, but the effect of asymptomatic PHPT on mortality and benefit of parathyroidectomy are controversial. An observational study of 16 374 patients with PHPT and 163 740 control patients indicated that those with PHPT had a higher risk of death (51.83 vs 30.95 per 1000 person-years) and parathyroidectomy reduced risk (hazard ratio, 0.59) . A smaller RCT of 191 patients reported no benefit of parathyroidectomy on mortality compared with observation at 10-year follow-up (25.3% vs 20.8%) …”

Section: Observations and Discussionmentioning

confidence: 99%

Hypercalcemia

Walker

Shane

2022

JAMA

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ImportanceHypercalcemia affects approximately 1% of the worldwide population. Mild hypercalcemia, defined as total calcium of less than 12 mg/dL (&lt;3 mmol/L) or ionized calcium of 5.6 to 8.0 mg/dL (1.4-2 mmol/L), is usually asymptomatic but may be associated with constitutional symptoms such as fatigue and constipation in approximately 20% of people. Hypercalcemia that is severe, defined as total calcium of 14 mg/dL or greater (&gt;3.5 mmol/L) or ionized calcium of 10 mg/dL or greater (≥2.5 mmol/L) or that develops rapidly over days to weeks, can cause nausea, vomiting, dehydration, confusion, somnolence, and coma.ObservationsApproximately 90% of people with hypercalcemia have primary hyperparathyroidism (PHPT) or malignancy. Additional causes of hypercalcemia include granulomatous disease such as sarcoidosis, endocrinopathies such as thyroid disease, immobilization, genetic disorders, and medications such as thiazide diuretics and supplements such as calcium, vitamin D, or vitamin A. Hypercalcemia has been associated with sodium-glucose cotransporter 2 protein inhibitors, immune checkpoint inhibitors, denosumab discontinuation, SARS-CoV-2, ketogenic diets, and extreme exercise, but these account for less than 1% of causes. Serum intact parathyroid hormone (PTH), the most important initial test to evaluate hypercalcemia, distinguishes PTH-dependent from PTH-independent causes. In a patient with hypercalcemia, an elevated or normal PTH concentration is consistent with PHPT, while a suppressed PTH level (&lt;20 pg/mL depending on assay) indicates another cause. Mild hypercalcemia usually does not need acute intervention. If due to PHPT, parathyroidectomy may be considered depending on age, serum calcium level, and kidney or skeletal involvement. In patients older than 50 years with serum calcium levels less than 1 mg above the upper normal limit and no evidence of skeletal or kidney disease, observation may be appropriate. Initial therapy of symptomatic or severe hypercalcemia consists of hydration and intravenous bisphosphonates, such as zoledronic acid or pamidronate. In patients with kidney failure, denosumab and dialysis may be indicated. Glucocorticoids may be used as primary treatment when hypercalcemia is due to excessive intestinal calcium absorption (vitamin D intoxication, granulomatous disorders, some lymphomas). Treatment reduces serum calcium and improves symptoms, at least transiently. The underlying cause of hypercalcemia should be identified and treated. The prognosis for asymptomatic PHPT is excellent with either medical or surgical management. Hypercalcemia of malignancy is associated with poor survival.Conclusions and RelevanceMild hypercalcemia is typically asymptomatic, while severe hypercalcemia is associated with nausea, vomiting, dehydration, confusion, somnolence, and coma. Asymptomatic hypercalcemia due to primary hyperparathyroidism is managed with parathyroidectomy or observation with monitoring, while severe hypercalcemia is typically treated with hydration and intravenous bisphosphonates.

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Analysis of Comorbidities, Clinical Outcomes, and Parathyroidectomy in Adults With Primary Hyperparathyroidism

Abstract: This cohort study examines the association of fractures, cardiovascular events, and mortality with untreated primary hyperparathyroidism and with surgical treatment.

Cited by 25 publications

References 42 publications

Adverse Cardiovascular Outcomes Among Older Adults With Primary Hyperparathyroidism Treated With Parathyroidectomy Versus Nonoperative Management

Adverse Cardiovascular Outcomes Among Older Adults With Primary Hyperparathyroidism Treated With Parathyroidectomy Versus Nonoperative Management

A Delicate Balance: Challenges in the Management of Primary Hyperparathyroidism and Congestive Heart Failure

Hypercalcemia

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