Surgical strategy in lithium-associated hyperparathyroidism: A population-based study.

BACKGROUND: The extent of parathyroidectomy (PTX) recommendation in patients with lithium-associated hyperparathyroidism (LAH) remains controversial. The primary objectives of this study were to analyze extent of surgery, complications, and long-term outcomes. METHODS: A population-based study, including all primary hyperparathyroidism (PHPT) patients who underwent PTX in Sweden between 2008 and 2017. Data on exhibited lithium prescriptions, morbidity, surgical approach, and outcomes were collected from relevant national registers and the Scandinavian Quality Register of Thyroid, Parathyroid, and Adrenal Surgery. Patients with lithium exposure before PTX were defined as having LAH. Descriptive summary statistics and regression models were used to evaluate differences in comorbidities, surgical approach, and outcomes between LAH and PHPT not exposed to lithium (non-LAH). RESULTS: Lithium exposure was significantly more common among PHPT (n = 202, 2.3%) than in controls (n = 416, 0.5%); OR 5.0 (95% CI 4.2-5.9). The risk of LAH correlated to the length of lithium exposure. In the LAH-group, the surgical procedures were more extensive and associated with a higher risk of postoperative bleeding, wound infections, persistent hypercalcemia, and hypocalcemia that remained after adjustment for the higher percentage of multiglandular disease. However, the cumulative risk of re-admission for PHPT was similar the first years after PTX and primarily elevated for patients with >5 years duration of lithium exposure prior to surgery. CONCLUSIONS: The findings support the perception of LAH as a complex entity. We recommend a functionally oriented approach, aimed to obtain and maintain normocalcemia for as long as possible, minimizing the risk of permanent hypoparathyroidism, and accepting some risk of recurrence.

Neuropsychiatric Comorbidity in Primary Hyperparathyroidism Before and After Parathyroidectomy: A Population Study.

BACKGROUND: Primary hyperparathyroidism (PHPT) is often accompanied by neuropsychiatric symptoms. This study aimed to map out psychiatric comorbidity as reflected by medical treatment for psychiatric symptoms. METHODS: A retrospective case-control analysis and a prospective cohort analysis of psychotropic drug utilization before and after PTX. A total of 8279 PHPT patients treated with parathyroidectomy in Sweden between July 1, 2008 and December 31, 2017 compared to a matched control cohort from the total population (n = 82,790). Information on filled prescriptions was collected from the Swedish Prescribed Drug Register (SDR). Socioeconomic data and diagnoses were added by linkage to national patient and population registers. Regression analyses were used to calculate relative drug utilization (OR) within 3 years prior to PTX and relative incidence of drug treatment (RR) within 3 years postoperatively. RESULTS: Utilization of antidepressant, anxiolytic and sleep medication was more comprehensive in PHPT patients compared with the controls prior to PTX. The most common were benzodiazepines [OR 1.40 (95% CI: 1.31-1.50)] and selective serotonin reuptake inhibitors [SSRI; OR 1.38 (95% CI: 1.30-1.47)]. Postoperatively, the excess prescription rate for anxiolytic benzodiazepines decreased within three years from a 30 to 19% excess and for benzodiazepines for sleep from 31 to 14%. No corresponding decrease in excess prescription rate was observed for SSRI. CONCLUSION: PHPT is associated with increased utilization of antidepressive medications and benzodiazepines before PTX. This study implies that psychiatric symptoms should be considered in PHPT patients and continuous medication should be reevaluated after PTX.

Prediction of cognitive response to surgery in elderly patients with primary hyperparathyroidism.

BACKGROUND: Primary hyperparathyroidism (pHPT) can be associated with potentially reversible cognitive impairment, which is occasionally mistaken for natural ageing and dementia. The aim was to evaluate short-term medical normalization of hypercalcaemia in surgical decision-making for elderly patients with mild cognitive deficiency. METHODS: Patients with pHPT were included in a prospective observational study. A test panel including the Montreal Cognitive Assessment (MoCA) and validated tools for estimation of psychological status (Hospital Anxiety and Depression Scale, HADS), and muscle strength (timed-stands test, TST) was applied at baseline, after 4 weeks of calcimimetic treatment, and after parathyroidectomy. Mild cognitive impairment was defined by a MoCA score below 26. A longitudinal increase in MoCA score of at least 2 points 6 months after surgery was considered clinically meaningful. RESULTS: Of 110 patients who underwent testing, 35 aged 50 years or more were identified to have mild cognitive dysfunction, including 19 who were aged at least 70 years (median MoCA score 23, i.q.r. 21-24). Calcimimetic treatment resulted in normalization of calcium levels, and improvements in MoCA and HADS scores, and TST time. Normal MoCA scores (at least 26) were reached in 17 patients by 6 months after surgery, of whom 10 were aged 70 years or older. Long-term increase in MoCA score correlated with the decrease in ionized calcium concentration (r = -0.536, P = 0.022). Baseline calcium concentration and improvement in MoCA with calcimimetic treatment were identified as independent predictors of favourable outcome after parathyroidectomy. CONCLUSION: Medical normalization of hypercalcaemia can aid in predicting outcome after parathyroidectomy.

Increased risk for tooth extraction in primary hyperparathyroidism and hypercalcemia: a population study.

The aim of this study was to analyze dental comorbidities in untreated primary hyperparathyroidism (pHPT). Patients with pHPT subjected to parathyroidectomy (PTX) at Karolinska University Hospital, Stockholm, during 2011-2016 (n = 982) were selected from the Scandinavian Quality Register of Thyroid, Parathyroid and Adrenal surgery and compared to a general population cohort (n = 2944), matched for age and gender. Dental data was obtained from the Swedish Dental Health Registry for the 3 years prior to PTX. The incidence rate ratios (IRRs) of tooth loss by extraction, periodontal interventions, and dental visit rate were analyzed by Poisson regression models. In order to analyze the impact of disease severity, the PHPT cohort was sub-grouped based on preoperative serum levels of ionized calcium (S-Ca2+). The total number of tooth extractions, periodontal interventions, and number of visits were similar in the cohorts. PHPT patients belonging to the quartile with the highest S-Ca2+ (≥ 1.51 mmol/L) had increased risk for tooth extraction (IRR 1.85; 95% CI 1.39-2.46). Female gender independently amplified the risk (IRR 1.341, P < 0.027). This study indicates an association between pHPT and oral disorders reflected by increased tooth loss by extraction related to high S-Ca2. Increased awareness of dental comorbidity in primary hyperparathyroidism may benefit a large group of patients with a common disease through earlier detection and prevention.

Short-term medical treatment of hypercalcaemia in primary hyperparathyroidism predicts symptomatic response after parathyroidectomy.

BACKGROUND: Primary hyperparathyroidism is often associated with non-disease-specific symptoms. The aim of this study was to evaluate whether normalization of hypercalcaemia with short-term medical treatment can be used to predict the effects of parathyroidectomy and guide in surgical decision-making. METHODS: This observational study included patients who received calcimimetic treatment for 4 weeks before parathyroidectomy (30-60 mg daily). A panel of tests was used to assess various aspects of quality of life (European Organisation and Treatment of Cancer QLQ-C30 core questionnaire, Hospital Anxiety and Depression Scale and Positive State of Mind questionnaire), cognitive function (Montreal Cognitive Assessment) and muscle strength (timed-stands test). The tests were carried out at baseline, after 4 weeks of calcimimetic treatment, and at 6 weeks and 6 months after parathyroidectomy. The predictive values of changes during calcimimetic treatment were determined for each test. RESULTS: The study included 110 patients of median age 62 years (91 women). Calcimimetic treatment resulted in normalization of calcium levels and improvements in quality-of-life parameters. The time spent on the timed-stands test was significantly shortened. Eleven of 38 participants with a baseline Montreal Cognitive Assessment score below 26, indicating mild cognitive impairment, reached scores of at least 26 during treatment with calcimimetic. Improvements during treatment with calcimimetic correlated well with postoperative outcomes (positive predictive values 74-96 per cent). CONCLUSION: The method described in this study may be used to aid surgical decision-making for patients with primary hyperparathyroidism and non-disease-specific symptoms by predicting the effects of normalization of hypercalcaemia.

ANTECEDENTES: El hiperparatiroidismo primario (pHPT) a menudo se asocia con síntomas no específicos de la enfermedad. El objetivo de este estudio fue evaluar si la normalización de la hipercalcemia a corto plazo con tratamiento médico se podría usar para predecir los efectos de la paratiroidectomía y guiar la toma de decisiones quirúrgicas. MÉTODOS: Estudio observacional (ClinicalTrials.gov, registro NCT02227264) que incluyó 110 pacientes programados para paratiroidectomía (mediana de edad 62 años; 91 mujeres). Intervención: tratamiento calcimimético, cuatro semanas, 30-60 mg al día. Medidas de resultado: Un panel de pruebas para evaluar los aspectos de la calidad de vida (cuestionario de calidad de vida core 30, QLQ-C30; escala hospitalaria de ansiedad y depresión (HAD) y estado mental positivo (PSOM); función cognitiva (evaluación cognitiva de Montreal, MoCa) y fuerza muscular (Timed-Stands Test, TST). Las pruebas se realizaron cuatro veces: al inicio del estudio (basal), después de cuatro semanas de tratamiento calcimimético, a las seis semanas y seis meses después de la paratiroidectomía. Para cada prueba se determinaron los valores predictivos de los cambios durante el tratamiento calcimimético. RESULTADOS: El tratamiento con fármacos calcimiméticos determinó una normalización en los niveles de calcio y una mejoría en los parámetros de calidad de vida. El tiempo del TST se redujo significativamente. Once de los 38 participantes con una puntuación MoCa basal < 26, definida como deterioro cognitivo leve, alcanzaron puntuaciones ≥ 26 durante el uso de la medicación. Las mejoras observadas durante el tratamiento mostraron una buena correlación con el resultado postoperatorio (valores predictivos positivos 74-96%). CONCLUSIÓN: Este estudio presenta un método basado en la predicción de los efectos de la normalización de la hipercalcemia para ayudar en la toma de decisiones quirúrgicas en pacientes con pHPT y síntomas no específicos de la enfermedad.

Primary hyperparathyroidism: should surgery be performed on all patients? Current evidence and residual uncertainties.

Primary hyperparathyroidism (pHPT) is the third most common endocrine disease and is characterized by hypercalcaemia and elevated or inappropriately 'normal' levels of the parathyroid hormone (PTH). The main target organs of PTH are the skeletal system and the kidneys. Before the 1970s, pHPT was a rarely detected disease associated with notable morbidity and premature mortality. Introduction of biochemical screening, allowing for a wide range of indications, has contributed to the detection of the full spectrum of the disease. A new entity with an isolated elevation of PTH, normocalcaemic HP, has emerged and is currently being explored. The highest incidence of pHPT, 3-5%, is observed amongst women, and the prevalence increases with age. The female-to-male ratio is 3-4 : 1 except in younger patients where distribution is equal and known hereditary causes account for approximately 10% of the cases. In the last few decades, it has become evident that fewer patients than previously believed are truly asymptomatic. The cause of pHPT is often a benign tumour, a parathyroid adenoma, and the only definite treatment is parathyroidectomy (PTX). No medical treatment, single or combined, can achieve a curing of pHPT. Recent data indicate that PTX, despite being proven to be cost-effective compared to conservative treatment, is underutilized, especially in elderly pHPT patients. The decision of PTX should always be based on a safe diagnosis, and the potential benefits of curative treatment should not be outweighed by the risks of surgery or anaesthesia.

Cardiac function in mild primary hyperparathyroidism and the outcome after parathyroidectomy.

OBJECTIVE: Primary hyperparathyroidism (PHPT) is associated with cardiovascular morbidity. The extent of cardiovascular abnormalities in patients with mild-asymptomatic disease is unclear. Using sensitive echocardiographic methods, we compared cardiac structure and function in patients with mild PHPT and in healthy controls, and evaluated the changes after parathyroidectomy (PTX). METHODS: In a prospective case-control design, we studied 51 PHPT patients without any cardiovascular risk factors/diseases and 51 healthy matched controls. Cardiac structure, and systolic and diastolic function were evaluated by echocardiography and Doppler tissue imaging (DTI). Blood pressure (BP) and heart rate were measured. RESULTS: We observed no differences in systolic or diastolic function or in cardiac morphology between the PHPT patients and the age-matched healthy controls. The regional peak systolic myocardial velocities (S') measured with DTI decreased at all sites (P<0.05) after PTX (tricuspid annulus 14.23+/-1.85 to 13.48+/-1.79, septal 8.48+/-0.96 to 7.97+/-0.85, and lateral 9.61+/-2.05 to 8.87+/-1.63 cm/s, part of the mitral annulus). At baseline, systolic BP was higher in patients compared to controls (127.6+/-17.1 vs 119.6+/-12.6 mmHg, P<0.05). After PTX, both systolic (127.6+/-17.1 vs 124.6+/-16.6 mmHg, P<0.05) and diastolic (80.3+/-9.6 vs 78.4+/-8.6 mmHg, P<0.05) BP decreased. CONCLUSIONS: Our results indicate that patients with PHPT without cardiovascular risk factors have a normal global systolic and diastolic function and cardiac morphology. BP and the systolic velocities were marginally reduced after PTX, but reflected the values of the control group. Our findings warrant further investigation of the clinical and prognostic significance of these possibly disease-related inotropic effects.

Primary hyperparathyroidism in pregnancy: a diagnostic and therapeutic challenge.

The risk of severe complications arising from primary hyperparathyroidism (pHPT) is increased during pregnancy. Gestational pHPT often goes undiagnosed, and by the time it is diagnosed, a majority of women have endured one or more failed pregnancies. During pregnancy, active transport of calcium ions from the mother to the fetus leads to suppression of the fetal parathyroids. When the prenatal pool of calcium is depleted, the newborn may develop neonatal hypocalcemic tetany. The mother, in turn, may suffer from worsening hypercalcemia and a hypercalcemic crisis after delivery. Awareness and confirmation of the diagnosis may be crucial for the outcome. The only definitive treatment of pHPT is parathyroidectomy, which should be recommended in most cases. Our two cases illustrate both the importance of and the difficulty in detecting pHPT during pregnancy, as well as some of the serious complications that may occur during pregnancy and after delivery.

Parathyroid Hormone's Acute Effect on Vasodilatory Function.

Parathyroid hormone (PTH) seems to affect the risk of cardiovascular disease. The aim of the present study was to investigate PTH's acute effect on endothelial vasodilatory function in forearm resistance vessels. Ten healthy subjects underwent forearm venous occlusion plethysmography. We measured forearm blood flow at baseline and at a stable, locally increased PTH level after intra-arterial infusion of metacholine and nitroprusside. The contralateral arm served as a control. Ionized calcium (Ca++) and PTH values were normal in all subjects at baseline (1.26 ± 0.02 mM/L, 3.6 ± 1.2 pM/L). After 30 minutes of PTH infusion, the PTH level increased in the active arm (13.8 ± 4.0 pM/L P < 0.01), while the Ca++ level was unchanged (1.25 ± 0.04; mM/L). Both the PTH and the Ca++ level in the contralateral arm remained unchanged, which indicates no systemic influence. The endothelial-dependent vasodilation was inversely correlated to the Ca++ level at baseline (r = -0.75, P < 0.05) and after PTH infusion (r = -0.68, P < 0.05). The vasodilatory function was not affected during PTH-infusion.

Postoperative mortality in parathyroid surgery in Sweden during five decades: improved outcome despite older patients.

OBJECTIVE: Primary hyperparathyroidism (pHPT) is a common endocrine disorder. In Europe, pHPT has been associated with premature death in cardiovascular disorders. Our question was whether the risk of postoperative death has been affected by the increased proportion of elderly patients referred for parathyroid surgery. METHODS: The nationwide Cancer Registry and Causes-of-Death Registry were used to analyze mortality among 14 635 Swedish patients subjected to parathyroid adenomectomy (PTx) during 1961-2004. Standard mortality ratios (SMR) and the 95% confidence intervals (CI) were calculated with the entire Swedish population as control, standardized for age, gender and calendar year. RESULTS: The observation period was more than 166 000 person-years. The overall perioperative (30-day) mortality rate was 1.3% (185/14 635; SMR 7.9; CI 6.82-9.15); 1.1% for women (132/11 500; SMR 7.56; CI 6.32-8.96), and 1.7% for men (53/3135; SMR 9.01; CI 6.75-11.78). Cardiovascular disorder was the dominant cause of death in both sexes and in all the investigated age groups (age 15-54 years; SMR 29.0; CI 9.42-67.71, age 55-74 years; SMR 6.12; CI 3.96-9.03, age 75 years: SMR 5.26; CI 3.74-7.19). The SMR decreased over the calendar year period notwithstanding a rising proportion of elderly individuals. In the most recent period, 1997-2004, the perioperative mortality rate was only 0.5%, which represents a normalization of the excess mortality risk during the first post-PTx year (SMR 1.17; CI 0.92-1.46). CONCLUSION: PTx is a safe procedure, regardless of patient age. Today, the perioperative mortality risk is not a reason for excluding elderly patients from parathyroid surgery.

Endothelial vasodilatory function and blood pressure response to local and systemic hypercalcemia.

BACKGROUND: Endothelial vasodilatory dysfunction occurs in primary hyperparathyroidism. Mechanistically it could be a sign of atherosclerosis, but improvement after parathyroidectomy suggests coupling to hypercalcemia and increased parathyroid hormone levels of patients. METHOD: A total of 12 volunteers underwent forearm venous occlusion plethysmography with systemic (intravenous) and local (brachial artery) infusion of calcium. Endothelium-dependent and endothelium-independent vasodilations were evaluated at stable hypercalcemia through infusion of methacholine and nitroprusside into the brachial artery, and an endothelial function index was calculated as the ratio between them. RESULTS: Normal ionized blood calcium values rose 0.24 +/- 0.09 mmol/L in the cubital venous blood during local calcium infusion and 0.32 +/- 0.16 mmol/L during the systemic infusion. The systemic infusion raised systolic blood pressure (114 +/- 13 to 121 +/- 10 mm Hg; P < .05). It decreased the function index (1.28 +/- 0.40 to 1.00 +/- 0.14; P < .05; n = 11) due to an elevated endothelium-independent vasodilation (EIDV) (P < .05), despite the fact that serum parathyroid hormone values decreased (P< .01). A similar trend in vasodilatory responses was seen during local calcium infusion when the function index correlated inversely to the local blood calcium (r = -0.58, P < .05; n = 12). CONCLUSIONS: Acute hypercalcemia results in dose-related impairment in endothelial vasodilatory function and increased systolic blood pressure. This substantiates the importance of hypercalcemia for cardiovascular complications and prospects for normalization by active treatment in primary hyperparathyroidism.

Left ventricular systolic and diastolic function and exercise testing in primary hyperparathyroidism-effects of parathyroidectomy.

BACKGROUND: Nontraditional manifestations of primary hyperparathyroidism (HPT) are controversial and may include morbidity, mortality, and risk factors for cardiovascular diseases. This study evaluates cardiovascular functions at rest and during exercise in HPT. METHOD: Thirty patients with HPT (mean serum calcium, 2.97 +/- 0.24 mmol/L) and 30 control people with normocalcemia, matched for age and sex, underwent symptom-limited exercise testing and echocardiography before and 13 months (mean) after having a parathyroidectomy. RESULTS: Despite similar maximal workload and blood pressures at rest in patients and healthy controls, HPT associated with higher systolic blood pressure during exercise (P =.03) and increased number of ventricular extrasystolic beats (P =.04). There was also an operatively reversible increase in ST-segment depression during exercise. Echocardiography showed an increased left ventricular (LV) isovolemic relaxation time (P =.02) and mitral deceleration time (P =.08), which indicate an LV diastolic dysfunction that could be partially reversed by operation. LV systolic function (ejection fraction and shortening fraction) tended to be elevated in HPT (P =.07 and.06, respectively) and diminished after parathyroidectomy. There was a trend toward higher LV mass, especially among the men with HPT (P =.06), which was unchanged postoperatively. CONCLUSIONS: HPT couples to reversible signs of myocardial ischemia and LV dysfunctions with a possible increased risk of life-threatening arrhythmia.

Endothelial vasodilatory dysfunction in primary hyperparathyroidism is reversed after parathyroidectomy.

BACKGROUND: Primary hyperparathyroidism (HPT) is accompanied by hypertension and a cardiovascular mortality. Impaired endothelium-dependent vasodilatation (EDV) occurs in hypertension but has not been fully investigated in HPT despite the vasoactive influences of parathyroid hormone. METHODS: Twenty-five HPT patients and 25 normocalcemic control subjects, matched for age and gender, underwent forearm venous occlusion plethysmography. EDV and endothelium-independent vasodilatation (EIDV) were evaluated during local infusion of metacholine (2 and 4 micrograms/min) and nitroprusside (5 and 10 micrograms/min), respectively. The endothelial function index was calculated as the ratio of forearm blood flows during the high doses of metacholine and nitroprusside. Ambulatory 24-hour blood pressures and thickness of the intima-media complex of the carotid arteries were also measured; the latter is considered an early marker of atherosclerosis. RESULTS: Endothelial function index was lower in the HPT patients compared with control subjects (1.01 +/- 0.26 vs 1.27 +/- 0.31, P = .003). Reinvestigation 10 months after parathyroidectomy showed normalization of the index (1.31 +/- 0.39, P = .01) due to a numeric increase in EDV and decrease in EIDV. The carotid intima-media thickness and blood pressure were similar in the groups and unaltered postoperatively. CONCLUSIONS: Endothelial vasodilatory dysfunction is another indicator of the vascular disturbance of HPT and can be normalized by parathyroidectomy.