Further insights into the pathogenesis of primary hyperparathyroidism: a nested case-control study.

CONTEXT: The pathogenesis of primary hyperparathyroidism (PHPT) is largely unknown. OBJECTIVE: The objective of the study was to ascertain the plasma levels of calcium, PTH, and 25-hydroxyvitamin D (25OHD) as measured prior to a clinical diagnosis of PHPT. STUDY SUBJECTS: Within three population-based cohorts, we identified participants diagnosed with PHPT after their inclusion. Cases (n = 117) were compared with age, gender, and season-matched controls (n = 233). RESULTS: Time from inclusion until a diagnosis of PHPT was median 5.6 yr. Parathyroidectomy was performed in 97%. At the cohort inclusion, undiagnosed PHPT was present in 63% of the cases. Among those without PHPT at inclusion (n = 43), 55% had normocalcemic hyperparathyroidism (vs. 21% in the matched controls, P < 0.01), and 31% had normoparathyroid hypercalcemia. Overall, 25OHD levels were lower in the cases. Compared with their matched controls, 25OHD levels were lower in normocalcemic hyperparathyroidism but not in normoparathyroid hypercalcemia. An adenoma was removed from 78% of the cases with normocalcemic hyperparathyroidism, whereas 39% of the cases with normoparathyroid hypercalcemia had parathyroid hyperplasia (P = 0.02). Overlap performance showed a positive predictive value for later PHPT of 95% for plasma calcium levels greater than 2.52 mmol/liter. Excluding cases with vitamin D insufficiency, the positive predictive value for later PHPT was 83% for PTH levels greater than 5.0 pmol/liter. CONCLUSION: Years prior to a clinical diagnosis of PHPT, calcium homeostasis shows signs of perturbations. Latent PHPT may be characterized by either normocalcemic hyperparathyroidism or normoparathyroid hypercalcemia. Such patients should be offered long-term follow-up to ascertain whether their biochemical profile represents an early state of PHPT.

Effect of surgery on cardiac structure and function in mild primary hyperparathyroidism.

CONTEXT: The cardiovascular (CV) risk profile is worsened in primary hyperparathyroidism (PHPT), and CV mortality is related to serum calcium levels. It is unknown whether CV mortality is increased in the most common form of PHPT and whether the increased CV risk is reversible after surgery. OBJECTIVE: To investigate reversibility of echocardiographic variables in patients with mild PHPT who were randomized to observation without surgery or operation, and followed for 2 years. DESIGN/SETTING/PATIENTS: Forty-nine patients (mean age 63 ± 7 years, 8 men) who had performed the 2-year visit in a randomized study on mild PHPT (serum calcium at baseline 2·65 ± 0·09 mm) (observation) vs 2·67 ± 0·06 mm (surgery) and where echocardiography had been performed, participated in the study. RESULTS: Calcium and parathyroid hormone (PTH) levels were normalized following surgery and were stable in the observation group. PTH levels at baseline were highly correlated with ventricular mass. Detailed echocardiography revealed a minor and borderline significant treatment effect of surgery on left ventricular mass index (LVMI) compared to observation (P = 0·066) and a significant 11% reduction in diastolic dimension of the interventricular septum (IVSd-mean) in the surgery group (P<0·01), with no alterations in the observation group. CONCLUSIONS: Based on detailed echocardiographic measures over a 2-year observation period, we found only minor differences between the two groups. However, the potential treatment effect on LVMI and the within-group differences in IVSd-mean suggest that longer follow-up may yield larger and clinically important differences.

Effect of surgery on cardiovascular risk factors in mild primary hyperparathyroidism.

CONTEXT: Mild primary hyperparathyroidism (pHPT) seems to have a good prognosis, and indications for active treatment (surgery) are widely discussed. The extraskeletal effects of PTH, such as insulin resistance, arterial hypertension, and cardiovascular (CV) risk, may however be reversible by operation. OBJECTIVE: Our aim was to study biochemical markers of bone turnover, indices of the metabolic syndrome, and various risk markers for CV disease in patients with mild pHPT randomized to observation without surgery or operative treatment and followed for 2 yr. DESIGN/SETTING/PATIENTS: A total of 116 patients (mean age, 63 +/- 8 yr; 19 men and 97 women) who on May 1, 2008, had performed the 2-yr visit in a randomized study on mild pHPT (serum calcium at baseline, 2.69 +/- 0.11 mmol/liter) and where frozen samples were available from baseline and follow-up participated in the study. RESULTS: Calcium and PTH levels were normalized after surgery, and biochemical markers of bone turnover decreased by 35%, followed by a significant increase in BMD in the spine (2.7%; P < 0.01) and femoral neck (1.1%; P < 0.02) compared with the observation group. No significant differences were observed between the groups for blood pressure, markers of insulin resistance, detailed cholesterol metabolism, adipokines, or parameters of inflammation and CV surrogate markers. CONCLUSIONS: We observed expected effects on biochemical markers of bone turnover and bone mass after surgical treatment of mild pHPT, with stable values in the group randomized to observation. For a variety of measures of the metabolic syndrome, adipokines, and CV risk factors, no benefit of operative treatment could be demonstrated. Neither did we observe any deleterious effects of conservative management in the 2-yr perspective.

Long-term outcome after mastectomy with immediate breast reconstruction.

INTRODUCTION: The purpose of this study was to investigate long term outcome for women who had undergone mastectomy and immediate breast reconstruction. MATERIAL AND METHODS: Patient files of 167 immediately reconstructed breast cancer patients were reviewed for late surgical complications. Furthermore, information of local recurrence rate, radiotherapy and death was obtained from the Danish Breast Cancer Cooperative Group register. Histopatological high and low risk patients were compared with respect to locoregional recurrence rate, recurrence free survival and death. Unpaired t-test and Fisher's exact test were used to test for significance. RESULTS: The overall rate of revision surgery was 27%. Reconstruction with implants was associated with a significantly higher rate of revision surgery compared to reconstructions with transverse rectus abdominis myocutaneous flap or latissimus dorsi flap without implant (36 vs. 14%; p=0.004). The locoregional recurrence rate was 6%. Patients with histopathologically high risk disease had increased death rate (22 vs. 6%; p=0.03) and shorter disease free survival (89+/-43 months vs. 104+/-35 months; p=0.048) compared with low risk disease. We found no increase in the occurrence of capsular contracture in our study group in patients who received radiotherapy. CONCLUSION: Immediate breast reconstruction seems to be oncologically safe. Breast reconstruction performed with implants was associated with a higher risk of late complications, as was histopathologically high risk disease with increased death rate and shorter disease free survival.

Medical observation, compared with parathyroidectomy, for asymptomatic primary hyperparathyroidism: a prospective, randomized trial.

CONTEXT: The clinical presentation of primary hyperparathyroidism (pHPT) has changed during the last half century, and the diagnosis is now more often made by chance in patients with no specific symptoms. OBJECTIVE: The present study is a randomized, controlled trial that investigates the effects of parathyroidectomy or medical observation in mild asymptomatic pHPT on morbidity and quality of life (QoL). DESIGN/SETTING/PATIENTS: A total of 191 patients (26 men) with asymptomatic pHPT [mean age 64.2 +/- 7.4 (sd) yr] were recruited in the study and randomized to medical observation (serum calcium level 2.69 +/- 0.08 mmol/liter) or surgery (2.70 +/- 0.08 mmol/liter). We here report baseline and 1 (n = 119) and 2 yr data (n = 99) on those who had completed the follow-up visits by the end of the inclusion period. RESULTS: At baseline, the patients had significantly lower QoL (SF-36) and more psychological symptoms, compared with age- and sex-matched healthy subjects. The two groups were similar at baseline, and no clinically significant changes in these parameters were seen during the observation time. Calcium and PTH normalized after surgery. The areal bone mineral density increased in the group randomized to operation, whereas the bone mineral density remained stable in the medical observation group. No change in kidney function (creatinine) or blood pressure was observed longitudinally or between the groups. CONCLUSIONS: Asymptomatic patients with mild pHPT have decreased QoL and more psychological symptoms than normal controls. No benefit of operative treatment, compared with medical observation, was found on these measures so far.

Characteristics of the Danish families with multiple endocrine neoplasia type 1.

Multiple endocrine neoplasia type 1 (MEN1) is caused by autosomal dominantly inherited mutations in the MEN1 gene. Here, we report 25 MEN1 mutations - of which 12 are novel - found in 36 Danish families with MEN1 or variant MEN1 disease. Furthermore, one FIHP family was found to have an earlier reported mutation. The mutations were predominantly found in exons 9 and 10 encoding the C-terminal part of menin. Seven of the mutations were missense mutations, changing conserved residues. Furthermore screening of 93 out of 153 consecutive patients with primary hyperparathyroidism (pHPT) identified five mutation carriers. Two of these belonged to known MEN1 families, whereas the only MEN1-related disease in the other three was pHPT. Screening of 96 consecutive patients with fore-/midgut endocrine tumours revealed five mutation carries out of 28 patients with sporadic gastrinomas, whereas no mutations were found in 68 patients with other fore-/midgut endocrine tumours. Moreover, screening of 60 consecutive patients with primary prolactinoma did not identify any mutation carriers. Our data indicate that MEN1 mutation screening is efficient in patients with familial MEN1. Screening should also be offered to patients with pHPT or gastrinomas after thorough investigation into the family history. In contrast, sporadic carcinoid tumours or primary prolactinomas are rarely associated with germ-line MEN1 mutations.

Cardiovascular events before and after surgery for primary hyperparathyroidism.

Cardiovascular disease [atherosclerosis and subsequent myocardial infarction (MI)] has been associated with primary hyperparathyroidism. We aimed at studying cardiovascular events before and after surgery and mortality after surgery for primary hyperparathyroidism using a historical follow-up design. A total of 674 patients who underwent surgery at three Danish centers between January 1, 1979 and December 31, 1997 were compared with 2021 age- and gender-matched controls. There was an increased incidence of acute MI up to 10 years prior to surgery [relative risk (RR) 2.5, 95% confidence interval (95% CI) 1.5-4.2] and within the first year following surgery (RR 3.6, 95% CI 1.7-7.6). The risk of MI subsequently declined to a normal level more than 1 year after surgery. Patients with MI prior to diagnosis also had a higher postoperative risk of new infarction than did patients without [odds ratio (OR) 6.0, 95% CI 1.2-30.0]. The risk of hypertension, stroke, congestive heart failure, and diabetes was increased before surgery. More than 1 year after surgery only hypertension and congestive heart failure were more frequent in patients than controls. Preoperative cardiovascular disease was associated with an increased risk of death (RR 1.8, 95% CI 1.1-2.8). Mortality following surgery was higher than in the general population between 1979 and 1990 but not between 1991 and 1997. We concluded that there was an increase in acute MI up to 10 years prior to surgery. The risk of MI decreased to a normal level after surgery, which may be important for preventing cardiovascular disease in patients with primary hyperparathyroidism.

Risk of renal stone events in primary hyperparathyroidism before and after parathyroid surgery: controlled retrospective follow up study.

AIM: To study the risk of renal stone episodes and risk factors for renal stones in primary hyperparathyroidism before and after surgery. DESIGN: Register based, controlled retrospective follow up study. SETTING: Tertiary hospitals in Denmark. PARTICIPANTS: 674 consecutive patients with surgically verified primary hyperparathyroidism. Each patient was compared with three age- and sex-matched controls randomly drawn from the background population. Hospital admissions for renal stone disease were compared between patients and controls. Risk factors for renal stones among patients were assessed. MAIN OUTCOME MEASURES: Number of renal stone episodes; comparison of hospital admissions for renal stones in patients and controls; assessment of risk factors for renal stones. RESULTS: Relative risk of a stone episode was 40 (95% confidence interval 31 to 53) before surgery and 16 (12 to 23) after surgery. Risk was increased 10 years before surgery, and became normal more than 10 years after surgery. Stone-free survival 20 years after surgery was 90.4% in patients and 98.7% in controls (risk difference 8.3%, 4.8% to 11.7%). Patients with preoperative stones had 27 times the risk of postoperative stone incidents than controls. Before surgery, males had more stone episodes than females and younger patients had more stone episodes than older patients. Neither parathyroid pathology, weight of removed tissue, plasma calcium levels, nor skeletal pathology (fractures) influenced the risk of renal stones. After surgery, younger age, preoperative stones and ureteral strictures were significant risk factors for stones. CONCLUSIONS: The risk of renal stones is increased in primary hyperparathyroidism and decreases after surgery. The risk profile is normal 10 years after surgery. Preoperative stone events increase the risk of postoperative stones. Stone formers and non-stone formers had the same risk of skeletal complications.

Primary hyperparathyroidism: renal calcium excretion in patients with and without renal stone sisease before and after parathyroidectomy.

The effect of parathyroidectomy on renal calcium excretion per 24 hours in patients with primary hyperparathyroidism with and without a history of renal stone disease was evaluated. Altogether, 91 patients operated on for primary hyperparathyroidism formed the study group for preoperative analysis. Of these patients, 42 were evaluated 1 to 3 years postoperatively. The median preoperative serum calcium level was 2.92 mmol/L, and it was the same for patients with or without renal stones. Preoperatively we found no differences in renal calcium excretion between patients with and without renal stone disease. The median renal calcium excretion was 6.80 mmol/24 hr. At 1 to 3 years after successful parathyroidectomy the group with renal stone disease had higher renal calcium excretion than the group without renal stones (p = 0.03). The reduced effect of parathyroidectomy on renal calcium excretion in the patients with renal stone disease indicates that factors not related to the hyperparathyroid state could contribute to disturbances in renal calcium excretion and hence stone formation. In conclusion, the pathologic basis for renal stone formation in patients with primary hyperparathyroidism might not be the hyperparathyroid state alone; stone formation could be related to other predisposing factors as well. Therefore, although parathyroidectomy can cure hyperparathyroidism, the curative effect on renal stone disease should be reconsidered.

Risk factors for severe postoperative hypocalcaemia after operations for primary hyperparathyroidism.

OBJECTIVE: To identify risk factors for severe hypocalcaemia after surgery for primary hyperparathyroidism. DESIGN: Retrospective study followed by a prospective study. SETTING: University hospital, Denmark. PATIENTS: 340 consecutive patients, operated on from 1991 to 1999, and 85 consecutive patients operated on in 2000. MAIN OUTCOME MEASURES: Predictive value of identified risk factors. RESULTS: Incisional biopsy or excision of more than 2 parathyroid glands, thyroid operation together with parathyroidectomy, preoperative serum concentration of parathyroid hormone of more than 25 pmol/L, or a history of previous operations on the neck, were identified retrospectively as risk factors for severe postoperative hypocalcaemia. In the prospective study these factors showed a sensitivity of 100% (9/9), and a specificity of 25% (9/36). We found no risk of severe hypocalcaemia after parathyroidectomy in patients without these risk factors. The risk increased to 37% (7/19) if serum concentration of parathyroid hormone was more than 25 pmol/L, or if thyroidectomy was done together with parathyroidectomy. CONCLUSIONS: Patients with no risk factors for severe hypocalcaemia can be discharged early from hospital. Special attention should be given to patients with one or more risk factors for severe hypocalcaemia.