ABSTRACT Mild or asymptomatic disease is now the dominating presentation of primary hyperparathyroidism (PHPT). However, bone involvement with decreased bone mineral density (BMD) and an increased risk of fractures has been demonstrated. Indications for parathyroidectomy (PTX) in mild PHPT have been debated for years. There is a need of long‐term randomized studies comparing PTX with observation without intervention (OBS). Here, we present bone health data from the Scandinavian Investigation of Primary Hyperparathyroidism (SIPH), a randomized controlled trial, comparing PTX to OBS. This study included 191 patients (96 OBS/95 PTX), and 129 patients (64 OBS/65 PTX) were followed for 10 years to the end of study (EOS). BMD was measured with dual‐energy X‐ray absorptiometry (DXA), peripheral fractures were noted, and spine radiographs were obtained for vertebral fracture assessment. There was a significant treatment effect of PTX on BMD compared with OBS for all analyzed compartments, most explicit for the lumbar spine (LS) and femoral neck (FN) ( p < 0.001). The mean changes in T ‐score from baseline to 10 years were from 0.41 for radius 33% (Rad33) to 0.58 for LS greater in the PTX group than in the OBS group. There was a significant decrease in BMD for all compartments in the OBS group, most pronounced for FN, Rad33, and ultradistal radius (UDR) ( p < 0.001). Even though there was a significant treatment effect of PTX compared with OBS, there was only a significant increase in BMD over time for LS ( p < 0.001). We found no difference between groups in fracture frequency in the 10‐year cohort, neither with modified intention‐to‐treat (mITT) analysis nor per protocol analysis. Because BMD is only a surrogate endpoint of bone health and PTX did not reduce fracture risk, observation could be considered a safe option for many patients with mild PHPT regarding bone health in a 10‐year perspective. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

BACKGROUND:Primary hyperparathyroidism (PHPT) is a common endocrine disorder associated with increased risk for fractures, cardiovascular disease, kidney disease, and cancer and increased mortality. In mild PHPT with modest hypercalcemia and without known morbidities, parathyroidectomy (PTX) is debated because no long-term randomized trials have been performed.OBJECTIVE:To examine the effect of PTX on mild PHPT with regard to mortality (primary end point) and key morbidities (secondary end point).DESIGN:Prospective randomized controlled trial. (ClinicalTrials.gov: NCT00522028).SETTING:Eight Scandinavian referral centers.PATIENTS:From 1998 to 2005, 191 patients with mild PHPT were included.INTERVENTION:Ninety-five patients were randomly assigned to PTX, and 96 were assigned to observation without intervention (OBS).MEASUREMENTS:Date and causes of death were obtained from the Swedish and Norwegian Cause of Death Registries 10 years after randomization and after an extended observation period lasting until 2018. Morbidity events were prospectively registered annually.RESULTS:After 10 years, 15 patients had died (8 in the PTX group and 7 in the OBS group). Within the extended observation period, 44 deaths occurred, which were evenly distributed between groups (24 in the PTX group and 20 in the OBS group). A total of 101 morbidity events (cardiovascular events, cerebrovascular events, cancer, peripheral fractures, and renal stones) were also similarly distributed between groups (52 in the PTX group and 49 in the OBS group). During the study, a total of 16 vertebral fractures occurred in 14 patients (7 in each group).LIMITATION:During the study period, 23 patients in the PTX group and 27 in the OBS group withdrew.CONCLUSION:Parathyroidectomy does not appear to reduce morbidity or mortality in mild PHPT. Thus, no evidence of adverse effects of observation was seen for at least a decade with respect to mortality, fractures, cancer, cardiovascular and cerebrovascular events, or renal morbidities.PRIMARY FUNDING SOURCE:Swedish government, Norwegian Research Council, and South-Eastern Norway Regional Health Authority.

Abstract Background It is unclear whether the increasing incidence of thyroid cancer (TC) due to increased diagnosis of small and indolent tumours might mask a real increase of clinically significant cancers. The aim of this study was to correlate surgery, pathology and outcome data of individual patients to the mode of primary detection (palpation, by imaging or incidental) to assess if TC incidence has increased. Methods The Swedish Cancer Registry identified all patients with TC in Västra Götaland County representing approximately 1.6 million inhabitants. Clinical information was retrieved from medical records of patient cohorts from three study intervals (2001–2002, 2006–2007 and 2011–2014) comprising 60 per cent of all TC patients. Data were also obtained from the NORDCAN registry to compare of TC incidence with other Nordic countries. Results Between 2001 and 2014, the annualized standard incidence rate/100 000 population (ASR) of TC increased from 3.14 to 10.71 in women and from 1.12 to 3.77 in men. This was higher than the mean incidence for Sweden but similar to that in Norway and Finland. Differentiated TC (DTC) increased more than threefold. The majority of tumours (64 per cent) were detected by palpation. Larger tumours (10–20, 21–40 and greater than 40 mm) increased as much as microcarcinomas (less than 10 mm). Only 5 per cent of the tumours were detected by imaging. All disease-specific deaths (8.5 per cent of DTC in the first two cohorts) and most patients with recurrent or persistent disease (6.6 per cent of DTC cases) were diagnosed due to tumour-related symptoms. Conclusion DTC in Western Sweden gradually increased between 2001 and 2014. The majority of tumours were detected by palpation suggesting a real increase in the incidence of clinically significant thyroid malignancies.

Introduction Mitotane is an adrenolytic drug that is used as an adjuvant to treat adrenocortical carcinoma. This study aimed to evaluate the clinical course and pathogenetic mechanisms underlying ovarian cyst formation in women of reproductive age diagnosed with adrenocortical carcinoma and being treated with mitotane as an adjuvant to surgery. Material and methods Five women presented with stage III-IV adrenocortical carcinoma and ovarian cyst formation during mitotane treatment. The clinical course of the disease was followed during and after treatment. The effects of mitotane on progesterone production and cell proliferation were studied in cultured human ovarian granulosa cells. Results Computed tomography and vaginal ultrasonography during mitotane treatment repeatedly demonstrated ovarian cysts of varying size without solid intralocular structures. Two women became amenorrheic during the treatment period. After mitotane cessation, the ovarian cysts disappeared and normal menstrual cycles resumed. One woman had an uncomplicated pregnancy two years after mitotane treatment. In one woman, who underwent salpingo-oophorectomy, histological analysis demonstrated benign ovarian cysts. Mitotane impeded the synthesis of progesterone, reduced the stimulatory effect of gonadotropins on progesterone formation, and reduced labeling with [H-3]thymidine in cultured granulosa cells. Conclusions Therapeutic concentrations of mitotane are associated with the formation of benign ovarian cysts and amenorrhea. Mitotane-induced suppression of ovarian steroidogenesis and impediment of the proliferative capacity of steroid-producing cells are suggested potential pathogenetic mechanisms underlying mitotane-induced ovarian dysfunction and cyst development. Mitotane treatment does not compromise future ovarian function.

Mitotane is an adrenolytic drug that is used as an adjuvant to treat adrenocortical carcinoma. This study aimed to evaluate the clinical course and pathogenetic mechanisms underlying ovarian cyst formation in women of reproductive age diagnosed with adrenocortical carcinoma and being treated with mitotane as an adjuvant to surgery. Five women presented with stage III-IV adrenocortical carcinoma and ovarian cyst formation during mitotane treatment. The clinical course of the disease was followed during and after treatment. The effects of mitotane on progesterone production and cell proliferation were studied in cultured human ovarian granulosa cells. Computed tomography and vaginal ultrasonography during mitotane treatment repeatedly demonstrated ovarian cysts of varying size without solid intralocular structures. Two women became amenorrheic during the treatment period. After mitotane cessation, the ovarian cysts disappeared and normal menstrual cycles resumed. One woman had an uncomplicated pregnancy two years after mitotane treatment. In one woman, who underwent salpingo-oophorectomy, histological analysis demonstrated benign ovarian cysts. Mitotane impeded the synthesis of progesterone, reduced the stimulatory effect of gonadotropins on progesterone formation, and reduced labeling with [ 3 H]thymidine in cultured granulosa cells. Therapeutic concentrations of mitotane are associated with the formation of benign ovarian cysts and amenorrhea. Mitotane-induced suppression of ovarian steroidogenesis and impediment of the proliferative capacity of steroid-producing cells are suggested potential pathogenetic mechanisms underlying mitotane-induced ovarian dysfunction and cyst development. Mitotane treatment does not compromise future ovarian function.

Context Mild primary hyperparathyroidism has been associated with increased body fat mass and unfavorable cardiovascular risk factors. Objective To assess the effect of parathyroidectomy on fat mass, glucose and lipid metabolism. Design, patients, interventions, main outcome measures 119 patients previously randomized to observation (OBS; n = 58) or parathyroidectomy (PTX; n = 61) within the Scandinavian Investigation of Primary Hyperparathyroidism (SIPH) trial, an open randomized multicenter study, were included. Main outcome measures for this study were the differences in fat mass, markers for lipid and glucose metabolism between OBS and PTX 5 years after randomization. Results In the OBS group, total cholesterol (Total-C) decreased from mean 5.9 (±1.1) to 5.6 (±1.0) mmol/L (P = 0.037) and LDL cholesterol (LDL-C) decreased from 3.7 (±1.0) to 3.3 (±0.9) mmol/L (P = 0.010). In the PTX group, the Total-C and LDL-C remained unchanged resulting in a significant between-group difference over time (P = 0.013 and P = 0.026, respectively). This difference was driven by patients who started with lipid-lowering medication during the study period (OBS: 5; PTX: 1). There was an increase in trunk fat mass in the OBS group, but no between-group differences over time. Mean 25(OH) vitamin D increased in the PTX group (P < 0.001), but did not change in the OBS group. No difference in parameters of glucose metabolism was detected. Conclusion In mild PHPT, the measured metabolic and cardiovascular risk factors were not modified by PTX. Observation seems safe and cardiovascular risk reduction should not be regarded as a separate indication for parathyroidectomy based on the results from this study.

Mild primary hyperparathyroidism (PHPT) is known to affect the skeleton, even though patients usually are asymptomatic. Treatment strategies have been widely discussed. However, long‐term randomized studies comparing parathyroidectomy to observation are lacking. The objective was to study the effect of parathyroidectomy (PTX) compared with observation (OBS) on bone mineral density (BMD) in g/cm2 and T‐scores and on biochemical markers of bone turnover (P1NP and CTX‐1) in a prospective randomized controlled study of patients with mild PHPT after 5 years of follow‐up. Of 191 patients with mild PHPT randomized to either PTX or OBS, 145 patients remained for analysis after 5 years (110 with validated DXA scans). A significant decrease in P1NP (p < 0.001) and CTX‐1 (p < 0.001) was found in the PTX group only. A significant positive treatment effect of surgery compared with observation on BMD (g/cm2) was found for the lumbar spine (LS) (p = 0.011), the femoral neck (FN) (p < 0.001), the ultradistal radius (UDR) (p = 0.042), and for the total body (TB) (p < 0.001) but not for the radius 33% (Rad33), where BMD decreased significantly also in the PTX group (p = 0.012). However, compared with baseline values, there was no significant BMD increase in the PTX group, except for the lumbar spine. In the OBS group, there was a significant decrease in BMD (g/cm2) for all compartments (FN, p < 0.001; Rad33, p = 0.001; UDR, p = 0.006; TB, p < 0.001) with the exception of the LS, where BMD was stable. In conclusion, parathyroidectomy improves BMD and observation leads to a small but statistically significant decrease in BMD after 5 years. Thus, bone health appears to be a clinical concern with long‐term observation in patients with mild PHPT. © 2017 American Society for Bone and Mineral Research.

Clinical PresentationA 24-year-old pregnant woman presented with hypertension at 7 weeks’ gestation. Two years earlier, she had been evaluated for elevated blood pressure (BP) of 150 to 170/110 to 120 mm Hg and found to have a serum potassium level of 2.6 mmol/L (reference range, 3.6-4.6 mmol/L) and plasma renin concentration of 362 mIU/L (reference range, 2.8-40 mIU/L) in the supine position. She underwent renal angiography, for which there were no findings of note. The patient was prescribed amlodipine, 5 mg, and irbesartan, 150 mg/d, and her BP responded promptly by decreasing to 115/70 mm Hg.Upon presentation, the patient denied symptoms aside from nocturia. She had no headache, chest pain, or edema. Her family history was not notable for any diseases or syndromes. She was not taking antihypertensive medication, and BP was 156/110 mm Hg. The rest of her examination findings were unremarkable, and she had no apparent obesity. She had a serum potassium level of 3.0 mmol/L, serum bicarbonate level of 23 mmol/L, serum creatinine level of 0.64 mg/dL (57 μmol/L; corresponding to estimated glomerular filtration rate > 90 mL/min/1.73 m2 as calculated by the 4-variable MDRD [Modification of Diet in Renal Disease] Study equation), and spot urine albumin-creatinine ratio of 42 mg/mmol. Plasma renin concentration was 846 mIU/L (reference range, 2.8-40 mIU/L) in the supine position, and serum aldosterone level was 2,370 pmol/L (reference range, 30-444 pmol/L) in the supine position.■What are the causes of hypertension in a young woman?■What induces a high renin state?■How can this patient’s diagnosis be confirmed?■What therapeutic approach should be advised?DiscussionWhat are the causes of hypertension in a young woman?The most common causes of hypertension in a young woman are essential hypertension or hypertension as part of metabolic syndrome. Secondary causes include fibromuscular dysplasia, overproduction of aldosterone, and hormonal causes such as those related to oral contraceptive use or pregnancy-induced hypertension. In this age group, additional endocrine explanations for secondary hypertension include thyroid or parathyroid disorders and low vitamin D levels. A rare but important cause is coarctation of the aorta. Finally, exogenous factors such as licorice consumption, substantial alcohol intake, and use of nonsteroidal anti-inflammatory drugs should be investigated and/or ruled out. In the present case, the patient was pregnant, but hypertension in gestational week 7 should not be regarded as gestational hypertension or preeclampsia.What induces a high renin state?Renin is produced by juxtaglomerular cells in the kidney and plays a major role in BP regulation by inducing the renin-angiotensin-aldosterone system. Hypertensive high renin states can be secondary or primary. Secondary causes of a high renin state include renovascular disease, most commonly fibromuscular dysplasia of the renal artery in young women. Additionally, hypertensive states per se are associated with a slight increase in renin levels, but this is much more pronounced in the malignant hypertensive condition. This might be explained by renovascular ischemia due to intimal hyperplasia. As for primary causes of hypertensive high renin states, renin-producing renal tumors can be seen with simultaneous high aldosterone levels.How can this patient’s diagnosis be confirmed?Duplex ultrasound examination of the kidneys and echocardiography were performed to exclude renal artery stenosis and coarctation of the aorta. Magnetic resonance tomography of the upper abdomen identified a mass in the caudal area of the left kidney (Fig 1). Plasma renin and aldosterone concentrations in the left renal vein were 1,230 mIU/L and >3,900 pmol/L, respectively. In a peripheral vein, values were 726 mIU/L and 1,330 pmol/L, respectively. This high secretion of renin from the left tumor-containing kidney supports the diagnosis of reninoma.111In-octreotide scintigraphy was performed, showing high uptake of the radionuclide in the left renal mass (Fig 1). This uptake is due to high expression of somatostatin receptor type 2 (SSTR2) by the tumor cells.1Weckbecker G. Lewis I. Albert R. Schmid H.A. Hoyer D. Bruns C. Opportunities in somatostatin research: biological, chemical and therapeutic aspects.Nat Rev Drug Discov. 2003; 2: 999-1017Crossref PubMed Scopus (465) Google Scholar This was further supported by immunohistochemical analysis of the surgical specimen, which demonstrated strong membranous staining of tumor cells by a monoclonal anti-SSTR2 antibody2Körner M. Waser B. Schonbrunn A. Perren A. Reubi J.C. Somatostatin receptor subtype 2A immunohistochemistry using a new monoclonal antibody selects tumors suitable for in vivo somatostatin receptor targeting.Am J Surg Pathol. 2012; 36: 242-252Crossref PubMed Scopus (96) Google Scholar (Fig 2).Figure 2Histopathology of the renal mass. (A) Tumor cells form loosely cohesive sheets with little cytologic atypia (hematoxylin-eosin stain; original magnification, ×400). (B) Tumor cells show cytoplasmic and membranous labeling by antibodies against somatostatin receptor subtype 2 (SSTR2; detection using Dako EnVision system [horseradish peroxidase–based staining]).View Large Image Figure ViewerDownload Hi-res image Download (PPT)What therapeutic approach should be advised?Most reninomas are benign, but metastatic cases have been reported.3Corvol P. Pinet F. Plouin P.-F. Bruneval P. Menard J. Renin-secreting tumors.Endocrinol Metab Clin North Am. 1994; 23: 255-270PubMed Google Scholar The patient underwent surgical resection of the tumor with normalization of BP (110/70 mm Hg without medication) and renin and aldosterone levels (18.0 mU/L and 232 pmol/L, respectively).Because the tumor was clearly visible on 111In-octreotide scintigraphy and expressed SSTR on immunohistochemical staining, a neuroendocrine phenotype for the tumor was identified. This suggests the opportunity to control hormone secretion and tumor cell proliferation in these tumors by long-acting somatostatin analogues or targeted radiotherapy in the case of unresectable masses.4Theodoropoulou M. Stalla G.K. Somatostatin receptors: from signaling to clinical practice.Front Neuroendocrinol. 2013; 34: 228-252Crossref PubMed Scopus (232) Google ScholarFinal DiagnosisHypertension due to a juxtaglomerular cell tumor (reninoma) secreting large amounts of renin. Clinical PresentationA 24-year-old pregnant woman presented with hypertension at 7 weeks’ gestation. Two years earlier, she had been evaluated for elevated blood pressure (BP) of 150 to 170/110 to 120 mm Hg and found to have a serum potassium level of 2.6 mmol/L (reference range, 3.6-4.6 mmol/L) and plasma renin concentration of 362 mIU/L (reference range, 2.8-40 mIU/L) in the supine position. She underwent renal angiography, for which there were no findings of note. The patient was prescribed amlodipine, 5 mg, and irbesartan, 150 mg/d, and her BP responded promptly by decreasing to 115/70 mm Hg.Upon presentation, the patient denied symptoms aside from nocturia. She had no headache, chest pain, or edema. Her family history was not notable for any diseases or syndromes. She was not taking antihypertensive medication, and BP was 156/110 mm Hg. The rest of her examination findings were unremarkable, and she had no apparent obesity. She had a serum potassium level of 3.0 mmol/L, serum bicarbonate level of 23 mmol/L, serum creatinine level of 0.64 mg/dL (57 μmol/L; corresponding to estimated glomerular filtration rate > 90 mL/min/1.73 m2 as calculated by the 4-variable MDRD [Modification of Diet in Renal Disease] Study equation), and spot urine albumin-creatinine ratio of 42 mg/mmol. Plasma renin concentration was 846 mIU/L (reference range, 2.8-40 mIU/L) in the supine position, and serum aldosterone level was 2,370 pmol/L (reference range, 30-444 pmol/L) in the supine position.■What are the causes of hypertension in a young woman?■What induces a high renin state?■How can this patient’s diagnosis be confirmed?■What therapeutic approach should be advised? A 24-year-old pregnant woman presented with hypertension at 7 weeks’ gestation. Two years earlier, she had been evaluated for elevated blood pressure (BP) of 150 to 170/110 to 120 mm Hg and found to have a serum potassium level of 2.6 mmol/L (reference range, 3.6-4.6 mmol/L) and plasma renin concentration of 362 mIU/L (reference range, 2.8-40 mIU/L) in the supine position. She underwent renal angiography, for which there were no findings of note. The patient was prescribed amlodipine, 5 mg, and irbesartan, 150 mg/d, and her BP responded promptly by decreasing to 115/70 mm Hg. Upon presentation, the patient denied symptoms aside from nocturia. She had no headache, chest pain, or edema. Her family history was not notable for any diseases or syndromes. She was not taking antihypertensive medication, and BP was 156/110 mm Hg. The rest of her examination findings were unremarkable, and she had no apparent obesity. She had a serum potassium level of 3.0 mmol/L, serum bicarbonate level of 23 mmol/L, serum creatinine level of 0.64 mg/dL (57 μmol/L; corresponding to estimated glomerular filtration rate > 90 mL/min/1.73 m2 as calculated by the 4-variable MDRD [Modification of Diet in Renal Disease] Study equation), and spot urine albumin-creatinine ratio of 42 mg/mmol. Plasma renin concentration was 846 mIU/L (reference range, 2.8-40 mIU/L) in the supine position, and serum aldosterone level was 2,370 pmol/L (reference range, 30-444 pmol/L) in the supine position.■What are the causes of hypertension in a young woman?■What induces a high renin state?■How can this patient’s diagnosis be confirmed?■What therapeutic approach should be advised? DiscussionWhat are the causes of hypertension in a young woman?The most common causes of hypertension in a young woman are essential hypertension or hypertension as part of metabolic syndrome. Secondary causes include fibromuscular dysplasia, overproduction of aldosterone, and hormonal causes such as those related to oral contraceptive use or pregnancy-induced hypertension. In this age group, additional endocrine explanations for secondary hypertension include thyroid or parathyroid disorders and low vitamin D levels. A rare but important cause is coarctation of the aorta. Finally, exogenous factors such as licorice consumption, substantial alcohol intake, and use of nonsteroidal anti-inflammatory drugs should be investigated and/or ruled out. In the present case, the patient was pregnant, but hypertension in gestational week 7 should not be regarded as gestational hypertension or preeclampsia.What induces a high renin state?Renin is produced by juxtaglomerular cells in the kidney and plays a major role in BP regulation by inducing the renin-angiotensin-aldosterone system. Hypertensive high renin states can be secondary or primary. Secondary causes of a high renin state include renovascular disease, most commonly fibromuscular dysplasia of the renal artery in young women. Additionally, hypertensive states per se are associated with a slight increase in renin levels, but this is much more pronounced in the malignant hypertensive condition. This might be explained by renovascular ischemia due to intimal hyperplasia. As for primary causes of hypertensive high renin states, renin-producing renal tumors can be seen with simultaneous high aldosterone levels.How can this patient’s diagnosis be confirmed?Duplex ultrasound examination of the kidneys and echocardiography were performed to exclude renal artery stenosis and coarctation of the aorta. Magnetic resonance tomography of the upper abdomen identified a mass in the caudal area of the left kidney (Fig 1). Plasma renin and aldosterone concentrations in the left renal vein were 1,230 mIU/L and >3,900 pmol/L, respectively. In a peripheral vein, values were 726 mIU/L and 1,330 pmol/L, respectively. This high secretion of renin from the left tumor-containing kidney supports the diagnosis of reninoma.111In-octreotide scintigraphy was performed, showing high uptake of the radionuclide in the left renal mass (Fig 1). This uptake is due to high expression of somatostatin receptor type 2 (SSTR2) by the tumor cells.1Weckbecker G. Lewis I. Albert R. Schmid H.A. Hoyer D. Bruns C. Opportunities in somatostatin research: biological, chemical and therapeutic aspects.Nat Rev Drug Discov. 2003; 2: 999-1017Crossref PubMed Scopus (465) Google Scholar This was further supported by immunohistochemical analysis of the surgical specimen, which demonstrated strong membranous staining of tumor cells by a monoclonal anti-SSTR2 antibody2Körner M. Waser B. Schonbrunn A. Perren A. Reubi J.C. Somatostatin receptor subtype 2A immunohistochemistry using a new monoclonal antibody selects tumors suitable for in vivo somatostatin receptor targeting.Am J Surg Pathol. 2012; 36: 242-252Crossref PubMed Scopus (96) Google Scholar (Fig 2).What therapeutic approach should be advised?Most reninomas are benign, but metastatic cases have been reported.3Corvol P. Pinet F. Plouin P.-F. Bruneval P. Menard J. Renin-secreting tumors.Endocrinol Metab Clin North Am. 1994; 23: 255-270PubMed Google Scholar The patient underwent surgical resection of the tumor with normalization of BP (110/70 mm Hg without medication) and renin and aldosterone levels (18.0 mU/L and 232 pmol/L, respectively).Because the tumor was clearly visible on 111In-octreotide scintigraphy and expressed SSTR on immunohistochemical staining, a neuroendocrine phenotype for the tumor was identified. This suggests the opportunity to control hormone secretion and tumor cell proliferation in these tumors by long-acting somatostatin analogues or targeted radiotherapy in the case of unresectable masses.4Theodoropoulou M. Stalla G.K. Somatostatin receptors: from signaling to clinical practice.Front Neuroendocrinol. 2013; 34: 228-252Crossref PubMed Scopus (232) Google Scholar What are the causes of hypertension in a young woman?The most common causes of hypertension in a young woman are essential hypertension or hypertension as part of metabolic syndrome. Secondary causes include fibromuscular dysplasia, overproduction of aldosterone, and hormonal causes such as those related to oral contraceptive use or pregnancy-induced hypertension. In this age group, additional endocrine explanations for secondary hypertension include thyroid or parathyroid disorders and low vitamin D levels. A rare but important cause is coarctation of the aorta. Finally, exogenous factors such as licorice consumption, substantial alcohol intake, and use of nonsteroidal anti-inflammatory drugs should be investigated and/or ruled out. In the present case, the patient was pregnant, but hypertension in gestational week 7 should not be regarded as gestational hypertension or preeclampsia. The most common causes of hypertension in a young woman are essential hypertension or hypertension as part of metabolic syndrome. Secondary causes include fibromuscular dysplasia, overproduction of aldosterone, and hormonal causes such as those related to oral contraceptive use or pregnancy-induced hypertension. In this age group, additional endocrine explanations for secondary hypertension include thyroid or parathyroid disorders and low vitamin D levels. A rare but important cause is coarctation of the aorta. Finally, exogenous factors such as licorice consumption, substantial alcohol intake, and use of nonsteroidal anti-inflammatory drugs should be investigated and/or ruled out. In the present case, the patient was pregnant, but hypertension in gestational week 7 should not be regarded as gestational hypertension or preeclampsia. What induces a high renin state?Renin is produced by juxtaglomerular cells in the kidney and plays a major role in BP regulation by inducing the renin-angiotensin-aldosterone system. Hypertensive high renin states can be secondary or primary. Secondary causes of a high renin state include renovascular disease, most commonly fibromuscular dysplasia of the renal artery in young women. Additionally, hypertensive states per se are associated with a slight increase in renin levels, but this is much more pronounced in the malignant hypertensive condition. This might be explained by renovascular ischemia due to intimal hyperplasia. As for primary causes of hypertensive high renin states, renin-producing renal tumors can be seen with simultaneous high aldosterone levels. Renin is produced by juxtaglomerular cells in the kidney and plays a major role in BP regulation by inducing the renin-angiotensin-aldosterone system. Hypertensive high renin states can be secondary or primary. Secondary causes of a high renin state include renovascular disease, most commonly fibromuscular dysplasia of the renal artery in young women. Additionally, hypertensive states per se are associated with a slight increase in renin levels, but this is much more pronounced in the malignant hypertensive condition. This might be explained by renovascular ischemia due to intimal hyperplasia. As for primary causes of hypertensive high renin states, renin-producing renal tumors can be seen with simultaneous high aldosterone levels. How can this patient’s diagnosis be confirmed?Duplex ultrasound examination of the kidneys and echocardiography were performed to exclude renal artery stenosis and coarctation of the aorta. Magnetic resonance tomography of the upper abdomen identified a mass in the caudal area of the left kidney (Fig 1). Plasma renin and aldosterone concentrations in the left renal vein were 1,230 mIU/L and >3,900 pmol/L, respectively. In a peripheral vein, values were 726 mIU/L and 1,330 pmol/L, respectively. This high secretion of renin from the left tumor-containing kidney supports the diagnosis of reninoma.111In-octreotide scintigraphy was performed, showing high uptake of the radionuclide in the left renal mass (Fig 1). This uptake is due to high expression of somatostatin receptor type 2 (SSTR2) by the tumor cells.1Weckbecker G. Lewis I. Albert R. Schmid H.A. Hoyer D. Bruns C. Opportunities in somatostatin research: biological, chemical and therapeutic aspects.Nat Rev Drug Discov. 2003; 2: 999-1017Crossref PubMed Scopus (465) Google Scholar This was further supported by immunohistochemical analysis of the surgical specimen, which demonstrated strong membranous staining of tumor cells by a monoclonal anti-SSTR2 antibody2Körner M. Waser B. Schonbrunn A. Perren A. Reubi J.C. Somatostatin receptor subtype 2A immunohistochemistry using a new monoclonal antibody selects tumors suitable for in vivo somatostatin receptor targeting.Am J Surg Pathol. 2012; 36: 242-252Crossref PubMed Scopus (96) Google Scholar (Fig 2). Duplex ultrasound examination of the kidneys and echocardiography were performed to exclude renal artery stenosis and coarctation of the aorta. Magnetic resonance tomography of the upper abdomen identified a mass in the caudal area of the left kidney (Fig 1). Plasma renin and aldosterone concentrations in the left renal vein were 1,230 mIU/L and >3,900 pmol/L, respectively. In a peripheral vein, values were 726 mIU/L and 1,330 pmol/L, respectively. This high secretion of renin from the left tumor-containing kidney supports the diagnosis of reninoma. 111In-octreotide scintigraphy was performed, showing high uptake of the radionuclide in the left renal mass (Fig 1). This uptake is due to high expression of somatostatin receptor type 2 (SSTR2) by the tumor cells.1Weckbecker G. Lewis I. Albert R. Schmid H.A. Hoyer D. Bruns C. Opportunities in somatostatin research: biological, chemical and therapeutic aspects.Nat Rev Drug Discov. 2003; 2: 999-1017Crossref PubMed Scopus (465) Google Scholar This was further supported by immunohistochemical analysis of the surgical specimen, which demonstrated strong membranous staining of tumor cells by a monoclonal anti-SSTR2 antibody2Körner M. Waser B. Schonbrunn A. Perren A. Reubi J.C. Somatostatin receptor subtype 2A immunohistochemistry using a new monoclonal antibody selects tumors suitable for in vivo somatostatin receptor targeting.Am J Surg Pathol. 2012; 36: 242-252Crossref PubMed Scopus (96) Google Scholar (Fig 2). What therapeutic approach should be advised?Most reninomas are benign, but metastatic cases have been reported.3Corvol P. Pinet F. Plouin P.-F. Bruneval P. Menard J. Renin-secreting tumors.Endocrinol Metab Clin North Am. 1994; 23: 255-270PubMed Google Scholar The patient underwent surgical resection of the tumor with normalization of BP (110/70 mm Hg without medication) and renin and aldosterone levels (18.0 mU/L and 232 pmol/L, respectively).Because the tumor was clearly visible on 111In-octreotide scintigraphy and expressed SSTR on immunohistochemical staining, a neuroendocrine phenotype for the tumor was identified. This suggests the opportunity to control hormone secretion and tumor cell proliferation in these tumors by long-acting somatostatin analogues or targeted radiotherapy in the case of unresectable masses.4Theodoropoulou M. Stalla G.K. Somatostatin receptors: from signaling to clinical practice.Front Neuroendocrinol. 2013; 34: 228-252Crossref PubMed Scopus (232) Google Scholar Most reninomas are benign, but metastatic cases have been reported.3Corvol P. Pinet F. Plouin P.-F. Bruneval P. Menard J. Renin-secreting tumors.Endocrinol Metab Clin North Am. 1994; 23: 255-270PubMed Google Scholar The patient underwent surgical resection of the tumor with normalization of BP (110/70 mm Hg without medication) and renin and aldosterone levels (18.0 mU/L and 232 pmol/L, respectively). Because the tumor was clearly visible on 111In-octreotide scintigraphy and expressed SSTR on immunohistochemical staining, a neuroendocrine phenotype for the tumor was identified. This suggests the opportunity to control hormone secretion and tumor cell proliferation in these tumors by long-acting somatostatin analogues or targeted radiotherapy in the case of unresectable masses.4Theodoropoulou M. Stalla G.K. Somatostatin receptors: from signaling to clinical practice.Front Neuroendocrinol. 2013; 34: 228-252Crossref PubMed Scopus (232) Google Scholar Final DiagnosisHypertension due to a juxtaglomerular cell tumor (reninoma) secreting large amounts of renin. Hypertension due to a juxtaglomerular cell tumor (reninoma) secreting large amounts of renin.

Current understanding infers a neural crest origin of thyroid C cells, the major source of calcitonin in mammals and ancestors to neuroendocrine thyroid tumors. The concept is primarily based on investigations in quail-chick chimeras involving fate mapping of neural crest cells to the ultimobranchial glands that regulate Ca2+ homeostasis in birds, reptiles, amphibians and fishes, but whether mammalian C cell development involves a homologous ontogenetic trajectory has not been experimentally verified. With lineage tracing, we now provide direct evidence that Sox17+ anterior endoderm is the only source of differentiated C cells and their progenitors in mice. Like many gut endoderm derivatives, embryonic C cells were found to coexpress pioneer factors forkhead box (Fox) a1 and Foxa2 before neuroendocrine differentiation takes place. In the ultimobranchial body epithelium emerging from pharyngeal pouch endoderm in early organogenesis, differential Foxa1/Foxa2 expression distinguished two spatially separated pools of C cell precursors with different growth properties. A similar expression pattern was recapitulated in medullary thyroid carcinoma cells in vivo, consistent with a growth-promoting role of Foxa1. In contrast to embryonic precursor cells, C cell-derived tumor cells invading the stromal compartment downregulated Foxa2, foregoing epithelial-to-mesenchymal transition designated by loss of E-cadherin; both Foxa2 and E-cadherin were re-expressed at metastatic sites. These findings revise mammalian C cell ontogeny, expand the neuroendocrine repertoire of endoderm and redefine the boundaries of neural crest diversification. The data further underpin distinct functions of Foxa1 and Foxa2 in both embryonic and tumor development.

BACKGROUND:Energy-based surgical devices (EBD) combining cutting and coagulation are increasingly used in thyroid surgery. However, there is a lack of information about potential benefits and risk of complications outside controlled trials. The aims of this national multicenter register study were to describe the use of EDB, their potential effect on complication rates, and on operation time.MATERIALS AND METHODS:The Scandinavian Quality Register for Thyroid and Parathyroid surgery includes 35 surgical units in Sweden and covered 88% of the thyroid procedures performed during 2008–2009. The use of the EBD was specifically registered for 12 months, and 1297 patients were included. Surgically related complications and operation time were evaluated. The clamp-and-tie group (C-A-T) constituted the control group for comparison with procedures where EBD was used.RESULTS:The thyroid procedures performed included C-A-T (16.6%), bipolar electrosurgery (ES: 56.5%), electronic vessel sealing (EVS: 12.2%), and ultrasonic dissection (UD: 14.5%). Mean operative time was longer with EVS (p < 0.001) and shorter with UD (p < 0.05) than in the other groups. The bipolar ES group and the EVS group had higher incidence of calcium treatment at discharge and after 6 weeks than the UD group. No significant difference in nerve injury was found between the groups. There was a significant more frequent use of topical hemostatic agents in the EBD group compared to C-A-T.CONCLUSION:In this national multicenter study, the use of UD shortened and EVS increased operating time. There was a higher risk of calcium treatment at discharge and after 6 weeks after use of EVS and bipolar ES than after UD use. There was a significant more frequent use of topical hemostatic agents in the EBD groups compared to C-A-T.

CONTEXTMild primary hyperparathyroidism (PHPT) is a common disease especially in middle-aged and elderly women. The diagnosis is frequently made incidentally and treatment strategies are widely discussed.OBJECTIVETo study the effect of parathyroidectomy (PTX) compared with observation (OBS) on biochemistry, safety, bone mineral density (BMD), and new fractures.DESIGNProspective, randomized controlled study (SIPH study), with a 5-year follow-up.SETTINGThe study was conducted at multicenter, tertiary referral centers.PATIENTSOf 191 randomized patients with mild PHPT, biochemical data were available for 145 patients after 5 years, with a mean age at inclusion of 62.8 years (OBS group, 9 males) and 62.1 years (PTX group, 10 males).INTERVENTIONParathyroidectomy vs observation.MAIN OUTCOME MEASURESBiochemistry, BMD, and new radiographic vertebral fractures.RESULTSSerum-calcium and PTH-levels normalized after surgery and did not deteriorate by observation. BMD Z-scores were normal at inclusion in the lumbar spine (LS) and femoral neck (FN). For LS, BMD Z-scores were stable for 5 years with observation, but decreased in FN (P < .02). After surgery, BMD Z-scores increased significantly in both compartments (P < .02 for both), with a highly significant treatment effect of surgery compared to observation (P < .001). During follow-up, five new clinically unrecognized vertebral fractures were found in 5 females, all in the OBS group (P = .058).CONCLUSIONEven though new vertebral fractures occurred only in the observation group, the frequency was not significantly different from the surgery group. Longer follow-up is needed before firm conclusions can be drawn about the long-term safety of observation, as opposed to surgery.

BACKGROUND:Patients with elevated calcium concentrations have an increased morbidity due to various underlying illnesses. However, there is a lack of studies of quality of life and health care consumption in patients with hypercalcaemia per se. The study aims to investigate quality of life and health care consumption, as measured by, sick leave, drug prescriptions and the number of visits and admissions to health care centres and hospitals, in primary care patients with elevated calcium concentrations.METHODS:A prospective, case control, study in primary care centre, in Sweden. Patients with elevated, (n=127, 28 men), and normal calcium concentrations, (n=254, 56 men), mean age 61.4 year, were recruited in the study and followed during 10 years. Eighty-six percent of those alive at the time of follow up participated in a follow up visit. The study participants completed a quality of life survey, SF-36, which also were compared with the Swedish SF-36 national normative database.RESULTS:Patients with elevated calcium concentrations had significantly lower quality of life both compared with the control group (patients with normal calcium concentrations) and compared with age and gender-matched reference material from the Swedish SF-36 national normative database. The group with elevated calcium concentrations had significantly more hospitalisations (p=0.017), subsequently cancer diagnoses (p<0.003), sick leave (p=0.007) and medication (p=0.002) compared with patients with normal calcium concentrations. Men with elevated calcium concentrations had more contacts with the psychosocial team (p=0.02) at the health care centre.CONCLUSIONS:Elevated calcium concentrations are associated with significantly reduced quality of life and increased health care consumption and should therefore be an important warning flag that should alert the physician to further investigate and care for the patient. This is the first study in this field and the results need to be confirmed in further studies.

Surgery is the only potential cure for patients with medullary thyroid carcinoma (MTC). Preoperative ultrasound, computed tomography and magnetic resonance imaging are not sensitive enough for detection of microscopic disease. The aim of this study was to investigate if routine preoperative 111In-labelled (DTPA-D-Phe1)-octreotide scintigraphy (SRS) could be used as a staging procedure in planning primary surgery in patients with MTC.

SummaryObjectivesTo study hyperthyroidism in long‐term iodine sufficiency (IS), as iodine supply affects its occurrence.DesignProspective descriptive study.PatientsIn 2003–2005, all referred cases of subclinical (SH) and overt hyperthyroidism (OH) were registered at diagnosis from a population (n = 631 239) in Gothenburg, Sweden.MeasurementsInformation on age, gender, smoking, thyroid associated ophthalmopathy (TAO), thyroid hormones and TSH receptor antibodies (TRab) was collected. Incidences were calculated. SH and OH cases with Graves' disease (GD), toxic multinodular goiter (TMNG) and solitary toxic adenoma (STA) were compared. In GD, TRab+ and TRab− cases and patients with (TAO+) and without TAO (TAO−) were compared.ResultsThe total incidence (n/100 000/year) of hyperthyroidism was 27·6; OH 23·8; SH 3·8; GD 21·4; TMNG 4·3; and STA 1·8. SH was more common among TMNG (40·2%) and STA (45·7%) than in GD (5·9%). SH‐GD patients were older, more often smokers and had lower TRab levels than OH‐GD patients. FreeT4 and T3 levels in GD were higher than in TMNG and STA. FreeT4, T3 and TRab decreased with age in patients with GD, P < 0·0001. TRab‐ patients had lower T3 than TRab+ patients, P < 0·001. TRab was positively correlated to FreeT4, P < 0·0001. TAO occured in 20% of patients with GD. TAO+ patients were younger than TAO‐ patients. Smokers did not have more TAO.ConclusionThe total incidence of hyperthyroidism was low. GD dominated with an age‐related decline of thyroid hormones and TRab levels. The spectrum of hyperthyroidism in this long‐term IS area may represent the future situation for countries with shorter history of IS.

Background Multifocal papillary thyroid carcinoma (MPTC) has been reported in literature in 18–87 % of cases. This paper aims to review controversies in the molecular pathogenesis, prognosis, and management of MPTC. Methods A review of English-language literature focusing on MPTC was carried out, and analyzed in an evidence-based perspective. Results were discussed at the 2013 Workshop of the European Society of Endocrine Surgeons devoted to surgery of thyroid carcinoma. Results Literature reports no prospective randomized studies; thus, a relatively low level of evidence may be achieved. Conclusions MPTC could be the result of either true multicentricity or intrathyroidal metastasis from a single malignant focus. Radiation and familial nonmedullary thyroid carcinoma are conditions at risk of MPTC development. The prognostic importance of multifocal tumor growth in PTC remains controversial. Prognosis might be impaired in clinical MPTC but less or none in MPTC <1 cm. MPTC can be diagnosed preoperatively by FNAB and US, with low sensitivity for MPTC <1 cm. Total or near-total thyroidectomy is indicated to reduce the risk of local recurrence. Prophylactic central node dissection should be considered in patients with total tumor diameter >1 cm, or in cases with high number of cancer foci. Completion thyroidectomy might be necessary when MPTC is diagnosed after less than near-total thyroidectomy. Radioactive iodine ablation should be considered in selected patients with MPTC at increased risk of recurrence or metastatic spread.

OBJECTIVE:To follow up patients with elevated calcium concentrations after 10 years.DESIGN:Longitudinal, using medical records, questionnaires, and clinical investigation.SETTING:Primary care in Tibro, Sweden, 2008-2010.SUBJECTS:127 patents with elevated calcium concentrations and 254 patients with normal calcium concentrations from the local community, attending the health care centre.MAIN OUTCOME MEASURES:Diagnoses and mortality in patients with elevated calcium concentrations in 1995-2000, compared with patients with normal calcium concentrations and the background population.RESULTS:The proportion of patients for whom no underlying cause was detected decreased from 55% at baseline to 12% at follow-up. Primary hyperparathyroidism was most common in women, 23% at baseline and 36% at follow-up, and the cancer prevalence increased from 5% to 12% in patients with elevated calcium concentration. Mortality tended to be higher in men with elevated calcium concentrations compared with men with normal calcium concentrations, and was significantly higher than in the background population (SMR 2.3, 95% CI 1.3-3.8). Cancer mortality was significantly increased in men (p = 0.039). Low calcium concentrations were also associated with higher mortality (p = 0.004), compared with patients with normal calcium concentrations.CONCLUSION:This study underscores the importance of investigating patients with increased calcium concentrations suggesting that most of these patients--88% in our study--will turn out to have an underlying disease associated with hypercalcaemia during a 10-year follow-up period. Elevated calcium concentrations had a different disease pattern in men and women, with men showing increased cancer mortality in this study.

Germline mutations in the susceptibility genes RET, SDHB, SDHD, and VHL have been reported in 7.5–24% of patients with pheochromocytoma (Pheo) or paraganglioma (PGL) and sporadic presentation. The purpose of the present study was to establish population-based data on the frequency of germline mutations in patients with apparently sporadic Pheo or abdominal PGL in Western Sweden.