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Primary hyperparathyroidism (PHPT) is the most common etiology of hypercalcemia in the ambulatory setting and usually presents with an intact parathyroid hormone (PTH) level that is elevated or inappropriately near the upper limit of the laboratory reference range. However, PHPT with low-normal PTH level is reported in the peer-reviewed literature, and this atypical presentation may delay diagnosis of PHPT. We present a case of PHPT with persistently low-normal PTH level in which the PTH dependence of hypercalcemia was demonstrated by the response to treatment with the calcimimetic agent cinacalcet.

Introduction: Osteoporosis is a chronical systemic metabolic disease of bone tissue, which is manifested by a decrease in the amount of bone mass and/or a decrease in its quality and may result in a fracture. Fractures are also common for primary hyperparathyroidism due to increased parathyroid hormone secretion. Surgical treatment will help increase bone density in most cases, nevertheless emphasis is placed on reducing risk factors for osteoporosis and fractures. Objective: Purpose of this thesis is to map the nutrition condition with focus on calcium and protein intake of postmenopausal women after successful surgical intervention for primary hyperparathyroidism (PHPT group), and to evaluate the results in relation with osteoporosis and fractures. Methods: Nutritional status was assessed using questionnaires of eating habits and analysis of three-day menus. Intakes of energy, protein, fat, sugar, fiber, free sugar, vitamin C, sodium, calcium nad phosphorus intake were calculated using Nutriservis PROFI program (and other nutritional databases). The degree of vitamin D saturation was obtained from serum calcidiol concentrations. Body composition and bone mineral density parametres were measured using dual energy X-ray absorptiometry. Results: Nutritional analysis of diets showed no statically...

Habilitacijos procedūrai teikiamoje mokslo darbų apžvalgoje apibendrinama minimaliai invazinės endokrininių liaukų chirurgijos patirtis Vilniaus universiteto Pilvo chirurgijos centre. Apžvelgtos minimaliai invazinės skydliaukės operacijos, išanalizuoti ir apibendrinti dviejų klinikinių studijų rezultatai. 2004-2006 m. atliktoje perspektyvioje atsitiktinių imčių studijoje ,,Endoskopinės adrenalektomijos dviejų metodų įvertinimas“ pateikti ir išanalizuoti 70 pacientų, operuotų dėl įvairios antinksčių patologijos dviem minimaliai invaziniais būdais (laparoskopiniu bei endoskopiniu retroperitoniniu), rezultatai. Išanalizuota operacijos trukmės priklausomybė nuo antinksčio naviko dydžio, paciento kūno masės, palyginta kraujo netektis operacijos metu, operacinių komplikacijų skaičius. Įvertinus visus duomenis, prieita išvados, kad abu operacijos būdai geri, tačiau laparoskopinės adrenalektomijos išmokstama greičiau. 2005-2007 m. atliktame darbe ,,Minimaliai invazinė fokusuota ir tradicinė paratiroidektomija, gydant pirminį hiperparatiroidizmą: perspektyvioji, atsitiktinių imčių studija“ pateikiami pirminiu hiperparatiroidizmu sergančių pacientų, operuotų dviem būdais, gydymo rezultatai. Atsitiktinių imčių būdu 47 pacientai suskirstyti į dvi grupes: operuotų minimaliai invaziniu būdu (24 pacientai) ir operuotų tradiciniu Kocherio būdu (23 pacientai). Išanalizuota prieskydinės liaukos adenomos instrumentinių tyrimų diagnostinė vertė, palyginta operacijos trukmė, komplikacijų... [toliau žr. visą tekstą] / The experience of minimally invasive endocrine surgery accumulated at Vilnius University Centre of Abdominal Surgery is presented in this review of scientific publications submitted for habilitation procedure. The material concerning minimally invasive thyroid gland operations is summarized and the results of two clinical trials are evaluated. The results of prospective randomized study “Evaluation of two methods endoscopic adrenalectomy” were presented and analyzed; this study included 70 patients who underwent surgery for various pathology of adrenal glands; one group of the patients underwent laparoscopic minimally invasive operation and another one – endoscopic retroperitoneal minimally invasive surgery. The relationship between the size of adrenal gland tumour, patients’ body weight and duration of operation was analyzed; blood loss and rate of operative complications were compared. The evaluation of all data showed that both methods of surgery were acceptable; however, laparoscopic adrenalectomy was more was easier to learn. Clinical study “Minimally invasive focused and traditional parathyroidectomy for treatment of primary hyperparathyroidism: a prospective randomized study” was performed during the period since 2005 till 2007; the results of treatment of patients by means of two methods of surgery were presented. The patients (n = 47) were randomized into two groups; one group included 24 patients who were operated on using minimally invasive technique and another... [to full text]

<p>Primary hyperparathyroidism (pHPT), characterized by elevated serum levels of calcium and parathyroid hormone (PTH), is associated with a number of metabolic derangements causing secondary manifestations. These include osteoporosis and increased risk of fractures, but also risk factors for cardiovascular morbidity and mortality. These risk factors include impaired glucose tolerance (IGT), dyslipidemia, increased body mass index and hypertension. While the skeletal abnormalities are mainly due to elevated PTH, the latter disturbances are still unexplained. Non-insulin dependent diabetes mellitus (NIDDM), IGT, dyslipidemia and hypertension are all included in the metabolic syndrome, also associated with morbidity and mortality in cardiovascular diseases.</p><p>In this thesis, decreased bone mineral density (BMD) and variables of the metabolic syndrome are explored in patients with mild and normocalcemic pHPT before and after parathyroidectomy. To further investigate the relationship between insulin sensitivity and calcium, a community-based cohort was investigated.</p><p>In two different patient cohorts of pHPT, lipoprotein alterations with decreased levels of HDL-cholesterol and elevated triglycerides were found in association with a high frequency of IGT, NIDDM and decreased insulin sensitivity. Parathyroidectomy had effects on the dyslipidemia and in part on the glucose metabolism. The disturbed glucose metabolism in pHPT was substantiated by results from the general population by a negative association between insulin sensitivity, measured by hyperinsulinemic clamp, and serum calcium.</p><p>In conclusion, normocalcemic, mild and overt pHPT are associated with a range of risk factors for cardiovascular diseases, development of NIDDM and decreased BMD in cortical as well as trabecular bone. These findings explain, at least in part, the elevated morbidity and mortality from cardiovascular disease as well as fractures, reported in pHPT patients. Moreover, in the general population, serum calcium is associated with decreased insulin sensitivity. Parathyroidectomy has positive effects on several, but not all, of the investigated metabolic parameters.</p>

Primary hyperparathyroidism (pHPT), characterized by elevated serum levels of calcium and parathyroid hormone (PTH), is associated with a number of metabolic derangements causing secondary manifestations. These include osteoporosis and increased risk of fractures, but also risk factors for cardiovascular morbidity and mortality. These risk factors include impaired glucose tolerance (IGT), dyslipidemia, increased body mass index and hypertension. While the skeletal abnormalities are mainly due to elevated PTH, the latter disturbances are still unexplained. Non-insulin dependent diabetes mellitus (NIDDM), IGT, dyslipidemia and hypertension are all included in the metabolic syndrome, also associated with morbidity and mortality in cardiovascular diseases. In this thesis, decreased bone mineral density (BMD) and variables of the metabolic syndrome are explored in patients with mild and normocalcemic pHPT before and after parathyroidectomy. To further investigate the relationship between insulin sensitivity and calcium, a community-based cohort was investigated. In two different patient cohorts of pHPT, lipoprotein alterations with decreased levels of HDL-cholesterol and elevated triglycerides were found in association with a high frequency of IGT, NIDDM and decreased insulin sensitivity. Parathyroidectomy had effects on the dyslipidemia and in part on the glucose metabolism. The disturbed glucose metabolism in pHPT was substantiated by results from the general population by a negative association between insulin sensitivity, measured by hyperinsulinemic clamp, and serum calcium. In conclusion, normocalcemic, mild and overt pHPT are associated with a range of risk factors for cardiovascular diseases, development of NIDDM and decreased BMD in cortical as well as trabecular bone. These findings explain, at least in part, the elevated morbidity and mortality from cardiovascular disease as well as fractures, reported in pHPT patients. Moreover, in the general population, serum calcium is associated with decreased insulin sensitivity. Parathyroidectomy has positive effects on several, but not all, of the investigated metabolic parameters.

Primary hyperparathyroidism (PHPT) is a common endocrine disease, existing in both genders and in all age groups. Postmenopausal women are at particular risk of developing the disease and estrogen decline after menopause is suggested to affect the progress. Although PHPT is mild in its presentation with subtle or no subjective symptoms, it is associated with an increased risk of associated morbidity and also mortality i.e cardiovascular complications, psychiatric instability, concomitant metabolic abnormalities, obesity and decrease in bone mineral density. The current cure is surgical removal of the diseased gland/s, but other medical alternatives have been investigated. The disease is thoroughly explored in postmenopausal women but less is known about other populations groups. Since progression of the disease generally is slow, the underlying disturbance of the calcium homeostasis can be suspected to have been established a long time prior to diagnose with potential to affect associated morbidity. The general aim of this thesis is to clarify the expression of PHPT in premenopausal women and in elderly men and to explore how frequent the disease in these populations occurs. The women and men were investigated through population-based studies. Baseline data and prevalence of PHPT in premenopausal women age 40-50 years were studied (Paper I), the prevalence was 5.1% in this population and was associated with decreased bone mineral density and associated obesity. In a three years follow up of the female cohort, the effects of menopausal transition and associated morbidity was investigated (Paper II). The prevalence and expression of PHPT in men between 69 and 81 years and impact on bone mineral density, physical performance, fall and fracture prevalence was explored through data from Mr Os Sweden (Papers III and IV). In this population prevalence of PHPT was 0.73% and associated with lower bone mineral density and inferior physical performance.

Cette thèse de mathématiques appliquées en physiologie rénale a pour thème principal l'étude de l'homéostasie du calcium à travers le développement d'un modèle mathématique à l'échelle de l'organisme. Nous cherchons à répondre à certaines questions soulevées par les néphrologues dans le cas de pathologies impliquant la formation de calculs rénaux ou de calcifications. Nous examinons notamment les cas de l'hypercalciurie observée durant l'hyperparathyroïdie primaire dont les causes ne sont pas élucidées ainsi que les mécanismes de complexation du calcium et phosphate et notamment les conséquences d'une infusion intraveineuse de phosphate sur l'homéostasie du calcium. Notre modèle est composé d'équations différentielles décrivant la dynamique du calcium dans les compartiments impliqué dans son métabolisme (intestin, os, reins) ainsi que les mécanismes de régulation par l'hormone parathyroïdienne (PTH), la vitamine D3 et le récepteur sensible au calcium (CaSR). Ce modèle est par ailleurs couplé à un modèle de l'homéostasie du phosphate. Les résultats de ce modèle suggèrent que la présence ou non d'une hypercalciurie lors de l'hyperparathyroïdie primaire peut être expliquée par des mécanismes antagonistes dans la branche ascendante large de Henle, avec d'un côté le CaSR inhibant la réabsorption de calcium et de l'autre la PTH diminuant l'excrétion de calcium. Nous concluons que l'infusion intraveineuse de phosphate induit une hypocalcémie majeure, due principalement à la précipitation du calcium et du phosphate dans le plasma et dans l'os. En outre, cette étude suggère un retard dans l'activation de la synthèse de PTH par le phosphate. / This thesis of applied mathematics in renal physiology focuses on the study of calcium homeostasis, through the development of a mathematical model at the organism scale. This model is built based upon recent experimental studies as well as previous models in the field. We aim to answer several questions raised by nephrologists regarding diseases involving calcium stone formation or calcifications. In particular, we are interested in the origins of the hypercalciuria observed during primary hyperparathyroidism, the causes of which remain to be elucidated, the effects of bone resorption inhibition by bisphosphonates on calcium metabolism, as well as the consequences of an intravenous infusion of phosphate on calcium homeostasis. Our model is composed of differential equations describing the dynamics of calcium in the compartments involved in its metabolism (intestine, bone and kidneys), as well as complex feedback mechanisms by parathyroid hormone (PTH), vitamin D3 and the calcium sensing receptor (CaSR). Besides, this model is coupled to a phosphate homeostasis model. This model suggests that the variable presence of hypercalciuria during primary hyperparathyroidism can be explained by counteracting mechanisms in the thick ascending limb of Henle, involving on one hand the calcium sensing receptor, which inhibits calcium reabsorption, and on the other hand PTH which decreases calcium excretion. We conclude that the intravenous infusion of phosphate triggers a major hypocalcemia, mainly due to the precipitation of calcium and phosphate in both bone and plasma. Moreover, this study suggests a delay in the activation of PTH synthesis by phosphate

Abstract Multiple endocrine neoplasia type 1 (MEN1) is an inherited syndrome characterized by parathyroid, gastroenteropancreatic and pituitary neuroendocrine tumours. In Northern Finland, two founder mutations of the MEN1 gene (1466del12, 1657insC) accounting for the majority of the MEN1 cases, have common ancestors born in the 18th and 19th centuries, respectively. Three small clusters of familial pituitary adenoma have also been detected, two of which could be linked by genealogy to a common ancestral couple born in the 18th century. Clinical evaluation of 82 MEN1 mutation carriers showed that age was a risk factor for most of the MEN1-related manifestations. In the whole group, nonfunctional pancreatic tumour (NFPT) was more common in the frameshift/nonsense mutation carriers (odds ratio 3.26; 95% confidence interval 1.27–8.33, P = 0.014), whereas gastrinoma was more common in the in-frame/missense mutation carriers (OR 6.77, CI 1.31–35.0, P = 0.022). In the founder mutation carriers, the 1657insC mutation predicted the risk for NFPT (OR 3.56, CI 1.29–9.83, P = 0.015), while the 1466del12 mutation was associated with the risk for gastrinoma (OR 15.1, CI 1.73–131.9, P = 0.014). The mean ages at death of the 32 obligatory MEN1 founder mutation carriers born between 1728 and 1929 were compared to those of the 29 spouses and sex-matched life expectancy estimates derived from Finnish national statistics. The ages at death of the mutation carrier males (61.1 ± 12.0 years) and females (67.2 ± 10.7 years) did not differ from the control groups. PAP (pituitary adenoma predisposition) locus was mapped in the chromosome region 11q12–11q13 by whole-genome single-nucleotide polymorphism genotyping. Combining the linkage and the gene expression array data, AIP (aryl hydrocarbon receptor interacting protein) was chosen for sequencing. The nonsense mutation Q14X was identified in the affected (acromegaly, gigantism, prolactinoma) family members and in four other patients. Loss of heterozygosity was detected in pituitary adenomas of AIP mutation carriers. Mutation analysis of MEN1, HRPT2 (hyperparathyroidism 2), CASR (calcium-sensing receptor), CDKN1B (cyclin-dependent kinase inhibitor 1B) and AIP genes was performed in primary hyperparathyroidism patients with features of inherited predisposition. One out of 29 patients was found to have the 1466del12 mutation, while no mutations were detected in other genes.

INTRODUÇÃO: Hiperparatireoidismo primário (HPT) é uma doença endócrina relativamente comum, caracterizada por hipercalcemia associada a concentrações de PTH elevadas ou inapropriadamente normais. A maioria dos pacientes (90%-95%) apresenta a forma esporádica da doença, enquanto a forma familiar pode ocorrer associada à neoplasia endócrina múltipla tipo 1 (NEM1) e tipo 2, HPT-tumor de mandíbula, HPT neonatal severo e HPT isolada familiar. HPT associado com NEM1 (HPT/NEM1) difere da forma esporádica em vários aspectos, entre eles: acometimento multiglandular das paratireóides (hiperplasia x adenoma); início da doença mais precoce (20 x 40 anos); afeta homens e mulheres em proporção semelhante (1:1), em contraste a 1:3 no HPT esporádico; diferentes tratamentos cirúrgicos (paratireoidectomia total ou subtotal x adenomectomia); maior taxa de recorrência após paratireoidectomia (PTx); e tende a ser menos agressivo que o HPT esporádico. No HPT esporádico, o perfil da perda mineral óssea e o impacto do tratamento cirúrgico na densidade mineral óssea (DMO) estão bem definidos. Por outro lado, dados sobre perda óssea no HPT/NEM1 e sua potencial recuperação após PTx são escassamente relatados. O objetivo deste estudo é avaliar o perfil densitométrico e o impacto do tratamento cirúrgico na DMO em pacientes com HPT/NEM1. MÉTODOS: Neste estudo, avaliamos inicialmente 36 pacientes (18 homens e 18 mulheres) com diagnóstico de HPT/NEM1 (média de idade ao diagnóstico de HPT de 38,99 ± 14.46 anos, 20-74 anos). Estes pacientes pertenciam a oito famílias não relacionadas previamente caracterizadas clinicamente e portadoras de mutações germinativas MEN1. Avaliamos a DMO no terço proximal do rádio distal (1/3 RD), fêmur (colo do fêmur e fêmur total) e coluna lombar (L1-L4) destes 36 pacientes. A DMO foi medida pela densitometria óssea de dupla emissão com fonte de raios X (DXA) e os valores expressos em índice T, índice Z e em valores absolutos (g/cm2). Após esta avaliação da DMO, vinte e quatro pacientes foram submetidos à paratireoidectomia total seguida por auto-implante em antebraço não dominante. Em um grupo selecionado de 16 pacientes foi avaliada a densidade mineral óssea antes e após (período médio de 15 meses) o tratamento cirúrgico. RESULTADOS: Desmineralização óssea (osteoporose/osteopenia) foi observada no 1/3 RD (28/34, 79,4%); colo do fêmur (26/36, 72,7%) e na coluna lombar (25/36, 69,4%). Osteopenia foi principalmente observada no colo do fêmur (19/36, 52,8%), seguida pelo 1/3 RD (14/34, 41,2%) e coluna lombar (11/36, 30,5%). Osteoporose foi observada principalmente na coluna lombar (14/36, 38,9%) e 1/3 RD (14/34, 41,2%); enquanto no colo do fêmur (7/36, 19,4%) a prevalência foi menor . Valores médios de índice T estavam severamente reduzidos no 1/3 RD (- 2,46±1,436 DP), seguido pela coluna lombar (-2,05±1,539 DP). O colo do fêmur foi o menos afetado (-1,60±1,138 DP). Nos 16 pacientes submetidos ao tratamento cirúrgico, no período médio de 15 meses após PTx, a DMO (g/cm2) aumentou significativamente na coluna lombar de 0,843 para 0,909 g/cm2 (+ 8,4%; p=0,001). A DMO (g/cm2) no colo do fêmur também aumentou significativamente de 0,745 para 0,798 g/cm2 (+ 7,7%; p=0.0001). No 1/3 RD não houve modificação estatisticamente significante da DMO (0,627 ± 0,089 para 0,622 ± 0,075; p=0,76). CONCLUSÃO: Nossos dados demonstraram que o rádio distal é o sítio ósseo preferencial para desmineralização óssea e que a coluna lombar pode não estar relativamente protegida na HPT/MEN1, como descrito no HPT esporádico. Um aumento significante foi observado na coluna lombar e no colo do fêmur em pacientes com HPT/NEM1, em um período médio de 15 meses após paratireoidectomia; enquanto no terço proximal do radio distal, não houve melhora significativa durante este estudo / INTRODUTION: Primary hyperparathyroidism (HPT) is a relatively common endocrine disorder, which is characterized by hypercalcemia and elevated or inappropriately normal levels of PTH. Most patients (90-95%) present with the sporadic form of the disease, whereas familial cases may occur associated with multiple endocrine neoplasias type 1 (MEN1) and type 2, jaw tumours, as well as severe neonatal form and familial isolated HPT. HPT associated with MEN1 (HPT/MEN1) differs from sporadic primary HPT (s- HPT) in the following aspects: it presents as a multiglandular parathyroid neoplasia (hyperplasia vs adenoma); it has an earlier disease onset (20 vs. 40 years of age); there is a sex ratio of 1:1 in contrast to the 1:3 ratio for s- HPT; different surgical treatment (total or subtotal parathyroidectomy x adenomectomy); there are higher recurrence rates after a parathyroidectomy (PTx); and it frequently tends to be less aggressive than s-HPT. In s-HPT, the bone loss profile and the impact of parathyroid surgery are well defined. In contrast, data on bone losses in HPT/MEN1 and the potential bone recovery after PTx have been scarcely reported. The aim of this study is to evaluate the bone mineral status and the impact of surgical treatment on bone mineral density (BMD) in HPT/MEN1 patients. METHODS: We studied 36 cases (18 males and 18 females) diagnosed with HPT/MEN1 (average age at the HPT diagnosis of 38.9 ± 14.46 years; range, 20-74 years). These patients belonged to eight unrelated MEN1 families previously clinically characterized and harboring germline MEN1 mutations. We have assessed the values of BMD in the proximal one third distal radius (1/3 distal radius), femoral (femoral neck and total) and lumbar spine (L1-L4) of these 36 HPT/MEN1 cases. BMD values were measured by dual-energy X-ray absorptiometry and the values expressed in T, Z-score and in absolute values. After BMD analyses, twenty four out of them were submitted to total parathyroidectomy followed by autoimplant in the non-dominant forearm. BMD measurements were evaluated before and in a mean period of 15 months after surgery, in a subset of 16 patients. RESULTS: Bone demineralization (osteoporosis/osteopenia) was seen at the proximal third of distal radius (28/34, 79.4%); femoral neck (26/36, 72.7%) and in the lumbar spine (25/36, 69.4%). Osteopenia was mostly found in femoral neck (19/36, 52.8%), whereas 1/3 distal radius (14/34, 41.2%) and lumbar spine (11/36, 30.5%) were also represented. Osteoporosis was mostly marked at lumbar spine (14/36, 38.9%) and 1/3 DR (14/34, 41.2%), but femoral neck (7/36, 19.4%) was also affected. Mean T score values at the 1/3 DR were severely reduced (-2.46±1.436 SD), followed by lumbar spine (-2.05 ± 1.539 SD). The femoral neck was the least affected site (-1. 60 ± 1.138 SD). In the 16 cases submitted to surgical treatment, in a mean period of 15 months after PTX, BMD (g/cm2) significantly increased at the lumbar spine from 0.843 to 0.909 g/cm2 (+ 8.4%; p=0.001). Femoral neck BMD (g/cm2) also increased significantly from 0.745 to 0.798 g/cm2 (+ 7.7%; p=0.0001). In the proximal one third of distal radius, BMD (g/cm2) remained unchanged (baseline, 0.627 ± 0.089 to 0.622 ± 0.075; p=0.76). CONCLUSION: Our data confirmed distal radius as the preferential site of bone demineralization and that lumbar spine may not be relatively protected in HPT/MEN1, as related in the s-HPT. A significant increase in the BMD has been verified in the lumbar spine and femoral neck BMD in 16 patients with HPT/MEN1, in a mean period of 15 months after parathyroidectomy. However, the proximal one third of distal radius BMD did not present significant improvement during this study