Evolution of Our Understanding of the Hyperparathyroid Syndromes: A Historical Perspective.

We review advancing and overlapping stages for our understanding of the expressions of six hyperparathyroid (HPT) syndromes: multiple endocrine neoplasia type 1 (MEN1) or type 4, multiple endocrine neoplasia type 2A (MEN2A), hyperparathyroidism-jaw tumor syndrome, familial hypocalciuric hypercalcemia, neonatal severe primary hyperparathyroidism, and familial isolated hyperparathyroidism. During stage 1 (1903 to 1967), the introduction of robust measurement of serum calcium was a milestone that uncovered hypercalcemia as the first sign of dysfunction in many HPT subjects, and inheritability was reported in each syndrome. The earliest reports of HPT syndromes were biased toward severe or striking manifestations. During stage 2 (1959 to 1985), the early formulations of a syndrome were improved. Radioimmunoassays (parathyroid hormone [PTH], gastrin, insulin, prolactin, calcitonin) were breakthroughs. They could identify a syndrome carrier, indicate an emerging tumor, characterize a tumor, or monitor a tumor. During stage 3 (1981 to 2006), the assembly of many cases enabled recognition of further details. For example, hormone non-secreting skin lesions were discovered in MEN1 and MEN2A. During stage 4 (1985 to the present), new genomic tools were a revolution for gene identification. Four principal genes ("principal" implies mutated or deleted in 50% or more probands for its syndrome) (MEN1, RET, CASR, CDC73) were identified for five syndromes. During stage 5 (1993 to the present), seven syndromal genes other than a principal gene were identified (CDKN1B, CDKN2B, CDKN2C, CDKN1A, GNA11, AP2S1, GCM2). Identification of AP2S1 and GCM2 became possible because of whole-exome sequencing. During stages 4 and 5, the newly identified genes enabled many studies, including robust assignment of the carriers and non-carriers of a mutation. Furthermore, molecular pathways of RET and the calcium-sensing receptor were elaborated, thereby facilitating developments in pharmacotherapy. Current findings hold the promise that more genes for HPT syndromes will be identified and studied in the near future. © 2018 American Society for Bone and Mineral Research.

Correlation of surgeon-performed parathyroid ultrasound with the Perrier classification and gland weight.

BACKGROUND: Ultrasound localisation of parathyroid glands correlates with gland weight. We hypothesise that gland identification is also dependent on anatomical location. Perrier et al. have described a uniform and reliable nomenclature for parathyroid locations. We aimed to correlate surgeon-performed ultrasound (SUS) with intra-operative Perrier classification and gland weight. METHODS: Review of a prospectively maintained single operator SUS database of 194 patients referred with non-familial primary hyperparathyroidism (PHPT) at a tertiary centre between 2010 and 2015. Patients underwent MIBI localisation as well as on table SUS. Intra-operative pathological gland locations were classified according to the Perrier nomenclature. RESULTS: Mean weight of pathological glands found and missed by SUS was 1.07 ± 0.1 g and 0.48 ± 0.08 g respectively (p = 0.0001, unpaired t test). The weight of glands identified was greater than that of missed glands for each of the Perrier locations (p < 0.001, Mann-Whitney). The proportion of pathological glands found at each Perrier location varied significantly (p < 0.0001, Chi Square); so we find proportionally more B-, D-, E- and F-type glands and miss more A- and C-type glands. The median weight of glands missed on SUS varied significantly across the Perrier groups (Kruskal-Wallis, p = 0.0034) and suggests that SUS can miss quite large glands (> 0.5 g) in locations B, C and F; whereas missed glands in locations A, D and E were all small (< 0.5 g). CONCLUSION: Whilst gland identification correlates well with gland weight, anatomical location has a significant impact on failure of localisation irrespective of gland weight. For the surgeon operating on PHPT patients with negative US localisation, particular attention should be paid to locations C, D and A as these are the sites where pathological glands are most often missed on pre-operative US.

Secondary and tertiary hyperparathyroidism.

We reviewed the etiology and management of secondary and tertiary hyperparathyroidism. Secondary hyperparathyroidism is characterized by an increase in parathyroid hormone (PTH) that is appropriate and in response to a stimulus, most commonly low serum calcium. In secondary hyperparathyroidism, the serum calcium is normal and the PTH level is elevated. Tertiary hyperparathyroidism is characterized by excessive secretion of PTH after longstanding secondary hyperparathyroidism, in which hypercalcemia has ensued. Tertiary hyperparathyroidism typically occurs in men and women with chronic kidney disease usually after kidney transplant. The etiology and treatment of secondary hyperparathyroidism is relatively straightforward whereas data on the management of tertiary hyperparathyroidism is limited to a few small trials with short follow-up.

Multivariate analysis of clinical, demographic, and laboratory data for classification of disorders of calcium homeostasis.

Parathyroid hormone (PTH) nomograms combine total calcium and intact PTH (iPTH) measurements to classify disorders of calcium homeostasis. Our objective was to determine if using a combination of laboratory, demographic, and clinical parameters improves the accuracy of classification of these disorders. Chart data were collected for 236 patients with physician-ordered iPTH and total calcium tests. Classification was done using 3 approaches: (1) PTH nomogram plotting total calcium and iPTH results against known cases; (2) review of all available chart data ("gold standard"); and (3) multivariate model (classification and regression tree [CART] or logistic regression) using 24 variables. The CART model was developed using the gold standard patient classification and validated using leave-one-out cross-validation. The CART model was significantly (P = .002) more accurate (80.6%) than the PTH nomogram (59.7%) and logistic regression (66.2%) at classifying calcium homeostasis disorders. The CART model used 6 of 24 variables (iPTH, calcium, creatinine, renal transplantation, percentage of females, and urea nitrogen) and had a misclassification error rate of 0.194 (27/139). Classification of disorders of calcium homeostasis based on the PTH nomogram can be improved by using the CART model developed in this study.

Intraoperative parathyroid hormone monitoring during parathyroidectomy for hyperparathyroidism in waiting list and kidney transplant patients.

This report describes the use of the intraoperative parathyroid hormone (ioPTH) assay during parathyroidectomy in waiting list and transplanted patients. ioPTH levels were determined in 40 patients on the waiting list for kidney transplantation with secondary hyperparathyroidism who underwent subtotal parathyroidectomy and 9 transplanted patients with tertiary hyperparathyroidism who underwent removal of hyperplasic glands. Rapid PTH levels decreased significantly at each time period; the percentage decrease in rapid PTH levels was 61.3% among patients with IPT II and 70.2% in patients with IPT III at 10 minutes and 86.5% in patients with IPT II and 91% in patients with IPT III at 15 minutes after excision of hypersecreting parathyroid tissue. A decrease of 50% or more from baseline PTH levels at 10 minutes and/or a decrease of 85% or more at 15 minutes predicted successful removal of abnormal parathyroid glands. The application of this technique during subtotal parathyroidectomy has proved useful for correct excision of parathyroid glands among waiting list patients with IPT II, while in kidney transplant patients with IPT III it allowed removal of only the pathological glands with a limited surgical approach.

P-glycoprotein expression influences the result of 99mTc-MIBI scintigraphy in tertiary hyperparathyroidism.

Precise localization of parathyroid glands using 99mTc-labeled hexakis-2-methoxyisobutylisonitrile (99mTc-MIBI) scintigraphy could be affected by various biological factors. There is increasing evidence that radiotracer retention could be controlled by members of multidrug resistance (MDR) system, especially P-glycoprotein (P-gp). Since the role of P-gp in tertiary hyperparathyroidism (T-HPTH) scintigraphic studies is poorly recognized, the aim of the study was to compare the correlation between parathyroid P-gp expression and results of their scintigraphy in T-HPTH versus primary hyperparathyroidism (P-HPTH). P-HPTH (n = 19) and T-HPTH (n = 18) patients were subjected to 99mTc-MIBI scintigraphy followed by surgical treatment. The parathyroid glands were assessed in routine hematoxylin-eosin staining and P-gp expression was analyzed using immunohistochemistry. Parathyroids collected during cadaver donor multi-organ harvesting were used as a control. It has been found that P-HPTH-derived parathyroid glands with predominating adenoma morphology expressed less P-gp, as compared to P-gp-rich T-HPTH glands, mainly displaying nodular or diffused hyperplasia phenotype. This finding reversely correlated with results of 99mTc-MIBI scintigraphy. However, we did not observe any difference in P-gp expression nor scintigraphy result between nodular or diffused hyperplasia. Altogether, these data suggest that P-gp overexpression in T-HPTH could be responsible for decreased sensitivity of 99mTc-MIBI scintigraphy in those patients. Therefore, the recently proposed reduced neck exploration or limited parathyroid resection on the basis of scintigraphy could create the risk of persisted/recurrent hyperparathyroidism. However, this problem requires further study.

Angiomixoma agresivo de vulva / Aggressive angiomyxoma of the vulva

El angiomixoma agresivo es una neoplasia poco frecuente que aparece fundamentalmente en la región pélvica y perineal de mujeres durante la edad reproductiva. Se caracteriza por un crecimiento lento y tendencia a la recurrencia local. Presentamos un caso de angiomixoma agresivo localizado en la vulva de una mujer de 44 años. Histológicamente la tumoración es de bordes infiltrativos, hipocelular, mixoide, con numerosos vasos sanguíneos de calibre variable y focos de extravasación hemática. Las células son de apariencia fibroblástica con inmunorreactividad para vimentina, desmina, actina, factor XIIIa y receptores de estrógenos y de progesterona. En el examen ultraestructural se observan células de tipo fibroblástico y miofibroblástico en el seno de un material extracelular pobre en colágeno (AU)

Diagnosis of normocalcemic hyperparathyroidism by oral calcium loading test.

We evaluated the oral calcium-loading test (OCLT) in diagnosing normocalcemic primary hyperparathyroidism. Calcium and PTH levels were measured before, 60, 120 and 180 min after oral 1 g of calcium gluconolactate administration in 102 consecutive females with high circulating PTH levels, and 25 controls. Patients were classified as follows: Group A, patients with a parathyroid adenoma identified by two imaging modalities. Sub-Group AO, hyperparathyroid patients [no.=13, mean age 59 yr (SD=10)] evaluated prior to parathyroidectomy. Sub-Group AH, non-operated hypercalcemic patients [no.=29, age 63 yr (SD=11)]. Sub-Group AN, normocalcemic non-operated women [no.=14, age 59 yr (SD=8)]. Group B, normocalcemic individuals [no.=46, age 58 yr (SD=11)] with negative parathyroid imaging. Group C, control patients [no.= 25, age 56 yr (SD=12)]. The concentrations of calcium and PTH overlapped in the normocalcemic groups during the OCLT. Product P, defined as circulating PTH nadir (pg/ml) x peak calcium concentration (mg/dl), better discriminated Sub-Group AN from Group B, AUC=0.98 (95% CI 0.95, 1.00) than did Ratio R, defined as relative PTH decline/relative calcium increment, AUC= 0.86 (95%CI 0.73, 0.99). Assuming normal threshold of Product P and Ratio R at 260 and 17 respectively, the combined parameters diagnose normocalcemic hyperparathyroid patients with 100% sensitivity and 87% specificity.

Surgical management of the parathyroids.

The recent advance of intraoperative PTH monitoring combined with preoperative localization techniques allow for minimally invasive parathyroid surgery in 75% to 85% of cases. In cases where a single adenoma is identified, minimally invasive techniques should result in a need for repeat surgery in only 2% of cases. The cost of intraoperative PTH assays of localization and gamma probes limits their availability. Complications of parathyroidectomy are uncommon, but appropriate management is important, particularly for patients with hypocalcemia.

[Surgical treatment of secondary and tertiary hyperparathyroidism]. / Il trattamento chirurgico dell'iperparatiroidismo secondario e terziario.

AIMS: To determine whether, in secondary and tertiary hyperparathyroidism (HPT), quick parathyroid hormone (PTH) assay can be used to prevent persistent or recurrent HPT. Another point was to determine, considering the PTH decrease, the cut-off point at which the operation could be considered well performed. METHODS: A retrospective study was performed evaluating all cases operated on since 1975 until 2002, 679 patients, and particularly the analysis of two groups of patients that underwent surgical treatment for secondary and tertiary HPT in the period 1995-2002. In the first group, (January 1995-October 1999) 207 (167 HPT II and 40 HPT III) neck explorations were performed without the aid of quick PTH assay; in the second group (November 1999-December 2002), 192 (153 HPT II and 39 HPT III) patients were operated on with blood samples for quick PTH. RESULTS: In the first group the percentage of success for secondary HPT was 93.8 versus 96.2 of the second group and 91.7 versus 94.2 for tertiary HPT. In reoperations the percentage of success was 72.7 in the first group and 87.5 in the second one. CONCLUSIONS: There are no substantial differences in persistences or recurrences between subtotal or total parathyroidectomy (PTx) with autotransplantation (AT). The choice of the gland to be left in the neck or transplanted in the forearm and the modalities of doing so are very important, considering the macroscopical and histological aspects. Intraoperative PTH monitoring is a useful aid during the first cervical exploration for secondary and tertiary HPT to prevent the development of persistent or recurrent HPT. The cut-off point for secondary HPT is 70% (in difficult cases with more than 2 assays, 75%) and for tertiary HPT 50% and 70% respectively.

Controversias en el diagnóstico y tratamiento del hiperparatiroidismo primario / Controversies in the diagnoses and treatment of primary hyperparathyroidism

Antecedentes: Una de las controversias en el manejo del hiperparatiroidismo primario es determinar la necesidad de estudios de localización, a la luz del costo-beneficio intraoperatorio que los mismos ofrecen. Lugar: Hospital de atención terciario dedicado al tratamiento de tumores. Objetivo: Demostrar si existe necesidad y ventajas de estudios previos. Diseño: Retrospectivo. Material y métodos: Se analizan los últimos 30 enfermos consecutivamente tratados. En todos, la calcemia y la paratohormona se hallaban elevados y la fosfatemia descendida. En 25/30 enfermos se realizaron estudios de localización, siendo la ecografía el de elección. En menor proporción se realizó rastreo con Selenio-metionina, TI201 y/o Tc99-Sestamibi. Resultados: Se halló adenoma en 23 e hiperplasia en 5. En 2 no se halló patología durante la 1º operación obligando a realizar estudios complementarios. En aquellos en que había coincidencia entre el estudio preoperatorio y el hallazgo intraoperatorio, la operación fue unilateral y demandó una media de 72 minutos. Cuando la exploración debió hacerse bilateralmente, la duración media fue de 110 minutos. El costo del estudio con Tc99-Sestamibi, es en nuestro medio de $ 150 (u$s 150). Conclusiones: Los estudios de localización no son imprescindibles pero facilitan la labor intraoperatoria. No obstante el porcentaje de éxito resulta similar. Si bien el tiempo operatorio desciende 30-45 minutos, el costo no es diferente con una u otra metodología

Controversias en el diagnóstico y tratamiento del hiperparatiroidismo primario / Controversies in the diagnoses and treatment of primary hyperparathyroidism

Antecedentes: Una de las controversias en el manejo del hiperparatiroidismo primario es determinar la necesidad de estudios de localización, a la luz del costo-beneficio intraoperatorio que los mismos ofrecen. Lugar: Hospital de atención terciario dedicado al tratamiento de tumores. Objetivo: Demostrar si existe necesidad y ventajas de estudios previos. Diseño: Retrospectivo. Material y métodos: Se analizan los últimos 30 enfermos consecutivamente tratados. En todos, la calcemia y la paratohormona se hallaban elevados y la fosfatemia descendida. En 25/30 enfermos se realizaron estudios de localización, siendo la ecografía el de elección. En menor proporción se realizó rastreo con Selenio-metionina, TI201 y/o Tc99-Sestamibi. Resultados: Se halló adenoma en 23 e hiperplasia en 5. En 2 no se halló patología durante la 1º operación obligando a realizar estudios complementarios. En aquellos en que había coincidencia entre el estudio preoperatorio y el hallazgo intraoperatorio, la operación fue unilateral y demandó una media de 72 minutos. Cuando la exploración debió hacers

Sporadic primary hyperparathyroidism in young patients: a separate disease entity?

HYPOTHESIS: Sporadic primary hyperparathyroidism (1 HPT) in young persons is thought to be extremely rare. The exact incidence is unknown and little is known of the characteristics of the disease. METHODS: From 1976 to 1998, 33 patients aged 19 years or younger underwent operation for sporadic 1 HPT at a single institution. Data were recorded regarding the clinical, surgical, pathologic, and biochemical aspects, as well as long-term patient follow-up. RESULTS: There were 17 male subjects and 16 female subjects ranging in age from 9 to 19 years (median age, 17 years). Thirty-one (94%) were symptomatic: 14 (42%) had renal stones, 9 (27%) had bone disease, 1 (3%) had pancreatitis, and 7 (21%) had vague nonspecific symptoms alone. The high incidence of symptoms was matched by correspondingly high biochemical values (mean serum calcium level, 3.02 mmol/L [12.1 mg/dL]) and large adenomas (mean weight, 967 mg). Five patients (15%) underwent exploration for persistent/recurrent 1 HPT. Thirty-one patients (94%) were normocalcemic postoperatively. One patient was temporarily hypocalcemic. No patient had vocal cord paralysis or paresis. Two patients developed recurrent disease in the mean follow-up period of 10.3 years. None have shown evidence of an inherited disorder. CONCLUSIONS: It appears that 1 HPT in young patients presents as a more severe disease, in terms of symptoms, biochemistry, and extent of pathologic findings. Physicians should be aware that 1 HPT does occur in young persons in a nonfamilial setting and that it may be responsible for a wide spectrum of symptoms. As in the adult population, 1 HPT is safely and effectively treated with surgical intervention.

[Anesthesia and postoperative recovery for parathyroid gland surgery]. / Anesthésie-réanimation pour chirurgie des glandes parathyroïdes.

Anesthesia for surgery of primary hyperparathyroidism (HPT) usually concerns asymptomatic elderly women with moderate hypercalcemia. Cardiovascular repercussions of the endocrine disorder are possible, but they are not frequent except for hypertension. Hyperparathyroid crisis is a life-threatening condition with severe hypercalcemia. Intravenous diphosphonates are very effective drugs to control hypercalcemia. The improvement is transient but allows curative parathyroidectomy to be performed with a minimal risk of cardiac arrhythmias. Anesthesia for surgery of secondary HPT concerns patients with chronic renal failure treated by hemodialysis. Cardiovascular disease is frequent and aggravated by the endocrine disorder. In patients with marked aortic stenosis or severe left ventricular dysfunction, parathyroidectomy should be performed by cervicotomy under local anesthesia. Hyperparathyroidism may persist after renal transplantation (tertiary HPT): in this case cardiovascular disease is minimal and the hypercalcemia is moderate. Parathyroidectomy is usually performed by cervicotomy under general anesthesia. Sternotomy is required in the case of an abnormal mediastinal location of a gland. An interaction between myorelaxants and hyperparathyroidism has been observed. Total blood calcium must be systematically assayed postoperatively because postoperative hypocalcemia is constant. Hypocalcemia is moderate in primary and tertiary HPT, due to transient functional hypoparathyroidism, with lowest observed the 2nd or 3rd postoperative day. Hypocalcemia should not be treated when asymptomatic because it resolutes on the 4th or 5th postoperative day. Intravenous calcium infusion may be necessary for 1 or 2 days, if serum calcium is below 1.9 mmol per liter with symptoms of tetany. Persistent hypocalcemia is due to an hungry bone syndrome or organic hypoparathyroidism that should be treated by oral vitamin D and calcium. In secondary HPT, hypocalcemia is early, marked and asymptomatic. Treatment must often be started on the 6th postoperative hour by intravenous calcium infusion, followed by oral vitamin D and calcium. The absence of postoperative hypocalcemia indicate incomplete removal of all abnormal parathyroid tissue. At the third postoperative day, a second cervicotomy may be performed to complete the neck exploration.

Cirurgia das glandulas paratireóides / Parathyroid surgery

As glandulas paratireoides podem ocasionar doencas graves, com etiologia diversa, desde alteracoes metabolicas ate mutacoes geneticas. Em geral, a cirurgia empregada para tratar a hiperfusao e bem sucedida, porem ha certas dificuldades que podem comprometer sua eficacia. Para permitir o entendimento das tecnicas empregadas no tratamento do hiperparatireoidismo, foram revistos os fundamentos basicos e clinicos, juntamente a dados de 215 casos operados passiveis de analise