Suppressibility of Parathyroid Hormone in Primary Hyperparathyroidism

ObjectiveTo describe an unusual case of pathologically confirmed primary hyperparathyroidism in a patient presenting with severe hypercalcemia and an undetectable parathyroid hormone (PTH) level.MethodsWe present a detailed case report and outline the serial laboratory findings. In addition, the possible causes of low serum PTH levels in the setting of primary hyperparathyroidism are discussed.ResultsA 16-year-old female patient presented with severe epigastric pain, found to be attributable to acute pancreatitis. At hospital admission, her serum calcium concentration was high (14.0 mg/dL); the patient also had a normal serum phosphorus level of 3.6 mg/dL and an undetectable PTH level (< 0.2 pmol/L). An evaluation for non-PTH-mediated causes of hypercalcemia revealed a partially suppressed thyroid-stimulating hormone concentration and a below normal 1,25-dihydroxyvitamin D level, consistent with her suppressed PTH. One week after the patient was dismissed from the hospital, repeated laboratory studies showed a serum calcium value of 11.1 mg/dL, a serum phosphorus level of 2.8 mg/dL, and an elevated PTH concentration of 11.0 pmol/L, consistent with primary hyperparathyroidism. A repeated 1,25-dihy-droxyvitamin D measurement was elevated. A parathyroid scan showed a parathyroid adenoma in the left lower neck area, and she subsequently underwent successful surgical resection of a pathologically confirmed parathyroid adenoma.ConclusionThis case demonstrates that the serum PTH level can be suppressed in patients with primary hyperparathyroidism. Moreover, it emphasizes the need for careful evaluation of the clinical context in which the PTH measurement is determined. Consideration should be given to repeating measurement of PTH and serum calcium levels when the initial laboratory evaluation of hypercalcemia is unclear because dynamic changes in calcium metabolism may occur in the presence of secondary contributing factors. (Endocr Pract. 2007;13:785-789)     

Radioimmunoassay of Parathyroid Hormone in Primary Hyperparathyroidism: Studies after Removal of Parathyroid Adenoma

Parathyroid hormone has been measured by radioimmunoassay in eight patients with hyperparathyroidism due to parathyroid adenoma. Secretion of hormone by the adenomatas was demonstrated direct by estimating the arteriovenous gradient of parathyroid hormone across the tumours. Serial estimations following surgical removal of the adenoma showed a rapid fall in the concentration of circulating parathyroid hormone. The calculated half-life of endogenously secreted parathyroid hormone in man varied from 11·4 to 28·8 min., with a mean of 19·8 min.     

Falsely Elevated Plasma Parathyroid Hormone Level Mimicking Tertiary Hyperparathyroidism

ObjectiveTo report a case of misdiagnosed tertiary hyperparathyroidism attributable to heterophile antibody interference in a parathyroid hormone (PTH) assay.MethodsWe present clinical and laboratory data relative to this case and review the pertinent English-language literature.ResultsA 36-year-old woman with a functioning renal allograft, PTH excess (3, 374 pg/mL) refractory to medical therapy, and a history of renal osteodystrophy presented for consideration of a third parathyroidectomy. Remedial parathyroidectomy was performed. The PTH levels did not decline postoperatively, but the patient developed severe hypocalcemia. Reanalysis of the patient’s serum specimens was performed with (1) addition of heterophile blocking agents to the murine-based immunoassay and (2) use of a different, goat antibody-based immunoassay. The true PTH level was found to be 5 pg/mL with use of both methods.ConclusionPrevious administration of muromonab-CD3 (Orthoclone OKT3) for immunosuppression may have resulted in the development of human antimurine heterophile antibodies, causing a falsely elevated PTH result. (Endocr Pract. 2011;17:e8-e11)     

Maternal Glomerular Filtration Rate in Pregnancy and Fetal Size

BackgroundThe relationship of maternal glomerular filtration rate (GFR) in pregnancy to fetal size needs to be better characterized as it impacts an ongoing debate about confounding effect of maternal GFR in investigations of important environmental contaminants. We aimed to characterize the size of the association between maternal GFR and infant birth weight.ResultsMaternal GFR-CG (β: 0.73 g/ml/min, p = 0.04) and GFR-MDRD (β: 0.83 g/ml/min, p = 0.04) were associated with infant birth weight in models adjusted for maternal weight in kilograms, preeclampsia, and gestational age at delivery (days). Partial correlation coefficients for the association between infant birth weight and GFR were 0.07 for both formulas. Although the birth weight-GFR association was stronger among the women with preeclampsia, the difference from women without preeclampsia was not statistically significant.ConclusionThese data support an association between GFR during pregnancy and infant birth weight, and indicate that GFR may confound selected epidemiologic associations.     

Interleukin-6 Induced Suppression of Bovine Parathyroid Hormone Secretion

Calcium disturbances in the critically ill coincide with elevations of proinflammatory cytokines. The effects of tumor necrosis factor- (TNF-) and interleukin-6 (IL-6) on parathyroid hormone (PTH) secretion were investigated. IL-6 and TNF- had no acute effect on PTH secretion in extracellular Ca²⁺ concentrations of 0.5, 1.25 and 3.0 mM. In contrast to TNF-, cultures for 24 h in the presence of l0 ng/mL of IL-6 showed decreased PTH secretion by 51% and 29% in 0.5 mM and 1.25 mMCa²⁺ respectively. Neither IL-6 nor TNF-, affected cytoplasmic Ca²⁺ of the cells. We conclude that PTH secretion in vitro can be suppressed by IL-6 at clinically relevant concentrations. This suppression may aggravate hypocalcemia of the critically ill and attenuate the conventionally strong stimulation of the PTH release by reduction in serum calcium.     

Calcium,Parathyroid Hormone,and Vitamin D in Patients with Primary Hyperparathyroidism: Normograms Developed from 10000 Cases

ObjectiveTo better define the typical and atypical biochemical profiles of patients with surgically proven primary hyperparathyroidism.MethodsIn this single-center, prospectively conducted study of consecutive patients with surgically proven primary hyperparathyroidism over a 7-year period, we analyzed serum calcium, parathyroid hormone, and 25-hydroxyvitamin D concentrations.ResultsA total of 10 000 patients were included, and more than 210 000 calcium, parathyroid hormone, and 25-hydroxyvitamin D values were evaluated. Both calcium and parathyroid hormone levels demonstrated a Gaussian distribution with the average calcium concentration being 10.9 ± 0.6 mg/dL and the average parathyroid hormone concentration being 105.8 ± 48 pg/mL. The average highest calcium and parathyroid hormone concentrations were 11.4 ± 0.7 mg/dL and 115.3 ± 50 pg/mL, respectively. At least 1 calcium value of 11.0 mg/dL was seen in 87% of patients, but only 21% had 1 or more calcium value above 11.5 mg/dL. Only 7% had a single serum calcium level reaching 12.0 mg/dL. Normocalcemic hyperparathyroidism was seen in just under 3% of patients who had identical findings at surgery. An average parathyroid hormone concentration less than 65 pg/mL was seen in 16%, with 10% of patients who had no high parathyroid hormone values. The average 25-hydroxyvitamin D concentration was 22.4 ± 9 ng/mL, with levels decreasing as calcium levels increased (P < .001); 36% had 25-hydroxyvitamin D levels below 20 ng/mL.ConclusionsPatients with PHPT present with a number of distinct biochemical profiles, but as a group, they present with a near-normal Gaussian distribution of both calcium and parathyroid hormone levels. Either serum calcium or parathyroid hormone remained normal in 13% of patients, yet the findings at surgery are similar to those of patients with elevated calcium or parathyroid hormone. Low 25-hydroxyvitamin D is an expected finding in patients with PHPT, decreasing as serum calcium levels increase. (Endocr Pract. 2011;17:384-394)     

Characteristics of Ectopic Parathyroid Glands in 145 Cases of Primary Hyperparathyroidism

ObjectiveTo determine the prevalence of primary hyperparathyroidism (PHPT) arising from ectopic parathyroid glands, to analyze the clinical, biochemical, and anatomic characteristics of such cases, and to compare these characteristics with those found in PHPT associated with orthotopic parathyroid glands.MethodsWe conducted a retrospective study of cases of PHPT evaluated and treated at a referral center. Differences between patients with orthotopic and ectopic parathyroid glands were analyzed statistically.ResultsDuring a recent 5-year period at our institution, 145 cases of PHPT were treated operatively by 3 experienced surgeons. An ectopic parathyroid location was detected in 13 cases (9%). Of the 13 ectopic glands, 4 (31%) were at the tracheoesophageal groove, 4 (31%) were intrathymic, 2 (15%) were intrathyroidal, and 1 each was located in the aortopulmonary window, the anterior (nonthymic) mediastinum, and the submaxillary region. Patients with PHPT attributable to ectopic adenomas had significantly higher serum calcium levels (12.6 ± 0.9 mg/ dL versus 11.4 ± 1.2 mg/dL; P = .05) and larger tumors (25 ± 6.1 mm versus 19 ± 7.6 mm; P = .05) than did patients with orthotopic parathyroid glands. Moreover, hyperparathyroidism-related bone disease was significantly more frequent in patients with abnormal ectopic parathyroid glands than in those with orthotopic parathyroid glands (23% versus 1.5%, respectively; P = .04).ConclusionIn 9% of all cases of PHPT in our study, the condition was associated with ectopically located parathyroid glands. Such cases are usually characterized by larger parathyroid glands, higher serum calcium levels, and a higher frequency of severe bone disease. (Endocr Pract. 2010;16:977-981)     

Aldosterone Secretion in Patients With Primary Hyperparathyroidism Without Arterial Hypertension

ObjectiveThere is a direct bidirectional link between parathyroid hormone (PTH) and the renin-angiotensin-aldosterone system (RAAS), but few studies evaluated the RAAS in patients with primary hyperparathyroidism (PHPT), mainly biased from concomitant antihypertensive treatment.MethodsWe retrospectively evaluated a consecutive series of 130 normotensive patients with PHPT comparing aldosterone (ALD) levels and plasma renin activity (PRA) with the demographic, biochemical, or clinical features of PHPT.ResultsNo correlation was found between ALD and PRA, and the demographic, biochemical, and bone densitometry parameters in patients with PHPT without hypertension, with the exception of a negative correlation between age and serum PRA. Moreover, there was no significant correlation between PTH and ALD levels even in patients whose PTH level was >100 ng/L (P = .088).ConclusionIn our normotensive patients with PHPT, the ALD, PRA, and aldosterone/renin ratio were not correlated to PTH and calcium levels. In addition, they were neither related to PHPT clinical presentation nor renal function, vitamin D status, bone mass loss, or the presence of comorbidities such as diabetes and obesity. Further studies are needed to clarify the complex interplay between PTH and the RAAS in the modern PHPT presentation.     

采用微渗透泵测定清醒大鼠肾小球滤过率

目的分析以荧光素异硫氰酸酯标记的菊粉（FITC．菊粉）作为标记物,通过微渗透泵,在大鼠清醒状态下,采用菊粉尿排泄率方法测定肾小球滤过率的可行性。方法将FITC-菊粉溶解在生理盐水中配成浓度为24％的溶液,经滤过后（浓度降至8％）装在微渗透泵内。大鼠腹腔植入2个盛有上述FITC-菊粉溶液的微渗透泵,随机分成2组（需要收集24h尿量组及无需收集尿量组每组各10只）,分别关在代谢笼内。植泵后第7天,需要收集24h尿量组收集24h尿量及代谢笼上残留的FITC-菊粉,在大鼠清醒状态下采集血液标本;无需收集尿量组仅采集血液标本。分别根据不同的公式计算GFR。GFR的计量单位为mL／min,分别用大鼠体重及双肾重量校正后的单位为mL／min·kg体重和mL／min·g体重。结果需要收集24h尿量和无需收集尿量2种方法计算出来的GFR分别为（2．31±0．33）mL／min和（2．53±0．33）mL／min,P=0．564,两者之间差异无统计学意义;与已发表文献相比大鼠GFR平均值3．24mL／min降低了30％,说明麻醉对GFR有较明显影响,去除麻醉因素的影响后,两者数值相近。结论采用微渗透泵方法,用FITC-菊粉作为标记物,可以比较准确地测定清醒状态下大鼠GFR,尤其是无需收集尿量方法更加简便。     

Serum Adiponectin and Glomerular Filtration Rate in Patients with Type 2 Diabetes

High serum adiponectin has been increased in several conditions of kidney disease. Only sparse and conflicting results have been reported in patients with type 2 diabetes (T2D), a subgroup of individuals who are at high risk for renal dysfunction. The aim of this study was to fill up this gap of knowledge by investigating such association in a large sample of Italian diabetic patients. The association between serum adiponectin levels and estimated glomerular filtration rate (eGFR by Chronic Kidney Disease-Epidemiology Collaboration CKD-EPI equation) was investigated in 1,243 patients with T2D from two cross-sectional Italian studies: 878 from San Giovanni Rotondo (SGR) and 365 from Foggia (FG). Serum adiponectin was inversely associated with eGFR in SGR [β (standard error, SE) for 1 standard deviation (SD) of adiponectin = -3.26 (0.64)] and in FG [β(SE)=-5.70(1.28)] sample, as well as in the two studies combined [β(SE)=-3.99(0.59)];(p<0.0001 for all). In this combined analysis, the association was still significant after adjusting for sex, smoking habits, body mass index (BMI), waist circumference, diabetes duration, glycated hemoglobin (HbA1c), albumin creatinine ratio (ACR) and anti-hyperglycemic, anti-hypertensive and anti-dyslipidemic treatments [β (SE)= -2.19 (0.59), p = 0.0001]. A stronger association between each SD adiponectin increment and low eGFR was observed among patients with micro-/macro-albuminuria, as compared to those with normo-albuminuria [adjusted β(SE)=-4.42(1.16) ml/min/1.73m² vs. -1.50 (0.67) ml/min/1.73m², respectively; p for adiponectin-by-albuminuric status = 0.022]. For each adiponectin SD increment, the odds of having eGFR < 60 ml/min/1.73m² increased by 41% (odds ratio, OR = 1.41; 95% confidence interval, CI 1.21–1.64) in SGR sample, 53% (OR = 1.53; 95% CI 1.21–1.94) in FG sample, and 44% (OR = 1.44; 95%CI 1.27–1.64) in the two studies considered together (p<0.0001 for all). In the combined sample, further adjustment for the above mentioned covariates did not change the observed association (OR = 1.36; 95%CI 1.16–1.60; p<0.0001). Our study, so far the largest addressing the relationship between serum adiponectin and GFR in T2D, strongly suggests that the paradoxical inverse association, previously reported in different clinical sets, is also observed in diabetic patients. Further studies are needed to unravel the biology underlying this counterintuitive relationship.     

Serum Resistin and Glomerular Filtration Rate in Patients with Type 2 Diabetes

BackgroundHigh serum levels of the pro-inflammatory adipokine resistin have been associated with decreased renal function in the general population. The goal of this study was to investigate whether such association is also present among diabetic subjects, who are at increased risk of renal function loss.MethodsThe cross-sectional association between serum resistin levels and estimated glomerular filtration rate (eGFR) was investigated in 1,560 type 2 diabetic (T2D) patients of European ancestry comprised in two different cohorts: 762 patients from San Giovanni Rotondo (SGR; Italy) and 798 patients from Boston (US).ResultsSerum resistin was inversely associated with eGFR in SGR [β (SE) for one SD of resistin increment = -1.01 (0.70) ml/min/1.73m², p = 0.019] and in Boston [β (SE) = -5.31 (0.74) ml/min/1.73m², p < 0.001] samples, as well as in the two studies combined [β (SE) = -3.42 (0.52) ml/min/1.73m², p < 0.001]. The association was unaffected by adjustment for smoking habits, BMI, waist circumference, diabetes duration, HbA1c, insulin treatment, hypertension and lipid-lowering therapy: β (SE) for one SD of resistin increment = -1.07 (0.70), p = 0.02; -5.50 (0.88), p < 0.001; and -2.81 (0.55) ml/min/1.73m², p < .001, in SGR, Boston and the two studies combined, respectively. The association was significantly stronger in men than in women (p for resistin-by-gender interaction = 0.003). For each resistin SD increment, the odds of having eGFR < 0 ml/min/1.73m² increased by 22% (OR = 1.22; 95% CI 1.02–1.44; p = 0.025) in SGR sample, 69% (OR = 1.69; 95% CI 1.38–2.07; p < 0.001) in Boston sample, and 47% (OR = 1.47; 95% CI 1.29–1.68; p < 0.001) in the two studies considered together. Similar associations were observed in the adjusted model: OR 95% CI for each SD resistin increment being 1.23 (1.03–1.46), p = 0.021; 1.52 (1.20–1.92), p < 0.001; 1.33 (1.16–1.53), p < 0.001, in SGR, Boston and the two studies combined, respectively.ConclusionsThis is the first report of an association between high serum resistin and low eGFR in patients with T2D of European ancestry.     

Improved Glomerular Filtration Rate Estimation by an Artificial Neural Network

Background

Accurate evaluation of glomerular filtration rates (GFRs) is of critical importance in clinical practice. A previous study showed that models based on artificial neural networks (ANNs) could achieve a better performance than traditional equations. However, large-sample cross-sectional surveys have not resolved questions about ANN performance.

Methods

A total of 1,180 patients that had chronic kidney disease (CKD) were enrolled in the development data set, the internal validation data set and the external validation data set. Additional 222 patients that were admitted to two independent institutions were externally validated. Several ANNs were constructed and finally a Back Propagation network optimized by a genetic algorithm (GABP network) was chosen as a superior model, which included six input variables; i.e., serum creatinine, serum urea nitrogen, age, height, weight and gender, and estimated GFR as the one output variable. Performance was then compared with the Cockcroft-Gault equation, the MDRD equations and the CKD-EPI equation.

Results

In the external validation data set, Bland-Altman analysis demonstrated that the precision of the six-variable GABP network was the highest among all of the estimation models; i.e., 46.7 ml/min/1.73 m² vs. a range from 71.3 to 101.7 ml/min/1.73 m², allowing improvement in accuracy (15% accuracy, 49.0%; 30% accuracy, 75.1%; 50% accuracy, 90.5% [P<0.001 for all]) and CKD stage classification (misclassification rate of CKD stage, 32.4% vs. a range from 47.3% to 53.3% [P<0.001 for all]). Furthermore, in the additional external validation data set, precision and accuracy were improved by the six-variable GABP network.

Conclusions

A new ANN model (the six-variable GABP network) for CKD patients was developed that could provide a simple, more accurate and reliable means for the estimation of GFR and stage of CKD than traditional equations. Further validations are needed to assess the ability of the ANN model in diverse populations.     

Using Mathematical Algorithms to Modify Glomerular Filtration Rate Estimation Equations

Background

The equations provide a rapid and low-cost method of evaluating glomerular filtration rate (GFR). Previous studies indicated that the Modification of Diet in Renal Disease (MDRD), Chronic Kidney Disease-Epidemiology (CKD-EPI) and MacIsaac equations need further modification for application in Chinese population. Thus, this study was designed to modify the three equations, and compare the diagnostic accuracy of the equations modified before and after.

Methodology

With the use of ^{99 m}Tc-DTPA renal dynamic imaging as the reference GFR (rGFR), the MDRD, CKD-EPI and MacIsaac equations were modified by two mathematical algorithms: the hill-climbing and the simulated-annealing algorithms.

Results

A total of 703 Chinese subjects were recruited, with the average rGFR 77.14±25.93 ml/min. The entire modification process was based on a random sample of 80% of subjects in each GFR level as a training sample set, the rest of 20% of subjects as a validation sample set. After modification, the three equations performed significant improvement in slop, intercept, correlated coefficient, root mean square error (RMSE), total deviation index (TDI), and the proportion of estimated GFR (eGFR) within 10% and 30% deviation of rGFR (P₁₀ and P₃₀). Of the three modified equations, the modified CKD-EPI equation showed the best accuracy.

Conclusions

Mathematical algorithms could be a considerable tool to modify the GFR equations. Accuracy of all the three modified equations was significantly improved in which the modified CKD-EPI equation could be the optimal one.     

Parathyroid Carcinoma: An Experience from the Indian Primary Hyperparathyroidism Registry

ObjectiveTo describe the details of widely invasive parathyroid carcinoma (WIPC) patients admitted in the Endocrinology department of our institute during the last 22 years and to compare their clinical, biochemical, and hormonal profile with minimally invasive parathyroid carcinoma (MIPC) and sporadic parathyroid adenoma patients.MethodsThis is a retrospective analysis of data from the Indian primary hyperparathyroidism registry.ResultsOf the 547 primary hyperparathyroidism patients in the registry, 5 (2 men and 3 women) had WIPC (0.9%) and 7 (1 man and 6 women) had MIPC (1.3%), with median ages of 45 (interquartile range, 41-51) years and 47 (interquartile range, 28-48) years, respectively. Among the patients with WIPC, renal manifestations were present in 5 patients, skeletal manifestations in 4 patients, and palpable neck masses in 4 patients. Three patients had distant metastases and 2 had cervical lymph node involvement. All 5 patients had surgical resection of their cancers, with persistent disease in 4 patients, but all patients died within 2 years after surgery. One patient with MIPC had a palpable parathyroid nodule; none had lymph nodal or distant metastases. None of the patients with MIPC died during the median follow-up of 18 (interquartile range, 12-18) months. Patients with WIPC had significantly higher serum calcium level compared with sporadic parathyroid adenoma patients with skeletal and renal manifestations.ConclusionAccurate histopathologic classification of parathyroid carcinoma is important as WIPC is associated with a more aggressive clinical course and a higher risk of mortality than MIPC.     

Endogenous Creatinine Clearance as a Clinical Measure of Glomerular Filtration Rate

Endogenous creatinine clearance was assessed by inulin in 91 simultaneous studies in 41 patients and proved an accurate measurement of glomerular filtration rate. For filtration rates <20 ml/min the creatinine clearance may slightly overestimate the glomerular filtration rate. Successive determinations of filtration rate by either method may vary by 20% even though the methods agree with each other. Glomerular filtration rate itself is variable, and in its clinical usage this should be recognized.     

The Influence of Postural Changes on the Glomerular Filtration Rate in Nephroptosis

The influence of postural changes on renal function was determined in 13 patients with nephroptosis and in 5 normal subjects by measuring GFR in the erect and supine positions. The results indicate that GFR was reduced in the erect position in 10 of 13 patients with either unilateral or bilateral nephroptosis whereas GFR was increased in the erect position in 4 of 5 patients without renal disease. One patient with bilateral nephroptosis and renovascular hypertension was studied before and after surgical correction of his disease. These observations indicate that patients with nephroptosis may have significant reductions in renal function when they assume an upright position, and suggest that GFR measurements in the supine and erect position in patients with nephroptosis can be helpful in evaluating this disease.     

A High-throughput Method for Measurement of Glomerular Filtration Rate in Conscious Mice

The measurement of glomerular filtration rate (GFR) is the gold standard in kidney function assessment. Currently, investigators determine GFR by measuring the level of the endogenous biomarker creatinine or exogenously applied radioactive labeled inulin (³H or ¹⁴C). Creatinine has the substantial drawback that proximal tubular secretion accounts for ~50% of total renal creatinine excretion and therefore creatinine is not a reliable GFR marker. Depending on the experiment performed, inulin clearance can be determined by an intravenous single bolus injection or continuous infusion (intravenous or osmotic minipump). Both approaches require the collection of plasma or plasma and urine, respectively. Other drawbacks of radioactive labeled inulin include usage of isotopes, time consuming surgical preparation of the animals, and the requirement of a terminal experiment. Here we describe a method which uses a single bolus injection of fluorescein isothiocyanate-(FITC) labeled inulin and the measurement of its fluorescence in 1-2 μl of diluted plasma. By applying a two-compartment model, with 8 blood collections per mouse, it is possible to measure GFR in up to 24 mice per day using a special work-flow protocol. This method only requires brief isoflurane anesthesia with all the blood samples being collected in a non-restrained and awake mouse. Another advantage is that it is possible to follow mice over a period of several months and treatments (i.e. doing paired experiments with dietary changes or drug applications). We hope that this technique of measuring GFR is useful to other investigators studying mouse kidney function and will replace less accurate methods of estimating kidney function, such as plasma creatinine and blood urea nitrogen.     

Measurement of Glomerular Filtration Rate by Inulin Clearance without Urine Collection

A continuous infusion method for measuring inulin clearance (and hence glomerular filtration rate) which does not require urine collection has been re-evaluated and found to give satisfactory results. In two non-oedematous and anephric patients the plasma level of inulin became virtually constant four hours after a single intravenous dose, and hence this is the minimum time required for the infusion with this method.