Albumin-Corrected Calcium and the Prevalence and Categories of Hypercalcemia in Hospitalized Patients With 1-Year Follow-Up of Undiagnosed Cases

ObjectiveTo assess the impact of using corrected calcium versus total calcium on hypercalcemia case detection in hospitalized patients.MethodsPatients hospitalized from June 2012 to June 2017 with a corrected calcium level of ≥10.5 mg/dL were identified by medical record review. One-year follow-up data through June 2018 were acquired. Albumin-corrected calcium level was calculated: (4 − albumin concentration in g/dL) × 0.8 + total serum calcium in mg/dL.ResultsA group of 1067 patients had a corrected calcium level of ≥10.5 mg/dL. The prevalence of hypercalcemia was 0.73% with total calcium and 1.09% with corrected calcium, respectively, with a 49% relative increase. Most patients (62%) had mild hypercalcemia (10.5-11.9 mg/dL); 3.7% had severe hypercalcemia (>14 mg/dL). With corrected calcium, the most common categories of hypercalcemia were malignancy (35.4%), hypercalcemia that was not further evaluated (31.1%), and hyperparathyroidism (22.4%). All patients in the unidentified category had albumin levels <2.8 g/dL. At the 1-year follow–up, 63% of the unidentified cases had normal calcium levels, and 26.8% had mild persistent hypercalcemia. Of those with persisting hypercalcemia at 1 year, 16.8% were diagnosed with hyperparathyroidism.ConclusionUsing albumin-corrected calcium resulted in an ∼50% increase in the detection of hypercalcemia cases. Although hypercalcemia resolved in majority of the undiagnosed cases at 1 year, a number of these remained abnormal. Detecting hypercalcemic disorders by correcting for low albumin level can help identify conditions such as hyperparathyroidism. Adding auto-calculated albumin-corrected calcium to routine laboratory tests could be a cost-effective intervention to improve the detection of hypercalcemic disorders.     

Primary hyperparathyroidism and familial hypocalciuric hypercalcemia: relationships and clinical implications

ObjectiveTo discuss the unusual occurrence of both familial hypocalciuric hypercalcemia (FHH) and primary hyperparathyroidism in the same patient and to explore potential mechanisms of association and issues related to clinical management.MethodsWe discuss the diagnosis, compare the clinical presentations of FHH and primary hyperparathyroidism, review the literature regarding patients who have presented with both disorders, and discuss management considerations. We also describe 2 patients who have both FHH (confirmed by genetic testing for a mutation in the gene encoding the calcium-sensing receptor [CASR]) and primary hyperparathyroidism.ResultsThe occurrence of both FHH and primary hyperparathyroidism in the same patient has been reported in a few cases, including 2 patients described here, one of whom was documented to have a novel CASR mutation. Inthose with clinical sequelae of hyperparathyroidism, parathyroidectomy has led to reduction, but not normalization, of serum calcium levels.ConclusionsThe coexistence of FHH and primary hyperparathyroidism should be considered in patients with hypercalcemia, hypophosphatemia, frankly elevated parathyroid hormone levels, and low urinary calcium excretion. Genetic testing for inactivating CASR gene mutations can confirm the diagnosis of FHH. Although surgical intervention does not resolve hypercalcemia, it may be beneficial by reducing the degree of hypercalcemia, alleviating the symptoms, and preventing potential complications of hyperparathyroidism. (Endocr Pract. 2012;18:412-417)     

The chloride phosphate ratio as the screening test for primary hyperparathyroidism

Serum chloride and phosphate concentrations were measured in 79 hypercalcemic patients. The chloride values were higher (mean 106.7 mEq/l) and phosphate lower (mean 2.08 mg/100 ml) in the 53 hyperparathyroid patients, where as the chloride concentrations were lower (mean 99.3 mEq/l) and phosphate higher (mean 4.07 mg/100 ml) in the 26 patients with hypercalcemia from other causes. The chloride phosphate ratio ranged from 19 to 32 in the subjects with hypercalcemia from other causes with 90 per cent of values less than 30. In patients with primary hyperparathyroidism we found 96 per cent of the values more than 34. From our experience with chloride phosphate ratio it seems to us that this ratio is a very useful and simple preliminary test for distinguishing patients with primary hyperparathyroidism from patients with hypercalcemia from other causes, with normal renal functions.     

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)     

Heart Block and Acute Kidney Injury Due to Hyperparathyroidism-Induced Hypercalcemic Crisis

We describe a patient who presented with multi-system organ failure due to extreme hypercalcemia (serum calcium 19.8 mg/dL), resulting from primary hyperparathyroidism. He was found to have a 4.8 cm solitary atypical parathyroid adenoma. His course was complicated by complete heart block, acute kidney injury, and significant neurocognitive disturbances. Relevant literature was reviewed and discussed. Hyperparathyroidism-induced hypercalcemic crisis (HIHC) is a rare presentation of primary hyperparathyroidism and only a small minority of these patients develop significant cardiac and renal complications. In cases of HIHC, a multidisciplinary effort can facilitate rapid treatment of life-threatening hypercalcemia and definitive treatment by surgical resection. As such, temporary transvenous cardiac pacing and renal replacement therapy can provide a life-saving bridge to definitive parathyroidectomy in cases of HIHC.     

Primary Hyperparathyroidism

ObjectiveTo review primary hyperparathyroidism and the key issues that are relevant to the practicing endocrinologist.MethodsThe latest information on the presentation, diagnosis, and traditional and nontraditional aspects of primary hyperparathyroidism is reviewed.ResultsThe diagnosis of primary hyperparathyroidism is straightforward when the traditional hypercalcemic patient is documented to have an elevated parathyroid hormone (PTH) level. Commonly, patients are identified who have normal serum calcium levels but elevated PTH levels in whom no secondary causes for hyperparathyroidism can be confirmed. Traditional target organs of primary hyperparathyroidism—the skeleton and the kidneys—continue to be a focus in the patient evaluation. Bone mineral density shows a typical pattern of involvement with the distal one-third radius being selectively reduced compared with the lumbar spine in which bone mineral density is generally well maintained. Neurocognitive and cardiovascular aspects of primary hyperparathyroidism, while a focus of recent interest, have not been shown to definitively aid in the decision for or against surgery. The recommendation for surgery in primary hyperparathyroidism is based on guidelines that focus on the serum calcium level, renal function, bone mineral density, and age. In patients who do not meet guidelines, a nonsurgical management approach has merit.ConclusionsPrimary hyperparathyroidism is continuing to show changes in its clinical profile, with normocalcemic primary hyperparathyroidism being a topic of great interest. Skeletal and renal features of primary hyperparathyroidism drive, in most cases, the decision to recommend surgery. In patients who do not meet any criteria for surgery, a conservative approach with appropriate monitoring is acceptable. (Endocr Pract. 2012;18:781-790)     

Primary Hyperparathyroidism,With A Focus On Management Of The Normocalcemic Form: To Treat Or Not To Treat?

Objective: The aim of this study was to determine reasonable care for normocalcemic primary hyperparathyroidism (NCPHPT) patients treated at the endocrine clinic.Methods: The study is based on 218 outpatient cases of primary hyperparathyroidism (PHPT), 187 (86%) of whom were NCPHPT. Subjective complaints, biochemical tests, imaging, and treatment outcome for NCPHPT patients were monitored and compared with the same parameters in patients with hypercalcemic hyperparathyroidism. The number of patients with newly diagnosed NCPHPT who became hypercalcemic and the time period in which it happened were also recorded.Results: Over 6 years of study, in total, 36 of 187 originally normocalcemic patients became hypercalcemic (19%); 24 of 36 within 2 years and 2 of 36 later than after 4 years. Sestamibi scintigraphy was performed in 103 normocalcemic patients (adenoma was detected in 5cases) and in 46 hypercalcemic patients with pathologically elevated serum calcium levels at the time of assessment (adenoma was detected in 32 of 46cases). Surgery was performed in 33 patients, 11 of whom were originally normocalcemic (i.e., 6% of all 187 originally normocalcemic patients), and 22 were hypercalcemic from the outset (i.e., 71% of all 31 originally hypercalcemic patients).Conclusion: Some NCPHPT patients converted to hypercalcemic, mostly within 2 years, but some after 4 years or later. Normocalcemic patients should be monitored on a long-term basis, as it is impossible to anticipate when and which normocalcemic patients will become hypercalcemic. Imaging is much less effective in normocalcemic than in hypercalcemic patients.Abbreviations:MIBI = sestamibiNCPHPT = normocalcemic primary hyperparathyroidismPHPT = primary hyperparathyroidismPTH = parathyroid hormone     

Familial benign hypercalcemia--from clinical description to molecular genetics.

Familial benign hypercalcemia (or familial hypocalciuric hypercalcemia), a syndrome of lifelong hypercalcemia inherited as an autosomal dominant trait, is distinct from the multiple endocrine neoplasia syndromes and other forms of inherited parathyroid disease. Familial benign hypercalcemia results from the inappropriate secretion of parathyroid hormone despite hypercalcemia, enhanced renal tubular reabsorption of calcium (independent of parathyroid hormone), and apparent tissue resistance to adverse effects of hypercalcemia. Heterozygosity for the familial hypercalcemia trait is benign, although homozygosity for the trait may lead to severe neonatal primary hyperparathyroidism. Genetic linkage studies show that most persons affected with familial hypercalcemia have a mutation on the long arm of chromosome 3 (3cen-q21), although one phenotypically indistinguishable family appears to have a mutation on the short arm of chromosome 19 (19p), and another family has neither 3q nor 19p mutations. One group has recently shown mutations in a putative parathyroid cell-surface calcium receptor that are plausible causes for the chromosome 3q variant of the familial hypercalcemia syndrome. Perhaps the other genes for this syndrome encode proteins representing hitherto-unknown regulators of systemic calcium metabolism independent of parathyroid cell calcium sensing or proteins involved in signal transduction from the calcium receptor.     

Differentiating Familial Hypocalciuric Hypercalcemia From Primary Hyperparathyroidism

ObjectiveBecause the clinical features of familial hypocalciuric hypercalcemia (FHH) overlap significantly with those of primary hyperparathyroidism (PHPT), various means of differentiating between the two diseases have been suggested. Here we present a review of the clinical delineation of these two diseases.MethodsReview of the English language literature on FHH and PHPT.ResultsFHH is a rare genetic disorder generally resulting in asymptomatic hypercalcemia of minimal clinical consequence. It is easily misdiagnosed as PHPT because both entities can manifest as hypercalcemia with an inappropriately normal or elevated level of parathyroid hormone. The 2 disorders differ in renal processing of calcium, and a number of indices of renal calcium excretion have been proposed to differentiate the 2 entities. However, the two disorders have considerable overlaps in their ranges on these indices making differentiation a challenge. There are many mutations in the calcium-sensing receptor (CaSR) gene associated with FHH and it is becoming increasingly recognized that the CaSR has broad functional variability.ConclusionThe calcium:creatinine clearance ratio (CCCR) is the consensus biochemical test to differentiate between PHPT and FHH. However, this test is still limited by a considerable indeterminate range, and definitive diagnosis of FHH requires genetic testing. A combination of clinical suspicion, biochemical testing, and genetic analysis is required to differentiate PHPT from FHH and thus spare patients with FHH from nontherapeutic operative treatment. (Endocr Pract. 2013;19:697-702)     

Interleukin-4 blocks parathyroid hormone-related protein-induced hypercalcemia in vivo.

Interleukin (IL)-4 inhibits bone resorption. In the present study, the effect of IL-4 on hypercalcemia in nude mice under two experimental conditions was assessed. IL-4 inhibited plasma calcium elevation induced by parathyroid hormone-related protein (PTHrP) infusion. In hypercalcemic nude mice bearing PTHrP-producing tumors, IL-4 lowered plasma calcium levels to almost the normal range. These results indicate that IL-4 blocks PTHrP-induced hypercalcemia in vivo.     

Prolonged Vitamin D Intoxication in a Patient with Hypoparathyroidism

Pitfalls in the management of hypoparathyroidism are illustrated by the case of a patient who developed hypervitaminosis D while receiving doses of calciferol and of calcium in amounts commonly recommended for treatment. Either the patient was very slow to obtain maximum vitamin D effect or else her sensitivity to vitamin D increased, because she did not become hypercalcemic until two years after treatment was started. The dose of vitamin D was halved to 50,000 units per day and the dose of calcium was lowered to 0.26 g. daily. She failed to remain under medical supervision for the next four years and presented with hypercalcemia and evidence of renal impairment. After vitamin D was discontinued she remained hypercalcemic for nine months.These findings are discussed in the light of current knowledge concerning the actions of parathyroid hormone and vitamin D. The influence of adrenocortical hormones on calcium metabolism is considered. The need to follow up hypoparathyroid patients closely, and to check the level of calcium in the serum, is emphasized.     

Calcium-Creatinine Clearance Ratio is not Helpful in Differentiating Primary Hyperparathyroidism from Familial Hypercalcemic Hypocalciuria: A Study of 1,000 Patients

Objective: With increasing recognition of more subtle presentations of primary hyperparathyroidism (pHPT), laboratory values are frequently seen in a range that would be expected for patients who have familial hypercalcemic hypocalciuria (FHH). Calcium-creatinine clearance ratio (CCCR) has been advocated as a diagnostic tool to differentiate between these two disorders. However, it is limited by an indeterminate range (0.01 to 0.02). The aim of this study was to assess the relevance of CCCR in a modern series of patients with surgically managed pHPT.Methods: We performed a retrospective cohort study of 1,000 patients who underwent parathyroid surgery for pHPT over 11 years. CCCR was evaluated by degree of biochemical derangement, single versus multiple gland disease, and interfering medications.Results: Patient demographics and resected histopathology were typical for a current series of patients with pHPT. In retrospect, none of the patients were suspected to have FHH postoperatively. CCCR was <0.01 for 19.0%, between 0.01 and 0.02 for 43.7%, and >0.02 in 37.3%. Distribution of CCCR for patients free from interfering medications and different histologic subtypes were the same. One-third of the cohort had mild calcium elevations, more typical for FHH. Of these, almost two-thirds had a CCCR in a range suspect for FHH (<0.02).Conclusion: To our knowledge, this is the largest series to evaluate the validity of CCCR for patients with surgically confirmed pHPT. The utility of CCCR in screening for FHH is limited, as 63% of modern patients with confirmed pHPT have low values.Abbreviations: CaSR = calcium sensing receptor; CCCR = calcium-creatinine clearance ratio; CeE = calcium excretion; FHH = familial hypercalcemic hypocalciuria; pHPT = primary hyperparathyroidism; PTH = parathyroid hormone     

Renal Calculi

The pathogenesis of renal calculi is reviewed in general terms followed by the results of investigation of 439 patients with renal calculi studied by the author at Toronto General Hospital over a 13-year period. Abnormalities of probable pathogenetic significance were encountered in 76% of patients. Idiopathic hypercalciuria was encountered in 42% of patients, primary hyperparathyroidism in 11%, urinary infection in 8% and miscellaneous disorders in 8%. The incidence of uric acid stones and cystinuria was 5% and 2% respectively. In the remaining 24% of patients in whom no definite abnormalities were encountered the mean urinary magnesium excretion was less than normal. Of 180 patients with idiopathic hypercalciuria, only 24 were females. In the diagnosis of hyperparathyroidism, the importance of detecting minimal degrees of hypercalcemia is stressed; attention is also drawn to the new observation that the upper limit of normal for serum calcium is slightly lower in females than in males. The efficacy of various measures advocated for the prevention of renal calculi is also reviewed. In the author''s experience the administration of thiazides has been particularly effective in the prevention of calcium stones. Thiazides cause a sustained reduction in urinary calcium excretion and increase in urinary magnesium excretion. These agents also appear to affect the skeleton by diminishing bone resorption and slowing down bone turnover.     

Failure of indomethacin to reduce hydroxyproline excretion or hypercalcemia in patients with breast cancer

Prostaglandin synthetase inhibitors have, in the past, been shown to inhibit osteolysis caused by breast carcinoma tissue . We therefore assessed the effect of Indomethacin and aspirin on some parameters of calcium metabolism in patients with breast cancer. Neither drug reduced the serum calcium in patients with hypercalcemia, nor reduced skeletal destruction as measured by the urinary hydroxyproline:creatinine ratio and urinary calcium in normocalcemic or hypercalcemic patients with osteolytic metastases. A possible reason for the discrepancy between results obtained and is that there are two phases of bone destruction in breast cancer; the early phase dependent and the late phase independent of prostaglandin synthesis.     

Echocardiographic Findings in Patients With Normocalcemic Primary Hyperparathyroidism Compared With Findings in Hypercalcemic Primary Hyperparathyroid Patients and Control Subjects

ObjectiveThere are no data regarding echocardiographic parameters in patients with normocalcemic primary hyperparathyroidism (NCPHPT). We compared the echocardiographic findings in postmenopausal women with NCPHPT with those in patients with hypercalcemic primary hyperparathyroidism (PHPT) and controls.MethodsSeventeen consecutive Caucasian postmenopausal women with NCPHPT were compared with 20 women with hypercalcemic PHPT and 20 controls. Obesity, diabetes, kidney failure, and previous cardiovascular diseases were considered exclusion criteria. Each patient underwent biochemical evaluation, bone mineral density scan, and echocardiographic measurements. Patients with parathyroid disorders underwent kidney ultrasound evaluation.ResultsPatients with PHPT had significantly higher mean total serum calcium, ionized calcium, 24-hour urinary calcium, and parathyroid hormone and lower mean phosphorus levels compared with those in the controls (all P < .05). The only differences between patients with NCPHPT and PHPT were significantly lower mean total serum calcium, ionized calcium, and 24-hour urinary calcium and higher phosphorus levels in patients with NCPHPT (all P < .05). The only biochemical difference between patients with NCPHPT and the controls was a higher level of mean parathyroid hormone in patients with NCPHPT. There were no differences in cardiovascular risk factors between patients with NCPHPT and PHPT and the controls. Hypertension was the most frequent cardiovascular risk factor, diagnosed in 65% of patients with PHPT. This high prevalence was not statistically significant compared with that observed in patients with NCPHPT (59%) and in the controls (30%). Echocardiography parameters were not different between patients with NCPHPT and PHPT and the controls when subdivided according to the presence of hypertension (ANOVA followed by Bonferroni correction).ConclusionIn a population with a low cardiovascular risk, we found no differences in cardiovascular risk factors and echocardiographic parameters between patients with NCPHPT and PHPT and the controls.     

Identifying Parathyroid Hormone Disorders and their Phenotypes through a Bone Health Screening Panel: It's not Simple Vitamin D Deficiency!

Objectives: To determine the utility of bone health screening panels in identifying disorders of parathyroid gland secretions.Methods: A retrospective analysis of biochemical parameters in a bone health screening panel (BHSP) was conducted. Low and high cutoffs were applied to determine hypofunctioning and hyperfunctioning conditions related to parathyroid hormone. Clinical phenotypes of parathyroid gland abnormalities were determined using a combination of levels of calcium, 25-hydroxyvitamin D, and intact parathyroid hormone (iPTH). A PTH nomogram was applied to calculate the maximum expected PTH for existing levels of 25-hydroxyvitamin D. Medical records of patients were reviewed for clinical validation of biochemical findings.Results: Sixty-eight percent of subjects showed abnormal PTH secretion. Primary hyper- and hypoparathyroidism were detected in 1% (n = 5) and 0.4% (n = 2) of subjects, respectively. Normocalcemic hyperparathyroidism and hypercalcemia with inappropriately high-normal PTH were identified in 8.5% (n = 37) and 2% (n = 10) of subjects, respectively. All subjects with primary and normocalcemic hyperparathyroidism had higher measured PTH than calculated maximum PTH using the PTH nomogram. Secondary hyperparathyroidism and functional hypoparathyroidism were present in 18% (n = 88) and 39% (n = 194) of subjects, respectively. High prevalence of bone pains, renal stones, and low bone mineral density were identified in patients with abnormal PTH secretion.Conclusion: Panel testing is useful in early diagnosis of metabolic bone disorders related to PTH. A BHSP helps identify normocalcemic hyperparathyroidism and hypercalcemia with inappropriately high PTH.Abbreviations:25OHD = 25-hydroxyvitamin DAKUH = Aga Khan University HospitalBHSP = bone health screening paneliPTH = intact parathyroid hormonemaxPTH = maximum parathyroid hormoneMBD = metabolic bone diseaseNCHPT = normocalcemic hyperparathyroidismPHPT = primary hyperparathyroidismPTH = parathyroid hormoneSHPT = secondary hyperparathyroidismVDD = vitamin D deficiency     

The calcium sensing receptor: from calcium sensing to signaling

The Ca2+-sensing receptor(the Ca SR),a G-protein-coupled receptor,regulates Ca2+ homeostasis in the body by monitoring extracellular levels of Ca2+([Ca2+]o) and responding to a diverse array of stimuli.Mutations in the Ca2+-sensing receptor result in hypercalcemic or hypocalcemic disorders,such as familial hypocalciuric hypercalcemia,neonatal severe primary hyperparathyroidism,and autosomal dominant hypocalcemic hypercalciuria.Compelling evidence suggests that the Ca SR plays multiple roles extending well beyond not only regulating the level of extracellular Ca2+ in the human body,but also controlling a diverse range of biological processes.In this review,we focus on the structural biology of the Ca SR,the ligand interaction sites as well as their relevance to the disease associated mutations.This systematic summary will provide a comprehensive exploration of how the Ca SR integrates extracellular Ca2+ into intracellular Ca2+ signaling.     

Primary hyperparathyroidism: a rare endocrinopathy in children. Two case reports

Primary hyperparathyroidism (PHPT) is thought to be a common disease in adults. However, it is a rare endocrine disorder in children and adolescents. We report two cases of primary hyperparathyroidism in children diagnosed at the Department of Endocrinology and Diabetes (EU and D) in the Children's Hospital (ChH), Kielce. The clinical course of the disease in these cases was fundamentally dissimilar, which confirms the observation that this rare endocrinopathy in children presents various clinical profiles, leading to diagnostic difficulties. In the first case, the severe course of PHPT was observed with signs suggesting a hypercalcemic crisis. In the second case, the patient was in a good condition with a mild hypercalcemia and symptoms limited to the skeleton, due to early identification of the disease. We believe these cases indicate the significant role of calcemia determination as a screening test in the diagnosis of PHPT, including in children.     

Comparative study of inhibitory effects by murine interferon γ and a new bisphosphonate (alendronate) in hypercalcemic,nude mice bearing human tumor (LJC-1-JCK)

The inhibitory effect of murine interferon (muIFN) on humoral hypercalcemia in nude mice bearing lower-jaw cancer (LJC-1-JCK), in which parathyroid-hormone(PTH)-related protein is responsible for causing humoral hypercalcemia by activating bone resorption, was examined in comparison with that of a new bisphosphonate, 4-amino-1-hydroxybutylidene-1,1-bisphosphonate (alendronate), muIFN was injected into tumor-bearing nude mice for 5 days before the establishment of hypercalcemia. The increase of plasma calcium concentration was delayed and this effect continued for more than 6 days even after the injection was stopped. Alendronate markedly suppressed hypercalcemia in tumor-bearing nude mice but this inhibitory effect continued for less than 6 days. Neither muIFN nor alendronate affected the tumor volume or serum PTH-related protein concentration. Injection of muIFN into mice for 3 days almost completely abolished the formation of multinucleated osteoclast-like cells from bone marrow cells in vitro, whereas injection of alendronate into mice had no effect. These findings suggested that muIFN suppressed the formation of osteoclasts, resulting in the prolonged decrease of plasma calcium concentration in hypercalcemic tumor-bearing nude mice, whereas alendronate is cytotoxic to functionally mature osteoclasts and inhibited osteoclastic bone resorption, resulting in a marked decrease in the plasma calcium concentration in tumor-bearing hypercalcemic nude mice.     

Primary neonatal hyperparathyroidism: a devastating neurodevelopmental disorder if left untreated

We describe a 29-year-old male with untreated primary neonatal hyperparathyroidism. Hypotonia, poor feeding, failure to thrive, and developmental delay were noted in early infancy and in incidental serum calcium of 3.8 mmol/L was dismissed as a laboratory error. Childhood was characterized by profound muscle wasting and progressive spastic quadriparesis. Distinctive skeletal deformities, facial dysmorphism, and perichondral calcifications are now evident in adulthood. Elevated serum calcium (range: 2.7-3.3 mM; normal less than 2.7 mM), serum immunoreactive parathyroid hormone (range: 1,405-1,817 pg/mL; normal 50-140 pg/mL), and markedly decreased urinary calcium excretion (0.04 mumol/dL glomerular filtrate; normal greater than 25) suggested the diagnosis of primary neonatal hyperparathyroidism. This was supported by evidence of hypocalciuric hypercalcemia--the autosomal dominant carrier state--in both the parents. Our case illustrates the profound neurodevelopmental deficits arising from sustained hypercalcemia in infancy and childhood. Although this disorder is not lethal, it should be considered a neonatal emergency, since surgical parathyroidectomy can result in cure.