Subject(s)
Calcium , Creatinine , Hypercalcemia , Parathyroid Hormone , Humans , Hypercalcemia/urine , Hypercalcemia/diagnosis , Hypercalcemia/blood , Parathyroid Hormone/urine , Parathyroid Hormone/blood , Calcium/urine , Creatinine/urine , Female , Male , Middle Aged , Aged , Adult , Urine Specimen Collection/methodsABSTRACT
BACKGROUND: Primary hyperparathyroidism and familial hypocalciuric hypercalcemia have similar biochemical profiles, and calcium-to-creatinine-clearance ratio helps distinguish the two. Additionally, 24-hour urine calcium >400 mg/day indicates surgery and guidelines recommend obtaining 24-hour urine calcium preoperatively. Our aim was to assess how 24-hour urine calcium altered care in the evaluation of suspected primary hyperparathyroidism. METHODS: Consecutive patients assessed for primary hyperparathyroidism from 2018 to 2020 were reviewed. Primary hyperparathyroidism was diagnosed by 2016 American Association of Endocrine Surgeons Parathyroidectomy Guidelines criteria. 24-hour urine calcium-directed change in care was defined as familial hypocalciuric hypercalcemia diagnosis, surgical deferment for additional testing, or 24-hour urine calcium >400 mg/day as the sole surgical indication. RESULTS: Of 613 patients, 565 (92%) completed 24-hour urine calcium and 477 (84%) had concurrent biochemical testing to calculate calcium-to-creatinine-clearance ratio. 24-hour urine calcium was <100 mg/day in 9% (49/565) and calcium-to-creatinine-clearance ratio was <0.01 in 17% (82/477). No patient had confirmed familial hypocalciuric hypercalcemia, although 1 had a CASR variant of undetermined significance. When calcium-to-creatinine-clearance ratio was <0.01, familial hypocalciuric hypercalcemia was excluded by 24-hour urine calcium >100 mg/day (56%), prior normal calcium (16%), renal insufficiency (11%), absence of familial hypercalcemia (3%), normal repeat 24-hour urine calcium (10%), or interfering diuretic (1%). 24-hour urine calcium-directed change in care occurred in 25 (4%), including 4 (1%) who had genetic testing. Four-gland hyperplasia was more common with calcium-to-creatinine-clearance ratio <0.01 (17% vs calcium-to-creatinine-clearance ratio ≥ 0.01, 4%, P < .001), but surgical failure rates were equivalent (P = .24). CONCLUSION: 24-hour urine calcium compliance was high, and results affected management in 4%, including productive identification of hypercalciuria as the sole surgical indication in 2 patients. When calcium-to-creatinine-clearance ratio <0.01, clinical assessment was sufficient to exclude familial hypocalciuric hypercalcemia and only 1% required genetic testing. 24-hour urine calcium should be ordered judiciously during primary hyperparathyroidism assessment.
Subject(s)
Calcium/urine , Hypercalcemia/congenital , Hyperparathyroidism, Primary/diagnosis , Urinalysis/methods , Aged , Creatinine/urine , Diagnosis, Differential , Feasibility Studies , Female , Genetic Testing , Humans , Hypercalcemia/diagnosis , Hypercalcemia/genetics , Hypercalcemia/urine , Hyperparathyroidism, Primary/urine , Male , Middle Aged , Parathyroidectomy/standards , Practice Guidelines as Topic , Retrospective Studies , Severity of Illness IndexABSTRACT
CONTEXT: Idiopathic infantile hypercalcemia (IIH) is an uncommon disorder with variable clinical features. The natural history and response to dietary calcium and vitamin D restriction in IIH remains unclear. OBJECTIVE: The aim of this study is to describe the clinical and biochemical response to dietary calcium and vitamin D restriction in a genetically characterized cohort of mild IIH. METHODS: This is a longitudinal, observational cohort study of 20 children with mild IIH monitored for a median of 21months. Biochemical measures, dietary assessment, and yearly renal ultrasound results, since the time of diagnosis, were obtained and assessed prospectively every 4 to 6 months. RESULTS: Median age at initial diagnosis was 4.5 months. Median levels of serum calcium (2.82 mmol/L) and 1,25 (OH)2D (192 pmol/L) were elevated, whereas serum PTH was reduced (10 ng/L). Urinary calcium:creatinine ratio was elevated for some, but not all individuals (median 1.49 mmol/mmol). All patients who were managed with a low-calcium diet showed an improvement in serum and urinary calcium measures, but the serum concentration of 1,25 dihydroxyvitamin D (1,25(OH)2D) and 1,25(OH)2D/PTH ratio remained elevated. In 2 of the 11 subjects, renal calcification worsened. There were no differences in response between individuals with CYP24A1 or SLC34A1/A3 variants. CONCLUSION: The clinical presentation of mild IIH is variable, and dietary calcium and vitamin D restriction does not consistently normalize elevated 1,25(OH)2D concentrations or prevent worsening of renal calcification in all cases. Therapeutic options should target the defect in vitamin D metabolism.
Subject(s)
Calcium, Dietary/metabolism , Diet/methods , Eating , Hypercalcemia/diet therapy , Vitamin D/metabolism , Adolescent , Calcium/blood , Calcium/urine , Calcium, Dietary/administration & dosage , Child , Child, Preschool , Female , Humans , Hypercalcemia/blood , Hypercalcemia/urine , Infant , Longitudinal Studies , Male , Nephrocalcinosis/diet therapy , Nephrocalcinosis/genetics , Parathyroid Hormone/blood , Prospective Studies , Vitamin D/administration & dosage , Vitamin D/analogs & derivatives , Vitamin D/bloodABSTRACT
CONTEXT: Idiopathic infantile hypercalcemia (IIH), an uncommon disorder characterized by elevated serum concentrations of 1,25 dihydroxyvitamin D (1,25(OH)2D) and low parathyroid hormone (PTH) levels, may present with mild to severe hypercalcemia during the first months of life. Biallelic variants in the CYP24A1 or SLC34A1 genes are associated with severe IIH. Little is known about milder forms. OBJECTIVE: This work aims to characterize the genetic associations and biochemical profile of mild IIH. METHODS: This is a cross-sectional study including children between age 6 months and 17 years with IIH who were followed in the Calcium Clinic at the Hospital for Sick Children (SickKids), Toronto, Canada. Twenty children with mild IIH on calcium-restricted diets were evaluated. We performed a dietary assessment and analyzed biochemical measures including vitamin D metabolites and performed a stepwise molecular genetic analysis. Complementary biochemical assessments and renal ultrasounds were offered to first-degree family members of positive probands. RESULTS: The median age was 16 months. Median serum levels of calcium (2.69 mmol/L), urinary calcium:creatinine ratio (0.72 mmol/mmol), and 1,25(OH)2D (209 pmol/L) were elevated, whereas intact PTH was low normal (22.5 ng/L). Mean 1,25(OH)2D/PTH and 1,25(OH)2D/25(OH)D ratios were increased by comparison to healthy controls. Eleven individuals (55%) had renal calcification. Genetic variants were common (65%), with the majority being heterozygous variants in SLC34A1 and SLC34A3, while a minority showed variants of CYP24A1 and other genes related to hypercalciuria. CONCLUSION: The milder form of IIH has a distinctive vitamin D metabolite profile and is primarily associated with heterozygous SLC34A1 and SLC34A3 variants.
Subject(s)
Hypercalcemia/genetics , Parathyroid Hormone/blood , Sodium-Phosphate Cotransporter Proteins, Type IIa/genetics , Sodium-Phosphate Cotransporter Proteins, Type IIc/genetics , Vitamin D/analogs & derivatives , Adolescent , Calcium/blood , Calcium/urine , Child , Child, Preschool , Creatinine/urine , Cross-Sectional Studies , Female , Genetic Variation , Heterozygote , Humans , Hypercalcemia/blood , Hypercalcemia/urine , Infant , Male , Vitamin D/blood , Vitamin D3 24-Hydroxylase/geneticsABSTRACT
La injuria renal aguda es una entidad clínica compleja, caracterizada por la disminución abrupta de la función renal. La hipercalcemia como etiología de la misma es poco frecuente. Los mecanismos involucrados en su desarrollo son múltiples y poco estudiados. Se presenta el caso de un paciente varón de 59 años que desarrolló un cuadro severo de falla renal aguda como complicación de crisis hipercalcémica por un adenoma de paratiroides. Se observó alteración en los marcadores de daño y función renal. La bioquímica urinaria mostró una necrosis tubular aguda. Los niveles de calcio, parathormona y calciuria se asociaron a endocrinopatía. La ecografía, el centellograma y la biopsia paratiroidea mostraron la presencia de un adenoma. Se presentaron otras complicaciones sistémicas concomitantes como pancreatitis y complicaciones cardíacas. El tratamiento paliativo fue la hemodiálisis y el definitivo la paratiroidectomía. El síndrome de hueso hambriento se presentó como una complicación postquirúrgica. Tras el alta, la recuperación de la función renal nunca fue total. El daño renal agudo asociado a disfunción sistémica por hipercalcemia puede llevar a una recuperación parcial de la función renal. Se debe considerar el desarrollo de enfermedad renal crónica posterior a la falla renal aguda por hipercalcemia como complicación de la misma.
Acute renal injury is a complex clinical entity, characterized by the abrupt worsening in renal function. Hypercalcemia as its etiology is rare. The mechanisms involved in its development are multiple and rarely studied. The case of a 59-year-old male patient who developed a severe acute renal failure as a complication of an hypercalcemic crisis due to a parathyroid adenoma is presented here. Alterations in markers of damage and renal function were observed. Urinary biochemistry showed acute tubular necrosis. Calcium, parathormone and urine calcium levels were associated with endocrinopathy. The ultrasound, the scintigraphy and the parathyroid biopsy showed the presence of an adenoma. There were other concomitant systemic complications such as pancreatitis and cardiac complications. Hemodialysis was the palliative treatment, while the definitive treatment was parathyroidectomy. The hungry bone syndrome occurred as a postoperative complication. After discharge, recovery of renal function was never complete. Acute renal damage associated with systemic dysfunction due to hypercalcemia can lead to a partial recovery of renal function. The development of chronic kidney disease after acute renal failure due to hypercalcemia should be considered one of its complications.
A Lesão renal aguda é uma entidade clínica complexa, caracterizada pela diminuição abrupta da função renal. A hipercalcemia como etiologia da mesma não é muito frequente. Os mecanismos que participam no seu desenvolvimento são múltiplos e pouco estudados. Apresenta-se o caso de um paciente, homem, de 59 anos, que desenvolveu um quadro severo de insuficiência renal aguda como complicação de crise hipercalcêmica por um adenoma da paratireóide. Foi observada alteração nos marcadores de dano e função renal. A bioquímica urinária mostrou uma necrose tubular aguda. Os níveis de cálcio, paratormona e calciúria foram associados a endocrinopatia. A ultra-sonografia, a cintilografia, e a biópsia da paratireóide mostraram a presença de um adenoma. Apresentaram-se outras complicações sistêmicas concomitantes como pancreatite e cardíacas. O tratamento paliativo foi hemodiálise e o definitivo, a paratireoidectomia. A síndrome do osso faminto apresentou-se como uma complicação pós-operatória. Após a alta, a recuperação da função renal nunca foi total. O dano renal agudo associado à disfunção sistêmica por hipercalcemia pode levar para uma recuperação parcial da função renal. Deve ser considerado o desenvolvimento da doença renal crônica posterior à insuficiência renal aguda por hipercalcemia como complicação da mesma.
Subject(s)
Humans , Male , Middle Aged , Acute Kidney Injury/diagnosis , Hypercalcemia/complications , Thyroid Gland/diagnostic imaging , Abdomen/diagnostic imaging , Hypercalcemia/urine , Kidney Tubular Necrosis, Acute/urineABSTRACT
OBJECTIVE: It is anticipated that an intake of vitamin D found acceptable by Endocrine Society Guidelines (10 000 IU/day) with co-administered calcium supplements may result in frequent hypercalciuria and hypercalcaemia. This combination may be associated with kidney stones. The objective of this study was to compare the episodes of hypercalciuria and hypercalcaemia from calcium supplements co-administered with 10 000 IU or 600 IU vitamin D daily. This design allows a comparison of the Institute of Medicine recommendation for the RDA of vitamin D along with the upper limit of calcium intake with the high intake of vitamin D suggested by the Endocrine Society. CONTEXT: Harms of currently recommended high intake of vitamin D have not been studied. DESIGN: The design was a randomized controlled trial with 2 groups with evaluation every 3 months for one year: (a) CaCO3 1200 mg/day with 10 000 IU vitamin D3 /day or (b) CaCO3 1200 mg/day with 600 IU vitamin D3 /day. PATIENTS: This study was conducted in an ambulatory research centre in healthy, white postmenopausal women. MEASUREMENTS: Serum and 24-hour urine calcium were measured. RESULTS: Hypercalcaemia and hypercalciuria occurred in both groups. At the final visit, 19/48 in the high dose D group had hypercalciuria. The odds of developing hypercalciuria were 3.6 [OR = 3.6(1.39, 9.3)] times higher in the high dose D group. The odds of developing hypercalcaemia did not differ between groups. CONCLUSIONS: The safe upper level of vitamin D recommended by the Endocrine Society when accompanied by calcium supplements results in frequent hypercalciuria. The risk of kidney stones at these levels should be investigated.
Subject(s)
Calcium/adverse effects , Vitamin D/adverse effects , Aged , Calcium/administration & dosage , Calcium/blood , Calcium/urine , Double-Blind Method , Female , Humans , Hypercalcemia/blood , Hypercalcemia/urine , Hypercalciuria/blood , Hypercalciuria/urine , Kidney Calculi/blood , Kidney Calculi/urine , Male , Middle Aged , Vitamin D/administration & dosageABSTRACT
Blue diaper syndrome (BDS) (Online Mendelian Inheritance in Man number 211000) is an extremely rare disorder that was first described in 1964. The characteristic finding is a bluish discoloration of urine spots in the diapers of affected infants. Additional clinical features of the first described patients included diarrhea, inadequate weight gain, hypercalcemia, and nephrocalcinosis. An intestinal defect of tryptophan absorption was postulated as the underlying pathology. However, functional evidence for this theory is lacking. No genetic cause has been identified so far. Here, we report on a boy who presented with neonatal-onset diarrhea, metabolic acidosis, transient hepatopathy, recurrent hypoglycemia, and blue-stained urine spots in his diapers. An ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry analysis of urine samples at different time points demonstrated the constant presence of indigo derivatives, thereby confirming the diagnosis of BDS. Of note, the visibility of indigo derivatives in the urine was highly dependent on the urine's pH. To identify the underlying genetic cause of the disease, whole-exome sequencing was performed, leading to the identification of a homozygous frameshift mutation in proprotein convertase subtilisin/kexin type 1 (PCSK1; NM_000439.4: c.679del, p.[Val227Leufs*12]). PCSK1 encodes prohormone convertase 1/3, and mutations within this gene have been reported as a rare cause of early-onset malabsorptive diarrhea and multiple endocrine dysfunction. In our report, we suggest that BDS can be caused by PCSK1 mutations.
Subject(s)
Amino Acid Metabolism, Inborn Errors/genetics , Eye Abnormalities/genetics , Frameshift Mutation , Hypercalcemia/genetics , Kidney Diseases/genetics , Proprotein Convertase 1/genetics , Amino Acid Metabolism, Inborn Errors/diagnosis , Amino Acid Metabolism, Inborn Errors/urine , Chromatography, Ion Exchange , Eye Abnormalities/diagnosis , Eye Abnormalities/urine , Humans , Hydrogen-Ion Concentration , Hypercalcemia/diagnosis , Hypercalcemia/urine , Infant, Newborn , Kidney Diseases/diagnosis , Kidney Diseases/urine , Male , Tandem Mass Spectrometry , Tryptophan/genetics , Tryptophan/urine , Urine/chemistry , Exome SequencingABSTRACT
Nephrolithiasis is a common urological disease and could be secondary to primary hyperparathyroidism (PHPT). PHPT is traditionally characterised with hypercalcaemia. Recently, a normocalcemic PHPT has been officially recognised at the International Workshops. Regarding this new phenotype, nephrolithiasis is frequently found in studies that evaluate low bone mass. However, until now, no study on aetiology of nephrolithiasis considered normocalcemic PHPT. Hypercalciuria related to PHPT is considered as an important risk factor of stone formation in hypercalcemic PHPT, but the precise relationships between hypercalcemic PHPT and nephrolithiasis and between normocalcemic PHPT and nephrolithiasis remain unclear. In patients with hypercalcemic PHPT, after a surgical cure of PHPT, the renal calcium excretion and stone recurrence rate reduce but remain higher above health controls. This finding implies that abnormalities not caused by PHPT also probably affect stone formation. According to the new guideline, the presence of stones indicates the need for parathyroidectomy in patients with either hypercalcemic or normocalcemic PHPT unless contraindications exist. Patients with contraindications for parathyroidectomy or those who do not want to receive parathyroidectomy should be monitored for signs of disease progression and given of medical management. Moreover, due to decreased but significantly higher frequency of nephrolithiasis above those of healthy controls, patients with nephrolithiasis associated with PHPT after parathyroidectomy still should be motivated to explore strategies to prevent stone occurrence.
Subject(s)
Hypercalcemia/etiology , Hypercalciuria/etiology , Hyperparathyroidism, Primary/complications , Nephrolithiasis/etiology , Bone Density , Calcium/blood , Calcium/urine , Disease Progression , Humans , Hypercalcemia/epidemiology , Hypercalcemia/prevention & control , Hypercalcemia/urine , Hypercalciuria/epidemiology , Hypercalciuria/prevention & control , Hypercalciuria/urine , Hyperparathyroidism, Primary/epidemiology , Hyperparathyroidism, Primary/surgery , Hyperparathyroidism, Primary/urine , Nephrolithiasis/epidemiology , Nephrolithiasis/prevention & control , Nephrolithiasis/urine , Parathyroidectomy , RecurrenceABSTRACT
The article analyzes the literature on the features of human calcium homeostasis. The authors describe the etiopathogenetic role of calcitropic hormones, the plasma and urine acid-base status, various ions, lifestyle and nutrition and other factors contributing to hypercalciuria due to increased intestinal absorption, bone resorption, impairment of tubular calcium reabsorption, etc. They discuss the role of calciuria as a factor in forming urinary calculi and present their own observations.
Subject(s)
Bone Resorption/urine , Calcium/urine , Hypercalcemia/urine , Intestinal Absorption , Kidney Diseases/urine , HumansABSTRACT
Context: There is no therapy for control of hypercalciuria in nonoperable patients with primary hyperparathyroidism (PHPT). Thiazides are used for idiopathic hypercalciuria but are avoided in PHPT to prevent exacerbating hypercalcemia. Nevertheless, several reports suggested that thiazides may be safe in patients with PHPT. Objective: To test the safety and efficacy of thiazides in PHPT. Design: Retrospective analysis of medical records. Setting: Endocrine clinic at a tertiary hospital. Patients: Fourteen male and 58 female patients with PHPT treated with thiazides. Interventions: Data were compared for each patient before and after thiazide administration. Main Outcome Measures: Effect of thiazide on urine and serum calcium levels. Results: Data are given as mean ± standard deviation. Treatment with hydrochlorothiazide 12.5 to 50 mg/d led to a decrease in mean levels of urine calcium (427 ± 174 mg/d to 251 ± 114 mg/d; P < 0.001) and parathyroid hormone (115 ± 57 ng/L to 74 ± 36 ng/L; P < 0.001), with no change in serum calcium level (10.7 ± 0.4 mg/dL off treatment, 10.5 ± 1.2 mg/dL on treatment, P = 0.4). Findings were consistent over all doses, with no difference in the extent of reduction in urine calcium level or change in serum calcium level by thiazide dose. Conclusion: Thiazides may be effective even at a dose of 12.5 mg/d and safe at doses of up to 50 mg/d for controlling hypercalciuria in patients with PHPT and may have an advantage in decreasing serum parathyroid hormone level. However, careful monitoring for hypercalcemia is required.
Subject(s)
Calcium/metabolism , Diuretics/therapeutic use , Hydrochlorothiazide/therapeutic use , Hypercalcemia/drug therapy , Hyperparathyroidism/drug therapy , Aged , Calcium/blood , Calcium/urine , Diuretics/adverse effects , Female , Humans , Hydrochlorothiazide/adverse effects , Hypercalcemia/blood , Hypercalcemia/urine , Hyperparathyroidism/blood , Hyperparathyroidism/urine , Male , Middle Aged , Parathyroid Hormone/urine , Retrospective Studies , Treatment OutcomeABSTRACT
KEY POINTS: Hypercalcaemia can occur under various pathological conditions, such as primary hyperparathyroidism, malignancy or granulomatosis, and it induces natriuresis and polyuria in various species via an unknown mechanism. A previous study demonstrated that hypercalcaemia induced by vitamin D in rats increased endothelin (ET)-1 expression in the distal nephron, which suggests the involvement of the ET system in hypercalcaemia-induced effects. In the present study, we demonstrate that, during vitamin D-induced hypercalcaemia, the activation of ET system by increased ET-1 is responsible for natriuresis but not for polyuria. Vitamin D-treated hypercalcaemic mice showed a blunted response to amiloride, suggesting that epithelial sodium channel function is inhibited. We have identified an original pathway that specifically mediates the effects of vitamin D-induced hypercalcaemia on sodium handling in the distal nephron without affecting water handling. ABSTRACT: Acute hypercalcaemia increases urinary sodium and water excretion; however, the underlying molecular mechanism remains unclear. Because vitamin D-induced hypercalcaemia increases the renal expression of endothelin (ET)-1, we hypothesized that ET-1 mediates the effects of hypercalcaemia on renal sodium and water handling. Hypercalcaemia was induced in 8-week-old, parathyroid hormone-supplemented, male mice by oral administration of dihydrotachysterol (DHT) for 3 days. DHT-treated mice became hypercalcaemic and displayed increased urinary water and sodium excretion compared to controls. mRNA levels of ET-1 and the transcription factors CCAAT-enhancer binding protein ß and δ were specifically increased in the distal convoluted tubule and downstream segments in DHT-treated mice. To examine the role of the ET system in hypercalcaemia-induced natriuresis and polyuria, mice were treated with the ET-1 receptor antagonist macitentan, with or without DHT. Mice treated with both macitentan and DHT displayed hypercalcaemia and polyuria similar to that in mice treated with DHT alone; however, no increase in urinary sodium excretion was observed. To identify the affected sodium transport mechanism, we assessed the response to various diuretics in control and DHT-treated hypercalcaemic mice. Amiloride, an inhibitor of the epithelial sodium channel (ENaC), increased sodium excretion to a lesser extent in DHT-treated mice compared to control mice. Mice treated with either macitentan+DHT or macitentan alone had a similar response to amiloride. In summary, vitamin D-induced hypercalcaemia increases the renal production of ET-1 and decreases ENaC activity, which is probably responsible for the rise in urinary sodium excretion but not for polyuria.
Subject(s)
Endothelin-1/physiology , Hypercalcemia/metabolism , Natriuresis/physiology , Polyuria/metabolism , Vitamin D/toxicity , Acute Disease , Animals , Cell Line, Transformed , Hypercalcemia/chemically induced , Hypercalcemia/urine , Kidney Tubules/drug effects , Kidney Tubules/metabolism , Male , Mice , Mice, Inbred C57BL , Natriuresis/drug effects , Polyuria/urineABSTRACT
Mutations of the CYP24A1 gene, encoding for the enzyme 25(OH)D-24-hydroxylase, can cause hypercalcemia, hypercalciuria, nephrolithiasis and nephrocalcinosis. We report the case of a 22-year-old male patient with recurrent nephrolithiasis, nephrocalcinosis, hypercalcemia with low parathyroid hormone levels, hypercalciuria and low bone mass. Gene sequencing showed that the patient had compound heterozygous mutations including a novel genotype of the CYP24A1 gene. Genetic CYP24A1 testing and biochemical analyses were offered to other family members; the father was heterozygous for the same novel genotype and was also affected with recurrent nephrolithiasis.
Subject(s)
Hypercalcemia/genetics , Hypercalciuria/genetics , Nephrocalcinosis/genetics , Nephrolithiasis/genetics , Osteoporosis/genetics , Vitamin D3 24-Hydroxylase/genetics , Adult , Calcium Phosphates/chemistry , Genotype , Humans , Hypercalcemia/blood , Hypercalcemia/urine , Hypercalciuria/blood , Hypercalciuria/urine , Kidney/metabolism , Kidney Calculi/chemistry , Male , Mutation , Nephrocalcinosis/blood , Nephrocalcinosis/diagnostic imaging , Nephrocalcinosis/urine , Nephrolithiasis/blood , Nephrolithiasis/diagnostic imaging , Nephrolithiasis/urine , Osteoporosis/blood , Osteoporosis/urine , Parathyroid Hormone/blood , Pedigree , Recurrence , Renal Elimination , Sequence Analysis, DNA , Tomography, X-Ray Computed , Young AdultABSTRACT
BACKGROUND: Partial duplication of 2p is a rare condition that causes facial anomalies, psychomotor delay, and growth failure. Hypercalcaemia is rare in children. So far, duplication of 2p has never been associated with hypercalcaemia. METHODS: Here, we report a girl with a partial duplication of 2p presenting with moderate to severe hypercalcaemia at the age of 2 years. She also had hypercalciuria, nephrocalcinosis, decreased renal function, and secondary hyperparathyroidism at presentation. She was thoroughly investigated, including genetic testing of the CYP24A1, CASR, ALPL, and NOD2 genes, to determine the cause of hypercalcaemia. RESULTS: 1,25-dihydroxyvitamin D levels were increased. Hypercalcaemia and hypercalciuria responded well to glucocorticoids but not to cinacalcet. Hyperparathyroidism resolved with improving renal function. Apart from the known duplication of 2p, no pathogenic variants were detected in the studied genes. The duplication of 2p contains the PPP3R1 gene, which encodes for the calcineurin B subunit. CONCLUSION: We conclude that partial duplication of 2p can be associated with hypercalcaemia and hypercalciuria and hypothesise that the underlying mechanism is an increased extra-renal, parathyroid hormone-independent 25-hydroxyvitamin D 1α-hydroxylase activity, leading to raised amounts of 1,25-dihydroxyvitamin D. The increased enzymatic activity could possibly be caused by calcineurin B subunit-related macrophage stimulation.
Subject(s)
Chromosome Duplication , Chromosomes, Human, Pair 2/genetics , Hypercalcemia/genetics , Child, Preschool , Female , Humans , Hypercalcemia/blood , Hypercalcemia/urineABSTRACT
We report a case of phaeochromocytoma associated with hypercortisolism and hypercalcaemia in a 62-year-old man. The patient presented to clinic, with a 3-year history of exertional headaches, and a 4-month history of increasing fatigue, sweating and palpitations, loss of appetite and weight, and sleepiness. He did not have a medical, family or social history that could account for these symptoms. 24â h urinary catecholamines, plasma metanephrines, 24â h urinary cortisol and adjusted serum calcium, were elevated. Overnight low-dose dexamethasone suppression test did not suppress morning plasma cortisol. Serum intact parathyroid hormone and parathyroid hormone-related peptide were low, and adrenocorticotropic hormone was normal. The patient was treated with intravenous 0.9% sodium chloride and disodium pamidronate to control hypercalcaemia. CT showed a 10â cm left adrenal mass. Following inpatient treatment with phenoxybenzamine, he underwent a left adrenectomy and histology confirmed a phaeochromocytoma. Postoperatively, he required long-term steroids for contralateral adrenal suppression. Adjusted serum calcium returned to normal postoperatively.
Subject(s)
Adrenal Gland Neoplasms/blood , Adrenal Gland Neoplasms/urine , Hydrocortisone/urine , Hypercalcemia/blood , Hypercalcemia/urine , Pheochromocytoma/blood , Pheochromocytoma/urine , Adrenal Gland Neoplasms/pathology , Calcium/blood , Follow-Up Studies , Humans , Hypercalcemia/pathology , Male , Middle Aged , Pheochromocytoma/pathology , Pheochromocytoma/surgeryABSTRACT
Calcium, the fifth most common element in the body, plays major physiological functions. Measurement of blood calcium is one of the most commonly ordered laboratory tests in assessments of calcium homeostasis and disease diagnosis. Hypercalcemia is an increased level of calcium in the blood. This disorder is most commonly caused by primary hyperparathyroidism and malignancy. However, other less common causes of elevated calcium levels need to be considered when making a differential diagnosis. This review is intended to provide readers with a better understanding of calcium homeostasis and the causes and pathophysiology of hypercalcemia. Most importantly, this review describes useful approaches for laboratory scientists and clinicians to appropriately diagnose and assess hypercalcemia.
Subject(s)
Hypercalcemia/diagnosis , Calcium/blood , Calcium/urine , Carcinoma, Neuroendocrine/blood , Carcinoma, Neuroendocrine/diagnosis , Carcinoma, Neuroendocrine/physiopathology , Carcinoma, Neuroendocrine/urine , Diagnosis, Differential , Humans , Hypercalcemia/blood , Hypercalcemia/etiology , Hypercalcemia/urine , Hyperparathyroidism, Primary/blood , Hyperparathyroidism, Primary/diagnosis , Hyperparathyroidism, Primary/physiopathology , Hyperparathyroidism, Primary/urine , Multiple Endocrine Neoplasia/blood , Multiple Endocrine Neoplasia/diagnosis , Multiple Endocrine Neoplasia/physiopathology , Multiple Endocrine Neoplasia/urine , Paraneoplastic Syndromes/blood , Paraneoplastic Syndromes/diagnosis , Paraneoplastic Syndromes/urine , Thyroid Neoplasms/blood , Thyroid Neoplasms/diagnosis , Thyroid Neoplasms/physiopathology , Thyroid Neoplasms/urineABSTRACT
The analysis of retainment and release kinetics of deposited in tissue structures calcium was made in the hypercalcemic conditions in 28 healthy volunteers (22 males and 6 females) of the age of 33 ± 6.5 years via drip infusion (Groups 1, 2) and in 9 individuals (3 males and 6 females) in 12 trials via stream infusion (Group 3). By the end of each hour after the termination of calcium infusion the amount of calcium retained in tissues was calculated (Mtis./kg); the parameters of its binding (specific buffer volume--ß3 sp, association constant--Ka, number of binding centers--n) were established using the Langmuir and Scetchard coordinates. The Group 1 volunteers (n = = 12) showed a section of positive cooperativity (a direct regression on Sketchard coordinates, Hill coefficient 3.36 ± 1.63) and 2 sections of the consecutive calcium separation from one set of noninteracting centers. 5 volunteers of Group 2 and 8 volunteers of Group 3 demonstrated a slight calcium delivery to tissues after 1 hour of observation which then followed for 2 volunteers of Group 2 and for 2 volunteers of Group 3. Other volunteers of Groups 2 and 3 showed a release of tissue-deposited calcium via the mechanism of the consecutive separation from one set of noninteracting centers with ßsp 3 times less and Ka 7 times higher than with the calcium infusion. The excretion of calcium in urine was the highest in Group 1 and the lowest in Group 3. The [Ca2+] and Mtis./kg values were normalized in Groups 1 and 2 the next morning and in Group 3 after 2-3 hours of observation. An assumption was made about the relationship between the tissue and kidney [Ca2+] normalizing mechanisms with hypercalcemia.
Subject(s)
Calcium Gluconate/pharmacokinetics , Calcium , Hypercalcemia/blood , Hypercalcemia/urine , Kidney/metabolism , Adult , Calcium/blood , Calcium/urine , Calcium Gluconate/administration & dosage , Female , Glomerular Filtration Rate , Humans , Hypercalcemia/chemically induced , Infusions, Intravenous , MaleABSTRACT
CONTEXT: Although AP2S1 has recently been shown to be a causative gene for familial hypocalciuric hypercalcemia type 3 (FHH3), knowledge about FHH3 remains poor. OBJECTIVE: Our objective was to report AP2S1 mutation and effects of low calcium formula in a patient with hypercalcemia and hypercalciuria. PATIENT: This Japanese female infant was found to have hypercalcemia by a routine laboratory test for poor weight gain on breast feeding. At 49 days of age, serum calcium (adjusted by Payne's formula) was 13.1 mg/dL, intact PTH 27 pg/mL, and urinary calcium-to-creatinine ratio 1.29 mg/mg. There was no evidence for hyperparathyroidism, PTHrP-producing neoplasm, and vitamin D excess. These data, except for hypercalciuria, appeared to be consistent with defective calcium-sensing receptor-mediated signaling. With use of low calcium formula containing 2.6 mg/dL of calcium, she showed catch-up growth, and serum calcium was decreased, as was urinary calcium-to-creatinine ratio. Furthermore, feeding with a mixture of low calcium formula and standard formula with a 2:1 ratio maintained serum calcium â¼12 mg/dL without markedly increasing serum PTH. RESULTS: Although no pathologic mutation was detected in CASR or GNA11, a presumably de novo heterozygous mutation (p.Arg15Leu), a previously reported causative mutation for FHH3, was identified in AP2S1 of this patient. CONCLUSIONS: The results imply that lack of hypocalciuria does not necessarily argue against the presence of AP2S1 mutations. The early infantile age of this patient would have played a certain role in the occurrence of hypercalciuria, and low calcium formula is worth attempting in infants with FHH.
Subject(s)
Adaptor Protein Complex 2/genetics , Adaptor Protein Complex sigma Subunits/genetics , Calcium, Dietary , Hypercalcemia/prevention & control , Mutation , Amino Acid Substitution , Contraindications , Female , Humans , Hypercalcemia/diet therapy , Hypercalcemia/etiology , Hypercalcemia/genetics , Hypercalcemia/physiopathology , Hypercalcemia/urine , Infant , Infant Formula , Treatment OutcomeABSTRACT
BACKGROUND: Hypercalcemia occurs more frequently than is recognized in patients who are immobilized, but most of these patients are asymptomatic. This study is to determine serum and urinary calcium levels, incidence of hypercalcemia and hypercalciuria in immobilized and ambulant trauma patients. METHODS: A prospective comparative study was carried out over a period of seven months. Total serum calcium level and 24-hour urinary calcium output were measured weekly over 4weeks in 55 immobilized trauma patients as study group and 51 ambulant trauma patients as control group. RESULTS: Mean total serum calcium of immobilized patients increased progressively (on admission: 2.315±0.056mmol/l and week 4: 2.552±0.231mmol/l, p<.001) while that of ambulant patients did not change significantly (on admission: 2.306±0.041mmol/l, and week 4: 2.300±0.028mmol/l, p=.348). There is a significant difference in overall mean total serum calcium between immobilized and ambulant patients (p<.001). In immobilized and ambulant patients, mean 24-hour urinary calcium increased progressively from baseline (3.044±0.480mmol/day and 3.056±0.540mmol/day respectively), till the end of the study (8.543±2.142mmol/day and 6.783±1.372mmol/day respectively). Overall mean 24-hour urinary calcium is significantly different between immobilized and ambulant patients {multivariate Pillai F (5,100)=883.124, p<.001}. Incidence of hypercalcemia increased progressively in immobilized patients (end of week 1=7.27% and end of week 4=29.09%) while none of the ambulant patients had hypercalcemia. Incidence of hypercalciuria also increased progressively in immobilized patients (end of week 1=7.27% and end of week 4=63.64%) while ambulant patients only had hypercalciuria at the end of week 3 (9.8%) and week 4 (21.57%). CONCLUSION: Mean total serum calcium increased with increased duration of immobilization in trauma patients. Both immobilized and ambulant trauma patients developed hypercalciuria but it is worse and earlier in the immobilized trauma patients.
Subject(s)
Ambulatory Care , Calcium/blood , Calcium/urine , Disabled Persons , Immobilization , Wounds and Injuries/blood , Wounds and Injuries/urine , Adolescent , Adult , Child , Female , Humans , Hypercalcemia/blood , Hypercalcemia/urine , Male , Middle Aged , Phosphates/blood , Phosphates/urine , Young AdultABSTRACT
Ronacaleret is an orally-active calcium-sensing receptor (CaSR) antagonist that has the potential for therapeutic utility in the stimulation of PTH release, notably as a bone anabolic agent comparable to recombinant human PTH(1-34) (rhPTH(1-34)). A recent study has shown that, despite the ability to increase circulating PTH levels in postmenopausal women in a dose-dependent manner, minimal effects of ronacaleret on bone mineral density have been observed. Therefore, the purpose of this study was to characterize the PTH profile as well as calcium metabolism parameters as a marker of PTH biological activity following the administration of ronacaleret or rhPTH(1-34). Administration of ronacaleret led to lower peak levels of PTH than were observed with rhPTH(1-34), however, greater total PTH exposure was observed. Further, chronic administration of either agent was associated with increases in urinary calcium excretion and serum calcium levels, with the magnitude of the changes following ronacaleret significantly greater than that for rhPTH(1-34). The greater magnitude of effects observed with ronacaleret is likely due to the greater total PTH exposure, and is potentially reflective of a state comparable to mild hyperparathyroidism. It is not clear whether the administration of all calcilytics would lead to a similar result, or is due to characteristics specific to ronacaleret.