Use of pre-operative calcium and vitamin D supplementation to prevent post-operative hypocalcaemia in patients undergoing thyroidectomy: a systematic review.

OBJECTIVE: This systematic review aimed to establish the evidence behind the use of pre-operative calcium, vitamin D or both calcium and vitamin D to prevent post-operative hypocalcaemia in patients undergoing thyroidectomy. METHOD: This review included prospective clinical trials on adult human patients that were published in English and which studied the effects of pre-operative supplementation with calcium, vitamin D or both calcium and vitamin D on the rate of post-operative hypocalcaemia following total thyroidectomy. RESULTS: Seven out of the nine trials included reported statistically significantly reduced rates of post-operative laboratory hypocalcaemia (absolute risk reduction, 13-59 per cent) and symptomatic hypocalcaemia (absolute reduction, 11-40 per cent) following pre-operative supplementation. CONCLUSION: Pre-operative treatment with calcium, vitamin D or both calcium and vitamin D reduces the risk of post-operative hypocalcaemia and should be considered in patients undergoing total thyroidectomy.

Denosumab-associated hypocalcemia: Does gender play a role?

OBJECTIVE: It is well recognized that the presentation, treatment, and outcomes of various diseases may differ between men and women. We recently reported a 7.4% rate of denosumab-associated hypocalcemia in community-dwelling osteoporotic patients. This study sought to investigate the role of gender in this complication. STUDY DESIGN: Retrospective community-dwelling cohort. METHOD: The databases of a large health maintenance organization were searched for adult patients treated with denosumab for osteoporosis in 2010-2018. Rates and predictors of denosumab-associated hypocalcemia (serum calcium ≤8.5 mg/mL) were analyzed by gender. RESULTS: The cohort included 1871 women and 134 men. Compared with the women, the men were characterized by older median age (81 vs. 77 years, p = 0.005), higher likelihood to receive denosumab as a first-line treatment (22% vs. 6%, p < 0.001), less treatment with calcium supplements (42% vs. 53%, p = 0.012), and lower median eGFR level (66.1 vs. 79.8 mL/min/1.73m2, p < 0.001). Denosumab-associated hypocalcemia developed in 133 women (7.1%) and 16 men (11.9%) (p = 0.04); the drug was discontinued in 75% and 61%, respectively. The strongest predictors of hypocalcemia in women were levels of pretreatment albumin-adjusted serum calcium (OR 0.08, 95% CI (0.04, 0.14)) and creatinine (OR 2.43, 95% CI (1.45, 4.05)). There were no predictors in men. On propensity matching of 126 men and 126 women, gender was not a predictor of hypocalcemia. CONCLUSION: Denosumab-treated men were significantly older than treated women and had a lower eGFR and more advanced osteoporosis. These findings suggest that selection bias rather than male genderper se underlies the higher rate of denosumab-associated hypocalcemia in men.

Preoperative Vitamin D Supplementation in Patients With Vitamin D Deficiency Undergoing Total Thyroidectomy.

BACKGROUND: Transient hypocalcemia due to parathyroid gland or vessel manipulation is a common complication following thyroidectomy. Considering the role of 25-hydroxyvitamin D (25(OH)D) in calcium hemostasis, this study aimed to evaluate the effect of preoperative vitamin D supplementation on hypocalcemia incidence in thyroidectomy patients. METHODS: In this randomized clinical trial, 100 patients scheduled for total thyroidectomy and suffering from preoperative moderate or severe vitamin D deficiency were enrolled. Patients were randomly allocated to either study or control groups using the sealed envelope method. Patients in the study group received vitamin D3 50,000-unit pearl weekly for 4 weeks prior to the operation. The control group received placebo. Total and ionized serum calcium levels were checked before surgery, the day after surgery, and 2 weeks postoperatively. RESULTS: No significant difference was observed in terms of demographic data. During serial total calcium checks (5 episodes), total calcium levels changed significantly in patients who had received vitamin D supplements compared to the control group (P = 0.043). Symptomatic hypocalcemia incidence was significantly lower in patients supplemented with 25-hydroxyvitamin D (25(OH)D) (P = 0.04). Also, the requirement for intravenous calcium administration in order to treat the hypocalcemia symptoms was significantly lower in the study in comparison to the control group (P = 0.03). CONCLUSIONS: Vitamin D supplementation in patients with vitamin D deficiency might lead to a lower incidence of early-onset symptomatic hypocalcemia; hence, requiring less calcium supplementation for the management of hypocalcemia.

Effect of subclinical and clinical hypocalcemia and dietary cation-anion difference on rumination activity in periparturient dairy cows.

Rumination involves a complex series of muscle contractions that bring a bolus of ingesta to the mouth for further mastication before it is swallowed again. Healthy cows ruminate 8 to 9 h/d. Hypocalcemia is known to disrupt nerve and muscle function. Our hypothesis was that hypocalcemia in periparturient cows would reduce rumination activity. Twenty-six Holstein cows entering their third lactation or greater were fed a control diet [dietary cation-anion difference (DCAD) = +196 mEq/kg of dry matter (DM)] or a low DCAD diet supplemented with anions (DCAD = -9 mEq/kg of DM) prepartum. Periparturient plasma Ca concentration and rumination rate were determined. Four of 12 control cows developed clinical milk fever, necessitating intravenous Ca therapy. Rumination rate decreased in all cows around the time of calving. Rumination rate on the first and second day of lactation was highly correlated with the cow's plasma Ca concentration on the first day of lactation. In one of our statistical models, a normocalcemic cow was defined as a cow whose plasma Ca concentration remained above 2.00 mM. Cows were retrospectively classified as normocalcemic, subclinically hypocalcemic, or clinically hypocalcemic (milk fever). Only 4 cows were considered normocalcemic, and all had been fed the low DCAD diet. Normocalcemic cows spent more time ruminating on the first day after calving than subclinically hypocalcemic cows or cows with milk fever. Cows with milk fever had a lower rumination rate than normocalcemic cows through d 3 of lactation. Rumination activity in cows with milk fever was almost nondetectable in the hours before and after intravenous Ca treatment for an extended period, despite the return of muscle function that allowed the cows to stand and eructate following treatment. Other statistical models using different definitions of normocalcemia gave qualitatively similar results. Diet had a great effect on plasma Ca concentration and rumination rate. Even when cows with clinical milk fever were removed from the control cow data set, cows on the low DCAD diet had significantly greater plasma Ca concentrations in the first 36 h after calving and a higher rumination rate on d 1 of lactation (248 ± 26 min) than control cows (158 ± 32 min).

Hypocalcemic cardiomyopathy: a rare presenting manifestation of hypoparathyroidism.

Hypoparathyroidism patients present with features of hypocalcemia like carpopedal spasm, numbness and paresthesias but hypocalcemic cardiomyopathy leading to congestive heart failure (CHF) is a rare presentation. We present here a case of 55-year-old Asian man who was a known case of dilated cardiomyopathy for 6 months, presented with the chief complaints of shortness of breath on exertion and decreased urine output. On general physical examination, features suggestive of CHF were seen. Chvostek and Trousseau's sign was positive. The patient had a history of cataract surgery of both eyes 15 years ago. Further investigations revealed hypocalcemia. Echo showed severe global hypokinesia of left ventricle with left ventricle ejection fraction 15%. This CHF was refractory to conventional treatment, though, with calcium supplementation, the patient improved symptomatically. On follow-up after 3 months, an improvement was seen in the echocardiographic parameters with ejection fraction improving to 25%.

Hypocalcemia-based prediction of hungry bone syndrome after parathyroidectomy in hemodialysis patients with refractory secondary hyperparathyroidism.

OBJECTIVE: This study was performed to explore the risk factors for hungry bone syndrome (HBS) and establish prediction equations for calcium supplementation after parathyroidectomy in hemodialysis patients with secondary hyperparathyroidism. METHODS: We retrospectively analyzed data from 252 hemodialysis patients undergoing successful total parathyroidectomy with autotransplantation. HBS was defined according to a minimum postoperative serum corrected calcium (PcCa) concentration of <2.0 mmol/L. Independent predictors of HBS were analyzed, and prediction equations for HBS were derived accordingly. Results The incidence of HBS was 71.4%. The serum corrected calcium and preoperative serum alkaline phosphatase (ALP) concentrations were independent predictors of HBS. The preoperative serum ALP, intact parathyroid hormone (iPTH), and hemoglobin concentrations were independent factors influencing the average descending velocity of the PcCa concentration before calcium supplementation (PcCa-V), intravenous calcium supplement holding time (IVCa-T), and intravenous calcium supplement dosage (IVCa), while the serum ALP and iPTH concentrations were independent predictors of the oral calcium supplement dosage (OCa). Four prediction equations for PcCa-V, IVCa-T, IVCa, and OCa were established. CONCLUSIONS: Establishment of prediction equations for HBS may contribute to a new individualized therapy for patients with HBS.

Vitamin D deficiency in mothers, neonates and children.

Vitamin D is produced in response to the exposure of skin to sunlight through UV-B synthesis. It can also be obtained from diet and dietary supplements. Vitamin D is essential for strong bones as it helps to absorb calcium from diet. Vitamin D deficiency mainly occurs if strict vegetarian diet is followed as mostly the source of vitamin D is animal based; therefore, exposure to sunlight is restricted or having dark skin color. Low vitamin D levels results in increased possibility of gestational diabetes among pregnant women, low birth weight and pre-eclampsia in infants, and mothers may suffer bone impairment, osteoporosis, hypocalcaemia, and hypertension. Vitamin D deficiency is directly linked with severe complication in mothers and neonates, causing rickets, poor fetal growth and infantile eczema in neonates. Higher prevalence rate of vitamin D deficiency has led professionals to emphasize on development of relevant precautionary measures.

Calcium homeostasis in diabetes mellitus.

Diabetes mellitus (DM) is becoming a lifestyle-related pandemic disease. Diabetic patients frequently develop electrolyte disorders, especially diabetic ketoacidosis or nonketotic hyperglycemic hyperosmolar syndrome. Such patients show characteristic potassium, magnesium, phosphate, and calcium depletion. In this review, we discuss a homeostatic mechanism that links calcium and DM. We also provide a synthesis of the evidence in favor or against this linking mechanism by presenting recent clinical indications, mainly from veterinary research. There are consistent results supporting the use of calcium and vitamin D supplementation to reduce the risk of DM. Clinical trials support a marginal reduction in circulating lipids, and some meta-analyses support an increase in insulin sensitivity, following vitamin D supplementation. This review provides an overview of the calcium and vitamin D disturbances occurring in DM and describes the underlying mechanisms. Such elucidation will help indicate potential pathophysiology-based precautionary and therapeutic approaches and contribute to lowering the incidence of DM.

Minimally symptomatic hypocalcaemia unmasking celiac disease.

INTRODUCTION: Celiac disease is an autoimmune disease of the small intestine which occurs in genetically predisposed people of all ages. A large clinical spectrum of manifestations accompanies the onset of the disease with diarrhoea, flatulence and weight loss being the most common. However, findings like osteoporosis, iron deficiency, anaemia and hypocalcaemia could also insinuate the existence of the disease. CASE PRESENTATION: We report the case of a 55-year-old man with numbness and tingling of the upper extremities due to hypocalcaemia that proved to be an uncommon case of celiac disease. CONCLUSION: A non-negligible number of adult patients with celiac disease can present with only minor and subclinical manifestations of the disease. As such, hypocalcaemia may be the sole manifestation of celiac disease. A high index of suspicion is needed for prompt diagnosis.

Denosumab-associated hypocalcaemia: incidence, severity and patient characteristics in a tertiary hospital setting.

PURPOSE: Denosumab-associated hypocalcaemia (DAH) has been reported in patients with osteoporosis or metastatic bone disease and is associated with stages 4 and 5 chronic kidney disease (CKD, estimated glomerular filtration rate <30 mL/min/1.73m2 ). Other risk factors for hypocalcaemia have not been fully elucidated. We aimed to investigate the incidence of hypocalcaemia amongst patients receiving denosumab and to identify clinical features associated with this adverse event. METHODS: Retrospective cohort study between June 2013 and June 2014 of patients administered denosumab (60/120 mg) at a tertiary hospital in Melbourne, Australia, to identify the incidence of an albumin-adjusted serum calcium concentration <2.10 mmol/L or ionized calcium <1.13 mmol/L within 6 months of treatment. Univariable and multivariable logistic regression analyses were performed to identify clinical features associated with DAH. RESULTS: One hundred and fifty-five patients were administered denosumab (100 osteoporosis, 55 bone metastases). Twenty-two patients (14% [95%CI 9.1-20.7]) developed hypocalcaemia: 55% were men, and 55% had osteoporosis. Eighty-six per cent had a 25-hydroxyvitamin D concentration >50 nmol/L, and 91% were on calcium/colecalciferol supplementation. Stages 4 and 5 CKD (adjusted odd ratio [aOR] 4.71, 95%CI 1.61-13.79, p = 0.005) and male sex (aOR 4.30, 95%CI 1.69-10.96, p = 0.002) were associated with DAH. No patients were documented as having hypocalcaemic symptoms. One patient received intravenous calcium gluconate treatment. CONCLUSIONS: The incidence of denosumab-associated hypocalcaemia was 14% (95%CI 9.1-20.7) within 6 months of treatment despite widespread use of appropriate calcium/colecalciferol supplementation. Stages 4 and 5 CKD and male sex were associated with subsequent hypocalcaemia. Copyright © 2016 John Wiley & Sons, Ltd.

Familial Hypomagnesemia with Secondary Hypocalcemia Mimicking Neurodegenerative Disorder.

BACKGROUND: Familial hypomagnesemia with secondary hypocalcemia is a genetic disorder of magnesium metabolism that presents with refractory seizures in infancy. CASE CHARACTERISTICS: We herein report an infant with familial hypomagnesemia who presented as medically-refractory seizures and had cerebral atrophy on neuroimaging. Interestingly he had lost previous two siblings because of lack of correct diagnosis. INTERVENTION: Child was given oral magnesium supplementation and the seizures got controlled. MESSAGE: Familial hypomagnesemia should be considered in any child with recurrent or refractory hypocalcemic seizures.

Risk factors for severe hypocalcemia after parathyroidectomy in prevalent dialysis patients with secondary hyperparathyroidism.

PURPOSE: Hypocalcemia is one of the common complications after parathyroidectomy (PTX). Severe hypocalcemia (SH) can lead to tetany, cardiac arrhythmia and even sudden death. However, predictors for the development of SH in patients with secondary hyperparathyroidism demonstrated in some small-scale studies with a limited sample size remain inconclusive. METHODS: A retrospective chart review of 420 consecutive dialysis patients who underwent PTX during a 12-year period was performed. We checked serum levels of calcium (Ca), phosphorus (P), alkaline phosphatase (ALP) and intact parathyroid hormone (iPTH) for three consecutive days postoperatively. SH was defined as the minimum values of serum calcium lower than 1.875 mmol/L (7.5 mg/dL) within 3 days after operation. RESULTS: The mean (±SD) age of our study population was 53 ± 12 years, and more than half (57 %) were female. SH occurred in 37 % of the patients after PTX. Using a multivariate stepwise logistic regression analysis, lower preoperative levels of Ca (odds ratio 0.69, 95 % CI 0.60-0.79, P < 0.001), higher preoperative levels of iPTH (odds ratio 1.04, 95 % CI 1.00-1.07, P = 0.048), P (odds ratio 2.43, 95 % CI 1.49-3.95, P < 0.001) and ALP (odds ratio 1.08, 95 % CI 1.05-1.11, P < 0.001) were found to be independent predictors of occurrence of SH following PTX. CONCLUSIONS: The readily obtainable preoperative laboratory parameters including Ca, iPTH, P, and ALP will allow identification of a subgroup of patients who are at greater risk for the development of SH following PTX.

Managing hypercalcaemia and hypocalcaemia in cancer patients.

PURPOSE OF REVIEW: Hypercalcaemia is commonly associated with cancer which is usually advanced and portends a poor prognosis. Hypocalcaemia is more often seen as a complication of therapy aimed at reducing skeletal morbidity rather than an effect of the cancer itself. We present an overview of calcium disorders in malignant disease. RECENT FINDINGS: A significant proportion of patients who have a cancer and become hypercalcaemic have an alternative cause for their hypercalcaemia.Evidence for the use of loop diuretics is lacking, and such agents should not be routinely used unless significant volume overload occurs during rehydration. Bisphosphonates are generally established as first-line therapy after volume expansion with saline. As knowledge of bone biology increases, there is interest in the use of the mAb denosumab, for the management refractory hypercalcaemia. Knowledge of the vitamin D status, and supplementation of vitamin D, may reduce the risk of hypocalcaemia when potent antiresorptive medications are being used. SUMMARY: Calcium disorders can be predicted in many tumour types and with antiresorptive therapy. A logical approach to prevention and management of these imbalances should be incorporated into cancer patient care.

Hypovitaminosis D and severe hypocalcaemia: the rebirth of an old disease.

Vitamin D deficiency, once thought to be eradicated, is becoming a frequent occurence in children, caused mainly by dietary insufficiency. The classical manifestation is rickets, but in infants severe hypocalcaemia may present as stridor, tetany, seizures or, rarely, heart disease. Here, we describe four infants who presented with complications of severe hypocalcaemia secondary to nutritional vitamin D deficiency. (1) Female, 4 months old, several spasms. (2) Male, 8 days old, generalised tonic-clonic seizure. (3) Male, 9 months old, tetany. (4) Male, 4 months old, cardiogenic shock. The cases highlight the importance of child vitamin D supplementation from birth and throughout childhood. We also note that the vitamin D state should be evaluated by the 25(OH)-D value and not the 1,25(OH)2-D.

Morbidity following thyroid surgery: does surgeon volume matter?

PURPOSE: The aim of our study was to analyze the relationship between surgeon volume and morbidity in patients operated on by surgeons with endocrine specialization (EndS group) and those operated on by general surgeons (GenS group) in a single tertiary institution. METHODS: We present the results of a prospective cohort study of all patients undergoing thyroid surgery in our institution between January 2008 and January 2010, all of whom attended for follow-up for at least 12 months. We assessed pre- and postoperative recurrent laryngeal nerve (RLN) function by laryngoscopy. We monitored serum calcium concentrations in all patients until these values were normal without vitamin D and oral calcium supplementation. RESULTS: We studied 225 patients: 30 in the GenS group (six surgeons performing <5 procedures per surgeon per year) and 195 in the EndS group (two surgeons performing >40 procedures per surgeon per year). The total number of exposed RLN was 46 and 325, respectively. The incidence of RLN palsy persisting beyond 12 months was higher in the GenS group (2/46 vs. 1/325 exposed RLNs, p = 0.04). The incidence of hypocalcaemia persisting beyond 12 months (bilateral procedures) was also higher in the GenS group (3/16 vs. 3/130 patients, p = 0.028). CONCLUSIONS: Morbidity in terms of permanent RLN palsy and hypocalcaemia was less frequent among patients operated on by endocrine-dedicated surgeons. Differences in surgical volume and specialized training in neck endocrine surgery may explain these variations in morbidity.

Hungry bone syndrome: still a challenge in the post-operative management of primary hyperparathyroidism: a systematic review of the literature.

Hungry bone syndrome (HBS) refers to the rapid, profound, and prolonged hypocalcaemia associated with hypophosphataemia and hypomagnesaemia, and is exacerbated by suppressed parathyroid hormone (PTH) levels, which follows parathyroidectomy in patients with severe primary hyperparathyroidism (PHPT) and preoperative high bone turnover. It is a relatively uncommon, but serious adverse effect of parathyroidectomy. We conducted a literature search of all available studies reporting a 'hungry bone syndrome' in patients who had a parathyroidectomy for PHPT, to identify patients at risk and address the pitfalls in their management. The severe hypocalcaemia is believed to be due to increased influx of calcium into bone, due to the sudden removal of the effect of high circulating levels of PTH on osteoclastic resorption, leading to a decrease in the activation frequency of new remodelling sites and to a decrease in remodelling space, although there is no good documentation for this. Various risk factors have been suggested for the development of HBS, including older age, weight/volume of the resected parathyroid glands, radiological evidence of bone disease and vitamin D deficiency. The syndrome is reported in 25-90% of patients with radiological evidence of hyperparathyroid bone disease vs only 0-6% of patients without skeletal involvement. There is insufficient data-based evidence on the best means to treat, minimise or prevent this severe complication of parathyroidectomy. Treatment is aimed at replenishing the severe calcium deficit by using high doses of calcium supplemented by high doses of active metabolites of vitamin D. Adequate correction of magnesium deficiency and normalisation of bone turnover are required for resolution of the hypocalcaemia which may last for a number of months after successful surgery. Preoperative treatment with bisphosphonates has been suggested to reduce post-operative hypocalcaemia, but there are to date no prospective studies addressing this issue.

Neuromuscular symptoms in a patient with familial pseudohypoparathyroidism type Ib diagnosed by methylation-specific multiplex ligation-dependent probe amplification.

Pseudohypoparathyroidism type Ib (PHP-Ib) is a rare genetic disorder characterized by hypocalcemia and hyperphosphatemia due to imprinting defects in the maternally derived GNAS allele. Patients with PHP-Ib are usually identified by tetany, convulsions, and/or muscle cramps, whereas a substantial fraction of patients remain asymptomatic and are identified by familial studies. Although previous studies on patients with primary hypoparathyroidism have indicated that hypocalcemia can be associated with various neuromuscular abnormalities, such clinical features have been rarely described in patients with PHP-Ib. Here, we report a 12-year-old male patient with familial PHP-Ib and unique neuromuscular symptoms. The patient presented with general fatigue, steppage gait, and myalgia. Physical examinations revealed muscular weakness and atrophies in the lower legs, a shortening of the bilateral Achilles' tendons and absence of deep tendon reflexes. Laboratory tests showed hypocalcemia, hyperphosphatemia, elevated serum intact PTH level, and impaired responses of urinary phosphate and cyclic AMP in an Ellsworth-Howard test, in addition to an elevated serum creatine kinase level. Clinical features of the patient were significantly improved after 1 month of treatment with alfacalcidol and calcium. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) and subsequent PCR analyses identified a methylation defect at exon A/B of GNAS and a microdeletion involving exons 4-6 of the GNAS neighboring gene STX16 in the patient and in his asymptomatic brother. The results suggest that various neuromuscular features probably associated with hypocalcemia can be the first symptoms of PHP-Ib, and that MS-MLPA serves as a powerful tool for screening of GNAS abnormalities in patients with atypical manifestations.

Jonathan E. Rhoads lecture 2012: improving patient care with practice-based research.

Practice-based research plays a pivotal role for improving patient care as its primary intent is to solve a clinical dilemma or problem encountered in clinical practice. Its results are immediately applicable to day-to-day clinical practice and essential to the growth of an evidence-based clinical practice. This review emphasizes the importance of this type of research. In addition, it serves to identify common sources for project conception and gives examples based on personal experiences of the author as a clinical practitioner, educator, and researcher. Common barriers to practice-based research are discussed as well as potential solutions offered for consideration.