Vitamin D Serum Levels in Subjects Tested for SARS-CoV-2: What Are the Differences among Acute, Healed, and Negative COVID-19 Patients? A Multicenter Real-Practice Study.

Vitamin D might play a role in counteracting COVID-19, albeit strong evidence is still lacking in the literature. The present multicenter real-practice study aimed to evaluate the differences of 25(OH)D3 serum levels in adults tested for SARS-CoV-2 (acute COVID-19 patients, subjects healed from COVID-19, and non-infected ones) recruited over a 6-month period (March-September 2021). In a sample of 117 subjects, a statistically significant difference was found, with acute COVID-19 patients demonstrating the lowest levels of serum 25(OH)D3 (9.63 ± 8.70 ng/mL), significantly lower than values reported by no-COVID-19 patients (15.96 ± 5.99 ng/mL, p = 0.0091) and healed COVID-19 patients (11.52 ± 4.90 ng/mL, p > 0.05). Male gender across the three groups displayed unfluctuating 25(OH)D3 levels, hinting at an inability to ensure adequate levels of the active vitamin D3 form (1α,25(OH)2D3). As a secondary endpoint, we assessed the correlation between serum 25(OH)D3 levels and pro-inflammatory cytokine interleukin-6 (IL-6) in patients with extremely low serum 25(OH)D3 levels (<1 ng/mL) and in a subset supplemented with 1α,25(OH)2D3. Although patients with severe hypovitaminosis-D showed no significant increase in IL-6 levels, acute COVID-19 patients manifested high circulating IL-6 at admission (females = 127.64 ± 22.24 pg/mL, males = 139.28 ± 48.95 ng/mL) which dropped drastically after the administration of 1α,25(OH)2D3 (1.84 ± 0.77 pg/mL and 2.65 ± 0.92 ng/mL, respectively). Taken together, these findings suggest that an administration of 1α,25(OH)2D3 might be helpful for treating male patients with an acute COVID-19 infection. Further studies on rapid correction of vitamin D deficiency with fast acting metabolites are warranted in COVID-19 patients.

Vitamin D ameliorates adipose browning in chronic kidney disease cachexia.

Patients with chronic kidney disease (CKD) are often 25(OH)D3 and 1,25(OH)2D3 insufficient. We studied whether vitamin D repletion could correct aberrant adipose tissue and muscle metabolism in a mouse model of CKD-associated cachexia. Intraperitoneal administration of 25(OH)D3 and 1,25(OH)2D3 (75 µg/kg/day and 60 ng/kg/day respectively for 6 weeks) normalized serum concentrations of 25(OH)D3 and 1,25(OH)2D3 in CKD mice. Vitamin D repletion stimulated appetite, normalized weight gain, and improved fat and lean mass content in CKD mice. Vitamin D supplementation attenuated expression of key molecules involved in adipose tissue browning and ameliorated expression of thermogenic genes in adipose tissue and skeletal muscle in CKD mice. Furthermore, repletion of vitamin D improved skeletal muscle fiber size and in vivo muscle function, normalized muscle collagen content and attenuated muscle fat infiltration as well as pathogenetic molecular pathways related to muscle mass regulation in CKD mice. RNAseq analysis was performed on the gastrocnemius muscle. Ingenuity Pathway Analysis revealed that the top 12 differentially expressed genes in CKD were correlated with impaired muscle and neuron regeneration, enhanced muscle thermogenesis and fibrosis. Importantly, vitamin D repletion normalized the expression of those 12 genes in CKD mice. Vitamin D repletion may be an effective therapeutic strategy for adipose tissue browning and muscle wasting in CKD patients.

1,25(OH)2D3 deficiency increases TM40D tumor growth in bone and accelerates tumor-induced bone destruction in a breast cancer bone metastasis model.

Breast cancer is one of the most common malignancies and bone is the commonest site of distant metastases. Evidences indicate that adequate supply of vitamin D will decrease the morbidity and mortality of breast cancer. However, the main role of vitamin D deficiency in breast cancer bone metastases remains unclear. In this study, the relationship between vitamin D and breast cancer bone metastases were evaluated. Results showed that 1,25(OH)2D3 can not only inhibit the proliferation, migration and invasion of breast cancer cell TM40D in vitro, but also attenuate the breast cancer cell TM40D-induced bone destruction in vivo, whose underlying mechanism was at least partially through decreasing the number of the osteoclasts. To our knowledge, this is the first to use 1-alpha-hydroxylase [1α(OH)ase] knockout mice which characterized vitamin D deficiency to establish the breast cancer bone metastases model. Based on this model, we also found that vitamin D deficiency will accelerate the osteolytic lesions, and 1,25(OH)2D3 supplement will restrain osteolytic lesions. Therefore, these findings suggest that vitamin D has the potential capacity to be a therapeutic agent for the breast cancer bone metastases.

1,25 Dihydroxyvitamin D circulating levels, calcitriol administration, and incidence of acute rejection, CMV infection, and polyoma virus infection in renal transplant recipients.

Observation that 1,25-Dihydroxyvitamin-D3 has an immunomodulatory effect on innate and adaptive immunity raises the possible effect on clinical graft outcome. Aim of this study was to evaluate the correlation of biopsy-proven acute rejection, CMV infection, BKV infection, with 1,25-Dihydroxyvitamin-D3 deficiency and the benefit of calcitriol supplementation before and during the transplantation. Risk factors and kidney graft function were also evaluated. All RTRs received induction therapy with basiliximab, cyclosporine, mycophenolic acid, and steroids. During the first year, the incidence of BPAR (4% vs 11%, P=.04), CMV infection (3% vs 9%, P=.04), and BKV infection (6% vs 19%, P=.04) was significantly lower in users compared to controls. By multivariate Cox regression analysis, 1,25-Dihydroxyvitamin-D3 deficiency and no calcitriol exposure were independent risk factors for BPAR (HR=4.30, P<.005 and HR=3.25, P<.05), for CMV infection (HR=2.33, P<.05 and HR=2.31, P=.001), and for BKV infection (HR=2.41, P<.05 and HR=2.45, P=.001). After one year, users had a better renal function: eGFR was 62.5±6.7 mL/min vs 51.4±7.6 mL/min (P<.05). Only one user developed polyomavirus-associated nephropathy vs 15 controls. Two users lost their graft vs 11 controls. 1,25(OH)2-D3 deficiency circulating levels increased the risk of BPAR, CMV infection, BKV infection after kidney transplantation. Administration of calcitriol is a way to obtain adequate 1,25(OH)2-D3 circulating levels.

1,25-Dihydroxyvitamin D3 Deficiency is Involved in the Pathogenesis of Diabetic Retinopathy in the Uygur Population of China.

1,25-Dihydroxyvitamin D3 [1,25(OH)2 D3 ] has recently been shown to have immunomodulatory property. This study aimed to investigate the expression and potential role of 1,25(OH)2 D3 in the pathogenesis of diabetic retinopathy (DR) in the Uygur population. Blood samples were obtained from 22 patients with proliferative DR (PDR), 29 patients with nonproliferative DR (NPDR), and 24 normal controls. ELISA was performed to estimate the serum levels of 1,25(OH)2 D3 . Peripheral blood mononuclear cells (PBMCs) were cultured with or without 1,25(OH)2 D3 in the presence of anti-CD3 and anti-CD28 antibodies to detect the secretion of cytokines and cell proliferation. The FACS cytometric bead array system was used to analyze cytokine levels in the serum and culture supernatants. The Cell Counting Kit was used to determine the rate of cell proliferation. In this study, we found that the patients with PDR showed a decreased serum level of 1,25(OH)2 D3 and increased production of IFN-γ, TNF-α, IL-6, and IL-17A, by anti-CD3 and anti-CD28 antibodies activated PBMCs. Furthermore, 1,25(OH)2 D3 significantly inhibited the proliferation of PBMCs, as well as the secretion of IFN-γ, TNF-α, IL-6, and IL-17A. Overall, our findings suggest a potential protective effect of 1,25(OH)2 D3 in DR, whereas supplementation with 1,25(OH)2 D3 might be an effective strategy for preventing the development of DR. © 2016 IUBMB Life, 68(6):445-451, 2016.

Prevalence of secondary hyperparathyroidism in patients with stage 3 and 4 chronic kidney disease seen in internal medicine.

OBJECTIVE: Despite the high prevalence of chronic kidney disease in the elderly population, few data are available on the frequency of secondary hyperparathyroidism in the Spanish population affected by this problem. We undertook a study on this issue in patients attending the internal medicine departments in our area. DESIGN AND METHODS: An observational, cross-sectional survey performed at internal medicine departments on 415 patients with stage 3 and 4 chronic kidney disease. Clinical history and risk factors were collected using a standardized protocol. Serum creatinine, phosphate, calcium, intact parathormone (PTH) and 25-hydroxy-cholecalciferol (25-OH-vitD) levels were measured in all patients. RESULTS: Among stage 3 patients, 62.9% had PTH levels ≥70pg/mL and 32.7% levels ≥110pg/mL. Median PTH level in stage 4 patients was 120pg/mL (p <0.001), and 77.9% of these patients had PTH ≥70pg/mL (p <0.001) and 54.1% ≥110pg/mL (p=0.015). Adequate 25-hydroxy-cholecalciferol levels were found in only 7.2% of stage 3 patients and 4.1% of stage 4 patients. Only 7.2% of stage 3 patients had hyperphosphatemia, as compared to 25.4% of stage 4 patients (p <0.001). CONCLUSIONS: Hyperparathyroidism is a common complication of stage 3 and 4 chronic kidney disease which is not associated to detectable changes in serum calcium and phosphate levels. It is therefore advisable to measure PTH levels in all patients with decreased glomerular filtration rate.

Cigarette smoke exposure is associated with vitamin D3 deficiencies in patients with chronic rhinosinusitis.

BACKGROUND: Cigarette smoke (CS) plays a role in the exacerbation of chronic rhinosinusitis (CRS); however, the mechanism for this is unknown. We hypothesize that CS impairs human sinonasal epithelial cell (HSNEC) conversion of 25(OH)D3 (25VD3) to 1,25-dihydroxyvitamin D3 (1,25VD3) and, furthermore, that supplementation with 1,25VD3 will reverse smoke-induced inflammatory responses by HSNECs. OBJECTIVE: We sought to determine the effect of CS on vitamin D3 (VD3) levels, conversion, and regulation of CS-induced inflammation in control subjects and patients with CRS. METHODS: Blood and sinus tissue explants were collected at the time of surgery from control subjects, patients with chronic rhinosinusitis without nasal polyps, and patients with chronic sinusitis with nasal polyps (CRSwNP). Expression of VD3 metabolizing enzymes were measured by using RT-PCR. Primary HSNECs were cultured from tissue explants. 25VD3 with and without cigarette smoke extract (CSE) was used to examine conversion of 25VD3 to 1,25VD3, as well as HSNEC production of proinflammatory cytokines. RESULTS: CS exposure was associated with reduced circulating and sinonasal 25VD3 levels in all groups compared with those seen in CS-naive, disease-matched counterparts. CS exposure decreased expression of CYP27B1 and was especially pronounced in patients with CRSwNP. CSE impairs control HSNEC conversion of 25VD3. HSNECs from patients with CRSwNP also demonstrate an intrinsic reduction in conversion of 25VD3 to 1,25VD3. Exogenous 1,25VD3 reduces CSE-induced cytokine production by HSNECs. CONCLUSIONS: Exposure to CS is associated with reduced 25VD3 levels and an impaired ability of HSNECs to convert 25VD3 to 1,25VD3. Addition of 1,25VD3 reduces the proinflammatory effects of CS on HSNECs. Impaired VD3 conversion by CS exposure represents a novel mechanism through which CS induces its proinflammatory effects.

Diagnóstico diferencial del raquitismo hipocalcémico. caso clínico / Differential diagnosis in hypocalcemic rickets: a clinical case

Introducción: La hipocalcemia es un hallazgo infrecuente en los pacientes atendidos en los servicios de urgencia pediátricos. El raquitismo se puede presentar como una hipocalcemia crónica la mayoría de las veces asintomática, sin embargo, algunos pacientes presentan tetanias hipocalcémica. Objetivo: Presentar el caso clínico de una niña con raquitismo hipocalcémico, cuyo diagnóstico fue tardío. Caso clínico: Prescolar de 2 años 5 meses con alteración en la marcha, mal incremento ponderal, espasmos musculares y signos de raquitismo activo. Los exámenes revelaron hipocalcemia severa, normofosfemia, fosfatasa alcalina y PTH elevada y niveles normales de 25 hidroxivitamina D. Se manejó con calcio y calcitriol, y se diagnosticó raquitismo vitamina D dependiente tipo I. Conclusión: Los síntomas y signos clásicos de raquitismo, así como la hipocalcemia, deben hacernos plantear hoy en día el diagnóstico de raquitismo. Un mejor conocimiento de esta patología permitirá evitar el retraso en el diagnóstico y un tratamiento más oportuno.

Introduction: Hypocalcemia is rare in patients attending pediatric emergency services. Rickets can present as a chronic hypocalcemia often asymptomatic, poor growth rate, psychomotor delay and bone abnormalities, but some patients may present tetanic seizures. Although its incidence has decreased, a resurgence of rickets has been described. Objective: To present a case of a child with hypocalcemic rickets, whose diagnosis was delayed. Case report: Preschool of 2,4 years old with gait disturbance, poor growth rate, muscle spams and signs of active rickets. Laboratory results showed hypocalcemia, normophosphemia, alkaline phosphatase, high PTH and normal 25-hydroxyvitamin D levels. She received treatment with calcium and calcitriol and had a good response; Vitamin D dependent rickets type I was diagnosed. Conclusion: Classics signs and symptoms of rickets, as hypocalcemic manifestations, should lead us today to diagnose rickets. Better knowledge of this disease will avoid retarded diagnosis and give a suitable treatment.

El sistema del factor de crecimiento fibroblástico 23/Klotho en el contexto del daño cardiovascular / Fibroblast growth factor 23/Klotho system in the context of cardiovascular damage

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1-α hydroxylation defect in postural orthostatic tachycardia syndrome: remission with calcitriol supplementation.

A 37-year-old woman presented with a history of reactive hypoglycaemia, non-classic adrenal hyperplasia (NCAH), osteopenia and fibromyalgia. After several months of palpitations, postural orthostatic tachycardia syndrome (POTS) was diagnosed by tilt table studies. Her heart rate (HR) reached 191 bpm at 60 degrees from horizontal. Investigation suggested increase in epinephrine and norepinephrine levels in response to tilt table. Her 25(OH) vitamin D level measured by immunoextraction radioimmunoassay was 35 pg/ ml (normal 9-54 pg/ml) while her 1,25(OH)(2) vitamin D3 level was 24 pg/ml (normal 30-67 pg/ml). Accordingly, she was started on calcitriol 0.25 mcg orally daily. At her next visit after 5 months, she reported remarkable improvement in her palpitations and had been working full time for the past 4 months. HR both seated and upright was 72 bpm. After 3 months, her 1,25(OH)(2) vitamin D3 level on calcitriol was 40 pg/ml. The authors suggest that 1-α hydroxylation defects should be sought and treated, if present, with calcitriol in patients with POTS.

Treatment of vitamin D deficiency: divergence between clinical practice and expert advice.

BACKGROUND: Current recommendations for the treatment of vitamin D deficiency vary from calciferol 800 IU per day to loading doses of vitamin D followed by maintenance therapy of up to 2000 IU per day. OBJECTIVE: To assess the preparations and doses of vitamin D used to load and maintain patients with serum 25-hydroxyvitamin D (25OHD) <25 nmol/l. METHODS: We examined all requests for serum 25OHD over a 12-month period, from September 2009 to 2010 in southwest Scotland. We wrote to all 33 general practices asking whether they usually started replacement therapy with a loading dose and/or recommended over-the-counter maintenance preparations. We accessed the Emergency Care Summary for all patients with serum 25OHD <25 nmol/l to determine whether they had been prescribed maintenance therapy. RESULTS: Serum 25OHD was requested in 1162 patients. Levels were <25 nmol/l in 282 (24%) patients, only 173 (61%) of whom were receiving vitamin D replacement therapy 3-15 months after diagnosis. Only four (1.4%) were prescribed a loading dose. One hundred and fifty-three (54%) were treated with cholecalciferol or ergocalciferol and 19 (7%) with alfacalcidol or calcitriol. The median dose of chole/ergocalciferol was 800 IU per day, usually in combination with 1200 mg calcium per day. CONCLUSIONS: We have shown a divergence between clinical practice and even the most conservative expert advice for vitamin D replacement therapy. Possible explanations are conflicting advice on treatment and difficulty obtaining suitable vitamin D preparations, particularly high dose vitamin D and vitamin D without calcium, in the UK.

Optimal vitamin D, calcitriol, and vitamin D analog replacement in chronic kidney disease: to D or not to D: that is the question.

PURPOSE OF REVIEW: Patients with chronic kidney disease (CKD) are often insufficient in 25(OH) vitamin D and are almost uniformly deficient in 1,25(OH)2 vitamin D, because of decreased renal hydroxylation resulting from hyperphosphatemia and elevated fibroblast growth factor-23 (FGF-23) levels. These same abnormalities lead to secondary hyperparathyroidism for which the administration of calcitriol or vitamin D analogs has been the mainstay of therapy for decades. This review summarizes new trials of vitamin D, calcitriol, and its analogs over the last 2 years. RECENT FINDINGS: In addition to the endocrine effects of the vitamin D axis on bone and mineral metabolism, studies have demonstrated there is also extrarenal conversion of 25(OH) vitamin D to 1,25(OH)2 vitamin D in multiple cells leading to autocrine effects. This advance has led to the speculation that CKD patients may also need to be supplemented with ergocalciferol or cholecalciferol. Unfortunately, to date, the majority of interventional studies have focused on biochemical end points. There are no randomized controlled trials demonstrating that therapy with any formulation of vitamin D results in improved patient level outcomes. SUMMARY: Despite the physiologic importance of vitamin D in health and disease, more research is required to determine which vitamin D derivative is required for optimal health in CKD patients.

1,25-dihydroxyvitamin D deficiency predicts poorer outcome after renal transplantation.

OBJECTIVE: To assess 1,25-dihydroxyvitamin D status and the effect of vitamin concentration on transplantation outcome in renal allograft recipients. PATIENTS AND METHODS: Ninety patients underwent renal transplantation between 2002 and 2005. All received alfacalcidol supplementation before surgery. 1,25-Dihydroxyvitamin D concentration was determined on day 3 posttransplantation and at 1-, 6-, 12-, 18-, and 24-month follow-up. RESULTS: Severe 1,25-dihydroxyvitamin D deficiency was noted in 83% of patients immediately posttransplantation. From 1 to 12 months thereafter, concentrations increased almost 3-fold, and remained constant to 24 months. In 50% of patients, the 1,25-dihydroxyvitamin D concentration reached a concentration of more than 30 pg/mL, similar to that in healthy volunteers; in the other 50%, the concentration reached 17.2 pg/mL. A high incidence of delayed graft function was observed in patients with 1,25-dihydroxyvitamin D deficiency (44% vs 6%). There was a negative correlation between the initial 1,25-dihydroxyvitamin D and serum creatinine concentrations at day 3 and month 6 (P < .03). Similarly, the 1,25-dihydroxyvitamin D concentration at 1 month was negatively correlated with creatinine concentration at months 1 through 24 (P < .01). Poor outcome was observed primarily in patients with 1,25-dihydroxyvitamin D deficiency; 2 patients developed cancer, 5 grafts were lost, and 4 patients died of cardiovascular events. CONCLUSIONS: 1,25-Dihydroxyvitamin D deficiency is highly prevalent in renal allograft recipients. Patients with 1,25-dihydroxyvitamin D deficiency are at greater risk of delayed graft function, and the graft is more likely to be lost. These findings suggest the necessity of adequate vitamin D supplementation both before and after transplantation.

Anaemia and mineral bone disorder in chronic kidney disease: a review of the current literature and implications for clinical nursing practice.

Secondary hyperparathyroidism (SHPT) is one of the factors reported to have a negative impact on anaemia of chronic kidney disease (ACKD) and its treatment. SHPT is one of the abnormalities resulting from altered bone mineral metabolism. Five possible mechanisms have been proposed as to how SHPT impacts on anaemia in this paper. Each of these mechanisms will be considered and the treatment options reviewed including the implications for erythropoietic stimulating agents (ESA) prescribing. Anaemia and SHPT are both strongly predictive of complications and death from cardiovascular events in patients with chronic kidney disease (CKD). Nursing care of this group of patients should, therefore, be holistic in order to ensure optimum management. Ways in which we can practice to enhance quality of life and outcomes in this patient population will be discussed.

Effect of 1,25(OH)2-vitamin D on bone mass in children with acute lymphoblastic leukemia.

BACKGROUND: Calcitriol deficit has been described in patients with acute lymphoblast leukemia (ALL). The aim of this randomized case-control trial is to investigate the effectiveness of calcitriol administration during the first year of treatment to protect bone mass. Sixteen children recently diagnosed with ALL, aged 1.7 to 11.5 years, average 5.5, completed the study. Anthropometrical measurements, food intake record, physical activity, and bone pain were registered. Dual energy x-ray absorptiometry was performed at the completion of remission induction chemotherapy (after 1 mo) to measure bone mineral density (BMD) at hip, lumbar spine and whole body, and total bone mineral content and 1 year after. Half of them were randomly assigned to receive calcitriol during 1 year. STATISTICAL: Kruskal-Wallis, Wilcoxon, Mann-Whitney, and Spearman. RESULTS: Both groups had similar anthropometric measurements and bone densitometric variables increments. Spine BMD significantly increased in calcitriol supplemented children with lower baseline BMD (r=-0.78 and P<0.05). CONCLUSIONS: One-year calcitriol administered to recently diagnosed ALL children did not show impact on bone mass. Greater increment in lumbar spine bone mass was observed in patients who received calcitriol and had lower baseline BMD.

Paricalcitol aggravates perivascular fibrosis in rats with renal insufficiency and low calcitriol.

Cardiovascular complications are a major problem in chronic renal failure. We examined the effects of plasma calcium, phosphate, parathyroid hormone (PTH), and calcitriol on cardiac morphology in 5/6 nephrectomized rats. Fifteen weeks after nephrectomy rats were given a control diet, high-calcium or -phosphorus diet, or given paricalcitol treatment for 12 weeks. Sham-operated rats were on a control diet. Blood pressure, plasma phosphate, and PTH were increased, while the creatinine clearance was reduced in remnant kidney rats. Phosphate and PTH were further elevated by the high-phosphate diet but suppressed by the high-calcium diet, while paricalcitol reduced PTH without influencing phosphate or calcium. The high-calcium diet increased, while the high-phosphate diet reduced plasma calcium. Plasma calcitriol was significantly reduced in other remnant kidney groups, but further decreased after paricalcitol. Cardiac perivascular fibrosis and connective tissue growth factor were significantly increased in the remnant kidney groups, and further increased in paricalcitol-treated rats. Hence, regardless of the calcium, phosphate, or PTH levels, cardiac perivascular fibrosis and connective tissue growth factor increase in rats with renal insufficiency in association with low calcitriol. Possible explanations are that aggravated perivascular fibrosis after paricalcitol in renal insufficiency may be due to further suppression of calcitriol, or to a direct effect of the vitamin D analog.

Dietary additions of lactose, casein and soy protein exerted only moderate effects on calcium homeostasis in calcitriol deficient piglets.

It has been reported from rats and mice that blood and bone calcium can be normalised in the absence of Vitamin D hormone or its receptor by dietary means. It was the aim of this study to test, whether a similar result can be obtained with pigs. Piglets with inherited calcitriol deficiency were fed with high calcium and Pi diets and supplemented with soy protein or casein and lactose or corn starch, which have been shown to normalise plasma and bone calcium in Vitamin D deficient rats and in mice. In the calcitriol deficient piglets none of the diets was capable to prevent the development of hypocalcemia. However, additions of lactose and soy protein improved somewhat plasma calcium (P < 0.001). Feeding of soy protein also had a significant positive effect on plasma phosphate concentration (P < 0.001). The study shows that in contrast to rats, calcitriol is essential for maintaining a normal plasma and bone calcium status. Responses of this type, when obtained with rats or mice can probably not directly be transferred to pigs and perhaps also not to humans.

Isolated adrenocorticotropic hormone deficiency presenting with hypercalcemia in a patient on long-term hemodialysis.

The authors report on a 44-year-old female hemodialysis (HD) patient who presented with hypercalcemia secondary to isolated adrenocorticotropic hormone (ACTH) deficiency. She had been suffering from nausea and abdominal pain caused by recurrent esophageal ulcer. Blood calcium (Ca) adjusted for serum albumin concentration was increased to 14.9 mg/dL (3.72 mmol/L) concurrently with fever and hypotension. Serum intact parathyroid hormone (PTH)-related peptide was not elevated, but serum intact PTH and 1,25-(OH)2 vitamin D3 were decreased to 31 pg/mL (ng/L) and 8.1 pg/mL (2.6 pmol/L), respectively. Endocrinologic examination found that plasma ACTH was reduced below 5.0 pg/mL (0.22 pmol/L). A single ACTH stimulation normally increased blood cortisol, whereas a single corticotropin-releasing hormone injection failed to increase plasma ACTH and cortisol. Pituitary magnetic resonance imaging disclosed no enlargement of pituitary gland. Circulating bone formation and absorption markers were not elevated. Blood Ca was normalized shortly after pamidronate disodium administration without glucocorticoid supplementation. This case suggested that secondary adrenal insufficiency caused by isolated ACTH deficiency could be an occult cause of severe hypercalcemia in HD subjects.