Intestinal Calcium Absorption Research Articles

Endoplasmic reticulum protein of 57 kDa sulfhydration promotes intestinal calcium absorption to attenuate primary osteoporosis

Endogenous hydrogen sulfide (H2S) plays an important role in bone metabolism. However, the exact role of H2S in intestinal calcium and phosphorus absorption and its potential in preventing and treating primary osteoporosis remains unknown. Therefore, this study aimed to investigate the potential of H2S in promoting intestinal calcium and phosphorus absorption and alleviating primary osteoporosis. We measured the apparent absorptivity of calcium, femoral bone density, expression and sulfhydration of the duodenal endoplasmic reticulum protein of 57 kDa (ERp57), duodenal cystathionine γ-lyase (CSE) expression, and serum H2S content in adult and old CSE-knockout and wild-type mice. We also assessed intracellular reactive oxygen species (ROS) and Ca2+ content in CSE-overexpressing or knockout intestinal epithelial cell (IEC)-6 cells. In senile mice, CSE knockout decreased endogenous H2S, ERp57 sulfhydration, and intestinal calcium absorption and worsened osteoporosis, which were partially reversed by GYY4137, an H2S donor. CSE overexpression in IEC-6 cells increased ERp57 sulfhydration, protein kinase A and C activity, and intracellular Ca2+, whereas CSE knockout exerted the opposite effects. Furthermore, hydrogen peroxide (H2O2) stimulation had similar effects as in CSE knockout, which were reversed by pretreatment with sodium hydrosulfide before H2O2 stimulation and restored by DL-dithiothreitol. These findings suggest that H2S attenuates primary osteoporosis by preventing ROS-induced ERp57 damage in intestinal epithelial cells by enhancing ERp57 activity and promoting intestinal calcium absorption, thereby aiding in developing therapeutic interventions to prevent osteoporosis.

THE EFFECT OF HIGH FLUORIDE INTAKE ON SODIUM, AND POTASSIUM AND CALCIUM LEVELS IN SHEEP BLOOD SERUM

This experiment was carried out to investigate levels of sodium, potassium and calcium in ovine blood serum for 12 weeks during which fluoride (100 ppm) was added to the ration. The rams remained physically in good condition and there were no lesions in the teeth, gums and joints. With the exception of an increase in sodium at the end of the first week, sodium and potassium levels were not influenced. This finding could point out to the possibility of failure of the added fluoride to induce significant changes in kidney and aldosterone functions regarding regulation of these two ions in blood. There was a general tendency of the total calcium level to decrease which reached statistical significance in samples of three weeks. Such decrease could be due to a decline in calcium intestinal absorption and an increase in bone deposition and excretion with urine.

A prospective study of vitamin D, proinflammatory cytokines, and risk of fragility fractures in women on aromatase inhibitors for breast cancer.

Vitamin D is critical to bone health by regulating intestinal absorption of calcium, whereas proinflammatory cytokines, including IL-1, IL-6, IL-12, and TNF-α, are known to increase bone resorption. We hypothesized that vitamin D and these cytokines at the time of breast cancer diagnosis were predictive for fragility fractures in women receiving aromatase inhibitors (AIs). In a prospective cohort of 1,709 breast cancer patients treated with AIs, we measured the levels of 25-hydroxyvitamin D (25OHD), IL-1β, IL-6, IL-12, and TNF-α from baseline blood samples. The associations of these biomarkers were analyzed with bone turnover markers (BALP and TRACP), bone regulatory markers (OPG and RANKL), bone mineral density (BMD) close to cancer diagnosis, and risk of fragility fractures during a median of 7.5 years of follow up. Compared to patients with vitamin D deficiency, patients with sufficient levels had higher bone turnover, lower BMD, and higher fracture risk; the latter became non-significant after controlling for covariates including BMD and no longer existed when patients taking vitamin D supplement or bisphosphonates or with history of fracture or osteoporosis were excluded. There was a non-significant trend of higher levels of IL-1β and TNF-α associated with higher risk of fracture (highest vs. lowest tertile, IL-1β: adjusted HR=1.37, 95% CI=0.94-1.99; TNF-α: adjusted HR=1.38, 95% CI=0.96-1.98). Our results do not support proinflammatory cytokines or vitamin D levels as predictors for risk of fragility fractures in women receiving AIs for breast cancer.

MAPK signaling pathway participates in the regulation of intestinal phosphorus and calcium absorption in broiler chickens via 1,25-dihydroxyvitamin D3

Four experiments were performed to investigate the role of the mitogen-activated protein kinase (MAPK) signaling pathway in intestinal absorption of phosphorus (P) and calcium (Ca) in broiler chickens. Experiment 1 assessed how dietary levels of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) influence the gene expression of intestinal P and Ca transporters in broilers. Experiment 2 evaluated the effects of 1,25(OH)2D3 administered via intraperitoneal injection on the extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (p38MAPK) signaling pathways. Experiments 3 and 4 investigated the effect of ERK and p38MAPK inhibitors on the expression of intestinal P and Ca transporters. The findings demonstrated that broilers (1-21 days old) fed a 1,25(OH)2D3-deficient diet (0.625 µg/kg) exhibited reduced body weight, tibia P and Ca levels, and mRNA levels of P transporters (NaPi-IIb, PiT-1, and PiT-2), Ca transporters (NCX1, PMCA1b, and CaBP-D28k), vitamin D receptors (VDR), ERK, and p38MAPK in the duodenum (Experiment 1) (P < 0.05). By comparison, the growth, bone quality, and mRNA levels of genes (except for duodenal NaPi-IIb) in broilers were similar to those in broilers fed the control diet when dietary 1,25(OH)2D3 was adequate (5 µg/kg) (Experiment 1) (P > 0.05). After intraperitoneal injection of 1,25(OH)2D3, the mRNA level of jejunal NaPi-IIb and the protein level of p-p38MAPK/t-p38MAPK in broilers (9-14 days old) decreased (P < 0.05), whereas the mRNA level of CaBP-D28k and the protein level of p-ERK/t-ERK increased (Experiment 2) (P < 0.05). The mRNA and protein expression of jejunal NaPi-IIb and the protein expression of CaBP-D28k in broilers (9-17 days old) treated with the ERK inhibitor PD98059 were greater than those in the control group (Experiment 3) (P < 0.05). Similarly, compared with control broilers, broilers (9-17 days old) treated with the p38MAPK inhibitor SB203580 showed elevated mRNA expression of jejunal NaPi-IIb and CaBP-D28k (Experiment 4) (P < 0.05). These results suggest that adequate supplementation with 1,25(OH)2D3 (5 µg/kg) can restore broiler growth and bone quality by upregulating the transcription of genes involved in intestinal P and Ca absorption. Additionally, the ERK and p38MAPK signaling pathways are implicated in the modulatory effect of 1,25(OH)2D3 on the absorption of P and Ca in broilers.

Physiology of Vitamin D-Focusing on Disease Prevention.

Vitamin D is a crucial micronutrient, critical to human health, and influences many physiological processes. Oral and skin-derived vitamin D is hydroxylated to form calcifediol (25(OH)D) in the liver, then to 1,25(OH)2D (calcitriol) in the kidney. Alongside the parathyroid hormone, calcitriol regulates neuro-musculoskeletal activities by tightly controlling blood-ionized calcium concentrations through intestinal calcium absorption, renal tubular reabsorption, and skeletal mineralization. Beyond its classical roles, evidence underscores the impact of vitamin D on the prevention and reduction of the severity of diverse conditions such as cardiovascular and metabolic diseases, autoimmune disorders, infection, and cancer. Peripheral target cells, like immune cells, obtain vitamin D and 25(OH)D through concentration-dependent diffusion from the circulation. Calcitriol is synthesized intracellularly in these cells from these precursors, which is crucial for their protective physiological actions. Its deficiency exacerbates inflammation, oxidative stress, and increased susceptibility to metabolic disorders and infections; deficiency also causes premature deaths. Thus, maintaining optimal serum levels above 40 ng/mL is vital for health and disease prevention. However, achieving it requires several times more than the government's recommended vitamin D doses. Despite extensive published research, recommended daily intake and therapeutic serum 25(OH)D concentrations have lagged and are outdated, preventing people from benefiting. Evidence suggests that maintaining the 25(OH)D concentrations above 40 ng/mL with a range of 40-80 ng/mL in the population is optimal for disease prevention and reducing morbidities and mortality without adverse effects. The recommendation for individuals is to maintain serum 25(OH)D concentrations above 50 ng/mL (125 nmol/L) for optimal clinical outcomes. Insights from metabolomics, transcriptomics, and epigenetics offer promise for better clinical outcomes from vitamin D sufficiency. Given its broader positive impact on human health with minimal cost and little adverse effects, proactively integrating vitamin D assessment and supplementation into clinical practice promises significant benefits, including reduced healthcare costs. This review synthesized recent novel findings related to the physiology of vitamin D that have significant implications for disease prevention.

#1834 Prevalence of nephrolithiasis in patients with idiopathic hypercalciuria after two decades of follow-up

Abstract Background and Aims Idiopathic hypercalciuria (IH) is the main metabolic abnormality that causes kidney stones. It is linked to high intestinal calcium absorption and osteopenia. However, not all patients diagnosed with IH develop kidney stones. In this study, we examined a cohort of patients diagnosed of IH during childhood to determine the prevalence of lithiasis in adulthood. Method Longitudinal study that evaluated the prevalence of lithiasis in 35 patients (12 female, 23 male) diagnosed of IH during childhood (mean age of 7.7 ± 3 years). The patients were followed until adulthood (mean age 28.2 ± 3.1 years) with a median follow-up of 18.2 years (IQR: 12.2-19.3). IH diagnosis was made by urinary calcium excretion higher than 4 mg/Kg/day in two consecutive samples. In both periods, clinical and demographic data were collected, including urinalysis and urinary ratios (calcium/creatinine, calcium/citrate, oxalate/creatinine, and citrate/creatinine) in an isolated sample of the first morning urine, as well as the performance of renovesical ultrasound. Results In pediatric age, 8 patients (26%) presented nephrolithiasis on ultrasound, and 14 (43.8%) in adulthood, 6 of them experiencing episodes of nephritic colic. During the study, we observed a decrease in urinary calcium excretion, as expressed by the calcium/creatinine ratio (adult age 0.16 ± 0.9 mg/dl vs. childhood 0.28 ± 0.1 mg/dl, p = 0.000), and an hypocitraturia increase (citrate/creatinine ratio in childhood 887 ± 349 mg/dl and in adulthood 357.7 ± 363 mg/dl, p = 0.000). A decreased citrate/creatinine ratio in adulthood was associated with nephrolithiasis (p &amp;lt; 0.007). Only 4 patients (50%) had nephrolithiasis at both ages. Conclusion These results suggest that hypercalciuria tends to correct spontaneously in adulthood, and although the prevalence of nephrolithiasis increased, it is more related to hypocitraturia.

Role of intestinal claudin-2 in calcium transport and kidney stone disease

Background: Kidney stone disease is characterized by intestinal hyperabsorption of calcium and hypercalciuria, leading to the formation of calcium crystals in the kidney. Claudin-2 is a tight junction protein that forms paracellular cation pores and mutations in its gene are associated with kidney stone disease. We have recently shown that mice deficient in Cldn2 are hypercalciuric due to both decreased renal reabsorption and increased intestinal absorption of calcium and develop medullary mineral deposits reminiscent of kidney stone formers. We, therefore, hypothesized that intestinal claudin-2 is important for calcium secretion, especially in the colon, and that loss of claudin-2 results in increased net intestinal calcium absorption, thereby contributing to kidney stone disease. Method: Villin-Cre (Vil1-Cre/1000Gum) mice were crossed to Cldn2 floxed mice to generate intestine-specific claudin-2 knockout mice. Successful knockout of claudin-2 was confirmed at the mRNA and protein level using qPCR, immunofluorescence staining, and western blot. Male and female littermates were characterized for hypercalciuria from age 3-10 weeks. Circulating levels of parathyroid hormone and 1,25-dihydroxyvitamin D (1,25(OH)2D) were measured by ELISA, and mRNA levels of seven paracellular and transcellular calcium transport genes in the ileum, cecum, distal colon, and nine in the kidney assessed by qPCR. Result: In females, Cldn2 expression was knocked out in the intestine but not in the kidney. However, in males, Cldn2 was knocked out in the intestine and also partially knocked out in the kidneys (where villin is also expressed). Knockout females had normal urine calcium, but knockout males had significantly higher urine calcium at weaning (3 weeks of age) compared to wildtype, which was normalized by 4 weeks of age. At 4 weeks, Cldn19 mRNA was downregulated in knockout mice of both sexes. Male knockout mice had a reduction in intestinal Cldn12, Cldn15, Slc8a1, and increased intestinal Cacnad1, increased renal Cyp27b1 expression, and increased circulating 1,25(OH)2D. Conclusion: Our results suggest that intestine-specific loss of claudin-2, which was only observed in villin-Cre, Cldn2 floxed females, does not cause hypercalciuria. Ongoing whole-body calcium balance and everted sac calcium permeability experiments will determine whether this is because intestinal calcium hyperabsorption is masked by compensatory mechanisms. NIH. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Complex clinical encounter series: osteoporosis presenting during pregnancy and lactation: wait and reassess.

Two months after her first pregnancy, a 35-yr-old exclusively breastfeeding woman bent to move her baby in the car seat and experienced sudden, severe pain from 5 spontaneous vertebral compression fractures. Genomic screen was negative but she had mild ankylosing spondylitis previously well controlled on etanercept. She was vegetarian with a high phytate intake. A lactation consultant had advised her to pump and discard milk between feeds, leading her to believe she produced twice as much milk as her baby ingested. She presented with a LS Z score of -3.6 and a TH Z score of -1.6. After 6 mo postweaning, she was treated with teriparatide (14 mo intermittently over 18 mo) and ultimately achieved a 50% increase in LS bone density and an 8% increase in TH bone density. Her fragility is explained by normal lactational bone loss amplified by excessive milk production and phytate-induced impairment of intestinal calcium absorption, ankylosing spondylitis, and the bend-and-lift maneuver. The marked increase in bone density resulted from the combined effects of spontaneous recovery and pharmacotherapy. Spontaneous recovery of bone mass and strength should occur during 12 mo after weaning in all women, including those who have fractured.

Structural characterization and calcium absorption-promoting effect of sucrose-calcium chelate in Caco-2 monolayer cells and mice.

Sucrose emerges as a chelating agent to form a stable sucrose-metal-ion chelate that can potentially improve metal-ion absorption. This study aimed to analyze the structure of sucrose-calcium chelate and its potential to promote calcium absorption in both Caco-2 monolayer cells and mice. The characterization results showed that calcium ions mainly chelated with hydroxyl groups in sucrose to produce sucrose-calcium chelate, altering the crystal structure of sucrose (forming polymer particles) and improving its thermal stability. Sucrose-calcium chelate dose dependently increased the amount of calcium uptake, retention, and transport in the Caco-2 monolayer cell model. Compared to CaCl2 , there was a significant improvement in the proportion of absorbed calcium utilized for transport but not retention (93.13±1.75% vs. 67.67±7.55%). Further treatment of calcium channel inhibitors demonstrated the active transport of sucrose-calcium chelate through Cav1.3. Cellular thermal shift assay and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) assays indicated that the ability of sucrose-calcium chelate to promote calcium transport was attributed to its superior ability to bind with PMCA1b, a calcium transporter located on the basement membrane, and stimulate its gene expression compared to CaCl2 . Pharmacokinetic analysis of mice confirmed the calcium absorption-promoting effect of sucrose-calcium chelate, as evident by the higher serum calcium level (44.12±1.90mg/L vs. 37.42±1.88mmol/L) and intestinal PMCA1b gene expression than CaCl2 . These findings offer a new understanding of how sucrose-calcium chelate enhances intestinal calcium absorption and could be used as an ingredient in functional foods to treat calcium deficiency. PRACTICAL APPLICATION: The development of high-quality calcium supplements is crucial for addressing the various adverse symptoms associated with calcium deficiency. This study aimed to prepare a sucrose-calcium chelate and analyze its structure, as well as its potential to enhance calcium absorption in Caco-2 monolayer cells and mice. The results demonstrated that the sucrose-calcium chelate effectively promoted calcium absorption. Notably, its ability to enhance calcium transport was linked to its strong binding with PMCA1b, a calcium transporter located on the basement membrane, and its capacity to stimulate PMCA1b gene expression. These findings contribute to a deeper understanding of how the sucrose-calcium chelate enhances intestinal calcium absorption and suggest its potential use as an ingredient in functional foods for treating calcium deficiency.

P-12 Postpartum vertebral compressive fractures in a young female with osteoporosis - A case report

Abstract Introduction Osteoporosis is а metabolic disorder characterized by low bone mass and deep changes in bone architecture that lead to an increased vertebral or hip fracture in elderly. Osteoporosis in young population is a very rare condition especially when is associated with compressive fractures. Pregnancy and postpartum-related osteoporosis is condition that occurs in the last trimester of pregnancy оr in the first months of lactation. It is self-limited condition that return to normal after 12-18 months. In rare cases leаds to spinal compressive fractures. Clinical Case We present a 33-year-old female with back pain that occurs after birth during the early lactation period. In consultation with an orthopedic surgeon, an X-ray was made on the thoracolumbar spinal column with a finding of vertebral compressive fractures. A DEXA scan (double energy-X rays of absorptiometry) is also made with the finding of vertebral osteoporosis and hip osteopenia. We calculate BMI and perform blood tests for vitamin D3, calcium, hormones and markers for bone metabolism. This was our patient's first birth, she was thin with height 157 cm, weight 42 kg and calculated BMI-17. Blood test showed very low concentration of vitamin D3- 16 ng/ml (20-44) with normal level of calcium- 1,20 mmol/l (1,10-1,40) and PTH-31,01 pg./ml (15-65). Thyroid, gonadal and adrenal axis was with normal function. We told the patient to stop the lactation and to take a supplementation of vitamin D3 2000 IE, Calcium 1000 mg and bisphosphonates (alendronate). After two years of treatment, we made a control DEXA scan. Our patient now has vertebral osteopenia, normal serum concentration of vitamin D (44 ng/ml) and her weight is 48 kg. She feels good, has no pain and no new fractures. Conclusion Pregnancy and lactation increase need for calcium and this condition is complemented by increased intestinal absorption of calcium and increased bone resorption of the mother's skeleton. Risk factors for low bone density are deficit of 1-25 OH vitamin D3, malnutrition, low body mass index, treatment with low dose of enoxaparin (LMWH), physical inactivity. Our patient has an increased risk of low bone density (she has a low body mass index, low serum concentration of 1–25 OH vitamin D3 and this was her first pregnancy). Normal serum level 1–25 OH vitamin D concentration is required to establish calcium metabolism and prevent low bone density, osteopenia or osteoporosis. Antiresorptive therapy with bisphosphonates lead to rapid improvement in bone density, prevent new fractures and relieves pain. Treatment of postpartum osteoporosis is debatable because this condition is reversible, so when we decide to treat or not to treat, we must consider present of fractures, pain and plan for future pregnancy.

Alteration in the gut microbiome is associated with changes in bone metabolism after laparoscopic sleeve gastrectomy.

Laparoscopic sleeve gastrectomy (LSG), the most common bariatric surgical procedure, leads to durable weight loss and improves obesity-related comorbidities. However, it induces abnormalities in bone metabolism. One unexplored potential contributor is the gut microbiome, which influences bone metabolism and is altered after surgery. We characterized the relationship between the gut microbiome and skeletal health in severe obesity and after LSG. In a prospective cohort study, 23 adults with severe obesity underwent skeletal health assessment and stool collection preoperatively and 6mo after LSG. Gut microbial diversity and composition were characterized using 16S rRNA gene sequencing, and fecal concentrations of short-chain fatty acids (SCFA) were measured with LC-MS/MS. Spearman's correlations and PERMANOVA analyses were applied to assess relationships between the gut microbiome and bone health measures including serum bone turnover markers (C-terminal telopeptide of type 1 collagen [CTx] and procollagen type 1N-terminal propeptide [P1NP]), areal BMD, intestinal calcium absorption, and calciotropic hormones. Six months after LSG, CTx and P1NP increased (by median 188% and 61%, P< .01) and femoral neck BMD decreased (mean -3.3%, P< .01). Concurrently, there was a decrease in relative abundance of the phylum Firmicutes. Although there were no change in overall microbial diversity or fecal SCFA concentrations after LSG, those with greater within-subject change in gut community microbial composition (β-diversity) postoperatively had greater increases in P1NP level (ρ= 0.48, P= .02) and greater bone loss at the femoral neck (ρ= -0.43, P= .04). In addition, within-participant shifts in microbial richness/evenness (α-diversity) were associated with changes in IGF-1 levels (ρ= 0.56, P< .01). The lower the postoperative fecal butyrate concentration, the lower the IGF-1 level (ρ= 0.43, P= .04). Meanwhile, the larger the decrease in butyrate concentration, the higher the postoperative CTx (ρ= -0.43, P= .04). These findings suggest that LSG-induced gut microbiome alteration may influence skeletal outcomes postoperatively, and microbial influences on butyrate formation and IGF-1 are possible mechanisms.

Vitamin D3 deficiency and coronavirus-related health problems

Introduction: In addition to boosting calcium absorption in the small intestine and preserving sufficient levels of calcium and phosphate in the serum to support proper bone mineralization, Vitamin D3 fortifies the immune system. Vitamin D3 deficiency can occur when regular intakes are gradually below recommended levels and when people get little sunshine exposure. Materials and Methods: The study was conducted using a case series study approach. A structured checklist was utilized on 107 individuals who had recovered from corona disease to identify the causes behind the unfavorable health effects they continue to experience. In addition, the patients underwent extensive laboratory blood testing in a specialized laboratory and received follow-up care for a period of 6 months. The results were analyzed using the Chi-square test and the Paired t-test using the SPSS software. Results: Despite the finding that 84.1% of the study group had Vitamin D3 levels below the normal range, their physical health conditions had considerably improved as a result of the treatment they received. Conclusion: The study found that patients with coronavirus infection had a high prevalence of Vitamin D3 deficiency. After 6 months, this percentage dropped considerably, raising the possibility that the coronavirus may have contributed to the drop in plasma Vitamin D3 levels. To find out how long-lasting COVID-19 symptoms are related to Vitamin D3 deficiency, more research is required. The following core competencies are addressed in this article: Medical knowledge, Patient care and procedural skills.

Pectin Modulates Calcium Absorption in Polarized Caco-2 Cells via a Pathway Distinct from Vitamin D Stimulation.

Pectin, a type of soluble fiber, promotes morphological changes in the small intestinal villi. Although its physiological significance is unknown, we hypothesized that changes in villus morphology enhance the efficiency of nutrient absorption in the small intestine and investigated the effect of pectin derived from persimmon on calcium absorption using polarized Caco-2 cells. In polarized Caco-2 cells, pectin altered the mRNA expression levels of substances involved in calcium absorption and the regulation of intracellular calcium concentration and significantly reduced calcium absorption. Although this was comparable to the results of absorption and permeability associated with the addition of active vitamin D, the simultaneous action of pectin and active vitamin D did not show any additive effects. Furthermore, as active vitamin D significantly increases the activity of intestinal alkaline phosphatase (ALP), which is known to be involved in the regulation of intestinal absorption of calcium and lipids, we also investigated the effect of pectin on intestinal ALP activity. As a result, it was found that, unlike the effect of active vitamin D, pectin significantly reduced intestinal ALP activity. These results suggest that pectin stimulates polarized Caco-2 cells through a mechanism distinct from the regulation of calcium absorption by vitamin D, modulating total calcium absorption from the elongated villi through morphological changes in the small intestine by suppressing it at the cellular level.

Influential Factors in Intestinal Absorption and Renal Reabsorption of Calcium

Calcium is one of the vital and essential elements in the body, serving as a primary constituent of bones and teeth. It plays a fundamental role in nerve signal transmission, muscle contractions, heart rate regulation, blood clotting, energy production, glandular secretion, and immune system maintenance. Calcium is abundantly found in dietary sources, with most of it residing in the teeth and bones within the body. Approximately 40% of daily dietary calcium is absorbed primarily at the beginning of the intestine and before gastric juice neutralization, while 60% of it is excreted through feces. Calcium absorption occurs in two forms, passive and active, through the intestines, and renal reabsorption takes place through the kidneys. Various factors such as intestinal environment, dietary components (including lactose, proteins, and amino acids),bile salts, parathyroid hormone, vitamin D, acidic pH, health status, age, and growth hormone influence intestinal calcium absorption positively. Conversely, fatty acids, phytic acid, aging, alkaline pH, iron, magnesium, calcitonin hormones, and glucocorticoids reduce calcium absorption. Parathyroid hormone, calcitonin hormone, vitamin D, and dietary regimen significantly contribute to the active reabsorption of calcium through renal tubules. Despite the considerable variations in the calcium content of dietary sources, a highly precise regulatory system controls vitamin D production, preventing fluctuations in plasma calcium ion concentrations. This regulation helps prevent hypocalcemia and hypercalcemia, which can lead to numerous irregularities in the body.

FRI595 Two Cases Of Severe Symptomatic Hypocalcemia Secondary To Vitamin D Deficiency Diagnosed Within The Same Week

Abstract Disclosure: F.I. Cooper: None. U. Jonsdottir: None. G. Guadalupe Rios: None. N. Vyas: None. S. Gurnurkar: None. Background: Vitamin D is a fat-soluble vitamin that plays a significant role in intestinal calcium absorption. Humans acquire vitamin D through sun exposure and diet, though few foods naturally contain vitamin D in the amount needed to prevent deficiency. Vitamin D deficiency can result in nutritional rickets, which may present with impaired growth, weakened bones, dental abnormalities, and fractures secondary to decreased calcium absorption. Hypocalcemia can lead to a wide variety of clinical manifestations from mild symptoms such as irritability, tremors, and muscle cramps to life threatening seizures and arrhythmias. Case: This case series describes two children presenting to our pediatric emergency department within the same week with severe hypocalcemia secondary to profound vitamin D deficiency. The first was a 2-year-old female with prior medical history of 29-week prematurity who presented with a first time generalized tonic clonic seizure. She had a limited diet that consisted mostly of non-fortified almond milk. As an infant, she was on breast milk but did not receive vitamin D supplementation. On presentation, she was noted to have exam findings and radiographic evidence of rickets. The second was a 13-year-old male with history of non-verbal autism presenting with one month of diarrhea, agitation, and progressive leg pain. The patient was described as a picky eater and spent minimal time outdoors. Both children were found to have severe hypocalcemia (6.6 mg/dL and 4.8 mg/dL, respectively) in the setting of vitamin D deficiency (vitamin D-25 6.8 ng/dL and 4.9 ng/dL, respectively). They were successfully treated acutely with intravenous calcium gluconate bolus (one dose of 495 mg and three 2,000 mg) and oral calcium, with normalization of ionized calcium levels and improvement of symptoms. They were treated long-term with oral calcium, calcitriol, and vitamin D supplementation. Conclusion: Vitamin D deficiency should be considered in severe symptomatic hypocalcemia in children. Vitamin D supplementation is necessary in all breast-fed babies and a large proportion of other children not meeting vitamin D requirements through diet and sun exposure. Presentation: Friday, June 16, 2023

SAT257 Efficacy Of Oral Cinacalcet In Non-PTH Non-Malignant Hypercalcemia From Excess 1,25 Dihydroxyvitamin D

Abstract Disclosure: S. Mohan: None. M.T. Sheehan: None. P.J. Tebben: None. R.A. Wermers: None. Introduction: Elevated 1,25-dihydroxyvitamin D (1,25(OH)2D) is a rare cause of non-parathyroid hormone (PTH) mediated hypercalcemia. An increase in the activating enzyme 1-alpha hydroxylase is seen in granulomatous diseases and lymphoma, while mutations in the CYP24A1 gene leads to reduced catabolism of 1,25(OH)2D. Cinacalcet has been shown to successfully treat 1,25(OH)2D-mediated hypercalcemia of malignancy. Extrapolating this, we report 3 patients with non-malignant 1,25(OH)2D-mediated hypercalcemia treated with cinacalcet. Case Series: The patients (2 male and 1 female) were 55-71 years old. At presentation to our clinic, all had hypercalcemia with serum calcium concentrations between 10.6-11.5 mg/dL (normal, 8.8-10.2 mg/dL). PTH ranged between 16-35 pg/ml (normal 15-65 pg/ml), PTH-related peptide was normal in all patients, 25-hydroxyvitamin D was 32-51 ng/ml, and 1,25(OH)2D was inappropriately normal between 31-77 pg/ml (normal 18-78 pg/mL) in the setting of hypercalcemia and chronic kidney disease in 2 patients with estimated glomerular filtration rates 35-42 ml/min. Other causes of hypercalcemia including sarcoidosis, tuberculosis and malignancy were ruled out. The female patient had hypercalciuria (288 mg/24 hours) without nephrolithiasis and both male patients had severe hypercalciuria (400-660 mg/24 hours) with recurrent nephrolithiasis. One male patient had biallelic variants in the CYP24A1 gene, while the other male patient was suspected to have similar mutations, but not identified on genetic testing. The female patient with a PTH of 35 pg/mL on our initial measurement had documented 1,25(OH)2D level of 82 pg/mL with PTH &amp;lt;20 pg/mL while previously hypercalcemic. Upon cinacalcet initiation all patients demonstrated normalization of calcium levels (8.6-9.5 mg/dl) with doses between 30-90 mg daily. The patient with CYP24A1 gene mutations experienced symptomatic hypocalcemia with calcium of 8.1 mg/dL requiring dose reduction and eventual discontinuation of cinacalcet due to limited clinical benefit. There were no consistent changes in 24-hour urine calcium or fractional excretion of calcium. Levels of 1,25(OH)2D increased and PTH decreased on cinacalcet while serum calcium levels were maintained within normal range, including 2 subjects with continued normocalcemia after 2 years of therapy. Conclusion: Cinacalcet may be a therapeutic option in non-malignant 1,25(OH)2D-mediated hypercalcemia. Further evaluation is needed to confirm efficacy, understand risks and benefits, and elucidate potential mechanisms of action. Mild decrease in PTH may lead to reduced skeletal calcium efflux while the maintenance of normocalcemia despite rising 1,25(OH)2D, which was also seen in our reported patients with malignant 1,25(OH)2D-mediated hypercalcemia, suggests cinacalcet may decrease intestinal calcium absorption. Presentation: Saturday, June 17, 2023

Breast Milk Epidermal Growth Factor Confers Paracellular Calcium Absorption in the Infant Small Intestine.

Breast Milk Epidermal Growth Factor Confers Paracellular Calcium Absorption in the Infant Small Intestine.

A review of the role of vitamin d in autoimmunity

Introduction: The main function of vitamin D is to increase the intestinal absorption of calcium, participating in the stimulation of active transport of this ion in enterocytes. Extra-renal hydroxylation of vitamin D also occurs, originating the vitamin that would act in an autocrine and paracrine manner, with functions of inhibiting cell proliferation, promoting cell differentiation, and immune regulation. Objective: It was to review the scientific literature on the role of vitamin D in autoimmunity. Methods: A search was carried out on scientific articles centered on the proposed theme: “Role of vitamin D in autoimmunity”. Several search engines that carried scientific information in the health area were used to carry out this study, such as Google Scholar and the Medical Publications database (PubMed), and Scientific Electronic Library Online (SCIELO). In collecting the information, the descriptors used to carry out this research were: vitamin D; vitamin D in preventing diseases; vitamin D and autoimmune diseases; vitamin D; autoimmune diseases. The inclusion criteria used in this study were publications of scientific articles available in full and with free electronic access, limited to a period between 2011 and 2022, and selected articles in Portuguese and English. Results and Conclusion: Based on this methodology, it was possible to analyze a population of 58 articles that were selected for the study and constituted the sample used in this review. Several studies point to the effects of vitamin D not related to calcium metabolism, such as antineoplastic activity (particularly concerning breast, colon, and prostate cancers, and lymphoproliferative diseases), antihypertensive and immunomodulatory. Vitamin D deficiency and its use for treatment have been described in various autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, lupus, inflammatory bowel disease, myasthenia gravis, scleroderma, alopecia areata, psoriasis, vitiligo, autoimmune hepatitis, type 1 diabetes mellitus, autoimmune thyroiditis, etc. The effects of vitamin D on the immune system are related to the tolerance of self-antigens, exerting an inhibitory effect on the Th1 and Th17 type lymphocyte pattern, and a promoting effect on the expression of the Th2 and Treg pattern through the action of vitamin D in all cells of the system through the vitamin D receptor. More studies are needed to establish safe and effective doses in the management of these properties of vitamin D.

Mathematical modeling of calcium homeostasis in female rats: An analysis of sex differences and maternal adaptations

Calcium plays a vital role in various biological processes, including muscle contractions, blood clotting, skeletal mineralization, and cell signaling. While extracellular calcium makes up less than 1% of total body calcium, it is tightly regulated since too high or too low extracellular calcium concentration can have dangerous effects on the body. Mathematical modeling is a well-suited approach to investigate the complex physiological processes involved in calcium regulation. While mathematical models have been developed to study calcium homeostasis in male rats, none have been used to investigate known sex differences in hormone levels nor the unique physiological states of pregnancy and lactation. Calcitriol, the active form of vitamin D, plays a key role in intestinal calcium absorption, renal calcium reabsorption, and bone remodeling. It has been shown that, when compared to age-matched male rats, females have significantly lower calcitriol levels. In this study we first seek to investigate the impact of this difference as well as other known sex differences on calcium homeostasis using mathematical modeling. Female bodies differ from male bodies in that during their lifetime they may undergo massive adaptations during pregnancy and lactation. Indeed, maternal adaptations impact calcium regulation in all mammals. In pregnant rodents, intestinal absorption of calcium is massively increased in the mother’s body to meet the needs of the developing fetus. In a lactating rodent, much of the calcium needs of milk are met by bone resorption, intestinal absorption, and renal calcium reabsorption. Given these observations, the goal of this project is to develop multi-scale whole-body models of calcium homeostasis that represents (1) how sex differences impact calcium homeostasis in female vs. male rats and (2) how a female body adapts to support the excess demands brought on by pregnancy and lactation. We used these models to quantify the impact of individual sex differences as well as maternal adaptations during pregnancy and lactation. Additionally, we conducted “what if” simulations to test whether sex differences in calcium regulation may enable females to better undergo maternal adaptations required in pregnancy and lactation than males.

Maternal Epidermal Growth Factor Promotes Neonatal Claudin-2 Dependent Increases in Small Intestinal Calcium Permeability.

A higher concentration of calcium in breast milk than blood favors paracellular calcium absorption enabling growth during postnatal development. We aimed to determine whether suckling animals have greater intestinal calcium permeability to maximize absorption and to identify the underlying molecular mechanism. We examined intestinal claudin expression at different ages in mice and in human intestinal epithelial (Caco-2) cells in response to hormones or human milk. We also measured intestinal calcium permeability in wildtype, Cldn2 and Cldn12 KO mice and Caco-2 cells in response to hormones or human milk. Bone mineralization in mice was assessed by μCT. Calcium permeability across the jejunum and ileum of mice were 2-fold greater at 2 wk than 2 mo postnatal age. At 2 wk, Cldn2 and Cldn12 expression were greater, but only Cldn2 KO mice had decreased calcium permeability compared to wildtype. This translated to decreased bone volume, cross-sectional thickness, and tissue mineral density of femurs. Weaning from breast milk led to a 50% decrease in Cldn2 expression in the jejunum and ileum. Epidermal growth factor (EGF) in breast milk specifically increased only CLDN2 expression and calcium permeability in Caco-2 cells. These data support intestinal permeability to calcium, conferred by claudin-2, being greater in suckling mice and being driven by EGF in breast milk. Loss of the CLDN2 pathway leads to suboptimal bone mineralization at 2 wk of life. Overall, EGF-mediated control of intestinal claudin-2 expression contributes to maximal intestinal calcium absorption in suckling animals.