Efficacy and Safety of High-dose Cholecalciferol in Patients With Inflammatory Bowel Disease Receiving Infliximab.

OBJECTIVE: Vitamin D deficiency is prevalent in patients with inflammatory bowel disease (IBD). The goal of this study was to assess the efficacy and safety of high-dose, interval cholecalciferol administration in patients with IBD receiving infliximab. METHODS: This prospective, longitudinal, open-label study enrolled pediatric and young adult patients with IBD and vitamin D deficiency. Subjects received 50,000 IU every 4 to 5 weeks (n = 11) or 100,000 IU every 6 to 8 weeks (n = 32) of oral cholecalciferol for 1 year. Dosing was directly observed and administered in conjunction with infliximab infusions. The primary endpoint was vitamin D sufficiency, defined as a 25-hydroxy-vitamin D (25-OHD) level ≥30 ng/mL. RESULTS: Forty-three participants constituted the primary analysis population. 25-OHD levels reached steady-state after the third dose, and mean increases in 25-OHD levels were 8 vs. 4.5 ng/mL in the 100,000 IU vs. 50,000 IU treatment groups, respectively. Only 43.8% of patients receiving 100,000 IU and 18.2% of patients receiving 50,000 IU achieved sufficiency. There was no difference in the 25-OHD level responsiveness in patients with Crohn disease versus those with ulcerative colitis (P = 0.72). There was no correlation between 25-OHD levels and clinical disease activity in patients with Crohn disease (P = 0.85) or ulcerative colitis (P = 0.24). CONCLUSIONS: Supplementation with cholecalciferol was well-tolerated and direct observation is a promising paradigm for ensuring compliance with therapy. Patients with IBD, however, appear to require high doses of cholecalciferol, with less than half of patients (37% overall) achieving vitamin D sufficiency. Additional studies are necessary to determine the optimal treatment regimens.

Bone Health in Pediatric Patients with IBD: What Is New?

PURPOSE OF THE REVIEW: Patients with inflammatory bowel disease (IBD) have increased bone fragility, demonstrated by increased fracture risk, and often have low bone density and altered bone geometry, but the underlying pathophysiology remains poorly understood. RECENT FINDINGS: Children and adolescents with IBD appear to have decreased bone formation, at diagnosis, which frequently improves with treatment of their underlying IBD. There is a growing body of evidence regarding how the immune system interacts with bone metabolism. There are likely multi-factorial etiologies that contribute to suboptimal bone accrual and subsequent lack of peak bone mass attainment in growing patients with IBD. There appears to be differential effects dependent upon IBD sub-type and bone compartment. Pediatric patients with IBD require recognition of several risk factors that may adversely impact their bone accrual. Future studies are necessary to further delineate the effects of IBD on pediatric bone health.

Adolescents and Bone Health.

Adolescence is a critical time for the acquisition of peak bone mass. There are modifiable factors that may influence bone health in an adolescent. For those at risk for bone fragility, initial management includes optimization of calcium and vitamin D, weight-bearing exercise, and maintenance of a normal body weight. In certain scenarios, bisphosphonate treatment is indicated, as is reviewed. How hormonal contraceptives affect bone mineral density is unclear, but in patients with risk factors or known bone fragility, prescribers should consider their skeletal effects. Some conditions, including restrictive eating disorders and primary ovarian insufficiency, warrant long-term monitoring of bone health.

Combined effects of cholecystokinin-8 and gastric distension on food intake in humans.

In a previous study (Kissileff HR, Carretta JC, Geliebter A, Pi-Sunyer FX. Am J Physiol Regul Integr Comp Physiol 285: R992-R998, 2003), when subthreshold gastric distension (300 ml) and a low dose of cholecystokinin octapeptide (CCK-8) (112 ng/min for 21 min) were concurrently administered to human participants, intake of a test meal was significantly reduced. However, the supra-additive interaction of CCK-8 and gastric distension was not significant. The purpose of the present study was to determine whether a significant interaction would be obtained when CCK-8 and gastric distension were each increased by 50% above levels used in the previous study. Twelve normal-weight, healthy participants were tested four times each with either CCK-8 (168 ng/min for 30 min) or saline infusion crossed with gastric distension (450 ml) or no distension. The combination of CCK-8 and gastric distension reduced food intake by a mean of 405 ± 86 g (SE) in comparison with the saline nondistension condition (P < 0.001), which is a 51% reduction. Although there were some differences in the protocols, the combined effect was double that seen in the previous study. Although the interactive effect was larger [118 ± 109 g (SE)] than it was previously [73 ± 86 (SE)], it was not significant (P = 0.29). There were also reports of a short-lived sick feeling after CCK-8, with and without distension, that was not observed in the previous study. Thus the combination of CCK-8 at 1.5 times threshold and gastric distension at 450 ml (increased from 300 ml) resulted in a combined effect to reduce food intake, which was also 1.5 times its previous value, and thus appears linear.

Evaluation of CSF and plasma biomarkers of brain melanocortin activity in response to caloric restriction in humans.

The melanocortin neuronal system, which consists of hypothalamic proopiomelanocortin (POMC) and agouti-related protein (AgRP) neurons, is a leptin target that regulates energy balance and metabolism, but studies in humans are limited by a lack of reliable biomarkers to assess brain melanocortin activity. The objective of this study was to measure the POMC prohormone and its processed peptide, ß-endorphin (ß-EP), in cerebrospinal fluid (CSF) and AgRP in CSF and plasma after calorie restriction to validate their utility as biomarkers of brain melanocortin activity. CSF and plasma were obtained from 10 lean and obese subjects after fasting (40 h) and refeeding (24 h), and from 8 obese subjects before and after 6 wk of dieting (800 kcal/day) to assess changes in neuropeptide and hormone levels. After fasting, plasma leptin decreased to 35%, and AgRP increased to 153% of baseline. During refeeding, AgRP declined as leptin increased; CSF ß-EP increased, but POMC did not change. Relative changes in plasma and CSF leptin were blunted in obese subjects. After dieting, plasma and CSF leptin decreased to 46% and 70% of baseline, CSF POMC and ß-EP decreased, and plasma AgRP increased. At baseline, AgRP correlated negatively with insulin and homeostasis model assessment (HOMA-IR), and positively with the Matsuda index. Thus, following chronic calorie restriction, POMC and ß-EP declined in CSF, whereas acutely, only ß-EP changed. Plasma AgRP, however, increased after both acute and chronic calorie restriction. These results support the use of CSF POMC and plasma AgRP as biomarkers of hypothalamic melanocortin activity and provide evidence linking AgRP to insulin sensitivity.

Childhood acromegaly due to X-linked acrogigantism: long term follow-up.

PURPOSE: Acromegaly in infancy is extremely rare. We describe a 32 year old woman who presented at 6 months of age with isolated macrocephaly, followed by accelerated linear growth. At 21 months of age, her head circumference was 55 cm (+5.5 SD), height was 97.6 cm (+4.4 SD) and weight was 20.6 kg (+6.2 SD). She had markedly elevated levels of growth hormone (GH) (135 ng/ml), IGF-1 (1540 ng/ml) and prolactin (370 ng/ml). A pituitary macroadenoma was surgically resected. Immunohistochemical staining was positive for GH. Post-operatively, she developed ACTH and TSH deficiency and diabetes insipidus. METHODS: Long term clinical follow-up and genetic testing with chromosomal microarray analysis. RESULTS: Despite GH deficiency, she grew well until 7 ½ years old, with subsequent decline in growth velocity, and received GH therapy for 5 years. Puberty was initiated with estrogen therapy. As an adult, she has no stigmata of acromegaly, with a height of 164.5 cm and non-acromegalic features. IGF-1 has remained in the low normal range. Prolactin has been mildly elevated. Serial MRIs have shown no evidence of tumor recurrence. She receives replacement therapy with hydrocortisone, levothyroxine and DDAVP. Chromosomal microarray analysis revealed that she has X-linked acrogigantism (X-LAG) due to a de novo duplication of Xq26.3 (516 kb). She recently became pregnant following ovarian stimulation and chorionic villus sampling revealed that she is carrying a male with the same duplication. CONCLUSION: This report provides detailed long term clinical follow-up of a patient with X-LAG syndrome.

Severe Hypercalcemia due to Hypervitaminosis D in a Breastfed Infant.

Vitamin D is one of the most commonly recommended dietary supplements and is often the first medication ever prescribed in infancy. However, with the variety of concentrations available, including many over-the-counter formulations, dosing errors can easily occur. We present a case of a breastfed infant with a calcium level greater than 23 mg/dL (5.75 mmol/L), whose severe hypercalcemia was due to hypervitaminosis D from accidentally overdosed vitamin D supplementation. We consider the differential diagnosis for her presentation and review the interventions required for treatment of her hypercalcemia. Notably, we reinforce the importance of carefully reviewing dosing of vitamin D supplementation with families. We also discuss the management of hypercalcemia, including the role of fluids, diuretics, and glucocorticoids, as well as the long-term sequalae of severe hypercalcemia.

Vertebral Compression Fractures in Very Early Onset Inflammatory Bowel Disease.

To describe clinical characteristics and outcomes of 3 patients with very early onset inflammatory bowel disease (VEOIBD) and vertebral compression fractures. Methods: Patients with VEOIBD receiving care at a single tertiary center were prospectively enrolled in a longitudinal data repository. Retrospective chart review was performed to identify clinical characteristics and comorbidities. Those with clinically apparent vertebral compression fractures subsequently underwent an additional chart review focused on bone health. Results: Three out of 216 (1.4%) patients with VEOIBD had symptomatic vertebral compression fractures. Of the 3 patients with vertebral compression fractures, all had Crohn's disease, 2 had monogenic inflammatory bowel disease, and all reported back pain. One patient notably had a normal dual-energy X-ray absorptiometry, highlighting a potential limitation of dual-energy X-ray absorptiometry to identify increased skeletal fragility in this population. Risk factors for suboptimal bone health included chronic inflammation secondary to poorly controlled inflammatory bowel disease, substantial glucocorticoid exposure, chronic use of other medications associated with suboptimal bone health including proton pump inhibitors and granulocyte colony-stimulating factor, and solid organ transplant. Patients treated with bisphosphonates had improved clinical outcomes, with resolution of back pain and increased bone mineral density. Conclusions: Vertebral compression fracture should be considered in the differential diagnosis of patients with VEOIBD and back pain, especially in those with other risk factors for suboptimal bone health. Treatment of compression fractures with bisphosphonates resulted in resolution of back pain and improved bone density.

Primary Hyperparathyroidism From Ectopic Parathyroid Adenoma in a 12-Year-Old With Slipped Capital Femoral Epiphysis.

Primary hyperparathyroidism has been reported in pediatric patients presenting with slipped capital femoral epiphysis (SCFE), but never in patients with ectopic parathyroid adenoma. A 12-year-old boy with obesity and autism spectrum disorder presented with a limp and was found to have bilateral SCFE. Calcium was elevated to 12.3 mg/dL with parathyroid hormone (PTH) of 1191 pg/mL. Neck ultrasound revealed no parathyroid adenoma. He was discharged following bilateral surgical pinning with plans for outpatient workup. Repeat labs 5 days later demonstrated calcium had risen to 16.7 mg/dL. Technetium-99m sestamibi scintigraphy and a computed tomography scan revealed a 2.7 × 1.6 × 1.9 cm intrathymic mediastinal lesion. He underwent a thoracoscopic resection of the mass, and intraoperative PTH levels fell appropriately. Pathology revealed a parathyroid adenoma. Postoperatively, the patient developed hungry bone syndrome followed by normocalcemic secondary hyperparathyroidism which resolved with high-dose vitamin D supplementation. Primary hyperparathyroidism presenting as SCFE in a pediatric patient has been reported in 13 previous cases. This is the first reported case of bilateral SCFE arising from an ectopic parathyroid adenoma. Thoracoscopic resection is a relatively new approach in pediatrics. Primary hyperparathyroidism can be associated with SCFE, especially bilateral, and should be considered in patients with traditional risk factors for SCFE. Pediatric patients with primary hyperparathyroidism and negative neck imaging should be further evaluated for ectopic parathyroid adenomas with nuclear medicine or cross-sectional imaging that includes the head, neck, and mediastinum. Thoracoscopic resection can be considered in pediatric patients with mediastinal ectopic parathyroid adenoma.

Bone marrow adiposity in pediatric Crohn's disease.

Patients with Crohn's disease often have low bone mineral density and an increased risk of osteoporosis. Although decreased bone formation can be seen at diagnosis, the underlying pathophysiology of suboptimal bone accrual remains poorly understood. We sought to evaluate a novel mechanism affecting osteogenesis in patients with Crohn's disease. In this case series, we evaluated bone marrow composition at the distal femur and proximal tibia of the left knee measured via magnetic resonance (MR) spectroscopy and relaxometry in five adolescents with the diagnosis of Crohn's disease. The subjects were enrolled prospectively between 2011 and 2013 at Boston Children's Hospital. Additional clinical information, including DXA scans to evaluate bone mineral density and body composition, and Crohn's disease history, such as glucocorticoid use and disease duration, were assessed. Healthy adolescents have persistent hematopoietic marrow with only 40 to 50 % fat in the long bone metaphyses. The current participants with Crohn's disease had increased marrow adiposity, with a mean fat fraction of 67.8 %. There appeared to be a trend towards higher fat fraction with shorter disease duration, while participants with the longest disease duration had the lowest fat fraction. Participants also had decreased bone density, increased fat mass, and lower lean mass, as assessed by DXA and compared to pediatric reference data. Our MRI results demonstrate increased marrow adiposity in children with Crohn's disease, especially early in the course of the disease. DXA may better demonstrate longer-term effects on bone. Additional studies are needed to evaluate bone marrow composition in these patients and to elucidate further the inverse relationship between marrow adipocytes and osteogenesis, as well as the relationship between bone marrow adiposity and body composition.

Digenic Heterozygous Mutations in SLC34A3 and SLC34A1 Cause Dominant Hypophosphatemic Rickets with Hypercalciuria.

CONTEXT: Hypophosphatemia and metabolic bone disease are associated with hereditary hypophosphatemic rickets with hypercalciuria (HHRH) due to biallelic mutations of SLC34A3 encoding the NPT2C sodium-phosphate cotransporter and nephrolithiasis/osteoporosis, hypophosphatemic 1 (NPHLOP1) due to monoallelic mutations in SLC34A1 encoding the NPT2A sodium-phosphate cotransporter. OBJECTIVE: To identify a genetic cause of apparent dominant transmission of HHRH. DESIGN AND SETTING: Retrospective and prospective analysis of clinical and molecular characteristics of patients studied in 2 academic medical centers. METHODS: We recruited 4 affected and 3 unaffected members of a 4-generation family in which the proband presented with apparent HHRH. We performed clinical examinations, biochemical and radiological analyses, and molecular studies of genomic DNA. RESULTS: The proband and her affected sister and mother carried pathogenic heterozygous mutations in 2 related genes, SLC34A1 (exon 13, c.1535G>A; p.R512H) and SLC34A3 (exon 13, c.1561dupC; L521Pfs*72). The proband and her affected sister inherited both gene mutations from their mother, while their clinically less affected brother, father, and paternal grandmother carried only the SLC34A3 mutation. Renal phosphate-wasting exhibited both a gene dosage-effect and an age-dependent attenuation of severity. CONCLUSIONS: We describe a kindred with autosomal dominant hypophosphatemic rickets in which whole exome analysis identified digenic heterozygous mutations in SLC34A1 and SLC34A3. Subjects with both mutations were more severely affected than subjects carrying only one mutation. These findings highlight the challenges of assigning causality to plausible genetic variants in the next generation sequencing era.

Poor Glycemic Control Is Associated With Impaired Bone Accrual in the Year Following a Diagnosis of Type 1 Diabetes.

CONTEXT: Type 1 diabetes (T1D) is associated with an increased fracture risk across the life course. The effects on bone accrual early in the disease are unknown. OBJECTIVE: To characterize changes in bone density and structure over the year following diagnosis of T1D and to identify contributors to impaired bone accrual. DESIGN: Prospective cohort study. SETTING: Academic children's hospital. PARTICIPANTS: Thirty-six children, ages 7 to 17 years, enrolled at diagnosis of T1D. OUTCOMES: Whole body and regional dual-energy X-ray absorptiometry and tibia peripheral quantitative computed tomography obtained at baseline and 12 months. The primary outcome was bone accrual assessed by bone mineral content (BMC) and areal bone mineral density (aBMD) velocity z score. RESULTS: Participants had low total body less head (TBLH) BMC (z = -0.46 ± 0.76), femoral neck aBMD (z = -0.57 ± 0.99), and tibia cortical volumetric BMD (z = -0.44 ± 1.11) at diagnosis, compared with reference data, P < 0.05. TBLH BMC velocity in the year following diagnosis was lower in participants with poor (hemoglobin A1c ≥7.5%) vs good (hemoglobin A1c <7.5%) glycemic control at 12 months, z = -0.36 ± 0.84 vs 0.58 ± 0.71, P = 0.003. TBLH BMC velocity was correlated with gains in tibia cortical area (R = 0.71, P = 0.003) and periosteal circumference (R = 0.67, P = 0.007) z scores in participants with good, but not poor control. CONCLUSIONS: Our results suggest that the adverse effects of T1D on BMD develop early in the disease. Bone accrual following diagnosis was impaired in participants with poor glycemic control and appeared to be mediated by diminished bone formation on the periosteal surface.

Familial X-Linked Acrogigantism: Postnatal Outcomes and Tumor Pathology in a Prenatally Diagnosed Infant and His Mother.

CONTEXT: X-linked acrogigantism (X-LAG), a condition of infant-onset acrogigantism marked by elevated GH, IGF-1, and prolactin (PRL), is extremely rare. Thirty-three cases, including three kindreds, have been reported. These patients have pituitary adenomas that are thought to be mixed lactotrophs and somatotrophs. CASE DESCRIPTION: The patient's mother, diagnosed with acrogigantism at 21 months, underwent pituitary tumor excision at 24 months. For more than 30 years, stable PRL, GH, and IGF-1 concentrations and serial imaging studies indicated no tumor recurrence. During preconception planning, X-LAG was diagnosed: single-nucleotide polymorphism microarray showed chromosome Xq26.3 microduplication. After conception, single-nucleotide polymorphism microarray on a chorionic villus sample showed the same microduplication in the fetus, confirming familial X-LAG. The infant grew rapidly with rising PRL, GH, and IGF-1 concentrations and an enlarging suprasellar pituitary mass, despite treatment with bromocriptine. At 15 months, he underwent tumor resection. The pituitary adenoma resembled the mother's pituitary adenoma, with tumor cells arranged in trabeculae and glandular structures. In both cases, many tumor cells expressed PRL, GH, and pituitary-specific transcription factor-1. Furthermore, the tumor expressed other lineage-specific transcription factors, as well as SOX2 and octamer-binding transcription factor 4, demonstrating the multipotentiality of X-LAG tumors. Both showed an elevated Ki-67 proliferation index, 5.6% in the mother and 8.5% in the infant, the highest reported in X-LAG. CONCLUSIONS: This is a prenatally diagnosed case of X-LAG. Clinical follow-up and biochemical evaluation have provided insight into the natural history of this disease. Expression of stem cell markers and several cell lineage-specific transcription factors suggests that these tumors are multipotential.

Genetic Disorders of Parathyroid Development and Function.

Hypoparathyroidism is characterized by hypocalcemia and hyperphosphatemia and is due to insufficient levels of circulating parathyroid hormone. Hypoparathyroidism may be an isolated condition or a component of a complex syndrome. Although genetic disorders are not the most common cause of hypoparathyroidism, molecular analyses have identified a growing number of genes that when defective result in impaired formation of the parathyroid glands, disordered synthesis or secretion of parathyroid hormone, or postnatal destruction of the parathyroid glands.

Effects of Opioid Antagonism on Cerebrospinal Fluid Melanocortin Peptides and Cortisol Levels in Humans.

CONTEXT: Hypothalamic proopiomelanocortin (POMC) is processed to α-melanocyte-stimulating hormone, which interacts with the melanocortin antagonist agouti-related protein (AgRP), to regulate energy balance. The POMC-derived opioid peptide ß-endorphin (ß-EP) also affects feeding behavior via interactions with brain µ-opioid receptors (MORs), including autoinhibitory interactions with MOR expressed by POMC neurons. The opioid antagonist naltrexone (NTX) stimulates POMC neurons in rodents and decreases food intake. OBJECTIVE AND DESIGN: The effect of NTX on brain POMC in humans was assessed by measuring POMC peptide concentrations in lumbar cerebrospinal fluid (CSF). AgRP and cortisol levels were also measured because both are inhibited by opioids. In a double-blinded crossover study, 14 healthy subjects were given NTX (50 mg daily) or placebo for either 2 or 7 days. RESULTS: CSF ß-EP levels increased after 2 and 7 days of NTX treatment; CSF POMC levels did not change, but the ß-EP-to-POMC ratio increased. CSF AgRP levels did not change, but plasma AgRP levels tended to increase after NTX (P = 0.06). Cortisol increased in plasma and CSF after NTX treatment; these changes correlated positively with changes in AgRP levels. CONCLUSION: Opioid antagonism stimulates POMC peptide release into CSF in humans. The increase in the CSF ß-EP-to-POMC ratio could indicate selective release of processed peptides or an effect on POMC processing. Furthermore, AgRP and cortisol stimulation by NTX may mitigate POMC-induced decrease in food intake. It remains to be determined if biomarkers in CSF and plasma could be used to predict responses to pharmacotherapy targeting the melanocortin system.

Unexpected widespread hypophosphatemia and bone disease associated with elemental formula use in infants and children.

OBJECTIVE: Hypophosphatemia occurs with inadequate dietary intake, malabsorption, increased renal excretion, or shifts between intracellular and extracellular compartments. We noticed the common finding of amino-acid based elemental formula [EF] use in an unexpected number of cases of idiopathic hypophosphatemia occurring in infants and children evaluated for skeletal disease. We aimed to fully characterize the clinical profiles in these cases. METHODS: A retrospective chart review of children with unexplained hypophosphatemia was performed as cases accumulated from various centres in North America and Ireland. Data were analyzed to explore any relationships between feeding and biochemical or clinical features, effects of treatment, and to identify a potential mechanism. RESULTS: Fifty-one children were identified at 17 institutions with EF-associated hypophosphatemia. Most children had complex illnesses and had been solely fed Neocate® formula products for variable periods of time prior to presentation. Feeding methods varied. Hypophosphatemia was detected during evaluation of fractures or rickets. Increased alkaline phosphatase activity and appropriate renal conservation of phosphate were documented in nearly all cases. Skeletal radiographs demonstrated fractures, undermineralization, or rickets in 94% of the cases. Although the skeletal disease had often been attributed to underlying disease, most all improved with addition of supplemental phosphate or change to a different formula product. CONCLUSION: The observed biochemical profiles indicated a deficient dietary supply or severe malabsorption of phosphate, despite adequate formula composition. When transition to an alternate formula was possible, biochemical status improved shortly after introduction to the alternate formula, with eventual improvement of skeletal abnormalities. These observations strongly implicate that bioavailability of formula phosphorus may be impaired in certain clinical settings. The widespread nature of the findings lead us to strongly recommend careful monitoring of mineral metabolism in children fed EF. Transition to alternative formula use or implementation of phosphate supplementation should be performed cautiously with as severe hypocalcemia may develop.

Health and social adjustment of homeless older adults with a mental illness.

OBJECTIVE: To better inform treatment strategies, this study compared mental health, substance use, physical health, and social support among young, middle-aged, and older homeless adults before and after participation in intensive case management services. METHODS: Data were obtained from the Access to Community Care and Effective Services and Supports (ACCESS) public database. Young (age 18 to 34; N=2,469), middle-aged (age 35 to 54; N=4,358), and older (age 55 or older; N=408) homeless adults with a mental illness were compared on the basis of demographic characteristics and measures of substance use, mental and general medical health, and social support at baseline by using Kruskal-Wallis and chi square tests and at three-month and 12-month follow-ups by using mixed-model analysis. RESULTS: Older adults had fewer severe mental health and substance abuse problems than the two groups of younger adults at baseline. At 12-month follow-up, all age groups had improvements in housing, substance use, and psychiatric symptoms, but rates of psychiatric symptoms had improved the most among young adults, and their scores for psychiatric symptoms were the lowest on average of any group. Compared with older adults, adults in the younger groups showed greater decreases in substance use. CONCLUSIONS: Older homeless adults appeared to follow a different treatment trajectory than their younger counterparts, possibly because of lower severity of mental illness at baseline, and may need specific interventions to address their unique pathways to homelessness.