Vijayalakshmi Bhatia

Corticosteroid physiology and principles of therapy

The adrenal cortex secretes glucocorticoids (GC), mineralocorticoids (MC) and androgens. GC maintain homeostasis, MC regulate fluid and electrolyte balance and adrenal androgens contribute to development of secondary sexual characteristics. Pharmacologic GC therapy is frequently indicated in the pediatric age group. Besides having many important side effects, prolonged high dose systemic GC therapy has a suppressive effect on endogenous steroid production. Therefore, GC therapy should be withdrawn gradually and stopped based on assessment of hypothalamo-pituitary-adrenal (HPA) axis recovery. Patients with HPA axis suppression require physiological replacement of GC along with enhancement of doses during periods of stress. Due to its immunosuppressive effects, issues about safety and efficacy of live virus vaccines in patients receiving systemic high dose GC therapy must be borne in mind.

Newborn screening for congenital hypothyroidism, galactosemia and biotinidase deficiency in Uttar Pradesh, India

ObjectiveTo assess feasibility and recall rates for newborn screening for congenital hypothyroidism, galactosemia and biotinidase deficiency in a predominantly rural and inner city population in and around the City of Lucknow in Uttar Pradesh, India.DesignProspective observational study.SettingTwo tertiary-care and 5 district hospitals in and around Lucknow.ParticipantsAll babies born in above hospitals during the study period.MethodsHeel prick samples were collected after 24 hours of life. Dried blood spot TSH, total galactose and biotinidase were assayed by immunofluorometry. Age related cut-offs were applied for recall for TSH. For galactosemia and biotinidase deficiency, manufacturer-suggested recall cut-offs used initially were modified after analysis of initial data.Main outcome measureRecall rate for hypothyroidism, galactosemia and biotinidase deficiency.ResultsScreening was carried out for 13426 newborns, 73% of all deliveries. Eighty-five percent of those recalled for confirmatory sampling responded. Using fixed TSH cut off of 20 mIU/L yielded high recall rate of 1.39%, which decreased to 0.84% with use of age-related cut-offs. Mean TSH was higher in males, and in low birth weight and vaginally delivered babies. Eleven babies had congenital hypothyroidism. Recall rates with modified cut-offs for galactosemia and biotinidase deficiency were 0.32% and 0.16%, respectively.ConclusionAn outreach program for newborn screening can be successfully carried out in similar socio-cultural settings in India. For hypothyroidism, the high recall rate due to early discharge was addressed by age-related cut-offs.

Vitamin D Deficiency in a Tropical Country — Treatment and Prevention in Children

Vitamin D has an important role to play in skeletal and extraskeletal health. Inspite of being a sun rich country, India has widespread vitamin D deficiency. Vitamin D deficiency can lead to serious consequences like hypocalcemic seizures and increased risk of respiratory tract infections in neonates and infants. International expert groups advocate universal supplementation for non-formula fed infants, pregnant and lactating women and those at risk of deficiency. A body of literature on vitamin D status in India is being generated, which may guide clinical practice in our country. Treatment of deficiency must be undertaken with minimally effective doses to avoid the risk of toxicity. Sensible sunshine exposure should be encouraged to facilitate vitamin D production from natural sources.

Sun exposure, UV irradiance and serum 25-hydroxycholecalciferol in pregnant women in rural north India

OBJECTIVE To document the effect of season and environmental pollution on UVB irradiance; and to estimate cutaneous vitamin D synthesis in village women in different seasons. DESIGN Radiant UVB energy was measured by a spectroradiometer in different seasons and, in April and May, on successive days in open areas at the city outskirts, at a crowded inner-city area and the villages of our participants. Clothing, outdoor activity pattern and serum 25-hydroxycholecalciferol (25(OH)D) levels were documented. SETTING Rural north India, latitude 26·8°N. SUBJECTS Pregnant women (n 139, aged 20-40 years). RESULTS UVB irradiance ranged from 56 µW/cm2 in January to 470 µW/cm2 in June. Proportion of skin exposed was 18·5 % in summer and 9·5 % in winter. Mean (sd) daily duration of sun exposure was 3·2 (0·2) h during winter and 2·1 (0·4) h during summer. Cutaneous vitamin D synthesis was estimated to be 19·25 µg (770 IU) during winter and 37·25 µg (1490 IU) during summer. Mean (sd) serum 25(OH)D was 28 (15) nmol/l during winter (92 % of participants with 50 nmol/l). Mean (sd) UVB irradiance at peak summer was significantly higher at the open areas and in the villages than at the inner-city location (340 (45) and 310 (60) v. 250 (50) µW/cm2, P=0·03). CONCLUSIONS In our population, at latitude 26·8°N, poor skin exposure is a limiting factor in all seasons. During winter, low UVB radiation energy also contributes. Particulate pollution limits UVB irradiance. Vitamin D supplementation during winter may be necessary.

Disorders of Mineral and Bone Metabolism

Bone is a metabolically active organ. It is the largest reservoir of calcium and phosphorus, which play important roles in intracellular signaling and secretion, neuromuscular excitability and muscular contractility and function. Bone is the site of action of parathyroid hormone, parathormone related peptide, calcitriol, and calcitonin, and the site of production of hormones such as fibroblast growth factor 23. These hormones and minerals, coupled with nutrition, exercise, and other hormones such as gonadal steroids and growth hormone, contribute to peak bone mass accrual. Several systemic conditions of childhood, such as renal failure, malabsorption, cancer, transplantation and cerebral palsy, to name a few, are associated with significant morbidity in bone health. The specific genetic etiology of several conditions of primary bone fragility and dysplasia have now been discovered, bringing the possibility of new forms of medical therapy.

Serum 25 hydroxyvitamin D profile after single large oral doses of cholecalciferol (vitamin D3) in medical staff in North India: A pilot study

BACKGROUND Vitamin D deficiency is widely prevalent in India and subjects who have almost no exposure to sunlight are severely deficient. Daily oral doses of cholecalciferol (vitamin D3) are costly as compared to stoss doses and further, take a long time for the serum levels to reach a plateau. Compliance to supplementation may also be better if a regimen involves single oral doses of vitamin D at specified intervals rather than daily doses. Evidence-based guidelines regarding the dosing and the frequency of dosing for prophylactic intermittent supplementation (stoss doses) in severely-deficient subjects are few. MATERIALS AND METHODS In a prospective intervention study, we serially assessed 30 asymptomatic healthy medical staff for serum 25-hydroxyvitamin D [25(OH)D] and parathyroid hormone (PTH); (a) at baseline; (b) monthly for 3 months after single oral 60,000 units (U) cholecalciferol; (c) monthly for 3 months after 120,000 (or 180,000 for those with elevated alkaline phosphatase) U cholecalciferol; and, (d) subsequently, at 3 months after a repeat dose of 60,000 U cholecalciferol by repeated measures analysis of variance. RESULTS The baseline serum 25(OH)D was 7.1 ± 5.4 ng/mL (< 10 ng/mL in 85% subjects) which increased to 18.7 ± 8.9 ng/mL at 1 month after 60,000 U of cholecalciferol (P < 0.001) and decreased to 11.1 ± 5.3 ng/mL by the 3 rd month. The higher dose of 120,000 (or 180,000) U increased mean 25(OH)D to 28.9 ± 9.9 ng/mL at the end of 1 st month, declining to 17.9 ± 4.9 ng/mL (P < 0.001) at 3 months. With the subsequent 60,000 U the serum 25(OH)D was 18.4 ± 3.9 ng/mL at 3 months. PTH showed a corresponding negative trend. No hypercalcemia was observed. CONCLUSIONS Vitamin D deficiency is highly prevalent amongst medical staff in Northern India. An initial dose of 120,000-180,000 U of cholecalciferol is required to elevate 25(OH)D out of the deficiency range. Maintenance dose is needed at 2 months.

Growth Charts Suitable for Indian Children – An Unending Saga?

What characteristics should a reference growth chart possess if it is to correctly classify the growth of children? Firstly, it should place 95 % of height readings of normal children between the 3rd and 97th centiles, i.e., 2 standard deviation (SD) above or below the mean. Secondly, children with physiological short stature e.g. familial short stature (FSS), would fall approximately between the 3rd and 1st centiles while children with pathological short stature would fall below the 1st centile (though it depends on how late the referral or evaluation for short stature had occurred). Thirdly, children classified as tall stature should lie above 95th or 97th centiles. Lastly, overweight children should have their body mass index (BMI) above the 85th centile and obese children above the 95th centile. Such a chart would enable pediatricians, family physicians and community health workers to judge which child requires detailed evaluation for height or weight related concerns, avoid unnecessary work up for those who don’t, and use the visual picture of where their child plots, to educate parents.

Cushing's syndrome.

Endogenous Cushing’s Syndrome (CS) is a relatively uncommon disease in children. The etiology is more often a primary adrenal cause in infants and younger children, and corticotroph adenoma in older ones. Diagnostic evaluation must be stepwise and methodical, aimed at first confirming the presence of the disease, and then looking for the etiology. The management should preferably the carried out at a centre which is experienced in the management of CS. Recent advances, including MRI, sensitive ACTH assays, inferior petrosal sinus sampling (IPSS) and transsphenoidal surgery (TSS) have dramatically improved the care of children with CS. However, the issue of high recurrence rates after TSS in children remains to be tackled. The prognosis of adrenal carcinoma still remains dismal.

Pediatric Endocrinology in India: Development, Progress, Problems and Challenges

The exponential growth of biological sciences and biotechnology has promoted the development of subspecialties / super specialties in medicine. In developing countries, socioeconomic factors influence and determine competing health priorities, often delaying the development of subspecialties in medicine. Tracing the history of development and progress of Endocrinology in general and Pediatric Endocrinology in particular, provides an overall perspective of the problems and challenges which lie ahead.

Pyruvate Carboxylase Deficiency Mimicking Diabetic Ketoacidosis

To the Editor: Pyruvate carboxylase (PC) deficiency is a rare autosomal recessive inborn error of metabolism (IEM) with a defect in pyruvate metabolism. It usually presents with hypoglycemia in infancy. We report an infant whose presentation mimicked diabetic ketoacidosis (DKA) but was later found to have pyruvate carboxylase deficiency with a novel homozygous mutation in the PC gene. A 7.5-mo-old baby presented with encephalopathy, polyuria, hyperglycemia, high anion gap metabolic acidosis, large ketonuria and hypokalemia.With an initial diagnosis of DKA, he was treated with intravenous fluids and insulin. Acidosis did not improve even after 28 h of insulin, despite normalization of blood glucose and blood ketone. A normal HbA1c (4.8%) and consanguineous parents suggested the presence of an IEM. He had high lactate (5.9 mmol/L) and normal ammonia levels (33 mg/dl). Gas chromatography–mass spectrometry (GC-MS) and tandem mass spectrometry (TMS) revealed high pyruvate levels and non-specific amino acid profile. Some amino acids in plasma including citrulline (2 umol/ L as against normal value of 19 to 52) were low. Urine biochemistry revealed mild proteinuria with acidification defect (pH > 6 with venous pH < 7.2). Clinical exome sequencing revealed a novel homozygous missense variant c.2668 G > T (V890F) in the PC gene. It was predicted to be pathogenic on bioinformatics prediction tools. The variant was confirmed by Sanger sequencing; the parents were heterozygous carriers (Fig. 1). During follow-up, he had regression of milestones, repeated admissions due to vomiting, diarrhea and infections and expired at the age of 1 y. The family was counseled regarding the risk of recurrence and prenatal diagnosis in subsequent pregnancies. Reports of organic acidemias mimicking DKA, such as methylmalonic acidemia, isovaleric acidemia, propionic acidemia, defects of cobalamin intracellular metabolism w i t h c omb i n e d me t hy lma l o n i c a c i d em i a a nd homocysteinemia as well as disorders of ketone utilization like βketothiolase deficiency and succinylcoenzyme A:3-ketoacidcoenzymeA transferase deficiency are found in literature [1, 2]. Most of them have abnormal organic acid profile and are often associated with hyperammonemia and hypoglycemia. Gluconeogenesis defect like fructose 1, 6-diphosphate dehydrogenase deficiency is also reported to mimic DKA [3]. PC deficiency has three types of presentation, based on severity [4]. Our child matched the type A phenotype, which presents in infancy with normal early development, moderate lactic acidosis, variable glycemia, renal tubular acidosis, failure to thrive and subsequently, delayed development [5]. They usually have a normal organic acid profile apart from high pyruvate, lactate and ketones. The prognosis is poor and most die during infancy. Thus to conclude, PC deficiency can mimic DKA; presence of consanguinity suggests the possibility of genetic metabolic disorders; GCMS/TMS may not provide confirmative metabolic profile in some disorders; Exome sequencing is a useful tool; the c.2668 G > T (V890F) is a novel pathogenic mutation which can cause PC deficiency. * Shubha R. Phadke shubharaophadke@gmail.com