Faculty Bibliography

BACKGROUND:Hyperosmolar diabetic ketoacidosis (H-DKA), a distinct clinical entity, is the overlap of diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS). AIM/OBJECTIVE:We describe the clinical presentation, metabolic aberrations, and associated morbidity/mortality of these cases with H-DKA. We highlight the problem areas of medical care which require particular attention when caring for pediatric diabetes patients presenting with H-DKA. METHODS:In our study we reviewed the literature back to 1963 and retrieved twenty-four cases meeting the criteria of H-DKA: glucose >600 mg/dL, pH < 7.3, bicarbonate <15 mEq/L, and serum osmolality >320 mOsm/kg, while adding three cases from our institution. RESULTS:Average age of presentation of H-DKA was 10.2 years ± 4.5 years in females and 13.3 years ± 4 years in males, HbA1c was 13%. Biochemical parameters were consistent with severe dehydration: serum osmolality = 394.8±55 mOsm/kg, BUN = 48±22 mg/dL, creatinine = 2.81±1.03 mg/dL. Acute kidney injury, present in 12 cases, was the most frequent end-organ complication. CONCLUSION/CONCLUSIONS:Multi-organ involvement with AKI, rhabdomyolysis, pancreatitis, neurological and cardiac issues such as arrhythmias, are common in H-DKA. Aggressive fluid management, insulin therapy and supportive care can prevent acute and long term adverse outcomes in children and adolescents.

Treatment to induce puberty in boys is indicated in those who do not undergo spontaneous development at a normal age. Stimulating development of the secondary sex characteristics is possible using gradually increasing doses of testosterone esters (TEs) via intramuscular (IM) administration, which is the most widely used method of testosterone (T) supplementation. When TEs are administered as monthly injection, serum T levels exhibit large fluctuations with supraphysiologic levels seen immediately after the injection followed by a decrease into the low range. Transdermal T (TT) has also been used for replacement therapy in adult males with hypogonadism and this provides steadier serum T levels. We report three adolescent boys with delayed puberty who were treated with TT gel for pubertal induction/continuation. This route was chosen as an alternative therapy due to their hepatic dysfunction, as is known that TT avoids the hepatic first-pass metabolism.

Background: Treatment for induction of puberty in boys is indicated in those who do not undergo spontaneous development. Stimulating development of the secondary sex characteristics are possible using gradually increasing doses of testosterone (T) derivatives. The most widely used T substitution is intramuscular(IM) injection of T esters. While free unesterified T has a half-life (<2hrs), T esters have a prolonged half-life (8 days). It is an effective, cheap treatment that results in adequate virilization. However, serum T exhibit large fluctuations with supraphysiologic levels immediately after the injection followed by a decrease into the low range. Also, inactivation of T occurs primarily in the liver, which can be a problem in cases with hepatic dysfunction. Transdermal testosterone (TT) gels are available to deliver T at a controlled rate into the systemic circulation (over 24 hrs) avoiding hepatic first pass, which can be beneficial in patients with hepatic dysfunction. However, the clinical experience of TT gel in adolescent boys is sparse. Objective: To report 3 adolescent boys with delayed puberty who were treated with TT gel for pubertal induction/continuation. This route was chosen as an alternative therapy due to hepatic dysfunction. Cases Report 1. A 16 yr old obese boy with delayed puberty due to testicular atrophy had elevated liver enzymes (2.5 X normal). He was started on TT (Fortesta gel 10 mg daily) for induction of puberty. Follow up at 3 and 6 months liver enzymes were trending down, while serum T levels were early pubertal (90ng/dl at 3 month, 65 ng/dl at 6 months). 2. A 14.25 yr old non obese boy with panhypopituitarism and delayed puberty was initiated on IM T (50mg) and was gradually increased. After 1 yrs of IM T, he was switched to TT gel for continuation of puberty because of rising liver enzymes. Follow up at 3 and 8 months liver enzymes were trending down, while serum T levels were mid pubertal (137ng/dl at 3 month, 118 ng/dl at 8 months). 3. A 14 yr old obese boy with panhypopituitarism and delayed puberty, was initiated IM T (50mg) and discontinued after the first dose. He was switched to TT gel (12.5mg/day) because of elevated liver enzymes. Follow up at 5 and 9 months liver enzymes were trending down, while serum T levels were mid pubertal (114 ng/dl at 5 month, 137 ng/dl at 9 months). Conclusion: Transdermal T gel has been widely used in adults, but the recommended dose is too high to be used to induce puberty in adolescents. However, the new preparations (TT gel), lower doses can be used for induction of puberty in adolescents. Transdermal T gel is a promising alternative agent for the treatment of pubertal induction/continuation, specifically in cases with hepatic dysfunction. We recommended that long term randomized controlled studies should be performed in this population

Background. Increased prevalence of type 2 diabetes mellitus (T2DM) makes it important for pediatricians to use effective screening tools for risk assessment of prediabetes/T2DM in children. Methods. Children (n = 149) who had an oral glucose tolerance test (OGTT) and glycated hemoglobin (HbA1c) were studied. American Diabetes Association recommended screening criteria-HbA1c >/=5.7% and fasting plasma glucose (FPG) >/=100 mg/dL-were compared against OGTT. The homeostatic model assessment of insulin resistance (HOMA-IR), a mathematical index derived from fasting insulin and glucose, was compared with OGTT. We studied whether combining screening tests (HbA1c and fasting glucose or HbA1c and HOMA-IR) improved accuracy of prediction of the OGTT. Results. HbA1c of >/=5.7% had a sensitivity of 75% and specificity of 57% when compared with the OGTT. Combining screening tests (HbA1c >/=5.7% and FPG >/=100 mg/dL; HbA1c >/=5.7% and HOMA-IR >/=3.4) resulted in improved sensitivity (95.5% for each), with the HbA1c-FPG doing better than the HbA1c-HOMA-IR combination in terms of ability to rule out prediabetes (likelihood ratio [LR]) negative. 0.07 vs 0.14). Conclusions. HbA1c of >/=5.7% provided fair discrimination of glucose tolerance compared with the OGTT. The combination of HbA1c and FPG is a useful method for identifying children who require an OGTT.

Background: The childhood obesity epidemic had led to an exponential rise in the prevalence of pre diabetes and /or Type 2 diabetes. Vitamin D deficiency results in decreased insulin sensitivity (ability of insulin to promote peripheral glucose uptake) and fasting hyperglycemia has been correlated with Vitamin D deficiency in obese adolescents and children.1,2 Aims: To study insulin sensitivity and secretory indices derived from an oral glucose tolerance test (OGTT) in obese adolescents with vitamin D deficiency before and immediately after normalization of serum 25(OH) vitamin D levels. Methods: In a single blinded randomized placebo controlled study (cross over design with planned sample size= 20) obese adolescents with vitamin D deficiency; 25 (OH) vitamin D < 20 ng/dl (50 nmol/L) were recruited. Adolescents were assigned to receive 50,000 IU of ergocalciferol (group A) once weekly or placebo (group B) for 6 weeks. At week 7, subjects were reassigned to receive vitamin D if they were in group B or placebo if they were in Group A. Study subjects had an OGTT and screening labs (25 (OH) Vitamin D, PTH, CMP, calcium, phosphorous and urine calcium/ creatinine ratio) at baseline, week 7 and then again at week 12 on the completion of study. Indices derived from OGTT were: 1) Whole body sensitivity index (WBISI):10,000/(fasting glucose(mg/dL)x fasting insulin(uIU/mL)x(mean glucose (mg/dL) x mean insulin (uIU/mL) 2) Insulinogenic index: 30 min insulin- fasting insulin (uIU/mL) / 30 min glucose- fasting glucose (mg/dL) Results: To date four subjects have completed the study: Hispanic females (mean +/- SD) age 16.1+/- 1years, BMI 34.5+/- 4.5. Baseline labs were: HbA1c 5.3+/- 0.2, fasting glucose 81+/- 5.1, and fasting insulin 16.5+/- 5.3uIU/ml. PTH 48.5+/- 13.8 ng/dl (15- 75), calcium 9.1+/- 0.1 mg/dl (8.3- 10.3), phosphorous 4.3+/- 0.2mg/dl ( 2.7- 4.5), alkaline phosphatase 95+/- 19 mg/dl (39- 390) and urine calcium/creatinine were normal at baseline and on completion as we monitored for hypercalcemia. Mean 25 (OH) Vit D was 19.4+/- 1.4 ng/dl before treatment. In 3 of 4 subjects vit D did not normalize to >30 ng/dl (23+/- 6.7 mg/dl) on completion of the study, while it did in one patient (30.2 ng/dl). The mean insulin during OGTT (total of six levels during OGTT) decreased by 57% from 88+/- 36 to 51+/- 10 IU/L from start to completion of the study, while mean glucose values and HbA1c remained unchanged. WBISI improved significantly from 2.2+/- 0.3 to 4.3+/- 0.6, a 51% increase in this sensitivity index. Conclusions: These results, though preliminary, suggest that even marginal increases in the Vitamin D levels in deficient insulin resistant obese adolescents appears to improve their hyperinsulinemia. More intriguing is that insulin sensitivity index WBISI improved after 6 weeks of vitamin D treatment, which if confirmed at study completion could have important therapeutic implications for insulin resistance

Abstract Background: Acute lymphoblastic leukemia (ALL) maintenance therapy (MT) has been occasionally associated with symptomatic hypoglycemia (SH), attributed to purine analog (mercaptopurine [6-MP]). This hypoglycemia has been hypothesized to affect substrate utilization of gluconeogenic precursor alanine in the liver. Case Report: An overweight 5-year-old boy with ALL was evaluated for SH (lethargy and vomiting) that occurred 8-10 h after fasting while receiving daily 6-MP. Hypoglycemic episodes (>20 episodes per month) occurred predominantly around midmorning but not during the 5-day dexamethasone pulse. The adrenocorticotropic hormone test yielded a normal cortisol response, which ruled out pituitary adrenal suppression. A 12-h overnight fasting glucose was 49 mg/dL, with suppressed insulin response <2 IU/mL, low C-peptide of 0.5 ng/mL, high insulin-like growth factor-binding protein >160 ng/mL, high free fatty acid of 2.64 mmol/L, and negative glucagon stimulation test (change in blood glucose [BG] <5 mg/dL). These results ruled out hyperinsulinism. The patient was placed on cornstarch therapy 5 h prior to dosing with 6-MP. This treatment reduced the SH events to fewer than two episodes per month. To study the efficacy of cornstarch, the patient was fitted with the iPro professional continuous glucose monitoring system (CGMS) (Medtronic MiniMed, Northridge, CA) with a preset low alarm at 70 mg/dL, which was worn for a period of 5 days while the patient was on cornstarch. With 1,000 sensor reading the BG range was 65-158 mg/dL, and the percentage mean absolute difference between sensor and finger-stick BG readings (the parent monitored his BG four times a day) was 9.4%. There were no hypoglycemic episodes detected by the CGMS while the patient was on cornstarch. After the cessation of chemotherapy, a 15-h fasting study was performed, and the CGMS was placed. Results showed resolution of hypoglycemia. Conclusions: The CGMS helped us devise an effective management plan for our patient. CGMS proved useful as an adjunct to characterize the pattern of hypoglycemia and to validate the benefit of cornstarch in hypoglycemia associated with 6-MP treatment of ALL.

Abstract Mutation of the Wilms tumor gene (WT1) is associated with two well-described syndromes called Denys-Drash (DDS) and Frasier (FS). Both are associated with nephropathy and ambiguous genitalia and have overlapping clinical and molecular features. The known risk of Wilms tumor in DDS and gonadoblastoma (GB) in FS patients requires tumor surveillance. The literature reports the occurrence of GB in DDS as lower than FS. This case highlights a very early presentation of bilateral GB in DDS and the consideration of early prophylactic gonadectomy at the time of diagnosis with DDS.

Background: ACTH-secreting macroadenomas account for 4-10% of Cushing's disease[1]; remission rates in patients with ACTH macroadenoma undergoing surgery are low(<65% in most series)[2]Case Report: A 16 year old female was evaluated for obesity(BMI > 97th percentile), hypertension, and oligomenorrhea. Cushing's syndrome was confirmed with elevated urinary cortisol level at 628.7mug/24 hr(42-218), elevated midnight serum cortisol (22mug/dl)[3], and no suppression of cortisol(21.8mug/dl) after 1-mg overnight dexamethasone suppression test. MRI brain showed an intra- and suprasellar mass consistent with a pituitary macroadenoma(1.3x1.6x1cm); MRI of the abdomen revealed no adrenal mass. Transphenoidal surgery(TSS) was performed. Histopathology confirmed tissue diffusely positive for ACTH immunostaining, consistent with an ACTH-secreting adenoma. MRI brain post-op showed no evidence of residual pituitary tumor. Prednisone was administered for 5 days post-op due to hypotension presumed resulting from cortisol withdrawal. Cortisol level on post-op day 5 was 2.2mug/dl. Morning cortisol levels ranged between 8.3-15.2 mug/dl(6-21), and 24-hr urinary free cortisol levels(UFC) ranged between 3.8-4.8 mug/24hr(3-55). Despite gradually increasing 24-hr UFC, sequential MRI brain revealed no evidence of tumor. Twelve months after surgery, relapsed CD was confirmed with elevated UFC 65 mug/24hr. Fifteen months after surgery, UFC was elevated at 239 mug/24hr. MRI revealed tumor in the pituitary floor with involvement of both lobes. Patient underwent a second TSS, however tumor was incompletely resected due to bilateral cavernous sinus invasion. Cortisol level at 8 PM on post-op day 4 was 25.6mug/dl. MRI brain confirmed residual tumor and stereotactic gamma knife radiosurgery was planned.Discussion: Current literature in CD suggests that serum cortisol levels below 2mug/dl on day 3-5 post TSS predict long term remission, while levels of 2-4.9mug/dl warrant follow-up but no immediate intervention.[4] Since our patient was on prednisone post TSS, the cortisol level of 2.2mug/dl on post-op day 5 cannot be definitively relied upon for its predictive value. In children with CD, low UFCs after TSS are not good predictors of sustained remission.[5] Since surgery is less often curative in CD patients with ACTH-secreting macroadenoma and since no single cortisol cut-off value excludes all patients with recurrence, close monitoring is warranted in all patients with pituitary ACTH macroadenoma