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Melena Bellin, MD Division of Pediatric Endocrinology

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1 Melena Bellin, MD Division of Pediatric Endocrinology

2 Content Pituitary/ Hypothalamic Tract Thyroid Adrenal
Ovary/ Testes and Puberty Growth and Growth Hormone Water and sodium balance Parathyroid, calcium, and bone Diabetes/ Pancreas

3 Hypothalamus and Pituitary

4 Hormones of the Pituitary Gland
Anterior Pituitary Growth Hormone (GH) Gonadotropins (FSH, LH) Adrenocorticotrophin (ACTH) Thyroid Stimulating Hormone (TSH) Prolactin Posterior Pituitary Antidiuretic Hormone (ADH) Oxytocin

5 THYROID DISEASE

6 Thyroid Axis T4/ Free T4 T3 TSH TRH 1o Hypothyroidism: Low FT4
High TSH

7 Hypothyroidism Congenital Hypothyroidism Acquired Hypothyroidism
Newborns or infants Usually diagnosed on newborn screen Congenital abnormality of the gland Acquired Hypothyroidism Children, adolescents, or adults F>M Autoimmune Central Hypothyroidism Much more rare Congenital or acquired hypothalamic or pituitary defect

8 Congenital Hypothyroidism
Most often ectopic or absent gland Rarely– dyshormongenesis, maternal thyroid disease Newborn asymptomatic If untreated- poor growth, cognitive impairment Newborn screen in MN– TSH Treat with synthroid

9 Untreated Congenital Hypothyroidism
Jaundice Poor feeding Hypotonia Macroglossia (large tongue) Large fontanelles, delayed closure Course facial features Mental retardation Short stature

10 Acquired Hypothyroidism
In children and young adults, usually autoimmune HASHIMOTO’S DISEASE Presentation: Varies, asymptomatic, goiter, fatigue, poor growth, constipation, eczema

11 Acquired Hypothyroidism
Diagnostic Tests: TSH ↑ Free T4 ↓ Antibodies: thyroglobulin, thyroid peroxidase Treatment: Synthroid (L-thyroxine), usually lifelong. Labs monitored every 6-12 mos.

12 Hyperthyroidism Very rare in young children (<3 years of age)
Almost always autoimmune: Early Hashimoto’s (before gland destruction) Grave’s disease LABS: TSH ↓↓ FT4 ↑ T3 ↑

13 Grave’s Disease Hyperthyroidism
Due to antibodies that act like TSH and stimulate the thyroid gland in an uncontrolled fashion-- Thyroid Stimulating Immunoglobulin (TSI) Always goiter Inattention, poor sleep, palpitations, tachycardia, high systolic BP, tremors, hot intolerance, increased appetite, wt loss

14 Grave’s Disease Treatment
Complicated Medications: Atenolol/ Propanolol (symptomatic tx) PTU Methimazole Radioablation Thyroidectomy

15 Thyroid Nodules Benign or cancerous
Evaluation may include thyroid function tests, ultrasound or radiouptake scan, fine needle aspiration or biopsy More likely to be cancer in children vs adults Cancer management: Radical thyroid dissection High dose radioablation for residual disease Yearly monitoring

16 Adrenal Glands

17 Adrenal Hormones Adrenal Cortex:
Cortisol: important for cardiovascular response to stress, maintaining BG when fasting Aldosterone: increases blood pressure; salt retention and potassium excretion DHEA-S & Androstenedione: small role in pubic hair development in puberty; in excess states- hirsutism/ virilization in girls Adrenal Medulla: Epinephrine: adrenaline response

18 Hypothalamic-Pituitary-Adrenal Axis:
CRH ACTH Cortisol

19 Renin-Aldosterone System:

20 Adrenal Insufficiency
Primary Adrenal Insufficiency Problem with the adrenal gland “Addison’s Disease”- usually autoimmune Cortisol +/- Aldosterone deficiency May present with vague symptoms or with shock (low BP, tachycardia) May have electrolyte abnormalities: Hypoglycemia, hyperkalemia, hyponatremia

21 Adrenal Insufficiency
Primary Adrenal Insufficiency: Diagnostic tests: AM cortisol ACTH (cosyntropin) stimulation test Electrolytes and renin for aldosterone def. Treatment: Cortisol replacement: hydrocortisone, prednisone, or decadron Need higher doses for illness- “stress dose” Florinef if aldosterone deficiency present

22 Adrenal Insufficiency
Central adrenal insufficiency: Problem with the pituitary gland or hypothalamus Also called secondary or tertiary AI By far most common cause: treatment with prednisone or other glucocorticoid for inflammatory condition Diagnosis: AM cortisol or ACTH stimulation (“low dose”) Treatment: Slowly wean hydrocortisone

23 Cushing’s Syndrome State of cortisol excess Etiology:
Exogenous prednisone Adrenal disease (tumor) Pituitary adenoma (ACTH- secreting) Para-neoplastic (non-pituitary ACTH production) Symptoms: obesity, poor stature growth, bruising, stria

24 Cushing’s Syndrome Diagnostic Tests:
24 hour urine– free cortisol Dexamethasone suppression test– pt takes decadron, which should shut down endogenous cortisol production Imaging Treatment depends on location of problem (pituitary, adrenal, vs cancer elsewhere)

25 Primary Hyperaldosteronism
Unregulated aldosterone excess Very rare Results in: Hypertension Low potassium level

26 Androgen Excess- PCOS Usually ovarian androgen overproduction, but need to rule out adrenal androgen Polycystic Ovarian Syndrome is characterized by presence of: Symptoms of androgen excess: hirsutism (excess hair growth), acne Biochemical abnormalities: elevated androgens, abnormal LH:FSH ratio Irregular menses (anovulatory cycles) Polycystic ovaries on ultrasound Is frequently associated with insulin resistance and obesity in 2/3rds of pts

27 Androgen Excess- PCOS Diagnostic Tests: Treatment: Clinical History
Labs: LH, FSH, testosterone, adrenal androgens +/- Ultrasound Treatment: Oral Contraceptives: Yasmin Spironolactone– diuretic with anti-androgen effect Metformin- if associated insulin resistance

28 Adrenal Androgen Excess- Congenital Adrenal Hyperplasia
Life-threatening enzyme block in cortisol synthesis If a defect in aldosterone synthesis also is present, also get salt wasting and hypotension--- Emergency! Androgen pathway not blocked---high ACTH levels stimulate androgen production in utero & after birth Female fetus: virilization (female should not see any androgen) Male fetus: normal genitalia (plenty of testicular androgen present)

29 Adrenal Androgen Excess- CAH
Most common cause of ambiguous genitalia of the newborn 21-hydroxylase enzyme deficiency in more than 90% of cases Diagnostic test: high 17-OH-progesterone level Treatment: Cortisol +/- Florinef replacement Some female infants undergo surgery for virilized genitalia

30 Gonads- Testes & Ovary

31 Hypogonadism- 1o or 2o

32 Assessing Puberty in Children
Tanner staging= description of breast and pubic hair development Prader beads= used to estimate testicular size (1-3 mL= prepubertal) Adrenarche or Pubarche= onset of pubic hair development Thelarche= onset of breast development Menarche= onset of menses

33 Delayed Puberty in Children
Girls > 13.0 years Boys> 14.0 years Can be due to: Constitutional delay of growth and puberty= normal variant. Family hx of “late bloomers” Hypothalamic/pituitary problem- often in context of anorexia or systemic illness. Sometimes specific genetic defects (Kallman’s syndrome) Ovarian or testicular failure

34 Delayed Puberty in Children
Kallman’s Syndrome: Specific genetic defects that result in failure of the GnRH-producing neurons of the hypothalamus Pubertal delay Often also have anosmia (lack sense of smell) Will need lifelong replacement of testosterone (boys) or estrogen (females)

35 Delayed Puberty in Children
Ovarian or Testicular Failure: Radiation Chemotherapy (cytoxan) Autoimmune (rare in children but cause of premature menopause in adult woman) Aneuploidy of sex chromosomes: Turner’s syndrome (XO) Klinefelter’s syndrome (XXY)

36 Turner’s syndrome Abnormal X chromosome– XO or mosaic XX/XO female
Short stature Streak ovaries- pubertal delay Other physical features Cardiac disease Structural Renal Anomalies Normal cognition (struggle w/math)

37 Klinefelter’s Syndrome
XXY karyotype Start puberty but then have testicular failure Tall Small testes Lack body hair Elevated FSH, low testosterone level

38 Precocious Puberty Girls < 8 years of age (controversial)
Boys <9 years of age Most often idiopathic central precocious puberty Other causes: tumors, excess adrenal or gonadal steroid production “Benign” variants: Premature Thelarche: isolated breast development Premature Adrenache: isolated pubic hair

39 Puberty Evaluation Often includes labs: FSH, LH, testosterone, estradiol, DHEA-S Lupron stimulation test: pituitary FSH and LH secretion have classic pubertal or prepubertal patterns Bone age

40 Treatments Delayed Puberty, often need T or E2: Precocious Puberty:
Testosterone- most common is IM injection; other options include patch, gel Estrogen- Premarin or ethinyl estradiol alone initially. Later estrogen + progesterone (OCP) for menstrual cycles Precocious Puberty: Depends on cause of puberty Most common is central puberty, treated with Depot Lupron (IM injection) or Supprelin implant

41 Treatments

42 Growth and Growth Hormone

43 GH Axis

44 Assessing Growth Endocrinological reasons for poor growth:
Growth Hormone Deficiency Hypothyroidism Cushing’s syndrome (very rare) Most children with poor growth will not have an endocrine problem. Consider also: Occult systemic disease- renal disease, CF Malabsorption- inflammatory bowel, celiac Poor nutrition

45 Diagnosing GH Deficiency
It’s complicated! GH is secreted in pulses from the pituitary gland. A random GH is never helpful for poor growth. First step: Check IGF-1 and IGF-BP3 (growth factors) Second step: GH stimulation testing Clonidine Arginine GH >10 is considered normal

46 Treating GH Deficiency
First, rule out tumor– Brain MRI Growth Hormone Treatment Daily SQ injections Very expensive– prior authorization from insurance

47 Growth Hormone Excess Very Rare Due to pituitary adenoma secreting GH
Gigantism in children Acromegaly in adults

48 Water and Sodium Balance
Largely regulated by ADH from posterior pituitary gland:

49 Water and Sodium Balance
ADH acts on the collecting ducts in the kidney to allow water absorption lack ADH- loose too much water High urine output Dehydration Hypernatremia too much ADH- absorb too much water Low urine output Retain free water hyponatremia

50 Diabetes Insipidus Condition in which the body cannot produce or cannot respond to ADH Cannot produce ADH= Central DI Cannot respond to ADH= Nephrogenic DI Presents with: Polyuria (excess urination) Polydipsia (excess thirst) Hypernatremia

51 Diabetes Insipidus Causes of central DI include: Tumors Trauma
Neurosurgery Treatment= ddAVP (synthetic ADH) Comes as oral tablets, nasal spray, or SQ injection Treatment of nephrogenic DI is more complex

52 SIADH Condition of excess ADH
Presents as low urine output, concentrated urine, and hyponatermia Often transient, in response to: Neurosurgery Meningitis Pneumonia or other pulmonary infection

53 Parathyroid, Calcium, Vitamin D, and Bone

54 Factors Regulating Calcium:
Parathyroid Hormone (PTH): Secreted by parathyroid gland in response to low calcium levels Retains calcium at the level of the kidney, activates vitamin D, and has some direct effect on bone Vitamin D: Necessary to absorb calcium normally from the gut Bone: Where most of our body’s calcium is stored; in the absence of dietary calcium intake, we leach calcium from bone to maintain blood levels

55 Hyperparathyroidism Tumor or hyperplasia of parathyroid glands
Excess secretion of PTH Characteristic findings: Hypercalcemia Low phosphorus Bone pain Risk of kidney stones and kidney damage Treatment: increase fluid intake, often need surgery to remove abnormal parathyroid tissue

56 Hypoparathyroidism Congenital underdevelopment of parathyroid glands
Acquired deficiency– autoimmune destruction Characteristic features: Low calcium- may present as tetany or seizure High phosphorus Treatment: Calcium and calcitriol (vitamin D) supplementation

57 DiGeorge Syndrome (chrom 22q11 del)
Congenital hypoplasia of parathyroid glands Associated with characteristic facial features, cardiac defects, thymic aplasia

58 Vitamin D Deficiency In very young children, causes rickets.
Rickets= bone deformities from calcium/ vitamin D deficiency. Most often occurs in purely breastfed infants in northern latitudes Reason for recommending vitamin D supplement in breast feeding infants Treat with high dose vitamin D

59 DIABETES MELLITUS PANCREAS, ISLETS, AND BETA-CELLS:

60 Diabetes Mellitus Type 1 Diabetes Type 2 Diabetes
Autoimmune destruction of beta-cells with eventual complete inability to secrete insulin Type 2 Diabetes Insulin resistance (need more insulin) Plus insulin insufficiency Looking at the underlying pathology in T1 vs T2 DM. Of course, T1DM is due to AI destruction of beta cells. T2DM is characterized by insulin resistance (nearly all youth obese), but importantly also relative insulin deficiency. There are many obese people who are not diabetic– ability of beta cells to compensate with increased insulin secretion to meet demands.

61 2009 ADA Diagnostic Criteria For Diabetes Mellitus
Casual (Random) Glucose Test > 200 mg/dL + symptoms Polyuria, polydipsia,hyperphagia, weight loss Fasting blood glucose > 126 mg/dL* < 100 mg/dl: Normal mg/dl: Impaired Fasting Glucose 2 Hour OGTT glucose > 200 mg/dL* < 140 mg/dl: Normal mg/dl: Impaired Glucose Tolerance *In absence of unequivocal hyperglycemia, requires confirmation on separate day* Unchanged from Diagnosis of type 1 diabetes and sometimes type 2 diabetes is typically straightforward- symptoms + elevated random glucose. For diabetes screening in the absence of symptoms, fasting BG 126 or greater, or 2-hr OGT above 200 make diagnosis, but should be confirmed on 2 separate days. Currently A1c is not a part of the diagnostic criteria for diabetes, but it may eventually be included here.

62 History of Diabetes Mellitus
1552 BC earliest written record of DM (Egyptian physician) 1st Breakthrough in understanding: 1889 The problem is within the pancreas “Cure” for diabetes (type 1) – insulin: 1922 insulin Quick overview of history of diabetes, to bring us to current treatment– insulin/ pills and home glucose monitoring

63 Not much change for the next 50 years!
1970 1980 1990 2000 Genetic Studies: HLA Association Human Insulin Islet Cell Antibodies Home Glucose Monitoring Pathology Studies: Insulitis Insulin pumps Insulin Autoantibodies DCCT GAD65 antibodies, IA-2 After the initial introduction of insulin therapy, not a lot changed in our understanding or treatment options for the next 50 years. It has been over the last 40 years, that we have come to understand more about the pathophysiology of type 1 diabetes. It was during this time that the high risk HLA types associated with diabetes were discovered and autoantibodies and the insulitis of diabetes was realized and T1D is now widely recognized as immune-mediated. We have also seen dramatic changes in therapeutic management. In the 70’s human insulin was discovered, we finally developed home glucometers. Hard to imagine now managing diabetes without home glucose monitoring. The DCCT provided conclusive evidence that tight control of BG does matter, and we have peakless basal insulin and rapid-acting insulins. But I think we all recognize now that insulin therapy, as good as it is, is not a cure. It comes with its own set of complications, which we will discuss. Rapid-acting Insulin Basal Insulin Marked changes in Therapy Type 1 diabetes is immune mediated

64 An islet in type 1 diabetes
IMMUNE CELLS Histopathology example– exocrine pancreas tissue, islet, and insulitis ISLET Exocrine Pancreas

65 GLUCOSE INTOLERANCE (OGTT)
Natural History of Type 1 Diabetes GENETICALLY AT RISK UNKNOWN TRIGGER CELLULAR (T CELL) AUTOIMMUNITY HUMORAL AUTOANTIBODIES (ICA, IAA, Anti-GAD65, IA2Ab, etc.) TIME BETA CELL MASS DIABETES “PRE”-DIABETES GENETIC PREDISPOSITION INSULITIS BETA CELL INJURY LOSS OF FPIR (IVGTT) GLUCOSE INTOLERANCE (OGTT) CLINICAL ONSET HLA region of chromosome in charge of managing development of t cells

66 Pediatric Type 2 Diabetes Mellitus
Acanthosis Nigricans Caglecartoons.com

67 Other Terminology in DM
Honeymoon Period: refers to period of time early after diagnosis of type 1 diabetes mellitus when blood sugars are easier to control. Basal or Background Insulin Bolus Insulin Glucagon: Used for hypoglycemic emergency to raise blood sugar

68 Blood Glucose Meters Common Brands: One Touch (Ultra, Link, Mini)
Bayer (Contour) Accucheck (Aviva) Freestyle (Lite)

69 Insulin- Vial and Syringe
Insulin Types: Lantus (glargine) Levimir (detrimir) Novolog (aspart) Humalog (lispro) Apidra (glulisine) NPH (“N”) Regular (“R”)

70 Insulin Pens Easy to carry and use
“Dial up” dose in 0.5 or 1 unit increments

71 Basal-Bolus Regimen Aspart Lispro Glulisine Glargine Detemir or or
Breakfast Lunch Dinner Lispro Aspart or Glulisine Plasma Insulin Glargine or Detemir 4:00 8:00 12:00 16:00 20:00 24:00 4:00 8:00 Time Slide courtesy of Jay Skyler, MD

72 Insulin Pumps Features: Components: Basal Rates Bolus “wizard” Alarms
Temp basal & patterns Components: Pump Catheter “site” Insulin Cartridge

73 Continuous Glucose Monitors
Measure interstitial glucose Requires calibration with blood glucose Readings every 2-5 minutes

74 Oral Medications Used for type 2 DM, rarely adjuvant to insulin in type 1 DM METFORMIN ROSIGLITAZONE/ PIOGLITIZONE (TZDs) GLIPIZIDE, GLYBURIDE (sulfonylureas)

75 Acute Complications of DM
Diabetic Ketoacidosis T1DM and new onset T2DM #1 cause of hospitalization in children with DM Cerebral edema occurs in 0.7-3% of DKA- 20% mortality Non-ketotic hyperosmolar coma Hypoglycemia

76 Chronic Complications of DM
MICROvascular disease Retinopathy Nephropathy/ Microalbuminuria Neuropathy MACROvascular disease Coronary artery disease LOWER hemoglobin A1c = LOWER risk of complications

77 Associated Conditions
Type 1 DM (autoimmunity) Thyroid disease (10-15%) Celiac disease (~5%) Adrenal insufficiency (<1%) T2 DM (metabolic syndrome) Obesity Dyslipidemia Hypertension PCOS Fatty liver


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