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EndocrinologyMelena Bellin, MD
Division of Pediatric Endocrinology
Pituitary/ Hypothalamic Tract Thyroid Adrenal Ovary/ Testes and Puberty Growth and Growth Hormone Water and sodium balance Parathyroid, calcium, and bone Diabetes/ Pancreas
Content
Hypothalamus and Pituitary
Anterior Pituitary Growth Hormone (GH) Gonadotropins (FSH, LH) Adrenocorticotrophin (ACTH) Thyroid Stimulating Hormone (TSH) Prolactin
Posterior Pituitary Antidiuretic Hormone (ADH) Oxytocin
Hormones of the Pituitary Gland
THYROID DISEASE
T4/ Free T4 T3 TSH TRH
1o Hypothyroidism: Low FT4 High TSH
Thyroid Axis
Congenital 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
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
Congenital Hypothyroidism
Untreated Congenital Hypothyroidism
Jaundice
Poor feeding
Hypotonia
Macroglossia (large tongue)
Large fontanelles, delayed closure
Course facial features
Mental retardation
Short stature
In children and young adults, usually autoimmune
HASHIMOTO’S DISEASE Presentation: Varies, asymptomatic, goiter,
fatigue, poor growth, constipation, eczema
Acquired Hypothyroidism
Diagnostic Tests:• TSH ↑• Free T4 ↓• Antibodies: thyroglobulin, thyroid
peroxidase
Treatment: Synthroid (L-thyroxine), usually lifelong. Labs monitored every 6-12 mos.
Acquired Hypothyroidism
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 ↑
Hyperthyroidism
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
Grave’s Disease
Complicated
Medications:• Atenolol/ Propanolol (symptomatic tx)• PTU• Methimazole
Radioablation
Thyroidectomy
Grave’s Disease Treatment
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
Thyroid Nodules
Adrenal Glands
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
Adrenal Hormones
Hypothalamic-Pituitary-Adrenal Axis:
CRH
ACTH
Cortisol
Renin-Aldosterone System:
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
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
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
Adrenal Insufficiency
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
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)
Cushing’s Syndrome
Unregulated aldosterone excess
Very rare
Results in:• Hypertension• Low potassium level
Primary Hyperaldosteronism
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
Androgen Excess- PCOS
Diagnostic Tests:• Clinical History• Labs: LH, FSH, testosterone, adrenal androgens• +/- Ultrasound
Treatment:• Oral Contraceptives: Yasmin• Spironolactone– diuretic with anti-androgen
effect• Metformin- if associated insulin resistance
Androgen Excess- PCOS
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)
Adrenal Androgen Excess- Congenital Adrenal Hyperplasia
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
Adrenal Androgen Excess- CAH
Gonads- Testes & Ovary
Hypogonadism- 1o or 2o
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
Assessing 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
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)
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)
Delayed Puberty in Children
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)
Turner’s syndrome
XXY karyotype
Start puberty but then have testicular failure
Tall
Small testes
Lack body hair
Elevated FSH, low testosterone level
Klinefelter’s Syndrome
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
Precocious Puberty
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
Puberty Evaluation
Delayed Puberty, often need T or E2: 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
Treatments
Treatments
Growth and Growth Hormone
GH Axis
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
Assessing Growth
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
Diagnosing GH Deficiency
First, rule out tumor– Brain MRI
Growth Hormone Treatment• Daily SQ injections• Very expensive– prior authorization from
insurance
Treating GH Deficiency
Very Rare Due to pituitary adenoma secreting GH Gigantism in children Acromegaly in adults
Growth Hormone Excess
Water and Sodium Balance
Largely regulated by ADH from posterior pituitary gland:
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
Water and Sodium Balance
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
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
Diabetes Insipidus
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
SIADH
Parathyroid, Calcium, Vitamin D, and Bone
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
Factors Regulating Calcium:
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
Hyperparathyroidism
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
Hypoparathyroidism
Congenital hypoplasia of parathyroid glands
Associated with characteristic facial features, cardiac defects, thymic aplasia
DiGeorge Syndrome (chrom 22q11 del)
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
Vitamin D Deficiency
PANCREAS, ISLETS, AND BETA-CELLS:
DIABETES MELLITUS
Diabetes Mellitus Type 1 Diabetes
◦ Autoimmune destruction of beta-cells with eventual complete inability to secrete insulin
Type 2 Diabetes◦ Insulin resistance (need more insulin) ◦ Plus insulin insufficiency
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◦100-125 mg/dl: Impaired Fasting Glucose
2 Hour OGTT glucose > 200 mg/dL*◦< 140 mg/dl: Normal◦140-199 mg/dl: Impaired Glucose Tolerance
*In absence of unequivocal hyperglycemia, requires confirmation on separate day*
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
1970
1980
1990
2000
Not much change for the next 50 years!
Islet Cell Antibodies
Genetic Studies: HLA Association
Pathology Studies: Insulitis
Insulin Autoantibodies
GAD65 antibodies, IA-2
Type 1 diabetes is immune mediated
Human Insulin
Home Glucose Monitoring
DCCT
Insulin pumps
Rapid-acting Insulin
Basal InsulinMarked changes in Therapy
An islet in type 1 diabetes
ISLET
IMMUNE CELLS
Exocrine Pancreas
Natural History of Type 1 Diabetes
CELLULAR (T CELL) AUTOIMMUNITY
LOSS OF FPIR (IVGTT)
GLUCOSE INTOLERANCE (OGTT)
HUMORAL AUTOANTIBODIES(ICA, IAA, Anti-GAD65, IA2Ab, etc.)
TIME
BETA
CEL
L M
ASS
DIABETES
“PRE”-DIABETES
GENETICPREDISPOSITION
INSULITISBETA CELL INJURY
GENETICALLY AT RISK
UNKNOWN TRIGGER
CLINICAL ONSET
Pediatric Type 2 Diabetes Mellitus
Caglecartoons.com
Acanthosis Nigricans
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
Other Terminology in DM
Common Brands: One Touch (Ultra, Link, Mini) Bayer (Contour) Accucheck (Aviva) Freestyle (Lite)
Blood Glucose Meters
Insulin Types: Lantus (glargine) Levimir (detrimir) Novolog (aspart) Humalog (lispro) Apidra (glulisine) NPH (“N”) Regular (“R”)
Insulin- Vial and Syringe
Easy to carry and use “Dial up” dose in 0.5
or 1 unit increments
Insulin Pens
Features: Basal Rates Bolus “wizard” Alarms Temp basal & patterns
Insulin Pumps
Components: Pump Catheter “site” Insulin Cartridge
Measure interstitial glucose Requires calibration with blood glucose Readings every 2-5 minutes
Continuous Glucose Monitors
Used for type 2 DM, rarely adjuvant to insulin in type 1 DM
METFORMIN
ROSIGLITAZONE/ PIOGLITIZONE (TZDs)
GLIPIZIDE, GLYBURIDE (sulfonylureas)
Oral Medications
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
MICROvascular disease Retinopathy
Nephropathy/ Microalbuminuria
Neuropathy
MACROvascular disease Coronary artery disease
LOWER hemoglobin A1c = LOWER risk of complications
Chronic Complications of DM
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