Transcript Endocrinology

Endocrinology
Calcium
An otherwise healthy 6-week infant presents
with a generalized seizure. She is exclusively
breast fed. The child is somewhat sleepy with a
non focal examination.
Lab data:
Glucose
Sodium
Calcium
Phosphorus
Magnesium
88 mg/dL
141 mEq/L
5.1 mg/dL
9.1 mg/dL
2.1 mg/dL
What is the diagnosis?
What are important considerations in this child?
Actions of PTH
Ca
1.
2.
3.
25 OH Vit D
1 hydroxylase
1,25 (OH)2 Vit D
Gut
NET EFFECT
PO4
6-week infant presents with seizure.
Calcium
5.1 mg/dL
Phosphorus
9.1 mg/dL
What is the diagnosis?
HYPOPARATHYROIDISM
What are important considerations in this
child?
Possible DiGeorge syndrome
(thymic aplasia, congenital heart disease
microdeletion of chromosome 22)
Biochemical changes in rickets
Ca
Stage 1
Stage 2
PO4
N
N
Bone
Urine
Minimal
changes
Rickets
Aminoaciduria
Phosphaturia
Which is consistent with
vitamin D deficiency rickets?
CALCIUM
PHOS
ALK PHOS
A. Normal
Normal
Low
B. Low
Low
Low
C. Low
Increased
Increased
D. Low
Normal
Normal
E. Normal
Low
Increased
Initial
Ca:
PO4:
Alk Phos:
9.7
3.1
2514
2 ½ weeks
9.8
3.5
2185
4 months
10.5
6.5
518
Choose correct answer
A. Vitamin D deficiency rickets
B. Renal osteodystrophy (renal rickets)
C. Both
D. Neither
1. Increased phosphate level
2. Increased PTH level
3. Increased creatinine level
THYROID
You are contacted by your state
Neonatal Thyroid Screening Program.
Baby X was born on 1/4/01.
His newborn screening tests, performed
on 1/6/01 revealed:
TSH
T4
37 IU/ml
10.1 g/dl
Normal range
< 20
9-19
You are contacted by your state Neonatal Thyroid
Screening Program. Baby X was born on 1/4/01.
His newborn screening tests, performed on 1/6/01
revealed:
Initial filter paper
TSH
T4
Normal range
>200 IU/ml
< 20
2.1 g/dl
9-19
Venipuncture: (1/25/01)
TSH 488 IU/ml
T4
1.2 g/dl
Normal range
(0.3-5.5)
(4.5-12.5)
Congenital hypothyroidism
 Thyroid dysgenesis/agenesis
 Prevalence 1 in 4,000 [Whites 1 in 2,000; Blacks
1 in 32,000]
 2:1 female to male ratio
 Clinical features include:
hypotonia, enlarged posterior fontanelle,
umbilical hernia, indirect hyperbilirubinemia
 Laboratory findings: Very high TSH and low T4
 Therapy: Thyroxine – keep TSH in normal range
6 month female with
congenital hypothyroidism
..following 4 months
therapy
You are contacted by Newborn screening
program for a baby whose newborn
thyroid screen at 3 days revealed a low T4
and normal TSH.
Repeat venipuncture showed:
T4
2.1 μg/dL
(4.5-12.5)
TSH
2.3 μIU/mL
(0.3-5.0)
What is the differential diagnosis?
Central hypothyroidism - rare
vs.
TBG deficiency
1:2800
Thyroxine (T4)
 Major product secreted by the thyroid
 Circulates bound to thyroid binding proteins
- thyroid binding globulin (TBG)
 Only a tiny fraction (< 0.1%) is free and diffuses
into tissues
 When we measure T4, we measure the T4 that is
bound to protein
 The level of T4 is therefore largely dependent on
the amount of TBG
 Changes in T4 may reflect TBG variation rather
than underlying pathology
Central
hypothyroidism
TBG
deficiency
Free T4
Low
Normal
TBG level
Normal
Low
T3RU
Low
High
17 year old female who complains
of easy fatigability
Thyroid function:
TSH
3.7 IU/ml
T4
13.4 g/dl
T3RU
20 %
Normal range
0.3-5.5
4.5-12
25-35
Conditions that cause alterations in TBG
Increased TBG
Infancy
Estrogen
- OC Pill
- pregnancy
Familial excess
Hepatitis
Tamoxifen treatment
Decreased TBG
Familial deficiency
Androgenic steroid treatment
Glucocorticoids (large dose)
Nephrotic syndrome
Acromegaly
15 year old with a goiter.
No family history of thyroid disease.
Thyroid function:
TSH 43 IU/ml
T4 6.0 g/dl
T3 140 ng/dl
Normal range
0.3-5.5
4.5-12
90-190
Primary hypothyroidism
Dr. Hakaru Hashimoto
Normal thyroid
Hashimoto thyroiditis
DC


16 year 7 month
Growth failure x 1 1/2 years
Labs:
TSH:
T4:
1008 µIU/ ml
<1.0 µg/dl
(0.3-5.0)
(4-12)
A-thyro Ab.
A-perox Ab.
232 U/ml
592 IU/ml
(0-1)
(<0.3)
Prolactin:
29
ng/ml
Cholesterol:
406 mg/dl
(2-18)
(100-170)
DC
Start of thyroxine
Hashimoto thyroiditis
Background:
Autoimmune destruction of the thyroid
Family history in 30-40%
Lymphocytic infiltration
Clinical:
Growth failure, constipation, goiter, dry skin, weight
gain, slow recoil of DTR
Laboratory:
High TSH
Anti-thyroglobulin and anti-peroxidase antibodies
Therapy:
Thyroxine
15 year old female with a history of easy fatigability.
Found to have an elevated pulse rate at recent MD visit
Thyroid function:
TSH < 0.1 IU/ml
T4
14.8 g/dl
T3
580 ng/dl
Normal range
0.3-5.5
4.5-12
90-190
Eye changes
Restlessness,
poor attention span
Goiter
Tachycardia, wide pulse
pressure
Increased GFR
- polyuria
Menstrual
abnormalities
Myopathy
Diarrhea
Therapy for Graves disease:
Antithyroid medication (Methimazole or Propylthiouracil [PTU])
Pros : 25% remission rate every 2 years
Cons: Drug induced side effects
- skin rashes, agranulocytosis, lupus-like reaction
Radioactive iodine (131I)
Pros : Easy. Essentially free of side effects
Cons: Long term hypothyroidism
Surgery
 Blockers if markedly hyperthyroid
Sexual differentiation
Ambiguous genitalia is found in a newborn.
The baby is noted to be hyperpigmented.
Ultrasound demonstrates the presence of a
uterus. The most useful test to aid in the
diagnosis of this medical condition is:
a)
b)
c)
d)
e)
Testosterone
17-hydroxyprogesterone
Serum sodium and potassium
DHEAS
DHEAS/androstenedione ratio
Cholesterol
Desmolase
Pregnenolone
17-OH
3--HSD
Progesterone
17 (OH) pregnenolone
3--HSD
17-OH
21-OH
DOCA
11-OH
Corticosterone
ALDOSTERONE
17 (OH) progesterone
DHEA
3--HSD
Androstenedione
21-OH
Compound S
11-OH
CORTISOL
TESTOSTERONE
If she has salt wasting congenital adrenal
hyperplasia, which abnormalities are likely to
develop
a)
b)
c)
d)
e)
Increased serum potassium
Decreased serum sodium
Decreased bicarbonate
Decreased plasma cortisol
Increased plasma renin activity
History
9 day old male infant
1 day history of decrease feeding, vomiting and lethargy.
Examination
Ill appearing infant with poor respiratory effort
Vital signs: T 99 F HR 100/min BP 61/40 RR 24/min
Resp:
Subcostal retractions but clear to auscultation
Cardiac:
Regular rate and rhythm. Normal S1 and S2
Abdomen: Soft, non distended. Non tender. No HSM
Neuro:
Lethargic. No focal deficit
Laboratory data:
WBC 16.7
Hb
16.4
Hct
49
Plt
537 K
CSF:
Chemistry: Protein 74
Microscopy: WBC 6
Na
K
Cl
CO2
Glucose
BUN/Creat
Glucose
RBC
82
100
121
9.3
83
6.7
163
33/0.2
Emergency therapy
Fluid resuscitation:
20 ml/kg Normal saline
Glucocorticoid
2 mg/kg Solucortef IV
Monitor EKG
Modes of presentation
Classical
Simple virilizing
Virilizing with salt loss
“Non classical” / Late onset
Therapy and evaluation of therapy
Glucocorticoid (Hydrocortisone)
Monitor growth, 17-OHP, urinary pregnanetriol
Fluorocortisol (Florinef 0.1 – 0.15 mg/day)
Blood pressure, plasma renin activity (PRA)
Supplemental salt (2.2 meq/kg/day Na)
Until introduction of infant food
History
15 year female presents with primary amenorrhea
Breast development began at 10 years
Examination
Height: 5 ft 7 in Weight 130 lb
Tanner 5 breast development
Scant pubic hair
What is your diagnosis?
Complete androgen insensitivity
XY Genotype
Testosterone
Estradiol
Androgen
Receptor
Estrogen
Receptor
Complete androgen insensitivity
 XY genotype
 Non functioning androgen receptor
 Sertoli cells – AMH
 Regression of Mullerian structures
 Leydig cells – testosterone
 No functioning receptor
 Therefore Wolffian regression
 Testosterone converted to DHT
– No functioning receptor
– Therefore normal female external genitalia
Puberty
6 year old female with breast
development
6 yr African American female with breast
development
History
Few months of breast development
– No pubic or axillary hair
– No vaginal discharge
Growth acceleration
No history of exposure to estrogen
Family history
Family history
– Mother had menarche at 9.5 years
ROS
– No Gelastic seizures
PE
Ht 75 %
Growth acceleration
– Last height 50 %
Wt 75 %
No hyperpigmented
lesions/ café au lait
macules
Breasts T-2
PH T-1, no estrogen
affect on the mucosa
No NF or McCune
Albright syndrome
Puberty
What
First sign:
– breast
development
– testicular
enlargement,
>2 cm
– Isolated pubic
hair is NOT
puberty
What
Associated
findings
– Growth
acceleration
– Maximum
accretion of
bone
– Psychological
changes
When?
Classic teaching
– 8 -13 in girls
(menarche ~ 2 years
after onset of puberty)
– 9 -14 in boys
This child:
Breast development:
Mother had menarche:
6 years
9.5 years
Why
Reactivation of
hypothalamic –
pituitary –gonadal
axis
Gonadatropin dependent
(central) precocious puberty
Clock turns on early
Idiopathic
> 95 % girls
~ 50 % boys
– Hypothalamic hamartoma (Gelastic seizures)
– NF (optic glioma)
– Head trauma
– Neurosurgery
– Anoxic injury
– Hydrocephalus
Precocious puberty in the male
Gonadotropins
Prepubertal
Pubertal
Gonadotropin independent
precocious puberty
Central precocious
puberty
LH
G
Leydig cell
Precocious puberty in the male
Gonadotropins
Prepubertal
Pubertal
Gonadotropin independent
precocious puberty
HCG
Central precocious
puberty
LH
*
*
G
McCune Albright
Familial male
syndrome
Precocious puberty
(testotoxicosis)
G
Leydig cell
1. Gonadotropin independent PP
2. Polyostotic Fibrous Dysplasia
3. Café au lait macules
Differential diagnosis of
precocious puberty
Boys
Girls
– β HCG secreting
tumors
– Testotoxicosis
– McCune-Albright
syndrome
– CAH
21-OH deficiency
– Adrenal/Testicular
Tumor
– Exogenous steroids
– McCune-Albright
syndrome
– Ovarian Cyst
– Feminizing adrenal
tumor
– Exogenous steroids
Evaluation
History
– FH
– Exposure
PE
– Growth curve
– Tanner stage
Pubic hair as well as genitals
– Neuro exam
– Skin Exam
Evaluation
Bone Age
Labs
– LH
– FSH
– Sex Steroids
± Stimulation Test
MRI (if pubertal gonadotropins)
Pelvic and adrenal sonogram (if
gonadotropins low)
Treatment
Why
– Psychosocial
– Height
What
– GnRH agonist
Case
16 year old dancer with no breast
development or menstrual period
HT 75%
WT 10%
Delayed puberty
Lack of breast
development by
13 years in girls
Lack of testicular
enlargement by
14 in boys
Delayed puberty
Hypogonadism
Hypergonadotropic
Hypogonadism (↑FSH, LH)
Primary gonadal failure
- Chromosomal
- iatrogenic (cancer therapy)
- autoimmune oophoritis
- galactosemia
- test. biosynthetic defect
Hypogonadotropic
Hypogonadism (FSH, LH)
Constitutional
delay
Central
Hypogonadism
- Isolate gonad. def.
- MPHD
- Kallmann (anosmia)
- Functional
Common Pubertal variants
2 year old girl with breast development
– No growth acceleration
– No bone age advancement
– No detectable estradiol, LH or FSH
Benign Premature Thelarche
Isolated breast development
– 80% before age 2
– Rarely after age 4
Incidence 21.2/100,000 (0.02%)
– Resolved in 6 mo-6 yr
Can be unilateral
FSH elevated
Small cysts on ovarian ultrasound
5year old girl with pubic hair
No growth acceleration
No breast development
No virilization
Benign Premature Adrenarche
Production of adrenal androgens before
true pubertal development begins
Presents as isolated pubic hair
– No growth acceleration
– No testicular enlargement in boys
Differential diagnosis
– CAH
– Virilizing tumor (adrenal/gonadal)
Growth
“Observations upon growth and
development are of the utmost importance
during infancy and childhood… Only by
this means are very many diseases
detected in their incipiency”
Causes of Growth Failure
Normal patterns of growth
Familial or genetic short stature
Constitutional growth delay
Primary growth disturbances
Intrauterine growth retardation
Genetic disorders
Chromosomal defects
(Turner, Down syndrome)
Syndromes
(Noonan, Prader-Willi,
Russell-Silver)
Disproportionate short stature
Skeletal dysplasias
Spinal irradiation
Systemic illnesses
Hypocaloric
- Malnutrition, GI disease
(IBD, celiac disease)
- Poorly controlled diabetes
Metabolic
- Renal (RTA, nephrogenic
diabetes insipidus, renal
failure)
- Hepatic
- Cardiac
(cyanotic heart disease)
- Hematologic
(chronic anemias)
- Respiratory
(CF, severe asthma
[hypoxemia])
Chronic infections
adapted Samuels, 2001
Causes of Growth Failure
Endocrine disorders
- Hypothyroidism
Congenital
Acquired
- Glucocorticoid excess
Exogenous steroid use
Endogenous
- Growth hormone deficiency
Isolated
Multiple hormonal deficiencies
adapted Samuels, 2001
Growth rates by age
0-12 months: 9-11
inches/year
– rapid catch up and down
12-36 months: 3-5
inches/year
– on own curve by 3 years
3- puberty: 2-2.5
inches/year
– Magical 2”/year
– greater than 3”/year may
signal early puberty
Mom is 4’11”
Dad is 5’4”
– How tall will their sons and daughters likely
be?
Calculation of Mid-parental height and
target height Range
MPH(boy)= Father’s Height +(Mother’s Height + 5”)
2
MPH(girl)= (Father’s height-5”)+Mother’s height
2
Target height range=MPH+4”
Calculating target height
Parental Heights:
Father: 6 ft
Mother: 5 ft 3 in
Assessment and when to refer
Growth velocity less
than 2 inches/year
Crossing centiles
after 3 years of age
Inappropriate height
for family
Abnormal timing of
puberty
Growth rates by age
Puberty
– delayed puberty,
compared to peers or
absolute:
> 13 year in girls,
>14 years in boys,
very common reason
for referral
– delayed puberty
causes you to fall off
your curve despite a
normal velocity
JC
4 5/12 boy referred for short stature
Fall off the growth chart for past 18 months
PMH negative
– Late teether
Father 5 ft 6 in, mother 5 ft 7 in
Tried “Pro HGH”
– No growth
Physical
PE
– 90.6 cm (-3SD),10.4 kg
– Non focal
Labs
Normal TFTs, CBC, SMAC, ESR, celiac
screen
IGF-1 24 ng/ml (17-124)
Bone age 2 8/12
GH stim test peak 5 ng/ml (>7.5 ng/ml)
MRI
GH rx
Indications
GH deficiency
Turner Syndrome
Chronic Renal
insufficiency
Prader Willi
SGA
Idiopathic short
stature
Diabetes
6 year old with 2 week history of polyuria,
polydypsia and enuresis
Weight loss
Anorexia
If he is tachypneic:
Think DKA
Diabetic Ketoacidosis
Hyperglycemia
– Usually greater than 300 mg/dl
Ketosis
Acidosis
– Ph < 7.3
Management
Fluid
– Treat shock
NS bolus @ 20 ml/kg
– Paradoxical drop in pH
– Rehydrate over 48 hours
Insulin
– Correct 100 mg/dl/hour
– May need to add dextrose
Factitious hyponatremia
– For every 100 mg/dl rise in glucose, 1.8 meq/l
decrease in sodium
Patients are total body potassium depleted
Monitor level of consciousness
– Never sedate
Categories
Type 1 (>90%)
– Insulin dependent
– Ketosis prone
– autoimmune
Type 2
– Insulin resistant
– Usually associated
with obesity
Treatment
Insulin
Diet
Secretagogues
Insulin sensitizers
MODY
– Maturity onset diabetes of youth
– Defective insulin secretion
– Non-ketotic
– Familial
DIDMOAD (Wolfram syndrome)
– DI, DM optic atrophy and deafness
Rapid
– Aspart (Novolog)
– Lispro (Humalog)
– Glulisine (Apidra)
Regular
NPH
Ultra long acting
– Glargine (Lantus)
– Detemir (Levemir)
Quick points
Up to 7 % of kids with Type 1 diabetes
have celiac disease
– Unexplained hypoglycemia
– Poor growth
– Abdominal symptoms
Other associated autoimmune diseases
– Hashimoto’s thyroiditis
– Addison’s disease
– Autoimmune oophoritis
Hypoglycemia
30 hour old male with glucose of 20 mg/dl
Definition of hypoglycemia?
Glucose < 40 mg/dl in newborn
Glucose < 50 mg/dl in child
Hypoglycemia
Decreased substrate
– Poor intake
– Defective glycogenolysis or gluconeogenesis
Increase utilization
– Sepsis
– Hyperinsulinism
Absent counter regulatory hormones
– GH
– Cortisol
Back to the NICU…
Hyperinsulinism
– Macrosomic
– Infant of a diabetic
mother (transient)
Hypopituitary
– Small
– Microphallus
– Midline defects
Critical Sample
Glucose
– Remember, drops 10mg/dl/hr in a red-top
tube
Insulin
Cortisol
Growth Hormone
Let’s make him a 4 year old
Mild URI symptoms
– Poor dinner, went to bed at 6 PM
6 AM found listless
EMS called
Fingerstick glucose 30
What do you think?
What should be done?
A bit more history
Otherwise healthy child
PMH, FH, ROS all negative
Height 50 %
Weight 10%
“acetone” on his breath
Differential
(as before plus….)
ketotic hypoglycemia
– “skinny little kid disease”
– Unable to liberate enough glucose from liver
stores to satisfy overnight fast
Remember, he ate poorly and slept long..
Disorders of intermediary metabolism
– MCAD, LCAD, etc
“hypoketotic hypoglycemia”
Ingestions
Evaluation
Critical sample
– GH, Cortisol, insulin, glucose
Acyl Carnitine profile (MCAD,LCAD)
Serum Acetone
Lactate
Urine ketones