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Objectives

• To understand the pathophysiology &


recognize the common manifestations of
the following conditions:
2. Hypopituitarism / Hyperpituitarism
3. Diabetes insipidus
4. Precocious puberty
5. Hypothyroidism / Hyperthyroidism
6. Thyroiditis
7. Hypoparathyroidism /
Hyperparathyroidism
Objectives
7. ACTH insufficiency
8. Congenital adrenal hyperplasia
9. Cushing syndrome
10. Pheochromocytoma
11. Hypogonadism (testes & ovaries)
12. Diabetes mellitus
• To devise an appropriate diagnostic &
therapeutic plan for each endocrinologic
condition.
Hormones
Hormones of the
Hypothalamus & Pituitary
• Anterior pituitary gland produce the ff:
2. Somatotropes – produce GH
3. Lactotropes – prolactin
4. Thyrotropes – TSH
5. Corticotropes – pro-opiomelanocortin,
the precursor of corticotropin (ACTH)
6. Gonadotropes – LH & FSH
• TSH, LH, FSH – glycoproteins
• ACTH, prolactin, GH - polypeptides
Hormones of the
Hypothalamus & Pituitary
• Protein hormones produced by the
anterior pituitary act on other
endocrine glands to affect almost
every organ
• Neurohypophysis produce the ff:
3. Arginine vasopressin (ADH)
4. Oxytocin
• Produced by neurosecretion in the
hypothalamic nuclei
General Approach
• Hyper states – suppression
test
• Hypo states – stimulation
test
GROWTH HORMONE
• Polypeptide metabolized rapidly in the liver
• Synergize with ACTH in increasing adrenal
size and with androgens in increasing the
size of accessory reproductive organs
• Increases hepatic glucose output & exerts
an anti-insulin effect in muscle (ketogenic)
 increase circulating FFA levels
Somatomedins
• Polypeptide growth factors secreted by
the liver and other tissues in response to
stimulation by GH
• Interacts with GH and has effects on
growth, bone, cartilage and protein
metabolism
3. Insulin-like GF I (somatomedin C) –
secretion is stimulated by GH
4. Insulin-like GF II – role in the growth of
fetus
HYPOPITUITARISM
• Deficiency of growth hormone with or
without a deficiency of other pituitary
hormones
• Congenital or acquired
• Clinical manifestations:
4. Of normal size & weight at birth
5. Atrophy of adrenal cortex, thyroid &
gonads result in weight loss, asthenia,
sensitivity to cold, absence of sweating
Hypopituitarism
3. Tendency to
hypoglycemia
4. Short & broad face,
prominent frontal bone,
depressed nasal bridge,
underdeveloped
mandible, short neck,
high-pitched voice, well
proportioned
extremities but small
hands & feet, delayed
sexual maturity
HYPOPITUITARISM
• Laboratory findings:
 Diagnosis of classic type is suspected in
cases of profound postnatal growth
failure (height > 3 SD below the mean for
age & gender)
 Definitive diagnosis: absent or low levels
of GH in response to stimulation
* Use of L-dopa, insulin, arginine, clonidine or
glucagon: peak level of GH < 10 ug/L in
each of 2 provocative tests – GH
deficiency
HYPOPITUITARISM
• Examine other pituitary functions: levels
of TSH, T4, ACTH, cortisol, DHEA,
gonadotropins may provide evidence of
other pituitary hormonal deficiencies
• X-ray/MRI findings: destructive or space-
occupying lesions: enlargement of the sella
or erosions & calcifications within or above
the sella turcica; delayed skeletal
maturation
Differential Diagnosis
of Short Stature
1. Congenital pathologic short stature –
prenatal onset; infant is born small and
growth slowly tapers off throughout
infancy; due to chromosomal abnormalities,
infections, teratogens, alcohol, extreme
prematurity
Differential Diagnosis
of Short Stature
2. Constitutional growth delay- normal
weight & length at birth; weight & height
decrease near the end of infancy, parallel
the norm through middle childhood, and
accelerates toward the end of
adolescence; normal adult size; bone age is
low and comparable to height age
* Height age is the age at which the standard (median) height
equals the present height
Differential Diagnosis
of Short Stature
3. Familial short stature- both infant
and parents are small; growth runs
parallel to and just below the normal
curves; bone age is normal
comparable to chronologic age
Differential Diagnosis
of Short Stature
4. Endocrine causes of decreased
linear growth/postnatal onset- length
decrease first or at the same time as
the weight; weight for height is
normal or elevated
Management
• Guidelines for GH treatment:
1. hGH 0.18-0.3 mg/kg/wk SC in 6-7
divided doses
2. Add LHRH agonist – interruption of
puberty will delay fusion & prolong
growth
3. Therapy until near final height is
achieved
* Criteria for stopping tx: growth rate < 1 in/yr & BA > 14 yrs
in girls & > 16 yrs in boys
HYPERPITUITARISM
• Primary type is rare in children
• Secondary type: seen in conditions in
which deficiency of a target organ
gives decreased hormonal feedback
• Pituitary hyperplasia – occurs in
response to stimulation by ectopic
production of releasing hormones or
systemic tumors
Pituitary Gigantism
• Young persons with open epiphyses,
overproduction of GH results in gigantism
• Persons with closed epiphyses –
acromegaly
• Cardinal clinical feature of gigantism:
longitudinal growth acceleration due to GH
excess
• Coarse facial features, enlarged hands &
feet, broad nose, enlarged tongue, visual
field defects
Diagnosis of GH excess
• Serum somatomedin C (IGF-I) is
uniformly increased in untreated cases;
more precise & cost-effective than serum
GH because GH levels fluctuate & have
short serum half-life (22 mins)
• All patients with acromegaly should have
baseline serum prolactin measured because
<40% of adenomas may secrete both
prolactin & GH.
Diagnosis of GH excess
• Gold standard: failure to suppress serum
GH levels to <5 ng/dL after a 1.75 g/kg
oral glucose challenge (measures the
ability of IGF-I to suppress GH secretion
because the glucose load results in insulin
secretion leading to IGFBP-I suppression,
leading to acute increase in free IGF-I)
• Serum IGF-I – sensitive screening test
for GH excess
Treatment of GH
Oversecretion
• Goals of therapy:
2. to remove or shrink the pituitary mass
3. to restore GH & secretory patterns to
normal
4. to restore IGF-I & IGFBP-3 levels to
normal
5. to retain the normal pituitary secretion
of other hormones
6. to prevent recurrence of disease
Treatment of GH
Oversecretion
• If with well-circumscribed pituitary
adenomas: transsphenoidal surgery
(complete removal of the tumor)
• Biochemical cure: GH level <1 ng/mL
within 2 hrs after a glucose load and
serum IGF-I (age adjusted normal
range)
• Pituitary radiation & medical therapy
• Somatostatin analog (Octreotide)
DIABETES INSIPIDUS
• Presents clinically with polyuria &
polydipsia and may result from
either vasopressin deficiency
(central DI) or vasopressin
insensitivity (nephrogenic DI)
DIABETES INSIPIDUS
• Vasopressin, secreted from the
posterior pituitary, is the principal
regulator of tonicity; has both
antidiuretic & vascular pressor
activity & synthesized in the
paraventricular & supraoptic nuclei of
the hypothalamus
DIABETES INSIPIDUS
• Vasopressin exerts its principal
effect on the kidney via V2
receptors located in the collecting
tubule, the thick ascending limb of
the loop of Henle & the
periglomerular tubules
• Activation of V2 receptor increase
in IC cAMP insertion of the
aquaporin-2 water channel into the
apical membrane
DIABETES INSIPIDUS
• Atrial natriuretic peptide (ANP) –
stimulates natriuresis (excretion of
excessive Na in the urine), inhibits
Na resorption & vasopressin
secretion
• ANP is expressed in endothelial cells
& vascular smooth muscle where it
relaxes arterial smooth muscles
DIABETES INSIPIDUS
• As plasma osmolality increases,
patient becomes thirsty & drinks
fluids--plasma is diluted before it
reaches the higher set level to
stimulate ADH release---initiates
cycle of polyuria & polydipsia
Central DI
• Genetic (autosomal dominant)
• Acquired:
3. Trauma (surgical or accidental)
4. Congenital malformation
5. Neoplasms (germinoma or pinealoma)
6. Infiltrative, autoimmune & infectious
disease
7. Drugs (ethanol, phenytoin, opiate
antagonists, halothane, alpha-adrenergic
agents)
Nephrogenic DI
• Genetic (X-linked, AR, AD): more
severe
• Acquired
 Hypercalcemia, hypokalemia
 Drugs (lithium, foscarnet,
amphotericin, methicillin,
rifampicin)
 Kidney disease (ureteral obstruction, CRF,
polycystic kidney disease)
Approach to DI
• Serum osmolality, Na, K, BUN,
creatinine, glucose, Ca, urine
osmolality, urine SG
• Diagnosis: serum osmolality >300
mOsm/L; urine osmolality <300
mOsm/L
• Differentiate central vs nephrogenic
type: water deprivation test: serum
osmolality 270-300 mOsm/L; with
pathologic polyuria & polydipsia
Diagnosis of Central DI
• Urine is inappropriately dilute (low
specific gravity <1.005) & osmolality
(50-200 mOsm/kg) in the presence
of serum osmolality (295 mOsm/kg)
& increased or normal serum sodium
• After Pitressin, urine osmolality
doubles.
Diagnosis of Nephrogenic
DI
• Urine SG <1.010, urine osmolality of
100-200 mOsm/kg (increased)
• Increased plasma osmolality 310-320
mOsm/kg
• After Pitressin, no change in urine
osmolality is noted.
Treatment of DI
• Central DI:
 Patients can maintain plasma osmolality &
Na in the high normal range
 Often best treated solely with fluid
therapy (3 L/m2/day)
 Long-acting vasopressin analog dDAVP
(desmopressin) intranasal (10 ug/spray) &
tablet (25-300ug every 8-12 hrs)
 Post-surgery: synthetic aqueous
vasopressin (Pitressin) – 1.5 mU/kg/hr
Treatment of DI
• Nephrogenic DI:
 Elimination of underlying disorder
 Ensure intake of adequate calories
for growth & to avoid severe
dehydration
 Use of thiazides with indomethacin &
amiloride to further reduce polyuria
Physiology of Puberty
• Prepubertal stage (between early
childhood and 8-9 yrs old): hypothalamic-
pituitary-gonadal axis is dormant; the
activity of the hypothalamus & pituitary is
thought to be suppressed by poorly
characterized neuronal restraint pathways
• Peripubertal stage (1-3 yrs before the
onset of puberty): low serum levels of LH
during sleep
• LH secretion occurs in a pulsatile fashion &
reflects episodic discharge of GnRH.
Physiology of Puberty
• Nocturnal pulses of LH – responsible of
enlargement & maturation of the gonads &
the secretion of sex hormones
• Early puberty – appearance of secondary
sex characteristics is the culmination of
the sustained active interaction among the
H-P-G axis
• Midpuberty – LH pulses become evident
during the daytime & occur at about 90-
120 min interval
Physiology of Puberty
• Mid- to late adolescence –
(+)feedback mechanism wherein
increasing levels of estrogen in
midcycle causing LH rise
• GnRH is the major hormone
responsible for the onset &
progression of puberty.
PRECOCIOUS PUBERTY
• Onset of secondary sexual
characteristics before 8 yrs old in girls
& 9 yrs old in boys
• Conditions causing precocious puberty:
3. Gonadotropin-dependent puberty (true
precocious puberty) – increased sex
hormone secretion & progressive sexual
maturation
 Idiopathic
 Brain tumors, severe head trauma,
hydrocephalus
 Prolonged & untreated hypothyroidism
PRECOCIOUS PUBERTY
2. Combined gonadotropin-dependent &
gonadotropin-independent puberty
3. Gonadotropin-independent (precocious
pseudopuberty) – no activation of the
normal HPG interplay & some sexual
chars.appear
 Ovarian tumors
 Exogenous estrogens/androgens
 Congenital adrenal hyperplasia
 McCune-Albright syndrome
 Adrenal tumors
PRECOCIOUS PUBERTY
4. Incomplete (Partial) precocious
puberty
 Premature thelarche – breast
development in the first 2 yrs of life,
regress after 2 yrs & rarely
progressive
 Premature adrenarche – pubic hair;
early maturational event of adrenal
androgen production
 Premature menarche
PRECOCIOUS PUBERTY
• Laboratory Findings:
2. Immunometric assay for LH (serum)-
serial blood samples obtained during
sleep & shows pulsatile LH secretion
3. GnRH stimulation test or an agonist
(leuprolide stimulation test) – diagnostic
tool esp.for boys where a brisk LH
response (LH peak >5-10 IU/L) with
predominance of LH over FSH that
occurs in the early phase
Laboratory Findings
3. Pelvic ultrasound – progressive
enlargement of the ovaries & uterus
4. Cranial CT scan/cranial MRI –
physiologic enlargement of the
pituitary gland; pedunculated mass
attached to the tuber cinereum of
the floor of the 3rd ventricle
Treatment
• Leuprolide acetate – 0.25-0.3 mg/kg IM
once every 4 wks (true precocious
puberty)
• If treatment is effective, serum sex
hormones decrease to prepubertal levels
(testosterone <20 ng/dL; estradiol <10
pg/mL); serum LH & FSH decrease to <1
IU/L
• Menarche & ovulatory cycles appear within
6-18 months of cessation of therapy
THYROID GLAND
• Development & Physiology:
 Fetal thyroid is seen at 7 wks of
gestation
 Thyroid follicle cell & colloid
formation at 10 wks of gestation
 Thyroglobulin synthesis occurs from
4 wks gestation onwards; iodine
trapping by 8-10 wks; T4 & T3
synthesis by 12 wks; TSH secretion
by 12 wks
Development &
Physiology
• Hypothalamic neurons synthesize
TRH by 6-8 wks of gestation
• Maturation of the hypothalamic-
pituitary-thyroid axis occurs occurs
over the 2nd half of gestation
• Normal feedback mechanisms mature
about 1-2 months postnatal life
Feedback control of thyroid
secretion
Development &
Physiology
• Functions of thyroid hormones:
 Increase oxygen consumption
(increased basal metabolic rate via
inc. Na-K-ATPase activity)
 Stimulate protein synthesis
 Affect CHO, lipid, vitamin
metabolism
 Influence growth & differentiation
(bone growth, CNS maturation)
HYPOTHYROIDISM
• Due to deficient production of
hormone or a defect in hormonal
receptor activity
• congenital or acquired
• Etiology of congenital
hypothyroidism:
4. Thyroid dysgenesis
5. Thyrotropin receptor-blocking antibody
6. Defective synthesis of thyroxine
7. Defect of iodide transport
8. Thyroid peroxidase defects of organification & coupling
Etiology of Congenital
Hypothyroidism
6. Defects of thyroglobulin synthesis
7. Defects in deiodination
8. Radioiodine
9. Thyrotropin deficiency
10. Thyroid hormone unresponsiveness
Clinical Manifestations
• Birthweight & length are normal
• Prolonged physiologic jaundice *
• Feeding difficulties, sluggishness,
lack of interest, somnolence
• Respiratory difficulties due to large
tongue
• Frequent constipation
• Large abdomen; usually with umbilical
hernia
Clinical Manifestations
• Hypothermic; cold & mottled skin; dry & scaly
• Edema of the genitals & extremities
• Retardation of physical & mental development
progresses
• Stunted growth, short extremities, depressed
nasal bridge, narrow palpebral fissures, swollen
eyelids, delayed dentition, short & thick neck,
deposits of fat above the clavicles & between the
neck & shoulders, coarse hair
• Delayed sexual maturation, motor & language skills
Diagnostics &
Therapeutics
• Low serum T4 & T3; elevated serum TSH
• X-ray: epiphyseal dysgenesis, deformity of
T12 or L1-2; large fontanels & wide
sutures; large sella turcica; cardiomegaly
• Tx: Sodium-L-thyroxine 10-15 ug/kg/day
• Monitor hormone levels & maintain
• Better prognosis if it occurred >2 years
old
THYROIDITIS
• Lymphocytic / Hashimoto / Autoimmune
• Most common cause of thyroid disease in
children & adolescents; also the most
common cause of acquired hypothyroidism
with or without goiter
• Etiology: organ-specific autoimmune
disease is characterized histologically by
lymphocytic infiltration between the
thyroid follicles (lymphoid follicle
formation with germinal centers)
THYROIDITIS
• HLA-DR4, HLA-DR5 associated with
an increased risk of goiter &
thyroiditis
• Thyroid antiperoxidase antibodies
(TPOAbs) seen in the sera of 90% of
children; inhibit enzyme activity &
stimulate natural killer cell
cytotoxicity
THYROIDITIS
• Girls > boys; more common >6 y/o
with peak during adolescence
• Most common manifestations are
goiter & growth retardation
• Thyroid is diffusely enlarged, firm &
nontender in most patients
• Most of the affected children are
euthyroid & asymptomatic
THYROIDITIS
• Variable clinical course (become small,
disappear, remain unchanged for years)
• Incidence in siblings or parents of
affected children 25%; autosomal
dominant
• Definitive dx: biopsy (rarely indicated)
• Thyroid function tests (normal)
• TSH may be slightly increased (subclinical)
THYROIDITIS
• Thyroid scan: 50% reveal irregular &
patchy distribution of the radioisotope
• Thyroid UTZ: scattered hypoechogenicity
• (+) Serum Ab titers to TPO
• Tx: if with evidence of hypothyroidism,
give sodium-L-thyroxine (50-150 ug/day)
• May be self-limited; periodic re-evaluation
• (+)nodules – biopsy (identify CA)
GOITER
• An enlargement of the thyroid gland
• May have normal function
(euthyroid), thyroid deficiency
(hypothyroidism) or overproduction
of hormones (hyperthyroidism)
• May be congenital or acquired;
sporadic or endemic
GOITER
• Results from increased pituitary secretion
of thyrotropic hormones in response to
decreased circulating levels of thyroid
hormones
• May also result from infiltrative processes
that may be inflammatory or neoplastic
• Congenital form: due to fetal T4 synthetic
defect or the administration of
antithyroid drugs or iodides during
pregnancy for the treatment of
thyrotoxicosis
GOITER
• Iodine deficiency – endemic goiter is
rare in populations living along the
sea
• RDA of iodine for infants is > 30
ug/kg/day
(cow’s milk > breast milk)
HYPERTHYROIDISM
• Results from excessive secretion of
thyroid hormone and due to diffuse
toxic goiter during childhood
• Germ line mutations of the TSH
receptor were reported in familial
(AD) cases
• May also be due to toxic uninodular
goiter (Plummer disease) or
hyperfunctioning thyroid carcinoma
Graves Disease
• Occurs in 1:5000 children with peak
incidence in the 11-15 y/o and a 5:1 female
to male ratio
• (+)family hx of autoimmune thyroid disease
• Enlargement of the thymus, splenomegaly,
lymphadenopathy, infiltration of the
thyroid gland & retro-orbital tissues
• Ophthalmopathy appears to be due to
antibodies against antigens shared by the
thyroid & eye muscle (TSH receptors
identified in retro-orbital adipocytes &
may be a target for antibodies)
Graves Disease
• Abs that bind to the extraocular
muscles & orbital fibroblasts
stimulate the synthesis of
glycosaminoglycans & produce
cytotoxic effects on muscle cells
Graves Disease
• Postulated failure of T suppressor
cells allows expression of T helper
cells, sensitized to the TSH Ag,
which interacts with B cells----
differentiate into plasma cells ---
produce TRSAb --bind to TSH
receptor & stimulates cAMP
• In whites, associated with HLA-B8 &
HLA-DR3
Graves Disease
• Peaks in adolescence
• Variable clinical course & thyroid size
• Interval between onset & diagnosis is
6-12 months
• Earliest sign may be emotional
disturbance with motor hyperactivity
• Tremor of fingers; voracious appetite
with loss or no increase in weight
Graves Disease
• Lagging of the upper eyelid, impaired
convergence, retraction of the upper
eyelid, infrequent blinking
• Flushed skin with excessive sweating
• Tachycardia, palpitations, dyspnea,
cardiomegaly, increased systolic & pulse
pressure, may have (+)apical systolic
murmur (MR) due to papillary muscle
dysfunction
Graves Disease
• Thyroid “crisis” or “storm” – acute
onset, hyperthermia, severe
tachycardia, restlessness, rapid
progression to delirium, coma & death
• “Apathetic” or “masked”
hyperthyroidism – extreme
listlessness, apathy, cachexia
• Both variants are rare in children.
Graves Disease
• Increased T4, T3; low TSH
• (+)TRSAb; its disappearance predicts
remission of the disease
• TSH receptor Abs are generally not
necessary for diagnosis but may be
useful in equivocal cases
• Radionuclide study: palpable nodule
and increased T3
Graves Disease
• Tx: preference of antithyroid drugs
over RAI or subtotal thyroidectomy
• PTU & Methimazole – both inhibit
incorporation of trapped inorganic
iodide into organic compounds; may
also suppress levels of TRSAb by
directly affecting intrathyroidal
autoimmunity
Graves Disease
• Methimazole 10x more potent than
PTU and has a longer serum half-life
• PTU is protein-bound and has a lesser
ability to cross the placenta & to
pass into breast milk; inhibits
extrathyroidal conversion of T4-T3
• Transient leukopenia as side effect
of Methimazole (asymptomatic)
Graves Disease
• PTU initial dose 5-10 mg/kg/day TID
• Methimazole 0.25-1 mg/kg/day OD or BID
• Careful surveillance needed
• Rising serum TSH to greater than normal
indicates overtreatment & leads to
increased size of the goiter
• Clinical response apparent in 2-3 wks;
adequate control evident in 1-3 months;
dose is decreased to the minimal level
needed to maintain a euthyroid state
Graves Disease
• Indications for surgery or RAI
treatment:
2. When adequate cooperation for medical
management is not possible
3. When adequate trial of medications has failed
to result in permanent remission
4. Severe side effects preclude further use of
antithyroid drugs
• Subtotal thyroidectomy – only when
the patient is in a euthyroid state
Graves Disease
• Radioiodine > 10 y/o; effective and
relatively safe; major consequence is
hypothyroidism which occurs in 10-20% of
patients after the 1st year & in 3% per
year thereafter
CALCIUM
HOMEOSTASIS
• PTH & Vit.D are the principal regulators
of calcium homeostasis
• Calcitonin & PTH-related peptide
(PTHrP) – important primarily in the fetus
• In the parathyroid gland, pre-pro-PTH & a
proparathyroid hormone are
synthesized--- pre-pro-PTH converted
to pro-PTH-converted to PTH (rapidly
cleaved in the liver & kidney into smaller
fragments)
CALCIUM
HOMEOSTASIS
• PTH has C-terminal, mid-region & N-
terminal fragments
 N-terminal – assay most useful for detecting
acute secretory changes
 C-terminus & mid-region – inert & represent 80%
of plasma immunoreactive PTH
 C-terminal assay – detects hyperparathyroidism
• When serum Ca falls, secretion of
PTH increases.
CALCIUM
HOMEOSTASIS
• PTH stimulates 1-a-hydroxylase in
the kidney--enhances production of
1,25-OH2D3--induces synthesis of
a Ca-binding protein (calbindin-D) in
the intestinal mucosa with Ca
absorption
• PTH mobilizes Ca by directly
enhancing bone resorption
CALCIUM
HOMEOSTASIS

• Hypocalcemia induces increased PTH


secretion; hypercalcemia depresses
PTH secretion.
CALCIUM
HOMEOSTASIS
• Calcitonin – 32-AA polypeptide;
secreted in parafollicular cells (C
cells) of the TG
 In the fetus, high levels augment bone metabolism
& skeletal growth stimulated by the normally high
fetal Ca levels.
 Main biologic effect: inhibition of bone resorption
by decreasing the number & activity of bone-
resorbing osteoclasts.
HYPOPARATHYROIDISM
• Hypocalcemia is common from 12-72
hrs of life esp.in premature infants,
in infants with asphyxia at birth & in
infants of diabetic mothers
Clinical Manifestations
• Muscular pain and cramps – early
• Numbness, stiffness, tingling of the
hands & feet
• (+)Chvostek or Trosseau sign or
laryngeal & carpopedal spasm
• Convulsions with loss of
consciousness
• Chronic: late teeth eruption,
irregular enamel formation, soft
teeth
Clinical Manifestations
• Dry & scaly skin
• Horizontal lines in nails of the
fingers & toes
• Mucocutaneous candidiasis
• Cataracts
• Permanent mental & physical
deterioration occur if initiation of
treatment is delayed.
Serum Calcium
• About 50% of calcium is ionized
• 40-45% is bound to albumin
• 5-10% is bound to other anions (sulfate,
PO4, lactate, citrate)
• Only ionized fraction is physiologically
active & can be rapidly measured
• Blood pH should always be performed with
ionized Ca (increased in acidosis;
decreased in alkalosis)
Laboratory Findings
• Serum calcium <5-7 mg/dL
• Serum phosphorus >7-12 mg/dL
• Serum ionized calcium (45% of the total)
is low
• Serum alkaline phosphatase is normal or
low
• Low level of 1,25 OH2D3
• Normal serum magnesium
• Low serum PTH
Laboratory Findings
• X-ray of the bones: increased
density limited to the metaphyses
• X-ray and CT of the skull:
calcifications in the basal ganglia
• ECG: prolonged QT interval
• EEG: widespread slow activity
Management
• Emergency treatment for neonatal tetany:
5-10 ml of 10% solution of calcium
gluconate IV at a rate of 0.5-1 mL/min
while HR is monitored
• 1,25-dihydroxycholecalciferol (calcitriol)
should be given – initial dose 0.25 ug/day &
MD 0.01-0.1 ug/kg/day; given in 2 equal
divided doses
Management
• Supplemental calcium gluconate or
glubionate to provide 800 mg of elemental
calcium daily
• Reduce high phosphorus content in diet
such as milk, eggs & cheese
• Frequent monitoring of serum calcium
levels
HYPERPARATHYROIDISM
• Excessive production of PTH due to
primary defect of the parathyroid
glands such as adenoma or
hyperplasia; may also be due to
vitamin D excess
• Increased PTH production is
compensatory aimed at correcting
hypocalcemic states of diverse
origins
HYPERPARATHYROIDISM
• Childhood occurrence is rare; usually
due to a single benign adenoma
manifested after 10 yrs of age
• Some occur as part of multiple
endocrine neoplasia (MEN) syndrome
(AD) characterized by hyperplasia or
neoplasia of the endocrine pancreas,
the anterior pituitary & parathyroid
glands
Clinical Manifestations
• Muscular weakness, anorexia, nausea,
vomiting, constipation, polydipsia,
polyuria, loss of weight, fever
• Progressively diminished renal
function in chronic cases
• Osseous changes may produce pain in
the back or extremities, gait
disturbances, fractures
Clinical Manifestations
• Abdominal pain
• Parathyroid crisis: serum calcium >15
mg/dL, progressive oliguria,
azotemia, stupor, coma
• Infants: failure to thrive, poor
feeding, hypotonia
• Chronic cases: mental retardation,
convulsions, blindness
Laboratory Tests
• Serum calcium should always be
measured at the same time as PTH.
• Primary case: increased serum Ca;
increased serum PTH; increased
serum chloride; decreased serum
phosphorus in 50% of cases
Laboratory Findings
• Serum & ionized calcium elevated
• Serum phosphorus is low <3 mg/dL
• Serum magnesium is low
• Low specific gravity of urine
• Serum nonprotein nitrogen & uric
acid inc.
• Elevated serum PTH
Laboratory Findings
• Most consistent X-ray finding is
resorption of subperiosteal bone
best seen along the margins of the
phalanges of the hands
• Skull X-ray: gross trabeculation or a
granular appearance due to focal
rarefaction
• Abdominal X-ray: renal calculi or
nephrocalcinosis
Management
• Surgical exploration is indicated in all
instances.
• All glands should be carefully
inspected.
• Removal of the adenoma
• Total parathyroidectomy for infants
with severe hypercalcemia
• Good prognosis if recognized early &
there is appropriate surgical
treatment
ADRENAL GLANDS
• Adrenal gland: 2 endocrine systems:
medullary gland & cortical system
• Adrenal cortex:
3. Zona glomerulosa – aldosterone
(15%)
4. Zona fasciculata – cortisol &
androgens
5. Zona reticularis – androgens (10%)
Hypothalamic-Pituitary-
Adrenal Axis
• Pulses of ACTH & cortisol occur
every 30-120 minutes, are highest at
about the time of waking, are low in
late afternoon & evening, and reach
their lowest point an hour or two
after sleep begins.
Hypothalamic-Pituitary-
Adrenal Axis
• In the hypothalamus (paraventricular
nucleus): CRH is synthesized which is the
most important stimulator of ACTH
secretion.
• AVP augments CRH action--neural stimuli
from the brain cause the release of CRH &
AVP-- pulsatile release in the
hypophyseal-portal circulation--pulsatile
release of ACTH
Role of ACTH
• Acute effects of ACTH:
 Stimulates cholesterol release
 Transport of cholesterol into
mitochondria
 Binds cholesterol to P450
cytochrome
 Releases newly synthesized
pregnenolone
Role of ACTH
• Long-term effects of ACTH
stimulation:
 increase the uptake of LDL
cholesterol
 Formation of the steroidogenic
enzymes
Renin-Angiotensin-Aldosterone
System
• Major regulators of aldosterone secretion
are the R-A system & potassium
• Renin produced by the JG apparatus
reacts with renin substrate --
angiotensin I--angiotensin-converting
enzyme cleaves-- angiotensin II---
angiotensin III (potent stimulators of
aldosterone secretion)
• Both angiotensin & K act by IC signal
transduction mechanisms to stimulate
conversion of cholesterol to pregnenolone.
Adrenal Steroids
• Glucocorticoids:
 Regulate RNA & protein synthesis
 Catabolic effect in muscles, skin,
connective, adipose & lymphoid tissues:
increased degradation of protein
 Anabolic in the liver: increase protein &
glycogen content, enhances
gluconeogenesis
 Effects of insulin & androgens are
antagonistic to those of glucocorticoids
Adrenal Steroids
• Mineralocorticoids
 Aldosterone maintains electrolyte balance-
blood volume & BP stabilization
 Controls Na & H20 reabsorption in the distal
tubules
• Androgens
 inc. retention of N, K, P, S04
 Promote growth & have androgenic effects
 DHEAS levels begin to rise before the other
hormonal changes of puberty occur
ADRENAL MEDULLA
• Catecholamines: dopamine, norepinephrine,
epinephrine
• Synthesis occur in the brain, sympathetic
nerve endings & in chromaffin cells
• Metabolites are excreted in the urine:
VMA, metanephrine, normetanephrine
• Both epi- & norepinephrine raise the mean
arterial BP, increase PVR-inc.systolic &
diastolic BP
• Epinephrine increases the PR-dec.PVR
ACTH INSUFFICIENCY
• Addison’s disease
• Deficient production of cortisol or
aldosterone due to congenital or acquired
lesions of the hypothalamus, pituitary
gland or adrenal cortex
• Etiology: congenital hypo- or aplasia of the
pituitary (abnormalities of skull & brain,
craniopharyngioma), adrenal hypoplasia
congenita, inborn defects of
steroidogenesis, autoimmune destruction
of the glands, CNS demyelination, etc.
Laboratory Tests
• Low serum Na & Cl, increased K
• Inc. urinary excretion of Na & Cl
• Nonprotein nitrogen plasma level is
high, hypoglycemia
• Most definitive test: measurement of
plasma or serum level of cortisol
before & after administration of
ACTH
Clinical Manifestations
• S/Sy begin shortly after birth (adrenal
hypoplasia, steroidogenesis defects):
failure to thrive, vomiting, lethargy,
anorexia, dehydration
• Older children: gradual, muscular
weakness, lassitude, anorexia, weight loss,
general wasting, hypotension, intense
craving for salt
Clinical Manifestations
• Increased skin pigmentation on face
& hands, most intense around the
genitals, umbilicus, axilla, nipples,
joints
• Failure of suntan to disappear may be
the first clue
Management
• D5 0.9 NSS IV – to correct hypoglycemia
& the Na loss
• Hydrocortisone succinate IV (25 mg for
infants & 75 mg for children) every 6 hrs
for the 1st 24 hrs
• After 48 hrs, may discontinue fluids &
shift to oral cortisol in 5-20 mg every 8
hrs
• Further reduction until maintenance levels
& a stable clinical situation are achieved.
• May add Florinef ( flurohydrocortisone)
0.05-0.3 mg daily
C0NGENITAL ADRENAL
HYPERPLASIA
• AR disorders of adrenal
steroidogenesis leading to a
deficiency of cortisol--inc.
secretion of corticotropin--
adrenocortical hyperplasia &
overproduction of intermediary
metabolites
• Deficiency of 21-hydroxylase
accounts for 90% of affected
patients
Clinical Manifestations
• NON-SALT-LOSING CAH
 Normal at birth but signs of sexual & somatic precocity
appear within the 1st 6 months of life
 Well developed muscles & BA > CA
 Stunted adult stature
 Small testes and enlarged penis
 Usually normal mental development
 Females: pseudohermaphroditism; enlarged clitoris, labial
fusion; internal genital organs are those of a normal female
 Masculinization progresses after birth
 Tall for age with advanced ossification
Clinical Manifestations
• SALT-LOSING CAH
 Severity of virilization is generally greater in this
type
 Symptoms begin shortly after birth: failure to
regain birthweight, progressive weight loss,
dehydration, prominent vomiting, anorexia
 Females: virilization of external genitals
 Males: genitals appear normal
Laboratory Findings
• Salt-losing type: low serum Na & Cl;
inc. K; low serum cortisol
• Inc.plasma renin; serum aldosterone
• 21-hydroxylase deficiency: increased
serum 17-OHP
• Pelvic ultrasound to visualize
presence of uterus in female
pseudohermaphrodites
Laboratory Findings
• Urinary 17-ketosteroid excretion &
plasma levels of DHEAS elevated
with CAH & cortical tumors but very
high values favor the diagnosis of
neoplasm
Management
• Glucocorticoids inhibit excessive
production of androgens & prevents
progressive virilization
• Hydrocortisone 10-20 mg/m2/day orally in
2-3 divided doses
• Monitor growth & hormonal levels
• Flurohydrocortisone (0.05-0.3 mg daily) &
NaCl 1-3 gms given to normalize plasma
renin activity
• Hydrocortisone continued indefinitely in all
patients with classic forms of CAH
Management
• Adequate indices of control: monitor
serum 17-OHP, androstenedione,
testosterone, renin preferably measured
at 8-9 am prior to taking the morning
medication
• Surgical correction of enlarged clitoris at
6-12 months old
• Outcome: short stature, disordered
puberty, menstrual irregularity, infertility
CUSHING SYNDROME
• Characteristic pattern of obesity with
associated hypertension which is the
result of abnormally high blood levels of
cortisol resulting from hyperfunction of
the adrenal cortex; ACTH –dependent or
independent
• Etiology: functioning adrenocortical tumor
(infants); pituitary adenomas; hyperplasia
of adrenals
Clinical Manifestations
• More severe in infants
• Rounded face, prominent cheeks, moon
facies, buffalo hump, generalized obesity,
abnormal masculinization, impaired growth,
hypertension, inc. susceptibility to
infection
• Older children: purplish striae on hips,
abdomen & thighs, delayed puberty,
emotional lability, weakness, headache,
renal stones
Laboratory Findings
• Serum cortisol levels are normally
elevated at 8 am & decrease to <50%
by 8pm---diurnal rhythm is lost
• Urinary excretion of free cortisol &
17-hydroxycorticosteroids are
increased
Management
• Unilateral adenalectomy for benign
cortical adenomas
• Bilateral tumors: subtotal adenalectomy
• Trans-sphenoidal pituitary microsurgery
for children
• Adequate preoperative & postoperative
replacement therapy
• Substantial catch-up growth; abnormal
bone density
PHEOCHROMOCYTOMA
• Catecholamine-secreting tumor arising
from the chromaffin cells
• Most common site of origin is the adrenal
medulla
• Tumors may develop anywhere along the
abdominal sympathetic chain, likely to be
located near the aorta at the level of the
IMA or at its bifurcation.
• Periadrenal area, urinary bladder, ureteral
walls, thoracic cavity, cervical region
PHEOCHROMOCYTOMA
• Occur in children 6-14 yrs old
• Tumors found more often on the right
side, about 1-10 cm in diameter
• Bilateral in >20% affected children
• Inherited as AD trait
• May be associated with other syndromes
such as neurofibromatosis, part of MEN
syndromes, tuberous sclerosis, Sturge-
Weber syndrome, ataxia-telangiectasia
Biosynthesis &
Metabolism
Phenylalanine Tyrosine

Dopamine
Dihydroxyphenylalanine

Norepinephrine Epinephrine

3-Methoxy-dopamine Normetanephrine Metanephrine

Homovanillic acid 3-Methoxy-4-hydroxy


mandelic acid (VMA)
Clinical Manifestations
• S/Sy result from excessive secretion of
epinephrine & norepinephrine
• May be symptom-free in between attacks
of hypertension
• Headache, palpitations, abdominal pain,
dizziness, pallor, vomiting, sweating,
convulsions
• Severe: precordial pain radiate into the
arms, pulmonary edema, cardio- &
hepatomegaly
Clinical Manifestations
• Good appetite but does not gain
weight due to hypermetabolism
• Polyuria, polydipsia, growth failure,
papilledema, hemorrhages, exudates
& arterial constriction on
ophthalmoscopy
Laboratory Findings
• Urine contains protein & few casts
• Gross hematuria suggests that the tumor
is in the bladder wall
• Dx: demonstration of elevated blood or
urinary levels of catecholamines & their
metabolites
• Predominant catecholamine in children is
norepinephrine derived from the adrenal
gland & adrenergic nerve endings
Laboratory Findings
• Total urinary catecholamine excretion
>300 ug/day
• Urinary excretion of vanillylmandelic acid
(major metabolite of epi-, norepi- &
metanephrine) is increased
• Vanilla-containing foods & fruits can
produce falsely elevated levels of VMA
• Ultrasound, CT scan, MRI: tumors
• I-metaiodobenzylguanidine taken up by
chromaffin tissue is useful for localizing
small tumors
Management
• Surgical removal of tumors
• Preoperative a- & B-adrenergic
blockers
• Thorough transabdominal exploration
of all the usual sites
• Accurate indicators of malignancy –
presence of metastatic disease or
local invasiveness that precluded
complete resection or both
Management
• Pediatric malignant tumors – rare
• Prolonged follow-up is indicated
because functioning tumors at other
sites may become manifested many
years after the initial operation
DEVELOPMENT OF
GONADS
• The undifferentiated, bipotential
fetal gonad arises from a thickening
of the urogenital ridge
• 6 wks of gestation – gonad contains
germ cells & stromal cells --Leydig
cells in testes; theca, interstitial or
hilar cells in the ovary; supporting
cells ---Sertoli cells in testes or
granulosa cells in ovaries
DEVELOPMENT OF GONADS
• In the absence of a testis-determining
factor (SRY or sex-determining region on
the Y chromosome), the gonad develops
into an ovary.
• 46,XX – needed for the development of
normal ovaries
• Development of the testis requires a Y
chromosome (short arm of the Y is critical
for sex determination)
Function of the Testes
• During the 1st trimester of pregnancy –
levels of placental chorionic gonadotropin
peak (8-12 wks) & stimulate the fetal
Leydig cells to secrete testosterone;
critical period for normal virilization of
the XY fetus
• Shortly after birth, transient increase of
gonadotropins (LH) occurs- sharp inc. in
serum testosterone which peak at 1-3
months old-- 6 mos.old levels dec. to low
prepubertal levels that persist until the
beginning of puberty
Function of the Testes
• Within specific target cells, 6-8% of
testosterone is converted by 5-
reductase to dihydrotestosterone &
0.3% is acted on by aromatase to
produce estradiol
• Half of circulating testosterone is
bound to sex-hormone-binding
globulin (SHBG) & half to albumin;
only 2% circulates in the free form
Function of the Testes
• Mullerian-inhibiting substance
(MIS) – earliest secreted product of
the Sertoli cells of the fetal testis;
causes involution of the embryologic
precursors of the cervix, uterus &
fallopian tubes during sexual
differentiation; secreted in males by
Sertoli cells both during fetal &
postnatal life’ in females, it is
secreted by granulosa cells only
postnatally
Function of the Testes
• Inhibin – glycoprotein secreted by
the Sertoli cells of the testes &
granulosa & theca cells of the ovary;
inhibits FSH secretion
• Activin – stimulates pituitary FSH
secretion
• Follistatin – protein produced by
gonads that inhibits FSH secretion
Function of the Ovaries
• Oocytes are present from the 4th mo of
gestation; need granulosa cells to form
primordial follicles
• Most important estrogens produced by the
ovary are: estradiol-17 (E2) & estrone (E1);
estriol is a metabolic product of these two
& all three may be found in the urine of
mature females
• Estrogens also arise from androgens in the
adrenal glands & in the testis.
Function of the Ovaries
• Ovary also synthesizes progesterone, a
progestational steroid; the adrenal cortex
& testis synthesize progesterone as a
precursor for other adrenal & testicular
hormones.
• Estrogens, like androgens, inhibit
secretion of LH & FSH.
• In females, estrogens also provoke the
surge of LH secretion that occurs in
midmenstruation.
Conversion of Androgens
to Estrogens

Androstenedione Testosterone

P450 Aromatase

Estrone (E1) 17B-Estradiol


(E2)
PRIMARY
HYPOGONADISM
• Hypergonadotropic hygonadism in the male
• Congenital anorchia occurs in 0.6% of boys
with nonpalpable testes (1/20,000 males)
• Have normal external genitals; noxious
factor damaged the fetal testes of the
genetic male fetus after sexual
differentiation took place
• Chromosomal aberrations
Noonan Syndrome
• Boys & girls have normal karyotypes
• Occurs in ½,000 live births
• Autosomal dominant
• Short stature, webbing of the neck,
pectus carinatum/excavatum, cubitus
valgus, right-sided CHD, hypertelorism,
downward slanted palpebral fissures,
ptosis, micrognathia, moderate MR in 25%,
SNHL; hepatosplenomegaly; delayed
puberty, cryptorchidism
• Human growth hormone has been used.
KLINEFELTER
SYNDROME
• 1/500-1/1,000 newborn males have
47,XXY chromosome – most common
sex chromosomal aneuploidy in males
• Due to meiotic nondisjunction of an X
chromosome during parental
gametogenesis; the extra X
chromosome is maternal in origin in
54% & paternal in 46% of patients.
Clinical Manifestations
• Dx rarely made before puberty due to
paucity of s/sy in childhood
• Considered in all boys with MR & in
children with psychosocial, learning, or
school adjustment problems
• Anxious, immature, excessively shy,
aggressive, antisocial acts
• Tall, slim, underweight, long legs, small
testes & penis, gynecomastia, azoospermia,
associated with leukemia & lymphoma (15-
30 yrs old)
Management
• Normal basal plasma levels of FSH & LH
before 10 yrs old.
• Midpuberty – testicular growth stops &
testosterone levels are low
• Replacement therapy with a long-acting
testosterone preparation at 11-12 yrs old
• Enanthate ester 25-50 mg IM every 3-4
wks with 50-mg increments every 6-9 mos
until a maintenance dose for adults is
achieved (200-250 mg every 3-4 wks)
HYPOFUNCTION OF THE
OVARIES
• Caused by congenital failure of
development, postnatal destruction
(primary hypogonadism), or lack of
stimulation by the pituitary
(secondary hypogonadism)
• Hypergonadotropic hypogonadism in
the female
• Diagnosis before puberty is difficult
Turner Syndrome
• 45,X chromosomal complement
• Unknown mechanism of chromosome loss
• Risk does not increase with maternal age
• Recognizable at birth: edema of the dorsa
of the hands & feet, loose skin folds at the
nape, LBW, decreased length, webbed
neck, low posterior hairline, small
mandible, prominent ears, epicanthal folds,
high arched palate, widely spaced nipples,
hyperconvex fingernails, delayed sexual
maturation
Turner Syndrome
• Short stature – cardinal finding in all girls
• Nonstenotic bicuspid aortic valves,
horseshoe kidney, complete absence of one
kidney, idiopathic hypertension, IBD
• Ultrasound of the heart, kidneys & ovaries
is indicated after the dx is established
• Most common skeletal abnormalities:
shortening of the 4th metatarsal &
metacarpal bones, epiphyseal dysgenesis in
the joints of the knees & elbows
Turner Syndrome
• Plasma level of gonadotropins (FSH) are
elevated---decrease from 2-8 yrs old--by 10-
11 yrs old rise to adult levels
• Tx: recombinant GH increases height velocity &
ultimate stature in most but not all children
(starting dose 0.375 mg/kg/wk)
• Replacement therapy with estrogens is indicated
(little consensus re: initiation)
Turner Syndrome
• Premarin (conjugated estrogen) 0.3-0.625
mg given daily for 3-6 mos – effective in
inducing puberty
• Estrogen is then cycled (taken on days 1-
23) & Provera (progestin) is added taken
on days 10-23 in a dose of 5-10 mg daily
• Withdrawal bleeding occurs in the
remainder of the calendar month
• Psychosocial support
47,XXX Females
• Most frequent X chromosome abnormality
occurring in about 1/1,000 liveborn girls
• Due to maternal meiotic nondisjunction
• Phenotype is of a normal female; normal
sexual development
• By 2 yrs old, delays in speech is evident,
lack of coordination, poor academic
performance, immature behavior
• Tall & gangly, well coordinated,
academically superior, socially outgoing
DIABETES MELLITUS
• Syndrome of metabolic disease
characterized by hyperglycemia due
to deficiency of insulin secretion or
insulin action or both resulting in
abnormal metabolism of CHO, CHON
& fat
• Most common endocrine-metabolic
disorder of childhood & adolescence
Etiologic Classification
• Type I – B-cell destruction leading to
absolute insulin deficiency: immune-mediated
or idiopathic
• Type II – insulin resistance with relative
deficiency or a secretory defect with insulin
resistance
• Drug- or chemical-induced – glucocorticoids,
thyroid hormone, diazoxide, thiazides,
dilantin, B-adrenergic agonists
• Infections – congenital rubella, CMV
• Gestational DM
• Neonatal DM
Impaired Glucose
Tolerance
• Refers to a metabolic stage that is
intermediate between normal glucose
homeostasis & diabetes
• Fasting glucose concentration of 109
mg/dL – upper limit of “normal”
• Many individuals are euglycemic;
manifest hyperglycemia only when
challenged with oral glucose load
Insulin
• Insulin is synthesized in the RER of
the B cells of the pancreas-
transported to the Golgi apparatus
---packaged in membrane-bound
granules--move to the cell wall &
their membranes fuse expelling the
insulin to the exterior--insulin
crosses the basal lamina of the B cell
& the fenestrated epithelium of the
capillary to reach the bloodstream
Effects of Insulin
• Adipose tissue
 Increase glucose entry
 Increase FA synthesis
 Increase glycerol phosphate synthesis
 Increase triglyceride deposition
 Activation of lipoprotein lipase
 Increase K uptake
 Inhibition of hormone-sensitive lipase
Effects of Insulin
• Muscle
 Increase glucose entry
 Increase glycogen synthesis
 Increase amino acid uptake
 Increase protein synthesis in ribosomes
 Decrease protein catabolism
 Decrease release of gluconeogenic amino acids
 Increase ketone uptake
 Increase K uptake
Effects of Insulin
• Liver
 Decrease ketogenesis
 Increase protein synthesis
 Increase lipid synthesis
 Decrease glucose output due to decrease
gluconeogenesis & increase glycogen synthesis
• General
 Increase cell growth
TYPE I DM
• Girls=boys; peaks at 5-7 yrs old & puberty
• Basic cause of the initial clinical findings is
the sharply diminished insulin secretion
• Mechanisms that lead to failure of
pancreatic B-cell function point to the
likelihood of autoimmune destruction of
pancreatic islets in predisposed individuals
• Associated with increased frequency of
HLA-B8, -DR3, -BW15, -DR4
TYPE I DM
• About 80-90% of newly diagnosed patients
have islet –cell antibodies (ICAs) directed
at cell surface.
• Some evidence of abnormal T-cell function
with an alteration in the ratio of
suppressor to killer T cells at the onset
• Tissue damage of pancreatic B cells is
mediated by T lymphocytes-- produce
cytokines-- induce destruction of islet
cells
Effects of Insulin
Deficiency
Insulin deficiency (& glucagon excess)

Dec.glucagon uptake CHON synthesis Lipolysis

Hyperglycemia, plasma AA; N loss plasma


FFA,
glycosuria, osmotic in urine
ketogenesis,
diuresis, E-disturbance
ketonuria,
-nemia
Dehydration, acidosis
Coma
Effects of Insulin
Deficiency
• With progressive deficiency--excessive
glucose production & impairment of its
utilization--hyperglycemia w/
glucosuria---resultant osmotic diuresis
produces polyuria, urinary losses of
electrolytes, dehydration, polydipsia-
hypersecretion of epinephrine, glucagon,
cortisol & GH which amplifies &
perpetuates metabolic derangements &
accelerates metabolic decompensation
Effects of Insulin
Deficiency
• Combination of insulin deficiency &
inc. counterregulatory hormones is
responsible for accelerated lipolysis
& impaired lipid synthesis-
inc.plasma total lipids, cholesterol,
TG, FFAketone body formation w/c
exceeds the capacity for peripheral
utilization & renal excretion--
metabolic acidosis & rapid deep
breathing
Clinical Manifestations
• Classic: polyuria, polydipsia,
polyphagia, weight loss (often in a
less than a month)
• Clue to polyuria: onset of enuresis in
a previously toilet-trained child
• Pyogenic skin infections & monilial
vaginitis in adolescent females
• Lethargy & weakness
Diagnosis
• Dependent on the demonstration of
hyperglycemia in association with
glucosuria with or w/o ketonuria
• Postprandial determinations of blood
glucose or screening oral glucose
tolerance tests yield low detection
rates in children
Diagnostic Criteria
• Symptoms of diabetes plus a random
plasma glucose >200 mg/dL or fasting
plasma glucose >126 mg/dL or a 2-hr
plasma glucose during the OGTT >200
mg/dL
• Polyuria, polydipsia, & unexplained
weight loss with glucosuria &
ketonuria
DIABETIC
KETOACIDOSIS
• Glucose >300 mg/dL, ketonemia,
acidosis (pH <7.3 & HCO3 <15 mEq/L),
glucosuria, ketonuria
• Precipitating factors like trauma,
infections, vomiting, psychologic
disturbances
Nonketotic Hyperosmolar
Coma
• Blood glucose >600 mg/dL, absence
of or only slight ketosis, nonketotic
acidosis, severe dehydration,
depressed sensorium or coma, various
neurologic signs
• Serum osmolarity is >350 mOsm/kg
• Pre-existing neurologic damage
Management
• 3 phases: ketoacidosis, postacidotic or
transition period for establishment of
metabolic control, continuing phase of
guidance of the diabetic child
• Ketoacidosis: expansion of intravascular
volume, correction of deficits in fluid,
electrolyte & acid-base status; initiation
of insulin therapy
• Blood pH & electrolytes; ECG; blood
culture; monitoring I & O
Management
• Initial hydrating fluid is isotonic saline
(hypotonic relative to the patient’s serum
osmolality)
• Rate of fluid replacement is adjusted to
provide 50-60% of the calculated deficit
within the 1st 12 hrs; the remainder is
given during the next 24 hrs
• Administration of glucose (5% solution in
0.2 N saline) is initiated when blood
glucose approaches 300 mg/dL to limit the
decline of serum osmolality & reduce
cerebral edema
Management
• Give potassium added after the
initial 20 ml/kg if UO is adequate.
• Bicarbonate only if pH <7.2 given
slowly
• Anticipate cerebral edema – limit
rate of fluid to 4 L/m2/day or less
• Insulin 0.1 U/kg of regular insulin
followed by constant infusion of 0.1
U/kg/hr
Management
• When acidosis has been corrected, the
continuous infusion may be discontinued &
insulin given subcutaneously at 0.2-0.4
U/kg every 6-8 hrs while maintaining the
glucose infusion until the child can fully
tolerate food.
• Monitor blood glucose before & 2 hrs
after each meal & the insulin dose
adjusted to maintain the blood glucose in
the range of 80-180 mg/dL.
Nutritional Management
• CHO 55%, fat 30%, CHON 15%
• 70% of CHO content should be derived
from complex CHO & intake of sucrose &
highly refined sugars should be limited.
• Polyunsaturated:saturated fat ratio 1.2:1
• Total daily caloric intake divided to
provide 20% at breakfast, 20% at lunch,
30% at dinner with 10% for each of the
midmorning, midafternoon & evening
snacks.
Monitoring
• Reliable index of long-term glycemic
control – measure glycosylated Hgb
• Glycohemoglobin (HbA1c) represents the
fraction of Hgb to which glucose has been
nonenzymatically attached in the
bloodstream
• The higher the blood glucose & the longer
the RBC’s exposure to it, the higher will be
the fraction of HbA1c-- reflects the
average blood glucose concentration of the
preceding 2-3 months
Glycohemoglobin
• Glucose combines with Hgb
continuously & nearly irreversibly
during the life span of RBC (120
days)
• Glycated Hgb is proportional to the
mean plasma glucose level during the
previous 6-12 weeks
• Glycated Hgb predicts risk of
progression of diabetic complications
Glycohemoglobin
• HbA1c measurements obtained 3-
4x/yr to get a profile of long-term
glycemic control
• The more consistently lower the
level, the better the metabolic
control, the more likely it is that
microvascular complications will be
less severe, delayed in appearance or
avoided.
Glycohemoglobin
• Use: monitor diabetic patients’
compliance with therapeutic regimen
& long-term blood glucose level
control
• In known diabetics: 7% indicates
good diabetic control; 10% indicates
fair diabetic control; 13-20%
indicates poor diabetic control
Somogyi Phenomenon
• Hypoglycemic episodes manifest as late
nocturnal or early AM sweating, night
terrors & headaches alternating rapidly
within 4-5 hrs with ketosis, hyperglycemia,
ketonuria & glucosuria suggest the
possibility of Somogyi phenomenon.
• Due to an outpouring of counterregulatory
hormones in response to insulin-induced
hypoglycemia.
Dawn Phenomenon
• Elevations of blood glucose occur
between 5-9 am without preceding
hypoglycemia
• Normal event; reflects the waning
effects of insulin probably due to
increased clearance of insulin &
nocturnal surges of GH that
antagonize insulin’s metabolic effects
Brittle Diabetes
• Implies that control of blood glucose
fluctuates widely & rapidly despite
frequent adjustment of insulin doses
• Somogyi & dawn phenomena are the most
common cause of “brittleness”.
• To distinguish: measure blood glucose at
3,4,7 am. If blood glucose >80 mg/dL in
the 1st 2 samples & markedly higher in the
last ---dawn (tx: inc. evening dose of
intermediate insulin 10-15%)
Brittle Diabetes
• If the 3 or 4 am blood glucose level
is 60 mg/dL or less followed by
rebound hyperglycemia at 7 am-
Somogyi (tx: reduction of the evening
intermediate-acting insulin of 10-15%
or a delay in its injection until about
9 pm is indicated)

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