Objectives

• To understand the pathophysiology & recognize

the common manifestations of the following
conditions:
1. Hypopituitarism / Hyperpituitarism
2. Diabetes insipidus
3. Precocious puberty
4. Hypothyroidism / Hyperthyroidism
5. Thyroiditis
6. 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:

1. Somatotropes – produce GH
2. Lactotropes – prolactin
3. Thyrotropes – TSH
4. Corticotropes – pro-opiomelanocortin, the
precursor of corticotropin (ACTH)
5. 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:
1. Arginine vasopressin (ADH)
2. 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
1. Insulin-like GF I (somatomedin C) – secretion is
stimulated by GH
2. 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:
1. Of normal size & weight at birth
2. 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:
1. Diagnosis of classic type is suspected in cases of
profound postnatal growth failure (height > 3 SD
below the mean for age & gender)
2. 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:
1. to remove or shrink the pituitary mass
2. to restore GH & secretory patterns to normal
3. to restore IGF-I & IGFBP-3 levels to normal
4. to retain the normal pituitary secretion of other
hormones
5. 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:
1. Trauma (surgical or accidental)
2. Congenital malformation
3. Neoplasms (germinoma or pinealoma)
4. Infiltrative, autoimmune & infectious disease
5. Drugs (ethanol, phenytoin, opiate antagonists,
halothane, alpha-adrenergic agents)
Nephrogenic DI

• Genetic (X-linked, AR, AD): more severe

• Acquired
1. Hypercalcemia, hypokalemia
2. Drugs (lithium, foscarnet, amphotericin, methicillin, rifampicin)
3. 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:
1. 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:
1. Immunometric assay for LH (serum)- serial blood
samples obtained during sleep & shows pulsatile
LH secretion
2. 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:
1. Thyroid dysgenesis
2. Thyrotropin receptor-blocking antibody
3. Defective synthesis of thyroxine
4. Defect of iodide transport
5. 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:

1. When adequate cooperation for medical management is
not possible
2. When adequate trial of medications has failed to result in
permanent remission
3. 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:
1. Zona glomerulosa – aldosterone (15%)
2. Zona fasciculata – cortisol & androgens
3. 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)