ENDOCRINOLOGY II

DR. FESTUS DELE AKEREDOLU

CONSULTANT PAEDIATRICIAN/PAEDIATRIC ENDOCRINOLOGIST
Endocrinology II
• Congenital adrenal hyperplasia
• Hypothyroidism
• Hyperthyroidism
CONGENITAL ADRENAL HYPERPLASIA
 ADRENAL GLANDS
• The adrenal glands lie on the
upper poles of the kidneys.
• Two Parts: outer cortex and
an inner medulla
• The cortex : 3 sections
• Zona glomerulosa –
Mineralocorticoid
(Aldosterone and DOC)
• Zona Fasciculata –
Glucocorticoid (cortisol)
• Zona reticularis – sex
hormones (DHEA, DHEAS,
Androstenedione)
STEROID BIOSYNTHESIS
CONGENITAL ADRENAL
HYPERPLASIA
• Group of autosomal recessive disorders of steroid biosynthesis.

• Results from complete or partial absence of an enzyme along the

pathway of all or one of the products.

• There are several different types depending on the enzyme deficiency.

• In patients with CAH, reduced cortisol synthesis interrupts

feedback inhibition of ACTH release from the pituitary,
continual stimulation of the adrenals by ACTH adrenal
hyperplasia.
Why is the diagnosis of CAH
important?-
• In new-born
• New-born babies with salt-losing forms of CAH die within days or
weeks if not treated (? SEPSIS)
• CAH is the most common cause of ambiguous genitalia – CAH girls
may be mistaken for boys (with “undescended testes”)
• In childhood
• –precocious puberty in boys
• –virilization in girls
• –short final height in both
 21 Hydroxylase deficiency
• Causes more than 95% of CAH.
• Classic 21-OH deficiency occurs in about 1 in 10,000-20,000 births.
• Approximately 67% of affected infants have the salt-losing form,
whereas 33% have the simple virilizing form of the disorder.
• This is an P450 enzyme (CYP21,)
• Hydroxylates progesterone and 17 OHP to yield DOC and 11-
deoxycortisol.
• Thus, Cortisol and Aldosterone are deficient in the most severe, “salt
wasting” form of the disease.
• Less severely affected patients can synthesize aldosterone but have
elevated levels of androgens: “Simple virilizing disease”
Clinical features
1. ALDOSTERONE AND CORTISOL DEFICIENCY: -

• Both hormones are deficient in the most severe, salt wasting form of the
disease.

• Include progressive weight loss, anorexia, dehydration, weakness,

hypotension, Symptoms &Signs of hypoglycemia, hyponatremia, and
hyperkalemia.

• These problems typically first develop in affected infants at about 2wks of

age.
Clinical features cont.
2. PRENATAL ANDROGEN EXCESS: -
• 17-OH progesterone is shunted into the pathway for androgen
biosynthesis, leading to high levels of androgens.
• This problem begins by 8-10 wk of gestation leading to abnormal
genital development in females.
• Clitoris resembles a penis and, because the urethra opens below this
organ, patient may be mistakenly presumed to be a male with
hypospadias and cryptorchidism.
• Male infants appear normal at birth
Clinical features
3. POSTNATAL ANDROGEN EXCESS: -

• Untreated children of both sexes develop additional signs of androgen

excess after birth.

• Rapid somatic growth and accelerated skeletal maturation with

premature closure of epiphysis (short final height)

• Pubic and axillary hair, acne and deep voice may develop

• In girls, breast development and menstruation usually do not occur

unless the excessive production of androgens is suppressed by steroid
therapy.
Clinical examination
• Careful and detailed external genital examination and correct
measurement with a clinical picture
Investigation
• Patients with salt-losing disease have hyponatremia, hyperkalemia,
acidosis and often hypoglycemia usually 1-2 wk or longer after birth.
• Markedly elevated 17-OH progesterone (17OHP)
• Cortisol level is low.
• Androstenedione and testosterone are elevated in affected females.
• Renin levels are high with low levels of aldosterone
• Internal genitalia: genitogram and USS, eventually laparascopy ±
biopsy
• Karyotype, FISH, molecular genetics
Management

• Multidisplinary
• Assign gender (neutral name)
• Glucocorticoid (Hydrocortisone) and mineralocorticoid (fludrocortisone)
replacement
• Surgical treatment (Genital reconstruction)
• CONTROVERSIES about Timing, Rights of the patients, Rights of the parents
• Follow-up – growth velocity, bone age, serum electrolytes etc
• Prognosis:
• Depends on the severity of impairment
• Generally good with early diagnosis and treatment
Prenatal diagnosis and treatment
Prenatal diagnosis is possible late in the first trimester by
analysis of DNA obtained by chorionic villus sampling or
during amniocentesis in the second trimester.

Dexamethasone administered to the mother crosses the

placenta and suppresses the secretion of steroids by the
fetal adrenal. This ameliorate the virilization of the
external genitalia in affected females.
 Prenatal diagnosis and
treatment
Conception
Start dexamethasone to mother
7w 20 mcg/Kg/day
10 w Chorionic villous biopsy
-If male or normal female:
Stop dexa!
-If affected female:
24 w Continue to term!

At birth: Confirm diagnosis

40 w Cortisol to newborn
NEWBORN SCREEN

Analyses 17-OH progesterone levels in dried blood obtained by heel-

stick.
Potentially affected infants are recalled for additional testing at 2wk
of age.
Seem to be effective in preventing many cases of adrenal crisis in
affected males.
The cut-off 17-OH progesterone levels for recalls are set so low that
there is high frequency of false-positive results (high sensitivity and
low specificity)
11β-hydroxylase (P450c 11β)
deficiency
• Incidence is 1 in 100,000
• Virilization of females
• Hypertension (+/-)
• Lab. diagnosis
• Elevated P-11-deoxycortisol, U-THS[Urinary tetrahydro-11-
deoxycortisol.
17-hydroxylase deficiencies!
deficiency
• Extremely rare (200 case only) in literature
• Hypertension(+/-) with hypokalemia
• 46,XY (genetically male child) has female external genitalia but no
uterus, no Fallopian tubes.
• 46,XX (genetically female child): Normal female, Failure of pubertal
development
• Lab: elevated progesterone
3β-HSD deficiency
• Defective production of all steroid
• Adrenal failure in early infancy
• Moderate virilization in females, varying genital ambiguity in males
• Non-classic form may have hirsutism and menstrual disorder
• Lab: elevated 17OH-pregnenolone and DHEAS
17,20 lyase deficiency (CYP17,
P450c17)
• Incidence: Very rare
• Phenotype –
• 46,XY: Feminine external genitalia no uterus, no Fallopian tubes –
• 46,XX: Normal female
• Lab: reduced androgens
StAR protein defect (Lipoid adrenal
hyperplasia)
• StAR (Steriodogenic acute regulatory protein) for movement of cholesterol
from the outer to inner mitochondrial membrane to synthesize
pregnenolone
• Loss of all steroidogenic capacity in adrenal gland and gonad
• Adrenal failure in early infancy
• Genetic males have female external genitalia
• 46,XX: normal female
• Frequently fatal if undiagnosed
• Incidence: Very rare
• Lab: “No” steroid hormones!
DISORDERS OF THE THYROID
GLAND
• Hypothyroidism
• Hyperthyroidism
 The thyroid follicles
THYROID GLAND
• The thyroid
gland is located
immediately
below the
larynx on each
side of and
anterior to the
trachea.

• It consists of
two lobes
joined by an The follicles are the structural, functional, and
secretory units of the thyroid gland
isthmus
 Embryogenesis
• The human thyroid gland develops from:
1. a median anlage (from the primitive pharyngeal floor)
2. a paired lateral anlagen (from the fourth pharyngeal
pouches)

• By 50 days they have fused and the thyroid gland has

migrated to its definitive location in the anterior neck.

• Within the thyroid gland, iodine concentration, TSH

receptors, thyroglobulin, and thyroid peroxidase mRNA and
protein can be demonstrated by 70 days.

• Transcription factors: NKX2-1, FOXE-1, paired box gene 8

(PAX8), Hhex
Thyroid hormone synthesis
• TSH regulates the process via the G–protein-linked plasma membrane TSH
receptor.

• TSH binding stimulates thyroglobulin synthesis and sodium-iodide symporter

(iodide transporter) uptake of circulating iodide. - Iodine trapping

• Iodide diffuses in the cytosol to the apical membrane and is transported to

the apical lumen by Pendrin.

• The tyrosine residues of thyroglobulin are iodinated at the apical cell

membrane and are catalyzed by thyroid peroxidase, the organification
enzyme. - Organification
Thyroid hormone synthesis
• The resulting monoiodotyrosine (MIT) and diiodotyrosine (DIT) residues
couple to form the iodothyronines thyroxine (T4) and triiodothyronine (T3)
within the stored thyroglobulin molecule. –Copulation

• TSH stimulates micropinocytosis of colloid droplets and progressive

thyroglobulin proteolysis within the resulting phagolysosomes.

• T4 and T3 are secreted into the circulation.

• The uncoupled MIT and DIT are deiodinated by iodotyrosine deiodinase

(DEHAL) to release iodide, which is largely recycled within the follicular cell.
Thyroid hormone synthesis
 Physiology
• The thyroid produces and secretes 2 metabolic
hormones:
• Thyroxine (T4 ) – the primary secretory product
• Triiodothyronine (T3) – the active hormone
• T3 is derived from 2 processes:
• About 80% of circulating T3 comes from deiodination of T4 in
peripheral tissue
• About 20% comes from direct thyroid secretion
• Type 1 deiodinase primarily in the liver and kidney
mediates conversion of T4 to the bioactive T3
• Type 2 deiodinase -in pituitary, brain, placenta, brown fat,
muscle and thyroid; produces T3 for “local” use as well as
plasma T3
Physiology/functions
• >99% of circulating T 4 and T 3 is bound to plasma carrier proteins
• Thyroxine-binding globulin (TBG), binds about 75%
• Transthyretin (TTR), also called thyroxine-binding prealbumin (TBPA), binds
about 10%-15%
• Albumin binds about 7%
• High-density lipoproteins (HDL), binds about 3%
• Required for homeostasis of all cells.
• Influences cell differentiation, growth, and metabolism
• Considered the major metabolic hormones because they target virtually
every tissue
Regulation of thyroid hormone
• Circulating level of TSH is
controlled by TRH from
hypothalamus and opposing
influences from thyroid hormones
• As the level of thyroid hormones
increases in response to TSH
stimulation (positive feedback), T4
and T3 block the TRH stimulated
release of TSH from the
thyrotrope( negative feedback)
HYPOTHYROIDISM
• Hypothyroidism is a deficiency in thyroid hormone secretion by the
thyroid gland and a reduction of thyroid hormone action at the
cellular level.
• The two major forms in children are:

• 1) congenital hypothyroidism: present at birth

• 2) acquired hypothyroidism: diseases that have an onset usually after

6 months of age
Hypothyroidism
• Two major subcategories are:

• 1) primary hypothyroidism: caused by a damaged, defective, or

absent thyroid gland

• 2) hypothalamic and pituitary hypothyroidism, or central

hypothyroidism: a failure of the mechanisms that stimulate thyroid-
stimulating hormone (TSH) synthesis, secretion, and biologic action
Congenital hypothyroidism
• Most cases of CH are sporadic.
• Only about 10% to 15% are caused by inherited defects in thyroid
gland stimulation, thyroid hormone synthesis (hormonogenesis), or
peripheral action.
• Occurs worldwide in 1 in 3,500 to 4,000 newborns
• It can be:
• Permanent CH
• Transient CH
Causes of permanent congenital
hypotyroidism
• Thyroid dysgenesis
• Athyreosis (agenesis)
• Ectopia
• Hypoplasia
• Dyshormonogenesis
• Iodide trapping defect (sodium iodide symporter mutations)
• Iodide oxidation defects Pendred syndrome (Pendrin mutations)
Thyroperoxidase mutations
• Thyroglobulin synthetic defects
• Iodotyrosine deiodinase defect
• Multiple hypothalamic hormone deficiencies
• Isolated TSH deficiency
Causes of transient congenital
hypothyroidism
• Iodine deficiency
• Maternal or neonatal exposure to iodine
• Maternal antithyroid drug therapy
• Maternal TSH receptor-blocking antibodies
• Accelerated degradation
• Large hemangiomas with type 3 deiodinase activity
• Medications
Clinical presentation -Newborn
• Prolonged gestation
• Delayed passage of meconium, constipation
• Prolonged indirect jaundice
• Poor feeding, poor management of secretions
• Hypothermia
• Decreased activity level
• Noisy respirations
• Hoarse cry
• Myxoedematous changes of
• Brain, vocal cords, eyelids, hands, scrotum, tongue
• Large fontanelles
• Goiter
• Umbilical hernia
• Macroglossia
Much later
• Delayed dentition

• Growth and Developmental delay

• Decreased growth velocity

• Bradycardia

• Obesity

• Dry coarse hair

• Delayed sexual development or even absent

Other findings
• Cardiac
• Bradycardia
• Enlarged cardiac silhouette, usually because of pericardial effusion
• Prolonged conduction time and low voltage on electrocardiogram (ECG)
Investigation and treatment
• The diagnosis is established by the measurement of serum TSH and free T4
(FT4).
• Low FT4 value for age - hypothyroidism.
• Elevated TSH for age - primary hypothyroidism.
• Normal or low TSH + low FT4 – Central hypothyroidism
• Other tests:
• X-Ray: absent distal femoral and proximal tibial epiphyses,
• ultrasonographic examination of the thyroid can document presence or absence of an
anatomically normal gland,
• Scintigraphy (123 I–sodium iodide) diagnosis of ectopic gland
• Levothyroxine (L-thyroxine) is the treatment of choice
• NB: L -T4 tablets should not be mixed with soy protein formulas,
concentrated iron, or calcium, because these can inhibit L -T4 absorption .
Acquired Hypothyroidism in children
• Causes
• Chronic autoimmune thyroiditis (most common)
• Autoimmune polyglandular syndrome (tpes I and II)
• Drug-induced hypothyroidism
• Antithyroid drugs (propylthiouracil, methimazole, carbimazole)
• Lithium, amiodarone,, anticonvulsants,
• Endemic goiter
• Iodine deficiency
• Environmental goitrogens
• Irradiation of the thyroid
• Therapeutic radioiodine
• External irradiation of nonthyroid tumors
• Surgical excision
• CNS tumours (craniopharyngioma)
• Subacute thyroiditis: transient phase
Autoimmune thyroid disease
(Hashimoto)
• Normal thyroid gland or goiter
• Pain in the cervical area, dysphagia
• Clinical signs of hypothyroidism:
• Decreased height velocity
• Delayed puberty
• Fatigue
• Low heart rate
• Constipation
• Skin/hair changes
• Slipped capita epiphysis
Autoimmune thyroid disease
(Hashimoto)
• Therapeutic goals: euthyroidism, optimal growth
• Laboratory tests:
• TSH elevated
• FT4 low
• Detection of thyroglobulin or TPO antibodies is diagnostic of chronic
lymphocytic (autoimmune) thyroiditis as the etiology.
• Thyroid ultrasonography typically shows diffuse enlargement and
heterogeneous echotexture
• X-ray may show delayed bone age

• Treatment: L-thyroxine
Hyperthyroidism
• Hyperthyroidism
• The synthesis and secretion of excess thyroid hormone from the thyroid gland

• Thyrotoxicosis
• Any state of excess circulating thyroid hormone (and its clinical
manifestations) regardless of its source.

• Graves disease is the most common cause of hyperthyroidism in

children
Graves disease
• An autoimmune disorder that results in the production of
thyrotropin (TSH) receptor–stimulating antibodies (TRSAbs)
that bind and activate the G protein–coupled TSH receptor
(TSHR ) to cause increased thyroid hormonogenesis and
diffuse glandular growth.

• The most common cause of hyperthyroidism in children.

• Has a peak incidence in the 11-15 yr old age group.

• There is a 5 : 1 female:male ratio.

Graves disease
• Goiter
• Classical signs of hyperthyroidism
• Changes in behaviour, irritability, emotional lability,
fatigue, nervousness, poor concentration.
• Palpitations
• Insomnia
• Excessive perspiration
• Increase appetite with weight loss or no weight gain
• Diarrhoea
• Decline in academic performance
• Heat intolerance
• Tremor
• Exophthalmia more common but less severe
Investigations
• TSH
 Below lower limit of normal in all patients
• FT4
confirms diagnosis
 Elevated, maybe normal in some patients
• FT3
• May not be systematically necessary if TSH low and FT4
high in a patient with a diffusely increased thyroid
gland
 Elevated (useful in particular if FT4 is not elevated)
Investigations
• Thyroperoxidase (TPO) antibodies
• Will be positive in the vast majority of the patients.
• Confirms presence of autoimmune thyroid disease
• Thyroid receptor antibodies (TRAb, TSI)
• Confirms the diagnosis
• Positive association with FT4 and FT3 values at baseline
• Predictive value for recurrence?
• Baseline CBC, liver function tests?
Treatment
• Antithyroid drugs
• Definitive Therapy
1) Radioiodine ablation or
2) Thyroidectomy
• Indications definitive therapy:
• when medical management is not possible due to patient nonadherence or
• severe side effects of antithyroid drugs
• when an adequate trial of medical management has failed to result in
remission, or
• if the patient prefers definitive therapy
THANK YOU