Endocrinology: Congenital Adrenal Hyperplasia, Adrenal Insufficiency & Hypothyroidism Flashcards
What is congenital adrenal hyperplasia (CAH)?
A congenital deficiency of the 21-hydroxylase enzyme.
This causes UNDERproduction of cortisol and aldosterone, and OVERproduction of androgens from birth.
How is congenital adrenal hyperplasia inherited?
Autosomal recessive
What is the main glucocorticoid hormone?
Cortisol
What is cortisol released in response to?
ACTH from the anterior pituitary
What is the main mineralocorticoid hormone?
Aldosterone
What is aldosterone released in response to?
Renin
Role of aldosterone?
Acts on the kidneys to increase Na+ reabsorption into the blood and increase K+ secretion into the urine.
i.e. aldosterone acts to increase sodium and decrease potassium in the blood.
What is the 21-hydroxylase enzyme responsible for?
Convering progesterone into aldosterone and cortisol.
Note - Progesterone is also used to create testosterone, but this conversion does not rely on the 21-hydroxylase enzyme.
Pathophysiology in congenital adrenal hyperplasia?
1) Defect in the 21-hydroxylase enzyme (this normally converts progesterone into aldosterone and cortisol).
2) There is extra progesterone floating about that cannot be converted to aldosterone or cortisol, so it gets converted into testosterone instead.
3) Result is low aldosterone, low cortisol and abnormally high testosterone.
4) Lots of ACTH secreted in response to low cortisol levels.
5) ACTH further stimulates the production of adrenal androgens
What is progesterone converted to in congenital adrenal hyperplasia?
Testosterone
Presentation of severe cases of congenital adrenal hyperplasia?
- Females usually present at birth with virilised genitalia: known as ‘ambiguous genitalia’ and an enlarged clitoris due to the high testosterone levels.
- Hyponatraemia, hyperkalaemia, hypoglycaemia
This leads to:
- poor feeding
- vomiting
- dehydration
- arrhythmias
Define virilised
To assume masculine characteristics, as through a hormonal imbalance or hormone therapy.
What electrolyte abnormalities may be present in severe cases of CAH?
Hyponatraemia
Hyperkalaemia
Hypoglycaemia
(due to low aldosterone & cortisol)
When do mild cases of CAH typically present?
Patients who are less severely affected present during childhood or after puberty.
Their symptoms tend to be related to high androgen levels.
Presentation of mild CAH in females?
- Tall for their age
- Facial hair
- Absent periods
- Deep voice
- Early puberty
Presentation of mild CAH in males?
- Tall for their age
- Deep voice
- Large penis
- Small testicles
- Early puberty
What is a key dermatological sign of CAH?
Skin hyperpigmentation
What causes hyperpigmentation in CAH?
Occurs because the anterior pituitary gland responds to the low levels of cortisol by producing increasing amounts of ACTH.
A byproduct of ACTH is melanocyte stimulating hormone.
This hormone stimulates the production of melanin (pigment) in skin cells.
What does management of CAH involve?
1) Cortisol replacement –> usually with hydrocortisone (similar to treatment for adrenal insufficiency)
2) Aldosterone replacement –> usually with fludrocortisone
3) Female patients with “virilised” genitals may require corrective surgery
What drug is used for cortisol replacement in CAH?
Hydrocortisone
What drug is used for aldosterone replacement in CAH?
fludrocortisone
What investigation is used to confirm the diagnosis of CAH?
ACTH stimulation testing
What is GH produced by?
Anterior pituitary
What is GH responsible for?
1) Stimulating cell reproduction and the growth of organs, muscles, bones and height
2) Stimulating release of insulin-like growth factor 1 (IGF-1) by the liver - important in promoting growth in children and adolescents.
GH can be congenital or acquired.
What is congenital GH deficiency due to?
Disruption to the growth hormone axis at the hypothalamus or pituitary gland.
It can be due to a known genetic mutation such as the GH1 (growth hormone 1) or GHRHR (growth hormone releasing hormone receptor) genes.
Can also be due to another condition such as empty sella syndrome where the pituitary gland is under-developed or damaged.
What can acquired GH deficiency be 2ary to?
Infection, trauma, or interventions such as surgery.
GH deficiency can occur in isolation or in combination with other deficiencies like hypothyroidism, adrenal insufficiency and deficiencies of the gonadotrophins (LH and FSH).
What is it called when the pituitary does not produce a number of pituitary hormones?
Hypopituitarism or multiple pituitary hormone deficiency.
How can GH deficiency present in in neonates?
- micropenis (males)
- hypoglycaemia
- severe jaundice
How can GH deficiency present in in older infants and children?
- Poor growth, usually stopping or severely slowing from age 2-3
- Short stature
- Slow development of movement and strength
- Delayed puberty
What investigations are required in GH deficiency?
1) GH stimulation test
2) Test for other associated hormone deficiencies, for example thyroid and adrenal deficiency
3) MRI brain: for structural pituitary or hypothalamus abnormalities
4) Genetic testing for associated genetic conditions such as Turner syndrome and Prader–Willi syndrome
5) Xray (usually of wrist) or DEXA scan (determine bone age and help predict final height)
What does a GH stimulation test involve?
Measuring the response to medications that normally stimulate the release of GH.
In GH deficiency, there will be a poor response to stimulation.
What medications are used in GH stimulation test?
I.e. which medications normally stimulate the release of GH?
1) glucagon
2) arginine
3) clonidine
What is arginine?
An amino acid naturally found in red meat, poultry, fish, and dairy.
Arginine increases GH.
What is clonidine?
A vasodilator (alpha agonist).
It increases GH.
Management of congenital GH deficiency?
1) Daily SC injections of GH (somatropin)
2) Treatment of other associated hormone deficiencies
3) Close monitoring of height and development
What medication is used for GH replacement?
Somatropin
What is adrenal insufficiency?
Where the adrenal glands do not produce enough steroid hormones, particularly cortisol and aldosterone.
What is Addison’s disease?
Autoimmune destruction of the adrenal glands, resulting in reduced cortisol and aldosterone.
What is the most common cause of primary hypoadrenalism in the UK?
Addison’s disease (80% of cases)
What is secondary adrenal insufficiency caused by?
Inadequate ACTH stimulating the adrenal glands, resulting in low levels of cortisol being released.
This is the result of loss or damage to the pituitary gland e.g. congenital underdevelopment (hypoplasia) of the pituitary gland, surgery, infection, loss of blood flow or radiotherapy.
What is tertiary adrenal insufficiency?
The result of inadequate CRH release from the hypothalamus.
What is 3ary adrenal insufficiency usually the result of?
Patients being on long term oral steroids (>3 weeks), causing suppression of the hypothalamus.
When the exogenous steroids are suddenly withdrawn the hypothalamus does not “wake up” fast enough and endogenous steroids are not adequately produced.
ACTH levels in Addison’s vs 2ary adrenal insufficiency?
Addison’s: high ACTH (in response to low cortisol)
2ary –> low
Renin levels in Addison’s?
High - in response to low aldosterone
Features of adrenal insufficiency in neonates?
- Lethargy
- Vomiting
- Poor feeding
- Hypoglycaemia
- Jaundice
- Failure to thrive
Features of adrenal insufficiency in older children?
- Lethargy & weakness
- Anorexia & weight loss
- Nausea & vomiting
- ‘Salt-craving’
- Hyperpigmentation (in Addison’s)
- Vitiligo
- Loss of pubic hair in women
- Hypotension
- Hypoglycaemia (due to lack of cortisol)
- Hyponatraemia and hyperkalaemia may be seen (due to lack of aldosterone)
Crisis: collapse, shock, pyrexia
What causes hyperpigmentation in Addison’s?
Low cortisol causes high ACTH levels.
Melanocyte-stimulating hormones are a byproduct of ACTH production –> hyperpigmentation.
Note - primary Addison’s is associated with hyperpigmentation whereas secondary adrenal insufficiency is not
What are some other causes of 1ary hypoadrenalism?
1) tuberculosis
2) metastases (e.g. bronchial carcinoma)
3) meningococcal septicaemia (Waterhouse-Friderichsen syndrome)
4) HIV
5) antiphospholipid syndrome
Investigations in suspected adrenal insufficiency?
1) U&Es (hyponatraemia and hyperkalaemia)
2) Blood glucose (hypoglycaemia)
3) Short synacthen test (ACTH Stimulation Test) –> test prior to steroid administration if possible
Cortisol, ACTH, aldosterone & renin levels in Addisons vs 2ary adrenal failure?
Addisons (1ary failure):
- Low cortisol
- High ACTH
- Low aldosterone
- High renin
2ary failure:
- Low cortisol
- Low ACTH
- Normal aldosterone
- Normal renin
What test can be used to confirm adrenal insufficiency?
Short Synacthen Test (ACTH Stimulation Test)
What does the short synacthen test involve?
1) Give synacthen (synthetic ACTH) - ideally in morning
2) Measure blood cortisol at baseline, 30 mins and 60 mins after
3) The synthetic ACTH will stimulate healthy adrenal glands to produce cortisol.
4) The cortisol level should at least double in response to synacthen.
5) A failure of cortisol to rise (less than double the baseline) indicates primary adrenal insufficiency (Addison’s disease).
What short synacthen test result indicates 1ary adrenal failure?
The failure of cortisol to rise less than double the baseline.
Management of adrenal insufficiency?
Replacement steroids titrated to signs, symptoms and electrolytes.
What drug is used to replace aldosterone & cortisol?
Aldosterone - fludrocortisone (mineralocorticoid)
Cortisol - hydrocortisone (glucocorticoid)
Management of steroids during acute illness?
The dose of steroid needs to be increased and given more regularly until the illness has completely resolved.
Blood sugar needs to be monitored closely and they need to eat foods containing carbohydrates regularly.
Management of patients on steroids who have an acute illness with D&V?
they need an IM injection of steroid at home and likely required admission for IV steroids.
What is an Addisonian crisis (AKA adrenal crisis)?
An acute presentation of severe Addisons, where the absence of steroid hormones result in a life threatening presentation.
Features:
- reduced consciousness
- hypotension
- hypoglycaemia
- hyponatraemia
- hyperkalaemia
What can an adrenal crisis be triggered by?
Can be 1st presentation of Addison’s disease.
Can be triggered by infection, trauma or other acute illness in someone with established Addison’s.
Can occur in patients on long term steroids that have suppressed their natural steroid production, if that patient stops taking the steroids abruptly.
Management of Addisonian crisis?
1) Immediate IV/IM hydrocortisone
2) IV 0.9% saline
3) Correct hypoglycaemia
4) Careful monitoring of electrolytes and fluid balance
What is congenital hypothroidism?
A condition present from birth where the thyroid gland is underdeveloped (dysgenesis) or absent, resulting in thyroid hormone deficiency.
How is congenital hypothyroidism often diagnosed?
Newborn blood spot screening test
How can congenital hypothyroidism present?
- Prolonged neonatal jaundice
- Poor feeding
- Reduced tone
- Constipation
- Increased sleeping
- Reduced activity
- Slow growth and development (if untreated0
What are the 2 main causes of congenital hypothyroidism?
1) Thyroid dysgenesis –> developmental abnormality of the thyroid gland.
2) Thyroid dyshormogenesis –> An enzymatic defect means the thyroid is unable to produce thyroid hormone normally.
Risk factors for congenital hypothyroidism?
1) Female
2) Prematurity
3) Low birth weight
4) Twins (as they are often premature and have a low birth weight)
What are some signs that may be picked up on examination in congenital hypothyroidism?
- Poor growth
- Macroglossia
- Myxedema
- Large fontanelles
- Hypotonia
- Bradycardia
- Distended abdomen with umbilical hernia
- Goitre
What is a potential complication of the correction of DKA in children?
Cerebral oedema
How can DKA lead to cerebral oedema?
Dehydration & hyperglycaemia cause water to move from intracellular space in the brain to the extracellular space.
This causes the brain cells to shrink and become dehydrated.
Rapid correction of dehydration and hyperglycaemia (with fluids and insulin) causes a rapid shift in water from the extracellular space to the intracellular space in the brain cells.
This causes the brain to swell and become oedematous, which can lead to brain cell destruction and death.
How soon after treatment of DKA does cerebral oedema typically occur?
4-12 hours
Clinical manifestations of cerebral oedema?
- headache
- altered mental status (monitor GCS)
- seizures
- focal neuro deficits
- if untreated: herniation & death
If there is a suspicion of cerebral oedema following DKA treatment, what is the investigation?
CT head
Management options for cerebral oedema 2ary to DKA treatment?
1) slow fluids
2) IV mannitol
3) IV hypertonic saline
What medication is indicated in cerebral oedema 2ary to DKA treatmnet?
IV mannitol
What type of fluid therapy is given in cerebral oedema?
HYPERtonic saline - decreases ICP
What is a risk factor for cerebral oedema in the treamtment of DKA?
How can this risk be mitigated?
Rapid correction of dehydration –> avoid fluid bolusus (unless required for resuscitation).
How much 0.9% saline should be given to children with DKA as an initial bolus:
a) for children in shock
b) for children not in shock
a) 20mL/kg of 0.9% sodium chloride over 15 minutes
b) 10mL/kg 0.9% sodium chloride over 1 hour
How much 0.9% saline should be given to children with DKA as ONGOING fluids:
a) for children in shock
b) for children not in shock
a) Up to 40mL/kg total if ongoing shock before inotropes considered. DO NOT subtract from ongoing fluid calculation (deficit + maintenance)
b) Calculate fluid deficit based on % dehydration. Subtract the initial 10mL/kg bolus from this and add maintenance
What 3 groups can fluids be considered in?
1) Resuscitation fluids
2) Deficit fluids
3) Maintenance fluids
What are deficit fluids?
This is calculated from the assumed dehydration level based upon the pH at presentation.
The initial 10mL/kg 0.9% sodium chloride given to those presenting without shock over the first hour is deducted from this.
What is the leading cause of death in children presenting with DKA?
Cerebral oedema
