Congenital Adrenal Hyperplasia Flashcards
Congenital Adrenal Hyperplasia -Features
Congenital adrenal hyperplasia: features
21-hydroxylase deficiency features
virilisation of female genitalia
precocious puberty in males
60-70% of patients have a salt-losing crisis at 1-3 wks of age
11-beta hydroxylase deficiency features virilisation of female genitalia precocious puberty in males hypertension hypokalaemia
17-hydroxylase deficiency features
non-virilising in females
inter-sex in boys
hypertension
Congenital Adrenal Hyperplasia - Example Question
A 23-year-old female presents with worsening acne and a marked increase in the development of body and facial hair which she finds very distressing. She is also overweight and is markedly stressed by her physical appearance and the development of stretch marks over her abdomen. She has tried multiple hair removal techniques with only mild success.
On examination, she has a body mass index of 28 kg/m², coarse hair over the anterior and posterior part of her chest and under her chin. Her Blood Pressure is 135/90mmHg.
Her lab results are as follows:
9:00 am Cortisol 345 nmol/l (170 700 nmol/l)
LH 17 iU/l (1 20 iU/l)
Basal FSH 7.1 iU/l (1.0 8.8 iU/l)
DHEAS 545 µg/dl (31 228 µg/dl)
Prolactin 160 mU/l (<360 mU/l)
17 OH Progesterone 1025 ng/dl (<80 ng/dl)
Testosterone 3.9 nmol/l (0.9 3.1 nmol/l)
Ultrasound abdomen and pelvis reveals two cysts in the right ovary.
Which of the following is the most appropriate treatment option for her condition?
Combined oral contraceptive pill Finasteride Surgical resection of the ovarian cysts > Reverse circadian rhythm steroids Metformin in combination with spironolactone
The diagnosis in this scenario is non-classical congenital adrenal hyperplasia which manifests in adolescence/adulthood. It is caused by a deficiency of the enzyme 21 hydroxylase in the steroid biosynthetic pathway. The result is a shift in the production of steroid hormones towards the androgenic pathway. Since cortisol secretion is reduced, feedback leads to increased ACTH production and resultant hyperplasia of the adrenals. The level of the compounds that are formed prior to the action of 21 hydroxylase is increased, therefore levels of 17 hydroxyprogesterone are elevated. Due to excessive androgen production, there is virilization and hirsutism.
Treatment involves steroids given in reverse circadian rhythm, i.e. a higher dosage at night and a lower dose in the morning.
The rationale behind this approach is due to the pathophysiology of CAH. The adrenal hyperplasia and the over-secretion of adrenal androgens are due to excessive ACTH production. When steroids are given in higher doses at night, ACTH is suppressed and the normal physiological steroid peak in the morning is also reduced.
Cysts in the ovaries are a common finding on routine ultrasound and do not necessarily represent polycystic ovarian syndrome.
For further review please see http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2266964/ entitled Approach to the Adult with Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency.
Congenital Adrenal Hyperplasia - Example Question
A 23-year-old female presented with acne and hirsutism worsening over the last 3 years. She attained menarche aged 10 and has irregular periods.
On examination, body mass index 29kg/m², heart rate 80/min, blood pressure 135/85 mmHg. Hirsutism and acanthosis nigricans are noticed along with mild clitoromegaly.
Bloods on 6th day after menstruation:
Estradiol 300 pmol/L (early follicular NR<300 pmol/L)
17OH-progesterone 20 nmol/L (NR<10 nmol/L)
Free Testosterone 3 nmol/L (NR<3 nmol/L)
LH 4 IU/L (NR 1-9 IU/L)
FSH 3 IU/L (NR 1-13 IU/L)
9am cortisol 150 nmol/L (NR 200-700 nmol/L)
What is the single most useful test?
CT adrenals Karyotype Pelvic USS > Short synacthen test MRI pituitary
This patient has hyperandrogenism (acne, hirsutism, high 17OH-progesterone) indicative of non-classical congenital adrenal hyperplasia.
CAH is caused by:
- 21 hydroxylase mutation (90% of CAH).
This mediates conversion of 17OH-progesterone to 11-deoxycortisol and progesterone to deoxycorticosterone. Loss of function results in reduced cortisol and aldosterone and subsequent elevation in ACTH. This causes overstimulation of the adrenal cortex (hyperplasia). The steroid precursors are forced down the sex hormone pathway leading to androgen excess (ambiguous genitalia, salt wasting, hypovolaemia and shock i.e classic type). Presentation of 21 hydroxylase deficiency can also be asymptomatic with androgen excess become a problem in late childhood i.e. non-classic (premature pubarche, accelerated bone age, acne, hirsutism, oligomenorrhoea and this mimics polycystic ovarian syndrome).
- 11-beta hydroxylase mutation (5% of CAH).
Raised BP as 11-deoxycortisol has some aldosterone activity. Also raised androgens.
- 17-alpha hydroxylase deficiency
Raised aldosterone but low androgens.
- 3-beta steroid dehydrogenase
Low aldosterone and low androgens.
The short synacthen test is helpful when 17OH-progesterone is only modestly elevated (if 17OH-progesterone is very high then it is diagnostic). Measuring 17OH-progesterone at 0 and 60 mins after ACTH causes elevated responses in patients with CAH (>35 nmol/L).
Congenital Adrenal Hyperplasia - Example Question
A 19 year-old woman presents for review. Her past medical history incudes hypertension, which is managed with ramipril and indapamide and 11-beta hydroxylase deficiency, which was identified at birth upon identifying cliteromegaly.
Which of the following is likely to be raised most markedly?
17-OH pregnenolone Oestradiol > 11-Deoxycortisol 17-OH progesterone Oestrone
11 Beta-hydroxylase is responsible for conversion of 11-deoxycorticosterone and 11-deoxycortisol to corticosterone and cortisol. In patients with 11-beta hydroxylase deficiency, this conversion does not occur in sufficient amounts and levels of these steroids accumulate in patient. Therefore, although 17-OH hormones may also be raised the 11-Deoxycortisol is the more significantly raised than the others.
Congenital Adrenal Hyperplasia - Mx during an infection: Example Question
A 22-year-old student comes to the Emergency department with a cough productive of rusty coloured sputum. She has been suffering from increased shortness of breath, night sweats and fevers for the past 48 hours. Current medication includes daily hydrocortisone for congenital adrenal hyperplasia and the combined oral contraceptive pill. Current bloods are shown below:
Hb 131 g/l Na+ 134 mmol/l Platelets 201 * 109/l K+ 4.1 mmol/l WBC 14.9 * 109/l Urea 7.0 mmol/l Neuts 10.1 * 109/l Creatinine 82 µmol/l Lymphs 1.2 * 109/l CRP 185 mg/l Eosin 0.4 * 109/l
Which of the following is the most appropriate way to manage her steroid hormone replacement?
How should you manage her steroid replacement?
Convert to 200mg hydrocortisone IV BD Increase the daily dose by 50% > Increase the daily dose by 100% Reduce the daily dose by 50% Keep the daily dose the same
Patients with congenital adrenal hyperplasia who are managed with steroid hormone replacement should be managed in the same way as patients with Addison’s disease. In other words, during a period of significant acute infection like the pneumonia here, the dose of corticosteroid should be doubled.
With the patient able to swallow, having presented early with her pneumonia, switching to IV hydrocortisone would represent excess steroid replacement and is not appropriate here. The other options including only small increases in steroid dose, reductions or maintaining the status quo, run the risk of adrenal crisis.
Non-classical Congenital Adrenal Hyperplasia
Non-classical congenital adrenal hyperplasia manifests in adolescence/adulthood. It is caused by a deficiency of the enzyme 21 hydroxylase in the steroid biosynthetic pathway. The result is a shift in the production of steroid hormones towards the androgenic pathway. Since cortisol secretion is reduced, feedback leads to increased ACTH production and resultant hyperplasia of the adrenals. The level of the compounds that are formed prior to the action of 21 hydroxylase is increased, therefore levels of 17 hydroxyprogesterone are elevated. Due to excessive androgen production, there is virilization and hirsutism.
Treatment involves steroids given in reverse circadian rhythm, i.e. a higher dosage at night and a lower dose in the morning.
The rationale behind this approach is due to the pathophysiology of CAH. The adrenal hyperplasia and the over-secretion of adrenal androgens are due to excessive ACTH production. When steroids are given in higher doses at night, ACTH is suppressed and the normal physiological steroid peak in the morning is also reduced.
CAH
Hyperandrogenism (acne, hirsutism, high 17OH-progesterone) is indicative of non-classical congenital adrenal hyperplasia.
CAH is caused by:
- 21 hydroxylase mutation (90% of CAH).
This mediates conversion of 17OH-progesterone to 11-deoxycortisol and progesterone to deoxycorticosterone. Loss of function results in reduced cortisol and aldosterone and subsequent elevation in ACTH. This causes overstimulation of the adrenal cortex (hyperplasia). The steroid precursors are forced down the sex hormone pathway leading to androgen excess (ambiguous genitalia, salt wasting, hypovolaemia and shock i.e classic type). Presentation of 21 hydroxylase deficiency can also be asymptomatic with androgen excess become a problem in late childhood i.e. non-classic (premature pubarche, accelerated bone age, acne, hirsutism, oligomenorrhoea and this mimics polycystic ovarian syndrome).
- 11-beta hydroxylase mutation (5% of CAH).
Raised BP as 11-deoxycortisol has some aldosterone activity. Also raised androgens.
- 17-alpha hydroxylase deficiency
Raised aldosterone but low androgens.
- 3-beta steroid dehydrogenase
Low aldosterone and low androgens.
The short synacthen test is helpful when 17OH-progesterone is only modestly elevated (if 17OH-progesterone is very high then it is diagnostic). Measuring 17OH-progesterone at 0 and 60 mins after ACTH causes elevated responses in patients with CAH (>35 nmol/L).
11 Beta Hydroxylase Deficiency
11 Beta-hydroxylase is responsible for conversion of 11-deoxycorticosterone and 11-deoxycortisol to corticosterone and cortisol. In patients with 11-beta hydroxylase deficiency, this conversion does not occur in sufficient amounts and levels of these steroids accumulate in patient. Therefore, although 17-OH hormones may also be raised the 11-Deoxycortisol is the more significantly raised than the others.
Raised BP as 11-deoxycortisol has some aldosterone activity. Also raised androgens + Hypokalaemia
HTN + Hypokalaemia (one of the causes of Hypokalaemia with HTN)
