Adrenal disorders Flashcards
Overview of the adrenal glands
Adrenal cortex = zona glomerulosa, zona fasciculata, zona reticularis
- Glomerulosa –> secretes mineralocorticoids (aldo) = under control of RAA system
- Fasciculata –> secretes glucocorticoids (cortisol) = under control of ACTH
- Reticularis –> secretes sex steroids = under control of ACTH
Adrenal medulla = secretes catecholamines
Hypothalamo-pituitary-adrenal axis
The hypothalamus is under the influence of several neurotransmitters responding to a diurnal rhythm (ACTH peaks in early morning and tails off over course of day with resultant low ACTH and cortisol levels at night). - This diurnal rhythm is used in detecting pathological states.
- Thus cortisol deficiency is demonstrated with a low blood level when physiologically it should be high (early a.m.).
- Cortisol excess is demonstrated with a high blood level, when it should be low (late p.m.).
- Cortisol is the major stress hormone and cortisol deficiency often first becomes clinically evident with a poor response to stress e.g. low blood pressure, blood sugar with an intercurrent infection or following surgery or trauma.
- CRH (corticotrophin-releasing hormone) secreted by the hypothalamus in response to central stimuli is the peptide releasing factor for ACTH.
- ACTH produced by the basophils of the pituitary is the trophic hormone for the adrenals and stimulates through several enzymatic steps the synthesis of cortisol.
Adrenal steroidogenesis
Cholesterol = precursor –> taken up by the adrenal and the side chain is cleaved to form pregnenolone
- sequential hydroxylations at C17, C21 and C11 to produce aldosterone, cortisol and testosterone
- ** REVIEW FLOWCHART
Causes of adrenal insufficiency
Primary adrenal insufficiency
- Addison’s disease –> caused by destruction of the adrenal gland
- women more commonly affected than men
- peak incidence in 4th decade
- increasing prevalence likely due to higher incidence of autoimmune adrenalitis
- low cortisol + high ACTH
Secondary adrenal insufficiency
- hypothalamic disease
- pituitary lesions
- exogenous steroid suppression –> if you’re taking exogenous steroids for a while, ACTH is suppressed, so when you stop taking them abruptly it will take a while for ACTH to rev back up and you get secondary adrenal insufficiency –> important to slowly taper exogenous steroids
- peaks in 6th decade
- more common in women
- low ACTH + low cortisol
Signs and symptoms of Adrenal insufficiency
Weakness, anorexia, weight loss, salt craving , hyperpigmentation (primary only), decreased body hair
- only see hyperpigmentation in primary –> POMC is cleaved into ACTH + MSH = increased pigmentation
Acute AI
- hypotension or hypovolemic shock
- abdominal pain, vomiting and fever
- kids –> hypoglycemic seizures
- type 1 DM –> recurrent hypoglycemia
Chronic AI
- fatigue, lack of stamina, loss of energy, reduced muscle strength
- weight loss
- nausea, anorexia
- hyperpigmentation (primary)
- arthralgia and myalgias
- often delayed dx due to non-specific nature of symptoms
Lab abnormalities in AI
- hyponatremia
- hyperkalemia - primary AI only
- –> in secondary AI, aldo axis is still intact under the influence of RAA
- hypoglycemia
- azotemia
- hypercalcemia –> increased intestinal absorption + decreased renal excretion of calcium
- –> often coincides with hyperthryoidism, causes increased bone turnover = hypercalcemia
- anemia - normocytic –> cortisol is required for maturation of blood progenitor cells
- eosinophilia –> use steroids to treat autoimmune disorders –> lack of steroids = increased eosinophils
Differential diagnosis for primary AI
- tuberculosis adrenalitis –> less common in developing world now, major cause in past
- autoimmune = 80-90% of cases in developed countries
- –> isolated 40% of time
- –> autoimmune polyglandular syndromes APS1 + 2 remainder
- X linked adrenoleukodystrophy
- CAH
- hemorrhage, infiltrative diseases, tumors, drugs
Differential diagnosis for secondary AI
- most commonly due to a tumor in pituitary-hypothalamic region
- autoimmune lymphocytic hypophysitis –> mostly related to pregnancy (80%); can have isolated ACTH deficiency
- POMC gene defects or cleavage enzyme defects
- PROP1 defect –> gene encoding transcription factor
- HESX1 gene –> septo-optic dysplasia = midline defects, optic nerve hypoplasia
CAH
Most commonly due to defect in 21-hydroxylase enzyme –> necessary for production of mineralocorticoids and glucocorticoids, but not sex steroids –> all precursors are shunted to sex steroid pathway
- can present with AI as an infant
- Adults get non-classical form which is milder
Impaired steroidogenesis
CAH
- Several causes from mutations in genes for synthetic enzymes.
- Loss of cortisol production and therefore loss of negative feed-back on the pituitary leads to high ACTH levels, adrenal hyperplasia and over-production of steroids not blocked by the specific enzyme deficiency.
- 21 – hydroxylase deficiency is the most common cause of salt-wasting adrenal crisis in the first 2 weeks of life.
- Affected females have ambiguous, virilized genitalia and are usually diagnosed at birth.
- Males often go undiagnosed until a crisis occurs.
Autoimmune polyendocrine syndrome type 1 (APS1)
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED)
- caused by mutations in the autoimmune regulator gene (AIRE)
- autosomal recessive
- arises in up to 15% of people with autoimmune adrenal insufficiency
Characterized by:
- AI
- hypoparathyroidism
- hypogonadism
- chronic mucocutaneous candidiasis
APS2
More common than APS1
- adrenal insufficiency and autoimmune thyroid disease
- primary hypogonadism
- type 1 diabetes
- vitiligo
- chronic atrophic gastritis –> pernicious anemia
- celiac disease
Autosomal dominant with incomplete penetrance
X linked adrenal leukodystrophy
ABCD1 gene defect –> encodes peroxisomal membrane protein-ALDP
- absence of ALDP leads to accumulation of very long chain fatty acids in adrenal glands and white matter of the brain
- presents as adrenal insufficiency with neurological impairment due to white matter demyelination
- 50% early childhood disease with rapid progression
- 35% early adulthood onset - slow progression, often only affects peripheral nerves and spinal cord
- AI can be sole manifestation in 15% of cases
Diagnostic tests for adrenal insufficiency
- morning cortisol/ACTH - normally cortisol is high in the morning; if we measure it and its low, highly suggestive of AI
- low aldo, high renin + low DHEA –> highly suggestive of primary AK
- 250 mcg ACTH stimulation –> Synthetic ACTH (cosyntropin) 250 mcg given IV or IM and cortisol levels checked at 30 and 60 minutes. Cortisol levels should peak above 20 mcg/dL. May get a small response in secondary adrenal insufficiency, since adrenals have atrophied, but may still retain some function. Same can occur in partial adrenal insufficiency.
- adrenal cortex of 21-hydroxylase antibodies –> present in 80% with autoimmune adrenalitis
- boys or men without clear autoimmunity or other identifiable cause –> should measure serum concentrations of very long chain FAs to look for x linked adrenoleukodystrophy
- imaging studies only indicated if hemorrhage, infection, infiltration or neoplasm suspected
- random cortisol levels not often helpful due to diurnal variation and pulsatility of its release
Treatment of AI
Normally we produce 5-10 mg/m2 cortisol per day
- supplement with 15-25 mg hydrocortisone in divided doses
- replacement dose followed by clinical grounds, no reliable testing
Fludrocortisone for 0.05-0.2 mg/daily –> aldo replacement – don’t need in secondary adrenal insufficiency with decreased ACTH because aldo levels should be normal
- monitor BP, electrolytes, plasma renin (renin should come down to normal)
- 20 mg HC ≈ 0.05 mg fludrocortisone
Androgens in women- DHEA or testosterone
- Emergency bracelet
- Stress doses – need higher doses in stressful states
- Acute crisis- hydrocortisone IV 50 mg q 6 hours, aggressive IV fluid resuscitation
Manifestations of adrenal hyperfunction
- Excess cortisol production –> Cushing’s syndrome
- Excess mineralocorticoid secretion –> hyperaldosteronism (Conn’s syndrome)
- Excess sex hormone secretion –> hirsutism or feminization
- Excess catecholamine secretion –> pheo
