(incomplete) Adrenal insufficiency, Addison's disease Flashcards
The histology of adrenal gland and endogenous cortisol secretion
Zona glomerulosa: mineralocorticoids
Zona fasciculata: glucocorticoids (cortisol)
Zone reticularis: glucocorticoids (androgen)
Medulla: cathecholamines
What are the functions of mineralocorticoids and glucocorticoids?
Mineralocorticoids
1. Regulates electrolyte balance
2. Regulates blood volume and blood pressure
Glucocorticoids - stress response
1. Increases blood sugar level
2. Increase protein catabolism
3. Mobilises fatty acids from adipose
Regulation of adrenal hormonal secretion
- Hypothalamus-Pituitary-Adrenal (HPA) axis
- Renin-angiotensin-aldosterone (RAAS) axis
HPA axis - glucocorticoid
1. CRH -> ACTH -> cortisol production
2. Cortisol exerts negative feedback to reduce stimulation
3. Cortisol usually highest in the morning on waking up (diurnal peak)
RAAS axis - mineralocorticoids
1. Response to triggers: RAAS, hyperkalaemia, ACTH
2. Aldosterone action increases sodium reabsorption and potassium exretion, leading to water retention
Adrenal insufficiency - inadequate production of glucocorticoids, mineralcorticoids (or both) by the adrenal gland
This can occur due to:
1. Primary insufficiency - dysfunction or destruction of adrenal cortex
2. Secondary insufficiency - inadequate ACTH production (by pituitary)
3. Tertiary insufficiency - inadequate CRH production (by hypothalamus)
What are the causes of adrenal insufficiency?
- denotes important to know causes
Primary - adrenal gland disease
*1. Autoimmune adrenalitis (Addison’s disease)
*2. Bilateral adrenal haemorrhage or thrombosis (coagulopathy, meningococcal sepsi)
3. Metastasis (lungs, breast, renal, GI, lymphoma)
*4. Infectious (PTB, HIV, CMV, histoplasma, cryptococcus)
*5. Congenital adrenal hyperplasia
6. Adrenalectomy (bilateral)
7. Infiltrative (amyloidosis, haemochromatosis)
8. Drugs
Secondary - pituitary disease
*1. Pituitary tumours and craniopharyngioma
*2. Pituitary surgery or irradiation
3. Lymphocytic hypophysitis
4. Infiltrative (as per primary - to pituitary)
5. Infection (as per primary - to pituitary)
*6. Sheehan’s syndrome (peripartum blood loss)
7. Traumatic brain injury to pituitary
Tertiary - hypothalamus disease
*1. Withdrawal of long term steroids
*2. Hypothalamic tumours and metastasis
3. Infiltrative (as per primary - to hypothalamus)
4. Infection (as per primary - to hypothalamus)
5. Cranial irradiation
6. Traumatic brain injury
Symptoms of adrenal insufficiency
A. Non-specific features
1. Weakness
2. Fatigue
* 3. Anorexia and wight loss
* 4. Orthostatic hypotension
B. Gastrointestinal disturbance
* 5. Vague abdominal pain
6. Nausea, vomiting
7. Constipation
C. Musculoskeletal and skin
8. Arthralgia and myalgia
* 9. Hyperpigmentation of buccal mucosa and gums
10. Darkened palmar crease, nail beds, scars
D. Neuropsychiatric symptoms
9. Salt craving
10. Psychiatric disturbance, confusion, stupor
How does adrenal insufficiency patients usually present?
- Non-specific weight loss
- Hyperpigmentation of buccal mucosa and gums, palm creases, nail beds, scars
(not seen in secondary/tertiary AI) - Orthostatic hypotension
- Hypoglycaemia
Laboratory investigations of adrenal insufficiency
Definitive investigations
1. 8am cortisol < 330 (depending on lab)
2. Short synacthen test - failure to respond
3. Serum ACTH - distinguishes 1/2/3 AI
(Primary AI: ACTH elevated; 2/3 AI: normal or low)
Supportive investigations
3. Insulin tolerance test - evaluates HPA response to insulin-induced hypoglycaemia
(CI in CAD, seizures)
4. Metyrapone test - blocks final step in cortisol biosynthesis (reduces cortisol, increases ACTH)
5. Glucagon stimulation test
6. CRH stimulation test
Important biochemical investigations
1. Hyperkalaemia and hyponatraemia
2. Azotemia
3. Hypercalcaemia (mild to moderate)
4. Hypoglycaemia
5. Normochromic normocytic anaemia, +/- eosinophilia and lymphocytosis
Imaging
1. CT adrenals for primary AI
2. MRI pituitary and hypothalamus for 2/3 AI
Short Synacthen test interpretation
How about low dose Synacthen test?
SST - Cosyntropin 250mcg administration
- Draw ACTH baseline and cortisol 0m, 30m, 60m
- Doubling of cortisol with Synacthen administration
Low dose Synacthen - 1mcg
- Some argued SST is supraphysiologic
- However data of low dose SST 1mcg do not establish any superiority
- High false positive result due to incorrect dilution of Synacthen
How does hyponatraemia occur in adrenal insufficiency?
- Glucocorticoid deficiency
- Elevated vasopressin levels with free water retention
- Shift of extracellular sodium into cells
- Reduced delivery of filtrate to diluting segments of nephron (reduced GFR)
Is dexamethasone detected in standard serum cortisol assay?
No. Thus dexamethasone can be given for treatment while basal cortisol and SST are performed.
Corticosteroid potency and conversion
Addison’s crisis
- Unexplained catecholamine-resistant hypotension
- Severe signs or symptoms of adrenal insufficiency
- Non-specific: weakness, fatigue, nausea, vomiting, abdominal pain, fever, AMS - Suspect adrenal haemorrhage if:
- Abdominal/flank pain, hypotensive/shock, fever, hypoglycaemia
Management of Addison’s crisis
- High dose IV dexamethasone or IV hydrocortisone
- IV fluid resuscitation
Corticosteroids in critical care settings
- CAPECOD trial
- APROCCHSS trial
- ADRENAL trial
CAPECOD trial
Community-Acquired Pneumonia : Evaluation of Corticosteroids
- Hydrocortisone lower risk of death by day 28
APROCCHSS trial
Activated Protein C and Corticosteroids for Human Septic Shock
- Mortality benefit from use of hydrocortisone and fludrocortisone
ADRENAL trial
Adjunctive Corticosteroid Treatment in Critically Ill Patients with Septic Shock
- Faster resolution of shock, but no change in mortality
Conclusion:
Trial IV hydrocortisone 200-400mg daily (50mg Q6H or 100mg Q8H), taper quickly when clinical status improves
