Biochemistry Pituitary and Adrenal Flashcards
Conditions with Increased ACTH (low cortisol/ increase primary production) also present with:
- Beta endorphins
- Melanocyte hormone (increased pigmentation)
Cleaved from: pro-opiocortin
From Cholesterol produces:
- Aldosterone
- Cortisol
- Testosterone (25%)
- Oestradiol
cortisol Epi production rate
Most important glucocorticoid
Production rate c. 25mg/day
Cortisol forms
90% protein bound (CBG and Albumin)
Free Fraction physiologically active
Cortisol Effects
Carbohydrate metabolism • Insulin antagonist • Gluconeogenesis Protein Catabolism Immunosuppression (can be done therapeutic) “Permissive action” • Catecholamines • Free water clearance – w/o cortisol inappropriate ADH production there H2O retention - hyponatraemia
Test for Cortisol
Total Cortisol level e.g. bound and free
Pathology of Cortisol
Significant abnormalities in proteins such as loss of proteins or an increase in proteins (pregnancy)
Increase production of Cortisol
Increase in total and increase in free fraction as binding proteins saturated.
Cortisol control
- Negative feedback
- Diurnal (lowest at midnight, rise am, decreases in day)
- Stress (exercise, emotion)
Primary Causes of Cortisol suppression:
- Congenital adrenal hyperplasia
- Enzyme defect
- Selective or total destruction via a variety of causes
Selective destruction of cortex causes
Autoantibodies
Total adrenal destruction cause
Bacterial and fungal infections
TB
Metastatic carcinoma
Amyloidosis
Secondary Adrenal Insufficiency causes
Steroids – ACTH deficiency due to hypothalamic or pituitary disease
Adrenal Insufficiency Consequences:
- Hypoglycaemia
- Hypo-natraemia
- Hyperkalaemia
- Hypotension
- Pigmentation
- Non-Specific
- Hypoglycaemia
Uncommon seen in neonates/cause adrenal crisis
- Hypo-natraemia
Destruction leads to aldosterone loss and so Sodium loss and…
- Hyperkalaemia
Potassium retention from aldosterone
- Hypotension
Primary Cause (lack of negative feedback = ADH inappropriate control
- Pigmentation
Primary Causes – due to cleavage to form ACTH and so melanocyte hormone produced
Addison’s Disease symptoms:
- Lethargy
- Anorexia
- Pigmentation of hands and mouth – look at non sun-exposed areas.
- Abdominal pain
- Weight loss
Acute Adrenal Crisis:
- Vomiting
- Nausea
- Dehydration
Laboratory Investigations available →
Serum Cortisol
Dynamic synacthen (synthetic ACTH) stimulation test
ACTH
Serum Cortisol
Problems as
- A strong diurnal rhythm
- If the patient is stressed false raised
Dynamic synacthen (synthetic ACTH) stimulation test
Short: 250 ug given IM Looking for: Rise on cortisol Normal’s: • Incremental rise >200 nmol/L • Absolute rise >600 nmol/L
ACTH
Differentiates 1o/20
Synacthen stimulation test:
- Normal rise (+200) and exceeds 600
- Flat basal, no increase aove +600 – abnormal
- Baseline normal, response abnormal – poor increase
- V. high – severe stress
- V. high – Iatrogenic (hydrocortisone)
Causes of poor increase
a. Early stages w/ reserved adrenal function
b. Patient on steroids recently
• Primary adrenal failure
lack aldosterone (cortisol) >Na loss and K secretion
Electrolytes failure
• >Hyponatraemia >low plasma osmolality >reduced ADH (not completey reduced) – as cortisol permissive
- Loss of water to correct hyponatraemia
- Salt loss continuous and therefore water loss will be as well
- IV V becomes depleted ADH will eventually be secreted and some reabsorption
Electrolytes in adrenal failure
• Hyponatraemia, hyperkalaemia, volume depletion
21-hydroxylase enzyme action
- Aldosterone (progesterone to Deoxycorticosterone)
- Cortisol (17-OH progesterone to Deoxycortisol)
Gland still stimulated therefore overproduction of androgens.
21-hydroxylase Deficiency
Reduced aldosterone an reduced Cortisol
CAH Presentation
Ambiguous external genitalia
CAH Epi
> 90% of cases of CAH
CAH Marker
Increased 17 alpha OH progesterone
CAH Classical Form
Incidence 1:5,000-1:20,000
Simple virilising
Salt wasting
Late onset
CAH Clinical Manifestations New Born
Ambiguous external genitalia
Pigmented scrotum
Salt wasting
Sudden unexplained death (males)
CAH Clinical Manifestations Adult
Hirsutism (females) – most common in PCOS
Menstrual cycle disorder
Subfertility
CAH Investigations
Blood
Urine
Karyotype
CAH Blood investigations
- 17 alpha hydroxyl progesterone (also following synactin as baseline not good but response is diagnostic)
- Electrolytes (hypo Na+, hyper K+)
- Glucose - neonates
- Increased Androstenedione
- Increased Testosterone
- Renin – mineral-corticoid treatment monitor
- 17-OHP profiles (shows under/over treatment monitoring)
CAH Renin results
Over: Renin reduced volume expands
Under: Renin increased volume depleted
CAH Urine
Electrolytes
Steroid profile
CAH Karyotype
For determining the sex
Hypercortisolism (Cushing’s) → 2 types
ACTH High
ACTH low
Hypercortisolism (Cushing’s) → ACTH high causes
Pituitary Cushing’s Disease
Ectopic (lung)
Hypercortisolism (Cushing’s) → ACTH low
Adenoma’s – adrenal feedback
Carcinoma – adrenal feedback
Iatrogenic - overtreatment
Clinical features of Cushing’s
- Mental disturbances
- Fat redistribution, truncal obesity striae
- Protein Catabolism
- Osteoporosis
- Poor wound healing
- Bruising
- Hyperandrogenism
- Hirsutism
- Acne
- Amenerrhoea
- Insulin resistance
- Glucose intolerance
- Salt retention
- Hypertension
- Immunosuppression
Initial Investigation – define excess cortisol production 7 ways
- Serum Cortisol
- Salivary Cortisol
- Urine Free cortisol
- Dexa suppression
- Yanovski
- CRH testing
- High dose dexa
➢ Serum cortisol
Midnight/ 08:00 am
• Limited value
• Increased in stress
• False negative values in Cushing’s patients
➢ Salivary cortisolNB increased in stress illness and obesity
Problems in urine collection
Many assays not specific for cortisol
Midnight/09:00
• Demonstrate loss of diurnal rhythm
• Easy to collect at home, stress free environment
➢ D
➢ Urine free cortisol
NB increased in stress illness and obesity
Problems in urine collection
Many assays not specific for cortisol
➢ Dexamethasone Suppression
1 mg over night test (to exclude Cushing’s) – 09:00 am cortisol should be <50 nmol/L
Dexamethasone problem
High false positive rate
• Absorption dexamethasone
• Failure to take tablet
• Increased metabolism
Dexamethasone false negative
Cyclical Cushing’s (wax/waning)
Low dose dexamethasone
0.5 mg 6 hourly for 48 hours
→ Normal suppress
→ Cushing’s – no suppression
➢ Yanovski
Define excess cortisol production: looking at CRH following dexamethasome
Yanovski test
Cushing’s syndrome = massive cortisol increase after 15 mins
Normal = Cortisol low
Serum Cortisol (09:00) =
523 nmol/L 9150-700)
UFC =
445/L/ 24 hrs (<120)
Post dexamethasone cortisol:
Serum Cortisol (09:00) = 531 nmol/L
➢ Ectopic V Pituitary ACTH production
- Bilateral Inferior Petrosal Sinus Sampling (BIPSS) – to differentiate
- Cushing’s disease – Increase ACTH in blood post pituitary
- Central – peripheral gradient +3
➢ High Dose Dexamethasone
2 mg 6 hourly for 48-72 hours
• Pituitary dependant (Cushing’s disease) suppress – w/ enough dexa
• Adrenal and Ectopic ACTH no suppression
Ectopic sources of ACTH response to CRH
Don’t respond
Cushing’s disease response to CRH
Exaggerated ACTH production
