Chemical pathology III - Dynamic Function Tests Flashcards
5 Features of Cushing’s syndrome
Easy bruising
Facial plethora
Proximal myopathy (or proximal muscle weakness)
Striae (especially if reddish purple and >1 cm wide)
In children, weight gain + slow growth
Signs of Cushing’s symdrome
Dorsocervical fat pad (“buffalo hump”), facial fullness (moon face), obesity, supraclavicular
fullness, thin skin, peripheral edema, acne, hirsutism, poor skin healing
In children: abnormal genital virilization, short stature, pseudoprecocious puberty or delayed
puberty
Symptoms of Cushing’s syndrome
Depression, fatigue, weight gain, back pain, changes in appetite, decreased concentration, decreased libido, impaired memory (especially short-term), insomnia, irritability, menstrual abnormalities
In children: slow growth
Flow of Cushing syndrome diagnosis?
- exclude exogenous glucocorticoid exposure
- Perform 1 of following tests
- 24-h urine free cortisol (UFC) (≥2 tests)
- Overnight 1-mg dexamethasone suppression test (DST)
- Late-night salivary cortisol (≥2 tests)
Which test is better for Dx of Cushing syndrome at pregnancy?
24-h urine free cortisol (UFC) (≥2 tests)
Better for pregnancy, cyclic Cushing’s syndrome, increased estrogen (oral contraceptives
in young ladies)
Limitations of 24-h urine free cortisol (UFC)?
Not reliable for renal failure patients
False positive by drug interference is high: carbamazepine, fenofibrate, synthetic glucocorticoids, drugs that inhibit 11β-HSD2
Overnight 1-mg dexamethasone suppression test (DST):
- Mechanism
- Indication
Mechanism:
In normal subjects, dexamethasone suppresses ACTH and therefore adrenal cortisol secretion
CS: incomplete suppression
Indication: For patients with severe renal failure, adrenal incidentaloma (e.g. pheochromocytoma)
Overnight 1-mg dexamethasone suppression test (DST):
- Procedure
- Interpretation
Procedure: take 1mg dexamethasone orally at 2300h + measure plasma cortisol at 0900h
the following morning
Interpretation:
Normal subjects: cortisol suppressed to <50 nmol/L*
CS: no suppression
6 conditions that can cause false positives on Overnight 1-mg dexamethasone suppression test (DST)
(failed suppression in the absence of Cushing’s syndrome)
1) Drugs that accelerate dexamethasone metabolism by inducing CYP3A4:
- antiepileptic drugs (phenobarbital, phenytoin, carbamazepine, primidone,
ethosuximide) - rifampin, rifopentine,
- pioglitazone (antidiabetic)
2) Women on OC pills / pregnancy associated with elevated corticosteroid-binding globulin (CBG)***
3) Severe depression, severe systemic illnesses
4) Renal failure on dialysis
5) Chronic alcohol abuse
6) Marked obesity
2 conditions that cause false negatives on Overnight 1-mg dexamethasone suppression test (DST)
(suppression in the presence of Cushing)
Very rare!
1) Cyclical Cushing’s
2) Slow metabolism of dexamethasone
e. g. Drugs that impair CYP3A4
(aprepitant/fosaprepitant, itraconazole, ritonavir (antiretroviral), fluoxetine
(SSRI), diltiazem, cimetidine)
Indication for Late-night salivary cortisol (≥2 tests)
cyclic Cushing’s syndrome, adrenal incidentaloma
Normal result = unlikely Cushing’s
Abnormal result= must exclude physiological causes of hypercortisolism (Pseudocushing’s)
Conditions that can cause pseudo-Cushing’s
- pregnancy,
- depression, other psychiatric conditions,
- alcohol dependence,
- glucocorticoid resistance,
- morbid obesity, poorly controlled diabetes mellitus
Name one glucocorticoid stimulation test.
Indication?
Low dose (1 μg) short synacthen test (= corticotropin stimulation test)
diagnosis of (primary) adrenal insufficiency
or acutely ill patients with unexplained symptoms / signs of adrenal insufficiency
Mechanism of Low dose (1 μg) short synacthen test
ACTH from anterior pituitary regulates adrenal glucocorticoid secretion
Whether adrenal cortex can produce cortisol upon stimulation by Synacthen® (tetracosactrin =
synthetic ACTH)
Symptoms of adrenal
insufficiency
Symptoms: fatigue, weight loss, postural dizziness, anorexia, abdominal discomfort
Signs of adrenal insufficiency
Hyperpigmentation (ACTH activates melanin over time)
Low blood pressure with increased postural drop
In children: failure to thrive
List 3 concurrent electrolyte deficiencies associated with Adrenal insufficiency
hyponatremia, hyperkalemia, hypoglycemia
Adrenal crisis
- Symptoms
- Signs
- Lab tests
- Treatment
Symptoms: severe weakness, syncope, abdominal pain, nausea, vomiting, back pain, confusion
(May mimic acute abdomen)
Signs: hypotension (volume depletion), abdominal tenderness/guarding, reduced
consciousness, delirium
laboratory tests: hyponatremia, hyperkalemia, hypoglycemia, hypercalcemia
immediate therapy -IV hydrocortisone
How to interpret Low dose (1 μg) short synacthen test
Peak cortisol levels <500 nmol/L (18 μg/dL) at 30 or 60 minutes = adrenal insufficiency*
Limitations of Low dose (1 μg) short synacthen test
1) assesses response of adrenal gland but not test the whole hypothalamus-
pituitary adrenal axis
2) Not reliable within 2 weeks of pituitary surgery
3) Not standardized cut-off values
4) Rare allergic reaction
Primary adrenal insufficiency.
- Dx cut-off value?
confirmed cortisol deficiency: plasma ACTH >2-fold the upper limit of reference range
Main etiologies of Primary adrenal insufficiency
- Autoimmune (most common in adult)
- Adrenal infiltration/ injury:
- Metastasis
- Infection
- Iatrogenic/ removal
- Infiltration (amyloidosis, haemochromatosis) - Congenital adrenal hyperplasia (most common in children) e.g.
- 21-hydroxylase deficiency - Congenital adrenal hypoplasia
- Others: drug-induced, ACTH insensitivity syndrome, other metabolic diseases…etc
Effect of 21-hydroxylase deficiency on androgen production
- Increase DHEA to testosterone and DHT conversion
- Increase 17-OH progesterone convertion to androstenedione to testosterone
- Increase 5α and 3α reduction of 17-OHP to 17OH-
allopregnanolone»_space; androstanediol»_space; oxidized to DHT
3 main types of diabetes
Type 1 diabetes (autoimmune
β-cell destruction)
Type 2 diabetes
(progressive loss of β-cell insulin secretion + insulin resistance)
Gestational diabetes mellitus (GDM)
Define fasting blood glucose level for Pre-diabetes, Diabetes and GDM
Fasting = no caloric intake for at least 8 hours
Pre-diabetes: 5.6 - 6.9 mmol/L»_space; impaired fasting glucose
Diabetes: ≥ 7.0 mmol/L on 2+ occasions
GDM: 5.1-6.9 mmol/L
Define blood glucose level for Pre-diabetes, Diabetes and GDM in OGTT test (2-hours after 75-g anhydrous glucose
dissolved in water)
Pre-diabetes: 7.8 mmol/L- 11.0 mmol/L
Diabetes: ≥11.1 mmol/L
GDM: 8.5-11.0 mmol/L
Define HbA1C levels for Pre-diabetes, Diabetes
Pre-diabetes: 5.7-6.4%
Diabetes: ≥6.5%
Define the test for hyperglycemia/ hyperglycemic crisis and cut-off Dx value
Random plasma glucose
≥ 11.1 mmol/L
Method for OGTT test.
Blood taken for Baseline blood glucose after fasting (e.g. early morning)
75 anhydrous glucose dissolved in 200mLwater»_space; drink over 3-5 minutes and wait 2 hours»_space; take blood for glucose level
- Do not restrict carbs for 3 days before test*
- Do not smoke/ exercise before or during test*
Contraindication for OGTT to Dx DM.
- Already diagnosed with DM
- Under stress: post-surgery, sepsis, trauma
- Hypokalemic Periodic paralysis (high carb meal can trigger attack)
- Vasovagal symptoms during test
Apart from DM, list 2 diseases that can use OGTT for Dx?
Acromegaly: raised baseline IGF-1 or GH fails to drop during OGTT
Adult growth hormone deficiency
