Adrenals Flashcards
what is Waterhouse-Fridreichsen syndrome
Adrenal infection & hemorrhage infiltration
Massive adrenal hemorrhage
Meningococcemia
Often meningitis
Adrenal hemorrhage ddx
Waterhouse-Fridreichsen syndrome
antiphospholipid syndrome
anticoagulant therapy
Metabolic causes of adrenal insufficiency
- Adrenoleukodystrophy (Schilder disease),
- peroxisome biosynthesis disorders (e.g., Zellweger syndrome spectrum),
- disorders of cholesterol synthesis and metabolism (e.g., Wolman disease/CESD (discussed in Section VI), SLOS),
- mitochondrial disorders (e.g., Kearns-Sayre syndrome)
what is adrenoleukodystrophy
peroxisomal disease - Defective oxidation of VLCFAs (peroxisomes)
-> Accumulation of VLCFAs in brain, adrenal, liver, testes
the most common metabolic cause of adrenal failure
Most cases are caused by mutations in the peroxisomal membrane protein ALDP encoded by the ABCD1 gene on chromosome Xq28
ALDP imports activated acyl-CoA derivatives of very long chain fatty acids (VLCFA) into peroxisomes where they are shortened by β-oxidation
Smith-Lemli-Opitz Syndrome
- genetics
- defect
- how to diagnose
autosomal recessive
defect in cholesterol biosynthesis resulting from abnormalities in the sterol Δ-7-reductase gene, DHCR7
More than 190 mutations
Postnatal biochemical analysis of sterol Δ-7-reductase activity, coupled with genetic analysis
Smith-Lemli-Opitz Syndrome
- clinical features
- microcephaly,
- developmental delay,
- a typical facial appearance (short nose with broad nasal bridge and anteverted nares, long philtrum, microretrognathia, blepharoptosis, low- set, posterior-rotated ears, cleft and/or high-arched palate),
- proximal thumbs, and
- syndactyly of the second and third toes (>97%)
- Cardiac, renal, lung, and gastrointestinal abnormalities are also common.
-Genital anomalies include hypospadias, cryptorchidism, and even ambiguous genitalia in males.
-Adrenal insufficiency is present in some cases, especially during times of stress or when LDL-derived cholesterol sources are inadequate (e.g., dietary insufficiency/bile salt depletion)
Lab findings in Addisons
low morning cortisol level with a high ACTH
Hyponatremia, hyperkalemia, low aldosterone, and elevated PRA
acidosis
21 hydroxylase deficiency CAH - gene
what does the enzyme do
CYP21A2 gene encoding adrenal P450c21
Progesterone to DOC (deoxycorticosterone): aldosterone deficiency
17OH progesterone to 11-deoxycortisol: cortisol deficiency
simple virilizing 21OHD CAH - features in boys
- early development of pubic, axillary and facial hair, acne, and phallic growth
- can grow rapidly and are tall for age when diagnosed, but their epiphyseal maturation (bone age) advances disproportionately rapidly, so that ultimate adult height is compromised
When treatment is begun at several years of age, suppression of adrenal testosterone secretion may remove tonic inhibition of the hypothalamus, occasionally resulting in true central precocious puberty, requiring treatment with a GnRH agonist
-may have small testes and azoospermia because of the feedback of the adrenally produced testosterone on pituitary gonadotropins
- testicular adrenal rest tumors (TARTs) - from High concentrations of ACTH
how to treat aldosterone def
Fludrocortisone
Na supplement
congenital adrenal hypoplasia - other names
Adrenal Hypoplasia Congenita
adrenal dysgenesis
X-Linked Adrenal Hypoplasia Congenita
- gene
mutations of the NR0B1 gene encoding DAX1 on chromosome Xp21
what is DAX1
nuclear transcription factor involved in adrenal and testicular development, as well as being expressed in pituitary gonadotropes
X-Linked Adrenal Hypoplasia Congenita
- features (male and female)
MALE
- adrenal insufficiency (either salt-loss and glucocorticoid insufficiency as infant or chronic through out childhood)
- Hypogonadotropic hypogonadism and incomplete pubertal development
- defect in spermatogenesis
FEMALE
- unaffected, but half of their sons will be affected.
Triple A (Allgrove) Syndrome - features
- gene
(1) ACTH-resistant adrenal (glucocorticoid) deficiency (80% of individuals)
(2) achalasia of the cardia (85%)
(3) alacrima (90%)
Mineralocorticoid insufficiency (15% of cases)
Progressive neurological symptoms (60%), such as intellectual impairment, sensorineural deafness, peripheral and cranial neuropathies, optic atrophy, parkinsonism, and autonomic dysfunction
~ 80% of affected patients have autosomal recessive mutations in AAAS
Cushing syndrome vs Cushing disease
“Cushing syndrome” describes any form of glucocorticoid excess;
“Cushing disease” designates hypercortisolism caused by pituitary overproduction of ACTH
causes of Cushing syndrome
exogenous
ACTH DEP:
pituitary
ectopic
ACTH INDEP:
unilateral disease
bilateral disease
- bilateral macro nodular adrenal hyperplasia
- primary pigmented nodular Adrenal disease
Signs of Cushing syndrome
The earliest, most reliable indicators of hypercortisolism in children are weight gain and growth arrest
also remember: substantial degree of bone loss and undermineralization in children
Central obesity,
“moon facies,”
hirsutism, and
facial flushing
Striae,
hypertension,
muscular weakness,
back pain,
“buffalo hump” fat distribution,
psychological disturbances,
acne,
easy bruising
*these are the signs and features of advanced Cushing syndrome, not children early in dz
how to GC inhibit growth?
by increasing hypothalamic secretion of somatostatin, suppressing growth hormone secretion and IGF-1 production, and by acting directly on the epiphyses to inhibit sulfation of cartilage, inhibit mineralization, and inhibit cell proliferation.
most common cause of Cushing syndrome in young children?
Adrenal carcinomas
adrenal carcinoma vs adenoma - what do they secrete?
Adrenal adenomas almost always secrete cortisol with minimal secretion of mineralocorticoids or sex steroids
Adrenal carcinomas tend to secrete both cortisol and androgens, and are often associated with progressive virilization.
tests for Cushing syndrome
SCREEN:
(1) diurnal ACTH and cortisol profiles from blood (the latter may be performed on saliva)
- Midnight salivary cortisol
- Midnight serum cortisol
(2) 24-hour urine free measurements
(3) overnight 1 mg dexamethasone suppression test
TEST:
CRH Test:
Place venous catheter in patient previous night
Give ovine CRH 1 ug/kg at 8am
ACTH and cortisol: time -5, 0, 15, 30, 45 min
Cortisol incr >20% from baseline = Cushing Dz
no response = ectopic ACTH, adrenal tumour
Liddle Test:
Dex 0.5mg q6h x 8 doses, then 2mg q6h x 8 doses
Measure cortisol and urinary cortisol
Paradoxical rise in urinary cortisol in Primary Pigmented Nodular Adenocortical Hyperplasia
aldosterone - where is it produced and what stimulus
glomerulosa cells
in response to
- depleted intravascular volume via the renin- angiotensin system
and/or
- high plasma potassium
hyperalodsteronism - features
hypertension,
polyuria,
hypokalemic alkalosis,
low plasma renin activity
hyperalodsteronism Ddx
(1) unilateral aldosterone-producing adenomas (APAs, Conn syndrome), accounting for 30% to 40% of cases
(2) bilateral idiopathic hyperaldosteronism, accounting for 60% to 70% of cases
- bilateral adrenal hyperplasia
Rare:
(3) familial hyperaldosteronism (FH)
(4) primary nodular adrenal hyperplasias
Conn Syndrome
Aldosterone-Producing Adenomas
Recurrent somatic mutations most commonly in the gene encoding the K+ channel KCNJ5 (also known as Kir3.4)
Pseudohypoaldosteronism
- what is it
- when does it present
- labs
- tx
- a salt-wasting disorder (mineralocorticoid deficiency)
aldosterone resistance - infancy
hyponatremia,
hyperkalemia,
increased plasma renin activity
elevated aldosterone
Treatment:
Resistant to mineralocorticoid therapy
Salt supplementation
DDX for Precocious Puberty Male - virilization
- how to test for each one
CAH (late onset/non-classic)
- 17OHP (baseline & stimulated)
Familial Testotoxicosis (or activating LH receptor mutation, AD mutation)
- Elevated testosterone and suppressed LH
- Missense mutation of exon 11 of the LH receptor gene
Androgen Secreting Adrenal tumor
- Abdo/adrenal US
Leydig cell tumor
- Extremely high testosterone
- Testicular imaging – US or MRI
McCune Albright (activating mutation in the G-protein alpha subunit)
- Bone scan & skeletal survey
- Gs-alpha mutation is somatic, invariably a substitution of glycine for arginine at codon 201
hCG secreting tumors – hepatoblastoma and germ cell
- HCG level
Exogenous androgens
- Testosterone level
Zones of the adrenals and what the produce
OUTER
Zona glomerulosa - aldosterone
Zona fasciculata - cortisol and androgens
Zona reticularis - cortisol and androgens
Medulla - catecholamines
INNER
how much of cortisol is protein bound?
what increases or decreases binding?
> 90% of cortisol is protein bound (CBG)
↑CBG: estrogen, hyperthyroid, diabetes
↓ CBG: hypothyroid, cirrhosis
what does cortisol do to ant pit?
↓ GH secretion
↓ TSH release, ↓ deiodinase action
↓ LH, FSH release
what increases Aldo and how
Angiotensin II and hyperkalemia stimulate transcription of CYP11B2, so increased aldo production and secretion.
important transcription factors for fetal adrenal development
SF-1
DAX1
StAR deficiency
Autosomal recessively inherited
Decreased (but not absent) pregnenolone synthesis
ACTH stimulates accumulation of cholesterol esters
Adrenal gland is enlarged
Lipid accumulation leads to adrenal cell destruction
46XY - phenotypic female
3βHSD deficiency
- what does it stand for
- what gene
- inheritance
- what is elevated
- 3β Hydroxysteroid dehydrogenase 2
- HSD3B2
- AR
- pregnenolone, 17-oh pregnenolone, DHEA
what does DHEA stand for
dehydroepiandrosterone
3βHSD deficiency
- clinical features
- diagnosis
- treatment
Clinical Presentation:
DSD in both 46XX and 46XY
Salt-wasting (if complete)
Late onset has also been reported
Diagnosis:
17-OH-Pregnenolone > 10,000 ng/dL
Treatment:
Glucocorticoids
Mineralocorticoids
Sex steroids
17α-hydroxylase / 17,20-lyase Deficiency
- gene
- clin pres
- dx
- tx
- CYP17A1
- Clinical Presentation:
NO or mild ADRENAL INSUFFICIENCY (corticosterone has GC activity)
Mineralocorticoid excess: Hypertension, hypokalemia, alkalosis
46XX: delayed puberty
46XY: phenotypic female or undervirilized, delayed puberty - Diagnosis:
Markedly elevated DOC, pregnenolone, progesterone
Elevated FSH and LH (gonadal failure) – because these enzymes are also present in the gonads - Treatment:
Glucocorticoids
Sex steroids
CYP17A1 mutation causes what
17α-hydroxylase / 17,20-lyase Deficiency
21-Hydroxylase Deficiency
- gene
- inheritance
CYP21A2
AR
Labs in 21OH CAH
salt wasing
simple virilizing
non classic
Salt-wasting:
↓ Na
↑ K
↑ PRA, ACTH
↑ 170HP (>10,000 ng/dL)
Simple virilizing
Normal electrolytes
↔ or ↑ PRA
↑ 17OHP
Nonclassic
Normal electrolytes, PRA
↑ 17OHP
21-Hydroxylase Deficiency
- treatment
Simple Virilizing Treated Same As Salt-wasting
a) HC 10-15 mg/m2/day
b) Florinef 0.1-0.2 mg/day
c) Sodium (neonates) 1-3 gram/day div q6
Nonclassic: ONLY TREAT IF SYMPTOMATIC
a) Glucocorticoids
b) Adult females may try OCPs or antiandrogens (spironolactone) as first-line
21-Hydroxylase Deficiency Outcomes
- Adult Short Stature
- Amenorrhea, Infertility:
- Persistent or episodic adrenal androgen incr may disrupt menstrual cycle
- Ovarian/H-P dysfunction due to perinatal exposure to androgens
- Ovarian adrenal rest
- Insulin resistance - Iatrogenic Cushing’s
- Testicular Adrenal Rest Tumors
- 46XX – around 5% have a male gender identify
- Psychological:
46XX –
may have more “masculine” behavior
Less likely to marry
Less likely to be sexually active
Poor body image
11β-hydroxylase Deficiency type 1
- gene
- inheritance
- clin pres
- dx
- tx
CYP11B1
AR
Clinical Presentation:
46XX: masculization of external genitalia
46XY: precocious virilization
Mineralocorticoid excess
Diagnosis:
Markedly elevated 11-deoxycortisol and DOC
Treatment:
HC
+/- antihypertensive
Adrenal insufficiency DDX
Autoimmune
- APECED/APS-1
- APS-2
Adrenal Hemorrhage
- Traumatic delivery
- Neisseria meningitis infxn (Waterhouse-Frederickson)
Infection- TB, fungi, HIV
Infiltrative - Amyloidosis, Hemochromatosis
Malignant- Metastasis, Lymphoma
Adrenoleukodystrophy
Drugs: Ketoconazole, etomidate, metyrapone, megace
Congenital adrenal hypoplasia
Congenital adrenal hyperplasia
Smith-Lemli-Optz
what are ACTH resistance syndromes?
1) Familial Glucocorticoid Deficiency
2) Triple A (Allgrove) Syndrome:
most common cause of Cushing syndrome in older children
Cushing Disease
what syndromes is Cushing disease associated with
MEN-1
Familial Isolated Pituitary Adenoma
Adrenal tumour - assoc w what tumour syndromes
LiFraumeni (AD, TP53 gene)
MEN1 (AD Menin gene)
medical Cushing syndrome treatments
Steroidogenic Inhibitors:
Mitotane (inhibits SCC And 11Bhydroxylase)
Metyrapone
Ketoconazole
Neuromodulatory effect on ACTH:
Bromocriptine
Octreotide
GR Antagonism:
Mifepristone
what pathway is each and what stimulates it
CYP11B1
CYP11B2
ACTH stimulations CYP11B1 (cortisol pathway)
angiotensin II stimulates transcription of CYP11B2 (aldosterone pathway)
isolated deficiency of CYP11B2 does not have increased ACTH and does not cause accumulation of DOC
Hypoaldosteronsim ddx
Aldosterone Synthase Deficiency (CYP11B2)
Pseudohypoaldosteronism
what are causes of secondary adrenal insufficiency in neonates
○ Septo-optic dysplasia
○ CRH deficiency
○ Isolated ACTH deficiency
○ Multiple anterior pituitary hormone deficiencies
○ Pituitary aplasia/hypoplasia
○ Proprotein convertase 1 deficiency
○ Maternal hypercortisolemia
○ Prolonged glucocorticoid use in BPD
causes of primary adrenal insufficiency
○ Autoimmune
○ Adrenal hemorrhage
○ Infection – TB, fungal, HIV, CMV
○ Metabolic:
■ Adrenoleukodystrophy
■ Zellweger
■ Smith-Lemli-Opitz
■ Wolman disease
■ Kearnes-Sayre syndrome (mitochondrial)
○ Metastatic disease
○ Familial GC deficiency
○ CAH
○ Congenital adrenal hypoplasia
○ Infiltrative disorders: amyloidosis, hemochromatosis
○ Drug-induced: ketoconazole, metyrapone, etomidate, mitotane
mechanisms in which cortisol response in septic shock is beneficial
- Increase cardiac output
- Increase peripheral vascular tone, by possibly augmenting effect of catecholamines
- Regulate RAAS (independent of mineralocorticoid receptor; through regulation of angiotensinogen)
- Direct stimulation of the mineralocorticoid receptor
causes for falsely elevated urine cortisol
i) Carbamazepine
ii) Fenofibrate
iii) Collecting for more than 24 hours
iv) Severe obesity
v) Chronic stress (ie. uncontrolled diabetes, psychiatric disorders, alcoholism, etc.)
vi) More than 5L of intake a day
vii) Pregnancy
viii) Glucocorticoid resistance
ix) Malnutrition
x) Intense chronic exercise
xi) Hypothalamic amenorrhea
Estrogen
causes for falsely low urine cortisol
renal impairment,
only mild/moderate hypercortisolism (therefore should not be used to exclude Cushing’s syndrome), cyclic Cushing’s and the urine is not collected when it is not occurring
Carney complex
- Rare multiple endocrine neoplasia syndrome
- Frequently associated with mutations in protein kinase A type I-alpha regulatory subunit gene (PRKAR1A)
- AD inheritance
● Distinctive pigmented lesions of the skin and mucosal surfaces – lentiginous
○ stable, well-demarcated, and small (typically <5 mm) tan, brown, or black pigmented macules
○ typically manifest in the first 2 years of life become more prominent at puberty fade in adulthood
● Cardiac and non-cardiac myxomatous tumors
○ Cutaneous myxomas are benign dermal tumors
■ Common locations – eyelids, external ear canal, areolae
○ Cardiac – occur at a younger age and may develop simultaneously in multiple chambers of the heart
■ May present as painful arterial embolism
○ Benign breast tumors
■ Myxomas, myoxoid fibroadenomas, ductal adenomas with tubular
■ Develop after puberty
● Multiple endocrine tumors
○ Primary pigmented nodular adrenocortical disease
■ ACTH-independent overproduction of cortisol and CS
○ Asymptomatic GH hypersecretion
■ In most cases without imaging evidence of pituitary adenoma
■ Acromegaly occurs in 10-15%, usually in 3rd to 4th decade
○ Large cell calcifying Sertoli cell tumor
■ 75% of male gynecomastia in prepubertal boys (due to increased aromatase conversion to estrogen) and premature epiphyseal fusion and induction of central precocious puberty
■ Majority benign
○ Thyroid nodules
■ Usually euthyroid; thyroid ca (papillary and follicular) <10%
○ Ovarian cysts, serous cystadenoma, teratomas, endometrioid carcinoma
what stimulates renin
- Reduced after arteriolar wall pressure (lower BP)
- Macula densa in the distal tubules measure Na concentration and it is increased when there is low Na
- Sympathetic system activation (sudden standing up, etc)
RAAS system
renin: cleaves angiotensinogen to angiotensin 1
ACE: converts angiotensin 1 to angiotensin 2 and 3
angiotensin 2/3: cause release of aldosterone
what does aldosterone do? (4)
constriction of vascular muscle,
release of norepinephrine,
increased sympathetic nervous system activity,
vasopressin release
syndromes associated with adrenal corticocarcinoma
- Hemihypertrophy syndromes like Beckwith-Wiedemann Syndrome
- Germline mutations or loss of heterozygosity of p53 tumour suppressor gene ie Li-Fraumeni Syndrome
- MEN1
- FAP (Familial adenomatous polyposis)
- Carney Complex
how does licorice cause hypokalemia
● Cortisol can also activate mineralocorticoid receptor in the kidneys
● 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2) metabolizes cortisol to cortisone (inactive) and protects the mineralocorticoid receptor from cortisol binding
● Licorice inhibits 11ß-HSD2 and gives cortisol free access to rise –> causing hypoK and HTN
what does 11 beta HSD2 enzyme do
prevents cortisol from binding to the mineralocorticoid receptor
what puffer causes most AI?
Fluticasone (usually 500 mcg daily or more).
HSD11B2
11ß-hydroxysteroid dehydrogenase type 2 causing apparent mineralocorticoid excess
● AR inheritance
● Defective conversion of cortisol to cortisone (inactive metabolite)
● Cortisol displaces aldosterone at the mineralocorticoid receptor when in excessive amounts acts as a potent mineralocorticoid = HTN, hypoK, alkalosis, low aldosterone
● There’s also defective conversion in the kidney - significantly elevated tetrahydrocortisol and tetrahydrocortisone ratio [(THF + 5a THF)/THE] in a 24-hour urine analysis.
● DOC and androgen levels not affected
● This disorder can cause life-threatening HTN that can cause stroke and intracranial bleed
● Nephrocalcinosis can also occur
investigations to do if you suspect Addisons prior to starting tx
● Cortisol
● ACTH
● 17-OHP
● Androstenedione
● Renin
● Aldosterone
● Na
● K
● Deoxycorticosteroid
● 17 hydroxypregnenolone
● DHEAS
● Pregnenolone
● Progesterone
● DHEA
● Testosterone
To further work up you can get:
● 21 hydroxylase antibodies
● Genetic testing
● VLCFA
● Adrenal imaging
