Adrenal 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 therapyq
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)gs in
Lab findings in Addison
Low cortisol
high ACTH
low Na
high K
Low Aldo
High renin (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 Aldo def
Fludrocortisone
Na supplement
Congenital adrenal hypoplasia other names
Adrenal Hypoplasia Congenita
adrenal dysgenesis
Congenital adrenal hypoplasia
- inheritance
- gene
x-linked
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)
Xlinked
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” = any form of glucocorticoid excess;
“Cushing disease” = hypercortisolism caused by pituitary overproduction of ACTH
Causes of Cushing syndrome
***exogenous
ACTH DEP:
pituitary
ectopic
ACTH INDEP:
unilateral adrenal disease
bilateral adrenal 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
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.
testing for CS
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
hyperaldo - features
hypertension,
polyuria,
hypokalemic alkalosis,
low plasma renin activity
hyperaldo 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
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
MIBG is good for
Pheo
PGL
neuroblastoma
ganglioneuroblastoma
carcinoid
MTC
what does DHEA stand fo r
dehydroepiandrosterone
Primary AI DDx
Autoimmune
- Addison
- APECED/APS-1
- APS-2
Metabolic:
- Adrenoleukodystrophy
- Zellweger
- Smith-Lemli-Opitz
- Wolman disease
- Kearnes-Sayre syndrome
CAH
- Congenital adrenal hypoplasia
- Congenital adrenal hyperplasia
Adrenal Hemorrhage
- Traumatic delivery
- Neisseria meningitis infxn (Waterhouse-Frederickson)
Infection
- TB
- HIV
Infiltrative - Amyloidosis, Hemochromatosis
Malignant- Metastasis, Lymphoma
Adrenoleukodystrophy
Familial GC deficiency
Drugs: Ketoconazole, etomidate, metyrapone, megace, mitotane
