Disorders of the Adrenal Cortex 1.2 (based on Harrisons) Flashcards
1
Q
What is the estimated prevalence of mineralocorticoid excess in hypertensive patients?
A
5-12%
2
Q
What is the most common cause of mineralocorticoid excess?
A
Primary aldosteronism
3
Q
What adrenal zone produces aldosterone?
A
Zona glomerulosa
4
Q
What is the more common cause of primary aldosteronism: bilateral micronodular hyperplasia or unilateral adrenal adenomas?
A
Bilateral micronodular hyperplasia
5
Q
What somatic mutations have been identified in aldosterone-producing adrenal adenomas?
A
Mutations in potassium channel GIRK4 (KCNJ5), Na+/K+-ATPase α-subunit (ATP1A1), plasma membrane calcium-transporting ATPase 3 (ATP2B3), and voltage-gated calcium channels (CACNA1D, CACNA1H)
6
Q
What is glucocorticoid-remediable aldosteronism (GRA) caused by?
A
A chimeric gene resulting from crossover between CYP11B1 and CYP11B2, leading to ACTH-regulated aldosterone production
7
Q
What family history feature can suggest glucocorticoid-remediable aldosteronism?
A
Dominant transmission of hypertension
8
Q
What is the key biochemical abnormality in the syndrome of apparent mineralocorticoid excess (SAME)?
A
Cortisol acts as a potent mineralocorticoid due to inactivating mutations in HSD11B2
9
Q
What dietary factor can inhibit 11β-HSD2 and mimic SAME?
A
Excess licorice ingestion
10
Q
Which congenital adrenal hyperplasia enzyme deficiencies can lead to mineralocorticoid excess?
A
CYP11B1 (11β-hydroxylase) and CYP17A1 (17α-hydroxylase) deficiencies
11
Q
What is the molecular mechanism of Liddle’s syndrome?
A
Mutations in the β or γ subunits of ENaC, leading to decreased degradation and constitutively active ENaC
12
Q
What is the clinical hallmark of mineralocorticoid excess?
A
Hypokalemic hypertension
13
Q
Why do only 50% of patients with primary aldosteronism exhibit hypokalemia?
A
Sodium retention leads to concurrent fluid retention, maintaining normal serum sodium levels
14
Q
What electrolyte abnormality, aside from hypokalemia, is common in mineralocorticoid excess?
A
Hypomagnesemia
15
Q
What are the potential muscular complications of severe hypokalemia?
A
Muscle weakness, proximal myopathy, hypokalemic paralysis, and tetany
16
Q
What additional health risks are associated with primary aldosteronism?
A
Increased risk of osteoporosis, type 2 diabetes, and cognitive dysfunction
17
Q
What is Connshing syndrome?
A
The co-occurrence of primary aldosteronism and mild autonomous cortisol excess (MACE)
18
Q
What are the indications for screening for mineralocorticoid excess?
A
Hypertension with drug resistance, hypokalemia, an adrenal mass, or onset before age 40
19
Q
What is the recommended initial screening test for mineralocorticoid excess?
A
Aldosterone-renin ratio (ARR) with plasma renin and aldosterone measurement
20
Q
What ARR value is considered positive for mineralocorticoid excess?
A
ARR >750 pmol/L per ng/mL per hour with a concurrently high normal or increased aldosterone
21
Q
What is the confirmatory test for mineralocorticoid excess?
A
Saline infusion test (failure of aldosterone to suppress <140 pmol/L)
22
Q
What alternative confirmatory tests exist for mineralocorticoid excess?
A
Oral sodium loading test or fludrocortisone suppression test
23
Q
What class of antihypertensive drugs must be discontinued at least 4 weeks before ARR testing?
A
Mineralocorticoid receptor antagonists
24
Q
What effect do beta blockers have on ARR testing?
A
They can cause false-positive results
25
What effect do ACE inhibitors or AT1R blockers have on ARR testing?
They can cause false-negative results in milder cases
26
What cardiovascular effects does aldosterone excess have aside from hypertension?
Increased cardiac remodeling and decreased vascular compliance
27
What renal effects does aldosterone excess have?
Direct glomerular damage in addition to hypertension-related renal damage
28
What additional findings may be present in severe hypokalemic metabolic alkalosis?
Muscle cramps and tetany
29
What is the next step after diagnosing hyperaldosteronism?
Adrenal imaging with fine-cut CT scanning.
30
Why is fine-cut CT scanning preferred for assessing hyperaldosteronism?
It provides excellent visualization of adrenal morphology and can detect most aldosterone-producing adenomas.
31
When should adrenal vein sampling (AVS) be performed in hyperaldosteronism?
In surgical candidates with no obvious lesion on CT or those >40 years old with a unilateral lesion to rule out incidental, non-functioning adenomas.
32
What confirms lateralization in AVS for hyperaldosteronism?
An aldosterone/cortisol ratio at least twofold higher on one side than the other.
33
Why is AVS a complex procedure?
It requires a highly skilled interventional radiologist, and the right adrenal vein can be difficult to cannulate.
34
What is the first-line medical treatment for hyperaldosteronism in non-surgical candidates?
MR antagonist spironolactone.
35
What is the starting dose of spironolactone for hyperaldosteronism?
12.5–50 mg bid, titrated up to 400 mg/day if needed.
36
What are the side effects of spironolactone?
Menstrual irregularity, decreased libido, and gynecomastia.
37
What is an alternative to spironolactone for hyperaldosteronism?
Eplerenone, starting at 25 mg bid, titrated up to 200 mg/day.
38
When should genetic testing be considered in hyperaldosteronism?
In patients with normal adrenal morphology and a family history of early-onset, severe hypertension to evaluate for glucocorticoid-remediable aldosteronism (GRA).
39
What is the treatment for glucocorticoid-remediable aldosteronism (GRA)?
Dexamethasone at the lowest dose possible to control blood pressure.
40
What lab findings suggest non-aldosterone-related mineralocorticoid excess?
Suppressed renin and suppressed aldosterone in the presence of hypokalemic hypertension.
41
What diagnostic test can identify syndromes like SAME, CYP11B1 deficiency, and CYP17A1 deficiency?
Urinary steroid metabolite profiling by gas chromatography/mass spectrometry (GC/MS).
42
What condition is suggested by an increased free cortisol/free cortisone ratio?
SAME (Syndrome of Apparent Mineralocorticoid Excess).
43
What treatment is effective for Liddle’s syndrome?
Amiloride.
44
What percentage of the general population has adrenal incidentalomas?
2–5%.
45
What is the prevalence of adrenal incidentalomas in 40-year-olds and 70-year-olds?
1% in 40-year-olds and 7% in 70-year-olds.
46
What is the most common type of adrenal nodule?
Endocrine-inactive adrenocortical adenoma.
47
What percentage of adrenal nodules are hormonally active?
Up to 25%.
48
What is the preferred imaging modality for adrenal mass evaluation?
Unenhanced CT.
49
Which adrenal tumors have high attenuation values (>20 Hounsfield units)?
ACC, pheochromocytoma, and lipid-poor adrenocortical adenomas.
50
What feature on unenhanced CT suggests a benign adrenal lesion?
Low attenuation values (<20 Hounsfield units).
51
When should fine-needle aspiration (FNA) be avoided for an adrenal mass?
When pheochromocytoma is suspected due to risk of hypertensive crisis or when ACC is suspected due to risk of needle track metastasis.
52
What adrenal tumors are commonly associated with hormone excess?
ACC, cortisol-producing adenomas, aldosterone-producing adenomas, and pheochromocytomas.
53
What diagnostic test is used to differentiate benign from malignant adrenal lesions based on steroid metabolism?
Urine steroid metabolomics.
54
What is the most common genetic mutation found in ACC?
TP53 mutations, seen in 25% of sporadic cases.
55
What is the treatment of choice for confirmed ACC?
Complete surgical removal.
56
What is the most important histopathologic prognostic factor in ACC?
Ki67 proliferation index.
57
What is the preferred adjuvant therapy for ACC after surgical removal?
Mitotane (o,p’DDD).
58
Why does mitotane require glucocorticoid replacement?
It disrupts cortisol synthesis and induces hepatic CYP3A4, accelerating glucocorticoid metabolism.
59
What is the first-line chemotherapy regimen for advanced ACC?
Cisplatin, etoposide, and doxorubicin plus mitotane.
60
What is the 5-year survival rate for ACC?
30–40%.
61
Which imaging modality is highly sensitive for detecting small ACC metastases?
18-FDG-PET.
62
Where does ACC most frequently metastasize?
Liver and lungs.
63
What is the prevalence of permanent adrenal insufficiency in the general population?
5 in 10,000
64
What is the most frequent cause of adrenal insufficiency?
Hypothalamic-pituitary origin (3 in 10,000 prevalence)
65
What is the prevalence of primary adrenal insufficiency?
2 in 10,000
66
What is the most common cause of primary adrenal insufficiency?
Autoimmune adrenalitis
67
What percentage of primary adrenal insufficiency cases are due to autoimmune adrenalitis?
0.5
68
What is the most common acquired cause of primary adrenal insufficiency?
Autoimmune destruction of the adrenal glands
69
What is the most common genetic cause of primary adrenal insufficiency?
Congenital adrenal hyperplasia (CAH)
70
What is the most common cause of secondary adrenal insufficiency?
Exogenous glucocorticoid use suppressing the HPA axis
71
What is the prevalence of adrenal insufficiency due to exogenous glucocorticoid treatment?
0.5–2% of the population in developed countries
72
What is APS1 and what gene mutation causes it?
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), caused by AIRE gene mutation
73
What is the inheritance pattern of APS1?
Autosomal recessive
74
What condition is invariably present in APS1?
Chronic mucocutaneous candidiasis
75
What is the more prevalent autoimmune polyglandular syndrome?
APS2
76
What genetic association is linked to APS2?
HLA-DR3 gene region
77
What autoimmune diseases are commonly associated with APS2?
Thyroid autoimmune disease, vitiligo, premature ovarian failure
78
What is X-linked adrenoleukodystrophy (X-ALD) and what gene is mutated?
A peroxisomal disorder caused by mutations in the ABCD1 gene
79
What is the incidence of X-ALD?
1:20,000 males
80
What are the three main clinical presentations of X-ALD?
Cerebral adrenoleukodystrophy, adrenomyeloneuropathy (AMN), isolated adrenal insufficiency
81
What infectious cause of adrenal insufficiency remains common in developing countries?
Tuberculous adrenalitis
82
What rare congenital conditions can cause primary adrenal insufficiency?
Mutations in genes like DAX-1, SF-1, StAR, CYP11A1, MC2R, MRAP, NNT, TXNRD2
83
What is Sheehan’s syndrome?
Pituitary apoplexy due to ischemic necrosis after postpartum hemorrhage
84
What is the primary clinical difference between primary and secondary adrenal insufficiency?
Primary involves both glucocorticoid and mineralocorticoid deficiency, while secondary only affects glucocorticoids
85
What skin finding is characteristic of primary adrenal insufficiency?
Hyperpigmentation due to excess ACTH
86
What electrolyte imbalances are common in primary adrenal insufficiency?
Hyponatremia (80% of cases) and hyperkalemia (40%)
87
What causes hyponatremia in secondary adrenal insufficiency?
Increased ADH release due to cortisol deficiency
88
What is adrenal crisis and what triggers it?
Acute adrenal insufficiency, often triggered by illness, surgery, or glucocorticoid withdrawal
89
What is the mortality rate of adrenal crisis?
0.5 adrenal crisis-related deaths per 100 patient-years
90
What is the first-line test for diagnosing adrenal insufficiency?
Short cosyntropin (ACTH stimulation) test
91
What is the diagnostic cortisol cutoff in the ACTH stimulation test?
<450–500 nmol/L (16–18 μg/dL) after 30–60 min
92
What test is used when early HPA dysfunction is suspected?
Insulin tolerance test (ITT)
93
What plasma hormone differentiates primary from secondary adrenal insufficiency?
ACTH (high in primary, low or inappropriately normal in secondary)
94
What imaging is used if autoimmune adrenalitis is ruled out?
Adrenal CT scan
95
What genetic test should be done in males with unexplained adrenal insufficiency?
Very-long-chain fatty acid levels to rule out X-ALD
96
What is the emergency treatment for adrenal crisis?
IV saline + 100 mg hydrocortisone bolus followed by 200 mg hydrocortisone over 24 hours
97
What is the standard daily glucocorticoid replacement for chronic adrenal insufficiency?
15–25 mg hydrocortisone in divided doses
98
What glucocorticoids are NOT preferred for adrenal replacement?
Prednisolone and dexamethasone (due to prolonged glucocorticoid exposure)
99
What additional monitoring should be done in patients on glucocorticoids?
Body weight, blood pressure, and screening for thyroid disease or premature ovarian failure
100
What mineralocorticoid is used for primary adrenal insufficiency?
Fludrocortisone (100–150 μg daily)
101
How is the adequacy of mineralocorticoid replacement assessed?
Blood pressure (sitting/standing), serum sodium, potassium, plasma renin levels
102
What should patients with adrenal insufficiency carry for emergencies?
Hydrocortisone self-injection kit, steroid emergency card, and bracelet
103
What is the recommended stress-dose adjustment for glucocorticoids during illness?
Double the routine oral dose or give 100 mg IV hydrocortisone if severe
104
Why might mineralocorticoid doses need adjustment in pregnancy?
Progesterone has antimineralocorticoid activity
105
When should adrenal androgen replacement be considered?
In women with persistent fatigue and low libido despite optimal replacement
106
What drug is used for adrenal androgen replacement?
DHEA (25–50 mg daily)
107
What is the primary cause of congenital adrenal hyperplasia (CAH)?
Mutations in genes encoding steroidogenic enzymes (CYP21A2, CYP17A1, HSD3B2, CYP11B1) or the cofactor enzyme P450 oxidoreductase.
108
What is the most common genetic mutation responsible for CAH?
Mutations in CYP21A2, responsible for 90–95% of cases.
109
How does 21-hydroxylase deficiency affect hormone synthesis?
It disrupts glucocorticoid and mineralocorticoid synthesis, leading to increased ACTH and adrenal androgen excess.
110
What are the three clinical phenotypes of CAH based on mutation severity?
Classic CAH (severe), simple virilizing CAH (moderate), and nonclassic CAH (mild).
111
What is the primary cause of adrenal androgen excess in CAH?
Increased ACTH due to impaired cortisol feedback, stimulating excess adrenal androgen production.
112
What are the clinical manifestations of androgen excess in CAH?
Virilization of external genitalia in neonatal girls, hirsutism, oligomenorrhea, and features resembling PCOS in women.
113
What is the usual presentation of CAH in neonatal boys in countries without newborn screening?
Life-threatening adrenal crisis (salt-wasting crisis) in the first few weeks of life.
114
What are the common childhood manifestations of simple-virilizing CAH?
Precocious pseudopuberty and advanced bone age.
115
How is CAH diagnosed?
Measurement of steroid precursors before the enzymatic block, preferably using mass spectrometry-based assays.
116
What is the primary goal of glucocorticoid treatment in CAH?
To replace missing glucocorticoids, suppress ACTH, and control androgen excess.
117
Why is glucocorticoid therapy in CAH more complex than in other causes of adrenal insufficiency?
It must mimic diurnal cortisol secretion while suppressing ACTH-driven androgen excess.
118
What are the main treatment goals of glucocorticoid therapy in children with CAH?
Optimize growth and puberty, prevent adrenal crisis, and treat 46,XX DSD.
119
What are the treatment goals of glucocorticoid therapy in adults with CAH?
Preserve fertility and prevent metabolic syndrome and osteoporosis from overtreatment.
120
How does CAH affect fertility in women?
Androgen excess leads to oligomenorrhea/amenorrhea and chronic anovulation.
121
What is testicular adrenal rest tissue (TART) in men with CAH?
Hyperplastic cells in the rete testis that may compromise sperm production and cause testicular fibrosis.
122
What is the recommended first-line glucocorticoid treatment for CAH?
Hydrocortisone, given in divided doses.
123
What is an alternative glucocorticoid for controlling androgen excess in CAH if hydrocortisone is insufficient?
Prednisone or prednisolone.
124
What glucocorticoid may be used for fertility treatment in CAH, and why should its use be limited?
Dexamethasone, but only for a short time due to adverse metabolic effects.
125
What is the advantage of modified and delayed-release hydrocortisone?
It mimics the physiological cortisol release pattern and allows for lower daily doses.
126
What biomarkers are used for biochemical monitoring in CAH?
Androstenedione and testosterone, aiming for normal sex-specific reference ranges.
127
What is an indicator of glucocorticoid overtreatment in CAH?
Low 17-hydroxyprogesterone (17OHP) levels within the normal range of healthy controls.
128
When should stress-dose glucocorticoids be given in CAH?
During surgery, acute illness, or severe trauma.
129
What is a potential adrenal consequence of poorly controlled CAH?
Adrenocortical hyperplasia, which can lead to macronodular hyperplasia and autonomous androgen production.
130
What benign adrenal tumors have increased prevalence in CAH?
Adrenomyelolipomas, which may require surgery due to growth.
131
Why do mineralocorticoid requirements change with age in CAH?
Children have relative mineralocorticoid resistance that diminishes as the kidneys mature.
132
What is the role of plasma renin monitoring in CAH?
It should be kept in the upper half of the normal range to guide mineralocorticoid therapy.
