DISORDERS OF THE ADRENAL GLAND

Dr. Jean Abigaile Caringal

ANATOMY OF THE GLAND Adrenal Cortex
ADRENAL GLAND
• a.k.a. Suprarenal gland
• 4 grams, 2 x 5 x 1
cm, pyramidal
• Arteries: from aorta,
inferior phrenic,
renal, intercostal
• Veins
• Right – direct to IVC
• Left – renal vein
*Right Adrenal Gland- Pyramidal
*Left Adrenal Gland- Cone-shaped

Cortex - outer
1. Glomerulosa – 15%
- Mineralocorticoids
- regulate mineral balance
- example: Aldosterone
2. Fasciculata – 75%
- Glucocorticoids
- regulate glucose metabolism
- example: Cortisol, Corticosterone,
Cortisone
3. Reticularis – 10%
- Androgens
- Stimulates masculinization
- example: Dehydroepiandrosterone
Medulla – inner
Adrenal medulla –
stress hormones,
stimulates sympathetic
ANS, examples:
Epinephrine,
Norephinephrine
*Contains the
Chromaffin Cells
(responsible for
Catecholamines
 • Adrenal mass – incidentaloma, cancer
• Congenital adrenal hyperplasia (CAH)
• ZG: MINERALOCORTICOIDS
(ALDOSTERONE, DEOXYCORTICOSTERONE)APA-

Aldosterone producing adenoma

Clinical presentation
• 3rd to 6th decades of life
• Moderate to severe HTN, resistant HTN – major clinical
finding

Renin and Angiotensin

Renin- produced by juztaglomerular apparatus of the kidney. Rate-
limiting step in RAA System. Controlled by 4 factors:
1. NaCl by the Macula Densa Cells
2. Renal Arterial Pressure
3. Sympathetic NS –in response to upright posture
4. Humoral: Potassium, Angiotensin II, ANP
Aldosterone – controlled by 3 primary factors:
1. Angiotensin II
2. Potassium  Extracellular Volume - IN
3. ACTH  Potassium - OUT
What can go wrong?
• Mineralocorticoid excess – Primary
hyperaldosteronism, Conn’s syndrome
• Glucocorticoid excesss – Cushing’s syndrome
• Glucocorticoid / mineralocorticoid deficiency –
Adrenal insufficiency
• Marked hypokalemia – muscle weakness (common in
Asians), cramping, headaches, palpitations, polydypsia,
polyuria, nocturia; frequently absent
• Edema is uncommon due to “mineralocorticoid escape”
• High-normal or slightly elevated serum Na+
• Chronic kidney disease; cardiovascular events
Diagnostic Approach
1. Case-detection Tests
2. Confirmatory Tests
3. Subtype Evaluation Tests
Diagnosis: Case-Detection Tests
 Diagnosis: Case-Detection Tests

• Restore serum K+ to normal before performing the tests

• Encourage patient to liberalize sodium intake

• Discontinue agents that markedly affect the ARR for at least Management and Treatment
4 weeks: Adrenal Vein Sampling (AVS) – “gold standard” test that
distinguishes between unilateral vs. bilateral diseases in patients
1.) Spironolactone, eplerenone, amiloride, and triamterene with PA
2.) Potassium-wasting diuretics Goals of therapy due to either unilateral or bilateral adrenal disease
3.) Products derived from licorice root (eg, confectionary are the same and include:
licorice, chewing tobacco)  Reversal of the adverse cardiovascular effects
 Normalization of the serum potassium
• Discontinue other medications that may affect the ARR for  Normalization of the blood pressure
at least 2 weeks:
Unilateral Disease (APAs or Unilateral Hyperplasia)
 Laparoscopic Adrenalectomy
1.) Adrenergic blockers, central-2 agonists (eg, clonidine, -
 Mineralocorticoid receptor antagonists are an effective
methyldopa), and nonsteroidal anti-inflammatory drugs
alternative in patients who are not candidates for surgery
ACE inhibitors, ARBs, renin inhibitors, and dihydropyridine calcium Bilateral Laparoscopic Hyperaldesteronism (IHA) or those who are
channel antagonists not candidates for surgery
Diagnosis: Confirmatory Test  Mineralocorticoid Antagonist Therapy
The exception to the requirement for confirmatory testing:
 Subtotal Adrenalectomy NOT suggested in these patients
1.) spontaneous hypokalemia
Sodium-restricted diet (<100 mEq/day)
2.) undetectable PRA or PRC
Maintenance of ideal body weight
3.) PAC >20 ng/dL
Tobacco avoidance
Regular aerobic exercise
Aldosterone suppression testing:
Mineralocorticoid receptor antagonist:
1.) Oral Sodium Loading Test
2.) Intravenous Saline Infusion Test • Spironolactone – drug of choice; 25-, 50-, 100 mg; SE:
breast tenderness and menstrual irregularities in women and
Diagnosis: Subtype Studies
impotence, decreased libido, and gynecomastia in men
• Eplerenone – highly selective, less side effect; expensive
ZF: GLUCOCORTICOIDS (CORTISOL)
• Cushing syndrome – signs and symptoms associated with
chronicexposure to inappropriately elevated glucocorticoids
• Cushing disease – for pituitary dependent Cushing
syndrome; most common cause of endogenous CS
• Iatrogenic Cushing syndrome – from exogenous
prolonged steroid intake (oral/IV, topical, inhalant); most
common cause
Classification of Cushing Syndrome  Immune-system – Anti-inflammatory action,
Immunosuppression
Clinical features of Cushing Syndrome
 Classic features:
centripetal obesity, moon face,
hirsutism, plethora
 Most common signs:
weight gain and obesity
 Thoracocervical fat pad
(buffalo hump)
 Typical, almost
pathognomonic – red- purple livid
striae greater than 1cm in width

The principal sites of action of glucocorticoids in humans,

highlighting some consequences of glucocorticoid excess
 Brain/CNS – depression, psychosis
 Endocrine System- decrease LH, FSH and TSH
 Eye- Glaucoma
 GI Tract- Ulcerations
 Carbohydrate/ Lipid Metabolism – increase hepatic
glycogen deposition, increase peripheral insulin
resistance, increase gluconeogenesis, increase free
fatty acid production, overall diabetogenic effect
 Cardiovascular/ Renal- Salt and water
retention, Hypertension
 Adipose Tissue Distribution- promotes visceral
obesity
 Bone and Calcium Metabolism – decrease bone
formation, decrease bone mass and
osteoporosis
 Skin/Muscle/Connective tissue – Protein
Catabolism/Collagen breakdown, Skin thinning
muscle atrophy
Clinical features of Cushing Syndrome
 Growth and Development – decrease linear
 Recurrent progressive moon facies
growth
  (+) Round face, plethoric, warm, oily facial
skin, (+) acne, (+) hirsutism
 No coarsening of features


 Thickened nail with whitish discoloration of
nail bed
 Prominent dorso - cervical fat and
supraclavicular fat pads


  Flabby abdomen 
 (+) abdominal reddish-purple striae (>1cm)  Pulses full and equal, no cyanosis
 Bipedal Edema gr. 1
How to Evaluate patients with CS:


 Thin skin


 Hirsutism


 Balding
TREATMENT:  Hypopituitarism
• Cushing’s Disease: Transphenoidal resection of  Selective removal of ACTH-secreting pituitary
adenoma
pituitary adenoma  Pituitary tumors and pituitary surgery,
• Adrenal neoplasms: adrenalectomy  craniopharyngiomas
• Ectopic ACTH: resection if possible  Pituitary apoplexy
• Bilateral adrenal hyperplasia: may need  Granulomatous disease
adrenalectomies (lifelong glucocorticoid and mineralocorticoid  Secondary tumor deposits
 Postpartum pituitary infarction (Sheehan syndrome)
replacement)
 Pituitary irradiation
• Nelson syndrome – postadrenalectomy  Gene mutations
hyperpigmentation with a locally aggressive pituitary tumor  Exogenous glucocorticoid therapy
Medications that inhibit steroidogenesis  AI should be anticipated in any subject who
has taken more than the equivalent of 30 mg
• Ketoconazole (400 to 1600 mg/day) hydrocortisone per day orally (>7.5 mg/day
• Metyrapone – inhibits 11 beta hydroxylase prednisolone or >0.75 mg/day dexamethasone)
• Mitotane – adrenolytic drug (can cause for longer than 3 weeks.
atrophy and necrosis)
• Somatostatin analogues – pasireotide

GLUCOCORTICOID DEFICIENCY
Primary Adrenal Insufficiency (Addison’s disease)
• Caused by disordered adrenal function
• Low cortisol production
• High plasma ACTH concentration
Secondary/Central Adrenal Insufficiency
• caused by disordered function of the hypothalamus
and pituitary gland
• Low cortisol production
• Normal or low plasma ACTH production
Major distinction:
Primary AI - mineralocorticoid deficiency almost always
present
VS
Central AI – only ACTH is deficient; RAAS is intact
CAUSES OF PRIMARY ADRENAL INSUFFICIENCY
 Autoimmune
 Sporadic
 Autoimmune Polyendocrine Syndrome Type I (APECED)
 Autoimmune Polyendocrine Syndrome
 Type II (Schmidt syndrome)
 Infections – TB, fungal, CMV, HIV
 Metastatic tumor
 Infiltrations
 Intra-adrenal hemorrhage (Waterhouse-
Friderichsen syndrome) after meningococcal CLINICAL FEATURES OF AI
septicemia • Signs that are specific to primary AI
 Adrenoleukodystrophies Hyperpigmentation
 Congenital adrenal hypoplasia
 ACTH resistance syndromes
 Bilateral adrenalectomy
AUTOIMMUNE ADRENALITIS – most common cause of
primary AI in Western World.
INFECTIOUS DISEASES – most common cause of primary
AI Worldwide.
• In autoimmune Addison’s disease- there may be asso.
CAUSES OF SECONDARY/CENTRAL ADRENAL INSUFFICIENCY Vitiligo
 Exogenous glucocorticoid therapy – most
common cause
 Insulin Tolerance Test (ITT)

 whole
Gold standard in the assessment of the
hypothalamic-pituitary-adrenal axis


Not performed: Ischemic heart disease, epilepsy, severe
hypopituitarism

 insulin given IV, until with adequate
0.15 u/kg regular
hypoglycemia
• Signs that are specific to primary AI 
   Normal response: plasma cortisol >18
Adrenal calcification ug/dl

 TREATMENT OF AI
Chronic Adrenal Insufficiency
  Primary AI: cortisol and aldosterone replacement
  Secondary AI: cortisol replacement
  Usual dose: Hydrocortisone 12 and 15 mg/m2
  Hydrocortisone 20 mg given in divided doses, 10
 mg on rising, 5 mg at lunchtime, and 5 mg in the
early evening
 First dose of the day taken before rising from
bed
 Fludrocortisone 50-200 ug/d single dose
Stress
CLINICAL FEATURES OF SECONDARY AI  Carry steroid cards, wear steroid alert
• Clinical features of primary AI also occur with secondary AI. bracelets or necklaces
 Double the dose with minor stresses such
 weakness, fatigue, muscle and joint pain, and
as febrile illnesses, accident, mental
psychiatric symptoms.
 Hypoglycemia is more common stress such as an important examination.
• Pituitary or hypothalamic tumor –headache, visual  For minor surgery – add 50-100mg
field defects, or signs and symptoms of hormone hydrocortisone
deficiency  For major operation – hive
PRIMARY AI VS. SECONDARY AI hydrocortisone 100mg IV before the
In Secondary AI: induction of anesthesia then q8 for the 1st
 24hrs.
Hyperpigmentation is not present, because
 (ACTH) secretion is not
corticotrophin
ACUTE ADRENAL INSUFFICIENCY/ADRENAL
increased.
 CRISIS/ADISSONIAN CRISIS
 present, and hypotension is
Dehydration is not  Medical emergency manifesting as hypotension and
less prominent. acute circulatory failure.

Hyponatremia and volume expansion may be
present(reflecting increased vasopressin
secretion)but hyperkalemia  is not (reflecting
the presence of aldosterone).

Gastrointestinal symptoms are less common,
suggesting that electrolyte disturbances may
 
be involved in their etiology.

Hypoglycemia is more common in secondary
adrenal insufficiency.
DIAGNOSTIC TESTS
ACTH stimulation test or SST (Synacthen
Stimulation Test)
 
Standard screening test; safer, cheaper, quicker
 
ACTH 250 mcg given IV or IM at any time of the day
  TREATMENT
Measure plasma cortisol at 0 and 30 minutes 
  Emergency measures: IV access, serum
NV: plasma cortisol >20 ug/dl (>550 nmol/L) 
electrolytes, glucose, plasma cortisol and
 ACTH (no need to wait for the results!)
AI: plasma
 cortisol < 20 ug/dl (550 nmol/L) or <18 ug/dl (500  
nmol/L) 2-3L of 0.9% Saline Solution or D5NSS
  
Hydrocortisone 100mg IV then q6
 
Supportive measures as needed

 undergo endocrine testing:
ZR: ANDROGENS (DHEAS)
 Adrenal androgens represent an important
component (>50%) of circulating androgens in
premenopausal females
 In males, this contribution is much smaller
because of the testicular production of
androgens, but adrenal androgen excess even
in males may be of clinical significance,
notably in patients with congenital adrenal
hyperplasia
CONGENITAL ADRENAL HYPERPLASIA

 Generally transmitted as autosomal-
recessive traits

 Caused by deficient adrenal corticosteroid
biosynthesis
 
Loss of negative feedback inhibition of
induces oversecretion of ACTH, resulting in adrenal
the HPA axis
hyperplasia
 
Specific forms are identified by the
abnormal pattern of steroid secretion and clinical manifestations

 is used to
Molecular genetic analysis
confirm the diagnosis
CAH due to 21-Hydroxylase Deficiency
• Approximately 90-95% of cases of CAH
• 3 clinical manifestations:
o Classical Salt-
wasting o Simple
virilizing
o Non-classical
• Abnormal hormone secretion without obvious clinical
manifestations of a hormone excess state – like
subclinical Cushing syndrome
• ALL patients with adrenal incidentaloma should
Endocrine work-up of adrenal incidentaloma
 24-hour urinary catecholamine collection or
measurement of plasma metanephrines
 24-hour urinary free cortisol (or a midnight
salivary cortisol level), and overnightdexamethasone
suppression tests
 Plasma aldosterone concentration, plasma
renin activity
 Serum 17-OHP, DHEAS
 Imaging: CT scan
ADRENAL CARCINOMA
• Primary adrenal carcinoma is very rare, with an annual
incidence of 1 per 1 million population.
• Women more affected than male - 2.5:1
• Predicitve of malignancy:
Size: <4cm = <2% vs >6cm = 25% 

CT scan description and Hounsfield unit:

Smooth, homogenous, <10 HU = benign
Irregular, inhomogenous, >20 HU =
 malignant
Follow-up of adrenal incidentaloma
• Excision of a tumor if the initial imaging phenotype is
suspicious
• For all adrenal masses >10 cm, including those masses
with benign imaging phenotypes – open adrenalectomy
rather than a laparoscopic procedure
• For incidentalomas with a benign appearance on
imaging -- repeat imaging study at 6 to 12 months
Removal of any tumor that enlarges by more than 1 cm in
diameter during the follow-up period

11 β-Hydroxylase Deficiency CAH

• 2nd most common form of CAH
• Reduced conversion of 11-deoxycortisol to cortisol
• Hyperandrogenism resulting from shunting of cortisol
precursors
• 2/3 of patients become hypertensive, with or without
hypokalemic alkalosis, attributed to deoxycorticosterone
induced sodium retention which results in volume expansion
• Hypertension does not correlate with the presence or
degree of hypokalemia or with the extent of virilization

TREATMENT OF CAH
• Glucocorticoid treatment - also aims to suppress the
increased ACTH drive and subsequent androgen excess.
• In childhood, optimization of growth and pubertal
development are important goals of glucocorticoid treatment,
in addition to prevention of adrenal crisis and treatment of
46,XX DSD.
• In adults - preserving fertility and preventing side
effects of glucocorticoid overtreatment

ADRENAL INCIDENTALOMA & ADRENAL CARCINOMA

