AD R E N A L

D IS E A S E DR ANDREW J BEHN
KE, MD, FACE

CSOM
SOR OF MEDICINE, VT
ASSOCIATE PROFES
 GOLDMAN-CECIL MEDICINE, 214, 1476-1484

GOLDMAN-CECIL MEDICINE, 215, 1484-1489

HARRISONS 20TH ED CHAPTER 379-380

FIRST AID FOR USMLE1 PG. 331- 334

READING RECOMMENDED TEXT

WILLIAMS TEXTBOOK OF ENDOCRINOLOGY, CHAPTER 15, 489-

555

GREENSPANS “BASIC AND CLINICAL ENDOCRINOLGY” CH 9-11

(285-395)
 Review Briefly review normal adrenal physiology (4-5)

Recognize Recognize disorders of adrenal function

Describe the clinical and hormonal aspects of Cushing's Syndrome (6-

Describe 18)

Explain the clinical presentation of Cortisol deficiency and it’s treatment

Explain ( 19-24).

Identify the consequences of mineralocorticoid excess and it’s usual

Identify presentation (25-29).
OVERVIEW/LO Discuss Discuss the effect that mineralocorticoid deficiency has on the human
body (30).

Recognize Recognize the cause and consequences of androgen excess. (31-36).

Review Review the evaluation of an adrenal nodule ( 37-38).

Describe the secretion and regulation of adrenal catecholamines(39-

Describe 41).

Recognize the pathology and clinical manifestations of

Recognize Pheochromocytomas.(42-46).
Citation: Disorders of the Adrenal Cortex, Jameson J, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J. Harrison's Principles of Internal
Medicine, 20e; 2018. Available at: https://accessmedicine.mhmedical.com/content.aspx?bookid=2129&sectionid=192287137 Accessed: May 14,
2020
Copyright © 2020 McGraw-Hill Education. All rights reserved
 • A DISEASE OF THE ADRENAL CORTEX
CUSHINGS • OVERPRODUCTION OF CORTISOL
SYNDROME • SYMPTOMS INCLUDE FACIAL PLETHORA,
OBESITY AND ABDOMINAL STRAIE
Body Compartment/System Signs and Symptoms
Body fat Weight gain, central obesity, rounded face, fat pad on back of neck (“buffalo hump”)

Skin Facial plethora, thin and brittle skin, easy bruising, broad and purple stretch marks,
acne, hirsutism
Bone Osteopenia, osteoporosis (vertebral fractures), decreased linear growth in children
Muscle Weakness, proximal myopathy (prominent atrophy of gluteal and upper leg muscles
with difficulty climbing stairs or getting up from a chair)
Cardiovascular system Hypertension, hypokalemia, edema, atherosclerosis
Metabolism Glucose intolerance/diabetes, dyslipidemia
Reproductive system Decreased libido, in women amenorrhea (due to cortisol-mediated inhibition of
gonadotropin release)
Central nervous system Irritability, emotional lability, depression, sometimes cognitive defects; in severe
cases, paranoid psychosis
Blood and immune system Increased susceptibility to infections, increased white blood cell count, eosinopenia,
hypercoagulation with increased risk of deep vein thrombosis and pulmonary
embolism
SIGN OR SYMPTOM PERCENTAGE

Decreased libido in men and women 100

Obesity or weight gain 97
Plethora 94
Round face 88
Menstrual changes 84
Hirsutism 81
Hypertension 74
Ecchymoses 62
Lethargy, depression 62
Striae 56
Weakness 56
Electrocardiographic changes or atherosclerosis 55
Dorsal fat pad 54
Edema 50
Abnormal glucose tolerance 50
Osteopenia or fracture 50
Headache 47
Backache 43
Recurrent infections 25
Abdominal pain 21
Acne 21
Female balding 13
DIAGNOSIS
Urinary free cortisol- 3x upper limit of normal
Midnight cortisol- > 7.5 mcg/dl
Salivary cortisol- > 100 ng/dl
Standard DST- > 1.8 mcg/dl
Low dose 2 day DST- > 1.8 mcg/dl ( may add CRH stimulation to improve sensitivity).
High dose DST- Urinary cortisol > 5 mcg/24 hr.
Affected by p450 drugs (alcohol, rifampin,phenetoin) as well as renal and hepatic failure
NEED 2 POSITIVE TESTS TO MAKE DIAGNOSIS!!!
 • PREGNANCY
• ●PATIENTS WITH SEVERE OBESITY,
ESPECIALLY THOSE WITH VISCERAL
OBESITY OR PCOS
• ●PATIENTS WITH PSYCHOLOGICAL STRESS,
ESPECIALLY PATIENTS WITH A SEVERE
PSEUDOCUSHINGS MAJOR DEPRESSIVE DISORDER AND
PHYSIOLOGIC MELANCHOLIC SYMPTOMS
HYPERCORTISOLISM
• ●POORLY CONTROLLED DIABETES
MELLITUS
• ●RARELY, CHRONIC ALCOHOLISM
• ●PHYSICAL STRESS (ILLNESS,
HOSPITALIZATION/SURGERY, PAIN)
• ●OBSTRUCTIVE SLEEP APNEA
CAUSES OF CUSHING'S SYNDROME
 EXOGENOUS ENDOGENOUS
Most common cause of ACTH independent—autonomous
Cushing syndrome: adrenal activation (20% of all
ETIOLOGY Glucocorticoid or ACTH
driven
cases) (Low ACTH, High Cortisol)
Adrenal adenoma (40-50%)

OF CUSHING May be factitious or

iatrogenic
Adrenal carcinoma (40-50%)
Primary pigmented nodular adrenal
disease
SYNDROME McCune-Albright syndrome
Massive macronodular adrenal disease
Gastric inhibitory polypeptide or food
induced
ACTH dependent—adrenal activation
by excessive ACTH (80% of all
cases) (High ACTH, High Cortisol)
Corticotrope adenoma (80%)
Ectopic ACTH secretion (20%)
Ectopic CRH secretion (rare)
 • 80 % OF ALL ENDOGENOUS CUSHING'S
SYNDROME.

• CAUSED BY A CORTICOTROPH TUMOR OF THE

PITUITARY.

• ONLY 50 % HAVE AN ABNORMAL MRI.(NEED

CUSHINGS CHEMICAL DIAGNOSES FIRST!)

DISEASE • PRIMARILY FEMALE ( 6:1 RATIO).

• USUAL AGE OF ONSET -40-50’S.
• ELEVATED ACTH (>15 PG/ML) AND CORTISOL.`
• MUST BE DISTINGUISHED BY ECTOPIC ACTH
PRODUCING TUMORS.
CAUSES OF ECTOPIC ACTH PRODUCTION
TUMOR TYPE PERCENTAGE
Carcinoma of lung (small cell or oat cell) 19-50
Carcinoid of bronchus 2-37
Carcinoid of thymus 8-12
Pancreatic tumors, carcinoid and islet cell 4-12
Pheochromocytoma, neuroblastoma, ganglioma, 5-12
paraganglioma
Medullary carcinoma of the thyroid 0-5
Miscellaneous * <1
MRI AND
PETROSAL VEIN
SAMPLING
 • SURGERY (90% CURE IN GOOD HANDS).
• SURGERY OF ADRENALS FOR ADRENAL
DISEASE OR IF PITUITARY SURGERY IS NOT
POSSIBLE (BEWARE OF NELSON’S SYNDROME).

• RADIATION- EXTERNAL BEAM OR GAMMA KNIFE.

• MEDICATION- NOT VERY EFFECTIVE
CUSHING'S • CABERGOLINE AND PASIREOTIDE MAY HELP.
DISEASE- • LARGE DOSE KETOCONAZOLE OR
TREATMENT METYRAPONE.

• MITOTANE AS A LAST RESORT.

 • LOSS OF CORTICOSTEROID AND MINERALOCORTICOID
ACTIVITY.

• MAY BE EITHER PRIMARY OR SECONDARY.

• PRESENTS WITH MALAISE, FATIGUE, ANOREXIA, WEIGHT LOSS,

JOINT AND BACK PAIN, AND DARKENING OF THE SKIN.
ADRENAL • ACUTE ADRENAL INSUFFICENCY PRESENTS WITH

INSUFFIENCY ORTHOSTATIC HYPOTENSION, AGITATION, CONFUSION,

CIRCULATORY COLLAPSE, ABDOMINAL PAIN, AND FEVER

• USUALLY RESULTS FROM AN AUTOIMMUNE CONDITION OR

RARE CONGENITAL DEFECT.

• ACTH IS CO-SECRETED WITH STIMULATED WITH

MELANOTRIPIN STIMULATING HORMONE (MSH).
AUTOIMMUNE POLYGLANDULAR SYNDROMES
TYPE 1
SPECIFIC CAUSES SUGGESTIVE CLINICAL FEATURES USEFUL ANCILLARY TESTS

Primary adrenal insufficiency Hyperpigmentation, orthostatic hypotension Hyperkalemia, elevated ACTH

Idiopathic autoimmune destruction Most common cause (80%) in developed countries; with or Antibodies to 21-hydroxylase are present; on imaging,
without other endocrinopathies, as below adrenal glands are small

Polyglandular failure type 1 Hypoparathyroidism, mucocutaneous candidiasis, vitiligo; age

<20 years

Polyglandular failure type 2 Insulin-dependent diabetes, autoimmune thyroid disease, On imaging, adrenal glands are small
alopecia areata, vitiligo; age >40 years

Infections: tuberculosis, systemic fungal diseases, AIDS- 15% of patients in U.S. series Adrenal glands tend to be large on CT and may be calcified
associated opportunistic infections (e.g., cytomegalovirus)

Space-occupying adrenal lesions Metastases from carcinoma of lung, breast, kidney, gut; Abnormal shape of adrenal glands on CT; evidence of
lymphoma or hemorrhage (heparin use) hemorrhage

Bilateral adrenalectomy or treatment with steroidogenesis Ketoconazole, mitotane, aminoglutethimide, trilostane, and
inhibitors metyrapone reduce cortisol levels

Adrenoleukodystrophy X-linked—screen males; in childhood, cognitive and gait Deficiency of peroxisomal very long chain acyl-coenzyme A
disturbances; in adults, spastic paraparesis synthetase leads to elevated plasma C 26:0 fatty acid levels
Secondary adrenal
insufficiency

Suppression of the adrenal axis Medication history; history of Adrenal glands are small on
by exogenous or endogenous Cushing syndrome imaging
glucocorticoids

Structural lesions of the
hypothalamus or pituitary gland
(tumors, destruction by
infiltrating disorders, x-
irradiation, and lymphocytic
hypophysitis)
Other pituitary deficiencies Adrenal glands are normal or
small on imaging; MRI or CT
may show pituitary or
hypothalamic lesion

Isolated ACTH deficiency

Head trauma
 DIAGNOSIS
• MORNING CORTISOL < 3 UG/DL ( OVER 18 UG/DL UNLIKELY).
• ACTH STIMULATION TEST – 250 UG IV.
> 18 UG/DL AT 30 – 60 MINUTES AFTER IS A NORMAL RESPONSE.
TREATMENT:
HYDROCORTISONE. 20-30 MG A DAY. MAY BE DIVIDED 20 AM 10 PM.
PREDNISONE 5 – 7.5 MG DAILY MAY ALSO BE USED.
NEED TO USE STRESS DOSE ( DOUBLE OR TRIPLE) IF SICK OR STRESSED.
 • OVER SECRETION OF ALDOSTERONE
• EITHER PRIMARY OR SECONDARY
• ALDOSTERONE RAISES SERUM SODIUM
MINERALOCORTICOID AND LOWERS SERUM POTASSIUM
EXCESS
( CONN’S SYNDROME) • USUALLY PRESENTS WITH HYPERTENSION
AND HYPOKALEMIA

• DIFFERENT CAUSES ARE BASED ON THE

ALDOSTERONE AND RENIN RATIO.
Citation: Disorders of the Adrenal Cortex, Jameson J, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J. Harrison's Principles of Internal
Medicine, 20e; 2018. Available at: https://accessmedicine.mhmedical.com/content.aspx?bookid=2129&sectionid=192287137 Accessed: May 14,
2020
Copyright © 2020 McGraw-Hill Education. All rights reserved
PRIMARY HYPERALDOSTERONISM: HIGH ALDOSTERONE, LOW RENIN
Aldosterone-producing adenomas (30-50%)
Bilateral zona glomerulosa hyperplasia
Familial hyperaldosteronism

Type 1: glucocorticoid-remediable hyperaldosteronism—this results from formation of a chimeric gene containing the regulator portion of 11 β-hydroxylase (normally regulated
by ACTH) and the synthetic region of aldosterone synthase; as a result, ACTH stimulates aldosterone synthase and hence aldosterone production
Type 2: adrenal adenomas or hyperplasia expressed in a familial pattern
Type 3: caused by mutant KCNJ5, often younger and more severe than Type 2
Aldosterone-producing adrenal carcinoma

APPARENT MINERALOCORTICOID EXCESS: LOW ALDOSTERONE, LOW RENIN

Licorice ingestion: licorice (candy or flavored tobacco) containing glycyrrhetinic acid (or similar compounds such as carbenoxolone) inhibits renal 11 β-hydroxysteroid
dehydrogenase type 2, reducing cortisol conversion to cortisone and enabling cortisol to act as an endogenous mineralocorticoid
SECONDARY HYPERALDOSTERONISM: HIGH
ALDOSTERONE, HIGH RENIN
•Renovascular hypertension and aortic stenosis
•Diuretic use
•Renin-secreting tumors
•Severe cardiac failure
MINERALOCORTICOID DEFICIENCY
• DIAGNOSED BY HYPONATREMIA AND HYPERKALEMIA. MAY BE HYPOTENSIVE.
• ORGANIZED AS HYPORENINEMIC OR HYPERRENINEMIC
• HYPORENINEMIC – MOST COMMON. USUALLY HAVE MILD KIDNEY DISEASE
(DIABETIC), NSAID USE,AUTONOMIC DYSFUNCION.

• HYPERRENINEMIC- CAH, ADRENAL INSUFFIENCY.

• TREATMENT- NA CL INTAKE AND MINERALOCORTICOID ( FLUDROXICORTISONE).
• USE RENIN RATES TO MEASURE ADEQUATE TREATMENT ( ONLY FOR HYPER-
RENINEMIC STATES).
 INCREASE OF DHES-S FROM ZONE RETICULARIS.

• DHEA-S GETS METABOLIZED TO TESTOSTERONE.

• OTHER ORGANS CAN MAKE ESTROGEN WHICH CAN BE

ANDROGEN CONVERTED TO TESTOSTERONE ( OVARIES,FAT).

EXCESS • PRESENTS WITH HIRSUTISM, AMENORRHEA,

MASCULINIZATION.

• MOST COMMON ADRENAL CAUSE IS 21-HYDROXYLASE

DEFICIENCY.

• NEW ONSET OF SYMPTOMS SUGGESTS AN ADRENAL

TUMOR.
ADRENAL NODULES
 • CENTER OF ADRENAL GLAND.

• RESPONSIBLE FOR PRODUCING CATECHOLAMINES.

• SOURCE OF CATECHOLAMINES IS TYROSINE.

•
ADRENAL
DOPAMINE --- NOREPINEPHRINE---EPINEPHRINE

• DOPAMINE AND NOREPINEPHERINE AND ALSO

MEDULLA •
FOUND IN THE PERIPHERAL SYMPATHETIC NERVES.
STIMULATE ALPHA, BETA, AND DOPAMINERGIC
RECEPTORS.

• SERUM HALF LIFE 10 SECONDS TO 2 MINUTES.

• METABOLIZED TO VMA AND EXCRETED IN URINE.

CATECHOLAMINE
METABOLISM
 • A1– MUSCLE CONTRACTION AND HIGH
BLOOD PRESSURE.

• A2 -- SUPPRESSION OF CONTRACTION AND

EFFECTS OF HYPOTENSION.
CATECHOLAMINES • B1– INCREASED HEART RATE AND
CONTRACTION.

• DOPAMINE– VASODILATION OF VASCULAR

BEDS.
 • ARISE FROM THE ADRENALS OR
PARAGANGLION CELLS

• 10% ARE MALIGNANT.

CATECHOLAMINE • RARE- 2-3 IN 1,000,000.
SECRETING • 30 % ARE FAMILIAL
TUMORS
• MEN 2A, 2B, VON HIPPEL- LINDAU,
NEUROFIBROMATOSIS, FAMILIAL
PARAGANGLIOMA
PARAGANGLIONOMA
 • HEADACHES, SWEATS , AND PALPITATIONS.
• SPELLS OF HYPERTENSION AND
ORTHOSTATIC HYPOTENSION.
CLINICAL • SPELLS LAST 15- 20 MINUTES.
MANIFESTATIONS
• CHF AND CONSTIPATION CAN OCCUR.
• NOT ASSOCIATED WITH FLUSHING.
Tricyclic antidepressants (including cyclobenzaprine)
TESTING- WATCH
Levodopa
OUT FOR:
Drugs containing adrenergic receptor agonists (e.g.,
decongestants)
Amphetamines • DIFFICULT TO
MEASURE.
Buspirone and antipsychotic agents
Prochlorperazine • MULTIPLE DRUGS
CAN CAUSE
Reserpine
INCREASED
Withdrawal from clonidine and other drugs CATECHOLAMINES:
Ethanol
TREATMENT
Alpha blockers first, then beta blockers.

Phenoxybenzamine is a long term alpha blocker used almost

exclusively in the pre-op management of Pheochromocytoms.

Surgery.
 • THE ADRENAL GLAND HAS A CORTEX CONTAINING 3 DIFFERENT
LAYERS (G,F,R)

• CUSHING'S DISEASE IS AN EXCESS OF CORTISOL CAUSED BY A

PITUITARY ADENOMA.

• CUSHING'S SYNDROME CAN BE FROM PRIMARY, SECONDARY, OR

ECTOPIC SOURCES.

• ADRENAL INSUFFIENCY PRESENTS WITH ELECTROLYTE

IMBALANCES AND HYPERPIGMENTATION IF PRIMARY.

SUMMARY • MINERALOCORTICOID EXCESS FREQUENTLY PRESENTS AS

UNPROVOKED HYPOKALEMIA.

• A CONGENITAL OF ADULT ONSET HYPERANDROGENISM IS NON

CLASSICAL 21 HYDROXYLASE DEFICIENCY.

• PHEOCHROMOCYTOMAS AND PARAGANGLIONOMS ARE RARE

TUMORS OF ADRENAL MEDULLARY CELLS THAT CLASSICALLY
PRESENT WITH HEADACHES, SWEATS, AND PALPITATIONS. PRE
TREAT WITH ALPHA BLOCKERS THEN BETA BLOCKERS BEFORE
SURGERY.