ADRENAL CORTEX DISEASE AND PHAEOCHROMOCYTOMAS

Luthfan Budi Purnomo

Sub Division of Endocrinology

Internal Medicine Department

Competencies Adrenal Cortex failure 3B Phaeochromocytomas 1 Addison’s disease 1

DiscussionAdrenal hormones: glucocorticoid, mineralocorticoid, and adrenal androgenAdrenal cortex diseases: Cushing’s syndrome and Addison’s disease, mineralocorticoid excessPhaeochromocytoma

Adrenal Gland: Anatomy

Cortex

Capsule

Zona glomerulosa

Zona fasciculata

Zona reticularis

Medulla

MineralocorticoidsAldosterone

100 to 150 ug/day

Cortisol 10 to 20 mg/day

Adrenal androgens20 mg/day

Norepinephrine (NE)Epinephrine (EPI)Bioactive amines

(lack 17α-hydroxylase)

(lack aldosterone synthase)

Hormones of Adrenal Cortex

Mineralocorticoid: (aldosterone 100-150ug/d), zona glomerulosa, predominantly under the control of the renin-angiotensin system, only 5-10% under ACTH regulation.

It maintenances normal Na+ and K+ concentrations and extracellular fluid volume

Glucocorticoid: (cortisol 10-20 mg/d), zona fasciculata and reticularis, under ACTH control

Adrenal androgen: zona fasciculata and reticularis, under ACTH control

Synthesis of adrenal cortex hormones

Cholesterol Pregnenolone

Progesterone 17-hydroxypregnenolone

Deoxycortisone 17-hydroxyprogesterone

Dehydroepiandrosterone (DHEA)

Corticosterone 11-deoxycortisol Androstenedione

Aldosterone Cortisol Cortisone

17-hydroxylase

Adrenocortical Diseases

Glucocorticoid Excess Cushing’s syndrome Pseudo-Cushing’s syndromesGlucocorticoid ResistanceGlucocorticoid Deficiency Primary hypoadrenalism Secondary hypoadrenalism Post-chronic corticosteroid

replacement therapy

Mineralocorticoid ExcessMineralocorticoid Deficiency Defects in aldosterone

synthesis Defects in aldosterone action hyporeninemic

hypoaldosteronismAdrenal incidentalomas,

Adenomas, and Carcinomas

Production and secretion of aldosterone

Kidney

Lungs

Adrenal

Na+

Blood pressure

Sympathetic input

Angiotensinogen

Angiotensin I

Convertingenzyme (ACE)

PituitaryK+

ACTH

Angiotensin II

Angiotensin III

Aldosterone

Renin

Mineralocorticoid excess

The majority of cases are due to aldosterone excess production (primary or secondary), and are typically associated with hypertension and hypokalaemia

Primary hyper-aldosteronism is a disorder of autonomous hyper-secretion with suppressed renin level

Secondary hyper-aldosteronism when hyper-secretion occurs secondary to elevated circulating renin level

Causes of mineraloorticoid excess

Primary hyperaldosteronism Conn’s syndrome (aldosterone-producing adrenal adenoma bilateral adrenal hyperplasia, glucocorticoid suppressible

hyper-aldosteronism (GSH), aldosterone-producing adrenal carcinoma

Secondary hyper-aldosteronism Renal artery stenosis, renal hypo-perfusion, cirrhosis,

congestive cardiac failure, nephrotic syndrome, renin-secreting tumor

Other mineralocorticoid excess syndromes Apparent mineralocorticoid excess, liquorice ingestion,

deoxycorticosterone and corticosterone, extopic ACTH secretion, congenital adrenal hyperplasia, exogenous mineralocorticoid

Pseudoaldosteronism due to abnormal renal tubular transport Batters syndrome, Gitelman’s syndrome, Liddle’s syndrome

Causes of primary hyperaldosteronism

Conditon Relative frequency

Age Sex Pathology

Aldosteronoma

(Conn’s adenoma)

70% 3rd – 6th decade Female> Beningn, <2.5 cm in diameter, adenoma

Idiopathic aldosteronism/ adrenal hyperplasia

Common Older than Conn’s

No sex difference

Macronodular or micronodular hypeplasia

Adrenal carcinoma Rare 5th -7th decade Female> >4 cm in diameter or larger, local invasion

Glucoorticoid suppressible hyperaldosteronism

Rare Childhood No sex differance

Bilateral hyperplasia of zona glomerulosa

Primary hyperaldosteronism: screening

Resistance to conventional antihypertensive therapy, hypertension with hypokalaemia, hypertension before age 40 years

Serum potassium (hypokalaemic alkalosis), 20-40% normokalaemia

Urinary potassium excretion >30 mmol/24 h with hypokalaemia

Plasma renin (supressed) Aldosterone: renin ratio (pmol/L:ng/ml/h >750) or

(ng/dl:ng/ml/h >30-50)

Drugs and investigation of renin-angiotensin II axis

Drugs Effect Duration of washout (weeks)

ACEI & Angiotensin II antagonistsDiureticsSpironolactoneBeta blockersCalcium channel blockers

PRA PRA PRA PRA PRA

22622

Confirmation

Oral salt loading (120 mmol sodium/d for 3 days) Postural test: failure of aldosterone to rise to more than a

third above baseline is suggestive of an adenoma (ACTH dependent)

Urinary 18 hydroxycortisol (elevated): GSH>> Conn’s> adrenal hyperplasia

Dexamethasone suppression test. Treatment with dexamethasone 0.5 mg/6 h for >3 days leads to lowering of aldosterone and blood pressure in GSH

Differential diagnosis of primary hyperaldosteronism

Test Upright posture

and time

ACEI Dexametha-sone

suppression

Normal PRA Aldosterone

Aldosterone producing PRAadenoma Aldosterone

Angiotensin- PRAresponsive adenoma Aldosterone

Idiopathic adrenal PRAhyperplasia AldosteroneGSH PRA Aldosterone

→

→

→

→

→

→

→

→

→

→

→

→

→

→

Treatment of primary hyperaldosteronism

Surgery Medical treatment: spironolactone (200-400

mg/d), or combination with ACEI and calcium channel blockers. Side effect: gynaecomastia, impotence, menstrual irrigularities, gastrointestinal effects

GSH: dexamethasone 0.5 mg on going to bed and 0.25 mg on waking, or spironolactone

Glucocorticoids

In the liver: increased glycogen deposition; increased gluconeogenesis

Muscle & Fat: inhibits glucose uptake & utilization; increased lipolysis FFA increased cholesterol & triglycerides; decreased HDL-cholesterol

Permissive effect of other hormones

increase blood glucose; protein & lipid catabolism

ACTION OF GLUCOCORTICOIDS

Brain/CNS: depression, psychosis Eye: glaucoma Endocrine system: LH, FSH release, TSH release,

GH secretion GI tract: peptic ulceration Carbohydrate/lipid metabolism: hepatic glycogen

deposition, peripheral insulin resistance, gluconeogenesis, free fatty acid production Overall diabetogenic effect

Adipose tissue distribution: promotes visceral obesity

ACTION OF GLUCOCORTICOID cont.

Cardiovascular/renal: salt and water retention, hypertension

Skin/muscle/connective tissue: protein catabolism/ collagen breakdown, skin thinning, muscular atrophy

Bone and calcium metabolism: bone formation, bone mass and osteoporosis, linear growth

Immune system: anti-inflammatory action, immuno-suppression

Adrenal Cushing’s syndrome

Cushing’s syndrome is resulting from cortisol excess The commonest cause is iatrogenic (exogenous steroid) ACTH- dependent and ACTH- independent ACTH- dependent: pituitary dependent (Cushing’s disease)

or ectopic secretion

Causes of Cushing’s syndrome@ Pseudo-Cushing’s syndrome: alcoholism (<1%), severe depression (1%)

@ ACTH-dependent: pituitary adenoma/Cushing’s disease (68%), Ectopic ACTH syndrome (12%), ectopic CRH secretion (<1%)

@ ACTH-independent: adrenal adenoma (10%), adrenal ca (8%), nodular hyperplasia (1%)

Prevalence of Symptoms and Signs of Cushing’s Syndrome and Discriminant Index Compared with Prevalence of Features in Patients with Simple Obesity

Findings (Symptoms) %Discriminan

t Index

Weight gainMenstrual irregularityHirsutismPsychiatric DysfunctionHeadacheMuscle weaknessFracturesLoss of scalp hair

9184826243291913

1.62.8

8.0

Prevalence of Symptoms and Signs of Cushing’s Syndrome and Discriminant Index Compared with Prevalence of Features in Patients with Simple Obesity

Findings (Signs) %Discriminant Index

Obesity Truncal GeneralizedPlethoraMoon faceHypertensionBruisingRed-purple striae

9746559488746256

1.60.83.0

4.410.32.5

Prevalence of Symptoms and Signs of Cushing’s Syndrome and discriminant Index Compared with Prevalence of Features in Patients with Simple Obesity

Findings (Signs) %Discriminant Index

Muscle weaknessAnkle edemaPigmentationHypertensionDiabetes Overt IGTOsteoporosis

5650 47450133750

ADRENAL INSUFFICIENCY

Inadequate adrenocortical function Destruction of adrenal cortex (primary or

Addison’s disease), or due to disordered pituitary and hypothalamic function (secondary)

The incidence of Addison’s disease 40-60/million adults

Secondary adrenal insufficiency is most commonly due to suppression of pituitary-hypothalamic function by exogenous glucocorticoid administration

Clinical Features of Primary Adrenal Insufficiency

SymptomWeakness, tiredness, fatigue

(100%)Anorexia (100%)Gastrointestinal symptoms

(92%) Nausea (86%) Vomiting (75%) Constipation (33%) Abdominal pain (31%) Diarrhea (16%)

Salt craving (16%)Postural dizziness (12%)Muscle or joint pains (6–13%)

Sign Weight loss (100%) Hyperpigmentation (94%) Hypotension (<110 mm Hg

systolic) (88–94%)

Vitiligo (10–20%) Auricular calcification (5%)

Laboratory Finding Electrolyte disturbances (92%)

Hyponatremia (88%) Hyperkalemia (64%) Hypercalcemia (6%)

Azotemia (55%) Anemia (40%) Eosinophilia (17%)

Addison’s Disease

Described by Thomas Addison in 1855 The incidence in the developed world of

0.8 cases per 100,000 and prevalence of 4 - 11 cases per 100,000 population

Associated with significant morbidity and mortality; can be easily treated

Essential of D/: Addison’s Disease

Weakness, easy fatigability, anorexia, weight loss; nausea & vomiting, diarrhea; abdominal pain, muscle & joint pains; amenorrhea

Sparse axillary hair; increased pigmentation of skin, esp. of creases, pressure area, and nipples

Hypotension, small heart Low sodium (Na), elevated K, Ca, and BUN;

neutropenia, mild anemia, relative lymphocytosis Low plasma cortisol, elevated ACTH

Therapy of Addison’s disease General measures

Treat all infections if occurred Increases the dose of hydrocortisone

appropriately Maximal dose of hydrocortisone for severe

stress is 50 mg IV or IM every 6 hours Advice patients to wear a medical alert

bracelet or medal reading “Adrenal insufficiency—takes hydrocortisone”

Therapy of Addison’s diseaseSpecific

Hydrocortisone – 15-25 mg/d Prednisone 2-3 mg/morning; 1-2 mg/early

evening Fludrocortisone acetate, has a potent Na-

retaining effect; 0.05-0.3 mg/d Dehydroepiandrosterone (DHEA) 50 mg/d

for some women improvement of the sense of well being, mood, and sexuality

Adrenal Crisis Dehydration, hypotension, or shock out of

proportion to current illness severity Nausea and vomiting with a history of

weight loss and anorexia Abdominal pain so-called acute abdomen Unexplained hypoglycemia Unexplained fever

Adrenal Crisis Hyponatremia, hyperkalemia, azotemia,

hypercalcemia, or eosinophilia Hyperpigmentation or vitiligo Other autoimmune endocrine deficiencies,

such as gonadal failure or hypothyroidism If suspected: give hydrocortisone 100-300

mg I.V.; refer to hospital

INTRODUCTION

The adrenal medulla is a part of the sympathetic nervous system that secretes catecholamines

The sympathetic nervous system secretes norepinephrine as a local neurotransmitter directly in target organ

The adrenal medulla secretes epinephrine and other substances into the general circulation for widespread distribution and effect

It’s importance is to maintain the body’s homeostasis during stress

HISTORY

Early 19th century adrenal medulla was distinguished from adrenal cortex

1886 pheochromocytomas were described by Frankel

1896 Manasse: chromaffin tumors 1901 J. Takamine: adrenalin T.B. Aldrich:

epinephrine 1926 successful surgery of pheochromocytoma

by C.H. Mayo and Roux

CATECHOLAMINES

Include: dopamine, nor-epinephrine, epinephrine Epinephrine is synthesized mainly in adrenal

medulla Nor-epinephrine is found in adrenal medulla,

central nervous system, peripheral sympathetic nerves

Dopamine: precursor of nor-epinephrine Catestatin inhibits catecholamine release

SYNTHESIS OF CATECHOLAMINES

TYROSINE L-dihydroxyphenylalanine (L-dopa)

Tyrosine hydroxylase

Dopamine

Dopamine-ß-hydroxylaseDopa decarboxylase

norepinephrine

Epinephrine PNMT

PNMT 4-phenylethanolamine-N-methyl transferase

In adrenal medulla: 80% epinephrine, 20% norepinephrine

Catecholamines are stored in granules Secretion is increased by exercise, angina

pectoris, myocardial infarction, hemorrhage, ether anesthesia, surgery, hypoglycemia, anoxia, and asphyxia

When released into circulation, catecholamines are bound to albumin

They are quickly metabolized into inactive compounds metanephrine, vanillylmandelic acid (VMA), and conjugated catecholamines

ADRENERGIC RESPONSES OF SELECTED TISSUES

Organ or tissue Receptor Effect

Heart (myocardium)Blood vessels

KidneyGutPancreas

LiverAdipose tissueMost tissuesSkin (apocrine glands)BronchiolesUterus

ß1Αß2ßΑ,ßΑßΑ,ßßßΑß2Αß2

Force and rate of contractionVasocontrctionVasodilation Renin released Motility and sphincter toneInsulin and glucagon releaseInsulin and glucagon release Glycogenolysis Lipolysis Calorigenesis SweatingDilationContractionRelaxation

ADRENAL MEDULLARY HYPOFUNCTION

Hypofunction of adrenal medulla alone: adrenocortical steroid replacement therapy following adrenalectomy.

Autonomic insufficiency (deficiency of adrenal medullary epinephrine secretion: minor defects in recovery from insulin-induced hypoglycemia

ADRENAL MEDULLARY HYPERFUNCTION

Catecholamines can increase blood pressure by increasing cardiac output, by increasing peripheral resistance, and by increasing renin release.

The adrenal medulla is not known to play a significant role in essential hypertension

PHEOCHROMOCYTOMA

Rare tumors, 2 patients per million people yearly or 0.1% of hypertensive population

Pheochromocytomas are usually derived from the adrenal medulla but may develop from chromaffin cells in or about sympathetic ganglia (extraadrenal or paragangliomas)

>1/3 of pheochromocytomas cause death prior to diagnosis. Cause of death: myocardial infarction, cerebrovascular accident, arrhythmias, irreversible shock, renal failure, dissecting aortic aneurysm

15% of pheochromocytoma are malignant

PATIENTS TO BE SCREENED FOR PHEOCHROMOCYTOMA

Young with hypertension Hypertensive patients with: symptoms of

pheochromocytoma, weight loss, seizures, orthostatic hypotension, unexplained shock, family history of pheochromocytoma or medullary carcinoma of thyroid, neurofibromatosis and other neurocutaneus syndromes, mucosal neuromas, hyperglycemia, cardiomyopathy

Marked lability of blood pressure Shock or severe pressor responses with: induction of

anesthesia, parturition, surgery, invasive procedures, antihypertensive drugs

Radiologic evidence of adrenal mass

COMMON SYMPTOMS IN PATIENTS WITH HYPERTENSION DUE TO PHEOCHROMOCYTOMA

Symptoms during or following paroxysms: headache (80%), sweating (70%), forceful heartbeat with or without tachycardia (60%), anxiety (50%) or fear of impending death, tremor (40%), fatigue or exhaustion, nausea and vomiting, abdominal or chest pain, visual disturbance

Symptoms between paroxysms: increased sweating, cold hands and feet, weight loss, constipation

Fatal paroxysms may be induced by opiates, histamine, glucagon

HYPERTENSION IN PHEOCHROMOCYTOMA

Hypertension (90%), paroxysms of severe hypertension (50%), orthostatic changes in blood pressure, it may drop even to hypotension levels after arising from supine position standing for 3 minutes (especially when accompanied by a rise in heart rate)

Epinephrine secretion may cause episodic hypotension and even syncope

DIAGNOSIS

Urinary test of metanephrine or catecholamine Analysis of a full 24-h urine sample is

preferable, (where possible) the collection should be made on rest no medication no recent exposure to radiographic contrast media, urine should be acidified

Normal upper limit of catecholamine 590-885 mmol (100-150 ug)/24 h

Normal upper limit of metanephrine 7 ummol (1.3 mg)/24 h

TREATMENT

Surgery Preoperative management: blockade of alpha

receptor by phenoxybenzamine. Initial dose 10 mg/12 h added by 10-20 mg every few days until blood pressure is controlled and paroxysms disappear. Patient should be monitored of supine and upright blood pressures

PROGNOSIS

After surgery: 5-year survival rate >95% with recurrence <10%

Malignant pheochromocytoma: 5-year survival rate <50%