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ADRENAL CORTEX DISEASE AND

PHAEOCHROMOCYTOMAS

Luthfan Budi Purnomo


Sub Division of Endocrinology
Internal Medicine Department

Competencies
Adrenal Cortex failure
3B
Phaeochromocytomas 1
Addisons disease
1

Discussion
Adrenal hormones: glucocorticoid, mineralocorticoid,
and adrenal androgen
Adrenal cortex diseases: Cushings syndrome
and Addisons disease, mineralocorticoid excess
Phaeochromocytoma

Adrenal Gland: Anatomy


Capsule

Zona glomerulosa
(lack 17-hydroxylase)

Zona fasciculata
Cortisol
10 to 20 mg/day

Zona reticularis

Mineralocorticoids
Aldosterone
100 to 150 ug/day

Cortex
Adrenal androgens
20 mg/day

(lack aldosterone synthase)

Medulla

Norepinephrine (NE)
Epinephrine (EPI)
Bioactive amines

Hormones of Adrenal Cortex

Mineralocorticoid: (aldosterone 100-150ug/d), zona


glomerulosa, predominantly under the control of the reninangiotensin 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
17-hydroxylase

Progesterone
Deoxycortisone

17-hydroxypregnenolone
17-hydroxy
progesterone

Corticosterone

11-deoxycortisol

Aldosterone

Cortisol

Dehydroepiandro
sterone (DHEA)
Androstenedione

Cortisone

Adrenocortical Diseases
Glucocorticoid Excess
Cushings syndrome
Pseudo-Cushings syndromes
Glucocorticoid Resistance
Glucocorticoid Deficiency
Primary hypoadrenalism
Secondary hypoadrenalism
Post-chronic corticosteroid
replacement therapy

Mineralocorticoid Excess
Mineralocorticoid Deficiency
Defects in aldosterone
synthesis
Defects in aldosterone action
hyporeninemic
hypoaldosteronism
Adrenal incidentalomas,
Adenomas, and Carcinomas

Production and secretion of


aldosterone
K+

Aldosterone

Pituitary
ACTH
Angiotensin III

Adrenal

Angiotensin II
Converting
enzyme (ACE)

Lungs

Angiotensin I
Renin
Angiotensinogen

Kidney

Sympathetic input
Blood pressure

Na+

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 hypersecretion occurs secondary to elevated circulating
renin level

Causes of mineraloorticoid excess

Primary hyperaldosteronism
Conns syndrome (aldosterone-producing adrenal adenoma
bilateral adrenal hyperplasia, glucocorticoid suppressible hyperaldosteronism (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, Gitelmans syndrome, Liddles syndrome

Causes of primary hyperaldosteronism


Conditon

Relative
frequency

Age

Sex

Pathology

Aldosteronoma
(Conns adenoma)

70%

3rd 6th decade

Female>

Beningn, <2.5 cm in
diameter, adenoma

Idiopathic
aldosteronism/
adrenal hyperplasia

Common

Older than
Conns

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), 2040% 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
ACEI & Angiotensin II antagonists
Diuretics
Spironolactone
Beta blockers
Calcium channel blockers

Effect
PRA
PRA
PRA
PRA
PRA

Duration of
washout (weeks)
2
2
6
2
2

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>> Conns>
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

Normal

Upright
posture
and time
PRA
Aldosterone

ACEI

Dexamethasone
suppression

Aldosterone producing PRA


adenoma
Aldosterone

Angiotensinresponsive adenoma

PRA
Aldosterone

Idiopathic adrenal
hyperplasia
GSH

PRA
Aldosterone
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 Cushings syndrome

Cushings syndrome is resulting from cortisol excess


The commonest cause is iatrogenic (exogenous steroid)
ACTH- dependent and ACTH- independent
ACTH- dependent: pituitary dependent (Cushings disease)
or ectopic secretion

Causes of Cushings syndrome


@ Pseudo-Cushings syndrome: alcoholism (<1%),
severe depression (1%)
@ ACTH-dependent: pituitary adenoma/Cushings 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 Cushings Syndrome


and Discriminant Index Compared with Prevalence of Features
in Patients with Simple Obesity

Findings (Symptoms)

Weight gain
Menstrual irregularity
Hirsutism
Psychiatric Dysfunction
Headache
Muscle weakness
Fractures
Loss of scalp hair

91
84
82
62
43
29
19
13

Discriminan
t Index
1.6
2.8

8.0

Prevalence of Symptoms and Signs of Cushings Syndrome


and Discriminant Index Compared with Prevalence of Features
in Patients with Simple Obesity
Findings (Signs)
Obesity
Truncal
Generalized
Plethora
Moon face
Hypertension
Bruising
Red-purple striae

%
97
46
55
94
88
74
62
56

Discriminant Index

1.6
0.8
3.0
4.4
10.3
2.5

Prevalence of Symptoms and Signs of Cushings Syndrome


and discriminant Index Compared with Prevalence of Features
in Patients with Simple Obesity
Discriminant Index
Findings (Signs)
Muscle weakness
Ankle edema
Pigmentation
Hypertension
Diabetes
Overt
IGT
Osteoporosis

%
56
50
4
74
50
13
37
50

ADRENAL INSUFFICIENCY

Inadequate adrenocortical function


Destruction of adrenal cortex (primary or
Addisons disease), or due to disordered pituitary
and hypothalamic function (secondary)
The incidence of Addisons disease 40-60/million
adults
Secondary adrenal insufficiency is most
commonly due to suppression of pituitaryhypothalamic function by exogenous
glucocorticoid administration

Clinical Features of Primary Adrenal


Insufficiency
Symptom
Weakness, 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 (613%)

Sign

Weight loss
Hyperpigmentation
Hypotension (<110 mm
systolic)
Vitiligo
Auricular calcification

(100%)
(94%)
Hg
(8894%)
(1020%)
(5%)

Laboratory Finding

Electrolyte disturbances
Hyponatremia
Hyperkalemia
Hypercalcemia
Azotemia
Anemia
Eosinophilia

(92%)
(88%)
(64%)
(6%)
(55%)
(40%)
(17%)

Addisons 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/: Addisons 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 Addisons 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
insufficiencytakes hydrocortisone

Therapy of Addisons disease


Specific
Hydrocortisone 15-25 mg/d
Prednisone 2-3 mg/morning; 1-2 mg/early
evening
Fludrocortisone acetate, has a potent Naretaining 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
Its importance is to maintain the bodys 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 hydroxylase

TYROSINE
Dopa decarboxylase

L-dihydroxyphenylalanine (L-dopa)
Dopamine--hydroxylase

Dopamine

norepinephrine

PNMT
Epinephrine
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)

Force and rate of contraction

Blood vessels

Vasocontrction

Vasodilation

Kidney

Renin released

Gut

Motility and sphincter tone

Pancreas

Insulin and glucagon release

Insulin and glucagon release

Liver

Glycogenolysis

Adipose tissue

Lipolysis

Most tissues

Calorigenesis

Skin (apocrine glands)

Sweating

Bronchioles

Dilation

Uterus

Contraction

Relaxation

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%