PENYAKIT PADA

KELENJAR ADRENAL
Calvin Damanik
Bagian Penyakit Dalam FK UMI
Medan

Histology
Cortex
90% of adult gland
Derived from mesoderm
Begins during 5th week of development
Mesothelial cell migration

Glomerulosa, fasciculata, reticularis

Zonation occurs until about 18
months of age

Histology
Medulla
Derived from neuroectoderm
Neural crest cell migration
Begins during 7th week of development
Primitive medulla by 20th week

Continues growth until cortex atrophy

(18 months)

Cross section through the adrenal

gland cortex and medulla

salt
sugar

sex

Cortisol and Glucocorticoid

Receptors
The vast majority of glucocorticoid activity in
most mammals is from cortisol, also known as
hydrocortisone.
Cortisol binds to the glucocorticoid receptor in
the cytoplasm and the hormone-receptor
complex is then translocated into the nucleus
Only about 10% of circulating cortisol is free.
The remaining majority circulates bound to
plasma proteins, particularly corticosteroidbinding globulin (transcortin).

Hypothalamus-Pituitary-Adrenal axis
Circadian regulation

CRH

Stress:
Physical stress
Emotional stress
Hypoglycemia
Cold exposure
Pain
Cortisol

Adrenal cortex

+ ACTH
ACTH

Anterior lobe
of pituitary gland

CRH=corticothropin releasing hormone; ACTH=adrenocorticothropin hormone.

Kirk LF. Am Fam Physician 2000

Aldosterone synthesis
ACTH also stimulates aldosterone synthesis.
However the ACTH stimulation is more
transient than the other stimuli and is
diminished within several days.
ACTH provides a tonic control of aldosterone
synthesis.
In the absence of ACTH, sodium depletion still
activates renin-angiotensin system to
stimulate aldosterone synthesis.
Aldosterone levels fluctuate diurnallyhighest
concentration being at 8 AM, lowest at 11 PM,
in parallel to cortisol rhythms.

Regulation of
aldosterone
secretion:
Activation of
reninangiotensin
system in
response to
hypovolemia is
predominant
stimulus for
aldosterone
synthesis.

Component
s of reninangiotensin
aldosterone
system

Action of aldosterone
on the renal tubule.
Sodium reabsorption
from tubular urine
into the tubular cells
is stimulated. At the
same time, potassium
secretion from the
tubular cell into urine
is increased. Na+/K+ATPase, and Na+
channels work
together to increase
volume and pressure,
and decrease K+.

Adrenocortical disorders

Cushings Syndrome
Excess Cortisol
Protein catabolic state
Liberation of amino acids by muscle
AA are transformed into glucose and
glycogen and then transformed into fat
Loss of calcium in urine
Weakened muscles and elastic tissues

Causes of Cushings Syndrome

ACTH Dependent (80%)
Cushings Disease (85%)

Primary excretion of ACTH from pituitary

95% have identifiable pituitary adenoma
Basophilic or chromophobe

Bilateral adrenocortical hyperplasia

70% of endogenous cases
F>M (3:1)

Ectopic source (15%)

Produce ACTH or CRH

Small cell lung CA (most common), carcinoid tumors,
medullary thyroid, pancreas, ovarian,
pheochromocytoma, small-cell CA of prostate

Causes of Cushings Syndrome

ACTH Independent
Exogenous steroid use (common)
PO or topical
Most common cause (overall)

Adrenal adenomas (10%)

Adrenal carcinoma (5%)
Most common cause in children

Cause of Cushings Syndrome

Pseudo-Cushings disease
Mimic clinical signs and symptoms
Non-endocrine causes
Alcoholism
Major depression
Morbid obesity
Acute illness

Cushings Syndrome
Diagnosis of Cushings syndrome
History / Physical Examination ------>
CLINICAL DIAGNOSIS (Symptoms and
signs)
Laboratory Examination (Screening Test
& Defenitive Test) THE PRINCIPLE OF
LABORATORY INTERPRETATION

Cushings Syndrome
Diagnosis of Cushings syndrome
Labs
24 hour urinary cortisol
2-3 consecutive days
Verify with creatinine values

Spot AM/PM serum cortisol

Circadian variation
AM ACTH surge causes increased cortisol
PM should see at least 50% drop in cortisol level

Low-dose dexamethasone suppression test

Cushings Syndrome
Dexmethasone suppression test
Synthetic glucocorticoid (30x more potent as
inhibitor)
Low dose
0.5mg po q6 hours x48 hours
Measure cortisol, 17-hydroxycorticosteroid
Fall in all steroid levels in pseudo-Cushing and
normals
Differentiates presence/absence of Cushings
syndrome

Alternative dosing
1mg po at midnight and measure 8am cortisol
Much less sensitive

Cushings Syndrome
Diagnose cause of Cushings syndrome
History (steroid use?)
Serum ACTH
Elevated : Cushings disease, ectopic ACTH
Suppressed: primary adrenal source
Correlate with cortisol levels

High-dose dexamethasone suppression test

Metyrapone test

Cushings Syndrome
Dexmethasone suppression test
High Dose

2mg po q6 hours x48 hours

Measure cortisol and urinary free cortisol
Ectopic ACTH and adrenal tumors- no suppression
Cushings disease- suppress to <50% of baseline
Usually only used if ACTH/Cortisol assays
unavailable or equivocal

Cushings Syndrome
Metyrapone test
Inhibits 11-B-hydroxylase
Blocks conversion of 11-deoxycortisol to
cortisol
Plasma cortisol levels fall and ACTH increases
Marked increase in 17-hydroxycorticosteroid
levels and 11-deoxycortisol levels
Cushings Disease- normal or supernormal increase
in levels
Ectopic ACTH or adrenal sources- no response

Risks adrenal insufficiency

Cushings Syndrome
Petrosal vein sampling
Measure petrosal venous sinus ACTH level
and correlate to plasma levels
Invasive with morbidity
Usually not used

Adrenal venous sampling

Measure cortisol and aldosterone
Not used anymore

Cushings Syndrome
Radiographic Localization
CT of sella turcica

Unenhanced and gadolinium enhanced MRI

Radionuclide imaging for somatostatin receptors
>60% sensitive
1st study if diagnosed with Cushings syndrome

CT of chest/abdomen with 3mm cuts through

adrenal
Adrenal hyperplasia
Thickening and elongation of adrenal rami bilaterally
Multinodularity of cortex bilaterally

Cushings Syndrome
Radiographic Localization
CT of adrenal glands
Adenomas- usually >2cm but <5cm
Low attenuation (lipid content)
Atrophy of opposite gland

Carcinoma- indistinguishable from adenomas

>5cm
Necrosis, calcifications, irregularity, invasion

MRI of adrenal- usually not needed

Signal intensity much higher than in spleen = carcinoma
Adjacent organ and/or vascular involvement

Cushings syndrome
suspect
11 pm salivary
cortisol
Disrupted circadian
rhythm

Normal

Cushings
syndrome
excluded
Repeat if high
index of suspicious

24-hour UFC
Filtered load of cortisol

Equivocal

Dexamethasone test

Low dose dexamethasone

Supression test
Attenuated negative feedback

Abnormal

Cushings syndrome
established

Confirm CS
ACTH
Undetectable
Adrenal
Unilateral
mass

Normal to increased
Pituitary MRI

Bilateral
masses

Pituitary
tumor

Normalequivocal
IPSS with
Search ectopic

Cushings Syndrome
Treatment: Surgical
Cushings disease
Transphenoidal hypophysectomy
>90% cure rate 1st time, 50% salvage cure 2nd
attempt
Exploration even if no obvious adenoma
Transient post-op diabetes insipidus, adrenal
insufficiency, CSF rhinorrhea, meningitis

Tansphenoidal irradiation
High success rate in kids (80%)
Low success in adults (20%)

Cushings Syndrome
Treatment: Surgical
Cushings disease
Bilateral adrenalectomy
If failed pituitary surgery
Life-long steroid replacement

Adrenal lesions/carcinoma
Removal of primary lesion
Survival based on underlying disease

Ectopic ACTH lesions

Remove lesion
Survival based on primary disease
May need bilateral adrenalectomy to control symptoms if
primary tumor unresectable

Cushings Syndrome
Treatment: Medical
Used as prep for surgery or poor operative candidate
Metyrapone- inhibits conversion of deoxycortisol to cortisol
Aminoglutethimide-inhibits desmolase
Cholesterol to pregnenolone
Blocks synthesis of all 3 corticosteroids
Side effects: N/V, anorexia, lethargy
Ketoconazole- an imidazole that blocks cholesterol
synthesis
Mitotane (O-P-DDD)-inhibits conversion to pregnenolone
Inhibits final step in cortisol synthesis
Destroys adrenocortical cells (spares glomerulosa cells)

Addisons Disease
Primary adrenal insufficiency
Causes
Infectious
TB most common cause in 3rd world countries
HIV, histoplasmosis, blastomycosis,
coccidiomycosis
Autoimmune disorders anti-adrenal antibodies
(most cause common)
Medications ketoconazole, aminoglutethamide,
etomidate
Adrenal hemorrhage
Lymphoma, bilateral adrenal metastasis, Kaposis
sarcoma
Infiltrative amylodosis, sarcoidosis,
adrenoleukodystrophy

Addisons Disease
Secondary adrenal insufficiency
Pituitary failure panhypopitutarism,
Sheehans syndrome (post-partum pituitary
injury)

Tertiary adrenal insufficiency

Adrenal suppression due to glucocorticoid
use
Chronic suppression
Sudden cessation of replacement glucocorticoids
Inadequate increase during stress, trauma,
surgery

Addisons Disease
Response to cosyntropin test or rapid ACTH stimulation
test
Cortisol

Aldosteron

Diagnosis

Comments

Increased
Decreased

Increased
Decreased

Decreased

Increased

Increased

Decreased

Normal
Primary adrenal
insufficiency
Secondary adrenal
insufficiency
Isolated
aldosterone
deficiency

End organ failure (Addisons

disesase)
Pituitary diseases,
hypothalamic disease
Very rare

Addisons Crisis
Acute adrenal insufficiency
Similar causes
Adrenal hemorrhage
Chronic steroid use and
trauma/stress/surgery

Hypotension, volume depletion, fever,

nausea and vomiting, tachycardia,
weakness, hypoglycemia
Premed prior to interventions

Addisons Crisis
Treatment acut of adrenal crisis
Glucocorticoid replacement
Administer hydrocortisone 100 mg every 6 hours for 24
hours
When the patient is stable, reduce the dosage to 50 mg
every 6 hours
Taper to maintenance theraphy by day 4 or 5 and add
mineralocorticoid theraphy as required
Maintain or increase the dose to 200-400 mg/d if
complications persist or occur

General and supportive measure

Correct volume depletion, dehydration, and hypoglycemia
with IV saline and glucose
Evaluate and correct infection and other precipitating
factors

PATOFISIOLOGI PENYAKIT ADDISON

Cortisol

Skin Hyperpigmentation

ACTH

Glukoneogenesis
Abd.Pain
Anorexia
Vomiting
Diarrhea

Glucose Uptake
Renal K Secretion
Renal Na secretion

HYPOGLYCEMIA
HIPERKALEMIA
HIPONATREMIA

+
Fluid Intake

DEHIDRASI
RENAL PERFUSION

B.U.N

HYPOTENSION
HYPOVOLEMIA

General Weakness
Decreased Body
Weight

Addisons Crisis
Maintenance therapy
Glucocorticoid and mineralocorticoid
Oral dose hydrocortisone : 10-20 mg in the
morning and 5-10 mg later in day.
Fludrocortisone : 0,05-0,2 mg/d orally in the
morning.

Response to theraphy
General clinical sign, good appetite and sense
of well being.
Signs of Cushings syndrome indicate
overtreatment

Disorders of adrenal
medullary function

Pheochromocytoma
Adrenal medullary tumor composed of
chromaffin cells and capable of secreting
biogenic amine and peptides, including
epinephrine, norepinephrine, and dopamine.
Such tumor arise from neural crest-derived cells
Because of this common origin, neoplasma of
the sympathetic ganglia , such as
neuroblastoma, paragangliomas, and
ganggliomneuromas, may produce similar
amines and peptides.

COMT = Catecholamine Ortho Methyl Transferase)

Receptor catecholamine :
Receptor (NE)
Receptor (EPI)

Pheochromocytoma
Signs and symptoms :
The classic triad of sudden severe
headaches,
diaphoresis, and palpitations
Hipertensive in 95-95% of cases and is
paroxismal in 25-50% of these.
Orthostatic hypotension, tremor, pallor, flushing,
anxiety and constipation

Nonclassic manifestations :
Hyperglycemia, severe diarrhea, hypercalcemia
Arrhytmia, congestive cardiomyopathy, seizure,
altered mental status, cerebral
infarction/hemorrhage

Pheochromocytoma
Diagnosis :
Demonstration of excessive amounts catecholamines in plasma
or urine or degradation product in urine
Urinary metanephrine, normetanephrine, vanilmandelic acid (VMA),
and free catecholamine in 24-hour periode
Direct measurement plasma NE and EPI. Levels > 2000 pg/ml are
abnormal and suggestive Pheochromocytoma

Clonidine suppression test

Clonidine orally 0,3 mg; plasma catecholamine : before oral clonidine
and again at 1,2 and 3 hr after oral clonidine
Plasma catecholamine >500pg/ml

Glucagon stimulation test

Pheochromocytoma
Treatment :
Surgical resection is only definitive therapy
Preoperative preparation : prazosin 1mg 3
times/day, advanced to 5 mg3 times/day (7-28
days before surgery)
Other agents labetalol or Ca channel blocker
Goals of theraphy : BP <160/90 mmHg.

Glucocorticoid therapy for non

endocrine disorders

Principles
Antiinflamatory and immunosuppressive
therapy; rheumatoid arthritis, SLE, asthma,
glomerulonephritis
Because of their side effect : minimum
effective dose and shortest possible duration
of therapy
Modes of administration : orally,
parenterally, topically or inhalation

Synthetic glucocorticoid
Relative Potencies of Steroid Hormones
Compound
Hydrocortisone
Cortisone
Prednisone
Methylpredniso
ne
Dexamethason
e
Fludrocortisone

Glucocortico Mineralocortico
id activity
id activity
1
0,7
4
5
30
10

1
0,7
0,7
0,5
0
400

Duration
Short
Short
Short
Short
Long
Long

Side effects
1. HPA axis suppression

Suppress CRH and ACTH secretion (negative feedback)

Doses of prednisone >5mg/d
It is difficult to predict the development or degree of supression :

Clinical feature Cushings syndrome

Glucocorticoid equivalen to 10-20mg of prednisone/day for 3 weeks or
more

2. Cushings syndrome

Steroid induced osteoporosis

Inhaled glucocorticoid : local effect (dysphonia and oral candiasis)
and systemic effect, glaucoma, cataracts, osteoporosis, and growth
retardation

3. Steroid withdrawal

Glucocorticoids must be tapered downward

Patients may develop fatigue, arthralgia, and desquamation of the
skin
Even after the dose to physiologic levels, HPA axis suppression
persists for 9-10 months or more

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