APPROACH TO PATIENT WITH

ADRENAL DISORDER
HISTORY

 The anatomy of the adrenal glands was described almost 450 years
ago.

 In 1855 Thomas Addison recorded autopsy findings of 11 cases

which were having Addison’s disease.

 In 1856 Brown- Séquard demonstrated that the adrenal glands were

“organs essential for life” by performing adrenalectomies in dogs,
cats, and guinea pigs.
 Between 1937 and 1955, the adrenocorticosteroid hormones were
isolated, and their structures were defined and synthesized.

 The control of adrenocortical function by a pituitary factor was

demonstrated in the 1920s, and this led to the isolation of sheep
adrenocorticotropic hormone (ACTH) by Li, Evans, and Simpson in
1943.
DEVELOPMENT

 The adrenocortical primordium develops at approximately 8 weeks

of gestation and can be differentiated into two distinct layers, the
inner fetal zone (FZ) and the outer definitive zone (DZ).

 After birth, the FZ regresses.

 Adrenal androgen production peaks in the third decade and
then declines at a variable rate. Mineralocorticoids and
glucocorticoids show a less age-specific variation
.
ANATOMY

 4 gm
 5*2*1 cms
 Above the kidney on its posteromedial surface
 The right adrenal vein is short, draining directly into the inferior vena
cava,
 whereas the longer left adrenal vein usually drains into the left renal
vein.
BLOOD FLOW

75%
PHYSIOLOGY

Cholesterol (LDL) Adrenal Cells

Mitochondria
ACTH

Pregnenolone
M

M
M
NEURAXIAL CONTROL OF CORTISOL
CRH (41)

Pre-pro-opiomelanocortin

ACTH Melanocortin-1 endorphin

MSH
Melanocortin-2 (Cortisol)
Feedback
inhibition is principally
mediated via the
glucocorticoid
receptor (GR).
 Patients with primary adrenal failure invariably have
both cortisol and aldosterone deficiency, whereas
patients with ACTH deficiency due to pituitary disease
have glucocorticoid deficiency but normal aldosterone
concentrations because the renin angiotensin system is
intact.
 More than 90% of circulating cortisol is bound
predominantly to the α2-globulin, cortisol-binding
globulin.
 This 383–amino acid protein is synthesized in the liver and
binds cortisol with high affinity.
 Levels are increased by estrogens and in some patients
with chronic active hepatitis; they are reduced by
glucocorticoids and in patients with cirrhosis, nephrosis,
and hyperthyroidism.
 The excretion of free cortisol through the kidneys results in
urinary free cortisol, which represents only 1% of the total
cortisol secretion.
 The circulating half-life of cortisol varies between 70 and 120
minutes.
 Approximately 50% of secreted cortisol appears in the urine as
THF, allo-THF, and THE; 25% as cortols/cortolones; 10% as C19
steroids; and 10% as cortolic/cortolonic acids. The remaining
metabolites are free unconjugated steroids (cortisol,
cortisone, and their 6β-, and 20α/20β- metabolites).
 Corticosterone and DOC, synthesized in both the ZF and
ZG, can act as mineralocorticoids, which becomes
significant in some clinical diseases, notably some forms
of congenital adrenal hyperplasia.
ALDOSTRONE

 Aldosterone is secreted from the ZG under the control of

three principal secretagogues: angiotensin II, potassium,
and, to a lesser extent, ACTH. Other factors, notably
somatostatin, heparin, atrial natriuretic factor, and
dopamine, can directly inhibit aldosterone synthesis.
 Angiotensin II and potassium stimulate aldosterone
secretion principally by increasing the transcription of
CYP11B2 through common intracellular signaling
pathways.
MECHANISM OF ACTION

 Both cortisol and aldosterone exert their effects after

uptake of free hormone from the circulation and binding
to intracellular receptors.
EFFECTS OF GLUCOCRTICOIDS

 Reduce glycogenolysis.
 Increase gluconeogenesis.
 Increase lipolysis.
 Reduce uptake of glucose in cells.
 Fat redistribution (long term effect).
ADRENO CORTICAL DISEASES
DISORDERS OF GLUCOCORTICOIDS

Cushing syndrome: State of glucocorticoid excess.

 The term Cushing syndrome is used to describe all causes, whereas

Cushing disease is reserved for pituitary-dependent Cushing
syndrome.
 The incidence of Cushing disease is estimated to be 2 to 3 cases per
1 million population per year.
 70% Iaotrogenic.
 Iatrogenic-induced Cushing syndrome occurs in patients who take
suppressive doses of corticosteroids for longer than 3 weeks.
Clinical features
 When iatrogenic causes are excluded, the most
common cause of Cushing syndrome is Cushing disease,
accounting for approximately 70% of cases.

 In 15% of cases, Cushing syndrome is associated with

nonpituitary tumors secreting ACTH—the ectopic ACTH
syndrome.

 Excluding iatrogenic cases, adrenal adenomas are

responsible for about 10% to 15% of Cushing syndrome
cases, and carcinomas for less than 5%. By contrast, 65%
of cases of Cushing syndrome in children have an
adrenal cause (15% adenomas, 50% carcinomas).
INVESTIGATIONS

 Does This Patient Have Cushing Syndrome ?

Late night salivary cortisol/circadian rhythm of plasma cortisol
midnight cortisol level greater than 200 nmol/L
Salivary cortisol >5.5nmol/L
Urinary free cortisol excretion
cortisol : S.creat (early morning) >25nmol/mmol.
Low-dose dexamethasone suppression test (1mg at 11PM)
< 50nmol/L ( between 8-9 AM )
2 out of 3

 Loss of diurnal variation with high night serum cortisol or salivary cortisol
 LDDST fails to suppress cortisol
 Increased 24 hour urine free cortisol
 What is the cause
Morning ACTH ( 9-52pg/ml Normal values ).
 Hypokalemic alkalosis is present in more than 95% of
patients with the ectopic ACTH syndrome but in fewer
than 10% of those with Cushing disease.
 Inferior petrosal sinus sampling ratio of ACTH >3 when
compared to plasma ACTH after 1 mcg/kg CRH ( 0, 1, 15
mins).
TREATMENT

 Surgery
 Drugs: Metyrapone- 11B- hydroxylase inhibitor
250mg BD to 1.5gm QID.
Ketoconazole
400-1600 mg/day.
Mitotane
5gm/day
GLUCOCORTICOID DEFICIENCY

 PRIMARY
 CENTRAL

 Major distinction between these forms of hypoadrenalism is that

mineralocorticoid deficiency invariably accompanies primary
hypoadrenalism, but this does not occur in central hypoadrenalism:
here only ACTH is deficient, and the renin-angiotensin-aldosterone
(RAA) axis is intact.
PRIMARY

 4-11 CASES PER 1 LAKH POPULATION.

 70% AUTOIMMUNE CAUSE.
SECONDARY

 Central hypoadrenalism may be defined as

hypocortisolemia secondary to a deficiency in ACTH.

 The prevalence of central hypoadrenalism is 125 to 280

per million.

 The most common reason is ACTH suppression by

exogenous glucocorticoid treatment.
CAUSES

 PRIMARY: Autoimmune
Infections ( Tuberculosis, Fungal, CMV, HIV )
METS
Infiltrates
Intra adrenal haemorrhage (sepsis)
Congenital hypoplasia (X-Linked )
ACTH resistance syndromes (Autosomal recessive)
Bilateral adrenalectomy
 CENTRAL: Exogenous glucocorticoids.
Hypopituitarism
Pituitary surgery and craniopharyngeoma
pituitary apoplexy
Granulomatous disease
Secondary tumour deposits
Sheehan syndrome
Isolated ACTH/Multiple pituitary hormone deficiency
Pituitary irradiation
Clinical
features
INVESTIGATIONS

 Basal cortisol >400 nmol/L.

 ACTH Stimulation test (250 mcg synthetic ACTH given IV)
0 and 30 mins Cortisol > 550 nmol/L
Response is unaffected by the time of day of the
test, and the test can be performed in patients who have
commenced corticosteroid replacement therapy, as long
as this therapy is of short duration and does not
include hydrocortisone (which would cross-react
in the cortisol assay).
 ITT ( Insulin tolerance test )
0.1- 0.15 U/Kg IV insulin
Cortisol 0, 30, 45, 60, and 120.
Cortisol > 500 nmol/L
C/I – IHD
Epilepsy
Severe hypopituitarism ( 9 AM cortisol < 180 nmol/L )
 The CRH stimulation test has been used to diagnose
adrenal insufficiency

 It differentiates primary from secondary causes.

 Patients with primary adrenal failure have high ACTH

levels that rise further after CRH stimulation.

 Patients with secondary adrenal failure have low ACTH

levels that fail to respond to CRH.

 Patients with hypothalamic disease show a steady rise in

ACTH levels after CRH administration
 Clinical improvement, especially in the blood pressure,
should be seen within 4 to 6 hours if the diagnosis is
correct.

 After the first 24 hours, the dose of hydrocortisone can

be reduced, usually to 50 mg intramuscularly every 6
hours and then to oral hydrocortisone, 40 mg in the
morning and 20 mg at 6 PM.

 This dose can then be rapidly reduced to a more

standard replacement dose of 20 mg on awakening
and 10 mg at 6 PM.
 In primary adrenal failure, mineralocorticoid
replacement is usually also required in the form of 0.05 to
0.2 mg/day.

 After the acute phase has passed, the adequacy of

mineralocorticoid replacement should be assessed by
measuring electrolytes, supine and erect blood
pressures, and plasma renin activity.
 Patients on glucocorticoid replacement therapy should
be advised to double their daily dose in the event of
intercurrent febrile illness, accident, or mental stress such
as an important examination.
 For patients with both primary and secondary adrenal
failure, beneficial effects of adrenal androgen
replacement therapy with 25 to 50 mg/day of DHEA
have been reported. To date, reported benefit is
principally confined to female patients and includes
improvement in sexual function and well-being.
MINERALOCORTICOID EXCESS

 Prevalence is 5 – 12 % .
 Much higher in hypertensive patients with hypokalemia.
CAUSES

 The most common cause of mineralocorticoid excess is

primary aldosteronism, reflecting excess production of
aldosterone by the adrenal zona glomerulosa.
Adrenal adenoma 60%
Bilateral adrenal hyperplasia
Glucocorticoid-remediable hyperaldosteronism
Syndrome of apparent mineralocorticoid excess
Cushing’s syndrome
Glucocorticoid resistance
Adrenocortical carcinoma
Congenital adrenal hyperplasia
Progesterone-induced hypertension
Liddle’s syndrome
CLINICAL FEATURES

 potassium depletion
 sodium retention
 hydrogen depletion that can cause metabolic alkalosis
 Aldosterone excess may cause direct damage to the
myocardium and the kidney glomeruli, in addition to
secondary damage due to systemic hypertension.
 Severe hypokalemia can be associated with muscle
weakness, overt proximal myopathy, or even
hypokalemic paralysis. Severe alkalosis contributes to
muscle cramps and, in severe cases, can cause tetany.
SALINE INFUSION TEST

 IV administration of 2 L of physiologic saline over a 4-h

period. Failure of aldosterone to suppress below 140
pmol/L (5 ng/dL) is indicative of autonomous
mineralocorticoid excess.
TREATMENT

 Surgery
 Mineralocorticoid receptor antagonist spironolactone. It
can be started at 12.5–50 mg bid and titrated up to a
maximum of 400 mg/d to control blood pressure and
normalize potassium.
 Selective MR antagonist eplerenone can also be used.
Doses start at 25 mg bid, and it can be titrated up to 200
mg/d.
 Sodium channel blocker amiloride (5–10 mg bid).
 Treatment of GRA consists of administering
dexamethasone, using the lowest dose possible to
control blood pressure. Some patients also require
additional MR antagonist treatment.

 An increased free cortisol over free cortisone ratio is

suggestive of SAME and can be treated with
dexamethasone.
ADRENAL MEDULA

 Biosynthesis of catecholamines
PHEOCHROMOCYTOMA

 Pheochromocytomas and paragangliomas are well-vascularized

tumors that arise from cells derived from the sympathetic or
parasympathetic paraganglia.
 The mean age at diagnosis is ∼40 years.
 0.1% of hypertensive patients.
 5% of incidentaloma.
CLINICAL FEATURES
 Paroxysms generally last <1 h and may be precipitated
by surgery,positional changes, exercise, pregnancy,
urination (particularlywith bladder
pheochromocytomas), and various medications
(e.g.,tricyclic antidepressants, opiates,
metoclopramide).
DIAGNOSIS

 Documentation of catecholamine excess.

Serum > Urine
> 3 times
 Localization of the tumor by imaging.
IMAGING

 CT
 MRILUORO
 MIBG
 FLUORO-DOPA PET
Differential diagnosis

 Essential hypertension,
 anxiety attacks,
 Use of cocaine or amphetamines,
 Mastocytosis,
 Carcinoid syndrome,
 Clonidine withdrawal,
 autonomic epilepsy.
TREATMENT

 Surgery is the treatment of choice.

 BP < 160/90.
 Phenoxybenzamine 0.5 to 4 mg/Kg
 Good hydration.
 Propranolol 10mg qid.
 Prazosin and phentolamine.
 Postoperatively, catecholamine normalization should be
documented.
 An adrenocorticotropic hormone test should be used to
exclude cortisol deficiency.
Syndromes with pheochromocytoma

 NF-1 ( 1% ).
 MEN 2 ( 50% ).
 VHL ( 20-30% ).
References

 Harrisons Principles of Internal Medicine, 19Ed.

 William's Endocrinology, 13th Edition.
 Ganong’s review of medical physiology, 24th edition.
THANK YOU