DISEASES OF THE ADRENAL

GLAND: OVERVIEW
BY
DR I C OKPARA
CONSULTANT CARDIOLOGIST/ASSOCIATE
PROFESSOR
 OUTLINE
• INTRODUCTION
• FUNCTIONAL ANATOMY AND PHYSIOLOGY
• CLASSIFICATION OF DISEASES OF THE
ADRENAL GLAND
• CLINICAL SYNDROMES
 INTRODUCTION
• The adrenal glands located on the cephalad
portion of each kidney, consist of a cortex and a
medulla.
• The adrenal cortex and medulla each have
separate endocrine functions.
• The adrenal cortex produces three classes of
corticosteroid hormones: glucocorticoids (eg
cortisol), mineralocorticoids (eg aldosterone) and
adrenal androgens (eg dehydroepiandrosterone-
DHEA).
 INTRODUCTION
• The adrenal medulla is an extension of the
sympathetic nervous system which secretes
catecholamines into capillaries rather than
synapses.
FUNCTIONAL ANATOMY AND PHYSIOLOGY

• The normal adrenal glands weigh 6 – 11g each. They are

located above the kidneys and have their blood supply
each.
• Arterial blood flows initially to the subcapsular region
and then meanders from the outer cortical zona
glomerulosa through the intermediate zona fasciculata
to the inner zona reticularis and eventually to the
adrenal medulla.
• The right suprarenal vein drains directly into the inferior
vena cava while the left suprarenal vein drains into the
left renal vein.
FUNCTIONAL ANATOMY AND PHYSIOLOGY

• Thus histologically the cortex is divided into 3

zones:
- outer zona glomerulosa: produces
mineralocorticoids.
- middle zona fasciculata: produces
glucocorticoids.
- inner zona reticularis: produces adrenal
androgens.
FUNCTIONAL ANATOMY AND PHYSIOLOGY

• Most of the adrenal cortex is made up of cells

which secrete cortisol and adrenal androgens
and form part of the hypothalamo-pituitary-
adrenal axis whereas mineralocorticoids are
regulated by the renin-angiotensin-
aldosterone system.
• The hypothalmus releases corticotropin-
releasing hormone(CRH) in response to stress.
FUNCTIONAL ANATOMY AND PHYSIOLOGY

• ACTH is released by the corticotrope cells of the

anterior pituitary in response to CRH stimulation
and acts as the pivotal regulator of adrenal cortisol
secretion.
• Cortisol is released by the adrenal gland in response
to ACTH.
• Adrenal cortisol secretion exhibits a distinct
circadian rhythm, starting to rise in the early
morning hours prior to awakening, with peak levels
in the morning and low levels in the evening.
 CLASSIFICATION OF DISEASES OF THE
ADRENAL GLAND
• Disorders of the adrenal gland are
characterized by deficiency or excess of one or
several of the 3 major corticosteroid classes.
• Hormone deficiency can be caused by
inherited glandular or enzymatic disorders or
by destruction of the pituitary or adrenal
gland by autoimmune disorders, infections,
infarction or iatrogenic events such as surgery
or hormonal suppression.
 CLASSIFICATION OF DISEASES OF THE
ADRENAL GLAND
• Hormone excess is usually the result of
neoplasia, leading to increased production of
ACTH by the pituitary or neuroendocrine cells
(ectopic ACTH) or increased production of
glucocorticoids, mineralocorticoids, or adrenal
androgen precursors by adrenal nodules.
• Adrenal nodules are increasingly identified
during adrenal imaging performed for other
reasons.
 CLASSIFICATION OF DISEASES OF THE
ADRENAL GLAND
Abnormality Primary Secondary
Hormone excess Non-ACTH dependent ACTH dependent Cushing,s
Cushing,s syndrome syndrome
Primary Secondary
hyperaldosteronism hyperaldosteronism
Phaeochromocytoma
Hormone deficiency Addison’s disease Hypopituitarism
Congenital adrenal Withdrawal of suppressive
hyperplasia glucocorticoid therapy
Hormone hypersensitivity 11 β-hydroxysteroid
dehydrogenase type 2
deficiency
Liddle’s sydrome
Hormone resistance Pseudohypoaldosteronism
Glucocorticoid resistance
syndrome
Non-functioning tumours Adenoma
Carcinoma (usually
functioning)
Metastatic tumours
 ADDISON’S DISEASE

BY
DR I C OKPARA
CONSULTANT CARDIOLOGIST/ASSOCIATE
PROFESSOR
 OUTLINE
• INTRODUCTION
• EPIDEMIOLOGY
• ETIOLOGY
• CLINICAL FEATURES
• INVESTIGATIONS
• CLINICOPATHOLOGIC CORRELATES
• TREATMENT
 INTRODUCTION
• Addison’s disease is adrenocortical
insufficiency due to destruction of the entire
adrenal cortex. It affects commonly
glucocorticoid and mineralocorticoid
function.
• It was first described by Thomas Addison in
1855 in his classic paper, on the Constitutional
and local effects of Disease of the Supra-Renal
Capsules1.
 EPIDEMIOLOGY
• Addison’s disease or primary adrenal insufficiency is a
rare cause of adrenal insufficiency with a prevalence of 2
in 10,000 in USA.
• Secondary adrenal insufficiency may arise due to
suppression of the hypothalamo-pituitary-adrenal axis
as a consequence of exogenous glucocorticoid treatment
is much more common occurring in 0.5 – 2% of the
population in developed countries.
• There is no racial predilection.
• Most common age of presentation of addison’s disease
is 30 – 50 years.
ETIOLOGY OF ADDISON’S DISEASE
• Addison’s disease is most commonly caused by
autoimmune adrenalitis. Isolated autoimmune
adrenalitis accounts for 30 – 40%, of cases while 60 -
70% develop adrenal insufficiency as part of
autoimmune polyglandular syndromes (APS).
• Rarer causes involve destruction of the adrenal
glands as a consequence of infection, hemorrhage,
lymphoma or infarction.
• Tuberculous adrenalitis and HIV/AIDS are frequent
causes of the disease in developing countries.
ETIOLOGY OF ADDISON’S DISEASE CONT’D

• TB of the adrenal glands is usually a post primary

disease due to hematogenous spread of infection to the
adrenal glands, but clinical evidence of primary infection
is not always present.
• Acquired immunodeficiency syndrome may give rise to
Addison’s disease in the setting of a low CD4 cell count
due to opportunistic infections such as
cytomegalovirus(CMV), MAI, cryptococcal infections.
• Malignant infiltration of the adrenal cortices, as with
Hodgkin and non-Hodgkin lymphoma may cause
Addison’s disease.
ETIOLOGY OF ADDISON’S DISEASE CONT’D
Diagnosis Gene Associated features
Autoimmune polyglandular AIRE Hypoparathroidism,
syndrome 1 (APS1) chronic mucocutaneous
candidiasis, other
autoimmune disorders
Autoimmune polyglandular Associations with HLA-DR3, Hypothyroidism,
syndrome 2 (APS2) CTLA-4 hyperthyroidism,
pernicious anemia, vitiligo,
type 1 DM
Congenital Adrenal CYP21A2, CYP1181
Hyperplasia
Adrenal hypoplasia
congenita (AHC)
Adrenalleuodystrophy X-ALD Demyelination of central
(ALD), nervous system(ALD) or
Adrenalmyeloneuropathy spinal cord (AMN)
(AMN)
Familial glucocorticoid Tall stature
deficiency.
 ETIOLOGY OF ADDISON’S DISEASE CONT’D
Diagnosis Gene Associated features

Adrenal infections Tuberculosis, HIV, CMV,

cryptococcosis,
histoplasmosis,
coccidioidomycosis
Adrenal infiltrations Metastasis, lymphomas,
sarcoidosis, amyloidosis,
hemochromatosis.
Adrenal hemorrhage Meningococcal
sepsis(Waterhouse-
Friderichsen syndrome),
primary antiphospholipid
syndrome.
Drug induced Mitotane.
Aminoglutethimide,
ketoconazole
Bilateral adrenalectomy Eg in the mgt of Cushing’s
or after bilateral
nephrectomy.
 CLINICAL FEATURES
• Most of the time the clinical features of Addison’s
disease are characterized by the loss of
glucocorticoid and mineralocorticoid secretions.
• In secondary adrenal insufficiency, only
glucocorticoid deficiency is present as the adrenal
itself is intact and thus still amenable to regulation
by Renin-Angiotensin-Aldosterone system.
• Adrenal androgen secretion may be disrupted in
both primary and secondary adrenal insufficiency.
 CLINICAL FEATURES
• Addison’s disease may present as:
1. Acute Addison’s disease
2. Chronic Addison’s disease.
 CLINICAL FEATURES OF CHRONIC
ADDISON’S DISEASE
Glucocorticoid Mineralocorticoid Adrenal Androgen Others
Deficiency Deficiency Deficiency
Fatigue, lack of Abdominal pain, Lack of energy Hyperpigmentation
energy, ↑TSH, nausea, vomiting of skin and mucous
hypoglycemia, membranes
Weight loss, Dizziness, postural Dry itchy skin (in
anorexia hypotension women)
Myalgia, joint pain Low blood pressure Loss of libido (in
women)
Fever Increased serum Loss of axillary and
creatinine due to pubic hair (in
volume depletion. women)
Normocytic, Hyperkalemia
normochromic
anemia.

Postural Hyponatremia
hypotension
CLINICAL FEATURES OF ACUTE ADDISON’S
DISEASE
An adrenal crisis may be triggered by an
intercurrent illness, surgery or other stress.
1. Prominent nausea and vomiting
2. Vascular collapse and hypovolemic shock
3. Features of acute abdomen.
4. Fever
5. Stupor or coma.
 INVESTIGATIONS
1. The rapid ACTH stimulation test: short (cosyntropin)2 test to
confirm adrenal insufficiency. Cortisol level should rise > 500 –
550nmol/L in normal individuals.
2. Measurement of plasma ACTH with increased or inappropriately
low levels defining primary or secondary adrenal insufficiency.
3. Plasma renin – in secondary hyperaldosteronism
4. Full blood count – normocytic normochromic anaemia
5. TSH levels – low in secondary hypoaldosteronism
6. Steroid autoantibodies.
7. Chest radiograph – paraneoplastic feature of lung Ca.
8. Adrenal imaging – primary tumour or disease.
CLINICOPATHOLOGIC CORRELATES
CLINICAL FEATURE PATHOLOGIC CORRELATE
hyperpigmentation Excess ACTH stimulation of melanocytes
to produce melanin
Weight loss Anorexia
Fatigue, anorexia Cortisol deficiency
Postural hypotension Volume depletion due to loss of
mineralocorticoid effect of aldosterone
Hypoglycemic episodes Due to increased insulin sensitivity
Myalgia and flaccid muscle paralysis Due to hyperkalemia
 TREATMENT
• ACUTE ADRENAL CRISIS
1. IV Normal Saline
2. IV Hydrocortisone 100mg stat. Then 100mg 4X daily for 12 – 24
hours.
3. Continue parenteral hydrocortisone 50 – 100mg IM 4X daily till
patient is well enough for reliable oral therapy.
4. Mineralocorticoid replacement can be initiated once the daily
hydrocortisone dose has been reduced to < 50 mg because at higher
doses hydrocortisone provides sufficient stimulation for
mineralocorticoids. Give 100 – 150 µg Fludrocortisone.
5. For acute hypoglycemia give IV 10% glucose.
6. Hyperkalemia should respond to volume replacement.
7. Treat precipitating cause eg infection and underlying pathology.
 TREATMENT OF CHRONIC ADDISON’S
DISEASE
• GLUCOCORTICOID REPLACEMENT
1. Oral Hydrocortisone 15 – 20 mg daily in divided
doses to replace the physiological cortisol
production eg 10mg on waking and 5 mg at
1500 hours.
2. Pregnancy may require an increase in
hydrocortisone by 50% during the last trimester.
3. If higher doses ≥30mg are being administered
watch out for side effects eg Osteoporosis.
ADVICE TO PATIENTS ON GLUCOCORTICOID
REPLACEMENT THERAPY.
1. In case of intercurrent illness eg fever, the dose
of usual oral hydrocortisone should be doubled.
2. IV hydrocortisone 100mg daily in cases of
prolonged vomiting, surgery or trauma.
3. To carry hydrocortisone self injection
emergency kit when travelling to remote areas.
4. Patient should carry a steroid card at all times.
This should give information regarding
diagnosis, steroid dose and doctor.
 TREATMENT OF CHRONIC ADDISON’S
DISEASE CONT’D
• MINERALOCORTICOID REPLACMENT
1. In primary adrenal insufficiency should be initiated at
a dose of 100 – 150µg fludrocortisone daily.
2. Evaluate adequacy of treatment by measuring sitting
and standing blood pressures.
3. Serum sodium, potassium and plasma renin should
be measured regularly.
4. Mineralcorticoid dose should be adjusted in hot
weather and may need to be adjusted during
pregnancy.
 TREATMENT OF CHRONIC ADDISON’S
DISEASE
• ADRENAL ANDROGEN REPLACEMENT
1. May be indicated in women with adrenal androgen
deficiency , including loss of libido.
2. May be indicated in patients with lack of energy
despite glucocorticoid and mineralocorticoid
replacement.
3. Administer DHEA 25 – 50 mg once daily.
4. Treatment is monitored by measuring DHEAS,
androstenedione, and sex hormone binding
globulin after the last DHEA dose.
 REFERENCES
1. Addison T. On the Constitutional and local effects of
Disease of the Suprarenal Capsules. London, UK : Samuel
Highley; 1855.
2. Oelkers W, Diederich S, Bahr V. Diagnosis and therapy
surveillance in Addison’s disease: rapid
adrenocorticotropin (ACTH) test and measurement of
plasma ACTH, renin activity, and aldosterone. J Clin
Endocrinol Metab. 1992 Jul. 75(1) : 259 – 264.
3. Wiebkt Arlt. Disorders of the adrenal cortex: (Eds)
Harrison’s Principles of Internal Medicine 19th Edition,
New York, The McGraw Hill companies 2015: 2309 – 2327.
 CUSHING’S SYNDROME
1. Introduction
2. Aetiology
3. Clinical features
4. Investigations
5. Treatment
 Introduction
• Cushing’s syndrome is caused by excessive
activation of glucocorticoid receptors.
• It may be endogenous or exogenous.
• The exogenous form is most commonly
iatrogenic due to prolonged administration of
synthetic glucocorticoids such as
prednesolone.
 Introduction cont’d
• Endogenous Cushing’s syndrome is
uncommon but due to chronic over-
production of corticol by the adrenal glands.
• This may be due to an adrenal tumour or
excessive production of ACTH by a pituitary
tumour or ectopic ACTH production by other
tumours.
 Aetiology/Classification
1. ACTH-dependent – Amongst endogenous
causes, pituitary dependent cortisol excess
by convention (Cushing’s disease) accounts
for approximately 80% of cases.
Ectopic ACTH syndrome (bronchial Ca, small-
cell lung Ca, other neuroendocrine tumours
accounts for 10% of cases.
 Aetiology/Classification
2. Non-ACTH dependent – Adrenal adenomas(15%),
adrenal Ca (5%), ACTH-independent macrododular
hyperplasia; primary pigmented nodular adrenal
disease; McCune-Albright syndrome (together
<1%).
3. Hypercortisolism due to other causes (pseudo-
Cushing’s syndrome)
-Alcohol excess
-Major depressive illness
-primary obesity
 Epidemiology
• Cushing’s disease and cortisol secreting
adrenal tumours are 4Xmore common in
women than men.
• In contrast ectopic ACTH syndrome is more
common in men.
 Clinical features
• The following features favour the diagnosis of
Cushing’s syndrome in an obese patient
1. Easy bruising
2. Moon face
3. Acne
4. Myalgia
5. Peptic ulcer
6. Hyperglycemia
 Clinical features cont’d
7. Menstrual disturbances
8. Hypertension
9. Central obesity
10.Striae
11.Proximal myopathy
12.Osteoporosis
13.Hirsuitism.
 Clinical features cont’d
• When the tumour secreting ACTH is
malignant, the onset is usually rapid and may
be associated with cachexia.
• For these reasons, the classical features of
Cushing’s syndrome are less common in
ectopic ACTH syndrome.
• If present suggest a less aggressive tumour eg
bronchial carcinoid.
 Clinical features cont’d
• In Cushing’s disease, the pituitary tumour is usually a
microadenoma (<10mm in diameter) hence other
features of pituitary macroadenoma
(hypopituitarism, visual failure or disconnection
hyperprolactinemia) are rare.
• It is important to exclude iatrogenic causes in all
individuals since inhaled or topical glucocorticoids
can induce the syndrome in susceptible persons.
• A careful drug history should be taken before
embarking on complex investigations.
 Investigations
• Cushing’s syndrome is confirmed by using 2 of
3 tests
1. Failure to suppress serum cortisol with low
doses of oral dexamethasone. Low
dexamethasone suppression test.
2. Loss of the normal circadian rhythm of
cortisol, with inappropriately elevated late-
night serum or salivary cortisol.
3. Increased 24-hour urine free cortisol.
 Treatment
• Treatment modalities include medical, surgical
or radiation therapies.
• Most patients are treated surgically.
• Cushing’s disease is treated by Transphenoidal
surgery carried out by an experienced surgeon
with selective removal of the adenoma.
• Laparoscopic bilateral adrenalectomy cures
non-ACTH-dependent cushing’s syndrome.
 Treatment cont’d
• But in patients with pituitary dependent Cushing’s
syndrome this can result in Nelson’s syndrome,
with an invasive pituitary macroadenoma and very
high ACTH levels causing pigmentation.
• The risk of Nelson’s syndrome may be reduced by
pituitary irradiation.
• Laparoscopic surgery is the treatment for adrenal
adenomas and carcinomas with radiotherapy of
the tumour bed for carcinomas.
 Treatment cont’d
• Ectopic ACTH-producing tumours should be
removed surgically.
• Medical treatment involves the use of drugs
that inhibit cortisol biosynthesis such as
metyrapone and ketoconazole. They may be
used post irradiation or in patients with
incurable malignancies.