ADRENAL DISORDERS

DR. W. T. Njumwa
Internal Medicine
Overview
• The adrenal glands are triangular- shaped
glands

• Located on top of each kidneys

• Endocrine organ responsible for the release
of:
– Catecholamines (adrenaline, noradrenaline),
– Glucocorticoids( cortisol)
– Mineralocorticoids (aldosterone)
– Sex steroids(dehydroepiandrostenedione (DHEA) and
androstenedione
Anatomy
• Also termed the 'suprarenal' gland

• Located on top of each kidneys in

retroperitoneum

• Weight = 4g

• Composed of: outer adrenal cortex &

inner adrenal medulla
Adrenal cortex
• Outermost aspect of the adrenal gland.

• It is composed of three layers:

• Zona Glomerulosa: produces mineralocorticoids – aldosterone.

• Zona Fasciculata: produces glucocorticoid hormone– cortisol

• Zona Reticularis: produces androgens–androstenedione dehydroepiandrosterone (DHEA).

Adrenal medulla
• Innermost aspect of the adrenal gland
• composed of a single layer.
• Responsible for the production of three hormones:
• Adrenaline
• Noradrenaline
• Dopamine
Role of Adrenal Glands
• They play a crucial role in:
• Water and electrolyte regulation

• Regulation of blood pressure

• Regulation of the sympathetic nervous system

• Carbohydrate and fat metabolism

• physiologic response to stress

• Sexual development and differentiation.

Regulation of adrenal gland secretion
Hypothalamic pituitary Adrenal-HPA-axis
DISORDERS OF ADRENAL GLAND
Disorders of adrenal cortex Disorders of the Adrenal medulla
• Cushing’s Syndrome • Phaeochromocytoma
• Adrenal Insufficiency • Neuroblastoma
• Hyperaldosteronism • Ganglioneuroma
• Adrenocortical Carcinoma
• Congenital Adrenal
Hyperplasia
DISORDERS OF ADRENAL CORTEX

Hyperfunctioning and Hypofunctioning

1. Hypercortisolism(cushing’s syndrome)
2. Hyporcortisolism (Adrenal insufficiency)
CUSHING’S SYNDROME

Definition
• Cushing’s syndrome is a metabolic disorder resulting from the excessive
production of cortisol (Hypercortisolism)

• The cause may be endogenous or exogenous

― Exogenous: due to prolonged administration of glucocorticoids(i.e Prednisone) for

diseases such as asthma or rheumatoid arthritis

― Endogenous: due to excess cortisol production by:

• ACTH Secreting pituitary adenoma
•
• Cushing's Syndrome- Clinical effects of increased glucocorticoid
hormone- all causes of excess cortisol

• Cushing's Disease- refers to Hypercortisolism caused by a ACTH

producing pituitary adenoma.
Epidemiology

• 2-3 per 100,000 population per year

• Common in ♀ -♂:♀ (3–15:1).
• Age—most common, 20–40 years.
Physiology
Cortisol secretion is controlled by the hypothalamus-
pituitary-adrenal axis.

1. Corticotropin-releasing hormone(CRH)
• Released by hypothalamus.
• Stimulates the release of adrenocorticotropic hormone (ACTH) from
anterior pituitary

2. Adrenocorticotropic hormone (ACTH)

• Released from anterior pituitary,
• stimulates the release of cortisol from adrenal cortex

3. Cortisol
• Cortisol is released from the adrenal cortex in response to ACTH.
• It exerts negative feedback on the release of both ACTH and CRH.
 HYPOTHALAMUS

CRH

Stimulation PITUITARY Negative feedback

ACTH
CORTISOL
ADRENAL
CORTEX
 Cortisol
• Cortisol exhibits diurnal variation-
during 24 hours

• It reaches a Zenith (highest point)

early morning- 8 am

• Nadir (lowest point) at around

midnight to 1 am.
Functions of Cortisol
• Regulation of metabolism:
• Cortisol increases the body's metabolism of glucose
• It also stimulates gluconeogenesis,( breakdown of protein and fat to produce glucose in the liver)

• Blood pressure regulation:

• Cortisol helps maintain blood pressure
• by increasing the sensitivity of blood vessels to vasoconstrictors like norepinephrine
• increasing the release of epinephrine and norepinephrine.

• Anti-inflammatory effects:
• Cortisol suppresses the inflammatory response by inhibiting the production of inflammatory cytokines and reducing the activity
of immune cells.

• Stress response:
• Cortisol is released in response to stress,
• helps the body adapt to stressful situations
• by increasing energy availability and altering immune function.

• Regulation of sleep-wake cycle:

• Cortisol levels typically follow a diurnal rhythm,
•
 Cushing Syndrome-Etiology

Cushing’s syndrome Etiology

ACTH-dependent ACTH-Independent
Cushing’s Syndrome-80% Cushing's Syndrome-20%
1. ACTH- Dependent Cushing Syndrome-80%
 Cortisol excess is driven by ACTH, either from the pituitary or ectopic source

• Cushing's disease: excess cortisol due to ACTH hypersecretion by pituitary

adenoma - 65 -70 % of all Cushing syndrome

• Ectopic ACTH- Secreting tumors-10-15%: Small cell lung tumors,NSCL

• Ectopic CRH secreting tumors: medullary thyroid ca, Neuroendocrine pancreatic ca

 The tumor secretion of ACTH causes bilateral adrenocortical hyperplasia and

hyperfunction.

 Excess ACTH production is often not inhibited by cortisol, dexamethasone, or other

2. ACTH- Independent Cushing Syndrome-20%
 cortisol excess is independent of ACTH

• Iatrogenic/factitious Cushing syndrome-

― Most common cause, due to excessive or prolonged administration of
corticosteroids, including skin creams, e.g. clobetasol.

• Primary adrenal lesions

― Tumors- Adrenocortical adenomas 10% and carcinomas 8%
― Hyperplasia- Nodular (macro- or micro-) hyperplasia 1%

 Result in cortisol excess and suppression of CRH and ACTH

 Clinical features-1
Associated with effects of excess cortisol.
• Weight gain (90%)
• Truncal obesity (centripetal obesity)
• An enlarged dorsocervical fat pad (buffalo hump)
• Moon face- thickening of facial fat, which rounds
the facial contour
• Acne, hirsutism
• Purple striae (65%)- Violaceous striae wider than
1 cm on abdomen or proximal extremities
• Thinning of the skin- to loss of SC tissue,
• Easy bruising (40%) With spontaneous
ecchymoses
 Clinical features-2
• Proximal Muscle Weakness with wasting (60%)-
difficulty in climbing stairs, arising from a low
chair or squatting
• Osteoporosis (40%) with low back pain and
vertebral collapse,
• Hypertension (85%) - new onset hypertension
• Glucose intolerance (80%) - ranging from
hyperglycemia to diabetes
• Dyslipidemia
• Menstrual dysfunction - oligomenorrhea or
amenorrhea
• Decreased libido
• psychiatric disturbances
Clinical features-3

buffalo hump

Moon face

Thinning of the skin& Easy bruising

 Clinical features-4

Violaceous striae on abdomen or proximal extremities

Diagnostic Tests

• 24-hour urinary free cortisol(UFC)

• Dexamethasone suppression test(DST)
• Plasma ACTH
• Serum cortisol levels
• Salivary cortisol levels
• Imaging- CT/MRI: Localisation of the ACTH source, rule out
pituitary or adrenal pathologies.
 Diagnostic Tests-1
 24-hour urinary cortisol
• Initial test in a patient with suspected Cushing's syndrome
• Involves collecting all urine produced in a 24-hour period
• and measuring the amount of cortisol present
• The 24 hour urine free cortisol reflects the average serum unbound cortisol
• The normal range urine cortisol levels- 3.5-45 µg/24hrs
• ↑Levels 3-4x →highly suggestive of Cushing's syndrome.
 Diagnostic Tests…
 Low-dose dexamethasone suppression

• 1 mg of dexamethasone is given at 11 pm.

• serum cortisol measured at 8 am

• In a normal individual administration of dexamethasone should
suppress the morning rise in serum cortisol >50%
• Unsuppressed cortisol level will occur in Cushing’s syndrome
Diagnostic Tests…
 Plasma ACTH
• ↓ACTH = ACTH independent cause of Cushing's syndrome
― Primary adrenal lesions: tumors (adenomas, carcinomas and

― hyperplasia) may result in cortisol excess and suppression of CRH and ACTH.

― Prolonged exposure to exogenous glucocorticoids, results in suppression of CRH and ACTH.

• ↑ACTH = ACTH dependent causes such as:

― Pituitary adenomas secreting excess ACTH

― Ectopic production: paraneoplastic syndrome in lung cancers where malignant cells produce ACTH and
are not subject to normal negative feedback mechanisms.

― NB: ectopic tissues will not be suppressed with high dose dexamethasone and continue to produce ACTH
Diagnostic Tests…
 Serum cortisol levels
― The morning cortisol test and the midnight cortisol test
― The morning cortisol test is usually done between 6 and 8 am when cortisol
levels are at their peak.
― A normal result for a morning cortisol test: 5 -23 mcg/dL
― A normal result for a midnight cortisol test often less than 50% of the morning
cortisol level

 Late night salivary cortisol at 11pm

― Earliest and most sensitive marker for the Cushing’s syndrome
― Rational: →absence of the normal fall of plasma cortisol at midnight due loss
of the diurnal cortisol rhythm in cushings syndrome
― In normal subjects, the cortisol at this time is at a nadir (<1.81mcg/dL )
Diagnostic Tests…
• After diagnosing cortisol excess we must identify the underlying
etiology
 Imaging- CT/MRI
• To identify the pituitary adenoma,
adrenal pathologies or malignancy
responsible for ectopic production of
the ACTH

• Pituitary MRI is investigation of

choice-pituitary Tumors

• Ectopic ACTH: CT/MRI of abdomen,

thorax and pelvis
• NB: However, it is essential to note that high cortisol levels
do not always mean a person has Cushing's syndrome.

• Other conditions such as obesity, diabetes, and depression

can also lead to increased cortisol levels.
Cushing's disease management
1.Surgical
• Transsphenoidal Resection-Pituitary Adenomas
― Gold-standard for treatment of Cushing's disease resulting from Pituitary Adenomas

• Surgical resection – Adrenalectomy: of adrenal lesions(Adenomas).

2. Pituitary radiotherapy
― Usually administered as second-line treatment,
― following unsuccessful transsphenoidal surgery.
― A more rapid response to radiotherapy is seen in childhood

3. Medical
― Used as a bridge to definitive surgical management
― Failure of surgical Therapy
― steroidogenesis inhibition {Cholesterol→cortisol}
Medical treatment of cushing syndrome
• Adrenal enzyme inhibitors
• Pituitary targeted therapy
• Glucocorticoid receptor antagonist
1. Adrenal enzyme inhibitors

• They inhibit one or more steps in cortisol synthesis

• used to control ACTH-dependent cortisol excess.
― Ketoconazole
― Metyrapone

― Mitotane Inhibits 11β-hydroxylase→ ↓↓in cortisol synthesis

― Etomidate

― Mitotane is also adrenolytic and is used for the treatment of

adrenocortical carcinoma.
2. Drugs that target a pituitary tumor

• Somatostatin analogue, pasireotide, and the dopamine

agonist, cabergoline, have shown benefit.

• ACTH-secreting tumor →Chemotherapy or immunotherapy

may reduce ACTH and cortisol levels in patients with ectopic
ACTH secretion.
3. Glucocorticoid-receptor antagonists

Mifepristone (RU-486)
• Anti-progestational drug .
• At higher doses, it acts as a glucocorticoid receptor
antagonist.
• Blocks peripheral action→ ACTH AND CORTISOL LEVELS
CONTINUE TO BE HIGH
• to control hyperglycemia secondary to hypercortisolism
Exogenous Cushings Syndrome management
Gradual tapering withdrawal of the glucocorticoid

• Patients who have developed Cushing's from exogenous

steroid use,

• will likely have developed suppression of their normal

endogenous glucocorticoid production

• Abrupt stopping could result in an Addison’s crisis

Prognosis of Cushing’s disease
• Untreated disease leads to an approximately 30–50% mortality at 5 years,
owing to vascular disease and ↑ susceptibility to infections.

• Treated Cushing’s syndrome has a good prognosis.

• Successful treatment for Cushing’s disease leads to a cortisol <50nmol/L

following surgery.

• Physical features associated with Cushing’s resolve within weeks or months

of successful treatment

• Hypertension and diabetes mellitus has been shown to resolve in up to 70-

ADDISON'S DISEASE

(Primary Adrenal Insufficiency)

Introduction
• Addison’s disease is caused by destruction or dysfunction of the
adrenal cortex.

• Leads to insufficient adrenocortical hormones (glucocorticoid +/-

mineralocorticoid)

• Patients can present with an 'Addisonian crisis', which refers to a

medical emergency caused by

• Profound glucocorticoid and mineralocorticoid deficiency that

Epidemiology
• Prevalence
• ~12 per 100,000 persons
• Incidence
• ~0.5 per 100,000 persons per year
• Age
• May occur at any age, with peak incidence in the fourth
decade
• Sex
• Autoimmune causes: overall female predominance
• Non-autoimmune causes: equal sex distribution
Adrenal insufficiency
• Primary adrenal insufficiency (Addison's disease): caused by
destruction or dysfunction of the adrenal cortex.

• Secondary adrenal insufficiency: caused by reduced ACTH

release, due to pituitary disorders

• Tertiary adrenal insufficiency: caused by a reduction in

corticotropin-releasing hormone, from Hypothalamus i.e
following chronic glucocorticoid use.
Etiology
Etiology…
Infective adrenalitis
• Tuberculosis
• Worldwide, the most common cause of adrenal insufficiency is Tuberculosis induced infective
adrenalitis. Thomas Addison first described the condition

• Fungal
• Histoplasmosis (endemic)
• Paracoccidioidomycosis (endemic)
• Coccidioidomycosis (opportunistic)
• Cryptococcosis (opportunistic)
• HIV- or AIDS-related
• HIV
• Cytomegalovirus
• Mycobacterium avium-intracellulare infection
• Opportunistic fungal infection (see above)
• Kaposi’s sarcoma
Etiology…
Autoimmune adrenalitis
• Autoimmune destruction of the adrenal cortex

• Autoantibodies target enzymes involved in the biosynthesis of

steroids (21-hydroxylase)
• Female predominance
Etiology…
Other causes

• Congenital abnormalities of cortisol synthesis

• 21-Hydroxylase deficiency is most common.

• Waterhouse-Friderichsen syndrome: adrenal haemorrhage occurs

secondary to Severe sepsis (e.g., meningococcus)

• Infiltrative disease as a result of malignant metastasis, or amyloid

deposits,Hemachromatosis may cause adrenal insufficiency.

• Bilateral adrenalectomy is an iatrogenic cause of Addison's disease.

Etiology…
Other causes…
• Medications
• Rifampin, phenytoin, ketoconazole, megestrol, and opiates may
cause or potentiate adrenal insufficiency.

• Adrenal Hemorrhage
• Anticoagulants- Heparin, warfarin

• Hypercoagulable states (adrenal infarction)

 Clinical Features

• Nonspecific and insidious onset • Hyperpigmentation (>90%)

• Common • Specific to primary adrenal insufficiency
• Fatigue (not seen in other types of adrenal
• Weakness (>90%) insufficiency)
• Malaise • Diffuse brownish darkening of exposed
• Abnormalities of GI function
• Anorexia (90%)
and unexposed skin
• Weight loss (>90%) • Elbows, knuckles, and creases of the
• Nausea and vomiting hand are particularly darkened
• Diarrhea or constipation
• Unlocalized, often severe abdominal pain
• Blue-black patches on mucous
• Personality changes membranes
• Often occur early in the disease and very responsive to
glucocorticoid replacement therapy
• Hypotension, with postural
• Irritability accentuation (< 110/70 mmHg) (>80%)
• Restlessness
• Impaired memory
• Syncope
• Depression • Dehydration with hyponatremia and
• May progress to frank psychosis (not as responsive to
glucocorticoid therapy) hyperkalemia
Adrenal insufficiency with
ecchymosis is suggestive
of meningococcal
.septicemia
 The primary cause of hyperpigmentation in Addison's
disease is related to elevated levels of adrenocorticotropic
hormone (ACTH) due to the lack of negative feedback from
cortisol.

1. Increased ACTH Levels: ACTH stimulates

melanocytes, to produce more melanin.

2. Melanocyte-Stimulating Hormone (MSH): ACTH is

a precursor to melanocyte-stimulating hormone
(MSH). Increased ACTH levels in Addison's disease
result in higher MSH levels, contributing to
hyperpigmentation.

3. Binding of ACTH to Melanocortin-1 Receptors:

ACTH can bind to melanocortin-1 receptors on
melanocytes, leading to the activation of these cells
and increased melanin production.

Hyperpigmentation is typically generalized and most prominent in areas exposed to sunlight and pressure points.
Hyperpigmentation
 Acute Adrenal Insufficiency
{Adrenal crisis/Addisonian crisis}
• Endocrine emergency, Life threatening complication

• Stressful situations, surgery, infection, and trauma are potential

events that increase adrenal requirements, especially in patients
with some underlying adrenal or pituitary insufficiency.

• The most common cause of adrenal crisis is abrupt withdrawal of

exogenous glucocorticoids in patients receiving chronic treatment
that resulted in hypothalamic-pituitary-adrenal–axis suppression
Adrenal crisis
C/F
• Severe vomiting and diarrhoea followed by dehydration
• Low blood pressure and shock
• Hypoglycemia
• Loss of consciousness

Management entails: IV fluids + IV hydrocortisone

Diagnostic Approach
Laboratory Tests:
• Decreased basal and stress-induced cortisol levels.
• Decreased aldosterone level (in primary adrenal insufficiency).
• Lack of increase in cortisol and aldosterone level after ACTH
stimulation
Diagnostic Approach
• Blood tests
• A deficiency in mineralocorticoids (aldosterone) may lead to hyponatremia (90%) and
hyperkaliemia (30-50% of cases).
• Hypoglycemia,

• Serum cortisol
• Measured at 8-9 am (when highest… in those with routine sleeping patterns)
• < 100 nmol/L: highly suggestive of adrenal insufficiency
• > 500 nmol/L: excludes adrenal insufficiency

• Plasma ACTH level

• High:≥ 100 pg/mL (22 pmol/L) indicative of primary adrenal insufficiency
• Normal: inconclusive
• Low: indicative of secondary/tertiary adrenal insufficiency
Diagnostic Approach…
• Corticotropin stimulation test
• A normal response to the corticotropin (ACTH) stimulation test excludes primary
adrenal insufficiency.

• Primary adrenal insufficiency

• Elevated baseline ACTH level ≥ 100 pg/mL (22 pmol/L)

• Secondary/tertiary adrenal insufficiency

• Low or inappropriately normal baseline ACTH level

• Other tests include the insulin hypoglycemia test, the

metyrapone test, and the corticotrophin-releasing hormone
stimulation test
Imaging
• Imaging studies are used to help determine the cause of primary
adrenal insufficiency.
• Abdominal CT
• Indicated to evaluate for adrenal infection, hemorrhage, infiltration, or metastases
• Adrenals are small and noncalcified in autoimmune Addison’s disease.
• Adrenals are enlarged in metastatic or granulomatous disease.
• Calcifications may be present in patients with tuberculosis, hemorrhage, and fungal infection.

• Chest radiography
• Indicated for evaluation of tuberculosis, fungal infections, and neoplasia when an
autoimmune cause is not apparent
Treatment Approach of Adrenal Insufficiency
Glucocorticoid replacement

• Life-long glucocorticoid (and often mineralocorticoid) replacement is required to treat

primary adrenal insufficiency

• Hydrocortisone (cortisol) is the preferred glucocorticoid preparation.

• hydrocortisone, 15-30 mg/day given in divided doses.

• Longer-acting glucocorticoid preparations (e.g., prednisone, dexamethasone) may be used

If hydrocortisone is unavailable

• Goal is to administer the lowest dose of glucocorticoid that will relieve symptoms
Treatment Approach of Adrenal Insufficiency
Mineralocorticoid replacement

• Mineralocorticoids are replaced with fludrocortisone, 50-300 mcg per day.

• The major reason for adding the mineralocorticoid is to minimize

development of hyperkalemia

• times of severe physical stress (e.g., febrile illnesses, after accidents), patients
should be instructed to double their daily dose until recovery.

• Treatment of secondary adrenal insufficiency is identical to primary disease

treatment with the exception that mineralocorticoid replacement is usually
not necessary.
Treatment Approach of Adrenal Insufficiency
Androgen replacement
• Dehydroepiandrosterone (DHEA) (optional)
• Not generally recommended as benefit is unproven.
The end point of therapy
• The end point of therapy for adrenal insufficiency is difficult to
assess in most patients, but a reduction in excess pigmentation is
a good clinical marker.

• Development of features of Cushing’s syndrome indicates

excessive replacement
Pharmacotherapy of Acute Adrenal
Insufficiency- Adrenal crisis
• Hydrocortisone given parenterally is the corticosteroid of choice because
of its combined glucocorticoid and mineralocorticoid activity.

• The starting dose is 100 mg IV by rapid infusion, followed by a continuous

infusion or intermit- tent bolus of 100 to 200 mg every 24 hours. IV
administration is continued for 24 to 48 hours.

• If the patient is stable at that time, oral hydrocortisone can be started at a

dose of 50 mg every 8 hours for another 48 hours.

• A hydrocortisone taper is then initiated until the dosage is 30 to 50

mg/day in divided doses.
Pharmacotherapy of Acute Adrenal
Insufficiency-Adrenal crisis…
• Fluid replacement often is required and can be accomplished with
IV dextrose 5% in normal saline solution at a rate to support
blood pressure.

• If hyperkalemia is present after the hydrocortisone maintenance

phase, additional mineralocorticoid usually is required.
Fludrocortisone acetate 0.1 mg orally once daily is the agent of
choice.
Patient education
• Patients must understand that treatment for Addison’s disease is
(for the majority) lifelong

• Intercurrent illness requires adjustment of the glucocorticoid

dose. For example, a temperature > 37.5 C should prompt a
doubling of dose.

• Patients should be able to promptly identify an Addisonian crisis

as well as carry a steroid card and MediAlert identification.
DISORDERS OF THE ADRENAL MEDULLA

 Phaeochromocytoma
 Neuroblastoma
 Ganglioneuroma
PHAEOCHROMOCYTOMA
• Tumor of the adrenal medulla, derived from chromaffin cells

• Associated with secretion of excess catecholamines (epinephrine

and norepinephrine ) into the bloodstream

• Primary clinical manifestations is hypertension

• Sporadic occur after 4th decade, hereditary(earlier)

• Known as 10% tumor
• 10% are familial(Inherited)
• 10% extra-adrenal
• 10% malignant
• 10% bilateral
• 10% children
Clinical features
• Arterial Hypertension
• Excessive perspiration
• Palpitations
• Headaches
• Hyperventilation
• Weight loss
• Later: Cardiomegaly, LV failure, CHF
Management

 Investigations
• Urinary catecholamines
• Dopamine, norepinephrine, and epinephrine
• Plasma metanephrine
• Metanephrines are metabolites of catecholamines
• Vanillylmandelic Acid, (VMA)
• metabolite of the catecholamines excreted in the urine
• CT Scan or MRI

 Management
• Short term manage:↑BP with B-blockers
• Surgical excision of tumors
Further Reading
• Hyperaldosteronism
• Adrenocortical Carcinoma
• Congenital Adrenal Hyperplasia
• Neuroblastoma
• Ganglioneuroma
References
• Harrisson’s,Manual of Medicine,19th Edition,Mc Graw-Hill
Education:New York,2016,
• Davidson’s principles of internal medicine,21st edition.
• Merck S. & Dohme C.,MSD Manual,Professional
version,Kenilworth:USA,2017;
• UpToDate 2024