QPT20206: PATHOPHYSIOLOGY OF ENDOCRINE

CHAPTER 7: ADRENAL GLAND

Adrenal Glands - Suprarenal glands

Paired organ each weight about 4 grams, pyramidal in shape, located on the top of the
kidneys, one on each side at the level of the T12
It enclosed by fibro elastic connective tissue capsule.
Each gland is divided into tow parts:
Cortex outer part of gland
Part of hypothalamus pituitary adrenal axis
Secrete a variety of steroid hormones
Medulla inner part of gland, (20% of gland)
Part of sympathetic nervous system
Secrete catecholamines
Both parts are structurally and functionally different

Adrenal Cortex
The large cortical cells are arranged into three layers or zones :

The Zona Glomerulosa

The thin outermost layer
Constitute about 15% of cortex

The Zona Fasciculata

The middle and largest portion
Constitute about 75% of cortex.

The Zona Reticularis: The innermost zone.

HISTOLOGY OF ADRENAL GLANDS

Zona Glomerulosa:

The secretory cells are arranged in irregular ovoid

clusters that are surrounded by trabeculae which contain
capillaries.

Produce meniralocorticods

Mainly aldosterone (because it contain enzyme

aldosterone synthase) - Hormones that help control the
balance of minerals (Na+ and K+) and water in the blood

Aldosterone secretion

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Zona Fasciculata:

The secretory cells are arranged in cords, often one cell thick, surrounded by fine strands of supporting tissue

Produce glucocorticods

Mainly Cortisol and Corticosterone (Hormone that play a major role in glucose metabolism as well as in protein and
lipid metabolism)

The human adrenal glands produce the equivalent of 3540 mg of cortisone acetate per day

The secretion of these cells is controled by hypothalamic-pituitary axis via ACTH

Cortisol and Chronic Stress

Prolonged exposure to high cortisol levels can lead to break down of muscle, excessive epinephrine release,
hyperglycemia, weakening of bone, destruction of the immune system, inhibition of reproductive function, and other
complications.
Zona Reticularis:

The innermost layer of the adrenal cortex, lying deep to the zona faciculata and superficial to the medulla.

These cells produce androgens

Dehydroepiandrosterone (DHEA)
Androstenedione
Synthesized from cholesterol

The androgens produced are released into the blood stream and taken up in the testis and ovaries to produce
testosterone and the estrogens respectively

Disorders of adrenal cortex

Hypofunction of the gland

Hyperfunction of the gland

ADRENAL HYPOFUNCTION
Introduction
Adrenal insufficiency leads to a reduction in the output of adrenal hormones
glucocorticoids and/or mineralocorticoids
Two types of adrenal insufficiency

Primary insufficiency

inability of the adrenal glands to produce enough steroid hormones

80% are due to an autoimmune disease

Secondary insufficiency

inadequate pituitary or hypothalamic stimulation of the adrenal glands

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Aetiology and Pathogenesis

Causes
Glucocorticoid treatment
Autoimmune adrenalitis
Tuberculosis
Adrenalectomy
Secondary tumor deposits
Amyloidosis
Haemochromatosis
Histoplasmosis, tuberculosis,
Adrenal haemorrhage
Metabolic failure in hormone production
Congenital adrenal hyperplasia e.g. 21-hydroxylase deficiency, 3--hydroxysteroid dehydrogenase
deficiency
Enzyme inhibition e.g. ketoconazole
Accelerated hepatic metabolism of cortisol e.g. phenytoin, barbiturates, rifampicin
ACTH blocking antibodies
Mutation in ACTH receptor gene
Adrenal hypoplasia congenita
Familial adrenal insufficiency

Addison disease

Autoimmune
Isolated or associated with other autoimmune disease
Presents with tiredness, weight loss, skin pigmentation
Aldestrone & cortisol low, high ACTH, high renin
Low sodium , high potasium
ACTH stimulation test
Adrenal antibodies
Treatment : cortisol + aldestrone
Addisons disease: pathogenesis
Progressive destruction of entire adrenal cortex , This is usually autoimmune based.
Most likely the result of cytotoxic T lymphocytes, although 50% of patients have circulating adrenal antibodies.

Adrenocortical Insufficiency- Pathophysiology

Glucocorticoids deficiency

decreased sense of well-being

hypoglycemia
gastrointestinal disturbances
water retention
reduced vascular adrenergic tone
The decreased negative feedback by cortisol

increased synthesis and secretion of ACTH and other POMC-derived peptides

Adrenocortical Insufficiency- Pathophysiology II
mineralocorticoid deficiency

increased sodium renal loss hyponatremia

increased renal retention of potassium and hydrogen ions hyperkaliemia and acidosis
Adrenal androgen deficiency

decrease in axillary and pubic hair and libido (in women)

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Addisons disease: Clinical features

Common

Less common

Tiredness, generalized weakness, lethargy

Hypoglycemia

Anorexia, nausea, vomiting

Depression

Hyponatremia

Confusion. Personality change.

Hyperkalemia ,Hypercalcemia
Convulsions
Dizziness and postural hypotension
Pigmentation
Loss of body hair (woman)
ADRENAL CRISIS

Medical emergency
Acute in onset; can be fatal if not promptly recognized and treated
Clinical features :
Severe hypovolaemia
Pain in the lower back, abdomen or legs
Severe vomiting and diarrhea, leading to dehydration
Hypoglycaemia
Low blood pressure
Possible mental confusion and loss of consciousness
Shock
Causes :
Precipitated by stress: infection, trauma or surgery in patients with incipient adrenal failure/treated with
glucocorticoids if dosage is not increase
Adrenal haemorrhage : due to cx of anticoagulant treatment
Meningococcal septicaemia

Investigations (Hormonal)

Plasma cortisol concentration

<50nmol/L at 0900H effectively diagnostic
>550nmol/L excludes the Dx
PLASMA ACTH MEASUREMENT
To differentiate between primary and secondary adrenal failure
P Primary insufficiency - ACTH increased
P Secondary insufficiency - ACTH decreased
ACTH stimulation test / Synacthen test

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Synacthen test
Baseline cortisol may be normal in Addisons disease
Synacthen test: uses synthetic ACTH analogue
Normal response: rise in cortisol
Metyrapone test
Measures the ability of the pituitary gland to release ACTH in response to
decreased blood cortisol levels.
Metyrapone inhibits cortisol production by blocking the conversion of 11deoxycortisol to cortisol by 11-beta-hydroxylase
CRH Stimulation Test
To differentiate between secondary adrenal insufficiency dt pituitary or
hypothalamic dis.
Results :
o
Pituitary disease blunted or nil response
o
Hypothalamic lesions positive response
Plasma renin and aldosterone
Give an indication of mineralocorticoid activity.
Adrenal insufficiency - Low aldosterone level with high renin

Management

Hormone replacement
Life-long replacement therapy
Hydrocortisone {Hydrocortisone {Cortef) or Prednisone (Deltasone)}
Mineralocorticoid (Fludrocortisone Acetate)
Secondary adrenocortical insufficiency
Hormone replacement
may also require more definitive treatment e.g. surgical removal of a pituitary tumour.
Adrenal crisis :
Adequate resuscitation e.g. IV fluids, IV glucose.
IV hydrocortisone 100mg which should be continued four times daily afterwards until the patient can take oral
medication.

ADRENAL HYPERFUNCTION
Cushing syndrome - High Cortisol
Hyperaldosteronism - High aldestrone
Pheochromocytoma - High catecholamine
Hyperaldosteronism

A medical condition where too much aldosterone is produced by the adrenal glands, which can lead to sodium
retention and potassium loss.
Types:
Primary hyperaldosteronism (hyporeninemic hyperaldosteronism) Conns syndrome
Secondary hyperaldosteronism

Primary aldosteronism
Conns Syndrome

Characterized by autonomous excessive production of aldosterone by adrenal glands

Presents with HPT, hypokalaemic alkalosis and renal K+ wasting

Causes

Adrenal adenoma
Bilateral hypertrophy of zona glomerulosa cells
Adrenal carcinoma - Rare cause

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Secondary aldosteronism

Is increased adrenal production of aldosterone in response to non-pituitary, extra-adrenal stimuli

Commoner than primary aldosteronism
Increase renin secretion (hyperreninemic hyperaldosteronism)
Common
CCF
Liver cirrhosis with ascites
Nephrotic Syndrome
Less common
Renal artery stenosis
Sodium losing nephritis
Renin-secreting tumours

Clinical features

Muscle weakness: Due to decrease K+

Muscle paralysis: severe hypokalaemia
Latent tetany and paraesthesiae-hypokalemia (low potassium level)
Polydipsia, polyuria and nocturia: due to hypokalaemic nephropathy
Hypertension : aldosterone induced Na retention with increase in ECF volume
Heart palpitations - due to low blood potassium levels
Increased risk for heart attacks, heart failure, strokes, kidney failure, and early death.

Investigation

Electrolyte & blood gasses:

Hypernatraemia
Hypokalaemica
Alkalosis
Urinary potassium loss, level > 30 mmol daily during hypokalaemia
Plasma aldosterone : renin activity ratio
Sensitive screening test
No need to standardize posture

Diagnosis

Perform saline infusion test (sodium loading)

Method : infusion of 1.25L of 0.9%saline over 2 hrs
Result: plasma aldosterone remains >240 pmol/l confirm Conns syndrome
Plasma Aldosterone level
Method:
Morning blood sample (pt stayed recumbent since waking)
Second sample after 4 hrs stayed ambulant
**Standing renal blood flow stim renin sec aldosterone level
Establish cause
Imaging techniques
CT scan
MRI
Can differentiate adenoma from hyperplasia
Treatment
Tumour: Remove surgically
Bilateral adrenal hyperplasia : Spironolactone

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Cushings Syndrome

Any condition resulting from overproduction of primarily glucocorticoid (cortisol)

Mineralocorticoid and androgen may also be excessive

Pseudo-Cushings syndrome

Appear cushingoid and have some biochemical abnormalities of true Cushings disease
Causes
Severe depression
Alcoholism
Obesity
Polycystic ovarian syndrome

Etiology ACTH dependent causes

Excessive cortisol (ACTH dependent)~75%

Pituitary disease
Adenoma (90%)
Hyperplasia (10 %)
Ectopic ACTH syndrome - Malignancy - ( bronchus, thymus, pancreas, ovary )
Ectopic CRH syndrome
Exogenous ACTH administration

Hypersecretion of ACTH and Cortisol is greater in ectopic ACTH syndrome than Cushing Disease
Etiology
Excessive Cortisol (ACTH independent) ~25%

Adrenal tumour: Adenoma, carcinoma

Nodular hyperplasia
Exogenous glucocorticoid administration
Excess cortisol binding globulin
Estrogen therapy : Osteoporosis, OCP
Pregnancy

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CHAPTER 7: ADRENAL GLAND
Clinical Features

Truncal obesity with deposition of adipose tissue in

characteristic site (moon face, buffalo hump) exact
mechanism unknown
Thinning of skin catabolic response
Purple striae catabolic response
Excessive bruising catabolic response
Hirsutism ( esp adrenal carcinoma ) - adrenal androgen
Menstrual irregularities - adrenal androgen
Skin pigmentation ( ACTH ) melanocyte stimulating activity
Hypertension mineralocorticoid effect sodium retention
Potassium wasting hypokalamic alkalosis
Glucose intolerance - hepatic gluconeogenesis and insulin
resistance
Muscle weakness and wasting catabolic response in
peripheral supportive tissue
Back pain ( osteoporosis and vertebral collapse) inhibit bone
formation
Psychiatric disturbances euphoria, mania, depression

Laboratory investigations
There are two diagnostic steps in the investigation of patient
suspected of having Cushing's syndrome

Screening test
for identification of Cushing's syndrome.
the demonstration of high plasma cortisol level
Identification of cause
1.

2.

3.

4.

Demonstration of increased cortisol

Assessment of circadian rhythm in cortisol secretion
24-Hour urinary free cortisol excretion
Overnight / low dose dexamethasone suppression
test
Assessment of circadian rhythm in cortisol secretion.
Measure 8 am and 11 pm serum cortisol level
Normal : Serum value @ midnight is 50% less than value @ 8 am
Cushings syndrome : rhythum is loss
Pseudo-Cushing
: normal circadian.
Measuring 24-hour urinary free cortisol

Low dose Dexamethasone suppression test :

0.5 mg Dexametason (oral) given 6 hourly for 2 days
blood for plasma cortisol collected 6 hour after last dose
urine for UFC is collected before & on the 2nd day of Dexa
Result:
P UFC suppress by 50% ( < 70nmol/24h) normal
P plasma cortisol suppress < 140 nmol/L pseudo- Cushing
P no suppression of UFC & Pl. cortisol Cushing's synd

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Elucidation of the cause

High dose Dexamethasone suppression test

Normal individuals suppress plasma cortisol to < 50 nmol/L.

Patients with Cushing's syndrome fail to show complete suppression of plasma cortisol levels. This test is highly
sensitive (> 97%).

Plasma ACTH

Normal < 50 ng/L

Low adrenal causes
Elevated
Slight pituitary dependent Cushings
Gross ectopic secretion of ACTH

CRH Test

Differentiate ectopic ACTH secretion and Cushings disease.

Cushings disease plasma ACTH increases 50% over baseline and cortisol increase by 20%
Ectopic ACTH or adrenal tumour no response

Imaging

CT scan of adrenal gland: TRO adrenal tumor

MRI of pituitary gland: majority microadenoma ( < 10mm). MRI reveal lesion in 50 - 60% of cases
CT scan/MRI of thorax & abdomen: ectopic ACTH producing tumor

Treatment
Depend of Cushing's syndrome depends on the etiology:

Adrenal adenoma
Adrenal Carcinoma
Surgery. In most cases, a surgeon removes the tumor through a cut made under the upper lip or at the bottom of the
nose, between the nostrils.
Radiation therapy. Radiation therapy targets the tumor with high-energy X-rays that kill tumor cells or keep them from
growing. It can be used if surgery is not successful at removing all tumor cells.
Drug ( block cortisol synthesis ) - Metyrapone