Disorders of the Adrenal Gland

• The basic substrate for steroidogenesis is Cholesterol which is either:
  • Derived from diet or
  • Endogenously produced
• It is taken up by the adrenal cortex via the LDL receptors.
• Separate zones of the cortex synthesize specific hormones:
• Z. glomerulosa:
  • Mineralocorticoids (Aldosterone 100-150mcg/day)
  • Under the control of Renin-Angiotensin system
• Z. fasciculata produces:
  • Glucocorticoids (Cortisol 10-20mg/day)
  • Under ACTH control
• Z.reticularis:
  • Adrenal androgens (DHEA and Androstenedione)
  • Under ACTH control

Glucocorticoids

• So named because of their effect on Glu metab
• But not limited to this
• Cortisol is the major glucocorticoid in humans.
• Daily secretion rate 10-30mg/day.
• Pronounced circadian rhythm:
  • Highest in the morning on waking
  • Lowest at night (middle of the night)
• Level also rises with stress, e.g.:
  • Illness
  • Infections
  • Trauma

Glucocorticoids Stimulate

• Gluconeogenesis
• Protein catabolism
• Fat deposition
• Sodium retention
• K+ loss
• Uric acid production
• Circulating neutrophils

Glucocorticoids Inhibit

• Protein synthesis
• Immune response
• Circulating lymphocytes
• Eosinophils

Mineralocorticoids

• Aldosterone is the most important.
• Binds to MR in the renal tubules:
  • Na+ retention
  • K+ loss
  • Proton loss (Metabolic alkalosis)

Adrenal Androgens

• The principal adrenal androgens are:
  • DHEA
  • Androstenedione
  • 11-hydroxyandrostedione
• They are weak androgens.
• Exert effects via peripheral conversion to Testosterone.
• Secretion is regulated by ACTH not FSH/LH.
• Androgens generally regulate male 2˚ sexual xtics.
• Cause virilizing symptoms in women.
• But, adrenal androgens have minimal effects in males.
• Male sexual xtics mainly determined by gonadal androgens.
• In females they are responsible for:
  • Adrenerche
    • Axillary hair
    • Pubic hair
  • Libido

HPA Axis

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HPA Axis

• This is a group of clinical features seen in a state of Hypercortisolism.
• i.e. excessive circulating Glucocorticoids
  • Exogenous
    • Use of synthetic steroids e.g. Prednisolone
    • Most common
  • Endogenous
    • Chronic excessive secretion of Glucocorticoids
    • Rare

Causes of Cushing’s Syndrome

• ACTH-independent (20%):
  • Adrenal adenoma
  • Adrenal Carcinoma
• ACTH – dependent (80%):
  • ACTH-secreting Pituitary adenoma (Cushing’s Disease) – 70%
  • Ectopic ACTH (10%)
    • Oat Cell Bronchogenic Ca, Bronchial carcinoids

Clinical Features

• Can be traced to steroid actions.
• Catabolic responses in supportive tissues cause:
  • Muscle weakness
  • Fatigability
  • Osteoporosis
  • Broad violaceous cutaneous striae
  • Easy bruisability
  • Poor wound healing, Leg ulcers
• Hypercortisolism promotes fat deposition in xtic sites:
  • Upper face (Moon Facies)
  • Interscapular area (Buffalo Hump)
  • Supraclavicular fat pads
  • Mesenteric bed (Truncal obesity)
• Impaired Glucose Tolerance
• Hypertension
• Emotional changes:
  • Irritability, emotional lability, depression
• Facial plethora
• Acne
• Hirsutism
• Oligomenorrhea

Diagnosis

• Demonstrate Hypercortisolism
• Not suppressed by exogenous glucocorticoids

Diagnosis (Out-patient)

• 24hr Urinary Free Cortisol (repeat 2-3X):
  • This is a useful out-patient screening
  • Repeatedly normal values make diagnosis unlikely
  • Test unreliable if there is impaired renal function
• Overnight Dexamethasone Suppression Test:
  • DXM 1mg orally at 12 midnight
  • Serum cortisol at 9am
  • Suppression of Cortisol to <50mmol/l makes diagnosis unlikely
• If the 2 out-patient tests are normal, Cushing’s is unlikely

Diagnosis (In-patient)

• Midnight cortisol level:
  • Loss of normal circadian rhythm of cortisol secretion is seen in Cushing’s.
  • Admit patient for 48 hrs
  • Cortisol sample at 12 midnight (no warning, sleeping)
  • Repeat sample at 9am
  • Midnight cortisol <50 is normal; elevated in Cushing’s
• Late-night salivary cortisol can also be used at home.
• Low dose Dexamethasone Suppression Test:
  • DXM 0.5mg 6hrly for 48hrs
  • 8 doses from 9am, Day 0
  • Serum cortisol at 9am on Days 0 and 2
  • There should be suppression to <50mmol/l by Day 2 in normal people
• High-dose DXMST:
  • 2mg 6hrly for 2 days
  • >50% suppression suggestive of pituitary-dependent Cushing’s
• CRH stimulation test:
  • Exaggerated ACTH and Cortisol response suggestive of Pituitary-dependent Cushing’s
• Plasma ACTH level:
  • Low in non-ACTH dependent Cushing’s
• Adrenal CT/MRI
• Pituitary MRI

Treatment

• Medical:
  • Metyrapone
  • Ketoconazole
  • Aminoglutethimide
  • Trilostane
• Surgical:
  • Adrenalectomy
  • Removal of ACTH-secreting pituitary adenoma
• Radiotherapy

Primary hypoadrenalism (Adreno-cortical Insufficiency)

• Destruction of over 90% of the steroid-secreting cortex (Addison’s Disease)
• Leading to Glucocorticoid, mineralocorticoid, and adrenal androgen deficiency
• Elevated CRH and ACTH via negative feedback
• Rare
• Incidence is 3-4/million per year

Addison’s - Causes

• Autoimmune adrenalitis (organ-specific autoantibodies esp 21hydroxylase):
  • Commonest, 90% of cases
  • Sporadic
  • Polyglandular syndrome
• Infection:
  • Bacterial:
    • TB
    • Meningococcemia (Waterhouse-Friderichsen Syndrome)
  • Viral:
    • HIV/AIDS
    • CMV
• Inflammatory:
  • Sarcoidosis
• Infiltrative:
  • Metastatic carcinoma (malignant destruction)
  • Haemochromatosis
  • Amyloid infiltration
• Iatrogenic:
  • Bilateral adrenalectomy
  • Drugs:
    • Metyrapone
    • Ketoconazole

SECONDARY Adrenal Insufficiency

• Pituitary Lesions:
  • Tumor
  • Pituitary Infarction
  • Postpartum Necrosis (Sheehan’s syndrome)
  • Pituitary Apoplexy
  • Infiltrative Diseases:
    • Sarcoidosis, Granulomatosis
  • Following Hypophysectomy
  • Steroid withdrawal – due to suppression of HPA axis by exogenous steroids

Clinical Features

• Traceable to pan-adrenocortical insufficiency
• Often very vague or non-specific:
  • Weight loss
  • Weakness
  • Malaise
  • Anorexia
  • Reduced libido
  • Depression
• Postural hypotension
• Dehydration
• Hyperpigmentation (especially scars and palmar creases)
• Hyponatremia
• Hyperkalemia

Diagnosis

• Random cortisol:
  • Low
  • >550nmol/l makes diagnosis unlikely
• Short ACTH (Synacthen, Cosyntropin, Tetracosatride) Test:
  • IV/IM Cosyntropin 250mcg stat
  • Serum Cortisol at 30 minutes
  • Normal response: Cortisol >600nmol/l
  • Impaired or absent cortisol confirms Addison
• Plasma ACTH level at 9am:
  • High ACTH in the presence of Low Cortisol confirms primary adrenal insufficiency
• Long ACTH stimulation Test:
  • IM Cosyntropin 1mg stat
  • Serum cortisol at 0, 1, 2, 3, 4, 5, 8, 24 hours
  • Normal cortisol response suggests secondary (pituitary) diagnosis
  • Low or No response suggests primary diagnosis
• Electrolytes and urea:
  • Hyponatremia
  • Hyperkalemia
  • Elevated blood urea
• RBS:
  • Hypoglycemia
• Adrenal antibodies

Treatment

• Replacement Steroid Therapy
  • Glucocorticoids:
    • Prednisolone
    • Hydrocortisone
    • Dexamethasone
  • Mineralocorticoids:
    • Fludrocortisone
  • Adrenal androgens:
    • DHEA

Adrenal crisis

• Synonyms:
  • Addisonian crisis
  • Acute adrenal insufficiency
• Medical emergency
• Life-threatening
• Requires urgent management
• Acute cortisol deficiency may be due to:
  • Hemorrhage e.g. Waterhouse-Friderichsen syndrome
  • Trauma
  • Infection
  • Surgery
  • Sudden withdrawal of steroid medications
  • Stress
• Can happen in a patient with known Addison’s or new patient

Clinical features

• Sudden penetrating pain
• Fever
• Collapse
• Confusion
• Severe vomiting and diarrhea
• Dehydration
• Hypotension

Lab parameters

• Hyperkalemia
• Hypocalcemia
• Hypoglycemia
• Hyponatremia
• Hypothyroidism

Management

• Prevention better than cure
• IV Normal saline 1L fast, then
• IV Hydrocortisone 100mg stat
• Then 6hrly
• IV Dextrose infusion
• Oral Hydrocortisone as soon as stable

• Autosomal recessive hereditary disease
• Due to deficiency of various synthetic enzymes in the steroid biosynthetic pathway
• There are 6 major types
• 21-hydroxylase deficiency is the major type
• 1 in 15,000 births
• As a result of this enzyme deficiency:
• Cortisol and Aldosterone secretions are reduced
• ACTH is elevated by negative feedback
• Leading to adrenal hyperplasia
• Diversion of steroid precursors into androgenic pathway
• Increased 17-hydroxyprogesterone, Androstenedione, and Testosterone
• Leading to virilisation

Virilising Features

• Ambiguous genitalia
• Clitoral Hypertrophy
• Urogenital anomalies
• Labioscrotal fusion
• Precocious Puberty
• Hirsutism
• They also have adrenal insufficiency (salt-losing state)

Treatment

• Replacement steroid therapy
• Corrective surgery
• Genetic counselling
• Antenatal diagnosis
• Mother can take DXM daily to prevent virilisation