Adrenal insufficiency

Summary
Adrenal insufficiency is the decreased production of
adrenocortical hormones (glucocorticoids, mineralocorticoids, and adrenal androgens) and
can be primary, secondary, or tertiary. Primary adrenal insufficiency (Addison disease) is
caused by a disorder of the adrenal glands. The most frequent cause of primary adrenal
insufficiency in the US by far is autoimmune adrenalitis, which may occur sporadically or as
a manifestation of polyglandular autoimmune syndromes. Secondary adrenal
insufficiency is the result of decreased production of ACTH (adrenocorticotropic hormone)
and tertiary adrenal insufficiency is the result of decreased production
of CRH (corticotropin-releasing hormone) by the hypothalamus. Decreased levels
of ACTH or CRH are seen following sudden cessation of a
prolonged glucocorticoid therapy or in pituitary/hypothalamic diseases. Patients with long-
standing adrenal insufficiency can present with postural hypotension, nausea, vomiting,
weight loss, anorexia, lethargy, depression, and/or chronic hyponatremia. Patients can also
present with loss of libido as a result of hypoandrogenism. Patients with primary adrenal
insufficiency also tend to develop hyperpigmentation of the skin, mild hyperkalemia,
and metabolic acidosis. Serum cortisol levels that remain low even after the administration
of exogenous ACTH (ACTH stimulation test) confirm the diagnosis
of adrenal insufficiency. Glucocorticoid replacement therapy with hydrocortisone is
required for all forms of adrenal insufficiency. The dose of glucocorticoids should be
increased during periods of stress (e.g., surgery, trauma, infections) in order to
prevent adrenal crisis, which is a severe, acute type of adrenal insufficiency that manifests
with shock, fever, impaired consciousness, and severe abdominal pain. Adrenal crisis is life-
threatening and should be treated immediately with high doses
of hydrocortisone and intravenous fluids.

Etiology
Primary adrenal insufficiency (Addison disease)
Primary adrenal insufficiency is caused by conditions that directly impair adrenal function.

 Autoimmune adrenalitis
o Most common cause in the US

o Associated with other autoimmune endocrinopathies (see autoimmune

polyglandular syndromes)

 Infectious adrenalitis
o Tuberculosis: most common cause worldwide, but rare in the US
 o CMV disease in immunosuppressed states (especially AIDS)

o Histoplasmosis

 Adrenal hemorrhage  [1][2]

o Waterhouse-Friderichsen syndrome

 Infiltration of the adrenal glands

o Tumors

o Amyloidosis

o Hemochromatosis

 Adrenalectomy

 Impaired activity of enzymes that are responsible for cortisol synthesis

o Cortisol synthesis inhibitors

o 21β-hydroxylase deficiency (see congenital adrenal hyperplasia)

Secondary adrenal insufficiency

caused by conditions that decrease ACTH production

 Sudden discontinuation of chronic glucocorticoid therapy or stress (e.g.,

infection, trauma, surgery) during prolonged glucocorticoid therapy
o Prolonged iatrogenic suppression of the hypothalamic-pituitary-adrenal
axis
o Impaired endogenous cortisol production in addition to discontinuation
of steroid treatment, decrease in dosage, or increase in requirement (e.g.,
stress) → acute glucocorticoid deficiency

 Hypopituitarism

Tertiary adrenal insufficiency

caused by conditions that decrease CRH production.

 The most common cause is sudden discontinuation of chronic glucocorticoid

therapy

 Rarer causes include hypothalamic dysfunction (e.g., due to trauma, mass,

hemorrhage, or anorexia): ↓ CRH → ↓ ACTH → ↓ cortisol release

Secondary and tertiary adrenal insufficiency are far more common than primary adrenal

insufficiency!

Pathophysiology
  Primary adrenal insufficiency (Addison disease)
o Damage to the adrenal gland → hypoandrogenism (most common in
female patients) , hypoaldosteronism, and hypocortisolism → ↑ ACTH  [7]

 ↑ Production of POMC (in order to ↑ ACTH production)

→ ↑ melanocyte-stimulating hormone (MSH) and hyperpigmentation of the
skin (bronze skin)

 Secondary adrenal insufficiency

o ↓ ACTH → hypoandrogenism and hypocortisolism

o Aldosterone synthesis is not affected (mineralocorticoid production is

controlled by RAAS and angiotensin II, not by ACTH).

 Tertiary adrenal insufficiency

o hypoandrogenism and hypocortisolism

o Aldosterone synthesis is not affected.

Clinical features
Hormonal Clinical features Laborato Primar Second Tertiar
changes ry y ary y
findings adrenal adrenal adrenal
insuffic insuffic insuffic
iency iency iency

Hypoaldost  Hypotension  H ✓  A  A
eronism yponat bsent bsent
remia
 H
yperka
lemia
 N
ormal
anion
gap me
tabolic
acidosi
s
 Hormonal Clinical features Laborato Primar Second Tertiar
changes ry y ary y
findings adrenal adrenal adrenal
insuffic insuffic insuffic
iency iency iency

Hypocortis  Weight  H ✓ ✓ ✓
olism loss, anorexia ypogly
cemia
 Fatigue, lethargy,
depression  H
yponat
 Muscle aches
remia
 Gastrointestinal
complaints (e.g., nause
a, vomiting, diarrhea)
 Sugar/salt cravings
 (Orthostatic) hyp
otension

Hypoandro  Loss of libido  ↓  ✓ ✓ ✓

genism DHEA-
 Loss of axillary
S
and pubic hair

Elevated A  Hyperpigmentatio  ↑  ✓  A  A
CTH n of areas that are not MSH bsent bsent
normally exposed to
sunlight
(e.g., palmar creases,
mucous membrane of
the oral cavity)

Most cases of adrenal insufficiency are subclinical and only become apparent during
periods of stress (e.g., surgery, trauma, infections), when the cortisol requirement is higher!

Primary adrenal insufficiency Pigments the skin. Secondary adrenal insufficiency Spares the

skin. Tertiary adrenal insufficiency is due to Treatment (cortisol).

Diagnostics
Diagnosis of adrenal insufficiency
General laboratory findings

 Serum electrolytes
o Hyponatremia

o Hyperkalemia
 o Normal anion gap metabolic acidosis

 Hypoglycemia

Diagnosis of hypocortisolism

 Best initial test

o Morning serum cortisol levels: < 3 μg/dL (< 80 nmol/L)
without exogenous glucocorticoid administration
confirms adrenal insufficiency.
o OR morning serum ACTH levels (often not quickly available)

 ↑ ACTH in primary adrenal insufficiency

 ↓ ACTH in secondary/tertiary adrenal insufficiency

 Confirmatory test
o ACTH stimulation test (cosyntropin test): measurement of
serum cortisol before and 30 minutes after administration
of exogenous ACTH (e.g., cosyntropin)

 Physiological response: exogenous ACTH → ↑ cortisol (failure
of cortisol to rise > 20 μg/dL after ACTH administration confirms primary
adrenal insufficiency)

Diagnosis of hypoaldosteronism

 ↑ Plasma renin concentration

Diagnosis of adrenal hypoandrogenism

 ↓ DHEA-S

Identifying the underlying cause of adrenal insufficiency

 Serum ACTH levels
o ACTH stimulation test: used to distinguish between primary and
secondary/tertiary adrenal insufficiency

 ↑ ACTH → primary adrenal insufficiency

 ↓ ACTH → secondary or tertiary adrenal insufficiency
o CRH stimulation test: used to distinguish between secondary and tertiary
adrenal insufficiency  [9]

 ↓ ACTH → secondary adrenal insufficiency

Treatment
Primary adrenal insufficiency
 Requires both glucocorticoid and mineralocorticoid replacement
 o Glucocorticoid replacement

 Hydrocortisone

 Increase glucocorticoid dose during stressful situations

o Mineralocorticoid replacement

 Fludrocortisone

Secondary and tertiary adrenal insufficiency

 glucocorticoid replacement; hydrocortisone

Glucocorticoid replacement therapy with hydrocortisone is required in all forms

of adrenal insufficiency!

If the dose of glucocorticoids is not increased during periods of stress, the patient may
develop an adrenal crisis!

Adrenal crisis (Addisonian crisis)

 Causes
o Stress (e.g., infection, trauma, surgery) in a patient with
underlying adrenal insufficiency
o Sudden discontinuation of glucocorticoids after
prolonged glucocorticoid therapy

 Clinical features
o Hypotension, shock

o Impaired consciousness

o Fever

o Vomiting, diarrhea

o Severe abdominal pain (which resembles peritonitis)

o Hypoglycemia, hyponatremia, hyperkalemia, and metabolic acidosis

 Therapy
o Administration of high doses of hydrocortisone: 100 mg IV every 8 hours

 Alternatively: dexamethasone
o Fluid resuscitation; hypotension; hyponatremia

o Correct hypoglycemia with 50% dextrose

o Intensive care monitoring

In order to avoid the development of secondary and tertiary adrenal insufficiency,

prolonged steroid therapy must be tapered slowly and should never be stopped abruptly.
The 5 S’s of adrenal crisis treatment are: Salt: 0.9% saline, Sugar: 50%
dextrose, Steroids: 100 mg hydrocortisone IV every 8 hours, Support: normal saline to
correct hypotension and electrolyte abnormalities, Search for underlying disorder

Adrenal crisis can be life-threatening. Therefore, treatment with high doses

of hydrocortisone should be started immediately without waiting for diagnostic
confirmation of hypocortisolism!

Autoimmune polyglandular syndromes

 Definition: a set of conditions characterized by autoimmune disease that causes
multiple endocrine deficiencies, which affect the hormone-producing (endocrine)
glands

 Types
o Type 2 (APS-2, Schmidt syndrome): defined by the occurrence of primary
adrenal insufficiency with thyroid autoimmune disease and/or type 1
diabetes mellitus  [16]

 Main manifestation: primary adrenal insufficiency

 Associated endocrine deficiencies (one or more of the

following may be present)

 Most commonly

 Thyroid autoimmune disease (e.g., Hashimoto

thyroiditis)

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