Secondary adrenal insufficiency

Adrenal insufficiency
Adrenal gland
ICD-10	E27.1-E27.4
ICD-9	255.4
MeSH	D000309

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Synonyms and keywords: hypocortisolism; hypocorticism; adrenocortical hypofunction

Overview

Adrenal insufficiency is a condition in which the adrenal glands, located above the kidneys, do not produce adequate amounts of steroid hormones (chemicals produced by the body that regulate organ function), primarily cortisol, but may also include impaired aldosterone production (a mineralocorticoid) which regulates sodium, potassium and water retention. Craving for salt or salty foods due to the urinary losses of sodium is common.

Adrenal insufficiency can also occur when the hypothalamus or the pituitary gland, both located at the base of the skull, does not make adequate amounts of the hormones that assist in regulating adrenal function. This is called secondary adrenal insufficiency and is caused by lack of production of ACTH in the pituitary or lack of CRH in the hypothalamus.

Classification

There are three major types of adrenal insufficiency.

• Primary adrenal insufficiency is due to impairment of the adrenal glands.
  • One subtype is called idiopathic or unknown cause of adrenal insufficiency.
  • 80% are due to an autoimmune disease called Addison's disease or autoimmune adrenalitis.
  • Other cases are due to congenital adrenal hyperplasia or an adenoma (tumor) of the adrenal gland.
• Secondary adrenal insufficiency is caused by impairment of the pituitary gland or hypothalamus. The most common cause in the United States is exogenous steroid use. Other causes are a pituitary adenoma or microadenoma, hypothalamic tumor (surgical removal of a pituitary tumor can also suppress production of ACTH and lead to adrenal deficiency); Sheehan's syndrome, which is associated with impairment of only the pituitary gland.
• Tertiary adrenal insufficiency is due to hypothalamic disease and decrease in corticotropin releasing factor (CRF).

Pathophysiology

• Primary adrenal insufficiency:

Here the defect lies in the adrenal glands. Autoantibodies, infections, drugs and mutations cause destruction of the adrenal glands leading to deficiency of adrenal hormones and thus causing symptoms.

• Secondary adrenal insufficiency:

ACTH deficiency caused by diseases of the pituitary gland is the main cause for adrenal insufficiency. ACTH deficiency leads to loss of stimulus for the production of adrenal hormones. ACTH levels in the blood can differentiate primary adrenal insufficiency from the secondary form. In the primary form the ACTH levels are high because of the loss of negative feedback from the adrenal hormones.

• Tertiary adrenal insufficiency:

The hypothalamus in the brain secretes a hormone called corticotropin releasing factor (CRF). This hormone provides the necessary stimulus to the pituitary for secreting ACTH which in turn activates the process of production of adrenal hormones. In diseases of the hypothalamus, the CRF is not produced leading to a decreased production of ACTH and in turn the adrenal hormones.

Causes

Common Causes

• Acute adrenal insufficiency
  • Addison's disease (autoimmune adrenalitis)
  • Septic shock
  • Waterhouse-Friderichsen syndrome
  • Addisonian crisis in case of:
    • Discontinuing corticosteroid therapy without tapering the dosage
    • Surgery, illness or any other form of stress in patients with long-term corticosteroid therapy
• Chronic adrenal insufficiency
  • Addison's disease
  • Congenital Adrenal Hyperplasia
  • Antiphospholipid syndrome
  • Haemochromatosis

Causes by Organ System

Cardiovascular	Arteritis, Hypotension, Hemorrhage, Infarction
Chemical / poisoning	No underlying causes
Dermatologic	POEMS syndrome
Drug Side Effect	Aminoglutethimide, Corticosteroid withdrawal, Trilostane
Ear Nose Throat	No underlying causes
Endocrine	Allgrove syndrome, Achalasia-addisonian syndrome, Adrenal aplasia / adrenal hypoplasia, Adrenal metastases, After surgery of cortisol-secreting tumor, Autoimmune polyendocrine syndrome type 2, Bilateral adrenalectomy , Congenital adrenal hyperplasia, Glucocorticoid deficiency 1, IMAGE syndrome, POEMS syndrome, X-linked adrenal hypoplasia congenita
Environmental	No underlying causes
Gastroenterologic	Allgrove syndrome, Achalasia-addisonian syndrome, Hemochromatosis
Genetic	Congenital adrenal hyperplasia, Cytochrome P450 oxidoreductase deficiency, Glycerol kinase deficiency, Hereditary ACTH resistance, IMAGE syndrome, X-linked adrenal hypoplasia congenita
Hematologic	Anticoagulation, Coagulopathy , Embolus, Leukemia, Lymphoma , Thrombosis
Iatrogenic	Iatrogenic, Radiation therapy
Infectious Disease	AIDS, Blastomycosis, CMV, Coccidiomycosis, Cryptococcosis, Histoplasmosis , Mycobacterium avium intracellulaire (MAI), Sepsis, Syphilis, Toxoplasmosis, Tuberculosis, Waterhouse-Friderichson syndrome
Musculoskeletal / Ortho	IMAGE syndrome
Neurologic	Adrenoleukodystrophy, Coma, Craniopharyngioma, Panhypopituitarism, POEMS syndrome
Nutritional / Metabolic	No underlying causes
Obstetric/Gynecologic	No underlying causes
Oncologic	Craniopharyngioma, Kaposi's sarcoma, Leukemia, Lymphoma
Opthalmologic	No underlying causes
Overdose / Toxicity	No underlying causes
Psychiatric	No underlying causes
Pulmonary	Sarcoidosis,
Renal / Electrolyte	Uremia, Waterhouse-Friderichson syndrome
Rheum / Immune / Allergy	Autoimmune, Autoimmune polyendocrine syndrome type 2, Sarcoidosis
Sexual	No underlying causes
Trauma	Trauma
Urologic	No underlying causes
Dental	No underlying causes
Miscellaneous	Amyloidosis, Idiopathic, Iatrogenic, Radiation therapy, Surgery, Surgical removal of pituitary, Surgical removal of hypothalamus

Causes in Alphabetical Order

Achalasia-addisonian syndrome Adrenal aplasia / Adrenal hypoplasia Adrenal metastases Adrenoleukodystrophy After surgery of cortisol-secreting tumor AIDS Allgrove syndrome Aminoglutethimide Amyloidosis Anticoagulation Arteritis Autoimmune Autoimmune polyendocrine syndrome type 2 Bilateral adrenalectomy Blastomycosis CMV Coagulopathy Coccidiomycosis Coma Congenital adrenal hyperplasia Corticosteroid withdrawal Craniopharyngioma Cryptococcosis Cytochrome P450 oxidoreductase deficiency Embolus Glucocorticoid deficiency 1 Glycerol kinase deficiency Hemochromatosis

Hemorrhage Hereditary ACTH resistance Histoplasmosis Hypotension Iatrogenic Idiopathic IMAGE syndrome Infarction Kaposi's sarcoma Leukemia Lymphoma Mycobacterium avium intracellulaire (MAI) Panhypopituitarism POEMS syndrome Radiation therapy Sarcoidosis Sepsis Surgery Surgical removal of hypothalamus Surgical removal of pituitary Syphilis Thrombosis Toxoplasmosis Trauma Trilostane Tuberculosis Uremia Waterhouse-Friderichson syndrome X-linked adrenal hypoplasia congenita

Risk Factors

The following conditions increase the risk of adrenal insufficiency:

• Genetic defects of adrenal gland
• Underactive parathyroid glands
• Pernicious anemia
• Chronic fungal infections
• Chronic active hepatitis
• Diabetes
• Vitiligo
• Tuberculosis
• Amyloidosis
• AIDS-associated infections
• Cancer

Diagnosis

Symptoms

There is often the slow insidious onset of the following symptoms (in alphabetical order):

• Dehydration
• Diarrhea
• Abdominal pain
• Disorientation
• Dizziness
• Muscle aches
• Nausea
• Tanning of the skin that may be patchy or even all over the body. Characteristic sites of tanning are skin creases (e.g. of the hands) and the inside of the cheek (buccal mucosa).
• Tiredness - fatigue
• Vomiting
• Weakness
• Weight loss

Physical Examination

Appearance

• The patient may be dehydrated and lethargic.

Vital Signs

• Low blood pressure that falls further when standing (orthostatic hypotension)
• Cardiovascular collapse may be present

Skin

• There can be tanning of the skin. Tanning of the skin that may be patchy or even all over the body. Characteristic sites of tanning are skin creases (e.g. of the hands) and the inside of the cheek (buccal mucosa).
• Vitiligo may also be present.
• Absence of axillary and pubic hair in females as a result of loss of adrenal androgens.
• Pallor may be present.

Neck

• Goitre may be present

Extremities

• Weakness

Neurologic

• Confusion may be present
• Seizures may be present.

Laboratory Findings

ACTH Stimulation Test

If the person is in adrenal crisis, the ACTH stimulation test may be given. If not in crisis, cortisol, ACTH, aldosterone, renin, potassium and sodium are tested from a blood sample before the decision is made if the ACTH stimulation test needs to be performed. X-rays or CT of the adrenals may also be done. The best test for adrenal insufficiency of autoimmune origin, representing more than ninety percent of all cases in a Western population, is measurement of 21-hydroxylase autoantibodies.

Source of pathology	CRH	ACTH	DHEA	DHEA-S	cortisol	aldosterone	renin	Na	K	Causes5
hypothalamus (tertiary)1	low	low	low	low	low3	low	low	low	low	tumor of the hypothalamus (adenoma), antibodies, environment (i.e. toxins), head injury
pituitary (secondary)	high2	low	low	low	low3	low	low	low	low	tumor of the pituitary (adenoma), antibodies, environment, head injury, surgical removal6, Sheehan's syndrome
adrenal glands (primary)7	high	high	high	high	low4	low	high	low	high	tumor of the adrenal (adenoma), stress, antibodies, environment, Addison's Disease, trauma, surgical removal (resection), miliary tuberculosis of the adrenal

1	Automatically includes diagnosis of secondary (hypopituitarism)
2	Only if CRH production in the hypothalamus is intact
3	Value doubles or more in stimulation
4	Value less than doubles in stimulation
5	Most common, does not include all possible causes
6	Usually because of very large tumor (macroadenoma)
7	Includes Addison's disease

Routine Investigations

• Complete blood count and differential count - Eosinophilia and lymphocytosis (increased number of eosinophils or lymphocytes, two types of white blood cells). Normocytic anemia may be present.
• Hypoglycemia, low blood sugar (worse in children)
• Serum electrolytes:
  • Hyponatraemia (low blood sodium levels)
  • Hyperkalemia (raised blood potassium levels), due to loss of production of the hormone aldosterone
  • Mild hypercalcemia - in 20% patients
  • Mild non–anion-gap metabolic acidosis
• Serum cortisol - decreased (<25mcg/dL)
• Urine and sweat sodium - elevated
• Elevated BUN and creatinine - when hypovolemia is the cause.
• Prolactin - mild elevation may be present.

Treatment

• Adrenal crisis

  • Intravenous fluids
  • Intravenous steroid (Solu-Cortef/injectable hydrocortisone) later hydrocortisone, prednisone or methylpredisolone tablets
  • Rest

• Cortisol deficiency (primary and secondary)

  • Hydrocortisone (Cortef)
  • Prednisone (Deltasone)
  • Prednisolone (Delta-Cortef)
  • Methylprednisolone (Medrol)
  • Dexamethasone (Decadron)

• Mineralocorticoid deficiency (low aldosterone)

  • Fludrocortisone Acetate

(To balance sodium, potassium and increase water retention)

Prevention

Acute adrenal insufficiency is fatal. When patients with adrenal insufficiency experience the following stress, they must be very careful.

• Surgery: People who are not currently taking glucocorticoids but who have taken long-term glucocorticoids in the past year, and people with chronic adrenal insufficiency should tell their doctor before surgery. These patients must be treated with intravenous glucocorticoids and saline before surgery and continues until the patient is fully awake after surgery and able to take medication by mouth.
• Illness: Patients with adrenal insufficiency should know the essentiality of increasing medication during such periods of stress. During illness, oral dosing of glucocorticoid needs to be adjusted to mimic the normal response of the adrenal glands on the body. When significant fever or injury happen, the patients may require triple oral dosing. Once recovery from the stress event, doses can be returned to maintenance levels. Be careful, when the conditions of severe infections, vomiting, or diarrhea occur, these signs suggest the possibility of addisonian crisis.
• Pregnancy: If nausea and vomiting in early pregnant woman with adrenal insufficiency interfere with taking medication by mouth, injections of the hormone may be necessary. During delivery, treatment is similar to that of people needing surgery.

See also

• Addison disease, primary adrenocortical insufficiency
• ACTH stimulation test
• Cushing's syndrome, overproduction of cortisol
• Insulin tolerance test, another test used to identify sub-types of adrenal insufficiency
• Adrenal fatigue (hypoadrenia), a term used in alternative medicine to describe a believed exhaustion of the adrenal glands

References

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