Adrenal insufficiency

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ayeesha Kattubadi, M.B.B.S[2]

Historical Perspective

In 1885, Thomas Addison first defined adrenal insufficiency as a disorder of impaired adrenocortical function leading to deficiency in glucocorticoids, mineralocorticoids, and adrenal androgens. Earlier, salt supplementation was used in the treatment of adrenal insufficiency. Hench, Kendall, and Reichstein were awarded the Nobel Prize in Physiology or Medicine in 1950 "for their discoveries relating to the hormones of the adrenal cortex, their structure and biological effects" which broadened the treatment options for adrenal insufficiency. The most common cause of primary adrenal insufficiency has been changing. In the 1920s, the most common cause of adrenal insufficiency was tuberculosis, since the 1950s it has been autoimmune polyglandular syndrome.

Classification

Adrenal insufficiency is classified based on the location of the pathology into  :

• Primary adrenal insufficiency
• Secondary adrenal insufficiency
• Tertiary adrenal insufficiency

In Primary adrenal insufficiency, the pathology lies in the adrenal glands leading to decreased production of cortisol and aldosterone.The most common cause of primary adrenal insufficiency is autoimmune adrenalitis. In secondary adrenal insufficiency, the pathology lies in the pituitary gland leading to reduced ACTH production, whereas in tertiary adrenal insufficiency the pathology lies in the hypothalamus leading to reduced CRH production. The most common cause of tertiary adrenal insufficiency is chronic glucocorticoid therapy. Secondary and tertiary adrenal insufficiency together are categorised into central adrenal insufficiency. The following table summaries the causes of adrenal insufficiency.

Causes of adrenal insufficiency
Primary adrenal insufficiency (Addison's disease)	Secondary adrenal insufficiency	Tertiary adrenal insufficiency
Autoimmune: Sporadic Autoimmune polyglandular syndrome type 1 (APS type 1) Autoimmune polyglandular syndrome type 2 (Schmidt's syndrome) Infections: Tuberculosis, Fungal infections, Cytomegalovirus, HIV Adrenal Metastasis Adrenal infiltration Adrenal hemorrhage: Waterhouse-Friderichsen syndrome, Drugs - Anticoagulants- Heparin, Warfarin) Adrenoleukodystrophy Congenital adrenal hypoplasia Bilateral adrenelectomy	Pituitary tumors Iatrogeneic: Pituitary surgery, Pituitary radiation Granulomatous diseases: Tuberculosis Sarcoidosis Histiocytosis Wegener's granulomatosis Metastasis Pituitary apoplexy Sheehan's syndrome (Peripartum pituitary necrosis) Genetic: Isolated ACTH deficiency, Multiple pituitary hormone deficiencies Trauma	Glucocorticoid therapy Cushing's syndrome (Excess endogenous glucocorticoid production) Drugs: Mifepristone Chlorpromazine Imipramine Hypothalamic tumors (Primary and metastatic) Iatrogenic: Hypothalamic surgery Hypothalamic radiation Granulomatous diseases: Tuberculosis Sarcoidosis Histiocytosis Wegener's granulomatosis Trauma

Pathophysiology

The pathogenesis of adrenal insufficiency varies based on the etiology as follows:

Autoimmune adrenalitis : Humoral as well as cell mediated immune mechanisms attack various enzymes involved in the synthesis of adrenal cortical enzymes. Strong genetic association has bene seen with HLA DR3/DQ2 and DR4/DQ8. On gross anatomy the adrenal gland is atrophied with preservation of adrenal medulla. Histopathology shows lymphocytic infiltration with fibrosis of the parenchyma. The patients are asymptomatic until up to 90% of the cortex is destroyed. Autoantibodies against 21-hydroxylase, an essential enzyme required in the biosynthesis of steroid hormones of the adrenal cortex are seen.

• Isolated autoimmune adrenalitis accounts for 30-40% cases.
• Autoimmune Polyglandular Syndrome (APS) account for 60-70%. Which is further subclassified as follows:

Autoimmune Polyglandular Syndrome Type 1 (APS type 1): Exhibits autosomal recessive mode of inheritance. It is also known as Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED). Caused due to mutations in the autoimmune regulator gene (AIRE). Apart from adrenal insufficiency it presents with chronic mucocutaneous candidiasis, hypoparathyroidism, total alopecia.

Autoimmune Polyglandular Syndrome Type 2 (APS type 2): It is more common than APS type 1 and has polygenic inheritance. Strong association has been shown with HLA DR3 of MHC. Apart from adrenal insufficiency it presents with autoimmune thyroiditis, vitiligo, premature ovarian failure, type 1 diabetes mellitus, pernicious anemia.

X linked Adrenoleukodystrophy(X-ALD)  : X-ALD occurs due to mutations in the peroxisomal ATP-binding cassette (ABC) transporter encoded by the ABCD1 gene. Disruption of this transport protein leads to the accumulation of Very Long Chain Fatty Acids (VLCFA). Male patients usually present in childhood or adolescence, whereas heterozygous females present between 40-50 years. The phenotypic expression is variable and can present as pre-symptomatic, cerebral inflammatory demyelination, myelopathy, adrenal insufficiency. The lifetime prevalence of adrenal insufficiency is 80% in males, with the highest risk being in the first decade. Adrenal insufficiency is extremely rare in females.

Chronic glucocorticoid use : Secondary or Tertiary adrenal insufficiency induced by chronic use of glucocorticoids is the most common cause of adrenal insufficiency. HPA axis suppression has been reported with oral, inhaled, topical, injectable, intraarticular, intradermal, paraspinal, or rectal glucocorticoid preparations. Exogenous glucocorticoid use causes feedback inhibition of the HPA axis leading to reduced synthesis of CRH and ACTH by hypothalamus and pituitary. As a consequence of reduced ACTH, the adrenal cortex slowly loses the ability to synthesise cortisol. The mineralocorticoid synthetic function of the adrenal cortex is retained as it depends on RAAS. HPA axis function recovers quickly if glucocorticoids were used for less than 10-14 days. If glucocorticoids were used for >2weeks, weaning and assessment of HPA integrity are recommended. In some cases the HPA axis may remain suppressed for as long as 6-12 months after glucocorticoid withdrawal.

The other causes of adrenal insufficiency are due to the destruction of the adrenal, pituitary or hypothalamus due to various causes as mentioned in the table above.

Differential diagnosis

Addison's disease differential diagnosis

Epidemiology

The most common cause of adrenal insufficiency is glucocorticoid-induced adrenal insufficiency. The most common cause of primary adrenal insufficiency varies based on geography. In the developed world, Tuberculosis was the most common cause, whereas, since the 1950s, the incidence of autoimmune adrenalitis is rising. The autoimmune polyglandular syndrome shows a female: male preponderance of 2:1, usually presenting in the age group of 30-50 years. In developing countries, Tuberculosis remains the most common cause.

Clinical Presentation

The presentation of adrenal insufficiency is non-specific and depends on the extent of loss of adrenal hormones. Common symptoms that are seen in Adrenal insufficiency :

• Fatigue and anorexia are the most common, seen in almost all cases. The fatigue worsens at night and with disease progression.
• Gastrointestinal symptoms include abdominal pain, nausea, vomiting, constipation, and diarrhea.
• Musculoskeletal symptoms include arthralgia, myalgia.

Signs and symptoms that are specific to primary adrenal insufficiency: Salt craving, postural dizziness, Hypotension, weight loss, vitiligo, auricular calcification, postural hypotension. Lab findings:

• Electrolytes: hyponatremia, hyperkalemia, hypercalcemia
• Hypoglycemia
• Azotemia
• Eosinophilia
• Anemia

Adrenal Crisis : About 50% of people with undiagnosed adrenal insufficiency present with adrenal crisis. It is also known as the Addisonian crisis. A life-threatening emergency arising due to an acute deficiency of adrenal cortisol. The mortality rate is 0.5/100 patients/year. It is often triggered by an acutely stressful event like infection, surgery, dehydration, etc. Presentation: Acute onset of Abdominal pain, nausea, vomiting, diarrhea, severe dehydration, dizziness, hypotension, shock, fever. Labs: Hyponatremia, hyperkalemia, hypercalcemia, eosinophilia, hypoglycemia.

Diagnosis

The diagnosis of adrenal insufficiency is a three-step process that can be performed simultaneously or in sequential order.

1. Prove the existence of adrenal insufficiency i.e. Syndromic Diagnosis.
2. Determine the nature of adrenal insufficiency i.e. Primary, Secondary, Tertiary Adrenal insufficiency by identifying the location of the defect in the HPA axis.
3. Determine the cause i.e. etiological diagnosis.

Tests used in syndromic diagnosis:

Serum basal cortisol: As cortisol secretion follows a circadian rhythm with a nadir around midnight and peak between 6-8 AM, serum basal cortisol measurement should be taken between 8 AM-9 AM. Serum cortisol level <5µg/dL confirms the presence of adrenal insufficiency. Total serum cortisol is composed of the protein-bound fraction (90%) and free cortisol (10%) which is the biologically active form. Corticosteroid-binding globulin (CBG) is the major transporter for cortisol. Conditions that alter CBG also alter the total serum cortisol, with no effect on free cortisol. Therefore caution has to be exercised while interpreting the levels of serum cortisol in conditions where CBG levels are altered.

Salivary cortisol levels: Salivary cortisol levels are measured at 8 am. Levels <0.18 µg/dL strongly predict adrenal insufficiency, whereas levels >0.58µg/L rule out adrenal insufficiency. The advantage of this test is that it is noninvasive so can be done by the patient at home and it only measures the free cortisol levels, so it’s not affected by changes in plasma proteins. The disadvantage is that it’s not a universally standardized test.

Urine free cortisol measurement: Low sensitivity and therefore not useful in diagnostic confirmation.

Dynamic tests: They are used in patients with indeterminate levels of basal plasma cortisol i.e. in between 5 µg/dL to 18 µg/dL. The different typed of dynamic tests are as follows –

Name of the test	Insulin Hypoglycemia test	ACTH stimulation test	Low dose ACTH stimukation test	Metyrapone stimulation	Glucagon stimulation
Agent to be administered	Regular insulin 0.1-1.15U/kg I.V	Cosyntropin 250mcg I.V	Consyntropin 1mcg I.V	Metyrapone 30mg/kg P.O	Glucagon 1mg I.M
Timing of sample collection	0-30-45-60-90 min	0-30-60 min	0-30-60 min	8 hours post metyrapone	90-120-150-180-210-240min
Parameter Tested	Plasma cortisol	Plasma cortisol	Plasma cortisol	11 deoxycortisol	Plasma cortisol
Comments	Gold standard	Safe	Manual preparation	Assesses whole HPA	Less accurate

Diagnostic algorithm:

Adrenal Insufficiency suspected

Serum basal cortisol

<5 µg/dL

5-18 µg/dL

>18 µg/dL

Confirms Adrenal Insufficiency

Dynamic tests

Rules out Adrenal Insufficiency

Primary Adrenal Insufficiency suspected

Secondary Adrenal Insufficiency suspected

ACTH stimulation test

ACTH stimulation test

Serum cortisol <18 µg/dL

Serum cortisol >18µg/dL

Serum cortisol <18 µg/dL

Serum cortisol 18-23µg/dL

Serum cortisol >23 µg/dL

Confirms Adrenal Insufficiency

Rules out Adrenal Insufficiency

Confirms Adrenal Insufficiency

Indeterminate

Rules out Adrenal Insufficiency

Insulin hypoglycemic test

Serum cortisol <18µg/dL

Serum cortisol >18µg/dL

Confirms Adrenal Insufficiency

Rules out Adrenal Insufficiency

Diagnosing the location of defect:

	Primary Adrenal Insufficiency	Secondary Adrenal Insufficiency
Clinical	Hyperpigmentation of skin and mucous membranes	No hyperpigmentation
Labs	Hyperkalemia, Hyponatremia	Hyponatremia
ACTH	Increased to two times upper limit of normal	Normal or decreased

Treatment

Treatment of adrenal insufficiency:

Management of adrenal insufficiency consists of glucocorticoid and mineralocorticoid replacement.

Glucocorticoid replacement therapy: Given in patients with a confirmed diagnosis of adrenal insufficiency.

Drug of choice	Hydrocortisone.
Dosage	15-25 mg is given in two or three divided doses.
Dosing frequency	Two divided doses – 2/3 of the total dose in the morning on awakening; 1/3 of the total dose in mid-afternoon Three divided doses (10mg at 7 AM, 5mg at 12 PM, and 2.5-5mg at 4:30 PM. Avoid dosing after 6 PM
Alternate drugs	Cortisone acetate 20-25mg, Prednisone (3-5mg/day); Use of dexamethasone is not recommended
Drug interactions	Drugs increasing glucocorticoid dose requirement: Anticonvulsants like Barbiturates, Topiramate, Anti-tubercular drugs, Estrogens, Tamoxifen Drugs decreasing glucocorticoid dose requirement: Licorice, Grapefruit juice, Colestipol
Monitoring	Monitoring is done based on clinical improvement. Symptoms that are suggestive of underdosing- Persistence or the incomplete resolution of fatigue, nausea, postural hypotension, myalgia. Symptoms that are suggestive of overdosing - weight gain, edema, abdominal striae. There is no role of measuring ACTH and serum cortisol levels.
Side effects	Weight gain, edema, increased appetite, weight gain, osteoporosis, dyslipidemia, increased cardiovascular risk.

Mineralocorticoid replacement therapy: Mineralocorticoids are given only in patients with primary adrenal insufficiency. A synthetic mineralocorticoid, 9 α-fludrocortisone is used in a dose of 0.05-0.2 mg/day in the morning. Dosage adjustments have to be made based on the clinical picture. Symptoms and signs of underdosing include hypovolemia, orthostatic hypotension, hyperkalemia, hyperuricemia, increased plasma renin activity. Symptoms and signs of overdosing include hypertension, hypokalemia, edema. If a patient on fludrocortisone develops hypertension, reduce the dose. If the blood pressure remains elevated, start an antihypertensive medication, and continue fludrocortisone.

The use of dehydroepiandrosterone (DHEA) is not routinely recommended. A six-month trial of DHEA can be considered in patients with significant impairment in quality of life, decreased libido, women, depressed mood despite glucocorticoid and mineralocorticoid therapy. If there is no improvement at the end of six months, its use has to be discontinued. DHEA is contraindicated in people with breast and prostate cancer.

Treatment of acute adrenal crisis: In patients suspected of having adrenal insufficiency, hydrocortisone 100mg IV/IM given immediately followed by a continuous infusion of 200mg in the next 24 hours. Alternately prednisolone can be used. Intravenous fluid replacement with 0.9% NS is also recommended to maintain blood pressure.