Adrenal insufficiency

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ayeesha Kattubadi, M.B.B.S[2] Muhammad Saad, M.B.B.S.[3]

Adrenal insufficiency is a clinical state where there is reduced production of adrenocortical hormones. The adrenal cortex is divided into three zones- zona glomerulosa, zona fasciculata and zona reticularis producing mineralocorticoids, glucocorticoids and androgens respectively. Adrenal insufficiency causes glucocorticoid and mineralocorticoid deficiency. It is classified as primary, secondary and glucocorticoid induced adrenal insufficiency. Its presentation depends on the rapidity and degree of hormone depletion. It can present acutely as adrenal crisis, especially when the body is under stress due infections, trauma etc. If it presents chronically it is called Addisons disease. Treatment consists of lifelong glucocorticoid and mineralocorticoid replacement.

Adrenal insufficiency was first discovered by Thomas Addison in 1849. ^[1]

Adrenal insufficiency may be classified according to location of pathology into three subtypes primary adrenal insufficiency, secondary adrenal insufficiency, and glucocorticoid induced adrenal insufficiency. ^[2]

It is thought that adrenal insufficiency is the result of multiple etiologies like autoimmune adrenalitis, X-linked adrenoleukodystrophy, chronic glucocorticoid use, adrenal hemoorage etc. The pathophysiology depends on each etiological subtype. ^{[3] [4][5] [6][7] [8]}

Common causes of adrenal insufficiency include autoimmune adrenalitis and chronic glucocorticoid use. ^{[2] [9]}

Addison’s disease must be differentiated from other diseases that cause hypotension, skin pigmentation, and abdominal pain such as myopathies, celiac disease, Peutz-Jeghers syndrome, anorexia nervosa, syndrome of inappropriate antidiuretic hormone (SIADH), neurofibromatosis, porphyria cutanea tarda, salt-depletion nephritis and bronchogenic carcinoma.

Adrenal insufficiency is a rare disorder. It may present in patients of all age groups. The incidence of autoimmune adrenalitis is more common in females in the age groups of 30 to 50 compared to males. Whereas, adrenal crisis does not show any female to male predilection. The most common cause of primary adrenal insufficiency in the developed world is autoimmune adrenalitis. Whereas, in the developing world it is Tuberculosis. The most common cause of central adrenal insufficiency is chronic glucocorticoid use. ^{[10] [11]}

Common risk factors in the development of adrenal insufficiency include chronic glucocorticoid use, tuberculosis, anticoagulant use, etc. ^[12].

There is insufficient evidence to recommend routine screening for adrenal insufficiency. ^[13]

Common complications of adrenal insufficiency include cardiovascular complications, disturbed sleep, reduced bone mineral density. Prognosis is generally excellent with replacement therapy. ^[14][4]

The ACTH stimulation test is considered the diagnostic test of choice.

The hallmark of adrenal insufficiency is fatigue. Most patients with adrenal insufficiency present with non specific symptoms. A positive history of fatigue,nausea and abdominal pain is suggestive of adrenal insufficiency. The most common symptoms of adrenal insufficiency include fatigue, anorexia, and weight loss. Common symptoms of adrenal insufficiency include abdominal pain, nausea, and vomiting. Less common symptoms of adrenal insufficiency include diarrhea, arthralgia, and myalgia. ^[15][13]

Patients with adrenal insufficiency usually appear dehydrated and weak. Physical examination of patients with primary adrenal insufficiency is usually remarkable for hyperpigmentation of skin. ^[15][16]

Laboratory findings consistent with the diagnosis of primary adrenal insufficiency include hyponatremia, hyperkalemia, and hypercalcemia, normocytic normochromic anemia, eosinophilia.^[13]

ECG findings seen in adrenal insufficiency are due to hyperkalemia. These changes include peaked T waves, short QT interval, prolonged PR interval, loss of P wave, widened QRS complex. ^[17]

X-ray may be helpful in the diagnosis of etiology of adrenal insufficiency, which include tuberculosis, sarcoidosis. ^[2]

There are no echocardiography findings associated with adrenal insufficiency. However, an echocardiography may be helpful in the diagnosis of cardiovascular complications of adrenal insufficiency, which include ischemic heart disease, heart failure, and dilated cardiomyopathy. ^[18]

CT scan may be helpful in the diagnosis of etiology of adrenal insufficiency, which include adrenal hemorrhage, tuberculous adrenalitis, and adrenal metastasis.^[2]

A pituitary MRI may be helpful in the diagnosis of secondary adrenal insufficiency^[2].

Pharmacologic medical therapy is recommended among patients with adrenal insufficiency Pharmacologic medical therapies for adrenal insufficiency include lifelong glucocorticoid and mineralocorticoid replacement therapy. Mineralocorticoid replacement therapy is only used in patients with primary adrenal insufficiency. ^{[9] [19][20]}

Surgical intervention is not recommended for the management of adrenal insufficiency. ^[21]

There are no established measures for the primary prevention of adrenal insufficiency. ^[22]

There are no established measures for the secondary prevention of 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]

Adrenal insufficiency was first discovered by Thomas Addison in 1849.

• Adrenal insufficiency was first discovered by Thomas Addison, a British physician and scientist, on 15 March, 1849. ^[1]

In 1950 Kendall, Richestein, Hench received Nobel Prize in Physiology and Medicine for their discovery of hormones of the adrenal cortex, their structure and biological effects. Following this steroids were used in the treatment of adrenal insufficiency. ^[2]

The following are a few famous cases of adrenal insufficiency:

• John F Kennedy ^[3]
• Jane Austen ^[4]

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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] Muhammad Saad, M.B.B.S.[3]

Adrenal insufficiency may be classified according to location of pathology into three subtypes primary adrenal insufficiency, secondary adrenal insufficiency, and glucocorticoid-induced adrenal insufficiency.^[1]

Adrenal Insufficiency may be classified according to location of pathology into three subtypes:

• Primary adrenal insufficiency
• Secondary adrenal insufficiency
• Glucocorticoid-induced adrenal insufficiency

In Primary adrenal insufficiency, the primary pathology lies in the adrenal glands leading to decreased production of cortisol, aldosterone and androgens. Although, the androgen deficiency manifests only in females as the adrenal gland is the only source of androgens in females.

In Secondary adrenal insufficiency the pathology lies in the pituitary gland leading to reduced production of ACTH which is characterized by decreased cortisol and androgens production with preserved aldosterone secretion.^[2]

Sometimes also known as tertiary adrenal insufficiency, glucocorticoid-induced adrenal insufficiency results from suppression of hypothalamic-pituitary-adrenal axis and is characterized by decreased production of cortisol and androgens with preserved aldosterone secretion.^[1] It is the most common type of adrenal insufficiency .^[3]Glucocorticoid induced adrenal insufficiency is the preferred term for adrenal insufficiency resulting from glucocorticoid use.^[3]

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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]

It is thought that adrenal insufficiency is the result of multiple etiologies like autoimmune adrenalitis, X-linked adrenoleukodystrophy, chronic glucocorticoid use, adrenal hemoorage etc. The pathophysiology depends on each etiological subtype.

Adrenal insufficiency arises due to the deficiency of adrenocortical hormones.The normal physiology of adrenocortical hormone production can be understood as follows:The adrenal cortex is divided into three zones from outside to inside as – Zona glomerulosa, zona fasciculata and zona reticularis which are responsible for the production of streroid hormones like mineralocorticoid, glucocorticoid and androgens respectively. ^[1] Hypothalamus produces corticotropin-releasing hormone(CRH) which induces the pituitary to secrete ACTH also known as corticotropin. ACTH then stimulates the adrenal glands to produce mineralocorticoids and glucocorticoids.

The pathophysiology of adrenal insufficiency depends on the etiological subtype.

Autoimmune adrenalitis: Both humoral and cell-mediated immune mechanisms attack enzymes involved in adrenocortical hormone synthesis. Autoantibodies against 21-hydroxylase, an enzyme required in the biosynthesis of adrenocortical hormones can be found. The patients remain asymptomatic until 90% of the cortex is destroyed. It can present as isolated autoimmune adrenalitis in 30-40% of cases or as an autoimmune polyglandular syndrome in 60-70% of cases. The autoimmune polyglandular syndrome is subclassified as autoimmune polyglandular syndrome type 1(APS type 1) and autoimmune polyglandular syndrome type 2 (APS type 2) ^{[2] [3]}

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 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. ^{[4] [5]}

Chronic glucocorticoid use: Chronic use of glucocorticoids can cause secondary or tertiary adrenal insufficiency and is the most common cause of adrenal insufficiency. Exogenous glucocorticoid use causes feedback inhibition of the HPA axis leading to reduced synthesis of CRH and ACTH by the hypothalamus and pituitary. As a consequence of reduced ACTH, the adrenal cortex slowly loses the ability to synthesize cortisol. The mineralocorticoid synthetic function of the adrenal cortex is retained as it depends on RAAS. HPA axis is usually suppressed when glucocorticoids were used for >2weeks. In some cases, the HPA axis may remain suppressed for as long as 6-12 months after glucocorticoid withdrawal. HPA axis can be suppressed with oral, inhaled, topical, injectable, intraarticular, intradermal, paraspinal, or rectal glucocorticoid preparations. ^{[6] [7]}

Autoimmune adrenalitis: Genes involved in the pathogenesis of autoimmune adrenalitis include HLA DR3/DQ2 and DR4/DQ8.

• The autoimmune polyglandular syndrome type 1 is transmitted in an autosomal recessive pattern. Gene involved in the pathogenesis is the autoimmune regulator gene (AIRE).
• The autoimmune polyglandular syndrome type 2 shows a polygenic inheritance. A strong association has been shown with HLA DR3 of MHC.

X-linked adrenoleukodystrophy: Genes involved in the pathogenesis of X-ALD include the ABCD1 gene which causes an alteration in peroxisomal ATP-binding cassette (ABC) transporter.

Autoimmune adrenalitis:

• Autoimmune polyglandular syndrome type 1 is also known as Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED). It is associated with chronic mucocutaneous candidiasis, hyperparathyroidism, total alopecia.

• Autoimmune polyglandular syndrome type 2 is associated with autoimmune thyroiditis, vitiligo, premature ovarian failure, type 1 diabetes mellitus, pernicious anemia.

X-linked Adrenoleukodystrophy: Apart from presenting as adrenal insufficiency it is also associated with cerebral inflammatory demyelination, myelopathy.

On gross pathology, the adrenal gland is atrophied in autoimmune adrenalitis. Autopsy findings show a decrease in the size and weight of the gland. In addition there may be hyperpigmentation of the gland. ^[8]

On microscopic histopathological analysis, infiltration of the adrenal cortex with chronic inflammatory cells like lymphocytes is a characteristic finding in autoimmune adrenalitis. The adrenal cortex can be atrophied with the preservation of the medulla. ^[8]

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

Addison’s disease differential diagnosis

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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] Muhammad Saad, M.B.B.S.[3]

Adrenal insufficiency is a rare disorder. It may present in patients of all age groups. The incidence of autoimmune adrenalitis is more common in females in the age groups of 30 to 50 compared to males. Whereas, adrenal crisis does not show any female to male predilection. The most common cause of primary adrenal insufficiency in the developed world is autoimmune adrenalitis. Whereas, in the developing world it is Tuberculosis. The most common cause of central adrenal insufficiency is chronic glucocorticoid use.

• The incidence of adrenal insufficiency is approximately 0.8 new cases per 100,000 individuals per year individuals in the developed world. ^[1]
• The incidence of adrenal insufficiency in Europe is approximately 4.4 to 6.2 new cases per 100,000 individuals per year .^[2]

• The prevalence of primary adrenal insufficiency is approximately 117 to 221 cases per 1 million in European populations.^{[3] [4] [5] [6]}
• The prevalence of secondary adrenal insufficiency is rare, ranging from 140 to 279 per 1 million individuals .^{[7] [8] [9]}

• The mortality rate of adrenal crisis is approximately 0.5/100 patients/year. ^[10]

• Patients of all age groups may develop adrenal insufficiency.
• Primary adrenal insufficiency commonly affects individuals between 20 to 50 years of age.^[11]
• Secondary adrenal insufficiency commonly affects individuals in the 60s. ^[12]
• The incidence of adrenal crisis increase with age greater than 60 years. ^[13]

• There is no racial predilection to adrenal insufficiency. ^[14]

• Females are more commonly affected by adrenal insufficiency than males. The female to male ratio is approximately 2 to 1 for primary adrenal insufficiency. ^[15]
• Acute adrenal crisis affects males and females equally. ^[16]

• The highest incidence of adrenal insufficiency has been reported in Iceland.^[17]

Worldwide, the most common cause of primary adrenal insufficiency was Tuberculosis. However, since the 1950s the incidence of autoimmune adrenalitis has been rising. Now, the most common cause of primary adrenal insufficiency in the developed world is autoimmune adrenalitis. ^[18]

The most common cause of primary adrenal insufficiency in the developing world is Tuberculosis. ^[19]

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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]

Common risk factors in the development of adrenal insufficiency include chronic glucocorticoid use, tuberculosis, anticoagulant use, etc.

Common risk factors in the development of chronic adrenal insufficiency include patients on chronic glucocorticoids , anticoagulants, tuberculosis, adrenal gland surgery, presence of other autoimmune conditions like Type 1 diabetes mellitus.

Following is the table showing the risk factors associated with increased risk of developing acute adrenal crisis ^[1].

Risk factors associated with increased risk of adrenal crisis
History	Drugs	Medical conditions
Prior history of [[adrenal crisis]] Known case of adrenal insufficiency	Suppression of HPA axis by exogenous steroids Increased risk of adrenal hemorrhage by anticoagulants Increased cortisol metabolism by Levothyroxine, Phenytoin, Phenobarbitol Decreased production of cortisol by Ketoconazole, Etomidate	Thyrotoxicosis Diabetes insipidus Diabetes mellitus Pregnancy

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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] Muhammad Saad, M.B.B.S.[3]

There is insufficient evidence to recommend routine screening for adrenal insufficiency. Newborn screening for congenital adrenal hyperplasia is recommended.

There is insufficient evidence to recommend routine screening for adrenal insufficiency. ^[1]The most common causes of primary adrenal insufficiency are autoimmune adrenalitis and congenital adrenal hyperplasia due to 21-Hydroxylase deficiency. Screening is recommended in childern suspected of developing congenital adrenal hyperplasia.^[2]

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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] Muhammad Saad, M.B.B.S.[3]

Common complications of adrenal insufficiency include cardiovascular complications, disturbed sleep, reduced bone mineral density. Prognosis is generally excellent with replacement therapy.

• The symptoms of adrenal insufficiency usually develop in the third to fifth decade of life, and start with symptoms such as fatigue, anorexia, weight loss, nausea, abdominal pain.
• If left untreated, chronic adrenal insufficiency in the presence of precipitating factors can develop adrenal crisis presenting with acute hemodynamic compromise. ^[1]
• Up to half of patients with primary adrenal insufficiency may experience adrenal crisis prior to diagnosis. ^[2]

• Common complications of adrenal insufficiency include: ^[3]
  • Increased risk of cardiovascular complications.
  • Sleep disturbance due to disruption of circadian rhythm.
  • Decreased bone mineral density as a consequence of glucocorticoid therapy.
  • Fertility and pregnancy complications: Reduced fertility, increased risk of fetal growth restriction, preterm birth, cesarean delivery

• Prognosis is generally excellent with replacement therapy and patients are able to work, travel and participate in sports^{[4] [5]}.
• Depending on the age of the diagnosis of adrenal insufficiency the prognosis may vary. If the patient is diagnosed before the age of 40, there is increased mortality.
• Mortality is increased in patients presenting with acute adrenal crisis, infection, or associated with type 1 diabetes mellitus ^[6].
• Patients with glucocorticoid-induced adrenal insufficiency may recover hypothalamic-pituitary-adrenal axis function over months to years after discontinuation of glucocorticoids ^[2].

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