Addison's disease

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

Addison disease develops as a result of bilateral adrenal cortex destruction or dysfunction leading to reduced cortisol and aldosterone production. Autoimmune destruction of the adrenal glands is the most common cause in the western world, but hemorrhage, adrenal vein thrombosis, carcinoma and infections such as tuberculosis are also known significant causes. Tuberculosis remains the most common cause worldwide of Addison disease. The onset of Addison disease is often gradual, and symptoms of the disease can be difficult to recognize. It may go undetected until an illness or other stress precipitates adrenal crisis. Treatment should not be withheld to confirm the diagnosis. Treatment should be the priority, as the disease is fatal if it remains untreated. Diagnosis is made with rapid, high-dose adrenocorticotropic hormone (ACTH) stimulation testing. If the patient is hypovolemic, dexamethasone and intravenous normal saline should be given before stimulation testing is performed. The mainstay of therapy is a combination of glucocorticoids and mineralocorticoids. Glucocorticoid doses need to be doubled when patients have an episode of minor fever, infection, minor trauma, or minor physical stress. Intravenous stress-dose corticosteroids are needed for surgery involving general anesthesia and for major trauma.

Addison’s disease is named after Dr. Thomas Addison, a British physician who first described the condition in his paper “On the Constitutional and Local Effects of Disease of the Suprarenal Capsules” in 1855.

Adrenal insufficiency disorders may be classified into two categories depending upon the duration of symptoms into acute or chronic forms, and based on etiology into primary or secondary adrenal insufficiency.

The hypothalamus releases corticotropin-releasing hormone (CRH), which stimulates the pituitary gland to release corticotropin (ACTH). ACTH travels via the blood to the adrenal gland, where it stimulates the release of cortisol. Cortisol is secreted by the cortex of the adrenal gland from a region called the zona fasciculata in response to ACTH. Elevated levels of cortisol exert negative feedback on the pituitary, which decreases the amount of ACTH released from the pituitary gland. When the adrenal glands do not produce enough cortisol and aldosterone, it results in Addison’s disease.

Common causes of Addison’s disease include autoimmune, tuberculosis, AIDS, CMV, hemorrhage, infarction, sarcoidosis and infections.

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.

The prevalence of Addison’s disease in the human population is estimated to be roughly 4-12 persons per 100,000 persons. The incidence of Addison’s disease is approximately 0.6 per 100,000 individuals worldwide. Addison’s disease can affect any age range. Addison’s disease occurs more frequently in females, with a ratio of 12.3 to 1.

Common risk factors in the development of Addison’s disease include other autoimmune diseases such as chronic thyroiditis, dermatitis herpetiformis, grave’s disease, hypoparathyroidism, hypopituitarism, myasthenia gravis, pernicious anemia, testicular dysfunction, type I diabetes and vitiligo.

According to American Endocrine Society clinical guidelines, there is insufficient evidence to recommend routine screening for Addison’s disease.

If left untreated, Addison’s disease can be life-threatening. Complications of Addison’s disease include hypoglycemia, addisonian crisis, hypoxia, hypovolemic shock, cardiac arrest, stroke. Prognosis is generally good in patients with Addison’s disease as long as they are on life time hormone replacement therapy.

Addison’s disease often has an insidious onset. In many cases, the disease is only recognized when the patient presents with an acute crisis precipitated by a stressful illness or situation. Acute adrenal insufficiency should be considered in patients presenting with abdominal pain, nausea, diarrhea, hypotension, and fever. A detailed and thorough history is necessary. Specific areas of focus when obtaining a history from the patient of Addison’s disease include recent changes in diet, any signs of postural hypotension and history of cancer or other autoimmune diseases, tuberculosis or any exposure to anyone who has been diagnosed with tuberculosis.

In many cases, Addison’s disease is only recognized when the patient presents with an acute crisis precipitated by a stressful illness or situation. Acute adrenal insufficiency should be considered in patients presenting with abdominal pain, nausea, diarrhea, hypotension, and fever. Patients with acute Addison’s disease usually appear dehydrated and lethargic. Physical examination of patients with Addison’s disease is usually remarkable for hypotension, hyperpigmentation of the skin, and muscle weakness.

Diagnosis of Addison’s disease is made by routine blood tests and specific tests. ACTH stimulation test is a specific test employed to determine the function of adrenal glands and to diagnose Addison’s disease. The prominent finding of a rapid ACTH stimulation test includes failure of cortisol to rise in response to ACTH injection. Other routine laboratory tests employed include plasma cortisol level, serum ACTH level, plasma renin activity, aldosterone levels and serum biochemistry.

An ECG may be helpful in the diagnosis of Addison’s disease. ECG findings in Addison’s disease is due to hyperkalemia which include peak T waves and widened QRS complex.

An abdominal x-ray may be helpful in the diagnosis of Addison’s disease. Findings on an abdominal x-ray suggestive of Addison’s disease include adrenal calcifications.

There are no specific CT findings associated with Addisons’s disease except for small adrenal remnants bilaterally and calcifications.

There are no specific MRI findings associated with Addison’s disease. While MRI is not capable of distinguishing between acute inflammatory and metastatic diseases of the adrenal glands, it may be equally efficacious as CT in suggesting the diagnosis of adrenal hemorrhage in patients with Addison’s disease.

There are no other imaging findings associated with Addison’s disease.

There are no other diagnostic studies associated with Addison’s disease.

Abdominal ultrasound is typically normal in Addison’s disease except for the small size of adrenal glands.

The mainstay of treatment for Addison disease is corticosteroid replacement, if there is persistent mineralocorticoid deficiency, it should be combined with fludrocortisone.

Surgical intervention is not recommnended for the management of Addison’s disease.

There are no established measures for the primary prevention of Addison’s disease.

Effective measures for the secondary prevention of Addison’s disease include wearing an identification bracelet stating the name of the disease to ensure proper emergency treatment during an adrenal crisis. Patients diagnosed with Addison’s disease and their family members should also be educated about risks of hormone replacement therapy and dose adjustments during periods of acute illnesses. Immediate medical attention must be given when severe infections, vomiting, or diarrhea occur.

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

Addison’s disease is named after Dr. Thomas Addison, a British physician who first described the condition in his paper “On the Constitutional and Local Effects of Disease of the Suprarenal Capsules” in 1855.^[1][2]

• In 1563, Bartholomeus Eustachius, an anatomy professor at the Collegio della Sapienza in Rome was the first to give a description of the adrenal glands in his publication “glandulae renibus incumbentes”.
• In 1586, Piccolomini was the first to name the glands as suprarenals.
• In 1651, Highmore was the first to suggest that the suprarenals act to absorb exudates from the large vessels.
• In 1656, Thomas Wharton was the first to describe the concept of the neuroendocrine function of the adrenal medulla.
• In 1805, Cuvier was the first to give a detailed description of medulla and cortex of adrenal glands.
• In 1852, Albert von Kölliker was the first to give a detailed microscopic description of the adrenal glands.
• In 1855, Thomas Addison was the first to identify and name Addison’s disease in his paper “On the Constitutional and Local Effects of Disease of the Suprarenal Capsules”.
• In 1856, Charles Brown-Séquard provided experimental proof of the vital role of the adrenals by performing adrenalectomies (the removal of adrenals) from several animal species.

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

The hypothalamus releases corticotropin-releasing hormone (CRH), which stimulates the pituitary gland to release corticotropin (ACTH). ACTH travels via the blood to the adrenal gland, where it stimulates the release of cortisol. Cortisol is secreted by the cortex of the adrenal gland from a region called the zona fasciculata in response to ACTH. Elevated levels of cortisol exert negative feedback on the pituitary, which decreases the amount of ACTH released from the pituitary gland. When the adrenal glands do not produce enough cortisol and aldosterone, it results in Addison’s disease.

• The paraventricular nucleus of the hypothalamus secretes corticotropin-releasing hormone (CRH).
• CRH stimulates the anterior lobe of the pituitary gland, which leads to the release of adrenocorticotropic hormone (ACTH)
• ACTH, in turn, acts on the adrenal cortex, which produces glucocorticoid hormones (mainly cortisol in humans).
• Glucocorticoids, in addition to having physiological functions in the body, also have a negative feedback effect on the hypothalamus and pituitary (suppression of CRH and ACTH production).

Harmone	Type of class	Function
Cortisol	Glucocorticoids	Helps maintain blood pressure and cardiovascular function Reduces inflammatory response Helps balance the effects of insulin by increasing blood glucose level Helps regulate the metabolism of proteins, carbohydrates, and fats Helps maintain proper arousal and sense of well-being
Aldosterone	Mineralocorticoids	Maintains blood pressure, fluid and electrolyte balance in the body by helping the kidney retain sodium and excrete potassium

Addison’s disease occurs when the adrenal glands do not produce enough cortisol and, in some cases, aldosterone. Adrenal insufficiency may arise due to insufficient release of cortisol from the adrenal glands. Insufficient cortisol secretion may be due to adrenal dysgenesis (the gland does not form adequately during development), impaired steroidogenesis (the gland is present but is biochemically unable to produce cortisol) or adrenal destruction (disease processes leading to the gland being damaged).^[1][2][3]

Mechanism of adrenal insufficiency	Definition	Pathophysiology
Adrenal dysgenesis	Gland does not form adequately during development	Mutations of the SF1 transcription factor, congenital adrenal hypoplasia (AHC) due to DAX-1 gene mutations Mutations of the ACTH receptor gene (or related genes, such as in the Triple A or Allgrove syndrome) DAX-1 mutations may cluster in a syndrome along with glycerol kinase deficiency with a number of other symptoms when DAX-1 is deleted together with a number of other genes
Impaired steroidogenesis	The gland is present but is biochemically unable to produce cortisol To form cortisol, the adrenal gland requires cholesterol, which is then converted biochemically into steroid hormones Interruptions in the delivery of cholesterol	Smith-Lemli-Opitz syndrome and abetalipoproteinemia [4] Congenital adrenal hyperplasia is most common (in various forms: 21-hydroxylase, 17α-hydroxylase, 11β-hydroxylase, and 3β-hydroxysteroid dehydrogenase) Lipoid congenital adrenal hyperplasia due to a deficiency of steroidogenic acute regulatory protein StAR and mitochondrial DNA mutations
Adrenal destruction	Disease processes leading to the gland being damaged	Autoimmune destruction of the adrenal cortex (often due to antibodies against the enzyme 21-Hydroxylase) is a common cause of Addison’s in teenagers and adults Adrenoleukodystrophy (ALD) Metastasis (seeding of cancer cells from elsewhere in the body) Hemorrhage (e.g. in Waterhouse-Friderichsen syndrome or antiphospholipid syndrome) Infections (tuberculosis, histoplasmosis, coccidioidomycosis) Deposition of abnormal protein in amyloidosis Some medications interfere with steroid synthesis enzymes (e.g. ketoconazole), while others accelerate the normal breakdown of hormones by the liver (e.g. rifampicin, phenytoin)

• Hereditary factors sometimes play a key role in the development of autoimmune adrenal insufficiency.^[5]
• Common genetic conditions associated with Addison’s diseases include:
  • Familial glucocorticoid insufficiency (associated with a recessive gene pattern)
  • Adrenomyeloneuropathy is known to be X-linked
• Addison disease is associated with a variety of autoimmune conditions that have been linked to genetic factors.
• Patients with autoimmune polyglandular failure might develop diabetes mellitus, pernicious anemia, and hypothyroidism secondary to antibodies which develop against the adrenal glands.

Addison’s disease is commonly seen associated with conditions such as:^[6]

• Autoimmune polyendocrine syndrome
• Autoimmune hypoparathyroidism resulting in hypocalcemia
• Vitiligo
• Premature ovarian failure
• Pernicious anemia
• Myasthenia gravis
• Chronic candidiasis
• Sjögren syndrome
• Chronic active hepatitis
• Diabetes mellitus type 1
• Hypothyroidism
• Hashimoto thyroiditis
• Graves hyperthyroidism
• Adrenoleukodystrophy

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

Common causes of Addison’s disease include autoimmune, tuberculosis, AIDS, CMV, hemorrhage, infarction, sarcoidosis and infections.

Life-threatening causes of Addison’s disease include:

• AIDS complications
• Adrenal infarction
• Bilateral adrenal hemorrhage(caused by trauma, anticoagulant therapy, or coagulation disorders).^[1]
• Cancerous destruction of the adrenal gland, secondary to infiltrative or metastatic disease.
• Tubercular and fungal destruction of adrenal glands.

Common causes of Addison’s disease include:^[2]

• Autoimmune/Idiopathic
• Tuberculosis
• AIDS
• CMV
• Hemorrhage
• Infarction
• Sarcoidosis
• Infections

Less common causes of Addison’s disease include:

• Sarcoidosis
• Amyloidosis
• Fungal infections
• AIDS complications
• Hemochromatosis
• Polyglandular autoimmune syndromes
• Adrenoleukodystrophy
• Adrenomyelodystrophy
• Congenital factors, including hypoplasia, familial glucocorticoid insufficiency, and enzyme defect

Cardiovascular	Arteritis, Hypotension, Hemorrhage, Infarction
Chemical / poisoning	No underlying causes
Dermatologic	No underlying causes
Drug Side Effect	Corticosteroid withdrawal, Pasireotide
Ear Nose Throat	No underlying causes
Endocrine	Adrenal aplasia / hypoplasia, Adrenal metastases, After surgery of cortisol-secreting tumor, Bilateral adrenalectomy , Congenital adrenal hyperplasia, Glucocorticoid deficiency 1
Environmental	No underlying causes
Gastroenterologic	Hemochromatosis
Genetic	No underlying causes
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	No underlying causes
Neurologic	Adrenoleukodystrophy, Coma
Nutritional / Metabolic	No underlying causes
Obstetric/Gynecologic	No underlying causes
Oncologic	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, Sarcoidosis
Sexual	No underlying causes
Trauma	Trauma
Urologic	No underlying causes
Dental	No underlying causes
Miscellaneous	Amyloidosis, Idiopathic, Iatrogenic, Radiation therapy, Surgery

• Adrenal aplasia / hypoplasia
• Adrenal metastases
• Adrenoleukodystrophy
• AIDS
• Amyloidosis
• Anticoagulation
• Arteritis
• After surgery of cortisol-secreting tumor
• Autoimmune/idiopathic
• Bilateral adrenalectomy
• Blastomycosis
• CMV
• Coagulopathy
• Coccidiomycosis
• Congenital adrenal hyperplasia
• Cryptococcosis
• Coma
• Corticosteroid withdrawal
• Drugs
• Embolus
• Glucocorticoid deficiency 1
• Hemochromatosis
• Histoplasmosis
• Hypotension
• Hemorrhage, infarction
• Iatrogenic
• Kaposi’s sarcoma
• Leukemia
• Lymphoma
• Mycobacterium avium intracellulaire (MAI)
• Neonatal
• Neoplasm
• Radiation therapy
• Sarcoidosis
• Sepsis
• Surgery
• Syphilis
• Thrombosis
• Toxoplasmosis
• Trauma
• Tuberculosis (20% of all Addison’s)
• Uremia
• Waterhouse-Friderichson syndrome

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

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.

Addison’s disease (primary adrenal insufficiency) must be first differentiated from secondary and tertiary adrenal insufficiency as all the three of them present with similar symptoms due to cortisol and mineralocorticoid hormone deficiencies.

• Serum ACTH level can help distinguish primary from secondary/tertiary adrenal insufficiency

Type of Adrenal insufficiency	Skin Pigmentation	ACTH	Normal ACTH
Addison disease	+	>60 ng/mL	5-30 ng/mL
Secondary / tertiary adrenal insufficiency	–	<5 ng/mL

Addison’s disease must be differentiated from other diseases that cause hypotension, skin pigmentation, muscle weakness and abdominal pain which include myopathies, celiac disease, Peutz-Jeghers syndrome, anorexia nervosa, syndrome of inappropriate antidiuretic hormone (SIADH), neurofibromatosis, porphyria cutanea tarda, salt-depletion nephritis and bronchogenic carcinoma.^{[1][2][3][4][5]}

Disease	Differentiating symptoms							Differentiating laboratory findings			Gold standard test
	Hypotension	Abdominal pain	Anorexia/ weight loss	Muscle weakness	Hypoglycemia	Skin pigmentation	Other symptoms	Hyponatremia	Cortisol levels	Other labs
Addison’s disease	+	+	+	+	+	+		+	Low		ACTH stimulation test
Myopathies (polymyositis, hereditary myopathies)	–	–	–	+	–	Heliotrope rash and Gottron’s sign	Muscle tenderness	–	Normal	–	Muscle biopsy
Celiac disease	–	+	+	–	–	Dermatitis herpetiformis	Greasy stools Increased fecal fat	–	Normal	–	Abnormal small bowel biopsy
Syndrome of inappropriate anti-diuretic hormone (SIADH)	–	–	–	–	–	–	–	+	Normal	Decreased osmolality Euvolemia Sodium in urine typically >20 mEq/L	Water deprivation test
Neurofibromatosis	–	–	+	+	–	Axillary- and inguinal-area freckling	Occasional development of peripheral sarcomas May have overgrowth of subcutaneous tissues	–	–	–	Biopsy of skin tissue
Peutz-Jeghers syndrome		+				+	Melanotic hyperpigmentation of the skin and mucous membranes	–	Normal		Colonic imaging showing the small intestinal polyps
Porphyria cutanea tarda	–	+	–	–	–	Blisters on sun-exposed sites	Associated liver disease (usually hepatitis C) Hypertrichosis	–	Normal or elevated	High level of porphyrins in the urine
Salt-depletion nephritis	+	Flank pain	–	–	–	–	Fever Dysuria Pyuria Oliguria	+	Elevated	<15:1 BUN:CR
Bronchogenic carcinoma	–	–	+	–	–	+	Cough Dyspnea Hemoptysis	–	Elevated	Increased ACTH and Hypokalemia	Cytological or histological evidence of lung cancer in sputum, pleural fluid, or tissue
Anorexia nervosa	+	–	+	+	+	–	Distorted body image Oligomenorrhea	–	Elevated	–	Psychiatric condition

Addison’s disease should be differentiated from other diseases causing secondary adrenal insufficiency due to hypopituitarism.^{[6][7][8][9][10][11][12]}

Diseases	Onset	Manifestations					Diagnosis
		History and Symptoms				Physical examination	Laboratory findings	Gold standard	Imaging	Other investigation findings
		Trumatic delivery	Lactation failure	Menstrual irregularities	Other features
Sheehan’s syndrome	Acute	++	++	Oligo/amenorrhea	Symptoms of: Adrenal insufficiency Hypothyroidism	Breast tissue atrophy Decreased axillary and pubic hair growth	Pancytopenia Eosinophilia Hyponatremia Low fasting plasma glucose Decreased levels of anterior pituitary hormones in blood	Clinical diagnosis Most senitive test: Low baseline prolactin levels w/o response to TRH	CT/MRI: Sequential changes of pituitary enlargement followed by: Shrinkage and necrosis leading to decreased sellar volume or empty sella	Pituitary hormone stimulation tests (Metoclopramide and clomiphene citrate stimulation tests)
Lymphocytic hypophysitis	Acute	+/-	+	Oligo/amenorrhea	Associated with autoimmune conditions Generalized headache Retro-orbital or Bitemporal pain Mass lesion effect such as visual field defects	DI Autoimmune thyroiditis	Decreased pituitary hormones(Gonadotropins most common) Hyperprolactinemia(40%) GH excess	Pituitary biopsy: lymphocytic infiltration	CT & MRI: Features of a pituitary mass Diffuse and homogeneous contrast enhancement	Assays for: Anti-TPO Anti-Tg Ab
Pituitary apoplexy	Acute	+/-	++	Oligo/amenorrhea	Severe headache Nausea and vomiting Paralysis of eye muscles (diplopia) Changes in vision	Visual acuity defects CN palsies (nerves III, IV, V , and VI)	Decreased levels of anterior pituitary hormones in blood.	MRI	CT scan without contrast: Hemorrhage on CT presents as a hyperdense lesion MRI: If inconclusive CT	Blood tests may be done to check: PT/INR and aPTT Pituitary hormonal assay
Empty sella syndrome	Chronic	–	+	Oligo/amenorrhea	Erectile dysfunction Headache Low libido	Signs of raised intracranial pressure may be present Nipple discharge	Decreased levels of pituitary hormones in blood.	MRI	Empty sella containing CSF	Pituitary hormone stimulation tests (Metoclopramide and clomiphene citrate stimulation tests)
Simmonds’ disease/Pituitary cachexia	Chronic	+/-	+	Oligo/amenorrhea	Cachexia Premature aging	Progressive emaciation Loss of body hair	Decreased levels of anterior pituitary hormones in blood.	MRI	Done to rule out any pituitary cause	Pituitary hormone stimulation tests (Metoclopramide and clomiphene citrate stimulation tests)
Hypothyroidism	Chronic	+/-	–	Oligomenorrhea/menorrhagia	Cold intolerance Constipation	Dry skin Bradycardia Hair loss Myxedema Delayed relaxation phase of deep tendon reflexes	Low T3,T4 Normal/ low TSH Rest of pituitary hormone levels WNL	TSH levels	Done to rule out any pituitary cause	Assays for anti-TPO and anti-Tg Ab FNA biopsy
Hypogonadotropic hypogonadism	Chronic	–	–	Oligo/amenorrhea	Hot flushes Energy and mood changes Decreased libido	Breast tissue atrophy Decreased maturation of vaginal mucosa	Low estrogen, testosterone High FSH/LH	FSH LH	Done to rule out any pituitary cause	Genetic tests  (karyotype) Measurement of total and free testosterone and 17-hydroxyprogesterone concentrations
Hypoprolactinemia	Chronic	–	+	–	Infertility Subfertiliy	Puerperal agalactogenesis	No workup is necessary	Decreased prolactin levels	Done to rule out any pituitary cause	Prolactin assay in 3rd trimester LH, FSH Thyrotropin and free thyroxine
Panhypopituitarism	Chronic	–	+	Oligo/amenorrhea	Polyuria Polydipsia Features of hypothyroidism and hypoadrenalism	Growth failure B/L hemianopsia Papilledema	All pituitary hormones decreased	MRI	Done to rule out any pituitary cause	Left hand and wrist radiograph for bone age
Primary adrenal insufficiency/Addison’s disease	Chronic	–	–	–	Hypoglycemia Hypotension	Dehydration Hyperpigmentation loss of pubic and axillary hair	Hyponatremia with/without hyperkalemia Plasma renin activity to aldosterone ratio	Abdominal CT	Abdominal CT	Serum cortisol testing Serum ACTH testing Anti-adrenal Ab testing
Menopause	Chronic	–	+/-	Oligo/amenorrhea	Hot flashes Insomnia Weight gain and bloating Mood changes	Vaginal atrophy Loss of pelvic muscle tone	↑ FSH ↓ Estradiol and inhibin	FSH > LH	Normal	Endometrial biopsy

References

1. ↑ Selva-O’Callaghan A, Labrador-Horrillo M, Gallardo E, Herruzo A, Grau-Junyent JM, Vilardell-Tarres M (2006). “Muscle inflammation, autoimmune Addison’s disease and sarcoidosis in a patient with dysferlin deficiency”. Neuromuscul. Disord. 16 (3): 208–9. doi:10.1016/j.nmd.2006.01.005. PMID 16483775.
2. ↑ Kumar V, Rajadhyaksha M, Wortsman J (2001). “Celiac disease-associated autoimmune endocrinopathies”. Clin. Diagn. Lab. Immunol. 8 (4): 678–85. doi:10.1128/CDLI.8.4.678-685.2001. PMC 96126. PMID 11427410.
3. ↑ Adams R, Hinkebein MK, McQuillen M, Sutherland S, El Asyouty S, Lippmann S (1998). “Prompt differentiation of Addison’s disease from anorexia nervosa during weight loss and vomiting”. South. Med. J. 91 (2): 208–11. PMID 9496878.
4. ↑ Lever EG, Stansfeld SA (1983). “Addison’s disease, psychosis, and the syndrome of inappropriate secretion of antidiuretic hormone”. Br J Psychiatry. 143: 406–10. PMID 6414566.
5. ↑ BELL R, PATTEE CJ (1956). “Addison’s disease associated with neurofibromatosis”. Can Med Assoc J. 75 (5): 415–7. PMC 1823303. PMID 13356214.
6. ↑ Sato N, Sze G, Endo K (1998). “Hypophysitis: endocrinologic and dynamic MR findings”. AJNR Am J Neuroradiol. 19 (3): 439–44. PMID 9541295.
7. ↑ Powrie JK, Powell M, Ayers AB, Lowy C, Sönksen PH (1995). “Lymphocytic adenohypophysitis: magnetic resonance imaging features of two new cases and a review of the literature”. Clin. Endocrinol. (Oxf). 42 (3): 315–22. PMID 7758238.
8. ↑ Honegger J, Schlaffer S, Menzel C, Droste M, Werner S, Elbelt U, Strasburger C, Störmann S, Küppers A, Streetz-van der Werf C, Deutschbein T, Stieg M, Rotermund R, Milian M, Petersenn S (2015). “Diagnosis of Primary Hypophysitis in Germany”. J. Clin. Endocrinol. Metab. 100 (10): 3841–9. doi:10.1210/jc.2015-2152. PMID 26262437.
9. ↑ Thodou E, Asa SL, Kontogeorgos G, Kovacs K, Horvath E, Ezzat S (1995). “Clinical case seminar: lymphocytic hypophysitis: clinicopathological findings”. J. Clin. Endocrinol. Metab. 80 (8): 2302–11. doi:10.1210/jcem.80.8.7629223. PMID 7629223.
10. ↑ Imura H, Nakao K, Shimatsu A, Ogawa Y, Sando T, Fujisawa I, Yamabe H (1993). “Lymphocytic infundibuloneurohypophysitis as a cause of central diabetes insipidus”. N. Engl. J. Med. 329 (10): 683–9. doi:10.1056/NEJM199309023291002. PMID 8345854.
11. ↑ Hsieh CY, Liu BY, Yang YN, Yin WH, Young MS (2011). “Massive pericardial effusion with diastolic right ventricular compression secondary to hypothyroidism in a 73-year-old woman”. Emerg Med Australas. 23 (3): 372–5. doi:10.1111/j.1742-6723.2011.01425.x. PMID 21668725.
12. ↑ Dejager S, Gerber S, Foubert L, Turpin G (1998). “Sheehan’s syndrome: differential diagnosis in the acute phase”. J. Intern. Med. 244 (3): 261–6. PMID 9747750.

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

The prevalence of Addison’s disease in the human population is estimated to be roughly 4-12 persons per 100,000 persons. The incidence of Addison’s disease is approximately 0.6 per 100,000 individuals worldwide. Addison’s disease can affect any age range. Addison’s disease occurs more frequently in females as compared to males with a ratio of 12.3 to 1.

The prevalence of Addison’s disease in the human population is sometimes estimated at roughly 4-12 people per 100,000 persons.

The incidence Addison’s disease is approximately 0.6 per 100,000 individuals worldwide.

• Addison disease can affect any age range.
• Addison’s disease typically presents in adults between 30 and 50 years of age as most are often diagnosed with autoimmune-associated diseases.^[1]

Addison’s disease occur more frequently in females as compared to males with a ratio of 12.3 to 1. ^[2]

There is no racial predilection to Addison’s disease.

Addison’s disease may be more common in areas where systemic fungal infections such as histoplasmosis can cause destruction of the adrenal cortex by disseminated infection or secondary to antifungal medications.

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

Common risk factors in the development of Addison’s disease include other autoimmune diseases such as chronic thyroiditis, dermatitis herpetiformis, grave’s disease, hypoparathyroidism, hypopituitarism, myasthenia gravis, pernicious anemia, testicular dysfunction, type I diabetes and vitiligo.

Common risk factors in the development of Addison’s disease include other autoimmune diseases:^[1]

• Chronic thyroiditis
• Dermatitis herpetiformis
• Graves’ disease
• Hypoparathyroidism
• Hypopituitarism
• Myasthenia gravis
• Pernicious anemia
• Testicular dysfunction
• Type I diabetes
• Vitiligo

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

If left untreated, Addison’s disease can be life-threatening. Complications of Addison’s disease include hypoglycemia, addisonian crisis, hypoxia, hypovolemic shock, cardiac arrest, stroke. Prognosis is generally good in patients with Addison’s disease as long as they are on life time hormone replacement therapy.

If left untreated, Addison’s disease can be life-threatening. Any stressful event or illness can cause a sudden worsening of symptoms, which can lead to severe dehydration and fatally low blood pressure and eventually death.

Complications of Addison’s disease include:^[1]

• Hypoglycemia
• Addisonian crisis
• Hypoxia
• Hypovolemic shock
• Cardiac arrest
• Stroke

• Prognosis is generally good in patients with Addison’s disease as long as they are on life-time hormonal therapy.^[2][3]
• Patients with Addison’s disease must be closely monitored for compliance with medications as acute cases can be life-threating and the mortality rates can go up to 95% in acute crisis.

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