• Sign Up

Use coupon code BLACKFRIDAY2020 at checkout for 30% off now through Monday!

Adrenal Insufficiency

Adrenal Insufficiency

Article Author:
Martin Huecker
Article Editor:
Elvita Dominique
11/18/2020 11:04:16 AM
For CME on this topic:
Adrenal Insufficiency CME
PubMed Link:
Adrenal Insufficiency


The adrenal gland is made up of two parts, the cortex, and the medulla. The adrenal cortex produces hormones which are necessary for normal body functioning, deficiency of these hormones results in adrenal insufficiency. The cortex is responsible for producing glucocorticoids, mineralocorticoids, and androgens. Destruction or the dysfunction of the adrenal cortex mainly causes glucocorticoid and mineralocorticoid deficiency. Primary adrenal insufficiency is also known as autoimmune adrenalitis or Addison disease.

Adrenal insufficiency ranges from mild nonspecific symptoms to life-threatening shock conditions. Due to its vague symptoms and varying degree of clinical presentation, a clinician must maintain a high level of suspicion for this disease. The decreasing or suppressed adrenal function may be masked until stress or illness triggers an adrenal crisis.

Adrenal insufficiency can be classified into primary, secondary, and tertiary causes. Primary adrenal insufficiency occurs when there is a pathology affecting the adrenal gland itself. Secondary adrenal insufficiency results from a decreased level of adrenocorticotrophin hormone (ACTH) released from the pituitary gland and tertiary adrenal insufficiency results from a decreased level of corticotrophin-releasing hormone (CRH) released from the hypothalamus.  

An important distinction in these patients is the presence of mineralocorticoid deficiency. Those with secondary or tertiary adrenal insufficiency will typically have preserved mineralocorticoid function due to the separate feedback systems. Mineralocorticoid levels are regulated by the renin-angiotensin system, independent of hypothalamic or pituitary signals.

Another important distinction is the acute versus chronic nature of the disease. Acute adrenal insufficiency patients often present in a critically ill state while chronic presentations can be insidious.[1][2][3][4][5]


Primary adrenal insufficiency is characterized by decreased aldosterone and cortisol production due to diminished gland function. It can either present acutely, which may present as an adrenal crisis, or it can be chronic, which is called Addison disease.

The most common cause of primary adrenal insufficiency/Addison disease relates to the autoimmune destruction of the adrenal cortex. Autobodies form against the steroid 21-hydroxylase enzyme in approximately 90% of patients.[6] Other insults to the adrenal gland that lead to primary insufficiency include adrenal hemorrhage, cancer, infections (HIV, syphilis, tuberculosis), and certain drugs such as etomidate, ketoconazole, fluconazole, or metyrapone. Phenytoin and rifampin increase the metabolism of cortisol and can, therefore, precipitate adrenal insufficiency in those predisposed.[7]

Adrenal hemorrhage can occur in patients who are taking anticoagulants or have a bleeding diathesis, or in the postoperative setting. 

Primary adrenal insufficiency can also be congenital. Congenital adrenal hyperplasia has been extensively studied and described in the literature. Panhypopituitarism and many genetic conditions can cause adrenal insufficiency. Pituitary hemorrhage or infarction (Sheehan syndrome) can cause secondary adrenal insufficiency. Other causes include pituitary tumors, hypophysectomy, and high dose pituitary or whole-brain radiation.[8]

Brain tumors and abrupt withdrawal from long term exogenous steroid use can cause tertiary adrenal insufficiency.


As many as 144 million individuals in the developed world may have Addison disease. When treated properly, patients can have a roughly normal lifespan. Untreated patients have a high mortality rate.[9][10]

The autoimmune form of adrenal insufficiency has a male-female predisposition based on the type of autoimmune condition. Females are more likely to have the polyglandular form while isolated adrenal damage is more common in males in the first two decades. By the fourth decade, the isolated form is more common in women.

Due to the diverse causes of adrenal insufficiency, no distinct group of individuals is at increased risk of disease.

The epidemiology of adrenal insufficiency in children is not well-defined. Congenital adrenal hyperplasia (CAH) is the most common etiology of primary adrenal insufficiency in children, occurring once in 14,200 live births.[11]


The pathophysiology of adrenal insufficiency depends on the etiology. With most forms of autoimmune (primary) adrenal insufficiency, the patient has antibodies that attack various enzymes in the adrenal cortex (though cell-mediated mechanisms also contribute). Various genetic factors have been identified that play a role in the development of primary adrenal insufficiency or autoimmune adrenalitis. These include the major histocompatibility complex (MHC) haplotypes DR3-DQ2 and DR4-DQ8.[12]

Secondary adrenal insufficiency refers to decreased adrenocorticotropic hormone (ACTH) stimulation of the adrenal cortex and therefore does not affect aldosterone levels. Traumatic brain injury (TBI) and panhypopituitarism are common causes.[13]

Tertiary adrenal insufficiency refers to decreased hypothalamic stimulation of the pituitary to secrete ACTH. Exogenous steroid administration is the most common cause of tertiary adrenal insufficiency. Surgery to correct Cushing disease can also lead to tertiary adrenal insufficiency.

The other forms of adrenal insufficiency usually relate to destruction by infectious agents or infiltration by metastatic malignant cells. Hemorrhagic infarction occurs due to sepsis with certain organisms (Neisseria species, tuberculosis, fungal infections, Streptococcus species, Staphylococcus speciesor due to adrenal vein thrombosis. Death associated with adrenal insufficiency is usually of septic shock, hypotension, or cardiac arrhythmias.[14][15]


The adrenal cortex is divided into three layers, each responsible for producing a specific hormone. Histopathology varies according to the pathological process involved in adrenal gland dysfunction. In autoimmune adrenalitis, there is atrophy of the adrenal gland with infiltration of lymphocytes along with fibrosis of the adrenal capsule. As adrenal insufficiency is caused by dysfunction of the cortex, the adrenal medulla is not affected and is spared. Adrenal insufficiency due to tuberculosis results in enlargement of the adrenal glands with the presence of caseating granulomas. The adrenal medulla is usually not spared, and the gland is characterized by diffuse calcification.[16]

In patients with acquired immunodeficiency syndrome (AIDS), there is infarction, hemorrhage, and necrotizing inflammation of the adrenal gland. [17]

History and Physical

Patients with adrenal insufficiency often present with hypotension, altered mental status, anorexia, vomiting, weight loss, fatigue, and recurrent abdominal pain. Reproductive complaints typically occur in women (amenorrhea, loss of libido, decreased axillary and pubic hair). Salt craving and orthostatic hypotension are common in patients with primary adrenal insufficiency, due to the volume depletion from the reduced mineralocorticoid function. Obtaining a history of exogenous corticosteroid use is crucial in making the diagnosis, especially in cases of chronic adrenal insufficiency.

Patients may have poor skin turgor and increased skin pigmentation. Patients may also manifest neuropsychiatric signs and symptoms. One might notice signs of Cushing syndrome, such as skin atrophy, striae, edema, obesity, muscle wasting, and neuropsychiatric disturbance.

As many as half of the patients will develop shock with no preceding hypotension. Hypotension can be present in any form of adrenal insufficiency. Fever should lead to an investigation for infectious etiology, although it can be present in any form of adrenal insufficiency.[5][18][6]


The diagnosis of primary adrenal insufficiency requires suspicion as it mostly presents with non-specific symptoms. Hyponatremia with hyperkalemia and hypoglycemia may be present. Serum cortisol, ACTH, renin, aldosterone, and chemistry panel should be obtained. Serum cortisol level can help make diagnoses in the presence of elevated ACTH and plasma renin activity. The ACTH stimulation test can be performed to determine if the cause is central or peripheral.[19]

The initial test in primary adrenal insufficiency should be measuring anti-21-hydroxylase antibodies. As these are responsible for the destruction of the adrenal cortex.[20]

Patients with secondary adrenal insufficiency are more likely to have hypoglycemia, but will not have dehydration, hyperkalemia, or skin hyperpigmentation.

Adrenal insufficiency presenting later in life is mostly due to a secondary cause. Consider testing for HIV and tuberculosis in patients with unclear etiology. Adrenal insufficiency secondary to tuberculosis is more common in patients belonging to developing countries.[21][22]

The most common laboratory findings in chronic primary adrenal insufficiency are anemia, hyponatremia, and hyperkalemia.

Treatment / Management

The treatment of adrenal insufficiency is glucocorticoid replacement. If the infection is the inciting event of a crisis or the cause of primary adrenal failure, it must be treated aggressively. Patients in shock will require intravenous hydration and often, dextrose.[23][24][25]

In patients with established adrenal insufficiency, hydrocortisone is the treatment of choice, with 100 mg intravenously every 8 hours being the standard dose. Hydrocortisone has some mineralocorticoid effect in case the patient has deficient aldosterone. In an undiagnosed patient, dexamethasone (4 mg initial bolus) should be used, as this does not interfere with cortisol assays. Mineralocorticoid replacement with fludrocortisone may be required but is not usually necessary in an acute adrenal crisis. 

If patients with adrenal insufficiency require surgery, a stress dose of glucocorticoids must be given and continued for 24 hours after the procedure.[4]

Patients with adrenal insufficiency undergoing surgery will need glucocorticoid prophylaxis preoperatively because cortisol deficiency increases vulnerability to stress.[26]

Differential Diagnosis

  • Adrenal Crisis
  • Adrenal Hemorrhage
  • Congenital adrenal hyperplasia
  • Eosinophilia
  • Histoplasmosis
  • Hyperkalemia
  • Sarcoidosis
  • Tuberculosis


People with adrenal insufficiency can live a normal and active life if they are properly monitored and treated. With proper treatment and regular follow-ups, children grow normally and achieve puberty without difficulty.


The most dangerous complication of adrenal insufficiency is adrenal crisis. If left untreated, adrenal crisis can result in death. Frequent low blood sugar levels can increase the risk of hypoglycemic shock.[27]


An endocrinologist should always be involved in the management of adrenal insufficiency. An infectious disease specialist should be consulted if the clinician has a suspicion of adrenal insufficiency secondary to an infective etiology. Surgical oncologists are always consulted in the setting of metastatic disease.

Deterrence and Patient Education

Patients and their family members should be educated on symptoms of adrenal crisis. As early diagnosis and prompt treatment lower the mortality rate. Patients should always carry an emergency medicine shot after consulting with their clinicians. Finally, all patients with a diagnosis of adrenal insufficiency should be urged to wear a medical ID bracelet.

Pearls and Other Issues

As mentioned above, patients in adrenal crisis manifest nonspecific symptoms and therefore can be difficult to diagnose. Those physicians who prescribe the glucocorticoids such as prednisone must also be aware of the need to limit the length of time the patient is on the medication and taper when discontinuing.

Enhancing Healthcare Team Outcomes

Adrenal insufficiency is a life-threatening disorder which if not recognized can lead to very high morbidity and mortality. Because of the varied presentation, it is best managed by an interprofessional team that consists of an endocrinologist, radiologist, an infectious disease specialist, intensivist, critical care nurse, and a pharmacist. While the cause of adrenal insufficiency is being investigated, the patient should immediately be managed with corticosteroids and mineralocorticoids because even with treatment, mortality rates remain high. The pharmacist should assist with medication reconciliation and appropriate dosing. Once treatment is initiated patients need close monitoring by a specialty trained critical care nurse with open and rapid communication with the clinicians. Any type of infection or stress can precipitate adrenal crises leading to death, hence patients and families should be educated by the nurses about the symptoms and when to return immediately to the emergency department.[28][29]


[1] Ceccato F,Scaroni C, Central adrenal insufficiency: open issues regarding diagnosis and glucocorticoid treatment. Clinical chemistry and laboratory medicine. 2018 Nov 14     [PubMed PMID: 30427776]
[2] Shaffer ML,Baud O,Lacaze-Masmonteil T,Peltoniemi OM,Bonsante F,Watterberg KL, Effect of Prophylaxis for Early Adrenal Insufficiency Using Low-Dose Hydrocortisone in Very Preterm Infants: An Individual Patient Data Meta-Analysis. The Journal of pediatrics. 2018 Nov 8     [PubMed PMID: 30416014]
[3] Kang TS,Choi HY,Park SH, Adrenal Insufficiency in a Patient with Acute Myocardial Infarction Plus Shock. Korean circulation journal. 2018 Dec     [PubMed PMID: 30403022]
[4] Garrahy A,Thompson CJ, Hyponatremia and Glucocorticoid Deficiency. Frontiers of hormone research. 2019     [PubMed PMID: 32097946]
[5] Martin-Grace J,Dineen R,Sherlock M,Thompson CJ, Adrenal insufficiency: physiology, clinical presentation and diagnostic challenges. Clinica chimica acta; international journal of clinical chemistry. 2020 Feb 6     [PubMed PMID: 32035851]
[6] Nicolaides NC,Chrousos GP,Charmandari E, Adrenal Insufficiency . 2000     [PubMed PMID: 25905309]
[7] Kara C,Ucaktürk A,Aydin OF,Aydin M, Adverse effect of phenytoin on glucocorticoid replacement in a child with adrenal insufficiency. Journal of pediatric endocrinology & metabolism : JPEM. 2010 Sep     [PubMed PMID: 21175098]
[8] Shivaprasad C, Sheehan's syndrome: Newer advances. Indian journal of endocrinology and metabolism. 2011 Sep     [PubMed PMID: 22029025]
[9] Rushworth RL,Torpy DJ,Stratakis CA,Falhammar H, Adrenal Crises in Children: Perspectives and Research Directions. Hormone research in paediatrics. 2018     [PubMed PMID: 29874655]
[10] Meyer G,Badenhoop K, [Addisonian Crisis - Risk Assessment and Appropriate Treatment]. Deutsche medizinische Wochenschrift (1946). 2018 Mar     [PubMed PMID: 29544234]
[11] Neary N,Nieman L, Adrenal insufficiency: etiology, diagnosis and treatment. Current opinion in endocrinology, diabetes, and obesity. 2010 Jun     [PubMed PMID: 20375886]
[12] Mitchell AL,Pearce SH, Autoimmune Addison disease: pathophysiology and genetic complexity. Nature reviews. Endocrinology. 2012 Jan 31     [PubMed PMID: 22290360]
[13] Alexandraki KI,Grossman A, Management of Hypopituitarism. Journal of clinical medicine. 2019 Dec 5     [PubMed PMID: 31817511]
[14] Nassoro DD,Mkhoi ML,Sabi I,Meremo AJ,Lawala PS,Mwakyula IH, Adrenal Insufficiency: A Forgotten Diagnosis in HIV/AIDS Patients in Developing Countries. International journal of endocrinology. 2019     [PubMed PMID: 31341472]
[15] Ventura Spagnolo E,Mondello C,Roccuzzo S,Stassi C,Cardia L,Grieco A,Raffino C, A unique fatal case of Waterhouse-Friderichsen syndrome caused by Proteus mirabilis in an immunocompetent subject: Case report and literature analysis. Medicine. 2019 Aug     [PubMed PMID: 31441842]
[16] Guo YK,Yang ZG,Li Y,Ma ES,Deng YP,Min PQ,Yin LL,Hu J,Zhang XC,Chen TW, Addison's disease due to adrenal tuberculosis: contrast-enhanced CT features and clinical duration correlation. European journal of radiology. 2007 Apr     [PubMed PMID: 17182208]
[17] Eledrisi MS,Verghese AC, Adrenal insufficiency in HIV infection: a review and recommendations. The American journal of the medical sciences. 2001 Feb     [PubMed PMID: 11217816]
[18] Harbeck B,Lehnert H, [Diagnosis and Management of Adrenal Insufficiency]. Deutsche medizinische Wochenschrift (1946). 2018 Aug     [PubMed PMID: 30134456]
[19] Cole S, Evaluation and Treatment of Adrenal Dysfunction in the Primary Care Environment. The Nursing clinics of North America. 2018 Sep     [PubMed PMID: 30100004]
[20] Reznik Y,Barat P,Bertherat J,Bouvattier C,Castinetti F,Chabre O,Chanson P,Cortet C,Delemer B,Goichot B,Gruson D,Guignat L,Proust-Lemoine E,Sanson MR,Reynaud R,Boustani DS,Simon D,Tabarin A,Zenaty D, SFE/SFEDP adrenal insufficiency French consensus: Introduction and handbook. Annales d'endocrinologie. 2018 Feb     [PubMed PMID: 29338844]
[21] Reddy R, Tuberculoma of the pituitary gland presenting as diabetes insipidus. Neurology India. 2017 Jul-Aug     [PubMed PMID: 28681785]
[22] Paragliola RM,Corsello SM, Secondary adrenal insufficiency: from the physiopathology to the possible role of modified-release hydrocortisone treatment. Minerva endocrinologica. 2018 Jun     [PubMed PMID: 28750490]
[23] Nour MA,Gill H,Mondal P,Inman M,Urmson K, Perioperative care of congenital adrenal hyperplasia - a disparity of physician practices in Canada. International journal of pediatric endocrinology. 2018     [PubMed PMID: 30214458]
[24] Yamamoto T, Latent Adrenal Insufficiency: Concept, Clues to Detection, and Diagnosis. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2018 Aug     [PubMed PMID: 30084678]
[25] Groleau C,Morin SN,Vautour L,Amar-Zifkin A,Bessissow A, Perioperative corticosteroid administration: a systematic review and descriptive analysis. Perioperative medicine (London, England). 2018     [PubMed PMID: 29977522]
[26] Byyny RL, Preventing adrenal insufficiency during surgery. Postgraduate medicine. 1980 May     [PubMed PMID: 7375407]
[27] Fischer JE,Stallmach T,Fanconi S, Adrenal crisis presenting as hypoglycemic coma. Intensive care medicine. 2000 Jan     [PubMed PMID: 10663290]
[28] Annane D,Pastores SM,Rochwerg B,Arlt W,Balk RA,Beishuizen A,Briegel J,Carcillo J,Christ-Crain M,Cooper MS,Marik PE,Umberto Meduri G,Olsen KM,Rodgers S,Russell JA,Van den Berghe G, Guidelines for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in critically ill patients (Part I): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017. Intensive care medicine. 2017 Dec     [PubMed PMID: 28940011]
[29] Guignat L, Therapeutic patient education in adrenal insufficiency. Annales d'endocrinologie. 2018 Jun     [PubMed PMID: 29606279]