Adrenal Insufficiency


Article Author:
Martin Huecker


Article Editor:
Elvita Dominique


Editors In Chief:
Jessica Snowden
Asif Noor
H Davies


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Kyle Blair
Trevor Nezwek
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Daniyal Ameen
Altif Muneeb
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes
Komal Shaheen
Sandeep Sekhon


Updated:
8/18/2019 4:33:34 PM

Introduction

Adrenal insufficiency ranges from mild nonspecific symptoms to life-threatening shock condition. Adrenal insufficiency is a diagnosis that will not be made unless the clinician maintains a level of suspicion. The decreasing or suppressed adrenal function may be masked until stress or illness triggers an adrenal crisis.[1][2][3]

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 acute versus chronic nature of the disease. Acute adrenal insufficiency patients often present in a critically ill state while chronic presentations can be insidious.

Etiology

Most cases of Addison disease are iatrogenic and caused by long-term administration of glucocorticoids, which suppress the feedback mechanisms. This suppression can be so severe that during a stress period, the brain and adrenal gland may not be able to respond adequately. Alternatively, if the exogenous glucocorticoids are discontinued without a taper, the patient may have an adrenal crisis.[4]

The most common cause of primary adrenal insufficiency relates to autoimmune damage to the adrenal cortex. Other insults to the adrenal gland that lead to primary insufficiency include adrenal hemorrhage, cancer, infections (HIV, syphilis, TB, bacterial), and certain drugs such as etomidate, ketoconazole, fluconazole, metyrapone. Phenytoin and rifampin increase metabolism of cortisol and can, therefore, precipitate adrenal insufficiency in those predisposed.

Adrenal hemorrhage can occur in patients on anticoagulation medications or 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.

Epidemiology

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.[5][6]

The autoimmune form of adrenal insufficiency and has 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.

Pathophysiology

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).

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. 

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 my 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.

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 investigation for infectious etiology, although it can be present in any form of adrenal insufficiency.

Evaluation

Diagnosis of primary adrenal insufficiency requires suspicion. Hyponatremia with hyperkalemia and hypoglycemia may be present. Serum cortisol, ACTH, renin, aldosterone, and chemistry panel should be obtained early. Serum cortisol levels can help make diagnoses in the presence of elevated ACTH and plasma renin activity. The ACTH test can be performed to determine if the cause is central or peripheral.[7]

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

Consider testing for HIV and tuberculosis in patients with unclear etiology.

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

Treatment / Management

The treatment of Addison disease 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.[8][9][10]

In patients with established adrenal insufficiency, hydrocortisone is the treatment of choice, with 100 mg IV 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.

Differential Diagnosis

  • Sepsis
  • Shock
  • Hemorrhage
  • Miliary tuberculosis
  • Fungal infection

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 interdisciplinary 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 to 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. Finally, all patients with a diagnosis of adrenal insufficiency should be urged to wear a medical ID bracelet. [11][12](Level V)


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Adrenal Insufficiency - Questions

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A 64 year old has been taking steroids for asthma for 5 years. She undergoes urgent surgery for a perforated ulcer. Two days later, she becomes hypotensive, febrile, and hypoglycemic. What is the most likely diagnosis?



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Chronic adrenal insufficiency is characterized by which of the following?



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A female complains of fatigue and weakness. She has had decreased appetite, weight loss, alternating diarrhea and constipation, and severe lightheadedness upon standing. The patient has no significant past medical history. Vital signs show a heart rate of 88 bpm, respiration rate of 18 breaths per minute, and temperature of 37.2 C. The exam is remarkable for pigmentation of the oral mucosa, proximal muscle weakness of the lower extremities, and hyperpigmentation of the palmar creases, knuckles, knees, and elbows. The rest of the exam is normal. What is the most likely diagnosis?



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A 27-year-old female patient is 1-month postpartum. She has symptoms of anorexia, weight loss, hyperpigmentation, bowel changes, and lightheadedness on standing. The cosyntropin stimulation test shows random serum cortisol is 11 micrograms/dL (normal greater than or equal to 20 micrograms/dL). Serum cortisol 1 hour after 0.25 mg cosyntropin N is 14 micrograms/dL. The rise in cortisol is expected to be greater 7 micrograms/dL. What is the most likely etiology of this patient's illness?



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Which of the following indicates primary, as opposed to secondary, adrenal insufficiency?



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A female presents with anorexia, weight loss, hyperpigmentation, bowel changes, and lightheadedness on standing. The cosyntropin stimulation test shows random serum cortisol of 11 micrograms/dL (normal is greater than or equal to 20 micrograms/dL). Serum cortisol 1 hour after 0.25 mg cosyntropin N is 14 micrograms/dL. (The rise in cortisol is expected to be > 7 micrograms/dL). Aldosterone level is 10 ng/dL. Which of the following is an appropriate treatment for this patient?



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A female patient has primary adrenal insufficiency. She is on hydrocortisone 15 mg a day and fludrocortisone 0.1 mg daily. She becomes acutely ill after eating raw oysters. She has severe, "cramping" abdominal pain and profuse watery diarrhea. After 12 hours, she is brought to the emergency room because she cannot stand. Vital signs show a heart rate of 135 bpm, respiration rate of 28 breaths per minute, blood pressure of 72/25 mm Hg, and temperature of 38.1°C. The exam shows tachycardia without extra heart sounds, dry oral mucosa, clear lungs, and diffuse abdominal tenderness. A rectal exam is heme negative. There are no skin rashes. Which of the following is most appropriate for the initial management of this patient?



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A female patient has primary adrenal insufficiency. She is on hydrocortisone 15 mg a day and fludrocortisone 0.1 mg daily. She becomes acutely ill after eating raw oysters. She has severe, "cramping" abdominal pain and profuse watery diarrhea. After 12 hours, she is brought to the emergency room because she cannot stand. Vital signs show a heart rate of 135 bpm, respiration rate of 28 breaths per minute, blood pressure of 72/25 mm Hg, and temperature of 38.1°C. The exam shows tachycardia without extra heart sounds, dry oral mucosa, clear lungs, and diffuse abdominal tenderness. A rectal exam is heme negative. Saline bolus is started. What should be the next step in this patient's management?



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An HIV positive male, admitted to the intensive care unit with septic shock secondary to lobar pneumonia, is being mechanically ventilated. After 2 days of intravenous ceftriaxone, trimethoprim-sulfamethoxazole, and erythromycin, his fever has resolved. Blood cultures are positive for Streptococcus pneumoniae. Oxygen saturation is 92% on room air and blood pressure is 80/40 mm Hg, despite adequate fluids and 2 micrograms/kg/min of norepinephrine. Further examination reveals warm skin and full peripheral pulses. What is the best next step in management?



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A 64-year-old has been taking corticosteroids for asthma for five years. She undergoes urgent surgery for a perforated ulcer. Two days later, she becomes hypotensive, febrile, and hyperglycemic. What is her most serious diagnosis?



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A patient with a non-small cell cancer undergoes a lobectomy. Postoperatively, he becomes hypotensive, hypothermic, febrile, and unresponsive to the usual pressor drugs. Which of the following is best for the immediate treatment of this patient?



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What percentage of cases of primary adrenocortical insufficiency are caused by an autoimmune reaction?



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What is the second most common cause of primary adrenocortical insufficiency in adults?



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What is the leading cause of primary adrenocortical insufficiency in a 55-year-old?



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Which is the most common cause of primary adrenocortical insufficiency in adults?



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Which is least likely be observed in adrenocortical insufficiency?



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A child presented with dark skin discoloration and lethargy. Laboratory examination revealed hyponatremia. Which of the following is the most likely cause of his symptoms?



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A patient had a transsphenoidal resection of a suprasellar tumor. Two weeks later she develops dizziness and lethargy. On exam she is dehydrated. Laboratories studies show a sodium of 125 mEq/L, potassium of 6.0 mEq/L, and glucose of 45 mg/dL. Which of the following is the most likely diagnosis?



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Adrenocortical function is assessed by having a patient severely restrict sodium to 10 mmol/day and then have a hormone level. Select the hormone abnormality being evaluated.



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Which describes secondary adrenal insufficiency?



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What cortisol level can safely rule out adrenal insufficiency after the administration of cosyntropin?



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Analysis of Laboratory tests in a 50-year-old woman who presents with features of adrenal insufficiency shows normal serum levels of sodium, potassium, and low cortisol levels. What is the most likely diagnosis?



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A patient has developed primary adrenal insufficiency. Which of the following is true regarding this medical condition? Select all that apply.



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Adrenal Insufficiency - References

References

Ceccato F,Scaroni C, Central adrenal insufficiency: open issues regarding diagnosis and glucocorticoid treatment. Clinical chemistry and laboratory medicine. 2018 Nov 14     [PubMed]
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]
Kang TS,Choi HY,Park SH, Adrenal Insufficiency in a Patient with Acute Myocardial Infarction Plus Shock. Korean circulation journal. 2018 Dec     [PubMed]
Harbeck B,Lehnert H, [Diagnosis and Management of Adrenal Insufficiency]. Deutsche medizinische Wochenschrift (1946). 2018 Sep     [PubMed]
Rushworth RL,Torpy DJ,Stratakis CA,Falhammar H, Adrenal Crises in Children: Perspectives and Research Directions. Hormone research in paediatrics. 2018     [PubMed]
Meyer G,Badenhoop K, [Addisonian Crisis - Risk Assessment and Appropriate Treatment]. Deutsche medizinische Wochenschrift (1946). 2018 Mar     [PubMed]
Cole S, Evaluation and Treatment of Adrenal Dysfunction in the Primary Care Environment. The Nursing clinics of North America. 2018 Sep     [PubMed]
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]
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]
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]
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]
Guignat L, Therapeutic patient education in adrenal insufficiency. Annales d'endocrinologie. 2018 Jun     [PubMed]

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