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    Primary Adrenal Insufficiency

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    Jul.30.2025

    Primary Adrenal Insufficiency

    Synopsis

    Key Points

    • Primary adrenal insufficiency is a disorder characterized by insufficient adrenocortical synthesis and secretion of glucocorticoids, with or without deficiency in mineralocorticoids and adrenal androgens r1
    • Typical manifestations of primary adrenal insufficiency include hyperpigmentation, hypotension, hyponatremia, and hyperkalemia
      • Chronic adrenal insufficiency presents with nonspecific symptoms at onset, including abdominal pain, generalized weakness, fatigue, salt craving, and weight loss
      • Acute adrenal crisis presents with cardiovascular collapse and hemodynamic instability
    • Diagnostic process includes demonstration of low serum cortisol levels along with high plasma adrenocorticotropic hormone levels, followed by investigation to identify the underlying cause
    • Principal treatment is hormonal replacement of glucocorticoids and mineralocorticoids
    • Do not await laboratory confirmation of disease if suspicion is high, before beginning treatment, because delays can result in poor outcomes
    • It is essential to intensively educate patients and families about the need to increase glucocorticoid doses during intercurrent illness and stress to avoid adrenal crisis

    Urgent Action

    • Adrenal crisis
      • Suspected adrenal crisis requires immediate therapeutic action
      • Begin therapy with IV fluids and hydrocortisone, even before diagnostic test results are available r2
      • Adults
        • Rapidly infuse 1 L of 0.9% isotonic saline IV within the first hour, followed by additional IV fluids as dictated by patient's volume status and blood pressure response (usual requirement is 4-6 L in 24 hours) r3
        • Administer high-dose hydrocortisone IV for 24 hours then reduce daily dose r3
      • Children
        • Rapidly infuse IV bolus of 0.9% isotonic saline 20 mL/kg; can repeat up to a total of 60 mL/kg within 1 hour to treat shock r1
        • Administer hydrocortisone using age- and BSA-appropriate dosing IV bolus r1
        • If child is hypoglycemic, administer IV dextrose bolus and/or continuous IV infusion r3

    Pitfalls

    • Do not delay prompt treatment of suspected adrenal crisis while awaiting results of diagnostic measures. Delayed treatment may be fatal r2c1
    • For treatment of adrenal crisis, do not administer mineralocorticoids, because they are not needed when supraphysiologic doses of glucocorticoids are given r4

    Terminology

    Clinical Clarification

    • Primary adrenal insufficiency is a life-threatening condition in which the adrenal cortex is unable to produce sufficient glucocorticoids r1
      • May or may not be accompanied by deficient mineralocorticoid and androgen production
    • When primary adrenal insufficiency is caused by autoimmune disease, it is often called Addison disease
    • Acute adrenal crisis is a severe manifestation of adrenal insufficiency marked by cardiovascular collapse and hemodynamic instability r4r5
      • Medical emergency requiring immediate treatment; delayed treatment can be fatal
      • Infections are the major precipitating causes of adrenal crisis

    Classification

    • Adrenal insufficiency has various causes and manifestations, depending on defect site
      • Primary adrenal insufficiency r6
        • Reduced or absent corticosteroid production caused by defect at adrenal gland level
          • Most frequently caused by autoimmune adrenalitis (Addison disease)
      • Secondary adrenal insufficiency r6
        • Reduced or complete absence of pituitary corticotropin (adrenocorticotropic hormone) secretion, ultimately resulting in adrenal cortex atrophy; defect is at pituitary level
      • Tertiary adrenal insufficiency r6
        • Reduced or complete absence of corticotropin-releasing hormone secretion, leading to reduced pituitary corticotropin (adrenocorticotropic hormone) secretion, then adrenal cortex hypofunction; defect is at hypothalamus level
          • Most common cause is hypothalamic suppression after prolonged use of supraphysiologic doses of glucocorticoids r6r7
            • Any dosing of glucocorticoid beyond physiologic daily dose equivalents can potentially suppress the hypothalamus-pituitary-adrenal axis
            • Risk of glucocorticoid-induced adrenal insufficiency after cessation of glucocorticoid therapy depends primarily on glucocorticoid potency, dose, route of administration, and duration of use
          • Other medications, including opioids,r8 can also be culprits
      • Critical illness–related corticosteroid insufficiency r9r10
        • Controversial concept in which ICU patients are unable to produce required amount of cortisol essential for survival
        • Caused, in part, by dysregulation of hypothalamus-pituitary-adrenal axis during prolonged critical illness
        • Altered cortisol metabolism, cortisol clearance, and tissue resistance to cortisol all contribute to this diagnosis

    Diagnosis

    Clinical Presentation

    History

    • In chronic adrenal insufficiency, symptoms are nonspecific and develop over months to years r11
      • Nonspecific nature of symptoms can lead to delayed or missed diagnosis
      • There is often a history of steadily declining general health over weeks to months or even years r12r13c2
    • Symptoms of chronic adrenal insufficiency include: r14r15
      • Fatigue c3
      • Generalized weakness c4c5
      • Weight loss c6
      • Anorexia c7
      • Nausea and vomiting c8
      • Abdominal discomfort c9
      • Postural dizziness c10
      • Salt craving c11
      • Arthralgia and myalgias c12c13c14c15c16
      • Depression c17
      • Failure to thrive (in children) c18c19c20c21
      • Early puberty
    • Adrenal crisis may be triggered by a major stressor, such as febrile illness (higher than 38 °C), severe infection, surgery, or trauma r1c22c23c24
      • Symptoms can develop rapidly (within a few hours)
    • Symptoms of acute adrenal crisis include:

    Physical examination

    • Signs of chronic primary adrenal insufficiency include: r13r15
      • Hyperpigmentation, particularly in skin creases, mucosal membranes, scars, knuckles, elbows, axillae, and breast areolas c33c34c35c36c37c38c39c40c41
        • Variably present and can be affected by a person's level of background pigmentation; comparison with a sibling can be helpful
        • May not be apparent on black or brown skin; important to assess buccal mucosa or surgical scars, if any r14
      • Low blood pressure with postural drop c42c43
      • In females, loss of axillary and pubic hair c44c45
      • Fever c46
    • Signs of adrenal crisis include:
      • Hypotension c47
      • Tachycardia c48
      • Abdominal tenderness, sometimes with guarding c49c50c51c52
      • Delirium c53
      • Reduced consciousness c54
      • Hypoglycemia (particularly in children) c55

    Causes and Risk Factors

    Causes

    • Autoimmunity (80%-90% of all cases) r15c56
      • Isolated (destruction of adrenal cortex by cell-mediated immune mechanisms)
      • Associated autoimmune diseases r16r17
        • Autoimmune polyendocrine syndrome type 1 (OMIM #240300) r18c57
        • Autoimmune polyendocrine syndrome type 2 (OMIM %269200) r19c58
    • Infectious adrenalitis c59
      • Tuberculosis c60
      • Cytomegalovirus c61
      • HIV/AIDS c62c63c64
      • Fungal infection (eg, candidiasis, histoplasmosis, coccidioidomycosis, paracoccidioidomycosis, cryptococcosis) c65c66c67c68c69
      • Histoplasmosis c70
      • African trypanosomiasis c71
      • Syphilis c72
    • Adrenal hemorrhage c73
      • Trauma (eg, direct body blows, motor vehicle crash) c74c75c76c77c78
      • Anticoagulant medication c79
      • Meningococcal sepsis (Waterhouse-Friderichsen syndrome) c80c81
      • Antiphospholipid syndrome c82
        • Characterized by recurrent arterial and venous thrombosis and complications during pregnancy c83c84c85
        • Can be isolated or manifest in context of connective tissue disorders or malignancy c86c87
      • Complication of COVID-19 infection r20
    • Adrenal infiltration
      • Primary amyloidosis c88
      • Metastases (primarily lung, breast, colon, and lymphomatous tumors) c89c90c91c92c93c94
      • Hemochromatosis c95
    • Bilateral adrenalectomy (indicated for intractable Cushing syndrome or bilateral pheochromocytomas) c96
    • Medication
      • Adrenal enzyme inhibitors of cortisol synthesis c97
      • Medication adverse effects
    • Adrenoleukodystrophy in males r24c105
      • Rare X-linked recessive disorder that affects males and is caused by variants in the ABCD1 gene (ATP-binding cassette, subfamily D, member 1)
        • Results in defective oxidation of very-long-chain fatty acids and their accumulation in the adrenal cortex and brain
      • Clinical features include neurologic impairment and primary adrenal insufficiency, which present in infancy or childhood (most commonly present from ages 2 to 8 years)
      • Adrenal insufficiency is often the initial clinical manifestation c106
    • Rare genetic causes
      • Congenital adrenal hyperplasia (rare in general but the most common cause in childrenr1) r25c107
      • Adrenal hypoplasia congenita c108c109
      • Adrenocorticotropic hormone insensitivity syndromes c110
        • Type 1: sequence variants in MC2R gene (adrenocorticotropic hormone receptor/melanocortin 2 receptor) c111
        • Type 2: sequence variants in MRAP gene (melanocortin 2 receptor accessory protein) c112
      • Familial glucocorticoid deficiency (sequence variants in various genes relevant to the pathway) c113

    Risk factors and/or associations

    Age
    • Can present at any age, most commonly in patients aged 20 to 50 years r11
    Other risk factors/associations
    • Associated autoimmune diseases
      • Autoimmune polyendocrine syndrome type 1 (OMIM #240300) r18r26c114
        • Rare, autosomal recessive disorder caused by biallelic variants in AIRE gene (autoimmune regulator)
        • Common among people from Sardinia, Finland, and Iran
        • Characterized by chronic mucocutaneous candidosis, hypoparathyroidism, and adrenocortical insufficiency, which usually begin before ages 5, 10, and 15 years, respectively r1
        • Other autoimmune disorders, such as type 1 diabetes and pernicious anemia, can develop later in life
        • Autoantibodies against interferon-ω and interferon-α are present in more than 95% of patients r26
      • Autoimmune polyendocrine syndrome type 2 (OMIM %269200) r19r26c115
        • Polygenic inheritance
        • Characterized by autoimmune adrenal insufficiency, autoimmune thyroid disease, and type 1 diabetes
        • Much more prevalent than autoimmune polyendocrine syndrome type 1, and onset is in adolescence or adulthood

    Adrenal crisis triggers r4

    • Interruption of glucocorticoid intake
      • Patients with existing adrenal insufficiency can trigger adrenal crisis by abruptly discontinuing glucocorticoids altogether
    • Failure to increase glucocorticoid intake adequately during stressful events, such as: r9
      • Infection
      • Surgery
      • Gastroenteritis
      • Trauma or illness
    • Endurance exercise r27

    Diagnostic Procedures

    Primary diagnostic tools

    • Suspect a primary adrenal insufficiency in patients with unexplained hyperpigmentation, or otherwise unexplained symptoms or signs consistent with the condition, including weight loss, salt craving, nausea or vomiting, anorexia, postural hypotension, hyponatremia, hyperkalemia, or (especially in children) hypoglycemia r3r5
      • Suspect adrenal crisis in patients who become acutely unwell with confusion, weakness, hypotension, hyperpigmentation, hyponatremia, hypoglycemia (especially in children), or circulatory shock
        • This is a life-threatening emergency that requires immediate treatment; if suspected, obtain laboratory tests but do not delay treatment while awaiting results
    • Initial laboratory tests for all patients include measurement of serum creatinine and BUN, electrolytes, glucose, and CBC r15r21c116c117
    • In patients with suspected acute adrenal crisis obtain cortisol, corticotropin [ACTH], aldosterone, and renin levels r15r21
      • Adrenal insufficiency diagnosis entirely depends on demonstrating inappropriately low cortisol secretion r15r28
    • Optimal diagnostic strategy for patients with non-acute presentation r3r5
      • Obtain morning serum cortisol level
        • Diagnosis of adrenal insufficiency is suggested when there is a low morning cortisol level c118c119c120
      • Collect basal blood sample to measure plasma renin activity and aldosterone level to determine if mineralocorticoid deficiency is present c121c122c123
        • Mineralocorticoid deficiency may be a laboratory sign that heralds early evolving phase of primary adrenal insufficiency r5r21
      • Most patients also require corticotropin stimulation test and measurement of stimulated cortisol level to secure diagnosis c124
        • Collect blood sample to measure plasma adrenocorticotropic hormone level and baseline cortisol level before administering IV bolus cosyntropin c125
        • Diagnosis of adrenal insufficiency is confirmed by a low stimulated cortisol level
    • Alternative diagnostic testing
      • Morning (8:00 AM) cortisol level in combination with adrenocorticotropic hormone level is less preferred as a preliminary test; if this strategy is used, ideally it is followed by corticotropin stimulation test, when feasible r3c126
        • Patients do not require corticotropin stimulation test if they have a very low (lower than 3 mcg/dL) morning serum cortisol level and markedly elevated (higher than 300 pg/mL) adrenocorticotropic hormone level. These patients unequivocally have primary adrenal insufficiency
      • Low-dose corticotropin stimulation test is recommended only when cosyntropin is in short supply r3
    • Establishing primary versus secondary adrenal insufficiency r5r21
      • Determine if cortisol deficiency is independent of adrenocorticotropic hormone level (primary adrenal insufficiency) or due to inadequate secretion of adrenocorticotropic hormone (secondary adrenal insufficiency)
        • High adrenocorticotropic hormone level is consistent with primary adrenal insufficiency, whereas adrenocorticotropic hormone level that is low or within reference range is more consistent with secondary adrenal insufficiency
    • Additional investigations to determine underlying cause
      • Once a laboratory diagnosis of primary adrenal insufficiency is secured, determine underlying cause r15
      • First, assess for autoimmune adrenalitis by obtaining autoantibodies against 21-hydroxylase (CYP21A2) using a validated assay c127c128
      • For autoantibody-negative patients, seek other causes r3
        • For infants, select children, and rare adults: assess for possibility of congenital adrenal hyperplasia c129c130c131
        • For infants: consider rare genetic syndromes (ie, adrenal hypoplasia congenita) c132
        • For adults: consider adrenal infiltrative or destructive processes and order CT or MRI of the adrenals c133c134
        • For males: consider adrenoleukodystrophy and order testing for plasma concentrations of very-long-chain fatty acids c135c136

    Laboratory

    • Serum or plasma cortisol level (reference ranges apply to both) c137c138
      • Cortisol levels are highest in early morning and lowest 1 hour after usual time of sleep onset
      • Basal morning (8:00 AM) cortisol level lower than 5 mcg/dL is suggestive, but not diagnostic, of adrenal insufficiency r1r21
      • Usually, primary adrenal insufficiency is highly unlikely if a basal morning cortisol level is higher than 18 mcg/dL r21
      • Do not use random serum cortisol levels to exclude adrenal insufficiency
      • Reported cortisol levels are assay dependent r1
        • Liquid chromatography–tandem mass spectrometry has reduced cross-reactivity with other steroid hormones; thus, it often measures lower cortisol levels than immunoassays
        • There is wide interassay variability among different immunoassays
      • Test confounders that require special consideration for interpretation
        • Total cortisol results can be affected by presence of nephrotic syndrome, cirrhosis, or critical illness; in these cases, the low cortisol binding globulin and/or albumin levels may lower total cortisol levels r29
        • Oral estrogen contraceptives increase cortisol-binding globulin; thus, total cortisol levels may overestimate so-called free cortisol r30
        • Cortisol results also can be affected by rare conditions and unusual situations such as cortisol-binding globulin deficiency, glucocorticoid resistance, or hypersensitivity to the injected corticotropin r31
    • Plasma corticotropin (or adrenocorticotropic hormone) c139
      • Primary adrenal insufficiency: 8:00 AM plasma corticotropin level is high r6
        • Secondary adrenal insufficiency: 8:00 AM plasma corticotropin level is low or within reference range
      • Combination of a morning plasma corticotropin level twice the upper limit of reference range with a low morning cortisol level is highly predictive of primary adrenal insufficiency r3
      • Adrenocorticotropic hormone reference range is approximately 20 to 52 nanograms/L (reference range is assay dependent) r15
    • Plasma renin and serum aldosterone r28c140c141c142
      • Reference ranges are laboratory specific
      • Elevated plasma renin level plus reference-range or low serum aldosterone level is suggestive of primary adrenal insufficiency and is a pattern often seen in early phases of disease r17
    • Autoantibodies against 21-hydroxylase c143
      • Are detected in approximately 85% of patients with primary adrenal insufficiency but only rarely in patients with other non–immune-related causes of adrenal insufficiency r15
    • Serum chemistry panel c144c145c146c147
      • Hallmark values include hyponatremia and hyperkalemia, owing to both mineralocorticoid deficiency and glucocorticoid deficiency r15
      • Hypoglycemia can occur, especially in children r15
      • BUN and creatinine levels may be increased due to hypovolemia
    • CBC c148c149c150c151c152c153c154
      • Normocytic anemia, eosinophilia, and lymphocytosis can occur and reflect glucocorticoid deficiency r15

    Imaging

    • CT of adrenals c155
      • To investigate underlying cause of biochemically confirmed, autoantibody-negative adrenal insufficiency
      • Imaging appearance of hemorrhage depends on duration of bleeding r32
        • Acute mild hemorrhage shows peripheral gland enhancement and central low attenuation together with periadrenal infiltration
        • With ongoing bleeding, the adrenal gland enlarges and gives the appearance of a mass
        • CT demonstrates an oval or rounded adrenal mass with attenuation value higher than simple fluid (ranging from 50 to 90 Hounsfield units) r33
      • Granulomatous diseases (eg, tuberculosis, histoplasmosis) appear with bilateral enlargement in early stages of disease and, after administering contrast material, show peripheral rim enhancement with a necrotic center r34
      • Metastases tend to be heterogeneous with irregular margins, particularly when metastases are large and have attenuation values of higher than 10 Hounsfield units on unenhanced CT r32
    • MRI of adrenals c156
      • To investigate underlying cause of biochemically confirmed adrenal insufficiency
      • Hemorrhage appearance depends on bleeding duration r32
        • In acute stage (up to 7 days), a hematoma has low signal intensity on T2-weighted images
        • In subacute stage (1-7 weeks), a hematoma is hyperintense on T1-weighted images
        • In chronic stage (more than 7 weeks), a hemorrhage has low signal intensity on both T1- and T2-weighted images
      • Metastases usually exhibit low signal intensity on T1-weighted images and high signal intensity on T2-weighted images, with heterogeneous enhancement after administration of contrast material r32

    Functional testing

    • Corticotropin stimulation test c157
      • In most cases, used to confirm primary adrenal insufficiency diagnosisr3 unless basal cortisol level result is unequivocally low (ie, lower than 3 mcg/dLr15) and adrenocorticotropic hormone is high (higher than 300 pg/mL)
      • Many protocol variations exist; one that is commonly used is as follows: r3
        • At time just before 0, draw blood for baseline levels of serum cortisol and adrenocorticotropic hormone
        • At time 0, administer IV bolus of cosyntropin
        • At time 30 minutes, draw blood for cortisol level
        • At time 60 minutes, draw blood for cortisol level
      • Test result interpretation
        • Peak cortisol level should equal or exceed 18 mcg/dL; a level below this threshold indicates adrenal insufficiency
      • Test caveats
        • Can use low-dose corticotropin stimulation test as an alternative, but use is recommended only if there is a cosyntropin shortage
          • Low-dose corticotropin stimulation test is no more accurate than standard-dose corticotropin stimulation test r35
        • Sensitivity of standard-dose adrenocorticotropic hormone stimulation test for diagnosis of primary adrenal insufficiency is about 92%; thus, testing captures most cases r3
        • Test is not affected by diurnal variations and can be done at any time of day r28
      • Test confounders that require special consideration for interpretation
        • Total cortisol levels can be affected by presence of nephrotic syndrome, cirrhosis, or critical illness. In these cases, low cortisol-binding globulin and/or albumin levels may lower total cortisol levels r29r36
        • Oral estrogen contraceptives increase cortisol-binding globulin levels; thus, total cortisol levels may overestimate free cortisol r30
        • Cortisol results also can be affected by rare conditions and unusual situations such as cortisol-binding globulin deficiency, glucocorticoid resistance, or hypersensitivity to the injected corticotropin r31
      • For children
        • Newer studies propose adding 15-minute and 30-minute serum or salivary cortisol levels to the low-dose corticotropin stimulation test to correctly identify adrenal insufficiency r25

    Differential Diagnosis

    Most common

    • Chronic fatigue syndrome r37c158
      • Chronic persisting or relapsing fatigue of a generalized nature, causing significant disruption of usual daily activities, and present for more than 6 months
      • Presents with pronounced disabling fatigue, lethargy, and cognitive impairment
      • Unlike adrenal insufficiency, onset is often sudden and associated with viruslike symptoms (eg, fever, sore throat, cervical lymphadenopathy); like adrenal insufficiency, condition can become chronic and disabling
      • Additional symptoms include musculoskeletal discomfort, sleep disturbances, headaches, and temporomandibular joint pain
      • Diagnosis of exclusion, based on clinical criteria
      • Differentiated from primary adrenal insufficiency based on laboratory testing; in chronic fatigue syndrome, cortisol levels after corticotropin stimulation testing fall within reference range
    • Major depressive disorder r38r39c159d1
      • Chronic and relapsing mental disorder, characterized by pervasive sadness and reduced pleasure in most activities (anhedonia) persisting for at least 2 weeks
      • Major depression is formally diagnosed based on clinical history and DSM-5 criteria
        • Depressed mood for most days over 2 weeks along with at least 2 characteristic symptoms
          • Anhedonia
          • Unintentional weight loss or gain
          • Insomnia or hypersomnia
          • Psychomotor agitation or retardation
          • Fatigue
          • Feelings of worthlessness or inappropriate guilt
          • Diminished ability to concentrate or indecisiveness
          • Suicidal ideation or attempt
      • Distinguished based on laboratory testing; in primary adrenal insufficiency, cortisol levels are by definition low, whereas in major depressive disorder, these levels are within reference range or high r40
    • Infectious mononucleosis r41c160d2
      • Illness characterized by the following symptoms, lasting several weeks: sore throat, cervical lymphadenopathy, fatigue, and fever. Most often seen in adolescents and young adults
        • Most often caused by Epstein-Barr virus c161
      • Fever, fatigue, and myalgias are common to both adrenal insufficiency and mononucleosis c162c163c164c165
      • Unlike adrenal insufficiency, most symptomatic cases of mononucleosis are associated with painful, exudative pharyngitis
      • Diagnosis of Epstein-Barr virus mononucleosis can be made clinically or, if necessary, established by laboratory testing r42
        • Serologic tests for IgM antibodies to viral capsid antigen are positive in the first 4 to 6 weeks, then return to negativity
        • Serologic test results for IgG antibodies to viral capsid antigen are positive after 2 to 4 weeks of infection (and positivity often persists indefinitely thereafter); for IgG antibodies to nuclear antigen, after 2 to 4 months of infection
      • Cortisol levels are not low in mononucleosis, and serologic test result for IgM against Epstein-Barr virus is negative in adrenal insufficiency
    • Hypothyroidism r25r43c166d3
      • Inability of thyroid gland to produce sufficient thyroid hormone to meet bodily metabolic demands
      • Classic symptoms include fatigue, weight gain, constipation, cold intolerance, dry skin, proximal muscle weakness, and hair thinning or loss
      • Some symptoms that overlap with adrenal insufficiency include fatigue and poor concentration; however, patients with adrenal insufficiency usually lose weight, whereas those with hypothyroidism often gain weight
      • The 2 conditions are distinguished based on cortisol levels, cosyntropin testing, and thyroid function tests
        • Slightly elevated TSH level sometimes can occur in untreated adrenal insufficiency owing to diminished cortisol and consequent abnormalities in TSH circadian rhythm r44
        • In isolated adrenal insufficiency (in absence of polyglandular endocrinopathy), peripheral thyroid hormone levels (eg, free T4, total T4) fall within reference range
        • Persistent TSH elevation should prompt an investigation of coexisting hypothyroidism r45
    • Gastrointestinal malignancy c167d4
      • Various gastrointestinal symptoms (nausea, vomiting, abdominal pain) are similar to these symptoms in the presenting stages of adrenal insufficiency r12d5
      • Gastric, pancreatic, and colon cancer all may present with symptoms that resemble the gastrointestinal distress typical of adrenal insufficiency d6
        • In both gastrointestinal malignancy and adrenal insufficiency, weight loss is unintentional and usually associated with absence of appetite
        • Abdominal pain is diffuse in adrenal insufficiency, whereas it may be prominent in the left upper quadrant in gastric cancer, epigastric and radiating to the back in pancreatic cancer, and segmental in colon cancer
      • Advanced stages of gastrointestinal cancers may exhibit signs of metastases (eg, elevated liver transaminase levels, jaundice)
      • Gastrointestinal malignancies are identified using endoscopy or abdominal CT
    • Sepsis r46c168d7
      • Life-threatening syndrome of organ dysfunction caused by dysregulated host response to infection
      • Features of sepsis that are common to adrenal insufficiency include weakness, vomiting, hypotension, and altered mental status
      • Differentiating features: sepsis usually arises with a very acute onset of fever (higher than 38.5 °C), often with shaking chills and rigors
      • Sepsis is formally confirmed by positive blood cultures or culture of an alternative source showing microbial infection, whereas primary adrenal insufficiency is verified by low cortisol response to corticotropin stimulation test and low adrenocorticotropic hormone level

    Treatment

    Goals

    • Replace glucocorticoids and mineralocorticoids in a physiologic manner; do not overreplace r1r15
      • Optimal glucocorticoid replacement mimics circadian rhythm of cortisol secretion
    • Restore and maintain blood pressure within reference range
    • Avoid adrenal crisis r1
    • In children, attain physical and pubertal growth within reference range r1r25

    Disposition

    Admission criteria

    Acute adrenal crisis

    Criteria for ICU admission
    • Hypovolemic or vasodilatory shock

    Recommendations for specialist referral

    • Consult endocrinologist for interpretation of diagnostic test results and management of corticosteroid replacement

    Treatment Options

    Acute adrenal crisis r3r22

    • Treatment of an adrenal crisis consists of IV administration of saline, dextrose, and hydrocortisone
    • Adults
      • Rapidly infuse 1 L of 0.9% isotonic saline or 5% dextrose in isotonic saline within the first hour, followed by continuous IV isotonic saline guided by individual patient responses (eg, blood pressure, clinical assessment of volume status) r3
      • Treat with high-dose hydrocortisone IV for 24 hours then reduce daily dose r3
      • Mineralocorticoids are not needed when supraphysiologic doses of glucocorticoids are given r4
        • No additional mineralocorticoids are necessary if total daily dose of hydrocortisone is higher than 50 mg r4
        • Administering IV saline along with large doses of hydrocortisone is almost always sufficient to normalize blood pressure and electrolyte levels; mineralocorticoids are usually unnecessary in the first phase of treatment
    • Children
      • Give rapid IV bolus of 0.9% isotonic saline 20 mL/kg; can repeat up to a total of 60 mL/kg within 1 hour for shock r3
      • Administer hydrocortisone IV using age- and BSA-appropriate dosing (required in children) r3
        • Do not use prednisone to treat adrenal crisis, owing to its first-pass metabolism in the liver r1
      • If child is hypoglycemic, administer IV dextrose bolus and/or continuous IV infusion r3

    Chronic management of adrenal insufficiency

    • Adults
      • Glucocorticoid replacement r3
        • Prescribe hydrocortisone or cortisone acetate in 2 or 3 divided oral doses per day r27
          • Highest dose is taken immediately upon waking in the morning
            • Twice-daily dose regimen (most commonly used): give second dose in early afternoon
            • Thrice-daily dose regimen: give second dose at lunch and third in afternoon
          • Thrice-daily dosing induces cortisol profiles that more closely mimic physiologic profiles than twice-daily dosing,r47 but less-frequent dosing may be associated with greater adherencer48
        • Alternative formulations and preparations for once-daily dosing are available and are more convenient
          • Prednisolone can be used, but adverse metabolic consequences (eg, weight gain, dyslipidemia) tend to occur
          • Once-daily dual release hydrocortisone tablet (Plenadren) is being studied and has orphan drug designation in the United States; it has been shown to have more favorable metabolic profiles, improve quality of life, and reduce fatiguer49r50
        • Do not use dexamethasone; it has greater likelihood of inducing cushingoid adverse events
      • Mineralocorticoid replacement r3
        • For patients with confirmed aldosterone deficiency, prescribe fludrocortisone
          • Begin mineralocorticoid replacement as soon as total daily dose of hydrocortisone is less than 50 mg per 24 hours r2
        • Titrate dosing to achieve blood pressure and blood electrolyte levels within reference range and to eliminate edema and salt cravings
          • Generally, use clinical measures to assess adequacy of mineralocorticoid replacement; however, if there is any uncertainty, one can ensure proper dosing by targeting plasma renin level to upper end of reference range r5
          • Reduce fludrocortisone dose if hypertension develops
        • Higher doses of fludrocortisone may be needed if prednisolone is prescribed (in place of hydrocortisone) because of its lower mineralocorticoid activity
        • Temporary increases in fludrocortisone (50%-100%) may be needed for hot weather or situations that lead to heavy sweating r3
      • Dehydroepiandrosterone replacement
        • Controversial owing to inconsistent data about any benefits r51r52
        • Some experts suggest that after optimizing glucocorticoid and mineralocorticoid replacement, clinician can consider a trial of dehydroepiandrosterone in females with low libido, depression, and fatigue r3
        • Beneficial effects of dehydroepiandrosterone therapy show high interindividual variation r52
          • May, in part, be due to its FDA designation as a dietary supplement (content is not regulated or verified)
        • If given, inform patients that it is not considered a standard of care for chronic adrenal insufficiency treatment and limit trial of dehydroepiandrosterone to 6 months. If beneficial responses do not occur, discontinue r3r52
          • For patients who are given a trial, monitor for clinical signs of androgen excess (eg, acne, hirsutism). Aim for serum dehydroepiandrosterone sulfate levels to fall within the middle of the reference range r52
    • Children
      • Glucocorticoid replacement r1
        • Treat with hydrocortisone in 3 or 4 divided doses throughout the day
          • Prescribe first dose (slightly higher than other doses) to be taken upon waking in the morning; last dose is taken 4 to 6 hours before bedtime
          • Avoid synthetic long-acting glucocorticoids (eg, prednisolone, dexamethasone) in children because these medications have potent suppressor effects on growth
          • Adrenal insufficiency due to congenital adrenal hyperplasia requires higher doses
      • Mineralocorticoid replacement r1
        • Children require mineralocorticoids in most if not all cases
        • Treat with fludrocortisone
        • Infants up to age 12 months should instead be given sodium chloride supplements of 1 to 2 g/day to ensure adequate sodium intake

    Drug therapy

    • Synthetic corticotropin for stimulation test
      • Cosyntropin
        • Standard dose
          • Cosyntropin Solution for injection; Infants: 15 mcg/kg/dose (Max: 125 mcg/dose) IV/IM as a single dose.
          • Cosyntropin Solution for injection; Children younger than 2 years: 125 mcg IV/IM as a single dose.
          • Cosyntropin Solution for injection; Children and Adolescents 2 to 17 years: 250 mcg IV/IM as a single dose.
          • Cosyntropin Solution for injection; Adults: 250 mcg IV/IM as a single dose.
        • Low dose
          • Cosyntropin Solution for injection; Infants, Children, and Adolescents: 1 mcg IV/IM as a single dose.
          • Cosyntropin Solution for injection; Adults: 1 mcg IV/IM as a single dose.
    • Glucocorticoids c169
      • Hydrocortisone c170
        • For acute adrenal crisis
          • Hydrocortisone Sodium Succinate Solution for injection; Infants : 2 mg/kg/dose, or 50 to 100 mg/m2/dose, or 10 to 25 mg IV/IM as a single dose, then 50 to 100 mg/m2/day or 10 to 25 mg/day continuous IV infusion or IV/IM in divided doses every 6 hours for 24 hours.
          • Hydrocortisone Sodium Succinate Solution for injection; Children 1 to 5 years: 2 mg/kg/dose (Max: 100 mg), or 50 to 100 mg/m2/dose, or 25 to 50 mg IV/IM as a single dose, then 50 to 100 mg/m2/day or 25 to 50 mg/day continuous IV infusion or IV/IM in divided doses every 6 hours for 24 hours.
          • Hydrocortisone Sodium Succinate Solution for injection; Children and Adolescents 6 to 17 years : 2 mg/kg/dose (Max: 100 mg), or 50 to 100 mg/m2/dose, or 50 to 100 mg IV/IM as a single dose, then 50 to 100 mg/m2/day IV or 50 to 100 mg/day continuous IV infusion or IV/IM in divided doses every 6 hours for 24 hours.
          • Hydrocortisone Sodium Succinate Solution for injection; Adults: 100 mg IV once, then 200 mg/day continuous IV infusion or 50 mg IV/IM every 6 hours for 24 hours, then 100 mg/day continuous IV infusion or IV/IM in divided doses.
        • For glucocorticoid replacement
          • Hydrocortisone Oral tablet; Infants, Children, and Adolescents: 8 to 10 mg/m2/day PO in 3 or 4 divided doses.
          • Hydrocortisone Oral tablet; Adults: 15 to 25 mg/day PO in 2 or 3 divided doses.
      • Prednisolone
        • Prednisolone Oral solution; Adults: 4 to 7.5 mg/day PO in 2 divided doses, or 1 to 2.5 mg/day PO in 2 divided doses when used in combination with hydrocortisone.
    • Mineralocorticoid c171
      • Fludrocortisone r28c172
        • Fludrocortisone Acetate Oral tablet; Infants†: 0.05 mg PO twice daily, initially. Adjust dose based on clinical response and tolerability. Dose range: 0.05 to 0.2 mg/day in 2 divided doses.
        • Fludrocortisone Acetate Oral tablet; Children† and Adolescents†: 0.05 mg PO twice daily, initially. Adjust dose based on clinical response and tolerability. Dose range: 0.05 to 0.2 mg/day in 2 divided doses.
        • Fludrocortisone Acetate Oral tablet; Adults: 0.05 to 0.1 mg PO once daily, initially. Adjust dose based on clinical response and tolerability. Dose range: 0.05 to 0.2 mg/day.

    Nondrug and supportive care

    • Patient education c173
      • Provide information about how to manage sick days and how to identify situations that require emergency glucocorticoids to be administered parenterally r14
        • Increase dosage of glucocorticoids during intercurrent illness, fever, and stress
          • Double usual hydrocortisone dose if fever is higher than 38 °C, or triple dose if fever is higher than 39 °C, until recovery r3
        • Increase consumption of electrolyte-containing fluids as tolerated
      • Teach patients how to self-inject glucocorticoids for impending crisis r14c174
        • Provide patient with a hydrocortisone emergency injection kit, which contains 100 mg hydrocortisone sodium succinate for injection (can be given by self or other layperson) r12
        • Advise patients to go to the emergency department if unable to self-inject intramuscular glucocorticoids at home
      • Advise patients to inform health care providers of their condition if undergoing medical or dental procedures r11
        • Steroid doses will need to be increased according to the degree of physiological stress induced
    • Medical emergency monitoring and call systems c175c176c177c178
      • Arrange for patients to obtain a medical alert bracelet c179c180

    Special populations

    • Patients with hypertension r53
      • First, optimize glucocorticoid replacement, and consider reducing dose if there are clinical signs of excessive dosing
      • Next, consider slightly reducing fludrocortisone dose if there are signs of mineralocorticoid excess (eg, edema, hypokalemia)
        • Plasma renin measurement can help determine proper mineralocorticoid replacement, if needed; plasma renin level is ideally toward the upper end of or above reference range r5
      • If hypertension persists, begin antihypertensive therapy r53
        • ACE inhibitor or angiotensin II receptor antagonist is preferred
        • Dihydropyridine calcium channel blockers are clinically useful as second line agents
        • Avoid diuretics and aldosterone antagonists (eg, spironolactone, eplerenone)
    • Pregnant patients r3
      • Monitor pregnant patients with primary adrenal insufficiency at least once per trimester for symptoms and signs of glucocorticoid under- and overreplacement
        • Monitoring parameters include gestational weight gain, orthostatic blood pressure, and blood glucose levels
      • Increase hydrocortisone dose in third trimester if patient develops signs of adrenal insufficiency
      • Give hydrocortisone stress dose, beginning at onset of labor and continuing during active labor
      • Postpartum dosing: double usual oral dose for 24 to 48 hours after delivery, then taper to normal dose
      • Use hydrocortisone preferentially over other glucocorticoid preparations (eg, cortisone acetate, prednisolone, prednisone); do not use dexamethasone, because it is not inactivated in the placenta
    • Surgical or ICU patients r12
      • Adjust glucocorticoid dose for surgical stress, trauma, or for illness requiring intensive care
        • Dosing for surgical procedures varies depending on the type or grade of procedure
        • Hydrocortisone stress dosing and administration of weight-appropriate continuous IV fluids with 5% dextrose and 0.45% sodium chloride may be required in those requiring intensive care
    • Shift workers
      • Change timing of glucocorticoid dosing so that larger dose of hydrocortisone is taken upon waking (eg, in the evening if patient sleeps during normal daytime hours) r6
    • Athletes
      • For very-long-duration endurance events, consider slightly increasing dose of corticosteroids
        • For example, during a marathon or triathlon, consider a 2.5- to 5-mg increase in hydrocortisone and 50- to 100-mcg increase in fludrocortisone, depending on environmental temperature and humidityr54
    • Patients with thyroid disease
      • Thyroid hormone increases metabolism and cortisol clearance r45
      • Patients with thyrotoxicosis who have adrenal insufficiency require higher replacement doses of glucocorticoids r45
      • Initiating thyroid hormone in patient with newly diagnosed hypothyroidism may induce adrenal crisis r5

    Monitoring

    • Monitor patients carefully throughout their lives to avoid over- or undertreating with glucocorticoids and mineralocorticoids
    • Monitor the following parameters at least annually in adults and children to ensure appropriate corticosteroid dosing r3r14
      • Body weight, appetite, and sleep c181c182c183
      • Postural blood pressure c184
      • Energy level c185c186
      • Signs of glucocorticoid excess (eg, dorsocervical fat pad prominence, hirsutism, facial rounding) c187c188
      • Signs of glucocorticoid underreplacement (eg, worsening hyperpigmentation, muscle weakness)
      • Blood electrolyte levels, for mineralocorticoid replacement c189
      • In children, growth velocity and weight gain c190c191c192c193
      • Bone density (at least once in adults in the 5 years after diagnosis)
    • Do not measure blood steroid hormone levels or use these levels to adjust glucocorticoid or mineralocorticoid dosing r6
      • There are no reliable hormonal markers to assess appropriate dosing of glucocorticoids
      • Adrenocorticotropic hormone level cannot be used to guide glucocorticoid dose adjustments, because targeting levels within the reference range leads to chronic overreplacement r1
      • Fludrocortisone requirements can be monitored periodically with serum sodium and potassium levels and plasma renin levels (in addition to clinical measures stated earlier) r6
    • Do measure morning serum dehydroepiandrosterone sulfate levels to monitor dehydroepiandrosterone replacement (if used) r3c194
    • At least annually, monitor patient for development of associated autoimmune diseases, particularly autoimmune thyroid disease r3c195c196
      • Watch for the following conditions: thyroid disease, diabetes mellitus, premature ovarian failure, celiac disease, and autoimmune gastritis with vitamin B₁₂ deficiency c197c198c199c200c201c202c203c204c205c206c207c208
      • Screening laboratory tests to do annually include CBC plus TSH, free T₄, and hemoglobin A1C levels r3
    • Patients receiving fludrocortisone should be monitored for: r28
      • Blood electrolyte levels
      • Symptoms of salt craving, light-headedness, blood pressure changes, and swelling of legs and feet

    Complications and Prognosis

    Complications

    • Adrenal crisis r11
      • Occurs in around 50% of patients diagnosed with adrenal insufficiency
    • Chronic overtreatment with glucocorticoids leads to several undesirable health outcomes, including: r1
    • Delayed treatment of hypoglycemia can lead to long-term neurologic deficits

    Prognosis

    • Chronic adrenal insufficiency
      • Increased mortality
        • Standardized mortality ratio in primary adrenal insufficiency is more than 2-fold, mainly owing to infections, cancer, and cardiovascular causes r56r57
      • Health-related quality of life is reduced, even in patients who receive standard corticosteroid replacement r48
    • Acute episodes of adrenal crisis
      • In most patients, treatment with parenteral glucocorticoids and correction of hypovolemia with isotonic saline is uniformly successful and leads to clinical recovery within 24 hours r12
      • For patients with long-standing untreated adrenal insufficiency presenting with confusion and somnolence, full recovery can take from several days to 1 week r12
      • Estimated mortality rate for adrenal crisis is 0.5% to 2% r4

    Screening and Prevention

    Screening

    Screening tests

    • Universal newborn screening for adrenoleukodystrophy has been implemented in most states in the US r58r59c213

    Prevention

    • Prevention of adrenal crisis in patients with known adrenal insufficiency
      • Monitor patient regularly (eg, every 6-12 months) for symptoms and signs of undertreatment c214c215
      • Educate patients and caregivers regarding symptom awareness and situations requiring adjustment of glucocorticoid replacement level and need to inform health care providers if undergoing medical or dental procedures c216
      • Adjust glucocorticoids according to illness severity or stressor magnitude c217c218
      • Provide patient with medical information card identifying the patient as requiring daily steroid replacement (a so-called steroid replacement card) c219
      • Provide patient with a hydrocortisone emergency injection kit, which contains hydrocortisone sodium succinate for injection that can be self-injected or given by another layperson c220c221c222
      • Encourage patients with adrenal insufficiency to wear medical call bracelet c223c224
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