Harrison's Practice: Primary Adrenal Insufficiency

Harrison's Practice

Primary Adrenal Insufficiency

Definition

Adrenal insufficiency
- A disease state caused by insufficient circulating adrenocortical hormones.
  - In clinical practice, the term primarily refers to glucocorticoid deficiency.
  - Isolated mineralocorticoid deficiency is termed hypoaldosteronism.
  - Adrenal androgen deficiency is of limited clinical importance.
- May be caused by abnormalities at each level of the hypothalamic-pituitary-adrenal axis.
  - Primary adrenal insufficiency (disease process resides in the adrenal gland) must be differentiated from secondary adrenal insufficiency (defect in pituitary ACTH secretion; see Hypopituitarism) and tertiary adrenal insufficiency [defect in hypothalamic corticotropin-releasing hormone (CRH) production; see Hypopituitarism].
- Hormone deficiency may be partial or complete.
- Clinical effects may be mild or severe, and are typically exacerbated by stressful conditions that demand higher cortisol levels.
Primary adrenal insufficiency (Addison’s disease)
- Caused by adrenal gland destruction or dysfunction.
- Autoimmune adrenal destruction is the most common cause (>70% of cases).
- When first described in the 19th century, tuberculosis affecting the adrenal glands was by far the leading cause.
Functional or relative adrenal insufficiency
- Subnormal cortisol production during critical illness, such as septic shock
- The elevated cortisol levels observed are viewed as insufficient to control the inflammatory response and maintain blood pressure.

Epidemiology

Prevalence
- ~12 per 100,000 persons
Incidence
- ~0.5 per 100,000 persons per year
Age
- May occur at any age, with peak incidence in the fourth decade
Sex
- Autoimmune causes: overall female predominance
  - When part of a polyglandular autoimmune syndrome, ~70% female
  - When an isolated finding:
    - First 20 years of life: primarily male
    - Age 40 and upward: primarily female
- Non-autoimmune causes: equal sex distribution

Risk Factors

Genetic
- Isolated autoimmune adrenal insufficiency (i.e., not associated with any other coexisting endocrine abnormalities)
  - Familial in one-third of cases
  - Strongly associated with human leukocyte antigen B8, DR3, and DR4 alleles
- Congenital abnormalities of cortisol synthesis
  - 21-Hydroxylase deficiency is most common.
- Autoimmune polyglandular syndrome (See Associated Conditions.)
  - Type I polyglandular autoimmune syndrome has an autosomal recessive inheritance pattern.
  - Type II polyglandular autoimmune syndrome has polygenic, autosomal dominant, and autosomal recessive inheritance patterns.
Medications
- Rifampin, phenytoin, ketoconazole, megestrol, and opiates may cause or potentiate adrenal insufficiency.
Anticoagulants (adrenal hemorrhage)
Hypercoagulable states (adrenal infarction)
Severe sepsis (e.g., meningococcus)

Etiology

Progressive destruction of the adrenal glands

>90% destruction is required to cause adrenal insufficiency.
Hyperpigmentation, which is unique to primary adrenal insufficiency, is due to increased melanin in the skin.
- Results from the increased pituitary secretion of ACTH, a powerful stimulator of melanin production.
Autoimmune causes (~80% of cases)
- Isolated adrenal insufficiency
- Type I or II polyglandular autoimmune syndrome (See Associated Conditions.)
Infectious causes
- Tuberculosis
  - Adrenal destruction results from hematogenous spread from active disease elsewhere in the body.
- Fungal
  - Histoplasmosis (endemic)
  - Paracoccidioidomycosis (endemic)
  - Coccidioidomycosis (opportunistic)
  - Cryptococcosis (opportunistic)
- HIV- or AIDS-related
  - HIV
  - Cytomegalovirus
  - Mycobacterium avium-intracellulare infection
  - Opportunistic fungal infection (see above)
  - Kaposi’s sarcoma
  - Medication effect
Metastatic cancer
- Lung
- Breast
- Melanoma
- GI
- Lymphoma
Bilateral adrenal hemorrhage
- Associated with sepsis due to Pseudomonas infection or meningococcemia (Waterhouse–Friderichsen syndrome)
  - Can in rare instances be caused by other organisms: Escherichia coli, Neisseria gonorrhoeae, Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus
- Anticoagulant therapy
Adrenal infarction
- Hypercoagulable states (e.g., antiphospholipid syndrome)
Infiltrative

Other etiologies

Under this heading are listed congenital causes, medication effects, and acute adrenal destruction.
Genetic causes (present primarily in infancy and childhood)
- Congenital adrenal hyperplasia (CAH) (caused by mutations in several of the steroidogenic enzyme genes)
- Adrenoleukodystrophy (caused by mutation in ABCD1, which encodes a peroxisomal membrane transporter responsible for transport of long-chain fatty acids into peroxisomes); associated with cellular accumulation of very-long-chain fatty acids
  - Adrenomyeloneuropathy is a milder variant of adrenoleukodystrophy.
- Congenital lipoid adrenal hyperplasia (caused by mutation in STAR [encoding steroidogenic acute regulatory protein], or rarely CYP11A [encoding cholesterol side chain cleavage enzyme])
- Rare
  - Adrenal hypoplasia congenita (caused by mutations in DAX1 or NR5A1, which encode Dax-1 and SF-1 transcription factors, respectively).
    - Associated with varying degrees of testicular dysgenesis and hypogonadotropic hypogonadism (See Hypogonadism.)
  - Smith–Lemli–Opitz syndrome (caused by mutation in DHCR7, which encodes delta-7-sterol reductase [7-dehydrocholesterol reductase])
  - IMAGe (intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies)
  - Kearns–Sayre syndrome
  - ACTH resistance (familial glucocorticoid deficiency), caused by mutations in MC2R, encoding the melanocortin 2 receptor (ACTH receptor), or mutations in MRAP, which encodes melanocortin 2 receptor accessory protein, thought to be involved in ACTH receptor trafficking.
    - Additional genetic heterogeneity exists.
  - Triple A syndrome (Allgrove’s syndrome): alacrima, achalasia, adrenal insufficiency (caused by mutation in AAAS, which encodes ALADIN, a nuclear pore protein)
Medication effects
- Inhibitors of cortisol synthesis enzymes (metyrapone, ketoconazole, aminoglutethimide)
- Drugs that accelerate glucocorticoid metabolism (phenobarbital, phenytoin, rifampin )
- Adrenolytic agents (mitotane)
Bilateral adrenalectomy
Acute adrenocortical insufficiency or adrenal crisis
- Rapid and overwhelming intensification of chronic adrenal insufficiency, usually precipitated by sepsis or surgical stress

Glucocorticoid resistance

Mimics some aspects of adrenal insufficiency or CAH because of cellular resistance to glucocorticoid action
Can be familial or sporadic, generalized or tissue-specific
Caused by mutations in NR3C1 (GCR), which encodes the glucocorticoid receptor
Phenotype includes an activated hypothalamo-pituitary-adrenal axis (increased ACTH, cortisol, adrenal androgens, 11-deoxycorticosterone, etc.), resulting in hirsutism and hypertension without cushingoid features.
- Clinical manifestations are highly variable.
- Few signs resembling glucocorticoid deficiency (e.g., fatigue) as resistance is compensated for by high cortisol levels.
- Increased anxiety (attributed to elevated CRH output)

Associated Conditions

Type I polyglandular autoimmune syndrome
- Autosomal recessive syndrome characterized by the combination of hypoparathyroidism, adrenal insufficiency, and chronic mucocutaneous candidiasis
- Also called autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy syndrome
- Additional autoimmune diseases that may coexist: pernicious anemia, chronic active hepatitis, vitiligo, alopecia, primary hypothyroidism, and premature gonadal failure
- Caused by inactivating mutations of the AIRE (autoimmune regulator) gene, which encodes a transcription factor that functions as an autoimmune suppressor
- Usually presents during infancy
Type II polyglandular autoimmune syndrome
- Complex genetic disorder characterized by the presence of ≥ 2 of the following autoimmune conditions: adrenal insufficiency, chronic lymphocytic thyroiditis, premature ovarian failure, type 1 diabetes mellitus, Graves’ disease
- Additional features that may coexist: pernicious anemia, vitiligo, alopecia, nontropical sprue, myasthenia gravis
- Polygenic, autosomal dominant, and autosomal recessive inheritance patterns have been described.
- Usually presents in childhood through adulthood
AIDS (See Etiology.)
- Clinically overt adrenal dysfunction is rare, but subtle impairments in adrenal reserve are common in hospitalized patients.
- Most often due to opportunistic infections, but may also be caused by medications
- Megestrol acetate may cause secondary adrenal insufficiency.

Symptoms & Signs

Symptoms and signs are relatively nonspecific and have an insidious onset in most cases (due to gradual adrenal destruction).
Common
- Fatigue
- Weakness (>90%)
- Malaise
- Abnormalities of GI function
  - Anorexia (90%)
  - Weight loss (>90%)
  - Nausea and vomiting
  - Diarrhea or constipation
  - Unlocalized, often severe abdominal pain
- Personality changes
  - Often occur early in the disease and very responsive to glucocorticoid replacement therapy
  - Irritability
  - Restlessness
  - Impaired memory
  - Depression
  - May progress to frank psychosis (not as responsive to glucocorticoid therapy)
- Hyperpigmentation (>90%)
  - Specific to primary adrenal insufficiency (not seen in other types of adrenal insufficiency)
  - Diffuse brownish darkening of exposed and unexposed skin
  - Elbows, knuckles, and creases of the hand are particularly darkened
  - Blue-black patches on mucous membranes
  - Darkened freckles
  - Persistent tan after sun exposure
- Hypotension, with postural accentuation (< 110/70 mmHg) (>80%)
  - Syncope
- Dehydration with hyponatremia and hyperkalemia
Less common
- Salt craving
  - Specific to primary adrenal insufficiency (due to aldosterone deficiency)
- Loss of axillary and pubic hair in women (loss of adrenal androgens)
- Calcification of auricular cartilage in men only
- Irregular areas of vitiligo
- Hypoglycemia
Signs and symptoms of acute adrenal insufficiency (adrenal crisis)
- Usually precipitated by an acute event (infection, trauma, other severe illness)
- Shock, often with fever and generalized abdominal tenderness, is the most common presentation.
- Less often, patients present with:
  - Significant hypoglycemia
  - Altered mental status
  - Coma
  - Nonspecific GI complaints
  - Weakness and fatigue

Differential Diagnosis

Consider hypothalamic-pituitary disease as causes of tertiary or secondary adrenal insufficiency.
Exclude recent exogenous glucocorticoid treatment.
Other causes of shock
- Septic
- Cardiogenic
- Hypovolemic
- Anaphylactic
Abdominal pain due to other causes
Hypotension due to other causes (e.g., medications)
Hyperkalemia due to other causes (e.g., renal failure, medications)
Occult cancer
Anorexia nervosa
Isolated idiopathic hypoaldosteronism
Other causes of hyperpigmentation
- Hemochromatosis (mucous membranes are unaffected)

Diagnostic Approach

Diagnosis of primary adrenal insufficiency evolves over 3 stages:
- Demonstrate an inappropriately low cortisol level
  - When screening is suggestive of adrenal insufficiency, dynamic testing is required for diagnosis.
    - ACTH stimulation testing is the preferred initial dynamic test to assess adrenal capacity for steroid production.
- Distinguish primary from secondary (and rarely, tertiary) insufficiency
  - Two guidelines help to distinguish primary adrenal insufficiency from secondary adrenal insufficiency:
    - Hyperpigmentation is seen only in primary adrenal insufficiency
    - Hyperkalemia also suggests primary adrenal insufficiency, because mineralocorticoid function is preserved in secondary adrenal insufficiency
  - Assignment of adrenal insufficiency to primary or secondary/tertiary causes is based on plasma ACTH levels.
  - ACTH level is elevated (>100 pg/mL) in primary adrenal insufficiency and normal or low in secondary adrenal insufficiency.
- Identify the specific cause of primary adrenal insufficiency

Laboratory Tests

General

Primary adrenal insufficiency
- Early phase
  - May show no demonstrable abnormalities in laboratory values
- More advanced stages
  - Serum potassium level is elevated.
  - Serum sodium, chloride, and bicarbonate levels may be reduced.
  - Basal levels of cortisol and aldosterone are subnormal.
- Other laboratory abnormalities
  - Mild to moderate hypercalcemia (up to 20% of patients)
  - Normocytic anemia
  - Relative lymphocytosis
  - Moderate eosinophilia
  - Hypoglycemia

Screening test

Serum cortisol (8 A.M.)
- Normal value (>18 μg/dL [>500 nmol/L]) excludes adrenal insufficiency.
- Abnormal value (< 3 μg/dL [< 80 nmol/L]) is highly suggestive of adrenal insufficiency.
- Indeterminate value: 3–18 μg/dL (80–500 nmol/L)
Plasma ACTH measurement (simultaneous)
- Must be collected in an ethylenediamine tetraacetic acid (EDTA) tube, placed on ice, and processed immediately for an accurate result
- ACTH level ≥ 100 pg/mL (22 pmol/L) is consistent with primary adrenal insufficiency.
Caveat: unrecognized glucocorticoid administration before testing, especially in hospitalized patients

Corticotropin stimulation test

A normal response to the corticotropin (ACTH) stimulation test excludes primary adrenal insufficiency.
The standard ACTH stimulation test does not entirely exclude recent onset adrenal insufficiency or partial secondary/tertiary adrenal insufficiency.
Rapid ACTH test protocol
- Measure baseline serum cortisol, aldosterone, and plasma ACTH levels.
- Administer corticotropin^_1-24 (Cortrosyn), 250 µg IV or IM.
- Measure serum cortisol and aldosterone at 30 and 60 minutes after administration.
  - Normal cortisol response: >18 μg/dL (>500 nmol/L) or increase >7 μg/dL (> 200 nmol/L) above baseline value
  - Normal aldosterone response: ≥5 ng/dL (≥150 pmol/L) over baseline value
Interpretation of ACTH stimulation testing
- Primary adrenal insufficiency
  - Elevated baseline ACTH level ≥ 100 pg/mL (22 pmol/L)
  - Abnormal cortisol and aldosterone responses
- Secondary/tertiary adrenal insufficiency
  - Low or inappropriately normal baseline ACTH level
  - Abnormal cortisol response
  - Normal aldosterone response
- These cutoffs are by nature arbitrary and serve as guidelines; results need to be interpreted in the clinical context.
Glucocorticoid therapy should not be delayed by ACTH stimulation testing in unstable patients.
- Baseline cortisol and ACTH levels should be obtained before administration of glucocorticoids.
  - This rarely delays treatment but is invaluable for diagnosis.
- Dexamethasone does not interfere with cortisol assays and may be administered in place of hydrocortisone during testing.
- Alternatively, ACTH levels should be determined at least 24–48 hours after glucocorticoid doses (in patients for whom it is safe to withhold therapy).

Secondary and tertiary adrenal insufficiency

See also Hypopituitarism.
The following tests are used predominantly for the evaluation of secondary adrenal insufficiency:
- Insulin tolerance test
  - "Gold standard" test for diagnosis of secondary or tertiary adrenal insufficiency
  - Hypoglycemia (induced by administration of regular insulin) is a potent stimulus for activation of the hypothalamic-pituitary-adrenal axis.
  - Normal cortisol response: >18 μg/dL (>500 nmol/L)
  - Contraindicated in patients with a history of coronary artery disease, cerebrovascular disease, or seizure disorder.
  - Must be closely supervised
- Metyrapone test
  - Metyrapone inhibits conversion of 11-deoxycortisol to cortisol, leading to feedback activation of the hypothalamic-pituitary-adrenal axis and subsequent increases in ACTH and 11-deoxycortisol levels.
  - 30 mg/kg is administered orally at 11 P.M.
  - Normal values at 8 A.M.
    - 11-deoxycortisol: >7 μg/dL (>200 nmol/L)
    - Cortisol: < 8 μg/dL (< 230 nmol/L ()
    - ACTH: >150 pg/mL
  - Currently has limited availability in the U.S.
- CRH test
  - In theory, may be used to differentiate secondary from tertiary adrenal insufficiency, but in practice of limited informative value.
  - Bolus injection of CRH stimulates ACTH secretion in 15–60 minutes.
  - Primarily used for patients in whom insulin tolerance testing is contraindicated, as the criteria for test interpretation are not well defined.

Additional testing

Low-dose (1 µg) ACTH stimulation test
- Has been proposed to detect secondary adrenal insufficiency
  - The 250 μg dose (a supraphysiologic stimulus) may be relatively insensitive for the diagnosis of partial adrenal insufficiency.
  - May be preferable in diagnosing relative insufficiency in critically ill patients.
- Use is controversial because of the lack of normative data, lack of commercially available 1 μg ampoules, and concerns about dosing accuracy due to adsorptive losses of ACTH during dilution.
Antibodies directed against 21-hydroxylase
- Present in > 80% of patients with recent onset autoimmune adrenalitis
- Measurement may be helpful in patients with isolated primary adrenal insufficiency and no family history.
Additional laboratory testing can establish the presence of other autoimmune disorders in patients with a syndrome of polyglandular failure.
- The association of adrenal failure with other detectable autoimmune endocrine abnormalities is usually sufficient to establish the diagnosis of autoimmune adrenal insufficiency.
Serum concentrations of very-long-chain fatty acids should be measured in males with isolated primary adrenal insufficiency.
- To evaluate for adrenoleukodystrophy or adrenomyeloneuropathy in the absence of evidence for autoimmune adrenal insufficiency
If CAH is suspected, appropriate precursor steroids proximal to the enzyme block (e.g., 17-OH-progesterone or 11-deoxycortisol) should be measured (see Congenital Adrenal Hyperplasia).

Imaging

Imaging studies are used to help determine the cause of primary adrenal insufficiency.
- Abdominal CT
  - Indicated to evaluate for adrenal infection, hemorrhage, infiltration, or metastases
  - Adrenals are small and noncalcified in autoimmune Addison’s disease.
  - Adrenals are enlarged in metastatic or granulomatous disease.
  - Calcifications may be present in patients with tuberculosis, hemorrhage, and fungal infection.
- Chest radiography
  - Indicated for evaluation of tuberculosis, fungal infections, and neoplasia when an autoimmune cause is not apparent

Diagnostic Procedures

Electrocardiography may show peaked T waves due to hyperkalemia.
CT-guided percutaneous fine-needle aspiration of the adrenal gland(s)
- Rarely needed, but can definitively identify metastatic disease
- May be useful in cases of neoplasia of unknown primary

Treatment Approach

Life-long glucocorticoid (and often mineralocorticoid) replacement is required to treat primary adrenal insufficiency.
Treatment should be individualized.
- Hydrocortisone (cortisol) is the preferred glucocorticoid preparation.
- Longer-acting glucocorticoid preparations (e.g., prednisone, dexamethasone) are suboptimal, as they are associated with a higher incidence of overreplacement.
- Goal is to administer the lowest dose of glucocorticoid that will relieve symptoms and avoid hyperpigmentation.
Increased doses are required for stress situations and for adrenal crisis.
Patients who cannot take oral medications or who experience significant stress and potential instability should receive parenteral corticosteroid supplementation.
Educate patients about the disease and prevention of adrenal crisis and complications.
Medical alert or similar identification should be carried by patient; it should list adrenal insufficiency and the need for corticosteroid replacement.
Clinical trial data support the concept that most patients with septic shock have relative adrenal insufficiency.
- It has been difficult to establish a level of cortisol in critically ill patients below which replacement glucocorticoids may improve prognosis.
- Once these patients are identified and treated for 7 days with standard stress doses of hydrocortisone:
  - 28-day survival is increased
  - They are more likely to have pressor agents withdrawn than placebo-treated subjects

Specific Treatments

Glucocorticoid/mineralocorticoid replacement therapy

Glucocorticoids
- Usual adult cortisol replacement dosage: 15–20 mg/d
- Two-thirds of dose taken on awakening and one-third taken in late afternoon, to stimulate normal diurnal adrenal rhythm
- Start with lower dose if patient has:
  - Hypertension
  - Diabetes mellitus
- Start with higher dose if patient is:
  - Obese
  - Taking anticonvulsive medications
Mineralocorticoids
- Usual replacement dosage: fludrocortisone, 0.05–0.1 mg/d PO
- Patients should maintain generous sodium intake.
- Some patients can be managed without mineralocorticoid replacement.
- Monitor for development of hypertension on fludrocortisone.
  - Adjust dose accordingly.
Dehydroepiandrosterone (DHEA) (optional)
- Not generally recommended as benefit is unproven.

Supplementary glucocorticoid dosing is based on the degree of medical or surgical stress.
- Febrile intercurrent illness: double cortisol dose
- Severe illness: increase cortisol dosage to 75–150 mg/d
- Minor surgery or moderately stressful procedures: single hydrocortisone dose of 50–100 mg IV
- Periods of strenuous exercise or exposure to very hot weather
  - Add salt to diet (e.g., 1 cup of beef or chicken bouillon 1–3 times daily).
  - May need to increase fludrocortisone dosage.

Adjustment of replacement therapy during major surgery

On day of surgery and after surgery
- Day of surgery: hydrocortisone, 10 mg/h continuous IV infusion, or hydrocortisone, 100 mg IV bolus injection every 8 hours
- Day 1 after surgery: hydrocortisone, 5–7.5 mg/h IV infusion
- Day 2: hydrocortisone, 2.5–5.0 mg/h IV infusion
- Days 3 and 4: hydrocortisone, 2.5–5.0 mg/h IV infusion or hydrocortisone, 40 mg/d PO at 8 A.M., 20 mg/d PO at 4 P.M.
- Day 5: hydrocortisone, 40 mg/d PO at 8 A.M., 20 mg/d PO at 4 P.M.,
- Day 6: hydrocortisone, 20 mg/d PO at 8 A.M., 20 mg/d PO at 4 P.M., fludrocortisone, 0.1 mg/d PO at 8 A.M.
- Day 7: hydrocortisone, 20 mg/d PO at 8 A.M., 10 mg/d PO at 4 P.M., fludrocortisone, 0.1 mg/d PO at 8 A.M.
- Thereafter, if the patient is improving and is afebrile, taper hydrocortisone dose by 20–30% daily to the preoperative maintenance dose.

Adrenal crisis

Goal: repletion of sodium and water deficits and high-dose replacement of glucocorticoids
- IV infusion of 5% glucose in normal saline with a bolus IV infusion of hydrocortisone, 100 mg, followed by continuous infusion of hydrocortisone, 10 mg/h
- Alternative steroid replacement: Administer 100-mg bolus of hydrocortisone IV every 6 hours.
- If crisis was preceded by prolonged nausea, vomiting, and dehydration, several liters of saline solution may be required in the first few hours.
- Vasoconstrictive agents (e.g., dopamine) may be indicated in extreme conditions as adjuncts to volume replacement.
- Steroid dose is tapered to maintenance levels after improvement, with reinstitution of mineralocorticoid therapy if needed.

Adrenal insufficiency in critical illness

One approach is to assume that an acutely ill patient with hemodynamic instability that is not the result of blood loss has relative adrenal insufficiency until proven otherwise.
- Treatment with supplementary cortisol should be initiated promptly following the measurement of a random cortisol level and/or performing a cosyntropin stimulation test.
  - Such patients should receive 50–75 mg of hydrocortisone IV every 6 h as bolus treatment or the same amount as a continuous infusion.
  - Additional treatment with fludrocortisone is not necessary.
- Treatment can be terminated if the initial cortisol levels are found to be appropriately elevated.
- Those patients with abnormal baseline testing should be treated for 1 week and then tapered.

Monitoring

Monitoring of long-term glucocorticoid replacement is mainly based on clinical assessment because of the absence of reliable objective measures.
- ACTH levels cannot be used for glucocorticoid dose adjustment because they are high before morning dosing and rapidly decrease after dosing.
- 24-hour urine free cortisol levels vary greatly among normal subjects and replaced patients.
- Clinical variables that indicate overreplacement (See Cushing’s Syndrome.)
  - Dorsicervical fullness
  - Facial plethora
  - Hypertension
  - Hyperglycemia
- Clinical variables that indicate underreplacement
  - Orthostatic symptoms (and signs)
  - Anorexia and weight loss
  - Dizziness
  - Nausea, vomiting, or abdominal pain
Monitoring of chronic mineralocorticoid therapy is based on appetite for salt, orthostatic symptoms, measurement of blood pressure (supine and upright), presence of edema, and serum electrolytes.

Complications

Inadequate cortisol production in adrenal insufficiency during critical illness can result in hypotension, reduced systemic vascular resistance, shock, and death.
Complications of overtreatment
- Weight gain
- Immunosuppression
- Infections
- Glucose intolerance or diabetes mellitus
- Osteoporosis
- Peptic ulcer, gastritis, or esophagitis
- Hypertension
- Volume overload (e.g., exacerbation of congestive heart failure)
- Psychological disorders
- Altered wound healing

Prognosis

Prognosis depends on the underlying cause of adrenal insufficiency.
If treatment is maintained properly and adrenal crisis is avoided, the prognosis for most types of adrenal insufficiency is excellent.

Prevention

Educate patients on stress-related glucocorticoid dose adjustment.
Educate patients and family members on the proper use methylprednisolone or dexamethasone injection to prevent adrenal crisis in emergency situations.

ICD-9-CM

255.4 Corticoadrenal insufficiency Primary adrenal insufficiency