Diagnosis and Management of Primary Adrenal Insufficiency (Addison’s Disease) and Cushing Syndrome

Clinical Presentation

Primary adrenal insufficiency presents with hyperpigmentation of sun‑exposed skin, creases, mucosa and scars due to loss of cortisol feedback and consequent ACTH elevation【@1】.
Typical symptoms of Addison’s disease include weight loss, postural dizziness, anorexia, abdominal discomfort and salt craving【@1】.
Patients often have low blood pressure with an exaggerated orthostatic drop【@1】.
In children, primary adrenal insufficiency frequently manifests as failure to thrive【@1】.
Cushing syndrome is characterized by marked weight gain and central (visceral) obesity as the principal clinical feature【@4】.

Hyponatremia together with hyperkalemia is a characteristic electrolyte pattern in primary adrenal insufficiency【@1】.
Occasional hypoglycemia and mild hypercalcemia may be observed in Addison’s disease, though they are uncommon【@1】.

In patients without autoimmune antibodies, abdominal CT is recommended to identify tuberculosis, neoplasms or infiltrative disease of the adrenal glands【@5】.
Screening for CYP21A2 autoantibodies helps to confirm an autoimmune etiology of primary adrenal insufficiency【@5】.

Hydrocortisone is the preferred glucocorticoid, administered in multiple divided doses to mimic the circadian rhythm (largest dose on waking, second dose after lunch, optional third dose 4–6 h before bedtime)【@5】.
Initial adult dosing is 15–25 mg per day; pediatric dosing is approximately 8 mg / m² body‑surface‑area divided into 3–4 doses【@1】.
All patients with confirmed aldosterone deficiency require mineralocorticoid replacement with fludrocortisone【@5】.
Dexamethasone should be avoided because of its high risk for Cushing‑like side effects【@5】.
Prednisone or prednisolone may be used, but retrospective data indicate that higher doses are associated with weight gain, dyslipidemia and new‑onset diabetes【@5】.
Replacement therapy should be monitored primarily by clinical assessment (signs of over‑replacement: weight gain, insomnia, edema; signs of under‑replacement: nausea, poor appetite, weight loss, lethargy, persistent hyperpigmentation)【@5】.
Plasma ACTH levels should not be used to titrate glucocorticoid dosing because adequately replaced patients often retain elevated ACTH, which can lead to overtreatment【@5】.
Patient education on “stress dosing” (increasing glucocorticoid dose during illness, fever or physiological stress) is essential to prevent adrenal crisis【@1】.

Surgical removal of the cortisol‑producing lesion is the first‑line therapy for Cushing syndrome【@4】.
The therapeutic goal is to normalize cortisol concentrations or receptor activity, thereby eliminating clinical signs and treating associated comorbidities such as hypertension, diabetes and osteoporosis【@4】.
Second‑line options—including medical therapy, bilateral adrenalectomy or radiotherapy for corticotrope tumors—should be individualized based on disease etiology and patient factors【@4】.
Cortisol‑lowering treatment should not be initiated when the diagnosis is not definitively established or when only borderline biochemical abnormalities are present without clear clinical features【@4】.
Ongoing management must include direct monitoring and treatment of comorbid conditions (e.g., blood pressure control, glycemic management, bone health)【@4】.

Health‑related quality of life in patients with Addison’s disease is often reduced, and the degree of impairment correlates inversely with the length of diagnostic delay, underscoring the importance of early recognition and treatment【@1】.

In an adult presenting with severe hyponatremia (≈115 mEq/L), marked weakness, and borderline hypotension, primary adrenal insufficiency should be suspected. 1
The electrolyte pattern of profound hyponatremia together with hyperkalemia reflects combined cortisol and aldosterone deficiency and is characteristic of primary adrenal insufficiency. 1
Extreme weakness is a cardinal symptom, frequently accompanied by fatigue, weight loss, postural dizziness, and loss of appetite. 1
Borderline or low blood pressure with an exaggerated orthostatic drop indicates volume depletion and loss of mineralocorticoid activity. 1
Hyperpigmentation of sun‑exposed skin, skin folds, mucous membranes, scars, and areolae is a specific sign of primary disease, caused by ACTH‑stimulated melanocytes. 1
Nausea, vomiting, abdominal pain, and anorexia are common gastrointestinal manifestations that can mimic an acute abdomen during adrenal crisis. 1

Serum electrolytes should be checked for hyponatremia and accompanying hyperkalemia, the latter being a hallmark of mineralocorticoid deficiency. 1
Blood glucose may be low (hypoglycemia), although this occurs less frequently. 1
Serum calcium can show a mild elevation in some patients. 1
Plasma ACTH is typically elevated in primary adrenal insufficiency, helping to differentiate it from secondary forms. 1

Detection of anti‑CYP21A2 antibodies confirms an autoimmune etiology, which accounts for up to 90 % of cases in Western populations. 1

Administer intravenous hydrocortisone immediately: 100 mg bolus followed by 50–100 mg every 6–8 hours, or a continuous infusion of 200 mg over 24 hours. 1
Provide isotonic saline infusion to restore intravascular volume and correct hypotension. 1
Do not postpone glucocorticoid therapy while awaiting complete diagnostic confirmation when clinical suspicion is strong; adrenal crisis is a medical emergency. 1

Even with standard therapy, patients often experience reduced quality of life; the degree of impairment correlates inversely with the length of diagnostic delay, underscoring the importance of early recognition. 1
Ongoing patient education on adjusting glucocorticoid doses during intercurrent illness, fever, or stress is essential to prevent future adrenal crises. 1