Addison’s Disease: Understanding the Average Age of Diagnosis and Beyond

Introduction

Addison’s disease, clinically known as autoimmune adrenalitis or primary adrenal insufficiency, is a rare but potentially life-threatening condition that arises when the adrenal glands fail to produce sufficient adrenocortical hormones. This autoimmune disorder leads to the gradual destruction of the adrenal cortex, impacting the production of crucial hormones like cortisol, aldosterone, and androgens. The progression of Addison’s disease is often insidious, with glucocorticoid deficiency typically preceding mineralocorticoid deficiency. However, it’s important to recognize that Addison’s can also manifest acutely, frequently triggered by concurrent illnesses. The spectrum of adrenal insufficiency symptoms is broad, varying with the rate and extent of adrenal gland impairment. As the most prevalent cause of primary adrenal insufficiency, Addison’s disease is often linked to elevated levels of 21-hydroxylase antibodies. Understanding the typical Addison’s disease average age of diagnosis, alongside its multifaceted nature, is crucial for timely intervention and effective management.

Addison’s disease is characterized by a subtle and progressive onset of non-specific symptoms, often leading to delays in diagnosis. The gradual worsening of symptoms can obscure early recognition, emphasizing the need for heightened clinical suspicion to prevent misdiagnosis. In many instances, Addison’s disease is only diagnosed when a patient presents with an acute adrenal crisis, marked by symptoms such as hypotension, hyponatremia, hyperkalemia, and hypoglycemia. Diagnosis is confirmed by identifying low cortisol and aldosterone levels, elevated renin levels, and a diminished cortisol response to ACTH stimulation. Adrenal crisis is a critical endocrine emergency demanding immediate recognition and treatment. For patients with a confirmed diagnosis of Addison’s disease who have been stabilized, lifelong hormone replacement therapy is essential. This maintenance therapy aims to replicate physiological glucocorticoid and mineralocorticoid levels. This article aims to provide a comprehensive understanding of Addison’s disease, focusing on the average age of diagnosis, causes, symptoms, diagnosis, and management strategies for healthcare professionals.

Etiology

Addison’s disease stems from the adrenal cortices’ compromised ability to produce adequate adrenocortical hormones. Adrenal insufficiency is broadly categorized into primary and secondary forms.

Primary Adrenal Insufficiency

Primary adrenal insufficiency, including Addison’s disease, results from direct damage to the adrenal cortex. This damage can be attributed to various factors such as autoimmune disorders, infections, hemorrhages, pharmacological agents, and infiltrative processes.

Autoimmune

Autoimmune destruction of the adrenal glands is the leading cause of Addison’s disease. This process involves the development of antibodies targeting the adrenal cortex. Autoimmune adrenal destruction may occur in isolation or as part of type 1 and 2 autoimmune polyglandular endocrinopathies. Individuals with autoimmune adrenal disease have a higher likelihood of developing polyglandular autoimmune syndromes.

• Type 1 Autoimmune Polyglandular Syndrome: Characterized by autoimmune polyendocrinopathy, candidiasis, and ectodermal dysplasia. The classic triad includes hypoparathyroidism, Addison’s disease, and mucocutaneous candidiasis.
• Type 2 Autoimmune Polyglandular Syndrome: Associated with several conditions:
  • Autoimmune thyroiditis (Schmidt syndrome)
  • Type 1 diabetes (Carpenter syndrome)
  • Other autoimmune conditions like pernicious anemia, vitiligo, or alopecia
  • Celiac disease has also been linked to Addison’s disease.

Infections

Infectious causes of Addison’s disease include sepsis, tuberculosis, cytomegalovirus, and HIV. While tuberculosis prevalence has decreased, HIV has become a significant cause of adrenal insufficiency related to adrenal necrosis. Other infectious agents include disseminated fungal infections like histoplasmosis and syphilis. Blastomycosis is another cause, particularly in South America.

Adrenal Hemorrhage

Bilateral adrenal hemorrhages can be triggered by disseminated intravascular coagulation (DIC), trauma, meningococcemia, and neoplastic processes. Waterhouse-Friderichsen syndrome, an adrenal crisis due to meningococcemia, is more prevalent in children and individuals with asplenia.

Infiltration

Adrenal infiltration is frequently observed in conditions like hemochromatosis, amyloidosis, and metastases. Other causes include sarcoidosis, lymphoma, and genetic disorders such as congenital adrenal hyperplasia and adrenal leukodystrophy. Wolman disease, a rare metabolic disorder, presents with diarrhea, hepatosplenomegaly, failure to thrive, and adrenal gland calcification. Antiphospholipid antibody syndrome has also been identified as a cause of adrenal insufficiency.

Medications

Certain medications can induce adrenal insufficiency by blocking cortisol synthesis. Ketoconazole directly inhibits adrenal enzymes, while etomidate can dose-dependently inhibit 11β-hydroxylase, reducing deoxycortisol conversion to cortisol.

Secondary Adrenal Insufficiency

Secondary adrenal insufficiency typically arises from exogenous steroid administration, leading to suppressed ACTH synthesis. This form involves pituitary-dependent ACTH secretion loss, reducing glucocorticoid production. Mineralocorticoid secretion, including aldosterone, usually remains normal. Secondary adrenal insufficiency is more common than primary, with symptoms often appearing after steroid discontinuation.

• Primary Insufficiency: Autoimmune-mediated adrenal gland dysfunction causing both cortisol and aldosterone deficiency.
• Secondary Insufficiency: Chronic glucocorticoid use leading to hypothalamic-pituitary dysfunction and primarily cortisol deficiency.

Epidemiology

Addison’s disease is a rare condition, with an annual incidence of approximately 0.6 cases per 100,000 people. The prevalence ranges from 4 to 11 affected individuals per 100,000 population. The average age of diagnosis for Addison’s disease in adults is typically between 30 and 50 years, with a higher prevalence in women. Risk factors for autoimmune Addison’s disease, the most common type, include the presence of other autoimmune conditions such as:

• Type 1 diabetes
• Hypoparathyroidism
• Hypopituitarism
• Pernicious anemia
• Graves’ disease
• Chronic thyroiditis
• Dermatitis herpetiformis
• Vitiligo
• Myasthenia gravis

Pathophysiology

In Addison’s disease, adrenal failure initially results in decreased cortisol production, followed by reduced aldosterone production. This hormonal deficiency leads to elevated adrenocorticotropic hormone (ACTH) and melanocyte-stimulating hormone (MSH) levels due to the loss of negative feedback inhibition.

History and Physical Examination

Addison’s disease typically manifests with a gradual and insidious onset of nonspecific symptoms, often delaying diagnosis. Symptoms may progressively worsen, making early recognition challenging. Maintaining a high level of clinical suspicion is crucial to avoid misdiagnosis. In many cases, diagnosis only occurs after a patient experiences an acute adrenal crisis, characterized by hypotension, hyponatremia, hyperkalemia, and hypoglycemia. This crisis can be triggered by stressful illnesses or factors like infection, trauma, surgery, vomiting, or diarrhea. Significant stress or illness can reveal underlying cortisol and mineralocorticoid deficiencies.

While Addison’s disease can occur at any age, it most commonly presents during the second or third decades of life, aligning with the average age of diagnosis being between 30 and 50. Initial symptoms include fatigue, generalized weakness, weight loss, nausea, vomiting, abdominal pain, dizziness, tachycardia, and hypotension. Clinicians should also assess for subcutaneous tissue wasting. Health decline may occur over weeks or months. Due to its variable presentation, a high index of suspicion is necessary when evaluating patients with unexplained fatigue, poor appetite, chronic abdominal pain, or weight loss. Addisonian crisis presents with severe dehydration, confusion, refractory hypotension, and shock, and is more common in primary adrenal insufficiency compared to secondary.

Physical examination should include assessing skin and mucous membranes for hyperpigmentation, a hallmark of Addison’s disease. Hyperpigmentation is typically generalized, most prominent in sun-exposed and pressure areas such as palmar creases, gingival mucosa, lips (especially the vermilion border), elbows, knuckles, posterior neck, breast areola, nipples, and nail beds. Hyperpigmentation may appear as bronzing or diffuse darkening of the skin, occurring in almost all Addison’s disease patients. However, rare cases of adrenal insufficiency without hyperpigmentation exist, which may delay diagnosis. Hyperpigmentation is not seen in secondary insufficiency due to low ACTH and MSH levels. Elevated ACTH and MSH are believed to cause hyperpigmentation by binding to melanocyte receptors. Additionally, patients may develop new nevi, and women may experience decreased axillary and pubic hair. Vitiligo may also be observed.

Image: Diagram illustrating common symptoms of Addison’s Disease, including fatigue, weight loss, hyperpigmentation, and muscle weakness.

Evaluation

Diagnosis of Addison’s disease involves demonstrating low cortisol and aldosterone levels, high renin levels, and a blunted cortisol response to ACTH stimulation. The recommended diagnostic approach is outlined below.

Diagnostic Laboratory Studies

• Cortisol Level: Characteristically low in Addison’s disease. Cortisol typically follows a diurnal pattern, with peak levels in the early morning. Early morning cortisol levels are preferred, but random levels can be indicative. A morning cortisol level >18 mcg/dL generally excludes Addison’s disease, while levels <3 mcg/dL strongly suggest adrenal insufficiency. Levels between 3 and 19 mcg/dL are equivocal, requiring further evaluation.

  • Normal cortisol level: morning cortisol >18 mcg/dL = Normal
  • Adrenal insufficiency: <3 mcg/dL = Adrenal Insufficiency
  • Equivocal; further evaluation recommended: 3 to 19 mcg/dL

• ACTH Level and Corticotropin Stimulation Test: ACTH levels are markedly elevated in primary adrenal insufficiency but not in central adrenal insufficiency. The ACTH stimulation test is crucial for confirmation, especially in equivocal cases. This test assesses the adrenal cortex’s ability to synthesize cortisol after ACTH administration. Plasma cortisol levels are measured at 0 minutes and 30 to 60 minutes post-ACTH administration. Corticotropin-releasing hormone (CRH) stimulates ACTH release. In primary adrenal insufficiency, ACTH is high and may rise further with CRH stimulation, but cortisol secretion remains low. In secondary adrenal insufficiency, ACTH levels are low and fail to respond to CRH.

  • Primary adrenal insufficiency: elevated ACTH
  • Central adrenal insufficiency: abnormally normal or low ACTH
  • ACTH Stimulation Test Interpretation:
    • Normal response: peak cortisol level >18 mcg/dL
    • Adrenal insufficiency: peak cortisol level <18 mcg/dL

• Aldosterone and Renin Level: Serum renin and aldosterone levels determine mineralocorticoid deficiency. In primary adrenal insufficiency, both cortisol and aldosterone are deficient. Aldosterone levels are low despite high plasma renin activity. In secondary adrenal insufficiency, aldosterone levels are typically normal. Increased plasma renin activity indicates adrenal cortex dysfunction and occurs when serum aldosterone is low.

• Comprehensive Metabolic Panel: Characteristic laboratory findings in Addison’s disease include hyponatremia, hyperkalemia, and hypoglycemia. Hyponatremia results from cortisol and aldosterone deficiency; aldosterone deficiency causes sodium wasting, and cortisol reduces antidiuretic hormone, increasing water absorption. Hypovolemia also triggers ADH secretion. Hyperkalemia is due to low aldosterone, causing natriuresis and potassium retention, typically seen in primary but not secondary adrenal insufficiency. Hypoglycemia is multifactorial, including decreased oral intake and glucocorticoid deficiency, which impairs gluconeogenesis. Hypercalcemia may also be present, reflecting extracellular fluid loss.

• Thyroid-Stimulating Hormone (TSH): Mild TSH elevation can occur in adrenal insufficiency due to decreased cortisol levels and abnormal TSH circadian rhythm. Persistent TSH elevation suggests hypothyroidism.

• Anti–21-hydroxylase Antibodies: These antibodies are markers of autoimmune adrenal gland destruction. The 21-hydroxylase enzyme is crucial for cortisol synthesis. Detecting these antibodies can help identify the underlying autoimmune cause of adrenal insufficiency and evaluate for other organ-specific autoimmune conditions.

Diagnostic Imaging Studies

Biochemical diagnosis of adrenal insufficiency should precede imaging studies, as radiographic findings are nonspecific. Chest radiographs may show a small heart due to decreased cardiac workload. Abdominal CT scans can be helpful in suspected adrenal hemorrhage, revealing bilateral adrenal gland enlargement. Adrenal gland calcification or hemorrhage may indicate tuberculosis. Small adrenal glands on imaging suggest autoimmune adrenal destruction. MRI of the hypothalamic-pituitary region is indicated if ACTH levels are inappropriately low in cortisol deficiency cases, along with a pituitary baseline profile.

Additional Diagnostic Studies

Further studies should target the underlying cause of adrenal insufficiency. A PPD test can evaluate for tuberculosis. Serum very long-chain fatty acid profiles are needed if adrenal leukodystrophy is suspected. Complete blood counts may reveal neutropenia, lymphocytosis, and eosinophilia. ECGs in hyperkalemia cases may show tall, peaked T waves. Histology from adrenal biopsies can identify infiltrative causes, with caseating granulomas suggesting tuberculosis and non-caseating granulomas indicating sarcoidosis.

Treatment / Management

Early recognition is crucial for managing acute adrenal insufficiency or Addisonian crisis, a severe endocrine emergency requiring immediate intervention. Untreated Addisonian crisis can be fatal. Treatment should not be delayed for confirmatory lab results, although blood samples for ACTH and cortisol levels should be drawn beforehand. Elevated ACTH with low cortisol is diagnostic of primary adrenal insufficiency. Plasma renin levels are often elevated, indicating mineralocorticoid deficiency and low aldosterone.

Acute Phase Therapy

Management of adrenal crisis includes:

• Fluid resuscitation: IV normal saline to restore intravascular volume.
• Dextrose: To correct hypoglycemia.
• Hormone deficiency correction: Glucocorticoid and mineralocorticoid replacement.

Hydrocortisone is the initial hormonal treatment. The recommended adult regimen for adrenal crisis is a 100 mg IV bolus of hydrocortisone, followed by 50 to 100 mg IV every 6 hours for 24 hours. In children, the dose is 50 mg/m2 IV bolus (max 100 mg), followed by 50 to 100 mg/m2. At these doses, the mineralocorticoid activity of hydrocortisone is sufficient, making additional mineralocorticoids like fludrocortisone unnecessary during the acute phase. Dexamethasone 4 mg IV bolus can be used in emergencies as it is less likely to interfere with serum cortisol assays and is long-acting. Initial fluid replacement with normal saline bolus followed by 5% glucose in isotonic saline is also recommended. Hypoglycemia should be treated promptly.

Maintenance Phase Therapy

Stabilized Addison’s disease patients require lifelong hormone replacement therapy to maintain physiological glucocorticoid and mineralocorticoid levels. Usual dosage regimens include:

• Glucocorticoid:
  • Hydrocortisone: 5 to 25 mg/day in 2 or 3 divided doses.
  • Prednisone: 3 to 5 mg/day.

Dosages are adjusted based on clinical response and electrolyte normalization, titrated to the lowest effective dose to minimize side effects. Plasma renin levels can guide dose adjustments. Serum ACTH levels are not reliable for dose adjustment. Concurrent medications affecting glucocorticoid metabolism, like rifampin, should be considered. Dexamethasone is not recommended for maintenance due to titration challenges and increased Cushing effect risk.

Fludrocortisone is administered to maintain plasma renin levels within the normal range. Elevated plasma renin activity indicates a need for a higher fludrocortisone dose. Mineralocorticoid dosage should be adjusted for stress. Treating underlying conditions like sepsis is crucial for optimal outcomes, and associated conditions should also be managed.

• Mineralocorticoid:
  • Fludrocortisone: 0.05 to 0.2 mg daily.
  • Hydrocortisone (in children): 8 mg/m2/day orally, initially divided into 3 or 4 doses.

Treatment Considerations

• Glucocorticoid secretion does not increase during stress in Addison’s disease patients. Hydrocortisone doses should be increased 2-3 times the daily maintenance dose during fever, infection, or other illnesses.
• Rifampin increases hydrocortisone clearance, requiring increased hydrocortisone doses.
• Thyroid hormone can increase hepatic cortisol clearance, potentially precipitating adrenal crisis. Glucocorticoid replacement can normalize TSH levels.
• Glucocorticoid therapy can worsen diabetes insipidus in patients with both conditions. Cortisol is needed for free water clearance, and cortisol deficiency may mask polyuria.
• Pregnancy, especially the third trimester, increases corticosteroid requirements.

Differential Diagnosis

The differential diagnosis of adrenal crisis includes conditions causing shock. Differential diagnosis of adrenal insufficiency is broad:

• Sepsis: Overlaps with adrenal insufficiency in symptoms like weakness, fatigue, vomiting, hypotension, and shock. ACTH stimulation test and ACTH levels differentiate the two.
• Shock: Any shock type with decreased serum cortisol suggests adrenal insufficiency.
• Chronic Fatigue Syndrome: Mimics adrenal insufficiency with persistent fatigue, but cortisol levels after corticotropin stimulation differentiate them.
• Infectious Mononucleosis: Similar presentation with fever, fatigue, and myalgias, but exudative pharyngitis and IgM antibodies to viral capsid antigens are present in mononucleosis.
• Hypothyroidism: Fatigue is common in both, but hypothyroidism is associated with weight gain. Cortisol levels differentiate them.

Toxicity and Adverse Effect Management

Delayed treatment of Addison’s disease can lead to severe morbidity and mortality.

Prognosis

Addison’s disease requires lifelong glucocorticoid and mineralocorticoid replacement. With proper management, most patients can live active lives. Careful monitoring is needed to balance treatment and avoid over- or under-replacement. Over-treatment with glucocorticoids can cause obesity, diabetes, and osteoporosis, while over-treatment with mineralocorticoids can cause hypertension. Up to 50% of patients may develop another autoimmune condition, necessitating ongoing monitoring. Thyroid hormone replacement before glucocorticoid administration can precipitate adrenal crisis due to increased cortisol clearance. Rapid recognition and treatment are essential in acute adrenal crisis.

Complications

Untreated Addison’s disease can progress to adrenal crisis, leading to hypotension, shock, hypoglycemia, acute cardiovascular decompensation, and death. Patients are at higher risk of death from infections, cancer, and cardiovascular causes. Delayed hypoglycemia treatment can have serious consequences. Supraphysiologic glucocorticoid replacement can cause Cushing syndrome. Growth suppression can occur in children, and premature ovarian failure may occur in up to 10% of women with Addison’s disease.

Consultations

An endocrinologist should be consulted for developing a treatment plan. Patients in adrenal crisis should be managed in consultation with intensivists and admitted to the ICU. Patients who are ill-appearing and in shock should also be admitted to the ICU.

Deterrence and Patient Education

Patient education is crucial for managing Addison’s disease:

• Medication doses and compliance, including increasing steroid doses during stress, fever, or surgery.
• Wearing an emergency medical alert bracelet.
• Self-care, including adequate sodium intake, weight, and blood pressure monitoring.

Pearls and Other Issues

Key points about Addison’s disease:

• Idiopathic autoimmune adrenocortical insufficiency is the most common cause.
• Symptoms are nonspecific, requiring high clinical suspicion for diagnosis.
• Serum morning cortisol <3 mcg/dL is highly suggestive of Addison’s disease.
• Primary adrenal insufficiency should be considered in acutely ill patients with volume depletion, hypotension, hyponatremia, and hyperkalemia.
• Consider adrenal insufficiency in critically ill patients not improving with fluid resuscitation, especially with hyperpigmentation, hyponatremia, or hyperkalemia.
• Treat Addisonian crisis immediately; do not delay for diagnostic confirmation.
• Hydrocortisone is the treatment of choice for adrenal crisis.
• Increase glucocorticoid doses during fever, infection, or stress.
• Titrate glucocorticoid dose to the lowest effective dose to minimize side effects.
• Thyroid hormone treatment can precipitate adrenal crisis.
• Obtain serum cortisol, plasma ACTH, aldosterone, and renin levels before ACTH stimulation test.
• Autoimmune Addison’s disease can be associated with other autoimmune disorders.

Enhancing Healthcare Team Outcomes

Addison’s disease is life-threatening and requires accurate diagnosis and prompt treatment by an interprofessional team including endocrinologists, intensivists, infectious disease specialists, and pharmacists. Patient education is critical. Nurses administer treatments, monitor patients, and update the team. Outcomes depend on the primary cause, but delays in treatment can lead to poor outcomes. All Addison’s disease patients should wear medical alert bracelets and be educated about symptoms, urging them to contact their primary care provider for warning signs. During stress, patients should double their steroid dose and consult their primary care provider.

Review Questions

Figure

Addison’s Disease symptoms StatPearls Publishing Illustration

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Disclosures: Sadaf Munir declares no relevant financial relationships with ineligible companies.

Disclosures: Bryan Quintanilla Rodriguez declares no relevant financial relationships with ineligible companies.

Disclosure: Muhammad Waseem declares no relevant financial relationships with ineligible companies.