Hypoadrenalism: Etiopathogenesis, Clinical Pearls, and Contemporary Diagnostic Approaches

 

Hypoadrenalism: Etiopathogenesis, Clinical Pearls, and Contemporary Diagnostic Approaches

Dr Neeraj Manikath , claude.ai

Abstract

Hypoadrenalism, or adrenal insufficiency, remains a diagnostic challenge with significant morbidity and mortality if unrecognized. This review synthesizes current understanding of the etiopathogenic mechanisms underlying primary, secondary, and tertiary adrenal insufficiency, highlights clinical pearls for recognition, and provides evidence-based approaches to diagnosis and initial management. Understanding the molecular and immunological basis of hypoadrenalism has transformed our approach to this endocrine emergency.

Introduction

Adrenal insufficiency affects approximately 100-140 per million individuals, with increasing recognition of milder and atypical presentations. The condition results from inadequate production or action of glucocorticoids, with or without mineralocorticoid deficiency, leading to potentially life-threatening metabolic decompensation. Despite advances in diagnostic testing, delays in diagnosis remain common, with median time to diagnosis often exceeding one year from symptom onset.

Classification and Etiopathogenesis

Primary Adrenal Insufficiency (Addison's Disease)

Primary adrenal insufficiency results from destruction or dysfunction of the adrenal cortex itself, affecting both glucocorticoid and mineralocorticoid production. The prevalence ranges from 90 to 140 cases per million population in developed countries.

Autoimmune Adrenalitis constitutes 80-90% of cases in developed nations. The pathogenesis involves T-cell mediated destruction of adrenocortical cells, with antibodies against 21-hydroxylase (21-OH) detected in over 90% of patients with autoimmune Addison's disease. The enzyme 21-hydroxylase, encoded by the CYP21A2 gene, is crucial for cortisol and aldosterone synthesis. Recent studies have identified specific HLA associations, particularly HLA-DR3-DQ2 and HLA-DR4-DQ8 haplotypes, conferring susceptibility.

Pearl: Autoimmune adrenalitis frequently occurs as part of autoimmune polyglandular syndromes (APS). APS type 1, caused by mutations in the AIRE gene, classically presents with the triad of chronic mucocutaneous candidiasis, hypoparathyroidism, and Addison's disease. APS type 2 (Schmidt syndrome) associates Addison's disease with autoimmune thyroid disease and/or type 1 diabetes mellitus. Always screen for associated autoimmune conditions when diagnosing autoimmune Addison's disease.

Infectious Etiologies represent the leading cause globally, particularly tuberculosis in endemic regions. Tuberculosis causes bilateral adrenal enlargement followed by calcification, visible on imaging in up to 50% of cases. The pathogenesis involves direct mycobacterial invasion with granulomatous destruction of adrenal tissue. Other infectious causes include cytomegalovirus (particularly in HIV/AIDS), histoplasmosis, and cryptococcosis.

Hack: In patients with unexplained adrenal insufficiency and bilateral adrenal enlargement or calcification on imaging, consider tuberculosis even without pulmonary symptoms. Request early morning sputum for acid-fast bacilli, interferon-gamma release assays, and consider CT-guided adrenal biopsy if diagnosis remains uncertain.

Genetic and Developmental Causes include congenital adrenal hypoplasia (mutations in DAX1/NR0B1 gene), familial glucocorticoid deficiency (mutations in MC2R encoding ACTH receptor), and adrenoleukodystrophy (ALD). ALD, an X-linked disorder caused by ABCD1 gene mutations, disrupts very long-chain fatty acid metabolism, leading to adrenal insufficiency in childhood or adulthood, often preceding devastating neurological manifestations.

Oyster: Adrenoleukodystrophy may present with isolated adrenal insufficiency years before neurological symptoms. Measure very long-chain fatty acids (VLCFA) in all males with primary adrenal insufficiency, especially those under 50 years, as early detection enables genetic counseling and monitoring for neurological disease.

Hemorrhagic and Infiltrative Disorders include bilateral adrenal hemorrhage (associated with sepsis, particularly meningococcemia—Waterhouse-Friderichsen syndrome, anticoagulation, or thrombophilia), metastatic disease (lung, breast, melanoma, lymphoma), amyloidosis, sarcoidosis, and hemochromatosis. Adrenal metastases are common in malignancy but rarely cause adrenal insufficiency unless >90% of tissue is destroyed bilaterally.

Secondary Adrenal Insufficiency

Secondary adrenal insufficiency results from ACTH deficiency due to pituitary disease or dysfunction, affecting only glucocorticoid production while preserving mineralocorticoid synthesis (regulated by the renin-angiotensin-aldosterone system).

Pituitary Pathology includes adenomas (particularly macroadenomas causing mass effect), pituitary apoplexy (sudden hemorrhage or infarction), Sheehan's syndrome (postpartum pituitary necrosis following obstetric hemorrhage), lymphocytic hypophysitis (autoimmune pituitary inflammation, often in pregnancy or postpartum), craniopharyngiomas, and iatrogenic causes following pituitary surgery or radiation.

Pearl: Lymphocytic hypophysitis shows female predominance and temporal association with pregnancy. MRI findings include pituitary enlargement with homogeneous enhancement and possible stalk thickening. Consider this diagnosis in peripartum women presenting with headache, visual symptoms, and hypopituitarism.

Tertiary Adrenal Insufficiency

Tertiary adrenal insufficiency results from hypothalamic dysfunction with CRH deficiency, most commonly iatrogenic from chronic glucocorticoid therapy causing suppression of the hypothalamic-pituitary-adrenal (HPA) axis.

Exogenous Glucocorticoid Suppression represents the most common cause of adrenal insufficiency overall. The risk depends on dose, duration, potency, and timing of administration. Suppression can occur with as little as 5mg prednisolone daily for three weeks, though individual susceptibility varies considerably. Evening doses suppress the axis more than morning doses due to interference with the normal circadian ACTH surge.

Hack: Patients on long-term inhaled or topical corticosteroids, particularly high-potency preparations like fluticasone or clobetasol, may develop HPA axis suppression. Consider testing if symptoms suggestive of adrenal insufficiency develop, especially during intercurrent illness. Inhaled fluticasone >500mcg daily carries appreciable risk.

Other Hypothalamic Causes include traumatic brain injury, subarachnoid hemorrhage, hypothalamic tumors (craniopharyngioma, germ cell tumors), infiltrative diseases (sarcoidosis, histiocytosis), and sudden discontinuation of chronic opioid therapy (opioids suppress CRH release).

Molecular Pathophysiology

The HPA axis functions through a negative feedback loop. Hypothalamic CRH stimulates pituitary corticotrophs to release ACTH, which binds melanocortin-2 receptors (MC2R) on adrenal zona fasciculata cells, activating steroidogenesis through the cAMP-PKA pathway. Cortisol inhibits CRH and ACTH release, completing the feedback loop.

In primary adrenal insufficiency, loss of cortisol negative feedback causes marked elevation of ACTH (often >100 pg/mL) and its precursor pro-opiomelanocortin (POMC). POMC cleavage produces melanocyte-stimulating hormone, causing characteristic hyperpigmentation in sun-exposed areas, palmar creases, buccal mucosa, and previous scars.

Pearl: Hyperpigmentation is pathognomonic for primary adrenal insufficiency and absent in secondary/tertiary forms (where ACTH is low). Its presence helps distinguish primary from central causes at the bedside.

In secondary and tertiary forms, ACTH deficiency leads to zona fasciculata and reticularis atrophy, while the zona glomerulosa remains functional under renin-angiotensin control. This explains preserved mineralocorticoid production and the absence of hyperkalemia or severe hypovolemia typical of primary disease.

Clinical Presentation and Diagnosis

Clinical Features

The presentation is often insidious with nonspecific symptoms including fatigue (100%), weight loss (97%), anorexia, gastrointestinal symptoms (nausea, vomiting, abdominal pain in 56-90%), postural dizziness (90%), and salt craving (in primary disease). Examination may reveal hypotension (postural or absolute, 88-94%), hyperpigmentation (primary only, 94%), and loss of axillary/pubic hair (secondary DHEA deficiency).

Oyster: The triad of hyponatremia, hyperkalemia, and hypoglycemia is highly suggestive but not always present. Hyponatremia occurs in both primary and secondary disease through different mechanisms: primary disease causes both mineralocorticoid deficiency (renal sodium loss) and cortisol deficiency (inappropriate ADH secretion); secondary disease causes only cortisol deficiency with preserved mineralocorticoid function, so hyperkalemia is typically absent.

Diagnostic Approach

Basal Testing: Morning (8:00 AM) serum cortisol is the initial test. Values >500 nmol/L (18 mcg/dL) virtually exclude adrenal insufficiency, while <140 nmol/L (5 mcg/dL) strongly suggests it. Intermediate values require dynamic testing. Simultaneously measure plasma ACTH to localize the defect: elevated ACTH (typically >100 pg/mL) indicates primary disease, while low-normal ACTH suggests secondary/tertiary disease.

Pearl: Cortisol is 90% protein-bound to cortisol-binding globulin (CBG). Conditions altering CBG (oral estrogens, pregnancy, cirrhosis, nephrotic syndrome, critical illness) affect total cortisol measurements. Consider free cortisol measurement or adjust interpretation accordingly. Salivary cortisol reflects free cortisol and may be useful in these situations.

Dynamic Testing: The ACTH stimulation test (corticotropin test) is the gold standard. Administer 250 mcg synthetic ACTH (cosyntropin) intravenously or intramuscularly, measuring cortisol at 0, 30, and 60 minutes. Peak cortisol >500-550 nmol/L (18-20 mcg/dL) is normal. This test reliably detects primary adrenal insufficiency and long-standing secondary disease but may be normal in acute secondary insufficiency (first 4-6 weeks) before adrenal atrophy develops.

Hack: In suspected secondary adrenal insufficiency with normal standard-dose ACTH test, consider the low-dose (1 mcg) ACTH stimulation test, which is more sensitive for detecting partial or early secondary insufficiency. However, this test is technically challenging and not widely standardized.

For tertiary/secondary disease suspected after pituitary surgery or glucocorticoid withdrawal, the insulin tolerance test (ITT) remains the gold standard, though it requires medical supervision due to induced hypoglycemia (blood glucose <2.2 mmol/L or 40 mg/dL). Peak cortisol >500 nmol/L excludes significant adrenal insufficiency. Contraindications include cardiovascular disease, seizure disorders, and severe hypopituitarism.

Alternative tests avoiding hypoglycemia include the glucagon stimulation test and metyrapone test, though these are less well validated.

Etiological Workup:

Once adrenal insufficiency is confirmed:

For Primary Disease:

  • 21-hydroxylase antibodies (positive in 90% of autoimmune cases)
  • Adrenal imaging (CT or MRI) to detect masses, hemorrhage, calcification, or infiltration
  • Very long-chain fatty acids (screen for adrenoleukodystrophy in males <50 years)
  • Screening for tuberculosis (chest X-ray, IGRA, early morning sputum if endemic)
  • Assessment for autoimmune polyglandular syndrome (thyroid function, anti-thyroid antibodies, fasting glucose, calcium, parathyroid hormone, vitamin B12, intrinsic factor antibodies)

For Secondary/Tertiary Disease:

  • Pituitary MRI with gadolinium contrast
  • Full pituitary function assessment (TSH, free T4, LH, FSH, testosterone/estradiol, prolactin, IGF-1)
  • Visual field assessment if macroadenoma present
  • Detailed medication history (glucocorticoids, opioids, immunotherapy agents)

Oyster: Immune checkpoint inhibitors (anti-CTLA-4, anti-PD-1, anti-PD-L1) used in cancer immunotherapy increasingly cause hypophysitis with secondary adrenal insufficiency, typically within 3-6 months of treatment initiation. Maintain high clinical suspicion in oncology patients on these agents presenting with fatigue, headache, or hypotension.

Adrenal Crisis: Recognition and Acute Management

Adrenal crisis is a life-threatening emergency with mortality reaching 6-8% despite treatment. Triggers include infection, surgery, trauma, pregnancy, or sudden glucocorticoid withdrawal. Presentation includes profound hypotension (refractory to fluids/vasopressors), shock, fever, severe abdominal pain (mimicking acute abdomen), altered mental status, nausea, vomiting, and characteristic biochemical findings (hyponatremia, hyperkalemia in primary disease, hypoglycemia).

Pearl: Consider adrenal crisis in any patient with unexplained shock, especially if associated with hyponatremia, hyperkalemia, hypoglycemia, or eosinophilia. The presence of eosinophilia in a critically ill patient is unusual and should trigger consideration of adrenal insufficiency.

Emergency Management Protocol:

  1. Draw blood for cortisol and ACTH immediately (do not wait for results)
  2. Administer hydrocortisone 100 mg IV bolus immediately
  3. Aggressive fluid resuscitation: 1L 0.9% saline over first hour, then 4-6L over 24 hours with glucose supplementation
  4. Continue hydrocortisone 50-100 mg IV every 6 hours or 200 mg/24hr as continuous infusion
  5. Identify and treat precipitating cause
  6. Monitor electrolytes, glucose, and vital signs closely

Hack: In suspected adrenal crisis, never delay treatment to await diagnostic confirmation. The diagnostic ACTH stimulation test can be performed days later after stabilization, as the supraphysiological hydrocortisone doses used acutely do not interfere significantly with subsequent testing.

Future Directions and Emerging Concepts

Recent research has identified novel etiologies including checkpoint inhibitor-induced hypophysitis, genetic causes identified through whole-exome sequencing, and improved understanding of steroidogenic enzyme defects. The role of adrenal autoantibodies beyond 21-hydroxylase (including antibodies to 17α-hydroxylase and side-chain cleavage enzyme) is being elucidated.

Modified-release hydrocortisone preparations better mimicking physiological cortisol circadian rhythm show promise in improving quality of life. Continuous subcutaneous hydrocortisone infusion is under investigation for refractory cases.

Screening strategies for at-risk populations (those on long-term steroids, checkpoint inhibitors, patients with autoimmune diseases) require refinement. Development of point-of-care cortisol testing may enable earlier diagnosis in emergency settings.

Conclusion

Hypoadrenalism remains a diagnostic challenge requiring high clinical suspicion, particularly in nonspecific presentations. Understanding the etiopathogenesis guides appropriate diagnostic investigation and enables targeted screening for associated conditions. Early recognition and prompt treatment of adrenal crisis saves lives. Postgraduates in internal medicine must maintain vigilance for this great masquerader of medicine, remembering that adrenal insufficiency should be considered in any patient with unexplained fatigue, weight loss, hypotension, or electrolyte disturbances.

Key Take-Home Messages

  1. Measure morning cortisol and ACTH simultaneously to screen and localize defect
  2. Hyperpigmentation distinguishes primary from secondary disease
  3. Screen males with primary disease for adrenoleukodystrophy
  4. Consider autoimmune polyglandular syndromes in autoimmune Addison's
  5. Eosinophilia in critical illness suggests adrenal insufficiency
  6. Never delay treatment of suspected adrenal crisis for diagnostic confirmation
  7. Checkpoint inhibitors increasingly cause hypophysitis—maintain suspicion in oncology patients
  8. Inhaled/topical corticosteroids can suppress HPA axis at high doses

Selected References

  1. Husebye ES, Pearce SH, Krone NP, Kämpe O. Adrenal insufficiency. Lancet. 2021;397(10274):613-629.

  2. Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and treatment of primary adrenal insufficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016;101(2):364-389.

  3. Charmandari E, Nicolaides NC, Chrousos GP. Adrenal insufficiency. Lancet. 2014;383(9935):2152-2167.

  4. Kazlauskaite R, Evans AT, Villabona CV, et al. Corticotropin tests for hypothalamic-pituitary-adrenal insufficiency: A metaanalysis. J Clin Endocrinol Metab. 2008;93(11):4245-4253.

  5. Arlt W, Allolio B. Adrenal insufficiency. Lancet. 2003;361(9372):1881-1893.

  6. Betterle C, Presotto F, Furmaniak J. Epidemiology, pathogenesis, and diagnosis of Addison's disease in adults. J Endocrinol Invest. 2019;42(12):1407-1433.

  7. Barroso-Sousa R, Barry WT, Garrido-Castro AC, et al. Incidence of endocrine dysfunction following the use of different immune checkpoint inhibitor regimens. JAMA Oncol. 2018;4(2):173-182.

  8. Hahner S, Ross RJ, Arlt W, et al. Adrenal insufficiency. Nat Rev Dis Primers. 2021;7(1):19.

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