What is the diagnosis for a patient with excessive fatigue, elevated ferritin levels, and an appropriate response to cosyntropin stimulation, with other hormonal levels being within normal limits?

Diagnosis: Secondary Adrenal Insufficiency with Hyperferritinemia from Inflammation or Metabolic Syndrome

This patient has secondary adrenal insufficiency (low ACTH with low cortisol but adequate cosyntropin response) as the primary cause of fatigue, with hyperferritinemia likely representing a secondary finding from inflammation, metabolic syndrome, or chronic disease rather than iron overload.

Primary Diagnosis: Secondary Adrenal Insufficiency

• The cortisol response to cosyntropin stimulation (baseline 4.4 → 20.8 → 24.2) demonstrates intact adrenal gland function, ruling out primary adrenal insufficiency 1
• The low-normal ACTH (12.5) combined with low baseline cortisol (4.4) indicates central (hypothalamic-pituitary) dysfunction causing secondary adrenal insufficiency 1
• This pattern explains the excessive fatigue, as cortisol deficiency is a primary cause of profound fatigue and weakness 1
• All other pituitary hormones (TSH, IGF-1, FSH, LH, prolactin, testosterone, FT3, FT4) are normal, suggesting isolated ACTH deficiency or partial hypopituitarism 1

Hyperferritinemia Assessment: Not Iron Overload

• The transferrin saturation of 42% is below the diagnostic threshold of ≥45% for iron overload, making hereditary hemochromatosis or primary iron overload extremely unlikely 2, 3, 1
• Over 90% of hyperferritinemia cases with transferrin saturation <45% are due to secondary causes including inflammation, metabolic syndrome, NAFLD, or chronic disease—not iron overload 3, 4
• Ferritin at 690 μg/L with normal transferrin saturation indicates ferritin elevation as an acute-phase reactant rather than true iron overload 3, 1
• When transferrin saturation is <45%, iron overload is unlikely and secondary causes predominate 3, 4

Differential Diagnosis for Hyperferritinemia in This Context

• Metabolic syndrome/NAFLD: Ferritin elevation reflects hepatocellular injury and insulin resistance rather than iron overload, and is one of the most common causes of hyperferritinemia in outpatients 3
• Chronic inflammation: Ferritin rises as an acute-phase reactant during subclinical inflammatory states, independent of actual iron stores 3, 4
• Secondary adrenal insufficiency itself: Chronic cortisol deficiency can contribute to metabolic dysfunction and inflammatory changes that elevate ferritin 3
• Cell necrosis or tissue damage from any chronic condition can release ferritin 3

Critical Diagnostic Pitfalls to Avoid

• Never diagnose iron overload based on ferritin alone without confirming transferrin saturation ≥45% 2, 3, 4, 1
• Do not initiate phlebotomy therapy when transferrin saturation is <45%, as this indicates the ferritin elevation is not from iron overload 3, 4
• Ferritin <1000 μg/L has a high negative predictive value for organ damage even if iron overload were present 2, 3, 1
• The appropriate cortisol response to cosyntropin (>18-20 μg/dL) rules out primary adrenal insufficiency, but does not exclude secondary adrenal insufficiency, which is the diagnosis here 1

Recommended Next Steps

• Pituitary MRI to evaluate for structural lesions (adenoma, empty sella, infiltrative disease) causing isolated ACTH deficiency 1
• Evaluate for other causes of secondary adrenal insufficiency including medication history (chronic opioids, glucocorticoids), recent glucocorticoid withdrawal, or autoimmune hypophysitis 1
• Assess metabolic syndrome components (fasting glucose, lipid panel, blood pressure, waist circumference) to explain the hyperferritinemia 3, 4
• Check inflammatory markers (CRP, ESR) to detect occult inflammation contributing to ferritin elevation 3, 4
• Liver enzymes (ALT, AST) to evaluate for NAFLD as a cause of hyperferritinemia 3, 4
• Do not pursue HFE genetic testing or liver biopsy for iron assessment, as transferrin saturation <45% excludes clinically significant iron overload 2, 3, 1

Treatment Implications

• Initiate glucocorticoid replacement therapy for secondary adrenal insufficiency, which should improve fatigue significantly 1
• Address the underlying cause of hyperferritinemia by treating metabolic syndrome (weight loss, exercise, dietary modification) or inflammatory conditions if identified 3, 4
• Phlebotomy is not indicated and would be inappropriate given the normal transferrin saturation 2, 3, 4
• Monitor ferritin levels after treating the underlying conditions; ferritin should normalize with resolution of inflammation or metabolic dysfunction 3