What is the possible diagnosis for a 39-year-old black woman with no pertinent medical history, who is struggling to lose weight, and has lab results showing low total iron binding capacity (hypotransferrinemia), absolute iron deficiency (iron deficiency), normal ferritin levels, and low morning cortisol (hypocortisolism) levels?

Lab Interpretation: Iron Deficiency with Possible Adrenal Insufficiency

This patient's labs reveal iron deficiency (low TIBC 231 with elevated ferritin 234) and concerning adrenal insufficiency (morning cortisol 4.2), while the elevated hematocrit and suppressed progesterone suggest relative energy deficiency in daily life (RED-S) or chronic energy restriction.

Primary Concern: Adrenal Insufficiency

• The morning cortisol of 4.2 mcg/dL is critically low and requires urgent evaluation, as stimulated plasma cortisol levels less than 18 mcg/dL at 30- or 60-minutes post-cosyntropin testing are suggestive of adrenocortical insufficiency 1.
• Unidentified adrenal insufficiency can result in serious adverse outcomes and should not be delayed in diagnosis 1.
• Immediate next step: Perform an ACTH stimulation test with cosyntropin 0.25 mg IV or IM, obtaining baseline cortisol and repeat measurements at exactly 30 and 60 minutes post-administration 1.
• The low progesterone (<0.1) combined with low cortisol suggests hypothalamic-pituitary-adrenal axis dysfunction, potentially from chronic energy deficiency 2.

Iron Status Interpretation

The combination of low TIBC (231, below range 250-450) with elevated ferritin (234) is paradoxical and does NOT represent typical iron deficiency anemia.

Understanding the Paradox

• Low TIBC typically indicates iron overload or chronic inflammation, not iron deficiency, as TIBC increases when serum iron concentration and stored iron are low 3.
• However, the elevated ferritin (234 ng/mL) in the context of struggling to lose weight and low cortisol suggests this is functional iron deficiency in the setting of chronic energy restriction 2.
• In low energy states, iron deficiency is the most common hematological change, with mechanisms including inadequate dietary intake, impaired absorption, and metabolic alterations 2.

Diagnostic Considerations

• The ferritin of 234 ng/mL is elevated and does NOT indicate iron deficiency in the absence of inflammation, as iron deficiency is diagnosed by ferritin <30 ng/mL in non-inflammatory states 3, 4.
• Ferritin is an acute-phase reactant and can be falsely elevated during illness, inflammation, or stress 3.
• Obtain C-reactive protein to assess for inflammation, as this affects interpretation of both ferritin and TIBC 2, 3.
• The low TIBC with high ferritin may indicate anemia of chronic disease (ACD) rather than true iron deficiency 2.

Hematocrit Elevation

• The hematocrit of 47.4% is elevated for a woman (normal range typically 36-44%), which is unusual in the context of suspected iron deficiency 2.
• This elevation may represent hemoconcentration from volume depletion or a compensatory response to chronic hypoxia.
• Alternatively, this could reflect relative polycythemia in the setting of chronic energy restriction and metabolic adaptation.

Relative Energy Deficiency Syndrome (RED-S)

The constellation of findings—difficulty losing weight, low cortisol, suppressed progesterone, and paradoxical iron markers—strongly suggests chronic energy deficiency.

Hormonal Pattern

• Low energy availability causes decreased progesterone, increased cortisol (though paradoxically this patient has LOW cortisol suggesting severe HPA axis suppression), and iron deficiency 2.
• The suppressed progesterone <0.1 indicates anovulation or hypothalamic amenorrhea, common in energy-deficient states 2.
• In severe energy deficiency, cortisol may be elevated initially but can become suppressed with chronic HPA axis dysfunction, which appears to be the case here 2.

Clinical Implications

• Iron deficiency in energy-deficient individuals worsens the hypometabolic state by impairing thyroid hormone synthesis and hepatic conversion of T4 to T3 2.
• Obtain thyroid function tests (TSH, free T4, free T3) as part of the evaluation, since low energy states cause decreased total T3, free T3, and free T4 2.
• Assess for eating disorders, restrictive diets, excessive exercise, or other causes of chronic energy deficit 5, 4.

Recommended Diagnostic Workup

1. Urgent ACTH stimulation test to confirm or exclude adrenal insufficiency 1
2. Complete iron panel: serum iron, transferrin saturation, C-reactive protein 3
3. Complete blood count with reticulocyte count and red cell indices 3
4. Thyroid function tests: TSH, free T4, free T3 2
5. Comprehensive metabolic panel to assess for other metabolic derangements
6. Detailed dietary and exercise history to evaluate for energy deficiency 5, 4

Potential Underlying Diagnoses

• Primary or secondary adrenal insufficiency (most urgent to rule out) 1
• Relative Energy Deficiency in Daily Life (RED-S) with HPA axis suppression 2
• Anemia of chronic disease rather than true iron deficiency 2
• Functional hypothalamic amenorrhea from chronic energy restriction 2

Critical Pitfalls to Avoid

• Do not assume iron deficiency based solely on difficulty losing weight—the ferritin is elevated and TIBC is low, which is atypical for iron deficiency 3, 4.
• Do not delay evaluation of the low morning cortisol—this requires urgent assessment as adrenal insufficiency can be life-threatening 1.
• Do not start iron supplementation without confirming true iron deficiency, as the current labs do not support this diagnosis and inappropriate iron therapy can be harmful 5.
• Do not overlook the possibility of eating disorders or chronic energy restriction in a patient struggling to lose weight with these hormonal abnormalities 2.