What are the appropriate next diagnostic and therapeutic steps for a 46‑year‑old woman with severe fatigue, an aldosterone level of 30 ng/dL, plasma renin activity of 0.93 ng/mL/h (aldosterone‑renin ratio 32.3), normal creatinine, serum iron of 14 µg/dL and transferrin saturation of 8%?

Immediate Next Steps for This Patient

This patient requires immediate iron replacement therapy for severe iron deficiency AND confirmatory testing for primary aldosteronism, followed by gastrointestinal evaluation to identify the source of iron loss.

Priority 1: Address Severe Iron Deficiency

The laboratory findings reveal profound iron deficiency with serum iron of 14 µg/dL and transferrin saturation of 8% (normal >30%). 1

Immediate Iron Replacement

• Start oral iron supplementation immediately (e.g., ferrous sulfate 325 mg daily) to address the severe iron deficiency that is likely the primary contributor to her fatigue. 1
• Serum ferritin should be measured if not already done, as ferritin <12 μg/dL is diagnostic of iron deficiency, though ferritin may be falsely elevated in inflammatory states. 1
• A complete blood count with MCV and hemoglobin is essential to confirm iron deficiency anemia. 1

Mandatory Gastrointestinal Investigation

GI investigations should be considered in all patients in whom iron deficiency has been confirmed unless there is a history of significant non-GI blood loss. 1

• Upper GI endoscopy with small bowel biopsies should be performed first, as 30-50% of patients will have an identifiable cause, and 2-3% of patients presenting with iron deficiency have celiac disease. 1
• Colonoscopy should follow, particularly given her age (46 years), to evaluate for colonic cancer, polyps, angiodysplasia, or inflammatory bowel disease. 1
• Document NSAID use and stop if present, as this is a common cause of occult GI blood loss. 1

Priority 2: Confirm Primary Aldosteronism

The aldosterone-renin ratio (ARR) of 32.3 with aldosterone 30 ng/dL and renin activity 0.93 ng/mL/h is positive for primary aldosteronism screening. 2

Why This Requires Confirmation

• An ARR ≥20-30 with plasma aldosterone ≥10-15 ng/dL meets screening criteria for primary aldosteronism. 2
• However, the specificity improves if minimum plasma renin activity of 0.5 ng/mL/h is used, and this patient's renin of 0.93 is above that threshold, making the positive screen more reliable. 2
• A positive screening test requires confirmation with additional testing to demonstrate autonomous aldosterone secretion. 2

Patient Preparation Before Confirmatory Testing

Critical: Ensure potassium repletion before any confirmatory testing, as hypokalemia suppresses aldosterone production and causes false-negative results. 2

• Check serum potassium and supplement to achieve 4.0-5.0 mEq/L range. 2
• Review current medications: Beta-blockers, centrally acting drugs, and diuretics should be stopped when feasible; long-acting calcium channel blockers and alpha-receptor antagonists are safe alternatives. 2
• Mineralocorticoid receptor antagonists must be withdrawn at least 4 weeks before testing if the patient is taking them. 2

Confirmatory Testing Options

Choose one of the following:

1. Oral sodium loading test (preferred if patient can tolerate): Liberal salt intake for 3 days, then measure 24-hour urine aldosterone. Failure to suppress aldosterone confirms autonomous production. 2

2. Intravenous saline suppression test: Infuse 2L normal saline over 4 hours; failure to suppress plasma aldosterone below 5 ng/dL confirms diagnosis. 2

• Testing should be performed with unrestricted salt intake and normal serum potassium levels. 2

After Confirmation: Subtype Determination

If primary aldosteronism is confirmed, referral to a hypertension specialist or endocrinologist is mandatory for: 2

• Non-contrast CT scan of adrenal glands as initial imaging. 2
• Adrenal venous sampling (AVS) before any surgical decision, as CT findings alone lead to unnecessary surgery in 25% of cases. 2
• Treatment depends on laterality: laparoscopic adrenalectomy for unilateral disease (curative in ~50%) or mineralocorticoid receptor antagonists for bilateral disease. 2

Why Both Conditions Matter for Her Fatigue

Iron Deficiency Impact

• Severe iron deficiency with transferrin saturation of 8% directly causes profound fatigue, weakness, and reduced exercise tolerance through impaired oxygen delivery. 1
• This is likely the dominant contributor to her severe fatigue and requires immediate correction. 1

Primary Aldosteronism Impact

• Primary aldosteronism causes 3.7-fold increased heart failure, 4.2-fold increased stroke, and 6.5-fold increased myocardial infarction compared to essential hypertension at equivalent blood pressure levels. 2
• Early diagnosis and treatment can reverse aldosterone-mediated target-organ damage and prevent these devastating complications. 2
• While less likely to be the primary cause of her fatigue, untreated primary aldosteronism carries dramatically higher cardiovascular risk. 2

Common Pitfalls to Avoid

• Do not assume dietary insufficiency explains iron deficiency without full GI investigation, even if dietary history is positive. 1
• Do not rely on presence or absence of hypokalemia to screen for primary aldosteronism—it is absent in approximately 50% of cases. 2
• Do not proceed to adrenalectomy based on CT findings alone—AVS is mandatory to prevent unnecessary surgery. 2
• Do not perform confirmatory testing for primary aldosteronism while patient is hypokalemic—this causes false-negative results. 2

Algorithmic Summary

1. Today: Start oral iron supplementation, check CBC with MCV, check serum ferritin, check serum potassium
2. Within 1-2 weeks: Arrange upper GI endoscopy with small bowel biopsies and colonoscopy
3. Simultaneously: Correct hypokalemia if present, review and adjust medications that interfere with aldosterone testing
4. After potassium normalization: Perform confirmatory testing for primary aldosteronism (oral salt loading or IV saline suppression)
5. If primary aldosteronism confirmed: Refer to endocrinology/hypertension specialist for CT imaging and adrenal venous sampling