What is the appropriate management for a post-menopausal or reproductive-age female with hyperferritinemia, elevated IGF-1, and significantly elevated FSH?

Diagnostic Evaluation and Management of Hyperferritinemia with Elevated IGF-1 and FSH

Immediate Diagnostic Priority: Measure Transferrin Saturation

Your ferritin of 329 ng/mL requires immediate measurement of fasting transferrin saturation (TS) to determine if this represents true iron overload or a secondary cause—this single test determines your entire diagnostic pathway. 1, 2

The FSH of 98.7 mIU/mL indicates you are post-menopausal or have primary ovarian insufficiency, which is critical context since normal ferritin thresholds differ by sex (>200 μg/L for women vs >300 μg/L for men in screening studies). 1 Your ferritin of 329 ng/mL is mildly elevated and falls well below the 1,000 μg/L threshold associated with organ damage risk. 1, 2

Algorithmic Approach Based on Transferrin Saturation

If TS ≥45%: Suspect Primary Iron Overload

• Order HFE genetic testing immediately for C282Y and H63D mutations to diagnose hereditary hemochromatosis. 1, 2
• C282Y homozygotes confirm HFE hemochromatosis and warrant therapeutic phlebotomy. 1, 3
• At your ferritin level (<1,000 μg/L), the risk of cirrhosis is extremely low (negative predictive value 94%), so liver biopsy is not indicated if liver enzymes are normal and you're under age 40. 1, 2
• Screen all first-degree relatives with both HFE genotype testing and iron studies (ferritin and TS). 1, 3

If TS <45%: Secondary Hyperferritinemia (Most Likely)

Over 90% of elevated ferritin cases with TS <45% are caused by inflammation, chronic alcohol consumption, cell necrosis, tumors, or metabolic syndrome/NAFLD—not iron overload. 2, 4

Order these specific tests immediately: 2, 3

• Complete metabolic panel including ALT, AST to assess hepatocellular injury
• Inflammatory markers: CRP and ESR to detect occult inflammation
• Complete blood count with differential to assess for anemia, polycythemia, or hematologic malignancy
• Creatine kinase (CK) to evaluate for muscle necrosis
• Alcohol consumption history (detailed quantification)
• Fasting glucose and lipid panel to assess for metabolic syndrome

The IGF-1 Elevation Requires Separate Evaluation

Your IGF-1 of 225 ng/mL must be interpreted against age-specific reference ranges, as IGF-1 declines significantly with age. 5 If this is elevated for your age:

• Measure serum growth hormone (GH) levels—the goal in acromegaly evaluation is to determine if GH and IGF-1 are both elevated. 5
• If GH >2.5 ng/mL with elevated IGF-1, consider pituitary MRI to evaluate for growth hormone-secreting adenoma. 5
• Acromegaly itself does not cause hyperferritinemia, so these are likely independent findings requiring parallel workup.

Most Likely Diagnoses Based on Your Pattern

Given ferritin 329 ng/mL in a post-menopausal woman (FSH 98.7):

1. Metabolic syndrome/NAFLD (most common cause): Look for elevated ALT, obesity, diabetes, hypertension, dyslipidemia. 2, 4
2. Chronic inflammation: Elevated CRP/ESR from rheumatologic disease, chronic infection, or occult malignancy. 2, 6
3. Chronic alcohol consumption: Even moderate intake increases ferritin through hepatocellular injury and increased iron absorption. 1, 2
4. Hepatocellular injury: Viral hepatitis (B or C), medication-induced liver injury, or acute hepatitis. 2, 4

Critical Pitfalls to Avoid

• Never use ferritin alone to diagnose iron overload—ferritin is an acute-phase reactant elevated in inflammation, liver disease, and malignancy independent of iron stores. 1, 2
• Do not assume iron overload when TS <45%—in the general population, iron overload is NOT the most common cause of elevated ferritin. 2
• Do not supplement with iron when ferritin is elevated, as this represents either iron overload or inflammatory iron sequestration, neither of which benefits from supplementation. 3
• Do not overlook liver biopsy if ferritin rises above 1,000 μg/L with abnormal liver tests, as this combination predicts cirrhosis in 80% of C282Y homozygotes. 1, 2

When to Refer to Specialists

• Gastroenterologist/hepatologist: If ferritin >1,000 μg/L regardless of TS, or if TS ≥45% with confirmed C282Y homozygosity. 2, 3
• Endocrinologist: If age-adjusted IGF-1 is elevated and GH >2.5 ng/mL to evaluate for acromegaly. 5
• Hematologist: If ferritin continues rising despite treating underlying causes, or if non-HFE hemochromatosis is suspected (elevated TS without C282Y homozygosity). 2, 3

Treatment Depends Entirely on the Underlying Cause

• If hereditary hemochromatosis (C282Y homozygote with TS ≥45%): Initiate therapeutic phlebotomy with target ferritin 50-100 μg/L, removing 500 mL blood weekly or biweekly. 1, 3
• If metabolic syndrome/NAFLD: Weight loss, diabetes management, and treatment of metabolic risk factors—not phlebotomy. 2, 3
• If inflammatory condition: Disease-specific anti-inflammatory therapy targeting the underlying condition. 2, 3
• If acromegaly confirmed: Octreotide or surgical resection of pituitary adenoma per endocrinology. 5