In a patient with mild hypercalcemia, normal 25‑hydroxyvitamin D, suppressed parathyroid hormone, and ferritin 656 ng/mL, does the elevated ferritin alter the diagnosis or management?

Does Ferritin 656 ng/mL Alter the Diagnosis in Mild Hypercalcemia with Suppressed PTH?

No, a ferritin of 656 ng/mL does not change the diagnosis or management of hypercalcemia with suppressed PTH—this ferritin level is a non-specific inflammatory marker that reflects an underlying condition rather than indicating iron overload or a separate disease process.

Understanding the Clinical Context

Your patient presents with:

• Mild hypercalcemia
• Normal 25-hydroxyvitamin D
• Suppressed parathyroid hormone
• Ferritin 656 ng/mL

The suppressed PTH with hypercalcemia points toward PTH-independent hypercalcemia (malignancy, granulomatous disease, vitamin D intoxication, or other non-parathyroid causes). The ferritin elevation is almost certainly a secondary phenomenon.

Why This Ferritin Level Doesn't Change Your Diagnosis

Ferritin as an Acute-Phase Reactant

• Ferritin is an acute-phase protein that rises during inflammation, infection, liver disease, malignancy, and tissue necrosis independent of actual iron stores 1, 2.
• Over 90% of elevated ferritin cases are caused by non-iron overload conditions including chronic alcohol consumption, inflammation, cell necrosis, tumors, and metabolic syndrome 2, 3.
• At 656 ng/mL, this level falls well below the thresholds associated with significant complications: ferritin >1,000 ng/mL indicates risk for liver damage in hemochromatosis, and >7,500 ng/mL is associated with documented organ damage 2.

Ruling Out Iron Overload

The single most important test is transferrin saturation (TS):

• If TS <45%, iron overload is excluded with >90% certainty, and the elevated ferritin represents a secondary cause 2, 3.
• If TS ≥45%, only then should you consider primary iron overload and proceed with HFE genetic testing for C282Y and H63D mutations 2, 3.
• Never diagnose iron overload based on ferritin alone without confirming TS ≥45% 2, 3.

Ferritin in the Context of Hypercalcemia

Malignancy-Related Hypercalcemia

• Malignancy is the most frequent cause of markedly elevated ferritin (153/627 cases in one series), with solid tumors and lymphomas both causing ferritin elevation 4.
• In cancer patients, ferritin elevation reflects tumor burden, inflammation, and cellular turnover rather than iron status 1.
• If your patient has PTH-independent hypercalcemia, the ferritin of 656 ng/mL may simply reflect an underlying malignancy that is causing both the hypercalcemia and the ferritin rise 4.

Granulomatous Disease

• Chronic inflammatory diseases elevate ferritin as an acute-phase reactant 2.
• Sarcoidosis and other granulomatous conditions cause hypercalcemia via increased 1,25-dihydroxyvitamin D production and simultaneously raise ferritin through chronic inflammation 2.

Adult-Onset Still's Disease (AOSD)

• AOSD causes extreme hyperferritinemia (4,000–30,000 ng/mL, occasionally up to 250,000 ng/mL) with glycosylated ferritin fraction <20% 1, 5.
• Your patient's ferritin of 656 ng/mL is far too low to suggest AOSD 1, 5.
• AOSD does not typically present with hypercalcemia, making this diagnosis unlikely in your clinical scenario 1.

Diagnostic Algorithm for Your Patient

Step 1: Focus on the Hypercalcemia

The suppressed PTH with hypercalcemia is the primary diagnostic concern:

• Measure PTHrP (parathyroid hormone-related peptide) to evaluate for malignancy-associated hypercalcemia.
• Measure 1,25-dihydroxyvitamin D to assess for granulomatous disease or lymphoma.
• Check serum protein electrophoresis (SPEP) and free light chains if multiple myeloma is suspected.
• Consider imaging (chest X-ray or CT) to evaluate for malignancy or sarcoidosis.

Step 2: Evaluate the Ferritin

Order transferrin saturation simultaneously with ferritin 2, 3:

• If TS <45%: The ferritin elevation is secondary to inflammation, liver disease, or malignancy. Treat the underlying hypercalcemia cause; the ferritin will likely normalize when the primary condition is addressed 2, 3.
• If TS ≥45%: Proceed with HFE genetic testing for C282Y and H63D mutations to evaluate for hereditary hemochromatosis 2, 3.

Step 3: Assess for Inflammation

• Check CRP and ESR to quantify the degree of systemic inflammation 2, 3.
• Elevated inflammatory markers support the interpretation that ferritin is an acute-phase reactant rather than indicating iron overload 2, 3.

Step 4: Evaluate Liver Disease

• Check AST, ALT, and consider abdominal ultrasound to assess for fatty liver, chronic liver disease, or hepatomegaly 2, 3.
• Liver disease (alcoholic, viral hepatitis, NAFLD) is a common cause of ferritin elevation in the 600–800 ng/mL range 2, 3.

Management Strategy

Treat the Hypercalcemia, Not the Ferritin

• The ferritin of 656 ng/mL does not require specific treatment unless TS ≥45% confirms iron overload 2, 3.
• Do not initiate phlebotomy or iron chelation based on ferritin alone 2, 3.
• Address the underlying cause of hypercalcemia (malignancy, granulomatous disease, etc.), and the ferritin will likely normalize as the primary condition is treated 2, 3.

When to Reassess Ferritin

• Recheck ferritin and TS after treating the hypercalcemia to confirm that ferritin normalizes with resolution of the underlying condition 2, 3.
• If ferritin rises above 1,000 ng/mL or TS becomes ≥45%, refer to hepatology or hematology for further evaluation 2, 3.

Critical Pitfalls to Avoid

• Do not assume iron overload when ferritin is elevated without confirming TS ≥45% 2, 3.
• Do not overlook malignancy as the unifying diagnosis for both hypercalcemia and elevated ferritin 4.
• Do not order HFE genetic testing when TS <45%, as this leads to misdiagnosis and unnecessary phlebotomy 2, 3.
• Do not treat the ferritin in isolation—focus on identifying and managing the cause of PTH-independent hypercalcemia 2, 3.