How should I evaluate and manage a markedly elevated ferritin level of 992 ng/mL?

Evaluation and Management of Ferritin 992 ng/mL

Immediately measure fasting transferrin saturation (TS) to determine whether this represents true iron overload or secondary hyperferritinemia from inflammation, liver disease, or metabolic causes. 1, 2

Initial Diagnostic Algorithm

The single most critical test is transferrin saturation, which distinguishes iron overload (TS ≥45%) from the 90% of cases caused by non-iron conditions. 1, 3

Step 1: Obtain Transferrin Saturation and Baseline Labs

Order immediately:

• Fasting transferrin saturation (morning sample preferred) 1, 2
• Complete metabolic panel including ALT, AST, bilirubin 1, 4
• Inflammatory markers: CRP and ESR 1, 2
• Complete blood count with differential 1
• Lipid panel and fasting glucose to assess for metabolic syndrome 1, 5

Step 2: Interpret Based on Transferrin Saturation

If TS ≥ 45%: Suspect Primary Iron Overload

• Proceed immediately to HFE genetic testing for C282Y and H63D mutations 6, 1, 2
• C282Y homozygosity or C282Y/H63D compound heterozygosity confirms hereditary hemochromatosis 1, 2
• At ferritin 992 ng/mL with TS ≥45%, you can initiate therapeutic phlebotomy without liver biopsy if the patient is <40 years old, has normal liver enzymes, and no hepatomegaly 6, 1
• The critical threshold is ferritin >1000 μg/L—below this carries a 94% negative predictive value for advanced fibrosis 6, 1

If TS < 45%: Iron Overload Excluded with >90% Certainty

When TS is <45%, the ferritin elevation reflects secondary causes, not iron overload. 1, 2, 3 Evaluate for:

Common causes (account for >90% of cases): 2, 3

• Chronic alcohol consumption: Check phosphatidyl ethanol or detailed alcohol history 2, 5
• Non-alcoholic fatty liver disease/metabolic syndrome: Suggested by elevated ALT with obesity, diabetes, dyslipidemia 1, 2, 5
• Inflammatory conditions: Elevated CRP/ESR with rheumatologic disease, inflammatory bowel disease 1, 2
• Liver disease: Viral hepatitis (check HBsAg, HCV antibody), alcoholic hepatitis 6, 1, 2
• Malignancy: Screen age-appropriately; malignancy was the most common cause in one large series 7
• Infection: Active infection raises ferritin as an acute-phase reactant 1, 2

Risk Stratification by Ferritin Level

At 992 ng/mL, you are just below the critical 1000 μg/L threshold:

• Ferritin <1000 μg/L: Low risk of organ damage; 94% negative predictive value for cirrhosis in hemochromatosis 6, 1, 5
• Ferritin >1000 μg/L: 20-45% prevalence of cirrhosis in C282Y homozygotes; liver biopsy should be considered if accompanied by elevated liver enzymes or platelet count <200,000/μL 6, 1, 4
• Ferritin >10,000 μg/L: Rarely represents simple iron overload; consider adult-onset Still's disease (glycosylated ferritin <20%), hemophagocytic lymphohistiocytosis, or macrophage activation syndrome requiring urgent specialist referral 1, 7, 8

Management Based on Underlying Cause

If Hereditary Hemochromatosis Confirmed (C282Y homozygote with TS ≥45%)

Therapeutic phlebotomy protocol: 6, 1, 4

• Remove 500 mL blood weekly or biweekly
• Check hemoglobin/hematocrit before each session; allow no more than 20% drop from baseline
• Check ferritin every 10-12 phlebotomies
• Target ferritin 50-100 μg/L for induction phase
• Once target reached, maintain with phlebotomy every 2-4 months
• Screen all first-degree relatives with TS, ferritin, and HFE genetic testing 6, 1, 4

Critical management points: 6, 1

• Avoid iron supplements entirely
• Avoid vitamin C supplements (accelerates iron mobilization)
• Avoid raw shellfish (Vibrio vulnificus risk in iron overload)

If Secondary Hyperferritinemia (TS <45%)

Treat the underlying condition, not the ferritin itself: 1, 2

• NAFLD/metabolic syndrome: Weight loss, metabolic control, address insulin resistance 1, 5
• Alcoholic liver disease: Alcohol cessation 2, 5
• Inflammatory conditions: Disease-specific anti-inflammatory therapy 1
• Infection: Treat underlying infection 1

Do NOT perform phlebotomy when TS <45%—iron is sequestered by inflammation, not truly overloaded. 1, 2

When to Refer to Specialist

Refer to gastroenterology/hepatology or hematology if: 1, 3

• Ferritin >1000 μg/L with elevated bilirubin
• Ferritin >1000 μg/L and cause remains unclear after initial workup
• TS ≥45% on repeat testing
• Clinical evidence of cirrhosis (platelet count <200,000/μL, hepatomegaly, elevated bilirubin)
• Confirmed C282Y homozygosity requiring phlebotomy management

Critical Pitfalls to Avoid

• Never diagnose iron overload based on ferritin alone without confirming TS ≥45%—ferritin is an acute-phase reactant elevated in inflammation, liver disease, malignancy, and tissue necrosis independent of iron stores 1, 2, 3
• Do not order HFE genetic testing when TS <45%—this leads to misdiagnosis and inappropriate phlebotomy 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 1, 2, 3
• Do not overlook liver biopsy in patients with ferritin >1000 μg/L and abnormal liver tests—this combination warrants histologic assessment for cirrhosis 6, 1, 4

Monitoring

If ferritin remains <1000 μg/L with normal TS and normal liver enzymes, no further investigation is needed and the patient can be followed in primary care. 5, 3 Recheck ferritin and TS in 3-6 months if secondary causes are being addressed. 1