Is there value in measuring Sex Hormone-Binding Globulin (SHBG) in patients with elevated ferritin levels, potentially indicating iron overload?

SHBG Measurement Has No Established Role in Evaluating Elevated Ferritin

There is no evidence-based indication to measure Sex Hormone-Binding Globulin (SHBG) when evaluating elevated ferritin levels, as SHBG does not appear in any diagnostic algorithm for hyperferritinemia or iron overload assessment. 1, 2, 3

The Correct Diagnostic Approach to Elevated Ferritin

The evaluation of elevated ferritin follows a well-established algorithmic pathway that does not include SHBG measurement:

Step 1: Measure Transferrin Saturation Immediately

• Fasting transferrin saturation (TS) is the single most important test to distinguish true iron overload from secondary causes of hyperferritinemia 1, 2, 3
• The American Association for the Study of Liver Diseases emphasizes that ferritin and TS must always be measured together to prevent diagnostic errors 1, 2
• TS ≥45% indicates possible iron overload and warrants genetic testing, while TS <45% indicates secondary hyperferritinemia from inflammation, liver disease, or metabolic causes 1, 2, 3

Step 2: Identify the Underlying Cause Based on TS Results

If TS ≥45% (Iron Overload Pattern):

• Proceed immediately to HFE genetic testing for C282Y and H63D mutations to diagnose hereditary hemochromatosis 1, 2, 3
• C282Y homozygotes or C282Y/H63D compound heterozygotes with elevated iron stores confirm HFE hemochromatosis 1, 3
• Consider non-HFE hemochromatosis genes (TFR2, SLC40A1, HAMP, HJV) if iron overload is confirmed but C282Y homozygosity is excluded 1

If TS <45% (Secondary Hyperferritinemia):

• Over 90% of cases are caused by chronic alcohol consumption, inflammation, cell necrosis, tumors, or metabolic syndrome/NAFLD—not iron overload 1, 3
• Check inflammatory markers (CRP, ESR) to detect occult inflammation 1, 2
• Assess liver enzymes (ALT, AST) for hepatocellular injury 1, 2
• Evaluate for metabolic syndrome, which accounts for one-third of NAFLD-associated hyperferritinemia 3

Step 3: Risk Stratification by Ferritin Level

• Ferritin <1000 μg/L: Low risk of organ damage (94% negative predictive value for advanced fibrosis) 1, 2, 3
• Ferritin >1000 μg/L: 20-45% prevalence of cirrhosis in C282Y homozygotes; strongly consider liver biopsy if accompanied by elevated liver enzymes or platelet count <200,000/μL 1, 2, 3
• Ferritin >10,000 μg/L: Rarely represents simple iron overload; requires urgent specialist referral for life-threatening conditions like adult-onset Still's disease or hemophagocytic lymphohistiocytosis 1, 4

Why SHBG Is Not Part of This Evaluation

The comprehensive diagnostic guidelines from the American Association for the Study of Liver Diseases, European Association for the Study of the Liver, and other major societies make no mention of SHBG in their hyperferritinemia algorithms 1, 2, 3. The key discriminators are:

• Transferrin saturation distinguishes iron overload from inflammatory causes 1, 2, 3
• HFE genetic testing confirms hereditary hemochromatosis 1, 2, 3
• Inflammatory markers (CRP, ESR) identify secondary causes 1, 2
• Liver enzymes and imaging assess organ damage 1, 2, 5

Critical Pitfalls to Avoid

• Never use ferritin alone without transferrin saturation to diagnose iron overload, as 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%, as secondary causes account for over 90% of outpatient hyperferritinemia 1, 3
• Do not overlook liver biopsy in patients with ferritin >1000 μg/L and abnormal liver tests, as this combination predicts cirrhosis in 80% of C282Y homozygotes when combined with platelet count <200,000/μL 1, 2