Diagnostic Workup to Differentiate Rheumatoid Arthritis from Hereditary Hemochromatosis
This patient must immediately obtain transferrin saturation and serum ferritin together—the single most critical step—because elevated alanine aminotransferase with hand pain creates a high pretest probability for hereditary hemochromatosis, which is frequently misdiagnosed as rheumatoid arthritis and requires fundamentally different treatment. 1
Step 1: Obtain Iron Studies Immediately
- Order fasting transferrin saturation (TS) and serum ferritin simultaneously as the essential first-line tests to distinguish true iron overload from inflammatory causes of elevated ferritin 1
- Morning blood draw is preferred, though fasting does not improve diagnostic utility 1
- Transferrin saturation ≥45% is the most sensitive early marker for hereditary hemochromatosis and triggers immediate genetic testing 1, 2
- Ferritin thresholds: >300 µg/L in men or >200 µg/L in women, combined with TS ≥45%, indicate biochemical iron overload requiring HFE genetic testing 1, 2
Step 2: Interpret Results Using This Algorithm
If TS ≥45% with Elevated Ferritin:
- Immediately order HFE genetic testing for C282Y and H63D mutations to confirm hereditary hemochromatosis 1, 2
- C282Y homozygosity confirms HFE-related hemochromatosis in 85-90% of clinically affected patients 3, 2
- This pattern strongly suggests hemochromatosis as the primary diagnosis, not rheumatoid arthritis 1
If TS <45% with Elevated Ferritin:
- Iron overload is excluded with >90% certainty 1, 4
- Elevated ferritin reflects hepatocellular injury, inflammation, or metabolic syndrome—not iron overload 1, 4
- Proceed with rheumatoid arthritis workup: anti-CCP antibodies, rheumatoid factor, inflammatory markers (CRP, ESR) 5
Step 3: Assess for Advanced Liver Disease
- Obtain ALT, AST, and platelet count to evaluate cirrhosis risk 1, 2
- The combination of ferritin >1,000 µg/L + elevated ALT/AST + platelet count <200,000/µL predicts cirrhosis in 80% of C282Y homozygotes 1, 2, 6
- Ferritin <1,000 µg/L has 94% negative predictive value for advanced fibrosis, making liver biopsy unnecessary 1, 4, 2
- Consider liver biopsy if ferritin >1,000 µg/L with elevated liver enzymes or thrombocytopenia 1, 2
Critical Distinguishing Features
Hemochromatosis Arthropathy:
- Targets 2nd and 3rd metacarpophalangeal (MCP) joints bilaterally—the hallmark pattern 1, 6
- Elevated ALT levels and MCP arthropathy are independently associated with iron overload (10.1-fold and 3.6-fold increased risk, respectively) 6
- Also affects ankles, hips, and wrists with exuberant osteophytes and rapid cartilage loss 1
- Chondrocalcinosis present in 50% of cases 1
- Does not respond to corticosteroids or DMARDs 7
Rheumatoid Arthritis:
- Primarily targets MCPJs, PIPJs, and wrists with symmetric distribution 1, 5
- Morning stiffness >1 hour, soft tissue swelling, and inflammatory signs 8, 5
- Anti-CCP antibodies and rheumatoid factor typically elevated 5
- Responds to disease-modifying antirheumatic agents 5
Common Diagnostic Pitfalls
- Never use ferritin alone to diagnose iron overload—it rises as an acute-phase reactant in inflammation, liver disease, and malignancy independent of iron stores 1, 4, 2
- Do not order HFE genetic testing when TS <45%, as this leads to misdiagnosis and unnecessary phlebotomy 4, 2
- Positive rheumatoid factor can occur in hemochromatosis due to chronic antigenic stimulation and does not confirm rheumatoid arthritis 7
- Hemochromatosis is frequently misdiagnosed as rheumatoid arthritis because both can present with MCP joint involvement and positive rheumatoid factor 9, 8, 7
- Failure to screen for hemochromatosis delays phlebotomy, which prevents cirrhosis and hepatocellular carcinoma 9, 7
If Hemochromatosis is Confirmed
- Initiate therapeutic phlebotomy immediately—the only effective treatment 3, 7
- Screen all first-degree relatives with HFE genetic testing and iron studies (TS and ferritin) 1, 3, 2
- Joint symptoms may improve with phlebotomy, though arthropathy does not respond uniformly 1, 9
- Avoid vitamin C supplements, as they accelerate iron mobilization and increase toxicity 3
- Avoid raw seafood due to Vibrio vulnificus infection risk in iron-overloaded patients 3
If Both Conditions Coexist
- The high prevalence of both diseases means they can occur simultaneously 8, 7
- Treat hemochromatosis with phlebotomy first, as this may improve joint symptoms and prevent organ damage 9, 8
- If inflammatory arthritis persists after iron depletion with elevated anti-CCP antibodies and ESR/CRP, initiate DMARD therapy for rheumatoid arthritis 8, 5