Adult-Onset Still's Disease (AOSD) is the most likely diagnosis and should be aggressively pursued with specific diagnostic criteria and IL-18 testing.
Primary Diagnostic Consideration
This clinical presentation—extremely elevated ferritin (~3000 µg/L), low transferrin saturation, low serum iron, prolonged fever (2 months), and negative infectious/malignant workup—is highly suggestive of Adult-Onset Still's Disease (AOSD). The hyperferritinemia with paradoxically low iron parameters reflects the inflammatory sequestration of iron, not true iron overload 1.
Key Diagnostic Steps
Immediately measure glycosylated ferritin (GF) percentage:
- GF ≤20% has 79.5% sensitivity and 66.4% specificity for AOSD 1
- The combination of ferritin >1000 ng/mL + GF ≤20% significantly increases diagnostic accuracy 1
- At ferritin 3000 µg/L, a cut-off of 2500 ng/mL shows 74% sensitivity and 73% specificity, while 5000 ng/mL shows 62% sensitivity but 92% specificity 1
Measure serum IL-18 levels:
- IL-18 >148.7 pg/mL demonstrates 70.4% sensitivity and 82.9% specificity for distinguishing AOSD from infections and other inflammatory conditions 1
- This is particularly valuable given your negative infectious workup
Assess S100A8/A9 (calprotectin) and S100A12 proteins:
- S100A8/A9 >45,488 ng/mL shows 63% sensitivity and 80.1% specificity for AOSD 1
- These markers help differentiate AOSD from rheumatoid arthritis and other autoimmune conditions
Clinical Context Understanding
The low transferrin saturation and low serum iron despite massively elevated ferritin is pathognomonic of inflammatory iron sequestration, not iron deficiency 2, 3. In inflammatory states, hepcidin increases and traps iron within ferritin stores, making it unavailable for erythropoiesis 4. This is functional iron restriction, not true iron deficiency—do not treat with iron supplementation.
Why This Isn't Iron Overload
Your transferrin saturation is LOW, which essentially rules out primary iron overload conditions like hemochromatosis 5. In true iron overload, you would expect:
- TSAT >60% (not present here)
- Ferritin >963 µg/L WITH high TSAT (you have high ferritin but LOW TSAT) 5
Apply Yamaguchi Criteria for AOSD
Evaluate for the following major criteria (need ≥5 total, with ≥2 major):
Major criteria:
- Fever ≥39°C for ≥1 week (you have 2 months of fever—check if spiking pattern)
- Arthralgias ≥2 weeks (assess wrists, knees, ankles specifically—these show highest involvement at 69%, 61%, 46% respectively) 1
- Typical rash (salmon-pink, evanescent, on trunk/extremities during fever spikes)
- Leukocytosis ≥10,000/µL with ≥80% granulocytes
Minor criteria:
- Sore throat
- Lymphadenopathy and/or splenomegaly (your PET-CT should have evaluated this)
- Liver dysfunction
- Negative RF and ANA
Critical Pitfalls to Avoid
Do not dismiss this as "reactive hyperferritinemia" simply because ferritin is elevated. Only 10% of hyperferritinemia cases represent true iron overload; the remaining 90% are inflammatory 2. Your constellation of findings—particularly the dissociation between high ferritin and low iron availability markers—demands active investigation for AOSD.
Do not order liver MRI for iron quantification. This would be appropriate if TSAT were >60%, but your low TSAT makes hepatic iron overload extremely unlikely 5.
Examine carefully for the characteristic Still's rash during fever spikes—it may be subtle and evanescent, appearing only when temperature is elevated.
Additional Workup
- Complete blood count with differential (looking for leukocytosis with neutrophilia)
- Comprehensive metabolic panel (assess for transaminitis)
- Rheumatoid factor and ANA (should be negative in AOSD)
- Throat examination and culture if sore throat present
- Repeat imaging if lymphadenopathy or organomegaly suspected but not clearly seen on PET-CT
Treatment Implications
If AOSD is confirmed, first-line treatment typically involves high-dose corticosteroids, with consideration for IL-1 or IL-6 inhibitors for refractory disease 1. The 2023 EULAR/PRES guidelines provide the most current management framework.