What is the best course of action for an 18-year-old female with hyperferritinemia, impaired renal function, and low alkaline phosphatase, presenting with migraines, joint pain, and fatigue?

Diagnostic Workup for Hyperferritinemia with Elevated Creatinine and Low Alkaline Phosphatase

This clinical triad of hyperferritinemia, elevated creatinine, and low alkaline phosphatase in an 18-year-old female with systemic symptoms (migraines, joint pain, fatigue) should prompt immediate evaluation for Adult-Onset Still's Disease (AOSD), followed by assessment for secondary causes of hyperferritinemia and consideration of rare genetic conditions.

Immediate Priority: Rule Out Adult-Onset Still's Disease

Key Diagnostic Features

• Ferritin elevation with low glycosylated ferritin (<20%) is highly suggestive of AOSD, with sensitivity of 79.5% and specificity of 66.4% when glycosylated ferritin ≤20% 1
• The combination of ferritin >5x upper limit of normal plus glycosylated ferritin ≤20% has specificity of 92.9% for AOSD 1
• Order glycosylated ferritin immediately - this single test can distinguish AOSD from other causes of hyperferritinemia 1

Clinical Context Supporting AOSD

• Joint pain and fatigue are cardinal features of AOSD 1
• Elevated creatinine may reflect renal involvement or macrophage activation syndrome (a serious complication of AOSD) 1
• ANA negativity does not exclude AOSD and is actually typical 1

Additional Testing for AOSD

• Serum S100A8/A9 (calprotectin): Cut-off of 45,488 ng/mL has 63% sensitivity and 80.1% specificity for AOSD 1
• Complete blood count looking for leukocytosis, thrombocytosis, or anemia 1
• ESR and CRP (typically markedly elevated in AOSD) 2
• Liver function tests (AST/ALT may be elevated during acute episodes) 1

Secondary Evaluation: Assess Transferrin Saturation

Measure fasting transferrin saturation (TSAT) to differentiate primary iron overload from secondary hyperferritinemia 2

If TSAT <45%

• This indicates secondary hyperferritinemia (>90% of cases), not primary iron overload 2
• Focus on identifying underlying inflammatory, infectious, or malignant conditions 2
• Evaluate for:
  • Chronic infection (check hepatitis B/C serology, HIV if risk factors) 2
  • Liver disease (AST, ALT, hepatitis panel, assess for NAFLD/metabolic syndrome) 2
  • Malignancy (especially with very high ferritin >10,000 μg/L - consider CT imaging) 2, 3
  • Renal dysfunction contribution (already identified with elevated creatinine) 3

If TSAT ≥45%

• Proceed with HFE genetic testing for C282Y and H63D mutations to evaluate for hereditary hemochromatosis 2
• Consider ferroportin disease if family history of hyperferritinemia (presents with low TSAT typically, but variants exist) 4

Address the Low Alkaline Phosphatase

Low alkaline phosphatase warrants specific investigation for hypophosphatasia, particularly given the systemic symptoms 5

Diagnostic Approach

• Measure bone-specific alkaline phosphatase - this may be low even when total ALP is normal or borderline 5
• Check vitamin B6 (pyridoxal-5-phosphate) level - elevated B6 supports hypophosphatasia diagnosis 5
• Review dental history: loose teeth, premature tooth loss, or "gray gums" in childhood are characteristic 5
• If bone-specific ALP is low (<5.3 μg/L) and B6 is elevated, proceed with ALPL gene testing 5

Clinical Significance

• Hypophosphatasia can cause chronic fatigue, muscle weakness, and joint pain - overlapping with this patient's symptoms 5
• Genetic confirmation guides treatment decisions (asfotase alfa may be indicated) 5

Evaluate Renal Function Deterioration

The elevated creatinine requires assessment of chronicity and etiology 1

Essential Testing

• Urinalysis with microscopy to assess for proteinuria, hematuria, or cellular casts 1
• Estimate GFR and compare to any prior values 1
• Urine protein-to-creatinine ratio 1

Specific Considerations

• If AOSD is confirmed, renal involvement may be part of the disease spectrum 1
• Chronic tubulointerstitial nephropathy can occur with systemic inflammatory conditions 1
• Rule out medication-related causes (NSAIDs for joint pain/migraines) 1

Iron Studies Interpretation

Despite hyperferritinemia, assess actual iron status 6

• Measure TSAT and serum iron 6
• Functional iron deficiency can coexist with elevated ferritin in inflammatory states (TSAT ≤20% with elevated ferritin) 6
• If TSAT ≤20%, iron supplementation may be needed despite high ferritin 6

Diagnostic Algorithm Summary

1. First-line tests (order immediately):

   • Glycosylated ferritin percentage 1
   • Fasting transferrin saturation 2
   • Bone-specific alkaline phosphatase 5
   • Vitamin B6 level 5
   • ESR, CRP 2
   • Complete metabolic panel with eGFR 1
   • Urinalysis with microscopy 1

2. Second-line tests (based on initial results):

   • If glycosylated ferritin <20%: S100A8/A9, consider rheumatology referral for AOSD workup 1
   • If TSAT ≥45%: HFE genetic testing 2
   • If bone-specific ALP low + elevated B6: ALPL gene testing 5
   • Hepatitis panel, liver imaging if liver dysfunction 2

3. Specialist referrals:

   • Rheumatology if AOSD suspected (glycosylated ferritin <20% with systemic symptoms) 1
   • Nephrology if eGFR <60 mL/min/1.73m² or significant proteinuria 1
   • Genetics/Metabolic if hypophosphatasia confirmed 5

Critical Pitfalls to Avoid

• Do not assume hyperferritinemia equals iron overload - measure TSAT first 2
• Do not dismiss low alkaline phosphatase as insignificant - it may indicate hypophosphatasia requiring specific treatment 5
• Do not delay AOSD evaluation - macrophage activation syndrome is life-threatening and requires urgent recognition 1
• Do not attribute all symptoms to a single diagnosis - multiple conditions may coexist (70% of patients with marked hyperferritinemia have multiple etiologies) 3
• Do not order phlebotomy without confirming iron overload (TSAT ≥45% and genetic confirmation) 2