Still's Disease: Understanding Ferritin Levels, Diagnosis, and Management

How high is ferritin in Still's disease?

Ferritin levels in Still's disease, particularly Adult-Onset Still's Disease (AOSD), are typically markedly elevated, often exceeding 1,000 ng/mL and sometimes reaching tens of thousands, serving as a critical diagnostic marker that is disproportionately high relative to iron stores.

Understanding Still's Disease (Adult-Onset Still's Disease - AOSD)

Still's disease, more commonly known in adults as Adult-Onset Still's Disease (AOSD), is a rare, systemic inflammatory disorder characterized by high fevers, joint pain (arthralgia or arthritis), and a characteristic rash. It is considered a form of systemic juvenile idiopathic arthritis (sJIA) that occurs in adulthood. AOSD is an autoinflammatory condition, meaning it involves dysregulation of the innate immune system, leading to widespread inflammation throughout the body. The exact cause remains unknown, but it is believed to involve a complex interplay of genetic predisposition and environmental triggers.

Ferritin: A Key Biomarker

Ferritin is a ubiquitous intracellular protein that stores iron and releases it in a controlled fashion. It acts as a buffer against iron deficiency and iron overload. Small amounts of ferritin are secreted into the blood, and the serum ferritin level is generally considered an accurate reflection of the body's total iron stores. However, ferritin is also an acute phase reactant, meaning its levels can rise significantly during inflammation, infection, and various other disease states, even in the absence of increased iron stores. This dual role makes ferritin a complex but highly informative biomarker.

Ferritin in Still's Disease: The Hyperferritinemia Phenomenon

One of the most striking and diagnostically significant features of AOSD is the presence of extremely high serum ferritin levels, a phenomenon known as hyperferritinemia. While elevated ferritin can be seen in many inflammatory conditions, the levels in AOSD are often extraordinarily high, frequently exceeding 1,000 ng/mL. It is not uncommon to see ferritin levels in the range of 5,000 ng/mL, 10,000 ng/mL, or even higher (e.g., 20,000 ng/mL or more) during active disease flares.

This hyperferritinemia in AOSD is often disproportionate to the actual iron stores in the body. Unlike iron overload conditions where high ferritin reflects excessive iron, in AOSD, it primarily reflects the intense systemic inflammation. The inflammatory cytokines, particularly IL-1, IL-6, and TNF-alpha, which are prominent in AOSD, directly stimulate ferritin synthesis and release from cells, leading to its dramatic elevation in the bloodstream.

Glycosylated Ferritin: A Crucial Distinction

To further aid in the diagnosis of AOSD and differentiate it from other causes of hyperferritinemia, clinicians often measure the percentage of glycosylated ferritin. Glycosylated ferritin is a specific form of ferritin that has carbohydrate chains attached to it. In healthy individuals and in most conditions causing elevated ferritin (such as iron overload, chronic liver disease, or common infections), the percentage of glycosylated ferritin is typically high (e.g., >50-80%).

However, in AOSD, the percentage of glycosylated ferritin is characteristically very low, often less than 20% and sometimes even below 10%. This low percentage of glycosylated ferritin, in the context of markedly elevated total serum ferritin, is a highly specific and sensitive diagnostic marker for AOSD. It helps distinguish AOSD from other severe inflammatory conditions, including sepsis, viral infections, or even other rheumatic diseases, where total ferritin might be high but glycosylated ferritin percentage remains normal or high.

Clinical Significance and Differential Diagnosis

The extreme hyperferritinemia and low glycosylated ferritin are critical for the diagnosis of AOSD. They are included in several diagnostic criteria sets (e.g., Yamaguchi criteria). Monitoring ferritin levels is also crucial for:

• Diagnosis: Helps confirm AOSD, especially when other inflammatory markers like C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are also elevated.
• Disease Activity: Ferritin levels often correlate with disease activity, rising during flares and decreasing with effective treatment.
• Differential Diagnosis: Differentiating AOSD from other conditions that can present with fever, inflammation, and high ferritin, such as:
  • Sepsis: While sepsis can cause high ferritin, the glycosylated ferritin percentage is usually normal.
  • Macrophage Activation Syndrome (MAS)/Hemophagocytic Lymphohistiocytosis (HLH): MAS is a severe, life-threatening complication of AOSD (and other rheumatic diseases) characterized by uncontrolled immune activation. MAS itself causes extremely high ferritin levels (often >10,000 ng/mL) and very low glycosylated ferritin, making the distinction from an AOSD flare challenging without other clinical signs of MAS (e.g., cytopenias, liver dysfunction).
  • Viral Infections: Certain viral infections (e.g., Epstein-Barr virus) can cause high ferritin, but typically not to the extreme levels seen in AOSD and usually with a normal glycosylated percentage.
  • Iron Overload Syndromes: These conditions have high ferritin but high glycosylated ferritin and other iron studies (e.g., transferrin saturation) that point to iron accumulation.

Management and Monitoring

Due to its role as an acute phase reactant and a marker of disease activity, serum ferritin is frequently monitored in patients with AOSD. A significant drop in ferritin levels, especially when coupled with clinical improvement, indicates a positive response to treatment with immunomodulatory drugs (e.g., corticosteroids, IL-1 inhibitors like anakinra, or IL-6 inhibitors like tocilizumab). Conversely, persistently high or rising ferritin levels may suggest ongoing disease activity, a developing complication like MAS, or inadequate treatment.

Conclusion

In summary, ferritin levels in Still's disease are remarkably high, often reaching thousands or tens of thousands of ng/mL. This extreme elevation, coupled with a characteristically low percentage of glycosylated ferritin, serves as a cornerstone for the diagnosis of Adult-Onset Still's Disease. Understanding this unique ferritin profile is essential for clinicians to accurately diagnose AOSD, differentiate it from other inflammatory conditions, and effectively monitor disease activity and treatment response.