Iron Overload, Immune Dysregulation, and Hormonal Imbalance: The Overlooked Link Between SJS, APS, Thyroid Dysfunction, and Severe Inflammatory Disorders

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High iron levels can have far-reaching effects on the human body—extending beyond liver damage and joint pain to influence hormone production, immune responses, and even life-threatening syndromes. This article explores the intricate connections between iron overload, autoimmune thyroid disease, antiphospholipid syndrome (APS), Stevens-Johnson Syndrome (SJS), and severe inflammatory conditions such as Hemophagocytic Lymphohistiocytosis (HLH). Understanding these connections is crucial for timely diagnosis, risk assessment, and effective intervention.

Iron Overload: A Catalyst for Systemic Dysregulation

Iron is an essential mineral, but in excess, it becomes toxic. Hereditary hemochromatosis, a genetic disorder marked by excessive iron absorption, is one of the most common causes of systemic iron overload. As iron accumulates, it promotes oxidative stress, cellular damage, and immune dysregulation, impacting multiple organs—including the thyroid, pituitary gland, liver, and heart.

Iron and the Immune System: Inflammation and Autoimmunity

Iron overload is not just a storage issue—it directly affects immune regulation:

  • Ferritin, the protein that stores iron, is also an acute-phase reactant, increasing during systemic inflammation.

  • High iron levels can stimulate macrophage activation, promoting autoimmune and inflammatory responses.

  • Hyperferritinemia is seen in severe immune conditions like HLH, systemic lupus erythematosus (SLE), and catastrophic APS (cAPS).

Stevens-Johnson Syndrome (SJS), HLH, and Iron: A Dangerous Intersection

Stevens-Johnson Syndrome (SJS) is a rare but severe mucocutaneous reaction, most commonly triggered by medications. In rare and devastating cases, it can progress to or mimic Hemophagocytic Lymphohistiocytosis (HLH), a condition marked by overwhelming immune system activation and multiorgan failure.

Case Highlight: SJS, HLH, and Hemochromatosis

One case described a patient with hemochromatosis who developed SJS-like symptoms, followed by a stroke and subsequent diagnosis of HLH. This case emphasized:

  • Iron overload may dysregulate immune surveillance, tipping the body into a hyperinflammatory state.

  • Ferritin, often extremely elevated in HLH (sometimes >10,000 µg/L), may serve both as a marker and mediator of inflammation.

  • Iron-induced immune dysfunction may complicate diagnosis and management of SJS and other inflammatory disorders.

Thyroid Dysfunction and Iron: A Silent but Serious Risk

Iron’s toxic effects extend to the endocrine system, particularly the thyroid and pituitary glands.

1. Iron Deposition in the Thyroid

  • Iron accumulates in the thyroid gland in hemochromatosis, leading to oxidative damage.

  • This can trigger autoimmune thyroiditis (especially Hashimoto’s), characterized by anti-TPO and anti-thyroglobulin antibodies.

2. Pituitary Gland Iron Accumulation

  • The pituitary gland, which produces TSH, is susceptible to iron buildup, potentially leading to central hypothyroidism.

3. Disruption of Thyroid Hormone Production

  • Iron is a cofactor for thyroperoxidase (TPO), necessary for thyroid hormone synthesis.

  • Paradoxically, excessive iron may impair TPO function, resulting in reduced T3 and T4 levels, despite adequate iodine intake.

Autoimmunity, APS, and Ferritin: The Inflammatory Triangle

Antiphospholipid Syndrome (APS)

APS is an autoimmune disorder that increases the risk of blood clots and pregnancy complications. In severe forms, such as catastrophic APS (cAPS), the condition becomes life-threatening.

Ferritin in APS:

  • High ferritin (>227 µg/L) in APS correlates with thrombotic risk and disease severity.

  • As an inflammatory marker, ferritin reflects disease activity but may not always indicate iron overload.

  • Anti-CMV antibodies and other viral triggers can further complicate APS and elevate ferritin levels.

Differential Diagnosis: Iron Overload vs. Inflammatory Elevation

Not all high ferritin indicates iron overload. Consider:

  • Ferritin + High TSAT (transferrin saturation) → suggests hemochromatosis or true iron overload.

  • Ferritin + Normal or Low TSAT → points to inflammation, liver disease, or infection.

Additional tests such as CRP, ESR, and soluble transferrin receptor (sTfR) may help clarify iron status in the context of inflammation.

Diagnosing Iron Overload: What to Test

Blood Tests:

  • Ferritin: Indicates stored iron; >300 µg/L in men or >200 µg/L in women is considered elevated.

  • TSAT: >45–50% is strongly suggestive of iron overload.

  • Serum Iron, TIBC (Total Iron Binding Capacity): Helps interpret TSAT.

  • HFE Genetic Testing: Confirms hemochromatosis (common mutations: C282Y, H63D).

Symptoms to Watch For: Iron Overload and Thyroid Dysfunction

General Symptoms

  • Fatigue

  • Brain fog

  • Abdominal pain

  • Joint pain

Skin and Appearance

  • Bronze or gray skin

  • Yellowing (jaundice)

Hormonal and Reproductive Symptoms

  • Irregular periods

  • Low libido or erectile dysfunction

Thyroid-Related Symptoms

  • Cold intolerance

  • Dry skin

  • Hair thinning

  • Constipation

  • Depression

What To Do If You Have High Iron and Thyroid Issues

1. Comprehensive Monitoring

Request regular testing for:

  • Ferritin, TSAT, serum iron, TIBC

  • TSH, Free T3, Free T4

  • TPOAb, TgAb (to assess thyroid autoimmunity)

2. Consult a Specialist

  • An endocrinologist can manage thyroid dysfunction.

  • A hematologist can evaluate and treat iron overload.

  • Consider evaluation for APS or HLH if inflammatory symptoms are severe.

3. Treatment Options

  • Therapeutic phlebotomy or iron chelation for iron overload.

  • Levothyroxine for hypothyroidism.

  • Immunosuppressants in severe autoimmune or inflammatory cases (APS, HLH).

Final Thoughts: Connecting the Dots

Iron plays a vital physiological role, but excess iron can fuel a cascade of inflammation, autoimmunity, and hormonal dysfunction. Key takeaways:

  • Iron overload may contribute to or exacerbate thyroid disease, APS, and even severe reactions like SJS/HLH.

  • Ferritin, while valuable, must be interpreted in context—consider inflammation and iron studies together.

  • Early detection, proper diagnosis, and interdisciplinary care can prevent long-term complications.

If you suffer from fatigue, cold intolerance, unexplained clotting events, or have a family history of hemochromatosis or autoimmune disease, it’s important to screen both iron and thyroid levels—and seek appropriate genetic or immune evaluation.

Sources

Cleveland Clinic: Iron Overload and Thyroid Function

ThyroidPharmacist (Dr. Izabella Wentz): Hashimoto’s and Iron Metabolism

Dove Medical Press: The Effects of Iron Overload on Endocrine Organs (PDF)

National Institutes of Health: Hemochromatosis and Thyroid Disease Association

References:

HYPOCORTISOLISM IN A PATIENT WITH COVID-19: A CASE REPORT AND DISCUSSION ON MANAGEMENT: https://pmc.ncbi.nlm.nih.gov/articles/PMC8503436/

The hyperferritinemic syndrome: macrophage activation syndrome, Still's disease, septic shock and catastrophic antiphospholipid syndrome https://pubmed.ncbi.nlm.nih.gov/23968282/

Haemochromatosis https://www.nhs.uk/conditions/haemochromatosis/

Hemochromatosis (Iron Overload)
https://my.clevelandclinic.org/health/diseases/14971-hemochromatosis-iron-overload

Central Hypothyroidism due to Pituitary Iron Overload
https://pmc.ncbi.nlm.nih.gov/articles/PMC8426606/#:~:text=According%20to%20a%20case%20report%2C%20central%20hypothyroidism,1219%20ng/mL%2C%20respectively%2C%205%20months%20before%20presentation

Association between serum ferritin and the severity of drug eruptions
https://pmc.ncbi.nlm.nih.gov/articles/PMC7031562/

Hyperferritinemia and inflammation in catastrophic antiphospholipid syndrome

© 2025-2030 Sieglinde W. Alexander. All writings by Sieglinde W. Alexander have a fife year copy right. Library of Congress Card Number: LCN 00-192742 ISBN: 0-9703195-0-9 

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