What conditions can cause a patient's serum iron to be markedly elevated?

Causes of Markedly Elevated Serum Iron

Extremely high serum iron levels are most commonly caused by acute iron poisoning/overdose, massive hemolysis or cell necrosis releasing intracellular iron, or acute alcoholic hepatitis disrupting iron metabolism—not chronic iron overload conditions like hemochromatosis, which typically show high transferrin saturation and ferritin rather than acutely elevated serum iron itself. 1

Understanding the Distinction: Serum Iron vs. Iron Overload Markers

It's critical to distinguish between serum iron (the circulating iron bound to transferrin at a single point in time) and iron overload markers (transferrin saturation and ferritin). Most chronic iron overload conditions present with elevated transferrin saturation (>45-50%) and ferritin, not dramatically elevated serum iron alone. 2, 3

• Transferrin saturation >45-55% is the key screening marker for hereditary hemochromatosis and primary iron overload disorders 2, 3
• Serum ferritin >200-300 μg/L (depending on sex) indicates increased iron stores 2, 3
• Isolated markedly elevated serum iron without proportionally elevated transferrin saturation suggests acute iron release rather than chronic overload 1

Primary Causes of Acutely Elevated Serum Iron

Acute Iron Poisoning/Overdose

• Ingestion of iron supplements or medications causes massive acute elevation of serum iron, often to toxic levels (>500 μg/dL) 4
• This represents a medical emergency requiring immediate chelation therapy 4

Acute Alcoholic Hepatitis

• Severe alcoholic hepatitis disrupts iron metabolism, releasing large amounts of iron into circulation and causing severely elevated serum iron and transferrin saturation that can mimic hereditary hemochromatosis 1
• Alcohol downregulates hepcidin transcription via oxidative stress, abrogating protective mechanisms against iron accumulation 2
• This can present with transferrin saturation >45% and markedly elevated ferritin despite the primary pathology being liver inflammation, not true iron overload 1
• Recognition of this pattern is critical to avoid unnecessary phlebotomy and ensure appropriate treatment of the underlying alcoholic hepatitis 1

Massive Hemolysis or Cell Necrosis

• Acute hemolytic episodes release intracellular iron stores into circulation 3, 4
• Extensive tissue necrosis (hepatocellular necrosis, rhabdomyolysis) liberates stored iron 3
• This causes acute elevation of serum iron and ferritin as an acute-phase reactant 3

Chronic Iron Overload Conditions (Elevated Transferrin Saturation, Not Necessarily Acute Serum Iron Spikes)

Hereditary Hemochromatosis

• HFE-related hemochromatosis (C282Y homozygosity or C282Y/H63D compound heterozygosity) presents with persistently elevated transferrin saturation >45-50% and progressive ferritin elevation, not acute serum iron spikes 2, 3, 5
• Diagnosis requires transferrin saturation ≥45% in females or ≥50% in males, plus ferritin >200 μg/L (females) or >300 μg/L (males) 2
• Non-HFE hemochromatosis involves mutations in TFR2, SLC40A1, HAMP, or HJV genes 3, 6

Secondary Iron Overload Disorders

• Transfusional iron overload from chronic transfusion therapy (thalassemia, myelodysplastic syndrome, sickle cell disease) causes progressive iron accumulation in reticuloendothelial system initially, then parenchymal organs 5, 4, 6
• Chronic liver diseases (viral hepatitis B/C, NAFLD, cirrhosis) can cause elevated ferritin and transferrin saturation through hepatocellular injury and altered iron metabolism 3, 5
• Hematologic disorders including thalassemia syndromes, myelodysplastic syndrome, myelofibrosis, sideroblastic anemias, and pyruvate kinase deficiency 5, 6

Diagnostic Algorithm for Markedly Elevated Serum Iron

Step 1: Assess Clinical Context

• Obtain detailed history of iron supplement ingestion, alcohol consumption, recent hemolysis, or tissue injury 1, 4
• Acute presentation with extremely high serum iron suggests poisoning or acute release rather than chronic overload 1, 4

Step 2: Measure Transferrin Saturation and Ferritin Simultaneously

• Never interpret serum iron in isolation—always calculate transferrin saturation (serum iron/TIBC × 100) 2, 3, 7
• If transferrin saturation <45% despite elevated serum iron, consider acute iron release from hemolysis, cell necrosis, or alcoholic hepatitis rather than primary iron overload 1, 7
• If transferrin saturation ≥45% with elevated ferritin, proceed to evaluate for hereditary hemochromatosis or secondary iron overload 2, 3, 5

Step 3: Evaluate for Acute Causes

• Check for evidence of hemolysis (elevated LDH, low haptoglobin, elevated indirect bilirubin) 4
• Assess liver function (ALT, AST, bilirubin) and obtain detailed alcohol history to evaluate for alcoholic hepatitis 1
• Check creatine kinase for rhabdomyolysis if muscle injury suspected 3
• Rule out iron poisoning with toxicology history and clinical presentation 4

Step 4: If Chronic Iron Overload Suspected (TS ≥45%)

• Order HFE genetic testing for C282Y and H63D mutations 2, 3, 5
• C282Y homozygotes or C282Y/H63D compound heterozygotes confirm HFE hemochromatosis 2, 5
• If HFE testing negative, evaluate for secondary causes: transfusion history, hematologic disorders, chronic liver disease 5, 6
• Consider liver MRI for hepatic iron quantification or liver biopsy if ferritin >1000 μg/L with abnormal liver enzymes 2, 3

Critical Pitfalls to Avoid

• Do not assume hereditary hemochromatosis based on elevated serum iron alone without confirming elevated transferrin saturation ≥45% 2, 7
• Recognize that severe alcoholic hepatitis can mimic hereditary hemochromatosis with markedly elevated serum iron, transferrin saturation, and ferritin—treat the underlying liver disease, not with phlebotomy 1
• Do not overlook acute iron poisoning in patients with extremely high serum iron levels and appropriate clinical context 4
• Remember that ferritin is an acute-phase reactant elevated in inflammation, infection, and liver disease independent of iron stores 2, 3
• Always measure transferrin saturation simultaneously with ferritin to distinguish true iron overload (TS ≥45%) from secondary hyperferritinemia (TS <45%) 2, 3, 7