What are the diagnostic criteria and symptoms of iron overload?

Diagnosis and Symptoms of Iron Overload

The diagnosis of iron overload should begin with serum transferrin saturation (>45%) and serum ferritin (>200 μg/L in women or >300 μg/L in men) measurements, followed by genetic testing for HFE mutations in suspected cases of hereditary hemochromatosis. 1

Diagnostic Approach

Laboratory Testing

1. Initial screening tests:

   • Transferrin saturation (TS): >45% is suggestive of iron overload 1
   • Serum ferritin: >200 μg/L in women or >300 μg/L in men 1

2. Confirmatory genetic testing:

   • Test for HFE gene mutations (C282Y and H63D) when iron overload is suspected 1
   • C282Y homozygosity or C282Y/H63D compound heterozygosity confirms hereditary hemochromatosis

3. Additional laboratory assessment:

   • Liver function tests (elevated transaminases may indicate liver damage)
   • Ferritin/AST ratio can help predict tissue iron overload with high sensitivity (83.3%) and specificity (78.6%) 2

Imaging Studies

• MRI with quantitative iron assessment: Non-invasive method to quantify iron deposition in liver and heart 1
• Echocardiography: May show biventricular dilatation and restrictive cardiomyopathy in cardiac iron overload 1
• Tissue Doppler imaging: Can detect early diastolic dysfunction before systolic dysfunction occurs 1

Tissue Biopsy

• Liver biopsy: Gold standard for diagnosing liver iron overload 1
  • Perls' Prussian blue stain assesses iron distribution
  • Quantitative iron measurement by atomic absorption spectrometry
• Myocardial biopsy: Less reliable due to patchy iron deposition in the heart 1

Clinical Symptoms and Signs

Asymptomatic Presentation

• Many patients are identified through abnormal iron studies on routine screening or family screening 1
• Patients should be evaluated for hemochromatosis even in the absence of symptoms if iron studies are abnormal 1

Systemic Symptoms

• Weakness and lethargy: Present in 19-83% of patients 1
• Fatigue: Common early symptom
• Weight loss
• Apathy

Organ-Specific Symptoms

1. Liver manifestations:

   • Abdominal pain (0-58% of patients) 1
   • Hepatomegaly (3-83% of patients) 1
   • Elevated liver enzymes
   • Progressive fibrosis leading to cirrhosis (3-94% of patients depending on stage of diagnosis) 1

2. Joint manifestations:

   • Arthralgias (13-57% of patients) 1
   • Arthritis, particularly in metacarpophalangeal joints

3. Endocrine manifestations:

   • Diabetes (6-55% of patients) 1
   • Loss of libido and impotence (12-56% of patients) 1
   • Amenorrhea in women with cirrhosis 1
   • Testicular atrophy (14-50% of patients) 1

4. Cardiac manifestations:

   • Congestive heart failure (0-35% of patients) 1
   • Arrhythmias
   • Early diastolic dysfunction detected by echocardiography 1

5. Skin manifestations:

   • Hyperpigmentation (5-82% of patients) 1
   • Loss of body hair (6-32% of patients) 1

Important Clinical Considerations

• Serum ferritin >1,000 ng/mL is associated with increased risk of hepatic fibrosis or cirrhosis 1
• Ferritin can be elevated in inflammatory conditions without true iron overload, as it's an acute phase reactant 1
• Cardiac iron deposition may occur despite normal serum ferritin levels 1
• All patients with evidence of liver disease should be evaluated for hemochromatosis 1

Diagnostic Pitfalls to Avoid

1. Relying solely on ferritin levels: Ferritin can be elevated in inflammation, infection, malignancy, and liver disease without true iron overload 1

2. Missing hereditary hemochromatosis in patients with mild symptoms: Many patients present with nonspecific symptoms that can be overlooked

3. Failing to screen family members: First-degree relatives of patients with hereditary hemochromatosis should be screened 1

4. Overlooking secondary causes of iron overload: Consider hematologic disorders (thalassemia, myelodysplastic syndrome), chronic transfusions, and chronic liver diseases 3

5. Delaying diagnosis until end-organ damage occurs: Cardiac involvement often develops late in the disease process when treatment may be less effective 1

Early diagnosis and treatment of iron overload are essential to prevent irreversible organ damage and improve mortality and quality of life outcomes.