What are the diagnostic steps for Hemochromatosis?

Diagnostic Approach to Hemochromatosis

The diagnosis of hemochromatosis should begin with serum transferrin saturation (TS) and ferritin measurements, followed by HFE genetic testing for C282Y and H63D mutations in patients with elevated iron studies, even if asymptomatic. 1, 2

Initial Diagnostic Steps

1. Serum Iron Studies:

   • Transferrin Saturation (TS)
     • Primary screening test
     • TS > 45% suggests iron overload
     • Confirm elevated TS with a second determination (fasting sample advisable but not mandatory) 1
   • Serum Ferritin
     • Complements TS measurement
     • Normal range in combination with TS < 45% has 97% negative predictive value for excluding iron overload in individuals < 35 years 1
     • Note: Ferritin can be elevated in non-iron overload conditions (inflammation, liver disease, lymphomas)

2. Genetic Testing:

   • HFE genotyping for C282Y and H63D mutations 2
   • Most common genotypes causing hemochromatosis:
     • C282Y homozygosity (most common)
     • C282Y/H63D compound heterozygosity

Target Populations for Screening

• Patients with abnormal liver function tests 1
• Patients with suspected organ involvement 1
• First-degree relatives of patients with hemochromatosis 1
• Patients with chance detection of biochemical/radiological abnormalities suggesting iron overload 1

Clinical Presentation

Hemochromatosis may present as:

• Asymptomatic: Abnormal iron studies on routine screening 1
• Nonspecific symptoms: Weakness, fatigue, lethargy, apathy, weight loss 1
• Organ-specific symptoms: 1
  • Abdominal pain (hepatomegaly)
  • Arthralgias (arthritis)
  • Diabetes (pancreatic involvement)
  • Amenorrhea (in cirrhosis)
  • Sexual dysfunction (pituitary involvement, cirrhosis)
  • Cardiac symptoms (heart failure, arrhythmias)

Diagnostic Algorithm

1. Initial Testing: Serum transferrin saturation and ferritin
2. If TS > 45% and/or elevated ferritin:
   • Proceed to HFE genetic testing for C282Y and H63D mutations
3. If C282Y homozygous or C282Y/H63D compound heterozygous:
   • Diagnosis of hereditary hemochromatosis confirmed
4. If genetic testing negative but iron overload suspected:
   • Consider non-HFE forms of hemochromatosis (mutations in HAMP, HJV, TFR2, or SLC40A1) 3
   • Consider secondary causes of iron overload

Additional Diagnostic Considerations

• Rule out other causes of elevated ferritin:

  • Inflammatory conditions (check CRP, ESR) 2
  • Liver diseases (hepatitis, NAFLD, alcoholic liver disease) 1, 2
  • Malignancy

• Further evaluation when diagnosis uncertain:

  • MRI to quantify hepatic iron concentration non-invasively 2
  • Liver biopsy (when necessary to assess liver damage or confirm diagnosis)

Interpretation of Ferritin Levels

Ferritin Level	Interpretation
>1000 μg/L	High risk of cirrhosis (20-45%) [2]
>100 μg/L	Possible anemia of chronic disease or iron overload [2]
50-100 μg/L	Target maintenance range for treated patients [2]

Common Pitfalls to Avoid

• Relying solely on ferritin: Ferritin is an acute-phase reactant and can be elevated in many inflammatory conditions without iron overload 1
• Missing non-HFE hemochromatosis: While rare, mutations in other genes can cause hemochromatosis 3
• Delayed diagnosis: Early diagnosis is crucial as phlebotomy can prevent or reverse organ damage from iron overload 4
• Confounding factors: Alcohol consumption can exacerbate iron overload and should be assessed 2, 5

When to Refer to a Specialist

• Ferritin >1,000 μg/L
• Elevated liver enzymes with suspected iron overload
• Confirmed genetic diagnosis requiring management
• Unclear diagnosis after initial evaluation 2

Remember that hemochromatosis is a systemic iron overload disorder that can lead to significant morbidity and mortality if left untreated, but early diagnosis and treatment with phlebotomy can prevent complications 6.