Evaluation and Management of Iron Deposits in the Liver
For individuals of European origin with iron deposits in the liver, immediately check transferrin saturation and serum ferritin, then perform HFE genotyping for p.C282Y if transferrin saturation is >50% in males or >45% in females with elevated ferritin (>300 µg/L in males, >200 µg/L in females). 1
Initial Biochemical Assessment
When iron deposits are identified in the liver, the diagnostic pathway depends on establishing whether true iron overload exists:
- Measure transferrin saturation (TSAT) and serum ferritin as the first-line tests 1, 2
- In males: TSAT >50% and ferritin >300 µg/L indicates biochemical iron overload
- In females: TSAT >45% and ferritin >200 µg/L indicates biochemical iron overload
- These thresholds are critical because they determine whether genetic testing is warranted 1
Genetic Testing Strategy
Proceed with HFE genotyping for p.C282Y in all patients meeting the biochemical criteria above 1. This is the most common cause of hereditary haemochromatosis in European populations:
- If p.C282Y homozygous: diagnosis of haemochromatosis is confirmed with biochemical iron overload alone—no imaging or biopsy needed 1
- If p.C282Y/p.H63D compound heterozygous or p.H63D homozygous: must confirm iron overload with MRI or liver biopsy before diagnosing haemochromatosis, and investigate other causes of iron overload 1
- Testing for p.H63D alone is controversial and not generally recommended to guide treatment 1
Quantifying Iron Overload
MRI should be used to quantify hepatic iron concentration in patients with unclear causes of hyperferritinemia or when genetic testing shows non-p.C282Y homozygous patterns 1. MRI is now the reference standard for:
- Non-invasive quantification of liver iron concentration 3, 4
- Assessing extrahepatic organ involvement (pancreas, heart, spleen) 1
- Monitoring treatment response 2
Liver biopsy is NOT recommended for diagnosing hepatic iron overload 1. Its role is limited to:
- Assessing liver fibrosis when ferritin >1,000 µg/L or liver enzymes are elevated 1
- Situations where cirrhosis status is unclear and would change management 1
Assessing Disease Severity and Complications
All patients with confirmed haemochromatosis must be assessed for liver fibrosis at diagnosis 1:
- Transient elastography can rule out advanced fibrosis if liver stiffness <6.4 kPa 1
- FIB-4 score can be used but has limited validation in haemochromatosis specifically 1
- Patients with ferritin <1,000 µg/L, normal transaminases, and no hepatomegaly have very low risk of advanced fibrosis 1
Screen for extrahepatic manifestations systematically 1:
- Skeletal: joint pain, arthritis, osteoporosis, fractures
- Endocrine: diabetes, erectile dysfunction, loss of libido, amenorrhea
- Cardiac: ECG and echocardiography if severe iron overload; cardiac MRI if signs of heart disease 1
Treatment Approach
Phlebotomy is first-line treatment 1, 5:
- Target ferritin <50 µg/L during induction phase
- Target ferritin <100 µg/L during maintenance phase 1
- For compound heterozygotes (p.C282Y/p.H63D) or p.H63D homozygotes with confirmed iron overload, phlebotomy may be used but requires individualized assessment 1
Iron chelation therapy is reserved for patients who cannot tolerate phlebotomy 5.
Critical Pitfalls to Avoid
- Do not rely on ferritin alone—it can be elevated due to inflammation, malignancy, or metabolic syndrome without true iron overload 2
- Do not perform liver biopsy to diagnose iron overload—MRI is superior and non-invasive 1
- Do not skip fibrosis assessment at diagnosis—patients with advanced fibrosis require HCC surveillance 1
- Do not diagnose haemochromatosis in p.C282Y/p.H63D or p.H63D homozygotes without confirming iron overload by MRI or biopsy 1
Family Screening
Test all first-degree adult relatives (>18 years) of p.C282Y homozygous patients for the p.C282Y variant 1. Early detection prevents progression to cirrhosis, HCC, and other irreversible complications 1, 6.