HFE C282Y Homozygous (c.845G>A) - Evaluation and Management
All patients with homozygous HFE C282Y mutations must undergo immediate biochemical assessment with transferrin saturation and serum ferritin, followed by risk stratification for liver fibrosis and initiation of therapeutic phlebotomy if iron overload is confirmed. 1
Initial Biochemical Assessment
The genotype alone does not determine disease—you must assess the phenotype. Measure:
- Transferrin saturation (TS) and serum ferritin as first-line tests 1
- Morning blood draw (fasting not required for TS) 1
- Serum iron and total iron binding capacity for additional context 1
Critical thresholds indicating iron overload:
Important caveat: Ferritin is an acute phase reactant—elevated levels may reflect inflammation, liver disease, metabolic syndrome, or alcohol use rather than iron overload alone 1. Consider these confounders before attributing elevated ferritin solely to hemochromatosis.
Risk Stratification for Liver Fibrosis
All C282Y homozygotes require non-invasive fibrosis assessment at diagnosis 1. This determines prognosis and guides surveillance:
Low-risk patients (no liver biopsy needed):
- Ferritin <1,000 μg/L
- Normal transaminases (ALT/AST)
- No hepatomegaly 1
High-risk patients requiring further evaluation:
- Ferritin >1,000 μg/L, OR
- Elevated liver enzymes 1
For high-risk patients:
- Transient elastography (FibroScan): Liver stiffness <6.4 kPa rules out advanced fibrosis 1
- FIB-4 score: Best-validated serum marker for fibrosis staging 1
- Liver biopsy: Consider if ferritin >1,000 μg/L with elevated transaminases, or if non-invasive tests suggest advanced fibrosis 1, 2
- The combination of ferritin >1,000 μg/L, elevated ALT/AST, and platelets <200 predicts cirrhosis in 80% of C282Y homozygotes 2
Additional imaging:
- Liver MRI: Quantify hepatic iron concentration if diagnosis unclear or to assess extrahepatic involvement 1
- Cardiac MRI: Only if signs of heart disease present 1
Treatment Decision
Therapeutic phlebotomy is indicated for C282Y homozygotes with confirmed iron overload (elevated TS and ferritin above thresholds) 2. The genotype confirms diagnosis, but treatment decisions are phenotype-driven.
Key evidence on disease penetrance: Only 28% of male and 1% of female C282Y homozygotes develop iron-overload-related disease 3. Most who will develop severe iron overload (ferritin >1,000 μg/L) have already done so by age 55 4. Serial ferritin measurements show that levels may spontaneously decrease in untreated homozygotes—progressive accumulation is not inevitable 5.
For patients with ferritin 300-1,000 μg/L: The evidence for treatment benefit is limited 6. However, given the low risk and high efficacy of phlebotomy, treatment is reasonable when iron overload is biochemically confirmed.
Family Screening
Screen all first-degree relatives with simultaneous genotype (HFE testing) and phenotype (ferritin and TS) 2. This single-visit approach is cost-effective.
For children of a C282Y homozygous proband:
- Test the other parent first
- If the other parent is negative for C282Y, the child is an obligate heterozygote and requires no further testing (no risk of iron loading) 2
Critical Pitfalls
- Do not treat based on genotype alone—up to 72% of male and 99% of female C282Y homozygotes never develop clinically significant disease 3
- Elevated ferritin without elevated TS suggests inflammation or other liver disease, not hemochromatosis-related iron overload 1
- Avoid raw shellfish if iron overloaded—hepcidin deficiency increases risk of severe Vibrio vulnificus infection 1
- Screen for hepatocellular carcinoma only if cirrhosis is present 2
- C282Y heterozygotes do not develop progressive iron overload and can be reassured 2