Hereditary Hemochromatosis: Screening, Diagnosis, Treatment, and Follow-Up Guidelines
Screening Recommendations
Routine population-wide screening for hereditary hemochromatosis is not recommended, but targeted case-finding should be performed in high-risk individuals. 1, 2
Who Should Be Screened:
- First-degree relatives of patients with confirmed hemochromatosis should undergo both HFE genetic testing (C282Y and H63D) and simultaneous phenotypic screening with transferrin saturation and serum ferritin 2, 3
- One-time screening of asymptomatic non-Hispanic white men has the highest yield among general population screening strategies 1, 2
- Patients with suggestive clinical manifestations including fatigue, right-upper-quadrant discomfort, metacarpophalangeal joint arthralgia, sexual dysfunction, heart failure symptoms, diabetes, hepatomegaly, skin hyperpigmentation, testicular atrophy, or unexplained elevated liver enzymes 2
- Siblings have the highest screening yield (33% C282Y homozygosity) compared to all first-degree relatives (23%) 3
Diagnostic Algorithm
Step 1: Initial Laboratory Testing
Measure transferrin saturation and serum ferritin simultaneously—never rely on a single test. 2, 3
Diagnostic thresholds triggering further evaluation:
Transferrin saturation is the most sensitive early marker and should be calculated as serum iron/total iron-binding capacity × 100 2
Combined TS and ferritin provide optimal diagnostic accuracy with 97% negative predictive value when both are normal in individuals <35 years 2
Step 2: Genetic Testing
If either TS ≥45% or ferritin exceeds sex-specific thresholds, immediately order HFE mutation analysis for C282Y and H63D variants. 2, 3
- C282Y homozygosity (C282Y/C282Y) confirms HFE-related hemochromatosis and accounts for 85-90% of clinically affected patients 2, 4
- Compound heterozygotes (C282Y/H63D) have lower penetrance and require individualized assessment based on iron studies rather than genotype alone 2
Step 3: Pre-Test Genetic Counseling
Before ordering genetic testing, discuss with patients: 2
- Efficacy and availability of phlebotomy treatment
- Costs of testing and ongoing monitoring
- Implications for insurability and employment
- Psychological impact of disease labeling
- Family screening implications
- Possibility of uncertain or variant genotypes
Step 4: Assessment for Advanced Disease
Liver biopsy is indicated when any of the following are present: 2, 3
- Serum ferritin >1,000 μg/L
- Elevated transaminases (ALT/AST)
- Palpable hepatomegaly
- Age >40 years in C282Y homozygotes
- Platelet count <200 × 10⁹/L
The combination of ferritin >1,000 μg/L, elevated ALT/AST, and platelets <200 predicts cirrhosis in 80% of C282Y homozygotes. 2
Important Diagnostic Pitfalls
- Ferritin can be falsely elevated due to inflammation, chronic liver disease, malignancy, non-alcoholic fatty liver disease, metabolic syndrome, and lymphomas—these must be excluded before attributing elevation to hemochromatosis 2, 3
- Normal ferritin does not exclude hemochromatosis in younger individuals, as only 70% of C282Y homozygotes exhibit elevated ferritin 2
- Transferrin saturation has biological variability—repeat testing to confirm abnormalities 2
- A normal TS with elevated ferritin may still indicate iron overload in non-HFE hemochromatosis or C282Y/H63D compound heterozygotes 2
Treatment
Phlebotomy Protocol
Therapeutic phlebotomy is the mainstay of treatment for confirmed hemochromatosis with iron overload. 3, 4, 5
- Remove one unit (approximately 500 mL) of blood weekly or biweekly during the induction phase 2
- Monitor hemoglobin/hematocrit before each phlebotomy to prevent anemia 2
- Check serum ferritin every 10-12 phlebotomies during induction 2
- Target serum ferritin of 50-100 μg/L for optimal iron depletion 2
- Once target ferritin is achieved, transition to maintenance phlebotomy with frequency guided by serial ferritin and transferrin saturation measurements 4
Dietary and Lifestyle Modifications
- Avoid vitamin C supplements, as these accelerate iron mobilization and increase toxicity 2
- Avoid alcohol to reduce risk of liver complications 2
- Avoid raw seafood due to increased risk of Vibrio vulnificus infection in iron-overloaded patients 2
- Dietary iron restriction is generally unnecessary 4
Treatment Benefits
Phlebotomy can improve heart function, reduce abnormal skin pigmentation, and lessen the risk of liver complications when initiated before end-organ damage occurs. 5, 6
- Skin pigmentation and cardiac damage may reverse with iron depletion 6
- Liver damage, endocrine dysfunction, and arthropathy are rarely reversible and may progress despite treatment 6
Follow-Up and Monitoring
For Confirmed Hemochromatosis Patients
- Monitor serum ferritin and transferrin saturation to guide phlebotomy frequency during maintenance phase 4, 7
- Screen for hepatocellular carcinoma with ultrasound and alpha-fetoprotein every 6 months in patients with cirrhosis 4
- Monitor for colorectal and breast cancers, as individuals with hemochromatosis have increased risk 5
For Compound Heterozygotes (C282Y/H63D)
- If iron studies are normal, perform annual monitoring of ferritin and transferrin saturation due to genetic predisposition 2
- If iron overload is confirmed, investigate for other contributing causes (alcohol, metabolic syndrome, liver disease) as compound heterozygosity alone rarely causes significant iron accumulation 2
- Consider phlebotomy only if confirmed iron overload is present, based on individualized clinical assessment 2
Family Screening Protocol
All first-degree relatives of an identified proband should undergo simultaneous HFE genetic testing and phenotypic screening (transferrin saturation and ferritin). 2, 3
- Test the other parent when screening children of a proband 3
- Penetrance is higher in family members than in the general population, making screening more cost-effective 3
- Offer genetic testing after 18 years of age to first-degree relatives 5
Special Considerations
Variable Penetrance
Only 10-50% of C282Y homozygotes develop end-organ damage, with higher penetrance in males and increasing with age 3, 4, 5
Non-Classical Presentations
- Isolated ferritin elevation with normal transferrin saturation is unusual for classic HFE-related hemochromatosis, which typically presents with elevated TS as the earliest marker 2
- Genetic testing is still indicated in patients with isolated ferritin elevation to detect non-classical forms 2
MRI for Hepatic Iron Quantification
MRI should be used to quantify hepatic iron concentrations in patients with unclear cause of hyperferritinemia, biochemical iron overload, or positive liver iron staining 2