Hemochromatosis Evaluation and Management
Direct Answer
In this 45-year-old Northern European adult with classic hemochromatosis features, immediately measure fasting transferrin saturation and serum ferritin, followed by HFE genetic testing for C282Y and H63D mutations; if C282Y homozygosity is confirmed with elevated iron parameters, initiate weekly phlebotomy immediately to prevent irreversible organ damage. 1, 2
Initial Diagnostic Evaluation
First-Line Laboratory Testing
- Measure transferrin saturation (TS) and serum ferritin simultaneously as the initial screening tests 1, 2
- Diagnostic thresholds suggesting hemochromatosis:
- These parameters should be obtained in the fasting state for optimal accuracy 2
Genetic Testing
- HFE gene testing for C282Y and H63D mutations is the next critical step after abnormal iron studies 1, 2
- C282Y homozygosity (C282Y/C282Y) accounts for >90% of clinically recognized hemochromatosis in Northern Europeans 1, 2
- The C282Y allele frequency is highest in Northern Europe (up to 12% in Ireland), making this patient's ancestry highly relevant 1
- Approximately 80.6% of patients with clinical hemochromatosis are C282Y homozygotes 1
Interpretation of Results
If C282Y Homozygous with Elevated Iron Parameters
- This confirms hereditary hemochromatosis and mandates immediate treatment 1, 2
- The combination of symptoms (fatigue, arthralgia, skin pigmentation, diabetes, elevated liver enzymes) with C282Y homozygosity represents phenotypic hemochromatosis requiring urgent intervention 1, 2
If Compound Heterozygous (C282Y/H63D)
- Compound heterozygosity alone is insufficient to cause hemochromatosis 1, 3
- Only 5.3% of hemochromatosis patients are compound heterozygotes, compared to 1.3% in control populations 1
- Must investigate for secondary causes of iron overload: diabetes (already present), fatty liver disease, obesity, alcohol consumption 1, 3
- Require tissue confirmation of iron overload by MRI or liver biopsy before initiating phlebotomy 1, 3
- Management is guided by phenotype and additional risk factors, not genotype alone 1, 3
If H63D Homozygous or Single Heterozygote
- These genotypes do not cause hemochromatosis 1
- H63D homozygosity is no more common in hemochromatosis patients than in the general population 1
- Search aggressively for alternative causes of iron overload 1
Assessment of Organ Damage
Liver Evaluation
- Measure serum transaminases (already noted as elevated in this patient) 2
- Assess for cirrhosis risk: patients with ferritin >1,000 µg/L, elevated transaminases, hepatomegaly, or age >40 years require further evaluation 3
- Liver biopsy or MRI to quantify hepatic iron concentration and assess fibrosis stage 1, 3
- Hepatocellular carcinoma risk is significantly elevated in patients with established cirrhosis 2
Cardiac Assessment
- Evaluate for cardiomyopathy and congestive heart failure, which occur in 0-35% of patients 2
- Consider echocardiography if cardiac symptoms are present 2
Endocrine Assessment
- Diabetes mellitus is already present in this patient, occurring in 6-55% of hemochromatosis cases 2
- Assess for hypogonadism and testicular atrophy (14-50% of male patients) 2
Musculoskeletal Assessment
- Arthropathy is present (arthralgias noted), occurring in 13-57% of patients 2
- Joint involvement is often early and may not reverse with treatment 2
Treatment Protocol
Phlebotomy for C282Y Homozygotes
- Initiate weekly phlebotomy immediately to achieve rapid iron depletion 2
- Remove 500 mL of blood (approximately 200-250 mg of iron) per session 2
- Treatment goal: reduce serum ferritin to <50 µg/L 2
- Monitor hemoglobin before each phlebotomy; hold if hemoglobin <11 g/dL 2
Maintenance Therapy
- After achieving iron depletion, continue maintenance phlebotomy every 2-4 months to maintain ferritin 50-100 µg/L 2
- Frequency is individualized based on rate of iron reaccumulation 2
Critical Timing Consideration
- Survival is normal if treatment is initiated before development of cirrhosis or diabetes 2
- This patient already has diabetes, making immediate treatment imperative to prevent further organ damage 2
- Life expectancy is normalized with early treatment, but irreversible organ damage cannot be reversed 2
Family Screening
First-Degree Relatives
- All first-degree relatives require screening with transferrin saturation, serum ferritin, and HFE genetic testing 2
- Siblings have a 25% chance of being C282Y homozygotes if both parents are carriers 2
- Children have at least 50% chance of carrying one C282Y allele 2
Critical Pitfalls to Avoid
Do Not Delay Treatment in C282Y Homozygotes
- The presence of diabetes and elevated liver enzymes indicates established organ damage 2
- Further delay will increase risk of cirrhosis, hepatocellular carcinoma, and cardiac complications 2
Do Not Diagnose Hemochromatosis Based on Compound Heterozygosity Alone
- C282Y/H63D compound heterozygotes require documented tissue iron overload before diagnosis 1, 3
- Most compound heterozygotes with elevated iron have coexisting metabolic syndrome, fatty liver, or alcohol use 1, 3
Do Not Rely on Ferritin Alone
- Ferritin is an acute-phase reactant and can be elevated by inflammation, liver disease, or malignancy 3
- Always interpret ferritin in conjunction with transferrin saturation 3, 2
Do Not Overlook Hepatocellular Carcinoma Surveillance
- Patients with cirrhosis require lifelong HCC surveillance with ultrasound and AFP every 6 months, even after successful iron depletion 2
- Cirrhosis-related HCC risk persists despite normalization of iron stores 2
Prognosis
With Early Treatment
- Normal life expectancy if phlebotomy is initiated before cirrhosis or diabetes develop 2
- This patient's existing diabetes indicates treatment was not initiated early enough for optimal outcomes 2
Major Causes of Death
- Decompensated cirrhosis 2
- Hepatocellular carcinoma 2
- Diabetes mellitus complications 2
- Cardiomyopathy 2