What is the diagnostic workup and treatment approach for a patient suspected of having hemochromatosis, particularly a middle-aged male with a family history of the condition and potential liver damage?

Diagnostic Workup for Hemochromatosis

Begin with simultaneous measurement of fasting transferrin saturation (TS) and serum ferritin as the essential first-line tests, followed by HFE genetic testing for C282Y and H63D mutations if either TS ≥45% or ferritin is elevated (>300 μg/L in men, >200 μg/L in women). 1, 2

Initial Laboratory Testing

• Obtain both transferrin saturation and serum ferritin simultaneously—never rely on a single test, as combined interpretation provides optimal diagnostic accuracy 1, 2
• Calculate transferrin saturation as serum iron/total iron-binding capacity × 100, with TS ≥45% serving as the primary screening threshold that triggers further evaluation 1, 2
• Blood samples should be drawn in the morning, though fasting does not significantly improve diagnostic utility 1
• Normal TS with normal ferritin has 97% negative predictive value for excluding iron overload in individuals <35 years 2

Genetic Testing Indications

Proceed with HFE genotyping for C282Y and H63D mutations when: 1, 2

• Transferrin saturation ≥45% and/or elevated ferritin
• Persistently elevated transferrin saturation on repeat testing
• Clinical signs of hemochromatosis (hepatomegaly, skin pigmentation, arthropathy of metacarpophalangeal joints II and III, diabetes, cardiac arrhythmia, hypogonadism) with elevated iron parameters 1
• Unexplained liver disease with increased hepatic iron on biopsy or MRI 1
• First-degree relatives of confirmed hemochromatosis patients should undergo both HFE genetic testing AND phenotypic screening (TS and ferritin) simultaneously 1, 3

Genetic Testing Interpretation

• C282Y homozygosity (C282Y/C282Y) confirms HFE-related hemochromatosis and accounts for 85-90% of clinically affected patients of European origin 2, 4, 5
• C282Y homozygotes have 91% prevalence among patients with confirmed hemochromatosis based on iron studies and liver biopsy 4
• Compound heterozygotes (C282Y/H63D) have lower penetrance and require individualized assessment based on iron parameters rather than genotype alone 2

Assessment for Advanced Disease and Liver Damage

Critical prognostic indicators requiring liver biopsy consideration: 2, 6

• Serum ferritin >1,000 μg/L combined with elevated ALT/AST and platelet count <200 predicts cirrhosis in 80% of C282Y homozygotes 2
• Ferritin <1,000 μg/L accurately excludes cirrhosis 2
• Age >40 years in C282Y homozygotes 2
• Hepatomegaly on physical examination 1, 2

Additional Liver Assessment

• Obtain complete hepatic panel including ALT, AST, and platelet count to assess for hepatic involvement 2
• MRI can quantify hepatic iron concentrations non-invasively when diagnosis is unclear or to assess disease severity 1, 2
• Liver biopsy provides definitive assessment of fibrosis stage and hepatic iron concentration when ferritin >1,000 μg/L or other high-risk features present 1, 2

Important Diagnostic Pitfalls

Exclude secondary causes of hyperferritinemia before attributing elevated iron studies to hemochromatosis: 1, 3

• Chronic alcohol consumption—can increase both ferritin and transferrin saturation through increased iron absorption and liver injury 1
• Non-alcoholic fatty liver disease and metabolic syndrome—commonly elevate ferritin as an acute phase reactant 1, 3
• Inflammatory conditions, malignancy, and cell necrosis—ferritin is an acute phase reactant and released from lysed cells 1, 2
• Advanced cirrhosis from any cause—can falsely elevate transferrin saturation due to low transferrin levels 1
• Acute liver failure or acute liver injury—may show elevated transferrin saturation unrelated to hemochromatosis 1

Hepcidin measurement is not recommended for diagnosis, as persistently elevated transferrin saturation is a sufficiently specific marker of hepcidin deficiency 1

Family Screening Protocol

All adult first-degree relatives (parents, siblings, children) of confirmed hemochromatosis patients require screening: 1, 3

• Perform both HFE genetic testing AND phenotypic screening (TS and ferritin) simultaneously 1, 3
• Siblings have 25% risk of being affected (autosomal recessive inheritance) and 33% show C282Y homozygosity when screened 1, 3
• Testing should be performed after age 18 years, as disease penetrance increases with age 1
• Genetic counseling should be provided before testing, discussing treatment efficacy, costs, implications for insurability and employment, and psychological impact 2, 3

Treatment Approach

Phlebotomy is the mainstay of treatment for confirmed hemochromatosis with iron overload: 2, 3, 6, 5

• Remove one unit (approximately 500 mL) of blood weekly or biweekly initially 2
• Monitor hemoglobin/hematocrit before each phlebotomy and serum ferritin every 10-12 phlebotomies 2
• Target serum ferritin of 50-100 μg/L for maintenance therapy 2
• Phlebotomy can improve cardiac function, reduce skin pigmentation, and prevent liver complications, but arthropathy and established cirrhosis are typically irreversible 7, 6

Dietary and Lifestyle Modifications

• Avoid vitamin C supplements, as these accelerate iron mobilization and potentially increase toxicity 2
• Avoid raw seafood due to risk of Vibrio vulnificus infection in iron-overloaded patients 2
• Avoid alcohol to prevent additional liver damage 2

Prognosis and Surveillance

• No cirrhosis or substantial hepatic fibrosis occurs in C282Y homozygotes diagnosed before age 40 years 4
• Patients with cirrhosis require hepatocellular carcinoma surveillance regardless of iron depletion status 5
• When diagnosed before organ damage occurs, treatment can prevent disease manifestations and lead to normal life expectancy 8, 6
• Only 10% of C282Y homozygotes develop end-organ damage, with higher penetrance in males and increasing with age 3, 5