What is the appropriate workup for a patient suspected of having hemochromatosis, particularly those with a family history or of Northern European descent?

Hemochromatosis Workup

Begin with simultaneous measurement of fasting morning transferrin saturation (TSAT) and serum ferritin as the essential first-line tests, followed by HFE genetic testing for C282Y mutation if iron parameters exceed diagnostic thresholds. 1

Initial Laboratory Testing

Obtain both tests together—never rely on a single test:

• Transferrin saturation (TSAT): Calculate as serum iron/total iron binding capacity × 100 1
• Serum ferritin 1
• Complete blood count with reticulocytes to exclude anemia and red cell disorders 1

Timing considerations:

• Draw blood samples in the morning, though fasting does not improve diagnostic utility 1
• TSAT shows significant variability, so repeat testing may be needed to confirm abnormalities 1

Diagnostic Thresholds Triggering Genetic Testing

Proceed to HFE genetic testing if:

• Males: TSAT >50% and/or ferritin >300 μg/L 1
• Females: TSAT >45% and/or ferritin >200 μg/L 1
• Either sex: Persistently elevated TSAT ≥45% even with normal ferritin 1

Critical Caveat: Exclude Secondary Causes First

Before attributing elevated iron studies to hemochromatosis, rule out:

• Chronic alcohol consumption (increases iron absorption and causes liver injury) 1
• Non-alcoholic fatty liver disease/metabolic syndrome (commonly elevates ferritin) 1
• Inflammatory conditions (ferritin is an acute phase reactant) 1
• Malignancy (ferritin is a tumor marker) 1
• Liver disease/cirrhosis (can elevate TSAT due to decreased transferrin) 1
• Hemolysis or transfusion-dependent conditions 1

Genetic Testing Protocol

For patients of European descent with elevated iron parameters:

• Test for C282Y mutation in HFE gene first (accounts for >80% of clinically overt hemochromatosis) 1, 2
• Also test for H63D mutation (compound heterozygosity C282Y/H63D can cause iron overload) 2, 3
• Obtain informed consent before genetic testing 1

For patients of non-European origin:

• Pre-test likelihood of C282Y is very low 1
• Consider direct sequencing of HFE and non-HFE genes (HJV, TFR2, CP, SLC40A1) without initial HFE genotyping 1

Family Screening Protocol

All adult (>18 years) first-degree relatives of confirmed C282Y homozygous patients require:

• Both HFE genetic testing AND simultaneous phenotypic screening (TSAT and ferritin) 1, 2
• Do not test children—risk of disease penetrance increases with age 1
• Siblings have highest yield: 33% show C282Y homozygosity vs 23% of all first-degree relatives 2, 3

Assessment for Advanced Disease and Complications

Once genetic diagnosis is confirmed, evaluate for end-organ damage:

Hepatic Assessment:

• Liver enzymes (ALT, AST) and platelet count 3, 4
• Critical prognostic marker: Ferritin >1,000 μg/L + elevated ALT/AST + platelets <200 predicts cirrhosis in ~80% of C282Y homozygotes 1, 3, 4
• Consider liver biopsy if: Ferritin >1,000 μg/L, elevated liver enzymes, hepatomegaly, age >40 years, or platelets <200 1, 3
• MRI for hepatic iron quantification if diagnosis unclear despite biochemical testing 1, 3

Cardiac Evaluation (for severe iron overload):

• ECG and echocardiography to screen for arrhythmias and cardiac dysfunction 1
• Cardiac MRI for myocardial iron quantification in patients with signs of heart disease or juvenile hemochromatosis 1

Musculoskeletal Assessment:

• Evaluate for arthropathy (particularly II and III metacarpophalangeal joints, ankles) 1
• Screen for osteoporosis (common and does not respond uniformly to phlebotomy) 1

Endocrine Evaluation:

• Assess for diabetes mellitus 1
• Evaluate for hypogonadism/hypopituitarism 1

Clinical Manifestations to Recognize

Common presenting symptoms (often present 10 years before diagnosis): 5

• Extreme fatigue (46% of symptomatic patients) 5
• Arthralgia (44% of symptomatic patients, particularly hands/wrists, ankles, hips) 1, 5
• Loss of libido (26% of symptomatic patients) 5
• Bronzed skin/melanoderma 1
• Signs of cirrhosis or liver disease 1, 5

Important Pitfalls to Avoid

Penetrance is variable and incomplete:

• Only 50% of C282Y homozygotes develop end-organ damage in population studies 1, 2
• Penetrance is higher in males and increases with age 1
• 84% of male and 73% of female C282Y homozygotes have elevated TSAT 1
• 88% of male C282Y homozygotes have ferritin >300 μg/L 1

Do not perform routine population screening:

• Population-wide screening is NOT recommended due to low penetrance and uncertain benefit 2, 3
• Targeted case-finding IS appropriate for: symptomatic individuals, abnormal liver function tests of unclear etiology, family history, or one-time screening of asymptomatic non-Hispanic white men 2, 3

Interpretation nuances:

• Normal ferritin (<1,000 μg/L) accurately excludes cirrhosis 4
• Normal TSAT with elevated ferritin may still indicate non-HFE hemochromatosis or compound heterozygosity 4
• Combined TSAT <45% and normal ferritin has 97% negative predictive value for excluding iron overload in patients <35 years 4