What is the appropriate workup for an adult patient, possibly of Northern European descent, with a transferrin saturation (TSAT) level of 70, suggesting iron overload, and potential risk factors for hemochromatosis or frequent blood transfusions?

Workup for Transferrin Saturation of 70%

A TSAT of 70% is pathognomonic for primary iron overload and requires immediate HFE genetic testing for C282Y and H63D mutations, followed by hepatic MRI if genetic testing is negative or inconclusive. 1, 2

Immediate Diagnostic Steps

1. Confirm Iron Overload Pattern

• Obtain serum ferritin immediately to complete the iron panel, as TSAT ≥45% combined with elevated ferritin creates the diagnostic pattern for hereditary hemochromatosis 3, 1
• A TSAT of 70% with elevated ferritin (>200 μg/L in females, >300 μg/L in males) confirms biochemical iron overload requiring genetic evaluation 1, 4
• Check complete blood count with reticulocytes to exclude anemia and red cell disorders that could cause secondary iron overload 3

2. Order HFE Genetic Testing

• Test for C282Y and H63D mutations immediately without delay, as this is the most cost-effective approach and C282Y homozygosity accounts for 85-90% of hereditary hemochromatosis cases 1, 4
• For patients of Northern European descent, HFE testing has the highest pre-test probability and should be performed first 3
• Do not wait for additional testing before ordering genetics, as early diagnosis prevents irreversible organ damage 1

3. If HFE Testing is Negative or Shows Only Heterozygosity

• Proceed to hepatic MRI with R2 quantification* to confirm tissue iron overload and guide further genetic testing for non-HFE hemochromatosis genes 1, 2, 5
• MRI can differentiate primary hemochromatosis (predominant hepatic iron with minimal splenic involvement) from secondary causes (increased splenic iron) 2
• Low spleen iron (R2* <50 s⁻¹) is significantly associated with genetic mutations in hemochromatosis genes 5
• Consider next-generation sequencing of non-HFE genes (HJV, TFR2, CP, SLC40A1) only after confirming true iron overload by MRI AND excluding secondary causes 3, 2

Assess for Organ Damage and Advanced Disease

Liver Assessment

• Check liver enzymes (ALT, AST) and platelet count immediately, as ferritin >1,000 μg/L with elevated transaminases and platelets <200 predicts cirrhosis in 80% of cases 3, 1, 4
• Patients with ferritin <1,000 μg/L, normal transaminases, and no hepatomegaly have very low risk of advanced liver fibrosis 3
• Consider liver biopsy or elastography if ferritin >1,000 μg/L, elevated liver enzymes, hepatomegaly, age >40 years, or platelet count <200 to assess for cirrhosis 1, 4

Cardiac Evaluation

• Obtain ECG and echocardiography to screen for arrhythmia and cardiac dysfunction in patients with severe iron overload 3
• If signs or symptoms of heart disease are present (conduction abnormalities or contractile dysfunction), proceed to cardiac MRI for myocardial iron quantification without delaying treatment 3

Endocrine and Metabolic Screening

• Screen for diabetes mellitus, as this is a common manifestation of hemochromatosis and unstable diabetes with elevated ferritin has an odds ratio of 40.1 for undiagnosed hemochromatosis 3, 6
• Assess thyroid and gonadal function, as these endocrine organs are commonly affected 1

Musculoskeletal Assessment

• Evaluate for arthropathy, particularly affecting the 2nd and 3rd metacarpophalangeal joints, ankles, hips, and wrists, as 86.5% of hemochromatosis patients report arthritis or joint pain 3
• Consider screening for osteoporosis, as this is common and does not respond uniformly to phlebotomy 3

Exclude Secondary Causes Before Attributing to Genetic Hemochromatosis

Systematically evaluate for secondary causes of elevated TSAT before concluding this is genetic hemochromatosis, particularly if HFE testing is negative 2:

• Assess for metabolic syndrome components (obesity, diabetes, dyslipidemia, hypertension), as these commonly contribute to hepatic iron accumulation 2
• Obtain detailed alcohol consumption history, as excessive alcohol elevates TSAT and increases risk of fibrosis when combined with iron overload 2
• Exclude chronic liver disease from other causes (viral hepatitis, NAFLD), as these can elevate ferritin independent of true iron overload 2, 4
• Rule out hematologic disorders causing ineffective erythropoiesis (thalassemia, sideroblastic anemia) 3, 7
• Consider inflammatory conditions and malignancy, as ferritin can be falsely elevated by inflammation, cell necrosis, and chronic disease 2, 4

Family Screening

• Screen all first-degree relatives with TSAT and ferritin, followed by HFE genetic testing if abnormal, as this is a heritable condition with high penetrance in C282Y homozygotes 1, 4
• Perform both phenotypic screening (iron studies) and genotypic testing simultaneously in relatives of confirmed cases 4

Critical Pitfalls to Avoid

• Never diagnose hemochromatosis based on genotype alone—diagnosis requires both genetic findings AND phenotypic evidence of iron overload 2
• Do not assume elevated ferritin equals iron overload, as ferritin can be falsely elevated by inflammation, liver disease, malignancy, and chronic inflammatory conditions 2, 4
• Do not delay genetic testing while pursuing other investigations—HFE testing should be ordered immediately when TSAT is ≥45% 1, 4
• Avoid relying on a single test—always obtain both TSAT and ferritin together for optimal diagnostic accuracy 4
• A TSAT of 70% is far above the diagnostic threshold of 45% and represents severe iron dysregulation requiring urgent evaluation 3, 1