Hereditary Iron Overload Assessment

Initial Evaluation

Assessment typically begins with a thorough patient history, including family history of liver disease, arthritis, diabetes, heart problems, and unexplained fatigue. Clinical examination may reveal signs such as skin pigmentation, enlarged liver, or joint pain.

Biochemical Markers

Serum Iron and Transferrin Saturation

Elevated serum iron and, more importantly, increased transferrin saturation (the percentage of transferrin bound to iron) are key indicators. Transferrin saturation values above 45% are often considered elevated. These are initial screening tests and can be influenced by other factors (e.g., inflammation, diet), thus requiring further investigation.

Serum Ferritin

Ferritin is a protein that stores iron, and its serum level reflects total body iron stores. Elevated ferritin levels are often found in individuals with iron overload. However, ferritin is also an acute-phase reactant and can be elevated due to inflammation, infection, liver disease, or malignancy, even in the absence of iron overload.

Genetic Testing

HFE Gene Mutation Analysis

Testing for mutations in the HFE gene is crucial. The most common mutations are C282Y and H63D. Genotype-phenotype correlation is important; not all individuals with HFE mutations develop significant iron overload. Compound heterozygosity (e.g., C282Y/H63D) and homozygosity (e.g., C282Y/C282Y) are commonly associated with a higher risk of iron accumulation.

Other Gene Mutations

In cases where HFE mutations are not identified, or the clinical picture is atypical, testing for mutations in other genes involved in iron metabolism may be considered. These include genes such as HAMP (hepcidin), TFR2 (transferrin receptor 2), SLC40A1 (ferroportin), and HJV (hemojuvelin). These mutations are less common but can cause different types of iron overload.

Liver Biopsy

Historically, liver biopsy was considered the gold standard for quantifying hepatic iron concentration (HIC) and assessing the extent of liver damage (fibrosis, cirrhosis). HIC is measured using chemical methods. Liver biopsy is less frequently performed now due to the availability of non-invasive methods.

Non-Invasive Liver Iron Quantification

MRI (Magnetic Resonance Imaging)

MRI techniques, particularly R2 and R2 mapping, are used to estimate liver iron concentration non-invasively. MRI can provide a quantitative assessment of iron overload in the liver and, to a lesser extent, in other organs like the heart. This method has largely replaced liver biopsy for initial iron quantification.

Differential Assessment

It is essential to rule out other causes of iron overload, such as secondary iron overload due to multiple blood transfusions, chronic liver disease (e.g., alcoholic liver disease, non-alcoholic fatty liver disease), and dysmetabolic hyperferritinemia. Transferrin saturation is often normal or only mildly elevated in these conditions.