Wenke Moris

Serum ferritin is one of the most frequently requested laboratory tests in both primary care and referral settings. Ferritin is a cellular iron storage protein and for that reason serum ferritin is a reliable surrogate marker of body iron stores. Low serum ferritin levels provide absolute evidence of reduced iron stores. However, high serum ferritin levels (hyperferritinemia) are far less specific for systemic iron overload since ferritin is also an acute phase protein and will increase in case of infection, neoplasm and acute or chronic inflammation. Hyperferritinemia is defined as serum ferritin concentrations >200 µg/L in women and >300 µg/L in men, and is found in around 12% of the general population. Since hyperferritinemia is common and often does not reflect iron overload it is a great challenge for physicians to determine its exact cause.

This thesis consists of two parts. In the first part the focus is on the diagnostic difficulties in patients with hyperferritinemia, in the second part on HFE-related hemochromatosis.

HFE-related hemochromatosis is a frequent cause of hyperferritinemia, and is associated with iron overload. The most prevalent form is homozygosity for the p.Cys282Tyr variant in the HFE gene and this is the most common autosomal recessive, genetic disorder found in Caucasians. It is most commonly seen in populations of Northern European origin, in which the prevalence is close to 1 per 200-250 persons. HFE-related hemochromatosis is characterized by low hepcidin levels which result in a persistent iron absorption leading to iron accumulation in the body's tissues and organs, particularly the liver, pancreas, joints, heart and the skin. Iron accumulation will eventually lead to organ damage resulting in hepatic cirrhosis, primary liver cancer, arthropathy, cardiomyopathy and diabetes mellitus. To maintain a normal life expectancy iron depletion therapy should be started in time in order to prevent iron accumulation and its complications.

Part 1- Understanding and interpreting hyperferritinemia
A frequent cause of hyperferritinemia is non-alcoholic liver disease (NAFLD), the most widespread liver disorder in Western society. In 30% of patients with NAFLD, hyperferritinemia is found, however its origin is a subject of discussion. Prior to starting therapy the etiology of hyperferritinemia should be investigated since iron depletion therapy is not advised in inflammation-related hyperferritinemia nor in patients with the dysmetabolic iron overload syndrome. In chapter 2 an extensive