Hyperferritinemia Causes and Diagnostic Approach

Primary Causes of Hyperferritinemia

The American College of Physicians recommends considering hereditary hemochromatosis (HFE gene mutations - C282Y homozygosity, C282Y/H63D compound heterozygosity) as a primary cause of hyperferritinemia 1
Non-HFE hemochromatosis (mutations in TFR2, SLC40A1, HAMP, HJV genes) is also a primary cause of hyperferritinemia 1
Transfusional iron overload (patients with serum ferritin levels exceeding 7,500 ng/mL) is a primary cause of hyperferritinemia, according to the American Journal of Kidney Diseases 2, 3

The Journal of Hepatology suggests that alcoholic liver disease is a secondary cause of hyperferritinemia 4, 1
Non-alcoholic fatty liver disease (NAFLD) is a secondary cause of hyperferritinemia, as stated by the Journal of Hepatology 4, 1
Viral hepatitis (B and C) is a secondary cause of hyperferritinemia, according to the Journal of Hepatology 4, 1

The Praxis Medical Insights guideline recommends checking transferrin saturation (TS) and serum ferritin as an initial assessment for hyperferritinemia 1
Morning blood samples for transferrin saturation are recommended (fasting not required), as suggested by the Journal of Hepatology 4
Serum ferritin is an acute phase reactant that increases during inflammation, as noted by the Praxis Medical Insights guideline 3

The Praxis Medical Insights guideline states that serum ferritin has high sensitivity but low specificity for iron overload, as it can be elevated in many inflammatory conditions 1
In hemodialysis patients with elevated ferritin due to inflammation, ferritin levels typically normalize within 4 months after resolving the inflammatory state, according to the Praxis Medical Insights guideline 5
Unexpected changes in serum ferritin levels should always be investigated, as significant fluctuations are not normal, as recommended by the Praxis Medical Insights guideline 5
The American Journal of Kidney Diseases notes that the association between increased ferritin levels and infections is due to infection causing increased ferritin levels, rather than iron overload causing increased risk of infection 2

The Journal of Hepatology warns against overlooking the possibility of multiple contributing factors to hyperferritinemia 4, 1
The Journal of Hepatology advises considering that serum ferritin concentrations are often elevated in conditions associated with fatty liver disease, which must be considered when investigating high ferritin 4
The Journal of Hepatology notes that chronic alcohol excess can increase serum ferritin through multiple mechanisms including increased iron absorption and liver injury 4