Diagnostic Approach to Persistent Hyperferritinemia

Prioritization of Laboratory Tests

The American Gastroenterological Association recommends that patients with hyperferritinemia should be evaluated for secondary causes, as over 90% of ferritin elevations are not due to iron overload 1
The European Association for the Study of the Liver suggests that CRP and BSG should be measured to assess for subclinical inflammation, which can contribute to elevated ferritin levels 1
The American College of Rheumatology recommends testing for interleukin-6 (IL-6) to detect occult inflammatory processes that may increase ferritin as an acute-phase protein 1
Glycosylated ferritin levels ≤20% are diagnostic for Adult-onset Still's Disease, although this is unlikely in an asymptomatic athlete 1

The National Institute of Diabetes and Digestive and Kidney Diseases recommends measuring soluble transferrin receptor (sTfR) to differentiate between true iron overload and ferritin elevation due to inflammation 1
Hepcidin levels are expected to be elevated in both iron overload and inflammation, and can help guide further evaluation 1
Zinc protoporphyrin is elevated in functional iron deficiency despite high ferritin levels 1

The American Diabetes Association recommends measuring fasting insulin and HOMA-index to assess for metabolic syndrome, which can contribute to hyperferritinemia 1
HbA1c levels can help exclude diabetes, and a level of 4.6% is considered low-normal 1
Extended liver fibrosis markers, such as FIB-4 score, APRI score, or direct Fibroscan, should be considered, as non-alcoholic fatty liver disease (NAFLD) is a common cause of hyperferritinemia 1

Serum protein electrophoresis (SPEP) has been performed and is unremarkable, but should be considered in the evaluation of hyperferritinemia 1
Retikulozytenzahl should be determined to exclude occult hemolysis 1

The American Heart Association recommends that patients with hyperferritinemia and splenomegalie should be evaluated for myeloproliferative syndrome, lymphoma, or portal hypertension 1
Intensive endurance athletes can develop elevated ferritin levels due to exercise-induced hemolysis and muscle cell necrosis 1
CK levels should be repeated after intense training to assess for muscle damage 1
Myoglobin levels after training can provide insight into exercise-induced muscle damage 1

The European Association for the Study of the Liver recommends that patients with ferritin <1000 µg/L have a low risk of organ damage, even with true iron overload 2, 1
Liver enzymes (GOT, GPT, Gamma-GT) are normal, which argues against advanced liver fibrosis 2
A platelet count >200 and normal transaminases can exclude cirrhosis with 80% certainty 2

The American Gastroenterological Association recommends that ferritin should never be interpreted in isolation, but always in conjunction with transferrin saturation 2, 1
C282Y heterozygosity alone does not cause clinically relevant iron overload, and a second cofactor (e.g. alcohol, NAFLD, hepatitis C) is required 2
Not every elevated ferritin requires phlebotomy, and iron overload is unlikely if transferrin saturation is <45% 2, 1
A vegetarian diet does not exclude iron overload, but makes it less likely 1