Because iron accumulates slowly and silently, the diagnosis of hereditary hemochromatosis is usually made through blood tests rather than through symptoms.
Screening blood tests
In the past, patients came to medical attention after the complications of iron overload appeared — cirrhosis, heart failure, diabetes mellitus and skin hyperpigmentation. Nowadays, thanks to screening tests, few patients present with severe complications at the time of diagnosis.
For the purpose of screening, the iron-related serum values that can be measured are total serum iron and TIBC, the total iron binding capacity. TS, or transferrin saturation, is calculated simply as total iron divided by TIBC. The normal value of TS is about 25–50%, and patients with values greater than 45% should be further evaluated.
Serum ferritin reflects the iron storage in the body: the higher the serum ferritin, the higher the level of iron storage. In patients with HH, iron storage in the cells is increased, especially in the hepatocytes, so ferritin is expected to be elevated. However, in a significant number of patients with confirmed HFE-related HH the serum ferritin level is normal, because iron accumulation is a progressive process: the earlier the screening, the lower this value will be. Ferritin is also raised by inflammation and by liver injury, so an elevated ferritin on its own is not specific for iron overload.
Genotyping and liver biopsy
When serum iron values are abnormal — above all an elevated TS — genetic testing for C282Y should be performed; it is the gold standard test for the diagnosis. In a patient homozygous for C282Y, a raised transferrin saturation together with a raised ferritin is sufficient to establish the diagnosis, and the need for imaging or biopsy then arises mainly in other genotypes or when the extent of liver damage must be assessed.
Liver biopsy should be done only in patients who are suspected to have liver damage, that is:
- abnormal liver enzymes
- serum ferritin ≥ 1000 ng/ml
If the patient does not meet any of these conditions, there is no need to perform a liver biopsy to evaluate the extent of liver damage.