Diagnosis of hereditary haemochromatosis

Dear Editor,

We read with interest the report by Malton and Turnock, ¹ describing their test strategy and flowchart for the diagnosis of hereditary haemochromatosis (HH) when elevated ferritin is encountered. The HFE gene is encoded on the short arm of chromosome 6 at location 6p21.3. The authors believe that recommending genetic testing would enhance GP education and increase early detection of HH, while potentially reducing unnecessary referral to secondary care. We would like to make the following comments.

The liver is the principal regulator of iron, involving a large number of regulatory genes such as C282Y HFE (common) and H63D (less common). Non-HFE mutations causing iron overload include those affecting haemojuvelin (IIA), hepcidin (IIb), transferrin receptor 2 (III) and ferroportin 1 (IV).

The major identifiable manifestation of homozygotic mutation of the gene most commonly implicated (C282Y HFE) is an increase in the prevalence of liver injury/hepatitis (resulting in increased serum aminotransferases). In such cases, ∼1% develop frank haemochromatosis. ² Furthermore, the expression of genetic mutations can be exacerbated by other factors such as alcoholism and metabolic syndrome. ³

Serum ferritin is an accurate measure of the body’s iron stores in patients without liver disease, malignancies or conditions causing chronic inflammation. ⁴ Ferritin concentrations more than twice the upper limit of the reference interval in men and postmenopausal women indicate iron overload, ⁵ especially when associated with high transferrin saturation. Ferritin and alanine transaminase (ALT) are stored in the cytosol of hepatocytes. This means that necrosis of hepatocytes from whatever causes releases both ferritin and ALT (hence their correlation in serum ⁶ ). Consequently, the addition of ALT when serum ferritin is markedly raised may be helpful.

Circulating iron represents <0.2% of total body iron. Measured serum iron includes iron sequestered from senescent red blood cells, iron from oral intake and iron mobilized from stores mainly the liver. Almost all iron entering into the circulation is bound to carrier proteins (mostly transferrin). Daily physiological fluctuations in iron can result in substantial intra- and interindividual variation (up to 30%) that may affect test interpretation. Iron concentrations are generally higher in fasting morning samples.^7–9 Iron may also be released from hepatocellular necrosis irrespective of the underlying causes.

In addition to transferrin, other plasma proteins such as lactoferrin also bind iron; hence, transferrin-bound iron is not the same as total iron-binding capacity (TIBC). Transferrin synthesis decreases in conditions causing liver injury such as hepatitis, ¹⁰ resulting in reduced iron-binding capacity and an increase in percentage saturation of transferrin serum iron saturation (TSAT) and/or TIBC.

It is important to consider the hepatocellular damage in patients with elevated ferritin. Elevated ferritin and TSAT/TIBC must be interpreted with caution in patients with raised ALT. Other causes, such as adverse reactions to drugs, viral infection, vaccination, should be considered. Simultaneous monitoring of ALT and iron parameters may be prudent before screening for genetic mutations causing iron overload.

In summary, abnormal iron studies are common in patients with hepatocellular damage, irrespective of cause, and this may potentially confound the diagnosis of HH. Interpretation must be made in the context of other clinical correlates including medications and serological tests. We agree with the authors that identifying those with HH is educationally valuable to clinicians in general and GPs in particular. It is also beneficial not only to the index patient but also potentially to the extended family.