Ferroportin disease is an autosomal dominant iron storage condition with different
phenotypic expression, where a clear genotype to phenotype correlation has been reported
for selected mutations. Ferroportin disease is primarily caused by private mutations
in the gene SLC40A1, which encodes an iron export protein. Genetic defects can cause
a loss of iron export function which is typically associated with low transferrin
saturation and hepatolienal siderosis. In contrast a gain of function is usually associated
with high transferrin saturation and hepatic siderosis, where the spleen is unaffected.
Liver disease has been described primarily in the latter group of patients. The toxic
effect of stored iron in patients with loss of function mutations is apparently mild.
Here we report a now 70-year old female patient who presumably contracted HCV at the
age of 44 through a blood transfusion. Chronic HCV infection was diagnosed at the
age of 68 when the patient also presented isolated hyperferritinemia and normal transferrin
saturation. To further evaluate the cause of high plasma ferritin concentrations,
magnetic resonance imaging was carried out, which showed markedly increased R2* frequencies
in the liver and spleen. Fibroscan showed no evidence of advanced liver fibrosis (6.7
kPa IQR 1.9kPa). Sequencing of the SLC40A1 gene revealed heterozygosity for the p.Arg178Gln
mutation. To assess the functional consequences of this mutation, the mutant protein
was recombinantly expressed in HEK cells. These cells had significantly higher cellular
ferritin concentrations compared to cells expressing wild type ferroportin. Furthermore,
studies by flow cytometry showed that the iron hormone hepcidin equally induces degradation
of the mutant and wild-type protein.
Taken together, p.Arg178Gln is a loss of function mutation. In conclusion, our observations
indicate that iron overload due to this mutation is not associated with an increased
risk of liver disease, despite chronic hepatitis C.
