A new syndrome of liver iron overload with normal transferrin saturation

Background We investigated patients who had unexplained hepatic iron overload and normal transferrin saturation. Methods 65 patients with a median liver iron concentration of 85 mu mol/g dry weight of liver (normal <36 mu mol/g), hyperferritinaemia (566 mu g/L; normal <400 mu g/L), and normal transferrin saturations (32%) were compared with genetic haemochromatosis (GH) controls including homozygous (matched for sex and serum ferritin concentration) and heterozygous individuals. Relatives of patients who had ratios of liver iron concentration to age greater than 1.9 were also studied. Findings The 65 patients were significantly older and had significantly less hepatic iron overload than individuals with genetic haemochromatosis. The frequency of HLA-A3 antigen was significantly lower in these patients than in individuals with homozygous (p<0.0001) or heterozygous (p<0.0002) GH. Five HLA-identical siblings of the patients had normal serum ferritin concentrations. Most of the patients (95%) had one or more of the following conditions; obesity, hyperlipidaemia, abnormal glucose metabolism, or hypertension. Interpretation We have found a new non-HLA-linked iron-overload syndrome which suggests a link between iron excess and metabolic disorders. The current diagnostic criteria for genetic haemochromatosis should be reviewed.