Abstract
We report the case of a 52 year old male with diabetes mellitus and long standing evidence of hepatic iron excess. Initially considered to have haemochromatosis, this patient was reevaluated when hepatic iron stores were found to be unaffected by a prolonged course of weekly phlebotomy. The development of neurological disease prompted diagnostic consideration of aceruloplasminaemia, which we confirmed by demonstration of a novel frameshift mutation in the ceruloplasmin gene. Our inability to resolve the patient's iron overload by regular phlebotomy is consistent with recent animal studies indicating an essential role for ceruloplasmin in cellular iron efflux. Evaluation of this case underscores the clinical relevance of aceruloplasminaemia in the differential diagnosis of hepatic iron overload and provides insight into the pathogenetic mechanisms of hepatocellular iron storage and efflux. Keywords: aceruloplasminaemia; ceruloplasmin; diabetes; haemochromatosis; iron
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Figure 1 .
(A) Masson-Goldman trichrome stain of the patient's liver revealed no fibrosis (P, portal tract). Original magnification ×170. (B) Perl's stain of the patient's liver revealed abundant haemosiderin pigment distributed evenly throughout the hepatic lobulus. Iron accumulation can be observed in both hepatocytes (arrows) and Kupffer cells (arrowheads), but not in the portal tract (P) or bile duct epithelia (bd). Original magnification ×170. (C) T2 weighted magnetic resonance tomography revealed signal attenuation in the basal ganglia consistent with iron accumulation.
Figure 2 .
(A) Immunoblot demonstrating absence of serum ceruloplasmin (Cp) in the patient compared with serum from a normal patient and purified ceruloplasmin (Vital Products Inc., St Louis, Missouri, USA). (B) Demonstration of the frameshift mutation insert T nucleotide 2510 in exon 14 of the ceruloplasmin gene by sequence analysis with an ABI Prism sequencer (PE Biosystems, Foster City, California, USA). (C) Restriction analysis of patient DNA demonstrates homozygosity of the insert T nucleotide 2510 mutation. As this frameshift mutation results in the removal of an NcoI restriction site, NcoI digestion of the ceruloplasmin exon 14 polymerase chain reaction product was performed on a control individual (homozygous WT, lane 1), patient (homozygous frameshift mutation, lane 2), and the patient's son (obligate heterozygote, lane 3). DNA size markers are indicated at the far right.