Hepatic iron overload in aceruloplasminaemia

Hellman, Nathan E.; Schaefer, Mark; Gehrke, Sven G.; Stegen, P; Hoffman, William J.; Gitlin, Jonathan D.; Stremmel, Wolfgang

doi:10.1136/gut.47.6.858

Cited by 65 publications

(36 citation statements)

References 12 publications

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“…LIC was strikingly elevated (535 mol/g dry weight [dw]; normal, 3-33) and hepatic iron index (LIC divided by years of age ϭ 8.6) was in the range observed in hereditary HFE. 18 However, common HFE mutations were negative. Rubeanic acid staining for copper was positive For personal use only.…”

Section: Resultsmentioning

confidence: 99%

“…9 Aceruloplasminemia has been described mainly in Japanese patients [3][4][5][6][10][11][12][13][14][15][16][17] and rarely in whites. 5,18 We report data on a 62-year-old Italian woman, compound heterozygote for 2 novel mutations that hamper Cp expression in hepatocytes. Our findings suggest that the disorder should be considered in the differential diagnosis of anemia associated with unexplained iron overload.…”

Section: Introductionmentioning

confidence: 99%

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Anemia and iron overload due to compound heterozygosity for novel ceruloplasmin mutations

Bosio

Gobbi

Roetto

et al. 2002

Blood

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Aceruloplasminemia is a recessive disorder characterized by anemia, iron overload, and neurodegeneration, caused by the absence of ceruloplasmin (Cp), a multicopper oxidase important for iron export. Few patients homozygous for loss of function mutations of the Cp gene have been reported. We describe a 62-year-old white woman with heavy liver iron overload, diabetes, anemia, and neurologic symptoms. She was compound heterozygote for 2 novel mutations that result in the absence of hepatocyte Cp: an adenine insertion at nucleotide 2917 causing a truncated protein and a C-G transversion causing a glutamine3glutamic acid substitution at position 146. Although rare in whites, aceruloplasminemia should be considered in the differential diagnosis of unexplained anemia associated with iron overload, because these features anticipate progressive neurologic symptoms. We propose that anemia, secondary to the impaired macrophage iron release, plays a major role in hepatic iron overload through increased absorption mediated by the erythroid regulator. IntroductionHereditary aceruloplasminemia is a rare autosomal recessive disease characterized by iron overload and progressive neurodegeneration. The disease is caused by the absence of ceruloplasmin (Cp), a copper-containing ferroxidase, which catalyses the oxidation of ferrous to ferric iron, a change required for release of iron to plasma transferrin. 1 It is hypothesized that in reticuloendothelial (RE) cells and hepatocytes Cp cooperates with the iron export protein ferroportin 1 (FPN1). 2 Cp deficiency results in iron deposition in the liver, pancreas, basal ganglia, and other organs. Patients develop diabetes mellitus, retinal degeneration, ataxia, and dementia late in life. 3,4 A mild-to-moderate degree of anemia with low serum iron and elevated serum ferritin is a constant feature. [3][4][5][6] The Cp gene maps to chromosome 3q21-24. 7 It consists of 19 exons 8 and encodes a protein of 1046 amino acids. 9 Aceruloplasminemia has been described mainly in Japanese patients 3-6,10-17 and rarely in whites. 5,18 We report data on a 62-year-old Italian woman, compound heterozygote for 2 novel mutations that hamper Cp expression in hepatocytes. Our findings suggest that the disorder should be considered in the differential diagnosis of anemia associated with unexplained iron overload. Based on the severity of liver iron loading, the mechanisms leading to iron overload in aceruloplasminemia are revisited. Study design Case reportThe proband is a 62-year-old Italian woman. No family history of diabetes, iron overload, anemia, or neurologic disorders was recorded. At age 38 years the patient developed insulin-dependent diabetes mellitus. A mild degree of anemia (hemoglobin 9.1 g/L) with normal mean corpuscular volume (MCV; 86 fL) and low-normal values of mean corpuscular hemoglobin (MCH; 27.2 pg) and mean corpuscular hemoglobin concentration (MCHC; 31.7 g/dL) was documented at age 51 years. Serum iron concentration was 33 g/dL, transferrin saturation 12%, and serum ferritin 819 ...

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Anemia and iron overload due to compound heterozygosity for novel ceruloplasmin mutations

Bosio

Gobbi

Roetto

et al. 2002

Blood

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“…The literature review identified 32 published cases [6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32]. Direct contact with the authors ascertained a further unpublished case.…”

Section: Resultsmentioning

confidence: 99%

The Neurological Presentation of Ceruloplasmin Gene Mutations

et al. 2008

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Aceruloplasminemia is an autosomal recessive disorder of iron metabolism resulting from mutations of the ceruloplasmin gene. To better define the neurological phenotype of aceruloplasminemia we reviewed reports of published cases and sought details of unpublished ones. We identified 32 published reports and 1 unpublished case. The age at diagnosis ranged from 16 to 71 years with a mean of 51. For the 28 homozygous cases the most common presentation was with cognitive impairment (12/28, 42%) accompanied by craniofacial dyskinesia (8/28, 28%), cerebellar ataxia (13/28, 46%) and retinal degeneration (21/28, 75%). Four heterozygotes presented with cerebellar signs or tremor, whilst 1 had chorea-athetosis. There were no genotype-phenotype associations, but homozygotes tended to have severer disease.

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“…Studies of individuals and mice with congenital absence of Cp support a role for this protein in the removal of iron from Kupffer cells for redistribution to the body. 21,22 Previously, it has been shown that hephaestin is a copper-dependent oxidase protein that can rescue the low-growth phenotype of S cerevisiae ⌬fet3 strain in iron-poor media. 23 Moreover, we have shown that hephaestin is present in a supranuclear compartment and on the basolateral surface of intestinal enterocytes.…”

Section: Introductionmentioning

confidence: 99%

Hephaestin is a ferroxidase that maintains partial activity in sex-linked anemia mice

Chen

Attieh

et al. 2004

Blood

137

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Hephaestin (Hp) plays an important role in intestinal iron absorption and is predicted to be a ferroxidase based on significant sequence identity to the serum multicopper ferroxidase ceruloplasmin. Here, we demonstrate that Hp has both amine oxidase and ferroxidase activity in cultured cells and primary intestinal enterocytes with the use of both gel and solution assays. The specificity of the activity is shown by immunoblotting, immunoprecipitation, and immunodepletion experiments. Surprisingly, the truncated hephaestin expressed in sex-linked anemia (sla) mice still has measurable, but decreased, oxidase activity. Molecular modeling of the truncated hephaestin suggests retention of a minimum catalytic core required for enzymatic activity. We suggest that hephaestin, by way of its ferroxidase activity, facilitates iron export from intestinal enterocytes, most likely in cooperation with the basolateral iron transporter,

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Hepatic iron overload in aceruloplasminaemia

Cited by 65 publications

References 12 publications

Anemia and iron overload due to compound heterozygosity for novel ceruloplasmin mutations

Anemia and iron overload due to compound heterozygosity for novel ceruloplasmin mutations

The Neurological Presentation of Ceruloplasmin Gene Mutations

Hephaestin is a ferroxidase that maintains partial activity in sex-linked anemia mice

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