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Abstracts

Hemochromatosis

ABSTRACTS

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Vitamin A intervention: short-term effects of a single, oral, massive dose on iron metabolism.

Bloem MW, Wedel M, van Agtmaal EJ, Speek AJ, Saowakontha S, Schreurs WH. Department of Clinical Biochemistry, TNO-CIVO Toxicology and Nutrition Institute, Zeist, The Netherlands.

Am J Clin Nutr 1990 Jan;51(1):76-9

A group of 134 school children aged 3-9 y, with signs of conjunctival xerosis, from the rural area of the Sakorn Nakhon province in Northeast Thailand were selected for a controlled study on the short-term effect (2 wk) of a single, oral high dose of vitamin A on iron metabolism. After collection of the baseline data, children within villages were randomly assigned to receive the capsules (n = 65) or serve as control subjects (n = 69). Two weeks after supplementation significant increases of retinol, retinol-binding protein, hemoglobin, hematocrit, serum iron, and saturation of transferrin were found in the supplemented group. Ferritin concentrations did not change significantly. These short-term changes completely exclude seasonal effects and change in morbidity. This study provides further evidence of a causal association between vitamin A and iron metabolism. In areas where vitamin A deficiency is endemic, periodic massive vitamin A dose programs can also improve iron status of the population.

[Primary hemochromatosis and dietary iron] (in Norwegian).

Borch-Iohnsen B Ernaeringsinstituttet Universitetet i Oslo.

Tidsskr Nor Laegeforen (Norway) Oct 10 1997, 117 (24) p3506-7

Primary haemochromatosis is characterized by an unusually high degree of iron absorption resulting in the accumulation of excessive amounts of tissue iron. Excess stores of iron are removed by repeated phlebotomy. Health personnel and a number of patients with primary haemochromatosis have expressed their desire for advice on special diets to try and reduce the number of phlebotomies per year. This article gives advice on how patients with primary haemochromatosis can decrease their dietary iron intake and how they can put together meals to obtain low bioavailability, and therefore a lower iron absorption. The diet should be varied and be rich in bread and cereals, and fruit and vegetables. The amount of meat, Norwegian brown whey cheese (iron supplemented) and alcohol should be limited. Tea or coffee with meals will reduce iron absorption. Food rich in ascorbic acid (fruit and fruit juice) should be avoided with meals. Ascorbic acid supplements are not recommended.

Effect of vitamin E supplementation on hepatic fibrogenesis in chronic dietary iron overload

Brown K.E.; Poulos J.E.; Li L.; Soweid A.M.; Ramm G.A.; O'Neill R.; Britton R.S.; Bacon B.R. B.R. Bacon, Div. of Gastroenterology/Hepatology, Dept. of Internal Medicine, Saint Louis Univ. Hlth. Sci. Center, 3635 Vista Ave., St. Louis, MO 63110-0250 USA

American Journal of Physiology - Gastrointestinal and Liver Physiology (USA), 1997, 272/1 35-1 (G116-G123)

It has been suggested that lipid peroxidation plays an important role in hepatic fibrogenesis resulting from chronic iron overload. Vitamin E is an important lipid-soluble antioxidant that has been shown to be decreased in patients with hereditary hemochromatosis and in experimental iron overload. The aim of this study was to determine the effects of vitamin E supplementation on hepatic lipid peroxidation and fibrogenesis in an animal model of chronic iron overload. Rats were fed the following diets for 4, 8, or 14 mo: standard laboratory diet (control), diet with supplemental vitamin E (200 IU/kg, control + E), diet with carbonyl iron (Fe), and diet with carbonyl iron supplemented with vitamin E (200 IU/kg, Fe + E). Iron loading resulted in significant decreases in hepatic and plasma vitamin E levels at all time points, which were overcome by vitamin E supplementation. Thiobarbituric acid-reactive substances (an index of lipid peroxidation) were increased three- to fivefold in the iron-loaded livers; supplementation with vitamin E reduced these levels by at least 50% at all time points. Hepatic hydroxyproline levels were increased twofold by iron loading. Vitamin E did not affect hydroxyproline content at 4 or 8 mo but caused an 18% reduction at 14 mo in iron-loaded livers. At 8 and 14 mo, vitamin E decreased the number of alpha-smooth muscle actin-positive stellate cells in iron-loaded livers. These results demonstrate a dissociation between lipid peroxidation and collagen production and suggest that the profibrogenic action of iron in this model is mediated through effects which cannot be completely suppressed by vitamin E.

Noninvasive prediction of fibrosis in C282Y homozygous hemochromatosis.

Guyader D; Jacquelinet C; Moirand R; Turlin B; Mendler MH; Chaperon J; David V; Brissot P; Adams P; Deugnier Y Clinique des Maladies du Foie and INSERM Unite 49, Rennes, France. Dominique.Guyader@univ-rennes1.fr

Gastroenterology (UNITED STATES) Oct 1998, 115 (4) p929-36

BACKGROUND & AIMS: The diagnosis of hemochromatosis is now possible for C282Y homozygous patients using noninvasive molecular genetic tests. The aim of this study was to define noninvasive factors predictive of severe fibrosis (bridging fibrosis or cirrhosis) to avoid unnecessary liver biopsies in such patients. METHODS: Clinical and biological data were recorded at the time of diagnosis in 197 French C282Y homozygous patients, 52 (26%) of whom had severe fibrosis. Variables significantly linked to severe fibrosis using univariate analysis were entered into a multivariate stepwise analysis. These variables were combined to obtain a simple index allowing for prediction of severe fibrosis. RESULTS: Serum ferritin, hepatomegaly, and serum aspartate aminotransferase were selected using multivariate analysis. Their combination applied to the 96 patients with ferritin level of </=1000 microgram/L, normal aspartate aminotransferase values, and absence of hepatomegaly showed that no severe fibrosis was encountered in this subgroup of patients. The results were validated in 113 C282Y homozygous patients in Canada with a good reproducibility of negative prediction but a poor reproducibility of the positive prediction of severe fibrosis. CONCLUSIONS: In C282Y homozygous patients, the diagnosis of severe fibrosis relies on liver biopsy, but absence of severe fibrosis can be accurately predicted in most patients on the basis of simple clinical and biochemical variables.

Does calcium interfere with iron absorption?

Hallberg L

Am J Clin Nutr 1998 Jul;68(1):3-4

No abstract.

Clinical trial on the effect of regular tea drinking on iron accumulation in genetic haemochromatosis

Kaltwasser J.P.; Werner E.; Schalk K.; Hansen C.; Gottschalk R.; Seidl C. J.P. Kaltwasser, Medizinische Klinik III, Zentrum der Inneren Medizin, Johann Wolfgang Goethe-Universitat, Theodor-Stern-Kai 7, D-60596 Frankfurt am Main Germany

Gut (United Kingdom) , 1998, 43/5 (699-704)

Background - Black tea is known to be a potent inhibitor of intestinal absorption of non-haem iron at least in healthy subjects. Aims - To investigate this effect in patients with genetic haemochromatosis, and, more importantly, the effect of regular tea drinking on the accumulation of storage iron in these patients over one year. Patients - Investigations were carried out on 18 patients with clinically proven genetic haemochromatosis. For the study of storage iron accumulation, they were separated into a group instructed to drink a particularly tannin rich tea regularly with meals and a control group. Methods - Intestinal iron absorption from a test meal was measured using whole body counting. Body iron stores were evaluated quantitatively by exhaustive phlebotomy, using haemoglobin, saturation of serum iron binding capacity, and serum ferritin for the assessment of body iron status. Results - A significant reduction in iron absorption was observed when the test meal was accompanied by drinks of tea instead of water. In the tea drinking group, the increase in storage iron was reduced by about one third compared with that of the control group. Conclusions - Regular tea drinking with meals reduces the frequency of phlebotomies required in the management of patients with haemochromatosis.

Antioxidants for hemochromatosis.

Last, W.

Int. Clin. Nutr. Rev. 1991; 11(2): 71-4.

No abstract available.

The effect of withdrawal of food iron fortification in Sweden as studied with phlebotomy in subjects with genetic hemochromatosis.

Olsson KS; Vaisanen M; Konar J; Bruce A Department of Medicine, Molndal Hospital, Sweden.

Eur J Clin Nutr (England) Nov 1997, 51 (11) p782-6

OBJECTIVES: The iron fortification of food in Sweden, the highest in the world, was withdrawn 1st January 1995, because the effect upon target groups was considered to be uncertain. We wanted to study the effect of such a dietary experiment.

DESIGN: Comparative cross over study.

SETTING: Out patient service and Blood Bank.

SUBJECTS: Sixteen men aged 24-73 y on maintenance phlebotomy after treatment for iron overload. One was excluded because of inflammatory disease.

INTERVENTIONS: Quantitative phlebotomy with serial measurements of Hb conc., % transferrin saturation and serum ferritin concentration.

MAIN OUTCOME MEASURES: Iron absorption was measured by phlebotomy during two periods, with and without iron fortification. 1 g Hb = 3.4 mg Fe.

RESULTS: Iron absorption was significantly reduced (P <0.001) when iron fortification was withdrawn from a mean of 4.27 +/- 1.2 to 3.63 +/- 1.1 mg/d. The difference of 0.65 mg/d (95% c.i.0.32-0.97) corresponds to the fraction of iron derived from fortification. Intervals between donations had to be extended from 59 +/- 15 to 69 +/- 17 d (P < 0.01) to avoid induction of iron deficiency anemia. The iron content of the fortified diet averaged 15.4 mg/d, of which the fortified fraction constituted 4.1 mg/d (27%). The relative bioavailability of carbonyl iron used as fortificant was 38%.

CONCLUSIONS: The relative bioavailability of carbonyl iron used as fortificant was higher than previously reported. Target groups such as menstruating females will probably be affected by a higher prevalence of iron deficiency when food is no longer fortified. People with genetic hemochromatosis will accelerate into clinical disease at a slower rate.

Classification and diagnosis of iron overload.

Piperno A Istituto di Scienze Biomediche, Azienda Ospedaliera S. Gerardo, Monza, Italy. alberto.piperno@unimi.it

Haematologica (Italy) May 1998, 83 (5) p447-55, 078

BACKGROUND AND OBJECTIVE: Iron overload is the result of many disorders and could lead to the development of organ damage and increased mortality. The recent description of new conditions associated with iron overload and the identification of the genetic defect of hereditary hemochromatosis prompted us to review this subject and to redefine the diagnostic criteria of iron overload disorders.

EVIDENCE AND INFORMATION SOURCES: The material examined in the present review includes articles published in the Journals covered by the Science Citation Index and Medline. The author has been working in the field of iron overload diseases for several years and has contributed ten of the papers cited in the references.

STATE OF THE ART AND PERSPECTIVES: Iron overload can be classified on the basis of different criteria: route of access of iron within the organism, predominant tissue site of iron accumulation and cause of the overload. Excess iron can gain access by the enteral route, the parenteral route, and placental route during fetal life. The different distribution of iron within parenchymal or reticuloendothelial storage areas indicates different pathogenetic mechanisms of iron accumulation and has relevant implications in terms of organ damage and prognosis of the patients. Iron overload may be either primary, resulting from a deregulation of intestinal iron absorption as in hemochromatosis or secondary to other congenital or acquired conditions. Diagnosis of iron overload can be suspected on the basis of clinical data, high transferrin saturation and/or serum ferritin values. However, several hyperferritinemic conditions are not related to iron overload, but may imply severe disorders (inflammations, neoplasia) or a deregulation of ferritin synthesis (hereditary hyperferritinemia-cataract syndrome), and iron overload secondary to aceruloplasminemia, and the recently described dysmetabolic-associated liver iron overload syndrome, are characterized by low or normal transferrin saturation levels. Liver biopsy is still very useful in the diagnostic approach to iron overload disorders, by defining the amount and the distribution of iron within the liver. The analysis of HFE gene mutations (C282Y and H63D) is a simple and strong tool in the diagnostic work out of iron overload conditions. (60 Refs.)

Heterogeneity of hemochromatosis in Italy.

Piperno A; Sampietro M; Pietrangelo A; Arosio C; Lupica L; Montosi G; Vergani A; Fraquelli M; Girelli D; Pasquero P; Roetto A; Gasparini P; Fargion S; Conte D; Camaschella C Istituto di Scienze Biomediche, Universita di Milano, Divisione di Medicina I, Ospedale San Gerardo, Monza, Italy.

Gastroenterology (United States) May 1998, 114 (5) p996-1002

BACKGROUND & AIMS: Patients with hemochromatosis show variable phenotype expression. We evaluated the frequency of hemochromatosis gene (HFE) mutations and the contribution of HFE genotype, ancestral haplotype, ethnic background, and additional factors (alcohol intake, hepatitis viruses, and beta-thalassemia trait) to the severity of iron overload in a large series of Italian patients with a hemochromatosis phenotype.

METHODS: HFE genotype was studied in 188 patients. Phenotype evaluation was available in 153 men and 20 women and was based mainly on iron removed. HFE genotype was determined by a polymerase chain reaction restriction assay and ancestral haplotype through D6S265 and D6S105 microsatellite analysis.

RESULTS: The frequency of C282Y homozygotes was 64%, with a decreasing gradient from north to south. C282Y homozygotes showed more severe iron overload than the other HFE genotypes. In the same group, ancestral haplotype was associated with a more severe phenotype. Additional factors may favor the development of a relatively mild hemochromatosis phenotype in patients nonhomozygous for the C282Y mutation.

CONCLUSIONS: Hemochromatosis in Italy is a nonhomogenous disorder in which genetic and acquired factors are involved. In patients with a single or no HFE mutation, further studies will enable a differentiation between true genetic disorders and interactions between genetic and acquired factors.

Hemochromatosis: advances in molecular genetics and clinical diagnosis.

Ramrakhiani S; Bacon BR Department of Internal Medicine, Saint Louis University School of Medicine, MO 63110-0250, USA.

J Clin Gastroenterol (UNITED STATES) Jul 1998, 27 (1) p41-6

Hereditary hemochromatosis (HH) is a human leukocyte antigen-linked inherited disease that is characterized by inappropriately high absorption of iron by the gastrointestinal mucosa. The spectrum of disease presentation is changing with more and more patients now being identified before they are symptomatic with complications of iron overload. A candidate gene for HH, called HFE, was identified in 1996, and a test for the gene is commercially available. A review of the recent identification of the gene and its implications for clinical diagnosis and therapy is presented. We also propose an algorithm for evaluation of patients for HH. Early diagnosis and appropriate therapy can prevent significant morbidity and mortality associated with the development of end-organ complications of HH. The understanding of the C282Y and H63D mutations is still evolving, and the algorithm and the contribution of various heterozygous mutations to the diagnosis and management of iron overload need to be confirmed by further clinical and genetic studies. (30 Refs.)

Understanding iron absorption and metabolism, aided by studies of hemochromatosis.

Roeckel IE; Dickson LG Central Kentucky Blood Center, Lexington 40504, USA.

Ann Clin Lab Sci (UNITED STATES) Jan-Feb 1998, 28 (1) p30-3

Duodenal iron absorption from food is selectively blocked to prevent iron intoxication. The prime example of pathologic increase in intestinal iron absorption is seen in patients with hemochromatosis . They suffer iron damage to the heart, liver, and other tissues resulting in premature death if the iron is not removed by vigorous phlebotomy. Examples of overcoming the intestinal barrier to iron are alcohol consumption, vitamin preparations with vitamin C, and iron consumed by individuals without anemia. Endogenous generation of excess iron by hemolysis, owing to abnormal hemoglobin or many transfusions, are not controlled by the intestinal barrier. (24 Refs.)

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Hereditary haemochromatosis mutation frequencies in the general population.

Bradley LA; Johnson DD; Palomaki GE; Haddow JE; Rob ertson NH; Ferrie RM Foundation for Blood Research, Scarborough, Maine 04070-0190, USA.

J Med Screen (England) 1998, 5 (1) p34-6

OBJECTIVES: This study aims to expand our knowledge of the general population frequency of two mutations, C282Y and H63D, identified in the candidate gene for hereditary haemochromatosis, and to determine whether the testing can be performed using routinely obtained cheek-brush (buccal) samples.

SETTING: Banked buccal lysate samples, randomised and coded for anonymity, from a cohort of couples who underwent prenatal cystic fibrosis screening in Maine.

METHODS: A multiplex ARMS test was performed on buccal cell lysates to identify the two mutations.

RESULTS: Genotype frequencies found among the 1001 subjects studied (502 women, 499 men) were: seven C282Y homozygotes, 22 C282Y/H63D compound heterozygotes, 97 C282Y heterozygotes, 17 H63D homozygotes, 246 H63D heterozygotes, and 612 individuals with no detectable mutation. The allele frequencies for C282Y and H63D were 0.066 and 0.151, respectively.

CONCLUSIONS: Observed genotype frequencies in Maine are consistent with expectations and with consensus data from five smaller studies. Combined mutational analysis data indicate that homozygosity for C282Y (the genotype found in about 85% of subjects with diagnosed hereditary haemochromatosis) occurs in 51 per 10,000 white subjects of northern European heritage; the corresponding total hereditary haemochromatosis prevalence of about 60 per 10,000 is consistent with previous estimates. The study also confirms that H63D would not be useful in general population screening for hereditary haemochromatosis.

Factors affecting the rate of iron mobilization during venesection therapy for genetic hemochromatosis.

Adams PC London Health Sciences Centre, University of Western Ontario, Canada.

Am J Hematol (United States) May 1998, 58 (1) p16-9

Although progressive iron accumulation is a characteristic feature of genetic hemochromatosis , the factors affecting the rate of iron mobilization by venesection have not been established. Venesection records were analyzed in 77 hemochromatosis homozygotes to study the factors affecting the rate of iron mobilization by venesection. The rate of iron mobilization was the iron removed divided by the time required to deplete iron stores (serum ferritin < 50 microg/L). Mean duration of venesection therapy was 1.4 years (range 0.44-3.6 years). All patients completed the therapy and there were no significant adverse effects. Rate of iron mobilization was higher in cirrhotics compared to non-cirrhotic patients (P = 0.04). Iron mobilization was inversely related to intestinal radioiron absorption (r = -0.45, P = .01). There was no significant relationship between iron mobilization and patient age, gender, serum ferritin, and hepatic iron concentration. Iron mobilization is increased in cirrhotics and patients with lower intestinal iron absorption. Venesection therapy is safe and well tolerated in all age groups.

Hemochromatosis and iron needs.

Halliday JW Queensland Institute of Medical Research, Bancroft Centre, Royal Brisbane Hospital, Queensland, Australia.

Nutr Rev (United States) Feb 1998, 56 (2 Pt 2) ps30-7; discussion s54-75

Although iron is an essential dietary requirement, the amount absorbed by the body is well regulated and depends on body iron stores and on dietary iron availability. There is very little iron excreted under normal conditions. Iron deficiency is a worldwide problem but iron overload, as seen in the inherited disease, hemochromatosis , is a major cause of morbidity in some Caucasian populations. This is a problem particularly where there is an adequate dietary iron intake and especially in males. A mutation has recently been described in an MHC Class l-like gene (HFE) that encodes for a protein (HFE) of 343 amino acids. The molecule contains a signal sequence peptide-binding region, alpha, and alpha(2) domains, and an immunoglobulinlike alpha(3) domain, in addition to a transmembrane region and a small cytoplasmic tail. It is a candidate gene for hemochromatosis. Several possibilities as to the function of this gene and the corresponding protein have been suggested but none has yet been confirmed. The mutation has been detected by several different groups in 80%-100% of subjects with the disease. However, in one study, 18%-20% of patients with the mutation did not exhibit significant iron overload. The discovery of this gene has important implications for both clinical studies and the elucidation of the pathways of iron metabolism. (41 Refs.)

Clinical trial on the effect of regular tea drinking on iron accumulation in genetic haemochromatosis

Kaltwasser J.P.; Werner E.; Schalk K.; Hansen C.; Gottschalk R.; Seidl C. J.P. Kaltwasser, Medizinische Klinik III, Zentrum der Inneren Medizin, Johann Wolfgang Goethe-Universitat, Theodor-Stern-Kai 7, D-60596 Frankfurt am Main Germany

Gut (United Kingdom) , 1998, 43/5 (699-704)

Background - Black tea is known to be a potent inhibitor of intestinal absorption of non-haem iron at least in healthy subjects.

Aims - To investigate this effect in patients with genetic haemochromatosis, and, more importantly, the effect of regular tea drinking on the accumulation of storage iron in these patients over one year. Patients - Investigations were carried out on 18 patients with clinically proven genetic haemochromatosis. For the study of storage iron accumulation, they were separated into a group instructed to drink a particularly tannin rich tea regularly with meals and a control group.

Methods - Intestinal iron absorption from a test meal was measured using whole body counting. Body iron stores were evaluated quantitatively by exhaustive phlebotomy, using haemoglobin, saturation of serum iron binding capacity, and serum ferritin for the assessment of body iron status.

Results - A significant reduction in iron absorption was observed when the test meal was accompanied by drinks of tea instead of water. In the tea drinking group, the increase in storage iron was reduced by about one third compared with that of the control group.

Conclusions - Regular tea drinking with meals reduces the frequency of phlebotomies required in the management of patients with haemochromatosis.

Defective iron metabolism in genetic hemochromatosis. The mechanisms remain unknown in spite of genetic advances]

Stal P; Hagen K; Hultcrantz R Gastroenterologiskt Centrum, Huddinge Sjukhus.

Lakartidningen (SWEDEN) Aug 5 1998, 95 (32-33) p3430-5

Genetic haemochromatosis (GH) is one of the most common hereditary diseases, with a prevalence of 1-5/1000 in the Western world. In 90 per cent of cases a mutation is found in an MHC-class-like gene designated HFE, involving a substitution at position 282 of the HFE protein and resulting in defective binding of beta(2)-microglobulin. Animals with beta(2)-microglobulin deficiency develop iron overload, indicating this protein to be involved in the regulation of iron metabolism. Hepatic iron overload results in increased production of oxygen free radicals and peroxidation of membrane lipids, thus causing damage to lysosomes, mitochondria and the endoplasmic reticulum. These cellular events may progress to cell death, fibrogenesis, and the development of liver cirrhosis which is associated with a 200-fold increase in risk of hepatocellular carcinoma. In addition to the risk of diabetes, arthralgia, cardiac arrhythmia, pituitary insufficiency and hypogonadism, iron excess is also associated with aggravation of the cytotoxic effects exerted on hepatocytes by other agents such as alcohol or hepatotrophic viruses. The treatment of iron overload in GH consists of weekly venesection until the serum ferritin level is normalized, followed by maintenance therapy. Survival rates are normal if the disease is detected and treated before complications have developed. (45 Refs.)

Clinical characteristics of hereditary hemochromatosis patients who lack the C282Y mutation. Shaheen NJ; Bacon BR; Grimm IS Division of Digestive Diseases and Nutrition, University of North Carolina, Chapel Hill 27599-7080, USA.

Hepatology (UNITED STATES) Aug 1998, 28 (2) p526-9

Approximately 85% of patients with typical hereditary hemochromatosis (HH) are homozygous for the C282Y mutation (C282Y/C282Y) in the recently identified candidate gene for HH. However, some HH patients are instead homozygous for the wild-type allele (wt/wt) at this locus. These wt/wt patients may represent a phenotypically similar, but genotypically different, heritable trait, or may be unrecognized cases of secondary iron overload. The purpose of this study is to provide an in-depth analysis of the wt/wt HH patients identified in the original description of the HH gene, and to compare them with 62 patients from the same analysis who were homozygous for the C282Y mutation. Eighteen of the 21 wt/wt HH patients from the original study were assessed for 14 historical and laboratory variables, including previously unrecognized causes of secondary iron overload, the heritability of iron overload and liver disease, and other clinical characteristics. Ten of these 18 wt/wt HH patients (55.6%) were found to have previously unrecognized causes for secondary iron overload compared with 3 of 62 (4.8%) of the C282Y/C282Y patients (P < .001). The remaining 8 wt/wt patients had no recognizable etiology of secondary iron overload. None of the 18 wt/wt patients had a family history of iron overload or liver disease, compared with 58% of the C282Y/C282Y patients (P< .001). When compared with C282Y homozygotes, the 8 wt/wt patients without secondary iron overload had a higher presenting hepatic iron index (HII) (9.5 vs. 4.7; P = .01). We conclude that, in this series of patients, over half of the wt/wt HH patients possessed previously unrecognized causes of secondary iron overload, and therefore, may have been misdiagnoses. If these cases are excluded, the number of false-negative tests is decreased, and the sensitivity of the mutational analysis is increased. However, there is a subgroup of wt/wt patients who have typical hemochromatosis without an identifiable cause of secondary iron overload. These patients may have more severe iron loading than C282Y homozygotes. (21 Refs.)

Haemochromatosis.

Worwood M Department of Haematology, University of Wales College of Medicine, Cardiff, UK.

Clin Lab Haematol (ENGLAND) Apr 1998, 20 (2) p65-75

Genetic haemochromatosis (GH) is the most common, autosomal recessive disorder in Northern Europe. The studies which led to the identification of the HFE gene are described. In the UK over 90% of patients with GH are homozygous for the C282Y mutation of this gene. This mutation is confined to populations of European origin. The significance of another mutation, H63D, in causing iron overload is less certain. Preliminary studies on the localization of the protein and the effects of the mutations are described. Genetic testing and the measurement of iron status now provide the means to allow for widespread testing for the prevention of iron overload and its consequences. However, questions remain about the clinical penetrance of GH. (81 Refs.)

Hemochromatosis: advances in molecular genetics and clinical diagnosis.

Ramrakhiani S; Bacon BR Department of Internal Medicine, Saint Louis University School of Medicine, MO 63110-0250, USA.

J Clin Gastroenterol (United States) Jul 1998, 27 (1) p41-6

Hereditary hemochromatosis (HH) is a human leukocyte antigen-linked inherited disease that is characterized by inappropriately high absorption of iron by the gastrointestinal mucosa. The spectrum of disease presentation is changing with more and more patients now being identified before they are symptomatic with complications of iron overload. A candidate gene for HH, called HFE, was identified in 1996, and a test for the gene is commercially available. A review of the recent identification of the gene and its implications for clinical diagnosis and therapy is presented. We also propose an algorithm for evaluation of patients for HH. Early diagnosis and appropriate therapy can prevent significant morbidity and mortality associated with the development of end-organ complications of HH. The understanding of the C282Y and H63D mutations is still evolving, and the algorithm and the contribution of various heterozygous mutations to the diagnosis and management of iron overload need to be confirmed by further clinical and genetic studies. (30 Refs.)

[Defective iron metabolism in genetic hemochromatosis. The mechanisms remain unknown in spite of genetic advances]

Stal P; Hagen K; Hultcrantz R Gastroenterologiskt Centrum, Huddinge Sjukhus.

Lakartidningen (Sweden) Aug 5 1998, 95 (32-33) p3430-5

Genetic haemochromatosis (GH) is one of the most common hereditary diseases, with a prevalence of 1-5/1000 in the Western world. In 90 per cent of cases a mutation is found in an MHC-class-like gene designated HFE, involving a substitution at position 282 of the HFE protein and resulting in defective binding of beta(2)-microglobulin. Animals with beta(2)-microglobulin deficiency develop iron overload, indicating this protein to be involved in the regulation of iron metabolism. Hepatic iron overload results in increased production of oxygen free radicals and peroxidation of membrane lipids, thus causing damage to lysosomes, mitochondria and the endoplasmic reticulum. These cellular events may progress to cell death, fibrogenesis, and the development of liver cirrhosis which is associated with a 200-fold increase in risk of hepatocellular carcinoma. In addition to the risk of diabetes, arthralgia, cardiac arrhythmia, pituitary insufficiency and hypogonadism, iron excess is also associated with aggravation of the cytotoxic effects exerted on hepatocytes by other agents such as alcohol or hepatotrophic viruses. The treatment of iron overload in GH consists of weekly venesection until the serum ferritin level is normalized, followed by maintenance therapy. Survival rates are normal if the disease is detected and treated before complications have developed. (45 Refs.)

Clinical characteristics of hereditary hemochromatosis patients who lack the C282Y mutation.

Shaheen NJ; Bacon BR; Grimm IS Division of Digestive Diseases and Nutrition, University of North Carolina, Chapel Hill 27599-7080, USA.

Hepatology (United States) Aug 1998, 28 (2) p526-9

Approximately 85% of patients with typical hereditary hemochromatosis (HH) are homozygous for the C282Y mutation (C282Y/C282Y) in the recently identified candidate gene for HH. However, some HH patients are instead homozygous for the wild-type allele (wt/wt) at this locus. These wt/wt patients may represent a phenotypically similar, but genotypically different, heritable trait, or may be unrecognized cases of secondary iron overload. The purpose of this study is to provide an in-depth analysis of the wt/wt HH patients identified in the original description of the HH gene, and to compare them with 62 patients from the same analysis who were homozygous for the C282Y mutation. Eighteen of the 21 wt/wt HH patients from the original study were assessed for 14 historical and laboratory variables, including previously unrecognized causes of secondary iron overload, the heritability of iron overload and liver disease, and other clinical characteristics. Ten of these 18 wt/wt HH patients (55.6%) were found to have previously unrecognized causes for secondary iron overload compared with 3 of 62 (4.8%) of the C282Y/C282Y patients (P < .001). The remaining 8 wt/wt patients had no recognizable etiology of secondary iron overload. None of the 18 wt/wt patients had a family history of iron overload or liver disease, compared with 58% of the C282Y/C282Y patients (P< .001). When compared with C282Y homozygotes, the 8 wt/wt patients without secondary iron overload had a higher presenting hepatic iron index (HII) (9.5 vs. 4.7; P = .01). We conclude that, in this series of patients, over half of the wt/wt HH patients possessed previously unrecognized causes of secondary iron overload, and therefore, may have been misdiagnoses. If these cases are excluded, the number of false-negative tests is decreased, and the sensitivity of the mutational analysis is increased. However, there is a subgroup of wt/wt patients who have typical hemochromatosis without an identifiable cause of secondary iron overload. These patients may have more severe iron loading than C282Y homozygotes. (21 Refs.)

Haemochromatosis.

Worwood M Department of Haematology, University of Wales College of Medicine, Cardiff, UK.

Clin Lab Haematol (England) Apr 1998, 20 (2) p65-75

Genetic haemochromatosis (GH) is the most common, autosomal recessive disorder in Northern Europe. The studies which led to the identification of the HFE gene are described. In the UK over 90% of patients with GH are homozygous for the C282Y mutation of this gene. This mutation is confined to populations of European origin. The significance of another mutation, H63D, in causing iron overload is less certain. Preliminary studies on the localization of the protein and the effects of the mutations are described. Genetic testing and the measurement of iron status now provide the means to allow for widespread testing for the prevention of iron overload and its consequences. However, questions remain about the clinical penetrance of GH. (81 Refs.)

Hemochromatosis and iron needs.

Halliday JW Queensland Institute of Medical Research, Bancroft Centre, Royal Brisbane Hospital, Queensland, Australia.

Nutr Rev (UNITED STATES) Feb 1998, 56 (2 Pt 2) ps30-7; discussion s54-75

Although iron is an essential dietary requirement, the amount absorbed by the body is well regulated and depends on body iron stores and on dietary iron availability. There is very little iron excreted under normal conditions. Iron deficiency is a worldwide problem but iron overload, as seen in the inherited disease, hemochromatosis , is a major cause of morbidity in some Caucasian populations. This is a problem particularly where there is an adequate dietary iron intake and especially in males. A mutation has recently been described in an MHC Class l-like gene (HFE) that encodes for a protein (HFE) of 343 amino acids. The molecule contains a signal sequence peptide-binding region, alpha, and alpha(2) domains, and an immunoglobulin-like alpha(3) domain, in addition to a transmembrane region and a small cytoplasmic tail. It is a candidate gene for hemochromatosis. Several possibilities as to the function of this gene and the corresponding protein have been suggested but none has yet been confirmed. The mutation has been detected by several different groups in 80%-100% of subjects with the disease. However, in one study, 18%-20% of patients with the mutation did not exhibit significant iron overload. The discovery of this gene has important implications for both clinical studies and the elucidation of the pathways of iron metabolism. (41 Refs.)

Long-term intraperitoneal deferoxamine for hemochromatosis

Swartz R.D.; Legault D.J. Michigan University Medical Center, 3914 TC-Box 0364, Ann Arbor, MI 48109-0364 USA

American Journal of Medicine (USA), 1996, 100/3 (308-312)

Intraperitoneal deferoxamine is a well-established treatment for aluminum accumulation syndrome in patients with end-stage renal disease receiving peritoneal dialysis, but the use of intraperitoneal deferoxamine has not been described outside of the setting of chronic renal failure. We present here a case of secondary hemochromatosis, complicated by cirrhosis and cardiomyopathy, in which a chronic peritoneal dialysis catheter was used both to treat ascites and to deliver parenteral deferoxamine for iron overload. Daily urinary iron excretion was similar to that achieved when using standard routes of deferoxamine administration. Over a 2-year period, reversal of both the biochemical indicators and the clinical manifestations of iron overload was accomplished.

Antioxidant activity of Vitamin-C in iron-overloaded human plasma

Berger T.M.; Polidori M.C.; Dabbagh A.; Evans P.J.; Halliwell B.; Morrow J.D.; Roberts II L.J.; Frei B. B. Frei, Whitaker Cardiovascular Inst., Boston University School of Medicine, 80 East Concord St., Boston, MA 02118 USA

Journal of Biological Chemistry (USA), 1997, 272/25 (15656-15660)

Vitamin-C (ascorbic acid, AA) can act as an antioxidant or a pro- oxidant in vitro, depending on the absence or the presence, respectively, of redox-active metal ions. Some adults with iron-overload and some premature infants have potentially redox-active, bleomycin-detectable iron (BDI) in their plasma. Thus, it has been hypothesized that the combination of AA and BDI causes oxidative damage in vivo. We found that plasma of preterm infants contains high levels of AA and F2-isoprostanes, stable lipid peroxidation end products. However, F2-isoprostane levels were not different between those infants with BDI (138 plus or minus 51 pg/ml, n = 19) and those without (126 plus or minus 41 pg/ml, n = 10), and the same was true for protein carbonyls, a marker of protein oxidation (0.77 plus or minus 0.31 and 0.68 plus or minus 0.13 nmol/mg protein, respectively). Incubation of BDI-containing plasma from preterm infants did not result in detectable lipid hydroperoxide formation (less than or equal to10 nM cholesteryl ester hydroperoxides) as long as AA concentrations remained high. Furthermore, when excess iron was added to adult plasma, BDI became detectable, and endogenous AA was rapidly oxidized. Despite this apparent interaction between excess iron and endogenous AA, there was no detectable lipid peroxidation as long as AA was present at >10% of its initial concentration. Finally, when iron was added to plasma devoid of AA, lipid hydroperoxides were formed immediately, whereas endogenous and exogenous AA delayed the onset of iron-induced lipid peroxidation in a dose-dependent manner. These findings demonstrate that in iron-overloaded plasma, AA acts an antioxidant toward lipids. Furthermore, our data do not support the hypothesis that the combination of high plasma concentrations of AA and BDI, or BDI alone, causes oxidative damage to lipids and proteins in vivo.

Antioxidant status and lipid peroxidation in hereditary haemochromatosis.

Young IS; Trouton TG; Torney JJ; McMaster D; Callender ME; Trimble ER Department of Clinical Biochemistry, Queen's University of Belfast, UK.

Free Radic Biol Med (United States) Mar 1994, 16 (3) p393-7

Hereditary haemochromatosis is characterised by iron overload that may lead to tissue damage. Free iron is a potent promoter of hydroxyl radical formation that can cause increased lipid peroxidation and depletion of chain-breaking antioxidants. We have therefore assessed lipid peroxidation and antioxidant status in 15 subjects with hereditary haemochromatosis and age/sex matched controls. Subjects with haemochromatosis had increased serum iron (24.8 (19.1-30.5) vs. 17.8 (16.1-19.5) mumol/l, p = 0.021) and % saturation (51.8 (42.0-61.6) vs. 38.1 (32.8-44.0), p = 0.025). Thiobarbituric acid reactive substances (TBARS), a marker of lipid peroxidation, were increased in haemochromatosis (0.59 (0.48-0.70) vs. 0.46 (0.21-0.71) mumol/l, p = 0.045), and there were decreased levels of the chain-breaking antioxidants alpha-tocopherol (5.91 (5.17-6.60) vs. 7.24 (6.49-7.80) mumol/mmol cholesterol, p = 0.001), ascorbate (51.3 (33.7-69.0) vs. 89.1 (65.3-112.9), p = 0.013), and retinol (1.78 (1.46-2.10) vs. 2.46 (2.22-2.70) mumol/l, p = 0.001). Patients with hereditary haemochromatosis have reduced levels of antioxidant vitamins, and nutritional antioxidant supplementation may represent a novel approach to preventing tissue damage. However, the use of Vitamin-C may be deleterious in this setting as ascorbate can have prooxidant effects in the presence of iron overload.

Iron storage, lipid peroxidation and glutathione turnover in chronic anti-HCV positive hepatitis.

Farinati F, Cardin R, De Maria N, Della Libera G, Marafin C, Lecis E, Burra P, Floreani A, Cecchetto A, Naccarato R Cattedra Malattie Apparato Digerente, Universita di Padova, Italy.

J Hepatol 1995 Apr;22(4):449-56

BACKGROUND/AIMS: Little is known about the pathogenesis of liver damage related to hepatitis C virus. The presence of steatosis or increased ferritin levels, and preliminary data on the relevance of iron as a prognostic factor prompted us to ascertain whether hepatitis C virus-related liver damage might be mediated by iron accumulation.

METHODS: We evaluated the degree of hepatic inflammation and steatosis, serum ferritin, transferrin saturation and iron levels, tissue iron concentrations and iron index, liver glutathione and malondialdehyde in 33 males and 20 females with chronic hepatitis C virus- or hepatitis B virus-related hepatitis (42 + 11). We also considered six patients with both alcohol abuse and hepatitis C virus, four males with chronic alcoholic liver disease and four males with genetic hemochromatosis, giving a total of 67. All diagnoses were histologically confirmed. Patients with cirrhosis were excluded.

RESULTS: Our data show that: 1. Steatosis is more frequent in hepatitis C virusand hepatitis C virus+alcohol abuse patients; 2. In males, serum ferritin andtissue iron are significantly higher in hepatitis C virus- than in hepatitis Bvirus-positive patients (p < 0.01 and 0.05); transferrin saturation is higher (p <0.05) in hepatitis C virus-positive than in hepatitis B virus-positive patients onlywhen males and females are considered together; 3. Serum ferritin and transferrin saturation only correlate with liver iron (r = 0.833 and r = 0.695,respectively, p = 0.00001); tissue iron is significantly higher in hepatitis C virus-than in hepatitis B virus-positive patients (p < 0.05); 4. In patients with chronichepatitis, serum ferritin is a better marker of liver iron storage than transferrinsaturation, both in males and in females; 5. Hepatitis C virus-positive patientshave higher malondialdehyde levels and activation of turnover of glutathione, probably in response to free-radical-mediated liver damage. Females have lowerliver iron levels but similar trends.

CONCLUSIONS: These findings suggest that hepatitis C virus-related liver damage is characterized by increased iron storage (possibly induced by the virus) whichelicits a free-radical-mediated peroxidation, with consequent steatosis and activation of glutathione turnover.