|
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.)
SUGGESTED
READING
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.
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