We aim to validate the TSAT/hepcidin ratio as a diagnostic tool with a high specificity and to establish a cut off point in order to discriminate between Iron Refractory Iron Deficiency Anemia (IRIDA) and iron deficiency anemia (IDA) not because of…
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Brief title
Condition
- Haematological disorders NEC
Synonym
Research involving
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Intervention
Outcome measures
Primary outcome
The main study outcome is a cut off point for the TSAT/hepcidin ratio that
discriminates IRIDA from iron deficient anemia (IDA) because of other reasons
than IRIDA with a high specificity.
Secondary outcome
The study will generate data on the mean and interquartile ranges of the
TSAT/hepcidin ratio of the IRIDA patients (n=17) and the mean and interquartile
ranges of the TSAT/hepcidin ratio of the control group diagnosed with IDA
because of other reasons than IRIDA.
The data on the TSAT/hepcidin ratios in controls with IDA because of other
reasons than IRIDA will be compared with data on TSAT/hepcidin ratios in
healthy individuals that have been established earlier in order to determine if
there is any difference between these groups (Galesloot et al).
Bi-allelic and mono-allelic TMPRSS6 variants may be found in the control
patients that have been referred to gastro-enterologist or gynaecologist for
analysis of IDA. In these control patients IDA has been incorrectly exclusively
attributed to gastrointestinal or gynaecological blood loss and/or
malabsorption since IRIDA has not been considered earlier.
Background summary
The transferrin saturation (TSAT)/hepcidin ratio could be a useful diagnostic
tool in diagnosing patients with Iron Refractory Iron Deficiency Anemia
(IRIDA). IRIDA is an inherited disorder caused by defects in TMPRSS6.
Matriptase-2, encoded by TMPRSS6, plays an essential role in down-regulating
hepcidin, the key regulator of iron homeostasis. Pathogenic TMPRSS6 mutations
result in uninhibited hepcidin production, causing IRIDA, a disease
characterized by a microcytic, hypochromic anemia not (properly) responding to
(especially oral) iron supplementation.
Until now, sequencing the exons of TMPRSS6 for pathological variants has been
the gold standard for diagnosing IRIDA. However, DNA studies are expensive and
not always conclusive. Our case series on the genotype-phenotype correlation in
IRIDA patients and their relatives support the notion that phenotypical
penetrance of TMPRSS6 defects is influenced by other (epi)genetic and
environmental factors such as growth, co-morbidity as inflammation and blood
loss, corroborating some previous observations in mice and man.On the other
hand, patients with a clinical phenotype of IRIDA, might lack an IRIDA genotype
(clinical observations, data not shown).
Since the cardinal feature of IRIDA is a discrepantly high serum hepcidin in
relation to the low iron body status, we hypothesize that the TSAT/hepcidin
ratio could be a useful diagnostic tool. In our small study population,
consisting of clinically presenting patients and their relatives, TSAT/hepcidin
ratio was able to discriminate between bi-allelic and mono-allelic IRIDA
patients, and between mono-allelic IRIDA patients and their phenotypically
unaffected relatives with the same heterozygous TMPRSS6 defect, even after iron
supplementation had been given, provided that inflammation was absent. However,
before its introduction as a diagnostic test in the work up of iron deficient
microcytic anemic patients suspected for the presence of IRIDA, the ratio needs
confirmation in phenotypically and genotypically proven IRIDA patients versus
patients presenting with an iron deficient microcytic anemia because of other
reasons, e.g., inadequate intake, blood loss or other forms of refractory IDA,
such as celiac disease, autoimmune gastritis, and Helicobacter pylori.
Study objective
We aim to validate the TSAT/hepcidin ratio as a diagnostic tool with a high
specificity and to establish a cut off point in order to discriminate between
Iron Refractory Iron Deficiency Anemia (IRIDA) and iron deficiency anemia (IDA)
not because of IRIDA.
Study design
Observational study
Study burden and risks
Participation in this study involves the collection of 11 ml blood at one time
point, apart from standard diagnostic procedures. Therefore the risks and
burden for the subjects can be considered as minimal.
Subjects will not receive any compensation or treatment because of
participation in the SATURNUS study and will not directly benefit from
inclusion. However, by participating in this study, subjects will contribute to
the development of a new diagnostic tool that will differentiate between IRIDA
and other causes of IDA.
There is a small chance a pathologicalTMPRSS6 variant is found in the
participants. When a participant has a pathological mono-allelic of bi-allelic
TMPRSS6 variant this means that he/she has a (mild) form of IRIDA, which might
explain the IDA, either or not in combination with other causes as blood loss
or malabsorption. This information is relevant since an explanation for IDA
might prevent an extensive work-up for IDA and since the diagnosis of IRIDA has
clinical consequences (parenteral iron required in most cases). Moreover, IRIDA
is a genetic, inherited disease. Diagnosis of IRIDA in the participant will
allow screening of first grade relatives for the presence of
genotypic/phenotypic IRIDA.
De Run 4600
Veldhoven 5504 DB
NL
De Run 4600
Veldhoven 5504 DB
NL
Listed location countries
Age
Inclusion criteria
Inclusion of subjects in the IRIDA group will take place from a population
earlier studied by Donker et al, for these subjects clinical data are already
available. (Donker et al, Am J Hematol 2016), Inclusion of subjects in the
non-IRIDA, iron deficiency anemia group will take place at the gynaecological
department (women suffering from menorrhagia) and at the gastrointestinal
department (gastrointestinal blood loss and/or malabsorption), the cardiology
department, the ER of the Maxima Medical Center
IRIDA group
In order to be included in this study an IRIDA patient should meet the
following criteria:
- Previous diagnosis as a mono-allelic or bi-allelic IRIDA patient with an
IRIDA phenotype detected after clinical presentation
- Presence of microcytic anemia (MCV < 80 fL and Hb <7.5 mmol/L for women, Hb <
8.5 mmol/L for men)
- Transferrin saturation (TSAT) < 10%
- Absence of inflammation (CRP < 10 mg/L)
- Not or partially responsive to oral iron (responsiveness to oral iron defined
as Hb increment of 2 g/dL after 3 weeks of iron therapy)
- Age above 18 years
-TSAT/hepcidin ratio available, determined in the absence of inflammation,
Based on these criteria 4 patients in a population of 21 will be excluded
because either the patient was < 18 years or the TSAT/hepcidin ratio was not
available, or not available in the absence of inflammation.
The other 17 IRIDA patients will be included in the study; 11 IRIDA patients in
the bi-allelic affected group, with a homozygous or a compound heterozygous
TMPRSS6 defect, and 6 subjects in the mono-allelic affected group with a
heterozygous TMPRSS6 defect., Control group, Because the controls in the
SATURNUS study all have a microcytic anemia comparable with the IRIDA group,
the phenotype is not discriminative. Therefore, in all controls genotyping of
the exons of TMPRSS6 will be performed. A relevant phenotype, see below, in
combination with the absence of pathological TMPRSS6 variants on both alleles
will be defined as non-IRIDA and will be eligible as control. , Inclusion of
subjects in the control group will take place at the above mentioned
departments of the Máxima Medical Centrum Veldhoven and Radboudumc Nijmegen.
In order to be eligible to participate in this study a subject should meet the
following criteria:
o Presence of microcytic anemia (MCV <80 fL and Hb <7.5 mmol/L L for women, Hb
< 8.5 mmol/L for men)
o Ferritin <40 µg/L
o Age >18 years
o Low TSAT (TSAT <10%)
o Absence of inflammation (CRP < 10 mg/L)
o Absence of pathological TMPRSS6 variants in exons of both alleles, - After
counselling of a potential eligible patient by the Emergency Room doctor, the
cardiologist, the gastro-intestinal specialist or the gynaecologist, blood is
withdrawn for the determination of Hb, MCV, ferritin and CRP level. Extra blood
is withdrawn and stored for the determination of hepcidin and for DNA studies
on TMPRSS6 defects in case the subject had indeed an iron deficiency anemia
without inflammation and has given informed consent. In case the subject does
not meet the inclusion criteria or does not give informed consent, this extra
material will be destroyed.
Exclusion criteria
IRIDA group: see above, D4a, inclusions already done, Control group
Subjects with the following criteria will not be able to participate in the
study because these criteria interfere with the TSAT and hepcidin values.
- Pregnancy
- Oral iron supplements in the last 3 months before referral to the
gynaecologist or gastrointestinal specialist
- Diagnosis with any disease associated with inflammation including
malignancies, chronic liver and kidney diseases
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL61876.015.17 |