Iridia information and guidelines presented in simple format

1. IRON REFRACTORY IRON
DEFICIENCY ANAEMIA
GUIDE & MODERATOR-DR. SONALI MOHAPATRA
PRESENTER- DR.KARTHIKA IK

2. OUTLINE
Background
Definitions
Iron
metabolism –
Review
Hepcidin-
iron
interaction
IRIDA-
Definition,
Diagnosis,
Management
Conclusion &
Take home
message

3. BACKGROUND
Iron deficiency anemia is a major health problem worldwide. 60–70% of children in 2–5 years- iron deficient
Iron deficiency of nutritional origin - most frequent cause of microcytic hypochromic anemia
Bleeding, gastro-intestinal malabsorption or Helicobacter pylori infection also lead to iron deficiency and
anemia.
A new cause of hereditary anemia has recently been described called iron refractory iron deficiency anemia
or IRIDA (OMIM #2062) , due to mutations in the TMPRSS6 gene , encoding Matriptase-2 (MT-2).
Prevalence of IRIDA- not known, under-diagnosed and should be taken into consideration when all other
known causes of iron deficiency anemia have been ruled out.

4. Iron- an important divalent metal required for many physiological functions
From carrying oxygen to catalyzing enzymatic reactions..
Hampers normal neurophysiological development and cognitive functioning of
brain, especially in growing children
Since there is no regulated excretory pathway for iron, the iron balance in body is
primarily controlled at the absorptive sites of duodenal enterocytes.
WHY IRON IS GOLD..?

5. DEFINITION OF ANEMIA- WHO

6. DEFINITIONS
As per WHO
criteria a Hb of
<110 gm/L in
children aged 0.5–
4.9 years and
Hb < 115 gm/L in
those aged 5–12
years of age
Anemia
Defined by WHO as a
ferritin of <12 μg/l in
children less than 5 years
and <15 μg/l in those 5–
12 years without evidence
of any anemia or fall in
Hb below normal
standard range
Iron
deficiency
Defined as Hb < 110
gm/L with a ferritin
<12 μg/l in children <5
years and Hb < 115
gm/L with a ferritin
<15 μg/l in children 5–
12 years
Iron
deficiency
anemia

7. DEFINITIONS CONTD
Refractoriness to oral iron therapy
• Less than 1 g/dl Hb increase after 4 weeks of oral iron therapy, provided patient
compliance is adequate and acquired forms of GI disorders have been ruled out
Gene variation
• Any form of mutation and or single nucleotide polymorphism (SNP) in either
coding or non-coding region of gene that may or may not affect protein function

8. Quick review on iron metabolism

9. HEPCIDIN OVERVIEW
The hormone hepcidin, a 25-amino-acid (aa) peptide, is the principal regulator
of iron absorption and its distribution to tissues.
Synthesized predominantly in hepatocytes
Low levels of expression in other cells and tissues, including macrophages,
adipocytes and brain
Also important for the autocrine and paracrine control of iron fluxes at the local
level.

14. IRON REGULATION AND HEPCIDIN
Iron deficiency, increased bone marrow erythropoietic states and hypoxia reduce hepcidin secretion
Inflammatory cytokines and increased iron stores increase hepcidin secretion.
The hepcidin acts on ferroportin channels at basal enterocytes in duodenum and on macrophages causing their
internalization and degradation thereby blocking iron absorption into circulation and release from macrophages
affecting recycling process
Injection of hepcidin into mice resulted in a dramatic drop in serum iron within just 1 h
Even though hepcidin is rapidly cleared from the plasma, the effect of a single dose was apparent for up to 72 h,
likely because of the time required to resynthesize sufficient amounts of the hepcidin receptor, ferroportin.

15. INTERESTING FACTS ON HEPCIDIN
The amphipathic structure of hepcidin and its extensive disulfide bonding are common characteristics of
antimicrobial and antifungal peptides.
Patients with hereditary hemochromatosis, a disease generally resulting from relative hepcidin deficiency,
are reported to develop infections caused by unusual microorganisms (Vibrio, Yersinia and Listeria),
But this susceptibility could be related to the bacteria benefitting from increased iron levels rather than
from the loss of any direct antibacterial effect of hepcidin.

16. HEREDITARY CONDITIONS – IRON RELATED ANEMIAS
Hereditary conditions in which dietary iron intake is adequate but there is a block related to proper
absorption of iron or its redistribution from stores
Rare inherited Iron–related anemias Gene affected
Defects of iron transport/uptake Hypotransferrinemia
DMT1 mutations
Defect of iron absorption IRIDA- TMPRSS
Defects of iron recycling Aceruloplasminemia
Defects of erythroid mitochondrial iron utilization X-linked sideroblastic anaemia
AR sideroblastic anaemia

17. IRIDA-History
First described by Buchanan and Sheehan in 1981 - 3 siblings - iron deficiency anemia despite
adequate intake of iron and no evidence of GI blood loss - no rise in Hb following oral FeSo4
therapy and responded partially to parenteral iron.
Brown et al., in 1988 documented 2 sisters in whom family history of microcytic
anemias- not responding to oral iron was apparent, treated with parenteral iron
only one of the sister in their report partially responded.
Pearson and Lukens in 1999 highlighted a case of two siblings who had severe
microcytic anemia but only partially improved with parenteral iron. Considering
familial involvement, an autosomal recessive disease was suspected
Concluded that a novel gene was likely responsible for preventing the absorption
of iron from enterocytes into circulation .
Finberg et al. in 2008 that classified these presentations as IRIDA along with
mutations in TMPRSS6 gene.

18. The TMPRSS6 gene encodes matriptase-2, a serine protease that represses hepcidin
expression by cleaving membrane-bound hemojuvelin

19. TMPRSS6 GENE AND PROTOCOL FOR MAKING GENETIC
DIAGNOSIS IN IRIDA
•The TMPRSS6 gene is located on chromosome 22
•Encodes for a transmembrane type II serine protease that suppresses hepcidin secretion by
cleaving hemojuvilin, a surface co-receptor in BMP-6-SMAD signaling pathway.
•The gene has 18 exons and encodes an 802 amino acid protein that has 4 domains
•Mutations like missense, frameshift, splicing etc in the serine protease domain are likely to affect
the protein function most severely.
•Considering the heterogeneous nature of mutations it is imperative to screen and sequence all 18
exons
•The mutation needs to involve both alleles either as a homozygous mutation or a compound
heterozygous mutation to qualify for a confirmed diagnosis of IRIDA since it is an autosomal
recessive disorder.

20. IRIDA- DEFINITION
Anemia with variable
degree of microcytic
hypochromic indices
Low-normal to normal
serum ferritin
Very low serum iron and
transferrin saturation
(TSAT)
Inappropriately high
serum hepcidin levels
compared to degree of
anemia
Oral iron refractoriness
as per standard criteria
for evaluation of
response to oral iron
Presence of homozygous
of compound
heterozygous mutations
in TMPRSS6 gene

21. WHEN TO SUSPECT IRIDA
Onset of anemia which
is mild-moderate
degree in infancy or
early childhood
Presence of history of
anemia in other siblings
or an elder sibling being
chronically treated for
iron deficiency without
much improvement
Microcytosis and
hypochromia extreme
compared to degree of
anemia (Very low MCV
and MCH)
Absence of
organomegaly and
absence/minimally
evident stigmata of
classical iron deficiency
like hair changes, dry
skin, koilonychia and
angular cheilitis
High RBC count and low
reticulocyte count

22. ALGORITHM

24. HURDLES IN DIAGNOSING IRIDA
Despite above suspicion, there is quiet a bit of overlap with other differential causes which may
lead to oral iron refractoriness and it is advised to stringently look for and treat these acquired GI
disorders .
IRIDA is an orphan condition and sequencing for the whole TMPRSS6 gene is cumbersome and
difficult.
Detailed history on compliance with oral iron therapy since in our population it is very likely that
parents might shift to an irregular daily iron schedule or completely stop oral iron when child
complains of mild side effects.
If there is such a suspicion related to compliance or if there is evidence of side effects experienced
by the child, it is better to change formulation of iron and go in for a repeat assessment 3–4 weeks
later.

25. TREATMENT OF IRIDA
Since the hallmark of IRIDA is oral iron refractoriness, treatment using IV iron for sustained
response though in many cases the response to IV iron too is partial.
However, the current recommendations and guidelines as published by Donker et al. suggest an
initial trial of iron (FeSo4 form) along with Vitamin C for 6–8 weeks before going ahead with IV iron
treatment
Many studies in fact have noted variable degree of responses to either high dose or prolonged oral
iron therapy in IRIDA
In fact few of the cases in these studies have shown that high dose (6–10 mg/kg/day) of elemental
iron for 17 months or so resulted in acceptable hemoglobin levels, though microcytosis and low
transferrin saturation persisted.

26. FUTURE TREATMENT
Anti-hepcidin antibodies were shown to correct the anemia of chronic diseases in a
mouse model based on injections of heat-killed Brucella abortus.
One Anticalin®Pieris AG, Germany has been developed that is highly specific for hepcidin
and is proposed to antagonize hepcidin for the treatment of anemia of chronic diseases.
An interesting alternative for the sequestration of hepcidin comes from the Spiegelmer®
technology (Noxxon Pharma) with a PEGylated anti-hepcidin L-RNA oligonucleotide, now
starting in phase I/IIa clinical trials in cancer patients.
Finally, the reduction of HAMP mRNA by siRNA technology (Alnyam, USA) has also proven
pre-clinical efficacy79 and the same company also plans to apply this technology

27. TAKE HOME MESSAGE
IRIDA has overlapping hematological features with classical iron deficiency
especially presence of low indices and low serum iron and TSAT
A structured approach is necessary in case a patient otherwise appearing as iron
deficient presents with oral iron refractoriness.
This should include thorough history taking to rule out compliance issues and a
testing for celiac disease and likely H. pylori infection.
Hepcidin/TSAT ratio if high is a sensitive marker to identify cases of IRIDA
phenotype and these cases should be likely subjected to TMPRSS6 gene analysis.

28. All 18 exons and exon-intron boundaries of TMPRSS6 gene should be sequenced and to
genetically confirm a case of IRIDA homozygous or compound heterozygous mutations are
required to be present.
Treatment in confirmed cases with IRIDA should be initiated with oral iron and vitamin C
for 6–8 weeks as guidelines.
Cases not responding or very minimally responding to above regimen should be planned
for IV iron treatment.
Siblings should be screened with a complete haemogram for presence of anemia and if
present should be offered targeted mutation sequencing for a genetic diagnosis.

29. •De Falco L, Sanchez M, Silvestri L, et al. Iron refractory iron deficiency anemia. Haematologica.
2013;98(6):845-853. doi:10.3324/haematol.2012.075515
•A structured approach to iron refractory iron deficiency anemia (IRIDA) diagnosis (SAID): The
more is “SAID” about iron, the less ,Prateek Bhatia,Richa Jain,Aditya Singh- Pediatric Hematology
Oncology Journal, Elsevier, August 2017
•A review on iron-refractory iron-deficiency anemia
Thangavelu Sangeetha, Varsha T, Mariappan Vignesh, Arumugam Vijaya Anand, Basavaraju
Preethi Year : 2019 | Volume: 6 | Issue Number: 2 | Page: 57-61
•Nelson’s textbook of Peadiatrics
REFERENCES

30. THANK YOU