4th Mediterranean Multidisciplinary Course on Iron Anemia April 29th–30th 2016, Madrid, Spain

43 Pages·2016·4.13 MB·English

by  Sandro Barni

Expert Review of Hematology
ISSN: 1747-4086 (Print) 1747-4094 (Online) Journal homepage: http://www.tandfonline.com/loi/ierr20
th
4 Mediterranean Multidisciplinary Course on Iron
th th
Anemia April 29 –30 2016, Madrid, Spain
Sandro Barni
th
To cite this article: Sandro Barni (2016) 4 Mediterranean Multidisciplinary Course on Iron
th th
Anemia April 29 –30 2016, Madrid, Spain, Expert Review of Hematology, 9:sup1, 1-42, DOI:
10.1080/17474086.2016.1217153
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EXPERTREVIEWOFHEMATOLOGY,2016
VOL.9,NO.S1,1–42
http://dx.doi.org/10.1080/17474086.2016.1217153
ABSTRACT BOOK
4th Mediterranean Multidisciplinary Course on Iron Anemia April 29th–30th 2016,
Madrid, Spain
Back to the future: a new iron era thisneworalironformulationforthedenovouserorforthose
shifting from other types of iron salts.
Sandro Barni The metabolism of iron in cancer patients was well
depicted by Paolo Pedrazzoli, who described iron parameters
OncologyDepartment,MedicalOncologyUnit,ASSTBergamo Ovest,
in oncology, a condition where increased iron storage and
Treviglio,Italy
reduced iron saturation determine the so-called functional
anemia. A new frontier of iron anemia in cancer patients is
Edited by Dr Sandro Barni, Director of Oncology Department, due to the use of molecular agents, targeting specific path-
MedicalOncologyUnit,ASSTBergamoOvestTreviglio(BG).The waysandcriticalfortumorgrowth.Someofthesetargets(e.g.
presentsupplementhasbeenpreparedincollaborationwithDr. cKIT, flt-3, and mTOR) can influence erythropoiesis in cancer
GermanoTarantino,ScientificDirector,PharmanutraSpA. patients leading to frequent cases of low-moderate grades of
Anemiaisaveryfrequentsymptomassociatedwithahigh anemia during treatment. The management of such type of
number of diseases as the most frequent laboratoristic sign, anemia is controversial because erythropoiesis-stimulating
complicating them as a side effect. agents are not labeled for this indication. Fausto Petrelli has
Inonco-hematology,anemiaplaysapivotalroleinaltering presented new literature data reviewing the frequency of
the quality of life, since it is one of the principal components anemia with targeted therapy in more than 90 clinical trials.
of fatigue, andindelaying or interfering with oncologictreat- The experience with Sucrosomial® Iron in preexisting low-
ments, worsening clinical course and prognosis. grade anemia before the start of chemotherapy is surprising
Thisyear,wehavepointedoutourattentionontheuseof and intriguing. Will it be the way we will manage these cases
preemptiveirontoavoidfutiletransfusions,ontheuseofiron of anemia with new oncologic drugs? Finally, Giulio Giordano
in all internal medicine branches disease (e.g. gastroenterol- presented a randomized study comparing high dose of
ogy), and on the approach to iron supplementations in hard- Sucrosomial® Iron to IV iron in hematologic patients. Last,
to-treat forms of anemia such as anemia due to molecular butnotleast,GarciaErceexplainedhowatransfusion-sparing
agents used in oncology, and functional anemia due to protocolcouldbeimplementedinourcountriesfromatrans-
chronic disease, best depicted by cancer-related anemia. fusional service point of view. Saving blood means saving
Sucrosomial® Iron represents a relatively new but still lives, costs, and toxicity of allogeneic blood transfusions.
uniquepreparationofferricpyrophosphateconveyedthrough The magisterial lecture, held by Mercè Cladellas, has under-
a phospholipid and sucrose esters of fatty acids matrix, that lined the negative effects of anemia in cardiology and cardiac
appears useful in all that conditions associated with chronic surgery and how the cardiology field could benefit from an
inflammation or iron deficiency in, and not only, onco-hema- effectiveironsupplementationintermsofprognosis,outcome,
tology diseases. Gastroenterology and nephrology specialists, andqualityoflife.Duetotheemergingimportanceofacorrect
for example, can now benefit from this new formulation, and iron supplementation in cardiac patient, this aspect should be
onco-hematologists can safely replace older iron tablets, studiedfurtherandincludedinthenextIronAnemiaCourse.
usually associated with bothersome gastrointestinal adverse The new frontiers of treating anemia in internal medicine
events,withSucrosomial®Iron,withsimilarefficacyofIViron, deserve today an appropriate international audience, well per-
potentially associated with acute side effects and ambulatory formed in this 4th Mediterranean Multidisciplinary Course on
rooms accesses. Iron Anemia held in Madrid on 29th and 30th April 2016, of
Someexpertsininternalmedicine,hematology,andoncol- which we report official congressional acts. The 4th
ogy subspecialties have discussed important setting where Mediterranean Multidisciplinary Course on Iron Anemia repre-
Sucrosomial® Iron could be widespread used. A preclinical sented a significant opportunity to share different opinions and
model of pharmacokinetic and liver toxicity of Sucrosomial® to convey various clinical experiences, mainly about the recent
Iron was presented by Italian scientists. Celiac disease, a evidencesonSucrosomial®Ironintreatingirondeficiencyanemia.
chronic condition with reduced iron absorption, and bariatric At the end of the course, I hope, we have added some
surgery, a branch of abdominal surgery specialties, represent morepiecesofinformationtotheknowledgelearnedfromthe
new platforms where Sucrosomial® Iron could be implemen- lastAnemiaCourseheldinRomein2015.Newlessonslearned
ted. Inflammatory bowel diseases are further chronic condi- today in Madrid are still of paramount importance. We can
tions where anemia of inflammation is the rule. Guillermo now, likely, appreciate a new product, such as Sucrosomial®
Bastida showed us the role of Sucrosomial® Iron in patients Iron, for managing hard-to-treat cases of chronically ill
intolerant to other oral iron formulation. Ideally, this means patients who require a treatment for anemia and that would
that all branches of internal medicine could be the arena for mean treating their fatigue, anorexia, mood depression,
©2016InformaUKLimited,tradingasTaylor&FrancisGroup
2 ABSTRACTS
malaise, which are all signs of an impaired quality of life. We reason, the organism has developed an efficient transport
havelearnedsomenewinsightsaboutsomecausesofanemia system [2]. The first barrier iron encounters is the apical
and, in particular, we would like to thank Antonello membrane of the duodenal enterocyte that is a specialized
Pietrangelo for the magisterial lecture he offered in the audi- absorbent cell of the intestinal epithelium involved in the
torium. Finally, I hope this meeting will teach us that taking iron transport. Iron is initially solubilized through reduction
care of (preemptive) management of anemia with iron pro- of Fe3+ to Fe2+. This is then carried to the cell interior by a
ducts will reduce the chance for our patients to receive futile transport process mediated by the carrier DMT1.
transfusions, potentially dangerous for most subjects, so Subsequently, iron is transferred to the basolateral side of
expensive in terms of resource consuming, cost, and side the enterocyte, where it may either be stored via binding to
effects. ferritin or cross the membrane and reach the systemic circu-
lation. Quite hypothetically another type of Fe3+ transport
across the intestinal epithelium could involve the cellular
Funding
endocytosis of a Fe3+ carrier, e.g. nano- or microparticulate.
The 4th Mediterranean Multidisciplinary Course on Iron Anemia is sup- From here, the importance is understood of the pharmaceu-
portedbyanunrestrictededucationalgrantfromPharmanutraSpA,Italy tical formulation which should directly carry the ferric ion in
andZambonS.A.U.,SpainandPortugal. the intestine and promote its absorption. The formulation
should not release the Fe3+ before reaching the general
circulation that is the site of action. Therefore, to evaluate
Declaration of interest
the ability of the carrier to transport Fe3+ across
SBarniandGTarantinohavenorelevantaffiliationsorfinancialinvolvement the epithelium, an ex vivo model based on excised rat intes-
withanyorganizationorentitywithafinancialinterestinorfinancialconflict
tine could be more predictive. The present work compares
with the subject matter or materials discussed in the manuscript. This
the data obtained by the two models, namely that based on
includesemployment,consultancies,honoraria,stockownershiporoptions,
experttestimony,grantsorpatentsreceivedorpending,orroyalties. theCaco-2cellsmonolayerandthatbasedontheexcisedrat
intestine,tounderstandthemechanismofthepermeationof
ironandtocomparethebioavailabilityoftheinnovativeoral
ABSTRACTS
ironformulationbasedonSucrosomial®Iron(SiderAL®)with
different iron formulations.
In vitro and ex vivo models to study Sucrosomial®
Iron pharmacokinetics
Methods
Ylenia Zambito
To determine iron uptake by Caco-2 cell monolayer, a pre-
DepartmentofPharmacy,UniversityofPisa,Pisa,Italy
viously reported method was used [1]. Tested samples are
listed in Table 1.
Introduction Eachsamplecontainedadifferentquantityofiron;therefore,in
ordertomakehomogeneouscomparisonbetweenformulations,
Iron deficiency is one of the most widespread nutritional defi-
ineachexperimentanequivalentdoseof200µgofironwasused.
ciencies. Oral therapy for iron deficiency is mainly based on
TheexperimentalprotocolusedisshowninFigure1.Briefly,Caco-
immediate-release formulations of ferrous iron. To overcome
2cellswereseededatadensityof105cells/wellin12-wellplates,
gastrointestinal epithelial barriers, there is a need for new
maintained in cell culture medium and used in the iron uptake
absorption enhancers. Recent data indicate that sucrose esters
experiments at 14 days post-seeding. Immediately before the
can enhance drug permeability through both transcellular and
intestinal digestion period, the growth medium was removed
paracellularroutes.Severalinvitroandexvivosystemshavebeen
andasterilizedinsertringwasinsertedcreatingthetwo-chamber
proposed to assess iron bioavailability. In order to understand
system.A1.5-mLaliquotoftheintestinaldigestwaspipettedinto
Sucrosomial® Iron absorption mechanism, we have performed
theupperchamberandtheinsertringanddigestwereremoved.
absorption study using Caco-2 cell model and a permeation
After 24-h incubation, cells were harvested for analysis. Each
studyusingexvivomodel.
treatmentwasperformedinduplicateforeachreplicationofthe
In fact, an experimental protocol that conjugates the
experiment.Caco-2cellferritincontentwasmeasuredthroughan
simulation techniques of the gastrointestinal digestion with
enzyme-linked immunosorbent assay (ELISA) kit (USCN Life
the iron internalizing phase by the Caco-2 cells has been set Science,USA)followingthemanufacturer’sinstructions.
up [1]. Such a protocol appears very useful and predictive of
the invivobehaviorsofar,asittakesintoaccountthe phase
Table1.Samplestested.
ofFe3+dissolutioninthegastrointestineandthesubsequent
Sample Formulation Composition
permeationacrosstheepithelium.Indeed,itcannotbetaken
1 Ferroussulfate(FS) Ironsalt
for granted that the latter phase is slower than the former
2 LowphospholipidsSideral Ironpyrophosphate,lecithinlower
and hence that it is the rate-determining one. It is known R.M.prototype(SLP) phospholipidconcentration,
thatatpHvalueshigherthan3,theFe3+iontendstoformFe sucrester
3 SIDERALR.M.(SRM) Ironpyrophosphate,lecithin,sucrester
(OH) , the water solubility of which is practically null. In fact,
3 4 SucresterSideralR.M. Ironpyrophosphate,lecithin,higher
the Fe3+ bioavailability is very poor just because of its poor prototype(SRMS) sucresterconcentration
solubility at the physiologic pH of the intestine. For this 5 Sunactive®(SUN),Taiyo Ironpyrophosphate,lecithin
EXPERTREVIEWOFHEMATOLOGY 3
Figure2.Caco-2cellferritinformationasmeasured24hafterthestartofthe
intestinal digestion period. *p<0.001, as compared to FS (one-way ANOVA
followedbyDunnett’smultiplecomparisontest).
number,tothoseofthehumanjejunum.ThesampleSRMshowed
ahighereffectivenessinenhancingFe3+permeabilityacrossthe
excisedratintestinethansamplesSLP,SRMS,andSUN.
Conclusions
ThedatadescribedinthisworkshowsthatSucrosomial®Iron
Figure1.Experimentalprotocoloncellculture. formulation promotes Sucrosomial® Iron absorption across
the intestinal epithelium.
For permeation studies, the intestinal mucosa was excised
from non-fasting male Wistar rats weighing 250–300 g. Rats References
were killed and the first 20 cm of jejunum was immediately
1.Glahn RP, Lee OA, Yeung A, et al. Caco-2 cell ferritin formation
removed.Theexcisedintestinewascutintostripsof1.5cm,rinsed
predictsnonradiolabeledfoodironavailabilityinaninvitrodiges-
freeofluminalcontents,andmountedinUssing-typechambers tion/Caco-2cellculturemodel.JNutr.1998;128:1555–1561.
(0.78cm2exposedsurfacearea)withoutstrippingofftheunder- 2.Srai SK, Bomford A, McArdle HJ. Iron transport across cell mem-
lying muscle layer. One milliliter of phosphate buffer pH 6.8, branes: molecular understanding of duodenal and placental iron
uptake.BestPracResClinHaematol.2002;15:243–259.
0.13 M, made isotonic by the addition of sodium chloride (PBS
3.Shyla B,Bhaskar CV, Nagendrappa G. Iron(III) oxidized nucleophilic
6.8),wasaddedtotheapicalsideand3mLofaphosphatebuffer
coupling of catechol with o-tolidine/p-toluidine followed by 1,10-
solution pH 7.4, 0.13 M, isotonic (PB 7.4), was added to the phenanthrolineasnewandsensitivityimprovedspectrophotometric
basolateralside(acceptormedium).Inordertoensureoxygena- methodsforironpresentinchemicals,pharmaceutical,ediblegreen
tionandagitation,amixtureof95%O and5%CO wasbubbled leaves, nuts and lake water samples. Spectrochimica Acta Part A,
2 2
MolecularandBiomolecularSpectroscopy.2012;86:152–158.
through each compartment. The Ussing chambers were then
placedinawaterbathat37°C.Aftera20-minequilibrationperiod,
themediumineachapicalcompartmentwasreplacedby1mLof Sucrosomial® Iron supplementation in anemic
pre-thermostatedsampledispersion,(correspondingto200µgof patients with celiac disease not tolerating oral
iron).TheapicaltobasolateraltransportofFe3+wasinvestigated. ferrous sulfate
At 30-min intervals for a total of 240 min, 1 mL sample was
Luca Elli
withdrawn from the acceptor compartment and substituted
with an equal amount of fresh pre-thermostated medium. The Center for the Prevention and Diagnosis of Coeliac Disease,
permeated Fe3+ amount was determined by a previously GastroenterologyandEndoscopy, UnitFondazioneIRCCS Ca’
describedmethod[3]. GrandaOspedaleMaggiorePoliclinico,Milan,Italy
Celiac disease (CD) is a common autoimmune disease of the
smallbowel. Its presentation is extremely heterogenouswith
Results and discussion
a broad range of manifestations with variable severity ran-
Data on iron uptake by the Caco-2 cell monolayer are shown ging from asymptomatic individuals to severe malnourish-
in Figure 2, where it can be seen that Caco-2 cell monolayers ment or infertility [1]. The worldwide prevalence of CD is
treated with SRM were able to significantly increase ferritin difficult to estimate and ranges from 1% to 3% of the
expression about 7.4 times than those treated with ferrous general population in Europe and the USA [2–6]. CD may
sulfate (FS) (Figure 2). present at any stage of the life; clinical pictures are defined
Among various ex vivo intestinal epithelium models, the as: classical, particularly common among children, character-
excisedratjejunummodelwaschosenforthepermeabilitystu- ized by malabsorption (diarrhea, statorrhea, lack of appetite,
dies because its tight junctions are similar, in tightness and growth retardation, and deficiencies in fat soluble vitamins,
4 ABSTRACTS
iron, calcium, and folic acid) and atypical, more common wasHblevels;secondaryoutcomeswerethelevelsofsympto-
during adolescence and adulthood and presenting with matic VASs.
laboratory abnormalities, irritable bowel syndrome, osteope- Nowadays, 34 treated CD patients have been enrolled (33
nia, fertility problems, and iron deficiency anemia (IDA) [7]. females,42±9yearsofage).Intotal,18(53%)subjectsreported
Both genetic and environmental factors are involved in the previoussideeffectswithsulfateiron(allfemales,44±10yearsof
development of CD. The disease is triggered and maintained age)andthusreceivedSucrosomial®Iron(Sideral®Forte30mg);
in genetically susceptible individuals, by an immunological 16(1 male,41 ± 8yearsof age)were administeredwith sulfate
responsefollowing the ingestionofwheatglutenandsimilar irontablets(ferrograd105 mg) oncea day for90 days.Patients
alcohol soluble proteins (prolamines) [8,9]. All patients were followed after 45 and 90 days from the beginning of the
express the human leukocyte antigen (HLA) type II DQ2 supplementation.Nostatisticaldifferenceswerepresentbetween
and/or HLA-DQ8 haplotypes [12]. Gluten peptides, after thetwogroupsaboutdemographic,clinicalcharacteristics,smok-
being deamidated by the transglutaminase 2 (TG2), bind inghabits,andnumberofusedtampons.Atenrolment,Hbwas
HLA-DQ2 and HLA-DQ8. The consequent result is a destruc- 10 ± 1 g/dL, Ht 34% ± 3%, MCV 74 ± 5 fl, iron 46 ± 27 g/dL,
tive intestinal CD4+ T cell response [8]. After their activation, transferrin saturation 11% ± 7%, ferritn 12 ± 14 ng/mL. Both
the CD4+ T cells produce cytokines, which support an therapiesinducedastatisticallysignificantincreaseofHb12±1
inflammatory cascade with an intestinal inflammation. All and12.3±1inpatientsadministeredwithSucrosomial®Ironand
this mechanism results in the alteration of the intestinal sulfate iron, respectively. No variation of VAS was evidenced
mucosa, characterized by villous atrophy, crypt hyperplasia, between patients assuming sulfate of Sucrosomial® Iron. Only
and infiltration of inflammatory cells [10]. CD is currently well-beingVASsignificantlyincreased,independentlybythetype
diagnosed with IgA anti-tissue transglutaminase (tTG) serol- ofsupplementationfrom4±2to6±2.
ogy tests, followed byconfirmatory biopsiesof the duodenal Among CD patients, 12 (33%) maintained villous atrophy
bulb and second part classified by the Marsh classification in spite of strict GFD (Marsh 3a, 3b or 3c); 6 assumed sulfate
[11]. CD frequently presents IDA, which usually reverts with iron and 6 sucrosimial iron. Also, in this case, both the
a gluten-free diet (GFD). However, some patients present therapies significantly increased the Hb levels and other
persistent IDA despite their clinical responsiveness to GFD. iron status parameter. Also, the levels of Hb after treatment
The contributions of malabsorption, inflammation, or genet- did not differ between patients with or without duodenal
ics to CD-associated IDA remain unclear, although response atrophy.
to iron supplementation could be improved by the use of a In conclusion, the presented preliminary findings indicate
tolerated iron or by the use of an iron formulation increas- that Sucrosomial® Iron is effective and well tolerated in CD
ing the intestinal absorption [12]. patients with a previous failure of sulfate iron.
Experimental section Sucrosomial Iron 30mg
14
Sucrosomial® Iron (Sideral® Forte), a preparation of ferric Sulfate Iron 105mg
13
pyrophosphate conveyed within a phospholipid membrane
associated with ascorbic acid, is a new-generation oral iron 12
which shows a high gastrointestinal absorption and high
b 11
bioavailability with a low incidence of side effects due to H
lack of any direct contact with intestinal mucosa. In compar- 10
ison with the other standard oral iron preparations,
9
Sucrosomial® Iron seems to be a promising new strategy of
8
iron replacement in CD patients. The ongoing study treated
T0 T45 T90
with Sucrosomial® Iron treated CD patients with IDA and a
previous therapeuticfailure using sulfate iron tablets. It wasa Day
prospective open study. All patients were following a strict
GFD for at least 12 months with normalization of anti-trans- n 30 Sucrosomial Iron 30mg
o
glutaminase IgA. Moreover, consecutive enrolled patients ati 25 Sulfate Iron 105mg
were previously investigated by means of duodenal histology ur
at 20
to look for possible correlations with atrophy degrees (Marsh s
n
scale). Clinical and demographic data were recorded, and ri 15
r
e
symptomatic response to iron tablets was evaluated through sf 10
n
10-cm long visual analog scales (VASs). Evaluated symptoms a
r
were: diarrhoea, constipation, epigastric, and abdominal pain, T 5
stoolconsistencysatisfaction.AspecificVASevaluatedgeneral
0
well-being. Other causes of IDA were investigated when clini- T0 T45 T90
cally indicated. Associated vitamin or folic acid deficiencies Day
were looked for and excluded. Primary outcome of the study
EXPERTREVIEWOFHEMATOLOGY 5
References of childbearing age, require oral iron supplementation after
the bariatric surgery.
1.BaiJC,FriedM,CorazzaGR,etal.Worldgastroenterologyorganisa-
Additionally, a non-negligible percentage of women, who
tion global guidelines on celiac disease. J Clin Gastroenterol.
2013;47:121–126. previouslyunderwentbariatricsurgery,requireparenteraliron
2.CatassiC,FabianiE,RatschIM,etal.ThecoeliaciceberginItaly.A therapysupplementationuntiltheestablishmentofthemeno-
multicentreantigliadinantibodies screeningforcoeliacdisease in pause.Thisfactisdueinparttolowerpre-surgeryirondepos-
school-agesubjects.ActaPaediatr.1996;412:29–35. itsinobesepatients,aphenomenonwhichalsotranslatesinto
3.CatassiC,KryszakD,BhattiB,etal.Naturalhistoryofceliacdisease
agreatvariabilityinthetimeofoccurrenceofthedeficit(from
autoimmunity in a USA cohort followed since 1974. Ann Med.
2010;42:530–538. months to years). Also, most of the obese women who
4.Catassi C, Ratsch IM, Fabiani E, et al. Coeliac disease in the year undergo bariatric surgery restore the menstrual period in
2000:exploringtheiceberg.Lancet.1994;343:200–203. almost 40% of the cases after a 4,6% weight loss. In many
5.FarrellRJ,KellyCP.Celiacsprue.NEnglJMed.2002;346:180–188. cases, despite taking high oral doses of conventional iron
6.Ferguson A. Coeliac disease research and clinical practice: main-
supplementation, often causing gastrointestinal intolerance,
taining momentum into the twenty-first century. Bailliere’s Clin
Gastroenterol.1995;9:395–412. they fail to achieve optimal levels, requiring therefore chronic
7.Ludvigsson JF, Leffler DA, Bai JC, et al. The oslo definitions for parenteral therapy.
coeliacdiseaseandrelatedterms.Gut.2013;62:43–52. In our series of patients (1100 patients who underwent
8.Schuppan D. Current concepts of celiac disease pathogenesis. bariatric surgery since the year 2000 until today), about 120
Gastroenterology.2000;119:234–242.
womenofchildbearingage,requireparenteraltreatmentwith
9.Schuppan D, Junker Y, Barisani D. Celiac disease: from pathogen-
esistonoveltherapies.Gastroenterology.2009;137:1912–1933. intravenous iron every 3 months, chronically, until the meno-
10.MarshMN.Thesmallintestine:mechanismsoflocalimmunityand pause is installed. The administration of intravenous iron, in
glutensensitivity.ClinSci.1981;61:497–503. thedayhospital,takesbetween2and3hours,for2consecu-
11.Rubio-Tapia A, Hill ID, Kelly CP, et al., American College of tive days, every 3 months, which represents an important
Gastroenterology. Acg clinical guidelines: diagnosis and manage-
distortion of work and daily life of the patients.
mentofceliacdisease.AmJGastroenterol.2013;108:656–676;quiz
Sucrosomial® oral Iron may represent a treatment alterna-
677.
12.Zamani F, Mohamadnejad M, Shakeri R, et al. Gluten sensitive tive in these cases. Due to its new technology, based on the
enteropathy in patients with iron deficiency anemia of unknown contactofsucrosomewithintestinalcellmembrane,the‘usual
origin.WorldJGastroenterol.2008;14:7381–7385. mechanisms’ of intestinal absorption of the iron are not so
important (such as gastric acid secretion, duodenum).
Therefore, the bioavailability of Sucrosomial® Iron rises to 3.5
ResponsetoSucrosomial®oralIronsupplementation
timescomparedwiththeconventionaliron.Sucrosomial®Iron
in patients underwent bariatric surgery
also has been proven to be effective and well tolerated,
Andreea Ciudin comparedwithoralsupplementsofconventionalironinpreg-
nancy,newborn,infant,chronickidneydisease,andinflamma-
EndocrinologyandNutritionDepartment,Valld´HebronUniversity
Hospital,Barcelona,Spain toryboweldisease.Thisformoforalironhasdemonstratedits
effectiveness even against conventional iron in patients with
intravenous therapy.
Introduction
To our knowledge, to date, there is no study using
In the postoperative period, all the techniques of bariatric Sucrosomial® oral Iron in patients undergoing bariatric sur-
surgeryinduceasignificantreductionintheintakeorabsorp- gery. In order to shed light on this issue, we have designed a
tion of most of the nutrients. Therefore, bariatric surgery can single-center, open, prospective, interventional trial, including
be associated with a risk of nutritional deficiency, which 40 women of childbearing age, who previously underwent
increases over the years. One of the nutrients whose absorp- RYGB, and currently require chronic intravenous iron therapy.
tion is affected in a significant way is iron, and the women of The subjects were divided into two parallel groups: 20 cases
childbearing age are the most vulnerable. The daily recom- and20controlsmatchedbyage,previouslevelofhemoglobin
mendation of iron intake in adults is 8 mg a day for men and (Hb),yearsaftersurgery,andpercentageofweightlost.The20
womenmorethan50years,and18mgperdayforwomenof cases were discontinued from the parenteral iron treatment
age less than 50 years. The incidence of iron deficiency and and were treated with oral Sucrosomial® Iron 28mg/day for
anemiaafterbariatricsurgeryisvariableaccordingtothetype three months. The 20 controls continued with 300mg iron
ofsurgeryandthetimeafterthesurgery.Forinstance,aftera sucrose endovenously every 3 months. Total hemoglobin
Roux-en-Y gastric bypass (RYGB), iron deficiency anemia is (Hb),ferritin, andtransferrin saturationindex(TSI)were deter-
diagnosed between 10% and 40% of all the cases. Bariatric minedbeforeandafter3monthsoftreatmentinbothgroups,
surgerytechniquesproducechangesofthedigestivetractand as well as tolerability.
dietary habits that favor the iron deficiency. These changes
are: (a) intolerance to red meat, leading to a decrease in the
intake;(b)decreasedgastricacidsecretionbyresectionofthe
Results
proximal stomach, with the consequent relative deficit of
parietal cells and iron absorption deficiency; (c) exclusion of NosignificantdifferenceswereseenbetweenthelevelsofHb
theduodenum,whichisthemainplaceofmolecularironand (12.67 ± 1.06 g/dL vs 12.267 ± 1,35 g/dL, p = 0.081), ferritin
hemeironabsorption.Mostofthepatients,especiallywomen (101.67 ng/dL vs. 88.89 nd/dL, p = 0.069), and TSI (24.11% vs.
6 ABSTRACTS
26.28%, p = 0.55) before and after the 3 months of treatment the patients is mixed, with an iron deficiency through contin-
with Sucrosomial® Iron. We did not find any adverse effect uousgastrointestinallossesassociatedtotheanemiaofchronic
during this period in the treatment group. Compared to the illnesses[6].Inaddition,wemustnotforgetthatthereareother
control group, the final Hb levels were similar (Hb 12.267 ± causes of anemia such as the deficiency of vitamin B12 or of
1.35 g/dL and 12.1 ± 1.74 g/dL, respectively, p = 0.09). folic acid, malnutrition, the malabsorption or the ingesting of
several medications (e.g. salazopyrine or thiopurines). The
importance of anemia, even in non-anemic iron deficiency,
Conclusion residesintheseriousdisruptionofqualityoflifethatitimplies.
Actually, the presence of anemia can condition a disruption of
Our study suggests that oral Sucrosomial® Iron might repre-
quality oflifesimilar tothat ofadvancedcancerpatients [2].
sentan alternative therapyinpatients whorequire parenteral
This is a very important aspect, since not long ago the
treatment with iron after bariatric surgery.
presence of anemia was only considered a marker of the
Final remark: Sucrosomial® Iron might be an alternative
activity of IBD, on occasion going unnoticed, in such a way
treatmentinpatientswithsevereirondeficiencyafterbariatric
that it was assumed that a certain anemia represented a
surgery, which currently requires parenteral iron therapy due
normal discoveryinIBDpatients and, assuch,did notrequire
to intolerance to existing oral products or therapeutic failure.
treatment. Now, it is well known that iron deficiency anemia
Atthesametime,itmighthelptoreducehealthcarecostsand
shouldbetreatedwithironassoonasitisdetected.Likewise,
improve the quality of life of these patients.
the therapeutic objective of the treatment should be to com-
pletely cure the anemia and the iron deficiency, and not only
to partially raise the hemoglobin or ferritin numbers.
Efficacy and tolerability of Sucrosomial® Iron
The treatment of the anemia should be started once the
supplementationinIBD patientswith irondeficiency
cause in known. In the case of treating an iron deficiency
anemia and intolerance to iron oral salts
anemia, iron should be administered at the same time as the
Guillermo Bastida Paz medication to control the inflammation.
UnidaddeEnfermedadInflamatoriaIntestinal,HospitalUniversitario Intravenous iron is very quick and efficient both for curing
ypolitécnicoLaFe,Valencia,Spain anemia and for maintaining the iron deposits in IBD patients
[6]. Because of its cost, and because of the need for it to be
Anemia is the most frequent systemic complication in inflam- administered in a hospital, current guidelines [1] recommend
matory bowel disease (IBD) [1–2], most of all in patients with the administration of intravenous formulas for those patients
Crohn’s disease (CD) [3]. Its prevalence is quite variable in the in which hemoglobin numbers are lower than 10 g/dL, in
different studies, according to its evaluation criteria and the thosewhotolerateironorallyorinthosewhorequireerythro-
types of patients included [4,5]. A systematic review of the poiesis-stimulating agents [1]. The majority of the patients is
literature describes prevalence of anemia in IBD of 16% in going to have mild anemia and will be treated with oral iron
outpatients with IBD and of up to 70% in inpatients. If we [7].Oralironisanefficient,simple,cheap,andsafetreatment.
take into account that the main cause of anemia is IBD itself, Theefficiencyoforalironvariesbetweendifferentstudies.For
we understandthatthecauseofthe anemiainthe majorityof example,inastudycarriedoutinSpain,oralironmanagedto
EXPERTREVIEWOFHEMATOLOGY 7
normalizehemoglobinnumbersinmorethan85%ofpatients. allwithpriorpoortolerationoforaliron.Ofthem,22(64.1%)
In this study, oral iron was well tolerated, without assessing of the patients showed CD, 16 (73%) in remission at the
theactivityofIBDandwithjust5%withdrawalthroughintol- beginningofthestudy.Intotal,17(35.9%)showedulcerative
erance.Thepatientsthatdidnottolerateordidnotcuretheir colitis(UC),8(67%)wereinremission.Theaverageageofthe
anemiawithoralironreceivedintravenousironwithexcellent patients was 42 years, the lower and upper limits were 21
results [7]. and 62 years.
However, these excellent results were not reproduced in In total, 79.5% of the patients showed symptoms of iron
all studies and undoubtedly oral iron presents clear and deficiency anemia. Asthenia was the most frequent symptom
significant limitations [8]. One of its greatest limitations among the patients, present in all patients, followed by diffi-
resides in the fact that a considerable percentage of IBD culty in concentrating and irritability in 48.4% and 45.2%,
patients show poor tolerance to treatment with oral iron. In respectively.
fact, on many occasions it can cause diarrhea, constipation, ThepatientsweretreatedwithadailydoseofSucrosomial®
or abdominal pain, on the one hand hindering the perfor- Iron over 3 months. The majority of the patients (90.5%) per-
mance (and with this real efficiency) and on the other it formed well. The tolerability of Sucrosomial® Iron, the primary
can mislead us with an outbreak. In fact, a systematic objectiveofthestudyinthispopulationofpatientsintolerantto
review describes that the appearance of secondary effects otheroralironformulaswasgood.Duringthestudy,thegeneral
lead to the suspension of oral iron in up to 21% of patients well-beingofthepatientwasrecorded.Almostallpatients,100%
with CD [4]. This percentage can reach a significant magni- and92%,hadagoodorslightlylowerthannormalopinionofthe
tude, for example, Lugg et al. describe the failure of oral 4and12weeks,respectively.Additionally,thepercentageofthe
iron in controlling anemia in two out of every three indivi- patients with gastrointestinal symptoms after taking the
duals with IBD, due in part to the secondary effects, which Sucrosomial®Ironat4and12weeks(abdominalpain,constipa-
appear in more than half of its patients [9]. These second- tion, loss of appetite, nausea, vomiting, change of color to the
ary effects could be related to experimental data and sug- feces,orthepresenceofametallictaste)didnotincreaseover
gest that the iron that is not absorbed could be toxic to themonitoring.
intestinal mucous and even precipitate outbreaks of Althoughthepercentageoftheadverseeffectsgatheredwas
IBD [10]. high (31 patients of 38 showed a total of 125 adverse occur-
Forallofthesereasons,weunderstandthataneworaliron rencesoverthecourseofthestudy),two-thirdsofthem,66.4%,
formula,withbettertolerability,wouldbeofgreatinterestdueto were of low intensity and only 6.4% were serious. The most
thehigherfrequencyofanemiaandirondeficiency ofpatients frequent secondaryeffectswerea changein colorofthe feces
withIDBaswellastheadverseeffectsassociatedtoclassiciron (63.2%),abdominalpain (44.7%),diarrhea(34.2%),constipation
formulas with ferrous salts (ferrous sulfate, ferrous gluconate, (23.7%), and a metallic taste (21%), although only 42.7% were
ferrous fumarate, and ferrous lactate). In this regard, a recent foundtorelatetothecase.Infact,in93.6%oftheoccurrences,
formula,Sucrosomial®Iron,couldhavesomeadvantages.Thisis there was no change with regard to taking Sucrosomial® Iron,
aSucrosomial®ferrouspyrophosphate,whichcontains30mgof 0.8%temporarilyinterruptedand5.6%permanently.
ironthatiscoveredinsucrosoma.Thesucrosomaisformedbya In relation to the efficiency, one-third of the patients nor-
liposome,asphericalstructureofaphospholipidicnaturesimilar malized the iron-deficient anemia data in 12 weeks.
to those cell membranes of the human body, which are Hemoglobin values increased at 12 weeks from the average
immersedinamatrixofsucroseestersoffattyacidsthatallow of11.1g/dLto11.8g/dL(p=0.0023)andthoseofferritinfrom
it to cross the gastric acid barrier, reaching the small intestine 11.47 mcg/L to 13.1 mcg/L (Figure 1).
unscathedandavoidingthepro-oxidanteffectofotherironsalts. The recovery of the data on iron deficiency was accompa-
Once there, the sucrosoma and the iron that it contains are nied by an improvement in the questionnaires on quality of
integrally absorbed through the intestinal M cells, without the life. The average rating in the questionnaire on quality of life
needforspecifictransporters[11].TheMcells,duetotheirlow ofIBD(CCVVEII-9)improvedfrom61.2pointsto66.8pointson
lysozymecontent,cantransportantigenswithalmostnoenzy- the final visit. The generic questionnaire on the quality of life,
maticdegradationandallowtheirliberationwithoutmodifying theEuroQoL,improvedinalldimensions(mobility,dailyactiv-
the lymphatic system. This differential absorption of the ities, pain/discomfort, and anxiety/depression) except in per-
Sucrosomial® Iron gives it greater availability. Therefore, the sonal care (Figure 2).
protectionofthesucrosomaavoidstheappearanceoftheclassic Therefore, Sucrosomial® Iron is well tolerated in patients
secondaryeffectsofthetreatmentwithotherironsaltsallowing with IBD with prior intolerance to oral iron, and should be
the microelement to overcome unscathed the gastric environ- considered as an alternative for the treatment of iron defi-
ment to be directly absorbed into the intestine and directly ciency anemia in those patients who do not tolerate classic
liberatedintotheliver[12]. prepared doses of oral iron.
Anobservationalandmulticentricstudyiscurrentlybeing
carried out to evaluate the tolerability of oral Sucrosomial®
Iron (dietary supplement Fisiogen Ferro Forte®) in the colli-
References
sion of the iron deficit in patients with IBD previously intol-
eranttothesaltsnormallyusedinoraliron.Theintermediate 1.Dignass AU, Gasche C, Bettenworth D, et al.; European Crohn’s
analysis has been made with the data gathered until and Colitis Organisation [ECCO]. European consensus on
September 2015. At this time, there were 39 valid patients, the diagnosis and management of iron deficiency and anemia
8 ABSTRACTS
Figure1.Increaseinhemoglobin,ferritin,andISAT(%)levels
SCOncologia,FondazioneIRCCSPoliclinicoS.Matteo,Pavia,Italy
Anemia is common in cancer patients, and is associated with
significant decrease in quality of life (QOL) and a negative
impact on prognosis. The etiology of cancer-related anemia
is multifactorial, but in most cases it is a consequence of the
chronic disease process associated with malignancy.
Alleviating anemia with erythropoiesis-stimulating agents
(ESAs) improves energy, activity, and overall QOL, particularly
among patients with mild-to-moderate anemia, and facilitate
patientcopingwithactivetreatments.However,researchsug-
gests that anemia is still under-recognized and undertreated.
Figure2.Assessmentofthequalityoflifebeforeandafterthetreatment This may be partly due to the limitations of current ESA
therapy, which includes a large percentage of patients who
in inflammatory bowel diseases. J Crohns Colitis. 2015;9:211– do not respond to this treatment, the need for frequent dos-
222. ing,andtherelativelyslowtimetoresponse.Adequatepatient
2.GascheC.AnemiainIBD:theoverlookedvillain.InflammBowelDis. selection for treatment with ESA or other drugs/procedure is
2000;6:142–150.
of pivotal importance in this setting.
3.Bergamaschi G, di Sabatino SA, Albertini A, et al. Prevalence and
Dysregulations of iron metabolism causing iron deficiency
pathogeneisofanemiaininflammatoryboweldisease.Influenceof
anti-tumor necrosis factor-alpha treatment. Haematologica. represent a major cause of anemia of chronic diseases (ACDs).
2010;95:199–205. Also, data from the dialysis and cancer populations has clearly
4.Kulnigg S, Gasche C. Systematic review: managing anemia in shownthatanimportantfactorwhichseriouslylimitsresponse
Crohn’sdisease.AlimentPharmacolTher.2006;24:1507–1523.
toESAisfunctionalirondeficiency(FID),whichisanimbalance
5.Gomollón F, Gisbert JP. Current management of iron deficiency
betweenironneedsintheerythropoieticmarrowandironsup-
anemia in inflammatory bowel diseases: a practical guide. Drugs.
2013;73:1761–1770. ply.FIDmaybeeitherpreexistingoroccurringduringESAther-
6.Rizvi S, Schoen RE. Supplementation with oral vs. intravenous apy,when red cells are producedata ratethatoutstripslabile
iron for anemia with IBD or gastrointestinal bleeding: is oral iron availability. As a consequence, iron supplementation may
iron getting a bad rap? Am J Gastroenterol. 2011;106:
stillbe requiredtoachieveormaintainanoptimalresponseto
1872–1879.
ESA.Inanemiccancerpatients,irondeficiencyhastobeinves-
7.Gisbert JP, Bermejo F, Pajares R, et al. Oral and intravenous iron
treatmentininflammatoryboweldisease:haematologicalresponse tigated by dosing transferrin saturation, a parameter that is
andqualityoflifeimprovement.InflammBowelDis.2009;15:1485– modestly influenced by inflammation. Ferritin, in contrast,
1491. belongs to the group of acute-phase proteins and often does
8.BermejoF,GarcíaS.Irondeficiencyanemiaininflammatorybowel
notreflectironstoresincancer,duetoitsinterdependencewith
disease.EnfermInflamIntestDia.2015;14:11–20.
inflammatoryreactions.Theironregulatorypeptide,hepcidin,is
9.LuggS,BealF,NightingaleP,etal.Irontreatmentandinflamma-
toryboweldisease:whathappensinrealpractice?JCrohnsColitis. thekeyfactorunderliningtheoccurrenceofirondysregulationin
2014;8:876–880. the ACDs, including cancer. Hepcidin is upregulated in ACD,
10.CarrierJ,AghdassiE,PlattI,etal.Effectoforalironsupplementa- resulting in the inhibition of iron transport across cell mem-
tion on oxidative stress and colonic inflammation in rats with
branes, which decreases the accessibility of storage iron and
inducedcolitis.AlimentPharmacolTher.2001;15:1989–1999.
gastrointestinal absorption of dietary iron, leading to an
11.HarokopakisE,HajishengallisG,MichalekSM.Effectivenessoflipo-
somespossessingsurface-linkedrecombinantBsubunitofcholera increased frequency of iron-restricted erythropoiesis, especially
toxin as an oral antigen delivery system. Infect Immun. duringtherapywithESA.Hepcidindisregulationmaywellrepre-
1998;66:4299–4304. sent the mechanism by which oral iron supplementation has
12.Torchilin VP. Lipid-core micelles for targeted drug delivery. Curr
beenreportedineffectiveincancerpatients.
DrugDeliv.2005;2:319–327.
Prospective trials published over the last decade demon-
stratethatanemicpatientswithcancerundergoingchemother-
Iron parameters in cancer patients and prediction of apy and receiving ESA respond better, without additional
hemoglobin response toxicity, when parenteral iron is administered. Such benefit is
more relevant when FID is present at baseline but appears to
Paolo Pedrazzoli, Simona Secondino, Sara Delfanti,
be independent of baseline iron variables in one large study.
Giovanni Rosti
EXPERTREVIEWOFHEMATOLOGY 9
Thisissueisclinicallyrelevantbecauseappropriateironsupple- Introduction
mentation, apart from allowing more patients to benefit from
Anemia is a common manifestation of cancer patients and is
ESA therapy, may represent a strategy to improve the cost
usually associated with advanced disease, malnutrition, and
effectivenessofESAinoncology,asithasoccurredinnephrol-
poor prognosis. It is one of the reasons for fatigue, delay/
ogy. However, the use of iron supplementation during treat-
reduction and change in dose intensity of cancer treatments,
ment with ESA is not rigorously pursued in anemic patients
poor activity of radiation therapy due to reduced oxygen
withcancerasithasinchronickidneydisease.Thisunderuseis
effect, increase use of blood transfusions, and finally of rise
likely to be related to: (i) the false perception that cancer
of financial burden in oncology setting. Rapid correction of
patients do not have decreased iron stores (as measured by
hemoglobin (Hb) levels is necessary for patients’ well-beings,
serum ferritin) and therefore thought not to require iron sup-
and needs iron plus or minus erythropoiesis-stimulating
plementation during ESA therapy, (ii) the often misinterpreted
agents (ESAs) and eventually, if they do not permit to correct
incidenceandclinicalnatureofseriousadverseeventsofintra-
Hb, red blood cells (RBCs) transfusions. Usually, ESAs asso-
venous iron, (iii) the lack of studies demonstrating the efficacy
ciated with parenteral iron are appropriate to treat moderate
oftraditionaloraliron agentstofavor response toESA.
(grade(G2))anemia,converselymoresevereandsymptomatic
Novel iron preparations capable of increasing iron absorp-
grade of anemia (G3–4) needs prompt transfusions. ESAs sig-
tionandbioavailability,includingthosecarriedbyaphospho-
nificantlyreducedtheuseofRBCtransfusions(relativerisk(RR)
lipid plus sucrester membrane, may well facilitate a more
0.65,95%CI0.62to0.68)accordingtoa2012Cochranemeta-
widespread use of iron supplementation in cancer anemia. A
analysis [1]. Nowadays, in chemotherapy-related form of ane-
randomized study is currently ongoing aimed to define the
mia, parenteral iron has showed a better and rapid response
potential benefit of Sucrosomial® Iron in improving response
of ESAs agents according to a meta-analysis of randomized
to ESA in anemic cancer patients.
trials[2].IronshouldbegivenduringESAtherapy,ifnecessary,
in order to maintain a transferrin saturation of ≥20% and a
serumferritinlevelof≥100ng/mL.Thereasonoffailureoforal
References iron formulation in cancer anemic patients seems related to
the hepcidin protein, an acute-phase protein produced pri-
1.CellaD,DobrezD,GlaspyJ.Controlofcancer-relatedanemiawith
marilybytheliver.Severalobservationsuggeststhathepcidin,
erythropoieticagents:areviewofevidenceforimprovedqualityof
lifeandclinicaloutcomes.AnnOncol.2003;14:511–519. andperhapsotherregulatorymoleculesproducedintheliver
2.Cella D, Stone AA. Health-related quality of life measurement in [3–5], plays a major role as a negative regulator of intestinal
oncology: advances and opportunities. Am Psychol. 2015;70:175– iron absorption and iron release from macrophages [6–7], by
185. interacting with, and inactivating, the iron export protein
3.SankaranVG,WeissMJ.Anemia:progressinmolecularmechanisms
ferroportin[8].Molecular-targeted agentsas monoclonalanti-
andtherapies.NatMed.2015;21:221–230.
bodies (e.g. anti-HER2, epidermal growth factor receptor
4.TessitoreN,SoleroGP,LippiG,etal.Theroleofironstatusmarkers
inpredictingresponsetointravenousironinhemodialysispatients (EGFR), or vascular endothelial growth factor (VEGF) agents)
on maintenance erythropoietin. Nephrol Dial Transplant. orsmallmolecules(multi-target)tyrosinekinaseinhibitors(e.g.
2001;16:1416–1423. sunitinib or sorafenib) are able to interfere with specific path-
5.PedrazzoliP,FarrisA,DelPreteS,etal.Randomizedtrialofintra-
way leading to a reduced/altered erythropoiesis as reflected
venous iron supplementation in patients with chemotherapy-
byhighrateofG1-2anemiainclinicaltrials.However,theuse
related anemia without iron deficiency treated with darbepoetin
alfa.JClinOncol.2008;25:1619–1625. ofEPOwithnewmolecularagentsisnotcurrentlylabeled,and
6.LudwigH,MüldürE,EndlerG,etal.Prevalenceofirondeficiency itssafetywithanti-angiogenetictherapiesisdebatable,dueto
acrossdifferenttumorsanditsassociationwithpoorperformance apossiblegrowthstimulationofEPOmediatedbyEPOrecep-
status,diseasestatusandanemia.AnnOncol.2013;24:1886–1892.
tors (EPO-R). In this setting, not functional EPO-R but EphB4
7.Auerbach M. Intravenous iron in chemotherapy-induced anemia.
protein, working as an EPO-R promoting tumor growth and
AmJHematol2014;89:1153.
8.Petrelli F, Borgonovo K, Cabiddu M, et al. Addition of iron to progression via Stat3 signaling, was recently discovered by
erythropoiesis-stimulatingagentsincancerpatients:ameta-analy- Pradeep and colleagues (Figure 1). In particular, abundance
sisofrandomizedtrials.JCancerResClinOncol.2012;138:179–187. ofEphB4receptoronhumanbreastandovariancancertissues
9.PedrazzoliP,RostiG,SecondinoS,etal.Ironsupplementationand
predicted poor survival, in particular, when EPO was asso-
erythropoiesis-stimulatory agents in the treatment of cancer ane-
mia.Cancer.2009;115:1169–1173. ciated [9,10]. As for now, data with EPO in patients treated
10.YuanL,GengL,GeL,etal.Effectofironliposomesonanemiaof with targeted agents for solid tumors were ever being con-
inflammation.IntJPharm.2013;454:82–89. ducted,andthetreatmentoftheseemergentformsofanemia
is unknown.
Anemia with molecular-targeted therapies used for
solid tumors: an updated pooled analysis of Etiology and frequency of anemia with molecular
literatureandnewperspectiveswithsucrosomaliron agents
Fausto Petrelli and Sandro Barni Thecausativeroleofanemiawithmolecularagentsispartially
unknown, but the general opinion is that they can interfere
OncologyUnit,ASSTBergamoOvest,Treviglio,Italy
with myelo- and erythropoiesis in bone marrow. If other