PROTEIN INTOLERANCE Many food proteins can act as antigens in humans. Cow s mi!" proteins are most fre#uent!

y imp!icated as a cause of food into!erance during infancy. $oy%ean protein ran"s second as an antigen in the first months of !ife& particu!ar!y in infants with primary cow s mi!" into!erance who are p!aced on a soy formu!a. 'rom schoo! age on& egg protein into!erance %ecomes more pre(a!ent.

Pathophysiology
The ma)or food a!!ergens are water*so!u%!e g!ycoproteins +mo!ecu!ar weight ,M-.& /0&000*10&0002 that are resistant to heat& acid& and en3ymes. Cow s mi!" contains more than 40 protein fractions. In the curd& 5 caseins +ie& $/& $4& $6& $52 can %e identified that account for a%out 708 of the mi!" proteins. The remaining 408 of the proteins& essentia!!y g!o%u!ar proteins +eg& !acta!%umin& !actog!o%u!in& %o(ine serum a!%umin2& are contained in the whey. Casein is often considered poor!y immunogenic %ecause of its f!e9i%!e& noncompact structure. :istorica!!y& !actog!o%u!in has %een accepted as the ma)or a!!ergen in cow s mi!" protein into!erance. :owe(er& po!ysensiti3ation to se(era! proteins is o%ser(ed in a%out ;<8 of patients with a!!ergy to cow s mi!" protein. The proteins most fre#uent!y and most intensi(e!y recogni3ed %y specific IgE are the !actog!o%u!in and the casein fraction. :owe(er& a!! mi!" proteins appear to %e potentia! a!!ergens& e(en those that are present in mi!" in trace amounts +eg& serum %o(ine a!%umin& immunog!o%u!ins& !actoferrin2. In each a!!ergen& numerous epitopes can %e recogni3ed %y specific IgE presence. Cow s mi!" proteins introduced with materna! diet can %e transferred to the human mi!". Many studies ha(e focused on the presence of %o(ine !actog!o%u!in throughout human !actation. The =I tract is permea%!e to intact antigens. The antigen upta"e is an endocytotic process that in(o!(es intrace!!u!ar !ysosomes. $tudies ha(e demonstrated that food a!!ergens are transported in !arge #uantities across the epithe!ium %y %inding to ce!! surface IgE>C?46& which opens a gate for intact dietary a!!ergens to transcytose across the epithe!ia! ce!!s that protect the antigenic protein from !ysosoma! degradation in enterocytes.,/. $ome antigens can mo(e through interce!!u!ar gaps@,4. howe(er& the penetration of antigens through the mucosa! %arrier is not usua!!y associated with c!inica! symptoms. Ander norma! circumstances& food antigen e9posure (ia the =I tract resu!ts in a !oca! immunog!o%u!in A +IgA2 response and in an acti(ation of suppressor C?7B !ymphocytes that reside in the gut*associated !ymphoid tissue +ora! to!erance2. In some chi!dren who are genetica!!y suscepti%!e& or for other as*of*yet*un"nown reasons& ora! to!erance does not de(e!op& and different immuno!ogic and inf!ammatory mechanisms can %e e!icited. -hether nonimmuno!ogic mechanisms can ha(e a ro!e in the de(e!opment of specific into!erances to food proteins is sti!! disputed. $ome e(idence suggests that reduced micro%ia! e9posure during infancy and ear!y chi!dhood resu!t in a s!ower postnata! maturation of the immune system through a reduction of the num%er of T regu!atory +Treg2 ce!!s and a possi%!e de!ay in the progression to an optima! %a!ance %etween T:/ and T:4 immunity& which is crucia! to the c!inica! e9pression of a!!ergy and asthma +hygiene hypothesis2.,6. =enetic (ariations in receptors for %acteria! products are !i"e!y to %e re!ated to a!!ergic sensiti3ations. On the other hand& intestina! infections may increase parace!!u!ar permea%i!ity& a!!owing the a%sorption of food proteins without epithe!ia! processing. As a conse#uence& infectious e9posures can %e an important contri%utory factor in the pathogenesis of food protein a!!ergies. Antigen upta"e has %een found to %e increased in chi!dren with gastroenteritis and with cow s mi!" a!!ergy. 'ood protein into!erance can %e IgE*mediated or non*IgE*mediated. Loca! production and systemic distri%ution of specific reaginic IgE p!ays a significant ro!e in IgE*mediated reactions to food proteins. Morpho!ogic studies ha(e demonstrated the ro!e of =I T !ymphocytes +ie& intraepithe!ia! !ymphocytes2 in the pathogenesis of =I food a!!ergy. The pathogenetic ro!e of the eosinophi!s in food*induced eosinophi!ic =I diseases has not %een defined. Cast e(idence descri%es the occurrence of immunog!o%u!in = +Ig=2 food protein anti%odies. :owe(er& their actua! ro!e in the pathogenesis of c!inica!!y re!e(ant symptoms is& at %est& dou%tfu!.

Cow s mi!" contains more than 40 protein fractions. In the curd& 5 caseins +ie& $/& $4& $6& $52 can %e identified that account for a%out 708 of the mi!" proteins. The remaining 408 of the proteins& essentia!!y g!o%u!ar proteins +eg& !acta!%umin& !actog!o%u!in& %o(ine serum a!%umin2& are contained in the whey. Casein is often considered poor!y immunogenic %ecause of its f!e9i%!e& noncompact structure. :istorica!!y& !actog!o%u!in has %een accepted as the ma)or a!!ergen in cow s mi!" protein into!erance. :owe(er& po!ysensiti3ation to se(era! proteins is o%ser(ed in a%out ;<8 of patients with a!!ergy to cow s mi!" protein. The proteins most fre#uent!y and most intensi(e!y recogni3ed %y specific IgE are the !actog!o%u!in and the casein fraction. :owe(er& a!! mi!" proteins appear to %e potentia! a!!ergens& e(en those that are present in mi!" in trace amounts +eg& serum %o(ine a!%umin& immunog!o%u!ins& !actoferrin2. In each a!!ergen& numerous epitopes can %e recogni3ed %y specific IgE presence. Cow s mi!" proteins introduced with materna! diet can %e transferred to the human mi!". Many studies ha(e focused on the presence of %o(ine !actog!o%u!in throughout human !actation. The ta%!e %e!ow reports a c!assification of different c!inica! presentations of food into!erance in chi!dren& %ased on their presumpti(e under!ying pathophysio!ogica! mechanisms. Ta%!e. C!assification of Main Ad(erse Reactions to 'ood +Open Ta%!e in a new window2 Type of Reaction Pathogenesis NonDimmune* ?isorders of digesti(e*a%sorpti(e mediated processes Clinical Entities =!ucose*ga!actose ma!a%sorption& !actase deficiency& sucrase*isoma!tase deficiency& entero"inase deficiency Pharmaco!ogica! reactions Tyramine in aged cheeses& histamine +eg& in straw%erries& caffeine2 Idiosyncratic reactions 'ood additi(es& food co!orants In%orn errors of meta%o!ism Pheny!"etonuria& hereditary fructose into!erance& tyrosinemia& ga!actosemia& !ysinuric protein into!erance IgE*mediated +positi(e Ora! a!!ergy syndrome& immediate =I radioa!!ergosor%ent test or s"in pric" test hypersensiti(ity resu!ts2 Occasiona!!y IgE*mediated Eosinophi!ic esophagitis& eosinophi!ic gastritis& eosinophi!ic gastroenteritis NonDIgE*mediated 'ood proteinDinduced entities& such as enteroco!itis& enteropathy& proctoco!itis& chronic constipation Innate and adapti(e immunity Ce!iac disease

Immune*mediated +food a!!ergy2

Autoimmune

Physical
Asua!!y& the =I manifestations are iso!ated& without any sign of atopic dermatitis& urticaria& rhinitis& con)uncti(itis& or whee3ing.

In proctoco!itis syndrome& the chi!d +usua!!y a young infant2 appears hea!thy& without any weight !oss or other physica! pro%!ems. In food*induced =I anaphy!a9is& these symptoms +eg& atopic dermatitis& urticaria& rhinitis& con)uncti(itis& whee3ing2 can occur& and& therefore& the chi!d must %e chec"ed for the presence of systemic signs of a!!ergic reaction. The infant with enteroco!itis syndrome can %e dehydrated as a conse#uence of diarrhea& (omiting& or %oth. $igns of dehydration inc!ude %!unted eyes& dry mucous mem%ranes& and hypoe!astic s"in. In the unusua! instances of nonce!iac food*induced enteropathy& infants present with signs and symptoms of ma!a%sorption syndrome. ?ystrophy& growth fai!ure& edema +hypoa!%uminemia2& ric"ets +(itamin ? ma!a%sorption2& and hemorrhages +(itamin E ma!a%sorption2 can a!! %e present.

Causes

Many food proteins can act as an antigen in humans. Cow s mi!" proteins are most fre#uent!y imp!icated as a cause of food into!erance during infancy. $oy%ean protein is the second most fre#uent antigen in the first months of !ife& particu!ar!y in infants with primary cow s mi!" into!erance.

History
The typica! history is that of an infant younger than 1 months who is fed for a few wee"s with formu!a and who then de(e!ops diarrhea and& e(entua!!y& (omiting. In the case of the common enteroco!itis syndrome& the infant can %ecome dehydrated and !ose weight. In the rare instance of cow s mi!" enteropathy& a ma!a%sorption syndrome de(e!ops& with growth fai!ure and hypoa!%uminemia 'ood a!!ergy*induced gastroesophagea! ref!u9F ?ietary antigens can induce gastroesophagea! ref!u9& main!y in infancy. The picture is usua!!y accompanied %y !ow*grade enteropathy& with food ad(ersi(e %eha(ior +sometimes with fai!ure to thri(e2& pro!onged (ira! infections& irrita%i!ity& and pro!onged (ira! infections. The fre#uent finding on esophagea! %iopsy is mucosa! eosinophi!ia. Infanti!e co!ic Infanti!e co!ic is the usua! name gi(en to a pro!onged pattern of crying or fussing in infants& e(en if the pathophysio!ogy of this distressing %eha(ior has not yet %een e!ucidated. Numerous theories on the pathogenesis ha(e %een pu%!ished& and many& often conf!icting& therapeutic approaches ha(e %een suggested. Cow s mi!" into!erance has %een imp!icated as a cause of co!ic& at !east in some formu!a*fed infants. $ome studies ha(e suggested that an e!imination diet that su%stitutes cow s mi!" formu!a with a soy*%ased formu!a or a protein*hydro!ysate can re!ie(e the symptoms of infanti!e co!ic in a significant percentage of cases. In these infants& cha!!enge with cow s mi!" proteins usua!!y causes a recrudescence of the crying crises. The infants who respond to the e!imination diet are usua!!y those with more pro!onged crying crises& and they often ha(e a fami!ia! history of a!!ergy. Most often& other signs of cow s mi!" protein into!erance de(e!op in the fo!!owing wee"s or months.

Physical
Asua!!y& the =I manifestations are iso!ated& without any sign of atopic dermatitis& urticaria& rhinitis& con)uncti(itis& or whee3ing.

The infant with enteroco!itis syndrome can %e dehydrated as a conse#uence of diarrhea& (omiting& or %oth. $igns of dehydration inc!ude %!unted eyes& dry mucous mem%ranes& and hypoe!astic s"in. In the unusua! instances of nonce!iac food*induced enteropathy& infants present with signs and symptoms of ma!a%sorption syndrome. ?ystrophy& growth fai!ure& edema +hypoa!%uminemia2& ric"ets +(itamin ? ma!a%sorption2& and hemorrhages +(itamin E ma!a%sorption2 can a!! %e present.

Laboratory Studies
$"in test responses to cow s mi!" or other food proteins and detection of food*specific immunog!o%u!in E +IgE2 anti%odies are usua!!y positi(e in chi!dren with IgE*mediated food a!!ergy. :owe(er& most of the food protein into!erances are not IgE*mediated. A dou%!e*%!ind& p!ace%o*contro!!ed& ora! food cha!!enge is the idea! method for confirming histories of ad(erse reactions to food proteins. :owe(er& this approach is rare!y used in c!inica! practice. In addition& e(en dou%!e*%!ind& p!ace%o*contro!!ed cha!!enges can ha(e pitfa!!s. Encapsu!ated food e9tracts minimi3e the potentia! to e!icit ora!& esophagea!& or airway reactions and cou!d a!so resu!t in increased ris" %ecause a%sorption of food might %e de!ayed.,4<. The fo!!owing tests are indicated in assessing food protein into!eranceF

$"in testing with food e9tracts o This is often used to screen patients with suspected IgE*mediated food a!!ergies. o $"in testing is usua!!y comp!eted %y the pric" techni#ue& which is a re!ia%!e means of detecting IgE anti%odies to food in chi!dren. o A positi(e s"in test resu!t mere!y imp!ies the presence of food*specific IgE anti%odies. A negati(e s"in test resu!t has a high predicti(e accuracy +estimated to %e GH<82. Anfortunate!y& a positi(e pric" test resu!t is a poor predictor of c!inica! symptoms during food cha!!enges. The positi(e

predicti(e accuracy wide!y (aries %ut has %een estimated to %e !ower than <08. In chi!dren younger than 4 years& the negati(e predicti(e accuracy of the s"in test resu!t is not as good as in o!der chi!dren@ howe(er& a positi(e test resu!t is more !i"e!y to %e significant. o Composition and #ua!ity of the e9tracts are a!so a significant consideration. $ometimes& testing a drop of the mi!" that is used to feed the chi!d +eg& formu!a mi!"& soy mi!"& others2 is prefera%!e. $erum immunoassaysF $erum immunoassays to determine food*speciIc IgE anti%odies are often used to screen for antigen*specific IgE in the patient s serum. En3yme*!in"ed immunosor%ent assays +ELI$As2 ha(e %een rep!acing methods that use radiation +eg& radioa!!ergosor%ent test ,RA$T.2. Anfortunate!y& determination of specific IgE in(o!(es the same pro%!ems as the s"in test. A negati(e test resu!t has a high predicti(e accuracy with a !ow sensiti(ity& whereas a positi(e test resu!t has a !ow predicti(e (a!ue.

Procedures
The fo!!owing procedures may %e indicatedF

Apper and !ower =I endoscopiesF Asua!!y& the c!inica! picture and the history are c!ear& and the recommended diagnostic process +see La%oratory $tudies a%o(e2 does not re#uire performance of endoscopic procedures. :owe(er& endoscopy may %e part of the differentia! diagnostic wor"up in cases in which c!inica! dou%t is ac"now!edged. o Apper endoscopy In cases with eosinophi!ic esophagitis& (arious degrees of hyperemia are macroscopica!!y o%ser(ed. In addition& furrowing of the mucosa& rings& and p!a#ues ha(e %een descri%ed. Microscopica!!y& eosinophi!s are o%ser(ed infi!trating the esophagea! wa!!. A!though no pathognomonic histo!ogic characteristics are associated with eosinophi!ic esophagitis& an eosinophi!ic count of more than 40 ce!!s per high*power fie!d is considered diagnostic of this recent!y descri%ed entity. Patchy !ymphonodu!ar hyperp!asia of the =I tract& at any site from the duodenum to the co!on& has %een suggested to %e re!ated to food a!!ergy. In patients presenting with signs or symptoms of enteropathy& an upper endoscopy with duodena! %iopsies may %e indicated in the diagnostic wor"up. The microscopic picture of enteropathy can tota!!y o(er!ap with that of ce!iac disease +ie& partia! to tota! (i!!ous atrophy& crypt hyperp!asia2& possi%!y with a more common occurrence of a patchy !esion rather than continuous !esion. o Lower =I endoscopy +co!onoscopy2F This procedure is comp!eted in the presence of signs or symptoms of co!itis or proctitis +main!y !ower =I %!eeding2 and whene(er the diagnosis of food* induced co!itis is not o%(ious. In food*induced co!itis& the procedure macroscopica!!y re(ea!s !inear erosions and mucosa! edema. Jowe! !esions are genera!!y confined to the dista! !arge %owe!. Microscopica!!y& foca! erythema and fre#uent nodu!arity with superficia! erosions are o%ser(ed. Eosinophi!ic infi!tration& most prominent in the !amina propria& can %e o%ser(ed in the %iopsy specimens %ut is %y no means a constant finding. Jiopsy o In a!!ergic eosinophi!ic esophagitis& esophagea! %iopsy re(ea!s infi!tration of the mucosa and su%mucosa with eosinophi!s. o In a!!ergic eosinophi!ic gastritis& gastric %iopsy re(ea!s mar"ed infi!tration of the mucosa and su%mucosa with eosinophi!s +especia!!y in the gastric antrum2. o In a!!ergic eosinophi!ic gastroenteritis& diagnosis re#uires a %iopsy specimen that re(ea!s an eosinophi!ic infi!tration of the mucosa and su%mucosa. Anfortunate!y& no standards for ma"ing the histo!ogic diagnosis are a(ai!a%!e. In infants and chi!dren without =I symptoms& eosinophi!ic counts in the gastric fundus and antrum are consistent!y !ow& %ut in the termina! i!eum& cecum& and pro9ima! co!on& eosinophi! counts as high as 60 per high*power fie!d can %e detected. o In enteroco!itis syndrome& the )e)una! %iopsy re(ea!s (i!!ous atrophy and infi!tration %y !ymphocytes& eosinophi!s& and mast ce!!s. o In nonce!iac food*induced enteropathy& the findings of the )e)una! %iopsy are simi!ar to those in ce!iac disease %ut usua!!y are !ess pronounced. A (arying degree of (i!!ous atrophy is present with crypt hyperp!asia and !ymphocytic infi!tration of the !amina propria. Often& the !esions ha(e a patchy distri%ution& o%ser(ed especia!!y in the !ast few years. $e(era! studies ha(e detected increased num%ers of IgE p!asmocytes in %iopsy specimens of patients with cow s mi!" protein into!erance.

Medical Care
The definiti(e treatment of food protein into!erance is strict e!imination of the offending food from the diet.

Jreastfeeding is the first choice in infants without !actose into!erance. The mother shou!d e!iminate cow s mi!" +and e(entua!!y eggs and fish or other imp!icated foods2 from her diet. As many as <08 of chi!dren affected %y cow s mi!" protein into!erance de(e!op soy protein into!erance if they are fed with soy*%ased formu!as. Therefore& soy*%ased formu!as shou!d not %e used for the treatment of cow s mi!" protein into!erance. Ase comp!ete mi!" protein hydro!ysates in infants who cannot %e %reastfed. Partia!!y hydro!y3ed formu!as are a%so!ute!y not indicated in chi!dren with cow s mi!" protein into!erance. Occasiona!!y& chi!dren may de(e!op into!erance toward comp!ete hydro!ysated formu!as. In these cases& use amino acidD%ased formu!as& which are now wide!y a(ai!a%!e and are %a!anced in trace e!ements and (itamins. Eosinophi!ic gastroenteritis can show c!inica! and histo!ogic impro(ement after ora! corticosteroid therapy. Topica! steroids& administered as inha!ed corticosteroids& ha(e a!so shown %eneficia! effect. Administration of food a!!ergens as immunotherapy carries a greater ris" of ad(erse and potentia!!y se(ere a!!ergic reactions compared with the administration of inha!ant a!!ergens.,41& 4;. Jased !arge!y on the c!inica! e9perience pu%!ished in European tria!s& the genera! impression is that food a!!ergen e9posure through the ora! or su%!ingua! routes is !ess ris"y than through the su%cutaneous route& %ut this perception has yet to %e deIniti(e!y demonstrated. Recom%inant monoc!ona! humani3ed anti*immunog!o%u!in E +IgE2 therapy has %een appro(ed for the treatment of asthma with associated en(ironmenta! a!!ergies& %ut the response can (ary with food a!!ergies. A H*her% formu!a %ased on traditiona! Chinese medicine is current!y under in(estigation as a treatment for food a!!ergy.,47. LACTO$E INTOLERANCE

Lactose& a disaccharide uni#ue to mamma!ian mi!"& is hydro!y3ed into the monosaccharides g!ucose and ga!actose at the %rush %order of enterocytes on the (i!!ous tip %y the en3yme !actase +a %eta*?*ga!actosidase "nown as !actase ph!ori3in hydro!ase2. Lactose appears to enhance the a%sorption of se(era! minera!s& inc!uding ca!cium& magnesium& and 3inc. The sma!! intestine is a ma)or site of a%sorption and is i!!ustrated in the image %e!ow. It a!so promotes the co!onic growth of Bifidobacterium and is the source of ga!actose& which is an essentia! nutrient for the formation of cere%ra! ga!acto!ipids. The gene for !actase is !ocated on chromosome 4. :ypo!actasia seems to %e strong!y corre!ated with genotype C>C of the genetic (ariant C**GT+*/6H/02 upstream of the !actase ph!ori3in hydro!ase gene. The mo!ecu!ar %ases of !actose into!erance ha(e %een re(iewed.,/. :uman and anima! studies suggest that numerous modu!ators resu!t in (aria%!e e9pression of !actase at different ages. Thyro9ine may promote the dec!ine in !actase en3yme e9pression that appears in chi!dhood& whereas hydrocortisone appears to increase !actase !e(e!s. A!though premature infants ha(e partia! !actase deficiency %ecause of intestina! immaturity& en3yme e9pression can %e induced %y !actose ingestion. Impro(ement of !actose digestion in a pre(ious!y into!erant chi!d or adu!t is caused %y growth of !actose*digesting %acteria rather than an induction in acti(ity of the !actase en3yme %ecause !actase is a noninduci%!e en3yme. Congenita! !actase deficiency is an e9treme!y rare autosoma! recessi(e disorder associated with a comp!ete a%sence of !actase e9pression. Chi!dhood*onset and adu!t*onset !actase deficiency are e9treme!y common and are inherited in an autosoma! recessi(e manner. The CC genotype of the /6H/0 C>T po!ymorphism of the LCT gene is !in"ed to such !ate*onset primary hypo!actasia. Persistent !actase acti(ity into adu!thood is inherited in an autosoma! dominant manner. Ac#uired !actase deficiency& which is a transient phenomenon %y definition& is due to damage of the intestina! mucosa %y an infectious& a!!ergic& or inf!ammatory process and reso!(es once the disease process is corrected and hea!ing of the intestina! mucosa restores the %rush %order en3ymes.

History
$ymptoms of !actose into!erance inc!ude the fo!!owingF

=I symptoms o J!oating& a%domina! discomfort& meteorism& and f!atu!ence that occur from / hour to a few hours after ingestion of mi!" or dairy products may signify !actose into!erance@ howe(er& other disorders such as mi!"*protein sensiti(ity& a!!ergic*type reactions to other su%stances in the mea!& or other saccharide into!erance may cause simi!ar symptoms. o Many indi(idua!s with !actose into!erance are concerned a%out the presence of !actose in many ora!!y administered drugs@ howe(er& one in(estigation conc!uded that no side effects are e9perienced %y adu!ts with hypo!actasia upon ingestion of !actose*containing drugs.,5. o Adu!ts and ado!escents who ha(e %een diagnosed with !actose ma!a%sorption appear a%!e to to!erate as much as /4 g of !actose in a sing!e dose +e#ui(a!ent to the !actose content found in / cup of mi!"2. E(en !arger amounts can %e to!erated if they are ingested with mea!s and distri%uted throughout the day. :owe(er& <0 g of !actose +the !actose content found in / #uart of mi!"2 usua!!y causes symptoms in adu!ts with !actose ma!a%sorption when administered as a sing!e dose outside of mea!s.
,4.

A!though !actose into!erance is often suspected in chi!dren with functiona! recurrent a%domina! pain& strong e(idence suggests that !actose into!erance p!ays no ro!e in such condition. Associated food o The rate of gastric emptying is important in the de(e!opment of symptoms& which may de(e!op if !actose mo(es #uic"!y to an intestine that is !ow in !actase. 'ats decrease the rate of gastric emptying& whereas car%ohydrates increase the rate of gastric emptying. Thus& if dairy products that contain !actose are ingested with car%ohydrates& especia!!y simp!e car%ohydrates& symptoms are more !i"e!y. o A!!ergies to food proteins& particu!ar!y mi!" and grain proteins& can mimic !actose into!erance in part. o Inf!ammation of the intestina! mucosa due to infection or protein*sensiti(e enteritis causes secondary !actose into!erance. $too! characteristicsF Loose& watery& acidic stoo! often with e9cessi(e f!atus and associated with urgency that occurs a few hours after the ingestion of !actose*containing su%stances is typica!. =astroenteritisF Infectious diarrhea& particu!ar!y (ira! gastroenteritis in younger chi!dren& may damage the intestina! mucosa enough to reduce the #uantity of the !actase en3yme. This does not resu!t in any significant pro%!em and does not re#uire any changes in formu!a. :owe(er& into!erance is rare!y more e(ident& especia!!y in ma!nourished infants& and re#uires a few days of !actose*free feedings. A%undant !iterature conc!usi(e!y shows that %reastfeeding can and shou!d a!ways %e continued throughout an episode of gastroenteritis& despite the high content of !actose in %reast mi!". 'ood a(oidanceF Many peop!e with !actose into!erance instincti(e!y a(oid products that contain !actose.
o

Physical

A%domina! painF Nonspecific& nonfoca! a%domina! pain and cramping are common and are sometimes associated with %!oating and f!atus. This pain may mi!d!y increase with pa!pation. 'oca! a%domina! pain significant!y worsened %y pa!pation& the presence of re%ound tenderness& or guarding shou!d a!ert the c!inician to a more serious and possi%!y surgica! =I diagnosis. Jor%orygmiF A significant increase in perista!tic acti(ity in the sma!! %owe! can cause an audi%!e or pa!pa%!e increase in %owe! acti(ity.

Causes
Low !actase acti(ity in the sma!! intestineF This a!!ows undigested !actose to pass into the co!on. In the co!on& %acteria ferment the sugar to hydrogen gas and organic acids. The gas produces distention of the %owe!& creating the sensation of %!oating& cramping& and a%domina! pain. Organic acids can %e a%sor%ed& %ut the #uantity produced is rare!y !arge enough to cause systemic symptoms or meta%o!ic acidosis.

Laboratory Studies
The fo!!owing !a%oratory studies are indicated in patients with !actose into!eranceF

J!ood testing o The adu!t*type hypo!actasia +most common!y caused %y the CC genotype of the /6H/0 C>T po!ymorphism of the LCT gene2 can now %e easi!y diagnosed %y a genetic ana!ysis. o $tudies ha(e determined that genetic test resu!ts and %reath test resu!ts are we!!*corre!ated& there%y e!iminating the need for such testing.,<. $too! ana!ysis o Reducing su%stances in the stoo! indicate that car%ohydrates are not %eing a%sor%ed. One common mista"e& especia!!y with super*a%sor%ent diapers& is to test the so!id portion of the stoo! instead of the !i#uid portion. o Acidic stoo! is defined %y a p: !e(e! of !ess than <.<. This is an indication of !i"e!y car%ohydrate ma!a%sorption& e(en in the a%sence of reducing su%stances.

Other Tests

?ietary e!imination o Reso!ution of diarrhea and symptoms when a suspected su%stance is remo(ed from the diet& as we!! as resumption of the diarrhea and symptoms when the su%stance is reintroduced& are (ery suggesti(e signs of into!erance. o Lac" of diarrhea reso!ution when a su%stance is remo(ed from the diet does not necessari!y indicate to!erance. Ma!a%sorption of one dietary component can resu!t in diarrhea and su%se#uent ma!a%sorption of other dietary components@ thus& the sensiti(ity of this procedure can %e !ow. o Con(erse!y& reso!ution of symptoms upon withdrawa! of !actose*containing foods from the diet may not confirm !actose into!erance. 'or instance& in the case of mi!" products& a patient can %e sensiti(e to the mi!" proteins& and symptoms of such an a!!ergy reso!(e once the mi!" or mi!" product is withdrawn from the diet. :ydrogen %reath test o Car%ohydrate ma!a%sorption resu!ts in %acteria! fermentation of the una%sor%ed sugar. This %iochemica! process re!eases hydrogen gas that is a%sor%ed into the %!ood and e9creted %y the !ungs. In the a%sence of hydro!ysis of !actose into its component monosaccharide sugars& ga!actose and g!ucose& !actose cannot %e a%sor%ed and passes into the !arge intestine. Thus& car%ohydrate ma!a%sorption can %e determined %y measuring the e9ha!ed hydrogen concentration after a car%ohydrate !oad is administered. o Ander norma! conditions& the fermenting %acteria reside on!y in the !arge intestine. -hen %acteria! o(ergrowth in the sma!! intestine occurs& upper sma!! %owe! fermentation of ingested %ut nonhydro!y3ed !actose occurs and causes an ear!y rise in the e9ha!ed hydrogen concentration +G40 ppm2. Ander such conditions& an additiona! !ater rise in e9ha!ed hydrogen occurs during !arge %owe! fermentation. o Anti%iotic administration may cause fa!se*negati(e resu!ts. 'or diagnosis of !actose into!erance& 0.<* / g>"g to /4*4< g of !actose is administered. o A tria! on 10 su%)ects suspected of !actose ma!a%sorption compared different %reath tests and conc!uded that there was unsatisfactory agreement %etween common!y used diagnostic tests.,1. The test with the %est diagnostic properties was !actose %reath test with 4< g !actose and measurement of the increase in the sum of :4 and C:594.

Procedures

Mucosa! %iopsy is a!most ne(er needed to diagnose !actose into!erance. :owe(er& it may pro(e usefu! as a part of the wor"up in patients with ma!a%sorption of o%scure cause. A sma!! intestina! mucosa! %iopsy samp!e is o%tained (ia endoscopy for direct assay of !actase acti(ity and other %rush %order disaccharidases. The presence of sma!! intestina! mucosa! in)ury can a!so %e assessed as a possi%!e cause of secondary !actase deficiency.

Histologic Findings

No a%norma! histo!ogic findings in the sma!! intestina! mucosa are present in adu!t*type !actose into!erance and the e9ceeding!y rare primary !actase deficiency. Ci!!ous %!unting and !amina propria inf!ammatory changes are seen in cases of secondary !actase deficiency.

Medical Care
Treatment of !actose into!erance may inc!ude the fo!!owingF

Lactase deficiencyF This can %e induced %y !actose on!y during the new%orn period. $tudies demonstrate the use of inducing !actase acti(ity %y tu%e feedings with mi!"*containing !actose in premature infants. Ear!y initiation of ha!f*strength !actose*containing formu!a or %reast mi!" resu!ts in rapid induction of !actase acti(ity in the %rush %order and !ess feeding into!erance. One study suggested that fu!!*strength !actose formu!a resu!ted in more feeding into!erance than !ow*!actose formu!a in premature infants@,;. thus& the precise !actose concentration of !actose for inducing !actase acti(ity is sti!! undetermined. Lactose into!eranceF This can %e impro(ed %y dietary manipu!ation. If the #uantity of !actose is increased s!ow!y o(er time& !acto%aci!!i are stimu!ated to grow in the co!on. A greater num%er of !acto%aci!!i a!!ow the !actose to %rea" down into monosaccharides. A!though this a!!ows much of the sugar to %e a%sor%ed& some of the resu!ting monosaccharides are sti!! fermented %y co!onic %acteria@ howe(er& the re!ati(e amount of co!onic fermentation is decreased. ?ietary aids o Lactase deri(ed from yeast can %e added to mi!" products as drops or ingested as chewa%!e ta%!ets prior to ingestion of !actose*containing su%stances. $tudies demonstrate (arying success. ?igesti(e supp!ementations are apparent!y !imited in their a%i!ity to digest !arge #uantities of !actose. o Kogurt with !i(e cu!tures is genera!!y we!! to!erated %y indi(idua!s with !actose into!erance. ?airy products with reduced or no !actose are wide!y a(ai!a%!e. o The ris"s of drastica!!y !imiting or e9c!uding a!! dairy products in popu!ations such as %!ac"s& who may %e at ris" for nutritiona! deficiencies& ha(e %een i!!ustrated.,7. The importance of maintaining a good inta"e of dairy products in the face of !actose into!erance has %een stressed.,7.

NEC Necroti3ing enteroco!itis +NEC2 is the most common =I medica!>surgica! emergency occurring in neonates. Necroti3ing enteroco!itis represents a significant c!inica! pro%!em and affects c!ose to /08 of infants who weigh !ess than /<00 g& with morta!ity rates of <08 or more depending on se(erity. A!though it is more common in premature infants& it can a!so %e o%ser(ed in term and near*term %a%ies. ?espite intensi(e study o(er the past 60 years& its etio!ogy remains e!usi(e. Necroti3ing enteroco!itis affects the =I tract and& in se(ere cases& can cause profound impairment of mu!tip!e organ systems. Initia! symptoms may %e su%t!e and can inc!ude one or more of the fo!!owingF

'eeding into!erance ?e!ayed gastric emptying A%domina! distention& a%domina! tenderness& or %oth I!eus>decreased %owe! sounds A%domina! wa!! erythema +ad(anced stages2 :ematoche3ia

$ystemic signs are nonspecific and can inc!ude any com%ination of the fo!!owingF

Apnea Lethargy ?ecreased periphera! perfusion $hoc" +in ad(anced stages2 Cardio(ascu!ar co!!apse

J!eeding diathesis +consumption coagu!opathy2

Nonspecific !a%oratory a%norma!ities can inc!ude the fo!!owingF

:yponatremia Meta%o!ic acidosis Throm%ocytopenia Leu"openia or !eu"ocytosis with !eft shift Neutropenia Pro!onged prothrom%in time +PT2 and acti(ated partia! throm%op!astin time +aPTT2& decreasing fi%rinogen& rising fi%rin sp!it products +in cases of consumption coagu!opathy2 A%norma! intestina! f!ora o In hea!thy indi(idua!s& the intestina! mi!ieu is characteri3ed %y a predominance of %ifido%acteria. $uch co!oni3ation is enhanced %y the presence of o!igofructose& a component of human mi!"& in the intestina! !umen. Infants who recei(e formu!a feedings without o!igofructose as a constituent ha(e %een noted to ha(e a predominance of c!ostridia! organisms. o Rat pups co!oni3ed with Staphylococcus aureus and Escherichia coli demonstrated increased incidence and se(erity of necroti3ing enteroco!itis compared with those whose intestines were popu!ated with (arious %acteria! species.,/. To!!*!i"e receptor signa!ing of intestina! mucosa! transmem%rane proteins is accomp!ished %y %inding of specific %acteria! !igands that mediate the inf!ammatory response@ the character of the intestina! %acteria! mi!ieu is thought to p!ay a ro!e in the up*regu!ation or down*regu!ation of intestina! inf!ammation (ia to!!*receptor signa!ing. o Many preterm infants recei(e fre#uent e9posure to %road*spectrum anti%acteria! agents& further a!tering the intra*intestina! %acteria! en(ironment. o E9perimenta! and meta*ana!ytica! e(idence suggests that e9ogenous administration of the pro%iotics %ifido%acteria and !acto%aci!!i or pro%iotics +nondigesti%!e su%stances that se!ecti(e!y promote the growth of %eneficia! pro%iotic!i"e %acteria norma!!y present in the gut2 may moderate the ris" and se(erity of necroti3ing enteroco!itis in preterm infants.,4& 6. Intestina! ischemia o Epidemio!ogica!!y& some ha(e noted that infants e9posed to intrauterine en(ironments mar"ed %y compromised p!acenta! %!ood f!ow +ie& materna! hypertension& preec!ampsia& cocaine e9posure2 ha(e an increased incidence of necroti3ing enteroco!itis. $imi!ar!y& infants with postnata!!y diminished systemic %!ood f!ow& such as is found in patients with patent ductus arteriosus or congenita! heart disease& a!so ha(e an increased incidence. :owe(er& a recent retrospecti(e ana!ysis compared outcomes of necroti3ing enteroco!itis in patients with congenita! heart disease with outcomes of necroti3ing enteroco!itis in patients without congenita! heart disease@ the study demonstrated impro(ed outcomes in patients with heart disease. This somewhat counterintuiti(e finding further emphasi3es the mu!tifactoria! pathophysio!ogy under!ying necroti3ing enteroco!itis.,5. o Anima! mode!s of induced intestina! ischemia ha(e identified its significant ro!e in the de(e!opment of necroti3ing enteroco!itis. Patho!ogica!!y& ischemia induces a !oca! inf!ammatory response that resu!ts in acti(ation of a proinf!ammatory cascade with mediators such as PA'& TN'*a& comp!ement& prostag!andins& and !eu"otrienes such as C5 and IL*/7. A!terations in hepato%i!iary ce!! )unction integrity resu!ts in !ea"age of these proinf!ammatory su%stances and %i!e acids into the intestina! !umen& increasing intestina! in)ury. Ce!!u!ar protecti(e mechanisms such as epiderma! growth factor +E='2& transforming growth factor L/ +T='*L/2& and erythropoietin are down*regu!ated& further compromising the infant s a%i!ity to mount a protecti(e response. $u%se#uent norepinephrine re!ease and (asoconstriction resu!ts in sp!anchnic ischemia& fo!!owed %y reperfusion in)ury. o Intestina! necrosis resu!ts in %reach of the mucosa! %arrier& a!!owing for %acteria! trans!ocation and migration of %acteria! endoto9in into the damaged tissue. The endoto9in then interacts synergistica!!y with PA' and a mu!titude of other proinf!ammatory mo!ecu!es to amp!ify the inf!ammatory response. o Acti(ated !eu"ocytes and intestina! epithe!ia! 9anthine o9idase may then produce reacti(e o9ygen species& !eading to further tissue in)ury and ce!! death. E9perimenta! administration of PA' inhi%itors in anima! mode!s has not %een shown to mitigate intestina! mucosa! in)ury. Many other modu!ators of the inf!ammatory response are %eing studied %oth in (i(o in anima! mode!s and in (itro in an attempt to mitigate or pre(ent the mor%idity and morta!ity caused %y fu!minant necroti3ing enteroco!itis. Intestina! mucosa! immaturity

In the preterm infant& mucosa! ce!!u!ar immaturity and the a%sence of mature antio9idati(e mechanisms may render the mucosa! %arrier more suscepti%!e to in)ury. Intestina! regu!atory T*ce!! aggregates are a first*!ine defense to !umina! pathogens and may %e induced %y co!!ections of sma!! !ymphoid aggregates& which are a%sent or deficient in the premature infant. o E9perimenta! and epidemio!ogic studies ha(e noted that feeding with human mi!" has a protecti(e effect@ howe(er& donor human mi!" that has %een pasteuri3ed is not as protecti(e. :uman mi!" contains secretory immunog!o%u!in A +IgA2& which %inds to the intestina! !umina! ce!!s and prohi%its %acteria! transmura! trans!ocation. Other constituents of human mi!"& such as inter!eu"in +IL2*/0& E='& T='*L/& and erythropoietin may a!so p!ay a ma)or ro!e in mediating the inf!ammatory response. O!igofructose encourages rep!ication of %ifido%acteria and inhi%its co!oni3ation with !actose*fermenting organisms. o :uman mi!" has %een found to contain PA' acety!hydro!ase& which meta%o!i3es PA'@ preterm human mi!" has higher PA' acety!hydro!ase acti(ity +as much as < times greater in one study,<. 2 than mi!" co!!ected from women who de!i(ered at term. Innate genetic predisposition o Twin studies ha(e suggested suscepti%i!ity to necroti3ing enteroco!itis may %e affected %y a genetic component. =i(en the fre#uent su%t!e and nonspecific nature of presenting symptoms& identification of a %iomar"er for infants at higher ris" of de(e!oping necroti3ing enteroco!itis cou!d ha(e significant impact on mor%idity and morta!ity rates. Anima! mode!s ha(e focused on sing!e* nuc!eotide po!ymorphisms +$NPs2 that negati(e!y affect innate immune responses to %acteria! antigens. One such $NP disco(ered in the gene that encodes car%amoy!*phosphate synthetase I& the rate*!imiting en3yme for the production of arginine& has %een reported!y associated with an increased ris" of necroti3ing enteroco!itis.,1. o Infants with distinct genotypes of (arious cyto"ines ha(e a!so %een associated with higher fre#uencies of necroti3ing enteroco!itis. =i(en the interp!ay of inherent& infectious& ischemic& inf!ammatory& iatrogenic& and en(ironmenta! factors& a!terations in e9pression of proinf!ammatory and>or anti*inf!ammatory mediators may p!ay a ro!e in neonata! suscepti%i!ity to the disease.,;& 7.
o

History
In patients with necroti3ing enteroco!itis +NEC2& epidemio!ogic studies demonstrate that demographics& ris" factors& patient characteristics& and c!inica! course differ significant!y %etween term and preterm infants.

Term %a%y o Compared with a preterm infant& the term %a%y with necroti3ing enteroco!itis presents at a younger age& with a reported median age of onset that ranges from /*6 days of !ife in the immediate postnata! period& %ut may appear as !ate as one month of age. o The term neonate who is immediate!y affected postnata!!y is usua!!y systemica!!y i!! with other predisposing conditions& such as %irth asphy9ia& respiratory distress& congenita! heart disease& meta%o!ic a%norma!ities& or has a history of a%norma! feta! growth pattern. o Materna! ris" factors that reduce feta! gut %!ood f!ow& such as p!acenta! insufficiency from acute disease +eg& pregnancy*induced hypertension2& chronic disease +eg& dia%etes2& or materna! cocaine a%use& can increase the %a%y s ris" for de(e!oping necroti3ing enteroco!itis. o $pecific signs and symptoms that may %e part of the history inc!ude %i!ious (omiting or gastric aspirates& a%domina! distention& passage of %!ood per rectum& a%domina! radiographs that re(ea! di!ated !oops of %owe!& pneumatosis intestina!is& free a%domina! air& and other signs of systemic infection& inc!uding shoc" and acidosis. Premature %a%y o Premature %a%ies are at ris" for de(e!oping necroti3ing enteroco!itis for se(era! wee"s after %irth& with the age of onset in(erse!y re!ated to gestationa! age at %irth. o Premature infants with patent ductus arteriosus are at higher ris" of de(e!oping necroti3ing enteroco!itis ear!ier in !ife& particu!ar!y if treated with indomethacin for pharmaco!ogic c!osure. :owe(er& patients with persistent patent ductus arteriosus that u!timate!y re#uired surgica! !igation had a higher necroti3ing enteroco!itis morta!ity rate than those whose patent ductus arteriosus were successfu!!y c!osed without surgery. o Patients are typica!!y ad(ancing on entera! feedings or may ha(e achie(ed fu!!*(o!ume feeds when symptoms de(e!op.

o o

o o

Increased incidence in the posttransfusion period has %een reported in otherwise hea!thy premature %a%ies who are feeding entera!!y and undergo %!ood transfusion for asymptomatic anemia of prematurity. Presenting symptoms may inc!ude su%t!e signs of feeding into!erance that progresses o(er se(era! hours to a day& su%t!e systemic signs that may %e reported enigmatica!!y %y the nursing staff as Macting different&M and& in ad(anced disease& a fu!minant systemic co!!apse and consumption coagu!opathy. $ymptoms of feeding into!erance can inc!ude a%domina! distention>tenderness& de!ayed gastric emptying as e(idenced %y increasing gastric residua!s& and& occasiona!!y& (omiting. $ystemic symptoms can insidious!y progress to inc!ude nonspecific signs and symptoms& such as increased apnea and %radycardia& !ethargy& and temperature insta%i!ity representing the primary manifestation+s2. Patients with fu!minant necroti3ing enteroco!itis present with profound apnea& rapid cardio(ascu!ar and hemodynamic co!!apse& and shoc". The %a%y s feeding history can he!p increase the inde9 of suspicion for ear!y necroti3ing enteroco!itis. Ja%ies who are %reastfed ha(e a !ower incidence of necroti3ing enteroco!itis NEC than formu!a*fed %a%ies. Rapid ad(ancement of formu!a feeding has %een associated with an increased ris" of necroti3ing enteroco!itis.,/4. :owe(er& mu!tip!e su%se#uent studies ha(e fai!ed to su%stantiate this finding.

Physical

The pertinent physica! findings in patients who de(e!op necroti3ing enteroco!itis can %e primari!y =I& primari!y systemic& indo!ent& fu!minant& or any com%ination of these. A high inde9 of c!inica! suspicion is essentia! to minimi3e potentia!!y significant mor%idity or morta!ity. =I signs can inc!ude any or a!! of the fo!!owingF o Increased a%domina! girth o Cisi%!e intestina! !oops o O%(ious a%domina! distention and decreased %owe! sounds o Change in stoo! pattern o :ematoche3ia o A pa!pa%!e a%domina! mass o Erythema of the a%domina! wa!! $ystemic signs can inc!ude any of the fo!!owingF o Respiratory fai!ure o ?ecreased periphera! perfusion o Circu!atory co!!apse o -ith insidious onset& the c!inica! signs may %e mi!d& whereas patients with fu!minant disease can present with se(ere c!inica! a%norma!ities. If a%domina! signs are present& surgica! consu!tation may %e ad(isa%!e. ?isease progression ranges from indo!ent to fu!minant& and ear!y and e9peditious in(o!(ement of surgica! co!!eagues can %e he!pfu!& especia!!y if appropriate surgica! care re#uires transfer to another faci!ity.

Laboratory Studies

Initia! presentation of necroti3ing enteroco!itis +NEC2 usua!!y inc!udes su%t!e signs of feeding into!erance& such as gastric residua!s& a%domina! distention& and>or gross!y %!oody stoo!s. A%domina! imaging studies are crucia! at this stage. In fact& radiographic studies shou!d %e o%tained if any concern a%out necroti3ing enteroco!itis is present. La%oratory studies are pursued& especia!!y if the a%domina! study findings are worrisome or the %a%y is manifesting any systemic signs. CJC count& with manua! differentia! to e(a!uate the -JC& hematocrit& and p!ate!et count& is usua!!y repeated at !east e(ery 1 hours if the patient s c!inica! status continues to deteriorate. o -JC countF Mar"ed e!e(ation may %e worrisome& %ut !eu"openia is e(en more concerning. A!though e!e(ated mature and>or immature neutrophi! counts may not %e good indicators of neonata! sepsis after the first 6 days of !ife& moderate*to*profound neutropenia +a%so!ute neutrophi! count ,ANC. N /<00>OL2 strong!y suggests esta%!ished sepsis.

RJC countF Premature infants are prone to anemia due to iatrogenic %!ood draws& as we!! as anemia of prematurity@ howe(er& %!ood !oss from hematoche3ia and>or a de(e!oping consumpti(e coagu!opathy can manifest as an acute decrease in hematocrit. o P!ate!et countF P!ate!ets are an acute phase reactant& and throm%ocytosis can represent physio!ogic stress to an infant& %ut acute necroti3ing enteroco!itis is more common!y associated with throm%ocytopenia +N /00&000>OL2. Throm%ocytopenia may %ecome more profound in se(ere cases that %ecome comp!icated with consumption coagu!opathy. Consumption coagu!opathy is characteri3ed %y pro!onged PT& pro!onged aPTT& and decreasing fi%rinogen and increasing fi%rin degradation products concentrations o J!ood cu!tureF O%taining a %!ood cu!ture is recommended %efore %eginning anti%iotics in any patient presenting with any signs or symptoms of sepsis or necroti3ing enteroco!itis. A!though %!ood cu!tures do not grow any organisms in most cases of necroti3ing enteroco!itis& sepsis is one of the ma)or conditions that mimics necroti3ing enteroco!itis and shou!d %e considered in the differentia! diagnosis. Therefore& identification of a specific organism can aid and guide further therapy. $erum e!ectro!ytes can show some characteristic a%norma!ities. O%tain %asic e!ectro!ytes +NaB& EB& and C!*2 during the initia! e(a!uation& fo!!owed seria!!y at !east e(ery 1 hours depending on the acuity of the patient s condition. o $erum sodiumF :yponatremia is a worrisome sign that is consistent with capi!!ary !ea" and Mthird spacingM of f!uid within the %owe! and peritonea! space. ?epending on the %a%y s age and feeding regimen& %ase!ine sodium !e(e!s may %e !ow*norma! or su%norma!& %ut an acute decrease +N /60 mE#>dL2 is a!arming and heightened (igi!ance is warranted. o Meta%o!ic acidosisF Low serum %icar%onate +N 402 in a %a%y with a pre(ious!y norma! acid*%ase status is a!so concerning. It is seen in con)unction with poor tissue perfusion& sepsis& and %owe! necrosis. Arteria! %!ood gasses o ?epending on presentation acuity& hypo(enti!ation and fran" apnea are seen in necroti3ing enteroco!itis. AJ= can aid in the determination of the infant s need for respiratory support. The AJ= can a!so pro(ide information of the acid*%ase status. o Acute acidosis is worrisome. Lactic acidosis resu!ts from decreased cardiac output +as in cardio(ascu!ar co!!apse and shoc"2& !eading to poor perfusion of periphera! tissues. Tissue necrosis may a!so add to the o%ser(ed meta%o!ic acidosis. An arteria! %!ood samp!e is a con(enient way to simu!taneous!y o%tain a %!ood cu!ture& CJC count& serum e!ectro!ytes& and AJ= for the initia! e(a!uation +note that arteria! %!ood has a !ower yie!d for demonstrating %acteremia than (enous %!ood2. ?epending on presentation acuity& inserting a periphera! arteria! !ine whi!e periphera! perfusion and intra(ascu!ar (o!ume is sti!! within the reference range may %e prudent. This periphera! arteria! !ine faci!itates seria! %!ood samp!ing and in(asi(e %!ood pressure monitoring that is essentia! if the %a%y s condition deteriorates. A!though a!! of these initia! !a%oratory studies ta"en together may aid in the diagnosis of necroti3ing enteroco!itis& they do not su%stitute for an appropriate appreciation of c!inica! presentation and appearance of the infant. The !a%oratory (a!ues can gi(e insight into the se(erity of the disease and can aid in the pro(ision of appropriate therapy.
o

I aging Studies

The mainstay of diagnostic imaging is a%domina! radiography. An anteroposterior +AP2 a%domina! radiograph and a !eft !atera! decu%itus radiograph +!eft*side down2 are essentia! for initia!!y e(a!uating any %a%y with a%domina! signs. Perform a%domina! radiography seria!!y at 1*hour or greater inter(a!s& depending on presentation acuity and c!inica! course. o Characteristic findings on an AP a%domina! radiograph inc!ude an a%norma! gas pattern& di!ated !oops& and thic"ened %owe! wa!!s +suggesting edema>inf!ammation2. $eria! radiographs he!p assess disease progression. A fi9ed and di!ated !oop that persists o(er se(era! e9aminations is especia!!y worrisome. o Radiographs can sometimes re(ea! scarce or a%sent intestina! gas& which is more worrisome than diffuse distention that changes o(er time. o Pneumatosis intestina!is is a radio!ogic sign pathognomonic of necroti3ing enteroco!itis. It appears as a characteristic train*trac" !ucency configuration within the %owe! wa!!. Intramura! air %u%%!es represent gas produced %y %acteria within the wa!! of the %owe!. Ana!ysis of gas aspirated from these air %u%%!es re(ea!s that it consists primari!y of hydrogen& suggesting that these are caused %y

%acteria! fermentation. Car%ohydrate +often !actose2 fermentation %y intestina! f!ora yie!ds hydrogen and car%on dio9ide and a series of short*chain organic acids& which can promote inf!ammation. o A%domina! free air is ominous and usua!!y re#uires emergency surgica! inter(ention +see Other Pro%!ems to %e Considered2. The presence of a%domina! free air can %e difficu!t to discern on a f!at radiograph& which is why decu%itus radiographs are recommended at e(ery e(a!uation. A su%t!e o%!ong !ucency o(er the !i(er and a%domina! contents is characteristic of intraperitonea! air on a f!at p!ate. It represents the air %u%%!e that has risen to the most anterior aspect of the a%domen in a %a%y !ying in a supine position. The free air can %e difficu!t to differentiate from intra!umina! air. o 'or this reason& !eft*side down +!eft !atera!2 decu%itus radiography is essentia! and a!!ows the detection of intraperitonea! air& which rises a%o(e the !i(er shadow +right*side up2 and can %e (isua!i3ed easier than on other (iews. O%tain this (iew with e(ery AP e9amination unti! progressi(e disease is no !onger a concern. o Porta! gas is thought to %e ominous when detected. Porta! gas appears as !inear %ranching areas of decreased density o(er the !i(er shadow and represents air present in the porta! (enous system. Its presence is considered a poor prognostic sign. Porta! gas is much more dramatica!!y o%ser(ed on u!trasonography. o Ascites is a !ate finding that usua!!y de(e!ops when peritonitis is present or after %owe! perforation. Ascites is o%ser(ed on an AP radiograph as centra!i3ed %owe! !oops that appear to %e f!oating on a %ac"ground of density. It is %etter appreciated on u!trasonography. A%domina! u!trasonography can %e he!pfu! when suspected necroti3ing enteroco!itis in neonates is e(a!uated. o Ad(antages inc!ude the fo!!owingF A(ai!a%!e at %edside Nonin(asi(e imagery of intra*a%domina! structures o ?isad(antages inc!ude the fo!!owingF Limited a(ai!a%i!ity at some medica! centers Re#uires e9tensi(e training to discern su%t!e u!trasonographic appearance of some patho!ogies A%domina! air +easi!y o%ser(ed on u!trasonography and in gross!y distended patients2 can interfere with assessing intra*a%domina! structures. o -ith a%domina! u!trasonography& a s"i!!ed c!inician can identify a !arger amount of diagnostic information faster and with !ess ris" to the %a%y than with the current standard e(a!uation methods. o A!trasonography can %e used to identify areas of !ocu!ation and>or a%scess consistent with a wa!!ed* off perforation when patients with indo!ent necroti3ing enteroco!itis ha(e scarce gas or a fi9ed area of radiographic density. o A!trasonography is e9ce!!ent identifying and #uantifying ascites. $eria! e9aminations can %e used to monitor the progression of ascites as a mar"er for the disease course. o Porta! air can %e easi!y o%ser(ed as %u%%!es present in the (enous system. o A!trasonographic assessment of ma)or sp!anchnic (ascu!ature can he!p in the differentia! diagnosis of necroti3ing enteroco!itis from other more %enign and emergent disorders. The orientation of the superior mesenteric artery in re!ationship to the superior mesenteric (ein can pro(ide information regarding the possi%i!ity of a ma!rotation with a su%se#uent (o!(u!us. If a (o!(u!us is present& the artery and (ein are twisted and& at some point in their courses& their orientation switches. This a%norma!ity can %e detected& e(en if the rotation is 610P& if the fu!! path of the (esse!s can %e o%ser(ed. ?opp!er study of the sp!anchnic arteries ear!y in the course of necroti3ing enteroco!itis can he!p distinguish de(e!oping necroti3ing enteroco!itis from %enign feeding into!erance in a mi!d!y symptomatic %a%y. A c!inica! study from Europe and a sma!! series in the Anited $tates demonstrated mar"ed!y increased pea" f!ow (e!ocity +G/2 of arteria! %!ood f!ow in the ce!iac and superior mesenteric arteries in ear!y necroti3ing enteroco!itis.,/1. $uch a finding at the presentation of symptoms can further aid in diagnosis and therapy& potentia!!y sparing those indi(idua!s at !ow ris" for necroti3ing enteroco!itis from unnecessary inter(entions.

Other Tests

Reports from outside of the Anited $tates suggest that more contemporary imaging techni#ues& such as contrast radiography& porta! (ein u!trasonography& MRI& and radionuc!ide scanning& may p!ay a ro!e in diagnosis. These techni#ues are not current!y in common use. =I tonometry is an infre#uent!y used techni#ue that may %e he!pfu! in distinguishing %enign feeding into!erance from ear!y necroti3ing enteroco!itis.

Procedures
Nonsurgica! procedures for necroti3ing enteroco!itis are as fo!!owsF

Apper =I +with or without2 sma!! %owe! fo!!ow*through is on!y performed acute!y when diagnosis other than necroti3ing enteroco!itis are %eing considered +eg& %owe! o%struction2 %ecause of %i!ious (omiting& a%domina! distention& or other symptoms. This procedure is common!y performed in infants with reso!(ed necroti3ing enteroco!itis who de(e!op a picture of =I o%struction& usua!!y due to a stricture or fi%rous %and. Perform this %efore contrast enema %ecause the presence of contrast in the co!on can o%scure pertinent findings. P!acement of a periphera! arteria! !ine may %e he!pfu! at the %eginning of the patient s treatment to faci!itate seria! arteria! %!ood samp!ing and in(asi(e monitoring. P!acement of a centra! (enous catheter for administration of pressors& f!uids& anti%iotics& and %!ood products is prudent as se(ere!y affected patients often ha(e comp!ications that inc!ude sepsis& shoc"& and disseminated intra(ascu!ar coagu!ation +?IC2. If the %a%y is rapid!y deteriorating& with apnea and>or signs of impending circu!atory and respiratory co!!apse& airway contro! and initiation of mechanica! (enti!ation is indicated. A%domina! decompression in infants with necroti3ing enteroco!itis is as fo!!owsF o ?ecompression is essentia! at the first sign of a%domina! patho!ogy. o Ase a !arge*%ore catheter with mu!tip!e side ho!es and a second !umen to pre(ent (acuum attachment to the stomach mucosa +eg& Rep!og!e tu%e2. o $et the catheter for !ow continuous or intermittent suction and monitor output. The tu%e shou!d %e irrigated with se(era! mi!!i!iters of norma! sa!ine to maintain patency. o If copious amounts of gastric>intestina! secretions are remo(ed& consider intra(enous +IC2 rep!acement with a physio!ogica!!y simi!ar so!ution. Maintaining e!ectro!yte %a!ance and intra(ascu!ar (o!ume is essentia!. Ascites can de(e!op during fu!minant necroti3ing enteroco!itis and can compromise respiratory function. Paracentesis may %e considered. P!ace an intra*a%domina! drain as an a!ternati(e to !aparotomy if the %a%y is not a surgica! candidate +eg& e9treme prematurity or cardio(ascu!ar co!!apse and shoc"2.

Histologic Findings

Inspecting the affected %owe! re(ea!s mucosa! ischemia progressing to ce!! death and s!oughing. Necrosis can %e !imited to the mucosa! !ayer& can %e o%ser(ed radiographica!!y as pneumatosis& or can affect the fu!! wa!!& resu!ting in perforation with su%se#uent peritonitis. Necrotic or perforated intestine must %e resected.

Medical Care
?iagnosis of necroti3ing enteroco!itis +NEC2 is %ased on c!inica! suspicion supported %y findings on radio!ogic and !a%oratory studies. Treatment of necroti3ing enteroco!itis depends on the degree of %owe! in(o!(ement and se(erity of its presentation. O%)ecti(e staging criteria de(e!oped %y Je!! ha(e %een wide!y adopted or modified to he!p tai!or therapy according to disease se(erity.

Je!! stage I * $uspected disease o $tage IA Mi!d nonspecific systemic signs such as apnea& %radycardia& and temperature insta%i!ity are present. Mi!d intestina! signs such as increased gastric residua!s and mi!d a%domina! distention are present. Radiographic findings can %e norma! or can show some mi!d nonspecific distention. Treatment is "ept on a diet of nothing*%y*mouth +NPO2 with anti%iotics for 6 days. Intra(enous +IC2 f!uids& inc!uding tota! parentera! nutrition +TPN2 o $tage IJ ?iagnosis is the same as IA& with the addition of gross!y %!oody stoo!. Treatment is NPO with anti%iotics for 6 days and IC f!uids. Je!! stage II * ?efinite disease

$tage IIA Patient is mi!d!y i!!. ?iagnostic signs inc!ude the mi!d systemic signs present in stage IA. Intestina! signs inc!ude a!! of the signs present in stage I& with the addition of a%sent %owe! sounds and a%domina! tenderness. Radiographic findings show i!eus and>or pneumatosis intestina!is. This diagnosis is sometimes referred to as Mmedica!M necroti3ing enteroco!itis as surgica! inter(ention is not needed to successfu!!y treat the patient. Treatment inc!udes support for respiratory and cardio(ascu!ar fai!ure& inc!uding f!uid resuscitation& NPO& and anti%iotics for /5 days. $urgica! consu!tation shou!d %e considered. After sta%i!i3ation& TPN shou!d %e pro(ided during the period that the infant is NPO. o $tage IIJ Patient is moderate!y i!!. ?iagnosis re#uires a!! of stage I signs p!us the systemic signs of moderate i!!ness& such as mi!d meta%o!ic acidosis and mi!d throm%ocytopenia. A%domina! e9amination re(ea!s definite tenderness& perhaps some erythema or other disco!oration& and>or right !ower #uadrant mass. Radiographs show porta! (enous gas with or without ascites. Treatment inc!udes support for respiratory and cardio(ascu!ar fai!ure& inc!uding f!uid resuscitation& NPO& and anti%iotics for /5 days. $urgica! consu!tation shou!d %e considered. After sta%i!i3ation& TPN shou!d %e pro(ided during the period that the infant is NPO. Je!! stage III * Represents ad(anced necroti3ing enteroco!itis with se(ere i!!ness that has a high !i"e!ihood of progressing to surgica! inter(ention o $tage IIIA Patient has se(ere necroti3ing enteroco!itis with an intact %owe!. ?iagnosis re#uires a!! of the a%o(e conditions& with the addition of hypotension& %radycardia& respiratory fai!ure& se(ere meta%o!ic acidosis& coagu!opathy& and>or neutropenia. A%domina! e9amination shows mar"ed distention with signs of genera!i3ed peritonitis. Radiographic e9amination re(ea!s definiti(e e(idence of ascites. Treatment in(o!(es NPO for /5 days& f!uid resuscitation& inotropic support& and (enti!ator support. $urgica! consu!tation shou!d %e o%tained. TPN shou!d %e pro(ided during the period of NPO. o $tage IIIJ This stage is reser(ed for the se(ere!y i!! infant with perforated %owe! o%ser(ed on radiograph in addition to the findings and treatment recommendations for IIIA. $urgica! inter(ention as out!ined %e!ow.
o

Surgical Care

'ree air (isi%!e on a%domina! radiograph is an indication for surgery. $urgica! treatment inc!udes resecting the affected portion of the %owe!& which may %e e9tensi(e. Initia!!y& an i!eostomy with a mucous fistu!a is typica!!y performed& with reanastomosis performed !ater. $trictures may occur& with or without a history of surgica! inter(ention& which may re#uire surgica! treatment. Patients who are e9treme!y sma!! and i!! may not ha(e the sta%i!ity to to!erate !aparotomy. If free air de(e!ops in such a patient& one may consider inserting a peritonea! drain under !oca! anesthesia in the nursery. The surgica! community remains di(ergent on the ris"s and %enefits of open !aparotomy (ersus peritonea! drain p!acement. Two retrospecti(e re(iews of the use of peritonea! drains as initia! therapy for perforated %owe! conc!uded that& a!though most patients u!timate!y re#uire open !aparotomy& initia! peritonea! drainage may a!!ow systemic sta%i!i3ation and reco(ery in the sma!!est& sic"est infants unti! they %ecome %etter surgica! candidates.,/;& /7. More recent prospecti(e randomi3ed tria!s ha(e fai!ed to show a difference in outcomes %etween the 4 approaches& a!though !oca! custom may continue to impact the decision for surgica! inter(ention in patients who are surgica! candidates. Any patient re#uiring surgica! inter(ention and many of those patients not progressing to surgery re#uire protracted courses of parentera! nutrition and IC anti%iotics. o $ecure centra! (enous access is optima! for ensuring uninterrupted de!i(ery of anti%iotics and nutrition as we!! as ma9imi3ing nourishment with centra! (enous formu!ations.

$ome units successfu!!y use percutaneous!y inserted centra! (enous catheters +PCCCs2& whereas other units prefer surgica!!y p!aced centra! !ines such as Jro(iac catheters. Joth types carry an increased ris" of infection& particu!ar!y if they are used to administer !ipids.

Consultations

Consu!t with a pediatric surgeon at the ear!iest suspicion of de(e!oping necroti3ing enteroco!itis. This may re#uire transferring the patient to another faci!ity where such ser(ices are a(ai!a%!e.

!iet

-hen necroti3ing enteroco!itis is suspected& entera! feedings are withhe!d and parentera! nutrition is initiated. Centra!!y de!i(ered formu!ations with appropriate nutritiona! components are infused for optima! IC nutrition +see $urgica! Care2. Entera! feedings are traditiona!!y restarted /0*/5 days after findings on a%domina! radiographs norma!i3e in the case of nonsurgica! necroti3ing enteroco!itis. :owe(er& %a!ancing the ris"s and %enefits of NPO (ersus entera! feeds may a!ter this time!ine. Reinitiating entera! feeds in postsurgica! %a%ies may ta"e !onger and may a!so depend on issues such as the e9tent of surgica! resection& return of %owe! moti!ity& timing of reanastomosis& and preference of the consu!ting surgica! team. Jecause of the high incidence of postsurgica! strictures& some c!inicians prefer to e(a!uate intestina! patency (ia contrast studies prior to initiating entera! feeds. -hen feeds are restarted& if human mi!" is not a(ai!a%!e& formu!as containing casein hydro!ysates& medium*chain trig!ycerides& and saff!ower>sunf!ower oi!s +eg& A!imentum& Pregestimi!& Nutramigen2 may %e %etter to!erated and a%sor%ed than standard infant formu!as.

Alergi susu sapi

Alergi susu sapi terjadi karena mekanisme pertahanan spesifik dan non-spesifik saluran cerna bayi belum sempurna. Susu sapi adalah protein asing utama yang diberikan kepada seorang bayi, Harus dibedakan antara alergi susu sapi suatu reaksi imunologis dan reaksi intoleransi yang bukan berdasarkan kelainan imunologis seperti efek toksik dari bakteri stafilokok, defek metabolik akibat kekurangan enzim laktase, reaksi idiosinkrasi atau reaksi simpang dari bahan-bahan lain yang terkandung dalam susu formula. Protein susu sapi merupakan alergen tersering pada berbagai reaksi hipersensitivitas pada anak. Susu sapi mengandung sedikitnya ! komponen protein yang dapat mengganggu respon imun yang menyimpang pada seseorang.. Protein susu sapi terbagi menjadi kasein and "hey. #asein yang berupa bagian susu berbentuk kental biasanya didapatkan pada terdiri dari $%-&%' dari protein susu sapi. Kasein dapat dipresipitasi dengan zat asam pada pH (,%. )hey terdiri dari !' total protein susu, tang terdiri dari * -lactoglobulin +,' total protein susu-, . -lactalbumin +('-, bovine immunoglobulin + '-, bovine serum albumin +/'-, dan sebagian kecil beberapa proteins seperti lactoferrin, transferrin, lipases +('-. 0engan pasteurisasi rutin tidak cukup untuk menghilangkan protein ini tetapi sebaliknya meningkatkan sifat alergenitas beberapa protein susu seperti blaktoglobulin. Karakteristik komponen protein susu sapi. BERAT MOLEKUL (kD

KOMPONEN PROTEIN

PER!ENTA!E PROTEIN TOTAL

ALER"INI!ITA!

!TABILITA! PADA !U#U $%% & 22 222 2 2 2

* -lactoglobulin 3asein . -lactalbumin Serum albumin 4mmunoglobulins

/&.1 !-1! /(. %$ /%!

/! & ( /

222 22 22 2 2

5anyak penelitian mengenai alergenitas protein susu sapi. 6erdapat lebih dari (! jenis protein yang berbeda dalam susu sapi yang berpotensi untuk menyebabkan sensitivitas. #andungan pada susu sapi yang paling sering menimbulkan alergi adalah lactoglobulin, selanjutnya casein, lactalbumin bovine serum albumin +5SA-. Analisa 4mmunoelectrophoretic menunjukkan bah"a casein berkurang alergenisitasnya setelah pemanasan sekitar / ! 3 selama /7 menit, sedangkan lactoglobulin, lactalbumin berkurang terhadap pemanasan lebih dari /!!3. 5SA and gammaglobulin kehilangan antigenisitasnya pada suhu antara $!3 . &!3. Pemanasan penuh akan terjadi denaturasi dari beberapa protein "hey. * .lactoglobulin merupakan penyebab alergen paling kuat. Penelitian lain menyebutkan antibodi 4g8 antibodi terhadap . -lactalbumin, * -lactoglobulin, bovine serum albumin, and bovine gamma globulin adalah penyebab alergi paling sering pada manusia, sedangkan caseins adalah penyebab alergi terbanyak. Penelitian terakhir menyebutkan casein-specific 4g8 didapatkan /!!' pada kelompok penderita alergi, 4g8 dari * .lactoglobulin sekitar /1', . -lactalbumin sekitar %'.

MANI'E!TA!I KLINI!
9ejala yang terjadi pada alergi susu sapi secara umum hampir sama dengan gejala alergi makanan lainnya. 6arget organ utama reaksi terhadap alergi susu sapi adalah kulit, saluran cerna dan saluran napas. :eaksi akut +jangka pendek- yang sering terjadi adalah gatal dan anafilaksis. Sedangkan reaksi kronis +jangka panjang- yang tyerjadi adalah astma, dermatitis +eksim kulit- dan gangguan saluran cerna. 5eberapa manifestasi reaksi simpang karena susu sapi melalui mekanisme 4g8 dan ;on 4g8. 6arget organ yang sering terkena adalah kulit berupa urticaria dan angioedema. Sistem saluran cerna yang terganggu adalah sindrom oral alergi, gastrointestinal anaphyla<is, allergic eosinophilic gastroenteritis. Saluran napas yang terjadi adalah asma, pilek, batuk kronis berulang. 6arget multiorgan berupa anafilaksis karena makanan atau anafilaksis dipicu karena aktifitas berkaitan dengan makanan Selain target organ yang sering terjadi tersebut di atas, manifetasi klinis lainnya berupa =anifestasi tidak biasa +anussual =anifestation-. 0iantaranya adalah manifestasi kulit berupa vaskulitis, fi<ed Skin 8ruption. Sistem saluran cerna yang terganggu adalah chronic Pulmonary disease +Heiner Syndrome-, hypersensitivity pneumonitis. Saluran cerna yang terjadi adalah konstipasi, gastroesophageal refluk, saluran napas seperti hipersekresi bronkus +napas bunyi grok-grok- dan obstruksi duktus nasolakrimalis +mata sering berair dan belekan- 6arget multiorgan berupa irritability>Sleeplessness in infants, artropati, nefropati dan trombositopeni :eaksi susu sapi yang timbul karena reaksi non 4ge berupa dermatitis atopik, ermatitis Herpetiformis, proktokolitis, entero colitis, alergi eosinophilic gastroenteritis, sindrom enteropati, penyakit celiac dan sindrom Heiner 6erdapat 1 pola klinis respon alergi protein susu pada anak ? :eaksi 3epat, "aktu dari setelah minum susu hingga timbulnya gejala. :eaksi sedang +pencernaa-, (7 menit hingga ! jam. Sedangkan :eaksi @ambat +kulit dan sal.cerna-, @ebih dari ! jam. :eaksi a"al kulit gejala timbul dalam (7 menit setelah mengkonsumsi susu. :eaksi tersebut dapat berupa bintik merah +seperti campak- atau gatal. 9ejala lain berupa gangguan system saluran napas seperti napas berbunyi .ngik. +"heezing-, atau rhinoconjuncyAtivitis +bersin, hidung dan mata gatal, dan mata merah-. 9ejala tersebut bias terjadi meskipun hanya mengkonsumsi sedikit susu sapi. Hill dkk telah mellaporkan bah"a hamper semua +, ' penderita dalam kelompok ini dalam pemeriksaan skin prick test terhadap susu sapi hasilnya positif.. Anafilaksis susu sapi adalah merupakan reaksi paling penting dalam kelompok ini. 0alam kelompok reaksi sedang gejala yang sering timbul adalah muntah, diare dimulai setelah (7 menit hingga ! jam setelah mendapatkan paparan dengan susu. =enurut penelitian sekitar sepertiga dari kelompok ini didapatkan hasil positif hasil tes kulit +skin prick test-. 9ejala yang timbul dalam reaksi lambat terjadi dalam sekitar ! jam setelah terkena paparan susus sapi. Bntuk terjadinya reaksi ini dibutuhkan jumlah volume susu sapi yang cukup besar. 0alam kelompok ini hanya sekitar !' yang didapatkan hasil uji kulit yang positif. Bji temple alergi + Patch 6est- yang dilakukan selama (& jam sering terdapat hasil positif pada kelompok ini. Sebagian besar terjadi dalam usia lebih dari % bulan. 6anda dan gejala yang sering timbul adalah diare, konstipasi +sulit uang air besar- dan dermatitis +gangguan kulit-

DIA"NO!I! ALER"I !U!U !API

0iagnosis alergi susu sapi adalah suatu diagnosis klinis berupa anamnesis yang cermat, mengamati tanda atopi pada pemeriksaan fisis, pemeriksaan imunoglobulin 8 total dan spesifik susu sapi. Bntuk memastikan alergi susu sapi harus menggunakan provokasi makanan secara buta +0ouble 5lind Placebo 3ontrol Cood 3halenge A 05P3C3-. 05P3C3 yang menjadi gold standard atau baku emas. ;amun cara 05P3C3 tersebut sangat rumit dan membutuhkan "aktu, tidak praktis dan biaya yang tidak sedikit. 5eberapa pusat layanan alergi anak melakukan modifikasi terhadap cara itu. 3hildren Allergy 3enter :umah Sakit 5unda Dakarta melakukan

modifikasi dengan cara yang lebih sederhana, murah dan cukup efektif. =odifikasi 05P3C3 tersebut dengan melakukan .8liminasi Provokasi =akanan 6erbuka Sederhana.. Anamnesis atau mengetahui ri"ayat gejala dilihat dari jangka "aktu timbulnya gejala setelah minum susu sapi atau makanan yang mengandung susu sapi. Harus diketahui ri"ayat pemberian makanan lainnya termasuk diet ibu saat pemberian AS4 dan pemberian makanan pendamping lainnya. Harus diketahui juga gejala alergi asma, rinitis alergi, dermatitis atopik, urtikaria, alergi makanan, dan alergi obat pada keluarga +orang tua, saudara, kakek, nenek dari orang tua-, dan pasien sendiri. 9ejala klinis pada kulit seperti urtikaria, dermatitis atopik, ras. Saluran napas? batuk berulang terutama pada malam hari, setelah latihan asma, rinitis alergi. 9angguan saluran cerna, muntah, diare, kolik dan obstipasi. Pemeriksaan fisik yang mungkin didapatkan hadala ada kulit tampak kekeringan kulit, urtikaria, dermatitis atopik allergic shiner.s, Siemen grease, geographic tongue, mukosa hidung pucat, dan "heezing +mengi-.

PIT'ALL DIA"NO!I! DAN PENAN"ANAN

Pitfall atau .kesalahan yang menjerumuskan. terjadi pada a"al penentuan diagnosis dilakukan hanya berdasarkan data laboratorium baik tes kulit atau 4g8 spesifik terhadap susu sapi. Padahal baku emas diagnosis adalah dengan melakukan menggunakan provokasi makanan secara buta +0ouble 5lind Placebo 3ontrol Cood 3halenge A 05P3C3-. Penelitian yang dilakukan penulis terungkap bah"a 7 anak dengan hasil 4g8 spesifik terhadap susu sapi positif, ternyata setelah dilakukan elimisasi provokasi terbuka sekitar (&' dapat toleran terhadap susu sapi .nutrien dense., (!' toleran terhadap susu sapi evaporasi, (' toleran terhadap susu formula sapi biasa. Pitfall diagnosis juga sering terjadi hanya berdasarkan anamnesa tanpa pemeriksaan penunjang dan 05P3C3. 5ila anamnesis tidak cermat sering terjadi kesalahan karena karena faktor yang mempengaruhi gejala yang timbul bukan hanya protein susu sapi. :eaksi simpang yang terjadi dapat juga diakibatkan oleh beberapa kandungan tambahan yang ada di dalam susu formula dan reaksi yang ditimbulkan karena diet ibu saat pemberian AS4. Caktor lain yang memicu timbulnya gejala adalah faktor terjadinya infeksi pada anak. Saat terjadi infeksi seperti batuk, pilek atau panas sering memicu timbulnya gejala alergi. =isalnya saat infeksi saluran napas akut pada penderita alergi sering disertai gejala diare, muntah dan dermatitis. 6erlalu cepat memastikan suatu anak menderita alergi susu sapi biasanya didasarkan ketidakcermatan dalam menganalisa permasalahan kesehatan pada penderita. 0alam menentukan apakah suatu anak mengalami alergi susu sapi diperlukan ketelitian dan kecermatan. 5ila anak minum PAS4 +Pengganti Air Susu 4bu- dan AS4 +Air Susu 4bu-, harus cermat dalam menentukan penyebab gangguan tersebut. 0alam kasus tersebut, PAS4 atau AS4 dapat dicurigai sebagai penyebab alergi. Pada pemberian AS4, diet yang dimakan ibunya dapat mempengaruhi bayi. 5ila pemberian PAS4 sebelumnya sudah berlangsung lebih dari / . minggu tidak terdapat gangguan, kemungkinan susu formula sapi tersebut bukan sebagai penyebab alergi. Harus diperhatikan apakah diet ibunya sebagai penyebab alergi. #adang ada beberapa anak dengan susu formula sapi yang satu tidak cocok tetapi susu formula sapi lainnya bisa diterima. Hal inilah yang menunjukkan bah"a komposisi dan kandungan lain di dalam susu formula tersebut yang ikut berperanan. Caktor yang berpengaruh mungkin saja karena perbedaan dalam proses pembutan bahan dasar susu sapi. 0engan pemanasan dan proses tertentu yang berbeda beberapa kandungan protein tertentu akan menghilang. Sebagian besar alergi susu sapi pada bayi adalah tipe cepat yang diperan oleh 4g8 dan gejala utama adalah ras kulit, eritema perioral, angioedema, urtikaria dan anafilaksis. Sedangkan bila gejala lambat pada saluran cerna berupa muntah, konstipasi dan diare dan gangguan kulit dermatitis herpertiformis biasanya bukan diperani oleh 4g8. Peranan ;on 4g8 inilah biasanya disebabkan bukan oleh kandungan protein susu sapi.. =elihat berbagai jenis kandungan protein dalam susu sapi dan beberapa zat tambahan seperti AA, 0HA, sumber komponen lemak +minyak safflo"er, minyak kelapa sa"it, minyak jagung, minyak kedelai- atau aroma rasa +coklat, madu dan stra"beri-. =asing masing kandungan tersebut mempunyai potensi berbeda sebagai penyebab alergi atau reaksi simpang dari susu formula.. #andungan 0HA dalam susu formula kadang dapat mengakibatkan gangguan pada anak tertentu berupa gangguan kulit. Sedangkan kandungan minyak kelapa sa"it dapat mengakibatkan gangguan saluran cerna berupa konstipasi. Aroma rasa susu seperti coklat sering menimbulkan reaksi batuk atau kosntipasi. 5egitu juga kandungan lemak tertentu, minyak jagung dan laktosa pada susu formula tersebut dapat mengakibatkan manifestasi yang hampir sama dengan alergi susu sapi. 5ila gangguan akibat susu formula tersebut hanya ringan mungkin penggantian susu sapi formula tanpa 0HA atau susu sapi formula tertentu keluhannya dapat berkurang. Dadi bila ada keluhan dalam pemakaian susu sapi formula belum tentu harus diganti dengan susu soya atau susu

hidrolisat. 6api bila keluhannya cukup berat mungkin penggantian susu sapi formula tersebut perlu dipertimbangkan untuk pemberian susu soya atau hidrolisat protein. 5ayi atau anak yang sebelumnya telah mengkonsumsi salah satu jenis susu sapi dan tidak mengalami keluhan dalam "aktu lebih minggu. 5iasanya setelah itu tidak akan mengalami alergi susu yang sama dikemudian hari. Hal ini sering disalah artikan ketika anak mengalami gejala alergi, kemudian susunya diganti. Padahal sebelumnya anak telah beberapa bulan mengkonsumsi susu yang diganti tersebut tanpa keluhan. Sering terjadi saat terjadi gangguan terdapat faktor penyebab lainnya. :i"ayat pemberian makanan lainnya atau adanya infeksi yang diderta anak saat itu dapat menimbulkan gejala yang sama. #asus yang seperti ini menunjukkan bah"a kita harus cermat dan teliti dalam mencurigai apakah seorang anak alergi susu sapi atau bukan. 5eberapa penelitian menunjukkan alergi susu sapi sekitar &!' akan menghilang atau menjadi toleran sebelum usia 1 tahun. Penelitian yang dilakukan penulis terhadap / ! penderita alergi susu sapi menunjukkan bila gejalanya ringan akan bisa toleran usia di atas / tahun. 5ila gangguannya berat, disertai gangguan kulit dan mengakibatkan batuk dan pilek biasanya akan tahan terhadap susu sapi di atas usia hingga 7 tahun. Pitfal penanganan yang sering terjadi adalah saat gejala alergi timbul, penderita paling sering direkomendasikan oleh para klinisi adalah pemberian susu partial hidrolisa. Padahal relkomendasi yang seharusnya diberikan adalah susu formula ekstensif hidrolisat atau susu soya, Pemberian partial hidrolisa secara klinis hanya digunakan untuk pencegahan alergi bagi penderita yang beresiko alergi yang belum timbul gejala. ;amun pada pengalaman beberapa kasus bila didapatkan gejala alergi yang ringan ternyata pemberian susu parsial hidrolisa bisa bermanfaat. Pemberian obat anti alergi baik peroral atau topikal bukan merupakan jalan keluar yang terbaik untuk penanganan jangka panjang. Pemberian anti alergi jangka panjang merupakan bukti kegagalan dalam mengidentifikasi penyebab alergi.

PEMBERIAN !U!U DAN MAKANAN UNTUK PENDERITA

Pemberian susu adalah merupakan masalah yang tersendiri pada penderita alergi susu sapi. Bntuk menentukan penderita alergi susu sapi pilihan utama adalah susu ektensif hidrolisat. 6etapi beberapa penderita juga bisa toleran terhadap susu soya. 5eberapa bayi dengan gejala alergi yang ringan dapat mengkonsumsi susu hodrolisat parsial. =eskipun sebenarnya susu ini untuk pencegahan alergi bukan untuk pengobatan. Secara klinis dan laboratoris seringkali sulit untuk memastikan anak menderita alergi susu sapi. 6idak mudah untuk menentukan pemilihan susu yang terbaik untuk anak tersebut. Seringkali sulit memastikan apakah seseorang alergi susu sapi atau intoleransi atau bereaksi terhadap kandungan tertentu dari kandungan yang ada di dalam formula. 0alam menghadapi kasus seperti ini klinik 3hildren Allergy 3enter :umah Sakit 5unda Dakarta melakukan eliminasi provokasi terbuka sederhana. Secara a"al penderita diberikan susu ekstensif hidrolisat. 5ila gejala alergi membaik selanjutnya dilakukan provokasi formula berturut turut yang lebih beresiko seperti soya, parsial hidrolisat, dan susu formula yang minimal kandungan AA, 0HA, minyak kelapa sa"it dan sebagainya. Cormula yang paling tepat adalah yang tidak menimbulkan gangguan. 5ila timbul gejala pada salah satu formula tersebut kita harus pilih formula satu tingkat lebih aman di atasnya. 5ila susu parsial hidrolisa dan soya timbul gangguan dilakukan provokasi terhadap susu laktosa dan lemah rantai tunggal +=onochain 6rigliceride>=36-. 5anyak keraguan terhadap kualitas gizi susu pengganti susu sapi. #eraguan tersebut seperti .soya tidak menggemukkan., .susu hipoalergenik tidak mebuat anak pintar karena tidak mengadung 0HA. dan sebagainya. Secara umum semua susu formula yang beredar secara resmi kandungan gizinya sama. #arena mengikuti standard :0A +:ecomendation 0ietery Allo"ence- dalam jumlah kalori, vitamin dan mineral harus sesuai dengan kebutuhan bayi dalam mencapai tumbuh kembang yang optimal. #eraguan bah"a susu formula tertentu tidak menggemukkan tidak beralasan karena kandungan kalori, vitamin dan mineral tidak berbeda. Penggunaan apapun merek susu formula yang sesuai kondisi dan usia anak selama tidak menimbulkan gangguan fungsi tubuh adalah susu yang terbaik untuk anak tersebut. 5ila ketidakcocokan susu sapi terus dipaksakan pemberiannya, akan mengganggu fungsi tubuh terutama saluran cerna sehingga membuat gangguan pertumbuhan dan perkembangan anak.. 5ritish ;utrition Coundation, 8SP9A; +8uropean Society for Pediatric 9astroenterology and ;utrition-, )HE +)orld Health Erganization- dan CAE +Cood Agriculture Erganization- merekomendasikan penambahan 0HA dan AA hanya perlu untuk susu formula bayi prematur. Secara teoritis dan bukti klinis penambahan tersebut hanya bermanfaat untuk bayi prematur, karena belum bisa mensintesa AA dan 0HA secara baik. Penambahan AA dan 0HA secara langsung tidak terlalu penting karena sebenarnya tubuh bayi cukup bulan sudah bisa mensitesa atau memproduksi sendiri AA dan 0HA dari asam lemak esessial lain. 5eberapa alternatif pilihan untuk pengganti susu sapi sangat bervariasi tergantung kondisi setiap anak. Susu pengganti tersebut meliputi AS4, susu soya, susu kambing4, susu ektensif hidrolisa, susu parsial hidrolisat, sintesi asam amino dan sebagainya.

Air !usu i(u AS4 adalah pilihan terbaik bagi bayi yang mengalami alergi susu sapi. Pemberian AS4 secara klinis sudah terbukti dapat mencegah kejadian alergi di kemudian hari. =eskpiun dapat mencegah alergi, tetapi diet yang dikonsumsi ibu ternyata juga bisa menimbulkan alergi pada bayinya. Sehingga sebaiknya ibu juga melakukan eliminasi diet tertentu yang dapat mengganggu bayi. 4bu harus menghindari berbagai jenis susu sapi atau bahan makanan yang mengandung susu sapi.

!usu !o)a
Susu formula soya adalah susu formula bebas laktosa untuk bayi dan anak yang mengalami alergi terhadap protein susu sapi. ;utrilon Soya adalah susu formula bebas laktosa yang aman dipakai oleh bayi> anak yang sedang menderita diare atau memerlukan diet bebas laktosa. Soya menggunakan isolat protein kedelai sebagai bahan dasar. 4solat protein kedelai tersebut memiliki kandungan protein tinggi yang setara dengan susu sapi. Seperti halnya pada AS4, kalsium dan fosfor pada susu formula soya memiliki perbandingan ? / untuk menunjang pembentukan tulang dan gigi yang kuat. Susu formula ini juga ada yang mengandung asam lemak esensial, yaitu Emega % dan Emega 1 dengan rasio yang tepat sebagai bahan dasar pembentukan AA F 0HA untuk tumbuh kembang otak yang optimal. Pemberian AA dan 0HA secara langsung pada formula ini tidak terlalu penting karena sebenarnya tubuh bayi cukup bulan sudah bisa mensitesa atau memproduksi sendiri AA dan 0HA dari asam lemak esessial lain yang ada dalam kandungan susu tersebut #arbohidrat pada formula soya adalah maltode<trin, yaitu sejenis karbohidrat yang dapat ditoleransi oleh sistem pencernaan bayi yang terluka saat mengalami diare ataupun oleh sistem pencernaan bayi yang memang alergi terhadap susu sapi. Susu formula soya +kedelai- kurang lebih sama manfaat nutrisinya dibandingkan formula hidrolisat ekstensif, tetapi lebih murah dan rasanya lebih familiar. Pada penelitian yang dilakukan terhadap /$! bayi alergi susu sapi didapatkan susu soya bisa diterima oleh sebagian besar bayi dengan alergi susu sapi baik 4g8 dan ;on 4g8 . Perkembangan 4g8 berkaitan dengan susu soya termasuk jarang. Susu soya direkomendasikan untuk alternatif pilihan pGertama pada penderita alergi susu sapi pada usia di atas % bulan. 6etapi bukan berarti penelitian ini merubah pemberian susu formula soya di ba"ah usia % bulan. Anak yang mengalami alergi susu sapi, ternyata didapatkan sekitar 1! . (!' mengalami alergi susu soya.

!usu Kam(ing
Pada beberapa negara secara tradisional susu kambing sering diberikan terhadap penderita alergi susu sapi. Susu kambing bukan merupakan susu dengan nutrisi yang lengkap untuk bayi.. #andungan vitamin tertentu sangat kecil, seperti asam folat, vitamin 5%, 5/ , 3, and 0, tetapi kaya mineral. Susu kambing dan susu sapimemiliki epitop yang identik sebagai bahan allergen. Sehingga susu kambing biasanya tidak bisa ditoleransi juga oleh penderita alergi susu sapi.

!usu 'ormula Ekstensi* #i+rolisa

Alternatif pengganti pada alergi susu sapi adalah susu formula yang mengandung protein susu sapi hidrolisa +melalui pemrosesan khusus-. Susu formula ini rasanya memang tidak begitu enak dan relatif lebih mahal.. Protein )hey sering lebih mudah di denaturasi +dirusak- oleh panas dibandingkan protein kasein yang lebih tahan terhadap panas. Sehingga proses denaturasi "hey dapat diterima oleh penderita alergi susu sapi, seperti susu sapi evaporasi. 8uropean Society of Paediatric Allergy dan 3linical 4mmunology +8SPA34- mendefinisikan formula ekstensif hidrolisa adalah formula dengan bahan dasar protein hidrolisa dengan fragmen yang cukup kecil untuk mencegah terjadinya alergi pada anak. Cormula ekstensif hidrolisa akan memenuhi criteria klinis bila secara klinis dapat diterima ,!' oleh penderita proven 4g8-mediated alergi susu sapi +,7' confidence interval- seperti yang direkomendasikan American Academy of Paediatrics ;utritional 3ommittee. Sejauh ini sekitar /!' penderita alergi susu sapi dapat menimbulkan reaksi terhadap susu formula ekstensif hidrolisa. Secara pasti penderita yang alergi terhadap formula ekstensif hidrolisa belum diketahui, diperkirakan lebih dari /,'. Pengalaman penggunaan hidrolisa kasein telah dilakukan hampir 7! tahun lebih, 5eberapa penelitian menunjukkan sangat efektif untuk penderita alergi susu sapi. Susu Hidrolisa kasein yang terdapat dipasaran adalah ;utramigen +=ead Dohnsondan Pregestimil +=ead Dohnson-. Sedangkan hidrolisa "hey dalam "aktu terakhir ini mulai dijadikan alternatif, dan tampaknya toleransi secara klinik hampir sama dengan hidrolisa kasein. 5eberapa contoh susu hidrolisa "hey adalah Aalfa-:e +nestle- dan Pepti- Dunior +;utricia-. Protein )hey lebih mudah didenaturasi dengan suhu panas tetapi kasein sangat tahan panas..

'ormula Parsial ,i+rolisa

Susu formula parsial hidrolisa masih mengandung peptida cukup besar sehingga masih berpotensi untuk menyebabkan reaksi alergi susu sapi.Susu ini tidak direkomendasikan untuk pengiobatan atau pengganti susu untuk penderita alergu susu sapi. Susu hipoalergenik atau rendah alergi ini contohnya ;A; HA dan 8nfa HA. Susu ini direkomendasikan untuk penderita yang beresiko tinggi alergi sebelum menunjukkan adanya gejala alergi. Penelitian menunjukkan pemberian Cormula hidrolisa Parsial mengurangi onset gejala alergi yang dapat ditimbulkan.

'ormula sintetis asam amino

;eocate adalah sintetis asam amino /!!' yang merupakan bahan dasar susu formula hipoalergenik. :asa susu formula ini relatif lebih enak dan lebih bisa rasanya lebih bisa diterima oleh bayi pada umumnya, tetapi harganya sangat mahal. ;eocate digunakan untuk mengatasi gejala alergi makanan persisten dan berat. Seperti =ultiple Cood Protein 4ntolerance, alergy terhadap e<tensively hydrolysed formulae, alergi makanan dengan gangguan kenaikkan berat badan, alergi colitis, 98: yang tidak berespon dengan terapi standar. =ultiple food protein intolerance atau =CP4 didefinisikan sebagai intoleransi terhadap lebih dari 7 makanan utama termasuk 8HC +e<tensive Hydrolysa =ilk- dan susu formula soya. =CPA +=ultiple food protein allergy- didefinisikan sebagai alergi lebih dari / makanan dasar seperti susu, tepung, telur dan kedelai. Susu ini juga digunakan sebagai placebo dalam 05P3C3 untuk mendiagnosis alergi susu sapi

Pem(erian Makanan
Penderita alergi susu sapi juga harus menghindari makanan yang mengandung bahan dasar susu sapi seperti skim, dried, susu evaporasi maupun susu kondensasi. @actaid, yaitu produk susu yang diproses secara khusus untuk mereka yang mengalami gangguan lactose intolerance. @actaid diduga masih mengandung protein susu sapi, jadi sebaiknya jangan diberikan kepada anak-anak yang menderita alergi. =entega atau susu mentega, Produk kedelai yang mengandung susu sapi, Produk-produk makanan yang mengandung kasein, kaseinat, sodium atau kalsium kaseinat, lactalbumin, dan wheyArtificial butter, Butter, Buttermilk, 3asein, #eju, Cream, #eju cottage, Yoghurt, #asein hidrolisat, Susu kambing, @aktalbumin, @aktglobulin, @aktosa, @aktulosa, Sour cream, Whey. Penderita alergi susu sapi biasanya juga mengalami alergi terhadap makanan lainnya. =akanan yang harus di"aspadai adalah telor, buah-buahan tertentu, kacang dan ikan laut. Penderita alergi susu sapi sangat jarang juga mengalami alergi terhadap daging sapi. 5anyak penderita alergi susu sapi dapat mengkonsumsi daging sapi tanpa mengalami gejala alergi.

PEN&E"A#AN ALER"I !U!U !API

Pencegahan terjadinya alergi susu sapi harus dilakukan sejak dini. Hal ini terjadi saat sebelum timbul sensitisasi terhadap protein susu sapi, yaitu sejak intrauterin. Penghindaran harus dilakukan dengan pemberian susu sapi hipoalergenik yaitu susu sapi yang dihidrolisis parsial untuk merangsang timbulnya toleransi susu sapi di kemudian hari. 5ila sudah terjadi sensitisasi terhadap protein susu sapi atau sudah terjadi manifestasi penyakit alergi, maka harus diberikan susu sapi yang dihidrolisis sempurna atau pengganti susu sapi misalnya susu kacang kedele. Alergi susu sapi yang sering timbul dapat memudahkan terjadinya alergi makanan lain di kemudian hari bila sudah terjadi kerusakan saluran cerna yang menetap. Pencegahan dan penanganan yang baik dan berkesinambungan sangat diperlukan untuk mencegah terjadinya alergi makanan yang lebih berta dikemudian hari..6indakan pencegahan alergi susu sapi juga hampir sama seperti yang dilakukan pada alergi lainnya. Secara umum tindakan pencegahan alergi susu sapi dilakukan dalam 1 tahap yaitu?

Pen-ega,an primer
0ilakukan sebelum terjadi sensitisasi. Saat penghindaran dilakukan sejak pranatal pada janin dari keluarga yang mempunyai bakat atopik. Penghindaran susu sapi berupa pemberian susu sapi hipoalergenik, yaitu susu sapi yang dihidrolisis secara parsial, supaya dapat merangsang timbulnya toleransi susu sapi di kemudian hari karena masihmengandung sedikit partikel susu sapi, misalnya dengan merangsang timbulnya Ig blocking agent. 6indakan pencegahan ini juga dilakukan terhadap makanan penyebab alergi lain serta penghindaran asap rokok. =eskipun demikian AAA4 hanya merekomendasikan penghondaran Hpemberian kacang-kacangan selama kehamilan.

Pen-ega,an sekun+er
0ilakukan setelah terjadi sensitisasi tetapi belum timbul manifestasi penyakit alergi. #eadaan sensitisasi diketahui dengan cara pemeriksaan 4g8 spesifik dalam serum atau darah talipusat, atau dengan uji kulit. Saat tindakan yang optimal adalah usia ! sampai 1 tahun. Penghindaran susu sapi dengan cara pemberian susu sapi non alergenik, yaitu susu sapi yang dihidrolisis sempurna, atau pengganti susu sapi misalnya susu kedele supaya tidak terjadi sensitisasi lebih lanjut hingga terjadi manifestasi penyakit alergi.. Pemberian AS4 ekslusif terbukti dapat mengurangi resiko alergi, tetapi harus diperhatikan diet ibu saat menyusui Selain itu juga disertai tindakan lain misalnya pemberian imunomodulator, !h"#immunoa$u%ants, probiotik. 6indakan ini bertujuan mengurangi dominasi sel limfosit 6h , diharapkan dapat terjadi dalam "aktu % bulan.

Pen-ega,an tersier
0ilakukan pada anak yang sudah mengalami sensitisasi dan menunjukkan manifestasi penyakit alergi yang masih dini misalnya dermatitis atopik atau rinitis tetapi belum menunjukkan gejala alergi yang lebih berat seperti asma. Saat tindakan yang optimal adalah pada usia % bulan sampai ( tahun. Penghindaran juga dengan pemberian susu sapi yang dihidrolisis sempurna atau pengganti susu sapi. Pemberian obat pencegahan seperti setirizin, imunoterapi, imunomodulator tidak direkomendasikan karena secara klinis belum terbukti bermanfaat.