malabsorption in infants and children

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1 rchives of Disese in Childhood, 1979, 54, Breth hydrogen test for detecting lctose mlbsorption in infnts nd children Prevlence of lctose mlbsorption in Jpnese children nd dults OSMU NOS, YOSHIHIKO IID, HIROSHI KI, TOKUZO HRD, MINORU OGW, ND HYKUJI YBUUCHI Deprtment ofpeditrics, University of Osk School of Medicine SUMMRY The breth hydrogen test (BHT) ws dpted for use in young infnts nd children. The dignostic criterion of sugr mlbsorption in the BHT ws determined by orl dministrtion of 0 5 g/kg of unbsorbble sugr (lctulose) to 21 helthy infnts nd children. mximum increse in breth hydrogen >0 05 ml/min per m2 ws observed in ll subjects. good correltion between results by the BHT nd by the ordinry lctose tolernce test ws obtined fter orl dministrtion of 2 g/kg lctose to 21 helthy infnts nd children, 2 congenitl lctse-deficient infnts, nd 7 dults. Using this test, 80 helthy Jpnese infnts nd children (ged between one month nd 15 yers) nd 18 dults were exmined for lctose mlbsorption fter dose of 1 g/kg lctose. ll infnts nd children under 2-yers old bsorbed lctose completely. The incidence of lctose mlbsorption ws 30 % in 3-yer, 36 % in 4-yer, 58 % in 5-yer, nd 86 % in 6-yer-old children, 85 % in schoolchildren, nd 89 % in dults. Thus the incidence of lctse deficiency grdully increses with ge from 3 yers, nd bout 90 % of ll norml Jpnese dults re lctse-deficient. t birth, humns hve bundnt lctse ctivity in the smll intestine but, in most ethnic groups, there is pronounced decrese in lctse ctivity during erly childhood (Hung nd Gyless, 1967; Johnson et l., 1977). The definitive dignosis of lctse deficiency requires the collection of biopsy specimens from the smll intestine nd demonstrtion of decresed lctse ctivity therein. ttempts hve therefore been mde to develop indirect methods for detecting lctse deficiency. Tolernce tests, lthough commonly used for this purpose, re influenced by mny fctors-such s, the rte of gstric emptying nd intermediry glucose metbolism. In ddition, these tests need lrge mount of lctose nd therefore give no informtion on the bility of the intestine to bsorb Deprtment of Peditrics, University of Osk School of Medicine, Jpn YOSHIHIKO IID, ssocite professor of peditrics HYK UJI YBUUCHI, professor ofpeditrics Deprtment of Peditrics, Osk University Hospitl, Jpn OSMU NOS, medicl stff HIROSHI KI, medicl stff TOKUZO HRD, medicl stff MINORU OGW, medicl stff smller, more physiologicl quntities. Moreover, the results re often unrelible (Krsilnikoff et l., 1975). Recently, mny investigtors hve shown tht the breth hydrogen test (BHT) (chnge in the concentrtion in the breth of hydrogen formed by bcteril metbolism of unbsorbed lctose in the colon) is simple, ccurte, nd sensitive indirect test for lctse deficiency in dults (Levitt, 1969; Bond nd Levitt, 1972; Newcomer et l., 1975). There hve been only few reports of this test on children under 5 yers (Mffei et l., 1977). We report the ppliction of this test in children, of from one month old upwrds, nd in dults to determine the incidence nd ge of onset of lctse deficiency in Jpnese children. Subjects nd methods Subjects. Hydrogen excretion ws studied in 80 helthy children (between one month nd 15 yers old), 2 infnts with congenitl lctse deficiency (dignosed by per-orl intestinl biopsy), nd 18 norml dults (between 20 nd 50 yers old). Of the 436

2 Breth hydrogen test for detecting lctose mlbsorption in infnts nd children children, 19 were infnts (between one nd 12 months old), 42 were preschool children (between 2 nd 6 yers old), nd 19 were schoolchildren (between 7 nd 15 yers old). Informed consent ws obtined from the dults nd the children's prents. Methods. The bility of the colonic flor of infnts to produce H2 during lctose fermenttion ws studied using fecl homogentes s described by Bond nd Levitt (1972). Fresh fecl specimens (2 g) from 50 infnts (15 newborn infnts feeding with brest milk, 6 newborn bbies with formul, 25 infnts with formul, nd 4 children) were homogenised in 4 ml of 0'10 mol/l phosphte-buffered sline (ph 7'0). ll infnts exmined were helthy nd not receiving tretment with ntibiotics. The homogentes were plced in series of 10 ml testtubes nd 1 ml 1 25% (mss/vol.) lctose solution ws dded to ech. The tubes were mixed, seled with rubber stoppers, nd plced in wter bth t 370C. needle ttched to 50-ml syringe ws inserted through the rubber stopper. fter one hour, the tubes were vigorously stirred, nd the gs in ech tube ws displced into the syringe by injecting wter into the test-tube through second syringe. The concentrtion of H2 ws determined by gs chromtogrphy. Respirtory H2 excretion The subjects were strved overnight, nd then the rte of respirtory H2 excretion ws determined t 0, 1, 2, 3, nd 4 hours fter crbohydrte loding by nlysis of 3-min smples of expired ir. s the H2 concentrtion of expired ir ws often too low to mesure ccurtely, rebrething technique, modifiction of the method of Levitt (1969), ws used to concentrte the breth H2. n infnt circle, which is normlly used for nesthesi of infnts, ws used s the collecting system. The pprtus contins flutter vlve, CO. bsorbent, 3-litre neoprene bg, nd 2nd flutter vlve. Hydrogen ws considered to be evenly distributed in volume of gs equl to tht present in the collecting system, plus the residul lung volume of the subject (estimted from nomogrm for norml Jpnese children (Nkjim, 1967)). The volume of the infnt circle (except for bg volume) ws mesured by the dilution method nd the verge vlue in 20 determintions ws 980 ± 20 ml. fter the collection period, the bg volume ws mesured. The totl volume ws tken s 980 ml, plus the bg volume, plus the residul lung volume. This totl volume multiplied by the concentrtion of H2 in the collecting system ws defined s the volume of H2 excreted during 3-min period. The system ws flushed with 02 between collections. With infnts of <6 months old, expired ir ws collected by modifiction of the to-nd-fro rebrething method of Kruss nd uld (1970). For this, neoprene rubber bg of 1 5 litres ws used, nd the volume of the collecting system ws nerly equl to the bg volume, becuse the ded spce ws very smll (bout 20 ml). s soon s possible fter collection, smples were nlysed for H2 by gs chromtogrphy using therml conductivity detector (Shimzu Seiskusho, Ltd, Model GC-4B, Kyoto, Jpn). 2-ml smple of gs ws introduced through gs smple vlve into stinless steel column, 2 m x 0 4 cm (inside dimeter), pcked with 80-mesh moleculr sieve 5. Oven temperture ws 750C. N2 (flow rte 20 ml/min) ws used s crrier gs. The smllest detectble mount of H2 ws 5 ppm (0 '05 ml in 10 litres), corresponding to the excretion of ml/min (s the minimum volume of the collecting system ws bout 1 * 5 litres). single H2 determintion took only few minutes. Plsm glucose Venous blood smples were obtined t 0, 30, 60, 90, nd 120 min fter glucose nd lctose loding. Plsm glucose ws determined by the glucose oxidse method. Results Out of fecl specimens from the 50 infnts, 48 smples produced considerble hydrogen. The men fsting breth H2 output of 80 subjects ws ± ml (1 SD)/min perm2(rnge 0 * 000 to 0 068). Usully the pek level for H2 concentrtion occurred 2 or 3 hours fter orl sugr dministrtion. The fsting levels were subtrcted from the pek levels, nd the results were expressed s the increse bove the fsting level. The reproducibility of the technique for collecting breth H2 ws studied in 4 infnts nd 4 children during lctulose (unbsorbble sugr) loding test by compring their rtes of breth H2 excretion during 2 consecutive 3-min periods (n = 16). The men difference between the 2 determintions ws 10-7 % with rnge of 1-3 to 15 % (rnge of H2 concentrtion ws 27 to 167 ppm). The chnge in breth H2 excretion in helthy subjects (7 infnts, 7 preschool children, nd 7 schoolchildren) fter orl ingestion of lctulose or glucose (n bsorbble sugr) is shown in Fig. 1. Breth H2 excretion incresed mrkedly (>0 * 05 ml/min per m2) in ech of the 21 subjects fter ingestion of 0 5 g/kg lctulose (10% solution), but did not increse bove the bsl level fter ingestion of 2 g/kg glucose. In fct, in the subjects given glucose, breth H2 excretion decresed grdully. In these 21 subjects, 2 congenitl lctse-deficient

3 438 Nose, lid, Ki, Hrd, Ogw, nd Ybuuchi (ml/ min per m2 ) Glucose lod Lctu lose lod 2g/Kg 05g/Kg 05 * 0.1 I Fig. 1 Mximum increse of breth H2 excretion fter orl dministrtion ofglucose (2 glkg) nd lctulose (O S g/kg), in children of vrious ges. Increse in H2 is expressed s ml/min per m2 body surfce re. infnts, nd 7 norml dults, we compred the reltionship between the mximum increse of breth hydrogen excretion nd the mximum increse of the blood sugr level fter orl ingestion of 2 g/kg (mximum 50 g) lctose (10% solution). Fig. 2 shows the mximum increse in blood sugr in ech subject plotted ginst the mximum increse in breth H2 excretion. Subjects who hd norml tolernce test-tht is, >20 mg/100 ml - (1 1 mmol/l) increse in blood sugr-showed less ~ cni ( C O 30 ', c) 20 * ~~~~~~~~~~~~~~~~~~ * I I *- *I *Ī I iu I. *. * thn 0 05 ml/min per m2 increse in H2 excretion, nd no clinicl response. On the other hnd, those who hd <20 mg/100 ml increse in blood sugr showed n increse in breth H2 excretion of >0 05 ml/min per m2 nd some of these subjects developed clinicl symptoms-such s dirrhoe, crmp, bloting, fltulence, or borborygmi-prticulrly the 6 dults nd 2 congenitl lctsedeficient infnts. To exmine the effect of ge on H2 excretion, we crried out the breth hydrogen test fter orl ingestion of 1 g/kg lctose (10% solution) in 80 helthy infnts nd children nd 18 dults. The mximum increse in breth H2 is plotted ginst ge in Fig. 3. ll the infnts nd children of under 2 yers could bsorb lctose completely, but 30% of the 3-yer-old children showed n increse of breth H2 >0 05 ml/min per m2, indicting lctose mlbsorption. The incidence of lctose mlbsorption ws 36% in 4-yer, 58% in 5-yer, 86% in 6-yer-old children, 85% in schoolchildren, nd 89% in dults. Discussion Mximum increse in breth H2 excretion (ml/min per m2 simple, relible, nd noninvsive test of sugr bsorption is required for dignosis nd for studying mlbsorption syndromes nd dult-type lctose mlbsorption in children. The technique of intermittent breth smpling for nlysis of breth H2 ws developed by Levitt (1969) nd is now estblished s the most ccurte indirect test of discchride intolernce in dults. However, this test hd not been pplied to infnts nd children with totl collection method, so we dpted it for use on children. We first tested whether the intestine of children contins the H2-producing bcteri tht re essentil Fig. 2 Reltionship of mximum increse in breth HI excretion with mximum increse in blood sugr level fter ingestion of 2 g/kg lctose ( infnts, * preschool children, 0 schoolchildren, 0 congenitl lctse-deficient infnts, o dults). Conversion: trditionl units to SI-blood glucose 1 mg/100 ml w mmol/l.

4 I L CL Breth hydrogen test for detecting lctose mlbsorption in infnts nd children *e. * 0.i (Month) * * so, giles so& mm*m4u - f )) * 0 (Yecr) ge for ppliction of this test. In vitro tests on the feces of 50 infnts of vrious ges showed tht lmost ll (96%) infnts hve colonic flor tht produce H2. Thus the breth H2 test my be pplied to infnts. The breth H2 collecting technique used by Newcomer et l. (1977) is n ccurte method for older children, but the pprtus is too big nd complex for children under 5 yers nd the rebrething time too long, so tht ccurcy my be poor. The methods of end-expirtory breth H2 smpling reported by Mffei et l. (1977) nd Cskey et l. (1977) cn give good informtion, but it is less precise thn the totl collection method (Metz et l., 1976). However, s the totl volume of collecting system is smll in our method, nd detectble increse in concentrtion of H2 gs in the system cn be obtined in 3 minutes, we chieved stisfctorily ccurte quntittive smpling of breth H2. To reduce the totl volume of the collecting system for infnts under 6 months, the expirtory ir ws smpled using to-nd-fro rebrething system. Our technique for collecting breth H2 gve reproducible results, even with children under 5 yers. ccording to Newcomer nd McGill (1977), 25 g (O 3J0 * 5 g/kg) of unbsorbed sugr my be enough to provide distinct increse in breth H2 in dults. On the other hnd, we found tht some ptients begn to develop clinicl symptoms-such s dirrhoe, borborygmi, nd bdominl distention-fter dministrtion of >0 5 g/kg lctulose, suggesting tht the presence of more thn 0*5 g/kg of unbsorbed sugr in the lrge intestine my cuse clinicl symptoms. So we tenttively mde * * 0. *. dult *- 0 Fig. 3 Mximum increse in breth H2 excretion fter ingestion of I g/kg lctose (mximum 50 g) t vrious ges. the presence of 0 5 g/kg unbsorbed sugr in the lrge intestine dignostic criterion of sugr mlbsorption. For exmple, if n infnt of 10 kg ws given 10 g lctose, hlf of which ws not bsorbed (bsorption rte 50% ), certin mount of H2 would be produced. On the other hnd, if mn of 50 kg ws given 50 g lctose, nd 5 g lctose ws not bsorbed (bsorption rte 90%/), H2 excretion derived from unbsorbed sugr my be the sme, since the mount of breth H2 my reflect the bsolute mount of unbsorbed sugr (Bond nd Levitt, 1976). We thus thought it resonble to estblish criterion of sugr mlbsorption in BHT, by dividing H2 excretion/min by body surfce re. We first ttempted to demonstrte n pprecible mximum increse in breth H2 fter orl dministrtion of 0 * 5 g/kg lctulose to helthy infnts nd children of vrious ges. s shown in Fig. 1, even in infnts, definite increse of breth H2 excretion (>0 05 ml/min per m2) ws detected fter dministrtion of 0 5 g/kg of unbsorbble sugr (lctulose). On the other hnd, when n bsorbble sugr (glucose) ws dministered (2 g/kg) to the sme subjects, no increse of breth H2 ws observed in ny ge group. These findings show tht our method is relible nd ccurte for evluting sugr bsorption. Moreover, s Fig. 2 shows, there ws good correltion between the results of the ordinry lctose loding test nd the results of the breth H2 test. We then crried out the breth H2 test fter orl ingestion of 1 g/kg lctose to determine the incidence of lctose mlbsorption. We chose this dose of lctose for the following resons: (1) it is more physiologicl thn tht ordinrily used (2 g/kg), becuse uptke of lctose, t one time, from the diet does not usully exceed 1 g/kg (Hegsted, 1976; Newcomer et l., 1978); (2) the bsorption of less

5 440 Nose, Iid, Ki, Hrd, Ogw, nd Ybuuchi thn hlf the dministered lctose my be resonbly defined s lctose mlbsorption. Thus, judging from the fermenttion of vrious sugrs (Bond nd Levitt, 1972) nd our results with lctulose loding, if hlf the lctose is not bsorbed fter lod of 1 g/kg, there should be n increse of breth hydrogen >0 05 ml/min per M2. Our results showed tht ll infnts nd children under 2 yers could bsorb lctose completely. Lctse deficiency seems to pper t 3 yers nd it grdully increses with ge; 85% of the children of over 6 yers, nd bout the sme percentge of dults, showed lctose mlbsorption. There hve only been two previous reports on the ge of onset nd prevlence of lctose intolernce in Jpnese people. Shibuy et l. (1970) reported somewht erlier ge of onset of lctose intolernce nd 100% incidence of lctose intolernce fter 8 yers by using the ordinry lctose tolernce test. s the ordinry lctose tolernce test gives bout 20% flse-positive results (Krsilnikoff et l., 1975), their results re not essentilly different from ours. Nito et l. (1973) investigted the effect of ge on lctse ctivity, nd found n dult-type pttern of lctse ctivity in children of over 6 yers. There re two reports of studies on mericn Indins using breth H2 nlysis. Newcomer et l. (1977) observed lctse deficiency by ge 5, but they did not obtin stisfctory results on younger children; Cskey et l. (1977) mde similr studies but their results re not comprble with ours becuse of the difference in method. The breth H2 test hs mny dvntges (Metz et l., 1976; Femndes et l., 1978) nd should hve wide ppliction for elucidting problems of sugr bsorption in children. We thnk Mrs Ichihr nd Mrs Nose for their help in prepring the mnuscript. This investigtion ws supported in prt by grnt from the Ministry of duction in Jpn. References Bond, J. H., Jr, nd Levitt, M. D. (1972). Use of pulmonry hydrogen (H) mesurements to quntitte crbohydrte bsorption. Study of prtilly gstrectomised ptients. Journl of Clinicl Investigtion, 51, Bond, J. H., nd Levitt, M. D. (1976). Quntittive mesurement oflctose bsorption. Gstroenterology, 70, Cskey, D.., Pyne-Bose, D., Welsh, J. D., Gerhrt, H. L., Nnce, M. K., nd Morrison, R. D. (1977). ffects of ge on lctose mlbsorption in Oklhom ntive mericns s determined by breth H2 nlysis. Digestive Diseses, 22, Fernndes, J., Vos, C.., Douwes,. C., Slotem,., nd Degenhrt, H. J. (1978). Respirtory hydrogen excretion s prmeter for lctose mlbsorption in children. mericn Journl of Clinicl Nutrition, 31, Hegsted, D. M. (1976). The lctose intolernce test nd milk consumption. Nutrition Reviews, 34, Hung, S., nd Gyless, T. M. (1967). Lctose intolernce in helthy children. New nglnd Journl of Medicine, 276, Johnson, J. D., Simoons, F. J., Hurwitz, R., Grnge,., Mitchell, C. H., Sintr, F. R., Sunshine, P., Robertson, W. V., Bennett, P. H., nd Kretchmer, N. (1977). Lctose mlbsorption mong the Pim Indins of rizon. Gstroenterology, 73, Krsilnikoff, P.., Gudmnd-H0yer,., nd Moltke, H. H. (1975). Dignostic vlue of discchride tolernce tests in children. ct peditric Scndinvic, 64, Kruss,. N., nd uld, P.. M. (1970). Mesurement of functionl residul cpcity in distressed neontes by helium rebrething. Journl of Peditrics, 77, Levitt, M. D. (1969). Production nd excretion of hydrogen gs in mn. New nglndjournl ofmedicine, 281, Mffei, H. V. L., Metz, G., Bmpoe, V., Shiner, M., Hermn, S., nd Brook, C. G. D. (1977). Lctose intolernce, detected by the hydrogen breth test, in infnts nd children with chronic dirrhoe. rchives of Disese in Childhood, 52, Metz, G., Blendis, L. M., nd Jenkins, D. J.. (1976). Letter: H2 breth test for lctse deficiency. New nglnd Journl of Medicine, 294, 730. Nito, H., Horino, K., Nkgw, H., rshim, S., Horiuchi, K., Mesk, T., Fujit, H., md, N., Hosoymd, T., Kdot, M., nd Iid, Y. (1973). Intestinl discchridse ctivity in Jpnese children. ct peditric Jponic, 77, Nkjim, H. (1967). Lung function of norml infnts. ct peditric Jponic, 9, Newcomer,. D., McGill, D. B., Thoms, P. J., nd Hofmnn,. F. (1975). Prospective comprison of indirect methods for detecting lctse deficiency. New nglnd Journl of Medicine, 293, Newcomer,. D., nd McGill, D. B. (1977). Letter: Breth H2 test for lctse deficiency. mericn Journl of Digestive Diseses, 22, Newcomer,. D., Thoms, P. J., McGill, D. B., nd Hofmnn,. F. (1977). Lctse deficiency: common genetic trit of the mericn Indin. Gstroenterology, 72, Newcomer,. D., McGill, D. B., Thoms, P. J., nd Hofmnn,. F. (1978). Tolernce to lctose mong lctse-deficient mericn Indins. Gstroenterology, 74, Shibuy, S., Ymshit, F., Funtsu, T., nd Funtsu, I. (1970). Lctose degrdtion cpcity mong Jpnese (in Jpnese). dvnced Medicine, 72, Correspondence to Dr Osmu Nose, Deprtment of Peditrics, Osk University Hospitl, Fukushimku, Osk, Jpn 553. Received 10 October 1978