Development of Carbohydrate Absorption in the Fetus and Neonate

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(

Development

of Carbohydrate

Absorption

in

the Fetus and Neonate

Munir Mobassaleh MD, Robert K. Montgomery, PhD,

Jeftrey A. Biller, MD, and Richard J. Grand MD

From the Department of Pediatrics, Division of Pediatric Gastroenterology and Nutrition, New England Medical Center, Floating Hospital, and Tufts University School of Medicine, Boston

ABSTRACT. Maturation of mechanisms for carbohydrate absorption occurs in a defined sequence during human fetal development. The intestinal enzymes, lactase, su-crase, maltase, isomaltase, and glucoamylase, are at

ma-ture levels in the term fetus. Mature levels of pancreatic

amylase activity and glucose transport occur postnatally,

and levels are low in both the term and preterm neonate.

In the preterm infant, sucrase, maltase, and isomaltase

are usually fully active, but lactase activity, which

in-creases markedly from 24 to 40 weeks, may be low de-pending upon fetal age. Despite these developmental patterns, clinical lactose intolerance is uncommon. Post-natal adaptive responses to ingested carbohydrates lead to competent carbohydrate absorption. Inadequately ab-sorbed carbohydrates are salvaged by cobonic flora through fermentation of carbohydrates to hydrogen gas

and short-chain fatty acids; the latter are readily

ab-sorbed by the colon. In this setting, carbohydrate tends to be absent from the stool. Noninvasive reflection of the status of carbohydrate absorption may be obtained from breath hydrogen testing, a technique of particular value in young infants. Pediatrics 1985;75(suppl):160-166; car-bohydrate, intestine, fetus, newborn.

Increasing interest in fetal and neonatal

proc-esses for the digestion and absorption of canbohy-dnate has developed over the past 20 years. Indeed,

with the survival of pneterm infants of younger

gestational age, data previously important only to developmental biologists has now become clinically relevant to the care and feeding of low-birth-weight

and premature neonates. The following discussion is a brief overview of the evolution of the different

mechanisms involved in carbohydrate digestion and

absorption.’3 In addition, methods of detection and

Read before the workshop on Current Issues in Feeding the Normal Infant, Palm Springs, CA, April 8-11, 1984.

Reprint requests to (R.J.G.) New England Medical Center, 171 Harrison Aye, Box 213, Boston, MA 02111.

American Academy of Pediatrics.

disorders of carbohydrate malabsorption will be

reviewed.

FETAL PREPARATION FOR CARBOHYDRATE

ABSORPTION

Various components of the mechanisms of can-bohydrate digestion and absorption appear at dif-ferent fetal ages.’3

Amylase

Salivary amylase (ptyabin, diastase) activity is

first detected at 20 weeks of gestation in the human fetus and is present thereafter.’ The role of this

enzyme in utero remains undefined, and its

adap-tive value in neonates is unclear. Zymogen granules in the acini of the fetal pancreas develop by 20

weeks of gestation4’5; however, it is not known whether amylase is present at the same time.

Am-ylase activity is first detected by 22 weeks of

ges-tation,6 but mature bevels of pancreatic amylase are often not reached until after birth. Interestingly, pancreatic amybase activity can be detected in

am-niotic fluid by the 16th week of gestation.7

Intestinal enzyme ontogenesis is a widely studied

field”2; however, care should be taken in extrapo-bating data from studies using experimental animals to the human. Developmental patterns of disac-chanidase activity in normal fetuses and newborns

is shown in the Figure.

Lactase

Before the 24th week of gestation, intestinal bac-tase activity is low.8’9 It then begins to increase, and during the third trimester, bactase activity increases markedly such that levels in term neonates are two

to four times those of infants 2 to 1 1 months of age

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DEVELOPMENTAL AGE

Figure. Development of disaccharidase activities in

hu-man fetal jejunum. Values in parentheses are number of

observations. For infants 2 to 11 months of age, n = 25. Where possible, data are means ± SD. Data adapted from Antonowicz et a!8 (solid circles), Dahlqvist and Lindberg’#{176}

(open circles), and Jirsov#{225}et a!” (triangles). (Reprinted with permission from Grand et al.’)

animals, the bate gestationab rise in lactase activity

is correlated with a concomitant increase in circu-bating corticosteroids.’2 It is of interest that there is a late gestational increase in cortisob production in the human fetus,’3 yet its relation to

disacchani-dase activity in the fetal intestine has not been investigated. Lactase activity studied in fetuses at 17 to 24 weeks of gestation was found to be highest

in the proximal jejunum,8 a distribution comparable to that in the adult.’4

In most mammals, lactase activity persists at high bevels during the nursing period, and declines to adult values after weaning,’2 a phenomenon not seen in humans. The postweaning decline in expen-imental animals is prevented by hypophysectomy on thynoidectomy; thyroxine administration causes precocious decline in lactase activity when given during nursing.’5

Sucrase, Maltase, and Isomaltase

Even in the youngest fetuses studied, the activi-ties of these enzymes are similar to those in the adult human intestine (Figure). Activity remains

unchanged throughout development except for a

brief surge seen at term.8’9 As with bactase, the topographic distribution of these a-glucosidases, in 17- to 24-week-old fetuses, is similar to that in the

adult intestine, with a maximal specific activity in the proximal jejunum.8”4

Perfusion of either glucose on lactose in fetal lambs olden than 130 days using duodenal catheters shows a comparable rise in blood glucose levels, time of peak bevel, and decline to control levels. These findings are not observed when maltose on sucrose are perfused.’6 Thus, when the appropriate enzyme is present, fetal intestine is capable of ab-sonbing disaccharides efficiently.

Mucosal

Glucose

Uptake

In 11-week fetuses, intestinal uptake of glucose against a concentration gradient is just detectable, and rises fourfold by 19 weeks of gestation.’7 Up-take in the jejunum is higher than that in the ileum of the younger fetuses, but is equal in the olden

fetuses. These observations have been confirmed by measuring jejunal transmurab potential

differ-ences as a reflection of the extent of sodium-de-pendent glucose uptake. Glucose-stimulated poten-tial differences increased markedly from 11 to 21 weeks of gestation.’8”9 Before 14.5 to 16 weeks of gestation, there was no increase in potential differ-ence after glucose infusion in the ibeum.’9 Subse-quentby, values were equal in both jejunum and ileum. Lactose, unlike sucrose, produced no in-crease in potential difference until the 15th week of gestation in human fetuses,’9 confirming the dependence of lactose absorption in the fetus upon the presence of bactase. Data obtained from fetal lambs show that fructose, like glucose, is also well absorbed from duodenab perfusates.’6

Sodium-dependent glucose absorption by in vitro perfused fetal rat colon has been demonstrated recently.2#{176} At term, glucose is absorbed at values comparable to those seen in the near-term ibeum. Transport is abolished by using a sodium-free me-dium. It is noteworthy that adult rat colon cannot

absorb glucose. The capacity of the human fetal

colon for glucose transport is unknown. Middle trimester fetal colon does contain vilbi and surface localization of alkaline phosphatase (a marker for small intestinal microvibbus membrane). The func-tional implications of this finding are unclean.2’

POSTNATAL DEVELOPMENT OF

CARBOHYDRATE ABSORPTION

Amylase

Amylase activity is detected in salivary glands at

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finding is uncertain. Available data suggest high rates of salivary flow in early infancy,23 but amylase secretion has not been completely delineated. Sali-vary amylase is inactivated in the acidic milieu of the stomach; thus, it may have limited contribution

to intraluminab digestion of carbohydrates in in-fants.

Amybase activity in pancreatic homogenates from

term neonates is approximately 10% of that found in adults.24 Furthermore, not every term neonate has detectable pancreatic amybase.6 Duodenal

am-ybase activity does not reach normal adult values until well after birth.2425 Lebenthal and Lee26 have

shown that there is no amylase in duodenal fluid of premature and term infants at birth. Pancreozymin and secretin have no effect on secretion of amybase

in these neonates, minimal effect in 1-month-old infants, but full response by 2 years of age. After

the first month of life, secreted amybase activity can be increased several hundredfold upon stimu-lation by pancreozymin and secretin, and this

ac-tivity increases tenfold in response to increasing

the quantity of ingested starch.25 This adaptive

response, and the presence of adequate intestinal

glucoamylase activity (see below), prevents clinical evidence of stanch intolerance in the vast majority of neonates despite a bow bevel of pancreatic

amy-base secretion.

Lactase

Lactase activity in term neonates is two to four times that of infants 2 to 1 1 months of age,8’9 at

which time bevels reach those of adults (Figure). The exact timing of this decline is not yet clean, but it is probably independent of nursing. Most premature infants do not seem to suffer clinically from lactose intolerance. Those infants fed lactose-containing formulas show no differences with

re-spect to weight gain, number of stools, or serum

albumin level as compared with a group fed

for-mulas containing glucose.’ Glucose bevels are bower

for premature infants than olden infants undergoing a lactose tolerance test27; however, no diarrhea was observed.

Interestingly, in experimental protein-energy malnutrition in the newborn animal, bactase-spe-cific activity is significantly higher than in fed

control animals, but total lactase activity of the entire intestine is unchanged.28’29

Sucrase, lsomaltase, and Maltase

a-Glucosidase activity throughout fetal life is comparable to that of the adult human intestine with a marked increase seen at term (Figure).8’9

In experimental animals, a-glucosidase activity increases in the suckling period when lactase

activ-ity starts to decrease.’2 This postweaning increase of activity, which is not seen in humans, can be precociously stimulated by early sucrose feeding’#{176} on administration of corticosteroids,30’3’ and it can be abolished by adrenalectomy.3#{176} Data concerning hormonal control ofthese enzymes are not available for humans

Mucosal

Glucose

Uptake

Glucose transport across the intestinal mucosa

continues to increase during the first few months of life, as evidenced by potential difference mea-surements. Younoszai,32 using data from various

perfusion studies, calculated that jejunal glucose absorption in infants up to 12 months of age is limited in comparison with that in adults. The apparent Michaelis constant for glucose absorption

in infants is 5.8 mM as compared with 20 mM on

greaten in adults.33 This increase in capacity for

glucose absorption after infancy is either the result of an increase in surface area and/or in the number of transport sites or an increased capacity of the sites already developed.32 McNeish et al,34 reviewing

several glucose perfusion studies in humans, showed that there was a significantly higher glucose potential difference in term infants v preterm in-fants who were appropriate for gestational age, a finding that suggests bate gestational maturation of

glucose transport mechanisms. Infants who are

small for gestationab age have the lowest values for

glucose absorption; indeed intrauterine growth ne-tardation may delay the maturation of glucose

transport processes.34

OVERALL ADAPTIVE RESPONSES TO

INGESTED CARBOHYDRATES

The overall adaptive responses to ingested can-bohydrates have been extensively studied in both

the term and preterm infant.3539 The preterm in-fant has significantly bower bactase activity at birth,

but with little apparent clinical significance. MacLean et al35 studied 22 such infants during the

first 7 weeks of life. Among these infants, 75% were

capable of breath hydrogen excretion by 2 weeks of life, and 100% by the end of the third week. Breath hydrogen levels were dependent upon the total daily

lactose intake, lactose intake pen meal, and

post-natal age. The authors concluded that at beast 66% of ingested lactose entered the colon and was fen-mented by bacteria. Interestingly, weight gain and stool output of these infants were normal. Thus,

despite elevated breath hydrogen bevels, which ne-flect inadequately absorbed carbohydrate in the

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Lactose assimilation in term neonates was stud-ied by measuring breath hydrogen and [‘3CO2] and fecab [‘3C]excretion.36 There was detectable pre-prandial breath hydrogen in all 19 infants studied. Hourly and cumulative recovery of [‘3C] in the breath of infants given [‘3CJ-1-lactose was identical with that of adults given naturally labeled glucose with the stable isotope [‘3C1, thus indicating the normal capacity of full-term neonates to digest and absorb lactose. (Breath [‘3C] represents the

necov-eny of this isotope from irigested carbohydrates after its absorption and oxidation in the body.) Patients given both [‘3C}-1-bactose and [‘3C]-1-gbu-cose separately showed that hourly recovery of breath [‘3C] were not significantly different; how-even, the cumulative recovery after eight hours was higher for ingested [‘3C]-1-glucose. Fecal [‘3C] after administration of [‘3C]-1-lactose was low.37 Thus, batose absorption is almost complete in term in-fants, atid cobonic salvage of inadequately absorbed carbQhydrates also occurs.

These conclusions have been confirmed by two additional studies. Lifschitz et al38 demonstrated the pnesene of elevated breath hydrogen levels after breast-feeding in newborn infants 4 to 5 weeks of age. Fecal pH was greaten than 5.5, and reducing substances were absent from all stools.m Chiles et al39 demonstrated that both term and preterm in-fants inadequately absorb lactose from the small intestine; however, reducing substances were ab-sent from stools, except after antibiotic therapy. This provides further documentation of the robe of cobonic salvage of carbohydrates not absorbed in the small bowel.4#{176}

The mechanism by which neonates achieve this carbohydrate salvage is presumed to be through cobonic bacterial fermentation of carbohydrates to hydrogen gas and short-chain fatty acids; the latter are readily absorbed by the colon. Indeed, perfusion of the human colon with various short-chain fatty acids labeled with [‘4C] is followed by a significant recovery (approximately 50%) of [‘4C02] in the breath.4’

Thus, incomplete lactose absorption appears to be a common and presumably normal occurrence in preterm and term infants. This represents nei-then a nutritional risk non a cause of diarrhea because inadequately absorbed carbohydrates are salvaged by cobonic flora, and sugar tends to be absent from the stools.

DISORDERS OF CARBOHYDRATE

ABSORPTION

Glucose-Galactose Malabsorption

This is a rare disorder detected in those neonates who develop diarrhea with acidic stools and who

have fecal reducing substances present after the first feeding of glucose water.42’43 The diagnosis in these patients with a congenital transport defect for glucose and galactose is detected by means of a flat glucose and a normal fructose tolerance test. Confirmation of the dignosis can be achieved by in vitro measurement of glucose transport in a small bowel biopsy or by intrabuminal perfusion.

Fructose malabsorption has not been commonly described. A recent report44 described a case of fructose malabsonption proven by a positive fruc-tose breath hydrogen test using a dose (1 g) less than that present in one apple or pear (4 to 7 g). All “normal” children tested had normal fructose breath hydrogen bevels following administration of 10 g of fructose.

Pancreatic Amylase Deficiency

This is seen with hereditary diseases of the exo-cnine pancreas, particubanby cystic fibrosis and Shwachman syndrome.45 The majority of patients with cystic fibrosis have absent on bow bevels of amylase activity; however, their symptoms are usu-ally more attributable to fat than to carbohydrate mabdigestion.

Shwachman syndrome, consisting of exocnine pancreatic insufficiency, and hematobogic and skel-etal abnormalities, is the second most frequent cause of pancreatic insufficiency in children.45 Am-ybase activity is low on absent in such infants, and they have diarrhea and malabsonption syndrome. Amylase deficiency in both cystic fibrosis and Shwachman syndrome is treated by administration of pancreatic supplements.

Primary

or Congenital Maltase-Glucoamylase

Deficiency

This has not been described; however, secondary deficiency due to mucosal injury is discussed below. Clinically, glucoamybase plays an important robe during the first few months of life, when pancreatic amylase bevels are low, particularly in babies fed starch on other forms of glucose polymers.46

Primary Deficiency

This follows an autosomab recessive pattern of inheritance; hetenozygotes have an intermediate en-zyme activity.47’48 Incidence is 0.8% in North

Americans47 and about 10% in the Eskimos of

Greenland.49 The small intestine has normal mon-phobogy.46

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Group Prevalence of Lactose

Malabsorption

(%) 100

95 95 94 81 73 64 56 24 15 2 young children, chronic diarrhea may occur without failure to thrive.51’52 Occasionally, the first manifes-tations appear in adulthood with complaints of diarrhea, abdominal cramps, and flatulence, which are intermittent in nature and mimic the “irritable bowel syndrome.” The diagnosis of sucrase-isomab-tase deficiency is most easily achieved by means of the sucrose breath hydrogen test.53’54

The induction of sucrase-isomaltase activity by means of dietary carbohydrate has been reported in both experimental animals and normal humans.55 In addition, there has been a report56 of one patient with sucrase-isomaltase deficiency who had an in-crease in enzyme activity fobbowing a diet high in fructose.

Primary Lactase Deficiency

This rare disorder consists of the absence of lactase activity in the intestinal brush border, non-mal small bowel mucosal histology, and normal bevels of other disacchanidases.46 Few previously reported cases fulfill the above criteria. Recent cases have been proven by lactose tolerance tests, fecal lactose measurements, small bowel histology, and enzyme activities.57 Clinically, this disorder is controlled by means of a lactose-free diet and con-rection of any underlying nutritional deficiencies.

Genetic “Late-Onset” Lactase Deficiency

This is the most common form of genetically determined lactase deficiency. This term is really a misnomer, as the great majority of the world’s populations develop low intestinal lactase levels during mid-childhood (Table). This finding is most prominent in African blacks. Those of Scandina-vian or Anglo-Saxon genetic background have ac-quined a high degree of lactose tolerance with pres-ervation of intestinal lactase activity.58

Accord-TABLE. Prevalence of Genetic Late-Onset Lactose Malabsorption Among Ethnic or Racial Groups*

Orientals in the United States Bantu

American Indians of Oklahoma Alaskan Eskimos

Black Americans Children in Ghana Indians in Bombay Mexican Americans White Americans White “Anglo-Americans” Danes

* Adapted from Montgomery et al.46

ingly, it is customary to expect normal lactase ac-tivity in white US children until 5 years of age, and in black children until 3 years of age.59’1’#{176}Lactose intolerance detected in children before these ages usually indicates an underlying mucosal lesion.

In subjects with “bate-onset” bactase deficiency, enzyme activity is usually 5% to 10% of normal activity. The properties of the residual enzyme are identical with those of normal subjects, leading to the belief that this deficiency represents an altera-tion in a regulatory gene encoding “turn-off” syn-thesis of lactase.6’

Secondary

Disorders of Carbohydrate

Absorption

These occur in a variety of clinical settings. Bac-tenial overgrowth or stasis syndrome may be asso-ciated with increased fermentation of dietary car-bohydrates in the small bowel. Clinical symptoms are similar to those seen in the presence of disac-chanidase deficiency. The diagnosis may be sus-pected when a very early peak of breath hydrogen is detected during carbohydrate challenge.

Carbohydrate malabsonption frequently occurs after mucosal injury of the gastrointestinal tract causing vibbus flattening or damage to the intestinal epithelium. Disorders that often produce this lesion include infectious entenitis, gluten-sensitive enter-opathy (celiac sprue), radiation entenitis, drug-in-duced entenitis, giardiasis, and inflammatory bowel disease.46

Lactase, present in smaller amounts, is usually the first affected disacchanidase, presumably be-cause of its distal location on the villus.62 Treat-ment of the primary disorder is mandatory for the return of bactase activity, which usually lags behind the return of normal morphobogy. Prolonged lactose intolerance, which may persist for months after healing starts, is unique to this disacchanidase, and its biochemical basis is unexplained.46

Secondary sucrase-isomabtase deficiency is usu-ally of less clinical significance than lactase defi-ciency. Enzyme activity is not totally lost and usu-ably does not reach the bow levels of primary su-crase-isomaltase deficiency, thus patients tend to tolerate some sucrose intake.46

Gbucoamybase deficiency is rebated to the severity of the mucosal lesion,63 and is of minimal clinical significance in most patients.

CONCLUSIONS

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clinical setting, careful attention must be paid to symptoms, the presence or absence of canbohy-drates in the stools, and the status of the patient. Breath hydrogen testing is a simple and noninva-sive technique of particular value in young infants for the detection of abnormalities in carbohydrate absorptlon.647#{176}

ACKNOWLEDGMENTS

This work was supported by National Institutes of Health (NIH) Grants AM14523, AM32658, AM07333, AM07471, and HD14498.

We thank Maniana Sybicki for technical assistance.

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1985;75;160

Pediatrics

Munir Mobassaleh, Robert K. Montgomery, Jeffrey A. Biller and Richard J. Grand