Gastroenterology and Nutrition

Development of the Gastrointestinal System

• 1.

  How does the primitive gut develop in the fetus, and what are its three divisions?

Folding occurs along the embryo in a cephalocaudal progression that leads to the incorporation of some of the endodermal-lined yolk sac into the embryo, which in turn results in the creation of the primitive gut. The primitive gut is composed of the foregut, midgut, and hindgut. The foregut is most cephalic and will become the esophagus and stomach. The midgut becomes the small intestines, and the hindgut becomes the colon ( Fig. 10-1 ).

• 2.

  When does the lung bud separate from the esophagus?

At approximately 4 weeks of gestation, the lung buds appear on the ventral surface of the foregut. This outpocketing from the esophagus will eventually separate completely, forming separate walls known as the esophagotracheal septum. This separation is critical, and any remnant in connection leads to esophageal atresia, a tracheoesophageal fistula, or both. The most common type of developmental abnormality that can occur as a result of this splitting is proximal esophageal atresia with a distal esophagotracheal fistula, which accounts for about 85% of all esophageal atresias.

• 3.

  When does the liver develop?

The liver forms at about the third week of gestation as an outgrowth, known as the hepatic diverticulum or liver bud, of the endodermal epithelium of the foregut. This connection grows and narrows to form the bile duct to connect the developing liver to the foregut. A small ventral outgrowth forms that will develop into the gallbladder and connecting cystic duct. The intrauterine failure to develop a complete biliary tree can lead to extrahepatic biliary atresia of embryonic or fetal form, which occurs in 10% to 35% of all cases. ¹

1 Petersen C. Biliary atresia: the animal models. Semin Pediatr Surg 2012;21(3):185–91.

• 4.

  How does the pancreas develop?

The pancreas develops in two separate locations as a bud from the endodermal-lined foregut. The dorsal pancreas develops from a bud on the dorsal surface opposite the developing biliary tree. The dorsal pancreatic bud is located within the dorsal mesentery and grows with a central dorsal pancreatic duct draining to the foregut through the minor papilla. The ventral pancreatic bud develops close to the developing bile duct. When the duodenum rotates to become C -shaped, the bud is rotated onto the dorsal surface along the dorsal pancreas in a position immediately below and behind it. The two developing pancreas parts grow together, and the dorsal pancreatic duct fuses with the ventral pancreas to form the main pancreatic duct (of Wirsung) draining through the major papilla into the duodenum ( Fig. 10-2 ).

• 5.

  What is the clinical significance of the embryologic development of the pancreas?

If the connection from the dorsal pancreas continues to drain directly into the duodenum by way of this secondary drainage system (the accessory pancreatic duct of Santorini), the condition is known as pancreas divisum. This connection drains through the minor papilla at a separate location and is the most common anomaly of pancreatic development. Any variation in this process can lead to completely separated drainage to a duplicate drainage of the pancreas. The clinical significance of this condition is the higher risk of pancreatitis in patients with pancreatic duct anomalies.

• 6.

  What is the significance of the rotation of the midgut?

During the sixth week of gestation the small intestines and the colon herniate into the umbilical cord as a result of the rapid growth of the liver. The intestine then rotates around a central axis formed by the superior mesenteric artery. This counterclockwise rotation is completed, and the intestine migrates back into the abdominal cavity to be fixed in position. This rotation results in the colon being located anterior to the small intestines, with the cecum being located in the right lower quadrant. An interruption during this physiologic herniation and rotation will result in abnormalities. When the gut fails to return to the abdominal cavity, an omphalocele is formed. This abnormality occurs in approximately 2.5 in 10,000 births. There is a high rate of associated developmental defects, such as cardiac abnormalities, spinal defects, and chromosomal abnormalities. Malrotation is another abnormality that occurs when the midgut fails to rotate completely. Malrotation can cause the inappropriately positioned small bowel to twist on the superior mesenteric artery and lead to vascular insufficiency and volvulus. The gold standard for diagnosis of malrotation remains the upper gastrointestinal tract series that shows the duodenal C -loop crossing to the left of midline at a level equal to or greater than the pylorus. ²

2 Martin V, Shaw-Smith C. Review of genetic factors in intestinal malrotation. Pediatr Surg Int 2010;26(8):769–81.

• 7.

  How does the hindgut develop?

The hindgut forms the most distal part of the primitive gut. It develops into the distal third of the transverse colon and the upper part of the rectal canal. Initially the urogenital system and the hindgut join together in the cloaca. The two systems separate from each other, and the rectal canal fuses with the surface to form an open pathway that will form the anus and rectum. Any abnormalities with this development can result in a continued connection, or urorectal fistula, between the urologic and gastrointestinal tracts. When the anorectal canal fails to fuse with the surface, a rectoanal atresia occurs with resulting imperforate anus. Imperforate anus occurs in 1 in 50,000 live births and has a high incidence of other associated birth defects. ³

3 Juang D, Snyder CL. Neonatal bowel obstruction. Surg Clin North Am 2012;92(3):685–711.

• 8.

  What is the enteric nervous system (ENS)?

The ENS is the nervous system that regulates intestinal smooth muscle to control gastrointestinal motility. The ENS is composed of a complex network of ganglia that function independently from the central nervous system. Although independent, the ENS can be influenced by vagal and pelvic nerves of the parasympathetic nervous system and spinal nerves. Within the ENS the interstitial cells of Cajal are the pacemaker cells and are responsible for the coordinated smooth muscle contractions within the gut.

KEY POINTS: GASTROINTESTINAL DEVELOPMENT

• 1.

  The most common form of transesophageal fistula is proximal esophageal atresia with a distal tracheoesophageal fistula.

• 2.

  Although most cases of biliary atresia are caused by a destructive, perinatal inflammatory process, a subset appears to be caused by a prenatal developmental abnormality of the extrahepatic biliary tree that is associated with other congenital anomalies, such as polysplenia.

• 3.

  Rotational abnormalities of pancreas development can be observed either as an annular pancreas presenting with obstruction or as ductal abnormalities presenting with pancreatitis later in childhood.

• 4.

  Delayed passage of meconium should raise consideration of both anatomic abnormalities (e.g., variants of imperforate anus) and motility disorders (e.g., Hirschsprung disease).

Meconium

• 9.

  What is meconium?

Meconium is the material and secretions created by or swallowed by the fetus in the gastrointestinal tract while in utero . It contains ingested amniotic fluid, lanugo, intestinal cells, bile salts and pigments, and pancreatic enzymes.

• 10.

  When is meconium normally passed in a term infant?

Normally, the initial passage of meconium occurs within the first 12 hours after birth. Meconium passage will occur in 99% of term infants and 95% of premature infants within 48 hours of birth.

• 11.

  What is the significance of the lack of passage of meconium at the normal time?

When meconium is not passed by 48 hours of life, the possibility of an anatomic or neuromuscular abnormality must be considered, such as Hirschsprung disease. ⁴

4 Kenny SE, Tam PK, Garcia-Barcelo M. Hirschsprung's disease. Semin Pediatr Surg 2010;19(3):194–200.

Fetal Growth and Assessment

• 12.

  Why is it important to routinely monitor fetal growth during pregnancy?

Intrauterine growth is one of the most important signs of fetal well-being and one of the most reliable indicators of the pathologic conditions that affect the mother and fetus during pregnancy. Early identification of alterations in fetal growth can allow for early intervention to prevent long-term complications for the fetus and newborn infant.

• 13.

  What do the terms low birth weight (LBW), very low birth weight (VLBW), and extremely low birth weight (ELBW) indicate?

  • ▪

    LBW: less than 2500 g

  • ▪

    VLBW: less than 1500 g

  • ▪

    ELBW: less than 1000 g

This classification is clinically relevant because neonatal morbidity and mortality are strongly correlated with the infant’s gestational age and birth weight.

• 14.

  What are the most common causes of intrauterine growth restriction (IUGR)?

Intrinsic (fetal causes):

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  Constitutional

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  Genetic

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  Toxic

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  Infectious

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  Teratogenic

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  Behavioral

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  Intrauterine constraint

Extrinsic (maternal/placental) causes:

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  Maternal age younger than 16 years or older than 35 years

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  Maternal illness

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  Placental dysfunction

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  Multiple gestation

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  Demographic

• 15.

  What causes neonates to be large for gestational age?

Infants with birth weight above the 90th percentile on the intrauterine growth chart are classified as large for gestational age. Maternal diabetes is the most common cause of fetal growth acceleration owing to the induction of fetal hyperinsulinism during gestation. Other causes include fetal hydrops (edema), Beckwith–Wiedemann syndrome, transposition of the great vessels, and maternal obesity.

• 16.

  Why is it clinically useful to classify small-for-gestational-age infants as symmetric or asymmetric?

Infants who are symmetrically growth retarded have proportionally reduced size in weight, length, and head circumference. This type of growth retardation starts early in pregnancy, and it is often secondary to congenital infection, chromosomal abnormalities, and dysmorphic syndromes. Most babies with IUGR, however, are asymmetrically growth retarded, with the most severe growth reduction in weight, less severe length reduction, and relative head sparing. Asymmetric IUGR is caused by extrinsic factors that occur late in gestation, such as pregnancy-induced hypertension. Distinguishing between symmetric and asymmetric IUGR is important because infants with asymmetric IUGR have a better long-term growth and developmental outcome.

Medical Problems of the Growth-Restricted Infant

• 17.

  What are the long-term risks of IUGR?

  • ▪

    Development: Because this group is heterogeneous, the outcome depends on perinatal events, the etiology of growth retardation, and the postnatal socioeconomic environment. In general, the asymmetric growth-retarded baby does not show significant differences in intelligence or neurologic sequelae but does demonstrate differences in school performance related to abnormalities in behavior and learning.

  • ▪

    Health effects: An increased risk of hypertension is found in adolescents and young adults. Growth-retarded infants with a low ponderal index (measurement of leanness calculated by body mass divided by height cubed) are at increased risk for syndrome X (non–insulin-dependent diabetes mellitus, hypertension, and hyperlipidemia) and death resulting from cardiovascular disease by the age of 65 years (Barker hypothesis).

  • ▪

    Growth: Fetuses that experienced growth failure after 26 weeks’ gestation (asymmetric growth retardation) exhibit a period of catch-up growth during the first 6 months of life. However, their ultimate stature is frequently less than an appropriate-for-gestational-age (AGA) baby.

Caloric Requirements

• 18.

  What is the significance of energy balance?

Energy, being neither created nor destroyed, conforms to classic balance relationships. Energy balance is a state of equilibrium when energy intake equals expenditure plus losses. If energy intake exceeds expenditure plus losses, the infant is in positive balance, and excess calories are stored. If energy intake is less than expenditure plus losses, the infant is in negative balance, and calories are mobilized from existing body stores. Maintenance, or basal, energy requirements are the energy needs required to cover basal metabolic rate or resting energy expenditure; total energy expenditure in infants is the sum of the energy required for basal metabolic rate, activity, thermoregulation, diet-induced thermogenesis, and growth. The energy balance equation may be stated as follows:

• 19.

  What are the caloric requirements for LBW infants?

LBW infants require at least 120 cal/kg/day, partitioned to approximately 75 cal/kg/day for resting expenditure and the remainder for specific dynamic action (10 cal/kg/day), replacement of inevitable stool losses (10 cal/kg/day), and growth (25 cal/kg/day) ( Table 10-1 ).

• 20.

  What is the respiratory quotient (RQ), and what is its significance?

The RQ is the ratio of the volume of carbon dioxide (CO ₂ ) produced to the volume of oxygen (O ₂ ) consumed per unit of time (V co ₂ /V O ₂ ). This ratio varies with the type of nutrient oxidized. In addition, the energy produced varies with the type of substrate burned. Thus various substrates have different RQs, and varying proportions of different nutrients result in different energy production per liter of O ₂ consumption or CO ₂ production. The RQs and caloric equivalents of O ₂ and CO ₂ for carbohydrate, fat, and protein are shown in Table 10-2 .

• 21.

  What is the energy cost of growth?

The energy cost of growth includes the energy used for synthesis of new tissues (e.g., absorption, metabolism, and assimilation of fat and protein) and the energy stored in these new tissues. The energy cost of growth varies with the type of tissue added during growth. The precise caloric requirements for growth are unknown. A wide range of values for energy cost of growth in neonates has been determined (1.2 to 6 kcal/g of weight gain). Separate evaluations of energy expenditure requirement for fat and protein deposition in premature newborns estimate that 1 g of protein deposition requires 7.8 kcal, and 1 g of fat requires 1.6 kcal.

Carbohydrate Requirements

• 22.

  How can carbohydrate requirements be estimated in newborn infants?

Strict carbohydrate requirements are difficult to estimate because glucose, a preferred metabolic fuel for many organs (including the brain), is synthesized endogenously from other compounds. Several methods have been used to assess carbohydrate requirements in neonates:

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  Breast milk intake of lactose (assuming breast milk provides optimal intakes of all nutrients)

• ▪

  Constant infusion of labeled glucose to determine the rates of glucose production and oxidation (as a reflection of overall carbohydrate metabolism)

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  Altering the amount of the carbohydrate intake in the diet and determining its effect on energy metabolism and nitrogen retention

• 23.

  The rate of endogenous glucose production in neonates has been estimated to range from 4 to 6 mg/kg/min. Do these values represent the ideal carbohydrate intake in neonates?

No. The rates of endogenous glucose production should be regarded as only the minimal carbohydrate requirement because of the methods and conditions in which these measurements were performed. These studies were done in neonates under basal or resting metabolic conditions and during fasting periods. In addition, these studies did not take into account the energy cost of physical activity, growth, and thermal effect of feeding. Higher values ranging from 5.8 to 6.8 mg/kg/min have been used as guidelines for the initiation of glucose infusion in neonates receiving parenteral nutrition with the ability to increase toward 13 mg/kg/min, depending on the infant.

• 24.

  What problems can be associated with excessive carbohydrate intake?

Excessive intake of carbohydrate in infant feedings may lead to delayed gastric emptying, emesis, diarrhea, and abdominal distention caused by excessive gas formation as colonic bacteria digest the extra carbohydrates. The excessive administration of intravenous glucose, at rates exceeding 13.8 mg/kg/min, may be associated with metabolic complications such as hyperglycemia, glycosuria, and osmotic diuresis. In addition, the excessive glucose metabolized is stored mainly as fat. Early overfeeding may be an important factor in later childhood and adult obesity, though more recent work suggests that genetic factors may be as important. ⁵

5 Zhao J, Grant SF. Genetics of childhood obesity. J Obes 2011;2011:845148.

• 25.

  Why do infant formulas contain comparable amounts of lactose and glucose polymers?

  • ▪

    Premature infants have a limited ability to digest lactose because intestinal lactase does not reach maximal activity until near term.

  • ▪

    Glucose polymers are well digested and absorbed by premature infants.

  • ▪

    The use of glucose polymers allows the osmolarity of the formula to remain low, even at high caloric density of 24 kcal/30 mL (<300 mOsm/L), thereby providing premature infants with adequate caloric intake and preventing such consequences as osmotic diarrhea.

• 26.

  What is the metabolic fate of the lactose malabsorbed by the small intestine?

The malabsorbed lactose is fermented in the colon, forming various gases such as CO ₂ , methane, and hydrogen and short-chain fatty acids such as acetate, propionate, and butyrate. These short-chain fatty acids are absorbed in the colon, reducing energy losses in the stools and maintaining the nutrition and function of the colon. Despite these putative benefits of lactose fermentation, metabolic concerns that result from the reduced digestion and absorption of lactose in the small intestine include the following:

• ▪

  Decreased insulin secretion and a reduced effect on protein synthesis

• ▪

  Lower adenosine triphosphate formation when lactose is fermented to acetate instead of following the glucose metabolic pathways

• ▪

  Possible increased risk of necrotizing enterocolitis

Protein Requirements

• 27.

  What are the essential amino acids?

The amino acids that cannot be synthesized in the body are regarded as essential amino acids:

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  Leucine

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  Threonine

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  Phenylalanine

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  Isoleucine

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  Methionine

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  Tryptophan

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  Valine

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  Lysine

• ▪

  Histidine

• 28.

  Which of the amino acids are considered conditionally essential for the preterm infant?

Cysteine, tyrosine, and taurine are essential because of immaturity of the enzymes (decreased activity) involved in their synthesis.

• 29.

  What is the whey-to-casein ratio of cow’s milk and human milk protein?

The whey-to-casein ratio of cow’s milk protein is 18:82 and that of human milk protein is 60:40. In total, most formulas contain up to 1.5 times more protein than human milk in order to approximate the protein quality of human milk. ⁶

6 Martinez JA, Ballew MP. Infant formulas. Pediatr Rev 2011;32:179–89.

• 30.

  How does the whey-to-casein ratio change during lactation?

The ratio of whey to casein is about 90:10 at the beginning of lactation and rapidly decreases to 60:40 (or even 50:50) in mature milk.

• 31.

  What is the predominant whey protein in human milk and cow’s milk?

The predominant whey protein in cow’s milk is beta-lactoglobulin, and the predominant whey protein in human milk is alpha-lactalbumin.

• 32.

  What are the non-nutritive roles of protein in human milk?

  • ▪

    Whey proteins are known to be involved in the immune response (immunoglobulins), lactose synthesis (alpha-lactalbumin), and other host defenses (lactoferrin).

  • ▪

    Casein phosphopeptides are believed to enhance the absorption of minerals.

  • ▪

    Casein fragments are thought to increase intestinal motility.

  • ▪

    Glycoproteins may promote the growth of certain beneficial bacteria.

• 33.

  Name the methods used for determining protein requirements.

  • ▪

    Factorial method (based on reference data of infant body composition)

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    Balance method (protein intake = protein retention − inevitable protein losses)

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    Indices of protein nutritional status (e.g., plasma albumin and transthyretin concentrations; protein intake required to maintain these indices within an acceptable range)

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    Stable isotope tracer techniques (insight into the way metabolism changes with clinical state or nutritional status and thus an assessment of protein requirement)

• 34.

  What is a lactobezoar?

Lactobezoars are intragastric masses composed of partially digested milk curd (i.e., casein, fat, and calcium). Rarely seen now, lactobezoars were reported in LBW infants (<2000 g) fed casein-predominant formulas because casein can form large curds when exposed to gastric acid that are difficult for the LBW infant to digest. Whey protein, however, is less likely to precipitate and is emptied more rapidly from the stomach.

• 35.

  What is the protein requirement of term and preterm infants?

The recommended protein intake for term infants is approximately 2 to 2.5 g/kg/day; for preterm infants it is 3 to 4 g/kg/day.

• 36.

  What factors may affect protein use in the neonate?

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    Energy intake

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    Quality of protein intake

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    Intake of other nutrients

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    Infections and stress

• 37.

  What is the protein content of currently available formulas?

Term formulas:

• ▪

  Milk-based formulas (e.g., Similac Advance, Enfamil LIPIL, Good Start Supreme): 2.1 to 2.8 g/100 kcal or about 1.5 to 1.8 g/100 mL

• ▪

  Soy-based formulas (e.g., Similac Isomil Advance, Enfamil Prosobee LIPIL, Good Start Supreme Soy): 2.3 to 2.5 g/100 kcal or about 1.4 to 1.6 g/100 mL

Preterm formulas (e.g., Similac Special Care, Enfamil Premature LIPIL):

• ▪

  2.5 to 2.9 g/100 cal, 1.6 to 2 g/100 mL

Follow-up formulas for LBW weight infants (e.g., Similac NeoSure Advance, EnfaCare LIPIL):

• ▪

  2.6 to 2.8 g/100 kcal, 1.6 to 1.8 g/ 100 mL

• 38.

  What is the rate of protein loss in premature infants who receive only 10% dextrose and water in the immediate newborn period?

ELBW infants (<1000 g) who receive only glucose lose approximately 1.2 g/kg/day. More mature infants lose protein at a slower rate (0.9 g/kg/day at 28 weeks and 0.7 g/kg/day at 31 weeks). Any protein deficits that are accrued must be replaced.

• 39.

  How can the protein losses be minimized?

Early provision of protein (1 to 1.5 g/kg/day) along with minimal calories (30 cal/kg/day) can minimize the protein losses in ELBW infants. Even with good early protein administration, however, rates of intrauterine growth are virtually never achieved and some degree of extrauterine growth failure is the norm.

• 40.

  How do protein requirements differ when protein is delivered parenterally versus enterally?

Protein requirements are higher parenterally because preterm infants retain only 50% of amino acids administered intravenously but 70% to 75% of formula or human milk protein.

• 41.

  What is the ideal calorie-to-protein ratio to ensure complete assimilation of protein?

  • ▪

    Enteral feedings: approximately 30 cal/g of protein

  • ▪

    Parenteral feedings: 20 to 30 cal/g of protein (based on limited data)