Human milk substitutes have been used in infant nutrition for centuries. Similarly, milk and milk products derived from both animal and vegetable sources have been an essential ingredient and constituent in human diets for all of recorded history. Notwithstanding the obvious benefit of milk to humankind, consumption of human milk substitutes may cause symptoms or, more rarely, disease. The pertinence to pediatrie practice cannot be overstated. Herein, selected clinical gastrointestinal disorders due to milk consumption are reviewed in a format designed to contribute to a clearer understanding of the confusing terminology relevant to milk-related disorders. Whenever possible, overlapping or unclear terminology is pointed out and suggestions for sensible terminology based on pathophysiology are presented. An understanding of these disorders will lead to a more rational basis for selection of infant formulas when faced with milk-related feeding problems in clinical practice. It is beyond the scope of this review to discuss the putative association between foreign milk protein consumption and type I diabetes mellitus.1 Also, the association of milk intake with nongastrointestinal diseases such as pulmonary hemosiderosis and various metabolic disorders such as galactosemia will not be considered.
BRIEF REVIEW OF THE COMPOSITION OF HUMAN MILK SUBSTITUTES
The carbohydrate and protein constituents in milk account for most gastrointestinal problems due to milk consumption. Rational clinical decisions about the use of human milk substitutes can be made only when the carbohydrate and protein sources available in common infant and pediatrie formulas are clearly known and understood. Inasmuch as clinicians receive a great deal of information about milk formulas from company representatives, it is likely that the "basics" are ultimately lost in the plethora of information about the latest developments and improvements in the companies' well-intended efforts to find a niche market for their own products. While research and development in this industry are critical, and practical advancements are still needed, the majority of disorders described herein can be treated by traditional preparations according to the principles outlined.
Infant formulas are conveniently described by the source of the protein, eg, cow's milk formula, soy formula, and casein hydrolyzed formula (Table 1). The digestibility of cow's milk protein often is defined by its acid solubility. Casein is the milk protein fraction that is insoluble in acid, including gastric acid. The whey fraction is soluble in acid. Human milk is about 60% whey and 40% casein, while cow's milk is 20% whey and 80% casein. The whey content in cow's milk formula is increased in the manufacturing process such that the final protein content is "whey predominant," like human milk. Soy protein isolate requires only the addition of methionine to become practically equivalent to cow's milk protein.
Historically, milk protein has posed a problem for the formula industry because of the large curd size of untreated milk and the antigenicity of milk proteins. These concerns have largely been addressed by two distinct manufacturing techniques, heat treatment and enzymatic hydrolysis. Presently, commercial infant formulas are heat treated to yield a smaller curd size and a softer consistency. Thus, lactobezoars are now uncommon. The technique of enzymatic hydrolysis has resulted in the emergence of several protein "hydrolyzed" formulas in which the average molecular weight of milk protein has been reduced from 70 kd to 0.2 kd. Hydrolyzed formulas are markedly reduced in antigenicity and are widely used in the management of malabsorption and milk protein sensitivity.
More than 25 milk proteins have been described. The most antigenic of these is the major whey protein, ß-lactoglobulin, although others undoubtedly contribute to antigenicity as well. It is estimated that as many as 30% to 40% of milk protein-sensitive infants are also sensitive to soy protein, suggesting shared antigenic determinants or a predisposition to sensitization due to gastrointestinal mucosal barrier dysfunction. Interestingly, circulating plasma immunoglobulin G and immunoglobulin M antibodies to milk proteins can be detected in nearly all individuals who consume milk. Immunoglobulin E antibodies may be responsible for mediating disease although the precise mechanisms by which this occurs remain to be fully elucidated.
Classification of Milk Based on Protein Source
The major carbohydrate in mammalian milk is lactose. In mature human milk, lactose concentrations are approximately 7 g/dL and commercial formulas closely approximate this amount. Much smaller amounts of carbohydrate in the form of oligosaccharides and glycoproteins also are found in human milk, but the significance of these is not completely understood and they are not included in commercial preparations. Many manufactured formulas include lactose as the primary carbohydrate source, but the relatively common occurrence of secondary lactase deficiency requires the availability of lactose-free formulas. A large number of lactose-free formulas are available (Table 2). In most instances, the carbohydrate source in lactose-free formula is sucrose, corn syrup solids (glucose polymers), or a combination thereof. Glucose polymers containing 3 to 5 glucose units per molecule are prepared from corn syrup. Because the carbohydrate content of a formula is the major contributor to osmolarity, the inclusion of glucose polymers in a formula is a useful technique to reduce osmolarity. In certain formulas, starch is added to assist in the emulsification of fat, but this starch is not a significant component of the net carbohydrate energy.
Lactose and Lactase
Lactose, a disaccharide comprised of glucose and galactose, is found only in milk and milk-derived products. Aged cheeses and processed cheeses have relatively less lactose than milk and other milk products such as heavy cream. Interestingly, yogurt containing active bacterial cultures has a relatively small amount of lactose due to hydrolysis to component monosaccharides by bacterial hydrolases.
Classification of Milk Based on Carbohydrate Source
In the small intestine, lactose is hydrolyzed to glucose and galactose by a brush border membraneassociated disaccharidase called lactase-phlorizin hydrolase, or, more simply, lacrase. The monosaccharides then are absorbed by sodium-coupled transport. Laclase activity is highest at the tip of the small intestinal villus and is quite low at due base of the villus. Inasmuch as the villus tip is the region of the intestinal epithelium most often injured by infection and other pathological processes, lactase activity is commonly decreased in association with injury. As discussed below, variation in the activity of lactase occurs during development, in association with small intestinal mucosal disease and as a result of genetic factors. Interestingly, the activity of lactase is not inducible by dietary lactose. Lactase deficiency (or insufficiency) can be viewed as a relative phenomenon; that is, relative to the quantity of ingested lactose. Thus, 4 g of dietary lactose may be well tolerated while 8 g may overwhelm reduced lactase activity and result in symptoms.
Etiology of Secondary Lactase Deficiency
Lactase Deficiency in the Premature Infant
Lactase activity is developmentally regulated. Levels are relatively low until about 36 weeks gestation at which time they approximate those found in term infants.2 Lactase activity is greatest in the first year of life, but in most children, activity remains relatively high until the second decade of life or beyond. Interestingly, levels of other disaccharidases such as sucrase and maltase do not exhibit such a prominent pattern of developmental regulation. Infant formulas designed for use in the premature infant are lactosereduced and contain glucose polymers to facilitate carbohydrate absorption and circumvent problems due to relative lactase deficiency.
Primary (Congenital) Lactase Deficiency
Congenital lactase deficiency is extremely uncommon. The largest series of patients reported to date includes 16 patients from Finland.3 These Finnish infants were identified in 12 families over a 17-year interval. All of these babies had diarrhea by day 10 of life and one half had diarrhea with the first feeding. Failure to thrive was common until the proper diagnosis was made and treatment with a lactose-free formula was begun. Growth and development was normal by 1 year of age. Congenital lactase deficiency should be suspected in neonates with congenital diarrhea, poor weight gain, and acidic stools with reducing sugars.
Secondary Lactase Deficiency
By far, the most common cause of lactase deficiency in the first few years of life is secondary lactase deficiency. A variety of common pediatrie gastroenterological disorders may sufficiently injure the small intestinal villus to cause a transient lactase deficiency (Table 3). Rotaviral enteritis is encountered most frequently. In infants with acute rotaviral gastroenteritis severe enough to merit hospitalisation, 88% were lactose malabsorbers and 60% were considered lactose intolerant during hospitalization.4 Most interesting was the analysis of the tempo of recovery of lactose absorption. Approximately 20% of babies had not recovered the capacity for lactose absorption 4 weeks after infection and not all had recovered when examined as late as 20 weeks afterward. Almost certainly, these observations are less dramatic in infants with milder rotaviral disease that can be managed as an outpatient.
There are no formal recommendations regarding the use of lactose-free formulas in infants with rotaviral disease. In the majority of instances, it will be appropriate to make this decision empirically or on the basis of simple laboratory tests. Hospitalized infants with acidic stools pH less than 6.5) or positive stool-reducing substances are obvious candidates for lactose-free formulas. Although secondary sucrase deficiency is less common than secondary lactase deficiency, it nevertheless occurs, and it seems logical that both a lactose-free and sucrose-free formula be used in severe cases. This logic can be taken one step further by recalling that disruption of the small intestinal epithelium by a viral enteritis may result in sensitization to milk protein.5 Thus, in selected severe cases, it may be appropriate to use a casein hydrolyzed formula without sucrose or lactose. In patients with mild outpatient rotaviral disease, no change in infant formula is required in most cases.
Genetic Late-Onset Lactase Deficiency
Genetic late-onset lactase deficiency is variously referred to as "acquired" lactase deficiency, "secondary" lactase deficiency, "primary adult-type" lactase deficiency, and "primary acquired" lactase deficiency. The term "genetic late-onset" is most descriptive and will be used herein. Genetic late-onset lactase deficiency is found in 60% to 100% of Asian, African, African-American, Native-American, Eskimo, and Middle Eastern people. It is uncommon (0% to 20%) in whites, especially those of Northern European descent. It is important to remember that the occurrence of genetic late-onset lactase deficiency is most unusual before the age of 5 in any population and is unusual before the age of 10 in whites.6
The molecular basis for the postnatal decline in lactase activity is complex. Various investigators have found low rates of lactase RNA transcription, as well as decreased synthesis and increased degradation of lactase protein. Notwithstanding this uncertainty, patients with genetic late-onset lactase deficiency have a permanent decrease in lactase activity which may or may not contribute to symptoms.
The clinical importance of genetic late-onset lactose intolerance is less clear than one might expect, as pointed out in a recent well-designed study.7 Thirty adults who classified themselves as "severely lactose intolerant" participated in a randomized, double-blind, crossover trial. The study patients received a daily dose (240 mL or 8 oz) of a lactose-containing milk for 1 week and then a lactose-free milk for 1 week. These preparations were adjusted to yield a similar taste to ensure the test subjects were blinded to the type of milk consumed. Perhaps surprisingly, there were no differ' enees in gastrointestinal symptom scores between the two milk preparations, despite the assertion by the test subjects that they were "severely" lactose intolerant. An accompanying editorial8 suggested that "the interplay of mind and body is critical in the development of abdominal symptoms." The relationship between genetic late-onset lactase deficiency and recurrent abdominal pain of childhood has been examined in several studies, but a clear association has not emerged.
Symptoms of Lactase Deficiency
The symptoms of lactase deficiency are related primarily to bacterial fermentation of the unabsorbed lactose as it reaches the colon. Excessive production of hydrogen gas may cause bloating, flatulence, and abdominal pain. Production of organic acids increases the osmolality of colonie contents and contributes to osmotic diarrhea. These symptoms may occur within minutes of ingestion, but more commonly occur 2 or 3 hours after ingestion.
Diagnosis and Treatment of Lactase Deficiency
Lactase deficiency may be suspected on clinical grounds and treated empirically in many, if not most, cases. However, it is certainly prudent to prove lactase deficiency or at least develop evidence in support of lactase deficiency in selected patients. An acidic stool pH (<6.5) and a positive stool-reducing sugar using the Clinitest method suggests carbohydrate malabsorption and lactase intolerance in infants on lactosecontaining formulas. Breath hydrogen analysis following the ingestion of a standard dose of lactose is a noninvasive, accurate technique for the diagnosis and is considered the test of choice. An increase in breath hydrogen content greater than 20 ppm 60 to 90 minutes after ingestion strongly suggests the diagnosis. Mucosal lactase activity can be measured in endoscopie biopsy samples, but this approach is rarely required in the clinical setting. If the clinical situation demands that lactose intolerance be treated, then lactose reduction or elimination is the preferred method. A wide variety of lactose-free formulas are available (Table 2). Older children can be treated with a lactose-reduced diet. Individuals desiring consumption of lactose-containing foods such as milk and ice cream in the face of significant lactose intolerance may use preparations such as Lactaid, although the efficacy is not ideal. Lactaid is a purified yeast enzyme with lactase activity. Treatment of milk prior to ingestion hydrolyzes much of the lactose and may permit consumption without symptoms.
Gastrointestinal Disorders Due to Ingestion of Milk Protein
GASTROINTESTINAL DISORDERS DUE TO INGESTION OF MILK PROTEIN
A variety of gastrointestinal disorders may result from ingestion of milk protein. These may be grouped under the general heading of "milk protein intolerance," "milk protein hypersensitivity," or "milk protein allergy." The terminology used in the medical lit' erature is dreadfully confusing and in need of standardization. It is simply not possible to confidently review the relevant literature and know exactly what is meant from a clinicopathologic perspective by general terms such as "milk protein intolerance" or "milk protein hypersensitivity." Exactly what symptoms are due to "allergy" or "intolerance" is frequently not clear. Current clinical and pathologic understanding of these conditions permits classification into the categories shown in Table 4, although overlap undoubtedly occurs. We have found this classification most helpful in understanding the pathophysiology and appropriate treatment of milk protein-related disorders. Pediatricians and, indeed, pediatrie gastroenterologists will find that the great majority of patients encountered with milk protein-related disorders will fit into the classification outlined below, and rational treatment decisions can be made using this schema.
Pediatricians know that a wide variety of complaints are possibly due to milk ingestion and that such complaints are among the most frequently encountered during an infant's first year of life. The true incidence of all the disorders (Table 4) is not known, but estimates vary between 0.3% and 7.5%. In a prospective study of 1158 Dutch newboms, approximately 20% had clinical symptoms that were considered possibly related to cow's milk consumption.9 Two formal elimination/rechallenge tests identified 2.8% as "milk protein intolerant." The mean onset of symptoms was 13 weeks, and the predominant symptoms included vomiting, diarrhea, growth failure, flatulence, crying, eczema, coughing, and wheezing. The intolerant children were statistically more likely to have generalized symptoms and a family history of atopy than milk protein- tolerant children. Interestingly, 75% were "tolerant" at 4 years of age. This epidemiologie study implies that only a small fraction of infants with complaints possibly related to cow's milk have "milk protein intolerance" when more rigid criteria are applied.
The diagnosis of the disorders discussed below can be achieved on the basis of clinical criteria in the majority of cases. Traditional laboratory methods such as the complete blood cell count and routine blood chemistries will support the clinical diagnosis. Radioallergosorbent tests and skin tests are commonly used to test for IgE-mediated hypersensitivity, but many milk-protein-related disorders may not be IgE mediated. These tests, as well as measurement of specific antimilk protein antibodies, are not sufficiently sensitive or specific to make them routinely useful in the office setting, especially in the first year of life. Protocols for formal elimination/rechallenge are cumbersome and should be reserved for atypical cases. Various diagnostic approaches for patients with food protein-related symptoms have been reviewed by Burks and Sampson.10
Systemic Hypersensitivity Due to Milk Protein Consumption
An extended discussion of systemic milk hypersensitivity is beyond the scope of the current presentation, but it is mentioned because gastrointestinal signs and symptoms may occur. In general, systemic adverse reactions to milk can be categorized as either type I hypersensitivity or delayed hypersensitivity.1' The former occurs within 1 hour of ingestion and is characterized by angioedema, urticaria, wheezing, irritability, vomiting, and diarrhea. Typically, the cutaneous manifestations predominate, and the clinical presentation and the gastrointestinal symptoms do not occur in isolation. The onset of delayed hypersensitivity reactions to milk proteins is usually longer than 1 hour after ingestion, and the gastrointestinal symptoms may predominate, although coincident systemic symptoms usually are noted.
Allergic colitis, sometimes referred to as milk colitis, is encountered relatively commonly in pediatrie practice.12 Typically, a 1- to 2-month-old infant presents with small volume, streaky, bright-red rectal bleeding in association with loose mucoid stools, and occasionally, oven diarrhea. Constitutional signs and symptoms such as weight loss, failure to thrive, fever, and anemia are not common.
Allergic colitis may occur in infants fed cow, soy, or human milk. Curiously, as many as one third of infants with allergic colitis are breast-fed, leading to the hypothesis that maternal consumption of cow or soy protein sensitizes the colon of breast-feeding infants. The precise mechanism by which the neonatal colon is affected in allergic colitis is not known, but factors such as immature mucosal permeability and immature mucosal immunity are likely operative.
Allergic colitis is diagnosed by careful history and physical examination, and a relatively limited laboratory investigation. Careful consideration of the possibility of surgical disorders should be given, but these can be dismissed on clinical grounds in most cases. A stool culture, complete blood cell count, and albumin level should be performed in nearly all cases while tests such as Qostndium difficile toxin assay, abdominal radiographs, and endoscopie examination can be reserved for atypical or especially severe cases. The differential diagnosis includes infectious colitis, Hirschprung's disease, necrotizing enterocolitis, lymphonodular hyperplasia, neonatal inflammatory bowel disease, pseudomembranous enterocolitis, and surgical disorders such as volvulus and intussusception. We reserve flexible endoscopie examination for cases with atypical features such as constitutional signs and symptoms, anemia, an unusual age of presentation, or a lack of response to elimination of intact milk protein. Most patients have a limited, focal, unimpressive endoscopie appearance, although ulcération and exudative colitis can be observed. Biopsies show focal dense eosinophilic infiltrates.
Allergic colitis is treated by elimination of the offending antigen by the use of soy protein formula or a casein hydrolyzed formula. We prefer the latter because of the relatively high incidence of soy protein sensitivity in patients sensitive to cow's milk. Breastfed infants are treated by elimination of cow and soy milk protein in the maternal diet, although the success of this approach has been questioned.13 Symptoms usually resolve in 1 to 2 weeks. Continued breast-feeding can be permitted in selected infants with a normal blood cell count, a normal albumin level, and minimal endoscopie findings, as long as excellent follow up can be arranged. No studies have addressed the duration of dietary restriction required for allergic colitis, but a minimum of 1 year's restriction is prudent. The prognosis is excellent. Although there has been some interest in the possibility that infants with a history of allergic colitis (or cow's milk intolerance) are at increased risk for the development of inflammatory bowel disease later in life, this hypothesis requires further study.
Milk Protein Enteropathy
Milk protein enteropathy also has been termed "milk protein sensitive enteropathy" or "allergic gastroenteritis." We prefer the inclusion of "enteropathy" in the terminology because it implies that pathology occurs in the small bowel mucosa, in contrast to allergic colitis. Symptoms of malabsorption predominate the clinical picture in infants with milk protein enteropathy. Table 5 reviews findings in 54 Finnish infants with a malabsorption syndrome that is due, in part at least, to milk protein enteropathy.14 Note that nearly all infants with milk protein enteropathy will have diarrhea and that significant growth failure is common. In contrast to allergic colitis, few infants have gross blood in the stool. Laboratory measurements support a diagnosis of malabsorption, and endoscopie biopsies almost always show some degree of villus injury and in most instances a "flat" mucosa.
Findings in Infants With Milk Protein Enteropathy*
In many cases, it is likely that milk protein enteropathy occurs following viral gastroenteritis. This sequence of events is difficult to prove, but experimental data support the general hypothesis that small bowel mucosal injury sufficiently disrupts barrier function that excessive milk protein antigens gain access to the mucosal immune system and elicit a immune response and secondary mucosal injury.5 Significant injury results in secondary lactase deficiency, motility disturbances, bacterial overgrowth with deconjugation of bile salts, and a cascade of events leading to clinically significant malabsorption. Thus, malabsorption of fat, protein, and carbohydrates may occur. Malnutrition contributes to perpetuation of the vicious cycle.
Resolution of milk protein enteropathy requires the reduction of milk protein antigen and attention to nutritional support. In most cases, reduction of milk protein antigen can be accomplished using a casein hydrolyzed formula (Table 1). Because of the complex series of secondary events noted above, provision of medium-chain triglycérides, and com syrup solids is highly desirable in children with a flat mucosa and failure to thrive. Pregestimil is the formula most commonly used in this context. Rarely, use of an amino acidbased formula or total parenteral nutrition is required.
Occult Gastrointestinal Blood Loss Due to Whole Milk Protein Ingestion
The association between gastrointestinal blood loss, iron deficiency anemia, and ingestion of whole cow's milk has been known for many years.15 This association occurs only in infancy and early childhood and is not observed in infants receiving standard heat-treated commercial infant formulas. A recent study concluded that normal infants lose nutritionally important amounts of iron in the gastrointestinal tract when they consume pasteurized cow's milk.16 The occult blood loss may occur in the absence of other gastrointestinal or systemic findings. The mechanism of blood loss is unclear, and a consistent histopathologic lesion has not been identified. Occult blood loss may contribute to the development of iron deficiency anemia, especially because the concentration and bioavailability of iron in whole milk is low. Collectively, these observations have resulted in the recommendation by the American Academy of Pediatrics that infants not be given whole milk feedings until 12 months of age.17
There are a variety of other gastrointestinal disorders that may or may not be due to hypersensitiv - ity to food proteins, perhaps including milk. Included in this group of disorders is eosinophilic gastroenteritis, which affects children older than the typical age range for milk protein sensitivity and does not respond to elimination diets.18 A recent report described successful treatment of recalcitrant gastroesophageal reflux in infants and children by use of an elemental (amino acid) diet,19 but these observations will require follow-up studies. Others have proposed that a significant number of infants with gastroesophageal reflux have milk protein allergy, but this view has not gained widespread acceptance. The association of infant colic with milk protein intolerance is tenuous.
1. Work Group on Cow's Milk Protein and Diabetes Mellitus. Infant feeding practices and their possible relationship to the etiology of diabetes mellitus. Pediatrics. 1994;94:752-754.
2. Antonowici I, Lebenthal E. Developmental pattern of small intestinal enteroliinase and disaccharidase activities in the human fetus. Gastroenterology 1977:72:1299-1303.
3. Savilahti E, Launiala K, Kuitunen P. Congenital lactase deficiency: a clinical study on 16 patients. Arch Dis Child, 1983;58:246-Z52.
4. Davidson GP, Goodwin D, Robb TA. Incidence and duration of lactose malabsorption in children hospitaliied with acute enteritis: study in. a well- nourished urban population. J Pediatr. 1984:105:587-590.
5. Kleinman RE. Milk protein enteropathy after acute infectious gastroenteritis: experimental and clinical observations. J Pediatr. 1991;118:S111-S115.
6. Welsh JD, Poley JR, Bhatia M, Stevenson DE. Intestinal disaccharidase activities in relation to age, race and mucosal damage. Gastroenterol. 1978;75:847-855.
7. Suarez FL, Savaiano DA, Levitt MD. A comparison of symptoms after the consumption of milk or lactose-hydrolyzed milk by people with self-reported severe lactose intolerance. N Engl J Med. 1995;333:1-4.
8. Malagelada JR. Lactose intolerance. N Engi J Med. 1995;333:53-54.
9. Schrandel JJP, van den Bogart JPH, Schrander-Stumpel CTRM, Kuijten RH, Kester ADM. Cow's milk protein intolerance in infants under 1 year of age: a prospective epidemiological study. Eur J Pediatr, 1993;152;640-644.
10. Burles KSJ, Sampson HA. Diagnostic approaches to the patient with suspected food allergies. J Pediatr. 1992;121:S64-S71.
11. Ford RPK, Hill DJ, Hosking CS. Cow's milk hypersensitivity: immediate and delayed inset clinical patterns. Arch Dis Child. 1983;58:856-862.
12. Odze RD, Wershil BK, Leichtner AM, Antoniolo DA. Allergic colitis in infancy. J Pediatr. 1995;126:163-170.
13. Lake AM, Whitington PF, Hamilton SR. Dietary protein- induced colitis in breastfed infants. J Pediarr. 1982;101:906-910.
14. Kuitunen P, Visakotpi JK, Savilahti E, Pelkonen P. Malabsorption syndtome with cow's milk intolerance: clinical findings and course in 54 cases. Arch Dis Child. 1975;50:351-356.
15. Sullivan PB. Cow's milk induced incestinal bleeding in infancy. Arch Dis Child. 1993;68:240-245.
16. Ziegler EE, Foman SJ, Nelson SE,. et al. Cow milk feeding in infancy : further observations on blood loss from the gastrointestinal tract. J Pediatr. 1990; 16:11-18.
17. Committee on Nutrition. The use of whole cow's milk in infancy. Pediatrics 1992;89:1105-1109.
18. Whitington PF. Whitington GL Eosinophilic gastroenteropathy in childhood. J Pediatr. Gastroenterol Nutr. 1988;7:379-385.
19. Kelly KJ, Lazenby AJ, Rowe PC, Yardley JH, Perman JA. Sampson HA. Eosinophilic esophagitis attributed to gastroesophageal reflux; improvement with an amino acid-based formula. Gastroenterology 1995;109;1503-1512.
Classification of Milk Based on Protein Source
Classification of Milk Based on Carbohydrate Source
Etiology of Secondary Lactase Deficiency
Gastrointestinal Disorders Due to Ingestion of Milk Protein
Findings in Infants With Milk Protein Enteropathy*