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IS IT MILK ALLERGY OR LACTOSE INTOLERANCE?
DIFFERENTIAL DIAGNOSIS OF ALLERGIC DISEASE: MASQUERADERS OF ALLERGY
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IS IT MILK ALLERGY OR LACTOSE INTOLERANCE? Sami L. Bahna, MD, DrPH
The terms allergy and intolerance are often used interchangeably in referring to adverse reactions to foods. Strictly speaking, allergy denotes a hypersensitivity reaction, i.e., a reaction that is immunologically mediated. lntolerance on the other hand is a general, nonspecific term meaning inability to withstand. In the case of cow’s milk (CM), intolerance is mostly due to inadequate digestion often of the milk sugar lactose and occasionally of its fat. It also can be caused by defective metabolism of specific milk constituents in certain inborn errors of metabolism, such as phenylketonuria and galactosemia. Other forms of intolerance, with varying symptoms, can be related to individual psychological factors or to aversion. Numerous health hazards of milk have been addressed e1se~here.I~ This article limits discussion to the most common two adverse reactions to milk that are frequently and interchangeably misdiagnosed, namely cow milk allergy (CMA) and lactose intolerance (LI). MILK ALLERGY
CMA denotes a hypersensitivity state to cow’s milk proteins (CMPs) that may involve different immunologic mechanisms and can result in a wide variety of manifestation^.^ Prevalence of CMA
Although it may appear at any age, CMA is primarily a childhood disease, with onset mostly during infancy. Its reported prevalence in From The University of South Florida/All Children’s Hospital, St. Petersburg, Florida
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young children varied between 0.5% and 7.5%? depending on several factors such as the type of study population, the feeding pattern, manifestations included, and criteria of establishing the diagnosis. A reasonable estimate of CMA prevalence in bottle-fed infants probably would be 3% to 5%, with high figures in those who have family history of atopy, prematurity, or gastrointestinal disorders such as cystic fibrosis or celiac disease. Its incidence in adults is probably less than 1%. Although a familial tendency has been noticed by the author and was reported by others,19 no specific genetic pattern has been documented. In one large family? probable CMA was present during early childhood in five out of six sisters (ages 10-25 years when studied). Three of the five affected sisters were married and had a total of five children (ages 7 months to 5 years), all of whom had CMA that started during early infancy. All 10 affected members had gastrointestinal manifestations, and 5 had respiratory symptoms as well.
Offending Milk Components
Hypersensitivity reactions are precipitated by milk proteins, that range from 2.8 to 4.1 g/dL with an average of 3.3 g/dL. CMPs are divided into caseins (76%-86%) and whey proteins (14%-24%); the latter include beta-lactoglobulin (70/0-12%), alpha-lactalbumin (2%-5%), serum albumin (0.7%-1.3%), and serum immunoglobulins (1.4%-2.8%)? Casein and beta-lactoglobulin are the most allergenic components as well as the most heat-resistant. Using cross immunoelectrophoresis, it was demonstrated that bovine casein contains at least seven individual fractions and whey contains at least 36 fractions.l8 It is presumed that each of these 43 fractions could induce an immunologic response that may result in a clinical reaction. The multiplicity of CMP fractions, the heat stability of the majority of them, and the wide consumption of CM, often in large quantities and high frequency, probably contribute to the prevalence of CMA and make milk the most common food allergen in children. Both the sensitizing and precipitating quantities of CMP vary widely from one individual to another. Perinatal sensitization can occur by very minute quantities of CMPs that pass from the maternal circulation to the fetus across the placenta12,13,20 or to the nursing infant through breast milk.21,24, 30 The precipitating quantity likewise can be very small and may produce severe reactions in extremely sensitive subjects. Although ingestion is by far the principal route of exposure, severe reactions through skin contact or by inhalation have been documented. An infant who had severe CMA has been reported to have two episodes of definite systemic anaphylaxis following application of a diaper rash ointment that contained 5% calcium caseinate.26Another case report was that of an adult who had gastrointestinal CMA since childhood and developed several episodes of bronchospasrn, all believed to be related to exposure to milk by i n h a l a t i ~ n . ~ ~
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Pathogenesis and Manifestations of CMA
There is sufficient evidence that CMA can be mediated by any of the four basic types of hypersensitivity reactions outlined by Gel1 and Coombs.*,7, In some patients, more than one type of such reactions may be involved simultaneously, even though there may be a single clinical manifestation.
Type I reactions, anaphylactic or immediate reactions, are predominantly mediated by IgE antibodies. The antigen-antibody interaction on the surface of mast cells or basophils results in release of histamine and other mediators. This is the best understood type and probably the most commonly involved in the rapid-onset manifestations such as vomiting, diarrhea, abdominal pain, atopic dermatitis, urticaria/angioedema, rhinitis, bronchospasm, and systemic anaphylaxis. Type I1 or cytotoxit reactions are mediated through complement activation by antibodies of the IgG, IgM, and occasionally IgA isotype. This type of reaction is perhaps responsible for the rare cases of milk-induced thrombocytopenia. Type I l l reactions, Arthus-type or immune complex reactions, require the formation of complexes of the antigen, its specific antibody (IgG, IgM, IgA, and occasionally IgE), and complement. The impaction of those complexes in the small blood vessels initiates an inflammatory process (vasculitis), the degree of which determines the extent of tissue damage and symptoms. This type of reaction is commonly encountered in milk-induced gastrointestinal bleeding, the rare milk-induced chronic pulmonary disease (Heiner syndrome), and in the rare instances of arthritis or cutaneous vasculitis. Type IV reactions, delayed or cell-mediated reactions to milk, seem to be rare and most difficult to document. In this type of reaction, sensitized T cells proliferate and release a variety of lymphokines on exposure to the offending antigen. It seems to be present together with type I11 reaction in Heiner syndrome and in some patients with gastroenteropathies. Diagnosis of CMA
Table 1 outlines the steps that may be followed in the diagnosis of CMA. In clinical practice, the medical history constitutes the most valuable tool. Because none of the CMA manifestations is pathognomonic, a careful physical examination is essential, and selected laboratory tests may be needed for differential diagnosis. An increased serum total IgE level or eosinophilia would merely support the diagnosis of allergy in general, but normal levels do not exclude allergy. Because the medical history may not suggest any specific offending food, selected allergy
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Table 1. DIAGNOSIS OF COW’S MILK ALLERGY Medical History
Physical Examination Laboratory Tests
Verification of Cause-and-Effect Relationship
Nature of symptoms Personal or family history of allergy Age at onset Feeding history Relation of symptoms to milk intake Relation of symptoms to other factors Manifestations of allergy Manifestations of nonallergic disease 1. To exclude or verify nonallergic disease (e.g., CBC, urinalysis, stool analysis, cultures, radiologic studies, immunologic screening, sweat electrolyte test, etc.) 2. To support allergy diagnosis Serum IgE level Eosinophils in circulation or local secretion 3. To screen for causative allergens Most commonly used tests Diagnostic elimination diets Food/symptom diary Skin testing Specific serum IgE antibodies (RAST or its analogues) Less commonly used tests Specific serum antibodies of IgG, IgM & IgA classes (enzyme-linked immunosorbent assay, fluorescent immunosorbenttest, precipitation, hemagglutination, complement fixation) Immune complexes in circulation or shock organ Leukocyte histamine release Leukocyte migration inhibition factor Lymphoblast transformation lmmunofluorescencestudies on intestinal biopsy Milk elimination-challengetest
Modified from Bahna SL, Gandhi MD: Milk hypersensitivity. 11. Practical aspects of diagnosis, treatment and prevention. Ann Allergy 50:295,1983; with permission.
skin tests (epicutaneous and, if negative, may be followed by intracutaneous) or specific IgE antibody titers in the serum (by the radioallergosorbent test or its analogues) might be h e l p f ~ l Neither .~ skin test nor RAST alone or in combination can exclude or confirm the role of food in question8 In a group of patients with CMA that was confirmed by double-blind challenge tests, the skin testing and RAST showed similar although suboptimal degrees of reliability.2The sensitivity (true positive test) was 44% for skin testing and 56% for RAST, and the specificity (true negative test) was 67% for both. The less commonly used tests mentioned in Table 1 are mostly research tools and are reviewed elsewhere!, Most of these tests are not available in routine laboratories and require special expertise in their performing and interpretation. Furthermore, none of them has shown reproducibility and reliability of a degree high enough to warrant its use in routine practice.
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To verify the cause-and-effect relationship between milk ingestion and the development of certain symptoms, an elimination-challengetest should be conducted.‘j Symptoms should be documented to improve following strict avoidance of milk without the intake of symptomatic medications, and they should recur upon milk challenge. The latter should be administered in titrated doses under supervision, preferably in a double-blind, placebo-controlled fashion. Open challenges may be acceptable in infants whose symptoms are usually objective and in whom a psychogenic component is unlikely. Treatment of CMA
Once milk has been verified as the offending food, treatment is basically milk avoidance, which should be as strict as possible. Information on milk-free diet and recipes are available from dietetic associations, some formula manufacturers, or certain books.’ As a milk-substitute for infants, soybean formula is likely to be tolerated in 70% to 80% of instances, otherwise a hypoallergenic formula (casein hydrolysate or an elemental formula) would be a better choice. Reactions to partiallyhydrolyzed formulas (e.g., Good Start, Beba HA, Nan HA, Nidina HA) are common and can be life-threatening.I5.35, 37 Allergic reactions to extensively hydrolyzed formulas are rare but can be severe in extremely allergic subjects.”, 40 Patients should be advised to read food labels for possible inclusion of casein, caseinate, or whey. Intermittent exposures to small quantities of milk, however, may not cause clinical symptoms but might stimulate the immune system and perpetuate the hypersensitivity state. Extremely sensitive subjects should wear a medical alert bracelet or necklace that identifies their medical problem and carry injectable epinephrine for immediate administration upon the appearance of the first symptom of a reaction until they are taken to a medical facility. They should also be cautioned against eating any food that is not certain to be milk-free. One of my patients is an infant who had a few episodes of anaphylaxis following eating small quantities of commercial baby vegetables and fruits that were flavored by small quantities of milk derivatives. An older child had anaphylaxis following eating a ”dairyfree’’-labeled sherbet that later was found to be contaminated with milk as a result of its production in equipment that was just used for ice cream preparati~n.’~ Overall, CMA is temporary, particularly with strict milk elimination. In children, the problem may disappear within months to a few years.1o, In adults, however, it tends to persist longer.44 ‘‘j
LACTOSE INTOLERANCE
LI is a state of indigestion of milk sugar as a result of a deficiency in the production of intestinal lactase enzyme relative to the quantity of
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lactose in the diet. Lactose is the only carbohydrate of mammalian milk, and it is not present in any other natural food. Pathogenesis and Manifestations of LI
Normally, lactose as a disaccharide needs to be digested in the small intestinal lumen by lactase enzyme (beta-galactosidase) into its monosaccharides, glucose and galactose, which are readily absorbed through the intestinal mucosa into the circulation. Disaccharidases are produced by the small intestinal epithelial cells situated on the brush border. Hence, they are easily knocked out upon mucosal damage, with lactase being the most vulnerable and the last disaccharidase to return to Except in the rare instances of congenital deficiency, human infants are born with an adequate lactase activity, although it is lower in premature than in full-term infants.l Therefore, newborns tolerate human milk well even though its lactose content is the highest of all mammalian milks (Table 2). In the absence of intestinal lactase, dietary lactose passes undigested to the colon where it holds water and becomes fermented by the bacterial flora and produces hydrogen gas and lactic acid. Hence, the clinical symptoms are mainly abdominal pain, bloating, flatulence, and acidic, frothy, watery diarrhea. Vomiting is uncommon. In any particular subject, the severity of symptoms depends on the quantity of lactose ingested relative to the lactase Prevalence and Types of Lactase Deficiency
There are three types of lactase deficiency (Table 3).25In the congenital fype, lactose is absent from birth and the infant would not tolerate any Table 2. LACTOSE CONTENT OF MAMMALIAN MILKS Liquid Milk Human milk Cow milk Whole Lowfat Nonfat Buttermilk Goat milk Reindeer milk Seal milk Whale milk Sea lion milk
Lactose g1100 g 6.2-7.5 3.7-5.1 3.7-5.5 4.3-5.7 3.7-5.0 4.1-4.7 2.4-2.6 2.6 1.8 0.0
Adapted from Scrimshaw NS, Murray EB: The acceptability of milk and milk products in populations with a high prevalence of lactose intolerance. Am J Clin Nutr 48(Suppl):l083, 1988; with permission.
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Table 3. TYPES OF LACTASE DEFICIENCY Congenital Acquired Delayed-Onset
Secondary
Absent from birth, probably autosomal recessive, very rare Hypolactasia of various degrees, autosomal recessive, manifest by teenage or early adulthood, marked racial predilection Transient hypolactasia secondary to small intestinal disease
milk-based formula or human milk. This type probably has an autosomal recessive inheritance and, fortunately, is very rare. In some infants, it may subside ~pontaneously.~~ In the acquired or delayed-onset type, the production of lactase begins to drop in early childhood, but the symptoms may not appear until teenage or early adulthood. This type also is inherited in an autosomal recessive manner and affects mostly darkskinned people and certain ethnic groups (Table 4). In the United States, LI in adults occurs in approximately 20% of whites, 80% of blacks, and 90% of Native Ameri~ans.~' Secondary lactase deficiency is common and is caused by small intestinal mucosal disease. If the latter is acute, such as Table 4. APPROXIMATE PREVALENCE OF ACQUIRED, DELAYED-ONSET LACTOSE INTOLERANCE IN ADULTS OF SELECTED RACIAL GROUPS Prevalence (Yo) Very High Prevalence (>To%) Eskimos Asians Native Americans Blacks High Prevalence (50%-70%) Middle Eastern Most Africans Most South Americans Mexicans Indians (Asian) Moderate Prevalence (25%-50%) Most Europeans Low Prevalence (10%25%) Whites Australian nonaboriginals Germans Most Scandinavians Very Low Prevalence (
80-1 00 75-1 00 60-100 65-1 00
40-80 40-80 45-75 50-70 35-70
35-60 15-25 15-20 15 8-1 5 3
Data from Scrimshaw NS, Murray €6:The acceptablity of milk and milk products in populations with a high prevalence of lactose intolerance. Am J Clin Nutr 48(Suppl):l083, 1988.
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in viral or bacterial gastroenteritis, lactose production usually normalizes within days to a few weeks of recovery. The degrees of lactase deficiency and mucosal damage do not always correlate.22Various degrees of lactose deficiency occur in association with milk-sensitive enteropathy, particularly in young infants.z3 Diagnosis of LI
LI is usually easily suspected in adults, particularly those of certain racial or ethnic groups, who develop the characteristic gastrointestinal symptoms shortly after ingesting milk. Bloating and abdominal pain occur within 30 to 60 minutes and diarrhea within a few hours. The stools are usually watery, acidic, and positive for reducing substances. The lactose tolerance test (LTT) used to be the standard diagnostic test in the past. After ingesting lactose (2 g/kg body weight, up to 100 g), blood glucose levels are checked every 15 to 30 minutes for 2 hours. Normally, blood glucose is expected to rise by more than 20 mg/dL above the fasting level. The breath hydrogen test is more reliable than the LTT and has been widely accepted as the standard diagnostic 43 It depends on the fact that the hydrogen produced in the colon is rapidly absorbed in the systemic circulation and excreted through the lungs. After overnight fasting, end-alveolar breath samples are collected before, then hourly for 4 to 8 hours after lactose ingestion. A rise in hydrogen content by more than 20 parts per million (ppm) above the fasting level indicates lactose malabsorption. To simplify the use of breath hydrogen test in clinical practice, a kit has been recently made commercially available (Lac Check Test Kit, Quin-Tron Instrument, Milwaukee, WI). It includes three plastic bags and instructions for the patient to collect breath samples at home; one after fasting overnight and two at 90 minutes and 180 minutes after a challenge dose of lactose. Then the three bags are sent to the laboratory for hydrogen analysis. Subjects who show abnormal LTT or breath hydrogen levels without developing symptoms are usually referred to as lactose malabsorbers. A very sensitive method for diagnosing lactose deficiency is measuring the enzyme activity in a jejunal rnucosal biopsy.34 This is a direct and definitive method but is invasive and is mostly used for research purposes. Treatment and Prognosis of LI
Except in the rare instance of congenital lactase deficiency, total avoidance of lactose is rarely necessary. In cases of secondary lactase deficiency, avoidance of lactose may be needed for one to several weeks after recovery from the primary gastrointestinal disease. Infants should be provided with a lactose-free milk substitute such as a soybean for-
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mula (Isomil, i-Soyalac, Mullsoy, Nursoy, Pro-Sobee, CHO-Free) or the newly developed milk-based formula Lacto-Free by Mead Johnson. In the common delayed-onset type of LI, although lactase deficiency continues for life, most patients have intestinal lactase activity of a sufficient degree that allows them to tolerate small quantities of lactose either as milk per se, milk-containing foods, or certain milk products. Fresh yogurt and aged cheeses, particularly cheddar and Swiss, are usually well t ~ l e r a t e dBecause .~~ fermented milk is rarely the special tolerance to yogurt may be attributed to enhanced intraintestinal activity of microbial beta-galactosidase enzyme (lactase) by yogurt.z8 Commercial yogurt preparations vary in their beta-galactosidase activity,32 therefore a particular patient may tolerate certain preparations more than others. Pasteurized and frozen yogurts have minimal betagalactosidase a~tivity.3~ Many lactose-intolerant subjects have a better tolerance to milk ingested with a meal31or mixed with cocoa.29 For patients with moderate to severe degrees of lactose intolerance, commercial lactase preparations (Lactaid) are available in tablet or solution form and can be taken orally just before lactose ingestion or, more effectively, be added to milk a short time before its consumption. Also available in supermarkets in the United States and probably in other countries as well are various preparations of homogenized milk to which lactase enzyme is already added, with a final lactose of 0% to 30% of the original content. In fact, a 1-week trial of lactose-free milk while avoiding all other forms of milk might be very helpful in differentiating between LI and CMA. Information on a lactose-free diet and recipes may be obtained from dietetic associations or from certain nutrition SUMMARY
CMA and LI are two completely different disorders that are often interchangeably misdiagnosed because both are caused by milk and their symptoms may be similar. They differ substantially in many aspects (Table 5). CMA is a hypersensitivity reaction to CMPs that occurs mostly in young children with a prevalence of 3% to 5%. It may be manifested in one or more body systems and can be life-threatening. In addition to the medical history, the problem may be suspected by a positive allergy skin test or an in vitro test and can be verified by challenge testing. Treatment is basically strict milk elimination. CMA is vastly temporary, particularly in children. LI is basically a benign gastrointestinal disorder caused by deficiency of lactase necessary for the digestion of the milk sugar lactose. Diagnosis can be verified by the breath hydrogen test, which is more sensitive than the LTT. It is mainly an acquired disorder of adolescents and adults, with remarkable racial predilection. It affects 70% to 90% of Asians, Native Americans, Eskimos, and blacks, but less than 5% of Danes. Most patients tolerate milk in limited quantities or in certain
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Table 5. COMPARISON BETWEEN COW MILK ALLERGY AND LACTOSE INTOLERANCE
Cow Milk Allergy Prevalence Common age Offender Mechanism Symptoms Morbidity Diagnosis Screening Definitive Treatment Prognosis Prophylaxis
abs
=
Lactose Intolerance
Low Infancy Bovine milk proteins Immunologic GI and/or other Can be high
High Adulthood Bovine or human milk sugar Enzyme deficiency GI only Low
Skin testing, RAST for IgE abs, Precipitating abs Elimination-challenge Symptomatic medication Avoid bovine milk Selected substitutes Usually self-limited Breast-feeding Special formulas
Stools’ appearance, pH, and reducing substances Breath hydrogen or LTT Enzyme replacement Decrease milk Selected substitutes Usually permanent None
antibodies
forms such as fresh yogurt, aged cheeses, and cocoa milk. Commercial lactase preparations may be taken before lactose ingestion or added to milk a short time before its consumption. The defect is permanent except when it is secondary to an acute gastrointestinal disease. ACKNOWLEDGMENT The author extends special thanks to Sylvia King for her secretarial assistance.
References 1. Abdo-Rassols F, Lifshitz F: Transient lactose intolerance in premature infants. Pediatrics 48:816, 1971 2. Bahna SL: Pathogenesis of milk hypersensitivity. Immunol Today 6:153, 198.5 3. Bahna SL: Milk allergy in infancy. Ann Allergy 59(Part 11):131, 1987 4. Bahna SL: Diagnostic tests for food allergy. Clin Rev Allergy 6:259, 1988 5. Bahna SL: New aspects of diagnosis of milk allergy in children. Allergy Proc 12:217, 1991 6. Bahna SL Blind food challenge testing with wide-open eyes. Ann Allergy 72:235, 1994 7. Bahna SL, Gandhi M D Milk hypersensitivity. I. Pathogenesis and symptomatology. Ann Allergy 50281, 1983 8. Bahna SL, Gandhi M D Reliability of skin testing and RAST in food allergy diagnosis. In Chandra RK fed): Food Allergy. St. John’s, Newfoundland, Canada, Nutrition Research Foundation, 1987, pp 139-147 9. Bahna SL, Heiner DC: Allergies to Milk. New York, Grune & Stratton, 1980 10. Businco L, Benincori N, Cantani A, et a1 Chronic diarrhea due to cow’s milk allergy. A 4- to 10-year follow-up study. Ann Allergy 55844, 1985 11. Businco L, Cantani A, Longhi MA, et al: Anaphylactic reactions to a cow’s milk whey protein hydrolysate (Alfa-Re, Nestle) in infants with cow’s milk allergy. Ann Allergy 62:333, 1989 12. Businco L, Marchetti F, Pellegrini G , Perlini R. Predictive value of cord blood IgE
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levels in “at risk” newborn babies and influences of type of feeding. Clin Allergy 13:503, 1983 13. Delespesse G, Sarfati M, Lang G, Sehen A H Prenatal and neonatal synthesis of IgE. Monogr Allergy 18:83, 1983 14. DiPalma JA, Collins M S Enzyme replacement for lactose malabsorption using a betaD-galactosidase. J Clin Gastroenterol 11:290, 1989 15. Ellis MH, Short, JA, Heiner DC:Anaphylaxis after ingestion of a recently introduced hydrolyzed whey protein formula. J Pediatr 118:74, 1991 16. Ford RPK, Hill DJ, Hosking CS: Cows’ milk hypersensitivity: Immediate and delayed onset clinical patterns. Arch Dis Child 58:856, 1983 17. Freed DLJ: Health Hazards of Milk. London, Bailliere Tindell, 1984 18. Geising B, Lowenstein H: Immunochemistry of food antigens. Ann Allergy 53:602,1984 19. Gerrard JW, Lubos MC, Hardy LW, et al: Milk allergy: Clinical picture and familial incidence. Can Med Assoc J 97780, 1967 20. Gerrard JW, Perelmutter L: IgE-mediated allergy to peanut, cow’s milk, and egg in children with special reference to maternal diet. Ann Allergy 56351, 1986 21. Gerrard JW, Shenassa M Food allergy: Two common types as seen in breast fed and formula fed babies. Ann Allergy 50:375, 1985 22. Harrison M, Walker-Smith JA: Re-investigation of lactose intolerance and small intestinal morphology, disaccharidase activity and lactose tolerance tests. Gut 18:48, 1977 23. Hill DJ, Davidson GP, Cameron DJS, Barnes GL: The spectrum of cow‘s milk allergy in childhood: Clinical, gastroenterological and immunological studies. Acta Paediatr Scand 68:847, 1979 24. Host A, Husby S, Osterballe 0:A prospective study of cow’s milk allergy in exclusively breast-fed infants. Acta Paediatr Scand 77663, 1988 25. Isokoski M, Sahi T, Villako K, Tamm A Epidemiology and genetics of lactose malabsorption. Ann Clin Res 13:164, 1981 26. Jarmoc LM, Primack WA: Anaphylaxis to cutaneous exposure to milk protein in a diaper rash ointment. Clin Pediatr 26:154, 1987 27. Jones RT, Squillace DL, Yunginger JW: Anaphylaxis in a milk-allergic child after ingestion of milk-contaminated kosher-pareve-labeled “dairy-free” dessert. Ann Allergy 68:223, 1992 28. Kohlars JC, Levitt MD, Aouji M, Savaiano D A Yogurt: An autodigesting source of lactose. N Engl J Med 310:1, 1984 29. Lee CM, Hardy CM: Cocoa feeding and human lactose intolerance. Am J Clin Nutr 49:840, 1989 30. Machtinger S, Moss R Cow’s milk allergy in breast-fed infants: The role of allergen and maternal secretory IgA antibody. J Allergy Clin Immunol 77341, 1986 31. Martini MC, Savaiano D A Reduced intolerance symptoms from lactose consumed during a meal. Am J Clin Nutr 4757, 1988 32. Martini MC, Smith DE, Savaiano DA: Lactose digestion from flavored and frozen yogurts, ice milk, and ice cream by lactose-deficient persons. Am J Clin Nutr 46:636, 1987 33. Newcomer AD, McGill DB: Clinical consequences of lactase deficiency. Clin Nutr 3:53, 1984 34. Newcomer AD, McGill DB: Distribution of disaccharidase activity in the small bowel of normal and lactase-deficient subjects. Gastroenterology 51:481, 1986 35. Ragno V, Giampietro P, Bruno G, Businco L Allergenicity of milk protein hydrolysate formulae in children with cow‘s milk allergy. Eur J Pediatr 152:760, 1993 36. Rosado JL, Solomons NW, Lisker R, Bourges H. Enzyme replacement therapy for primary adult lactase deficiency. Effective reduction of lactose malabsorption and milk intolerance by direct addition of P-galactosidase to milk at mealtime. Gastroenterology 871072, 1984 37. Rugo E, Wahl R, Wahn U: How allergenic are hypoallergenic infant formulae? Clin Exp Allergy 22635, 1992 38. Sategna-Guidetti C, Cruto E, Capobianco P: Breath hydrogen excretion after lactose and whole milk ingestion. A prospective comparison in lactase deficiency. J Clin Gastroenterol 11:287, 1989
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39. Savaiano DA, AbouElAnouar A, Smith DE, Levitt MD. Lactose malabsorption from yogurt, pasteurized yogurt, sweet acidophilus milk, and cultured milk in lactasedeficient individuals. Am J Clin Nutr 40:1219, 1984 40. Saylor JD, Bahna SL: Anaphylaxis to casein hydrolysate formula. J Pediatr 11871,1991 41. Scrimshaw NS, Murray EB: The acceptability of milk and milk products in populations with a high prevalence of lactose intolerance. Am J Clin Nutr 48(Suppl):1083, 1988 42. Skinner S, Martens RA: The Milk Sugar Dilemma: Living with Lactose Intolerance, ed 2. East Lansing, Michigan, Medi-ed Press, 1987 43. Solomons NW: Evaluation of carbohydrate absorption: The hydrogen breath test in clinical practice. Clin Nutr 3:71, 1984 44. Stoger P, Wuthrich B: Type I allergy to cow milk proteins in adults. Int Arch Allergy Immunol 102:399, 1993 45. Sunshine P, Kretschmer N: Studies of small intestine during development. 111. Infantile diarrhea associated with intolerance to disaccharides. Pediatrics 39:38, 1964 46. Vargiu A, Vargiu G, Locci F, et al: Hypersensitivity reactions from inhalation of milk proteins. Allergy 49:386, 1994 Address reprint requests to: Sami L. Bahna, MD, DrPH Division of Allergy /Immunology All Children’s Hospital, Box 699 801 Sixth Street South St. Petersburg, FL 33701
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IS IT MILK ALLERGY OR LACTOSE INTOLERANCE? Sami L. Bahna, MD, DrPH
The terms allergy and intolerance are often used interchangeably in referring to adverse reactions to foods. Strictly speaking, allergy denotes a hypersensitivity reaction, i.e., a reaction that is immunologically mediated. lntolerance on the other hand is a general, nonspecific term meaning inability to withstand. In the case of cow’s milk (CM), intolerance is mostly due to inadequate digestion often of the milk sugar lactose and occasionally of its fat. It also can be caused by defective metabolism of specific milk constituents in certain inborn errors of metabolism, such as phenylketonuria and galactosemia. Other forms of intolerance, with varying symptoms, can be related to individual psychological factors or to aversion. Numerous health hazards of milk have been addressed e1se~here.I~ This article limits discussion to the most common two adverse reactions to milk that are frequently and interchangeably misdiagnosed, namely cow milk allergy (CMA) and lactose intolerance (LI). MILK ALLERGY
CMA denotes a hypersensitivity state to cow’s milk proteins (CMPs) that may involve different immunologic mechanisms and can result in a wide variety of manifestation^.^ Prevalence of CMA
Although it may appear at any age, CMA is primarily a childhood disease, with onset mostly during infancy. Its reported prevalence in From The University of South Florida/All Children’s Hospital, St. Petersburg, Florida
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young children varied between 0.5% and 7.5%? depending on several factors such as the type of study population, the feeding pattern, manifestations included, and criteria of establishing the diagnosis. A reasonable estimate of CMA prevalence in bottle-fed infants probably would be 3% to 5%, with high figures in those who have family history of atopy, prematurity, or gastrointestinal disorders such as cystic fibrosis or celiac disease. Its incidence in adults is probably less than 1%. Although a familial tendency has been noticed by the author and was reported by others,19 no specific genetic pattern has been documented. In one large family? probable CMA was present during early childhood in five out of six sisters (ages 10-25 years when studied). Three of the five affected sisters were married and had a total of five children (ages 7 months to 5 years), all of whom had CMA that started during early infancy. All 10 affected members had gastrointestinal manifestations, and 5 had respiratory symptoms as well.
Offending Milk Components
Hypersensitivity reactions are precipitated by milk proteins, that range from 2.8 to 4.1 g/dL with an average of 3.3 g/dL. CMPs are divided into caseins (76%-86%) and whey proteins (14%-24%); the latter include beta-lactoglobulin (70/0-12%), alpha-lactalbumin (2%-5%), serum albumin (0.7%-1.3%), and serum immunoglobulins (1.4%-2.8%)? Casein and beta-lactoglobulin are the most allergenic components as well as the most heat-resistant. Using cross immunoelectrophoresis, it was demonstrated that bovine casein contains at least seven individual fractions and whey contains at least 36 fractions.l8 It is presumed that each of these 43 fractions could induce an immunologic response that may result in a clinical reaction. The multiplicity of CMP fractions, the heat stability of the majority of them, and the wide consumption of CM, often in large quantities and high frequency, probably contribute to the prevalence of CMA and make milk the most common food allergen in children. Both the sensitizing and precipitating quantities of CMP vary widely from one individual to another. Perinatal sensitization can occur by very minute quantities of CMPs that pass from the maternal circulation to the fetus across the placenta12,13,20 or to the nursing infant through breast milk.21,24, 30 The precipitating quantity likewise can be very small and may produce severe reactions in extremely sensitive subjects. Although ingestion is by far the principal route of exposure, severe reactions through skin contact or by inhalation have been documented. An infant who had severe CMA has been reported to have two episodes of definite systemic anaphylaxis following application of a diaper rash ointment that contained 5% calcium caseinate.26Another case report was that of an adult who had gastrointestinal CMA since childhood and developed several episodes of bronchospasrn, all believed to be related to exposure to milk by i n h a l a t i ~ n . ~ ~
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Pathogenesis and Manifestations of CMA
There is sufficient evidence that CMA can be mediated by any of the four basic types of hypersensitivity reactions outlined by Gel1 and Coombs.*,7, In some patients, more than one type of such reactions may be involved simultaneously, even though there may be a single clinical manifestation.
Type I reactions, anaphylactic or immediate reactions, are predominantly mediated by IgE antibodies. The antigen-antibody interaction on the surface of mast cells or basophils results in release of histamine and other mediators. This is the best understood type and probably the most commonly involved in the rapid-onset manifestations such as vomiting, diarrhea, abdominal pain, atopic dermatitis, urticaria/angioedema, rhinitis, bronchospasm, and systemic anaphylaxis. Type I1 or cytotoxit reactions are mediated through complement activation by antibodies of the IgG, IgM, and occasionally IgA isotype. This type of reaction is perhaps responsible for the rare cases of milk-induced thrombocytopenia. Type I l l reactions, Arthus-type or immune complex reactions, require the formation of complexes of the antigen, its specific antibody (IgG, IgM, IgA, and occasionally IgE), and complement. The impaction of those complexes in the small blood vessels initiates an inflammatory process (vasculitis), the degree of which determines the extent of tissue damage and symptoms. This type of reaction is commonly encountered in milk-induced gastrointestinal bleeding, the rare milk-induced chronic pulmonary disease (Heiner syndrome), and in the rare instances of arthritis or cutaneous vasculitis. Type IV reactions, delayed or cell-mediated reactions to milk, seem to be rare and most difficult to document. In this type of reaction, sensitized T cells proliferate and release a variety of lymphokines on exposure to the offending antigen. It seems to be present together with type I11 reaction in Heiner syndrome and in some patients with gastroenteropathies. Diagnosis of CMA
Table 1 outlines the steps that may be followed in the diagnosis of CMA. In clinical practice, the medical history constitutes the most valuable tool. Because none of the CMA manifestations is pathognomonic, a careful physical examination is essential, and selected laboratory tests may be needed for differential diagnosis. An increased serum total IgE level or eosinophilia would merely support the diagnosis of allergy in general, but normal levels do not exclude allergy. Because the medical history may not suggest any specific offending food, selected allergy
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Table 1. DIAGNOSIS OF COW’S MILK ALLERGY Medical History
Physical Examination Laboratory Tests
Verification of Cause-and-Effect Relationship
Nature of symptoms Personal or family history of allergy Age at onset Feeding history Relation of symptoms to milk intake Relation of symptoms to other factors Manifestations of allergy Manifestations of nonallergic disease 1. To exclude or verify nonallergic disease (e.g., CBC, urinalysis, stool analysis, cultures, radiologic studies, immunologic screening, sweat electrolyte test, etc.) 2. To support allergy diagnosis Serum IgE level Eosinophils in circulation or local secretion 3. To screen for causative allergens Most commonly used tests Diagnostic elimination diets Food/symptom diary Skin testing Specific serum IgE antibodies (RAST or its analogues) Less commonly used tests Specific serum antibodies of IgG, IgM & IgA classes (enzyme-linked immunosorbent assay, fluorescent immunosorbenttest, precipitation, hemagglutination, complement fixation) Immune complexes in circulation or shock organ Leukocyte histamine release Leukocyte migration inhibition factor Lymphoblast transformation lmmunofluorescencestudies on intestinal biopsy Milk elimination-challengetest
Modified from Bahna SL, Gandhi MD: Milk hypersensitivity. 11. Practical aspects of diagnosis, treatment and prevention. Ann Allergy 50:295,1983; with permission.
skin tests (epicutaneous and, if negative, may be followed by intracutaneous) or specific IgE antibody titers in the serum (by the radioallergosorbent test or its analogues) might be h e l p f ~ l Neither .~ skin test nor RAST alone or in combination can exclude or confirm the role of food in question8 In a group of patients with CMA that was confirmed by double-blind challenge tests, the skin testing and RAST showed similar although suboptimal degrees of reliability.2The sensitivity (true positive test) was 44% for skin testing and 56% for RAST, and the specificity (true negative test) was 67% for both. The less commonly used tests mentioned in Table 1 are mostly research tools and are reviewed elsewhere!, Most of these tests are not available in routine laboratories and require special expertise in their performing and interpretation. Furthermore, none of them has shown reproducibility and reliability of a degree high enough to warrant its use in routine practice.
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To verify the cause-and-effect relationship between milk ingestion and the development of certain symptoms, an elimination-challengetest should be conducted.‘j Symptoms should be documented to improve following strict avoidance of milk without the intake of symptomatic medications, and they should recur upon milk challenge. The latter should be administered in titrated doses under supervision, preferably in a double-blind, placebo-controlled fashion. Open challenges may be acceptable in infants whose symptoms are usually objective and in whom a psychogenic component is unlikely. Treatment of CMA
Once milk has been verified as the offending food, treatment is basically milk avoidance, which should be as strict as possible. Information on milk-free diet and recipes are available from dietetic associations, some formula manufacturers, or certain books.’ As a milk-substitute for infants, soybean formula is likely to be tolerated in 70% to 80% of instances, otherwise a hypoallergenic formula (casein hydrolysate or an elemental formula) would be a better choice. Reactions to partiallyhydrolyzed formulas (e.g., Good Start, Beba HA, Nan HA, Nidina HA) are common and can be life-threatening.I5.35, 37 Allergic reactions to extensively hydrolyzed formulas are rare but can be severe in extremely allergic subjects.”, 40 Patients should be advised to read food labels for possible inclusion of casein, caseinate, or whey. Intermittent exposures to small quantities of milk, however, may not cause clinical symptoms but might stimulate the immune system and perpetuate the hypersensitivity state. Extremely sensitive subjects should wear a medical alert bracelet or necklace that identifies their medical problem and carry injectable epinephrine for immediate administration upon the appearance of the first symptom of a reaction until they are taken to a medical facility. They should also be cautioned against eating any food that is not certain to be milk-free. One of my patients is an infant who had a few episodes of anaphylaxis following eating small quantities of commercial baby vegetables and fruits that were flavored by small quantities of milk derivatives. An older child had anaphylaxis following eating a ”dairyfree’’-labeled sherbet that later was found to be contaminated with milk as a result of its production in equipment that was just used for ice cream preparati~n.’~ Overall, CMA is temporary, particularly with strict milk elimination. In children, the problem may disappear within months to a few years.1o, In adults, however, it tends to persist longer.44 ‘‘j
LACTOSE INTOLERANCE
LI is a state of indigestion of milk sugar as a result of a deficiency in the production of intestinal lactase enzyme relative to the quantity of
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lactose in the diet. Lactose is the only carbohydrate of mammalian milk, and it is not present in any other natural food. Pathogenesis and Manifestations of LI
Normally, lactose as a disaccharide needs to be digested in the small intestinal lumen by lactase enzyme (beta-galactosidase) into its monosaccharides, glucose and galactose, which are readily absorbed through the intestinal mucosa into the circulation. Disaccharidases are produced by the small intestinal epithelial cells situated on the brush border. Hence, they are easily knocked out upon mucosal damage, with lactase being the most vulnerable and the last disaccharidase to return to Except in the rare instances of congenital deficiency, human infants are born with an adequate lactase activity, although it is lower in premature than in full-term infants.l Therefore, newborns tolerate human milk well even though its lactose content is the highest of all mammalian milks (Table 2). In the absence of intestinal lactase, dietary lactose passes undigested to the colon where it holds water and becomes fermented by the bacterial flora and produces hydrogen gas and lactic acid. Hence, the clinical symptoms are mainly abdominal pain, bloating, flatulence, and acidic, frothy, watery diarrhea. Vomiting is uncommon. In any particular subject, the severity of symptoms depends on the quantity of lactose ingested relative to the lactase Prevalence and Types of Lactase Deficiency
There are three types of lactase deficiency (Table 3).25In the congenital fype, lactose is absent from birth and the infant would not tolerate any Table 2. LACTOSE CONTENT OF MAMMALIAN MILKS Liquid Milk Human milk Cow milk Whole Lowfat Nonfat Buttermilk Goat milk Reindeer milk Seal milk Whale milk Sea lion milk
Lactose g1100 g 6.2-7.5 3.7-5.1 3.7-5.5 4.3-5.7 3.7-5.0 4.1-4.7 2.4-2.6 2.6 1.8 0.0
Adapted from Scrimshaw NS, Murray EB: The acceptability of milk and milk products in populations with a high prevalence of lactose intolerance. Am J Clin Nutr 48(Suppl):l083, 1988; with permission.
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Table 3. TYPES OF LACTASE DEFICIENCY Congenital Acquired Delayed-Onset
Secondary
Absent from birth, probably autosomal recessive, very rare Hypolactasia of various degrees, autosomal recessive, manifest by teenage or early adulthood, marked racial predilection Transient hypolactasia secondary to small intestinal disease
milk-based formula or human milk. This type probably has an autosomal recessive inheritance and, fortunately, is very rare. In some infants, it may subside ~pontaneously.~~ In the acquired or delayed-onset type, the production of lactase begins to drop in early childhood, but the symptoms may not appear until teenage or early adulthood. This type also is inherited in an autosomal recessive manner and affects mostly darkskinned people and certain ethnic groups (Table 4). In the United States, LI in adults occurs in approximately 20% of whites, 80% of blacks, and 90% of Native Ameri~ans.~' Secondary lactase deficiency is common and is caused by small intestinal mucosal disease. If the latter is acute, such as Table 4. APPROXIMATE PREVALENCE OF ACQUIRED, DELAYED-ONSET LACTOSE INTOLERANCE IN ADULTS OF SELECTED RACIAL GROUPS Prevalence (Yo) Very High Prevalence (>To%) Eskimos Asians Native Americans Blacks High Prevalence (50%-70%) Middle Eastern Most Africans Most South Americans Mexicans Indians (Asian) Moderate Prevalence (25%-50%) Most Europeans Low Prevalence (10%25%) Whites Australian nonaboriginals Germans Most Scandinavians Very Low Prevalence (
80-1 00 75-1 00 60-100 65-1 00
40-80 40-80 45-75 50-70 35-70
35-60 15-25 15-20 15 8-1 5 3
Data from Scrimshaw NS, Murray €6:The acceptablity of milk and milk products in populations with a high prevalence of lactose intolerance. Am J Clin Nutr 48(Suppl):l083, 1988.
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in viral or bacterial gastroenteritis, lactose production usually normalizes within days to a few weeks of recovery. The degrees of lactase deficiency and mucosal damage do not always correlate.22Various degrees of lactose deficiency occur in association with milk-sensitive enteropathy, particularly in young infants.z3 Diagnosis of LI
LI is usually easily suspected in adults, particularly those of certain racial or ethnic groups, who develop the characteristic gastrointestinal symptoms shortly after ingesting milk. Bloating and abdominal pain occur within 30 to 60 minutes and diarrhea within a few hours. The stools are usually watery, acidic, and positive for reducing substances. The lactose tolerance test (LTT) used to be the standard diagnostic test in the past. After ingesting lactose (2 g/kg body weight, up to 100 g), blood glucose levels are checked every 15 to 30 minutes for 2 hours. Normally, blood glucose is expected to rise by more than 20 mg/dL above the fasting level. The breath hydrogen test is more reliable than the LTT and has been widely accepted as the standard diagnostic 43 It depends on the fact that the hydrogen produced in the colon is rapidly absorbed in the systemic circulation and excreted through the lungs. After overnight fasting, end-alveolar breath samples are collected before, then hourly for 4 to 8 hours after lactose ingestion. A rise in hydrogen content by more than 20 parts per million (ppm) above the fasting level indicates lactose malabsorption. To simplify the use of breath hydrogen test in clinical practice, a kit has been recently made commercially available (Lac Check Test Kit, Quin-Tron Instrument, Milwaukee, WI). It includes three plastic bags and instructions for the patient to collect breath samples at home; one after fasting overnight and two at 90 minutes and 180 minutes after a challenge dose of lactose. Then the three bags are sent to the laboratory for hydrogen analysis. Subjects who show abnormal LTT or breath hydrogen levels without developing symptoms are usually referred to as lactose malabsorbers. A very sensitive method for diagnosing lactose deficiency is measuring the enzyme activity in a jejunal rnucosal biopsy.34 This is a direct and definitive method but is invasive and is mostly used for research purposes. Treatment and Prognosis of LI
Except in the rare instance of congenital lactase deficiency, total avoidance of lactose is rarely necessary. In cases of secondary lactase deficiency, avoidance of lactose may be needed for one to several weeks after recovery from the primary gastrointestinal disease. Infants should be provided with a lactose-free milk substitute such as a soybean for-
IS IT MILK ALLERGY OR LACTOSE INTOLERANCE?
195
mula (Isomil, i-Soyalac, Mullsoy, Nursoy, Pro-Sobee, CHO-Free) or the newly developed milk-based formula Lacto-Free by Mead Johnson. In the common delayed-onset type of LI, although lactase deficiency continues for life, most patients have intestinal lactase activity of a sufficient degree that allows them to tolerate small quantities of lactose either as milk per se, milk-containing foods, or certain milk products. Fresh yogurt and aged cheeses, particularly cheddar and Swiss, are usually well t ~ l e r a t e dBecause .~~ fermented milk is rarely the special tolerance to yogurt may be attributed to enhanced intraintestinal activity of microbial beta-galactosidase enzyme (lactase) by yogurt.z8 Commercial yogurt preparations vary in their beta-galactosidase activity,32 therefore a particular patient may tolerate certain preparations more than others. Pasteurized and frozen yogurts have minimal betagalactosidase a~tivity.3~ Many lactose-intolerant subjects have a better tolerance to milk ingested with a meal31or mixed with cocoa.29 For patients with moderate to severe degrees of lactose intolerance, commercial lactase preparations (Lactaid) are available in tablet or solution form and can be taken orally just before lactose ingestion or, more effectively, be added to milk a short time before its consumption. Also available in supermarkets in the United States and probably in other countries as well are various preparations of homogenized milk to which lactase enzyme is already added, with a final lactose of 0% to 30% of the original content. In fact, a 1-week trial of lactose-free milk while avoiding all other forms of milk might be very helpful in differentiating between LI and CMA. Information on a lactose-free diet and recipes may be obtained from dietetic associations or from certain nutrition SUMMARY
CMA and LI are two completely different disorders that are often interchangeably misdiagnosed because both are caused by milk and their symptoms may be similar. They differ substantially in many aspects (Table 5). CMA is a hypersensitivity reaction to CMPs that occurs mostly in young children with a prevalence of 3% to 5%. It may be manifested in one or more body systems and can be life-threatening. In addition to the medical history, the problem may be suspected by a positive allergy skin test or an in vitro test and can be verified by challenge testing. Treatment is basically strict milk elimination. CMA is vastly temporary, particularly in children. LI is basically a benign gastrointestinal disorder caused by deficiency of lactase necessary for the digestion of the milk sugar lactose. Diagnosis can be verified by the breath hydrogen test, which is more sensitive than the LTT. It is mainly an acquired disorder of adolescents and adults, with remarkable racial predilection. It affects 70% to 90% of Asians, Native Americans, Eskimos, and blacks, but less than 5% of Danes. Most patients tolerate milk in limited quantities or in certain
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Table 5. COMPARISON BETWEEN COW MILK ALLERGY AND LACTOSE INTOLERANCE
Cow Milk Allergy Prevalence Common age Offender Mechanism Symptoms Morbidity Diagnosis Screening Definitive Treatment Prognosis Prophylaxis
abs
=
Lactose Intolerance
Low Infancy Bovine milk proteins Immunologic GI and/or other Can be high
High Adulthood Bovine or human milk sugar Enzyme deficiency GI only Low
Skin testing, RAST for IgE abs, Precipitating abs Elimination-challenge Symptomatic medication Avoid bovine milk Selected substitutes Usually self-limited Breast-feeding Special formulas
Stools’ appearance, pH, and reducing substances Breath hydrogen or LTT Enzyme replacement Decrease milk Selected substitutes Usually permanent None
antibodies
forms such as fresh yogurt, aged cheeses, and cocoa milk. Commercial lactase preparations may be taken before lactose ingestion or added to milk a short time before its consumption. The defect is permanent except when it is secondary to an acute gastrointestinal disease. ACKNOWLEDGMENT The author extends special thanks to Sylvia King for her secretarial assistance.
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39. Savaiano DA, AbouElAnouar A, Smith DE, Levitt MD. Lactose malabsorption from yogurt, pasteurized yogurt, sweet acidophilus milk, and cultured milk in lactasedeficient individuals. Am J Clin Nutr 40:1219, 1984 40. Saylor JD, Bahna SL: Anaphylaxis to casein hydrolysate formula. J Pediatr 11871,1991 41. Scrimshaw NS, Murray EB: The acceptability of milk and milk products in populations with a high prevalence of lactose intolerance. Am J Clin Nutr 48(Suppl):1083, 1988 42. Skinner S, Martens RA: The Milk Sugar Dilemma: Living with Lactose Intolerance, ed 2. East Lansing, Michigan, Medi-ed Press, 1987 43. Solomons NW: Evaluation of carbohydrate absorption: The hydrogen breath test in clinical practice. Clin Nutr 3:71, 1984 44. Stoger P, Wuthrich B: Type I allergy to cow milk proteins in adults. Int Arch Allergy Immunol 102:399, 1993 45. Sunshine P, Kretschmer N: Studies of small intestine during development. 111. Infantile diarrhea associated with intolerance to disaccharides. Pediatrics 39:38, 1964 46. Vargiu A, Vargiu G, Locci F, et al: Hypersensitivity reactions from inhalation of milk proteins. Allergy 49:386, 1994 Address reprint requests to: Sami L. Bahna, MD, DrPH Division of Allergy /Immunology All Children’s Hospital, Box 699 801 Sixth Street South St. Petersburg, FL 33701