Food Intolerances and Eosinophilic Esophagitis in Childhood

Dig Dis Sci (2009) 54:8–14 DOI 10.1007/s10620-008-0331-x REVIEW Food Intolerances and Eosinophilic Esophagitis in Childhood Oner Ozdemir Æ Emin Mete Æ Ferhat Catal Æ Duygu Ozol Received: 12 February 2008 / Accepted: 6 May 2008 / Published online: 2 July 2008 Ó Springer Science+Business Media, LLC 2008 Abstract Food intolerance is an adverse reaction to a particular food or ingredient that may or may not be related to the immune system. A deficiency in digestive enzymes can also cause some types of food intolerances like lactose and gluten intolerance. Food intolerances may cause unpleasant symptoms, including nausea, bloating, abdominal pain, and diarrhea, which usually begin about half an hour after eating or drinking the food in question, but sometimes symptoms may delayed up to 48 h. There is also a strong genetic pattern to food intolerances. Intolerance reactions to food chemicals are mostly dose-related, but also some people are more sensitive than others. Diagnosis can include elimination and challenge testing. Food intolerance can be managed simply by avoiding the particular food from entering the diet. Babies or younger children with lactose intolerance can be given soy milk or hypoallergenic milk formula instead of cow’s milk. Adults may be able to tolerate small amounts of troublesome foods, so may need to experiment. Eosinophilic esophagitis (EE) is defined as isolated eosinophilic infiltration in patients with reflux-like symptoms and normal pH studies and whose symptoms are refractory to acid-inhibition therapy. Food allergy, abnormal immunologic response, and autoimmune mechanisms are suggested as possible etiological factors O. Ozdemir SEMA Teaching & Training Hospital, Istanbul, Turkey E. Mete
F. Catal Division of Allergy, Department of Pediatrics, Fatih University Faculty of Medicine, Ankara, Turkey D. Ozol (&) Division of Pulmonology, Fatih University Faculty of Medicine, Hosdere cad no: 145, Ankara 06540, Turkey e-mail: dozol@hotmail.com; ozolduygu@yahoo.com 123 for EE. This article is intended to review the current literature and to present a practical approach for managing food intolerances and EE in childhood. Keywords Food intolerance
Lactose
Eosinophilic esophagitis In general, adverse food reactions include any abnormal reaction that results from the ingestion of a food. Although there are different classifications and adverse reactions to food that can be caused by several mechanisms, two main types of reactions are widely accepted: food allergy and food intolerance. Food allergy manifestations may be categorized into IgE-mediated and nonIgE-mediated. In IgE-mediated food allergy, food allergens bind with food-specific IgE antibodies residing on mast cells and basophiles to activate the cells to release potent mediators. In non-IgE-mediated food allergic disorders, activation and recruitment of lymphocytes and eosinophils are cardinal features of the diseases and symptoms are typically late onset [1]. Food intolerance (FI) is an adverse response caused by some unique physiologic characteristic of the host such as metabolic disorders and they are caused by non-immunological mechanisms (e.g., diarrhea in individuals with lactase deficiency). These two terms, however, differ from one another, both linguistically and scientifically (see Tables 1 and 2). Food intolerance is also not the same as food poisoning, which is caused by toxic substances that would cause symptoms in anyone who ate the food. Symptoms occur each time the food is eaten, but particularly if larger quantities are consumed. Symptoms of food intolerance include gas, intermittent diarrhea, constipation, irritable Dig Dis Sci (2009) 54:8–14 bowel syndrome, skin rash, migraine headaches, and an unproductive cough [2]. A deficiency in digestive enzymes can also cause some types of food intolerances, like lactose and gluten intolerance. Lactose intolerance is a result of the body not producing enough lactase used to break down the lactose in milk. Gluten intolerance results in damage to villi in the small intestine, which decreases the absorption of water and nutrients from foods. Sensitivity to naturally occurring food chemicals such as salicylates, amines, and glutamate, can also cause symptoms of intolerance [3, 4]. Salicylates are chemicals that can occur naturally in many foods. Salicylate sensitivity causes many symptoms, the most common of which are hives, stomach pain, headaches, and mouth ulcers. Salicylate-containing foods include apples, citrus fruits, strawberries, tomatoes, and wine. However, reactions to chocolate, cheese, bananas, avocado, tomato, and wine point to amines as the likely food chemicals. In this article we basically discuss lactose intolerance, infantile colic, and eosinophilic esophagitis (EE). Lactose Intolerance It is estimated that more than 70% of adults have trouble digesting lactose [5]. Although this disorder is usually not dangerous, it can lead to distressing symptoms and multiple office visits to the primary care physician. There appears to be an equal prevalence of lactose intolerance among males and females. Interestingly, up to 45% of women who are lactose intolerant will regain the ability to digest lactose during pregnancy [6]. Insufficient intestinal lactase enzyme secretion results in lactose maldigestion, with consequent gastrointestinal (GI) symptoms. Lactose intolerance is the inability to digest lactose into its constituents, glucose and galactose. Lactase enzyme (b-galactosidase) in the brush border of the small intestinal mucosa hydrolyzes lactose, a disaccharide, into the readily absorbed glucose and galactose [7]. Undigested lactose becomes thick as it passes through the small intestines. This thickened lactose combines with colonic bacteria to produce excess hydrogen gas. Lactose that is not absorbed also causes an intraluminal osmotic effect resulting in flatulence, bloating, and loose stools. Another significant change with lactose intolerance is the decrease in stool pH secondary to production of lactic acid and short-chain fatty acids from the fermentation of lactose by colonic bacteria. Although multiple etiologies of lactose intolerance exist, the most common being that of primary lactose intolerance, a common disorder in which a low level of lactase develops after weaning. Humans normally lose 90–95% of birth 9 Table 1 Classifications of adverse food reactions other than food allergy Adverse food reactions Nonimmune (Intolerances) Lactase deficiency Toxic reactions (bacterial food poisonings, ptomaine poisoning) Enzyme deficiencies (G-6PD, Fructose-1-phosphate aldolase, PKU, Wilson disease) Pharmacologic reactions (caffeine-causing jitteriness, licoriceinduced hypertension) Irritation (spices or chemical contaminants) Psychological reactions (strongly held beliefs against any food) Idiosyncratic reactions Unknown (Celiac and behavior disorders) lactase levels by early childhood, and there is a continuous decline in lactase during the course of a lifetime [8, 9]. This situation is also referred to as hypolactasia or delayed-onset (adult-type) lactase deficiency. It appears to be inherited as an autosomal recessive disorder and presents with varying degrees of hypolactasia. Primary lactose intolerance has a high degree of race dependence. The prevalence is above 50% in South America, Africa, and Asia, reaching almost 100% in some Asian countries. In the United States, the prevalence is 15% among Whites, 53% among MexicanAmericans and 80% in the Black population. In Europe, it varies from around 2% in Scandinavia to about 70% in Sicily. Australia and New Zealand have prevalence’s of 6% and 9%, respectively [9]. Recently, adult lactose intolerance has been found to be associated with a singlenucleotide polymorphism, C-13910T, located upstream of the lactase gene. Additionally, in symptomatic patients, genotyping for the DNA variant c.1993 + 327C is found to be a reliable test for adult-type hypolactasia [10–12]. Secondary LD is common in the presence of disorders of the small intestine. There is decreased enzyme activity because of diffuse intestinal insult, e.g., celiac disease [13], inflammatory bowel disease, intestinal resection, bacterial overgrowth, and the human immunodeficiency virus (Table 3). Incidence of secondary lactose intolerance is variable, depending on its underlying etiology. Up to 50% of infants with acute diarrhea have transient lactose intolerance during acute viral syndromes. Most commonly implicated are rotavirus and giardiasis [14]. When the epithelium heals, the activity of lactase returns to normal. However, secondary maldigestion does not automatically lead to severe symptoms of intolerance. Congenital LD is an extremely rare disorder where enzyme activity is absent from birth. It also appears to be inherited as an autosomal recessive trait, however in some infants may subside spontaneously. There have been only a 123 10 Dig Dis Sci (2009) 54:8–14 Table 2 Comparison of food allergy and intolerance Food allergy Mechanisms Immunological Food intolerance Nonimmunological reaction Deficiency in digestive enzymes History Allergy Atopy Migraine Irritable bowel symptoms Prevalence 8% of babies under 12 months Much more common 3% of children under 5 years Milk Milk Eggs Food chemicals Peanuts Sulphite preservatives Timing Fish Mostly quick Can be delayed up to 48 h Symptoms Itching Rashes Swelling Swelling Rash Irritable bowel symptoms Spreading hives Colic Vomiting Bloating Diarrhea Diarrhea Asthma Vomiting Urticaria Migraines Food kinds infants whose diarrhea quickly leads to dehydration. The infant must be fed a lactose-free diet. A thorough history and physical examination will yield evidence to point the clinician in the right direction (Table 4). If definitive tests are required to diagnose lactose intolerance, the most practical is the hydrogen breath test [16]. This test is noninvasive, relatively inexpensive, and not labor-intensive. Breath hydrogen levels are measured before and after oral administration of a 50-g bolus of lactose. The hydrogen level will rise secondarily to hydrogen release from the combination of unabsorbed lactose and colonic bacteria. Measurement of stool pH will also lead to evidence of lactose intolerance. Another definitive test is through a small-bowel biopsy for assay of lactase activity. The drawbacks of this test include invasiveness and accuracy. Accuracy may be questionable if the lactase deficiency is patchy; therefore, small-bowel biopsy is rarely performed in clinical practice. Another alternative is the lactose absorption test. This test quantifies the amount of lactose digested after a specific amount of lactose is ingested. Approximately 70% of patients with primary lactose intolerance will respond to a lactose-restricted diet. The remaining 30% are believed to have an underlying irritable bowel syndrome. The gastrointestinal symptoms of patients Headaches Table 4 Comparison between cow milk allergy and lactose intolerance Parameters Cow milk allergy Lactose intolerance Prevalence Low High Racial variation Low High Table 3 Causes of secondary hypolactasia Small bowel HIV enteropathy Common age Infancy Adulthood Regional enteritis Offender Bovine milk proteins Mammalian milk sugar Sprue (celiac and tropical) Mechanism Immunologic Enzyme deficiency Whipple’s disease (intestinal lipodystrophy) Symptoms GI, skin, respiratory, anaphylaxis GI only Morbidity Can be high Low Usually elevated Normal Screening Skin and in vitro testing Stool’s appearance, pH and reducing substances Confirmation Challenge test Breath hydrogen, lactose tolerance test, Jejunal biopsy Severe gastroenteritis Multisystem Carcinoid syndrome Cystic fibrosis Diabetic gastropathy Kwashiorkor Diagnosis Total IgE level Zollinger-Ellison syndrome Iatrogenic Chemotherapy Colchicine-induced in patients with familial Mediterranean fever Radiation enteritis few dozen documented cases in the world, most of them in Finland [15]. This type of lactose intolerance is usually apparent in the first week of life. Consumption of any amount of lactose is intolerable and even dangerous for 123 Treatment Symptomatic medication Reduce milk intake Selected substitutes Selected substitutes Avoid bovine milk Lactase replacement Prognosis Mostly self-limited Mostly permanent Prophylaxis Breast-feeding None Special formulas Dig Dis Sci (2009) 54:8–14 who consume milk products can be reduced with the use of commercially available preparations such as Lactaid or Lactrase. Pharmaceutical preparations of fungal or yeastderived b-galactosidase have been developed for the treatment of lactose maldigestion [17]. There is evidence that these preparations increase lactose digestion and alleviate symptoms. Compared to lactose in yoghurt or in pre-hydrolyzed milk, these products seem less efficient. Soy milk and rice milk are also well tolerated. Some patients increase their tolerance to lactose with repeated intake. Since abdominal symptoms of lactose malabsorption may be caused by metabolic activity of colonic bacteria, rifaximin, a non-absorbable rifampycin derivative against colonic bacteria, may be useful in the treatment of lactose intolerance [18]. Lactose intake limited to less than 240 ml (8 oz.) of milk per day usually causes negligible gastrointestinal symptoms. By eliminating milk products, many patients require calcium supplementation to prevent the effects of osteoporosis. This supplementation can be accomplished using calcium carbonate. Yogurt and fermented products such as cheese are better tolerated than milk products. Many foods that are rich in calcium and low in lactose include green vegetables, oysters, sardines, molasses, and tofu. Individuals with severe lactose intolerance should also watch for hidden lactose, which is often added to prepared foods. Hidden sources of lactose include bread and other baked goods, processed breakfast cereals, mixes for pancakes, biscuits, and cookies, salad dressings, margarine, instant potatoes, soups, breakfast drinks, candies, nonkosher luncheon meats, and other snacks. Moreover, lactose is used as the base for prescription drugs and over-the counter medications. Secondary lactose intolerance is generally a self-limiting condition that resolves with treatment of the primary disorder. Effective treatment of the underlying condition, such as administration of metronidazole for treatment of giardiasis or a gluten-free diet for management of celiac disease, may not only ameliorate symptoms but also improve lactose intolerance. Patients with bacterial overgrowth may benefit from antibiotics such as tetracycline, metronidazole, or ciprofloxacin. Consumption of milk in subjects with lactase persistence has been associated with an increased risk of cataract. Another disease that is suggested as being linked with the ability to digest lactose is ovarian cancer [19]. Infantile Colic Less than 5% of babies with problem crying have an identifiable organic cause such as gastro-esophageal reflux (GER), food allergy, or intolerance to cow’s milk/soy protein/lactose [20]. GER may be a significant causative 11 factor in about 5% of infants with colic. In some irritable infants, FA may play a causal role. Food allergens commonly implicated include cow’s milk protein and soy protein, both of which can be found in human breast milk. Intolerances or allergies to either cow’s milk or soy protein are both temporary and result from intact protein being absorbed as a result of increased mucosal permeability in the infant’s GI tract. The intolerance gradually disappears over the first few months of life as the mucosal junctions tighten. The role of lactose intolerance as a cause of infant irritability remains debatable. It has been hypothesized that some babies have a transient underlying lactase deficiency leading to a build-up of lactose derived from breast milk or formula. Gut bacteria break down the lactose, converting it to lactic acid and hydrogen. A clinical response to a lactose-free diet confirms the diagnosis. Whether the problem is an intolerance or an allergy to cow’s milk or soy protein, it has been shown that complete removal of cow’s milk or soy protein from the infant’s or breast-feeding mother’s diet will result in immediate improvement in 10–35% of colicky infants [21]. Some infants are allergic to both cow’s milk and soy protein, and changing to extensively hydrolyzed formulas or to amino acid formulas can be effective [22]. Eosinophilic Esophagitis Over the past 10 years, EE has generated a large amount of interest among pediatric gastroenterologists [23]. This disorder, initially mistaken for GER, is a problem that appears to be increasing in incidence. Currently, most authors agree that EE appears to be caused by a combination of an allergic and immunologic response. However, the etiology of EE is not fully understood and the question remains whether or not EE is based on allergic disorder, an abnormal immunologic response [24]. One potential cause implies that inhaled allergens may contribute to subsequent EE [25]. Another possible etiology suggests that EE may be a subset of eosinophilic gastroenteropathy, an autoimmune disorder. Recently, the gene encoding the eosinophilspecific chemoattractant eotaxin-3 is demonstrated by our and other groups to be the most highly induced gene in EE patients compared with its expression level in healthy individuals [26]. EE occurs in children and adults, but rarely in infants, and boys appear to be affected more often than girls. Approximately half of the patients with EE have a strong medical history of allergic symptoms including asthma, rhinitis, and eczema. In a study, asthma was the most common airway diagnosis. Rhinosinusitis was the most common otolaryngological diagnosis. Food allergy was present in 60% of the children tested. Other major medical 123 12 comorbidities existed in more than half of the children with EE, of which psychiatric disorders and other disorders of the aerodigestive tract were the most common [27]. In addition, up to 50% of patients also have a strong family history of another individual in the family with EE or a history of other allergic symptoms. Typical symptoms include vomiting, regurgitation, heartburn, poor eating, and water brash. As children become adolescents, dysphasia becomes more prominent. Peripheral eosinophilia and increased immunoglobulin E levels have been reported in 20–60% of patients. Although identifying the specific foods that cause EE remains difficult, the common allergic antigens included milk, soy, eggs, and wheat. Because EE is not an IgE-mediated disease, allergy testing often cannot determine the foods causing EE. In EE, a type IV (cell-mediated) reaction, rather than a type I reaction is most likely involved [28]. In patients with type IV food hypersensitivity, symptoms often occur hours to days after ingestion of the causative food, and, recent evidence has demonstrated an increased chance of diagnosis with the use of skin patch testing [29, 30]. Currently, a definitive diagnosis of EE is made by identification of an isolated eosinophilic infiltration in the esophagus of patients who have reflux-like symptoms and normal pH studies and who are refractory to acid inhibition [31]. Although some gastroenterologists continue to rely on visual inspection of the esophagus, histological evidence of an isolated EE confirms the diagnosis [24]. The diagnosis of EE is made only by endoscope with biopsy. Children with EE had 330 esophageal eosinophils/HPF, whereas children with GERD had\5/HPF. Abnormal esophageal findings include a ringed-like (‘‘trachealization’’) esophagus, longitudinal linear furrows, or multiple small white papules suggestive of Candida. These small white patches represent eosinophilic abscess formation [32]. The recognition of typical endoscopic picture with careful biopsies extended to the whole esophagus, even in emergency, could more quickly lead to the correct diagnosis and avoid severe complications of eosinophilic oesophagitis in children, as stricture and failure to growth [33]. The diagnosis is also dependent on patients demonstrating a clinical and histological improvement to a food elimination trial or corticosteroid therapy. At times, because of the intense eosinophilic infiltration, the esophagus may be extremely narrowed. The most severe complication is esophageal stenosis. Especially adult onset EE is associated with esophageal strictures and mucosal rings. Adult patients subsequently require long-term acidsuppression therapy and repeated esophageal dilatation. Endoscopic dilation of fibrotic strictures should be carefully performed because of the risk of perforation. Straumann [34] treated 11 EE patients with esophageal dilation and reported complete improvement in six and partial relief in four patients without relevant complications. On the other hand, 123 Dig Dis Sci (2009) 54:8–14 Kaplan [35] reported that mucosal rents occurred with simple passage of the endoscope in five of eight patients and a perforation after simple passage of the endoscope in one patient. A trial of steroids to reduce active inflammation should be considered before endoscopic dilatation to prevent complications. Endoscopic dilatation should be considered only in patients with EE who do not respond to medical therapy and have rings that appear to be obstructing the lumen. The treatment of EE continues to be somewhat controversial and widely debated. Medical and surgical treatment for GERD may both be effective. Several studies have shown convincing evidence that food allergy is the most common cause of EE; thus, the removal of the causative food antigens should heal the disease. A good response to a strict elimination diet with an amino acid-based formula (elemental diet) usually through a nasogastric tube is shown [36]. The identification of the offending allergens is often difficult; therapy is focused to eliminate the supposed antigenic stimulus to control the acute symptoms and to induce long-term remission. These types of treatment included the use of systemic corticosteroids, topical ingested steroids, cromolyn sodium, and leukotriene receptor antagonists. Patients treated with swallowed fluticasone have improved endoscopic, histologic, and immunologic parameters associated with EE. However, patients with identifiable allergies who fail dietary elimination may have a blunted response to treatment [37]. The theory behind using Montelukast for symptomatic treatment of EE is that Montelukast selectively blocks the D4 receptor of cysteinyl leukotriene present on the eosinophils and by blocking the deformed receptor the inflammatory action of the eosinophil is reduced [38]. The safety and efficacy of using a mono-antibody directed against IL-5 in patients with hypereosinophilic syndrome reported by Rothenberg. Anti-IL-5 is safe, effective, reduces eosinophil counts, and has potential glucocorticoid-sparing effects [39]. In conclusion, the mainstay of diagnosis and management of food intolerance is the correct identification and avoidance of the offending antigen. Lactose intolerance, a condition in which a person cannot digest the sugar found in dairy products, is one of the most common food intolerances. The elimination diet and oral challenge test is the only way to diagnose food intolerance. All suspected foods are completely removed from the diet for 1–3 weeks. A small amount is then reintroduced and if symptoms reappear, the intolerance is confirmed. Eosinophilic esophagitis is a rapidly emerging, chronic inflammatory disorder. Prolonged inflammation evokes structural alterations and a fragile esophageal wall prone to perforation/rupture and food impaction. A definitive diagnosis of EE is made by identification of more than 24 eosinophils per high power Dig Dis Sci (2009) 54:8–14 field in an esophageal biopsy specimen of patients who have reflux-like symptoms and normal pH studies and who are refractory to acid inhibition. Food allergy, abnormal immunologic response, and autoimmune mechanisms are suggested as possible etiological factors for EE. References 1. Ozol D, Mete E (2008) Asthma and food allergy. Curr Opin Pulm Med 14:9–12. doi:10.1097/MCP.0b013e3282f1981c 2. Olives JP, Breton A (1998) Food allergies and intolerances in children. Rev Prat 48(4):389–393 3. Ortolani C, Pastorello EA (2006) Food allergies and food intolerances. 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