Protein Intolerance



Protein Intolerance


Jonathan E. Teitelbaum

W. Allan Walker



Allergy is derived from the Greek word for “other.” Food allergy or protein intolerance is an immunologic reaction to a dietary protein component considered foreign, or “other than oneself.” The manifestations of this immune reaction are complex and varied. The development of food intolerance depends on many variables and reflects the interaction between genetic factors and environmental exposure. Because the pathophysiologic mechanisms are incompletely understood, food allergies have been suspected in numerous clinical situations ranging from altered behavior to anaphylaxis. This chapter focuses on those reactions with a suspected immune basis that are reproducible with food challenge. Particular attention is paid to the gastrointestinal manifestations of food allergy seen in infants and likely to come to the attention of pediatricians.


COMMON FOOD ANTIGENS

Typically, antigens responsible for food allergies are 10- to 40-kd glycoproteins or acid proteins resistant to enzyme and heat denaturation. Allergic reactions to cow’s milk protein are the most significant in infancy. Whether these reactions occur because cow’s milk protein is the first foreign antigen introduced into the diet of an inappropriately reacting neonate or because of its antigenic nature is not certain. The whey protein beta-lactoglobulin, a dimer of 24 kd, which is part of the calycine family, was thought to be the prime allergen. However, now recognized are more than 30 antigenic proteins, including caseins, bovine serum albumin, gamma globulin, and alpha-lactalbumin, all of which can trigger immune-mediated responses.

Soy proteins can induce allergic disease with clinical symptoms and intestinal biopsies resembling those of cow’s milk allergy. Soy allergy is an especially common occurrence in Japan, where soy constitutes a major dietary source of protein. In Scandinavian countries, allergy to fish protein is a common occurrence. Eggs, peanuts, and other legumes, nuts, citrus fruits, and yeast also have highly antigenic proteins. The enteropathy associated with gluten sensitivity (e.g., celiac disease) is a special type of food intolerance and is discussed in Chapter 361.


ANTIGEN PROCESSING IN THE GASTROINTESTINAL TRACT

The relationship between the movement of antigens through the intestine and the development of symptoms is complex. After migration, dietary antigens may be expelled in the feces or can cross the mucosal barrier and encounter the local or systemic immune system. Proposed mechanisms of antigenic transfer include passage through M cells, enterocytes (via endocytosis and exocytosis), or intercellular gaps.

Several physical barriers limit the number of foreign antigens that gain access to the immune system. Nonspecific barriers to this process include proteolytic enzymes of the stomach and pancreas and lysosomal enzymes of the intestinal epithelial cells, which degrade complex proteins into smaller peptides and amino acids. Gastrointestinal (GI) peristalsis leads to presentation to the local immune system of fewer antigens per unit of time. Mucous secretions overlying the enterocyte provide a physical barrier.

Specific immunologic components of antigen handling include the gut-associated lymphoid tissue (GALT): the large number of phagocytes, eosinophils, mast cells, and T and B lymphocytes found in the lamina propria, Peyer patches, and among the epithelial cells (intraepithelial lymphocytes) throughout the GI tract. Immunoglobulin A (IgA) is made and secreted in response to certain food antigens and plays a crucial role in the host defense.

An important aspect of this complex system is its alteration with age and illness. Developmental aspects of the immune system may be important in its formation. Infants younger than 1 year old have lower levels of intestinal IgA, fewer intraepithelial lymphocytes, and higher permeability to antigens than do older children. In vitro studies suggest that in states of tolerance, protein-specific IgA antibodies prevent the triggering of a local or systemic reaction by a given antigen. However, when the immune system is regulated improperly, a nonspecific IgA response to numerous antigens occurs. In addition, mononuclear cells, perhaps responding to antigens presented on the class II major histocompatibility complex of the enterocyte, release such cytokines as tumor necrosis factor–alpha (TNF-α). In vitro studies suggest that TNF-α enhances eosinophil cytotoxicity and perturbs epithelial barrier function by opening the tight junction, thus rendering it more permeable to macromolecules. The immune dysregulation and increase in intestinal permeability to antigens likely contribute to an allergic response.

Recently, researchers have appreciated that gut microflora play an important role in regulating the intestinal and systemic immune system and in inducing tolerance. This role is related to the hygiene hypothesis that was born out of epidemiologic data that showed an inverse correlation between family size and allergic rhinitis. The concept then was generalized to other atopic diseases. Thus, reduced contact with microbes and a diminished burden of infectious disease at an early age may lead to weakened immunologic drive in the Th1 direction and result in overactivity of Th2 responsiveness. This is relevant because Th1 cells generally secrete cytokines which activate other T cells (i.e., interleukin 2, interferon gamma) or other inflammatory cells (i.e., TNF) and thus initiate and augment inflammatory reactions and enhance MHC expression. On the other hand, Th2 cells secrete cytokines that activate B cells (i.e., interleukin 4 and 5) or induce T cells and other hematopoietic cells (i.e., interleukin 6) to grow and differentiate, thus leading to enhanced B cell antibody production and inhibition of Th1 cytokine production. Indeed, the fetal immune response is thought to be Th2-predominant, and the acquisition of certain bacteria, more commonly found in the colon of breast-fed infants, is thought to dampen this Th2 response. However, one should realize that this paradigm is overly simplified, and ongoing research is devoted to defining what are likely novel
regulatory T cell classes that are essential in the acquisition and maintenance of mucosal and systemic tolerance.


COW’S MILK–PROTEIN INTOLERANCE

Allergic reactions to foods have been described since ancient times. Hippocrates noted that some infants developed prolonged diarrhea, vomiting, and urticaria, which resolved with elimination of cow’s milk from the diet. Cow’s milk allergy still was considered to be a rare occurrence before 1950. However, since 1960, when food technology advanced the development and acceptance of cow’s milk-based artificial formulas, the incidence of cow’s milk-protein intolerance has increased.

Based on an increased understanding of the underlying immunopathophysiology, children with cow’s milk allergy can be classified into one of two groups. The first are immediate reactions, those occurring within 2 hours after exposure, and likely represent a type I or IgE-dependent mechanism. This group of reactions is discussed more completely in Chapter 422, Food Allergies. The second group with delayed reactions, occurring more than 2 hours after ingestion, likely represent a type II, III, or IV non–IgE-dependent, T cell–mediated reaction. Most gastrointestinal reactions are of this latter group.

Several prospective studies with a variety of clinical and laboratory definitions of milk allergy placed the prevalence of cow’s milk-protein intolerance at 0.5% to 7.5% among Europeans and North American infants. Infants have presented within 28 hours of birth with cow’s milk allergy, suggesting intrauterine sensitization. Most children develop symptoms by the time they are 3 months old; however, if affected children are not exposed to cow’s milk formula early in infancy, the reaction can be delayed. Retrospective studies indicate that 50% of affected patients have a reaction within the first week after exposure and 75% do by 4 weeks after exposure. Risk factors include a family history of atopy and early dietary exposure to cow’s milk. Exclusively breast-fed infants can develop symptoms of protein intolerance to those proteins that pass through the mother’s milk.


Gastrointestinal Manifestations

Symptoms referable to the GI tract (including diarrhea, vomiting, and weight loss) are among the most common ones associated with cow’s milk allergy, occurring in 50% to 80% of allergic patients. Several clinical entities have been described (Box 357.1).


Colitis

The presentation of milk-induced colitis ranges from asymptomatic occult GI blood loss to explosive, grossly bloody diarrhea and hypovolemic shock. The typical child generally is healthy, with specks or streaks of blood and mucus in his stool. The stool often is noted to be somewhat looser and more frequent, and some colicky pain may be associated with the passage of the stool. Because the blood loss often is minimal, anemia rarely occurs. The differential diagnosis includes infectious colitis (e.g., Salmonella, Shigella, Yersinia, Campylobacter, Escherichia coli O157:H7, and Clostridium difficile), anal fissure, necrotizing enterocolitis, arteriovenous malformations, inflammatory bowel disease, intussusception, volvulus, Meckel diverticulitis, polyps, Hirschsprung enterocolitis, and bowel infarction (Box 357.2).

Because the rectosigmoid area commonly is abnormal, the diagnosis can be confirmed by flexible sigmoidoscopy. Endoscopic findings include a friable mucosa and increased nodularity suggestive of lymphonodular hyperplasia. More severe cases may have multiple superficial erosions or, rarely, frank ulcerations with exudate. Microscopically, the presence of focal infiltrates of eosinophils in all mucosal compartments, particularly the lamina propria, often is striking. Histologic analysis shows maintenance of the mucosa without features of chronicity. Crypt abscesses with neutrophils and eosinophils can occur. A retrospective study of affected patients noted that the presence of no fewer than 60 eosinophils per high-powered field in the lamina propria and of degranulated eosinophils correlates with allergic colitis rather than with infectious colitis.

Jul 24, 2016 | Posted by in ORTHOPEDIC | Comments Off on Protein Intolerance

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