Clinical Manifestation of Gastrointestinal Food Allergies

Clinical Manifestation of Gastrointestinal Food Allergies

Disorder

Mechanism

Symptoms

Diagnosis

Pollen-food allergy syndrome (oral allergy syndrome)
IgE mediated
Mild pruritus, tingling, and/or angioedema of the lips, palate, tongue or oropharynx; occasional sensation of tightness in the throat and rarely systemic symptoms
Clinical history and positive SPT responses to relevant food proteins (prick-plus-prick method); ± oral challenge—positive with fresh food, negative with cooked food
Gastrointestinal “anaphylaxis”
IgE mediated
Rapid onset of nausea, abdominal pain, cramps, vomiting, and/or diarrhea; other target organ responses (ie, skin, respiratory tract) often involved
Clinical history and positive SPT responses or RAST results; ± oral challenge
Allergic eosinophilic esophagitis
IgE mediated and/or cell mediated
Gastroesophageal reflux or excessive spitting-up or emesis, dysphagia, intermittent abdominal pain, irritability, sleep disturbance, failure to respond to conventional reflux medications
Clinical history, SPTs, endoscopy and biopsy, elimination diet and challenge
Allergic eosinophilic gastroenteritis
IgE mediated and/or cell mediated
Recurrent abdominal pain, irritability, early satiety, intermittent vomiting, FTT and/or weight loss, peripheral blood eosinophilia (in 50%)
Clinical history, SPTs, endoscopy and biopsy, elimination diet and challenge
Food protein–induced proctocolitis
Cell mediated
Gross or occult blood in stool; typically thriving; usually presents in first few months of life
Negative SPT responses; elimination of food protein → clearing of most bleeding in 72 h; ± endoscopy and biopsy; challenge induces bleeding within 72 h
Food protein–induced enterocolitis
Cell mediated
Protracted vomiting and diarrhea (± bloody) not infrequently with dehydration; abdominal distention, FTT; vomiting typically delayed 1-3 h after feeding
Negative SPT responses; elimination of food protein → clearing of symptoms in 24-72 h, challenge → recurrent vomiting within 1-2 h, ∼15% have hypotension
Food protein–induced enteropathy celiac disease (gluten-sensitive enteropathy)
Cell mediated
Diarrhea or steatorrhea, abdominal distention and flatulence, weight loss or FTT, ± nausea and vomiting, oral ulcers
Endoscopy and biopsy IgA; elimination diet with resolution of symptoms and food challenge; celiac-IgA anti-gliadin and anti-transglutaminase antibodies
Clinical Manifestation of Gastrointestinal Food Allergies, Specific disorders and symptom complexes In addition to considering whether gastrointestinal reactions caused by food allergy are isolated or associated with other allergic disease and are acute or chronic, it is helpful to consider particular symptom complexes/clinical syndromes in which food allergy is a possible cause. The following section specifically addresses the role of food allergy in these disorders.Immediate (IgE-mediated) gastrointestinal reactions to food protein

  • Immediate gastrointestinal hypersensitivity  In immediate gastrointestinal hypersensitivity, ingestion of the causal protein results in immediate (from minutes to 1–2 hours) gastrointestinal symptoms that may include nausea, vomiting, abdominal pain, and diarrhea. Considered here as a distinct syndrome, it is more commonly associated with reactions in other organ systems, such as during systemic anaphylaxis in patients with other atopic diseases. For example, children with atopic dermatitis undergoing oral food challenges with foods to which they have specific IgE antibody will sometimes manifest only gastrointestinal symptoms. In addition to a suggestive history, tests for specific IgE antibody to the causal protein will be positive.
  • Oral allergy syndrome  Oral allergy syndrome is a form of contact allergy confined almost exclusively to the oropharynx. Symptoms include pruritus and angioedema of the lips, tongue, and palate and are of rapid onset, typically while eating certain fresh fruits and vegetables. The reaction generally occurs in adults with pollen allergy (hayfever) sensitized to cross-reacting proteins in particular fruits and vegetables. Examples include reactions to melons in individuals with ragweed allergy and to apples in those with birch pollen allergy. The proteins are labile, and cooked forms of the fruits and vegetables generally do not induce symptoms. Allergy skin tests using fresh extracts of the implicated food are characteristically positive.
  • Dietary protein–Induced proctitis/proctocolitis of infancy   Food allergy is the major cause of rectal bleeding due to colitis in infants. Infants with this disorder are typically healthy but have specks or streaks of blood mixed with mucus in otherwise normal-appearing stool. Occasionally there is associated fussiness or increased frequency of bowel movements. The presence of vomiting, chronic diarrhea, significant anemia, or growth failure should raise suspicion of enteropathy or enterocolitis syndrome, a potentially more serious condition discussed below. The mean age at diagnosis is approximately 60 days, but there is often a history of bleeding that precedes diagnosis by several weeks and may be mistakenly attributed to perirectal fissures. Bleeding rarely occurs in the first week of life. On endoscopic examination, patchy erythema and loss of vascularity may be limited to the rectum, or it may extend throughout the colon. Lymphonodular hyperplasia may be seen but is not unique to this condition. Histologically, high numbers of eosinophils or eosinophilic “abscesses” in the lamina propria (>60), crypt epithelium, and muscularis mucosa are typically observed. Multinucleated giant cells in the submucosa have been reported. Cryptitis and crypt abscesses containing polymorphonuclear (PMN) cells are uncommon in this condition, as are chronic changes such as glandular distortion and Paneth cell metaplasia. The immunologic mechanisms responsible are unknown. Although peripheral eosinophilia and positive radioallergosorbent tests (RASTs) to milk have been reported, the findings are not consistent. The dietary proteins frequently implicated include cow’s milk and soy. The condition also occurs in exclusively breast-fed infants and in infants fed protein hydrolysate formulas that contain minute amounts of allergenic protein.In cow’s milk or soy formula–fed infants, substitution with a protein hydrolysate formula generally leads to cessation of obvious bleeding within 72 hours, although it is unknown how long occult bleeding continues. The majority of infants who develop this condition while ingesting protein hydrolysate formulas will experience resolution of bleeding with the substitution of an amino acid–based formula. Management in breast-fed infants is more difficult. Restriction of cow’s milk, egg, or soy from the mother’s diet usually results in prompt resolution of symptoms. In cases in which there is no response to maternal dietary manipulation, there are no data currently available to know whether breast-feeding may be safely continued in an infant who otherwise appears healthy.Thus, the diagnosis of dietary protein proctocolitis is primarily clinical. Withdrawal of the presumed allergen and resolution of symptoms are usually sufficient to make the diagnosis, and the majority of infants will tolerate cow’s milk and soy products by 1–2 years of age. Continued bleeding may be an indication for more invasive testing (i.e., biopsy) and monitoring for anemia.
  • Dietary (food) protein–Induced enteropathy This is a symptom complex of malabsorption, failure to thrive, diarrhea, emesis, and hypoproteinemia in infants that is usually related to an immunologic reaction to cow’s milk protein. The syndrome may also occur following infectious gastroenteritis in infants. Patchy villous atrophy with cellular infiltrate on biopsy is characteristic. Diagnosis is based on the combined findings from endoscopy/biopsy, allergen elimination, and challenge. There are case reports in which similar symptoms occur with foods other than milk (eggs, rice, poultry, fish, or shellfish), occasionally affecting older individuals, but larger series are lacking. Although it shares features with celiac disease, this disorder generally resolves in 1–2 years.
  • Dietary (food) protein–Induced enterocolitis syndrome Food protein–induced enterocolitis syndrome (FPIES), as defined by Powell,31, 32 describes a symptom complex of profuse vomiting and diarrhea diagnosed in infancy. Because both the small and large bowel are involved, the term “enterocolitis” is used. Although the clinical syndrome may represent a more severe form of food protein–induced enteropathy (abdominal symptoms and malabsorption with associated villous blunting, there are particular features, including signs of systemic reactivity and implications for long-term clinical management, that warrant its discussion as a distinct clinical entity.Powell described 9 infants with severe, protracted diarrhea and vomiting. The symptoms developed 4–27 days after birth (mean, 11 days) while the infants were receiving cow’s milk–based formula. Switching to a soybean–based formula resulted in transient improvement, but symptoms generally recurred in 7 days. Seven of the 9 infants were below birth weight, and 8 of 9 presented with dehydration. Eight of the infants appeared acutely ill and underwent sepsis evaluations (negative). All infants were noted to have low serum albumin levels, increased peripheral blood PMN leukocyte counts, and stools that were positive for heme and reducing substances. The hospital course usually involved improvement while on intravenous fluids, followed by recurrence of dramatic symptoms with reintroduction of soy- or cow’s milk–based formula, including the development of shock in several infants. Follow-up with oral challenges was carried out with cow’s milk and soybean formulas (30–100 mL of formula) at a mean age of 5.5 months, and 14 of 18 challenges were positive. Ten of 14 challenges resulted in vomiting (onset, 1–2.5 hours after ingestion; mean, 2.1 hours), and all experienced diarrhea (onset, 2–10 hours; mean, 5 hours) with blood, PMN cells, eosinophils, and increased carbohydrate in the stool. There was an increase in PMN cell counts in all positive challenges, peaking at 6 hours after ingestion, with a mean increase of 9900 cells/mm3 (range, 5500–16,800 cells/mm3). Only isolated gastrointestinal symptoms were reported.The results of these studies led Powell to propose particular criteria for a positive oral challenge to diagnose food protein–induced enterocolitis of infancy. Confirmation of the allergy included a negative search for other causes, improvement when not ingesting the causal protein, and a positive oral challenge resulting in vomiting or diarrhea, evidence of gastrointestinal inflammation through stool examination for heme, eosinophils, and an increase in the peripheral PMN leukocyte count of >3500 cells/mL. Infants with symptoms consistent with severe enterocolitis who fulfilled, or who are highly likely to have fulfilled, these criteria are included in many reports of milk or soy allergy of infancy. Additional information about the clinical characteristics of these infants has emerged. In a review of 17 infants hospitalized with FPIES, Murray and Christie reported 6 infants who presented with acidemia (mean pH, 7.03) and methemoglobinemia. The association of methemoglobinemia with FPIES was noted in the investigators’ published experience with FPIES. Several other clinical features of infantile FPIES have emerged from studies by Sicherer et al. (16 patients) and Burks et al. (43 patients). All of the infants studied had negative skin prick tests or RASTs to the causal proteins (cow’s milk or soy). Approximately half of the infants reacted to both cow’s milk and soy. After 2 years from the time of presentation, sensitivity to milk was lost in 60%, and to soy in 25% of the patients. Treatment with a hydrolyzed cow’s milk formula is advised, although some patients may react to the residual peptides in these formulas, thus requiring an amino acid-based formula. Most of these infants become tolerant of the causal protein 1–2 years after the diagnosis, but a subset may have more prolonged sensitivity.Because infantile FPIES is a diagnosis that can be made clinically, there are no series in which biopsies are performed solely in patients fulfilling Powell’s criteria. Thus, specific descriptions of the histologic findings are lacking, and only assumptions can be drawn by considering descriptions from case reports or series that likely included these patients. Endoscopic and biopsy findings in FPIES are nonspecific. Colonic biopsies performed in symptomatic patients reveal crypt abscesses and a diffuse inflammatory cell infiltrate with prominent plasma cells; small bowel biopsies reveal edema, acute inflammation, and mild villous injury. In some cases, focal erosive gastritis and esophagitis are found with prominent eosinophilia and villous atrophy.In an unpublished study, the investigators observed adults who experience a delayed onset of severe, repetitive vomiting and delayed diarrhea after ingestion of shellfish. The response is not associated with specific IgE antibody and occurs stereotypically with repeated exposure. This may represent a variation of enterocolitis syndrome that occurs in adults.
  • Gastroesophageal reflux associated with CMA in infants CMA and gastroesophageal reflux (GER) are both common conditions in the first year of life that have similar symptoms, such as vomiting and irritability. In 1985, Forget et al. showed that infants who seem to have GER but who do not respond to medical therapy might have CMA. A number of recent studies have attempted to show that CMA may induce symptoms of GER and may be associated with distinctive serologic and pH probe characteristics.Staiano et al. identified a cohort of infants with vomiting and showed that 16% of patients had both GER and CMA, whereas 16% had CMA alone. GER was defined on the basis of a positive pH probe and esophagitis on biopsy. CMA was defined on the basis of resolution of symptoms after removal of cow’s milk protein and a recurrence upon oral challenge 4–6 weeks later. Small intestinal biopsies and intestinal permeability studies were performed, and the latter was >95% predictive of CMA, even when intestinal biopsy specimens were normal. Although intestinal permeability studies are often used in clinical research, they are not standard diagnostic modalities in children. However, the data suggest that the standard evaluation for infants who vomit (including pH probe, barium study, or endoscopy) may be inadequate to identify patients allergic to cow’s milk.Cavataio, Iacono, and colleagues have investigated these issues in several prospective, controlled trials, showing that up to 42% of infants under 1 year of age with GER also have CMA. These investigators were the first to identify pH probe characteristics unique to patients with CMA. In this “phasic” pH probe recording, a progressive, gradual, and prolonged fall in pH after milk ingestion occurs, perhaps because of delayed gastric emptying or a functional incompetence of the lower esophageal sphincter as a result of CMA. These findings differ sharply from the typical pH probe findings in infants with “classic” GER, which features a sharp drop in pH and a rapid, random return to baseline caused by transient relaxation of the lower esophageal sphincter. The investigators also performed numerous evaluations to screen for CMA in these patients, including skin prick tests, total serum IgE, blood and fecal eosinophils, and quantitative serum IgG to β-lactoglobulin. Assuming values >36% above background as a positive threshold for the anti–β-lactoglobulin assay, they showed 100% sensitivity and 78% specificity for the diagnosis of CMA.The data presented by these investigators remain controversial. Their study population may not be representative of classical GER because those with CMA-associated GER also had a higher incidence of concomitant diarrhea or atopic dermatitis, thereby potentially overestimating the prevalence of CMA-associated GER. In addition, the significance of circulating antibodies to exogenous protein is debatable because all infants develop antibodies to cow’s milk that gradually decline in the first 2 years of life, even in the absence of allergic symptoms.  However, allergic patients tend to have higher levels of allergen-specific IgG antibodies, so there may be validity in the cutoffs used by these investigators. The phasic pattern on pH probe analysis is extremely compelling but has not been shown by other investigators.Further research is needed before solid conclusions about the cause-and-effect relationship of CMA in infants with GER can be made. Technically, primary GER is always a diagnosis of exclusion once obstruction, metabolic disorders, and other inflammatory conditions are ruled out. However, many practitioners are reluctant to perform the invasive testing required to exclude other conditions in the vomiting infant, resorting to formula changes before a clear diagnosis is made. A response to a casein hydrolysate may be indicative of CMA but may also result from altered gastrointestinal motility caused by other properties of the formula. No studies evaluating the response to hypoallergenic formulas in infants with isolated GER, in the absence of underlying small bowel pathology, have been performed.
  • Eosinophilic gastroenteritis Eosinophilic gastroenteritis (EG) is characterized by infiltration of the gastric or intestinal walls with eosinophils, peripheral eosinophilia (50%), and absence of vasculitis. Other causes of eosinophilia (e.g., parasites, H. pylori, or inflammatory bowel disease) must be ruled out. Patients present with postprandial nausea, abdominal pain, vomiting, diarrhea, protein-losing enteropathy, and weight loss; depending on the depth of infiltration, abdominal bloating, obstruction, and ascites can also develop. The diagnosis rests on biopsy, although there may be patchy disease and infiltration may be missed unless multiple biopsies are performed. The spectrum of EG was described in a large series by Talley et al. (median age, 36 years). Food intolerance or allergy was reported by half of the 23 patients with mucosal disease, but not by any patients with muscle layer or subserosal disease. However, formal studies to determine the role of food allergy were not undertaken. Case reports reflect improvement with elimination diets, but results in adults are generally transient and poor. Justinich et al. reported complete resolution of EG in a teenage boy who previously required continuous steroid therapy for management through treatment with an elemental formula. Treatment with steroids seems most successful. Improvement with sodium cromoglycate has been reported (case reports) but is limited, and there is a report of improvement with montelukast. Controlled trials are lacking for any therapies.Considering the increased incidence of atopy and reported food intolerance in patients with EG and an element of success for dietary therapy, it seems prudent to consider food allergy in the evaluation of EG. Once a diagnosis is secured, a trial elimination diet may be warranted, primarily in patients with mucosal disease and a history of atopy or food intolerance. Current evidence is not convincing for successful treatment of EG with diet alone in most patients, so alternative treatments should be considered (e.g., anti-inflammatory treatments). Clearly, more formal studies of the role of food allergy in this disorder are warranted.
  • Eosinophilic esophagitis and GER in adults and children  In 1982, Winter et al. noted the presence of intraepithelial eosinophils (IEs) in the esophagus of children with proven GER and showed that increased acid exposure directly correlated with the numbers of eosinophils in esophageal epithelium. Since then, the presence of IEs has been considered a central feature in the diagnosis of GER. In adult patients with GER, IEs found on esophageal biopsy have been shown to be the most consistent histologic finding. However, there has been increasing evidence that elevated numbers of eosinophils in the esophagus indicate an intrinsic disorder, perhaps a variant of EG. In addition, recent literature has proposed that GER in infants may be caused, in many instances, by allergy to cow’s milk protein, raising the question of whether reflux itself, and not just eosinophilic esophagitis, may be caused, in some cases, by dietary protein sensitization, as discussed above.EG may diffusely involve the entire gastrointestinal tract or the esophagus, stomach, intestine, or colon separately. Patients with isolated esophageal involvement, eosinophilic gastroenteritis (EE), have a predominance of dysphagia (~85%), caused by either strictures (often proximal) or a variety of manometric abnormalities. The latter include diffuse esophageal spasm, increased lower esophageal sphincter pressure, and achalasia. These motor disturbances may result from infiltration of eosinophils into the muscular layers of the intestinal wall or to the elaboration of eosinophil products. Although case reports have noted an absence of documented GER by pH probe in these patients, it is not clear that this is true in all patients. A predominance of young males has been noted in several reviews.Some investigators have evaluated the number of IEs/high-power field (HPF) to differentiate EE from GER. Attwood et al. retrospectively reviewed the histology of esophageal biopsies and identified those patients with >20 IEs/HPF. He compared these patients by pH probe to individuals with documented GER who had a mean number of IEs/HPF of 3.3. The patients with high numbers of IEs were likely to be young and male, and all had normal pH probes. Patients with GER were more likely to have gross abnormalities on endoscopy, including erosions and Barrett’s esophagus, and intraepithelial neutrophils on histology.A number of other recent studies have attempted to evaluate the meaning of high numbers of IEs in esophageal biopsy specimens. Ruchelli et al. retrospectively reviewed a series of 102 children undergoing evaluation for symptoms of GER who showed at least 1 eosinophils/HPF on esophageal biopsy. They compared the number of IEs to the clinical outcome after GER therapy. Patients who failed treatment had a significantly stronger history of allergy (wheezing, rhinitis, urticaria, or atopy) than responders and also had significantly more IEs on biopsy. A threshold of >7 IEs/HPF had a positive predictive value of 85% for determining ultimate failure with medication. Patients in the treatment failure group (12 patients) responded to steroids (8 patients) or an amino acid–based formula (4 patients). The retrospective nature of this study limits its value, as does the fact that 2 patients in the treatment failure group had evidence of diffuse EG. In addition, proton pump inhibitors were not available during this era, so treatment failure may reflect failure to suppress acid adequately rather than imply a different disease. However, the favorable response to diet or anti-inflammatory therapy does suggest a separate disease entity in which a primary allergic or inflammatory disorder may be present. Lee et al. retrospectively reviewed esophageal biopsy specimens containing >10 IEs/HPF. Most of these patients were younger than 25, and 1 had diffuse allergic eosinophilic gastroenteritis. There was documentation of GER by either pH probe or barium studies in a majority of patients, suggesting that the presence of high numbers of eosinophils does not exclude a diagnosis of GER. However, response to therapy was not included in the study. In addition to elevated numbers of eosinophils, Justinich et al. have noted that individuals with EE, in contrast to those with GER, have increased mucosal mast cells (using special stains) on esophageal biopsy (6.9 vs. 32/HPF); the utility of this finding as a diagnostic method requires further study.A recent retrospective review by Walsh et al. also evaluated children who had failed therapy for GER. All index children had IEs in the esophagus after treatment for GER (mean, 30). Only half these patients had pH probe monitoring, which was normal in all. Patients in this treatment failure group were successfully managed with steroids, elemental diets, or oral cromolyn. Orenstein et al. reviewed their experience with 30 pediatric patients with EE and noted that typical endoscopic findings included a granular appearance with furrows or visible rings, typically without ulcers.Thus, a dense eosinophilic infiltrate, relatively benign endoscopic features, and lack of improvement with GER treatment may denote a primary disorder of esophageal inflammation, likely to respond to anti-inflammatory medications (steroids) rather than antireflux medications. The additional question is: does food allergy induce or contribute to this disorder? Orenstein et al. documented positive prick skin tests or RASTs in 13 of 19 children with EE (median, 7 foods). Dietary elimination was undertaken in 12 of the 13 with positive tests. Of 10 who were compliant with the diet, all were believed to benefit with resolution of symptoms. Seven of the patients had concomitant therapies (steroid, 3; antireflux medications, 2; cromolyn, 1; or fundoplication, 1). However, lapses in the diet were accompanied by recurrence of symptoms in the months after diagnosis, despite other therapies. No formal food challenges were performed, and food allergy was not evaluated in those with negative tests for IgE antibody. In a study that specifically addressed the role of food allergy in children with EE, Kelly et al. evaluated patients who failed standard GER treatment or fundoplication (6 patients) and who had persistent IEs on esophageal biopsy. These patients were offered treatment with an amino acid–based formula. Eight of 10 patients became symptom-free, and 2 had significant reduction in symptoms within 2–6 weeks after starting the dietary program. Repeat endoscopy showed a decline in median numbers of IEs, from 40 to 0.5. Furthermore, patients underwent open food challenges, and in most cases a select number of foods (typically milk, soy, eggs, peanuts, and wheat) were identified as reproducing symptoms within 1–8 hours of ingestion. Many patients in the study had documented GER before enrollment. Prick skin tests to foods were positive in 6 of 10 patients but correlated poorly with positive challenge results. Interestingly, the patient population included 1 patient with tracheal-esophageal fistula and 2 with cerebral palsy, conditions that are normally associated with a high degree of refractory GER, presumed to be on the basis of abnormal anatomy and motility.Taken together, these studies support a role for food allergy in the pathogenesis and treatment of EE, at least in children. It is unknown whether the disease is underdiagnosed in adults who may not have biopsies performed when visual inspection of the esophagus is benign. Evaluation for food allergy is justified, particularly in the subset with indicative histories or positive tests. In addition, the presence of documented GER on pH probe or barium study does not exclude the diagnosis of food allergy. Those patients who fail to improve with standard medication regimens and who have persistent esophagitis after GER therapy may benefit from other therapies before surgery is considered. For EE, steroids have been effective, including case reports of metered-dose inhaled steroids that are swallowed, but a trial of an elemental diet may be beneficial in many of these patients. Careful reintroduction of foods may identify specific dietary allergens.
  • Celiac disease Celiac disease represents an immune response to a food protein (gluten) and therefore may be considered a food allergic disorder. However, a full discussion of diagnosis and management is beyond the scope of this report. Ingestion of whole cow’s milk by infants less than 6 months of age may lead to occult blood loss from the gastrointestinal tract and iron deficiency anemia. The use of infant formulas generally results in resolution of symptoms. There is limited evidence that infantile colic is associated with food (cow’s milk) allergy in a subset of patients (sometimes on an IgE-mediated basis), but more studies are needed to define the relationship. Cow’s milk intolerance has also been suggested as a cause of chronic constipation in older infants and toddlers.Investigators have shown the presence of eosinophilic proctitis in children with chronic constipation, resolution of constipation after withdrawal of cow’s milk from the diet (and substitution with soy-based formula), and recurrence upon reintroduction of cow’s milk. However, further studies are needed to confirm these associations. Elemental diets have been shown to induce remission in Crohn’s disease; however, recent meta-analyses have shown that they are inferior to steroids at inducing and maintaining remission despite their popularity in some countries. No data have conclusively shown that specific immunologic responses to food alter the course of Crohn’s disease or are responsible for its development. The relationship of irritable bowel syndrome to food allergy has not been systematically studied
  • Differential diagnosis of adverse food reactions

    Gastrointestinal disorders (vomiting and/or diarrhea)
    Structural abnormalities
    Hiatal hernia
    Pyloric stenosis
    Tracheoesophageal fistula
    Hirschsprung’s disease
    Enzyme deficiencies (primary vs secondary)
    Disaccharidase deficiency (lactase, sucrose-isomaltase, glucose-galactose)
    Galactosemia
    Phenylketonuria
    Malignancy
    Other
    Pancreatic insufficiency (cystic fibrosis, Schwachman-Diamond syndrome)
    Gallbladder disease
    Peptic ulcer disease
    Contaminants and additives
    Flavorings and preservatives
    Sodium metabisulfite
    Monosodium glutamate
    Nitrites/nitrates
    Dyes
    Tartrazine, ? other azo dyes
    Toxins
    Bacteria (Clostridium botulinum, Staphylococcus aureus )
    Fungal (aflatoxin, trichothecene, ergot)
    Seafood-associated disorders
    Scrombroid poisoning (tuna, mackerel)
    Ciguatera poisoning (grouper, snapper, barracuda)
    Saxitoxin (shellfish)
    Infectious organisms
    Bacteria (Salmonella, Shigella, Escherichia coli,Yersinia, Campylobacter )
    Parasites (Giardia, Trichinella, Anisakis simplex )
    Virus (hepatitis, rotavirus, enterovirus)
    Mold antigens (?)
    Accidental contaminants
    Heavy metals (mercury, copper)
    Pesticides
    Antibiotics (penicillin)
    Pharmacologic agents
    Caffeine (coffee, soft drinks)
    Theobromine (chocolate, tea)
    Histamine (fish, sauerkraut)
    Tryptamine (tomato, plum)
    Serotonin (banana, tomato)
    Tyramine (cheeses, pickled herring)
    Glycosidal alkaloid solanine (potatoes)
    Alcohol
    Psychologic reactions

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