Allie was 16 years old when she first presented in my office with episodic abdominal pain in the lower right quadrant, onset 6 weeks prior, ranging from 2 to 10 on a visual analog pain scale (0=no pain, 10=worst possible pain). Her pain was not associated with reflux, fever, or blood in her stools. Allie had a prior diagnosis of eosinophilic esophagitis (EE), however treatment with diet and a proton pump inhibitor had not been successful.
Allie was feeling despondent, and not at all herself. She was missing school because of the pain episodes and was worried that standard interventions had not been successful.
Probably the most important thing to remember when working with teenagers is that the plan must be straightforward, and the teen must be in agreement with the approach. Allie was bright and willing. However, we still had to come up with an approach that was doable to her. And one which armed her with the information she needed to stay well, but that also put her in the driver’s seat.
A little bit about EE (more as you read through and at the end) – EE is on the rise, particularly since the early 2000s. It is more likely to occur in adults than in children, however it can occur in younger individuals and is increasingly considered a later-stage manifestation of the atopic march. EE was only first characterized in 1993, and presents most commonly with heartburn, epigastric pain, dysphagia, and nausea and vomiting. Eosinophilia and elevated total IgE are common laboratory findings. More than 50 percent of those suffering from EE also have a history of atopic and allergic disease, particularly food allergies; however, airborne allergens have also been identified as triggers for EE. EE has been referred to by allergists as “eczema of the esophagus.”
Initial Workup for Allie
History of Current Symptoms: The first of the episodes had taken place 6 weeks before her first visit to our clinic, had followed a large meal, which was associated with vomiting and diarrhea. The pain woke her from sleep and was 10/10. She was taken to her local hospital’s emergency department, where an abdominal CT scan showed no radiographic evidence of appendicitis but did show some gastric thickening. Laboratory studies showed an elevated white-blood-cell count (18.0) and an increased sedimentation rate. Ibuprofen offered some pain relief, and she was referred to a gastroenterologist. He performed an endoscopy and colonoscopy, diagnosed eosinophilic esophagitis, and prescribed a proton pump inhibitor (PPI). The PPI provided no relief.
Allie also noted that menstrual cramping precipitated a pain attack; however, a gynecological examination was unremarkable, and the gynecologist felt that the pain was likely to be of gastrointestinal (GI) origin.
Medical History: Allie’s medical history was significant for allergies to fruit; trees, including Birch; weeds; and pollen. Two to 3 years prior to her visit to the clinic, she had experienced an anaphylactic reaction while eating a raw apple, but she did not have the same reaction to cooked apples. She then developed a similar reaction to most fruit, including bananas and melons but not berries and grapes. As for other food sensitivities, she reported that wheat and tomato were the primary foods that triggered symptoms, and both of those foods have been associated with EE. Allie’s family members also suffered from severe allergies and atopic disease.
Review of Systems: In a review of her systems, Allie reported ongoing constipation and flatulence. Her medications included Zyrtec, ibuprofen, and an Epi-pen. She had no history of excessive antibiotic or steroid use.
Allie was a picky eater, drank an occasional soda, loved pizza, and primarily ate a standard American diet (SAD). She did not drink coffee.
Physical Exam. Allie experienced pain when the right lower quadrant of her abdomen was palpated, although she had no rebound tenderness or guarding. She also experienced pain during a straight leg raise (SLR) exam for her right leg. She had keratosis pilaris on the posterior aspect of her upper arms, and she had mild macroglossia.
Laboratory Workup After the First Visit
As we finished up our initial visit, my focus for lab testing was going to be on evaluating GI, immune function and nutritional status (especially for nutrients related to immune function). We also needed to rule out Celiac disease. Nothing too out of the ordinary for a Functional Medicine workup.
I did include a recommendation for IgG4 testing. Research identifying the presence of IgG4 and other food-immune complexes deposited at the site of esophageal inflammation of adult EE patients suggests a pathogenic role.
Laboratory tests. The following tests were ordered (results indicated in parentheses):
- Complete blood count (CBC), with a manual differential [5.6 (4.0-10.0)]
- Celiac profile (IgA total, antigliadin antibody, and tissue transglutaminase) [negative]
- Sedimentation rate (ESR) [normal]
- C-reactive protein (CRP) [normal]
- Urinary analysis (UA) [normal]
- Complete metabolic panel (CMP) [normal]
- Vitamin D
- RBC essential elements
- Ferritin
- Gastrointestinal microbiota and function stool test (GIfX)
- Food allergy and sensitivity panels for immunoglobulin E (IgE) [positive for wheat, rye, corn, rice, tomato, oat, orange, strawberry, apple, peach, grape, melon]
- Immunoglobulin G4 food panel (IgG4)
As occasionally happens, Allie did not complete all of the lab work, including the IgG4 food sensitivities panel, vitamin D, ferritin, RBC essential elements, and the stool test. With the benefit of hindsight, I could have opted for collection of a blood-spot specimen for IgG4 food testing and dysbiosis markers for urinary organic acids, as the ease of collection may have improved Allie’s compliance. That said, with the laboratory data and clinical history that we had, we were able to move forward with a sound and largely successful treatment plan.
Follow up Visit at 6 Weeks
Diagnoses: Based on the prior history, examination and testing, I diagnosed: (1) eosinophilic esophagitis, (2) constipation, (3) atopic disease, (4) food and environmental allergies, (5) premenstrual syndrome, (6) intestinal permeability, and (7) possibly eosinophilic gastroenteritis (EG).
Impressions: Although Allie had been diagnosed with EE, she did not present with heartburn, which is the main symptom associated with the condition. Her chief complaint was pain in the right lower quadrant of her abdomen. Endoscopy demonstrated eosinophilic infiltration of the esophagus but apparently not of the stomach or small intestine. Her abdominal CT scan identified the gastric thickening that has been associated with EG. She also had peripheral eosinophilia and a number of IgE food allergies. Although I did not request a second endoscopy, my suspicion was that Allie may have had eosinophilic infiltration of both the esophagus and stomach. The latter diagnosis is difficult to make, given the patchy distribution of eosinophils in the stomach. EE and EG can often present together.
Allie had a strong personal and family history of atopic and allergic disease, including a recent-onset allergy to a number of fruits, including raw apples. She also had significant environmental allergies, including to birch pollen, weeds, and grasses. Her heightened state of allergic inflammation increased her risk for development of EE or EG. Her fruit allergy and apple anaphylaxis specifically suggested cross-reactivity to an environmental allergen. Up to 70 percent of those individuals with a birch allergy have a cross-reaction to fruits, most commonly apples and other stone fruits; ie, fruits with a large, hard seed.
Allie had experienced anaphylaxis to raw apples but could tolerate them when they were cooked. That fact shows that an antigenic peptide was no longer a problem for her when it was altered by cooking. Termed conformational epitopes, reaction to heat-labile peptides can be outgrown. Insufficient stomach acid, as is encountered with acid-blocking therapy, can contribute to this type of IgE food allergy, however, and may explain why the incidence of anaphylaxis is on the rise in adults. Tolerance to cooked apples and other cooked, cross-reactive fruits in a birch-allergic individual also suggests that the antigenic proteins are both of the PR-10 family. Other protein families shown to be associated with EE include profilins and lipid transfer proteins.
The approach in Allie’s case was straightforward. She needed: (1) to eliminate foods associated with her IgE food allergies, which are known triggers and mediators of eosinophilic esophagitis/gastroenteritis, and (2) to reduce her Th2 allergic bias and inflammatory response by treating her intestinal permeability and balancing her gastrointestinal microbiota using probiotics, vitamin D, glutamine, zinc carnosine, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and an elimination diet.
Recommendations:
- An elimination diet based on the laboratory results for IgE and known allergens
- One-half tsp per day of a probiotic powder at 200-billion colony forming units (CFUs), mixed in juice or water
- A nutraceutical supplement containing glutamine, zinc carnosine, slippery elm, and DGL, as directed, with the ability to mix it with juice or water
- 2 capsules once per day of EPA/DHA 360/250
- 2 drops daily of vitamin D, at 2000 IU per drop
While there are a number of additional laboratory evaluations and treatment interventions that might have been relevant for Allie, she was not willing to adhere to a broader plan. We had to keep it manageable for her. Without the patient’s cooperation, nothing can be accomplished.
Follow up Visit at 2 Months
At Allie’s two-month follow-up, she had returned to school; seen improvement in her symptoms when she avoided antigenic foods, especially the wheat and tomatoes in pizza; found probiotics to be helpful with pain and constipation; and had no severe pain episodes. She continued, however, to experience sporadic pain, admitting that she was not perfect in following her diet.
More About EE
EE is only does not generally respond to antireflux therapy. Diagnosis is difficult, but key signs and symptoms are a lack of a favorable response to acid-blocking therapy and a history of allergic disease. Diagnosis can be confirmed with an esophageal biopsy, identifying eosinophil infiltration. Interventions include use of steroids and avoidance of trigger foods. A high degree of relapse exists with the condition because of poor dietary compliance.
The treatment approach commonly used for EE is suppression of inflammation with steroid therapy with short-term removal of offending foods. However, an attempt to reduce allergic bias and inflammation and treat intestinal permeability is not a part of the standard approach and may also explain the high rate of relapse with the condition.
EE patients often present with polysensitization, including allergies not only to multiple foods but also environmental allergies. Furthermore, an increased incidence of EE onset occurs during allergy season. Some research shows that food sensitizations in EE patients are mainly caused by cross-reactivity to food allergens after primary birch-pollen sensitization, which appears to have be the case with Allie. Studies have been mixed however, with regard to outcomes of birch desensitization reducing apple cross-reactivity (additional ref here).
EG is considered relatively rare and often is misdiagnosed, although it is also rising in incidence. The most common complaint of patients is nonspecific abdominal pain. Diagnosis involves a positive identification of eosinophil infiltration of mucosa—which is most common—or of the muscule tissue or serosa of the stomach and/or intestinal tract, with eosinophilia and elevated IgE on laboratory evaluation. EG is also strongly associated with atopic and allergic disease, particularly food allergies.
The treatment approach commonly used for EE or EG is suppression of inflammation with steroid therapy with short-term removal of offending foods. An attempt to reduce allergic bias and inflammation and treat intestinal permeability is not a part of the standard approach and may explain the high rate of relapse with the condition. In theory, if a treatment restores the intestinal mucosa, certain foods can at some point be reintroduced and tolerated. It makes mechanistic sense that successful desensitization to environmental allergens using immunotherapy would also reduce food cross-reactions. Therefore, treatment should take this into account with the goal being to remove offending foods, reduce general inflammation and reduce Th2 bias.