The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 61

75. What other diseases and disorders are commonly associated with mast cell disease?

I often joke that it would be easier to list what conditions are not commonly associated with mast cell disease because so many conditions occur alongside it. However, there are some conditions that you see a lot in the mast cell population relative to others. In every instance, mast cell disease has the potential to irritate the other condition and vice verse.

Clonal hematologic disorders. Systemic mastocytosis is so frequently accompanied by other blood disorders that it has a diagnosis specifically for this phenomenon: systemic mastocytosis with associated hematologic disorder (SM-AHD). It is estimated that up to 40% of patients with SM eventually develop another clonal hematologic disorder. A clonal hematologic disorder is a condition in which your bone marrow makes too many blood cells. Examples include chronic myelogenous leukemia, acute myeloid leukemia, polycythemia vera, myelofibrosis, and essential thrombocythemia.

Unlike mastocytosis, MCAS can occur secondarily to lots of conditions. In some instances, it’s not clear if the MCAS is secondary to a condition or the condition is secondary to MCAS or neither.

Heritable connective tissue diseases. Ehlers Danlos Syndrome (EDS), is the most common connective tissue disease in the mast cell population. There are multiple types of EDS. While hypermobility type EDS (formerly called Type III) is the most common in MCAS patients, other forms occur also. Other connective tissue diseases seen in mast cell patients include Marfan Syndrome and Loeys-Dietz Syndrome.

Dysautonomia. Dysautonomia is a condition in which your body’s autonomic nervous system doesn’t regulate essential bodily functions correctly. POTS is the most common form of dysautonomia found in mast cell patients but other forms occur, too.

Mast cell patients commonly have MCAS, EDS and POTS together. They cooccur so commonly that some experts think that that this presentation is actually one overarching disease rather than three separate ones affecting mast cell patients.

Eosinophilic GI disease. Mast cells are closely related to eosinophils. They activate eosinophils and eosinophils activate them. Mast cell patients sometimes have eosinophil GI disease where eosinophils activate to lots of triggers and damage the GI tract.

Immunodeficiency. Conditions that specifically impair a person’s immunity, especially those that affect T or B cells, like SCID or CVID, are not unusual in mast cell patients.

Gastrointestinal disease. Mast cells normally live in the GI tract so they are very sensitive to GI inflammation. MCAS can occur secondarily to lots of GI diseases. Crohn’s, ulcerative colitis, inflammatory bowel disease, and irritable bowel syndrome are examples. GI disorders that specifically affect motility are also seen in mast cell disease, like gastroparesis and chronic intestinal pseudoobstruction.

Allergies. Some mast cell patients have true IgE allergies or other allergic disorders like atopic dermatitis.

Autoimmune disease. Autoimmune disease is more common in MCAS patients than in SM patients. The specific disorder could be virtually any autoimmune condition, including rheumatoid arthritis, lupus, Hashimoto’s thyroiditis, autoimmune urticaria, and many others.

Adrenal insufficiency. The body’s mechanisms for produce stress hormones like cortisol can become dysregulated in mast cell patients. This results in a situation in which the body does not make enough steroids of its own to take care of the body during periods of stress. Patients with adrenal insufficiency are dependent upon daily steroids to stay safe.

Chiari malformation. This condition affects the space around a person’s brainstem, causing a wide array of symptoms. Some patients have surgery for this condition.

Asthma. It is difficult to draw an exact line where mast cell disease ends and asthma begins in mast cell patients as the symptoms can be virtually identical.

This list is not exhaustive. Many other conditions sometimes occur in mast cell patients.

For additional reading, please visit the following posts:
The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 31
The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 32

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 57

71. What other diseases “look like” mast cell disease?

Mast cell diseases have many symptoms that are also commonly found in other disorders. This is one of the reasons why it is difficult to diagnose correctly. The following conditions have symptoms that can look like mast cell disease.

Neuroendocrine cells are specialized cells that help to pass signals from the nervous system to nearby cells, causing those cells to release hormones. There are many types of neuroendocrine tumors. Some conditions that look like mast cell disease are caused by these tumors. Symptoms from them are caused by the response of too much hormone.

Carcinoid syndrome is the result of a rare cancerous growth called carcinoid tumor. This tumor releases too much serotonin into the body. This can cause flushing, nausea, vomiting, diarrhea, difficulty breathing, and cardiovascular abnormalities such as abnormal heart rhythm. Mast cells also release serotonin but they release much less than carcinoid tumors.

VIPoma means vasoactive intestinal peptide –oma. When a word has –oma at the end, it means that it is a tumor. A VIPoma is a tumor that starts in the pancreas. It releases a chemical called vasoactive intestinal peptide. VIPoma can cause flushing, low blood pressure, and severe diarrhea leading to dehydration. A VIPoma can also abnormalities in the composition of the blood. Many patients have low potassium, high calcium, and high blood sugar.

Pheochromocytomas start as cells in the adrenal glands. They release excessive norepinephrine and epinephrine. They can cause headaches, heart palpitations, anxiety, and blood pressure abnormalities, among other things.

Zollinger-Ellison syndrome is a condition in which tumors release too much of a hormone called gastrin into the GI tract. This causes the stomach to make too much acid, damaging the stomach and affecting absorption.

Some blood cancers can cause mast cells to become overly activated. They may also cause an increase in tryptase, an important marker in diagnosing systemic mastocytosis.

Some other cancerous tumors like medullary thyroid carcinoma can cause mast cell type symptoms including flushing, diarrhea, and itching.

Most diseases with any allergic component can look like mast cell disease.

Eosinophilic gastrointestinal disease occurs when certain white blood cells called eosinophils become too reactive, causing inflammation to many triggers. Furthermore, people are more frequently being diagnosed with both EGID and mast cell disease.

Celiac disease is an autoimmune disease in which gluten causes an inflammatory reaction inside the body. The damage to the GI tract can be significant. Malabsorption is not unusual. Children with celiac disease may grow poorly. Bloating, diarrhea, ulceration, and abdominal pain are commonly reported.

FPIES (food protein induced enterocolitis syndrome) can cause episodes of vomiting, acidosis, low blood pressure and shock as a result of ingesting a food trigger.

Traditional (IgE) allergies can also look just like mast cell disease. They are usually distinguished by the fact that mast cell patients may react to a trigger whether or not their body specifically recognizes it as an allergen (does not make an IgE molecule to the trigger). Confusingly, it is possible to have both traditional IgE allergies and mast cell disease.

Postural orthostatic tachycardia syndrome (POTS) is commonly found in patients with mast cell disease. However, POTS itself can have similar symptoms to mast cell disease. Palpitations, blood pressure abnormalities, sweating, anxiety, nausea, and headaches are some symptoms both POTS and mast cell disease have. There are also other forms of dysautonomia which mimic the presentation of mast cell disease.

Achlorhydria is a condition in which the stomach does not produce enough acid to break down food properly. This can cause a lot of GI pain, malabsorption, anemia, and weight loss.

Hereditary angioedema and acquired angioedema are conditions that cause a person to swell, often severely. Swelling may affect the airway and can be fatal if the airway is not protected. Swelling within the abdomen can cause significant pain and GI symptoms like nausea and vomiting.

Gastroparesis is paralysis of the stomach. People with GP often experience serious GI pain, vomiting, nausea, diarrhea or constipation, bloating and swelling.

Inflammatory bowel diseases and irritable bowel syndrome can all cause GI symptoms identical to what mast cell patients experience.

This list is not exhaustive. There are many other diseases that can look similar to mast cell disease. These are the ones I have come across most commonly.

For more detailed reading, please visit the following posts:

Gastroparesis: Part 1
Gastroparesis: Treatment (part 2)
Gastroparesis: Diabetes and gastroparesis (Part 3)
Gastroparesis: Post-surgical gastroparesis (Part 4)
Gastroparesis: Less common causes (Part 5)
Gastroparesis: Autonomic nervous system and vagus nerve (Part 6)
Gastroparesis: Idiopathic gastroparesis (Part 7)

Food allergy series: Food related allergic disorders
Food allergy series: FPIES (part 1)
Food allergy series: FPIES (part 2)
Food allergy series: Eosinophilic colitis
Food allergy series: Eosinophilic gastrointestinal disease (part 1)
Food allergy series: Eosinophilic gastrointestinal disease (part 2)
Food allergy series: Eosinophilic gastrointestinal disease (part 3)
Food allergy series: Eosinophilic esophagitis (Part 1)
Food allergy series: Eosinophilic esophagitis (Part 2)
Food allergy series: Eosinophilic esophagitis (Part 3)

Angioedema: Part 1
Angioedema: Part 2
Angioedema: Part 3
Angioedema: Part 4

Deconditioning, orthostatic intolerance, exercise and chronic illness: Part 1
Deconditioning, orthostatic intolerance, exercise and chronic illness: Part 2
Deconditioning, orthostatic intolerance, exercise and chronic illness: Part 3
Deconditioning, orthostatic intolerance, exercise and chronic illness: Part 4
Deconditioning, orthostatic intolerance, exercise and chronic illness: Part 5
Deconditioning, orthostatic intolerance, exercise and chronic illness: Part 6
Deconditioning, orthostatic intolerance, exercise and chronic illness: Part 7

Allergic effector unit: The interactions between mast cells and eosinophils

Eosinophils are granulocytes that can localize to the tissues under certain conditions, including allergic response. Eosinophilic granules contain the positively charged proteins major basic protein, eosinophil peroxidase, eosinophil cationic protein, and eosinophil-derived neurotoxin. Like mast cells, eosinophils release these granules in response to many things, including inflammatory signals, parasitic infection, tissue damage and allergic inflammation. They express many receptors, including receptors for platelet activating factor (PAF) and histamine receptors. PAF and histamine are both released by mast cells.

Mast cells and eosinophils are overwhelmingly found together in late and chronic stages of allergic inflammation. They function in such close concert that mast cells, eosinophils and their effects have been termed the allergic effector unit (AEU). Mast cells release signals that affect eosinophil behavior and receive signals from eosinophils. These cells often also function while in physical contact with one another. When eosinophils are in physical contact with mast cells, they live longer than normal. CD48, 2B4, DNAM-1 and Nectin-2 are all involved in the mast cell – eosinophil contact mechanism.

Major basic protein can activate mast cells and eosinophil peroxidase is taken up by mast cells as a signaling molecule. Tryptase draws eosinophils to mast cells and causes release of eosinophil peroxidase, IL-6 and IL-18 from eosinophils. Histamine and prostaglandin D2 also signal eosinophils to migrate towards mast cells. Mast cell secreted eotaxin activates eosinophils by the histamine 4 (H4) receptor. Both cell types secrete leukotrienes and both express leukotriene receptors.

When grown together, researchers are able to investigate the behavior of mast cells and eosinophils together. This is called co-culture. In 29% of cases, eosinophils will migrate towards resting (non-activated) mast cells. In 45% of cases, eosinophils will migrate towards IgE activated mast cells. In 47% of cases, eosinophils will migrate towards mast cells activated through a non-IgE pathway. The specific attractant signal has not been identified.

When co-cultured with eosinophils, basal mast cell mediator release was 5% higher. When the mast cells were activated by IgE, degranulation was 15% higher. In order to activate mast cells, eosinophils must be in contact with them. However, mast cells can activate eosinophils without contact. In co-cultures with mast cells, eosinophil peroxidase constituted 47% of eosinophil released proteins, compared with 18% normally.

In low term co-cultures, both mast cells and eosinophils stayed activated. TNF was high in the co-culture, but not IL-6, IL-8 and IL-10. Importantly, low relative numbers of mast cells could activate eosinophils, but mast cell activation was most effective when eosinophils were more numerous. Eosinophils are thought to reduce the threshold of mast cell responsiveness to IgE.

 

References:

Elishmereni M, Bachelet I, Nissim Ben Efraim AH, Mankuta D, Levi-Schaffer F. Interacting mast cells and eosinophils acquire an enhanced activation state in vitro. Allergy 2013; 68: 171–179.

Elishmereni M, Alenius HT, Bradding P, Mizrahi S, Shikotra A, Minai-Fleminger Y, et al. Physical interactions between mast cells and eosinophils: a novel mechanism enhancing eosinophil survival in vitro. Allergy 2011;66:376–385.

Minai-Fleminger Y, Elishmereni M, Vita F, Soranzo MR, Mankuta D, Zabucchi G et al. Ultrastructural evidence for human mast cell-eosinophil interactions in vitro. Cell Tissue Res 2010;341:405–415.

Puxeddu I, Ribatti D, Crivellato E, Levi- Schaffer F. Mast cells and eosinophils: a novel link between inflammation and angiogenesis in allergic diseases. J Allergy Clin Immunol 2005;116:531–536.

Food allergy series: Eosinophilic colitis

Eosinophilic colitis is a controversial diagnosis. It can occur secondary to a number of conditions, including worm infestation and medical reactions, but cases without a primary cause have been reported less than 100 times in literature.

Eosinophilic colitis patients often have generic lower GI symptoms, including abdominal pain, constipation, diarrhea, and rectal bleeding. More severe cases can cause malabsorption, protein losing enteropathy, colonic wall thickening, obstructive features, eosinophilic ascites and weight loss. Unusually, these symptoms have a relapsing-remitting course, with sudden, inexplicable remission from symptoms. Eosinophilic colitis affecting infants has been segregated into its own diagnoses, which are allergic proctocolitis and FPIES. These are both due to allergic reactions from food proteins.

Eosinophilic colitis most often affects otherwise healthy infants or young adults, in whom it is more often chronic. The only defined feature is a dense eosinophilic infiltration in the colon. Infiltration can be contiguous or diffuse. Endoscopy reveals edema and patchy granularity. Crypt abscesses and lymphonodular hyperplasia may be present.

One study on typical eosinophil values in patients without history of GI issues found that there was a mean eosinophil count of 17/hpf. However, the range of cell count was wide, from 1-52. 28% of biopsies averaged more than 20 eosinophils/hpf. A mean of 35/hpf was found in the cecum, with a mean of 10/hpf in the rectum. Another study found 5-35 eosinophils/hpf in the colon, with count decreasing closer to the rectum. A diagnostic marker of greater than 60 eosinophils/ 10 hpf has been suggested for eosinophilic colitis. Others have used greater than 30/hpf.

Eosinophilic colitis patients sometimes have peripheral eosinophilia and are more likely to have an elevated total serum IgE level. Some patients with eosinophilic colitis have self reported other types of EGID, but there is not yet a biopsy proven link. Interestingly, eosinophilic colitis is not related to a history of atopy. It has been linked to scleroderma and liver transplantation in children. Two cases of eosinophilic colitis have occurred in children with autism. Eosinophilic colitis is thought to occur via a CD4+ Th2 lymphocyte mediated mechanism rather than an IgE mediated mechanism.

Due to its rarity, eosinophilic colitis has not been well researched and is not well understood. In particular, the relapsing-remitting course is baffling. It is worthwhile to note that eosinophils are seen readily using the standard H&E stain employed as a first measure in hospital labs, so they are unlikely to go unseen like mast cells. Some doctors believe it presents as a part of a larger syndrome that is sometimes missed when evaluating patients.

Treatment is much the same as other eosinophilic GI diseases. Elimination dieting is strongly recommended. Corticosteroids, such as budesonide, are often employed. Azathioprine is sometimes used. Ketotifen may be used in place of steroids.

 

References:

Alfadda, Abdulrahman A., et al. Eosinophilic colitis: epidemiology, clinical features, and current management. Ther Adv Gastroenterol (2010) 4(5): 301-309.

Gonsalves, N. Food allergies and eosinophilic gastrointestinal illness. Gastroenterol Clin North Am 36: 75-91, vi.

Food allergy series: Eosinophilic esophagitis (Part 3)

A first step in addressing EoE should be to eliminate primary GERD or PPI responsive esophageal eosinophilia. This is done by using proton pump inhibitors (PPI’s) at doses of 20-40 mg, 1-2/daily for 8-12 weeks in adults and 1 mg/kg per dose, twice daily for 8-12 weeks in children. This treatment is effective when esophageal eosinophilia is due to GERD.

There is a subset of patients with primary EoE and secondary GERD. These patients may or may not meet conventional pH criteria for diagnosing reflux. In these patients, PPI’s alone are not sufficient to treat EoE.

Dietary management is a mainstay of EoE treatment. It is extremely effective in children, with near-complete resolution of symptoms and histological abnormalities. Strict use of amino acid based formula, dietary restriction based on extensive allergy testing, and elimination of most likely allergens have all been used. Elemental therapy is the most effective. Food tolerance is unlikely to be achieved, even after long term elimination. Methods at achieving food tolerance in EoE patients have not been well studied.

Corticosteroids are effective in adults and children, but disease almost always recurs even stopped. Systemic steroids should be used in emergencies only due to the host of long term problems associated with chronic use. Topical steroids are usually effective, but steroid resistance has been reported and local fungal infections can occur. Fluticasone and oral viscous budesonide have been effective in studies. Budesonide can potentially reverse esophageal fibrosis.

Some medications used to manage mast cells, which are often elevated in EoE patients, have been trialed for EoE. Cromolyn sodium has not apparent therapeutic effect for EoE patients. Leukotriene receptor antagonists might be effective at high dosages, but this is unclear. One study on TNF-a blocker did not show benefit. Disappointingly, clinical response to anti IL-5 was variable. Anti-IL-5, anti-IL-13 and anti-eotaxin are possible future therapies.

Food impaction, in which food is retained in the esophagus, requires emergency intervention. This has been found to occur in 11-55% of EoE adults across multiple studies.

Esophageal rings are commonly found in EoE patients and inherently imply stricturing. Strictures larger than 1 cm are found in 11-31% of adults with EoE. 10% of adults have narrow caliber esophagus.

19 patients with EoE have reported perforations that were spontaneous or not due to dilation. Of 14 of these, two suffered full perforations, in which esophageal or gastric contents were found in the chest cavity. Surgical intervention was required. The remaining 12 patients had partial perforations, in which limited air or contrast media moved into the mediastinum from the esophagus. Five patients had partial perforations following endoscopy without dilation. Of the 19 total, 7 needed surgery. None were fatal.

Three instances of circumferential intramural dissection have been noted, and many cases of intramural tearing, either spontaneous or subsequent to endoscopy. Intramural tears are deep lacerations reaching the esophageal submucosa. Circumferential intramural dissection occurs where the esophageal lumen comes away from the esophageal wall in a way that affects a contiguous ring.

There is no evidence that esophageal cancer or generalized EGID results as a complication or progression of EoE. Six patients have reported concurrent Barrett esophagus. However, merely having EoE is not predictive for Barrett esophagus.

Dilation is still considered controversial in the management of EoE with high grade stricturing. This is in part because of a study done before 2008 that found that in a group of 84 adults, 5% suffered perforation and 7% hospitalized for chest pains following the procedure. These rates are much higher than in patient groups who underwent dilation for non-EoE reasons. However, three more recent retrospective studies reported lower rates of complications. Of 404 patients who underwent 839 dilations, only 3% of procedures resulted in perforations – a rate of 0.8%. Perforations were partial and did not require surgery. Chest pain occurred in 5%. One patient had major bleeding that required intervention. Dilation can induce long lasting relief from dysphagia when high grade stricturing is present. Many patients have reported a preference for periodic stricturing rather than daily medication or food elimination.

 

References:

Liacouras, Chris A., et al. Eosinophilic esophagitis : Updated consensus recommendations for children and adults. J Allergy Clin Immunol 2011, pp. 3-20.

Furata, Glenn T., et al. Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment. Gastroenterology 2007; 133:1342-1363.

Food allergy series: Eosinophilic esophagitis (Part 2)

Diagnosis of EoE can be difficult. Endoscopy with biopsy is the only reliable method currently available. Often in these patients, the esophagus may look unremarkable, so biopsies are recommended regardless of gross appearance. 2-4 biopsies from the proximal and distal esophagus should be collected. Biopsies of the gastric antrum and duodenum may also be taken to rule out other conditions.

Fibrosis of the lamina propria is present in most biopsies of both child and adult patients. Though less prevalent, this finding is still found sometimes in GERD cases. Basal zone hyperplasia, elongation of rete pegs and dilated intercellular spaces are EoE associated findings. Additionally, mast cells are increased in biopsies from EoE patients more so than GERD patients. IgE bearing cells are found more often in EoE than GERD.

There is some dispute over whether the peak value (the cell count in the single high powered field with the most eosinophils) is more representative than the average value (the average of cell counts in several high powered fields.) Some studies have found a correlation between eosinophil count and symptom presentation, while others have not. There are also some patients with active eosinophilic inflammation in the esophagus with few symptoms.

Other diagnostic methods should be included to rule out other conditions.   Esophageal manometry and pH testing in EoE children demonstrated that dysfunctional peristalsis correlated with difficulty swallowing. Esophageal manometry with pressure topography can reveal abnormal pressurization patterns in EoE that are not found in GERD. Endoscopic ultrasound has shown thickening of both the muscles and the mucosa in EoE. Impedance planimetry, a method that measures both pressure and volume changes, has recorded significant changes in compliance and distensibility of the esophageal wall in EoE patients. Barium contrast swallow testing was normal in 12/17 children with EoE, including four who had required endoscopy for food impaction. X-ray can detect stricturing of the proximal cervical esophagus. Some studies have linked motility issues to EoE, while others have found the opposite.

pH testing is usually undertaken to exclude GERD. In multiple studies, transnasal and wireless capsule pH measuring systems have shown variability in acid pH. When coupled with impedance testing, pH testing seems to correlate better with symptoms, but this has not been fully investigated yet. In children, both acid and non-acid reflux is comparable to controls.

40-50% of EoE patients have an increase in circulating eosinophils. When EoE is effectively treated with topical corticosteroids, peripheral eosinophilia has been shown to decrease. One study noted that in EoE patients, esophageal eosinophils display HLA DR, which means that they act as antigen presenting cells. Antigen presenting cells recruit other cells in the immune system and generate a strong inflammatory response.

Periostin, an extracellular matrix protein, is increased in the esophagus of EoE patients. Importantly, it correlates with eosinophil levels in EoE patients. Expression of eotaxin 1 and 3 is also increased in EoE. Fibroblast growth factor 9, IL-13, IL-15 and TGFB-1 can be elevated in both EoE and GERD.

A crucial finding in EoE research was the characterization of a signature transcriptome, which measures which genes the cells are using and which proteins they are making. This transcriptome is distinct from nonspecific chronic esophagitis, which has a peak eosinophil count or 6 or fewer eosinophils/hpf. Studies have demonstrated that the transcriptome can distinguish from GERD. Eotaxin 3 is hugely overexpressed in EoE patients. IL-13 is also overexpressed, with data to indicate that it may be the key regulator in EoE disease processes. In patients who have successfully achieved symptom remission, abnormal gene expression has returned to normal. However, some genes in epithelial cells continue to be expressed abnormally, which may factor into relapse.

Genetic studies have revealed that the first genome wide susceptibility locus for EoE is at 5q22. The study that found this common variable included 550,000 common genetic variants collected from various institutions. In this susceptibility locus lie genes associated with thymic stromal lymphopoietin (TSLP), a cytokine that influences behavior of Th2 cells. In a second study that looked at 53 potential genes that affected allergic or epithelial responses, or both, the TSLP gene was also identified as a susceptibility locus for EoE. This continued to be true when the data was controlled for atopic conditions. The TSLP receptor gene on the X chromosome has also been tied to EoE in male patients. These findings make a strong case for EoE as a Th2 mediated disease.

Another genetic factor found to be overrepresented in EoE patients was a common deletion variant in the filaggrin gene, 2282del4. This mutation has been associated strongly with atopic dermatitis. However, even in EoE patients who don’t have atopic dermatitis, this genetic variant is found more frequently than in the general population.

 

References:

Liacouras, Chris A., et al. Eosinophilic esophagitis : Updated consensus recommendations for children and adults. J Allergy Clin Immunol 2011, pp. 3-20.

Furata, Glenn T., et al. Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment. Gastroenterology 2007; 133:1342-1363.

Food allergy series: Eosinophilic esophagitis (Part 1)

Eosinophilic esophagitis (EoE) is a well studied, well defined eosinophilic disease localized to the esophagus. With a few exceptions, it is usually diagnosed pathologically by a peak value of 15 eosinophils/hpf in esophagus biopsy samples. Currently, endoscopy with biopsy evaluation is the only diagnostic for EoE considered accurate, but patient symptoms must be considered to make a diagnosis.

EoE patients are mostly male, with three times more males than females affected. Most patients are atopic, with a history of other allergic conditions. EoE usually presents in childhood or in third or fourth decade of life, but can onset at any time.

Adult EoE patients present with more uniform symptoms. They have dysphagia (difficulty swallowing), food impaction and upper abdominal pain. About 15% of dysphagia cases are caused by EoE. Food impaction requiring endoscopic intervention occurs in 33-54% of EoE adults. Children with EoE have less specific symptoms and are more likely to have vomiting and generalized abdominal and chest pain.

As mentioned above, other atopic conditions are commonly found in EoE patients. 50-60% of EoE patients have had at least one atopic condition. 40-75% have allergic rhinitis, 14-70% have asthma and 4-60% have eczema.

15-43% of EoE patients have immediate IgE mediated food hypersensitivity reactions. Food induced anaphylaxis is more likely in EoE patients than in other populations. Furthermore, a history of IgE mediated food allergy is correlated with EoE in both adults and children.

Most EoE patients are sensitized to food allergens or aeroallergens as determined by skin prick testing or serum IgE values. Local IgE production and FceRI positive cells (cells that can be activated by IgE) are elevated in biopsies from EoE patients. Six separate articles have documented seasonality in symptom severity and presentation in EoE.

High amounts of eosinophils in the esophagus (esophageal eosinophilia) can be caused by a number of conditions in addition to EoE. This includes the broader classification of EGID, GERD, Celiac disease, Crohn’s disease, hypereosinophilic syndrome, achalasia, drug hypersensitivity, vasculitis, pemphigoid vegetans, connective tissue disease, graft versus host disease, and infection. It is necessary to effectively rule out these other conditions before diagnosing EoE, and this can be difficult. Particularly, it can hard to distinguish between EoE and GERD.

Some studies have reported that significant eosinophil driven inflammation occurs in the proximal esophagus of adults with EoE but not with GERD. Surface layering of eosinophils is more typical of EoE than GERD. Some reports indicate that extracellular eosinophilic granules, including eosinophil peroxidase, major basic protein and eosinophil derived neurotoxin, are more indicative of EoE than FERD.

The cut off of 15 eosinophils/hpf is also problematic for diagnosing EoE. Surface layering and microabscesses are only found when 15/hpf are present. Additionally, basal zone hyperplasia is 44% more likely with 15/hpf and over 100% more likely with 20/hpf. Some studies have found that a large proportion of adults meeting this threshold actually have GERD. Further confusing the issue, there is a growing subpopulation of GERD excluded patients diagnosed with EoE that demonstrate a response to PPIs. This situation is increasingly being referred to as PPI responsive esophageal eosinophilia rather than EoE.

 

References:

Liacouras, Chris A., et al. Eosinophilic esophagitis : Updated consensus recommendations for children and adults. J Allergy Clin Immunol 2011, pp. 3-20.

Furata, Glenn T., et al. Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment. Gastroenterology 2007; 133:1342-1363.

Food allergy series: Eosinophilic gastrointestinal disease (part 3)

The exact incidence of primary EGID is not known, but it has become an increasingly common diagnosis in the last ten years. EGID has been associated with food allergy and atopic conditions. 70% of patients have a family history of allergies. 50% of the time, EGID is seen without accompanying blood eosinophilia. EGID, like many conditions, is thought to have both an environmental and a genetic component. 10% of patients with EGID have an immediate family member with an EGID. Both inhaled and ingested allergens can be provocative for EGID patients.

Patients suffer from a variety of symptoms, including abdominal pain, GI motility issues, vomiting, diarrhea, dysphagia, microcytic anemia, hypoproteinemia and failure to thrive. Visually, the GI tract can be normal, so multiple biopsies from each segment are crucial for diagnosis. Malabsorption and protein losing enteropathy are often coincident in EGID patients.

EGID patients are particularly sensitive to foods. Eggs, milk and fish are the most common problematic foods for EGID patients. Though food specific IgE is often found in EGID patients, food anaphylaxis is rare in this population. Due to the coexistence of EGID and food specific IgE, it is considered a mixed IgE- cell mediated allergic disorder.

Elimination diets and avoidance of aeroallergens are first line treatments for these conditions. Elemental diet improves symptoms and lowers number of eosinophils in EE patients. Significant histological improvement of esophageal inflammation is documented in more than 70% of patients studied. Complete resolution of eosinophilic gastroenteritis is usually seen when the patient transmissions to an elemental amino acid based diet. Unfortunately, reintroduction of foods typically causes immediate onset of symptoms, and thus tolerance is not usually obtainable.

Steroids are often used for EGID acute management. Topic al steroids are sometimes used long term management when diet restriction has not improved symptoms. When treated with oral steroids for four weeks, decrease in eosinophilic count was seen and 65% of patients had complete resolution of symptoms. However, symptoms returned in most patients when steroids were stopped.

Montelukast blocks the D4 receptor of cysteinyl leukotrienes in eosinophils. Leukotrienes are responsible for eosinophil attraction, constriction of smooth muscle, airway swelling, and mucus hypersecretion. However, when leukotriene levels were measured in biopsies from EGID patients, only eosinophilic gastroenteritis patients showed a statistically significant increase in leukotrienes. Still, patients report symptom improvement for the duration of treatment, with relapse when it is removed.

A pilot study treated four patients with eosinophilic gastroenteritis with one dose of anti-IL-5 antibody, mepolizumab. IL-5, eotaxin, is a molecule released by T cells and mast cells that is critical in eosinophil activation. After treatment, there was a mean decrease of 70% in peripheral eosinophilia and 50-70% decrease in tissue eosinophilia (3 out of 4 patients.) Symptoms improved minimally. One patient had a 43% increase in GI eosinophil count following treatment. Approximately two months after treatment, half of the subjects had a significant increase in peripheral eosinophil counts and worsening of symptoms.

One EE patient received three doses of mepolizumab at four week intervals. This induced a ten fold decrease in mean tissue eosinophils, reduced inflammation and stricture, resulted in cessation of vomiting, and allowed the patient to successfully introduce solids. This result in encouraging, but controlled trials need to be undertaken.

Mast cells are both increased and activated in esophageal biopsies from patients with EGIDs. An association between mast cell numbers and severity of esophageal epithelial hyperplasia and eosinophil count has been recorded. Omalizumab has been observed in some studies to lower eosinophil counts in blood and lungs of asthmatics. Foroughi and colleagues ran a 16 week open label study with omalizumab of nine patients with allergic eosinophilic gastroenteritis, with confusing results. A study using anti-TNF medications did not appear promising.

 

References:

Mueller, Susanna. Classification of eosinophilic gastrointestinal diseases. Best Practice & Research Clinical Gastroenterology 2008, 22 (3): 425-440.

Spergel, Jonathan, et al. Variation in prevalence, diagnostic criteria, and initial management options for eosinophilic gastrointestinal diseases in the United States. JPGN 2011, 52 (3): 300-306.

Jawairia, Mahreema, et al. Eosinophilic gastrointestinal diseases: review and update. ISRN Gastroenterology (2012).

Food allergy series: Eosinophilic gastrointestinal disease (Part 2)

The following are conditions that can cause a secondary increase in eosinophil count in the GI tract. These conditions should be ruled out before giving a diagnosis of EGID, which is inherently primary.

Allergy associated colitis affects adults, with females accounting for 2.5x more patients than males. The age of diagnosis ranges from 20s to 60s. It affects the colon and ileum, with rectum being unaffected. Eosinophils are found in the mucosal, muscular and submucosal layers. Studies have defined it as anywhere from 10-60 eosinophils/hpf, more than one eosinophil/hpf in the intraepithelial layer, or merely having clusters and evidence of degranulation. It is thought to be driven by an allergic response and has been found in association with NSAID allergy.

Hypereosinophilic syndrome (HES) can sometimes affect the colon. People with this condition produce too many circulating eosinophils, as evidenced by persistently high eosinophil count and affect to one or more of the heart, nervous system or bone marrow. Rarely, it can cause elevated eosinophils in the mucosal layer or deep bowel wall of the colon. The mechanism behind this is unclear, but thought to be due to IL-5 stimulating eosinophils inappropriately.

Crohn’s disease can affect the entirety of the GI tract and mostly presents initially in young adults. It can affect continuous or discontinuous portions of tissue. Ulceration, erosion, infiltrates of various inflammatory cells, including eosinophils, lymphoid nodules, granulomas, fibrosis, and vascular and neural lesions are often found on biopsy. It is thought to be due to cooperation of several factors.

Ulcerative colitis affects either diffuse or continuous areas of the left sided colon and rectum. Eosinophils are often found in the mucosa or superficial supermucosa. Edema, erosion, ulceration, granulocytes, and presence of plasma cells are common findings. The etiology is unclear.

Collagenous colitis is mostly found in middle aged and elderly patients, which are predominantly female. It can affect the colon and rectum and is usually discontinuous. Eosinophils are found in the mucosal layer, along with subepithelial collagen deposition, white cells in the intraepithelial layer,and various inflammatory infiltrates. It is thought to sometimes be associated with drug reactions.

Lymphocytic colitis can affect a person of any age. It affects diffuse portions of the colon and eosinophils are found in the mucosal layer. Intraepithelial lymphocytes are often found (surface epithelium >20 IELs per 100 epithelial cells). The etiology is unknown.

Autoimmune colitis occurs in conjunction with other autoimmune conditions. It can affect people of all ages, with activity in the small and large bowels. Eosinophils are found in the mucosal layer of affected tissue, with evidence of degranulation and crypt destruction. Mast cells are often found in the same tissue portions.

Graft versus host disease is a complication of bone marrow transplant and can affect anyone who has been a recipient of one. GvHD can affect the entirety of the body, and therefore can affect the whole length of the GI tract. Eosinophils are often identified in the mucosal layers, along with apoptotic crypt destruction, mixed inflammatory infiltrates and interepithelial lymphocytes.

Peripheral/intestinal T-cell lymphoma overwhelmingly affects adults over 50. It predominantly affects small bowel, but also the stomach and colon. Inflammatory infiltrates with many eosinophils and tumor cells are sometimes found. It is sometimes seen along with gluten-sensitive enteropathy.

 

References:

Mueller, Susanna. Classification of eosinophilic gastrointestinal diseases. Best Practice & Research Clinical Gastroenterology 2008, 22 (3): 425-440.

Spergel, Jonathan, et al. Variation in prevalence, diagnostic criteria, and initial management options for eosinophilic gastrointestinal diseases in the United States. JPGN 2011, 52 (3): 300-306.

Alfadda, Abdulrahman. Eosinophilic colitis: epidemiology, clinical features and current management. Ther Adv Gastroenterol 2010, 4(5) 301-309.

Food allergy series: Eosinophilic gastrointestinal disease (Part 1)

Eosinophil gastrointestinal diseases (EGID) is an umbrella term that encompasses a plethora of primary conditions associated with inappropriate activity of eosinophils. Eosinophils are white blood cells that share a number of functions with mast cells. They are important to immune response to infections, especially parasites, as well as allergy. Eosinophils typically account for 6% or less of the total white blood cell count. They are found in a number of places in the body, but are not usually found in the lung, skin or esophagus without some underlying pathology. Like mast cells, they have granules filled with chemicals and can degranulate in response to stimulus. They release some chemicals in common with mast cells and some not.

Eosinophils are increased in a number of GI conditions, including allergy associated colitis in adults, allergic proctocolitis in infants, eosinophilic gastroenteritis and eosinophilic esophagitis. They are also elevated in inflammatory bowel disease, reflux esophagitis, celiac disease and other types of colitis. Increased eosinophils can be induced by several other conditions or disease states, including infection, use of certain medications, collagenous and lymphocytic colitis, connective tissue disease, neoplasia, graft vs host disease and autoimmune colitis. It can also be associated with allergy or idiopathic. Despite a fair amount of research, many papers use varying criteria for determination of disease and excess eosinophil count. This ambiguity has contributed to much confusion and will be discussed in detail in upcoming posts. Still, pathologically, eosinophils are rarely found in number in any tissue sample and if present indicate inflammation or disease.

A number of conditions can cause secondary increase of eosinophils in the GI tract. EGIDs are primary conditions and are listed below.

Eosinophilic gastroenteritis most often affects adults, with females being slightly more likely to develop it. Infants rarely have this condition, but some have been identified. Virtually the entire GI tract can be affected, but most often the stomach and small intestine. The eosinophils can be diffuse and localized to only one organ or portion of the organ. They can cause lesions mistaken for tumors. This condition is characterized by edema, “numerous” eosinophils in almost any layer, and ulcerations that can look like tumors. Eosinophilic gastroenteritis is idiopathic, but 50-70% are thought to be due to allergic responses, especially from medications.

Eosinophilic esophagitis usually first presents in people under 30. Males are more commonly affected. It is defined as 15 or more eosinophils/hpf (peak count) with eosinophils mostly found in the mucosa or muscular wall of the esophagus. Microabscesses and basal cell hyperplasia are sometimes found. It is subclassified as being allergic or non-allergic.

Eosinophilic colitis is a more controversial entity marked by nonspecific symptoms, unclear diagnostic criteria, and relapsing-remitting course. It is exceptionally rare. This will be discussed in detail in an upcoming post.

Eosinophilic gastroenteritis has much the same profile as eosinophic gastroenteritis, but the disease process is limited to the small intestine.

Allergic proctocolitis affects the rectum and/or colon of children under 2 years of age. Eosinophils can be found diffusely or focally in these patients. It is defined as more than 6 eosinophils/hpf in the lamina propria layer, and/or “elevated” eosinophils in the intraepithelial or muscular layers (considered 1-2 or “numerous” in various studies.) This is the result of food allergy, especially cow’s milk or soy.

References:

Mueller, Susanna. Classification of eosinophilic gastrointestinal diseases. Best Practice & Research Clinical Gastroenterology 2008, 22 (3): 425-440.

Spergel, Jonathan, et al. Variation in prevalence, diagnostic criteria, and initial management options for eosinophilic gastrointestinal diseases in the United States. JPGN 2011, 52 (3): 300-306.

Alfadda, Abdulrahman. Eosinophilic colitis: epidemiology, clinical features and current management. Ther Adv Gastroenterol 2010, 4(5) 301-309.