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

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 40

49. What is the relationship between FPIES and MCAS?

FPIES is food protein induced enterocolitis syndrome, a severe type of food allergy. It causes continuous vomiting and diarrhea upon ingestion of a trigger. FPIES reactions can cause dehydration and dangerous drop in blood pressure. I cannot emphasize enough that FPIES can be extremely serious and that the reactions can be life threatening if they are not managed properly.

FPIES almost exclusively affects children starting in infancy and resolves around the age of 5. The reasons for this are unknown. FPIES is a diagnosis of exclusion. There are no tests to identify FPIES.

An important point is that trigger avoidance is generally sufficient for management in children with FPIES. When the child is not being exposed to a trigger, they should not have lingering symptoms.

If a child with FPIES continues to have symptoms, the conventional thinking is often that there must be a trigger that has not yet been eliminated from their diet. In children with continuing symptoms, they frequently have more traditional allergy type symptoms than the profuse GI issues seen with FPIES exposures. This is where FPIES starts to overlap with MCAS. MCAS can cause the same reactions to foods seen in FPIES. MCAS can also cause daily symptoms even if food triggers are avoided. Increasingly, children who were initially diagnosed with FPIES are later diagnosed with MCAS.

There are a few possible scenarios here. Firstly, it is possible that the child has FPIES and has MCAS secondarily to the FPIES. It is also possible that the child was misdiagnosed with FPIES and had MCAS all along. It may also be that FPIES is some form of MCAS. They have a lot in common.

Because there is no test for FPIES, and it is very difficult to accurately perform mediator testing to look for mast cell disease in infants, it is hard to be definitive at that age anyway. In some cases, investigation of MCAS as a possible diagnosis for these children only occurs when they fail to “grow out of” FPIES around age 5. Having anaphylaxis also provides a clue towards MCAS as a potential diagnosis.

For more detailed reading, please visit these posts:

Food allergy series: FPIES (Part 1)

Food allergy series: FPIES (Part 2)

Food allergy series: Mast cell food reactions and the low histamine diet

The Provider Primers Series: Mast cell activation syndrome (MCAS)

Food allergy series: FPIES (part 2)

FPIES is usually diagnosed clinically. Endoscopy and biopsy are not necessary to diagnose, but is sometimes done to rule out other conditions.

Scopes have shown a variety of inflammatory changes in the GI tract of FPIES kids. Diffuse colitis, friable mucosa, rectal ulceration and bleeding have been observed.  Increased levels of TNFa and decreased receptors for TGF-b have been found in the GI tract. Baseline intestinal absorption is usually normal.

Biopsies have shown villous atrophy, tissue edema, crypt abscesses, increased white blood cells, including eosinophils and mast cells, and IgM and IgA containing plasma cells. Radiology showed air fluid levels (collection of both fluid and gas in the intestines), narrowing and thickening of the mucosa in the rectum and sigmoid colon and thickening of the circular folds in the small intestine. When surgery has been performed, distension of the small bowel and thickening of the jejunum has been seen.

Food specific IgE is not usually present. In one study, 21% of patients with solid food FPIES had detectable food specific IgE. 18-30% with FPIES to cow’s milk or soy have IgE for it. If IgE is found, the course of FPIES is longer. One study found a decrease in food specific IgG4 in FPIES patients along with an increase in food specific IgA.

FPIES is managed by removing the offending food. Exclusive breastfeeding can be protective. If not breastfed, use of casein hydrolysate formula is recommended. Less commonly, amino acid formula or IV fluids may be needed. Doctors recommend introducing yellow vegetables and fruits as solids rather than cereal at six months of age. Grains, legumes and poultry should be avoided for the first year of life. Once tolerance is established to one food in a high risk category, like grains, the child is more likely to tolerate other foods in the same category.

Oral food challenges (OFC) should be undertaken to determine if tolerance to the food has been achieved. A conservative approach recommends challenges every 18-24 months in patients without recent symptoms. OFCs are high risk procedures for FPIES children. The following procedure should be observed:

  • Any FPIES OFC must be physician supervised. Generally, inpatient settings are preferred, but if an outpatient setting can provide appropriate supportive care, it may be acceptable. Intravenous access should be secured prior to beginning and IV fluids and medications should be immediately available in case of reaction. ICU care is not recommended unless there is a history of near fatal reactions.
  • Blood should be drawn immediately before beginning the OFC to provide baseline complete count count and neutrophil count.
  • Over the first hour, 0.06-0.6g/kg body weight of food protein should be administered in three equal doses. It should not exceed 3g of total protein or 10g of total food or 100ml of liquid for initial feeding.
  • If patient has no reaction, give a full serving of food as determined by their age.
  • Observe patient for several hours afterward.
  • In the event of reaction, administer 20 ml/kg boluses of normal saline.
  • In the event of severe reaction, including repetitive vomiting, profuse diarrhea, lethargy, hypotension or hypothermia, administer 1 mg/kg methylprednisolone intravenously, up to 60-80mg total. About 50% of patients who react to FPIES OFCs will need IV fluids and steroids.
  • Epinephrine must be available during FPIES OFCs for treatment of hypotension and shock. In FPIES cases, epinephrine does not resolve vomiting and lethargy.
  • In children with positive skin tests and/or food specific IgE, antihistamines should also be available during OFCs.
  • Blood should be drawn six hours after OFC to compare to baseline values. If patient has diarrhea, stool guaiac tests should be done, and stool samples should be tested for white bloods, red blood cells and eosinophils in feces.

An OFC is considered either positive or negative. Positive means there is a reaction. Negative means there is not. It is positive if the patient experiences vomiting, lethargy or diarrhea in an appropriate time frame. In the absence of symptoms, if the neutrophil count is over 3500/ul, or white blood cells, frank or occult blood, and/or eosinophils are present in feces, the challenge is still considered positive.  More than 10 leukocytes/hpf in gastric juice at the 3 hour mark has been suggested as a positive marker, but needs further investigation. In the study that noted this marker, gastric juice was obtained via orogastric feeding tubes.

One study looked at the resolution of FPIES over a ten year period. 160 subjects were included in the study. 54% were male. Median age of diagnosis was 15 months. 180 OFCs were done for 82 patients, of which 30% had obtained an FPIES diagnosis based on previous OFCs. 44% of patients reacted to cow’s milk; 41% to soy; 22.5% to rice; and 16% to oat. 65% had only one food sensitivity, 26% had two, and 9% had three or more. Most had some form of atopic disease and 39% had detectable food specific IgE. 24% had IgE specific for the food causative for their FPIES reaction. Of the patients with IgE for cow’s milk, 41% of them moved from an FPIES reaction type to an IgE allergy reaction type.

60% of FPIES cases resolve by three years of age. This finding is an average and different populations see much different results. In South Korea, 90% of patients resolve by three years of age. In the US, only 25% resolve by this age. The differences observed are thought to be due to other factors, such as the frequency of food specific IgE and atopic disease. The median age for FPIES resolution depended largely on the food: 4.7 years for rice, 4 years for oat, 6.7 years for soy, 5.1 years for milk. If milk IgE was present, the patient did not become tolerant of milk during the course of study.

FPIES overwhelmingly affects very young children. However, there are rare cases of older children and adults developing FPIES at a later age. These cases involve fish and shellfish as the offending foods.

 

References:

Leonard, Stephanie, Nowak-Wegrzyn, Anna. Food protein induced enterocolitis syndrome: an update on natural history and review of management. Ann Allergy Asthma Immunol. 2011; 107:95-101.

Caubet, Jean Christoph, et al. Clinical features and resolution of food protein induced enterocolitis syndrome : 10-year experience. J Allergy Clin Immunol. 2014; 134(2): 382-389.

 

Food allergy series: FPIES (part 1)

Food protein induced enterocolitis syndrome (FPIES) is the most severe GI food hypersensitivity that is not IgE mediated. FPIES is thought to be caused by a delayed, cell mediated allergic pathway. This condition results in profuse, repetitive vomiting, diarrhea, acute dehydration, lethargy and weight loss. It can eventually lead to failure to thrive.

Upon challenge, an FPIES patient will typically begin with severe, repetitive vomiting 1-3 hours after ingestion; diarrhea, 2-10 hours after diarrhea; lethargy; pallor; low blood pressure; hypothermia; and abdominal distention. They will often show a spike in neutrophils, being highest around 6 hours after exposure; elevated platelets; metabolic acidosis; high methemoglobin; white blood cells in feces, including eosinophils; fecal blood, frank or occult; increased carbohydrates in stool; and elevated white blood cells in gastric juice. Vomiting is seen in 100% of episodes; lethargy in 85%; pallor in 67%; diarrhea in 24% and hypothermia in 24%.

Chronic symptoms from repeat ingestion of responsible food include intermitten, chronic vomiting; frequent, watery diarrhea, often with blood or mucus; lethargy; dehydration; abdominal distention; weight loss; and failure to thrive. Patients with chronic symptoms are often anemic; have low serum albumin; have elevated white blood cells, especially eosinophils; have metabolic acidosis, in which the body produces too much acid and the kidneys cannot remove it quickly enough; have methemoglobinemia, too much of a form of hemoglobin that binds oxygen poorly; intramural gas, gas within the wall of the bowel; and air fluid levels, a radiologic finding often associated with bowel obstruction.

About 75% of FPIES patients appear seriously ill. 15% are hypotensive enough to require hospitalization.

FPIES almost exclusively begins in infancy. Age of onset is typically between 1 and 3 months of age, but can be as late as 12 months. It is slightly more common in males, with male cases accounting for 52-60% of cases. Symptoms generally begin within 1-4 weeks of introducing cow’s milk or soy. Sometimes these substances are tolerated, but FPIES to a solid food shows, with rice being the most common offending solid. Egg is extremely rare as a cause of FPIES reactions.

FPIES has been well studied. About 30% of FPIES patients go on to develop atopic conditions, with 25-65% getting atopic dermatitis; 3-20%, asthma; and 20%, allergic rhinitis. 40-80% of patients have a family history of atopic disease and 20% have a family history of food allergies.

A history of FPIES to one grain gives a 50% chance of reaction to other grains. In cases of solid food FPIES, 80% react to more than one food. 65% were previously diagnosed with FPIES to cow’s milk or soy. 35% were breastfed.

Patients usually improve significantly within 3-10 days of beginning casein hydrolysate-based formula with or without IV fluids. In infants who have generic GI symptoms early on, switching to a hypoallergenic formula can prevent fullblown FPIES.

References:

Leonard, Stephanie, Nowak-Wegrzyn, Anna. Food protein induced enterocolitis syndrome: an update on natural history and review of management. Ann Allergy Asthma Immunol. 2011; 107:95-101.

Caubet, Jean Christoph, et al. Clinical features and resolution of food protein induced enterocolitis syndrome : 10-year experience. J Allergy Clin Immunol. 2014; 134(2): 382-389.

Food allergy series: Food related allergic disorders

The term “food allergy” is generally used by medical professionals to refer to IgE mediated allergic responses. However, it is used in a broader sense by patients who have similar conditions because the term is more likely to be understood. The truth is that there are several types of allergic disorders provoked by foods. They are all listed below and will be expounded upon in the coming days.

IgE antibodies mediate the following types of reactions. All of them have immediate onset of symptoms following interaction with the antigen.

  • Oral allergy syndrome. This presentation is usually mild. It causes itching and mild swelling in the mouth, progressing into the throat about 7% of the time, with less than 2% of cases progressing to anaphylaxis. OAS occurs due to sensitization to pollens. These pollens have specific shapes that are recognized by the IgE molecules; certain raw fruits and vegetables may shapes that are close enough to be recognized by the same IgE molecules. This is known as crossreactivity. Cooking the food changes the shapes seen by the IgE molecules and is therefore cooked forms are usually safe. In birch pollen sensitive people, apples, peaches, pears and carrots can cause crossreaction; in ragweed sensitive people, melons can be problematic. This is usually diagnosed by skin testing with the raw fruits/ vegetables. OAS can persist and be problematic during the season when the offending pollens are most prevalent.
  • Asthma irritation, including rhinitis. This can be caused by inhaling the food protein. It is most common in infants and children with the exception of work exposures in adults, like Baker’s asthma. This most commonly occurs with the eight major allergens: egg, milk, wheat, soy, peanut, tree nuts, fish and shellfish. Skin testing and serum IgE measurement can be used for diagnosis.
  • Urticaria and angioedema. This occurs when an offending food is ingested or contacts the skin (contact urticaria.) Food exposures cause 20% of acute urticaria cases and 2% of chronic urticaria cases. It is much more common in children and usually occurs after exposure to the eight major allergens. Skin testing and serum IgE measurement can be used for diagnosis.
  • GI hypersensitivity.Immediate onset vomiting can occur in response to the major food allergens. Skin testing and serum IgE measurement can be used for diagnosis.
  • Food associated, exercise induced anaphylaxis. This occurs following ingestion of food after recent completion of exercise. It is thought that exercise affects the way the GI tract absorbs and digests allergens. This most commonly affects adults, with wheat, shellfish and celery being the most common foods to provoke this reaction. Skin testing, serum IgE measurement, component testing and exercise testing can be used for diagnosis.
  • Delayed food-induced anaphylaxis to meat. This occurs several hours after ingesting the meat. It occurs when the body generates antibodies to carbohydrate a-Gal, which can be induced by tick bites. Beef, pork and lamb are known to cause reactions in a-Gal sensitive people. Testing should include serum IgE to a-Gal.
  • Anaphylaxis. I have addressed this in detail before. It can occur in response to any food, but the eight major allergens are most common. It results in massive mast cell degranulation, leading to cardiovascular collapse.

Some allergic responses to food are due to both IgE mediated reactions and delayed cell-mediated reactions.

  • Atopic dermatitis. In children with AD, about 35% of moderate/severe rashes are due to food reactions. This is thought to be due to food reactive T cells locating to the skin. It is most common in infants and least common in adults. All major allergens can be causative, but egg and milk are the most common. AD is usually self limiting. Skin testing and serum IgE measurement can be used for diagnosis.
  • Eosinophilic GI disease (EGID.) Eosinophils are inflammatory cells that share a lot of functions and behaviors with mast cells. Like mast cell disease, eosinophilic disease can affect a variety of organs, most commonly the GI tract. Symptoms are widely variable and related to level of inflammation and infiltration. It often causes difficult or painful swallowing, weight loss, obstruction and edema. EGID is related to the activity of several mediators, include IL-5, eotaxin, which causes eosinophils to home to various inflamed locations. Much like mast cell disease, it can occur in response to a wide array of foods. Elimination diets are first line treatments for EGID. Endoscopy, kin testing and serum IgE measurement can be used for diagnosis, but elimination diets are often used empirically for diagnosis.

Some allergic type responses to food are not due to IgE antibodies.

  • Food protein induced enterocolitis syndrome (FPIES.) Usually found in infants, repeat exposure to certain proteins causes chronic vomiting, diarrhea, low energy and poor growth. Exposure again following a period of abstinence from offending substance can cause vomiting, diarrhea and 15% drop in blood pressure. These reactions occur about two hours after ingestion. Cow’s milk, soy, rice and oat are the most frequently reported sources, but many others have been recorded. In FPIES children, their cells are more responsive to TNF-a and less responsive to TGF-b. FPIES usually resolves with age, but can be difficult to diagnose due to skin testing and serum IgE testing usually being negative.
  • Food protein induced allergic proctocolitis. This causes mucuosy, bloody stools as a result of eosinophilic response in infants. This occurs in response to milk through breast feeding and resolves when the substance is removed from the mother’s diet.
  • Heiner syndrome. This rare condition is marked by pulmonary infiltration, upper respiratory symptoms, iron deficiency anemia and failure to thrive. It occurs in infants and is triggered specifically by milk. It is thought that there may be a milk specific IgG reaction.
  • Celiac disease. This autoimmune disease causes malabsorption and enteropathy. It is a response to gliadin, a gluten protein in wheat and other grains. It can cause bone abnormalities, IgA deficiency, dermatitis herpetiformis and a variety of other complications. It can present at any age and is lifelong. Blood testing during food challenges, GI biopsies, and testing for HLA DQ2 and DQ8.

Cell mediated reactions are not due to IgE antibodies.

  • Allergic contact dermatitis. This type of eczema occurs in response to metals in foods. This occurs mainly in adults. It is diagnosed by atopy patch testing.

Mast cell reactions to food are related to inappropriate degranulation which has not been fully characterized. Mast cell food reactions will be discussed more completely in an upcoming post.

 

Reference:

Sicherer, Scott, Sampson, Hugh. Food allergy: Epidemiology, pathogenesis, diagnosis and treatment. J Allergy Clin Immunol 2014, 133 (2): 291-307.