Protein Intolerance

Etiology

Protein intolerance is caused by the inability to digest or effectively break down amino acids. When food proteins are not digested well, they can act as antigens resulting in food protein allergies. Most frequently, cow's milk proteins are the cause of food intolerance during infancy.[1] Food-protein-induced enterocolitis syndrome is also commonly attributed to intolerance to cow's milk proteins. The affected individuals present with diarrhea, edema, and hypoalbuminemia. With an increase in age and the introduction of different foods, egg protein intolerance, soy, and peanut allergy become more prevalent.[2]

Protein intolerance can be seen in the following conditions:

Immunological food protein intolerance: It can be IgE mediated or non-IgE mediated.

IgE mediated conditions include:

• Cow's milk allergy
• Oral allergy syndrome
• Immediate GI hypersensitivity
• Eosinophilic esophagitis
• Eosinophilic gastritis
• Eosinophilic gastroenteritis

Non-IgE mediated conditions include:

• Food protein-induced enterocolitis
• Food protein-induced enteropathy
• Food protein-induced allergic proctocolitis

Autoimmune reaction: Autoimmune reaction to gluten proteins is found in celiac disease, non-celiac gluten sensitivity, wheat allergy, gluten ataxia, and dermatitis herpetiformis.[3] 

Enzyme deficiency: Enterokinase (enteropeptidase) deficiency 

Metabolic disorders:

• Phenylketonuria (PKU)
• Maple syrup urine disease (MSUD)
• Tyrosinemia
• Homocystinuria

Genetic/inherited disorder: Urea cycle disorders, lysinuric protein intolerance

Pharmacological: Chronic use of medications to suppress gastric acid production[4]

Toxic reactions to biogenic amines: 

• Tyramine in aged cheeses
• Histamine

 Undefined: Irritable bowel syndrome

Epidemiology

Food intolerance has been observed to affect 15% to 20% of the population.[5] Cow’s milk allergy (CMA), a response to proteins in the cow’s milk, is the most common food allergy in early life with an estimated range of prevalence from 0.5% to 3% at age 1 year.[1][2][6] However, based on the natural history of CMA, it’s resolution is common, and its prevalence is expected to be lower in adults.

In an Australian study, one in 10,000 infants less than 2 years of age were found to have food protein-induced enterocolitis syndrome (FPIES). FPIES is found to occur predominantly in infants and is associated with common food triggers (proteins in cow milk, soy, rice, oats, and egg), but the epidemiological data are still lacking.[7]

Celiac disease has been considered a major public health concern and is reported worldwide. It is most prevalent in Western Europe and the United States but is underdiagnosed in most affected people. A meta-analysis done in 2018 has noted a 1.4% prevalence of celiac disease based on serological tests, and 0.7% based on biopsy.[8] 

Although no sex predilection is known, FPIES and eosinophilic gastroenteritis have a slight male predominance, whereas women are slightly more likely to be affected by celiac disease.

Pathophysiology

Dietary protein macromolecules are formed of sequences of amino acids connected by peptide linkages. These linkages must be hydrolyzed and exposed to enzymatic actions before free amino acids can be absorbed. The process of digestion of proteins starts in the stomach by pepsins with the help of hydrochloric (HCl) acid. This partially digested protein then reaches the duodenum where a high pH stops the peptic activity, and pancreatic enzymes (trypsin, chymotrypsin, carboxypeptidases) take over the process of digestion. The small chains of amino acids produced in the lumen are now subjected to membrane digestion at the brush border of the enterocytes. The membrane exopeptidases hydrolyze amino acid chains to form individual amino acids that are absorbed into the enterocytes and to the bloodstream to be utilized in the body.

Protein intolerance can occur due to any abnormalities in the digestion or metabolism process. When food proteins are incompletely denatured by the gastric acid, they are found to result in the sensitization of the protein in the gut leading to food allergies. Hypoacidic conditions, as seen in patients treated long-term for dyspeptic disorders, are frequently found to develop food protein allergies.[4]

History and Physical

Clinical features of food protein intolerance involve a spectrum of organ systems and vary among different disorders. However, patients mostly present with gastrointestinal manifestations. In non-immunological food protein intolerances, the amount of food ingested tends to be more directly related to the severity of symptoms. Excessive intestinal gas, bloating, abdominal pain, and diarrhea are common presenting symptoms. Whereas, in immunological food protein allergies, even trace amounts of the sensitized food protein can trigger an explosive reaction and may involve the skin and blood vessels. The IgE-mediated reactions occur within minutes to an hour of food protein ingestion, and symptoms range from skin rashes, urticaria, angioedema, wheezing, to anaphylaxis, whereas non-IgE mediated reactions may occur in hours to days.

A typical presentation in infants can be seen as an infant younger than 6 months of age developing diarrhea, and in due course, vomiting after being fed with formula milk for a few weeks. Food-induced proctocolitis syndrome is a common condition where healthy infants present with diarrhea but do not lose weight. Whereas, in cases of FPIES, the infant can become dehydrated and lose weight.

Here are some of the symptoms and physical findings that are seen among different disorders of protein intolerance:

Oral allergy syndrome: The reaction mainly arises due to cross-reactivity between pollen and plant-derived food (fruits and vegetables), and the symptoms are localized to the mucous membrane within the oral cavity.[9] Symptoms include itching and burning sensation in the lips, tongue, palate, and throat. Angioedema and vomiting may occur.

Immediate GI hypersensitivity: Patients develop nausea, abdominal pain, and vomiting within 1 to 2 hours of sensitized food protein ingestion, often followed by diarrhea. The affected individuals have intermittent abdominal pain, poor appetite, and poor weight gain. 

Eosinophilic esophagitis (EoE): Patients present with difficulty in swallowing, solid food impaction, abdominal pains, regurgitation or vomiting, and decreased appetite. Younger children may present with feeding difficulties and poor weight gain. The symptoms frequently overlap and are often confused with gastroesophageal reflux disease (GERD). However, patients with EoE are often found to have a history of other autoimmune and allergic conditions as well.[10]

Eosinophilic gastritis: They usually present with features of gastritis, such as abdominal pain, postprandial vomiting, early satiety, anorexia, and failure to thrive. The disease is very responsive to dietary restriction therapies in children. Approximately 50% of these patients have atopic features as well.

Eosinophilic gastroenteritis: It is an uncommon disorder with a chronic relapsing course characterized by infiltration of eosinophils in the mucosa of the GI tract. The presentation may vary. Pediatric patients can present with failure to thrive, growth retardation, delayed puberty, or amenorrhea. Frequently, the adults present with abdominal pain, dysphagia, or diarrhea. They may also present with features of protein-losing enteropathy, GI bleeding, or malabsorption.[11]

Food protein-induced enterocolitis syndrome (FPIES): The patients can present with vomiting one to three hours after feeding. They may also have abdominal distention, bloody diarrhea, anemia, and weight loss, and are commonly provoked by cow’s milk or soy protein-based formulas. On physical examination, signs of dehydration may be evident. There is an absence of respiratory symptoms or the classic IgE-mediated allergic skin reactions.

Food protein-induced enteropathy: Patients with food protein-induced enteropathy present with steatorrhea and failure to thrive in the early few months of life.

Food protein-induced allergic proctocolitis: It is commonly seen in healthy breast-fed infants. They develop symptoms of blood-streaked stools in the first few months of life.

Celiac disease: Patients with celiac disease commonly present with diarrhea, foul-smelling stool, steatorrhea, borborygmi, flatulence, and loss of weight. Patients complain of weakness and fatigue, usually related to poor nutrition. Signs of anemia may be evident. Dermatitis herpetiformis, a pruritic papulovesicular rash involving the extensor surfaces of the extremities, trunk, and buttocks, may be noted.

Enterokinase deficiency: Infants with this enzyme deficiency develop diarrhea from birth and fail to thrive. With the chronic malabsorption of protein, they are prone to develop hypoproteinemic edema. Oral administration of pancreatic extract results in expeditious control of symptoms and helps with growth acceleration.[12]

Inborn errors of metabolism: These disorders result in an accumulation of metabolites upstream of the defective enzyme (amino acids and/or ammonia), causing intoxication. The symptoms vary according to the enzymes affected.

Toxic reactions to biogenic amines: Ingestion of some biogenic amines contribute to toxic reactions. Patients may present with headache, palpitations, vomiting, diarrhea, and allergy. Consuming aged cheese containing tyramine in conjunction with the use of monoamine oxidase inhibitors (MAOIs) is found to cause headaches and hypertensive crisis.[13] Histamine is more toxic and can result in effects like hypotension, skin irritation, headache, palpitations, asthma attacks, etc. This symptomatology is known as “scombroid fish poisoning,” which is seen after consumption of fish from Scombridae and Scomberesocidae families (tuna, mackerel, bonito, bluefish, etc.) containing high levels of histamine.[14]

Dermatological manifestations:

Protein intolerance is frequently associated with dermatologic atopic conditions. A study done in Italy showed 71% of the children with concomitant cow’s milk allergy to have a comorbid atopic dermatitis.[15] Other dermatological symptoms include urticaria, rashes, and angioedema.

Evaluation

There is no one specific test to diagnose food protein intolerance. The condition is evaluated primarily based on a detailed history and physical examination. The clinicians need to recognize and differentiate immunological from non-immunological food protein intolerance to prevent and manage symptoms. In IgE-mediated food allergies, positive skin prick test responses to food proteins along with the detection of food-specific IgE antibodies are usually evident. However, most food protein intolerances are not IgE mediated.

When food protein intolerance is suspected, the following measures and tests are helpful in diagnosis:

1. Food diary: Keeping a food diary is important as it helps the clinicians to map the symptoms and find out the relationship of food to the patient's symptoms.
2. Skin prick test: This test screens for IgE-mediated food protein allergies. Although a positive test result may show the presence of IgE antibodies, it has a low predictive value, whereas a negative test result has high predictive accuracy.
3. Atopic patch test: The test is used to screen for delayed intolerances to food proteins (cell-mediated reactions). 
4. Serum specific IgE assay: It is also done to screen for antigen-specific IgE in the patient's serum.
5. Diet elimination: If food protein intolerance or allergy is suspected, the patient should consume a diet free of the suspected protein for 2 to 4 weeks. If symptoms improve, an oral food challenge test may be performed as a diagnostic test.
6. Oral food challenge test: It is a gold-standard test performed under medical supervision to diagnose or rule out food allergy. A diagnosis of food protein intolerance can be made when symptoms subside following dietary elimination of the concerned food, and then symptoms recur after the introduction of the same food. The reactions and symptoms must be reproducible with repeated diet elimination and food challenge tests. Some GI reactions may demonstrate delayed-onset reactions, causing symptoms to occur hours or days after the ingestion.
7. Radioallergosorbent test (RAST): This test detects allergen-specific Ig-E antibodies via radioimmunoassay. It is useful in determining the causes of allergies and is frequently positive in immediate GI hypersensitivity.
8. Differential leukocyte count: This test supports the diagnosis of allergic eosinophilic gastritis, allergic eosinophilic gastroenteritis, and other allergic conditions when peripheral eosinophilia is seen.
9. Stool test: Stool tests may show occult blood or fecal leukocytes and indicate the presence of inflammation.
10. Biopsy: In allergic eosinophilic esophagitis, gastritis, and gastroenteritis, a biopsy shows eosinophilic infiltration of the mucosa and submucosa. Jejunal biopsy in enterocolitis syndrome and celiac disease shows villous atrophy and intestinal infiltration by lymphocytes.

Treatment / Management

The only definitive management of food protein intolerance is the strict elimination of the offending food protein in the diet. Patients should be counseled on monitoring the ingredients of manufactured food and compliance with the elimination diet. Patients on long-term elimination diets should also have access to appropriate diet counseling, ideally by a nutritionist or dietitian, and regular monitoring of growth, especially in children.

In breastfed infants, the mothers should be advised to avoid cow's milk and dairy products. Extensively hydrolyzed formula with documented hypoallergenicity must be recommended as the choice for the treatment of cow's milk allergy, especially in non-breastfed infants and young children. For patients with more severe symptoms, amino acid formulas can also be recommended.[16]

Steroids are the mainstay treatment in IgE-mediated immunological food protein intolerance, including eosinophilic gastrointestinal disorders.[17]

Infants with acute FPIES with mild symptoms (without lethargy, pallor, or listlessness) can be treated at home with oral rehydration. But for severe symptoms, they must be managed at a medical facility with IV fluids. Intramuscular epinephrine and antihistamines do not have any role in the management of FPIES reactions.

If acute allergic reactions or anaphylaxis is suspected, the probable offending food must be immediately avoided, and emergency medical care should be provided. They may be given a prescription for an auto-injectable epinephrine device and instructed for their proper use.

Differential Diagnosis

Some common differential diagnoses for food protein intolerance are discussed below:

1. Intestinal infections: Intestinal infections may also present with similar symptoms as, or predispose to, protein intolerance. Patients with intestinal infections frequently have signs of infection and can be treated with antimicrobials.
2. Celiac disease: Celiac disease is a widely multifactorial disease with a strong hereditary component and HLA (DQ2 and DQ8) association. They can manifest with an autoimmune reaction to the gluten protein in foods. Testing for serum anti-tissue transglutaminase IgA antibodies (anti-tTG IgA) can help with the diagnosis of celiac disease or rule it out as a cause for protein intolerance.
3. Gastroesophageal reflux disease (GERD): Pediatric patients show symptoms like sleep disturbances, vomiting, poor appetite, poor growth, wheezing, and stridor. Adults experience heartburn, vomiting, and regurgitation. GERD can be managed with or without pharmacotherapy and surgical options. They do not have a relation to a particular food protein.
4. Inflammatory bowel disease (IBD): They include Crohn disease and ulcerative colitis, which may present with common GI symptoms like diarrhea, rectal bleeding, and abdominal pain. However, it is important to rule out IBD as they are systemic chronic diseases and require extensive management.

Prognosis

The prognosis of many protein intolerances is good as long as a strict diet elimination is maintained. Many studies have shown the prognosis of cow's milk protein intolerance to be favorable, with the majority of patients outgrowing their allergy throughout childhood and early adolescence.[2] However, some children with IgE-mediated protein intolerance have been found to develop allergic rhinoconjunctivitis and asthma.

Complications

Protein is an essential nutrient for the health and development of our bodies. The general complications of protein intolerances leading to protein deficiency are loss of muscle mass, delayed growth, failure to thrive, and a weakened immune system. Affected individuals may have symptoms such as swelling in the legs, face, and other parts, dry and brittle hair, fatigue, and frequent infections.

In adults, allergic reactions to cow's milk proteins are often complicated by lactose intolerance, which increases with age. IgE-mediated allergic conditions may cause anaphylactic reactions and angioedema, which can be life-threatening without management. Diarrhea and vomiting associated with FPIES and eosinophilic gastroenteritis may lead to complications, including severe dehydration and hypovolemic shock.