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

Angioedema: Part 3

Acquired angioedema (AAE) is characterized by a deficiency of C1INH not associated with a genetic defect; overactivation of the classical complement pathway; and frequent angioedema episodes. AAE is rare, about ten times less common than HAE. However, the two conditions are clinically identical. AAE often presents with low CH50, C2, C4 and sometimes C1q, with low or poorly functioning C1INH.

AAE was originally associated with lymphoma and has since been found secondary to a number of autoimmune and hematologic diseases, particularly lymphoproliferative conditions and monoclonal gammopathy of unknown significance (MGUS, which often precedes multiple myeloma). Historically, AAE has been divided into two groups: type I, which I just described; and type II, in which there are IgG antibodies to C1INH that inactivate C1INH. However, further research found that anti-C1INH antibodies are also found in type I. It has since been recognized that these are really different presentations of the same condition, with lymphoma cells depleting C1INH more readily. There have been documented instances in which achieving remission from lymphoma cured the associated AAE.

There are other types of angioedema that are difficult to classify. Idiopathic angioedema is the instance of three episodes in 6-12 months without a clear trigger or pathology. It is distinguished from hereditary angioedema by the shorter duration of symptoms. Further testing demonstrates normal levels and function of C1INH in these patients. This is sometimes called “idiopathic non-histaminergic AAE” to distinguish from an allergic process.

Type III HAE patients are sometimes positive for mutations in the Factor XII gene. However, in some patients, no mutation is found. All type III patients demonstrate normal level and function of C1INH. Type III patients experienced four attacks per year on average, with 42.9% having swelling in the airway. 85% had abdominal attacks, with some severe enough to result in emergency (though unnecessary) surgical procedures and ascites, free fluid in the abdomen.

In the patients with the Factor XII mutation, attacks were most likely to occur during high estrogen states, but were not exclusive to these periods. Initial attacks for this patient group usually occurred while on oral contraceptives or during pregnancy. However, men and children were also found to have Factor XII mutations. Initial attacks were less likely to affected by estrogen state in type III HAE with no FXII mutation or in idiopathic non-histaminergic angioedema. .

23% of type III patients exhibited elevated D-dimer levels outside of attack periods. Some also had extended clotting times. In the FXII mutated group, bruising was seen in a number of patients when swelling in the swollen portions of anatomy, but strictly in the skin. 27.9% of pregnancies in this group terminated in spontaneous miscarriage. Two births were extremely premature and one liveborn child died shortly after birth with no obvious cause of death.

References:

Zuraw, B. L., et al. A focused parameter update : Hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibitor-associated angioedema. J Allergy Clin Immunol 2013; 131(6); 1491-1493e25.

Kaplan AP, et al. Pathogenic mechanisms of bradykinin mediated diseases: dysregulation of an innate inflammation pathway. Adv Immunol 2014; 121:41-89.

Kaplan AP, et al. The plasma bradykinin-forming pathways and its interrelationships with complement. Mol Immunol 2010 Aug; 47(13):2161-9.

Firinu, Davide, et al. Characterization of patients with angioedema without wheals: the importance of F12 gene screening. Clinical Immunology (2015) 157, 239-248.

Csuka, Dorottya, et al. Activation of the ficolin-lectin pathway during attacks of hereditary angioedema. J Allergy Clin Immunol 134 (6) 1388-1393.e3.

Ohsawa, Isao, et al. Clinical manifestations, diagnosis, and treatment of hereditary angioedema: survey data from 94 physicians in Japan. Ann Allergy Asthma Immunol 114 (2015) 492-498.

Kajdacsi, E., et al. Endothelial cell activation during edematous attacks of hereditary angioedema types I and II. J Allergy Clin Immunol 133 (6); 1686-1691.

Triggianese, Paola, et al. The autoimmune side of hereditary angioedema: insights on the pathogenesis. Autoimmunity Reviews 2015 (ahead of press).

Madsen, Daniel Elenius, et al. C1-inhibitor polymers activate the FXII-dependent kallikrein-kinin system: implication for a role in hereditary angioedema. Biochimica and Biophysica Act 1850 (2015) 1336-1342.

Lasek-Bal, Anetta, et al. Hereditary angioedema with dominant cerebral symptoms finally leading to chronic disability. Clinical Neurology and Neurosurgery 135 (2015) 38-40.

 

 

 

Chronic urticaria and angioedema: Part 4

There are a number of other conditions that present with similar features to chronic urticaria and angioedema.

Conditions that can present similarly to chronic urticaria are listed below.

Chronic urticarial vasculitis is associated with low or normal complement levels and confusingly can be a primary autoimmune disorder, or a process secondary to another autoimmune disease, like lupus. Urticarial vasculitis lesions sometimes resolve quickly but can last for several days. A lesion biopsy can distinguish between CU and chronic urticarial vasculitis. Painful or burning lesions suggest urticarial vasculitis, with raised lesions that don’t blanch, and may leave hyperpigmented areas in place of resolved lesions. Hepatitis B and C can cause urticarial vasculitis.

Swelling of the upper eyes can be mistaken for angioedema, but in some people may be a symptom of thyroid ophthalmopathy, thyroid driven eye disease. Development of urticaria for during pregnancy is not unusual. Cyclical urticaria can be from autoimmune progesterone dermatitis. Episodes of angioedema with accompanying weight gain can be caused by Gleich syndrome (episodic angioedema with eosinophilia).

Cutaneous mast cell patients demonstrate a variety of urticaria-like lesions, including urticaria pigmentosa, mastocytomas and telangiectasia macularis eruptive perstans. Mast cell activation syndrome can also cause angioedema and urticaria, but generally these are not the only symptoms.

Erythema multiforme looks like urticaria but is often due to viral infections, mycoplasma infections or some medications. Bullous pemphigoid can initially present with hive-like welts or small plaques that do not always blister in early disease. Swelling of the lips in the absence of eczema can indicate cheilitis granulomatosa.

Schnitzler syndrome can cause non-itching hives that exclude the face, bone pain and intermittent fevers. These patients also have IgM or IgG monoclonal gammopathy.

 

Angioedema in the absence of urticaria is rare. There are a few conditions that can cause it.

Hereditary angioedema (HAE) is caused by C1 esterase inhibitor deficiency (in type I, 80%-85% of cases); or dysfunction (in type II, 15-20%).  People with HAE do not have coincident urticaria. HAE is inherited in an autosomal dominant pattern, but up to ¼ of patients develop the condition through spontaneous mutation rather than through inheritance of the gene. About 40% of patients have their initial attacks before the age of 5.

Acquired angioedema (AAE) is caused by antibodies to C1 esterase inhibitor, which is usually caused by cancers of B cells. AAE is more likely to develop in older patients (usually fourth decade of life or later) and family history of angioedema is generally absent. AAE is also more likely to develop when an autoimmune disease or proliferative blood disorder is present.

Angioedema associated with these conditions can affect any part of the body, including limbs and abdomen. Patients with abdominal angioedema are often misdiagnosed as having an “acute” abdomen that requires surgical intervention. It is not unusual for patients to present initially only with abdominal swelling. Both HAE and AAE have a number of common triggers, including infection, emotional or physical stress. or trauma. Importantly, they are not caused directly by histamine and other mast cell mediators and as such are not responsive to antihistamines and corticosteroids.

There is also a form of angioedema specifically induced by treatment with ACE inhibitors. It can be relieved by discontinuing ACE inhibitor therapy.  Idiopathic angioedema can also occur in the absence of urticaria but is more likely to respond to prophylactic antihistamine use than HAE or AAE.

 

Edited to add: I removed the following line from the first HAE paragraph: “Type III is estrogen mediated and only found in adult women.”  This statement is inaccurate,  I mistakenly included i, as I had originally noted it when reading a paper from 2007.  I am doing a follow up post on HAE that will elaborate further on the different subtypes and treatment.  Many thanks to the reader who caught it!

 

References:

Jonathan A. Bernstein, et al. The diagnosis and management of acute and chronic urticaria: 2014 update. J Allergy Clin Immunol Volume 133, Number 5.

Zuberbier T, Maurer M. Urticaria: current opinions about etiology, diagnosis and therapy. Acta Derm Venereol 2007;87:196-205.

Ferdman, Ronald M. Urticaria and angioedema. Clin Ped Emerg Med2007; 8:72-80.

Kanani, Amin, et al. Urticaria and angioedema. Allergy Asthma and Clinical Immunology 2011, 7(Suppl 1):S9.