Mast Cell Activation Syndromes

Definition

More than 20 years ago, doctors suggested that some people experience episodes of mast cell activation without having a detectable mast cell disease that causes cells to multiply abnormally. Over the years, as better methods to identify abnormal mast cells were developed, it became clear that some patients had symptoms of mast cell mediator release without meeting the criteria for systemic mastocytosis (SM). This led to the concept of Mast Cell Activation Syndromes (MCAS), which includes both clonal (cell-related) and nonclonal forms of mast cell diseases. ^{6, 18}

Diagnosis and Proposed Classification

In 2010, a group of experts met to focus on the role of mast cell activation in diseases. They published guidelines for classifying and diagnosing mast cell diseases, where mast cell activation is key. ⁶

Mast cells release chemicals (called mediators) that can cause various symptoms, such as flushing, itching, hives, headaches, and digestive issues like diarrhea, nausea, and stomach pain. Low blood pressure can also be a symptom. To diagnose MCAS, a patient needs to show symptoms in two or more organ systems at the same time. These symptoms must happen repeatedly or be ongoing, and not be caused by any other condition. Treatment is often required. ^6,

The second step in diagnosis is showing that mast cells are causing the symptoms. One way to prove this is by measuring a rise in tryptase, a chemical released by mast cells, after a flare in symptoms. If the tryptase level is at least 20% higher than the patient’s usual level, plus 2 ng/mL, it can confirm mast cell activation. If tryptase testing isn’t available or doesn’t meet the criteria, doctors can also check for other chemicals, like histamine or prostaglandin, in a 24-hour urine test. ^{6, 18}

The third part of the diagnosis is based on how well the patient responds to treatment (based on response criteria¹⁵). If symptoms improve significantly with medications that block histamine or other mast cell mediators, this can confirm a diagnosis of MCAS. ^{6, 18}

During the 2024 TMS MastCellCon conference, Dr. Mariana Castells gave a presentation on diagnosing and treating MCAS. It includes an overview of the new variants also described below. You can download her presentation slides HERE.

Mast Cell Activation Syndrome Variants

PRIMARY MCAS

Primary MCAS happens when a group of mast cells in the body grows abnormally due to a genetic change. This can be linked to conditions like mastocytosis or Monoclonal Mast Cell Activation Syndrome (MMAS). If a person has primary MCAS along with mastocytosis, they must meet the criteria for both MCAS and mastocytosis to be diagnosed. MMAS is a different condition where the person has abnormal mast cells and meets the criteria for MCAS but doesn’t have enough signs to be diagnosed with mastocytosis.^1-10

SECONDARY MCAS

Secondary MCAS occurs when mast cells become activated due to another illness or condition. When doctors know about secondary MCAS, they can treat both the mast cell activation and the primary condition. One common example is an IgE-dependent allergy. There are also other diseases that can lead to secondary MCAS, which have been studied and discussed by experts. ^{1-3, 11}

Combined MCAS

Combined MCAS occurs when a patient meets the criteria for primary MCAS and secondary MCAS and HαT may also be detected. ¹⁷

HαT + MCAS

This designation is made when HαT is detected and all diagnostic MCAS criteria are fulfilled.¹⁷

IDIOPATHIC MCAS

Idiopathic MCAS is diagnosed when the MCAS criteria are met, but no other disease or condition is found to explain the mast cell activation. In this case, it’s considered nonclonal, meaning it doesn’t involve abnormal cell growth as seen in other types of MCAS. Specialists have studied and discussed idiopathic MCAS in the medical field, and these experts have also provided doctors a review of other possible causes of MCAS to aid physicians in ruling out these other possible causes before giving a diagnosis of idiopathic MCAS. ^{1-3, 9-13}

External Resources about MCAS

• What to Know About MCAS, a Condition That Can Feel Like a Nonstop Allergic Reaction, by Erica Sloan, published in Self Magazine in December 2024. This article quotes two physicians from our medical advisory board.

Past TMS Webinars relevant for MCAS

Please visit the following article for more information on mast cell activation syndromes, including potential causes, symptoms, variants, effects of comorbidities and other possible diagnoses to exclude:

Valent P, Hartmann K, Bonadonna P, Niedoszytko M, Triggiani M, Arock M, Brockow K. Mast Cell Activation Syndromes: Collegium Internationale Allergologicum Update 2022. Int Arch Allergy Immunol. 2022;183(7):693-705. doi: 10.1159/000524532. Epub 2022 May 23. PMID: 35605594; PMCID: PMC9393812.