Overview

Mastocytosis describes disorders that occur due to an aberrant accumulation of mast cells in tissues. In systemic mastocytosis, gastrointestinal tract involvement is frequent, with patients experiencing discomforting symptoms, that can impact their quality of life. However, these symptoms are not specific and limited to mastocytosis, which complicates a complete diagnosis and appropriate treatment administration. 

Introduction

Definition of mastocytosis 

Mastocytosis is an abnormal increase in mast cells in tissues, often leading to pathologically associated problems. The most commonly affected tissues are the skin, bone marrow, spleen, lymph nodes, gastrointestinal tract, lung, and bones. 

Overview of mast cells and their function

Mast cells are immune cells defending our body against pathogens, parasites, and foreign substances. Their cell progenitors reside in the bone marrow and travel through the blood to the connective tissue of various organs, where they mature. They are among the first cells in our body, that recognise foreign elements, either in soluble form or as part of a microorganism, leading to their activation.¹ This results in the release of harmful proteases and important mediators for the inflammatory process, such as histamine and tryptase. Mast cells have a central role in allergic reactions as they can get triggered by common allergens.²

Explanation of mastocytosis

Some individuals have increased numbers of mast cells and their mediators, often leading to problems affecting specific tissues or with a more systemic effect. The resulting disorders are attributed to mastocytosis. The clinical symptoms, the affected organs, and the associated gene variations are used for the classification of mastocytosis. Two major subtypes have been described, cutaneous mastocytosis, affecting the skin and mostly associated with pediatric cases, and systemic mastocytosis, which involves other organs and is further categorised into subtypes. Several instances of mastocytosis are linked to variants of a surface protein of mast cells, called receptor tyrosine kinase (KIT).³ Commonly affected organs include the skin, bone marrow, the gastrointestinal tract, the lung, the spleen, and lymph nodes. 

Importance of recognising gastrointestinal symptoms 

Prevalence in mastocytosis patients 

Gastrointestinal symptoms often present in people with mastocytosis. The symptoms can vary and are not specific to the disorder, therefore appropriate diagnosis by clinicians is frequently delayed. Therefore, it is important to include all factors and tests to conclude the right diagnosis. 

Impact on quality of life

Gastrointestinal symptoms can range from mild to severe. Severe cases in combination with frequently observed delays in diagnosis can negatively affect the life quality of individuals. Apart from physical symptoms, patients also experience psychological disturbance, such as anxiety and uncertainty. Therefore it is important to recognise and assess efficiently gastrointestinal symptoms attributed to mastocytosis, distinguishing them from other disorders. 

Overview of gastrointestinal symptoms

Gastrointestinal symptoms are frequent in people with systemic mastocytosis. They can either be a secondary effect, meaning a consequence of mast cells secreted mediators, or due to the accumulation of mast cells in the gut. In any case, studies report about 60-80% of patients with gastrointestinal symptomatology.⁴ Some symptoms are frequent, while others are less common.

Common Symptoms: 

• Diarrhoea
• Bloating
• Nausea
• Abdominal pain
• Vomiting 

Less Common Symptoms: 

• Malabsorption and weight loss
• Ulcers and gastrointestinal bleeding

Less common symptoms are associated with more severe forms of the disease, and specifically gastrointestinal ulcers and bleeding are often a consequence of mast cell leukaemia, which is a subtype of systemic mastocytosis.⁴

Pathophysiology of gastrointestinal symptoms in mastocytosis

What is the physiological role of mast cells in the gastrointestinal tract?

Mast cells are found in the mucosa or connective tissue of various organs that are in contact with microbes, and they have a major role in maintaining balance and fighting potentially harmful microorganisms or substances. The gut is an organ rich in bacteria beneficial for the host. Mast and other immune cells tolerate harmless bacteria, however they fight harmful bacteria, without causing extreme damage to the gut tissue. Mast cells additionally confront foreign substances in the body, mostly as a result of food digestion. They also can promote tissue repair and healing after a threat has been eliminated.^{5, 6}

Abnormal activation and proliferation

Abnormal activation and proliferation of mast cells are linked to inflammation and damage in the gut. Certain variants of the cell surface protein KIT can lead to the proliferation of the cells and their accumulation in the gastrointestinal tract. Upon encounter with microbes or substances, they can secrete components that affect surrounding cells, accumulating and activating them, with certain symptoms developing. It is important to note that an aberrant increased number of mast cells can be the causal or a secondary event of gut inflammation, as it is observed also in cases of inflammatory bowel disease (IBD).⁵ 

Mechanisms of symptom development in the gut 

Following the proliferation and activation of mast cells, several events lead to symptom development:

Release of mediators

Histamine and tryptase are among the most abundant mediators found in the granules of mast cells. They have several effects on their surrounding environment, commonly found in allergic reactions. They can increase the size and permeability of vessels, allowing fluid accumulation, which leads to local swelling and lower blood pressure. They can also trigger mucous production by surrounding cells, which would contribute to pathogen trapping. Moreover, it acts on smooth muscles, which control gastrointestinal movements. Contraction of these muscles in combination with mucous accumulation can cause discomfort, pain and diarrhoea.^{5, 6} 

Release of cytokines

The granules of mast cells contain cytokines, which are chemical messages important for the communication of cells. This can lead to an enhanced inflammatory response and the accumulation of several immune cells, that can secrete harmful mediators damaging the gut tissue and creating ulcers and bleeding. Extensive damage can impact gut permeability and lead to dysbiosis with harmful bacteria dominating the gut.^{5, 6} This can also lead to bloating and gas in the gut.

Release of reactive oxygen species

Mast cells also contain reactive oxygen species and 'microbial traps' that upon release can directly damage the surrounding tissue.⁶ 

Diagnosis

Symptoms and medical history 

Gastrointestinal symptoms in mastocytosis are not specific to this condition but can be found in a variety of disorders, which can complicate and delay the diagnostic process. It is important to listen to the symptomatology and medical history of patients.

Diagnostic tests 

After the clinical examination, certain diagnostic tests and criteria can contribute to a diagnosis. Blood tests, endoscopy, imaging tests, and biopsies are used to detect abnormalities suggesting mastocytosis. Gut involvement indicates systemic mastocytosis, for which a major and a minor criterion, or three minor criteria need to be fulfilled for the diagnosis. 

The major criterion is mast cell aggregates, with an abnormal accumulation of at least 15 mast cells in the bone marrow or another organ including the gut. Histological assessment following a gut biopsy is useful for detecting such aggregates.⁷ 

Minor criteria examine the shape and morphology of mast cells, proteins found on their surface, such as KIT, and importantly tryptase levels found in the blood. A level exceeding 20 ng/mL is another criterion for mastocytosis.⁷  

Management and treatment

Treatment strategies for the gastrointestinal manifestations of mastocytosis either directly at mast cells or aim to relieve the symptoms that are caused: ⁴

H1 and H2 antihistamine

Antihistamines block the receptors of histamine and therefore the effects caused by this mediator. They are used as first-line treatment for managing gastrointestinal symptoms from mastocytosis.

Proton pump inhibitors (PPIs) 

Proton pump inhibitors (PPIs) block channels in the gut, so that less acid is produced. They are used as second-line treatment. 

Cromolyn sodium

Cromolyn sodium stabilises mast cells and is used as a third-line treatment, especially for symptoms, such as diarrhoea and nausea.

Leukotriene inhibitors 

Leukotriene inhibitors might also be used to reduce symptoms.

Corticosteroids 

Corticosteroids are used in more severe situations, for example in case an organ is damaged. They can also reduce malabsorption.

Inhibitors interfering with the proliferation and survival of mast cells

Several cases, for example, some caused by leukemias require specific inhibitors aiming at the proliferation and survival of mast cells. Specific variants of KIT are often the target of such therapies.⁴ 

Dietary and lifestyle modifications 

Several diet modifications are usually combined with treatments to minimise gastrointestinal symptoms. Avoidance of several trigger foods that lead to exacerbation of symptoms is recommended. A diet low in histamine might be recommended. Certain supplements that can contribute to restoring the tissue might be beneficial.

Monitoring and follow-up 

As monocytosis is a chronic disorder without a permanent cure, individuals need to check and understand what works better for them. Through regular checks and monitoring with their doctor, they can manage their symptoms and minimise further damage to the gut.

Conclusions and future directions

Aberrant activation and proliferation of mast cells can promote inflammation in the gastrointestinal tract. Several problems can be caused as a result, affecting both the physical and mental health of patients. It is important to recognise symptoms and perform the appropriate tests to accelerate the diagnostic procedure in the future. In this way, tissue damage can be limited and life quality can be improved. The effects can vary among individuals and treatments target primarily to relieve symptoms. New therapies that target specific variations of KIT are also currently being investigated.⁸

Summary

Mast cells are immune cells found in many organs, including the gut. They are important defenders in the first line of the body's tissues, acting against pathogens and foreign substances. However, increased numbers can be harmful to the host. Mastocytosis describes disorders caused by increased numbers of mast cells in tissues. Gut manifestations are frequent with unpleasant symptoms for the patients including bloating, diarrhoea, vomiting, and in some cases malabsorption and weight loss. Symptoms are non-specific and can therefore lead to differential diagnosis. It is important to examine each case thoroughly and combine medical history data before reaching a diagnosis and administration of treatment.