Introduction  

Mastocytosis is associated with an excess of mast cells within the body. These mast cells are part of the immune system, and protect our bodies from invading pathogens. Systemic means that the condition affects the whole body. Masto refers to the mast cells and cytosis refers to the cells. Therefore, systemic mast cell cytosis means an increased amount of mast cells within the whole body. There are two main types of mastocytosis. Cutaneous mastocytosis is when the mast cells accumulate in the skin, but not elsewhere in the body. This tends to occur mainly in young children. Systemic mastocytosis usually occurs in adults and affects all the organs of the body, including the skin. This article focuses only on systemic mastocytosis and how the disease affects adults who are diagnosed with the condition. The cytoplasm of the mast cell contains granules that hold cytokines, histamine and other cellular mediators which are associated with allergic responses to allergens and also anaphylaxis and allergic reactions.¹⁸ Mast cells are a type of white blood cell found in the connective tissue of most of the organs in the body. The mast cells are produced within the bone marrow, and then circulate around the body. The mast cells also secrete these granules into the extracellular space and are mononuclear in nature.⁶

What is the role of mast cells in the immune system?

The mast cells have a “ligand-independent activation of the receptor tyrosine kinase”⁴ This means that the activation of the tyrosine kinase causes an allergic reaction due to an over-expression of mast cells within the body. Abnormal mast cell behaviour occurs in systemic mastocytosis. The mast cells start to produce excessive amounts of histamine and tryptase resulting in an allergic response. 

Types of systemic mastocytosis

Indolent systemic mastocytosis

Indolent systemic mastocytosis (ISM) is the least severe sub-type of mastocytosis. It accounts for 90% of cases of systemic mastocytosis. The prevalence of ISM is 1–5 people per 10,000. Usually, there is a mutation called KIT D816V. As mast cells are made in the bone marrow, a test for genetic abnormalities is completed with PCR (polymerase chain reaction), and also cytology and histology testing of bone marrow samples to determine a diagnosis of ISM.^2,3 Doctors may also measure the tryptase levels in the blood. If the level is increased, this shows that the patient is experiencing anaphylaxis and/or mastocytosis.⁷

Smouldering systemic mastocytosis

This condition (SSM) is in between indolent and aggressive systemic mastocytosis. The symptoms are more pronounced than in indolent cases, but the life expectancy is not massively altered. It is unlikely that organ damage will occur due to the infiltration of mast cells.⁸

Aggressive systemic mastocytosis

ISM and SSM are generally less severe than ASM. This is because in ASM, the mast cells have infiltrated many organs, and this can cause organ failure. The levels of histamine and tryptase being produced is also greater which can lead to increased instances of anaphylaxis.⁷

Mast cell leukaemia

Sometimes systemic mastocytosis can also be associated with a haematological malignancy such as leukaemia. In this instance the condition is much more aggressive and potentially fatal. This would need to be treated with chemotherapy and or radiotherapy. 

A bone marrow biopsy is taken and a result of 20% mostly immature mast cells is required to confirm that there is a diagnosis of mast cell leukaemia. 

Symptoms and clinical presentation

Common symptoms and signs

• Itching in the skin 

the skin may also look flushed

• Stomach upsets such as diarrhoea
• Depression⁹ 

Depression occurs in 40–70% of people diagnosed with systemic mastocytosis. Other neurological symptoms include irritability and a lower threshold for stress¹²

• Iron deficiency anaemia and eosinophilia¹⁰

Iron deficiency anaemia is a condition in which the patient has low levels of iron in their blood, causing tiredness and weakness. The iron is needed by the haemaglobin in the blood which carries the iron so that the body can absorb oxygen 

• Osteoporosis¹¹

Osteoporosis is a condition that affects the bones in the body. The bones are at an increased risk of fracturing. Before osteoporosis is diagnosed, there is a precursor condition called osteopenia. This is when the bones have a lower density than normal¹¹

• Enlarged lymph nodes and spleen¹³
• IgE mediated anaphylaxis 
• Syncope (fainting) 
• Peptic ulcer disease¹⁵

Variability in symptom severity

The severity of symptoms will depend on the sub-type of systemic mastocytosis. Symptoms will also vary from person to person and may also be triggered by different factors which may be easier or harder to avoid such as cold weather or airborne allergens like pollen. The spectrum of different presentations can make a diagnosis difficult.¹⁴ 

Triggers for mast cell activation

• NSAIDS (medications such as ibuprofen) 
• Weather (cold or hot) 
• Allergens – pollen, dust or other airborne allergens are common in causing allergic reactions. 

Diagnosis

Clinical evaluation and medical history

A precise clinical evaluation and medical history is essential in a diagnosis of systemic mastocytosis. 

 Laboratory tests

Genetic testing

Mutations in the KIT gene are associated with 90% of systemic mastocytosis cases. There has also been some research into other genetic and epigenetic causes of SM and how different mutations can cause overexpression of mast cells within the body. The mutation in the KIT gene (KIT receptor tyrosine kinase) is caused by a single nucleotide polymorphism in which an aspartic acid is changed to a valine. The location of this mutation is called D816V. This is a type of myeloproliferative disorder in which abnormal levels of mast cells cause an increase in the levels of histamine and tryptase in the body, resulting in anaphylaxis and other associated symptoms relating to allergic reactions. The mutation is located on chromosome 4q12.¹⁶

Bone marrow and skin biopsies

Sometimes mast cells accumulate in the skin (cutaneous) which can be biopsied by taking a sample of skin that is affected. Bone marrow biopsies are usually taken from the back of your hip bone, as it is easy to access and has a large amount of bone marrow. The bone marrow biopsy will show whether there is a higher than normal level of mast cells within the bone marrow. 

Blood and urine tests 

Tryptase levels are used as a test for determining if a patient is experiencing anaphylaxis or a flare up of mastocytosis. 

Liver biopsy

If a blood test shows poor liver function then a biopsy can be taken to determine if the patient has liver failure. 

Imaging scans

Imaging studies such as X-ray, ultrasound, bone scan and CT scan can be used to determine if there is mast cell infiltration of different organs. Depending on the location and symptoms that are present will determine what type of scan is involved.¹

Treatment options

Management of symptoms and acute episodes

Anaphylaxis is the most severe symptom associated with an acute episode of systemic mastocytosis. Adrenaline is usually the main form of initial treatment in the form of an epipen. Topical corticosteroids are used to treat skin lesions. Other treatment options include antihistamines and sodium cromoglicate. Psoralen plus ultraviolet A treatment can be used to help with the skin lesions in systemic mastocytosis.¹

Medications for mast cell stabilisation

Mast cell stabilisers: cromolyn sodium, lodoxamide, and pemirolast 

For treatment of mastocytosis. midostaurin, imatinib, and avapritinib¹

Targeted therapies and bone marrow transplant

Potential complications and the impact on quality of life are mainly due to the need for lifestyle modifications. The prognosis for people with systemic mastocytosis (SM) will vary depending on what triggers the acute episodes, and whether these triggers are easy to avoid. For example, if physical exertion causes an acute attack of mastocytosis, then the patient may need to avoid an active job. However, if cold weather is the cause of SM attacks, then the patient may struggle more in the winter when the weather is colder, but have little to no problems during times of warm weather. Research is being undertaken into the different biomarkers associated with mast cell activation and proliferation (which is a main part of mastocytosis).⁵ 

Promising treatment approaches

It is possible that stem cell therapies will be created in the future to target the overproduction of mast cells. Stem cell transplants are currently not very effective for mastocytosis, however, if future research into this technique reduces the risk of rejection and graft versus host disease then this may be an avenue worth exploring. 

Coping with systemic mastocytosis

Support groups,patient resources and psychological and emotional support are available for people with SM. There are a number of different charity organisations that help people deal with a diagnosis of SM, and there is also support from immunologists and family doctors. 

Summary

The importance of early diagnosis and appropriate management cannot be understated in SM due to the high risk of fatal anaphylaxis. Patients must carry epipens containing adrenaline in order to reduce the symptoms of anaphylaxis and to make sure that the initial acute episode is dealt with in a timely manner. It is important to remember that there is a spectrum of different degrees of symptoms, which can make the disease hard to diagnose. If organ damage occurs then this can significantly affect life expectancy. Support is available for people with systemic mastocytosis from their GP and other charity organisations that support people with rare immunological conditions.