Systemic Mastocytosis

What is Systemic Mastocytosis?

Mastocytosis is a group of conditions caused by an overproduction and buildup of unusual mast cells in the body’s tissues. Mast cells are a kind of white blood cells that are part of our immune system and help in fighting infections. Mastocytosis could be limited to the skin, known as cutaneous mastocytosis, or it could affect other parts of the body, referred to as systemic mastocytosis. Skin mastocytosis generally presents minor complications, while systemic mastocytosis is a severe form of the condition. In systemic mastocytosis, the overactive mast cells release a large number of substances that can affect blood vessels, potentially leading to a wide range of symptoms. The most common symptoms linked with mastocytosis include prickling and redness of the skin, itching, diarrhea, and severe allergic reactions known as anaphylaxis.

What Causes Systemic Mastocytosis?

Mast cells are a type of immune cell that originates from a specific cell group called the myeloid lineage. You will typically find these cells in our body’s connective tissues. These cells are triggered into action via reactions known as immunoglobulin E (IgE) and non-IgE mechanisms. Essentially, their primary role is to participate in allergic and over-reactive immune responses.

In the IgE mechanism, an allergen – a substance causing an allergic reaction – forms a bond with the IgE receptor on the mast cells. Once bonded, the mast cells spring into action and start a process called degranulation.

There are also non-IgE mechanisms that lead to the activation of mast cells. These can include a wide range of triggers, like emotions, physical stimuli, food, certain drugs (like opioids and nonsteroidal anti-inflammatory drugs), alcohol, heat, exercise, specific proteins known as cytokines, venoms from animals, and even hormones.

When mast cells are activated, they release various substances. Among the most common are histamines, proteases, cytokines, growth hormones, tumor necrosis factors, and phospholipases. Also, mast cells carry granules filled with tryptases and chymases.

Tryptase, in particular, is always secreted by mast cells. That’s why it can serve as an important factor in diagnosing certain conditions, as high levels might indicate an active allergic or immune response.

Risk Factors and Frequency for Systemic Mastocytosis

Systemic mastocytosis is an uncommon condition that affects both men and women equally. It is mostly noted on the skin, with 80 percent of instances appearing during a person’s childhood. Interestingly, many of these cases get better or even disappear completely by the time the individual reaches their teenage years. For adults, however, systemic mastocytosis accounts for over 95 percent of cases and typically lasts for a longer duration.

Signs and Symptoms of Systemic Mastocytosis

Systemic mastocytosis is a medical condition where multiple organs are involved because of the release of certain body chemicals, known as vasoactive mediators. Here are some of the symptoms and effects related to different parts of the body:

• Episodic mediator release and anaphylaxis: This sudden discharge of body chemicals can cause episodes of blood vessel widening, low blood pressure, skin redness, itching, fainting, abdominal pain, nausea, vomiting, diarrhea, fatigue, and headache. Anaphylaxis, a severe allergic reaction, may show similar symptoms and can occur in both skin and systemic mastocytosis. These reactions can result from an immune system-mediated allergy or the nonspecific activation of mast cells.
• Gastrointestinal complaints: Problems related to the digestive system due to the release of mast cell chemicals are common in systemic mastocytosis. Symptoms can include abdominal pain, diarrhea, nausea, vomiting, peptic ulcer disease, and gastrointestinal bleeding.
• Neuropsychiatric symptoms: Emotional and cognitive effects are commonly seen in adult patients. They may suffer from depression, mood changes, decreased focus, poor short-term memory, increased sleepiness, irritability, and emotional instability. These symptoms often fall under the term “mixed organic brain syndrome”.
• Musculoskeletal symptoms: Diffuse pain in large bones and a pain type similar to fibromyalgia may occur. Also, decreased bone density is seen in some patients, putting them at risk of developing osteopenia and osteoporosis. Up to half of patients may have mild to moderate anemia and roughly one quarter have higher than normal levels of a type of white blood cell called eosinophils.
• Gastrointestinal and liver abnormalities: Peptic ulcer disease, malabsorption, fatty stools, and liver enlargement are often observed when mast cells infiltrate the intestine or liver, particularly in a severe form of the disease. Liver function tests may be elevated.
• Lymphoid tissues and spleen: The lymph nodes and spleen often are affected in all types of systemic mastocytosis. Lymph nodes enlargement can occur in 20 to 60% of patients with a mild form of the disease, and in most patients with severe forms of the disease. Enlarged spleen can be seen in half of patients with the mild form, and in over 70% of those with severe forms of systemic mastocytosis.

It is crucial to recognize and manage these symptoms to provide patients with the best possible care.

Testing for Systemic Mastocytosis

If doctors suspect you to be suffering from a condition associated with abnormal mast cells, different tests and evaluations will be undertaken to determine the exact issue you are facing. It all starts with the doctor gathering a complete medical history from you and conducting a detailed review of your symptoms. Triggers of mast cell activation, such as NSAIDs (non-steroidal anti-inflammatory drugs), heat, opioids (painkillers), anesthetics, anxiety and stress among others need to be documented. The doctor will also ask if you have ever previously experienced severe allergic reactions, known as anaphylaxis, in response to any specific foods, medications or other triggers which required epinephrine, a medicine used in severe allergic reactions.

Some tests that will be performed include:

• A complete blood count, and tests that assess how well your kidney and liver are functioning. Other tests will measure levels of tryptase (a chemical released by mast cells), albumin, and calcium in the blood.
• A bone marrow examination — this is where a small sample of your bone marrow is taken and tested. The tests will look for signs of disease and will also check for certain genetic changes (CD25, tryptase, and KIT mutations).
• A bone density test — this measures how strong your bones are, as people with systemic mastocytosis (a disorder caused by too many mast cells) have a higher risk of developing poor bone health.

Depending on your symptoms, additional procedures can be performed:

• A CT scan of your abdomen might be necessary if there are abnormalities in your blood count, or if you have an enlarged liver or spleen, or swollen lymph nodes.
• If you are experiencing any gastrointestinal symptoms, an endoscopy might be performed. An endoscope is a flexible tube that can be passed through your mouth and down into your stomach to allow the doctor to see what might be causing your symptoms.
• Biopsies, or small sample collection, of liver and lymph nodes might be necessary if there are signs that the liver isn’t functioning properly or if you are showing symptoms related to these areas.

Once the tests and procedures are done, they can help diagnose a condition called systemic mastocytosis, according to the World Health Organization (WHO) criteria:

1. Major criterion: There are clusters of abnormal mast cells in the bone marrow or other tissues outside of the skin.
2. Minor criteria: High levels of tryptase in the blood, unusual expression of CD25 on mast cells, the presence of the KITD 816V mutation, or an unusually large number of abnormal mast cells.

For the diagnosis to be accurate, you need to meet one major and one minor criterion or three minor criteria.

Your doctor may also evaluate the function of your organs by looking for:

• B findings: Large amounts of mast cells in the bone marrow or unusually high levels of tryptase in the blood, or an enlarged liver, spleen or lymph nodes.
• C findings: Issues affecting your blood cells, visible enlargement of the liver or spleen, breaks or decay in the bones, or malabsorption issues due to mast cells affecting your gastrointestinal tract.

Treatment Options for Systemic Mastocytosis

Treatment for systemic mastocytosis, a condition that affects immune cells in the body, varies depending on the symptoms and subtypes of the condition.

Specific symptoms usually dictate treatment. For example:

• If you experience symptoms like flushed skin or itchiness, the use of antihistamines (medicines that are used to treat allergy symptoms) are recommended.
• Those who continue to suffer from these symptoms, despite using antihistamines, may benefit from a group of drugs called antileukotrienes.
• If you have regular bouts of severe allergic reactions (anaphylaxis) despite avoiding known triggers, you may need to carry injectable epinephrine (a medicine used to treat severe allergic reactions) with you at all times.
• Omalizumab, a drug that prevents a type of antibody called IgE from binding to immune cells, may be considered. It has been shown to reduce the frequency of anaphylaxis in certain individuals.
• Aspirin may help those experiencing prominent flushing (a feeling of warmth and redness in the skin) unresponsive to antihistamines, provided they can tolerate non-steroidal anti-inflammatory drugs (NSAIDs), a group of medicines commonly used to relieve pain and reduce inflammation.
• For those experiencing stomach problems, drugs like oral cromolyn sodium, H2 antihistamines, proton pump inhibitors (medicines that reduce the production of stomach acid), and orally administered glucocorticoids may be useful.
• If you have problems with weakening of bones (osteoporosis) and fractures, it’s advised to maintain a good daily intake of calcium and vitamin D. Certain drug combinations may also help.
• For those not responding to normal therapies, other options include low-dose maintenance glucocorticoids (a type of steroid hormone) or drugs that reduce the number of cells in the body (cytoreductive measures).

The chosen treatment can also depend on the specific type of systemic mastocytosis:

• Indolent or smoldering systemic mastocytosis: For these types, cytoreductive therapy can be considered if severe allergic reactions keep happening despite other treatments. However, this is viewed as a last resort.
• Aggressive systemic mastocytosis: For more aggressive forms of this condition, different drugs are recommended based on the type of genetic changes present in your body. In some cases, bone marrow transplant may be suitable.
• SM-AHN (systemic mastocytosis with an associated hematologic neoplasm): For this type, treatment mainly targets the associated blood disorder. After initial treatment, a type of stem cell transplant may be considered for ongoing maintenance.
• Mast cell leukemia: With this type, there’s no standard treatment method, and it generally has a poor prognosis.

If you also have an allergy to insect venom, venom immunotherapy (a treatment designed to reduce your body’s allergic response to venom) can help reduce the risk of future severe allergic reactions.

What else can Systemic Mastocytosis be?

Systemic mastocytosis, a condition that affects many body systems, can be confused with several other conditions. These include:

• Carcinoid syndrome
• VIPoma (a rare type of pancreatic tumor)
• Zollinger-Ellison syndrome (a medical condition affecting the stomach)
• Acute urticaria (sudden hives or skin rash)
• Inflammatory bowel disease
• Irritable bowel syndrome
• Malabsorption (a condition that disrupts normal digestion)
• Myeloproliferative disease (a group of blood cancers)

What to expect with Systemic Mastocytosis

The type of systemic mastocytosis a person has is one of the most important factors in predicting how the disease will progress.

Systemic mastocytosis is a condition where mast cells, a type of white blood cell, build up in different parts of the body like skin, bone marrow and internal organs. Some characteristics of this disease can increase the risk of death due to the disease getting worse, no matter which type of systemic mastocytosis a patient has. These characteristics include:

1) Low platelet count: Platelets are small blood cells that help stop bleeding. A count less than 150 × 10/l indicates a low level.

2) Low level of serum albumin: Albumin is a protein in your blood. If the level falls under 35 g/L, this is considered low and could indicate a problem.

3) Low hemoglobin levels: Hemoglobin is the part of your red blood cells that carries oxygen. If you have less than 100 g/L or require a transfusion of red blood cells, your levels are considered low.

4) High level of lactate dehydrogenase (LDH): LDH is an enzyme found in many body tissues. An elevated level can indicate tissue damage.

5) Older age at the start of systemic symptoms: Those who begin showing symptoms over the age of 60 have a higher risk.

6) High level of alkaline phosphatase: This is an enzyme found in your liver, bones, and other tissues. A high level could indicate disease.

7) Enlargement of the liver and spleen, also known as hepatosplenomegaly.

8) Ascites, which is the build-up of fluid in the abdominal cavity.

9) Too many immature white blood cells, called blasts, in the bone marrow.

10) Weight loss

11) If you have a mutation, or change, in a specific gene called ASXL1, you could have a higher risk.

Possible Complications When Diagnosed with Systemic Mastocytosis

Systemic mastocytosis is a disorder that has been linked to several other health conditions. These include:

• Monoclonal gammopathy, a condition where the body produces too many abnormal white blood cells
• Hairy cell leukemia, a rare type of blood and bone marrow cancer
• Non-Hodgkin lymphoma, a group of blood cancers
• Polycythemia vera, a slow-growing blood cancer
• Primary thrombocythemia, a disorder that leads to high platelet levels
• Anemia, a condition characterized by a lack of healthy red blood cells
• Hepatosplenomegaly, a condition where both the liver and spleen swell
• Hypereosinophilic syndrome, a disease characterized by high counts of a type of white blood cell
• Castleman syndrome, a rare disease that affects the lymph nodes
• Coagulopathy, a condition that affects the blood’s ability to clot properly
• Recurrent anaphylaxis, repeated severe and rapid allergic reactions

Preventing Systemic Mastocytosis