Mastocytosis

Mastocytosis is a group of rare disorders of both children and adults caused by the presence of too many mast cells (mastocytes) and CD34+ mast cell precursors in a person's body.

Pathophysiology
Mast cells are located in connective tissue, including the skin, the linings of the stomach and intestine, and other sites. They play an important role in helping defend these tissues from disease. By releasing chemical "alarms" such as histamine, mast cells attract other key players of the immune defense system to areas of the body where they are needed.

Mast cells seem to have other roles as well. Because they gather together around wounds, mast cells may play a part in wound healing. For example, the typical itching felt around a healing scab may be caused by histamine released by mast cells. Researchers also think mast cells may have a role in the growth of blood vessels (angiogenesis). No one with too few or no mast cells has been found, which indicates to some scientists that we may not be able to survive with too few mast cells.

Mast cells express a cell surface receptor termed c-kit (CD117), which is the receptor for scf (stem cell factor). In laboratory studies, scf appears to be important for the proliferation of mast cells, and inhibiting the tyrosine kinase receptor with imatinib (see below) may reduce the symptoms of mastocytosis.

Classification
Mastocytosis can occur in a variety of forms.


 * Most cases are cutaneous (confined to the skin only). There are several forms of cutaneous mastocytosis. The most common is called urticaria pigmentosa (UP). It is most common in children. Telangiectasia Macularis Eruptiva Perstans (TMEP) is a much rarer form of cutaneous mastocytosis that affects adults.


 * Systemic mastocytosis involves the internal organs, usually in addition to involving the skin. Mast cells collect in various tissues and can affect organs such as the liver, spleen, lymph nodes, and bone marrow.
 * Other types of mast cell disease include:
 * Mast cell leukemia
 * Mast cell sarcoma

History
Scientists first described urticaria pigmentosa in 1869. Systemic mastocytosis was first reported by scientists in 1936.

Symptoms
When too many mast cells exist in a person's body and undergo degranulation, the additional chemicals can cause a number of symptoms which can vary over time and can range in intensity from mild to severe. Because mast cells play a role in allergic reactions, the symptoms of mastocytosis often are similar to the symptoms of an allergic reaction. They may include, but are not limited to:
 * Fatigue
 * Skin lesions (urticaria pigmentosa) and Itching
 * Abdominal discomfort
 * Nausea and vomiting
 * Diarrhea
 * Food and drug intolerance
 * Olfactive intolerance
 * Infections (bronchitis, rhinitis, and conjunctivitis)
 * Ear/nose/throat inflammation
 * Anaphylaxis (shock from allergic or immune causes)
 * Episodes of very low blood pressure (including shock and faintness)
 * Bone or muscle pain
 * Decreased bone density
 * headache
 * Ocular discomfort
 * Malabsorption

Diagnosis
Doctors can diagnose urticaria pigmentosa (cutaneous mastocytosis, see above) by seeing the characteristic lesions that are dark-brown and fixed. A small skin sample (biopsy) may help confirm the diagnosis.

By taking a biopsy from a different organ, such as the bone marrow, the doctor can diagnose systemic mastocytosis. Using special techniques on a bone marrow sample, the doctor looks for an increase in mast cells. Another sign of this disorder is high levels of certain mast-cell chemicals and proteins in a person's blood and sometimes in the urine.

Epidemiology
No one is sure how many people have either type of mastocytosis, but mastocytosis generally has been considered to be an "orphan disease" (orphan diseases affect 200,000 or fewer people in the United States). Mastocytosis, however, often may be misdiagnosed, and occur more frequently than assumed.

Treatment
There is currently no cure for mastocytosis. However, there are a number of medicines to help treat the symptoms of mastocytosis:
 * Antihistamines block receptors targeted by histamine released from mast cells. Both H1 and H2 blockers may be helpful.
 * Leukotriene antagonists block receptors targeted by leukotrienes released from mast cells.
 * Mast cell stabilizers help prevent mast cells from releasing their chemical contents. Cromolyn Sodium Oral Solution (Gastrocrom / Cromoglicate) is the only medicine specifically approved by the U.S. FDA for the treatment of mastocytosis. Ketotifen is available in Canada and Europe, but is only available in the U.S. as eye drops (Zaditor).
 * Proton pump inhibitors help reduce production of gastric acid, which is often increased in patients with mastocytosis. Excess gastric acid can harm the stomach, esophagus, and small intestine.
 * Epinephrine constricts blood vessels and opens airways to maintain adequate circulation and ventilation when excessive mast cell degranulation has caused anaphylaxis.
 * Albuterol and other beta-2 agonists open airways that can constrict in the presence of histamine.
 * Corticosteroids can be used topically, inhaled, or systemically to reduce inflammation associated with mastocytosis.


 * Antidepressants are an important and often overlooked tool in the treatment of mastocytosis. The stress and physical discomfort of any chronic disease may increase the likelihood of a patient developing depression. Depression and other neurological symptoms have been noted in mastocytosis. Some antidepressants such as doxepin are themselves potent antihistamines and can help relieve physical as well as cognitive symptoms.


 * Dihydropyridines are calcium channel blockers that are sometimes used to treat high blood pressure. At least one clinical study suggested that Nifedipine, one of the dihydropyridines, may reduce mast cell degranulation in patients that exhibit urticaria pigmentosa. A 1984 study by Fairly et al. included a patient with symptomatic urticaria pigmentosa who responded to nifedipine at dose of 10 mg po tid. However, Nifetipine has never been approved by the FDA for treatment of mastocytosis.

In rare cases in which mastocytosis is cancerous or associated with a blood disorder, the patient may have to use steroids and/or chemotherapy. The novel agent imatinib (Glivec or Gleevec) has been found to be effective in certain types of mastocytosis.

There are clinical trials currently underway testing stem cell transplants as a form of treatment.

There are support groups for persons suffering from mastocytosis. Involvement can be emotionally therapeutic for some patients.

Research
National Institute of Allergy and Infectious Diseases (NIAID) scientists have been studying and treating patients with mastocytosis for several years at the National Institutes of Health (NIH) Clinical Center.

Some of the most important research advances for this rare disorder include improved diagnosis of mast cell disease and identification of growth factors and genetic mechanisms responsible for increased mast cell production. Researchers are currently evaluating approaches to improve ways to treat mastocytosis.

Scientists also are focusing on identifying disease-associated mutations (changes in genes). NIH scientists have identified some mutations, which may help researchers understand the causes of mastocytosis, improve diagnosis, and develop better treatments.