Erythromelalgia

Definition

The myeloproliferative diseases are four conditions-essential thrombocythemia, polycythemia vera, chronic myelocytic leukemia, and agnogenic myeloid metaplasia-characterized by overproduction of normal-looking blood cells.

Because chronic myelocytic leukemia has its own individual entry, it is not covered in depth in this entry.

Description

The prefix "myelo-" refers to marrow. Bone marrow, a reddish substance in the middle of some bones, produces blood cells. In the myeloproliferative diseases, the body makes too many blood cells. Blood contains red blood cells to carry oxygen, white blood cells to fight infections, and platelets to begin blood clotting. Myeloproliferative diseases develop when a myeloid progenitor cell-a cell that makes red blood cells, platelets, and certain types of white blood cells-becomes overactive. The abnormal progenitor cell continues to make normal blood cells, but it makes too many of them. This excess of blood cells results in varying symptoms, depending on the progenitor cell involved.

Other problems develop when some of the abnormal myeloid progenitor cells travel to the spleen, liver, or lymph nodes and begin making blood cells there. Most often, they migrate to the spleen. An enlarged spleen can crowd other organs in the abdomen and cause discomfort or digestive troubles. It is also susceptible to painful damage from blocked arteries. Massively swollen spleens can use large amounts of energy and cause muscle wasting and weight loss.

In the later stages of myeloproliferative diseases, the bone marrow can become scarred. This may leave no space for progenitor cells. As a result, blood cell production can drop to dangerously low levels. The abnormal progenitor cells may also mutate and develop into leukemia. These two serious complications are rare in some myeloproliferative diseases but very common in others.

Types of myeloproliferative disease

The four myeloproliferative diseases include essential thrombocythemia, polycythemia vera, chronic myelocytic leukemia, and agnogenic myeloid metaplasia.

In essential thrombocythemia (primary thrombocythemia), the myeloid progenitor cell makes too many platelets. Blood containing too many platelets may either clot too easily or too slowly. Blood that clots too easily can lead to a variety of health problems, including strokes or heart attacks. Blood that clots too slowly can cause symptoms such as easy bruising, frequent nosebleeds, bleeding from the gums, or life-threatening hemorrhages. Excessive numbers of platelets can also cause headaches or erythromelalgia, an unusual condition characterized by warmth, redness and pain in the hands or feet. Typically, patients with this disease have long periods without symptoms, interspersed with clotting or bleeding episodes. Some patients may have no symptoms at all. Rarely, this disease ends in scarring of the bone marrow or leukemia. Patients with bone marrow scarring have symptoms identical to agnogenic myeloid metaplasia.

In polycythemia vera (primary polycythemia, Vaquez disease), the bone marrow makes too many red blood cells. Large numbers of red blood cells can make the blood too thick. Viscous blood flows sluggishly, pools in the veins, and delivers oxygen poorly. Patients may experience headaches, dizziness, fatigue, chest pains, or weakness and cramping in the calves while walking. The abnormal blood flow can also result in bleeding tendencies or blood clotting inside the veins. Many patients also have increased numbers of white blood cells or platelets, but most symptoms are caused by the sluggish blood flow. The spleen often enlarges. Polycythemia rarely leads to leukemia, but occasionally ends in bone marrow scarring.

In chronic myelocytic leukemia (chronic myelogenous leukemia), the myeloid progenitor cell makes a type of white blood cell called a granulocyte. With this condition, platelets can also increase. In the early stages of this disease, the white blood cells look outwardly normal. However, in 90-95% of patients, two chromosomes-number 9 and number 22- inside the progenitor cell have broken and exchanged parts. This chromosome rearrangement is known as the Philadelphia chromosome, and this genetic abnormality destabilizes these cells and inevitably they become cancerous.

Agnogenic myeloid metaplasia (idiopathic myelofibrosis, myelofibrosis with myeloid metaplasia) begins like other myeloproliferative diseases, with overproduction of blood cells. However, bone marrow scarring develops very quickly and causes most of the symptoms. Blood cell numbers drop, causing fatigue and weakness from anemia. Many of the cells found in the blood are also immature or oddly shaped. Although myeloid progenitor cells in the spleen and liver can partly compensate, the enlargement of these organs creates additional problems. Occasionally, this disease also ends in leukemia.

Demographics

Essential thrombocytopenia, polycythemia vera, and agnogenic myeloid metaplasia are usually diagnosed late in life, at an average (median) age of 60.

Essential thrombocythemia may be slightly more common in women and agnogenic myeloid metaplasia and polycythemia vera slightly more common in men; however, estimates vary. At one time, polycythemia vera was thought to develop more often in Jews. More recent statistics do not confirm this.

Causes and symptoms

No consistent chromosomal abnormalities have been discovered in essential thrombocythemia, polycythemia vera, or agnogenic myeloid metaplasia. The causes of these diseases are unknown.

Myeloproliferative diseases share many features, such as enlargement of the spleen and abnormalities in blood clotting. Symptoms that can be seen in any of these diseases include:

• fatigue

• poor appetite (anorexia)

• weight loss

• night sweats

• fullness in the stomach after eating only a small amount

• abdominal pain or discomfort, especially in the upper left side

• nosebleeds, bleeding from the gums, easy bruising, or intestinal bleeding

• symptoms of blood clots including strokes, heart attacks, pain and swelling in the legs, or difficulty breathing

• disturbances in vision

Other symptoms of essential thrombocythemia can include:

• weakness

• dizziness

• headaches

• prickling or tingling in the skin

• erythromelalgia (warmth, redness, and pain in the extremities)

Other symptoms of polycythemia vera can include:

• headaches

• dizziness

• ringing in the ears

• pain in the chest (angina)

• weakness or cramping pains in the legs that disappear during rest

• redness of the face

• a blue tinge to the skin and other body surfaces (cyanosis)

• high blood pressure

• itching, especially after a warm bath or shower

• tingling or prickling of the skin

• erythromelalgia

• ulcers

• kidney stones

• gout

Other symptoms of agnogenic myeloid metaplasia can include:

• fever

• gout

• bone pain

Diagnosis

The diagnosis of a myeloproliferative disease relies mainly on a physical examination, examination of a blood sample, and sometimes a bone marrow biopsy. In the blood samples, the doctor will find excessive numbers of the cells characteristic of each disease. Chromosome studies on the blood can often distinguish chronic myelocytic leukemia from the other three diseases. Bone marrow samples reveal increased cell production and sometimes scarring. An enlarged spleen can often be detected during a physical examination, but occasionally ultrasound or computed tomography scans may be necessary.

Myeloproliferative diseases can resemble normal reactions to infections and other diseases. Various tests may be done to rule out such diseases.

Clinical staging, treatments, and prognosis

Staging

There is no staging system for essential thrombocythemia, polycythemia vera, or agnogenic myeloid metaplasia.

Treatments

Essential thrombocythemia

Treatments for essential thrombocythemia lower the risk of bleeding or blood clots. One option is hydroxyurea (Hydrea), a drug that suppresses platelet production. Hydroxyurea has few side effects but can occasionally cause a rash, intestinal upsets, sores on the skin, or a fever. This drug may also slightly increase the risk of leukemia. Anagrelide (Agrylin), an alternative, is effective in more than 90% of patients. It does not promote leukemia but can cause dizziness, headaches, fluid retention, rapid heartbeats, diarrhea, and rare cases of heart failure. Hydroxyurea and anagrelide both increase the risk of miscarriages during the first trimester in pregnant women.

A patient under 60 who has never had a blood clot has a 3% chance of developing one in the future. Some doctors recommend treatment for these patients only during high-risk situations such as surgery. Low doses of aspirin are sometimes used to control symptoms such as erythromelalgia.

Polycythemia vera

Periodically removing small amounts of blood, called phlebotomy, is a safe and very effective way to treat polycythemia vera. In some studies, phlebotomy has increased the risk of blood clotting. However, this may not occur when the hematocrit (the percentage of red blood cells in the blood) is kept below 45% in men and 43% in women. Phlebotomy can result in symptoms of iron deficiency such as abnormal food cravings (particularly a craving for ice).

Patients who are unlikely to develop blood clots may not need any other treatments. Patients with a higher risk of clotting are sometimes given hydroxyurea. This drug has relatively few side effects, but it may increase the chance of developing leukemia. In some studies, 3-5% of patients taking hydroxyurea eventually developed leukemia, compared to 1.5-2% treated with phlebotomy alone. Alternatives to hydroxyurea include interferon alpha and anagrelide. These drugs do not increase the risk of leukemia, but they tend to have more side effects. Interferon alpha may be particularly difficult to tolerate. Its side effects include flu-like symptoms (fever, chills, postnasal drip and poor appetite), fatigue, weight loss, depression, insomnia, memory loss, and nausea.

Radioactive phosphorus is used mainly in elderly patients who do not expect to need many years of treatment. In 80-90% of patients, this treatment can suppress the disease symptoms for six months to several years. However, up to 17% of patients develop leukemia within 15 years.

Other symptoms of polycythemia vera are treated with a variety of drugs. Itching is sometimes suppressed by phlebotomy, but antihistamines are often needed as well. Other options include extracorporeal photochemotherapy, hydroxyurea, or interferon alpha. Allopurinol (Zyloprim) prevents kidney stones and gout. Aspirin can suppress the symptoms of erythromelalgia.

One of the most difficult complications to treat is enlargement of the spleen. In the early stages of the disease, this enlargement can often be controlled by phlebotomy. Later, interferon alpha, hydroxyurea, or surgical removal may be necessary. Surgery to remove a very large spleen is difficult and can be fatal in up to 10% of patients. Complications can include infections, bleeding, serious blood clotting, or increased numbers of white blood cells and platelets. Radiation treatments directed at the spleen may be another option, but they can suppress the bone marrow.

Agnogenic myeloid metaplasia

Agnogenic myeloid metaplasia can be cured by a bone marrow transplant from a healthy donor. In patients eligible for this treatment, it is successful in about a third. Bone marrow transplantation may not be feasible for many patients, particularly those who are older or in poor health. This procedure can have serious or fatal complications including infections, organ damage, and bleeding. In addition, compatible donors are not available for all patients.

Other treatments for this disease are not curative and are mainly intended to improve the quality of life. Anemia is often treated with regular transfusions of red blood cells. Adverse effects can include heart failure or damage to the liver from excess iron. Drugs can sometimes make red blood cells last longer. Corticosteroids combined with an androgen (fluoxymesterone) are effective in about a third of all patients. Danazol, another androgen, works in about 20%. These drugs may damage the liver and can produce masculine traits in women. Injections of erythropoietin, a hormone that stimulates red blood cell production, also work in a few patients.

About half of all patients with anemia improve after surgical removal of the spleen (splenectomy). This surgery can also help patients who have abdominal discomfort, weight loss, muscle wasting, or high blood pressure in the liver. However, it can be dangerous and sometimes fatal. Removal of the spleen may make the disease progress more quickly, but this is not certain.

A painfully enlarged spleen can also be treated with hydroxyurea, interferon alpha, or radiation treatments. Hydroxyurea has few side effects, but it may increase the risk of leukemia. Interferon alpha shrinks the spleen in 30-50% of patients, but has many side effects. Radiation treatments can decrease the symptoms for three to six months, but sometimes fatally suppress the blood-producing cells.

Prognosis

Patients with essential thrombocythemia can expect a near normal life-span. Average (median) survival is 12 to 15 years. The chance of developing either leukemia or serious scarring of the bone marrow is less than 5%.

Without treatment, patients with polycythemia vera usually die from bleeding or blood clotting within months. With treatment, average (median) survival is about 10 years in older patients and more than 15 years in younger patients. Many patients can reach their normal life expectancy if they do not develop bone marrow scarring or leukemia. The risk of bone marrow scarring after 10 years is approximately 15-20%. If polycythemia vera is treated with phlebotomy alone, the risk of developing leukemia is 2%.

Unless they receive a successful bone marrow transplant, most patients with agnogenic myeloid metaplasia become progressively worse. The anemia becomes more severe and the liver and spleen continue to swell. Average (median) survival in this disease is 3.5 to 5.5 years, but survival is often unpredictable and may be much longer or much shorter. Leukemia develops in about 5-20% of patients. In other patients, death occurs from heart failure, infections, bleeding or blood clots.

Alternative and complementary therapies

In traditional Chinese and Japanese medicine, herbal preparations are used to treat symptoms of chronic illnesses such as fatigue, loss of appetite, and night sweats, or to decrease red blood cell formation in polycythemia vera. Patients who are interested in non-traditional complementary remedies should discuss them with their doctor. Some may have dangerous side effects or be harmful when combined with traditional therapies.

Coping with cancer treatment

Acetaminophen and antidepressant drugs can help reduce some of the side effects of interferon alpha. Taking this drug at night may also make it easier to tolerate.

Clinical trials

The following therapies are being tested in clinical trials. Patients should check with their medical insurers before enrolling in a clinical trial. Insurers may not pay for some treatments but this varies with the insurer and each individual case.

Interferon alpha injections are being tested in essential thrombocythemia. This drug can lower platelet numbers and decrease the size of the spleen in about 80% of patients.

Several new drugs are in clinical trials. Thalidomide and SU5416 are being tested in patients with agnogenic myeloid metaplasia. R115777 and 12-O-tetradecanoylphorbol-13-acetate (TPA) are in clinical trials open to patients with various myeloproliferative diseases.

Another possible treatment for agnogenic myeloid metaplasia is to purify the normal progenitor cells and return them to the body after destroying the abnormal progenitor cells with chemotherapy.

Prevention

The following environmental factors have been linked to myeloproliferative diseases:

• working as an electrician or in a petroleum manufacturing plant

• prolonged use of dark hair dyes

• exposure to nuclear bomb blasts or thorium dioxide

Special concerns

Whether polycythemia vera, essential thrombocythemia, and agnogenic myeloid metaplasia progress to leukemia is influenced by the specific treatment strategies. Patients should be aware that some treatments, particularly radioactive phosphorus, can substantially increase the risk of developing cancer.

KEY TERMS

Androgen

A drug related to the male sex hormones.

Autoimmune disease

A disease that develops when white blood cells attack normal cells or organs.

Biopsy

A sample of an organ taken to look for abnormalities. Also, the technique used to take such samples.

Bone marrow

A group of cells and molecules found in the centers of some bones. It makes all of the cells found in the blood.

Computed tomography (CT)

A special x-ray technique that produces a cross-sectional image of the organs inside the body.

Corticosteroids

A class of drugs, related to hormones naturally found in the body, that suppresses the immune system. One example is prednisone, sold under many brand names including Deltasone.

Erythromelalgia

A condition characterized by warmth, redness and pain in the hands and especially the feet.

Erythropoietin

A drug that stimulates the bone marrow to make more red blood cells. It is also known as epoetin alfa.

Extracorporeal photochemotherapy

A technique in which the white blood cells are exposed to a chemical called a psoralen, temporarily separated from the rest of the blood and treated with UVA light, then returned to the body.

Gout

A painful swelling of the joints that results from an accumulation of uric acid. This disease often affects the big toe.

Granulocyte

One of three types of white blood cells (neutrophils, eosinophils, and basophils) that contain visible granules.

Lymph node

A small organ full of white blood cells, found in clusters throughout the body. Lymph nodes are where reactions to infections usually begin.

Median

A type of average. The median is the number in the middle of a sequence of numbers.

Myeloid progenitor cell

A cell normally found in the bone marrow that makes red blood cells, platelets, and some white blood cells (granulocytes and monocytes).

Phlebotomy

The removal of blood.

Platelets

Tiny fragments of cells that begin the blood clotting process. They are found in the blood.

Red blood cells

The cells in the blood that carry oxygen.

Spleen

An organ in the abdomen near the stomach. The spleen makes white blood cells, stores red blood cells, and removes old blood cells from the circulation.

Transfusion

A transfer of blood or blood products from one person to another.

Ultrasound

A technique that uses sound waves to form an image of organs inside the body.

White blood cells

The cells in the blood that fight infections. There are several types of white blood cells. Also known as immune cells.

QUESTIONS TO ASK THE DOCTOR
• Does my condition require treatment?

• What treatment would you recommend I try?

• What risks and side effects should I expect?

• How will it affect my quality of life?

• Are there any alternative treatments that might work equally well?

• Are there any activities I should avoid? For how long?

• Are there any symptoms I should watch for? Who should I contact if I experience them? How urgent is it to let someone know immediately?