The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 19

I answered the 107 questions I have been asked most in the last four years. No jargon. No terminology. Just answers.

28. Why are so many mast cell patients anemic?
• Anemia occurs when a person has too few red blood cells or not enough hemoglobin. Red blood cells are essentially envelopes that serve specifically to hold hemoglobin. Hemoglobin is a molecule made with iron that picks up oxygen. When you have either too few red blood cells or they don’t have enough hemoglobin, not enough oxygen gets to all the parts of the body that need it.
Patients with chronic illness of many kinds often have anemia. This is called anemia of chronic inflammation or anemia of inflammatory response.
• This type of anemia occurs because of the overactivity of a hormone called hepcidin. This hormone tells cells in the GI tract to hold onto any iron they find. This means they do not pass the iron along to the blood so it can make hemoglobin. Since the body isn’t making enough hemoglobin, the body doesn’t get enough oxygen.
• Mast cell patients often have anemia of chronic inflammation so they may be anemic regardless of how much iron they have in their diet. However, increased supplementation sometimes helps.
• There are several forms of iron that can be taken by mouth. IV iron is also an option. Some people have luck cooking in cast iron pans or using the “Lucky Iron Fish” to get even more iron into their diet in hopes that they can take up a little bit more.
Having enough iron available also decreases mast cell activation. Mast cells make smaller amounts of inflammatory molecules when the body has sufficient iron.
• Mast cell patients may also selectively malabsorb iron in their GI tracts. This means that even if they are absorbing enough of other nutrients, they may not absorb enough iron properly due to inflammation. This sometimes improves with antihistamines.
• Mast cell patients usually take histamine H2 blockers. This decreases the strength of stomach acid which can affect absorption of nutrients like iron. Taking PPIs can do the same thing.
• Malabsorption of other nutrients, like copper, can contribute to anemia.
• Insufficient amounts of B12 or folate can cause also contribute to anemia.

For more detailed reading, please visit these posts:
Anemia of chronic inflammation
MCAS: Anemia and deficiencies
Effect of anemia on mast cells

Take home points: November 2015

Immunoglobulin free light chains: A possible link between autoimmune disease and mast cell activation

  • Light chains are part of antibodies that fight infections and responds to allergens
  • Free light chains are pieces of antibodies that broke off and do not work as antibodies
  • Elevation of immunoglobulin free light chains has been linked to many diseases, including lupus, rheumatoid arthritis, inflammatory bowel disease and food allergy
  • Free light chains correlate with symptom severity and flares in some conditions
  • Free light chains may be able to activate mast cells without IgE involvement
  • Free light chains may be the link between mast cell activation and autoimmune disease

Explain the tests: Complete blood count (CB) with differential and platelets (Part One)

  • A complete blood count (CBC) counts white blood cells, red blood cells and platelets in blood
  • It also looks at the shape, size and variation in size of cells

Explain the tests: Complete blood count (CBC) – Low red cell count (Part two)

  • Mature red blood cells live in the blood for 100-120 days
  • Hemolysis is when red blood cells burst and a little bit of hemolysis is normal
  • Red blood cells transport oxygen from lungs to tissues
  • Red blood cells have hemoglobin inside them
  • Hemoglobin is a protein with iron in the middle and it carries oxygen
  • Low red blood cell count or hemoglobin is called anemia
  • Red blood cell count can be low for several reasons, including nutritional deficiency and production dysregulation in bone marrow
  • Mast cell patients often suffer from anemia of chronic inflammation, which can cause low red count
  • Patients with inflammatory bowel disease can have low red count due to bleeding
  • Swelling of spleen can cause low red count

Explain the tests: Complete blood count (CBC) – Low red cell count (Part two)

The process of making red blood cells is called erythropoiesis.  Mature red cells live in the blood for 100-120 days before they die.  As they get older, red cells are removed from the blood stream.  A small amount of red cells burst in the blood stream before they are removed.  This is called hemolysis.  Most red cells are removed by special white cells called macrophages in the liver, spleen and lymph nodes.  When the production and destruction of red cells are not balanced, red cell count is abnormal.

Red blood cells (erythrocytes) are responsible for transporting oxygen from the lungs to the tissues.  Red blood cells have lots of hemoglobin inside their cells.  Hemoglobin is a protein that has a form of iron at its center called heme.  Hemoglobin binds oxygen so that it can be brought to other parts of the body.  When red blood cell count or hemoglobin is low, the body cannot get enough oxygen to the tissues.  This is called anemia.

A number of conditions can cause low red blood cell count.  They can be placed into three categories: not making enough red blood cells; breaking down too many red blood cells; and blood loss.  Additionally, changes in amount of fluid in the blood stream can artificially alter red blood cell and hemoglobin levels.

Normal range for red blood count:

  • Adult women: 3.9-5.0 million cells/µL
  • Adult men: 4.3-5.7 million cells/µL

Reasons for not making enough red blood cells:

  • Low levels of erythropoietin, a molecule that tells the bone marrow to make red cells
  • Deficiency or abnormality of hemoglobin
  • Nutritional deficiency
  • Damage to stem cells
  • Inability to make red cells from stem cells

Some conditions that interfere with making enough red blood cells:

  • Viral infections, such as parvovirus B19, herpes viruses and hepatitis. Some viruses induce pure red cell aplasia, which affects the cells that become red blood cells.
  • Overproliferation of white cells, such as lymphomas, leukemias, autoimmune lymphoproliferative disease. These conditions can also induce pure red cell aplasia. If too many of one cell type is in the bone marrow, it reduces the space for other cell types.  In this example, too many white cells are produced, so there is not enough space for red cells.
  • Myelodysplastic syndromes. In MDS, the stem cells that develop into blood cells are thought to harbor damaging mutations.  The process of making blood cells is very disordered in MDS.
  • Aplastic anemia. In aplastic anemia, blood stem cells are damaged.
  • Deficiency of vitamin B12, iron or folate. Iron deficiency interferes with production of hemoglobin, while B12 or folate deficiency prevents normal cell division to make new cells.
  • Chronic kidney disease. Kidney cells release erythropoietin to stimulate making new red cells.  If the kidney cells are damaged, they may release less erythropoietin.
  • Chronic inflammation. Chronic inflammation can interfere with absorption and use of iron.
  • Thalassemia causes hemoglobin to be misshapen.
  • Medications, like mycophenolate.

Reasons for increased destruction of red cells

  • Misshapen red cells
  • Abnormalities of red cell membranes
  • Hemoglobinopathies, conditions in which hemoglobin is defective
  • Attack by antibodies
  • Mechanical damage

Some conditions that cause increased destruction of red cells:

  • Hemolytic anemias. This is a general category that encompasses many conditions, including antibody mediated hemolysis, enzyme deficiencies and membrane abnormalities.
  • Membrane abnormalities, like in G6PD deficiency (favism). The membrane is weakened in this condition.
  • Hereditary spherocytosis and hereditary elliptocytosis. In these genetic conditions, red cells are misshapen.
  • Antibodies targeting red cells, such as autoimmune hemolytic anemia and transfusion reaction.
  • Hemoglobinopathies, like sickle cell disease and hemoglobin C disease. Enough hemoglobin is made, but it is structurally abnormal.
  • In this condition, there is a genetic mutation that interferes with production of hemoglobin.
  • Mechanical damage, such as in hemodialysis or malaria. In these conditions, the red cells die for physical reasons.

Reasons for blood loss

  • Trauma or surgery.
  • Gastrointestinal bleeding. This can be caused by inflammatory bowel disease, ulceration, varices or infection.
  • Excess blood loss due to menstruation or fibroids
  • Anemia of prematurity. This is caused by the need for frequent blood draws for testing coupled with low production of red cells by premature babies.

Situations that cause artificially low red blood cell count:

  • Pregnancy, due to increased blood volume.
  • Hypervolemia, from high water or sodium consumption or retention.
  • Hypervolemia, from recovery of third spaced fluids.


Special notes on low red cell count for mast cell patients:

  • Many mast cell patients suffer from anemia of chronic inflammation, which can result in low red cell count.
  • Some patients have inflammatory bowel disease, which can result in low red cell count.
  • Swelling of the spleen (splenomegaly) can cause low red cell count.  Splenomegaly is a B finding for SM patients.  Two B findings result in diagnosis with smoldering systemic mastocytosis (SSM).
  • Overactivity of the spleen (hypersplenism) can cause low red cell count.  Hypersplenism is a C finding for SM patients, resulting in diagnosis with aggressive systemic mastocytosis (ASM).
  • Use of some chemotherapy drugs can impair production of blood cells, including red cells.


MCAS: Anemia and deficiencies

Anemia is the most common issue affecting red blood cells in MCAS patients.  It can be macrocytic (big cells), normocytic (normal size), or microcytic.  Usually mild to moderate, but occasionally the diagnosis is mistaken for pure red cell aplasia on bone marrow examination.  When macrocytosis is predominant, BMB must be performed to rule out myelodysplastic syndrome (MDS.) 
Cobalamin deficiency is common, even when pernicious anemia is ruled out.  Copper deficiency is sometimes the cause for microcytic anemia, although in MCAS, it sometimes causes normocytic or macrocytic anemia.  This may be caused by absorption, but is also a side effect of overdose of zinc, a common ingredient in over the counter medications taken by MCAS patients to reduce symptoms. Folate deficiency is less frequently found in MCAS and is often due to hemolysis from an acquired condition like acquired chronic autoimmune hemolytic anemia, sometimes found to occur secondary to mast cell disease.  Other hemolytic conditions, like paroxysmal nocturnal hematouria, should be ruled out.
Many MCAS patients have selective iron malabsorption, which sometimes resolves with antihistamine treatment.  GI bleeds must be excluded.  Oral iron absorption tests can be done to test iron malabsorption.  A recent procedure calls for a blood sample to establish baseline plasma iron, administration of 100mg dose of oral sodium ferrous citrate, and another blood sample to test plasma iron two hours later.  Increase of less than 50 ug/dl is considered evidence of malabsorption.
Iron malabsorption can happen for several reasons in the context of MCAS.  Iron deficiency can be from MCAS immune dysfunction that leads to generation of antibodies against the acid secreting cells of the stomach.  When the concentration of stomach acid is too low (achlorhydria), the absorption of non heme dietary iron is dramatically reduced.   H2 antihistamines and PPI medications can interfere with iron absorpotion.   Hepcidin, the production of which is stimulated by mast cell mediators like IL-6 and TNFa, slows down the rate with which GI cells transfer the iron into the blood stream for use.
MCAS patients sometimes exhibit low serum iron and ferritin, but have normal MCV and RCDW, which indicates no deficiency is present.  This profile is thought to allude to correct transport of iron to the blood stream but poor utilization in the bone marrow. 

Afrin, Lawrence B. Presentation, diagnosis and management of mast cell activation syndrome.  2013.  Mast cells.
Kobune M, et al.  Establishment of a simple test for iron absorption from the gastrointestinal tract.  Int. J. hematol. 2011; 93:715-719.
Hitchinson C, et al. Proton pump inhibitors suppress absorption of dietary non-haem iron in hereditary hemochromatosis.  Gut 2007 Sep; 56(9):1291-1295.

Effect of anemia on mast cells

A paper released in September 2012 addressed the effect of iron availability on mast cell degranulation.
Inside the bodies of mice, it was observed that mice with decreased iron stores had more severe inflammatory reactions.  Importantly, iron supplementation decreased the severity of the inflammation, particularly in the context of allergic asthma.  Increased iron inhibited the production of inflammatory molecules in pulmonary tissues, including various interleukins and interferons. 
Outside of the body, mast cells were incubated with and without iron for 30 minutes.  IgE was then added to activate the mast cells.  The mast cells that were incubated with iron degranulated 30% less than those without iron present.  Spontaneous degranulation, without IgE crosslinking, was not affected.  The presence of iron also dramatically affected the production of inflammatory molecules by mast cells.  Production of TNF, MCP-1 and IL-6 decreased by 94%, 29% and 27%, respectively.  MCP-1 attracts macrophages. 
Iron supplementation decreased the severity of allergic asthma, and decreased mast cell degranulation by IgE crosslinking 30%, as well as decreasing production of inflammatory molecules by mast cells.

Hale LP, Kant EP, Greer PK, Foster WM (2012) Iron Supplementation Decreases Severity of Allergic Inflammation in Murine Lung. PLoS ONE 7(9): e45667. doi:10.1371/journal.pone.0045667

Anemia of chronic inflammation

Anemia is the condition of having either too few red blood cells or too little hemoglobin.  Hemoglobin is a protein found in red blood cells that transports oxygen.  Hemoglobin is one of the hemeproteins, meaning that it has an iron atom in the middle of a structural ring.  The iron allows hemoglobin to transport oxygen from the lungs to the capillaries, small blood vessels.  Thus, anemia can result in less than enough oxygen in the organs.  Iron status (how much iron a person has available for use) affects how well the body can oxygenate the tissues and generate energy.

Anemia is fairly common.  It is generally caused by blood loss, destroying too many blood cells (hemolysis) or not diminished hematopoiesis (the process of making red blood cells.)  Typical symptoms include weakness, fatigue, palness and shortness of breath.  More serious cases can cause heart palpitations, chest pain, fast heart rate and even heart failure.    There are many types of anemia.
One type of anemia is anemia of chronic disease, also called anemia of inflammatory response.  This type of anemia is seen in chronic illness.  In recent years, we have learned that this is most likely caused by overactivity of hepcidin, a hormone.  Hepcidin is the chief controller of iron levels in the body.  It can slow the body taking up iron from the diet and prevent iron from being released from its stores.
Overloading with iron will activate the body to make hepcidin.  This will result in a decrease in available iron, an increase of iron inside the cells that store it, and decreased absorption of iron in the gut.  Iron stores are composed mostly of cells in the reticuloendothelial system (RES), an older name for the mononuclear phagocyte system (MPS.)  These are cells that “eat” disease causing organisms, damaged cells or cellular debris, like macrophages.  Some of the cellular debris is pieces left over from broken down red blood cells, including heme.  Your body stores excess iron inside these cells to save for a time when it is needed. 
Your hepcidin level is regulated in response to many things, including anemia and inflammation.  Acute hemolysis, or destruction of red blood cells, from repeated blood draws decreased the amount of hepcidin your body made, even if the level was very high before.  This means that having blood drawn frequently signals to the body that it needs to keep its iron in its stores and shouldn’t take up any more from your diet.   
Acute inflammation decreases hepcidin, making iron more available.  But chronic inflammation increases hepcidin over 6X, making iron much less available to your body.  When your body is inflamed, its cells produce inflammatory molecules, like cytokines.  Some of these molecules, like IL-6, tell your liver to make more hepcidin.  If your body frequently sends out inflammatory signals, it can actually make it so that your cells are less able to release their iron.  It can also make your bone marrow less able to make red blood cells. 
When your body releases inflammatory cytokines, your body thinks it is fighting an infection.  These cytokines tell your body to make white blood cells, which your body thinks it needs to fight the infection.  White and red blood cells are made from the same stem cells in the bone marrow.  If the body is making more white cells, it is inherently making less red blood cells.  In this way, chronic inflammation increases the level of hepcidin, so the body keeps iron in its stores and stops absorbing additional iron, while also stimulating white blood cell production and decreasing red blood cell production. 
There are other ways in which decreased iron affects red blood cells, including interfering with the release of erythropoietin from the kidney.  This is the molecule that tells your bone marrow to make red blood cells.  When iron is deficient, the survival of red blood cells is also shorter.
So regardless of dietary iron intake, many people with chronic inflammation are functionally anemic.