The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 69

83. Are there any supplements that help manage mast cell symptoms?

  • Yes.
  • Mast cell patients are often vitamin or mineral deficient.
  • Iron deficiency is extremely common. This is likely due to anemia of chronic inflammation. Basically, if your body is inflamed long enough, your body hoards the iron and stops moving it from your GI tract into your bloodstream where it can be used. Iron supplements are pretty harsh so patients don’t always tolerate oral supplements. IV iron is an option if your iron is low enough. I personally like the Lucky Iron Fish for increasing iron. It’s pretty neat.
  • Many mast cell patients are magnesium deficient. The exact cause of this is unknown. Lots of us take magnesium supplements.
  • For reasons that aren’t clear, a lot of mast cell patients are vitamin D deficient. Vitamin D acts on mast cells. There is some evidence to suggest that vitamin D can decrease mast cell activation. I personally found that effectively supplementing vitamin D has helped me a lot. A lot of symptoms I blamed on mast cell disease were actually vitamin D deficiency.
  • A number of supplements can decrease mast cell activation or block the action of mast cell mediators. There are a ton of natural mast cell stabilizers. They are sometimes used to help patients manage symptoms, especially in Traditional Chinese Medicine, which in recent years has been studied in clinical trials. Quercetin and resveratrol are commonly used by mast cell patients.
  • I take turmeric daily to reduce inflammation. Turmeric or curcumin can decrease prostaglandin production.
  • Holy Basil is a popular supplement in the mast cell community. It also decreases prostaglandin production. It can also block the histamine H2 receptor. While I often see people say that holy basil is as effective as an H2 blocker as H2 antihistamines like ranitidine or famotidine, I have never been able to find any evidence that this is true. But it does definitely have some ability to block the histamine H2 receptor.
  • Vitamin B12 deficiency sometimes occurs in mast cell patients, especially those with mast cell activation syndrome. This can have some interplay with MTHFR mutations, which can affect the form of vitamin B12 best suited to your body.
  • Vitamin C decreases the amount of histamine released by mast cells. It is recommended by some prominent mast cell researchers and many patients respond well.
  • Alpha lipoic acid is sometimes used, particularly for neurologic symptoms and neurologic pain.
  • I’m not sure if CBD oil is considered a supplement but it is widely used with excellent results. Be aware that the popular notion that marijuana derivatives do not interact with any medications is inaccurate. It especially can interact with tricyclic antidepressants to cause dangerous tachycardia.
  • Keep in mind that all supplements have the potential to interact with medications or to affect a person adversely if they have certain diseases. Exactly how much this happens is hard to pinpoint because over the counter supplements are held to a much lower standard for this type of study than FDA approved medications.
  • Always discuss any supplements you plan to try with your managing provider. Vitamins and minerals can cause toxicity and too much can cause very serious side effects and complications.
  • Do not assume that just because something is derived from nature, or because it is available without a prescription, that something is automatically safer for you than medications.
  • This is not really in my wheelhouse so I would encourage you to ask other patients what has helped them or to consult with a nutritionist.

For additional reading, please visit the following posts:

Effect of vitamin D on mast cells
Naturally occurring mast cell stabilizers: Part 1
Naturally occurring mast cell stabilizers: Part 2
Naturally occurring mast cell stabilizers: Part 3
Naturally occurring mast cell stabilizers: Part 4
The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 19
MTHFR, folate metabolism and methylation

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

Interplay between mast cells and hormones: Part 4 of 8

Hormone Location released Major functions Interaction with mast cells Reference
Ghrelin Stomach, jejunum, duodenum, colon, brain, lungs, liver, adipose tissue, placenta, lymphatic system Stimulate appetite

Can cross BBB

Induced mast cell degranulation

Dose dependently induced histamine release

Inhibits many inflammatory molecules, like TNF, IL-8, MCP-1, IL-1b, IL-6, CRP, IL-12, VCAM-1, MMP2, MMP9, GM-CSF and IL-17

Opposes action of leptin, a mast cell mediator

Level is increased by lack of sleep, promoting excessive hunger.

Hirayama T, et al. Ghrelin and obestatin promote the allergic action in rat peritoneal mast cells as basic secretagogues. Peptides 2010: 31(11), 2109-2113.

Baatar D, et al. The effects of ghrelin on inflammation and the immune system. Molecular and Cellular Endocrinology 2011: 340(1), 44-58.

Glucagon Pancreas Regulates amount of available glucose

Triggers breakdown of glycogen and production of glucose in liver, raising blood sugar

Released when blood sugar is too low

Can increase level of cAMP in myocardium to overcome effect of beta blockers

Anecdotal reports that glucagon may be able to relax esophagus sphincter to pass impacted food

 

 

In anaphylaxis patients on beta blockers, glucagon can be used to reduce resistance to epinephrine and increase blood pressure

May be considered to treat Kounis Syndrome where epinephrine is contraindicated

Histamine H3 receptor may regulate glucagon release from pancreas

 

Nakamura T, et al. Role of histamine H3 receptor in glucagon secreting aTC1.6 cells. FEBS Open Bio 2015: 5, 36-41.

Thomas M, Crawford I. Glucagon infusion in refractory anaphylactic shock in patients on beta blockers. Emerg Med J 2005: 22, 272-276.

Glucagon-like peptide 1 (GLP-1) Small intestine Increases release of insulin and nausea

Decreases release of glucagon, desire to eat and amount of food consumed

Increases anxiety

 

Possible relationship   between GLP-1 and histamine in the brain, but still unclear

GLP-1 level is modulated by leptin, a mast cell mediator Increases ACTH and cortisol

Gotoh K, et al. Glucagon-like peptide-1, corticotropin-releasing hormone, and hypothalamic neuronal histamine interact in the leptin-signaling pathway to regulate feeding behavior. FASEB J 2005: 19(9), 1131-1133.
Gonadotropin releasing hormone Hypothalamus Stimulate FSH and LH release from pituitary

Part of HPG axis

Drive secondary sex characteristics

Regulate sex hormone release

Histamine induces GnRH release in some studies Noris G, et al. Histamine directly stimulates gonadotropin-releasing hormone secretion from GT1-1 cells via H1 receptors coupled to phosphoinositide hydrolysis. Endrocrinology 1995: 136(7), 2967-2974.
Growth hormone releasing hormone Hypothalamus Stimulate growth hormone release from pituitary

Regulates bone growth

Regulates metabolism of proteins, carbohydrates and lipids

Induces mast cell degranulation and release of serotonin and histamine, causing low blood pressure Macia RA, et al. Hypotension induced by growth hormone releasing peptide is mediated by mast cell serotonin release in the rat. Toxicology and Applied Pharmacology 1990: 104(3), 403-410.
Hepcidin Liver Decreases iron absorption in intestines

Decreases iron release by macrophages

Chronic inflammation causes elevated hepcidin, making iron less available. This is called anemia of chronic inflammation. Weiss G. Anemia of chronic disorders: new diagnostic tools and new treatment strategies. Seminars in Hematology 2015: 52(4), 313-320.
Human chorionic gonadotropin (HCG) Placenta Maintains hormone release in ovaries during pregnancy

Inhibition of immune defense against fetus

Not known to directly affect mast cell activation or histamine release Schumacher A, et al. Endocrine factors modulating immune responses in pregnancy. Front Immunol 2014: 5, 196.

 

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. 

References:
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.

Metabolic issues associated with MCAS

MCAS patients often have a whole host of metabolic irregularities.  Abnormal levels of electrolytes are very common, as are mild increases in liver function tests, including aspartate transaminase, alanine transaminase and alkaline phosphatase.  Magnesium levels low enough to cause symptoms is not common, although the reason for this is not known.
Vitamin D deficiency is often present in MCAS.  In one study looking at children with asthma, low vitamin D was correlated with decreased lung function and exercise sensitivity.  In MCAS patients, there is no obvious relation to osteoporosis.  Many people receive vitamin D supplements to correct low levels, but it is not clear if there is any benefit to this.

Hypothyroidism (including Hashimoto’s thyroiditis) and elevated levels of TSH are often seen in MCAS patients.  Previous studies have linked hypothyroidism to increased mast cells in bone marrow.  In mice, TSH has shown to increase both the mast cell population in the thyroid and to trigger degranulation.  Hyperthyroidism is sometimes seen in MCAS patients, but much less frequently.  Antithyroid antibodies (TPO) are often high, sometimes extremely high, and sometimes without obvious clinical thyroid disease.

Hyperferritinemia is not unusual in mast cell disease, including MCAS.  18% of ISM patients have high serum levels of ferritin.  It is often misinterpreted as hemochromatosis, even in the absence of the HFE mutation.  MCAS patients with a history of red cell transfusion are often told they have hemosiderosis, even when serum ferritin is much higher than to be expected from hemosiderosis.  High ferritin in MCAS patients is probably secondary to systemic inflammation.  The widely variable nature of the ferritin levels is indicative of inflammation.
MCAS is also associated with obesity and diabetes mellitus (types I and II), all of which are systemic inflammatory conditions.  MCAS patients often have lipid abnormalities.  Hypertriglyceridemia is the most common presentation, but there are many variations.  Lipid issues that have been resistant to treatment with statins are often reversed quickly when MCAS patients are effectively managing their mast cell issues. 
MCAS is also heavily associated with metabolic syndrome.  (There will be a full post on this tomorrow.)

References:
Afrin, Larry B.  Presentation, diagnosis and management of mast cell activation syndrome.  2013.  Mast cells.
A Melander, C Owman, F Sundler.  TSH-induced appearance and stimulation of amine-containing mast cells in the mouse thyroid.  Endocrinology, 89 (1971), pp. 528–533

Siebler T, Robson H, Bromley M, Stevens DA, Shalet SM, Williams GR.  Thyroid status affects number and localization of thyroid hormone receptor expressing mast cells in bone marrow.  Bone. 2002 Jan;30(1):259-66.

Chinellato I, Piazza M, Sandri M, Peroni DG, Cardinale F, Piacentini GL, Boner AL.  Serum vitamin D levels and exercise-induced bronchoconstriction in children with asthma.  Eur Respir J. 2011 Jun;37(6):1366-70. 

Zhang J, Shi GP. Mast cells and metabolic syndrome. Biochim. Biophys. Acta 2012 Jan, 822(1):14-20.

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.

Reference:
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.