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.