The Good, The Bad, The Ugly, Histamine

Though the average person knows little about histamine besides the commonly prescribed "antihistamine" for seasonal allergies, they can cause many serious issues in those with a compromised body.  Because of the damage done through untreated, Chronic Lyme Disease, my body has become overrun with this important, yet very annoying compound that my cells are constantly releasing.  Despite what the results of any allergy blood test may or may not show, those with overactive histamine tend to react to practically anything from taste, touch, and even smell.  However, most doctors do not seem to take the statement “I’m allergic to everything” very well, and most people are left to deal with the debilitating symptoms alone.  
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What is Histamine? 

Chemically speaking, histamine is one of five biogenic amine neurotransmitters; dopamine, norepineprhine (noradrenaline), epinephrine (adrenaline), histamine, and serotonin.  From the decarboxylation group of the amino acid histidine, this small molecule is destroyed and thus regulated through the enzymes DAO (diamine oxidase) and HMT. Histamine is made throughout the bodies tissue, especially in the GI track, skin, and lungs.  However, it is also produced by the immune system as an inflammatory response. Histamine not only regulates immune reactions, but also the various cells involved; macrophages, dendritic, T-lymphocytes, B-lymphocytes, endothelial, antigen-specific Th1, and Th2.  Together, these various cells play a very important role in the bodies detoxification, vascular, and immune system.  While histamines are important parts of the human body, they can easily become a source of chronic inflammation, due to binding to receptors on these cells. This suppresses the cells from maturing, being active, and polarizing, which then alters their immune regulation, and further causing them to attack the body even when there is not a foreign substance present.  There are four known histamine receptors in the body that are found on different cells; H1, H2, H3, and H4.  These receptors are proteins throughout the body that bind with histamine to create certain effects.  H1 receptors are found on endothelial cells, H2 on gastric parietal cells, H3 in the central nervous system (CNS), and H4 on mast, eosinophils, T, and dendritic cells. 

Because there are more than one type of histamine receptor, treating those with histamine induced allergies can not simply be fixed by taking over the counter, antihistamine drugs such as Benadryl and Claritin (a diphenhydramine or loratadine).  Both of these pills only stop histamine from binding to H1 receptors, while the remaining H2, H3, and H4 are left unblocked and thus unrestrained.  Therefore, while one's itchy eyes might be gone, GI, brain, and immune system symptoms will still very likely be present. 

Receptor Overview 

In short, H1 receptors are involved in allergies that occur in the nasal airways and lung.  

They are found in blood vessels, smooth muscle tissue, the central nervous system, and heart.  Just one of many, hayfever is a perfect example of over-active H1 receptors, and can be treated by standard antihistamine drugs such as Benadryl, that block histamine from binding to these receptors.  Endothelial cells are also responsible for H1 receptor histamine release.  These cells supply all tissues throughout our body with blood through the lining of blood vessels.  Without these important cells, it would be impossible for tissue to grow and repair.  Because histamine is also a neurotransmitter that communicates with the brain, taking antihistamines cause the active receptors to be suppressed, simultaneously making you sleepy.   Other H1 antagonists that inhibit histamine action (or the enzyme that stops the enzyme histidine from making histamine) include, Zyertec, Zantac, and Allegra. 

H2

Histamine H2 receptors are found on gastric parietal cells, which produce hydrochloric acid (HCI) in the stomach.  Though too little can cause inadequate digestion, too much can create ulcers and peptic acid disease.  There are three types of stimulators that aid in acid secretion; acetylcholine, gastrin, and histamine H2 receptor (which is the primary modulator).  Therefore, if the amount of released histamine is low, then weak acid secretion will follow. H2  receptors are also on cells of the heart, uterus, and vascular, smooth muscles.  When histamine reacts with these, relaxation in the smooth muscles occur, causing veins to dilate, and altered bladder, intestine, and heart function.  However, when a H2 antihistamine is taken, pro-inflammatory antibodies, T cells, and cytokines are decreased, subsequently compromising the motility of the gut. 

H3

H3 histamine receptors (along with 1 and 2) play a large role in regulating neurotransmitter activity in our central nervous system (CNS). Through the TMS (tuberomammillary nucleus) that is located in the posterior hypothalamus, histamine is released, sending messages throughout the brain and exciting certain cells.  This increases wakefulness in an individual, thus significantly effecting one’s sleep and wake cycle, as well as daily brain function.  TMS neurons are ultimately responsible for memory, sleep, energy, arousal, learning, reaction time, and food consumption, as they are the sole source of histamine projection in the brain.  H3 receptor in particular, is thought to decrease the release of other brain neurotransmitters that control both skeletal and smooth muscles (acetylcholine), arousal (dopamine and norepinephrine), and drowsiness (serotonin), while simultaneously increasing H1 and H2 receptors.  It also controls activity of hormone secretion through the pituitary "master gland.”  High amounts of H3 histamine are also a major component of many neurodegenerative diseases, such as Alzheimer's, M.S, and Parkinson's, while low amounts cause seizure disorders like Epilepsy.   It can also be linked to neurotic actions, due to exciting NMDAR (N-methyl-D-aspartate receptors) that control memory function and strength or weakening of brain synapses. An example would be Chronic Lyme Disease, where Borrelia Burgdoferi spirochetes have been attacking the immune system for years, manifesting as both a neurological and autoimmune disease.  Severe neuroborreliosis (damaged CNS disorder) is just one outcome of untreated spirochetes, and has been shown to be directly linked with high histamine markers in the brain.  Doctors have found that herbal supplements and drugs (when needed) reduce histamine activity, and thus can help patients manage the resulting brain fog and congestion. 

H4

H4 receptors are located throughout the bodies mast cells, eosinophil cells, T cells, and dendritic cells, all of which regulate the immune system’s response.

Mast cells are in highest concentration where the body is exposed to external environment, such as the skin, yet are ultimately derived from bone marrow, and are present throughout the lining of the respiratory, digestive, urinary system, and blood vessels.   These cells play a large role in producing immediate allergic inflammation, followed by cytokine and chemokine production, which both act as messengers between cells that ultimately makes the inflammation chronic.   Mast cells also aid in fighting off various parasites, regulating the degree of which the immune system responds, repair of old vessels into new ones, tissue repair, and variety of allergic diseases (asthma, rhinitis, dermatitis, anaphylaxis, etc), due to controlling pro-inflammatory white blood cells (eosinophils), and thus causing over activity of histamine related immune responses. Out of the five immunoglubulin subtypes, Immunoglubulin E tends to bind to mast cell receptors,  which is why doctors typically test for overgrowth  through IgE blood tests. When an antigen cross links on the surface of mast cells, they react through releasing histamine and other bioactive mediators.  This causes conditions such as Mastocytosis, or MACD (Mass cell activation disorder).  However, IgE testing is not always accurate, as one can have a severely active mast cells regardless of what a test may indicate. 

H4 receptors also activate dendritic cells, which capture and process antigens, provide the body with various immune responses, and activate B and T lymphocyte cells, which together, serve as immunity mediators.  Interestingly enough, dendrite cells also minimize autoimmune responses, showing that they play a large role in manipulating the immune system. However, when histamine receptors bind to these cells, the opposite happens, causing inflammation. 

T cells, another type of white blood cell that find and destroy immune system invaders, gets its name for maturing in the thymus gland.  The subset helpers of this immune response cells are TH1 and TH2, which are involved in both autoimmune diseases as well as allergic reactions, through the secreting of cytokines (much like mast cells).  An example would be when IFN-gamma  production is up-regulated in T cells, causing the formation of eczema. 

All together, H4 receptors are what increase the amount of immune cells in inflammatory health issues including allergic reactions, both autoimmune and allergic diseases (asthma, colitis, RA, cancer, M.S., etc).  Therefore, not only do they control the original signal of inflammation, but also the maintenance. This means that, while they recruit mast cells to respond to the initial allergy, H4 receptors make this state of inflammation continue, or in other words, chronic.  

Rheumatoid arthritis, which is characterized by joint tissue inflammation, erosion, and destruction of cartilage, is just one disorder where histamine acts as a pro-inflammatory mediator.  Thus, how severe or long one’s RA is, can be linked back to H4 receptors on joint, collagen, and white blood cells, as well as on the blood vessel wall. 

Histamine Metabolism 

Histamine is regulated in the body through two major enzymes; DAO and HMT.

Histamine N-methyltransferase (HMT) is responsible for more than half of histamine control throughout the central nervous system (CNS) through converting the N-methyltransferase into N-methylhistamine, which de-activates the effects of the histamine molecule. Both endothelial and epithelial cells (which make up the tissue of skin and blood vessels) are found in the main respiratory system airways of the body and contain HMT enzymes.  Though a healthy human being creates enough HMT to degrade histamine and therefore regulate the function of those airways, insufficient amounts of this enzyme can cause constriction of the smooth muscles (bronchoconstriction), causing asthma symptoms.  

DAO

The remaining 30-45% of histamine in our body is metabolized through DAO, which is present mainly in the lining of our intestines, but also the liver, skin, kidney, placenta, and white blood cells (neutrophils and eosinophils).  In order for histamine in the gut to stay balanced, this enzyme must be present. Diamine Oxidase is responsible for breaking down histamine into imidazole acetaldehyde, which destroys any allergic reactions from occurring.  However, if DAO production is compromised, histamine builds up, causing numerous issues throughout the body.  There are many different reasons why this important enzyme would be suppressed, one of them being the use of pain killers, sleeping aids, asthma medications, muscle relaxants, and antibiotics.  However, this GI barrier is also effected through genetic mutations. In general, if the lining of the gut is damaged, whether due to a SAD (standard American diet), chronic illness, and (or) infection, DAO secretion becomes very weak.  This not only causes histamine to build up in the gut, but it can also lead to a leaky gut, which allows proteins to cross into the bloodstream, causing an autoimmune response.  Therefore, having a leaky gut can be caused by numerous reasons that go hand in hand with insufficient DAO production, as health complications leading up to this condition almost always result from a poor immune system (in which histamine becomes over active). 

Though healthy people are able to break down ingested histamine, those with a compromised gut do not have this advantage. SIBO, which results from bacteria becoming overgrown in the small intestine, subsequently creates extreme amounts of histamine in the gut.  Other bacteria, such as Lactobacillus, Streptococcus, Aeromonas, E.Coli, Plesimonas Staphlococcus, are also histamine producing.  Interestingly enough, vitamin B6 is an important co-enzyme to DAO, and is typically found low in individuals with histamine intolerance due to inadequate amounts of DAO.  Some foods, both processed and not, are naturally high in histamine.  Fermented items (alcohol, cheese, sauerkraut, etc), spinach, tomatoes, fish, pork, and citrus fruits, are some of the highest histamine containing foods.  While a low-histamine diet is beneficial for some individuals, it does not necessarily cure the issue at hand.  Usually, the foods highest in histamines (such as alcohol) should already be taken out of ones diet if they suffer from a compromised immune system. Therefore, following both a healing diet and lifestyle can be a major factor in ultimately turning histamine-intolerance into efficient regulation.

My Experience 

Throughout the years of chronic illness, my allergies have simultaneously grown, to the point that I will (and do) react to literally everything.  Whether food, environment, or a personal care item, histamine has become a big enemy of mine on a daily basis. Originally, this molecule was trying to help defend my immune system, however, in the process, it has caused a seemingly irreversible attack on my body.   

Symptoms & Causes 

There are many reasons for histamine overgrowth in my body, due to untreated Lyme spirochetes, which resulted in numerous bacterial infections (SIBO, parasites, aeromonas, bartonella, babesia, etc), all of which breath histamine into my system.  Though I do take the natural route for treating these infestations, antibiotics were also used, which is another cause for DAO enzyme suppression.  With an untreated immune, neurological, and bacterial disease, leaky gut is something I have also developed.  However, regardless of all of the other co-factors leading up to my histamine-intolerance, the main point is that it has become a big problem in my health journey.  Foods that would otherwise be healing to the body, I react too, whether from previously activated mast cells, or simply histamine thinking they are foreign, bad guys.  A typical day consists of hot flashes, nigh sweats, swollen hands and legs, nasal congestion to the point where I cannot breath, full body itchiness, sore, stinging eyes, pregnant bloating, fatigue, headaches, dilated veins, skin reactions, and when very out of control, anaphylaxis reactions, where my throat closes and I am unable to breath, talk, eat, drink, and thus function normally.  All of these symptoms are due to differing histamine receptor cells being overactive, which then causes numerous immune system reactions. 

I am not going to lie, coping with all of these things can be very debilitating, therefore pushing me to write a post on how important and BIG histamine really does play in one’s health.  

I also implemented a 5-7 rotation diet about a year ago, where I do my best to literally rotate every food that I consume so that I do not eat the same more than a week apart.  This has helped me pinpoint what I call "allergens of the week," allowing me avoid them for 1-2 weeks, where then my body is no longer reacting to them.  Because my range of foods is limited as it is, protein sources, which are naturally high in histamine, are the main emphasis of my rotation.  To make things less confusing, I keep an on-going document on my desktop of the ingredients I have eaten that day.  Through this, I am able to keep track of how many days it has been since last ingesting a certain food, allowing me to plan future meals.  This list also allows me to determine any correlated allergic reaction symptoms with specific foods.  

Treatment

Though I have been experiencing histamine-related symptoms for years now, it was not until this past summer that I began seeing a Chinese herbalist/allergist/immunologist M.D for treatment.  Through her, I take what she calls “tea,” which is actually different Chinese herb combinations in pill form.  She also has me drinking actual, herbal tea, taking baths in specific bath salt remedies, and morning/night cream supplements.  My doctor explains her FAHF-2 (Food Allergy Herbal Formals) as able to reset the immune system to no longer react to ingested foods that it perceives as being infectious diseases.  Through the binding of immunoglobulin E (IgE) to mast and basophil (pituitary, hormone producing) cells, the body becomes over-active with released histamine, even to things are not inherently dangerous such as food or pollen.  By taking the herbal formulas, Th2 (immune response) cell activity is lowered, without taking away the protective, beneficial mechanism of subset Th1 cells (which is to protect the body from bacteria and viruses).  Scientifically, this is called immune modulation, where allergic reactions are decreased and thereby treated through changing the pathological immune response.  By reseting the immune system, foods are no longer seen as foreign toxins by internal cells, which then stops them from reacting and producing harmful molecules.  

Though a low histamine diet can be somewhat helpful depending on the degree of one's histamine activity, eating your way out of an intolerance is very unlikely.  Because of the numerous diets I must follow to maintain my present health (Ketogenic as part of the PK Protocol, AIP for  the effects of Chronic Lyme, and Low-FODMAP for SIBO), eating low-histamine is anything but possible.  Though many foods naturally high in histamine are already eliminated through the Low-FODMAP and AIP approach, foods such as fish, are simply items I cannot afford to take out of my diet.  

For those of you who cannot see a doctor studying the area of histamine treatment, taking supplements DAO or Quercetin, have proven to be very beneficial in certain individuals (I take them as well).  Of course, learning and being aware of which foods are high in histamine is also beneficial, as this can help you make educated decisions regarding meals.  

The Importance 

Overall, the extent to of which I have explained histamine and histamine receptors may have been somewhat overwhelming.  For those without a scientific brain, I probably should had advised taking notes early on in the article.  However, regardless of how much you remember of all the small, yet incredibly important chemical reactions that occur with histamine, the one thing that you should take away is that, histamine, along with the receptors on various cells throughout the body, are a HUGE, underestimated factor in one's overall health.  Even if you do not suffer from chronic food allergies, other factors of life such as hormones, appetite, weight, mood, learning, eating, and sleep, are all significantly effected by histamine (and that is only  scratching the surface).  Though even colleagues of my immunologist initially say that it is impossible, the truth is, getting out of the histamine-reaction-damage cycle is possible.  However, studying the body in such a way is very cutting-edge, and thus not very popular in the conventional medical world.  Yet the verdict is still clear, the body can heal itself, all that it needs is the proper tools to do it.  Therefore, though I still suffer from the effects of over-active histamine on a daily basis, I do not believe my life will be this way forever.  

As of now, histamine, and all that goes along with this small molecule, is still very misunderstood and (or) being investigated.  Many people are ignored, mistreated, and told they are crazy for thinking they are allergic to everything.  However, having a weakened immune system, and thus body, is not very hard now in days, especially when following a SAD (Standard American Diet).  It is time that we stopped underestimating the effects of modern living, and start realizing just how powerful the body really is.  

(Pin Post for Later) 

Further Reading & Resources
Paleo Mom Histamine Archives
The Low Histamine Chef 
Headache, Hives, & Heartburn
Histamine Home Remedies 
Quercetin 

Ephesians 2:10 " For we are God’s masterpiece. He has created us anew in Christ Jesus, so we can do the good things he planned for us long ago"