ENTEROIMMUNOLOGY OF FOOD HYPERSENSITIVITY AND ALLERGY

LIFE-THREATENING ALLERGY (ANAPHYLAXIS)
Allergy manifests with hives, itching, swelling, difficulty breathing, and even anaphylaxis, and involves mast cell degranulation and release of histamines and other mediators. The histamine triggers vasodilation in the skin leading to hives and itching and swelling in the airway including the larynx and can shut off breathing. This is a life-threatening situation called anaphylaxis.

DETAILS ABOUT ANAPHYLAXIS
The serology of this kind of inflammation involves IgE production and is known as type 1immune hypersensitivity. IgG-mediated sensitivity is not an allergy. There is no evidence that IgG-mediated hypersensitivity is associated with anaphylaxis. Immunologically, the process begins with Th2 lymphocytes which produce IL4 which triggers B lymphocytes to make IgE antibodies. The IgE antibodies then bind to mast cells and await allergen contact. IgE mediated food allergies can lead to intense intestinal cramps and if the allergens to transport to the lungs, this can cause asthma.

MISCELLANEOUS
· The inflammatory response associated with parasites is similar to that of allergies in that they involve parasitic inflammatory responses involving Th2 lymphocytes and eosinophils.
· A food allergy response leading to abdominal cramps may be due to serotonin production which is associated with gut inflammation.
· Serotonin is a vasoconstrictor and can lead to abdominal cramps.
· Histamine is a vasodilator and promotes white blood cell movement towards the intestinal area of concern.
· IgE antibodies involved in the body’s response to parasites because of the mechanism mentioned above.

FOOD ALLERGY
Food allergies causing IgE reaction should be avoided because of the risk of hives and potentially anaphylaxis. The most common food allergens are milk, eggs, peanuts, tree nuts, fish, shellfish, soy, and wheat; interestingly all of these foods are GMO or extremely processed.

Diagnostically, skin prick testing has a high rate of false-positive, so patients may test positive for antibodies but may not actually have a true allergy. The best type of IgE testing is ImmunoCAP Fluorescent Enzyme Immunoassay. IgE blood testing is preferred to provocation testing due to the false positives associated with provocation testing.

Gastrointestinal allergies or food allergies should be associated with abdominal symptoms of nausea, vomiting, diarrhea, abdominal pain after eating certain foods. Constitutional symptoms such as brain fog and fatigue may be associated with leaky gut and a microbiome-based imbalance or an inflammatory response to the food not necessarily allergy inflammation.

MAST CELL ACTIVATION DISORDER

Mast cell activation disorder can affect any organ. Symptoms include fatigue, weakness, chills, sweats, constitutional symptoms, difficulty focusing, sinusitis, rhinitis, wheezing, mucous production in the throat causing throat clearing, tachycardia, diarrhea, abdominal pain, any abdominal symptom, bladder pain, cystitis, skin rashes, headaches, depression, neuropsych disorders, and even coagulopathy. Anaphylaxis may even occur without IgE antibodies triggering event. Foods associated with mastocytosis include anchovy, sardines, potatoes, tomatoes, green peas, spinach, nuts, peanuts, tree nuts, strawberry, banana, oranges, spicy foods, hot beverages, fermented beverages, wine, beer, cheese, sauerkraut.

Mast cell proliferation can occur on the skin, connective tissues, mucosa, blood vessels, the lining of the intestine, eyes, respiratory tract, endothelial cells, epithelial cells, and fibroblasts. Mast cells only mature cells in the body with CD117 receptors. When CD117 receptors are activated, cell division is triggered and this can lead to excess cell division of mast cells and this leads to an activation disorder of mast cells. Mast cells can be activated by IgE and by anti-IgE IgG, i.e., IgG that targets IgE which is associated with chronic urticaria. Mast cell IgE activation can also be triggered by dietary lectins and the IgG receptors that can activate mast cells can be up-regulated by Interferon-gamma which is controlled by gut bacteria. Mast activation syndrome is a major underlying cause of interstitial cystitis and irritable bowel syndrome.

The diagnostic criteria for mast cell activation disorder is clinical but elevated levels of serum tryptase, serum chromogranin A, heparin, urinary n-methylhistamine, urinary prostaglandin d2, urinary leukotriene e4 are all associated with mast cell activation disorder but often these are all normal.

Treatment of mast cell hyperactivation disorder can be done with antihistamines or NSAIDs or naturopathic antihistamines such as lavender and quercetin. Serum histamine levels are also associated inversely with vitamin C levels and so vitamin C levels can decrease histamine levels. Inflammatory cytokines originating from the gut microbiome can also trigger mast cell activation. Bacterial overgrowth is associated with LPS production which increases mast cell activity. Mast cell survival can be decreased by decreasing NF-kB production (nuclear factor kappa beta) and melatonin and curcumin do this.

PSEUDOALLERGY FROM BIOACTIVE AMINE TOXICITY

Pseudoallergy associated with biogenic amines can provoke a similar array of reactions but there are no triggering antigens, antibodies or degranulation of mast cells or basophils. Pseudoallergy is not an immune response but it is a toxic reaction from histamine and other biogenic amines in the food itself. Dietary biogenic amines are present in aged cheese, fine red wine and rich chocolate, all of which are common triggers for migraine. We also have gut bacteria that make toxic biogenic amines such as trimethylamine which is produced in bacterial fermentation of the protein in meat that can trigger pseudoallergy. Furthermore, histidine can be converted by intestinal bacteria into histamine and histidines present in high amounts present in chicken. Tyrosine can be converted into tyramine, lysine can be converted into cadaverine, and cysteine can be converted by bacteria in the gut such as Desulfovibrio pyrogen into hydrogen sulfide. Any amino acids can be converted into ammonia. Histamine is not necessarily associated with tinnitus.

DAO, also known as AOC1 which is amine oxidase copper containing 1, the remainder of this was referred as DAO, is present on epithelial cells in the intestine and this enzyme clears biogenic amines from blood plasma and destroys bioamines in food preventing absorption. However, loss of DAO can occur leading to a buildup of histamine in the intestine. Alcohol can suppress DAO activity or inadequate S-Adenosyl methionine levels (SAM-e) and can also impair MAF/DAO levels and in the setting of intestinal increased permeability from leaky gut, there could be increased absorption of bioamines in the intestine. The foods that are high in bioamines content are pickle foods, smoked and fermented foods, meats, seafood, alcohol, fermented beverages, fermented dairy, fermented soy products, chocolate, fermented vegetables, legumes, peanuts, fruits including avocado, banana, red plums, pineapple, raspberry, Brazil nuts, cactuses, vanilla, eggplant, all the ripe fruits and vegetables that have been fermented, yeast and yeast extracts including bread. The content of the fermented food depends on the culture used.

Serotonin syndrome or even in mild levels of serotonin toxicity is now associated with gut inflammation and can lead to manic symptoms, tachycardia, sweating, headaches, agitation, restlessness, flushing, diarrhea, and can be triggered in the right setting by certain foods especially butternuts, black walnuts, English walnuts, pecans, and plantains.

It needs to be emphasized that vitamin C is essential to maintain DAO activity. Foods containing sulfide that can promote direct mast cell activation include baked goods, soup mixes, jams, frozen canned vegetables or foods, pickled foods, grays, fried fruits, potato chips, molasses, shellfish and wine, and nutrients that can decrease sulfide induced mast cell degranulation include B vitamin, selenium, vitamin D, copper, niacin, zinc, SAM-e, taurine, alpha lipoic acid, melatonin. There are sulfide containing food additives such as potassium bisulphite, potassium metabisulphite, sulfur dioxide, sodium bisulphite, sodium metabisulphite, and sodium sulfite.

LEUKOTRIENE INDUCED MAST CELL ACTIVATION AND SALICYLATES

There are leukotriene associated hypersensitivities as well that can trigger mast cell activity such as salicylates. A study published in 1985 by Swain analyzed the salicylate content of multiple foods and this became the primary source of knowledge of how to avoid salicylate sensitivity. Salicylates are not common in food but they are common in wine and alcohol. The main herb to avoid salicylate toxicity or sensitivity is Willow bark, aspirin products, and wintergreen. There are salicylate type antioxidants that are beneficial found in coconuts, strawberries, and carrots, however, there are preservatives such as sodium benzoate which can trigger salicylate sensitivity. Leukotriene induced mast cell activation or salicylate toxicity or sensitivity can be addressed by consuming leukotriene inhibiting phenol compounds such as elderberry, Loganberry, capers, black olives, turmeric, cloves, clove oil, soy products, chocolate, peppermint, oregano oil, and cumin caraway.

PSEUDOALLERGY FROM BIOACTIVE AMINE TOXICITY

Food allergy IgE mediated inflammation in response to food can cause responses within few minutes up to a few hours can cause, rashes, wheezing, edema, and anaphylaxis and can cause itching, anxiety, bronchoconstriction wheezing and nausea.

IgG-mediated inflammation can cause irritability, abdominal pain, and fatigue which is associated with mast cell activation and could be tested with IgG or IgG core antibody testing. The most common allergens include milk, wheat, baker’s yeast and beer, also soybean.

There are four subclasses of IgG antibody: IgG1 is an early response, IgG4 is the most common associated with food immunogenicity and it is similar to secretory IgA. IgG4 can cause immune complexes to be performed and activate the complement cascade which can cause mast cell degranulation and this process can trigger Th17 induced inflammation which can lead to autoimmune disease.

SUMMARY: Plan of action is thus following:
1. IgG testing can indicate which foods are causing mast cell symptoms.
2. Improving digestion by decreasing stomach pH and digestive enzymes can help with decreasing the immunogenicity of large proteins such as biogenic amines and common allergens of dairy and wheat should be avoided. The most common dietary lectin that causes damage to the intestine is wheat and gluten and potatoes should be avoided too temporarily since there are antitrypsin proteins that are mostly denatured by cooking but sometimes potatoes can lead to excess antitrypsin enzymes and prevent enzymatic degradation of proteins in food. Also, the resolution of bacterial dysbiosis should be done. Mast cell activation is associated with bacterial overgrowth syndrome so antimicrobials may be useful. Rotation of foods can be helpful as well and easing anti-inflammatory efforts such as vitamin C, melatonin, acetylcysteine, glutathione, alpha-lipoic acid, magnesium, fish oil may be beneficial. Foods that are removed can be reintroduced after three months.

CCIM PARKINSONS’ DISEASE TREATMENT PROGRAM

SUMMARY: Parkinson’s disease is characterized by destruction of dopamine producing neurons in the substantia nigra, a loss of these neurons leads to the motor symptoms associated with the disease. There is also impaired synaptic transmission in the prefrontal cingulate cortex and substantia nigra and dysfunction in these areas can lead to the nonmotor symptoms. Another feature of Parkinson’s disease is the accumulation of Lewy bodies in various parts of the brain and body. Besides the aforementioned parts of the brain, other areas that are included in Lewy body deposition include cerebral cortex, vagus nerve, sympathetic ganglia and the intestinal nerves. The Lewy bodies are cellular membranes composed of misfolded alpha-synuclein. Alpha-synuclein is a protein that is made and involved in neurotransmitter release in neurons. Recent research has articulated the gut microbiome as a major cause of misfolded alpha-synuclein in the nervous system leading to Parkinson’s disease.

Changes in the gut microbiome and the gut bacteria lead to activation of pattern recognition receptors which promote disease onset. Pattern recognition receptors are receptors that function as a surveillance system for bacteria and viruses in our body. Research has shown that certain types of bacteria specifically gram negative aerobes contribute to alpha-synuclein misfolding and accumulation.

Alpha-synuclein is a protein mostly made in the nervous system but is made in blood cells and cells made by the bone marrow. It is found in presynaptic terminals of neurons and is important in healthy neurotransmitter production and function. Fibrillated alpha-synuclein is associated with Lewy bodies that lead to destruction of the nerves in the areas of the brain described above. Alpha-synuclein is critical for the development of dopaminergic neurons and plays an important role in the transport of dopamine. The role of alpha-synuclein as an essential to dopamine neuronal function explains why dopaminergic neurons are preferentially destroyed in Parkinson’s disease since alpha-synuclein fibrillation and Lewy body deposition is the main feature of the disease. When alpha-synuclein accumulates in the nervous system of the intestine called enteric nervous system, colonic dysmotility is induced. Therefore, it can be deduced that alpha-synuclein pathology in the gut may be associated with gastrointestinal symptoms such as constipation which is a characteristic of the disease. Alpha-synuclein may be generated in the enteric nervous system and when propagated through the enteric nerves can actually arrive in the central nervous system by way of the vagus nerve. Recent research has shown that the vagus nerve can transport proteins and chemicals and metabolites via retrograde axonal transport from the intestine to the brain. Furthermore, proteins and metabolites from bacteria or viruses can also enter the brain by transporting along the unmyelinated preganglionic fibers of the vagus nerve.

Intestinal permeability induced by gut dysbiosis is known to decrease short chain fatty acid production and patients with low short chain fatty acid production have increased permeability of the blood brain barrier making the brain even more susceptible to inflammatory metabolites made by gut bacteria that travel to the brain via the vagus nerve. Research is therefore articulating that not only can alpha-synuclein from the gut to the brain via the vagus nerve but also it can develop in the brain as a result of altered short chain fatty acid production from the gut.

Furthermore, alpha-synuclein fibrillation can be enhanced by certain inflammation inducing bacterial metabolites such as lipopolysaccharide which is commonly made by encapsulated gram negative aerobic bacteria which are characteristically dominant in the intestines of patients who have consumed an abundant amount of antibiotics. Animal studies have shown that altered short chain fatty acid production can induce microglial activation in the brain which can also promote alpha-synuclein aggregation and fibrillation.

Researchers have shown that patients with Parkinson’s have higher levels of Enterobacteria compared to healthy patients and excess Enterobacteria are associated with worse motor symptoms in patients with Parkinson’s. Also patients with Parkinson’s are known to have lower levels of butyrate producing bacteria such as Faecalibacterium prausnitzii. Also patients have lower levels of beneficial short chain fatty acids specifically acetate, proprionate and butyrate. Short chain fatty acids are known to be essential to maintaining a healthy blood brain barrier and the blood intestinal barrier. Short chain fatty acids are one of the few substances that can actually cross the blood brain barrier as a result of normal physiology. Decreased levels of intestinal short chain fatty acids can lead to increased gut and blood brain permeability and is associated with triggering alpha-synuclein aggregation and fibrillation.

Recent studies have shown that lipopolysaccharide is a major contributor to aggregation and fibrillation of alpha-synuclein leading to the Parkinson’s disease. Furthermore, there is other data suggesting that alpha-synuclein may function as a messenger to alert the microglia of the presence of pathogenic bacteria which essentially function as a threat to the immune system. Microglial cells are the essential white blood cells of the brain and appear to be controlled by the gut microbiome and gut bacteria.

Alpha-synuclein has been shown to be associated with gut inflammation independent of any neurologic disease. Alpha-synuclein appears to be present and express during both acute and chronic gastrointestinal inflammatory processes and contributes to activation of the immune cells which promote repair in such states.

Constipation is one of the most common symptoms in patients with Parkinson’s and often the constipation is extremely severe causing patients to have a bowel movement only once or twice a week or even less frequent. The cause of such constipation and why it is so difficult as constipation routinely is treated with laxatives or stool softeners is that the cause of it may be altered gut microbial profile and so the constipation in Parkinson’s cannot be meaningfully treated without manipulating the gut bacteria in a beneficial way.

At the Columbia Center for Integrative Medicine, we offer our gut microbiome assessment and repair program for patients with Parkinson’s disease. Typically, patients begin by having severe constipation and movement symptoms along with autonomic symptoms such as postural instability, dizziness and possibly impairment of bladder or bowel sphincter control. Patients with Parkinson’s in our experience typically have had an extraordinary amount of exposure to antibiotics both from exposure to antibiotics in the food system as well as from prescribing doctors in the community. Typically, this leads to antibiotic resisting gram negative aerobes that secrete lipopolysaccharide dominating the intestine.

Our PCR and cultural diagnostic techniques typically pick up a domination of gram negative aerobes, a loss of short chain fatty acid producing Firmicutes species, a loss of short chain fatty acids, increased intestinal permeability, altered TGF-beta levels, and an abnormal total quantity of gut bacteria. We assess all of this as part of our diagnostic methods and we focus on balancing the bacterial system by first suppressing gram negative aerobic bacteria, increasing short chain fatty acid producing bacterial levels, lessening intrinsic inflammation within the intestine, increasing beneficial immunomodulatory substances such as IgA, vitamin A, and vitamin D. We expect constipation to resolve as the first sign of progress followed by improvement in movement disorders.

In conjunction with our gut microbiome repair programs, we also offer IV vitamin C at high doses which has been shown to be beneficial for patients with Parkinson’s as vitamin C promotes a decrease in brain inflammation while promoting dopamine production. We work tirelessly to suppress alpha-synuclein production and microglial activation via our gut microbiome repair program. We monitor patients enterobacterial levels and also focus on lifestyle and diet. Diet ends up being the major contribution of gut microbiome bacterial diversity and overall balance. Evidence shows that dietary interventions represent an essential approach in the treatment and may be even prevention of neurodegenerative and CNS disorders. One diet that has been shown to be evidence based for patients with gut dysbiosis is a keotgenic diet which is significantly low in simple carbohydrates which has been shown to increase cerebral blood flow and increase levels of Akkermansia and Lactobacillus while increasing blood brain barrier integrity.

Dushyant Viswanathan, MD, ABIM, ABOIM, AACE

CCIM PARKINSON'S DISEASE TREATMENT PROGRAM SUMMARY: Parkinson’s disease

CCIM PARKINSON'S DISEASE TREATMENT PROGRAM

SUMMARY: Parkinson’s disease is characterized by destruction of dopamine producing neurons in the substantia nigra, a loss of these neurons leads to the motor symptoms associated with the disease. There is also impaired synaptic transmission in the prefrontal cingulate cortex and substantia nigra and dysfunction in these areas can lead to the nonmotor symptoms. Another feature of Parkinson’s disease is the accumulation of Lewy bodies in various parts of the brain and body. Besides the aforementioned parts of the brain, other areas that are included in Lewy body deposition include cerebral cortex, vagus nerve, sympathetic ganglia and the intestinal nerves. The Lewy bodies are cellular membranes composed of misfolded alpha-synuclein. Alpha-synuclein is a protein that is made and involved in neurotransmitter release in neurons. Recent research has articulated the gut microbiome as a major cause of misfolded alpha-synuclein in the nervous system leading to Parkinson’s disease.

Changes in the gut microbiome and the gut bacteria lead to activation of pattern recognition receptors which promote disease onset. Pattern recognition receptors are receptors that function as a surveillance system for bacteria and viruses in our body. Research has shown that certain types of bacteria specifically gram negative aerobes contribute to alpha-synuclein misfolding and accumulation.

Alpha-synuclein is a protein mostly made in the nervous system but is made in blood cells and cells made by the bone marrow. It is found in presynaptic terminals of neurons and is important in healthy neurotransmitter production and function. Fibrillated alpha-synuclein is associated with Lewy bodies that lead to destruction of the nerves in the areas of the brain described above. Alpha-synuclein is critical for the development of dopaminergic neurons and plays an important role in the transport of dopamine. The role of alpha-synuclein as an essential to dopamine neuronal function explains why dopaminergic neurons are preferentially destroyed in Parkinson’s disease since alpha-synuclein fibrillation and Lewy body deposition is the main feature of the disease. When alpha-synuclein accumulates in the nervous system of the intestine called enteric nervous system, colonic dysmotility is induced. Therefore, it can be deduced that alpha-synuclein pathology in the gut may be associated with gastrointestinal symptoms such as constipation which is a characteristic of the disease. Alpha-synuclein may be generated in the enteric nervous system and when propagated through the enteric nerves can actually arrive in the central nervous system by way of the vagus nerve. Recent research has shown that the vagus nerve can transport proteins and chemicals and metabolites via retrograde axonal transport from the intestine to the brain. Furthermore, proteins and metabolites from bacteria or viruses can also enter the brain by transporting along the unmyelinated preganglionic fibers of the vagus nerve.

Intestinal permeability induced by gut dysbiosis is known to decrease short chain fatty acid production and patients with low short chain fatty acid production have increased permeability of the blood brain barrier making the brain even more susceptible to inflammatory metabolites made by gut bacteria that travel to the brain via the vagus nerve. Research is therefore articulating that not only can alpha-synuclein from the gut to the brain via the vagus nerve but also it can develop in the brain as a result of altered short chain fatty acid production from the gut.

Furthermore, alpha-synuclein fibrillation can be enhanced by certain inflammation inducing bacterial metabolites such as lipopolysaccharide which is commonly made by encapsulated gram negative aerobic bacteria which are characteristically dominant in the intestines of patients who have consumed an abundant amount of antibiotics. Animal studies have shown that altered short chain fatty acid production can induce microglial activation in the brain which can also promote alpha-synuclein aggregation and fibrillation.

Researchers have shown that patients with Parkinson’s have higher levels of Enterobacteria compared to healthy patients and excess Enterobacteria are associated with worse motor symptoms in patients with Parkinson’s. Also patients with Parkinson’s are known to have lower levels of butyrate producing bacteria such as Faecalibacterium prausnitzii. Also patients have lower levels of beneficial short chain fatty acids specifically acetate, proprionate and butyrate. Short chain fatty acids are known to be essential to maintaining a healthy blood brain barrier and the blood intestinal barrier. Short chain fatty acids are one of the few substances that can actually cross the blood brain barrier as a result of normal physiology. Decreased levels of intestinal short chain fatty acids can lead to increased gut and blood brain permeability and is associated with triggering alpha-synuclein aggregation and fibrillation.

Recent studies have shown that lipopolysaccharide is a major contributor to aggregation and fibrillation of alpha-synuclein leading to the Parkinson’s disease. Furthermore, there is other data suggesting that alpha-synuclein may function as a messenger to alert the microglia of the presence of pathogenic bacteria which essentially function as a threat to the immune system. Microglial cells are the essential white blood cells of the brain and appear to be controlled by the gut microbiome and gut bacteria.

Alpha-synuclein has been shown to be associated with gut inflammation independent of any neurologic disease. Alpha-synuclein appears to be present and express during both acute and chronic gastrointestinal inflammatory processes and contributes to activation of the immune cells which promote repair in such states.

Constipation is one of the most common symptoms in patients with Parkinson’s and often the constipation is extremely severe causing patients to have a bowel movement only once or twice a week or even less frequent. The cause of such constipation and why it is so difficult as constipation routinely is treated with laxatives or stool softeners is that the cause of it may be altered gut microbial profile and so the constipation in Parkinson’s cannot be meaningfully treated without manipulating the gut bacteria in a beneficial way.

At the Columbia Center for Integrative Medicine, we offer our gut microbiome assessment and repair program for patients with Parkinson’s disease. Typically, patients begin by having severe constipation and movement symptoms along with autonomic symptoms such as postural instability, dizziness and possibly impairment of bladder or bowel sphincter control. Patients with Parkinson’s in our experience typically have had an extraordinary amount of exposure to antibiotics both from exposure to antibiotics in the food system as well as from prescribing doctors in the community. Typically, this leads to antibiotic resisting gram negative aerobes that secrete lipopolysaccharide dominating the intestine.

Our PCR and cultural diagnostic techniques typically pick up a domination of gram negative aerobes, a loss of short chain fatty acid producing Firmicutes species, a loss of short chain fatty acids, increased intestinal permeability, altered TGF-beta levels, and an abnormal total quantity of gut bacteria. We assess all of this as part of our diagnostic methods and we focus on balancing the bacterial system by first suppressing gram negative aerobic bacteria, increasing short chain fatty acid producing bacterial levels, lessening intrinsic inflammation within the intestine, increasing beneficial immunomodulatory substances such as IgA, vitamin A, and vitamin D. We expect constipation to resolve as the first sign of progress followed by improvement in movement disorders.

In conjunction with our gut microbiome repair programs, we also offer IV vitamin C at high doses which has been shown to be beneficial for patients with Parkinson’s as vitamin C promotes a decrease in brain inflammation while promoting dopamine production. We work tirelessly to suppress alpha-synuclein production and microglial activation via our gut microbiome repair program. We monitor patients enterobacterial levels and also focus on lifestyle and diet. Diet ends up being the major contribution of gut microbiome bacterial diversity and overall balance. Evidence shows that dietary interventions represent an essential approach in the treatment and may be even prevention of neurodegenerative and CNS disorders. One diet that has been shown to be evidence based for patients with gut dysbiosis is a keotgenic diet which is significantly low in simple carbohydrates which has been shown to increase cerebral blood flow and increase levels of Akkermansia and Lactobacillus while increasing blood brain barrier integrity.

Dushyant Viswanathan, MD, ABIM, ABOIM, AACE



Source

HIGH DOSE IV VITAMIN C TREATMENT PROGRAM

Clinical uses of IV Vitamin C:

  • Neurologic illness- Alzheimers, Parkinsons
  • Mood disorders- Schizophrenia, Depression, Anxiety
  • Infections: Viral infections, bacterial infections, Fungal infections, sepsis
  • Chronic inflammation and chronic fatigue
  • Cancer

SUMMARY:  Vitamin C as a therapeutic treatment offers many potential benefits for patients with complex complicated medical illness.  For neurodegenerative disease and psychiatric disorders, evidence suggests that vitamin C has a number of benefits for the neurologic structures of the brain.  Vitamin C promotes neuronal maturation and differentiation, myelin formation, synthesis of catecholamine, modulation of neurotransmission and antioxidant protection.  There is plentiful animal evidence to show that deletion of the vitamin C transport in the brain can lead to widespread cerebral hemorrhage and death, so the brain essentially requires vitamin C for basic functioning.  It is suggested that vitamin C use in the course of neurologic diseases and display potential therapeutic roles especially on neurodegenerative diseases such as Alzheimer’s, Parkinson’s, Huntington’s disease, multiple sclerosis, ALS, psychiatric disorders including mood disorders, and schizophrenia.  Vitamin C as an antioxidant directly scavenges reactive oxygen species and nitrogen species that are produced as a byproduct in normal cellular metabolism.  Vitamin C inactivates super oxide radicals a major byproduct of mitochondrial metabolism.  Vitamin C also helps recycle other antioxidants such as vitamin E.  Vitamin C can help lessen the potential oxidative damage induced by vitamin E metabolism; therefore vitamin C is considered very neuroprotective.  

Vitamin C modulates neurotransmitter function by binding neurotransmitters to receptors as well as regulating the release from presynaptic vesicles.  Vitamin C is a cofactor for the synthesis of catecholamines especially dopamine and norepinephrine.  Vitamin C appears to be a substrate for dopamine beta-hydroxylase and catalyses the formation of norepinephrine from dopamine.  

Vitamin C also modulates activity of some other receptors such as glutamate and the GABA receptors and therefore can help modulate and lessen damage excitotoxic damage from excess glutamatergic neurotransmission.  Vitamin C inhibits the binding of glutamate to the NMDA receptor.  Vitamin C also decreases the energy barrier for GABA activation so it promotes GABAergic transmission which ultimately will lessen the beneficial conditions such as anxiety disorders.  Vitamin C can also act as a dopamine receptor antagonist which is why it is useful for manic mood disorders such as bipolar and schizophrenia.  

Vitamin C also promotes optimizing neuronal metabolism by changing the preference for lactate over glucose as the energy substrate to sustain synaptic activity, so when it is released from glial cells and is taken up by neurons where it restrains glucose transport and tubulization so then lactate ends up being the major metabolic substrate for neuronal metabolism as an energy source.

Vitamin C is also involved in collagen synthesis which is important for the brain.  Collagen is important for regeneration of blood vessels and neuro sheath formation, therefore, it could be said that vitamin C helps optimize and repair the blood brain barrier which is routinely damaged in patients with chronic progressive neurodegenerative illnesses such as Parkinson’s’ and dementia.  

Vitamin C has been shown to have alleviating effects on seizure activity by the above mechanisms and reduces seizure induced damage on the hippocampus.  Both in-vivo, animal and in-vitro studies have shown that vitamin C is beneficial for Alzheimer’s.  

Murakami et al reported that a six-month treatment of vitamin C can result in reduced A-beta oligomer formation and can significantly decrease in a measurable way brain oxidative damage and can attenuate behavioral decline in an Alzheimer’s mouse model.  Studies have shown that also patients with Alzheimer’s have a lower vitamin C plasma level. Other randomized controlled trial involved 276 elderly patients demonstrated that 16-week treatments with vitamin C and beta-carotene significantly improved cognitive function especially with higher doses of beta-carotene.  

Vitamin C is important in helping patients with Parkinson’s disease.  Glutamate mediated excitotoxicity is associated with the pathophysiology of Parkinson’s and this is lessened as a consequence of vitamin C treatment.  Vitamin C plays a role in dopaminergic neuron differentiation.  Vitamin C also plays a role in alpha synuclein oligomerization, alpha synuclein shown to be produced in the intestine as a consequence of excess LPS production from pathogenic gram negative aerobes in the intestine and the alpha synuclein travels to the brain via the vagus nerve via retrograde axonal transport to promote damage in dopaminergic neurons in the brain leading to the movement disorders associated with Parkinson’s.    Human studies have shown that vitamin C deficiency in mild Parkinson’s patients is widespread, however, the plasma level of vitamin C is not as relevant as intracellular vitamin C concentration and this has been confirmed by a study performed Ide et al.  It has been shown that lymphocytic vitamin C levels in patients with severe Parkinson’s is symmetrically lower compared to those with less severe Parkinson’s.  There is one cohort study involving 1036 Parkinson’s patients showing that dietary vitamin C intake will decrease Parkinson’s risk.  There have been multiple case reports showing that IV vitamin C therapy can lessen movement disorders in Parkinson’s patients.  Vitamin C also increases L-dopa level which is a precursor for dopamine.  

For multiple sclerosis, vitamin C has been shown to be useful since it can help lessen oxidative damage and lessen myelin destruction which is characteristic in multiple sclerosis.  Multiple sclerosis patients also have a low vitamin C level compared to healthy individuals.  Multiple studies have shown that multiple sclerosis patients treated with antioxidants especially vitamin C have decrease in relapse frequency and decreased corticosteroid requirements.  

Because of the effects on neurotransmission, vitamin C has also been shown to be useful for depression modulating catecholamine production, optimizing GABAergic production, GABAergic stimulation and lessening excitotoxicity from NMDA receptor activation.  Vitamin C has an antidepressant like effect via potassium channel inhibition and by activation of phosphatidlinositol 3-kinase in the brain.  Furthermore, vitamin C deficiency is very common in patients with chronic depression.  For its beneficial of anti-GABAergic effects and its anti-glutamate toxicity effects, vitamin C treatments have been shown to be useful for anxiety as well.  

A study performed by De Olivera et al examined the effects of short term vitamin C treatments in high school students in a randomized double blind placebo controlled trial.  This treatment led to higher vitamin C concentrations associated with decreased anxiety levels and optimized heart rate levels so there was less tachycardia associated with panic disorder and anxiety.  A six-week vitamin C treatment led to decreased anxiety measured by patient’s symptom scores.  Vitamin C has also been shown to decrease anxiety in diabetic patients. Vitamin C deficiency has been associated with worsened schizophrenia and the studies do show that vitamin C as an antioxidant alleviates the effects of free radicals in the treatment of schizophrenia. 

CONCLUSION:  Vitamin C has been useful for Alzheimer’s to by lessening oxidative stress, decreasing amyloid  aggregation, decreasing neuronal loss, improving the integrity of the blood brain barrier and lessening phosphrylation of tau protein at Ser-396. Vitamin C has been shown to be helpful for Parkinson’s by lessening alpha synuclein oligomerization, increasing dopaminergic neuron differentiation and protecting against glutamate mediated excitotoxicity and by its beneficial effects on dopamine production. Vitamin C has also been useful for multiple sclerosis by lessening oxidative stress and myelin destruction. For psychiatric disorders such as depression, anxiety and schizophrenia, vitamin C has been shown to be beneficial by modulating catecholamine and GABAergic systems, inhibiting excess NDMA activation, locking potassium channels, decreasing oxidative stress, improving redox mechanisms.

VITAMIN C TREATMENT FOR INFECTIONS

SUMMARY:  Data published by the Riordan Clinic has shown that vitamin C has successfully treated polio, diphtheria, Herpes zoster, shingles, Herpes simplex, chickenpox, influenza, measles, mumps and pneumonia.  

The mechanism is that the antioxidant property of vitamin C promotes a reducing environment in the blood stream and tissues, enhancing the body’s response to oxidative stress from inflammation thereby helping the immune system to fight microbes and viruses that propagate in stressful situations.  Vitamin C therefore functions as an antiviral drug and also enhances immune system function.  White blood cells have vitamin C in intracellular level and use vitamin C at the site of infection.  Vitamin C also enhances the production of interferon which then helps prevent cells from being infected by viruses and vitamin C stimulates activity of antibodies and cytokines in mega doses and promotes mitochondrial energy production and can help specialize immune cells ingest bacteria such as phagocytes.  Vitamin C also interferes with viral DNA and RNA replication; in-vitro experiments have shown that vitamin C can in just isolated way kill influenza viruses.  

The antiviral activity of vitamin C is not virus specific, researches have shown that we can kill any kind of virus whether they are enveloped or non-enveloped, double stranded DNA or single stranded RNA.  Multiple in-vivo studies from across the world have shown that vitamin C IV treatments have been useful for complicated viral infections.  One study in Germany involved 67 patients with shingles that received 7.5 gm IV vitamin C daily for 2 weeks in addition to standard treatment for shingles and patients that received the vitamin C had less Herpes zoster associated pain, less rashes, and less general complaints.  Vitamin C can also treat patients with EBV which is the common cause of chronic fatigue syndrome.  EBV is linked to malignancies such as lymphoma and autoimmune diseases.  The Riordan Clinic has shown that doses from 7.5 to 50 gm IV can decrease viral antibody levels and the benefits seem to be dependent upon the number of treatments given as patients given 10 or more treatments had greater reduction in viral antibody titers reflecting less viral inflammation.  Overall 148 animal studies have been published by 2005 about the benefits of vitamin C as a treatment for infections. 

In addition to antiviral effects, vitamin C appears to have an antifungal and antiparasitic effect also.  Vitamin C has also been shown to reduce mortality in multiple infections specifically tuberculosis, bacterial sepsis, toxic shock, rabies, Candida, and protozoa, and all the studies have been in animals.  Vitamin C has been known to routinely treat the common cold.  Multiple studies have also shown the benefits of vitamin C to treat pneumonia, both bacterial and viral pneumonia.  There is a study from UK in 1994 performed by Dr. Hunt who carried out a randomized double blind placebo controlled trial on elderly people in the UK, their mean age was 81 years hospitalized for acute bronchitis from pneumonia.  Vitamin C treatments reduced the respiratory symptom score in the more ill patients and decreased mortality.  Vitamin C appears to have beneficial effects on infections caused by virus, bacteria, Candida, and protozoa.  Vitamin C also can decrease the pain associated with oral Herpes.  

Many patients have been treated by the Riordan Clinic for cancer with IV vitamin C; the bone, bladder, blood cancers, skin cancers, kidney cancer, pancreatic cancer, lung cancer, prostate cancer, and breast cancers have all been successfully treated with vitamin C either as adjunctive treatments or to lessen mortality.  The pathophysiology of its anticancer effect is that continuous perfusion of vitamin C at high doses trigger redox cycling which can lead to a build of hydrogen peroxide in tumor cells which is toxic to tumor cells, essentially leads to tumor cell apoptosis.  

The cytotoxic effects can be attenuated by combing vitamin C with lipoic acid.  Studies from many laboratories in a variety of animal models including used in hepatoma, pancreatic cancer, colon cancer, sarcoma, leukemia, prostate cancer and mesothelioma confirmed that ascorbate concentrations sufficient for cytotoxicity can be attained in-vivo and that treatments can reduce tumor growth.  Vitamin C also is associated with angiogenesis inhibition as ascorbate inhibits endothelial cell tubule formation in a concentration depending fashion. 

 IV vitamin C is significant anti-inflammatory for cancer patients and can measurably decrease C-reactive peptide.  IV vitamin C can also decrease PSA levels.  Riordan Clinic has published multiple case reports of patients with multiple types of complicated cancers from stage 3, large B cell lymphoma to grade 4 renal cell carcinoma with lung mass or stage 3C ovarian cancer with these patients improving and going into remission.  

Patients must be screened from G6PD deficiency as this is an absolute contraindication for vitamin C treatment as it can induce hemolysis in patients with G6PD deficiency.  The Riordan Clinic has administered 40000 IV vitamin C treatments and side effects of high dose IV vitamin C are rare.  

Research and experience has shown that therapeutic goal of reaching a peak plasma concentration of 20 mmol which is 350 to 400 mg/dL is efficacious. 

Patients can start at 15 gm two to three times a week and escalate to reach that goal therapeutic level to max of 100 gm treatment at any given time.  At CCIM, a maximum IV in vitamin C dose would be 100 gm treatment administered 3 times per week, with a goal plasma level of 350-400 mg/dl. 

Dushyant Viswanathan, MD, ABIM, ABOIM, AACE

REFERENCES: 

1.  Journal of Nutrients. 2017 July; 9(7):659

2.  Date published by the Riordan Clinic in February 2014.  

3.  Journal of Nutrients. 2017 April; 9(4):339.