Is it theoretically possible to treat filaggrin deficiency with a dietary supplement?

Is it theoretically possible to treat filaggrin deficiency with a dietary supplement?

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"Filaggrin is a highly abundant protein expressed in the uppermost part of the epidermis that is critical to the formation and hydration of the stratum corneum-the outermost dead cell layers responsible for the barrier function of the skin. Filaggrin deficiency leads to a 'leaky' skin barrier that allows higher than normal water loss (explaining the dry, scaly skin), as well as allowing entry of allergens through the epidermis where they trigger inflammatory and allergic immune responses (atopic eczema and allergies)."

Not that such a supplement exists, but is it biologically possible to treat filaggrin deficiency with something taken orally?

Direct replacement of a protein through oral supplementation is extremely unlikely. Our digestive tract is designed to break down proteins into their constituent amino acids.

In the stomach pepsin breaks proteins into polypeptides which then pass into the small intestine. At this point (second part of duodenum) multiple enzymes (proteases) enter having been released from the pancreas in response to eating. These enzymes further reduced the polypeptides into smaller components such as you end up with component parts of the original protein.

These component parts are then transported across the intestine into the blood through cells lining the intestinal lumen (enterocytes). Enterocytes also have proteolytic action on long chains of amino acids.

As a result of this process, the original structure of the ingested protein is destroyed. However you do end up with the constituent amino acids. If your fillagrin or any other protein deficiency is as a result of lack of nutrients then in response your body may be able to synthesise the required protein. If on the other hand your deficiency is due to a gene defect, despite having the building blocks for the protien you will continue be deficient.

I highly doubt it. Filaggrin is a human protein which is expressed in the skin and stored as profilaggrin. The profilaggrin has a molecular weight of about 350 kDa (which is rather big) and is cut into smaller units of filaggrin, which then crosslinks kreatin fibers of the epidermal keratinocytes. This enhances the durability of the skin. Mutations in the filaggrin gene have been associated with dry skin and excema. See here for more information:"Filaggrin - revisited."

To supplement the profilaggrin, you would have to bring this rather large protein into the skin. You could think about making a cream with the smaller filaggrin in it to promote crosslinking of the upper skin. The question here would be how effective such a treatment ist and how deep the crosslinking would be.

Yes, according to this study 4g of histdine administered daily does the trick:

The Top Ten Pet Supplements: Do They Work?

Much has been written here about the dietary supplement business, a multibillion dollar industry with powerful political connections, and about the woeful inadequacy of regulation which allows widespread marketing of supplements without a solid basis in science or scientific evidence.

The veterinary supplement market is a pittance compared to the human market, but still a billion-dollar pittance that is growing rapidly. Unfortunately, the resources available for good quality research in veterinary healthcare are also a pittance, and it is not at all unusual for our pets to suffer, or even be euthanized, as a result of treatable diseases for want of money to pay for needed care. So $1 billion a year spent on nutritional supplements may not be such a good deal if these products don’t effectively prevent or treat disease.

The variety of supplements available is staggering. Many proprietary concoctions of vitamins, minerals, herbs, and other ingredients are marketed for health maintenance, “boosting the immune system,” retarding aging, or treating specific diseases. A comprehensive review of this multitude of moving targets is impossible. But the lion’s share of the pet supplement market goes to a few specific compounds, so I will focus on these. Most of these ingredients are also among the most popular supplements for humans, so there will be substantial overlap with previous discussions of the plausibility and evidence for many of these substances.

1. Glucosamine

The biggest name in the veterinary supplement world by a large margin is glucosamine. It is sold alone or in combination with chondroitin, MSM, green-lipped mussle extract, and a zillion other ingredients. It is sold over-the-counter and through veterinarians and as an additive in commercial pet foods, and it is ubiquitous. It is also widely believed by pet owners and veterinarians to be an effective treatment for osteoarthritis.

Glucosamine for arthritis in humans has been discussed at length here before. There is some reasonable plausibility to the underlying theory, but decades of clinical trials have failed to find any consistent benefit, and the balance of the evidence strongly suggests it is no better than a placebo in treating arthritis in humans. Given the subjective nature of pain and the multitude of ways biologically inert interventions can influence people’s perceptions of their own discomfort, this placebo effect might be of marginal value in humans, but the same kind of psychology does not apply to dogs and cats, though it certainly does apply to their owners.

There is very little clinical research on glucosamine as a treatment for arthritis in dogs and cats. In preparing a recent brief literature review, I found only two clinical trials in dogs. One found no benefit for glucosamine and the other, which had a weaker design, s howed littl e benefit. Both showed far greater and more predictable benefit to non-steroidal anti-inflammatory (NSAID) therapy, which is a consistent feature of clinical research on glucosamine.

Because cats are poorly tolerant of NSAIDs, there is particularly great interest in glucosamine and other nutraceutical therapies for osteoarthritis in this species. Nevertheless, I have found no published clinical trials studying this supplement in arthritis cats. The closest is a study of a diet containing glucosamine, chondroitin, and a number of other supplements purported to have benefits in managing arthritis. I have addressed this study in detail elsewhere, but in brief there were not consistent differences between the experimental diet and the control diet even on subjective measures of comfort and no differences at all on objective measures of activity. And, of course, the role of glucosamine, if any, in any effect that might have been seen would not be demonstrable in a study of a diet with many other ingredients.

Glucosamine is also marketed for treatment of feline interstitial cystitis, an uncomfortable and potentially very serious chronic inflammatory disease of the urinary bladder. However, the only clinical trial to investigate this use did not find any evidence of benefit.

2. Fish Oil

After glucosamine, one of the most popular supplements for pets is fish oil. In humans, the most common use of this supplement is for lowering blood lipid levels and prevention of cardiovascular disease. There is some controversy about exactly how much of which components is useful for which specific conditions, and whether eating fish is better than taking fish oil supplements, but in general there is good evidence for some benefit in cardiovascular disease prevention.

Cats and dogs don’t have the problems humans do with atherosclerosis and cardiovascular disease, so this is not a reason for use of fish oils. Instead, this supplement is most commonly used in the treatment of skin allergies. A 2010 narrative review of the evidence for various approaches to treating canine skin allergies concluded that there was some evidence that fish oil supplements can improve coat quality and reduce the dosage of steroid medications needed to control itching, but that these effects are small and not great enough to substitute for other therapies. There is also not evidence to support the use of any particular source, dosage, or formulation of fish oil over any other.

The other common use of fish oils in pets is for treatment of arthritis. There is weak evidence in humans for the use of fish oil supplements as an adjunctive treatment in patients with rheumatoid arthritis, but in general this is not a well-supported intervention for degenerative osteoarthritis in people. There have been several studies of fish oil as a therapy for osteoarthritis in dogs, which I have reviewed in detail (here and here). These are pretty well-designed studies, all by the same group of investigators, and as is common for studies of dietary supplements, they report mostly negative results but then focus on the few statistically significant findings, generally with subjective measures, to conclude the studies are proof of a benefit. The idea that fish oil supplements might have some small benefit for arthritis in dogs and cats is not out of the question, but so far the evidence is not encouraging.

3. Probiotics

Mark Crislip has eloquently addressed the theory and science of probiotics for humans, and the bottom line for pets appears to be much the same. We understand very little about the important and complex ecology of the gastrointestinal tract, about what bugs are there and what they do for or to us. So while the idea of influencing this flora to restore or maintain health makes some sense, adding a few Lactobacillus to the mix and expecting it to have a major effect seems a bit like tossing a few grass seeds into the Amazon rain forest and expecting a golf course to grow there (thanks Mark!).

Clinical studies in humans support some benefits for some conditions, particularly antibiotic-associated diarrhea, but many of the claims made for probiotic products, especially for health maintenance or “boosting the immune system” are unsupported. There is less research on probiotics for dogs and cats, but there are some encouraging studies which show a likely benefit of some products for acute idiopathic diarrhea in dogs (e.g. here and here, analyzed in detail here). There are also serious problems with the quality control of largely unregulated veterinary probiotics. A recent study found the majority of products tested had inaccurate labels, with many not containing the amount or species of organisms claimed on the label. There are also many products marketed with ridiculous and completely unsupported claims.

So overall, the idea of probiotics as a therapy for gastrointestinal disease seems promising, and there are some early suggestions that some products may be useful for some conditions. But this optimism must be tempered by the very limited, preliminary understanding we have of gut ecology and how to manipulate it, the minimal reliable clinical trial evidence to support probiotic use, and the concerns about poor quality control and exaggerated, unscientific claims for probiotic products.

4. Multivitamins

Multivitamins are widely touted as a preventative health measure or as “insurance” for a nutritionally imperfect diet. As Harriet Hall has discussed previously, taking a multivitamin is more a form of self-administered psychotherapy than a preventative health practice. A 2006 review of the available evidence, as well as more recent studies, do not support claims of health benefits in humans from vitamin supplementation in the absence of confirmed deficiencies. And there are circumstances in which vitamin supplementation can be harmful (for example raising cancer risk, interfering with cancer therapy, or even increasing mortality).

As usual, there is virtually no research on the subject in dogs and cats. Commercial pet diets are nutritionally balanced in a way that the rather haphazard eating habits of most humans is not, so there is even less reason to think a multivitamin would be necessary in dogs and cats eating such a diet. In fact, such supplementation could very well lead to excessive, even toxic levels of fat soluble vitamins or some minerals. Homemade and raw food pet diets, however, are more likely to be nutritionally inadequate, so multivitamin supplementation might be more appropriate when feeding such diets. However, the bottom line is there is no good quality epidemiological or experimental research to suggest that dietary deficiencies are common or that non-targeted vitamin supplementation of apparently healthy pets eating a balanced diet has any value. And there is some evidence that supplementation under certain circumstances can be harmful (for example, calcium in growing large-breed dogs).

The lack of evidence may preclude a definitive statement that such supplements are unnecessary or harmful, but it also makes the confident, sweeping claims of supplement marketers entirely unjustified.

5. Lysine

Lysine is an amino acid which is hypothesized to be useful in the prevention and treatment of Feline Herpesvirus (FHV-1) infections. This virus is extremely common, and many cats will be exposed and become infected as kittens. Clinical symptoms include sneezing, nasal congestion, and conjunctivitis, and they range from mild and self-limiting to very severe. Most cats will get over the initial infection, but many remain chronically infected. With suppression of immune function from stress, medication, or disease, the virus can re-emerge and cause symptoms again. A small subset of cats may develop chronic, ongoing symptoms associated with this infection. Vaccination reduces the severity of symptoms but does not prevent infection.

Lysine is proposed to interfere with the replication of FHV-1 by blocking the uptake of another amino acid, arginine. There are theoretical concerns that lysine supplementation could make cats arginine deficient, but experimental studies suggest this is unlikely in practice. So it appears to be safe, but does it work?

Well, maybe. For once, numerous studies have been done, but there is no clear, consistent pattern of results. Some show that oral supplementation is ineffective and might even make infection worse (Drazenovich, 2009 Rees, 2008 Maggs, 2007). Others do seem to demonstrate some benefit (Maggs, 2003 Stiles, 2002). So while lysine supplementation appears to be safe and there is a plausible rationale for its use, no definitive conclusion about its efficacy is justified.

6. Milk Thistle

Milk thistle is an herbal product that is widely recommended and used. Like glucosamine, it is a supplement which has leapt over the gap between alternative and conventional medicine. The active ingredient is a cluster of compounds called silymarin. There has been extensive in vitro research on silymarin, and it has a wide range of potentially useful effects. It appears to interfere with pro-inflammatory chemicals, functions as an anti-oxidant, and may interfere with the metabolism of some chemicals into toxic compounds in the liver. It also has some activity which could be potentially harmful, including interfering with the metabolism of a number of drugs and stimulating the effects of hormones like estrogen.

The primary uses of silymarin in humans are to protect or treat liver damage from toxins and infectious diseases, to improve the condition of diabetics, and to protect the kidneys from toxins. In dogs and cats the primary use of for non-specific “support” of the liver regardless of the specific disease.

In humans, clinical trial evidence is mixed. A couple of studies have suggested it reduces insulin resistance in diabetic and may lower blood lipid levels. A Cochrane review of 13 studies including 915 people “could not demonstrate significant effects of milk thistle on mortality or complications of liver disease in patients with alcoholic and/or hepatitis B or C liver disease.” High quality trials were negative, and low quality trials suggested a benefit.

Very little research exists in dogs and cats. A small study of 20 cats given acetaminophen, a known liver toxin, found that those given a single oral dose of silymarin did not show the elevation of liver enzyme levels seen in those not given the compound. A similar study in dogs found some differences in elevations of kidney values between those that got silymarin and those that didn’t following exposure to a kidney toxin, though there was not a completely consistent pattern.

A study done in 1978 showed that dogs given a toxic mushroom compound orally and then given silymarin intravenously did not show the increase in liver enzymes that was seen in control dogs. Another in 1984 found that 30% of the control dogs died whereas none of the dogs given IV silymarin along with the mushroom toxin died, and the livers from the treated dogs did not appear damaged by the toxin. What relevance this has for the value of oral supplementation isn’t clear.

As far as risks, there appear to be few. Nausea, diarrhea, and other gastrointestinal effects are sometimes seen in humans and animals, and allergic reactions have been reported in humans.

So overall, the in vitro and laboratory animal evidence indicates it is plausible that milk thistle extract might have beneficial effects, though harmful effects in some situations could be possible as well. In humans, the clinical trials show weak evidence for benefit in some conditions and no evidence of benefit in others. Very little experimental, and apparently no high quality or controlled clinical research exists in dogs and cats. So once again, harm seems unlikely and a benefit is possible for some dose and some form of silymarin in some conditions, but we lack the information to use the compound rationally or to know for certain if it is even useful in most cases.

7. S-adenosyl methionine (SAM-e)

SAM-e is a chemical which occurs throughout the body and has a fascinating array of in vivo functions and in vitro effects. In humans, it is marketed for use in depression and arthritis, and a variety of other conditions. The clinical trial evidence is mixed and not generally high quality (for example, Cochrane Reviews for arthritis and alcoholic liver disease, Mayo Clinic summary for various conditions).

In pets it is primarily promoted as protecting the liver from damage due to disease of toxins, often in combination with Milk Thistle, though its use for arthritis and other conditions is also sometimes recommended. While the theoretical arguments for these uses, especially in the case of liver disease, are plausible, there is virtually no clinical research that the compound actually benefits patients when given as an oral supplement. There is one study which found no significant benefit in preventing liver changes associated with steroid use, one case report claiming some possible benefit in a dog with acetaminophen toxicosis, and one clinical study that suggest some possible value in treating age-related cognitive dysfunction in dogs. And despite how widely used this supplement is, and how sweeping the claims made for it often are, that’s about it.

8. Digestive Enzymes

The claims made for digestive enzyme supplements are often sweeping and dramatic, and they can make you wonder how anyone ever digests their food without them. The usual arguments are that these enzymes exist in raw foods but are destroyed in the production of commercial pet foods, so if you are so foolish as to feed a nutritionally balanced commercial diet, you’d better give your pet these supplements, or else! These exaggerated, unsupported, sometimes outright mythical claims for raw food diets in humans and dogs have been discussed here before. They are based on fundamental misconceptions about digestive physiology and nutrition, and they hold no water.

Healthy humans and dogs have all the enzymes they need to effectively digest foods. The organs that produce such enzymes do not become stressed or fatigued by doing what is, after all, their normal function. Commercial diets and their constituent ingredients are extensively tested for digestibility, and there is no evidence that any deficiency of enzymes in these foods creates nutritional deficiencies or any specific health problem.

In addition to use in healthy individuals, enzymes are also recommended for cancer treatment, anti-inflammatory effects, and treatment of many other disease conditions. Though the occasional study is published to support these recommendations, often in “integrative medicine” journals, there is no consistent, high-quality clinical evidence in humans that digestive enzymes are effective therapy for any condition other than true pancreatic enzyme deficiency. And there is evidence that this approach may be ineffective or even harmful.

There is, surprise surprise, no clinical research at all on the subject in cats and dogs. Apart from pancreatic insufficiency, in which enzyme supplementation is often effective, the claims made for the use of enzyme supplements are based solely on anecdote, theory, or extrapolation from in vitro research.

9. Coenzyme Q10

Like most dietary supplements, coenzyme Q10, also known as ubiquinone, is recommended for a wide range of apparently unrelated conditions. It is recommended in humans for cardiovascular disease, Alzheimer’s disease, migraines, diabetes, and many others, as well as a general tonic and, of course, the inevitable “boosting” of the immune system. In dogs and cats it has primarily been recommended for treatment or prevention of heart disease and age-related cognitive dysfunction.

There is controversy about many of the recommended uses in humans, with mixed and generally low-quality clinical trial evidence for most uses. And, as you will no doubt have anticipated by now, there is virtually no reliable research on its use in pets. One small experimental study failed to find evidence of decreased Coenzyme Q10 levels in dogs with congestive heart failure. There appear to be no clinical trials for any specific indication, and the recommendations for this supplement are again based entirely on theory, anecdote, and pre-clinical research or clinical research conducted in humans.

10. Azodyl

Azodyl is a proprietary mixture of probiotic organisms and prebiotics (substances intended to promote the growth of supposedly beneficial gastrointestinal bacteria) that is marketed for the treatment of kidney failure in dogs and cats. The theoretical argument advanced to support its use is “enteric dialysis,” the idea that populating the gastrointestinal tract with bacteria that breakdown some of the nitrogenous wastes the kidneys normally remove from the body can lower the levels of these substances and improve clinical symptoms of renal failure. While this idea is not inherently unreasonable, it does suffer from the weakness of other probiotic therapies in that it requires relatively small additional to the gastrointestinal flora to have significant systemic physiologic effects, which may or may not actually be possible. In any case, it is not a concept that has been validated in practice.

A single pilot clinical trial of the product in humans, sponsored by the manufacturer, has been published. This identified statistically significant changes in one out of three laboratory measures and in a subjective assessment of clinical symptoms. An unblinded, uncontrolled case series in 7 cats reported small changes in laboratory values in 6 of the subjects. And similar small studies in vitro and in rats and miniature pigs, again all supported by the manufacturer, have reported some positive changes in some measures of kidney disease.

Overall, the theory is possible but of uncertain plausibility in the real world, and the clinical evidence is limited and highly vulnerable to bias in terms of methods and funding source.

Bottom Line

So to answer the original question, do these popular supplements work? Well, glucosamine almost certainly does not, and the case for multivitamins and digestive enzymes are extremely weak. Fish oil likely does have small benefit for allergies, and no definitive conclusion can be made concerning arthritis, though the early veterinary trials haven’t been promising. Probiotics are a promising avenue for research, and there is reasonable evidence for some benefit in acute idiopathic diarrhea, but overall they are really not ready for prime time. Lysine, SAM-e, Milk Thistle, and Coenzyme Q10 all have reasonable theoretical foundations based on preclinical research, and none have adequate clinical evidence to draw any firm conclusions.

So should veterinarians and pet owners use these products? The decision whether or not to employ a particular medical intervention is always a matter of balancing the urgency of acting with the risks and benefits of the therapy, and always in the context of the limitations on the available information. In cases where the therapy is very unlikely to provide a benefit, such as glucosamine, there is really no rational argument for its use even if it is harmless, and the resources wasted on such treatments could better be spent on more plausible therapies or research to find better treatments.

In cases where there is a plausible theoretical rationale but inadequate clinical evidence to make a firm conclusion, I am personally reluctant to recommend using such supplements because in the face of such uncertainty we are as likely to do harm as good. For example, Milk Thistle and the combination SAM-e and Milk Thistle products seem to induce loss of appetite in cats and dogs fairly frequently in my experience, and they are usually given to patients who are pretty sick and already taking many other medications. So in the absence of stronger evidence of benefit it seems imprudent to use them routinely. However, in urgent cases where there is no validated therapy and the clinical circumstances are dire, I can’t fault anyone for grasping at straws, and I have certainly done so myself.

And, of course, if there is a sound theoretical rational and some reasonable clinical evidence, as in the case of fish oils for allergies and probiotics for acute uncomplicated diarrhea, use of such supplements seems perfectly reasonable. We must be careful not to let the perfect become the enemy of the good, and in veterinary medicine where the quantity and quality of the research evidence will always be less than optimal, we are justified in trying out things that are reasonable but unproven if the clinical circumstances warrant it.

Of course, the marketing used to promote these supplements goes well beyond anything justified by real scientific evidence and is almost universally untrustworthy. Likewise, the testimonials and anecdotes about their effects, whether from patients, pet owners, veterinarians, or Nobel Laureates, are all just stories with almost no probative value. And since most good ideas in medicine ultimately fail to become real, effective clinical therapies, it is likely that many even of the more plausible of these products will turn out not to be useful or to have unknown risks. Without adequate supporting evidence and without effective quality control, regulation, and post-market surveillance, we can never be sure we are helping and not harming our patients by using them.

However, it is also possible that some of these products will survive the rigors of real scientific investigation, if they are ever subjected to them, and will turn out to be truly useful therapies. And in the meantime, it may be reasonable to use some of them if the existing evidence and clinical need of the particular case are sufficient to justify doing so.

What Is An NMN Supplement?

This article will address both NMN (Nicotinamide mononucleotide) and NR (nicotinamide riboside) supplements as both are precursors to NAD+ and both are used to maintain and replenish NAD+ levels.

NMN, Nicotinamide mononucleotide is a type of bioactive nucleotide (organic molecule), a precursor to NAD+ (nicotinamide adenine dinucleotide), which enables cells to produce energy. NMN supplements are designed to help boost the body’s NAD+ levels. In the Clinical Trial segment, we will discuss how NMN may play a role in addressing serious illnesses attributed to declining NAD+ levels.

NR (nicotinamide riboside) is a form of Vitamin B that may be the most efficient route to form NAD+ or nicotinamide adenine dinucleotide. NR is the raw material from which your body makes NAD+ through a series of chemical transformations.

Both supplements increase NAD+ levels to stimulate energy, for DNA repair and Sirtuin activity. To grasp this new category of supplements’ significance, it’s essential that we develop an understanding of NAD+ and its function.

What Causes Eczema?

So, what causes it? Unfortunately, there are numerous theories and possibilities when it comes to the causes of this condition, one of them being that your immune system is literally “overreacting” to certain irritants. In most cases, however, the actual cause of eczema remains a mystery. When it comes to eczema flare-ups, these can be triggered by temperature changes, contact with texturized or scratchy materials, chemicals in certain products such as detergents allergies, as well as respiratory infections.

How do we get to the very root of the issue? The answer often starts with our nutrition and making certain we get a healthy, balanced diet with the right nutrients. Today we’re exploring the role of supplementing with Fish Collagen Peptides from wild-caught cod when it comes to managing eczema and maintaining healthy skin.

Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel (2011)

Choline has multiple roles as an essential nutrient. A major dietary component found in eggs and liver, its absorption in the intestine is mediated by choline transporters. The majority of choline is used to synthesize phosphatidylcholine, the predominant lipid in cell membranes. As well as being essential in the synthesis of membrane components, choline accelerates the synthesis and release of acetylcholine, an important neurotransmitter involved in memory storage and muscle control. Choline is an essential element in neurodevelopment. As a major dietary source of methyl groups, choline also participates in the biosynthesis of lipids, regulation of metabolic pathways, and detoxification in the body.

Health outcomes associated with choline involve memory, heart disease, and inflammation, which also explain the consideration of choline as a plausible intervention in traumatic brain injury (TBI). Although there are no human studies examining the effect of supplementation during pregnancy on enhanced memory of the newborn, there are animal studies showing that choline supplementation provided during hippocampal development has an effect on maintaining memory in older age. This effect appears to involve changes in gene expression via gene methylation. Changes in homocysteine due to choline supplementation are also hypothesized to reduce cardiovascular disease (CVD) risk. In the Framingham Offspring Study, combined dietary intakes of choline and betaine were associated with lower concentrations of homocysteine, a marker for inflammation. During the ATTICA study, a cross-sectional survey (1,514 men and 1,528 women with no history of CVD) of health and nutrition being carried out in the region of Attica, Greece, the association between inflammatory markers and choline intakes was measured. Participants who consumed higher levels of choline (> 310 vs. < 250 mg/day) had lower concentrations of C-reactive protein, interleukin-6, and tumor necrosis factor-alpha (Detopoulou et al., 2008). For an overview of the metabolism, functions, and health effects of choline, the reader is referred to previous reviews (IOM, 1998 Zeisel, 2006 Zeisel and da Costa, 2009 Zeisel et al., 1991).

Because of its undesirable organoleptic characteristics when administered in doses that exceed the capacity of the small intestine to absorb it, choline is not readily accepted by patients. The most common form of choline in the diet is phosphatidylcholine, an ester of

choline that is not used as a substrate by gut bacteria and does not result in fishy body odor (Zeisel et al., 1983). Most studies reviewed in this chapter used an intermediary in the synthesis of phosphatidylcholine, CDP-choline. CDP-choline is composed of cytidine and choline and is hydrolyzed in the small intestine before absorption as citidine and choline. After absorption, citidine and choline are rephosphorylated and then CDP-choline is resynthesized again. CDP-choline also serves as a donor of choline in the synthesis of acetylcholine. This chapter includes evidence for the potential use of CDP-choline in TBI.


Choline has a critical role in neurotransmitter function because of its impact on acetylcholine and dopaminergic function. Studies in animals suggest that CDP-choline supplements increase dopamine receptor densities and can ameliorate memory impairment. In Parkinson&rsquos disease, for example, CDP-choline may increase the availability of dopamine. A Cochrane review of randomized trials testing the efficacy of CDP-choline in the treatment of cognitive, emotional, and behavioral deficits associated with chronic cerebral disorders in the elderly revealed no evidence of a beneficial effect on attention, but some evidence of benefit on memory function and behavior (Fioravanti and Yanagi, 2005). The brains of those with Alzheimer&rsquos disease have decreased phosphatidylcholine and phosphatidylethanolamine, and it has been suggested that CDP-choline may provide benefit by repairing cell membrane damage and enhancing acetylcholine synthesis. Both sphingomyelin and phosphatidylcholine, major constituents of brain membranes, are synthesized from the precursor choline (Zeisel, 2005). The role of choline in regulating the synthesis of phospholipids (e.g., phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, and sphingomyelin) as constituents of cell membranes is reviewed in Saver (2008). This review also includes a discussion of the evidence showing that choline promotes rapid repair of injured cell surfaces and mitochondrial membranes as well as maintenance of cell integrity and bioenergetic capacity. Increases in biomarkers representative of CDP-choline activity, such as phosphodiesters, were observed on proton magnetic resonance spectroscopy and were associated with improvements in verbal memory in humans (Babb et al., 2002 Fioravanti and Yanagi, 2005).

It is hypothesized that CDP-choline may exert neuroprotective effects in an injured brain through its ability to improve phosphatidylcholine synthesis (Adibhatla and Hatcher, 2002). In addition to its neuroprotective capability, CDP-choline potentiates neurorecovery, which has led to its evaluation as treatment for both stroke and TBI in animal models and in human clinical trials (Cohadon et al., 1982 Levin, 1991 Warach et al., 2000). The positive effects seen in models of ischemia and hypoxia may be explained by increased Bcl-2 expression, decreased apoptosis, and reduced expression of pro-caspase. Inhibiting caspase activity may decrease apoptotic activity and calcium-mediated cell death. Supporting these ideas, in vitro studies have also revealed that choline deficiency induces apoptosis in the liver by mechanisms independent of protein 53, which likely involve abnormal mitochondrial membrane phosphatidylcholine, leakage of oxygen radicals, and activation of caspases (Albright and Zeisel, 1997 Albright et al., 1996, 1998, 1999a, 199b, 2003 Chen et al., 2010). In humans, a choline-deficient diet also causes DNA damage and apoptosis (da Costa et al., 2006).

In addition, CDP-choline is hypothesized to attenuate the loss of phospholipid and increase in fatty acids after global and focal cerebral ischemia by preventing activation of phospholipase A2. CDP-choline may also act to protect against oxidative stress since it has

been shown to increase total glutathione levels, glutathione reductase activity, decreased oxidized glutathione, and glutathione oxidation ratio (Adibhatla and Hatcher, 2005).

In rat models, the availability of choline to the fetus influences neurogenesis in the fetal brain (Craciunescu et al., 2003), and choline status in early life influences neurogenesis rates in the adult hippocampus (Glenn et al., 2007), an area of the brain that is often dysfunctional in TBI. Additionally suggesting choline mechanisms of action relevant to TBI are the fact that in rodents, choline deficiency is associated with lipid peroxidation in liver (Ghoshal et al., 1984, 1990) and that deletion of a choline metabolism gene results in mitochondrial dysfunction in the liver, sperm, testis, heart, and kidney (Johnson et al., 2010). A list of human studies (years 1990 and beyond) evaluating the effectiveness of CDP-choline in providing resilience or treating TBI or related diseases or conditions (i.e., subarachnoid hemorrhage, intracranial aneurysm, stroke, anoxic or hypoxic ischemia, epilepsy) in the acute phase in humans is presented in Table 9-1 this also includes supporting evidence from animal models of TBI. The table includes the occurrence or absence of adverse effects in humans.


In 1998, the Institute of Medicine (IOM) recognized choline as an essential nutrient (IOM, 1998 Zeisel and da Costa, 2009) and set the Adequate Intake (AI) for choline at 550 mg/day and 425 mg/day for men and women 19 years of age and older, respectively. These levels were set based on the dietary intakes of the U.S. population, and on the development of liver damage seen with lower intake. The Tolerable Upper Intake Level (UL) for choline is 3.5 g/day for adults 19 years of age or older, based on fishy body odor and hypotension (IOM, 1998).

Choline is found in a variety of foods including eggs and liver. Deficiency has been clearly linked to atherosclerosis, neurodevelopmental diseases, and liver disease (Penry and Manore, 2008). The human body is unable to synthesize sufficient choline via direct methylation of phosphatidylethanolamine to phosphatidylcholine, so choline must also be acquired via the diet. Analysis of choline intake has suggested a high level of deficiency in the U.S. population (Fischer et al., 2005 Jensen et al., 2007). Choline deficiency has been linked to a variety of secondary disease processes, such as liver disease cardiac, neurodegenerative and neurodevelopmental problems and breast cancer (Li and Vance, 2008 Zeisel, 2006). In addition, it is estimated that up to 50 percent of the population carries genetic variations that require increased choline intake (Zeisel and da Costa, 2009).

Direct choline therapy, when administered in doses higher than the intestine can absorb, often leads to malodor that is unacceptable to participants. The use of forms of choline that are efficiently absorbed and avoid this problem is desirable. All the studies reported by the committee have used CDP-choline, an endogenous compound and intermediary of the synthesis of phosphatidylcholine. CDP-choline was originally identified as the key intermediary in the biosynthesis of phosphatidylcholine by Kennedy in 1956 (2003), and is now also sold as a dietary supplement. However, there is no evidence that CDP-choline is the most effective form, and other forms of choline could be tested in future TBI studies.

CDP-choline has been used in the treatment of cerebrovascular disorders for many years, under a variety of protocols and to ameliorate various conditions. In several European countries, for example, CDP-choline is frequently prescribed for cognitive impairment and in the treatment of Parkinson&rsquos disease.

CDP-choline is generally considered safe the side effect most noted in clinical trials has been mild diarrhea, with leg edema, back pain with headache, tinnitus, insomnia, vision


Glutathione is an endogenous antioxidant that is frequently depleted in patients with oxidative stress or systemic inflammation, including those with chronic obstructive pulmonary disease and acute respiratory distress syndrome. After systemic administration, N-acetylcysteine is rapidly converted to cysteine, which is a precursor to glutathione, leading to significant increases in plasma and alveolar glutathione concentrations. Furthermore, N-acetylcysteine itself is a direct scavenger of ROS, leading to antioxidant effects. Administration in vitro and in vivo leads to anti-inflammatory effects (eg, decreased IL-6 and TNF alpha concentrations) and antioxidant effects in a number of pulmonary diseases, including viral pneumonia and acute respiratory distress syndrome. 9

N-acetylcysteine also has activity as a mucolytic due to its ability to disrupt disulfide cross-bridges in the glycoprotein matrix of respiratory mucus. However, these effects have not consistently translated to clinical outcome benefits in patients with hyper-inflammatory diseases, 10 and N-acetylcysteine is not routinely used as an anti-inflammatory or antioxidant in clinical practice. Because patients with COVID-19 have evidence of systemic inflammation (includ ing possible cytokine release syndrome), often have their course complicated by acute respiratory distress syndrome, and may have respiratory mucus buildup limiting adequate airflow (such as endotracheal tube obstruction due to mucus), systemic or aerosolized N-acetylcysteine (or both) may be beneficial in this specific patient population.

There does not seem to be a role for N-acetyl-cysteine supplementation to prevent COVID-19. However, through the varied mechanisms described, N-acetylcysteine administration may improve outcomes in patients with established COVID-19 and should be further studied.

What Causes Pellagra?

Consider the history of pellagra, a disease sometimes described by three Ds – dermatitis, diarrhea, and dementia. Death once loomed as a possible fourth ‘D’. In the early 1900s, as economic conditions worsened in the southern United States, the disease became epidemic in just a few short years.

What caused pellagra, and what could be done to treat it or prevent it? The history tells us something about scientific errors – and if, when, and how they are corrected (Rajakumar, 2000 Marks, 2003 Mooney et al., 2014).

Everyone seemed to acknowledge, even without systematic research, that pellagra was closely related to poverty. But that could hardly be regarded medically as a cause. In the next several years, many theories emerged. Pellagra was due to poor sanitation (some sort of infection), consumption of corn (moldy, spoiled?), poor environmental conditions, or seasonal influences. Because the first set of cases had been reported in an insane asylum, and pellagra was found frequently in prisons, orphanages, and cotton mill villages, and given that it shared features with tuberculosis, infection seemed most likely.

To help resolve the uncertainty, in 1912, mining baron Robert Thompson and cotton broker Henry McFadden commissioned a report from the New York Post–Graduate Medical School. The team traveled to Spartanburg, South Carolina, to collect epidemiological data firsthand. They issued their first report in 1914. They confirmed the contexts of poverty and sanitation. Having examined the role of diet, they excluded the possibility of any particular dietary item, such as corn. Their overall conclusion confirmed the earlier assumption of an infectious agent.

In the meantime, Casimir Funk introduced the concept of vitamins, and hinted in 1913 that pellagra, like scurvy and beriberi, might be a vitamin deficiency, too. Today, of course, we are inclined to celebrate his insight. Pellagra, we now know, is a niacin (vitamin B3) deficiency. But in the context of the time, without clear evidence, his proposal could only be regarded as speculative. Niacin was not yet known. Funk's “correction” was not truly effective.

In a separate 1914–15 study, initiated by the U.S. Public Health Service, Joseph Goldberger focused on diet and tried generally more varied diets in four different institutions. The effect on reducing pellagra was favorable. Goldberger's conclusions reflect our modern views, so his work tends to be rendered intuitively as groundbreaking. A classic study overturning the earlier misconceptions. Self-correction at work. Yet Goldberger's data were very broad. While the results indicated diet as a possible factor, Goldberger could not identify any particular deficiency, whether amino acid, mineral, or another factor. Ironically, he gave low probability to the role of any unknown vitamin. So, even though Goldberger was “right,” his conclusions were justly regarded as incomplete and inconclusive. Correction is not as easy as identifying an alternative or producing a handful of confirming evidence.

A few years later, in 1916, the Thompson Commission published its final report. Drawing on additional research – and despite Goldberger's findings – they strongly echoed their earlier conclusions that pellagra was infectious. The tentativeness seemed resolved. End of story? Ironically – perhaps paradoxically – the apparent resolution to the theoretical uncertainty by a prestigious commission rejected the (ultimately) correct answer.

Even more remarkable, perhaps, were two supplemental sections to the final report by independent researchers invited by the commission to contribute their views. The first was by Charles Davenport, a noted biologist from Cold Spring Harbor Laboratory in New York. How did Davenport address the diet-versus-infection controversy? By dismissing both! The significant cause of pellagra, he concluded, was, instead, hereditary! Davenport presented over three dozen pedigrees, mapping the occurrence of pellagra across generations in families (Figure 1). Davenport acknowledged that the disease was “probably communicable,” as the Thompson Commission contended, but he stressed that “constitutional factors” shaped the spread of the disease:

When both parents are susceptible to the disease, at least 40 per cent., probably not far from 50 per cent., of their children are susceptible an enormous rate of incidence in a disease that affects less than 1 per cent., of the population on the average.… We can understand this on the ground of inheritable differences in constitution of the children, just as brown eyes and blue eyes occur in the same family.

For Davenport, family differences (for example, whether mental, dermal, or intestinal symptoms of pellagra predominated) reflected biotypes or bloodlines that “afford the best proof that there is, indeed, a hereditary factor in pellagra” (Davenport, 1916, p. 15). More evidence, then. But it hardly promoted correction. Davenport's interpretation (we may easily observe in retrospect) was surely influenced by his belief in eugenics. For him, many undesirable human conditions could be attributed to genetics, rather than discomforting social inequities or politics. He thus discounted the correlation of pellagra with economic impoverishment. And poverty was surely “inherited” – culturally. Historically, Davenport's high-profile pronouncement led away from, not towards, correction.

Amid the controversy about whether pellagra was caused by diet or infection, Charles Davenport presented this pedigree as evidence that pellagra had, instead, a significant hereditary factor. Davenport's error further confounded the debate, rather than contributing to a “self-correcting” process in science.

Amid the controversy about whether pellagra was caused by diet or infection, Charles Davenport presented this pedigree as evidence that pellagra had, instead, a significant hereditary factor. Davenport's error further confounded the debate, rather than contributing to a “self-correcting” process in science.

The second addition to the commission's 1916 report was from Edward Vedder, who had worked earlier on beriberi, recently identified as a vitamin deficiency. Vedder vigorously defended the skeptical position that “much of the evidence that has been presented as a proof of the infectious nature of pellagra can be reasonably explained in accordance with a deficiency hypothesis” (Vedder, 1916, p. 172). Still, while maintaining that “the hypothesis that pellagra is caused by a deficiency is very plausible and must be taken into consideration in subsequent studies of this disease,” he refrained from endorsing it fully. He regarded “the question as to whether pellagra is an infection or a deficiency disease to be entirely open” (p. 137). Unfortunately, perhaps, that caution was not widely accepted in the shadow of the Thompson Commission's and Davenport's strong claims. It may seem to us, now, that Vedder was correcting science at this point. But in the context of the time, this required knowing (anachronistically, in advance of the future history) to trust Vedder, not Davenport or the commission, as the voice of science (Sacred Bovines, May, 2012). That is the conundrum or error. Based on the 1916 report, science seemed to have just “self-corrected.” But, ironically, it had not.

Meanwhile, Goldberger had continued his work under the Public Health Service. In a new study also published in 1916, he and labor economist Edgar Sydenstricker echoed the diet deficiency hypothesis. But now they linked poor diet directly to low wages and the high cost of food, which they presented as the root cause:

[T]he proportion of families affected with pellagra declines with a marked degree of regularity as income increases.

They further blamed the agricultural system in the South, which was focused on cotton as a cash crop, at the expense of growing local vegetables, which, where available, tended to alleviate the risk of pellagra. That is, the problem was fundamentally or primarily socioeconomic, not biological. Their emphasis on the social system – faulting the tenant system and agricultural economy – would continue at least until 1927 (Marks, 2003, quotation on p. 45). That did not really help foster understanding of any specific nutritional dimension of pellagra. Even Goldberger and his colleagues (heroes, today) seemed not always to contribute methodically to correcting the science.

Because most scientists considered the question resolved, they did not seek further evidence. That was due to Goldberger's work alone. In 1922, he finally narrowed down the apparent deficiency to an amino acid – either tryptophan or cysteine – while simultaneously rejecting a role for vitamins. Again, what appears as self-correction supports the wrong conclusion. By 1924, Goldberger reversed himself again, accepting vitamin H as a factor. The subsequent publications (in 1927) began to gain some traction among other scientists. Goldberger had found a simple nutritional supplement, yeast, that seemed effective in treating pellagra in both dogs and humans. Hospitals and other institutions had a concrete (and affordable) remedy that could be implemented. Scientific opinion followed. But still without full clarity on what caused pellagra. Goldberg died of cancer in 1929, and without his effort, the search for dietary clues to pellagra waned.

Although Goldberger was largely correct, nicotinic acid (vitamin B3) was not identified until 1937. In summary, correcting early theories about spoiled rice and infection was anything but straightforward. Many opportunities to shift closer to the ultimate solution were missed. Equally important, perhaps, was the challenge of any policymaker during the period. Could they have effectively relied on a scientific consensus to identify with certainty the cause of pellagra? The Thompson Commission, in the implicit role of a panel of experts resolving errors, was wrong. Davenport introduced yet more error. Vedder's cautions were overshadowed. Goldberger's claims were vague or inconsistent. Correcting the rejections itself took time. The process hardly conjures an image of systematic or methodical “self-correction.” Nor any explicit test for knowing when corrections might finally be done.

Yes, correction did occur. But not self-correction. The convoluted history of pellagra does not exhibit any uniform progress towards a solution. One should consider the many particular factors that did yield gains. Substantial effort separated Funk's proposed explanation of a vitamin deficiency and general acceptance of the corrected theory over two decades later. Corrections are not guaranteed, and sometimes the new, corrected theory is, ironically, actively rejected.

5. Zinc in Wound Healing𠅌linical Perspectives

The role zinc plays in wound healing can be viewed from two perspectives: first, the impact of zinc deficiency and second, the effect of zinc supplementation (topical/local or systemic) on wound repair. The association between zinc deficiency and delayed wound healing has been described [32,35]. Treating zinc deficiency results in improved wound healing compared to those with zinc deficiency. For example, in patients considered to be at risk of refeeding syndrome, it may be appropriate to give a loading dose of 10� mg of Zn, followed by the daily maintenance dose of 2.5𠄵 mg [4]. However, the impact of zinc supplementation on wound healing in patients without zinc deficiency is less well known. There are very few well-done clinical studies on the topic and what little information currently available is inconsistent. For example, the Cochrane database reports 6 small studies on patients with arterial or venous ulcers and found that oral zinc supplementation did not improve wound healing [162]. Contrarily, another meta-analysis of topical zinc therapy with zinc oxide paste-medicated dressing containing zinc concentration between 6�% for chronic venous leg ulcers showed improved healing, though the authors point out that the studies were small and of sub-optimal quality [163]. Cereda and co-authors performed a randomized, prospective trial in malnourished patients with chronic pressure ulcers [164]. They found a significant reduction in the size of the ulcers after 12 weeks of supplementation with a high calorie, high protein oral formula that was also supplemented with arginine, anti-oxidants and zinc (either orally or tube fed with 18� mg zinc daily). It is unknown how significant of a role the zinc supplementation played in this study. Attia and colleagues reported on 90 non-diabetic patients with uncomplicated wounds who were topically treated with one of two zinc-containing fluids (regular crystalline insulin or aqueous zinc chloride solutions at 0.2 mg/100 mL per 10 cm 2 wound) versus a control of 0.9% normal saline. The groups treated with the zinc-containing fluids had significantly improved healing [165]. On the other hand, a study of 42 patients with pressure ulcers treated with oral l -carnosine versus zinc containing polaprezinc (at 34 mg per day) showed no difference in healing [166]. It is clear that more studies utilizing more stringent controls will be necessary to fully understand the clinical potential of zinc supplementation.

Due to the loss of zinc during injury, zinc therapy has been used in wound care to enhance healing in zinc-deficient patients [32,167]. Topical zinc sulphate (ZnSO4) application, usually at an optimal 3% concentration, has been widely used in wound healing for its antioxidant effect [30]. Other forms of application include 1% ZnCl2 or the largely insoluble zinc oxide (ZnO). ZnO provides prolonged supply of zinc to wounds and enhance its healing ability. Additionally, ZnO increases collagen degradation in necrotic wounds [168]. It has been shown that topical zinc application induces mRNA expression of metallothionein, which could account for its anti-UV photoprotective effect [30,169]. A standard regimen for severe burn care includes regular daily dietary zinc supplementation equivalent or exceeding 22 mg [39,170]. Moreover, recent advances in drug delivery with zinc oxide nanoparticle (ZnO-NPs) technology has received considerable attention for the treatment of wounds due to their effective cell penetration, immunomodulation and antimicrobial capacity [171,172]. However, in-depth pharmacodynamics and toxicology studies are still needed prior to widespread applications [173].

Biology and Diseases of Reptiles

Dorcas P. O’Rourke DVM, MS, DACLAM , Kvin Lertpiriyapong DVM, PhD , in Laboratory Animal Medicine (Third Edition) , 2015

2 Hypovitaminosis A

Vitamin deficiency commonly arises in reptiles fed an unbalanced diet lacking adequate levels of vitamin A. This condition is most commonly seen in chelonians, especially box turtles ( Boyer, 1996b ). Tortoises are generally not affected. Theoretically, any reptile is susceptible and this condition has also been observed in farm-raised crocodiles and captive green anoles ( Miller et al., 2001 ). Hyperkeratosis and squamous metaplasia of the respiratory, ocular, and gastrointestinal epithelia are most evident. The most prominent clinical signs are those involving the ocular system and upper respiratory tract, including cellular debris beneath the eyelids, and nasal and ocular discharges. Additional signs include anorexia, weight loss, and lethargy. Middle ear infections and egg retention are also common in box turtles. Kidney failure and fatty degeneration have also been noted in some species of reptiles. Diagnosis is made by evaluation of the diet, cytology of ocular discharge, or assay for serum or liver vitamin A concentrations. Normal liver vitamin A level has been reported to be >1000 IU/g in monitors and snakes. Retinol concentration can also be used for an assessment of vitamin A. Mean plasma retinol in tortoises ranges from 0.09–0.77 μg/ml ( Raphael et al., 1994 ). Treatment includes vitamin A injections (500–5000 IU/kg, SC, one or two treatments every 14 days), debridement of cellular debris from the eyes, treatment of secondary bacterial infections, and correction of dietary vitamin A deficiency. Nephrotoxic drugs should be avoided due to potential renal failure. Food rich in carotenes, especially the betacarotenes, consisting of dark leafy greens and yellow-colored or orange colored vegetables or fruits should be provided on a regular basis. Liver in whole mice or fish provides a good source of vitamin A for aquatic species. Commercial reptile diets are also available and are good sources of vitamin A.

Interactions: Blood Thinners, Warfarin and Vitamin K

General Precautions

Some drugs may cause vitamin K deficiency by reducing its production, regeneration, and uptake.

Alternatively, vitamin K may interfere with the effects of drugs that prevent blood clotting (blood thinners).

To help avoid interactions, your doctor should manage all of your medications carefully. Be sure to tell your doctor about all medications, vitamins, or herbs you&rsquore taking and discuss how they may affect your vitamin K status.

Warfarin and Blood Thinners

Blood thinners such as warfarin prevent the formation of blood clots by blocking vitamin K regeneration. People on these drugs should carefully monitor their vitamin K status and maintain a consistent intake of this vitamin, since high doses (above 100 mcg/day) may interfere with the therapy [17, 18].

Bacterial overgrowth in the bowel may cause a leaky gut. This increases vitamin K1 uptake and may require the use of a higher blood thinner dose [19].

However, it may be desirable to reverse the effects of blood thinners with vitamin K in certain situations.

When taken for long periods or at excessive doses, blood thinners may cause bleeding disorders. Supplementation with vitamin K reversed them in 12 clinical trials on almost 2.5k people [20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31]

People about to undergo surgery should discontinue blood thinners to prevent life-threatening bleeding during the procedure. Vitamin K helped restore normal blood clotting after stopping the drugs in trials on over 300 people, but was unnecessary in some. Talk to your doctor to understand how you should prepare for surgery [32, 33, 34, 35, 36].

Antibiotics and Other Drugs

Antibiotics may cause vitamin K deficiency by killing the gut bacteria that produce it. Cephalosporin antibiotics may additionally block vitamin K action in the body. However, vitamin K supplementation is only needed in case of long-term antibiotic use [37].

Drugs that block fat and cholesterol uptake in the gut may also cause vitamin K deficiency. They include:

Theoretically, high intakes of vitamin K1 may increase the effects of antidiabetes drugs (like glimepiride, glyburide, and many others) and lead to dangerously low blood sugar. Do not suddenly increase your vitamin K1 intake if you are on antidiabetics. Consult your healthcare provider first, as they may make dosage adjustments to your medications regimen.

Supplement and Nutrient Interactions

The following interactions with supplements are possible based on their theoretical effects or animal experiments:

    : may increase the effects of vitamin K2 due to a similar mechanism of action. This may increase the risk of excessive blood clotting, especially in people taking blood thinners [40]
  • Herbs and supplements that may lower blood sugar (such as berberine, bilberry, ginger, and many others): may increase the effects of vitamin K on lowering blood sugar. In diabetics, this might result in excessive blood sugar drops
  • Vitamin A: may reduce the effects of vitamin K in high doses : may reduce the effects of vitamin K in high doses, potentially increasing the risk of bleeding in people who are taking blood thinners or have low vitamin K intake

Human studies would need to confirm these interactions in humans, but caution is advised.

Supplement-supplement and supplement-drug interactions can be dangerous and, in rare cases, even life-threatening. Always consult your doctor before supplementing and let them know about all drugs and supplements you are using or considering.


Vitamin K supplements are considered to be generally safe. By mouth, they may cause stomach upset and nausea. Possible side effects of vitamin K injections include itching and redness. On the other hand, synthetic vitamin K3 can be toxic and is no longer in use in North America.

Vitamin K can interact with many drugs, supplements, and nutrients. One of the most dangerous interactions is with warfarin, a blood thinner. People who take warfarin need to maintain steady vitamin K intake, as any variation can dangerously alter bleeding and blood clotting time.

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