Image from: http://www.doctortipster.com/wp-content
We in functional medicine have long been aware that children can start out with a clearly identified food allergy. As the child ages, the primary allergic symptoms fade and some other clinically relevant presentation appears in its place. For example: we’ll see a classic milk allergy in infancy -- often as milk colitis. The child outgrows the milk colitis. The parents reintroduce milk as per the instruction of the pediatrician; the child then develops recurrent otitis media (ROM). More often than not, no connection is made to the reintroduction of milk, and the child continues to suffer with ROM. The ear infections will eventually wind down as the child hit his teens, but other medical issues pop up in its place: inflammatory arthritis, eczema, migraine headaches, various gastroenteropathies or sinusitis.
This is an all-too-common clinical scenario that has been largely unrecognized in medicine. However, if the individual is fortunate enough to have a functional medicine clinician identify the pattern, the food(s) will be removed and wellness is restored.
There is a dearth of research validating the observation of this age-specific food allergy phenotype.
A reasonable body of research exists that identifies the myriad clinical presentations that milk allergy can take, from colitis to sinusitis, migraine headache and eczema. Research on the evolving age-specific phenotypic expression of milk allergy, however, is far more limited.
In 2014 at the American Headache Society’s 56th annual meeting, Dr. Amy Gefland presented her research identifying infant colic as an early form of migraine. When I saw the news, I was quite excited that science was starting to connect the dots that we observe in clinical practice. I immediately scoured the report for any mention of an association with milk allergy. I was thrilled to see that she did indeed find that milk allergy-induced colic could also be associated with later migraine.
My suspicion was that we’d see a corresponding change in food specific antigen/antibody formation track with the phenotypic change (the transition from colic to migraine). So, milk/IgE antigen/antibody complexes would abound in the younger milk allergy presentation; but as the individual ages and migraines begin, milk/IgG4 complexes would be seen in the place of IgE complexes.
The IgE to IgG4 immunoglobulin class shift is well understood in the process of developing tolerance. For instance: when allergy shots are used to treat hay fever, a corresponding drop in IgE and rise in IgG4 can be observed, as symptoms of hay fever abate.
I strongly suspect, however, that while the formation of food/IgG4 complexes (as opposed to environmental antigen/IgE complexes) means an end to the acute IgE allergic response, the accumulation of these complexes over the long term can lead to problems.
In the case of milk allergy, the sheer quantity of dairy we consume (about 1.5 cups daily in the US) dwarfs the trace amounts of inhalant allergens we’re exposed to. It’s possible -- as has been proposed -- that these food/antibody complexes can be deposited in tissue and generate immune-reactivity.
Most recently, food/IgG4 complexes have been observed in high quantity in biopsy specimen and serum of adults with eosinophilic esophagitis (EoE). These complexes, rather than IgE, are thought to be central in the pathogenesis of EoE. In fact, when the researchers blocked IgE formation using omalizumab, there was no noted improvement in EoE symptoms, nor in eosinophil deposition in the esophagus as compared with placebo.
We are getting closer to fleshing out the complexity surrounding the age-related allergic phenotype. While I have seen eczema, migraine, colitis and sinusitis directly connected to food/IgG4 serum levels, (and clinical improvement with elimination of offending foods), piecing together the full allergy story from childhood IgE food allergy to adult IgG4 food sensitivity remains to be fully elucidated.
IgE and IgG4 results in an 8 year old with severe atopic dermatitis covering about 80% of his body. The first panel shows serum IgE foods and the second panel is serum IgG4 foods. After removal of the top offenders, his atopic dermatitis cleared completely. He was able to introduce all foods except dairy, which always caused a flare in eczema. His IgG4 to dairy remained high long after IgE levels normalized.
IgG4 food antibodies identified in the serum of a 60 year old woman with migraine headaches. Removal of these foods (especially egg) resulted in a significant reduction in migraine frequency and intensity.
IgG4 food antibodies in the serum a 21 year old male with severe allergic sinusitis. Removing these foods resulted in complete resolution of his symptoms.
IgG4 food antibodies in the serum of a 66 year old female with seronegative inflammatory arthritis and psoriasis. Removal of these foods resulted in a resolution of psoriasis and improvement in arthritis.
It’s winter. Chances are that if you live anywhere cold and dry, your lips have been chapped at least once this season. For most of us, we slather on the lip balm and all is well. But for some folks, the chapped lip experience is an entirely different animal: A relentless cycle of peeling and healing, peeling and healing that no amount of lip balm resolves. Lips are fissured and inflamed, making speaking, eating or smiling painful endeavors. Individuals with chronic chapped lips (cheilitis simplex or the more severe exfoliative cheilitis) become self-conscious of their appearance. Such was the case with Mary, a bright 24 year old woman (and naturopathic medical student!) who first came to see me this past Fall.
While Mary mentioned her lips at our first meeting, her main complaint was small intestinal bacterial overgrowth (SIBO). She had a positive hydrogen/methane breath test ordered by another physician, but hadn’t yet resolved the symptoms of gas, bloating and severe abdominal pain. This was clearly our first goal.
Mary had these same gut issues dating back to her teen years, which coincided with the start of her cheilitis.
We addressed her gut with a combination of a FODMAP diet, botanicals (my current favorite protocol includes enteric-coated peppermint oil and berberine) and betaine-HCL with meals. Mary avoided all probiotics which can worsen SIBO symptoms. We identified nutrient needs, including zinc (which I prescribed as zinc carnosine- great for healing an inflamed gut) magnesium, vitamins A and E and CoQ10. Mary was already taking a B complex with a good amount of B12, riboflavin, methylated folate and methylcobalamin.
While she probably didn’t need more B’s, I decided to increase them short term on the off-chance they helped with her lips. Angular cheilitis-sores along the corners of the mouth-is known to be associated with a riboflavin deficiency but can also be seen with folate, niacin, B12, B6 or zinc deficiencies. And all of these nutrients could be low in SIBO, caused by bacterial-induced hypochlorhydria and maldigestion.
As Mary began to feel better on the SIBO protocol, she contacted me rather urgently via email, reminding me of her painful lips. She included a photo. Her lips were worse than ever, she said. Peeling, healing, peeling, healing. It didn’t look good. We were clearly unsuccessful with the high-dose B trial. And all the lip potions in the world made no difference.
Baseline photo of Mary’s chapped lips
I’ll admit her chapped lips were a head scratcher for me. Especially given how chronic and totally unresponsive to treatment they were! She wasn’t a lip licker or biter. She was well-hydrated. Her diet was good, and her nutrient needs were met. She does tend a bit towards anxiety, but it just didn’t strike me as a fundamental player in her chapped lips, as it can be for some, because she had good tools for addressing her stress.
A clue was the temporal association with the onset of both SIBO and chapped lips. Could there be some microbial overgrowth also perpetuating the cheilitis? Dr. Alex Vasquez calls this “multifocal dysbiosis” that is, microbial imbalances occurring at different areas in the body, driven by systemic issues. I’ll admit: it seemed long shot, but a shot nonetheless. A look in the literature identified that both candida albicans and various bacteria have been associated with exfoliative cheilitis, but most often in immunocompromised folks. Since she is a patient who lives out of state, I didn’t take a swab for culture. But fortunately for us, functional medicine is generally quite safe, and a trial with a botanical antimicrobial concoction wouldn’t hurt.
I decided to go with a combination of coconut oil and berberine-about 1 TBS of coconut oil mixed with 500mg berberine, applied liberally and often. Easy. She wanted to add probiotics to the mixture. It seemed a reasonable idea to me.
A couple week later, Mary emailed me with glee- her lips were so much better! She needed to apply the combination often, but it really seemed to be helping. All of these ingredients could be useful on their own, I suppose. And those coconut oil acolytes out there I am sure will suspect it’s the key. But together, the combination worked and continues to work. See her follow up photo below.
Mary’s lips after treatment. Much better.
Incidentally, Mary’s case made me think of another. I treated a patient with trigeminal neuralgia when I worked at a tertiary care pain clinic some years ago. Facial pain was so severe in this woman that she maintained an unsupervised liquid diet for years. It was simply too painful for her to chew. She presented with classic angular cheilitis and not surprisingly, it cleared immediately when she started a good, high dose B complex. Multiple B deficiencies- induced by a poor diet- were the key to resolving her issue.
Wikipedia has a pretty nice short page on the various types and causes of cheilitis. DermNet also has a good section. The last link is a case report using a 10% calendula ointment for chelitis.
The 2014 flu epidemic: Let’s do what works!
The flu is here. Very early in the season, it’s already at epidemic proportions, hitting those most vulnerable to its ravages -- kids and the elderly -- as it does each year. The virus mutated early, greatly limiting the efficacy potential of the flu vaccine.
That said, the vaccine has had limited efficacy for years now. And we’ve known this. Influenza-like activity has been on a steady incline for the last decade, resulting in more hospitalizations and deaths, especially among the elderly.
I remind you of the statements made by Dr. Michael T. Osterholm, et al, from the Center for Infectious Disease Research and Policy, in 2012:
“The perception that current vaccines are already highly effective in preventing influenza is a major barrier to game-changing alternatives. Indeed, hundreds of influenza vaccine efficacy and effectiveness studies have been conducted since the 1940s, and vaccine efficacy in healthy adults of 70% to 90% is frequently cited. However, the preponderance of the available influenza vaccine efficacy and effectiveness data is from studies with suboptimal methodology, poorly defined end points, or end points not proven to be associated with influenza infection.” [Osterholm ea.The Compelling Need for Game Changing Influenza Vaccines. 2012 ]
As cited in the New York Times in 2012, Osterholm stated:
“We have over-promoted and overhyped this vaccine. It does not protect as promoted. It’s all a sales job: it’s all public relations.”
In early 2013, I experienced the flu for the first, and hopefully last, time. It wasn’t fun. I blogged all about it, with a particular focus on the influenza vaccine.
But, you know what? This blog isn’t about the vaccine. It’s about what we can do. Now. Today. Immediately, to protect ourselves, our loved ones and our patients. As Osterholm suggests, the perception that the flu vaccine is enough, just isn’t enough.
I’ve updated a table that I created some years ago. Add your suggestions in the comment section below. And here’s a handy download to use -- with your functional medicine clinician, of course -- around how to help PREVENT and, if needed, help TREAT influenza. While I don’t mention any medications in the table, it does appear that Tamiflu may help IF you start it at the very first signs. Which, incidentally applies to the nutrients listed below: The earlier the start with treatment, the better the outcome. Download the PDF.
2014-2015 Treatment Ideas for Influenza and Influenza-Like Illnesses - Kara Fitzgerald, ND
Healthy people fare well with influenza. Not surprisingly then, those with nutrient deficiencies and chronic diseases, such as diabetes, don’t do well. But fear not. Integrative medicine shines in this arena. Just think: change your lifestyle, improve your tolerance of influenza. I created this table in response to the H5N1 avian flu scare in 2007 for Metametrix Clinical Lab staff. It’s not exhaustive, but it’s a place to start. Discuss botanical and supplement dosages with your physician. Homeopathy is always safe and can be particularly helpful in some cases. When I had the flu (2013), I used Eupatorium with good results. It didn’t get me out of bed, but it reduced my severe body aches enough to comfortably stay in bed. And it might’ve shortened the duration of the flu somewhat.
2014-2015 Treatment Ideas for Influenza and Influenza-Like Illnesses - Kara Fitzgerald, ND
Specialty testing consideration – optimize wellness
Basic good, health habits
Immune-boosting supplements: use on-going and at onset of flu season as needed
Influenza treatment considerations
Homeopathic Remedies specific for influenza-like symptoms. Use the remedy most specific to the presenting symptoms.
Consider using 30C and dosing hourly. Benefit should be noted relatively quickly (a couple of hours); if not, try a different remedy.
Consult with your clinician as needed.
Treat nutritional deficiencies, use on-going nutrient support as directed by healthcare provider/ testing
Genus epidemicus. The first priority in homeopathy is to discover the “genus epidemicus,” that is, the remedy most suited to the symptoms specific to this year’s flu.
Read about the concept here: http://www.wholehealthnow.com/homeopathy_pro/wt10.html
Good: Organix Comprehensive Profile
Wear mask in season to reduce exposure and transmission
Antioxidant support: A,C,E, selenium, zinc
Nebulized glutathione or NAC (with or without supportive herbs)
Gelsemium-: marked debility, weakness, sleepiness Oscillococcinum: a long-used influenza remedy; a nosode from duck liver and heart
Aconite: sudden onset after exposure or shock
Eupatorium Perfoliatum: high fever; severe, unbearable aching
Oxidative stress markers, Organix basic or Organix dysbiosis markers
De-stress activities: Adequate sleep
Very high-dose short term vitamin A
Zinc: Apply to throat using lozenges or spray. Zinc is locally antimicrobial: Kills on contact.
Arsenicum: influenza with gastroenteritis, vomiting and diarrhea
Amino Acid 20
Exercise -- it’s immune boosting
Immune polysaccharides, such as, cordyceps, arbinogalatan (add mushrooms to your diet, even button mushrooms have good polysaccharides)
Broth: chicken, veggie, bone. Add garlic. Lots of it
Carbo Vegetalis: copious expectoration, severe apathy, difficulty breathing, cold but averse to being covered; paroxysm of cough
Fatty Acid profile or blood spot fatty acids
Dietary considerations: Decrease simple carbohydrates (prepared foods, sweets), minimize caffeine and alcohol intake.
Lots of fresh veggies & low sugar fruits. Good protein and fats.
Drink clean water and green tea.
From: Heritage Eye Care
Death, Taxes and… Presbyopia?
So here I am, comfortably into my 40s. In many ways, this is a grand time of life: satisfying career, happy home, a greater sense of well-being and contentment. But over the last couple of years, spectacles sit on the bridge of my nose more often than not, for any close-up activity. It started in my 30s: +1 “readers” when I was using the computer a lot. Not a big deal. And the tortoise shell frames looked cute, I thought. But then, seemingly overnight, the +1s became +1.5s; and shortly thereafter, +2.0s. Recently, when I was gunning for a pair of +2.5s, I said,“Enough!” I expressed my dismay to an ophthalmologist friend; he laughed and said, “Welcome to middle age!”
Death and taxes. Maybe. But presbyopia? Noooooo! Isn’t there something that functional medicine can offer which will curtail this rather irritating but inevitable rite of passage?
First of all, what IS presbyopia?
100% of us experience it between 40 and 50 years of age. That’s right, 100%. This means that more than a billion of us are presbyopic right now. (By comparison, the epidemic of diabetes claims about 350 million.) The change actually starts happening at about 20 years of age -- but we don’t notice it.
Figure 1: Basic anatomy of the eye.
Figure 2: The very basics of presbyopia
A few main processes seem to be occurring that underlie presbyopia. Understanding these gives us insight into a possible functional approach to treatment. One, the lens becomes sclerotic (hardened); and lens transparency (which is near-perfect in youth) is progressively lessened. This means that both seeing AND focusing on close objects (accommodation) becomes more difficult. The lens also continues to grow throughout life (about 20 µm per year), which means that the distance between the lens and the ciliary muscles (part of the ciliary body; see figure 1) is shortened. The ciliary muscles respond to this reduced distance by shortening themselves. The end result is that the force the ciliary muscles can apply to the lens is lessened, resulting in decreased ability to accommodate, or focus, on objects close up. Make sense? Think of it like tight hamstrings and reduced ability to fully extend your legs (only your legs don’t keep growing throughout life).
If you’re a functional medicine clinician, no doubt you’re wondering right now what causes the lens rigidity and loss of transparency. You’ve probably got a few ideas. Increased oxidative stress? Certain environmental factors? Yes to both.
Indeed, our ability to transport the all-important glutathione to the lens nucleus declines with age. Oxidized glutathione and dehydroascorbate (oxidized vitamin C) accumulate as we age. And we are less able to clear out the denatured/oxidized lens proteins via the ubiquitin-proteasome pathway as we get older. Furthermore, the accumulation of damaging advanced glycation end products (AGEs) -- sugars binding to lens proteins -- leads to loss of lens transparency. This is akin to the elevation of hemoglobin A1C that we see in diabetics.
Concurrently, the lenses are exposed to more oxidizing (hence damaging) environmental agents over the course of aging: UVA, cigarette smoke, chemicals (such as hair dyes) -- all have been shown to damage the lens and contribute to presbyopia. This is of course compounded by our reduced ability to respond to the oxidative assault.
Incidentally, these same underlying biochemical lesions -- left unchecked -- can form the basis of certain types of cataracts and macular degeneration.
Armed with this information, the start of a good treatment approach becomes clear. Note that these nutrients have shown benefit for cataracts and macular degeneration, not presbyopia. I am extrapolating that they should be at least somewhat useful for presbyopia, given the shared biochemical changes of each condition:
But I’d be remiss to stop here. In fact, I’ve followed a modified version of the above without sufficient benefit; although I do think it’s important, make no mistake. We have to dig a little deeper. Regarding changes to the lens size and ciliary muscle length: surgical procedures are on the horizon and could be a realistic option at some point. This is akin to getting LASIX. We should also consider:
I will be trying a few of these ideas- evolving my current protocol of eye exercises, lower strength glasses and supplements. I’ll add in the glutathione/carnosine drops, and consider trying Glasses Off. I’ll keep you posted!
A patient named Barbara bounded into my office. She threw herself into a chair, and looked at me with eyes of terror, guilt and shame. I knew from her countenance that it was confession time. She launched into her story, retelling an all-too-familiar tale: She hadn’t stuck with her anti-inflammatory diet. Her food cravings, she explained, were out-of-control, and she was miserable. Her weight was exploding, her abdomen was bloated and her head ached. But perhaps most importantly, she was depressed, anxious and felt like a failure….
“I can’t do this horrible diet!! I’m sooooo miserable, but I must have my comfort foods!!”
We’d been down this road together many times before. I was feeling discouraged right along with her.
Exasperated, I blurted out, “Who am I speaking with -- Barbara, or her gut bugs?”
The question momentarily silenced both of us. It was an epiphany. For Barbara and for me. Here was this lovely young woman, so eager to get well, but repeatedly failing in her attempts. Her short-lived moments of healthy eating demonstrated that the rewards would be high with regard to symptom resolution; but she so often plunged to epic lows as she gave in to the “voices” that whispered insistently, “Donuts, pizzzzzza, fried chicken….”
At that moment, sitting in a chair in my office, Barbara no longer appeared to me as Barbara. Rather, I was now speaking with a teeming, nefarious gut microbiome, out for its own selfish survival, host be damned! Petulant and irrational, these critters allowed for no negotiation. It was the puppet master; Barbara, its unwitting marionette….
We’ve known for years that our gut bugs -- all 100+ trillion of them -- profoundly influence human physiology. Imbalances in our microbiome are associated with autoimmune disease, diabetes, heart disease, allergic disease and even obesity.
We’ve also known that the inflammation generated by an imbalanced microbiome can influence our mood; that is, our gut bugs can produce (or influence the production of) inflammatory cytokines that increase excitotoxic neurotransmitter release, deplete our feel-good neurotransmitters and make us feel lousy.
And those of us who treat patients have observed for a long time now that food cravings appear to be influenced by these same bugs: We are what our gut bugs eat; and when the ugly bugs are gunning for control, the outcome isn’t pretty. Conversely, when the diet is clean and balanced, cravings resolve or are minimal, health is restored and psychological well-being is established.
Being a bit of a research junkie (influence by my microbiome?) I have been looking for a satisfying scientific explanation for what we see clinically. Finally, such a paper has been written -- published this month in the journal Bioessays, Is eating behavior manipulated by the gastrointestinal microbiota? Evolutionary pressures and potential mechanisms by Alcock, Maley and Aktipis. This article delivers the best collection of arguments for why ‘we are what our gut bugs eat’ that I’ve seen yet.
Evolutionary conflict between host and microbes leads to host manipulation. This makes good sense. Diets as actions of will-power fail time and again. Counting calories doesn’t work. Gut bugs appear to be able to manipulate host eating behavior in ways that promote their fitness and survival at the expense of host fitness.
Microbial genes outnumber ours 100 to 1, giving bugs the clear numbers advantage. A larger, but less diverse, microbial population (often seen in disease states) has a powerful capacity for host manipulation by virtue of its ability to produce higher quantities of host behavior-altering neuroactive compounds. Further, microbes may engage in large-scale host manipulation/coordination through quorum sensing.
For Barbara, the good news: Hang in with the dietary changes, and the cravings WILL stop.
We can, fortunately, change the make-up and behavior of our microbiome by altering our eating. And it can happen quite quickly. Thus, moving away from a damaging diet -- and sticking with it just long enough -- can reduce cravings and restore microbial diversity. Further, altering the microbiome through prebiotics, probiotics, fecal transplant and (perhaps) antibiotics may be realistic and potent interventions for cravings, mood, obesity and unhealthy eating.
The players we want in abundance:
A potent well-designed cocktail of pre- and probiotics may be exactly what Barbara needs to move her through the craving stage just long enough to resume being in the driver’s seat, or at least in a comfortable passenger’s seat, with a happy microbiome.
Essential fatty acids, isoprostanes, and the origin of life.
Sometimes I rather humorously, and embarrassingly, ask my patients if they remember what was happening while they were in utero. Generally, they don’t recall. The reason I ask, after rephrasing the question (“Has your mom shared with you any difficulties she had when she was carrying you?”), is that I am looking for antecedet factors. Maybe mom was on antibiotics. Maybe she was under a lot of stress. Maybe she drank alcohol or smoked. Maybe she was given the now-recognized teratogen and carcinogen, DES (diethylstilbestrol). All of these are potential influences on my patient’s current presentation, and are thus important questions to explore.
Well, what if we drill down even further. To the time life began. When we were single cells, or even before. Maybe we were just starting to engulf the bacteria that later became the mitochondria… remember? There was just a smidgen of oxygen hanging around, but it was increasing. And along with oxygen came oxidation and free radical formation. We are now a free radical-obsessed culture of functional clinicians. Quenching their formation at every turn. “More antioxidants!” we shout. But back in the day, in this primordial, pre-enzymatic soup, non-enzymatic oxidation fueled important reactions essential to the development of life. And it’s quite plausible that the products of these reactions are still important players in physiology today.
When I first learned about isoprostanes, non-enzymatically produced before-time-began non-classical eicosanoids, I whispered “ghost eicosanoids.” I was immediately hooked.
Isoprostanes: Ghost eicosanoids? There are likely hundreds of these free-radically formed non-classic eicosanoids secretly going about their business in our bodies; some damaging, but some participating in normal physiology…
Eicosanoids -- produced from the COX and LOX enzymes -- form a hormone-like signal molecule system of exquisite power and complexity. They are derived from the omega-6 and omega-3 20-carbon fatty acids, and made in every single cell in the body. Eicosanoids from arachidonic acid (AA) are generally, but not always, major players in inflammation; whereas those eicosanoids derived from eicosapentaenoic acid (EPA) and dihomogammalinolenic acid (DGLA) are anti-inflammatory in their (direct or indirect) effects. In general, the goal with our inflamed patients is to reduce the quantity of AA-derived eicosanoids and improve the quantity of EPA and DGLA-derived eicosanoids.
There are hundreds of eicosanoids.
And there are hundreds of isoprostanes. All are produced by free radical action on DHA, EPA, AA and other fatty acids. (Any fatty acid with three or more double bonds can form isoprostanes!) If you consider the complexity of eicosanoid biochemistry, you can get an idea of where we are headed with isoprostane research.
The arachidonic acid-derived F2-isoprostanes are by far the best understood of the bunch. They are similar in structure to the potent pro-inflammatory arachidonic acid-derived PGE2 and PGF2, but exist in much greater quantity. In plasma, F2-isoprostanes are a whopping 10-fold greater than PGF2, and rise considerably higher in those under a great deal of oxidative stress.
F2-isoprostanes are bad actors. They can cause vasoconstriction in the kidneys, lungs, liver, bronchi, blood and lymph vessels, uterus and GI tract. They are associated with increased perception of pain and are elevated in acutely hyperglycemic diabetics. They’re also high in smokers. And heart disease. And autism. In the white matter of the brain of those with early stage Rett Syndrome, a specific isoprostane isomer produced by free radical action on myelin-sourced adrenic acid was found to be up to two orders of magnitude higher than healthy controls, indicating early evidence of brain damage.
More than just biomarkers of oxidative damage, F2-isoprostanes are DIRECTLY damaging. We can readily measure F2-isoprostanes in urine. And we can readily turn production of them around with basic healthy living habits, diet and antioxidants.
But don’t quench all the free radicals just yet: There are other isoprostanes that participate in normal physiology.
Isoprostanes are highest during fetal and early neonatal life. They’re probably important players in development. The placenta is a major producer of isoprostanes.
There are many, many isoprostanes produced by EPA and DHA that have important biological roles. Further, EPA and DHA robustly reduce levels of AA-derived F2 isoprostanes. DHA-derived isoprostanes are cancer-fighting, and certain isoprostane analogues are potently anti-inflammatory.
Fortunately for us, when we’re “back in the trenches” on Monday morning, what we’re going to do with our patients with regards to isoprostanes isn’t too different from what we’ve been doing all along: increasing intake of omega-3 fatty acids, decrease intake of omega-6 fatty acids. Give extra antioxidants if F2’s are high. Nice and straightforward. At least for the time being, anyway. Stay tuned.
Start your journey on isoprostanes here: AOCS Lipid Library
Nails. They’re a handy surface to decorate; they help us pick up objects, scratch an itch and protect our fingers and toes.
But did you also know that nails can tell us a lot about your health and your well-being?
For most of us, fingernails are completely renewed in about six months.
That means that our nails are a six-month medical record incomparable to any physical exam component. A window into our metabolic soul...
Take a second and check them out now.
What do you see? Are they smooth, without pits or grooves? Are they uniform in color, strong, and free of spots and discoloration?
In my practice, I check everyone’s nails -- preferably unpolished! And when I see something interesting and useful, I’ll file the pictures and track changes over time. Watching the changes of nails can let us know we’re on track with treatment. In this blog I want to share with you a few interesting cases, hopefully inspiring you to take a look at your own nails and to add this easy and useful investigation to the routine physical examination of your patients.
Anatomy of a nail
Image from Freethought Forum.
Nails are comprised primarily of the sulfur-rich protein, keratin, derived from tightly packed keratinocytes, the main cell type of the epithelium. Keratin is a highly biosorbent compound -- it readily binds many essential and toxic metals and other chemicals. (UB biochemistry students: see the keratin protein structure below.) In fact, while writing this blog, I stumbled upon a rather nifty green chemistry paper looking at the feasibility of using modified keratin-rich chicken feathers for cleaning toxic waters. Great idea!
The human nail is thought to reflect total body status of many nutrients. Toxic, or imbalanced, levels of certain compounds can displace the normal distribution of nutrients in the nails, as well. We would expect, therefore, that such changes might be reflected visually.
“The nail growth, color, structure, and composition can vary by influence of several factors as nutritional and toxicological aspects, diseases and infections, gender, and age. All these indications make the human nail a potential source of information of the body status.”
“Virtually every nutritional deficiency can affect the growth of the nail in some manner.”
Further, we would also expect that nutrient-influenced nail changes to be relatively common, given the widespread evidence of nutrient insufficiencies and toxin presence.
Amazingly -- but not surprisingly -- doctors were keenly aware of the utility of the nail physical exam prior to the introduction of routine laboratory analysis. Indeed, some of our richer resources come from publications released in the early 20th century.
Biochemistry students: Look at the alpha helix and beta pleated sheets of keratin. The sheets are held together by hydrogen bonding. Cysteine (actually, cystine) is abundant in keratin, comprising up to 24% of total amino acid content. Therefore, many disulfide bridges are present in keratin, making it very ridged and stable.
This is the image of the thumb nail of a 60-year old woman presenting with inflammatory arthritis. The nail is slightly yellow, and prominent vertical ridging (onychorhexis) and white bands (leukonychia striata) are noted.
Onychorrhexis can be a normal variant -- many of us have subtle ridging. However, when we see it more pronounced, especially when accompanied with brittle features, we can consider nutrient deficiencies, including protein and minerals. The leukonychia may point to specific deficiencies in selenium or zinc. Finally, the yellow color change (after ruling out smoking or recent nail polish) can be seen in autoimmunity, including rheumatoid arthritis; pulmonary disease and infection. Vitamin E may help to reverse yellowing.
A 16-year old girl presented with koilonycha, a spooning of the nails. This condition is commonly associated with iron deficiency, but zinc deficiency may also cause it. Her labs revealed very low zinc status, followed by a low-normal ferritin (iron status), but no anemia. Seshadri (see link below) mentions scurvy (vitamin C deficiency), pellagra (niacin deficiency), and riboflavin deficiency, as other possible causes of koilonychia. Protein malnutrition may also contribute.
A 63-year old woman presented with severe hand eczema with trachyonychia (20-nail dystrophy). Trachyonychia is a fairly common finding in those with hand eczema, ichthyosis vulgaris and alopecia areata. It’s also quite challenging to reverse. Her nutrient deficiencies included minerals zinc, selenium, copper and manganese; vitamins B12, folate and D.
After much work “inside-out” (improving diet and nutrient status), as well as “outside-in” (building her epidermal barrier), her hand eczema improved. Some months later, her nails grew back normally. The barrier work using fatty acids, occlusive and humectant topicals, as well as bleach baths, were essential to success. Needless to say, she was thrilled with the change, and relieved to be off the steroid merry-go-round.
Hand eczema in my experience isn’t so responsive to the “inside-out” approach that can work miracles with an atopic dermatitis that spares the hands. Hand eczema is often associated with a mutation in the epidermal barrier protein filaggrin.
Another pearl I’d like to mention is the relationship between osteopenia/osteoporosis and nail changes. If you observe brittle nails in a post-menopausal woman or an older man, check bone density. And, as bone density improves, observe the nails get stronger, too.
A few notes on well-being and nails: A cursory glance at your patient’s nails may reveal onychotillomania (nail picking) or onychophagia (nail biting). Such findings can be good openers for a chat about stress and anxiety. Improved well-being often correlates with favorable nail changes.
I encourage you to continue your exploration into nails and nutrients. Here’s a nice table with a link to the full text paper below.
Not long ago, sandwiched between a story on toast and the five-second rule, and a selfie of Zac Efron eating a worm, was this journalistic pearl:
Do Parkinson’s drugs make people more creative?
It prompted me to recall another Daily Mail gem:
Casino for RATS -- complete with ‘slot machines’
Creativity and rat casinos. What could these possibly have in common? Dopamine, of course, and the impact of high levels of it in the brain.
If we look at CNS dopamine in a vacuum, that is, if we put down for a minute the complex neurological interconnections between dopamine and other CNS neurotransmitters (including serotonin, GABA, epinephrine, norepinephrine, glutamate), we might think of dopamine as being the stuff of life, good and bad. And indeed, much data corroborates this notion: Pleasure and reward, concentration, creativity, anxiety, PTSD, obsession, addiction, pain, sleep, sexual arousal, fine motor coordination, restless legs. Dopamine, too much or too little, seems to be involved in all of these states and more.
Virtually ALL drugs of abuse increase dopamine, either directly or indirectly: Alcohol by 100%; methamphetaime by 1000%.
Figure 1: Dopaminergic neurons interact closely with serotonergic neurons in the brain influencing a number of behaviors and functions.
The Parkinson/Creativity story describes a small but compelling study published last month in the Annals of Neurology. The results showed that patients with Parkinson's Disease (PD) treated with dopaminergic drugs demonstrated significantly enhanced verbal and visual creativity, as compared to a neurologically healthy control group. Faust-Socher, et al., speculated that this creative burst was due to the reduction of latent inhibition, leading to a widening of the associative network and increased divergent thinking.
Give PD patients dopamine, they get creative…
But what about rats and casinos?
In this study, increasing dopamine availability (in the form of a D2 agonist quinpirole) enhanced the expectation of rewards (gambling behavior); whereas decreasing dopamine activity (by inhibition of dopamine receptor D4) decreased the ‘slot machine’ play of the rats. The authors concluded that inhibition of dopamine availability (by blocking D4 receptors) could be a way to treat compulsive gamblers.
Rats plus dopamine equals gambling.
But what about in humans?
Increased CNS dopamine in some PD patients has been linked not just to creativity, but also to addictive behaviors, including compulsive gambling, shopping, sexual behaviors and others.
And what about a whole family with a genetic mutation that causes high brain dopamine?
In some patients, I look for mutations in genes involved in producing the enzymes (COMT and MAO) that metabolize dopamine, epinephrine and norepinephrine (Figure 2).
Figure 2. Count the times COMT is involved in metabolizing not just dopamine, but epinephrine and norepinephrine.
COMT (membrane-bound catechol-o-methyltransferase) is the enzyme that metabolizes dopamine, epinephrine and norepinephrine (Figure 2). The soluble form of COMT, which outside of the brain is found in liver, kidneys and gut, metabolizes estrogen.
The COMT Val158Met genetic mutation significantly slows down the rate of dopamine, epinephrine and norepinephrine clearance in the frontal cortex of the brain. Of note, this mutation slows prefrontal metabolism of dopamine by up to 50% (Figure 3). This means there is a lot more dopamine around stimulating the post synaptic neurons. While the prefrontal cortex COMT enzyme has a higher affinity for dopamine metabolism, epinephrine and norepinephrine are also metabolized more slowly and therefore around longer.
Figure 3. In this figure, we see that in post mortem prefrontal cortex tissue COMT activity in homozygous COMT V158M (listed here as met/met) as 35%-50% lower than the wild type COMT val/val. Full text here.
A rather remarkable family…
I have worked with members of this family of five -- mom, dad, and three children, two adult females and an adult male -- for a number of years now. Over the course of time, we’ve amassed a good deal of laboratory data, and most recently, quite a bit of genetic data.
This family is homozygous for the COMT Val158Met mutation. Myriad conditions associated with the mutation have been found, including:
*The COMT enzyme requires the methylation cofactor s-adenosylmethionine (SAM). If the slow COMT mutation is consuming increased quantities of SAM to push the enzyme to work (my hypothesis) perhaps this is why methylation is seen as compromised, causing higher homocysteine. This is discussed in an earlier blog I wrote on Parkinson’s Disease and Lead Toxicity.
What’s fascinating about this isn’t any one single issue in the family, but that the collective familial pattern does point to some kind of dopamine imbalance, and not all of it negative!
Thoughts on treatment
Goals include preserving the beneficial attributes associated with the COMT Val158Met, while tweaking the negative effects of it. Major priorities have included supporting a reduction in epinephrine- that is, nudging toward a parasympathetic, calming responses rather than living in the epinephrine-charged fight-or-flight tendency that the COMT Val158Met mutation may encourage.
Beyond reducing epinephrine, HPA balance is important with adrenal supportive therapies.
We also need to reduce the estrogen burden and support appropriate metabolism. This is readily done through an anti-inflammatory, lower sugar diet, and supplements that reduce estrogen production and improve estrogen metabolism. I just blogged on this topic in relation to men - but I used the same general ideas with the two daughters.
Finally, behavioral modifications have been particularly important with this family. In one study, those with the COMT Val158Met mutation were apt to choose high risk, addictive behaviors under stress, whereas receiving calming support during stress reduced the behaviors.
My good friend Dr. Tom Sult will be challenging me on this blog, no doubt. And his feedback is always welcome. Is this case as simple as one genetic mutation, one set of inevitable outcomes? The answer is a resounding no. A single genetic mutation doesn’t an addict or brilliant musician make. Rather, there is a complex interplay between environmental exposures, including diet and lifestyle habits, parental influence, ethnicity, toxin exposures, exercise, sleep, play, age and on and on. All coalesce to make the whole person, or in this case, the whole family.
Note that everything I’ve stated is backed up by a peer-reviewed publication. Indeed, The COMT Val158Met research is extensive and fascinating. And NOT all findings agree. For instance: COMT Val158Met has been associated with uterine fibroids in certain ethnic groups, but not all. I reviewed many, many papers, links and citations for this piece. Rather than listing them all here, I invite you to start your COMT exploration here: http://www.snpedia.com/index.php/Rs4680
Dr. Richard S. Lord, nutritional biochemist extraordinaire and Chief Science Officer at Metametrix Clinical Laboratory (now Genova) recently retired after 25 years. Richard was the director of the Medical Education team when I was in Atlanta at the lab. Richard was and continues to be, my teacher. There has been no greater influence on my thinking as a clinician and scientist than Dr. Lord. He inspired me to always question, embrace the uncertainty, trust the data, and argue my point (with evidence, of course!) RSL, this blog is for you!
When I interviewed for the postdoctorate position at Metametrix Clinical Laboratory in 2004, I was a bright-eyed student finishing my final year in naturopathic medical school. I was nervous and excited. The lab was a marvel of glass and metal. Gleaming rows of instruments: LC MS/MS, GC/MS, HPLCs and on…. Lots of machines that go “bing” as Monty Python said.
There was a library with thousands of journals and almost as many textbooks - and a librarian, Cathy Morris, dedicated to obtaining full text article requests.
I was in awe.
My interview with Dr. Lord that day was not unlike skimming along the white tips of ocean waves on a speed boat. I may have only caught every fifth concept that he expounded on but I was transfixed. There was no other place on earth I wanted to be!
Richard’s focus in that 2004 interview and for some months thereafter was around the clinical implications of low plasma homocysteine. He was gracious in allowing me to participate in writing the company’s white paper introducing the concept.
I know, you’re a good integrative clinician, and low plasma homocysteine is old hat to you at this point. But at the time, virtually no one was thinking about its relevance as an essential precursor to glutathione, taurine and sulfate; that low levels of homocysteine suggested that the body’s ability to respond to oxidative stress with glutathione and to engage in phase II biotransformation, was at serious risk.
If we thought about homocysteine at all, it was as a cardiovascular risk marker, where only high levels were considered relevant.
Now, transmethylation and transsulfuration are key pathways memorized by all students of integrative and functional medicine. Methylated folate, B12, n-acetyl cysteine are prescribed routinely.
Dr. Richard Lord put low homocysteine on the map and educated us as to its relevance. Quest Diagnostics later adopted a lower limit after Metametrix started reporting it.
From Laboratory Evaluations in Integrative and Functional Medicine, Bralley and Lord, 2008
I was moved by the magic, the power, of nutritional biochemistry and the intellectual journeys I took with Richard. It seemed to me then--and it still does today--that the solution is present in understanding as fully as possible the question.
We could look “under the biochemical hood” of the individual, piece together their metabolic story and correct it with pinpointed nutritional and dietary interventions.
And it worked!
We could effectively reduce disease risk, oxidative stress, and inflammation; improve mitochondrial function, energy, mood, sleep; identify and reduce toxic burden and reverse neurological deficits and tweak the gut microbiome. Sometimes, we could turn the disease process around completely, uncover and successfully treat genetic conditions otherwise missed. Nothing was outside our reach of investigation. It was a grail quest.
I remember consulting with a doctor regarding a patient’s organic acid results. This individual had a seizure disorder, onset at 16, which was non-responsive to any medication.
Her organic acids revealed a very elevated beta hydroxyisovalerate (BHIV), a catabolic intermediate compound derived from the amino acid valine that accumulates with a biotin deficiency. In her case, given the severity of her condition, there was likely a mutation in the biotin-dependent carboxylase enzymes required to metabolize BHIV. The mutation wasn’t apparent at birth, when organic acids are routinely tested, looking for inborn errors of metabolism. It was too mild to be seen with the broad reference ranges able to identify only the severest cases. She wasn’t symptomatic until 16 years of age. It took the more sensitive reference ranges we employed at the lab to identify it.
The young woman was treated safely with high doses of biotin, which pushed the faulty carboxylase enzymes to function. And her seizures resolved.
Another great case involved a young man with Melnick-Needles Syndrome. MNS is an extremely rare condition caused by a mutation in the gene that codes for filamin A, a protein that provides structure for cells. Being such a fundamental player in sustaining life, a filamin A mutation is often fatal shortly after birth.
We carefully individualized his nutrient intake of amino acids, fatty acids, vitamins, minerals to meet his exact needs by looking at his laboratory data every six months. It worked for him.
At the time of my last consultation regarding this patient, he was graduating high school. He was the oldest known living individual with MNS.
These are the sexy, current terms used to describe what was started at Metametrix in 1984, when Dr. Andy Bralley began measuring plasma amino acids - the first steps of an investigation into the proteome. With Dr. Lord, our lab was the first to launch an organic acids test sensitive enough to pick up subtle nutrient perturbations correctible with diet and nutrient interventions: insight into the metabolome.
With the launch of DNA analysis of gut bacteria, fungi and parasites, we could look into an individual’s microbiome.
Taking everything together, including looking at toxic compounds, we were, and are, glancing into the exposome.
Andy and Richard, along with many other great folks, including our education team of Cass Nelson Dooley, Betsy Redmond and Terry Pollock, worked overtime providing the scientific rationale for these investigations in the form of a textbook: Laboratory Evaluations in Integrative and Functional Medicine. Published in 2008, with more than 3800 citations, it remains the functional laboratory standard.
The Medical Education department, led by Dr. Lord, knew its work was essential, important, reflecting the company’s mission statement: To improve health worldwide by providing clinical laboratory testing services in the areas of nutrients, toxicants, hormonal imbalances, biotransformation and detoxification, gastrointestinal function, and the microbiome.
I was reading an article the other day lamenting that men in the US are being all feminized due to the politically correct environment in which we apparently exist. But is this the issue? Can we blame politics for hypogonadism? I think not. However, I do agree wholeheartedly that there is a change occurring.
I tell you folks, the feminization of men is biochemically, not politically, mediated.
I am serious. It’s tragic. And as a red-blooded woman who appreciates men being men, I am not happy about it. But if the obesity, cardiovascular disease, diabetes, cancer and autoimmune epidemics aren’t arousing you to action, maybe the terrible and sad fate of testosterone in this inflammatory soup of modern life will.
Superlatives and hyperbole. But it’s all true.
Let’s take a look at that Big Gulp Coke that Sarah Palin promoted so heavily last year as a natural-born right of all Americans. Let’s track the main Coke ingredient, sugar, down through a primary biochemical pathway in the body and see what happens to it.
The short view: Sugar trashes testosterone. Period.
The slightly longer view: The mechanism by which this happens underlies all chronic inflammatory diseases; from the ubiquitous metabolic syndrome to cancer, autoimmunity and cardiovascular disease.
Some behind-the-scenes biochemistry. And a couple of cases outlining what to do about it:
Sugar stimulates insulin (and chronic sugar ingestion keeps this going and going and going). Insulin promotes the genetic upregulation of the desaturase enzymes that convert the too-highly-abundant-in-the-American-diet linoleic acid (vegetable oils -- think fried foods, potato chips) to arachidonic acid (AA). Arachidonic acid is the parent compound of the exquisitely potent pro-inflammatory molecules called 2- and 4-series eicosanoids. These AA-derived eicosanoids are the most fundamental drivers of all things inflammation in the body. Aracidonic acid is cleaved from the lipid membrane for metabolism to eicosanoids by the enzyme phospholipase A2 (PLA2). A main end-product of this cascade of events is prostaglandin E2 (PGE2). PGE2 promotes genetic upregulation of aromatase (CYP19), the enzyme that converts testosterone to estrogen.
So, high sugar = low testosterone= high estrogen: The feminization of men.
What we can do about it. A couple patient cases.
George is a 57 year old male patient of mine who I’ve been seeing for six years. In fact, we just met last week, hence this blog topic. I began to treat George when I was working at Advanced Diagnostic Pain Treatment Center. He arrived on seven heavy-hitting medications ranging from Fentanyl and oxycodone to atenolol and Avodart (BPH). A handful of NSAIDs were thrown in for good measure. We effectively addressed his complaints, including BPH, hypertension, hyperlipidemia and inflammatory arthritis. He tapered off all of his medications. He quit smoking. He lost weight. He’s been doing well for years, except he’s complained of difficulty with abdominal adiposity and poor muscle mass, despite regular weight and cardio workouts. (He just ran a ½ marathon.) His free and total testosterone levels were actually within normal limits, but his total estrogen level was high. So for George, his good lifestyle (and tapering off opioids- which lower T) has kept his T within normal limits, but he’s still converting too much testosterone to estrogen. George lamented that this was due to genetics. That all the men in his family were cursed with the dreaded “man boobs.”
He also had high total estrogen.
And a love of beer.
We started a fairly straight forward plan. We got extra serious about the diet: very low/no grains (sadly, beer is gone right now); high veg and fiber, with good proteins. He periodically achieves ketosis, which he measures himself in urine. We increased his fish oil intake to inhibit desaturase conversion of linoleic acid to arachidonic acid. (We’re trying to stop production of AA-derived PGE2> aromatase> testosterone> estrogen). I added zinc, chrysin and a natural hops-derived aromatase inhibitor. We started a relatively modest dosage of 50mg DHEA per day. His blood sugar tends to run around 100, so I added berberine 500mg daily. (I know this is lower than the 1500mg/day recommended amount for type II diabetes, but we’re fine-tuning here.) His baseline total estrogen was high at 132. After ten weeks of this protocol, his estrogen was 109; fasting blood sugar 93. A nice drop!
Most importantly is that George is reaping the benefits. He reports more muscle definition (he’s now getting compliments from his gym buddies), better energy, reduced body fat and improved libido and performance. He’s gained muscle weight but his clothes fit better. And the dreaded man boobs? Gone. George is thrilled with his results and wants to continue on the plan. He’s empowered. He’s no longer a victim of his genetics.
On the extra-cautious side, we’ve watched his PSA (free and total), and they’re both consistently low.
George’s baseline total estrogen and free testosterone:
George’s follow-up total estrogen (testosterone pending, but it will be higher based on his clinical response):
One more quick case. With George, we had to really get in there with some fine-tuning to drop his total estrogen. On the other hand, Bill (46 years old, normal weight-for-height) came to my office with complaints of inflammatory arthritis, severe seasonal allergies and GI issues (all inflammatory-driven). Secondary issues included fatigue and loss of muscle mass and definition, despite pushing himself through regular work-outs.
Bill’s treatment plan was relatively straight forward. We focused on his chief complaints with the goal of reducing total body inflammation (which drives up PGE2 and increases estrogens; even allergies contribute here). We did so through a hypoallergenic, lower carbohydrate diet; high dose fish oils, gut repair nutrients (including glutamine, licorice, slippery elm); and a few antimicrobial and anti-inflammatory botanicals (which further inhibit production of PGE2). I also added a hops-derived aromatase modulator and a modest 25mg DHEA/daily. Sublingual immunotherapy was used for allergies. Needed nutrients included B12, B complex, vitamin D and magnesium.
Like George, Bill had normal baseline total and free testosterone. This is really important. While you will commonly see low testosterone in your patients, sometimes values are within normal limits, thus it’s essential to look at total estrogen to get the full picture of what’s happening on the inflammatory front.
Bill’s baseline total estrogen, total and free testosterone.
Bill’s follow-up total estrogen, total and free testosterone.
As you can see from Bill’s baseline and follow-up labs, his estrogen is dropping nicely with the protocol. This result correlated with better muscle mass and exercise tolerance. He also shed a few extra pounds, noticeable in the abdominal region. By reducing total inflammation though a number of mechanisms, including lower carbs and sugar, we achieved a significant drop in estrogens.
As clinicians treating the “Low T” hypogonadal epidemic, we need to take a full systems approach. Endocrine disruption happens from all sides. Yes, diet is our greatest leverage point in virtually all disease. But stress will increase testosterone’s conversion to estrogen and reduce total sex hormone availability. And remember- glucocorticoids are diabetogenic. Toxins- especially plastics and all of the “cides”-pesticides, herbicides, insecticides are xenoestrogens. Think about the sexually ambiguous salmon swimming in polluted waters... Of course, numerous medications will deplete testosterone- opioids, statins. Nutrient depletions will contribute and complicate matters- vitamin D repletion alone has been shown to increase testosterone. Gut and liver health: Can your patients’ biotransform and eliminate estrogens?
Finally, testosterone replacement therapy for hypogonadism is all the rage. Lots of media promotion for treating “Low T” but I’ll tell you this: if you do NOT address the underlying inflammation, then a portion of that nice large pool of exogenous testosterone will indeed be driven on to estrogen.
Links for further reading.
http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2265.2012.04401.x/abstract;jsessionid=39FE5839B989B83E037C9DA2BF0C6A1F.f03t04?deniedAccessCustomisedMessage=&userIsAuthenticated=false (low grade inflammation and hypogonadism)
http://care.diabetesjournals.org/content/28/7/1636.long (testosterone, blood glucose, mitochondria)
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3173509/ (BPH, testosterone, blood glucose)
http://www.lipidworld.com/content/13/1/6 (GGT, ALT, AST, obesity, CVD CHD DM PLA)
http://www.medscape.com/viewarticle/589222_4 (metsyn ferritin CVD PLA)
http://tae.sagepub.com/content/1/5/207.abstract (low T and metsyn, abnormal lipids)
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3150075/#R12 (CHD stroke subclinical inflammation and Lp-PLA2)
http://www.ncbi.nlm.nih.gov/pubmed/20362028 (PLA2 cancer)
http://www.ncbi.nlm.nih.gov/pubmed/15670148 (PLA autoimmune)
http://www.ncbi.nlm.nih.gov/pubmed/15670148 (A lot about PGE2)