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)
I recently saw a patient who had been diagnosed with idiopathic Parkinson’s disease (PD) in 2000 when she was just 39 years old. Her history was compelling in that everyone in her family was well --no neurological diseases, parents hearty and healthy at 80 -- and she herself was a healthy child. However, she has a daughter with autism.
It turns out this woman and her husband renovated a lead-saturated 100-year-old Chicago house over the course of 10 years -- in the 1990s. She gave birth to her daughter-who was later diagnosed with the neurological condition autism--while in the house in 1998, around the time she first noticed a tremor.
When urine toxic metals were recently assessed in this patient, her lead (Pb) level was extremely high. In fact, it was eleven times the cut-off limit (her result was 22ug/24 hours; the cut-off limit is 2ug/24h hours). This finding suggests that she has a significant, long-time body burden of lead.
Yes, lead toxicity is a contributing cause of PD and has been implicated in autism.
In PD, lead has been shown to directly damage dopaminergic neurons and contribute to CNS oxidative stress. (In autism, the issue seems to be, in addition to CNS oxidative damage, compromised removal (biotransformation) of lead due to lesions in glutathione conjugation and methylation- more on that below.)
There are currently about one million individuals diagnosed with PD in the US; as with most neurological diseases, its numbers are rising rather rapidly. Diagnosis is made only after the disease shows up clinically— that is, after 60-80% of dopaminergic neurons in the substantia nigra are lost. There are no great biomarkers to conclusively identify disease before this late stage, BUT, if we think about it from a functional/systems medicine perspective, early clues abound.
There is no smoking gun genetic mutation in PD. Yes, there are some genetic mutations that increase risk, (here’s a recent free full text published by PLOS genetics and written by 23 & Me), but having a PD-associated mutation and developing PD isn’t a slam dunk. It’s now well accepted that Parkinson’s Disease, like most complex, chronic conditions is largely caused by chronic environmental exposures, including pesticides, herbicides, toxic metals and the like.
Understanding the toxic connection, it becomes urgent that we regularly evaluate toxin exposures in our patients by taking a careful environmental exposure history and using appropriate labs- such as urine and/or blood toxic metals. When we find concerns, we need to address them immediately by removing the exposure sources and treating the patient, ideally BEFORE they develop clinically apparent complications such as PD.
When I was completing postdoctoral training at a clinical laboratory, we conducted an informal “data mining” project, looking at nutrient imbalances and the presence of toxins in individuals diagnosed with Parkinson’s disease. I was struck by consistent patterns of imbalances. For instance, of the 32 individuals diagnosed with PD who had metals tested, over 60% had higher-than-average to very high lead levels. Additionally, 12 people had higher mercury and 11 had higher aluminum levels.
Of the 10 individuals with PD who had homocysteine levels assessed, all were on the higher side, ranging from 8.7 to 22.6. Six of the 10 individuals with PD had frankly elevated homocysteine. By comparison, a control group of six adults not diagnosed with PD, the homocysteine range was a much lower 5.4 to 9.3.
Incidentally, the highest homocysteine level (22.4) was in the same individual who had the highest lead level.
Methylation and sulfuration: I know you know it by heart…
There are a few ways to think about these data
BUT….We certainly cannot take PD patients off L-dopa. It’s a critical treatment given the damaged dopaminergic neurons.
Our focus must be around carefully supporting normal methylation/sulfuration in this population. Anyone practicing functional medicine knows the drill: folate, B12, betaine and glutathione or the glutathione precursor n-acetylcysteine.
The dance for us as clinicians in treating the individual with PD is to normalize/assist in the removal of toxins by addressing methylation and sulfuration, but not boost methylation so aggressively that we promote excess metabolism of L-dopa. (When PD patients are given the COMT cofactor s-adenosylmethionine, it worsens symptoms.) It is therefore imperative that we monitor homocysteine, toxin levels and clinical symptoms when implementing this approach. Make sense?
Understand that while addressing methylation/sulfuration in the PD population is an essential component to a functional/systems approach, it’s only one area in a much larger systems approach. And as with autism, the earlier we start, the better the outcome. Ideally, we’re preventing the disease by getting there before it starts…….
Living in an old house is the most common cause of lead exposure in the US. And it’s not just renovating an old house. Just generating airborne lead-ladened paint particles from opening and closing windows is a huge exposure source, and inhalation is the most efficient route of lead absorption. But GI absorption is significant as well. Crops grown in lead-exposed soil (think soil saturated with leaded gas) bioaccumulate the toxin. We can use the bioaccumulation phenomenon to remediate soil, but just don’t eat those plants!
We can also find lead in common household items- such as the ceramics we eat on- especially those made in China. I recommend patients purchase at-home lead test kits for testing. I like 3M Lead Check sticks. Get them at Amazon.
A patient recently emailed this: A positive finding for lead on a ceramic dinner plate.
Blood lead cut-off levels have been lowered and lowered over time. This is a figure borrowed from the CDC. See Lead, No Safe Exposure Levels.
It’s been a busy, productive and rather amazing Fall. Lots to write about. In celebration of the gorgeous New England weather, I’ve been spending much time on my bike the last couple of months, and it feels great!
Riding on Ridgefield back roads. Nothing beats it.
I just returned from speaking at the Nutri Advanced conference in London where Drs. Jeff Bland, Andrea Girman and Joe Pizzorno also presented. It was a great conference—the largest yet. UK is embracing Functional Medicine. And London was also absolutely lovely the week I was there.
The Millennium bridge, crossing the Thames from St. Paul’s to the Tate Modern. With Dr. Andrea Girman. We just saw the play Light Princess- words and music by Tori Amos. Amazing!
As always, I was thrilled to hear Dr. Bland speak. A founding father of Functional Medicine (he coined the term), his words nourish intellectually and also spiritually. Listening to him feels like receiving transmission from a Zen master who happens to have a PhD in nutritional biochemistry.
Jeff presented on epigenetics, that is, the way in which environment can shape our DNA expression and determine whether or not we get a particular disease.
So, just because you have the DNA associated with a particular disease doesn’t mean you’re getting the disease. This is such an empowering statement. I’ll say it again: Just because you have the DNA, doesn’t mean you’re getting the disease.
Jeff provided a potent example of this truth: The BRCA1 and BRCA2 mutations are very closely associated with breast and ovarian cancer. Indeed, if you have a BRCA mutation, your lifetime risk of developing breast cancer is greater than 80%. Recall that Angelina Jolie—who has the BRCA1 mutation--just had a double mastectomy to significantly reduce her risk of developing breast cancer.
If you have a BRCA mutation, it seems that you’re going to get cancer, regardless of your health choices, doesn’t it? I certainly admire Angelina’s courage to reduce her risk.
However, if we look into the history of the BRCA mutations and cancer risk, we find that before 1940, the risk was 24% with the BRCA mutation, not 82%, as it is today. Clearly, environment is playing a big role in the development of breast cancer even with the BRCA mutations.
What’s going on?
Dr. Mary King, the scientist who discovered the BRCA mutations, recognized the environmental influence on cancer risk. She specifically cited adolescent obesity, lack of exercise and early age of menarche as factors in the rise of BRCA-associated cancers.
I began thinking about the BRCA mutations and environmental influence in 2007 when I was working at Metametrix Laboratory. My attention was on the influence of fatty acids on hormone-sensitive cancers. A big question for me was: What does a functioning BRCA protein do in the body? As I was drilling down into the literature, I made a fascinating discovery that I rarely see discussed. This discovery gave me a clear treatment direction on how we might reduce risk for individuals with the BRCA mutation.
What does a normally functioning BRCA protein do in the body?
Functioning BRCA proteins are huge, complex structures involved in a good deal of regulatory activity in the body. They are recognized as tumor suppressor genes; they repair DNA.
A lesser recognized BRCA1 role has to do with its ability to potently down-regulate (inhibit) the body’s production of the enzyme aromatase.
What does aromatase do in the body, and why do we want to inhibit it?
Aromatase is the enzyme involved in making estrogen. And in this particular context, estrogen promotes cancers like breast and ovarian. You’ve likely heard of aromatase inhibitors -- drugs that are commonly used to treat these cancers. (Note that estrogen has many essential, healthy, anti-inflammatory roles as well; but that’s for another discussion.)
Not surprisingly, if you look at aromatase in those with the BRCA1 mutation, it’s a lot higher than it should be. So there’s a lot more estrogen than there should be -- hence the cancer risk.
Back to the fatty acid story.
When I discovered the BRCA1/aromatase link, I also learned that the pro-inflammatory fatty acid, called arachidonic acid, makes a compound called PGE2. PGE2 inhibits the good deeds of a normal BRCA1 and promotes aggressive aromatase expression. This results in lots of estrogen production and increased breast and ovarian cancer risk.
In other words, PGE2, from arachidonic acid, can behave like a BRCA1 mutation.
Arachidonic acid (AA) is an omega 6 fatty acid. Some AA is essential for a normal immune response; but anyone eating a typical diabetogenic diet — nutrient-void, too much sugar, simple carb and inflammatory omega 6 fats -- is making way too much arachidonic acid (and therefore PGE2). Globally — not just in the West -- most of us eat this unhealthy diet.
Therefore, one of the most fundamental ways we combat breast and ovarian cancer is by eating a healthy, anti-inflammatory diet. Those with the BRCA mutation? All the more necessary, even urgent, is the anti-inflammatory diet.
Returning to Dr. King’s observations, everything that she suggests will reduce excess or toxic estrogen exposures: More exercise, less obesity (starting early), better diets, later menarche. And of course, all of these are known to reduce cancer risk. (Early menarche is influenced by early estrogen exposures. Therefore, if you want to influence your daughter’s menarche, these changes should be made even before you conceive her, but certainly in early childhood.)
I want this blog to feel empowering for those with the BRCA mutations, or those concerned about hormone-sensitive cancers. The reality is there is much we can do to minimize the impact of estrogens on the body. Any good integrative doctor can come up with a robust to-do list. The fact is, many, many botanicals can interfere with the production of PGE2. If we pack our body full of the good omega 3 fatty acids, also, we will inhibit PGE2 availability. And as I mentioned, perhaps the most powerful factor is an anti-inflammatory eating plan.
Here are just a few of my anti-inflammatory/estrogen modulating/cancer-protective favorites:
What are yours?
Gluten Free and Thyroid Disease Free: An Update on Lilly
The last time we met, Dear Reader, before I high-tailed it on out of the blogosphere for the summer, I introduced you to Lilly and her thyroid woes. Below are her original thyroid studies that she obtained from her primary care doctor and brought to our first meeting. Lilly did not want her endgame to be levothyroxine for life. She sought a second opinion.
June, 2013. Lilly’s baseline thyroid laboratory results demonstrated autoimmune hypothyroidism (also called Hashimoto thyroiditis).
What do these results mean?
As I said in my original post, Lilly’s elevated TSH (thyroid stimulating hormone) demonstrated that her body was working awfully hard trying to get her thyroid to do its job. And the thyroid peroxidase antibody elevation --albeit mild—revealed that Lilly’s own immune system was attacking her thyroid gland. Certainly these results were a big piece of the fatigue puzzle.
Why was Lilly’s immune system attacking her thyroid gland? I must admit, I was pretty certain gluten was involved. I wrote in my post:
It is well-documented that autoimmune hypothyroidism is associated with gluten intolerance. Indeed, celiac disease is associated with myriad autoimmune conditions, including type 1 diabetes, lupus, pernicious anemia, autoimmune hepatitis, Sjogren’s syndrome, Raynaud’s syndrome, myasthenia gravis, and autoimmune hypothyroidism.
Also recall, Dear Reader, that Lilly was entirely loath to remove gluten—her nightly crusty bread with olive oil-- from her diet. Lilly thought the whole gluten-free epidemic was another overhyped phase. (Who can blame her?) She said: “I was tested for celiac disease eight years ago and I am negative. I don’t have a gluten issue.”
I didn’t debate. But I knew that my laboratory investigations with her would include looking for gluten reactivity in its many forms. Here is what I found:
June, 2013. This lab result demonstrates that Lilly’s immune system was reacting to gluten. She didn’t have celiac -- those tests were negative -- but she was definitely sensitive to gluten.
So what did we do?
The lab result was enough to convince Lilly to stop gluten for a while. We negotiated an eight week trial. She understood that it was possible that gluten could be impacting her thyroid. She was 100% motivated to abstain from it entirely for the agreed upon time.
Not surprisingly, Lilly had micronutrient deficiencies as well, including B12 and magnesium. Again, even though she didn’t have celiac disease, it looked like her body was having a hard time absorbing the nutrients it needed. While this is extremely common and well-documented in celiac, it’s less-recognized in gluten sensitivity.
Our treatment plan was straightforward: Avoid gluten, take B12 and minerals. I also ordered a thyroid-centric supplement (containing the nutrients selenium, zinc and tyrosine, designed to support thyroid function) that Lilly took for a little while but stopped when she ran out.
When I chatted with Lilly in July, she told me her gut was better. Gut? Lilly didn’t report any gut issues at our first meeting. It’s interesting how we can identify issues we have tolerated – sometimes for years --only after they’re no longer there! She also said her energy was much, much better. We both knew she was on the right track.
In August, 2013, eight weeks after she started the supplements, Lilly had follow-up testing:
August, 2013. Just eight weeks after the start of going gluten free, Lilly’s thyroid function tests were normal. Her TSH and her antibodies were no longer elevated. Good job, Lilly -- No medication needed!
In functional medicine, we like to see TSH less than 2.00. Lilly’s is almost, but not quite, there. I suggested to Lilly that she restart the thyroid supplement I originally prescribed to see if we can get her into optimal range. I also suggested we continue with the gluten free plan, seeing that she’s doing so well.
Lilly responded immediately, agreeing to take the thyroid support, and proclaiming:
“No gluten since we started and no desire to have any ever again :-)”