Conservative Functional Medicine and the Appropriate Use of Oral Antibiotics for a Perimenopausal Woman

TREATING CLINICIAN: Robert Abbott, MD

Patient Info:

• Stacy is a 48-year-old outgoing, active female
• Previous Dx:
  • Infertility
  • Endometriosis
  • Arthritis
• Rx:
  • None
• Chief Complaints :
  • Overweight
  • Vertigo
  • Hot Flashes
  • Insomnia
  • Joint and Muscle Pain

Visit 1 (Day 1) – History and Exam:

Initial Impression:

• Stacy is a 48-year-old, active but overweight female with a fairly high symptom burden who seeks to have sustainable weight loss and to address her primary symptoms holistically. She appears very knowledgeable about nutrition and has tried numerous nutritional templates and diets, but she has not utilized many supplements or gut-based therapies. Her baseline stress management practices and activity/exercise seem to be fairly reasonable.
• Dx/Rx:
  • Infertility
  • Endometriosis
  • Arthritis
• Previous Testing:
  • N/A
• Onset:
  • Reports fertility issues through 2008, 2012-2014
  • Used intrauterine insemination and gave birth vaginally to a healthy boy in 2010 without major complications
  • In 2012, she tried intrauterine insemination for a second time but was unsuccessful. She did not want to pursue IVF.
  • She had a repeat laparoscopic surgery in 2013. She could not conceive thereafter.
  • Skin infection in March 2020 requiring antibiotics
  • May 2020 – stressful life period, noted last menstrual cycle at this time (Time of this exam – October 2020)
  • Has been experiencing hot flashes, increased fatigue, insomnia, dizziness/vertigo, and some brain fog- neurocognitive challenges over the last 3 months
  • Recently completed another course of antibiotics for concerning “sinus type” infection
• Family History:
  • Obesity, cardiovascular disease, and autoimmune disease prevalent on both sides of her family
• Prior Treatments:
  • Probiotics – helpful during previous courses of Abx
  • Various nutritional supplements – helpful, but not currently taking any
• Notes/DDX:
  • For Stacy, I am suspecting perimenopausal hormonal fluctuations, suboptimal diet, insomnia/inadequate sleep and underlying gut dysfunction are the primary drivers of her symptoms. I also want to be aware of potential cardiometabolic dysfunction given her weight and cardiovascular disease in light of her family history.
• Prognosis:
  • I expect Stacy to do very well with additional support from a nutritionist and a health coach.
• Previous Diets:
  • Various diets including Paleo, Low Carb, Dairy, and Gluten-free – all helpful in various ways

Visit 2 (a few days later) – Testing and Initial Recommendations

Testing:

• Tests Ordered
  • CBC with Diff
  • CMP, GGT, Uric Acid
  • Iron Profile, B12, Folate, Homocysteine, Magnesium, Vitamin D, Zinc, Copper
  • hs-CRP
  • Expanded lipid profile, lp(a), apo(b), Fasting Insulin, HbA1c
  • TSH, Free T4, Free T3
  • FSH, LH, Estradiol
• Rationale
  • This blood chemistry profile is my expanded profile for overweight/obese perimenopausal women. The labs assess basic cellular function and nutritional status as well as cardiometabolic health, cardiovascular disease risk, and hormones including LH, FSH, and estradiol that can assist in determining hormonal status in women with a recent cessation of menstrual cycles or irregular, infrequent menstrual cycles.

Recommendations:

• Sleep Hygiene Practices
• Daily Meditation Practice
• Suggest Ancestral/Paleo Diet template with an exploration of intermittent fasting if desired
• Encouraged more time in nature
• Rationale
  • I want to support her in making some foundational dietary and lifestyle changes and have recommended the Paleo diet with an exploration of intermittent fasting rather than anything more restrictive.

Visit 3 – Lab Interpretation and Treatment Evaluation

Subjective Assessment:

• She reports the worsening of previously undisclosed rash in left axilla and inflammatory papular type lesions around the left upper extremity. She has been using coconut oil without much change.

Objective Assessment:

• My exam of her skin reveals erythematous, eczematous like papular rash extending from the axilla over the anterior LUE with some scaling. I also note 7-10, 1-2 cm boil in the left lateral axilla as well as around the anterior RUE. No streaking noted.

Lab Interpretation:

• Glu: 103
• WBC: 6.1, normal diff
• normal TSH, Free T4
• TC: 199, LDL-C:117, apoB: 90
• lp(a): 315
• A1c: 5, fasting insulin: 4.3, HOMA-IR: 1.09
• B12: 390
• Folate 16.2
• Mg: 1.9
• Cu: 131
• Zn: 67
• hs-CRP >10.0
• homocysteine: 10.8
• FSH: 103.6, LH: 60.4
• E2: 50

Diagnosis:

1. Gut Dysbiosis
2. Abdominal Adhesions?
3. Female Hormone Imbalance, LH-FSH pointing to menopause transition
4. Autoimmunity?
5. Overweight
6. Chronic Sinusitis, Mycotoxicity, Nasal Dysbiosis
7. Elevated lp(a)
8. Nutritional Deficiencies – Mg, Zn, B12, B Vitamins
9. Sleep-disordered breathing?
10. Soft Tissue Skin Infection – Staph/Strep based bacterial skin infection vs. fungal components

Impression:

• Stacy appears to be in perimenopause, moving into the menopausal state with rising LH, FSH but high normal estradiol.
• She has a few nutritional deficiencies that could be from a combination of decreased dietary intake, maldigestion/malabsorption, and increased utilization given activity and recent infectious/inflammatory states.
• She appears acutely with elevated hs-CRP that could be related to her soft tissue skin infection that appears to have both bacterial and fungal elements.
• Her blood sugar markers are suboptimal but could be influenced acutely because of the suspected skin infection.
• She appears to have a genetically elevated lp(a) that could be contributory to her cardiovascular disease risk and explain some of her family history. Her apo(B) is within normal limits.

Recommendations:

• Zinc
• Magnesium Malate
• Targeted B Complex
• 100 Billion CFU Lactobacillus/Bifidobacterium Probiotic
• S. boulardii
• Curcumin
• Adaptogens

Soft Tissue Skin Infection

• Lotrisone – 1 application to affected area BID for 10 days
• Amoxicillin 500 mg BID for 10-14 days
• Bactrim DS 800 mg/160 mg BID for 10-14 days

Rationale:

• I am concerned enough about the patient’s skin symptoms in connection with her lab work that I feel the benefits outweigh the risks for treatment with oral antibiotics to address a suspected systemic, soft tissue/skin infection. I also would like to provide her with a topical anti-fungal anti-inflammatory for a rash that appeared after previous antibiotics and appears distinct from the other lesions. Antibiotics have garnered much fear and a bad reputation in the field of functional medicine, but I feel that their use in this case alongside supportive probiotics is indicated. In addition, I would like to support her with nutritional supplements as indicated from the lab work, optional adaptogens to support her energy, and a curcumin supplement to function as an anti-inflammatory phytonutrient.

Visit 4

Subjective Assessment:

• The scaling skin rash has completely resolved, and the boil type lesions are all healing without new lesions. The patient reports improving energy, less fatigue and improved sleep. She states that she did not realize she felt as poorly as she did – she did not realize that the skin infection was affecting her as systemically as it was. She is grateful for my suggestions to use medication despite her initial hesitancy and concern about side effects and whether it would stop any progress she could make with her other symptoms.

Impression:

• Stacy’s skin infections are healing and she is feeling much better following the 10 days of medication.

Recommendations:

• No further antibiotics or topical antifungals/steroids
• Continue with other supplements and dietary/lifestyle suggestions
• Follow up with the nutritionist

Visit 5 - With Nutritionist

Subjective Assessment:

• Fewer hot flashes
• No new skin lesions
• Improved energy and sleep
• Less joint pain
• Slight weight loss – perhaps 2-3 lbs

Impression:

• Overall she has done very well with the suggested dietary suggestions. She may be consuming more foods off the Paleo template than the suggested 20%. However, I do believe she has radically increased her nutrient density and lessened the inflammatory content of her diet.

Recommendations:

• Provided refined suggestions for her 80-20 Paleo diet
• Discussed techniques to consider that could help create a caloric deficit for weight loss
• Continue current supplements

Visit 6 - With Nutritionist

Subjective Assessment:

• Reports near elimination of hot flashes
• She feels her bothersome symptoms in nearly all areas have improved
• Still struggling some with achieving consistent weight loss

Impression:

• Stacy has continued to do well, but has stagnated some with her weight loss efforts. This is likely related to lack of precision with caloric awareness and a more expansive diet during the holiday period. She will likely do well by exploring a low carbohydrate to ketogenic diet to help improve insulin sensitivity and hopefully create a caloric deficiency without micromanaging calories.

Recommendations:

• Initiation of a Ketogenic Diet
  • 40g of CHO/day
• Complete labs after 2 weeks on the diet and follow-up with MD 4-6 weeks thereafter

Clinician’s Comments and Teaching Points

I share this case to illustrate a few key points.

• First, I believe functional medicine is foundationally a diet and lifestyle based treatment approach. Initial treatments should be conservative and leverage the power of diet and lifestyle to improve health. In this patient, we started first with lifestyle and nutritional guidance that was not overly restrictive despite the patient having some expressed inclinations to lose weight. Weight loss can be a byproduct of many treatment approaches. You can support an individual desiring weight loss in an iterative process and do not have to start every person on Day 1 with a calorie counted ketogenic diet (most people aren’t ready and can’t do that, and it may not be necessary).
• Second, all perimenopausal women with hormonal type symptoms do not need (or want) hormone replacement therapy. It would have been really easy to start this patient on Day 1 with bioidentical hormones, to help her feel “better” and youthful, to help her move through perimenopause with “greater ease” and to lose weight. These intentions, however, are misguided and can ultimately hurt many patients. I may at some point discuss hormone replacement with the patient if she expresses interests or questions, but it is not a foundational treatment in my opinion.
• Third, oral antibiotics are not the devil. From my medical assessment of her skin condition, and the corresponding labs, I felt she required medications to help her immune system move past some infectious type symptoms. Through an encouraging and nuanced discussion, I helped her see the risks and benefits and she ultimately had a great outcome. While every case will not turn out this way (that’s the nature of probabilities, risk and benefits), I hope you see that medications, even oral antibiotics, can be used in a judicious and appropriate manner, and help patients in their overall healing.

Exploration of Recent Medscape Article (MTHFR & Folic Acid): Online Misinformation Fuels a Fight Over Folic Acid

Medscape Article and Intention of our Review

In a recent Medscape article, author Christina Szalinski addressed the perception of increasing online misinformation about the utility of folic acid versus folate(s) to prevent neural tube/birth defects, the espoused importance of genetic testing for methylation “defects” and the conflicts that have arisen between proponents of folic acid supplementation and fortification vs. proponents of suspending fortification and recommending folates from food/supplements alongside genetic testing to identify methylation “defects.”

https://www.medscape.com/viewarticle/943516#vp_1

Given the contentious nature of the topics discussed in the Medscape article and the current climate around methylation, folate and genetics, we have provided you with a critical and balanced analysis of the article’s main points in an effort to help you as a clinician adopt better practices.

Essential Summary Points

1. The Medscape article was overall well written, balanced and brought up some important points to consider for clinicians across all scopes of practice.
2. Testing for MTHFR variant status as routine clinical practice in all patients may have many pitfalls. This form of genetic testing does not appear to readily change clinical practice with regards to nutritional supplementation and is likely unnecessary in the care of most patients.
3. Both the potential benefits of folic acid supplementation/folic acid fortification and the risks from folic acid supplementation appear overstated. Individuals from both traditional and functional medicine may be purporting degrees of benefit and/or risk that do not correspond to population level data.
4. Clinical data suggests, on average, that individuals can achieve similar blood folate and homocysteine levels with equivalently dosed folic acid and folate supplements.
5. Folate supplements are more expensive than folic acid supplements. Third party testing does not suggest rampant fraud or poor manufacturing practices for the most common consumer brand B complexes, folate and folic acid supplements.

Medscape Article Claim #1

Hickey says we now know that there are few health risks that come from having common MTHFR variations, and there is no reason for these common variations to lead to any changes in medical care. Having MTHFR variations can contribute to low folate, which can have negative health effects, but these issues are uncommon due to food fortification, according to Shane.

The strongest, most well-established association between common MTHFR variants and a medical condition is that certain variations slightly increase the risk of neural tube defects in newborn babies. However, Shapira of the CDC says this association is due to low folate. Those who could become pregnant need higher levels of folate. “Consuming 400 micrograms of folic acid each day increases the amount of folate in a woman’s blood to a level that’s high enough to help prevent the formation of these neural tube defects,” says Shapira. He added that folic acid is protective regardless of a person’s MTHFR gene variants.

Verdict

Essentially True

• Closer monitoring of RBC folate levels and homocysteine may be clinically reasonable in those with either a homozygous C677T or homozygous 1298T MTHFR variation, but responses to folic acid and folate supplementation do not appear drastically different than in those without these MTHFR variations.
• Similar homocysteine and serum folate levels can be reached whether one uses folic acid or folate supplements.
• Individuals with marginal deficiency who consume 400 micrograms of folic acid over 9 months can reach adequate levels (this is not overnight!)

Evidence

• 1) “These findings suggest differential effects of l-5-MTHF compared with folic acid supplementation on blood folate concentrations but no differences on plasma total homocysteine lowering in Malaysian women.”
  • l-5-Methyltetrahydrofolate Supplementation Increases Blood Folate Concentrations to a Greater Extent than Folic Acid Supplementation in Malaysian Women
• 2) “Low-dose L-MTHF is at least as effective as folic acid in reducing tHcy concentrations in healthy persons.”
  • Comparison of the effect of low-dose supplementation with L-5-methyltetrahydrofolate or folic acid on plasma homocysteine: a randomized placebo-controlled study
• 3) “These data suggest that low dose [6S]-5-MTHF and folic acid supplementation increase blood folate indices to a similar extent.”
  • Increases in blood folate indices are similar in women of childbearing age supplemented with [6S]-5-methyltetrahydrofolate and folic acid
• 4) The WHO in 2015 set a desired RBC Folate level in conceiving women for the prevention of neural tube defects at >400 ng/mL or >906 nmol/L.
• 5) For individuals, on average with deficient RBC Folate levels ~ 600 nmol/L, it would take 9 months of folic acid supplementation at 400 micrograms/day to get to ~1000 nmol/L
  • Systematic Review and Bayesian Meta-analysis of the Dose-response Relationship between Folic Acid Intake and Changes in Blood Folate Concentrations

Reflections on Genetic Testing

• As anecdotal evidence, I have had patients receive conflicting genetic results from different genetic testing organizations including consumer based companies as well as academic laboratories.
• Should we as clinicians put full faith into genetic results and create entire treatment protocols based on a genetic result that may not be accurate?
• In my clinical practice, I achieve consistently positive results without the use of consumer based genetic testing. This does not mean it couldn’t be helpful, it simply means you can be a successful clinician without using this new and potentially flawed type of information.

Medscape Article Claim #2

By the early 1990s, researchers had shown folic acid’s effectiveness in preventing neural tube defects.

A 2015 CDC report estimated that fortification alone prevents about 1,300 neural tube defects from occurring in the U.S. each year.

Verdict

Possibly Misleading and Remains Controversial

• To my relative surprise, there is quite a bit of murkiness and controversy about the actual role of folic acid (through supplementation or fortification) to reduce the rates of neural tube defects to a clinically significant degree.
• The inputs into appropriate neural tube and embryonic development are complex and multifactorial in nature. Isolating one nutrient such as folate as the essential component in this complex, dynamic process is likely myopic and could be potentially harmful.
• Research AFTER systematic food fortification (with folic acid) regarding independent folic acid supplementation does not show a clear signal for decreased neural tube defects. The benefits of additional folic acid supplementation may be overstated.

Evidence

• 1) Interestingly, data AFTER 1998, following systemic food fortification does not illustrate a clear clinical effect for the prevention of neural tube defects with folic acid supplementation.
  • Folic Acid Supplementation for the Prevention of Neural Tube Defects: An Updated Evidence Report and Systematic Review for the US Preventive Services Task Force
• 2) “The continued occurrence of neural tube defects, the majority of which are isolated, after folic acid fortification of cereal grain flours suggests that additional prevention measures are necessary to reduce further the prevalence of these serious defects of the brain and spine.”
  • Neural Tube Defects and Associated Anomalies before and after Folic Acid Fortification
• 3) “We found a very weak correlation between NTD prevalence and the level of folic acid fortification, irrespective of the cereal grain fortified (wheat, maize or rice). Stratification of the data based on socioeconomic status (SES) indicated a strong linear relationship between reduced NTDs and better SES. We conclude that national fortification with folic acid is not associated with a significant decrease in the prevalence of NTDs at the population level.”
  • Folic Acid Fortification and Neural Tube Defect Risk: Analysis of the Food Fortification Initiative Dataset
• 4) The authors of the study cited below seem clearly upset about the previously mentioned study that suggested the existence of stronger associations between SES and NTD’s than fortification with folic acid. Their abstract is quite hard to disentangle, but suffice to say it appears these researcher’s “feelings were hurt” and this discussion is nuanced and complicated.
  • The Fallacy of Using Administrative Data in Assessing the Effectiveness of Food Fortification. Comment on: “Folic Acid Fortification and Neural Tube Defect Risk: Analysis of the Food Fortification Initiative Dataset. Nutrients 2020, 12, 247”

Medscape Article Claim #3

Folate supplements are essential, experts say, because it’s nearly impossible to get the amount known to prevent the birth defects by eating folate-rich foods alone.

“Folic acid is actually the only type of folate that has been shown in studies to help the closure of the neural tube,”

says Stuart Shapira, the associate director for science and chief medical officer for the CDC’s National Center on Birth Defects and Developmental Disabilities.

Verdict

Mostly True, But Misleading

• Folic acid, not folate, is the form of folate that has been rigorously studied for its potential role in the prevention of neural tube defects.
• One would need to consume more naturally occurring or supplemental folate to equal amounts of folic acid examined in research, but this is not “nearly impossible” with some nutritional guidance.

Evidence

• 1) In this latest systematic review assessing the role of folic acid supplementation to prevent neural tube defects, it appears that indeed only folic acid (not folate) either with, without or within a multivitamin has been extensively studied for its role in preventing neural tube defects.
• 2) Claims about folates or folate supplements providing the same benefits as folic acid for the prevention of neural tube defects (if present) are not technically supported, however, it would seem incredibly unlikely from a biochemical perspective that they would not have a near equivalent effect. (Note: see previous research above showing similar effects on blood folate and homocysteine levels with both folic acid and folate supplements.)
  • Folic Acid Supplementation for the Prevention of Neural Tube Defects: An Updated Evidence Report and Systematic Review for the US Preventive Services Task Force
• 3) The WHO in 2015 set a desired RBC Folate level in conceiving women for the prevention of neural tube defects at >400 ng/mL or >906 nmol/L.
• 4) For individuals, on average with deficient RBC Folate levels ~ 600 nmol/L, it would take 9 months of folic acid supplementation at 400 micrograms/day to get to ~1000 nmol/L
  • Systematic Review and Bayesian Meta-analysis of the Dose-response Relationship between Folic Acid Intake and Changes in Blood Folate Concentrations
• 5) Data suggests you need more folates from food or supplements to equal biochemically active levels of folic acid assessed in research. 0.6 mcg folic acid appears biochemically similar to 1 mcg of folate from food or supplements.
• 6) When examining the best sources of folate from food, it appears challenging (but not virtually impossible) to take a person following an average diet who is deficient based on RBC folate concentrations to sufficient over 6-9 months with food based folates instead of folic acid supplementation.

Dietary folate equivalent (DFE)

1 mcg DFE = 1 mcg food folate
1 mcg DFE = 0.6 mcg folic acid from fortified foods or dietary supplements consumed with foods
1 mcg DFE = 0.5 mcg folic acid from dietary supplements taken on an empty stomach

Folate: Fact Sheet for Health Professionals

Medscape Article Claim #4

A search for MTHFR on YouTube, podcasts, search engines, and other social media channels turns up a host of articles, videos, and interviews warning, without solid evidence, that folic acid is poison for those with MTHFR variations (which they often call “mutations”) or that the conditions associated with MTHFR variations are actually triggered or made worse by folic acid.

They often recommend changing one’s diet to include more folate-rich foods, avoiding foods fortified with folic acid, and replacing folic acid supplements with different, costlier ones in order to alleviate MTHFR-ascribed symptoms.

Verdict

Essentially True (folic acid has been incorrectly maligned)

• The author provides links in the commentary above to various examples of the online misinformation.
• VERY HIGH DOSE maternal supplementation with folic acid is associated in a few studies with higher rates of infant asthma.
• Large scale studies including the previously mentioned JAMA study do not support significant harm from folic acid supplementation.

Evidence

• 1. There were no signals for significant harms from micronutrient supplementation that included folic acid.
• 2. GI side effects including nausea and GI distress were noted more often in connection with iron supplementation than folic acid.
• 3. Side Note – There was no mortality benefit for infants with mothers receiving multiple micronutrient supplementation.
  • Multiple-micronutrient supplementation for women during pregnancy
• 4. There is an association with very high dose folic acid supplementation (5-7 MILLIGRAMS) and infant asthma.
• 5. Excessive folic acid supplementation beyond 2 mg (2000 micrograms) should likely be avoided for most individuals.
• 6. Appropriate dosing (400-1200 mcg) may even provide a benefit for reduction in rates of infant asthma
  • High dose of maternal folic acid supplementation is associated to infant asthma
  • Maternal high-dose folic acid during pregnancy and asthma medication in the offspring

Medscape Article Claim #5

L-methylfolate is more difficult, and therefore more costly, to make into a supplement and is less stable than folic acid. And because it is less stable, it can be hard to know exactly how much someone is getting if it’s been sitting on the shelf, since over-the-counter supplements are largely unregulated by the FDA and are exempt from requirements demonstrating that their ingredients are made carefully — or that they even work.

Verdict

Partially True

• Folate supplements are indeed more expensive than folic acid supplements almost universally.
• The Consumer Labs third party testing of numerous B vitamin supplements detailed below that included those containing folate and folic acid did not reveal widespread discrepancies from reported and tested values of nutrients. Assuming “guilty before proven innocent” is perhaps more fear-mongering than third party testing indicates.

Evidence

• 1. Via Consumer Lab’s third party assessment, the cheapest, verified methyl folate supplement costs ~ $0.08 per tablet versus ~$0.02 for an equivalent verified folic acid supplement.
• 2. Only 1 supplement containing folic acid showed a discrepancy with the reported value. The amount identified in testing was actually higher than was listed on the supplement.
  • Consumer Labs: Review of B Vitamins

Final Reflections

1. Our understanding of methylation, MTHFR variations and the effects of folic acid and folate supplementation is constantly evolving. Consensus on best practices with regards to the role of MTHFR genetic testing and folic acid vs. folate supplementation remains controversia
2. Educating individuals about whole food, anti-inflammatory diets containing folate rich foods is encouraged and supported.
3. Basic blood chemistry tests such as RBC folate, serum folate and homocysteine should be run BEFORE genetic tests.
4. For conceiving mothers with marginal folate status, be mindful that supplementation with either folic acid or folate will take upwards of 9 months to get to sufficient levels.
5. For cost conscious patients, choosing a folic acid supplement over a methylated folate is reasonable and appears to achieve similar effects as a folate supplement without harm.