Practitioner Research Review – February 2017

Dr. Michael Ruscio’s Monthly – Future of Functional Medicine Review Clinical Newsletter

Practical Solutions for Practitioners

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Research

*Please note: the case study and research studies are not meant to be mutually reinforcing. There is often concept overlap, however the research studies are a collection of the most clinically meaningful research that has been published recently.

Effects of low-carbohydrate diet therapy in overweight subjects with autoimmune thyroiditis: possible synergism with ChREBP.

https://www.ncbi.nlm.nih.gov/pubmed/27695291

Study purpose:

  • To assess the impact of a diet devoid of carbohydrates (bread, pasta, fruit, and rice) and free from goitrogenic foods (including dairy) on thyroid function, thyroid autoimmunity and body composition
    • – said simply a low carb diet.

Intervention:

3 weeks on respective diet

  • Treatment (low carb diet), n = 108
    • – Carbohydrates 12%–15%, proteins 50%–60%, and lipids 25%–30%.
      • – Dr. R’s note: this may equate to roughly 200 grams of carbs/day
    • – Instructed to eat large leafy and other types of vegetables and only lean parts of red and white meat, avoiding goitrogenic food.
    • – The following items were also excluded from the diet: eggs, legumes, dairy products, bread, pasta, fruits, and rice. “This protein-rich diet plan was implemented for 3 weeks”
  • Control, n = 72
    • – A simple, low-calorie diet without restrictions regarding the types of food to consume, but adhered to the recommended dietetic allowances, as suggested by the National Research Institute on Food and Nutrition
      • – Dr. R’s note: traditional dietary advice

Main Results:

  • Treatment
    • – Significant reduction of thyroglobulin (Tg) antibodies -40% and anti-peroxidase (TPO) antibodies -44%
  • Control (untreated)
    • – Significant increase in thyroglobulin (Tg) antibodies +9%. The level of anti-peroxidase (TPO) antibodies increased without reaching statistical significance +16%.

Additional Results:

  • No significant changes in thyroid hormones were reported between groups
  • Low carb diet group experienced slightly better improvements in body composition
  • 83% of patients with high levels of autoantibodies were breath test positive to lactase which may suggests carbohydrate malabsorption

Authors’ Conclusion:

  • The dietary regime described in this study could be implemented for the treatment of patients with autoimmune thyroid because of the possibility to reduce the inflammation state in general and of the thyroid gland

Interesting Notes:

  • “It is therefore evident that an improvement in the general conditions of the patients undergoing an ad hoc dietary regime leads to both a reduction of body weight and levels of autoantibodies”. Translation – ad hoc meaning not highly planned, so this diet was followed loosely.

Clinical Takeaways:

  • A SIMPLE lower carb diet (around 200 grams/day) that removes diary and bread but focuses on meats and vegetables can both dampen thyroid autoimmunity and improve body composition.

Dr. Ruscio’s Comments

The reduction of carbs and allergens (gluten, diary) likely played the largest role, while the impact of avoiding goitrogens was likely minimal. This is because reduction of iodine has been shown to lower thyroid antibodies so one would think eating goitrogens (which impede iodine absorption) may actually help thyroid autoimmunity.

The carb reduction may also have been helpful because the majority of patients expressed a degree of carbohydrate malabsorption. We could speculate that a reduction of carbs (which these subjects poorly absorbed) reduced the amount of available substrate for the microbiota to feed on and may have corrected underlying overgrowths or imbalances thus improving the environment and immune status in the gut, thus improving systemic immune function.

How does this study support a cost effective and efficient FM model? Impressive results in thyroid autoimmunity were obtained without needing food allergy testing, and without needing a highly meticulous or restrictive diet.


Insufficient documentation for clinical efficacy of selenium supplementation in chronic autoimmune thyroiditis, based on a systematic review and meta-analysis.

https://www.ncbi.nlm.nih.gov/pubmed/27683225

Study purpose:

  • To summarize the available data in order to determine if selenium therapy is effective for autoimmune thyroid.

Intervention:

  • Trials of low quality or at risk of biased were not included, thus this review summarized data from 9 clinical trials for the systematic review and data from 5 clinical trials for the meta-analysis.

Main Results:

  • The meta-analysis did not show selenium supplementation to be beneficial
  • In other studies benefit has been shown for;
    • — Quality of life,
      • — In a meta-analysis from 2010, based on four trials, [9], the authors reported decrease in thyroid peroxidase autoantibody (TPO-Ab) levels and improvement in well-being and/or mood, after 3 months of selenium supplementation, as compared to placebo. https://www.ncbi.nlm.nih.gov/ pubmed/20883174
      • — Similar conclusions were reached in another meta-analysis from 2014, including nine trials [10]. https://www.ncbi.nlm.nih.gov/pubmed/25574167
    • — But not all data agree
      • — Finally, a Cochrane Collaboration systematic review from 2013, also including four studies, [11] reached no conclusion regarding effects on HRQL, and did not perform a meta-analysis of change in TPO-Ab https://www.ncbi.nlm.nih.gov/ pubmed/23744563
    • — Thyroid ultrasound

Additional Results:

  • Two studies using selenium for 6-12 months showed no change in quality of life
    • — Two double-blinded trials used the SF-36 form [20, 42], and both reported no significant changes following six [42] or twelve [20] months of selenium supplementation in patients not treated with LT4.
  • However, 2 other studies using selenium for 3 months + thyroid hormone replacement, showed increase in QOL when compared to thyroid hormone replacement alone
    • — Two studies used the SF-12 form and found significant improvement in well-being by 200 μg/d sodium selenite for three months, as compared to placebo [17, 36]. In both trials, selenium supplementation was administered adjuvant to LT4,
  • This may mean selenium is helpful in the short term and/or that it is helpful when co-administered with thyroid hormone in those who require the hormone.

Authors’ Conclusion:

  • “Our conclusion is that current evidence does not justify the emerging use of selenium supplementation in the treatment of AIT.”

Interesting Notes:

  • “Chronic autoimmune (AIT) or Hashimoto’s thyroiditis affects 1–2% of the population with increasing prevalence with age and a female preponderance.”
  • “In communities replete in iodine intake, it is the predominant cause of hypothyroidism.”
  • “In a recent narrative review it was suggested that selenomethionine might be more effective than selenite in lowering thyroid autoantibody levels. However, no such trends were observed for any of the clinical outcomes assessed in our study”

Clinical Takeaways:

  • Selenium may not be the thyroid panacea it has been suggested to be, however it may help with thyroid gland health and with quality of life. The effect of selenium appears limited to the short term, 3-6 months.

Dr. Ruscio’s Comments

A previous meta-analysis based upon 4 trials did show benefit, however these studies only looked at a 3 month window https://www.ncbi.nlm.nih.gov/pubmed/27702392.  A key insight provided by this paper was looking at the level of impact of selenium in studies that were 3 months, compared to 6 months, compared to 12 months.  Looking at this data it’s clear that the effect at 3 months is present however by 12 months no benefit is show and the placebo was actually shown to be more powerful.

So what does this mean?  It means selenium may have its highest utility when used in the short term.  This is good news because this means we should use a more conservative treatment duration with our patients.  Also recall from a previous issue that you may not need to keep administering selenium until antibodies or “normal”.  Achieving TPO less than 500 may be adequate


A Randomized Clinical Trial of Berberine Hydrochloride in Patients with Diarrhea-Predominant Irritable Bowel Syndrome.

http://www.ncbi.nlm.nih.gov/pubmed/26400188

Study purpose:

  • To assess berberine’s utility in the treatment of diarrheal type IBS

Intervention:

  • 132 patients randomized to receive 400mg of berberine hydrochloride daily, (delivered twice daily at 200mg) or placebo for 8 weeks – double blinded.
  • Patients were followed for an additional 4 weeks post treatment

Main Results:

  • A reduction of diarrhea frequency, abdominal pain frequency, and urgent need for defecation frequency were significantly more pronounced in the berberine group than the placebo group.
  • A trend of improvement was observed with berberine hydrochloride for IBS symptom score, depression score, and anxiety score and IBS quality of life, compared with placebo.

Additional Results:

  • After being off berberine for 4 weeks the treatment’s group’s symptoms approximated that of the control – meaning the effect of berberine was not long lasting.

Authors’ Conclusion:

  • “berberine hydrochloride, conveniently delivered, is well tolerated and reduces diarrhea frequency, abdominal pain frequency, and overall IBS-D symptoms score as well as anxiety and depression scores; consequently, berberine improves the quality of life of IBS-D patients.”

Interesting Notes:

  • Prevalence of IBS diagnosed by the Rome III criteria in the general population is 1.1–29.2%.
  • The placebo response rate in randomized clinical trials conducted in Europe may vary from 0 to 91.7%, with a mean value of 43%.
  • Studies have shown that berberine has antidepressant-like effect & has inhibitory action on monoamine oxidase enzyme

Clinical Takeaways:

  • Berberine appears to be an effective treatment for diarrheal type IBS and may also benefit mood and quality of life. A lower dose, 400mg/day, may be effective. The effect however, may not be long term.

Dr. Ruscio’s Comments

Both the placebo group and the berberine group improved, remember, placebo can account for sizable improvements in IBS (43% on average). However, the treatment group experienced significantly better improvements than the placebo group. After being off berberine for 4 weeks the treatment’s group’s symptoms approximated that of the control – meaning the effect of berberine was not long lasting.

What does this mean? Perhaps a higher dose or longer duration of treatment would lead to longer lasting results? Perhaps if a healthy diet was implemented at the same time the results would have been more prolonged? It essentially tells us that management/treatment of IBS is likely not a mono-therapeutic endeavor.


The Intestinal Microbiota And The Role Of Probiotics In Irritable Bowel Syndrome: A Review

https://www.ncbi.nlm.nih.gov/pubmed/26840477

Study purpose:

  • To review the available data so as to determine if probiotics are a viable treatment for IBS.

Intervention:

  • This was an informal review, meaning it was not a systematic review or meta-analysis. Roughly 15-20 clinical studies were reviewed. And the paper cited 74 references total.

Main Results:

  • Probiotics are helpful for global symptoms, pain, bloating and flatulence.

Additional Results:

  • N/A

Authors’ Conclusion:

  • “… probiotics, which are generally regarded as safe and may act on the global symptoms, bloating and flatulence, which have considerable appeal. Furthermore, a rather impressive scientific rationale has emerged for the use of probiotics in gastrointestinal conditions, including IBS.”
  • “However, recommendations regarding individual species or strains continue to be limited by a lack of data and the poor quality of much of the available data.”

Interesting Notes:

  • “A number of reviews as well as a recent well conducted systematic review and meta-analysis have demonstrated that probiotics have a therapeutic benefit in the IBS and may improve global symptoms, abdominal pain, bloating and flatulence.” https://www.ncbi.nlm.nih.gov/pubmed/25070051
  • ‘IBS is a disorder is defined by the coexistence of abdominal discomfort or pain associated with an alteration in bowel habits.’
  • “Irritable bowel syndrome is a common, chronic relapsing gastrointestinal disorder that affects 7%–22% of the population worldwide.”
  • “The cardinal symptom in IBS is abdominal pain occurring in association with an alteration in bowel habit; diarrhea and/or constipation.”
  • “It should be remembered that although dysbiosis has been recognized in various intestinal diseases, in most cases a definitive cause-and-effect relationship remains to be established.” Dr. R’s note: I think this point is most salient with regards to the changes we see in the microbiota (not including SIBO, SIFO, or infection) – we are unclear if the altered microbiota in IBS is a cause or a result of the disease.
  • This paper lists the four main classes of probiotics as
    • – Lactic bacteria that include Lactobacillus, Lactococcus, Bifidobacterium and Streptococcus
    • – Saccharomyces (S. Boulardi)
    • – Escherichia
    • – Bacillus
  • It is known that Lactobacillus and Bifidobacterium species have anti-inflammatory effects in the intestine and their depletion could contribute to lowgrade inflammation. Proinflammatory cytokine levels (e.g. interleukin (IL)-6, IL-8, tumor necrosis factor-α, and IL-1β) are elevated in the systemic circulation of patients with IBS.”

Clinical Takeaways:

  • Probiotics are a viable treatment for IBS.

Dr. Ruscio Comments

The ‘best’ probiotic type or dose has yet to be defined so determine this empirically – perform a therapeutic trial with one of the major probiotic classes at a time and evaluate the response. Use what works. If nothing works, use nothing. Treat based upon symptoms, not labs, as we do not know if ‘microbiota lab changes’ are causal.

Remember that probiotics have been noted to improve GI barrier health, modulate the immune system (especially small intestinal immunity – GALT/MALT), reduce inflammation, have antibacterial actions and shown to be an efficacious treatment in SIBO. It is likely because of all these reasons that we see improvements in IBS with probiotics.

Does this mean EVERYONE will improve? No. The most common reaction I have seen is bloating. If someone bloats then either use less probiotics, another probiotic, or no probiotic at all.

I’d like to hear your thoughts or questions regarding any of the above information. Please leave comments or questions below – it might become our next practitioner question of the month.

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