Practitioner Research Review – June 2018

*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.

Combination L-T3 and L-T4 Therapy for Hypothyroidism

https://www.ncbi.nlm.nih.gov/pubmed/23974776

Study purpose

• Review the data regarding combination T4-T3 therapy for hypothyroidism

Intervention:

• Review, non-systematic

Main Results:

CONTEXT

• Certain genetic polymorphisms can interfere with the conversion of T4 into T3.  These patients may do better on combination therapy.
  • Interest in this issue has focused on the importance of the deiodinases in maintaining the euthyroid state and the role of genetic polymorphisms in the deiodinase genes that would affect thyroid hormone concentrations in both blood and tissues. One such polymorphism in the D2 gene, Thr92Ala, is associated with reduced T4 to T3 activation in skeletal muscle and thyroid, linked to obesity and alterations in thyroid-pituitary feedback, and in responses to thyroid hormone treatment.
  • Other workers observed that patients with the D2-Thr92Ala polymorphism may prefer combination therapy with T3/T4 in regard to neurocognitive function and general sense of well-being.
• “A suggestive clue to the presence of this polymorphism could be a higher than normal free T4/free T3 ratio.” Note: they do not offer a specific ratio
• “Perhaps 20% of hypothyroid patients continue to complain of symptoms suggesting thyroid hormone deficiency in spite of treatment.”
• Administering T4 with T3 may be more proximal to normal physiology
  • Concerns regarding therapy with T4 alone have led to increasing interest in the concept of adding T3 to traditional T4 therapy to potentially mimic hormonal secretion patterns from the intact normal thyroid gland more physiologically.

FINDINGS

• The majority, but not all, of the data show no benefit from T4 plus T3 therapy (supported below).
• One of the reasons for this is due to symptoms of hyperthyroidism or overdose.  Those with cardiovascular disease may be at increased risk of harm from T3 therapy.
  • One of the earliest studies over 40 years ago by Smith et al. [12] examined the responses to T4 therapy alone versus combined with T3 (80 mcg T4/20 mcg T3) in 87 hypothyroid patients. No patient preference was expressed by 48% of patients, 38% preferred T4 alone, and 18% preferred T3.
  • Twenty-four patients recorded unpleasant symptoms such as palpitations, irritability, nervousness, tremors, sweating, or headaches.
  • A possible cardiac risk to T3 therapy has been of concern to clinicians for some time, and Peters et al. [13] described a 2.6 relative risk of angina or myocardial infarction and a 4.8 relative risk of a coronary event during the follow-up of 181 of 1049 patients with cardiac admissions who had elevations in either total or free T3 levels. Smith et al. further concluded that ‘The shortcomings of combined therapy deduced from this study suggest that thyroxine has overall advantages for thyroid hormone replacement therapy.’
• The authors point out there are several studies showing no additional benefit of T4 plus T3 therapy.  Leading three meta-analyses to conclude the same (1, 2, 3).
  • a host of follow-up reports of studies that failed to confirm their observations, with all studies indicating no benefit to combined L-T4 and L-T3 therapy [15–26], with only one exception [27]. These reports were subsequently summarized in three meta-analyses [28–30] that came to the same conclusion.
• Upon a cursory search, it does appear there is even more data to support this (4, 5) and that this was not selective citation by the authors.  I was able to find one review (6) concluding that we should consider adding T3 to T4 therapy, but this appeared more of an outlier finding than a trend.
• Hyperthyroid symptoms are somewhat commonly reported in the above studies as well as in other studies.
• The authors draw an important distinction regarding the dose of T3.  In short, they feel the dosing used in the above studies to be supraphysiological and argue a lower, more physiological dose, may lead to benefit sans the hyperthyroid side effects.
  • The argument can be made that those patients showing some ostensible benefit from T3 coadministration received supraphysiologic dosages of T3.
  • In the case of thyroidal secretion of T3, there is 3.3 mcg/m2 per day produced, which for a body surface area of 1.78 m2, amounts to only 5.9 mcg per day, far less than the 10–25 mcg given in the above trials. Thus, we cannot invoke inadequate T3 dosage as the explanation for the failure of these trials to provide a benefit of T3 combination therapy. We know that 80% of circulating T3 is derived from the monodeiodination of T4 in peripheral tissues, and thus of a total daily T3 production rate of 25–30 mcg/day, 19–24 mcg are derived from T4 and only 6 mcg from the thyroid gland.
• The authors do reference 4 studies that have found T4 plus T3 therapy beneficial (7, 8, 9, 10)
  • What is the ideal dose from these studies?
    • The following range of doses was used:
      • 10 mcg – 20 mcg T3 to replace 50 mcg of T4
      • Note: micrograms can be written as either mcg or ug (µg).
• In the study by Nygaard mentioned above, 49% of patients preferred T4 plus T3 while only 15% preferred T4 monotherapy.  The authors feel the benefits here could have been due to the higher dose of T3 used.  Note: I realize there is an apparent contradiction here.
  • 49% of the patients preferred T4 + T3 therapy, compared with only 15% who preferred T4 monotherapy (P≤0.002).
  • The strengths of this study include its crossover design, the relatively large number of patients, and the stability maintained of TSH levels. However, given the dosage titration method employed, patients were treated with relatively more T3 daily than in most of the prior studies, averaging between 7.5 and 12.5 mcg daily,
  • The patients’ usual dose of L-T4 was substituted with either 20 or 50 mcgs of L-T3 with adjustments in L-T4 dosage as necessary to achieve stable TSH levels between 0.1 and 5.0 mU/l.
• One study in hypothyroid patients found better outcomes with T3 alone when compared to T4 alone.
• A pivotal study, one I have discussed prior, found that roughly 50% of patients preferred desiccated thyroid hormone (T4 plus T3) compared to 20% preferred T4 alone.  This study showed 3 lbs of weight loss, which has been found in another study also and improved subjective measures.
  • Although there was no improvement noted in QOL, patients on desiccated thyroid extract enjoyed weight loss of approximately 3 lbs in spite of having a slightly higher serum TSH level, while having higher serum T3 and lower serum T4 levels. This degree of weight loss, presumably attributable to higher T3 levels, is comparable to that seen in the study of Celi et al.

Additional Results:

• One study found a 16% prevalence of the D2 polymorphism which impedes conversion of T4 to T3.

Authors Conclusion:

• “In spite of these more recent studies that would appear to reopen the debate on combination T3/T4 therapy, compelling data that would form the basis for a guideline to such therapy are lacking.”
• “Until the ideal compound and a more evidence-based approach becomes available, clinicians treating such a patient with symptoms suggestive of insufficient thyroid hormone replacement could consider adding T3 as a therapeutic trial, 5 mcg two to three times daily.”

Clinical Takeaways:

• The majority of the data shows no additional benefit from T4-T3 combination therapy.  
• Some evidence suggests up to 50% of patients may do better on a T4-T3 combination than on T4 alone.  However, data here are preliminary and inconsistent.
• A desiccated form may be better than adding T3 to a T4 formula.  Or, use of a relatively high dose of T3 (20 or 50 mcg) in addition to T4.
• The above may be due, in part, to genetic polymorphisms interfering with the conversion of T4 to T3.
• Hyperthyroidism is a document side effect when using T3.

Dr. Ruscio Comments

Do patients recalcitrant to T4 monotherapy require the addition of T3?  In some cases, yes. However, we may be putting the proverbial cart before the horse if administering T3 before ensuring a) adequate absorption and b) that the non-responsive symptoms are not secondary to an issue in the GI.  Both require addressing the gut before embarking to optimize T3 levels through a T3 medication.

Do you find the data showing no benefit, and even detrimental hyperthyroid side effects, surprising?  This more closely reflects what I see in the clinic; far fewer patients find improvement from a T4 plus T3 treatment plan than natural medicine presumptions would have you believe.  Some do, yes. But my observation has been this is not the majority.

T3 therapy does appear to have a time and a place, but there is still much to be learned here.  I hope the above data helps calibrate the clinician to a paradigm more proximal to what one will encounter in practice.

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A Critical Appraisal of the Recent Reports on Sunbeds from the European Commission’s Scientific Committee on Health, Environmental and Emerging Risks and from the World Health Organization.

https://www.ncbi.nlm.nih.gov/pubmed/29374748

Study purpose

• In short, a European Commission published a position paper stating there are no health benefits from sunbed use and that use may contribute to melanoma risk.  Dr. Michael Holick et al. published a response stating that the EU’s paper was biased and incomplete, concluding “current scientific knowledge does not support the conclusion sunbed use increases melanoma risk.”
  • The European Commission’s Scientific Committee on Health, Environmental and Emerging Risks and the World Health Organization recently published reports which concluded that a large proportion of melanoma and non-melanoma skin cancer is attributable to sunbed use, and that there is no need to use sunbeds as there are no health benefits and they are not needed to achieve an optimal vitamin D level. The overall conclusion from both bodies was that there is no safe limit for UV irradiance from sunbeds. We are, however, deeply concerned that these assessments appear to be based on an incomplete, unbalanced and non-critical evaluation of the literature.

Intervention:

• A rebuttal based on a more thorough review of the literature than performed by the EU group.

Main Results:

• The EU paper concluded:
  • “i) sunbed use is responsible for a noticeable proportion of both melanoma and non-melanoma skin cancer (NMSC) and for a large percentage of melanomas arising before the age of 30 years;
  • ii) sunbed exposure has little health benefit;
  • iii) there is no need to use sunbeds to achieve an optimal vitamin D level; and
  • iv) because of evidence of the carcinogenic effects of sunbed exposure and of the nature of skin cancer induction, there is no safe limit for UV irradiance from sunbeds”
• Holick et al responded; “Notably, both reports ignore
  • i) meta-analyses that show no association of sunbed use with increased melanoma risk in Europe;
  • ii) epidemiological and animal studies that show no increase in melanoma risk following chronic and sub-erythemal UV exposure;
  • iii) beneficial health effects of UV radiation; and
  • iv) consequences of vitamin D deficiency.”
• Holick et al (I will use “Holick” going forward for brevity) state that a causal relationship is far from proven and is precluded by a number of confounders.
  • Our present scientific knowledge on this topic is based on observational studies (case–control and cohort studies) that demonstrate associations that are confounded by other known factors and that do not demonstrate causation
• Holick criticizes a systematic review with the meta-analysis by Boniol et al (11).  This study concluded,
  • “Sunbed use is associated with a significant increase in risk of melanoma. This risk increases with number of sunbed sessions and with initial usage at a young age (<35 years). The cancerous damage associated with sunbed use is substantial and could be avoided by strict regulations.”
• Yet Holick comments,
  • Overall the quality of the entire evidence is poor due to lack of interventional studies and severe limitations of case–control and cohort studies that include unobserved or unreported confounding.
• And Holick cites another systematic review with meta-analysis which supports his contention that,
  • Current scientific knowledge is mainly based on observational studies with poor quality data, which report associations but do not prove causality. At present, there is no convincing evidence that moderate/responsible solarium use increases melanoma risk. (12)
• Holick continues that it is crucial to distinguish cause from the association, and that this is especially important because some evidence suggests tanning bed use is associated with an unhealthy lifestyle (smoking, drinking, and over-exposing to sun during summer months)  So, it might be the unhealthy lifestyle that is responsible for increase skin cancer risk.  Holick cites a systematic review supporting his contention, (13)
  • The typical sunbed user is female, between 17 and 30 years old, and tends to live a comparatively unhealthy lifestyle: Users smoke cigarettes and drink alcohol more frequently and eat less healthy food than non-users. Users are characterized by a lack of knowledge about health risks of UVR.

Additional Results:

• Holick cites the best data we have does not show an association between tanning bed use and melanoma.
  • It has to be recognized that the “best data from published peer-reviewed scientific studies available to date” do not show a statistically significant association of sunbed use with melanoma risk in Europe (14)
• Holick also points out the EU position paper ignores a large body of evidence finding no association between UV exposure and melanoma.
  • The large body of evidence from epidemiological and animal studies that demonstrates no increase in melanoma risk following chronic (moderate) UV exposure (59-66) (15, 16, 17, 18, 19, 20, 21, 22)
• Holick also cites evidence supporting sun exposure as being able to decrease melanoma risk,
  • Occupational exposure to UV radiation was associated with a reduced risk of melanoma in a European population with lightly pigmented skin (23)
• And that sun exposure was associated with reducing the risk of all-cause mortality.
  • As an example, a large cohort study reported a longer life expectancy amongst participants with active sun exposure habits, which was related to a decrease in cardiovascular disease (CVD) and non-cancer-related mortality (24)
• Holick cites another similar cohort study to the one mentioned above, that found sun exposure reduce cardiovascular mortality.  However, this study also found sunbed use associated with increased all-cause and cancer mortality (25).  It’s important to note that those with the highest use of sunbeds, >12 times per year, experienced a doubling in their hazard ratio risk of all-cause mortality.  But, in another study wherein people used tanning beds less, <12 times per year, they had a 13% reduced all-cause mortality.
  • Solar UV exposure was associated with reduced overall and CVD mortality, whereas artificial UV exposure was associated with increased overall and cancer mortality among Swedish women.
  • In the study of Lindqvist et al., all users of sunbeds (namely mostly those using a sunbed <12-times per year, i.e. sensible users) were at 13% lower risk of all-mortality
• What does all this mean?  I suggest that the dose of tanning bed use could be an important detail.  Perhaps one could derive benefit from lighter use, less than 12 times per year, and may experience detriment from heavier use, more than 12 times per year.

Limitations:

• Some of Holick’s supports appear reaching in attempts to cast a positive light on sun exposure and tanning bed use.  I fear his position may be slightly biased in a pro-sun direction. He does make some excellent points, however. It is possible his rebuttal paper appeared ‘reaching’ because he was attempting to showcase the other side of the evidence.  Overall, I find Holick’s commentary to be more in alignment with the data than the European Union’s paper. However, there could be a nuance to this body of literature that requires a level of expertise that is beyond my current scholarship.

Authors Conclusion:

• “In conclusion, our present scientific knowledge does not support the notion that sunbed use per se may increase melanoma risk.”

Interesting Notes:

• Lighter skin, with the ability to tan, may have been an adaptation allowing those in less sunny climates to retain vitamin D production.
  • In fact, one of the leading theories of the evolution of skin pigmentation is that it is a compensatory mechanism for vitamin D production in low UVB environments (26)
  • Facultative pigmentation, or tanning, developed in populations where levels of UVB varied strongly by season
• Mechanisms via which UV exposure exerts it’s beneficial effects
  • Modulation of melatonin
  • Anti-hypertensive
  • Stimulates beta-endorphin production
  • Anti-carcinogenic

Clinical Takeaways:

• Sun exposure is health promoting
• Tanning bed use may or may not pose a health risk, the data appear mixed
• Light use of tanning beds, less than 12 times per year, may pose minimal risk combined with health benefit

Dr. Ruscio Comments

Unsurprisingly, this is a contentious issue.  Holick does an excellent job pointing out a weakness in anti-tanning data sets and supporting the health benefits of both sun exposure and tanning bed use.  Until more conclusive data are produced, I would recommend against tanning. Perhaps one could make a theoretical argument that limited doses of tanning, before vacation and in attempts to condition skin so as to reduce the chances of burning, could be justifiable.

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Elemental Diet and the Nutritional treatment of Crohn’s Disease

https://www.ncbi.nlm.nih.gov/pubmed/25584170

Study purpose

• Expound upon benefits and clinical uses of elemental diets

Intervention:

• Editorial commentary regarding elemental diets

Main Results:

• Since this was not a clinical trial, systematic review or meta-analysis there are no formal ‘results’, but there are interesting points.  See below.

Authors Conclusion:

• “Such specialist support is not available in all centers and some gastroenterologists lack confidence in managing nutrition problems. This may deter many from trying this approach, despite its proven lack of side effects such as osteoporosis and safety in pregnancy (15, 16). However, surely it must be available in tertiary centers dealing with complex refractory cases of Crohn’s disease.”

Interesting Notes:

• An abnormal microbiota (and subsequent production of toxins) may lead to the immune system tagging the microbiota with immunoglobulins, thus signaling for the immune system to attack.
  • Although in health we live in peace with our microflora, the colonic microflora is abnormal in Crohn’s disease (4). This may lead to production of toxic chemicals such as alcohols, aldehydes and the ethyl esters of fatty acids (5).  It is believed that this is the reason for the loss of normal immune tolerance to the gut flora in Crohn’s disease, which results in the coating of faecal bacteria by immunoglobulin.
• I would add to this –  an abnormal immune system may lead to abnormal tagging of normal microbiota.  Then, the abnormalities seen in the microbiota are merely a result of the inappropriate immune tagging.
• By ‘starving’ the microbiota, we can reduce production of toxins it produces thus decreasing the immune tagging.
  • Elemental diet has been shown to reduce the production of bacterial metabolites (5) within 2 weeks and significantly to reduce bacterial coating with immunoglobulin (8).
• I would again add to this that by reducing the number of bacteria we could provide the immune system less to tag, thus calming down an overzealous immune response.
• The elemental diets work well for Crohn’s disease
  • Overall, the results of enteral feeding are excellent with 80-100% of compliant patients going into remission within 2-3 weeks

Clinical Takeaways:

• An elemental diet is an effective tool for Crohn’s disease.

Dr. Ruscio Comments

Elemental diets can be highly effective.  When writing my book, I scoured the literature looking for side effects or nutrient deficiency documentation and could find none. Regarding IBD specifically, there are promising data for probiotics with ulcerative colitis, but the data are not as promising for probiotics and Crohn’s.  Probiotics are worth a trial, but the elemental diet is an effective secondary consideration.

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Rapid-Fire Research – Ultra-Concise Summaries of Noteworthy Studies

Positive effects of resistant starch supplementation on bowel function in healthy adults: a systematic review and meta-analysis of randomized controlled trials

https://www.ncbi.nlm.nih.gov/pubmed/27593182

• Animal experimental studies have found that resistant starch can significantly improve bowel function, but the outcomes are mixed while conducting human studies.
• We conducted a systematic review and meta-analysis of randomized controlled trials to evaluate the relationship between resistant starch supplementation and large intestinal function.
• The pooled findings revealed that resistant starch:
  • significantly increased fecal wet weight (WMD 35.51 g/d, 95% CI 1.21, 69.82) and
  • butyrate concentration (SMD 0.61, 95% CI 0.32, 0.89),
  • significantly reduced fecal PH (WMD -0.19, 95% CI -0.35, -0.03),
  • but the increment of defecation frequency was not statistically significant (WMD 0.04 stools/g, 95% CI -0.08, 0.16).
• To conclude, our study found that resistant starch elicited a beneficial effect on the function of the large bowel in healthy adults.
• Dr. R’s comments
  • Resistant starch can be helpful, it can be thought of as a prebiotic rich fiber.  However, it’s important to distinguish between mechanistic improvement juxtaposed to clinical benefit.  This meta-analysis found improved biomarkers (aka mechanism) but did not find an improved clinical outcome of improving bowel frequency.  RS is still worth considering, but these results are helpful in having a realistic expectation regarding outcomes with RS.

Lubiprostone Accelerates Intestinal Transit and Alleviates Small Intestinal Bacterial Overgrowth in Patients With Chronic Constipation.

https://www.ncbi.nlm.nih.gov/pubmed/27650225

• Lubiprostone (aka Amitiza) is an effective treatment for chronic constipation (CC). The mechanism of action of lubiprostone is through increased fluid secretion and lubrication of the intestinal lumen. The effects of lubiprostone on gastrointestinal transit and small intestinal bacterial overgrowth (SIBO) have not been adequately explored. The current study was designed to investigate whether lubiprostone (1) alters gastrointestinal transit and (2) affects SIBO in patients with constipation.
• Lubiprostone significantly
  • softened the stool and increased the frequency of BM from a median of 2 to 4 times per week.
  • The CTT and SLBTT were significantly shorter in responders to lubiprostone
    • colon transit time (CTT), combined small and large bowel transit time (SLBTT)
• The higher frequency of BM after treatment was significantly correlated with the acceleration of CTT, SLBTT and whole gut transit time.
• 68% patients were positive for SIBO at baseline. 41% SIBO-positive patients became SIBO-negative after lubiprostone treatment (P < 0.05).
• CONCLUSIONS: In CC, lubiprostone improves the frequency of BMs, softens the stool, accelerates intestinal transit and decreases accompanying SIBO. The improvement of SIBO could be explained by the cleansing effect of increased intestinal fluid and mucus combined with enhanced intestinal motility with lubiprostone.
• Dr. R’s comments:
  • It’s important to remain open to drug treatment for constipation in patients who have been non-responsive to other therapies.  The relationship between SIBO and constipation is bi-directional; SIBO can cause constipation and constipation can also cause SIBO.  In some cases, the key to resolving SIBO is resolving constipation. See two podcasts we have recorded on constipation with Dr. Satish Rao and Dr. Leonard Weinstock (use homepage search box).

Is Thyroid Autoimmunity Itself Associated with Psychological Well-Being in Euthyroid Hashimoto’s Thyroiditis?

https://www.ncbi.nlm.nih.gov/pubmed/28260699

• Mental health was negatively correlated with anti-TPO (r=-0.287, p<0.01). HRQoL is impaired and depression and anxiety scores are high in patients with euthyroid HT independent of levothyroxine replacement.
• Therefore, our results indicate that thyroid autoimmunity itself may have an impact on psychological well-being in euthyroid patients with HT.
• Dr. R’s comments:
  • We have discussed this previously, the relationship between thyroid antibodies and well-being being independent of thyroid hormone levels.  The contentious part of this issue is what we should consider pathological levels of thyroid antibodies. I have published one podcast on this and will be releasing another soon.

Selenium Supplementation Could Restore Euthyroidism in Subclinical Hypothyroid Patients with Autoimmune Thyroiditis.

https://www.ncbi.nlm.nih.gov/pubmed/28042649

• The thyroid is an organ with one of the highest selenium concentrations, containing many selenoproteins implicated in thyroid hormone metabolism. Treatment with levothyroxine has been recommended for all subclinical hypothyroid patients with TSH levels > 10 mU/L, whereas for those with TSH < 10 mU/L treatment remains controversial.
• A randomized controlled prospective study was performed to investigate the effects of Se treatment on patients with autoimmune thyroiditis and mild sub-clinical hypothyroidism (TSH < 10 mU/L).
• MATERIAL AND METHODS: A total of 196 patients with autoimmune thyroiditis were recruited in the study. Patients were assigned to receive (case) or not receive (control) an oral selenomethionine treatment. Cases received 83 mcg selenomethionine/day orally for four months. All the patient’s charts were submitted to thyroid hormonal profile (TSH, fT4) and TPOAb evaluation upon enrolment and at the end of the study.
• RESULTS: In total 192 patients completed the study.
  • 33/192 (17.2%) participants restored euthyroidism (Responders).
  • Responders were significantly more frequent among Cases than Controls (30/96 [31.3%] vs. 3/96 [3.1%], p < 0.0001).
• CONCLUSION: Selenium supplementation could restore euthyroidism in one-third of subclinical hypothyroidism patients with autoimmune thyroiditis.
• Dr. R’s comments:
  • Selenium is a consideration for those with subclinical hypothyroidism.  Here is an important observation from this study
    • Thyroid peroxidase antibodies significantly decreased only among supplemented patients both in Responders and in Non-Responders
  • So, it appears that decreases in TPO were not solely responsible for the resurrection of thyroid function.  Also, remember that over 50% of SCH will spontaneously remit with no treatment.

Effects of Eight Weeks of Time-Restricted Feeding (16/8) on Basal Metabolism, Maximal Strength, Body Composition, Inflammation, and Cardiovascular Risk Factors in Resistance-Trained Males.

https://www.ncbi.nlm.nih.gov/pubmed/27737674

• CONCLUSIONS: Our results suggest that an intermittent fasting program in which all calories are consumed in an 8-h window each day, in conjunction with resistance training, could improve some health-related biomarkers, decrease fat mass, and maintain muscle mass in resistance-trained males.
• Dr. R’s comments:
  • Intermittent fasting can be helpful for both metabolism and digestive function.  In this study, a 16 hour fast was used. This would equate to having dinner at 6 pm and then not eat again until 10 am the next day.

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.