Future of Functional Medicine Review Clinical Newsletter

Research Briefs for Practitioners – May 2021

by Dr. Ruscio, DNM, DC, Gavin Guard, PA-C, MPAS, CISSN, Pn1, and the Ruscio Institute for Functional Medicine Clinical Team

Medically reviewed & fact checked by a
board-certified doctor
Medically reviewed & fact checked by a
board-certified doctor
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Episode 4

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Featured Study

Effect of APOE Genotype on Plasma Docosahexaenoic Acid (DHA), Eicosapentaenoic Acid, Arachidonic Acid, and Hippocampal Volume in the Alzheimer’s Disease Cooperative Study-Sponsored DHA Clinical Trial

  • Previous knowledge:
    • APOE 4/4 carriers have faster clearance of lipoproteins in blood
    • Lower hippocampal volume predicts incidence of Alzheimer’s disease
  • 275 participants, randomized to 2 g/d DHA
  • After 18 months of supplementation, APOE 4/4 carriers had:
    • Less increase in plasma DHA levels
    • More reduction in hippocampus volume
  • Commentary: It may be worth measuring fatty acids in patients and foregoing genotype testing given high intra-individual variability found in study.

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Gastrointestinal Studies

  • An elemental diet is effective in the management of diversion colitis
    • Diversion colitis = inflammation of a section of bowel that has been isolated from functioning bowel after surgery
    • Case report of 29 yo female w/ Crohn’s and diversion colitis
    • Given exclusive elemental diet followed by LOFFLEX diet
    • Improvements:
      • Bowel movement frequency
      • Taken off biologic medication

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Thyroid & Hormone Studies

  • Relation of kidney function and homocysteine in patients with hypothyroidism
    • 450 participants w/ hypothyroidism
    • Patients with hypothyroidism had:
      • Higher serum homocysteine
      • Higher creatinine levels
      • Lower eGFR levels
    • Levothyroxine treatment resulted in significantly decreased Hcy and increased eGFR
    • Commentary: Hypothyroidism is associated with high homocysteine and lower kidney function

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Diet & Lifestyle Studies


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Episode 3

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Featured Study

Incidence of thyroid diseases: Results from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil)

  • 10,000 euthyroid participants followed over 4 years
  • Incidence of thyroid disease at 4-year mark
    • Overall thyroid disease: 7%
    • Overt HYPERthyroidism: 0.2%
    • Subclinical HYPERthyroidism: 0.5%
    • Overt HYPOthyroid: 2%
    • Subclinical HYPOthyroid: 4%
  • Higher incidence in women
  • Presence of TPO antibodies at baseline was associated with higher incidence of overt thyroid diseases
  • Commentary: The prevalence and incidence of thyroid disease is much less than what some would have you believe.

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Gastrointestinal Studies

  • Screening and eradication of Helicobacter pylori for gastric cancer prevention: The Taipei global consensus
    • Consensus of 28 experts in 11 countries
    • Worldwide fraction for H. pylori in gastric cancer is >85%
    • Eradication of H. pylori reduces the risk of gastric cancer in asymptomatic subjects (backed by 10 RCTs ) and is recommended unless there are competing considerations
    • Young individuals would benefit most from H. pylori eradication
    • If 1st-degree relative w/ gastric cancer, screen and treat H. pylori
    • Confirmation test after H. pylori eradication therapy is recommended for symptomatic H. pylori infected
  • Rapid gastric emptying in diabetes mellitus: Pathophysiology and clinical importance
    • Rapid gastric emptying is common in T2 Diabetics
    • What comes first: Hyperglycemia or rapid gastric emptying?
      • Hyperglycemia may be the main driver for fast gastric emptying
    • Whey protein 15 minutes before meals can:
      • Reduce postprandial glucose excursions
      • And slow down gastric emptying rates
    • Commentary: Consider pre-loading meals w/ whey protein to reduce rapid gastric emptying and glucose excursions.

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Thyroid & Hormone Studies

  • The effect of ketogenic diet on thyroid functions in children with drug-resistant epilepsy
    • 66 children on keto diet 12+ months
    • Median serum FT4 and TSH concentrations, and the frequencies of patients with low FT4 and high TSH concentrations did not change significantly
    • Commentary: This contradicts some papers (1) regarding a ketogenic/low carb diet and its effect on thyroid.
      • Some individuals may need more carbohydrates to match energy levels (especially females); “GnRH neuron activity and LH pulsatility are actually regulated by brain glucose availability. The adult female human brain oxidizes about 80g of glucose each day at a continuous rate. This must be provided daily by dietary carb, because the brain’s rate of energy expenditure can deplete liver glycogen stores in less than a day.” –Loucks 2013

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Autoimmunity Studies


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Diet & Lifestyle Studies

  • Association between autonomic function and obstructive sleep apnea: A systematic review
    • 71 studies
    • Sleep apnea associated with:
      • Increased sympathetic activity
      • Reduced parasympathetic activity
      • Reduced heart rate variability
    • Commentary: Consider limbic retraining in those who have a history of childhood trauma, severe anxiety (especially around their health), or who have poor coping/stress management skills. Limbic activation may contribute to sleep apnea.

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Episode 2

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Featured Study

Association between statin use and cognitive function: A systematic review of randomized clinical trials and observational studies

  • 24 studies with 1.4 million participants
  • 21 observational studies, 3 RCTs
    • All 3 RCTs, which ranged from 3-6 years of follow-up, showed no significant association between statin use and adverse cognitive effects
    • The follow-up for observational studies ranged from 3-15 years
      • 10 studies: Reduced incidence of dementia
      • 7 studies: No association with incident dementia
      • 3 studies: Decline in cognition was similar to no statin
      • 1 study: Cognitive decline with statin use
    • There was no evidence of adverse cognitive effects, including incidence of dementia, decrease global cognition or specific cognitive domains associated with statin use in individuals aged ≥60 years
    • Commentary: Some experts argue that statin use may actually be associated with a reduced rate of Alzheimer’s

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Gastrointestinal Studies

  • Diet supporting therapy for inflammatory bowel diseases
    • 50% improvement in IBD in 1 week after 5g/day of serum bovine immunoglobulin
      • Corroborated in 5 other studies
    • Mesalazine works better when given with curcumin
    • Other beneficial therapies
      • Essential fatty acids
      • Vitamin D
      • Phosphatidylcholine
      • Nettle
  • Celiac disease antibody levels reflect duodenal mucosal damage but not clinical symptoms
    • 96 celiac patients categorized to having either high (>70) or low tTG-IgA levels
    • Duodenal mucosa was more severely damaged in the high antibody group than in the low antibody group at baseline AND after gluten-free diet
    • At baseline: Ironically, the high tTG-ab group had fewer GI symptoms (43% vs. 68%) but lower vitamin D levels and higher rate of microcytosis. After a gluten-free diet, these differences were no longer detected.
    • Commentary: Symptoms are not always associated with physical damage.
  • Hookworm Treatment for Relapsing Multiple Sclerosis: A Randomized Double-Blinded Placebo-Controlled Trial
    • 66 pts w/ relapsing MS not on disease-modifying treatment
    • Randomized to receive hookworm treatment or placebo x9 mo
    • Results:
      • No significant difference in MRI results between the groups
      • Treatment with hookworm was safe and well-tolerated
      • Increase in regulatory T cell activity
      • Fewer relapses in the hookworm group (14 vs 30%)
    • Commentary: MRI change results did not reach significance because of a low level of baseline disease activity.
  • Pleiotropic Effects of Modified Citrus Pectin
    • Citrus pectin is modified to allow for systemic absorption
    • Average dose 10-15g/d
    • Prostate Cancer
      • Decrease PSA levels, possible prolongation of life, benefit in pain, QOL
    • Detox
      • 4 clinical studies
        • increased urinary excretion of lead, arsenic, and cadmium
        • 74% reduction in lead or mercury
        • “Dramatically decreased” the levels of lead in blood and increased the levels of lead in urine in children hospitalized with lead toxicity- this is good!
        • Increased fecal uranium excretion in a family with low-level chronic exposure from their environment
      • Commentary: Overall, pectin has greatest potential use for detox (especially of heavy metals). Use 10-15 g dose.

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Thyroid & Hormone Studies

  • The Influence of Reducing Diets on Changes in Thyroid Parameters in Women Suffering from Obesity and Hashimoto’s Disease
    • RCT of 100 obese women with Hashimoto’s
    • Treatment group received antibody (IgG) and instructed to follow hypocaloric custom elimination diet. Control group followed hypocaloric diet w/o elimination.
    • After 6 months
      • Elimination group had greater reduction of TSH levels (48 vs 25%)
      • Improvement in fT4 and fT3 in both groups
      • Greater reduction in TPO-Ab in elimination group
      • Greater reduction in BMI in elimination group
        • But NOT clinically significant (average of 5# more at 6 mo)
      • Commentary: A basic or extended elimination diet may be performed without IgG testing.
  • Iodine Absorption in Celiac Children: A Longitudinal Pilot Study
    • Measure iodine absorption in 36 children/adolescents with newly diagnosed celiac disease before starting GF diet
    • Iodine absorption in celiac children is impaired compared to the general population
    • Absorption increases slightly, but not significantly, during the GFD
  • What Is the Quality of Life in Patients Treated with Levothyroxine for Hypothyroidism and How Are We Measuring It? A Critical, Narrative Review
    • Review of 58 studies
    • Improved QOL after 3-6 months with thyroid hormone replacement
    • “Combination treatment with LT4 and liothyronine was not generally associated with better QoL.”
      • 6 of 8 studies: No difference in QOL
        • This was true even in a thyroid-specific QOL questionnaire
        • When benefits were found, found in some but not all QOL domains
        • Patients preferred T4/T3 combo 50-70% of the time
      • TSH in the high-normal range (>2.5 but not out of range) is NOT associated with poor QOL in most (but not all) studies.
      • Commentary: Despite T4/T3 combo therapy being preferred by a good portion of patients, this cannot be explained by improvement of QOL.
  • The Stability of TSH, and Thyroid Hormones, in Patients Treated With Tablet, or Liquid Levo-Thyroxine
    • Narrative review
    • “An altered intestinal absorption of L-T4 (caused by gastrointestinal disorders, some nutrients, or drugs) is considered the principal cause of refractory hypothyroidism.”
    • 40%–48% of patients receiving L-T4 are under- or over-treated
    • Increased need of thyroid medication in those with:
      • Less gastric acid production (H pylori or atrophic gastritis) leads to need of up to 34% more medication
      • Lactose Intolerance
      • Presence of parietal cell antibodies
        • Case series of 5 patients with autoimmune gastritis + hypothyroidism
          • Patients receiving T4 tablets switched to the same dosage of liquid L-T4→ circulating TSH normalized in all patients
          • Four patients were switched back to T4 tablets at the same dosage, and TSH worsened again.
        • Meta-analysis suggested that subjects receiving T4 tablets with suboptimal TSH values can achieve the desirable TSH following the switch to liquid L-T4 using the same dose
        • In one study, hypothyroid subjects with no confirmed malabsorption
          • TSH level was in the normal range in 11/18 patients receiving T4 tablets
          • After switching to liquid T4, 16/18 had TSH in normal range
        • Commentary: This review supports our philosophy of a gut-first approach before moving to thyroid hormone alternatives. Again, follow the algorithm and don’t rush improvements.
  • Risk of Cancer in Long-Term Levothyroxine Users: Retrospective Population-based Study
    • 600,000 on Levothyroxine, 2.4 million controls
    • Levothyroxine users showed a 50% higher risk of any cancer (adjusted odds ratio: 1.5) compared with controls
    • Increase in:
      • Brain cancer (AOR: 1.9)
      • Skin cancer (AOR: 1.4)
      • Pancreatic cancer (AOR: 1.3)
      • Female breast cancer (AOR: 1.2)
    • Commentary: Remember, this is an observational study and does not prove causation.
  • Evidence-Based Use of Levothyroxine/Liothyronine Combinations in Treating Hypothyroidism: A Consensus Document
    • Consensus statement from American, British, and European Thyroid Associations
    • 14 RCT examining T4/T3 combo
      • 2 trials: Better mood/QOL
      • 1 trial (33 patients): better cognition
    • Meta-analysis referenced in study
      • 27% of patients preferred monotherapy
      • 25% had no preference
      • 48% preferred combination therapy
    • Monitoring T3 levels in those on combo therapy
      • Measuring T3 is problematic due to 24 hr variability
    • Commentary: The majority of studies do NOT show that the average hypothyroid patient benefits from combination therapy.

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Diet & Lifestyle Studies

  • The use of ketogenic diets in cancer patients: a systematic review
    • 39 studies, 770 patients
    • Most studies had a low quality, high risk of bias and were highly heterogeneous
    • No conclusive evidence for anti-tumor effects or improved survival
    • Mild to moderate side effects
    • Low adherence rates
    • Commentary: Consider the potential risks of popular diets (e.g. social isolation, stress, side effects)
  • Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): A case-control study
    • 15,000 cases (new acute MI), 15,000 controls
    • Current smoking and raised ApoB/ApoA1 ratio were the two strongest risk factors for MI
      • Smoking Odds Ratio: 2.9
      • High ApoB/ApoA (>2) OR: 3.25
      • HTN OR: 1.9
      • T2DM OR: 2.4
    • Nine modifiable risk factors account for over 90% of the risk
      • “Effect of these risk factors is consistent in men and women, across different geographic regions, and by ethnic group, making the study applicable worldwide.”
    • Smoking and abnormal lipids account for ⅔ of risk
    • Commentary: Although family history is important, more time should be spent measuring and managing modifiable risk factors.

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Episode 1

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Featured Study

The association between anti-thyroid antibodies and quality of life in patients with Hashimoto’s thyroiditis: A systematic review and meta-analysis

  • Of the 13 studies examining euthyroid Hashimoto patients
    • Negative association between quality of life and antibodies: 5 studies
    • Positive association between symptoms and antibodies: 3 studies
    • Negative association between executive function and antibodies: 2 studies
    • Negative association between mental health and antibodies: 12 studies
  • However, this study showed:
    • Significant correlation between TSH and TPO Abs observed only in patients with antibody levels >500 IU/mL
    • But even if Abs >500, only a 0.5 increase in TSH at 10-year mark

Commentary: This new study suggests that we cannot completely ignore TPO antibody levels. However, we should be cautious not to create unwarranted fear around mildly elevated levels (<500). Nonetheless, antibody levels may be associated with decreased quality of life and mental health despite minimal risk of significantly altering TSH levels and increased risk of overt hypothyroidism.


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Gastrointestinal Studies


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Thyroid & Hormone Studies

  • Hashimoto’s thyroiditis worsens ovaries in polycystic ovary syndrome patients compared to Anti-Müllerian hormone levels
    • Quantified ovarian reserve by measuring Anti-Müllerian hormone (AMH) in 46 patients w/ both PCOS and Hashimoto’s
      • AMH: Biomarker of ovarian function. Menopausal women have undetectable levels.
    • Fertility rate significantly lower in those w/ both PCOS and Hashimoto’s
    • AMH values
      • Lower in those with both PCOS and Hashimoto’s
      • Negatively associated with TPO antibodies and duration of Hashimoto’s
    • CONCLUSION: “We recommend evaluating both thyroid autoantibodies and hormone levels in PCOS patients at the first visit”
    • Commentary:
      • Hashimoto’s and PCOS have high prevalence together
      • Low AMH associated with ovarian failure and infertility
      • Negative correlation with TPO Abs and AMH levels
      • We should be cognizant of fertility issues in AITD and PCOS patients and consider further hormonal testing

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Diet & Lifestyle Studies

  • New Insights into the Pathogenesis of Non-Alcoholic Fatty Liver Disease: Gut-Derived Lipopolysaccharides and Oxidative Stress
    • Patients with NAFLD had a:
      • 64% additional risk of having fatal or nonfatal cardiovascular events (ie: myocardial infarction, stroke, angina, or coronary artery disease)
      • 40% increase of their LPS serum level
        • Ameliorated by multispecies probiotic supplementation in dose-dependent manner
      • 2x rate of intestinal permeability
      • 3x rate of SIBO
        • Antibiotics can reduce liver function tests in animal models
        • Human study: Rifaximin treatment was associated with reduced liver function tests, NAFLD-liver fat score, and inflammatory cytokines
      • Vitamin E at high daily dosages (~800 IU/d) lead to resolution in 36% of those with non-alcoholic steatohepatitis (NASH)
      • Silymarin
        • Reduces liver function tests in NAFLD patients
        • Long-term treatment may also improve NASH
      • Commentary: reduce sources of inflammation to prevent and manage NAFLD. Often this comes from the gut.

Discussion

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