Future of Functional Medicine Review Clinical Newsletter

Research Briefs for Practitioners – July 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 12

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Featured Study


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Gastrointestinal Studies

  • Elevated Faecal Calprotectin in Patients with a Normal Colonoscopy: Does It Matter in Clinical Practice? A Retrospective Observational Study
    • 1,200 patients referred for colonoscopy, measured fecal calprotectin day before, followed for 3 years
    • Of the 600 who had normal colonoscopy
      • 34% had elevated calprotectin (>50 μg/g)
      • 66% had normal calprotectin
    • Association of elevated calprotectin and UPPER GI diseases (e.g. gastritis)
      • BUT, this association was not seen after adjusting for NSAID, PPI, age, and gender
    • No increased risk of LOWER GI disease in those w/ elevated calprotectin but had NORMAL colonoscopy
    • Commentary: An elevated calprotectin does NOT indicate increased future risk of GI disease in those with NORMAL colonoscopy.
  • Histamine Intolerance: The Current State of the Art
    • Review of histamine intolerance
    • In study of 27 headache patients, DAO deficiency in 85%
      • After patients followed low histamine diet x4 weeks:
        • Significant increase in DAO activity
        • remission or reduction in frequency of headaches in 90%
      • In another study of 137 migraine patients, 87% had DAO deficiency
      • In a pediatric population under 15 years of age, DAO deficiency in 88% of patients with abdominal pain, diarrhea and vomiting
      • Efficacy of low histamine diet ranges from 33-100%
        • Majority of studies (10 of the 13) reviewed found an improvement in symptoms in >50% of patients
      • Efficacy of DAO supplementation of 93% in one small study of 14 participants
      • Commentary: Histamine may play a role in headaches/migraines/functional GI disorders. Most importantly, a low histamine diet can lead to clinical improvements.

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Autoimmunity Studies

  • Intestinal permeability in spondyloarthritis and rheumatoid arthritis: A systematic review of the literature
    • Is intestinal permeability part of the pathogenesis of spondyloarthritis (SA) and rheumatoid arthritis (RA)
    • Systematic review of 23 studies
    • Increased permeability in:
      • large majority of studies for SA regardless of the method used
        • Effect seen independent of NSAID use
      • only ½ of studies looking at RA
    • Commentary: Increased intestinal permeability may play a role in the pathogenesis of some autoimmune disease, some more than others.

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Diet & Lifestyle Studies

  • Nutraceuticals in Patients With Heart Failure: A Systematic Review
    • 40 studies over 6 months w/ at least 50 patients
    • Decreased mortality for use of
      • CoQ10
      • Polyunsaturated fatty acids (PUFAs)
    • Underpowered or too small of studies to show benefit:
      • Magnesium
      • Thiamin
      • Vitamin E
      • L-carnitine
      • Beetroot juice
      • L-arginine
      • Vitamin D
    • Commentary: Good evidence exists for using CoQ10 and PUFAs in those w/ heart failure.
  • Snoring and environmental exposure: results from the Swedish GA2LEN study
    • Study published in British Medical Journal
    • Cross-sectional analysis, 25,000 healthy participants in Sweden
    • Of the 4,000 (16%) habitual snorers, there was a higher rate of reported
      • water damage (8.3% vs 7%)
      • floor dampness (4.6% vs 3.8%)
      • And visible mold (5.2% vs 3.8%) in their homes when compared to non-snorers
    • Compared to non-snorers, habitual snorers had higher reports of:
      • Annoyed/irritated by air pollution
        • sometimes 16.2% vs 13.9%
        • daily 4.6% vs 3.1%
      • Annoyed by traffic fumes
        • somewhat 19% vs 18.5%
        • very 5% vs 3.6%
    • Commentary: This study points to the possible CLINICAL EFFECT that mold exposure has on non-specific health outcomes such as snoring/apnea/sleep health. Those who snored, had higher rates of possible mold exposure and chemical sensitivity. However, the percent differences of snorers vs non-snorers is not that different and we should be careful w/ confirmation bias.
  • Aspirin in the primary prevention of cardiovascular disease on diabetic patients: Systematic review and meta-analysis
    • 7 RCT, 28,000 patients
    • Aspirin used in the primary prevention of cardiovascular disease (CVD) in diabetic patients associated with:
      • NO significant reduction in all-cause mortality
      • 8% reduction in major adverse cardiovascular events (MACE)
      • 30% relative increase in major bleeding and 40% relative increase in major GI bleeding
    • Commentary: Aspirin use among diabetic patients in primary prevention appears to be associated with increased risk of major bleeding, a modest decrease of MACE, but lack of mortality benefit.
  • Remnant lipoproteins: are they equal to or more atherogenic than LDL?
    • Review the potential harmful effects of remnant lipoproteins (e.g. remnant VLDL)
    • Main findings:
      • Remnant VLDL particles accumulate significantly in those with high triglycerides and are cleared very slowly
      • Remnant VLDL particles may increase cardiovascular risk
      • In randomized trials involving statin-treated patients with cardiovascular disease, remnant cholesterol levels were associated with atherosclerosis independently of LDL-cholesterol.
    • Commentary: Overall findings from multiple types of studies indicate that remnant lipoproteins are a major contributor to atherosclerosis.

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Episode 11

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Featured Study


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Gastrointestinal Studies

  • Serum Zinc and Selenium in Children with Inflammatory Bowel Disease: A Multicenter Study in Japan
    • Retrospective study of pediatric patients w/ IBD in Japan
      • 98 w/ Crohn’s disease (CD)
      • 118 w/ ulcerative colitis (UC)
      • 43 healthy controls
    • Measured serum zinc and selenium
    • Rates of zinc and selenium deficiency were much more common in CD compared to UC and controls
      • Selenium deficiency:
        • CD: 15%
        • UC: 6%
        • Controls: 0%
      • Zinc deficiency:
        • CD: 60%
        • UC: 52%
        • Controls: 37%
      • Commentary: I suspect that since CD can affect the small bowel, nutrient absorption can be impaired much more compared to UC which solely affects the large bowel.

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Thyroid & Hormone Studies


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Autoimmunity Studies


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Diet & Lifestyle Studies


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Episode 10

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Featured Study

  • Iron deficiency without anaemia: a diagnosis that matters
    • 2 billion people with iron deficiency anaemia (IDA), 2.4 billion people with iron deficiency without anaemia (IDWA)
    • Iron deficiency (ID)= refers to low iron stores, regardless of whether anaemia is present or not
    • Symptoms of anemia such as fatigue can be present without anaemic hemoglobin levels
    • Causes of iron deficiency:
      • inadequate dietary intake
      • increased body needs
      • reduced absorption
      • chronic inflammation
      • chronic blood loss
    • Gut-iron connection
      • gastric acid is required for the reduction of Fe3+ to Fe2+, which is more readily absorbed
      • pylori infection may cause ID due to reduced iron absorption and blood loss
      • Celiac disease and inflammatory bowel disease can lead to ID secondary to chronic inflammation
    • Accurate diagnosis:
      • Ferritin is an indicator of iron stores and is the most sensitive and specific biomarker for assessing ID.
        • Cutoff: <30 μg/L
        • But, cut-off values for ferritin in ID are increased to 100 μg/L in states of chronic inflammation
      • Transferrin saturation (TSAT) levels below 20% are also diagnostic of ID
      • Serum iron levels fluctuate throughout the day and should not be used for diagnosis
      • Other markers
        • Serum transferrin receptor (sTFR) is a valuable indicator of ID
          • it is unaffected by inflammation (unlike ferritin)
          • Would be HIGH in iron deficiency
        • When hemoglobin levels are normal, a low reticulocyte hemoglobin count (RHC) indicates early ID
      • “Clinicians should consider the fact that normal hemoglobin ranges have been set using population data. Essentially, what may be a normal hemoglobin level for one person may be abnormal for another, especially if a patient has a hemoglobin level in the low-normal range but their usual hemoglobin levels are higher.”
    • Treatment of ID
      • “A recent systematic review concluded that iron supplementation in IDWA improves subjective measures of fatigue.”
      • ID (even without anemia) should be treated when identified, with a target ferritin of 100 mg/L
      • Using single doses on alternate days as opposed to multiple doses on consecutive days has been shown to result in higher absorption
        • The recommended oral dose is 28–50 mg iron daily or 100 mg on alternate days for 25 days
      • Once ferritin levels have corrected, patients should be followed up with blood tests every 6–12 months
    • Commentary: Save this algorithm in your notes. Iron deficiency (even without frank anemia) is worth diagnosing accurately and treating when indicated but don’t forget the gut-iron connection.


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Gastrointestinal Studies

  • Changes in serum zonulin in individuals with morbid obesity after weight-loss interventions: a prospective cohort study
    • 160 adults w/ morbid obesity
    • Tracked serum zonulin at baseline, 6 months after diet/lifestyle interventions, and 6 months after bariatric surgery
    • Zonulin reduced after the conservative weight loss intervention, and further reduced after bariatric surgery.
    • Reduction in zonulin was associated with improvement of diarrhea, markers of glucose intolerance and liver disease, but not associated with the change in BMI
    • Commentary: Higher quality diet and improved blood sugar control may improve leaky gut independent of weight loss.
  • Gluten-induced Neurocognitive Impairment: Results of a Nationwide Study
    • Survey of 1,400 individuals w/ gluten intolerance (celiac or NCGS)
    • 89% of CD and 95% of NCGS reported some type of neurocognitive impairment
    • Most common symptoms: difficulty concentrating, forgetfulness, and grogginess
    • Commentary: brain fog is a common symptom of gluten intolerance
  • Efficacy of probiotics in multiple sclerosis: a systematic review of preclinical trials and meta-analysis of randomized controlled trials
    • 3 RCT (173 MS patients), 22 preclinical studies
    • Clinical studies
      • significant beneficial effects of probiotic supplementation on mental health
        • BUT, low quality of evidence
      • probiotic intake improved insulin resistance, inflammatory markers, and oxidative stress markers
    • Preclinical studies
      • reduces the incidence and severity of MS
      • delays MS progression (15 studies)
      • improves motor impairment (3 studies)
      • favorable alterations of immune and inflammatory markers (20 studies)
      • Improvement of intestinal microbiome composition (4 studies)
    • Commentary: Probiotics show promise in MS.
  • What is the appropriate cut-off value of CRP to predict endoscopic remission in patients with ulcerative colitis in clinical remission?
    • Conventionally, a CRP <0.3 is the cutoff of clinical remission in those with ulcerative colitis
    • 132 patients w/ ulcerative colitis who underwent endoscopic evaluation, measured CRP values
    • CRP levels significantly lower in those in remission (0.05) vs. those not in remission (0.14)
    • CRP cutoff <0.09 to predict remission
      • Sensitivity: 71%
      • Specificity: 72%
    • Commentary: this study suggests that a much lower CRP level of <0.09 is needed to accurately predict clinical remission in those with ulcerative colitis. In UC patients in remission, it may be helpful to lower the CRP cut-off value that predicts remission other than 0.3 mg/dL, which is usually considered normal.
  • Gluten and FODMAPs Relationship with Mental Disorders: Systematic Review
    • 13 trials
    • limiting or ruling out gluten or FODMAPs in the diet might be beneficial for symptoms such as:
      • depression
      • anxiety (all 7 studies found a positive effect)
      • cognition deficiency (improvements in cognition in 1 trial)
      • schizophrenia and autism spectrum (to a lesser degree)
    • Commentary: this review highlights the gut-brain axis and exemplifies the improvement in symptoms when treating the gut.

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Thyroid & Hormone Studies

  • Risk of All-Cause Mortality in Levothyroxine-Treated Hypothyroid Patients: A Nationwide Korean Cohort Study
    • 500,000 w/ overt hypothyroidism on levothyroxine, 1.5 million healthy controls
    • Followed over 6 years
    • Hypothyroidism was significantly associated with increased all-cause mortality (HR 1.14) even w/ levothyroxine treatment
    • This association was independent of age, sex, and cardiovascular disease
    • Commentary: all-cause mortality was significantly higher in levothyroxine-treated hypothyroid patients than in non-hypothyroid controls.

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Autoimmunity Studies

  • Probiotic baths for atopic dermatitis
    • Randomized, double-blind trial of 22 patients w/ atopic dermatitis
    • Applied 10 minute partial bath in probiotics (4.5 billion CFU/liter) every day
    • After 14 days, probiotic lead to:
      • Significant reduction in atopic dermatitis symptoms (baseline score: 63, day 7: 47, day 14: 35)
      • Reduction in dry skin and itchiness
      • Reduction in aureus gene copy numbers by 83%
    • Commentary: This study shows a few points:
      • Probiotic have an antimicrobial effect
      • Probiotics can be safely given topically and can correct dermal dysbiosis
      • Probiotics should be considered in atopic diseases

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Diet & Lifestyle Studies

  • Serum Ferritin Correlates With Liver Fat in Male Adolescents With Obesity
    • Adolescent males; 44 w/ fatty liver, 15 without fatty liver
    • Measured various biomarkers and MRI of liver
    • ferritin was associated with MRI liver fat
    • “Our data indicate that serum ferritin in male adolescents with obesity is mainly determined by liver fat content and inflammation but not by body iron status.”
    • Commentary: remember that ferritin usually is increased in chronic inflammation.
  • Exposure to endocrine disruptors and risk of breast cancer: A systematic review
    • What’s the association between human exposure to endocrine disruptors (EDs) and the risk of breast cancer?
    • 37 studies
    • Most studies reported that exposure to organochlorine pesticides, phthalates, heavy metals, and polycyclic aromatic hydrocarbons was associated with increased breast cancer risk.
    • Commentary: remember that EDs can be found in plastics, cleaning products, personal care products, and some food.

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Episode 9

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Featured Study

Persisting symptoms in patients with Hashimoto’s disease despite normal thyroid hormone levels: Does thyroid autoimmunity play a role? A systematic review

  • 5-10% of Hashimoto patients experience symptoms despite being biochemically euthyroid
  • Review of the relationship between thyroid antibodies and symptoms
  • 30 studies
  • 5 of 7 case cross-sectional studies found an association between thyroid autoimmunity and more symptoms or lower quality of life (QoL)
  • 16 of 23 prospective studies found a comparable association.
    • However, the total number of people studied in the other 7 studies showing no association between symptoms and thyroid autoimmunity was much higher (20,000 in no association studies, 8,000 in association studies)
  • Commentary:
    • In total, the majority of included studies reported an association between thyroid autoimmunity and persisting symptoms or lower QoL in biochemically euthyroid patients.
    • The negative association between antibodies and symptoms was calculated after correcting for TSH and thyroid function
      • In other words, higher antibodies are associated with more symptoms independent of TSH or fT4
    • Thyroid antibodies may affect brain tissue, hence the continuation of low thyroid symptoms.

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Gastrointestinal Studies

  • Long-term Intake of Gluten and Cognitive Function Among US Women
    • Prospective study, 13,500 women without celiac disease
    • NO significant differences in standardized cognitive scores were found across highest and lowest quintiles of gluten intake
    • Commentary: In this study, gluten consumption was not associated with cognitive function in absence of celiac disease.
  • Dietary Therapies and Eosinophilic Esophagitis
    • Expert opinion
    • Endorses elemental diet
    • Elimination diet
      • 6-food elimination diet (milk, wheat, soy, egg, nuts, and seafood): 70-74% effective over 6 weeks
      • 4-food elimination diet (milk, wheat, soy, and egg): 45-60% effective over 6 weeks
      • 2-food elimination diet (milk and wheat): 30-40% effective over 6 weeks

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Diet & Lifestyle Studies

  • Blood Lead Level and Renal Impairment among Adults: A Meta-Analysis
    • 43 studies
    • Lead blood level definitions
      • High= 42 µg/dL
      • Moderate= 22 µg/dL
      • Low= 2.9 µg/dL
    • Mean lead levels of the exposed participants was higher than that of the non-exposed participants
    • Renal markers (BUN, creatinine) were significantly higher in exposed vs non-exposed participants
    • Commentary: This study shows that exposure to lead is associated with higher blood lead levels.

Discussion

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