Future of Functional Medicine Review Clinical Newsletter

Research Briefs for Practitioners – September 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 20

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Featured Study

  • Benefits and Harms of Levothyroxine/liothyronine vs. Levothyroxine Monotherapy for Adult Patients with Hypothyroidism: Systematic Review and Meta-analysis
    • Compare the benefits and harms of combined T4/T3 therapy w/ T4 monotherapy for those w/ hypothyroidism
    • 18 studies
    • Results:
      • No difference in thyroid biomarkers
      • No difference in quality of life
      • No difference in “psychological distress”
      • No difference in depression
      • No difference in fatigue
      • Similar adverse effects
      • Small preference for combined therapy (43% combined, 23% T4 monotherapy, 20% no preference)
    • Commentary: This is aligned w/ our clinic’s hierarchy of starting w/ combined T4 monotherapy for those w/ diagnosed frank hypothyroidism. Even though there was a slight preference for combined therapy, it’s important to note that there was a LACK of CLINICAL OUTCOMES differences between the two groups.

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Gastrointestinal Studies

  • Gluten-free diet can ameliorate the symptoms of non-celiac autoimmune diseases
    • Does a gluten-free diet (GFD) help reduce symptoms of autoimmune diseases other than celiac disease?
    • Systematic review of 83 studies, 1,408 patients
    • GFD reduced symptoms of other autoimmune diseases in 911 of 1,408 (64.7%)  patients
    • Commentary: A GFD can help reduce symptoms in non-celiac autoimmune diseases.
  • Prevalence of Microscopic Colitis in Diarrhea-predominant Irritable Bowel Syndrome Patients: Cohort Study From Upper Egypt
    • Prospective study of 129 IBS-D patients
    • Took biopsies to assess for other diagnosis
    • Results:
      • 86 (71.7%) cases with nonspecific colitis
      • 26 (21.7%) cases with microscopic colitis  
      • 8 (6.7%) cases with ulcerative colitis
    • Commentary: This is a relatively high prevalence of concomitant colitis (especially microscopic colitis) in those w/ IBS-D
    • Dr. Ruscio’s comments: It’s important to not get overly caught up in pursuing a diagnosis because this can distract one from working through the GI algorithm (e.g. personalizing therapies to the patient in the most logical sequence). For example here, a patient could have been only diagnosed with microscopic colitis, potentially leading the provider away from the fact that their signs/symptoms were similar to IBS and also overlooking the vast array of therapies we have for IBS and perhaps even forgetting that there is much therapeutic overlap between the more general IBD subtypes; Crohn’s Disease and UC.  
  • Comparative study of allicin-containing quadruple therapy vs. bismuth-containing quadruple therapy for the treatment of Helicobacter pylori infection: A prospective randomized study
    • Compare allicin-containing quadruple therapy w/ bismuth-containing quadruple therapy
    • 220 H pylori-colonized patients randomized to 14 days of:
      • Allicin-containing quadruple therapy 
      • Bismuth-containing quadruple therapy
    • Eradication was confirmed by urea breath test
    • Results:
      • Eradication rate: 
        • 86% for allicin
        • 92% for bismuth
      • Symptom improvement:
        • 96% for allicin
        • 97% for bismuth
      • Adverse events:
        • 11% for allicin
        • 15% for bismuth
    • Commentary: Allicin-containing quadruple therapy might be regarded as a promising alternative to bismuth-containing quadruple therapy in H. pylori eradication.
    • Dr. Rusico’s reminder: Be evidence-based, but not evidence limited… it’s OK to experiment with treatments if there is not published data, don’t be afraid to think (reasonably) outside the box. 

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Thyroid & Hormones Studies

  • Use of Hormone Therapy in Postmenopausal Women with Alzheimer’s Disease: A Systematic Review
    • Does hormone replacement therapy (HRT) improve cognitive function/Alzheimer’s Disease (AD)?
    • 25 studies (14 observational studies, 11 clinical trials)
    • Of the 14 observational studies
      • 8 studies show IMPROVEMENT of cognitive function/AD risk
        • More of a beneficial effect in younger postmenopausal women
      • 5 studies show NO difference in cognitive function/AD risk
    • Of the 11 clinical trials
      • 7 show IMPROVEMENT of cognitive function
      • 4 show NO difference  
    • Commentary: The MAJORITY of the studies show a benefit of HRT for cognitive function/Alzheimer’s Disease risk, especially when started early on in menopause.

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Diet & Lifestyle Studies

  • Effect of a very low-carbohydrate ketogenic diet vs recommended diets in patients with type 2 diabetes: A meta-analysis
    • Compared a very-low carb ketogenic (VLCK) diet (carbohydrate intake < 50 g/d or < 10% of total energy) with standard recommended diet for type 2 diabetes 
    • 8 RCTs, 648 participants
    • Compared to standard diet, the VLCK diet resulted in:
      • Greater decrease in A1C (-0.61% difference at 3 months, -0.58% at 6 months)
      • Greater weight loss (-2.9 kg at 3 months, -2.8 kg at 6 months)
      • Greater reduction in triglycerides
      • Greater reduction in use of antidiabetic medications
    • However, there were NO DIFFERENCES after 12 months follow up
    • Commentary: A VLCK diet may lead to short-term improvements WITHOUT long-term gains. I suspect this may be because of a lack of substantial body composition improvements made with these diets, or compliance.

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Episode 19

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Featured Study

  • A Systematic Review of the Clinical Use of Curcumin for the Management of Gastrointestinal Diseases
    • 21 studies, 1,478 GI patients
    • Beneficial effects shown in:
      • Peptic ulcer disease: 2 out of 2 (100%) studies
      • IBS: 4 out of 7 (57%) studies
      • Ulcerative colitis: 6 out of 7 (86%) studies
      • H pylori eradication: 2 out of 4 (50%) studies
      • Crohn’s Disease: 2 out of 4 (50%) studies
      • Proctosigmoiditis: 1 of 1 (100%) study
    • No effect:
      • Familial adenomatous polyposis: 1 out of 1 study
    • Commentary: The majority of studies in this review show a BENEFIT of curcumin for GI disorders. This may be due to the thwarting of systemic inflammation stemming from the GI tract. Here at RIFM, we usually prioritize other therapies (diet, lifestyle, probiotics, elemental dieting) BEFORE adding in agents like curcumin. Nonetheless, they can be beneficial in those w/ digestive disorders.

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Gastrointestinal Studies

  • Sex differences in zonulin in affective disorders and associations with current mood symptoms
    • Aimed to measure possible association between serum zonulin levels and states of depression
    • 55 depressed patients, 37 healthy controls
    • Results:
      • Serum zonulin higher in women than men
      • NO difference in those with and without depression
    • Commentary: Serum zonulin may NOT be the best marker of intestinal permeability. I highlight this study to show that it’s hard to make treatment recommendations based on this common marker used in functional medicine. 
  • Infant acid suppression use is associated with the development of eosinophilic esophagitis
    • Does acid suppression therapy (e.g PPI, histamine antagonist) in infancy predispose an individual to develop eosinophilic esophagitis (EoE) later in age?
    • Retrospective study of 526 EoE patients, 2,630 age-matched healthy controls
    • Acid-suppression therapy in infancy was associated with increased likelihood of EoE 
      • PPI (5.7% EoE cases vs. 1.6% controls)
      • H2 antagonists (8.8% EoE cases vs. 4.5% controls)
    • Of the EoE cases, acid suppression during infancy increased the likelihood for the diagnosis with EoE at an EARLIER age
    • Commentary: We should warrant better stewardship of acid-suppression therapy and be familiar with this possible risk factor for EoE.
  • Meal Eating Characteristics of Patients with Gastroparesis
    • Cross-sectional analysis of 192 gastroparesis patients
    • Results:
      • 93% had early satiety/ postprandial fullness
      • Quicker eating associated with MORE nausea, loss of appetite, and fullness
    • Commentary: Consider working on meal-hygiene (e.g. take 15 minutes to eat a meal, chew thoroughly) in those w/ GI symptomatology.

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Thyroid & Hormones Studies

  • It’s All Due to the Thyroid: Lessons Learnt From a Patient’s Perspective
    • Case report of 79 yo, w/ past medical history of Hashimoto’s
    • Patient had symptoms of fatigue, dysphagia, and proximal muscle weakness
    • Attributed these symptoms to hypothyroidism
    • However, the patient already had an existing diagnosis of dermatomyositis and Zenker’s diverticulum which could explain her above symptoms
    • Commentary: Here are my take home points from this case report:
      • This corroborates our findings at the clinic of patients mistakenly attributing their symptoms to their thyroid function
      • GI disturbances can mimic hypothyroid symptoms 
        • Given that GI disorders are more likely (functional GI disorders 40% vs 5% hypothyroid), work to address the GI first
      • Remember to revisit and expand your differential even in patients w/ confirmed past diagnosis
  • The influence of thyroid autoimmunity on pregnancy outcome in infertile women: A prospective study
    • 590 infertile women on levothyroxine
    • Results:
      • Fertility was NOT affected by TPOAb levels or other thyroid metrics
      • However, miscarriages were HIGHER in those w/ higher TPOAb levels (46 IU/mL miscarriage vs. 19 IU/mL non-miscarriage)
    • Commentary: Higher TPOAb titer should be considered as one of the risk factors for miscarriage in infertile women, even if they have been treated with Levothyroxine for hypothyroidism. Reducing TPOAbs titer levels may be indicated in a subset of women w/ a history of miscarriages

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Diet & Lifestyle Studies

  • Effect of Intermittent Fasting on Non-Alcoholic Fatty Liver Disease: Systematic Review and Meta-Analysis
    • 6 studies, 417 patients w/ fatty liver
    • Intermittent fasting associated w/ IMPROVEMENT in:
      • Body weight (-2.45 kg)
      • BMI (-0.5)
      • AST (-11.3) 
      • ALT (-10.5)
    • NO differences in triglycerides, total cholesterol, and other cardiometabolic markers
    • Commentary: Intermittent fasting associated w/ improvements in anthropometric parameters and liver function in those w/ fatty liver. Other studies suggest that just 5% weight loss (e.g. from 200 lbs to 190 lbs) is associated w/ significant reductions in hepatic steatosis. 

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Episode 18

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Featured Study

  • Small intestinal bacterial overgrowth and evaluation of intestinal barrier function in patients with ulcerative colitis
    • 96 ulcerative colitis (UC) patients, 40 healthy controls underwent lactulose breath testing
    • SIBO positive patients randomized to:
      • Mesalazine (x6 wks)
      • Mesalazine (x6 wks) + Rifaximin (x2 wks)
    • Results:
      • UC patients had higher rates of SIBO compared to controls (56% vs 25%)
      • Mesalazine + Rifaximin group had:
        • Higher rates of positive symptom improvement (93% vs 64%)
        • Higher rates of complete remission (57% vs 27%)
        • Lower inflammatory markers (ESR, CRP) than mesalazine alone
    • Commentary: Rifaximin (and other antimicrobials) can play a crucial role in IBD cases as this trial presents, and is superior to mesalazine alone.

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Gastrointestinal Studies

  • Functional Gastrointestinal Disorders and Associated Health Impairment in Individuals with Celiac Disease
    • What is the rate of functional GI disorders (FGID) in Celiac Disease (CD) patients w/ persistent GI symptoms despite gluten-free diet?
    • 863 CD patients on gluten-free diet (GFD) for 1+ year
    • 61% were adherent to GF diet 
    • Of the CD patients, FGID found in:
      • 51% of adherent patients
      • 75% to non-adherent patients
    • GFD-adherent subjects with FGIDs were more likely to have high level of anxiety (5% vs. 2%, OR 2.8)
    • Commentary: 
      • One in two people with CD, will have ongoing GI symptoms despite a GFD for a long period of time (1+ years). 
      • Those w/ FGID and CD are 3x more likely to experience anxiety as those without FGID. 
  • Guidance on the interpretation of faecal calprotectin levels in children
    • Fecal calprotectin (FC) measurements from 3,000 children
    • Of those with FC > 50 μg/g WITHOUT typical IBD symptoms (bloody diarrhea, nocturnal abdominal pain, weight loss), 76% did NOT have IBD
    • Commentary: 
      • An elevated FC level WITHOUT typical IBD symptoms may NOT constitute IBD.
      • Remember that other conditions (e.g. IBS) can also increase FC levels. 
  • Cytomegalovirus colitis induced segmental colonic hypoganglionosis in an immunocompetent patient: A case report
    • Case report 
    • 48 yo women with NO past medical history, admitted to hospital for abdominal pain and constipation
    • PCR test showed cytomegalovirus (CMV) infection
    • Treated w/ ganciclovir and PCR levels dropped
    • Returned 8 months later for severe abdominal pain 
    • Surgical removal of colon revealed reduced ganglionic cells (nerve cells that allow the bowel to relax)
    • Commentary: CMV infection can:
      • Occur in patients with no underlying disease
      • Contribute to colitis 
      • Associated w/ reduced ganglion cells→ poor motility

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Autoimmunity Studies


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Thyroid & Hormones Studies


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Diet & Lifestyle Studies


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Episode 17

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Featured Study

  • Compared with classic Hashimoto’s thyroiditis, chronic autoimmune serum-negative thyroiditis requires a lower substitution dose of L-thyroxine to correct hypothyroidism
    • Cross sectional study
    • 581 w/ autoimmune thyroid disease (AITD) on ultrasound
    • Separated into 2 groups depending on TPO-Ab levels:
      • Seronegative autoimmune thyroiditis (SN-AITD)= hypoechoic ultrasound WITHOUT antibodies
        • 21% of patients
      • Hashimoto’s thyroiditis (HT)= presence of antibodies
        • 79%
    • Findings:
      • HT had higher TSH (7.3 vs 6.9) and higher portion of patients with OVERT hypothyroidism (15% vs 5%)
      • At 9 year follow up, ONLY 16% of SN-AITD patients developed TPO-Ab and/or Tg-Ab
      • Thyroid-volume significantly decreased in HT patients, but NOT in those with SN-AITD
      • Dose of LT4 was smaller in SN-AITD patients as compared with the HT (60 mcg/d vs 71 mcg/d)
    • Commentary: AITD patients without antibodies may not need as high of thyroid medication and only a MINORITY develop antibodies at a 9 year followup.

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Gastrointestinal Studies

  • Randomized, Placebo Controlled Trial of Experimental Hookworm Infection for Improving Gluten Tolerance in Celiac Disease
    • 54 patients w/ Celiac Disease
    • Randomized to one of groups x94 weeks followed by escalation of gluten consumption:
      • 20 Hookworm (HW20) larvae
      • 40 Hookworm (HW40) larvae
      • Placebo
    • Results:
      • Side effects from gluten consumption significantly reduced in hookworm-treated participants (0 in HW40, 1 in HW20, 4 in placebo)
      • Similar deterioration in duodenal villous health
      • Symptoms were lower in hookworm-positive participants after intermittent gluten challenge (39 vs 46)
    • Commentary: Hookworm infection does NOT restore tolerance to sustained moderate consumption of gluten (2 g/d). But, it was associated with improved symptom scores after intermittent consumption of lower, intermittent gluten doses.
  • Pattern of methane levels with lactulose breath testing; can we shorten the test duration?
    • Retrospective study of 745 breath tests
    • SIBO prevalence
      • 33% overall SIBO positive
      • 15% methane positive
      • 3% methane + hydrogen positive
    • Of the methane-positive results:
      • 96.4% had methane levels ≥10 ppm within 90 min 
      • 76% had levels ≥10 ppm at time 0 (baseline)
        • 82% if had constipation
    • In all cases of constipation, methane over 10 ppm in ALL cases
    • Commentary: The vast majority of methane-positive SIBO cases had elevated methane within 90 minutes. Constipation increases the likelihood of high baseline methane. Most guidelines suggest a positive for methane is 10 ppm. Be careful not to use the older thinking of 3 or 4 ppm

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Thyroid & Hormones Studies

  • Dysregulation of the Hypothalamic-Pituitary-Testicular Axis due to Energy Deficit
    • Narrative review of relationship between testosterone and energy intake
    • “Case series and mechanistic studies demonstrate that energy deficit (both acutely over days or chronically over months) either due to inadequate energy intake and/or excessive energy expenditure can lower serum testosterone concentration as a result of hypothalamic-pituitary-testicular axis dysregulation in men.”
    • Commentary: Low testosterone may be a result of insufficient caloric intake

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Diet & Lifestyle Studies


Discussion

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