Over-Testing and Incorrect Hypothyroid Diagnosis Leads to Needless Patient Suffering - FFMR Model Saves the Day Again

Guest Case Study by Dr. Robert Abbott

Dr. R’s commentary:

• This is another great guest case study from Dr. Robert Abbott
• Be prepared to be shocked by how awful the functional medicine/natural medicine practice mode is when looking at the care this patient received before getting to Dr. Abbott’s office (pardon the strong language here but this is beyond out of control at this point).
• In short: A patient was incorrectly diagnosed hypothyroid, was on thyroid medication that was causing reactions, and her prior positive response to GI treatments was glossed over.
• I am so thankful for the FFMR readership because we are changing things and truly helping patients by doing so.
• Thank you Rob

Patient Info:

• Susan, 31 y/o, female
• Previous Dx
  • Hypothyroid
  • Celiac Disease
  • GAD, panic attacks, PTSD
• Rx
  • Compounded T4/T3 75/7.5 mcg 1 capsule daily since 2014
  • Naltrexone, 3 mg, 1 capsule daily since 2016
  • Escitalopram, 20 mg, 1 tablet daily, since December 2017
  • Clonazepam, 0.5 mg, 1 tablet twice daily, since December 2017
• Chief Complaints
  • Hormone fluctuations/PCOS
  • Anxiety and panic attacks
  • Metabolic dysregulation and insulin resistance
  • Poor sleep
  • Digestive issues: constipation, nausea, bloating
  • Weight loss resistance

Previous Treatments and Therapies

• Follows an AIP dietary template – now in the reintroduction phase
• Worked with a health coach and NTC to address nutrition for autoimmune disease
• Worked with various integrative health providers
• Addressed clinically diagnosed SIBO in 2017 with prescription antimicrobials

Current short and long-term health goals

• Conceive off of anxiety medications
• Address digestive complaints
• Investigate and address hormonal concerns – previous Dx of PCOS
• Weight loss
• Optimize nutrition for conception
• Improve anxiety, eliminate panic attacks

Visit 1 (Day 1) – History and Exam:

SUBJECTIVE

Susan presents as a 31 y/o F who has been diagnosed with three different autoimmune conditions over the past 3 years and continues to be bothered by continued psychological concerns included anxiety and panic attacks as well as GI symptoms including constipation, nausea and bloating.  She has worked extensively with a health coach to implement dietary changes following an AIP template to address multiple AI diseases. She has performed numerous reintroductions with the protocol and feels at a stable place nutritionally. She is seeking support primarily to eventually conceive and desires to titrate off and stop current psychiatric medications given this goal.

Past Medical History/Timeline

• PMHx is significant for generalized anxiety disorder, PTSD, and panic attacks beginning around 2011 during a period of growth and processing of early life trauma. She did not begin any psychotropic medications at this time.
• She struggled with multiple health complaints through 2011 into 2012 and was finally diagnosed with Celiac Disease in 2012 via antibody testing. States she did not pursue diagnostic endoscopy. Is unable to provide the laboratory results confirming this diagnosis.
• Reported some improvement with the removal of gluten, however, she struggled with extreme anxiety, more fatigue, and GI complaints into 2014. She began seeing multiple integrative health practitioners and was eventually diagnosed with adrenal fatigue, candida, and hypothyroidism. She was put on compounded combination thyroid hormone replacement.
• Following this diagnosis she improved only marginally, still suffering from fatigue and joint pains mainly in her upper extremities. She was diagnosed in 2015 with RA, PCOS, and a mutation in the MTHFR gene.
• She eventually moved from California to Maryland in 2016 and began suffering flares of anxiety, fatigue, and GI symptoms prompting her to begin work with the previously mentioned health coach who guided her into following the autoimmune protocol. She reported treatment for clinically diagnosed SIBO in 2017 and did one round of prescription antimicrobials with significant improvement.
• She began psychotropic medications in late 2017 as she deepened her work with the nutritionist. She was prescribed Clonazepam 0.5 mg twice daily and Escitalopram 20 mg daily.
• She reported significant improvements in 2018 with most symptoms resolving and now in late 2018 is desiring to continue the exploration into previously outlined areas with the main central goal of optimizing the environment for conception.
• She reports being given numerous supplement recommendations previously with the most recent recommendations noted below. She stated this was a burden and that she was not taking nearly any of these recommended products.

Medical Symptoms Questionnaire

• GI Tract: constipation, bloating, belching
• Ears: itchy ears, tinnitus
• Emotions: anxiety, mood swings
• Energy: fatigue, lethargy, restlessness
• Eyes: itchy eyes, swollen eyelids
• Nose: hay fever, stuffy nose
• Head: insomnia, headaches, and dizziness
• M/S: arthritis
• Skin: hives
• Weight: excessive weight and food cravings
• GU: genital itch

OBJECTIVE

Supplements

1. MTHF 1 mg daily
2. B-12 1 mg daily
3. Rhodiola Rosea, 100 mg twice daily
4. Nanoemulsified DIM, 20 mg, 4 pumps twice daily
5. Nanoemulsified D3K2, 5000 IU, 2 pumps daily
6. Spore-based broad-spectrum probiotic & prebiotic, 620 mg, 1 capsule daily
7. Fish Oil 445mg, 4 capsules twice daily
8. Colostrum, 1000 mg, 2 capsules daily
9. Magnesium glycinate, 120 mg, 6 capsules at night before bed
10. Digestive Enzymes, 1 capsule before meals
11. Digestive Bitters, 1 dropper full after meals
12. Zinc, 30 mg, 1 capsule daily
13. Beef Liver, 4 capsules daily
14. Restorative Gut Nutrients product, 150 mg, 1 tsp three times daily

Allergies

1. Gluten – reactions range from severe headaches to hives, digestive issues, severe bloating
2. Cow Dairy – stomach pains, diarrhea, constipation, flatulence, bloating
3. Soy – bloating, constipation
4. Peanuts – bloating, constipation
5. Nightshades – makes joint symptoms worse

Lifestyle & Diet Review

Non-smoker, non-drinker who enjoys her work as a freelance writer. She has recently significantly increased her physical activity including more formal workouts. She follows an AIP dietary template. Main stressors appear to be around health and life in general. Sleep seems to be problematic even with good sleep hygiene. Positive eustress is noted with recent engagement and planning of a wedding.

Laboratory Assessment

2015 Comprehensive Stool Analysis

1. Pancreatic insufficiency – low fecal elastase
2. Dysbiosis
3. Candida overgrowth
4. Elevated EPX and sIgA

August 2017 Comprehensive Stool Analysis

1. No signs of fat malabsorption or insufficiency
2. No Candida
3. Normal fecal elastase

2017 Bloodwork

1. Elevated monocytes, eosinophils, normal WBC
2. Glucose 99, hgba1c 5.2
3. ALT at 112, AST at 49
4. TSH 3.4 with normal range Free T4 (1.48 ng/dL)
5. TPO Ab and TGA normal
6. Vit D 25: 57.2, Vit D: 1,25 74.0, Concordant
7. Negative ANA and Anti-CCP, normal ESR
8.  Iron Profile – normal
9. DHEA- S – elevated
10. Testosterone- high normal
11. Negative Candida Ab’s

Additional Previous Bloodwork

1. Negative Western Blot for Lyme, Negative Babesia Ab’s
2. Negative EBV, appears to have had no exposure previously based on titers

Genetics Overview

1298C MTHFR Homozygote

COMT V158M -/- (GG) (Lowest Dopamine – Warrior Phenotype)

Celiac Genetics- one allele for DQ2.5

Clinician Summary

Since 2014, Susan has had significant laboratory testing, the majority of which has been excessive, wasteful, and clinically unimportant. I am appalled at the course of laboratory testing that was pursued by multiple providers.

Not listed above included a homeopathic sensitivity test for multiple food and environmental antigens, multiple cortisol and hormonal panels that proved entirely useless, repetitive, and excessive bloodwork including workups for chronic Lyme, chronic EBV, and other chronic infections. Upon further discussion, she was diagnosed with hypothyroidism despite normal TSH and Free T4, but was started on medication because “other markers pointed to her thyroid needing support.” She has never at any point showed elevated thyroid antibodies, had a negative Rheumatoid Factor as well as a negative anti-CCP Ab (a specific test for rheumatoid arthritis (RA) that can sometimes be elevated prior to the onset of clinical symptoms), but was still told her joint symptoms were related to RA. While she could not provide the celiac antibody testing results, genetic testing confirmed she did at least have one risk allele for the DQ2.5 risk haplotype.

It is notable that she showed clear GI dysfunction in 2015 with improvement in a repeat stool sample in 2017 (the same year she pursued antimicrobial treatment for SIBO), however, testing and treatment throughout and following was pursued in other domains rather than GI health.

It is disheartening to see that she had been on thyroid medication that she likely did not need, was diagnosed with RA, which she does not have, was tested for every chronic thing under the sun without clinical reason, placed on numerous supplements despite a persistence with overt GI dysfunction and symptoms pointing to imbalances in energy production and the GI tract.

What is perhaps even more troubling is the worsening of anxiety and panic following the use of thyroid hormone replacement. She additionally noted that there was a period of time where the doctor did not refill her thyroid medication and she went several weeks without it and began to actually feel a little better, but dismissed this as she felt it was simply getting back to baseline after having a slight worsening acutely after stopping the thyroid replacement.

ASSESSMENT

Working Differential of Concerns

1. HPA Axis Dysregulation
2. Female Hormone Imbalance (elevated Androgens, DHEA, PCOS)
3. Dysbiosis with potentially pathogenic organisms
4. Methane Predominant SIBO
5. SIFO
6. Maldigestion/Malabsorption
7. Immune Dysregulation
8. Iatrogenic thyroid suppression
9. Nutrient deficiencies secondary to maldigestion/malabsorption and SIBO
10. Mast cell activation (coming from GI tract?)

Global Assessment 

Susan is a young, overweight female with an extensive past medical history most notable for celiac disease, hypothyroidism, rheumatoid arthritis, panic disorder, PCOS, anxiety, and PTSD who presents for her initial intake visit seeking to make progress regarding her hormonal imbalances/PCOS, neuropsychological symptoms, and digestive issues including constipation and bloating. She has already made significant progress in working with a health coach to implement AIP, introductions, and other positive lifestyle changes. She persists with excessive weight, hormonal imbalances, controlled anxiety, and less frequent panic attacks, but has remained on medication with the desire to discontinue medications prior to conception.

She has had extensive previous testing include functional nutritional and stool testing, but none since 2017. A review of these findings can be seen above in the note. Most concerning, however, is clinically observed fat malabsorption as noted by the patient’s self-report of pale stool as well as previously noted 2015 stool studies showing pancreatic insufficiency.

She is very motivated with external sources of support and accountability. She has additionally suffered some fairly significant trauma with subsequent therapy and mourning assisting in her progress positively forward. Her faith and relationships appear to be her strengths and anchors in life in addition to pursuing her passions in writing.

Given her symptoms, the patient will likely benefit from updating current blood work, performing a stool test with a potential SIBO breath test if stool testing is inconclusive and GI symptoms persist. Longer-term we can potentially assess hormones given previously elevated DHEA-S and androgens via blood testing and urinary hormone testing. Organic acid testing including fatty acid composition, toxic element screen, repeat assessment of thyroid function, vitamin D, and an iron profile will all be helpful to optimize the environment for conception, however, current concerns must focus on gut health and its assessment.

I expect the patient to make positive improvements by supporting digestion, examining gut and hormonal health with a trajectory for optimal improvement over 6-9 months. I suspect she does not need thyroid hormone replacement and does not appear to have clinical indicators of RA. We will need to pursue titration off and stopping the thyroid hormone as well as exploring dietary modifications to support weight loss.

PLAN

Core Treatment Pathways

1. Digestive Enzymes and Probiotics
2. Core Nutritional Support
3. AIP Reintroductions with an exploration of the ketogenic diet

Lifestyle Treatment

Nutrition

AIP with reintroductions, explore low FODMAP and keto if needed

Movement/Exercise

Has increased this and will encourage continuing current structured workouts

Sleep

Will review hygiene and explore needs for additional supplementation

Stress Management

Appears motivated to combine spiritual practice with contemplative stress management

Community/Relationships

Strong and nourishing

Wisdom

Strong faith as evangelical Christian, appears motivated to combine spiritual practice with contemplative stress management

Play

Enjoys her work and has several hobbies

Nature/Environment

Will encourage time in nature even more despite the winter as we move into the spring months

Initial Supplementation

Noted to not be taking many of the supplements previously recommended by other providers. We will advise that she should discontinue these and optionally can continue using essential oil products as desired.

1. Betaine HCl
2. Digestive Enzymes
3. Vit D/K2
4. Saccharomyces Boulardii
5. Cod Liver Oil

Additional Testing Considerations

1. GI-MAP stool testing
2. Blood chemistry panel: CBC CMP, Vit D, Lipids, Homocysteine, HbA1c, DHEA-S, SHBG/Free Androgen Index, repeat thyroid after stopping medication

Future Pre-Conception Testing

1. DUTCH urinary hormone testing
2. Genova Diagnostics NutrEval organic acid testing
3. Blood chemistry: iron panel, repeat thyroid, defer B12 and folate as will be doing organic acid methylmalonic acid and FIGLU

Visit 2 (2 weeks later) – Testing and Initial Recommendations

Visit Summary

During this visit, we discussed Susan’s most recent visit with her nutritionist and health coach, our interpretation of previous laboratory testing as well as initial recommendations for supplementation and testing. Susan very much appreciated the small amount of initial supplementation and also agreed to pursue stool testing first, followed by breath testing if it was inconclusive and she still persisted with GI symptoms. She liked the idea of pursuing further dietary re-introductions as well as intermittent fasting, extended fasting, and a ketogenic macronutrient template. She expressed that she had had negative reactions to GABA supplements in the past and this would not be a good alternative as she sought to titrate off psychotropic medications.

She agreed and was willing to stop thyroid hormone replacement and pursue blood chemistry testing including thyroid function in 6-8 weeks after stopping the medication. We discussed given her longer-term vision of conceiving, non-pharmacologic, and supplement therapies that would be aligned with this goal. She agreed to pursue urinary hormone testing at a later date as well as nutritional organic acid testing closer to the desired date of conception.

Clinician Commentary

In functional medicine, we cannot get caught up with fancy testing and supplementation or get dragged into the weeds of things that are not foundational. We must do our due diligence to construct a pathway of healing and exploration that is logical, iterative, and affordable. We must start with foundational lifestyle therapies, explore areas that appear clinically impacted with specific testing that will actually change or dictate treatment, and only use supplementation for very specific needs. As Dr. Ruscio has pointed out in previous newsletters, we must not become cynical, but rightly inquire about previous medical history as we may discover an erroneous diagnosis and perhaps even medications that are unnecessary and harmful. Performing significant testing while potentially enlightening is almost always practically and clinically unhelpful as certain areas will improve with other foundational therapies and it is impractical to try to address identified heavy metal toxicity, gut dysfunction, methylation issues, female hormone imbalance, and impaired detoxification all at once- hence the need to outline an iterative approach for you and the patient. You may not get the person better overnight and you may recommend things that don’t work along the way, but the process must be methodical and iterative as well as doable for the patient.

Visit 3 (4 weeks later)

Visit Summary

Implementation visit with nutritionist focused on dietary reintroductions, the use of Cronometer to track macro- and micro-nutrients given desire to follow a ketogenic template. She expresses improvements in bloating and bowel movements with the enzymes. She reports stopping her thyroid medication.

Visit 4 (2 weeks later)

Visit Summary

Implementation visit with nutritionist focused on new dietary recommendations amidst other lifestyle changes. She is preparing for a trip to California. Has completed the stool test and it will result in the next 2 weeks. Has maintained previous gains with regards to GI symptoms and improving energy. She is not noticing any major negative effects from stopping thyroid medication.

Visit 5 (4 weeks later)

SUBJECTIVE

Visit Summary

The patient meets with me once again to review stool testing and recent blood chemistry. She has continued with previous gains, rating her health as an 8/10 with continued improvement since the previous visit. She is following a ketogenic dietary template closely as well as practicing intermittent fasting.

In exploring symptoms it appears she is still bothered a little with intermittent constipation described as both infrequent stools and hard stools: Bristol 1-2. It does seem that these symptoms are worsened during the second half of her menstrual cycle after ovulation and subside with menstruation.

She has begun tapering Clonazepam with her psychiatrist and plans to be off completely in 2 weeks with subsequent titration in Escitalopram. She states she stopped her thyroid medication at the end of January and feels completely normal.  She reports finishing planning for her wedding in 2 months, which is a stress relief.  She has not had any new acute concerns.

OBJECTIVE

Laboratory Findings and Review

GI MAP 3/5/2019

No pathogenic organisms

No opportunistic overgrowth

Blood Chemistry 3/15/2019

1. Blood sugar well balanced – HbA1c 5.1
2. High DHEA-S with normal bioavailable testosterone, still higher androgens
3. Balanced kidney, liver function, electrolytes
4. Low normal protein, low creatinine – low muscle mass?
5. Slightly elevated WBC count, elevated eosinophils could be a sign of an allergic-type response
6. Ideal Vitamin D
7. Ideal blood fats – cholesterol, triglycerides
8. Normal thyroid function

ASSESSMENT

Susan reports continued improvements in her health and is very happy overall with her progress. GI MAP testing showed no imbalances with no pathogenic overgrowth or even the remote presence of a potential pathogen. Additionally, sIgA, calprotectin, steatocrit, and fecal elastase are all normal. Susan’s stool test does not seem to indicate any primary gut pathology and it would be unlikely that she would have small intestinal bacterial overgrowth with an entirely normal stool test. Additionally, she still seems to have issues with elevated DHEA-S and other female hormones with progesterone changes after ovulation likely impacting gut motility. Fiber intake, hydration, magnesium supplementation all appear optimal at this time, although she could benefit from the targeted inclusion of certain fibers, changing to magnesium citrate and using DIM or adaptogens around the second half of her cycle to prevent worsening constipation.

Thyroid function (now 7 weeks post stopping medication) shows normal free T4 and free T3 with TSH within range and near the previous baseline noted while on thyroid hormone replacement. She does appear to have some immune dysregulation and potential mast cell phenomenon as she has noted some isolated hives and her bloodwork continues to show slightly elevated eosinophils and monocytes. Our next step of action should be to explore female hormone testing to corroborate elevated DHEA-S, assessing estrogen and progesterone metabolism to fine-tune and better support female hormones and detoxification.

Additionally, she may benefit from a trial of antihistamines and quercetin to see if this has any effect with infrequent hives and skin rashes. I do not feel given her overall improvements and current state of health that further extensive testing is necessary. We can continue with current plan including the titration off of psychotropic medication, reassessing thyroid function as well as a performing an iron panel in 2 months alongside organic acid testing to optimize nutrition and fetal environment for conception. We will also monitor her during the titration off SSRI, given recent stoppage of thyroid hormone to ensure continued motility. Short term prokinetic support with 5-HTP and Vitamin B6 may be explored.

PLAN

New Supplementation

1. Explore DIM 300 mg
2. Quercetin 3x daily before meals
3. Change magnesium glycinate to magnesium citrate
4. Explore the use of 5 HTP and Vitamin B6 – prokinetic if necessary given titration off SSRI

New Medications

1. Can explore the use of antihistamine as desired.

New Testing

1. DUTCH urinary hormone testing
2. Repeat targeted blood chemistry in 8-12 weeks

Clinical Commentary

Given the patient’s clinical trajectory, concerns for hormonal imbalances contributing to symptoms, and the overall goal of desiring conception in the near future, I feel it is prudent to utilize hormonal and organic acid testing given the importance of optimizing the pre-conception environment and her previous health concerns.

I do not usually perform such testing in patients at her stage of health and improvement, but I have been using these tests specifically for soon-to-be mothers with the focus on optimizing essential fatty acid status, assessing for folate or B12 needs, assessing iron status, thyroid function, heavy metal toxic burden, and mineral status, and in this patient’s case, looking for possible low progesterone given the elevated androgens that could make early miscarriage more likely.

Despite utilizing more testing than normal in this case, I am still remaining targeted asking very specific questions that have large implications and would change/dictate my medical recommendations.

Significance of Anti-TPO as an Early Predictive Marker in Thyroid Disease

https://www.hindawi.com/journals/ad/2019/1684074/

Study Purpose

• Assess impact early screening with TPO and TG antibodies can have on the course of hypothyroid and hyperthyroid patients, hopefully in preventing morbidity.

Intervention:

• Retrospective
• 4,581 subjects were tested multiple times for TSH, FT4, anti-TPO, and anti-Tg
• followed up for 2 years.

Main Results:

• Subjects were organized into two groups
  • A1: euthyroid to SCH or overt hypothyroid.
  • A2: euthyroid to SCHyper or hyperthyroid
• With an antibody predictive finding for TPO only, TG was not predictive. (Note, this finding has been echoed a few times now, consider not testing TG antibodies).
  • A1: 73% of hypothyroid (overt and SCH) had elevated antibodies.
  • A2: 68.6% of hyperthyroid (overt and SCHyper) had elevated antibodies.
  • With TPO antibodies levels > 250 IU/mL predicting onset
    • According to our results, 73% of hypothyroid subjects (from group A1) and 68.6% of hyperthyroid subjects (from group A2) had anti-TPO 252 (±33) and 277 (±151) days prior to the onset of the thyroid dysfunction, respectively.
    • …there was no significant difference in the subjects who had anti-Tg earlier than the control group.
• Important:
  • We should also be asking, how many of those with antibodies became hypothyroid. We already know antibody elevation (and TSH elevation) precedes overt hypothyroidism. However, the field often overestimates the risk of those with elevated antibodies have. Best data here suggest around 9-19% with positive antibodies become hypothyroid, meaning the majority remain normal and healthy.
  • YES, autoimmunity is the most common cause of hypothyroidism, but it might not be that common for autoimmunity to cause hypothyroid, 9% to 19% risk estimates. Not to diminish its importance, but the bottom line is that patients are being lead to believe they have a major chance of developing hypothyroidism if they have antibodies. This is not what the data support.
  • Group A1 had a total of 152 subjects who developed hypothyroidism, and 127 of them converted to subclinical hypothyroidism (83.5%) and 25 converted to overt hypothyroidism (16.5%) during their 2-year follow-up visits. Group A2 had a total of 118 subjects who developed hyperthyroidism and 95 of them converted to subclinical hyperthyroidism (80.5%) and 23 converted to overt hyperthyroidism (19.5%) during the 2-year follow-up visits.

• TPO elevations appear before TSH, strengthening the rationale of TPO screening in addition to using TSH.
  

Additional Results:

• Overt hypothyroidism is not that common, roughly 0.3%. Note, this is supported by the rampant over/incorrect diagnosis occurring within our community, just see the case study above as an example.
  • It is estimated that approximately 4.6% of the US population is suffering from hypothyroidism (0.3% clinical and 4.3% subclinical) [2].
• While treatment of SCH is not needed for the majority of patients, unless TSH>10, the authors reinforce the importance of screening in women of childbearing age as SCH treatment improves pregnancy outcomes.
  • However, studies have demonstrated the cost-effectiveness of universal screening for pregnant women compared with screening only for high-risk pregnant women with no screening [13]. Not only pregnant women but also women who are in their childbearing age should be tested and treated early since data suggest that subclinical hypothyroidism is associated with ovulatory dysfunction and infertility [14].

Limitations:

• Only one study
• Retrospective design
• Shorter follow up period

Authors Conclusion:

• Our results showcase that anti-TPO appears before the onset of thyroid hormone dysfunction; hence testing anti-TPO in conjunction with TSH would greatly aid to identify potentially risk individuals and prevent long-term morbidity.
• According to our results, 73% of hypothyroid subjects and 68.6% of hyperthyroid subjects had anti-TPO 252 (±33) and 277 (±151) days prior to the onset of the thyroid dysfunction, respectively.

Clinical Takeaways:

• TPO antibody elevation predicts elevation of TSH and formation of hypothyroid
• However, be careful to also consider that the minority of patients with elevated TPO antibodies become hypothyroid (at least according to the best available data I have seen)
• What to tell your patients:
  • TPO antibodies can be used as a screening tool and to predict potential future hypothyroidism.
  • Your risk of hypothyroidism is minimal if you do have positive antibodies (9-19%).

Dr. Ruscio Comments

This area of practice needs serious revision. The thyroid evangelists have lost any mornings to reality or math. Likely not their fault, I see this as a top-down education problem wherein a select group of figureheads has severely misread the data. Please share this message. We all need to work together to correct this.

Human helminth therapy to treat inflammatory disorders - Where do we stand?

BMC Immunol. 2015 Mar 26;16:12. doi: 10.1186/s12865-015-0074-3.

Study purpose

• Review data on helminth therapy for inflammatory conditions

Intervention:

• Review, non-systematic

Main Results:

• Two types of helminths have been studied Trichuris suis (TSO aka pig whipworm) and Necator americanus (human hookworm). Since human hookworm can colonize long term and cause anemia, it poses a higher potential for risk.
  • To date two species of helminths have been tested for human helminth therapy as a clinical treatment, Trichuris suis, the pig whipworm, and the human hookworm Necator americanus. After ingestion of T.suis ova (TSO), the eggs hatch and the worms colonise the caecum and colon of the human gut for only a short period of time (weeks) meaning that treatments need to be repeated
  • Larvae of the human hookworm Necator, however, are administered percutaneously and migrate through the vasculature and lungs to the small intestine where they survive by feeding on blood from the mucosa, giving rise to long lasting infections (years) and may at higher doses cause clinical symptoms such as gastrointestinal symptoms and anemia. In its natural state this infection is a major public health problem across the globe and large-scale deworming programs are in place to combat the morbidity associated with natural infection [13].
• Summary of interventional study findings for TSO in GI conditions: preliminary and lower quality data showed benefit, further and higher quality has not shown benefit.
  • In initial safety studies patients with Ulcerative colitis (UC) or Crohn’s disease were given viable, embryonated T.suis eggs (TSO) and not only was the treatment well tolerated but a significant dis-ease remission was observed and although the beneficial effect was temporary, repeated doses of TSO sustained this clinical improvement suggesting a promising new therapy for IBD [16, 17].
  • A placebo-controlled, double blind, randomised trial in Ulcerative colitis patents followed, showing significantly improved disease activity index in TSO treated patients compared to placebo, although the remission rate was no difference between the two groups [18].
  • Further development and safety testing of TSO under GMP was performed and a small randomized double-blind placebo-controlled study reported that Crohn’s patients receiving a single dose of up to 7500 TSO did not show any short (2 weeks) or long term (6 months) adverse effects [19].
  • However, in October 2013 Coronado biosciences announced in a press release that the results from the first larger study (TRUST-1, trial identifier NCT01576471), a Phase 2 clinical trial evaluating TSO in 250 US patients with moderate-to-severe Crohn’s disease, did not meet its primary endpoint of improving responses, either in terms of improving dis-ease activity index or remission rates, although a non-significant improvement was noted in patients with a more severe disease score [20].
  • Shortly after, a second Corona press release announced the discontinuation of the Phase 2 study of 240 European Crohn’s patients (FALK, trial identifier NCT01279577) after an independent monitoring committee recommended its discontinuation due to “lack of efficacy” [21].
• Summary of interventional study findings for human hookworm in GI diseases: minimal benefit has been documented according to preliminary data.
  • In a small trial where 9 Crohn’s patients were infected with 25–50 larvae and followed over 20 weeks, 7 patients experienced improved disease score while 2 experienced a worsening effect [22].
  • A second study examined hookworm versus placebo therapy in a cohort of 20 coeliac disease (gluten allergy) patents followed by wheat challenge after 20 weeks. The dose of 5–10 larvae was generally well tolerated and immunological analysis demonstrated reduced inflammatory cytokine (IFN-γ and IL-17) responses in duodenal biopsies from hookworm compared to placebo-treated patients [23], however, there was no difference in the symptomatic response to wheat challenge with all subjects experiencing the same levels of clinical symptoms regardless of treatment [24]. Further clinical trials of using hookworm infections in coeliac patients are still expected.
• Helminths and asthma. The relationship is unclear. Some data suggest protection (for example against asthma) while other data do not. Note: it is possible that helminths represent a proxy for a ‘dirtier’ environment and thus are not a single factor responsible for the potential immuno-benefit. Other data fully refute the helminth-protective hypothesis and suggest helminth infections increase the risk of asthma.
  • Several studies from helminth endemic areas have suggested that certain helminth infections may protect against allergy and asthma but a systematic review of 33 published studies concluded that there was no overall protective effect of helminth infections in general on asthma [25].
  • However, concurrent hookworm infection was associated with a protective effect, which was infection-intensity dependent.
  • In contrast, concurrent Ascaris lumbricoides infection, another common intestinal nematode infection, was associated with a significantly increased risk of asthma.
• Helminth and atopic A similar finding has been demonstrated, helminths may help or harm.
  • Studies on the relationship between helminth infection and atopy have also generated mixed results with both positive and negative associations depending on the species of worms involved [26] and deworming studies in helminth endemic communities have either shown no evidence for increased skin prick test (SPT) reactivity [27], or increased SPT reactivity [28, 29].
• Helminth and seasonal allergy. Seasonal allergy findings are also discouraging, mainly finding no benefit and even gastrointestinal side effects. However, these studies are small and further research may elucidate more encouraging findings.
  • A randomized clinical trial using 8 doses of TSO, or placebo, at an interval of 21 days in 100 patients with grasspollen-induced allergic rhinitis showed no significant effect on rhinitis symptoms, grass-specific IgE levels, or SPT reactivity, despite inducing T.suis-specific antibody responses and gastrointestinal symptoms [33]
  • Similarly, a small randomized safety study in individuals with allergic rhinoconjunctivitis treated with hookworm larvae or placebo, and followed for 12 weeks, reported no significant effects on lung function, SPT or rhinoconjunctivitis symptoms, despite clear evidence of hookworm-induced responses such as increased eosinophilia and gastrointestinal symptoms [34].
  • Another small randomized control trial in patients with asthma again showed no significant benefit of hook-worm infection on clinical symptoms, bronchial responsiveness or SPT reactivity [35].
• Helminths and Multiple Sclerosis. Data here are encouraging with a more consistent benefit being shown.
  • a prospective study demonstrated that 12 MS patients infected with a variety of helminth infections had significantly fewer relapses and lower MRI activity when compared to 12 non-helminth infected MS patients over a time period of 4.5 years [38].
  • In a follow-up study, it was further shown than when these patients received anti-helminthic treatment their clinical presentation deteriorated and this was associated with a reduction in IL-10 and TGF-β, and an increase in IFN-γ and IL-12 secretion from MBP peptide stimulated PBMCs [39] thus providing further support that helminth therapy may be of some benefit in MS patients.
  • Subsequently, a phase 1 study for TSO treatment in 5 multiple sclerosis patients reported fewer new lesions during and up to two months after TSO treatment as well as increased serum levels of IL-4 and IL-10 [40].
  • Several Phase 1/2 clinical trials using TSO or hookworm in MS patients are currently registered as recruiting or ongoing (NCT00645749, NCT01413243, NCT01470521). In addition to MS, a number of clinical trials are currently registered for the use of TSO in patients with psoriasis, autism, and rheumatoid arthritis.

Additional Results:

• Helminth infection used to be common.
  • Helminth infections, in particular intestinal worms, were up to a few decades ago common in all parts of the world but have now been more or less eradicated in high-income countries, despite still being a major public health problem in the rest of the world.
• Helminths exert both an inflammatory and anti-inflammatory/immunoregulatory effect.
  • Work in mouse models have clearly established that immunity to intestinal helminths is dependent on a Type 2 cytokine response, involving the secretion of IL-4, IL-5, IL-9 and IL-13 and the subsequent activation of intestinal mast cells, eosinophils, goblet cells, enterocyte proliferation and intestinal contractility (reviewed in [7]).
  • In addition to a Type 2 response, various immunoregulatory mechanisms are induced, including increases in regulatory T cell (T reg) numbers and IL-10 and/or TGF-β levels, resulting in a highly anti-inflammatory environment.

Limitations:

• There are several factors that murky the read here; data is preliminary, the impact of other environmental factors, the timing of helminth inoculation – just to name a few.

Authors Remarks:

• [Translating animal findings] into clinical helminth therapy forms have proved less successful in the few published clinical trials conducted so far
• It may be that for worms to be successful in controlling inflammation we need to be exposed to them before the onset of the inflammatory condition or even that we need to be exposed to them at a young age to allow our immune system to co-develop together with them.

Clinical Takeaways:

• The only condition in which benefits have shown benefit somewhat consistently is MS.
• The latest meta-analyses and systematic reviews report promising results for RA and metabolic outcomes but not for IBD.
• What to tell your patients:
  • While helminths have received attention from certain media outlets, the data supporting their use does not currently exist, other than potentially for MS.

Dr. Ruscio Comments

In the patients I have seen who have experimented with helminths, the above findings have been reflected, with little to no benefit shown. That being said, my sample size was far too small to make any conclusion. So, I turn to the data as outlined above and in light of these findings will not be encouraging patients to seek further counsel in this area, other than consideration in those with MS.

Weight-loss interventions and gut microbiota changes in overweight and obese patients: a systematic review.

Obes Rev. 2017 Aug;18(8):832-851. doi: 10.1111/obr.12541. Epub 2017 May 19.

Study Purpose

• Understand the impact of weight loss and gut microbiota

Intervention:

• Systematic review
  • This review identified 43 studies using the keywords ‘overweight’ or ‘obesity’ and ‘microbiota’ and related terms; among these studies,
    • 17 used dietary interventions,
    • 11 used bariatric surgery
    • and 15 used microbiota manipulation.

Main Results:

• Dietary interventions impact on microbiota and weight
  • Changes in nutrient intake had an impact on the microbiota. Weight loss did not correlate with microbiota changes.
  • Conclusion: “Considering these trials, we could not relate the amount of weight loss to specific changes in the gut microbial composition.”
    • Restrictive diets decreased the microbiota abundance, correlated with nutrient deficiency rather than weight loss and generally reduced the butyrate producers Firmicutes, Lactobacillus sp. and Bifidobacterium sp.
• Most studies found probiotics did not impact weight but did influence the microbiota (note: the effect size here is usually small regarding weight). 5 studies using probiotics were performed, mostly unable to demonstrate an impact on weight.
  • The impact of six types of probiotics on weight loss was assessed in five studies (23, 53, 57, 58, 63).
  • In four studies performed to test 5 [80%] different probiotic strains [Lactobacillus rhamnosus, Lactobacillus fermentum, Lactobacillus amylovorus, Bifidobacterium animalis or a mix of strains], there was no impact on body weight.
  • Of those, the study using L. rhamnosus reported a pronounced treatment–sex interaction, with a reduction in the Lachnospiraceae family along with a body weight and fat percentage reduction after a probiotic intervention in women (23).
  • Body fat was also decreased after L. fermentum and L. amylovorus intake (58). One study [25%] on Lactobacillus plantarum associated probiotic intake with weight loss (57)
  • Probiotics differed in strain and duration with diverse effects on the microbiota, and they tended to reduce body fat.
• Prebiotics impacted the microbiota and led to reduced weight about half the time
  • Prebiotics had a bifidogenic effect and increased butyrate producers, likely due to cross-feeding interactions, contributing to the gut barrier and improving metabolic outcomes.
  • Over half of these studies [55%] reported no impact on body weight (50, 54, 56, 60, 62), while the remaining trials showed weight loss (51, 52, 55, 61). In addition, 75% of studies reported body fat reductions (50, 51, 52, 60, 61, 62).
• Pro-, pre-, and synbiotics impact on metabolic markers; glucose and BP – In general no impact.
  • In general, the manipulation of gut microbiota with the use of pro-, pre- or symbiotics had no impact on BP or metabolic markers such as FBG and blood lipids

Additional Results:

• The cause and effect between microbiota and weight is not clear.
  • The association between microbiota and obesity exists, yet the causative versus consequential association and the magnitude of its contribution in humans, remains unclear.
• One of the challenges with microbiota research is the varying methods used to assess the microbiota.
  • Several molecular biology techniques were used to assess the gut microbiota, and some studies employed more than one approach. Five studies [11%] obtained a microbial community fingerprint using denaturing gradient gel electrophoresis [DGGE], 20 studies [46%] used at least one technique for targeted analysis (fluorescence in situ hybridization [FISH] using probes or group-specific real-time [quantitative] polymerase chain reaction [qPCR]), 13 studies [30%] performed metabarcoding 16S rRNA and 10 studies [23%] used metagenomics [shotgun sequencing]
  • 1 [9%] used only DNA targeted probes [FISH]
  • 3 [28%] used only metabarcoding 16S rRNA
  • 3 [28%] used only shotgun sequencing
  • 4 [36%] remaining trials combined techniques including the aforementioned ones, namely species-specific qPCR, DGGE and computational tools

Authors Conclusion:

• In summary, the available results in humans suggest that any intervention type for weight-loss impacts the gut microbiota; however, the relationship between the gut microbial composition and weight management remains to be determined.
• Note:
  • But be careful, statements such as
  • Microbial richness plays a role in individual responses to dietary interventions, and low microbial gene counts indicate a poor response to the intervention. However, weight-loss diets were able to increase the microbial gene richness in some studies, suggesting an advance from risk detection to risk alleviation (34)
  • Often convolute the fact that the impact of diet is more meaningful than the impact of baseline microbiota characteristics (detailed in Healthy Gut, Healthy You).

Interesting Notes:

• Surgery is an effective option for severe cases
  • Bariatric surgery is currently the most effective option for the long-term treatment of severe obesity, promoting significant weight loss and mortality reduction (19). Despite its relative effectiveness, a significant number of patients experience poor weight-loss outcomes, and long-term weight regain can reach up to 75% (21, 22).

Clinical Takeaways:

• The cause-effect relationship between the microbiota and weight is still unclear.
• What to tell your patients:
  • Therapies that manipulate your microbiota may improve weight or body composition, but the findings here have been inconsistent. The best approach is to use these therapies to improve your health (gas, bloating, reflux, etc..) and hope for fat loss as a byproduct.

Dr. Ruscio Comments

Not much to add here. Fortunately, it seems that those in the field who have touted the microbiota as the next weight loss miracle have now changed their tunes. Improving GI health can lead to weight loss, but it is unpredictable, so don’t overpromise with your patients.

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

Role of Probiotics in Prophylaxis of Helicobacter pylori Infection.

Curr Pharm Biotechnol. 2019;20(2):137-145. doi: 10.2174/1389201020666190227203107.

• “In a double-blind, randomized, controlled clinical trial, it was concluded that administration of the probiotic bacteria,  johnsoniiLA1 on a regular basis, might decrease the pathogenic colonization in children without symptoms and may effectively modulate the degree of infection with H. pylori along with resultant gastritis in pediatric populations wherein this infection is highly prevalent [28, 127].”
• “In yet another study, it was observed that the degree of inhibition of the pathogen in children was largely dependent on the specific probiotic strain administered in the clinical trial [28, 128].”
• Note: what is interesting here is both Lactobacillus johnsonii or boulardii offered benefit, so the specificity might not be that important, although more data here is needed to definitively answer this question.