Guest Case Study by
Gavin Guard, PA-C, MPAS, CISSN
- Sally, 45 years old, female
- Previous Dx
- Hypothyroidism, 2009
- Levothyroxine, 125 mcg
- Chief Complaints
- “Thyroid symptoms”- gaining weight, fatigue (severe)
- Bloating, distension, constipation (severe)
- Allergies (moderate)
- Insomnia (mild)
- Sally is a pleasant and educated 45-year-old woman with a history of hypothyroidism who presented to me with bloating, constipation, fatigue, and a desire for weight loss. She has been taking thyroid medication of some kind for over 10 years.
- Hypothyroidism, Levothyroxine 125 mcg
- Previous Testing:
- Reports last feeling well in 2009 before the death of grandmother, which was a large stressor for her.
- Diagnosed with hypothyroidism by a naturopathic doctor in a health food store, but she does not currently have labs to document validity of this diagnosis.
- Mild improvements at best with a more Paleo type diet.
- No clear improvements after starting desiccated thyroid medication. This is current medication.
- Family History:
- Polycythemia, father and maternal grandmother
- Prior Treatments:
- Nature -Throid
- General paleo diet
- Multiple detox “cleanses”
- Dysbiosis, SIBO, pathogen
- Incorrect thyroid diagnosis?
- Nutritional deficiencies
- Digestive insufficiency
- Good to excellent with gut-directed and nutritional therapies
- Previous Diets:
- Tests Ordered
- Quest panel: TSH, fT4, TPO Abs, CBC, CMP, C-peptide, HbA1c, lipid panel, vitamin D, and iron panel
- Basic blood chemistry to assess for thyroid function, underlying thyroid autoimmunity, glucose regulation, and basic nutrient levels.
- Exercise: 8-10k steps/d. Continue other exercise routines
- Distress tolerance: Stress seems to be well-managed, no changes indicated.
- Nutrition: Increase protein intake, start 30-day Paleo reset.
- Medications: Can take Flonase and Zyrtec PRN for symptomatic relief of allergies
- Supplements: D/C prenatal vitamin 3 days prior to thyroid tests. Make sure to take iron away from levothyroxine.
- I like to break up my treatment plans into subsections to make it easier for both myself and my patients to understand and implement. General goals include mastering fundamentals (increasing non-exercise activity levels, food quality, taking medications correctly without potential compounds hindering absorption).
- Sally is following the dietary and lifestyle treatment plan. She has some fear of stopping thyroid medication.
- Bloating – Improved
- Constipation – Better
- Rash – New, but unchanged (previously unmentioned)
- fT4 1.8
- TPO Abs <1
- TSH 0.10 (L)
- Ferritin 38
- All other markers wnl
- Iatrogenic subclinical hyperthyroidism
- Early iron deficiency?
- Sally appears with iatrogenic subclinical hyperthyroidism with her lab results noting an absence of thyroid antibodies, high-normal Free T4, and low TSH. Her previous diagnosis of hypothyroidism appears remarkably unlikely. Her clinical picture has involved a mixture of hyper- and hypothyroid type symptoms, however, she currently states that she is “wired” and “worked up”. I anticipate that improving her gut with diet and supplementation will likely improve her fatigue. Increasing ferritin >100 could also contribute to improving energy levels.
- Dr. Ruscio: Be on the lookout for the above as a key sign of iatrogenic hyperthyroidism…. I wouldn’t be surprised if insomnia improves also
- Low FODMAP dietary guidance
- Allocating carbs at night for sleep
- Suggest decreasing thyroid medication to at least 100 mcg and recheck levels in a few weeks. Note: Medical consult suggested further decrease, but patient and patient’s PCP reluctant.
- Nutrient Replacement:
- Omega 3
- Vitamin D
- Magnesium – support bowel motility
- Triple probiotic therapy
- F/U in 4 weeks
- Patient is feeling better w/ treatment plan. Patient reports that she did lower medication to 100 mcg as suggested. She is now willing to lower thyroid medication dose further.
- Lower thyroid dose to 75 mcg and f/u in 2 weeks.
- Better – Insomnia, weight loss (~10 pounds), bloating (went from 10 to 3), constipation
- Dr. Ruscio: There it is folks! Boy, the damaging over-treatment with thyroid vectors…. Probiotics likely helped here also
- Same – energy
- Worse – N/A
- TSH 0.08 (L)
- fT4 wnl
- Sally is making progress w/ basic gut-directed therapies. She has lost weight and is noticing improvements in her bloating with triple probiotic therapy. She is still having occasional brain fog and fatigue. She continues to show laboratory evidence of subclinical hyperthyroidism (TSH of 0.08) even after decreasing to 75 mcg.
- Take 20-30 minute naps as needed during the day
- Continue low FODMAP and carb snacks before bedtime
- Continue supplement plan (triple probiotics, nutrient replacement)
- Decrease thyroid medication to 50 mcg and f/u in 4 weeks
- Suggested 3-hour lactulose breath test
- Note: At my current point in clinical training, I would not suggest this testing given the patient’s improvement with previous therapies.
- Better – Happy with lowering thyroid meds, “more energy than ever before”, weight loss, reduced bloating, allergies, rash
- Same – Insomnia (thinks it could be related to female cycle)
- She reports some poor libido but feels this is likely more related to concerns about body image and perceived stress
- She reports that she is getting tired of low FODMAP restrictions and would like to reintroduce some foods
- Genova Diagnostics Lactulose Breath Test
- Methane: Peak (71 H)
- Hydrogen: Baseline: 0, 90 min peak (60 H)
- Sally is continuing to improve with probiotic therapy, lifestyle, and nutritional support. She continues to improve with decreasing thyroid medication. Her breath test showed some evidence of methane and hydrogen SIBO, which could certainly correlate with her clinical picture of constipation, bloating, and cognitive fatigue. Depending on her treatment trajectory, herbal antimicrobial therapy directed at the newly identified SIBO could be reasonable, however, this is likely already improving with the current treatment regimen. This could very well be the source of her symptoms and she is on unnecessary thyroid medication.
- Strategic reintroduction of dairy and grains (these were the foods she was missing the most)
- Lower thyroid medication to 25 mcg and consider a trial of stopping the medication if she continues to feel well
- DrR: Remember, you can retest 6-8 weeks after cessation to affirm euthyroidism
- Will we have her discontinue the multivitamin and Omega-3 supplement given overall financial constraints
- Consider increasing magnesium to bowel tolerance
- Suggest tracking insomnia and libido with menstrual cycle
- DrR: This is where female hormone supporting herbs can be helpful
- Wear blue-light blocking glasses 2-hours prior to bedtime
This was a very timely case given all that I have learned from the FFMR clinical newsletter and the confidence I received from taking a simple, yet efficacious, gut-directed approach to solving this patient’s symptom burden. Her diagnosis of hypothyroidism was questionable, to say the least. The fact that she responded so quickly to basic gut-directed therapy is evidence of the far-reaching impact the gut has on overall health and seemingly unrelated symptoms (fatigue, insomnia, etc.).
Looking back on this case, I would most likely do less thyroid testing and go off the patient’s symptom improvement. However, the patient was very hesitant to decrease her dose at all given the fact that she had been on it for over 10 years. The fact that she had both typical hypothyroid symptoms (constipation, low energy) and hyperthyroid symptoms (feeling “wired”, insomnia) is evidence that thyroid medication can eventually lead to a “burnout” picture in patients who don’t actually need it. DrR: Great point.
This is further complicated by her history of being on combination T3/T4 therapy by functional medicine clinicians that did not assess whether or not this was necessary. However, a good history and simplified gut-directed therapy allowed me to identify and address the root cause of her symptomatology. I am grateful for Drs. Ruscio and Abbott for their practical, cost-effective, and efficient approach to functional medicine and have become a proponent of this style of functional medicine.
Working closely with Gavin Guard, PA-C as part of his maturation as a functional medicine clinician, and specifically working with him as part of this patient’s care, we were provided with continued evidence for what appears to be fairly rampant misdiagnosis/overdiagnosis of hypothyroidism within the functional medicine community. We were also provided with further evidence that a foundational therapeutic hierarchy that utilizes dietary and lifestyle approaches along with gut-directed interventions can provide significant improvement for patients suffering from a myriad of symptoms. We must be prudent to recognize that even patients carrying a diagnosis of hypothyroidism for many years, and even those receiving medication from traditional providers, may not actually have hypothyroidism. Primary care providers very often will simply continue medications for patients who enter the practice with “established” diagnoses such as hypothyroidism without much thought.
For this month’s issue, we take a deeper dive into the world of thyroid replacement therapy for hypothyroidism.
Clinical Question to Answer:
- Does the ratio of combination T4/T3 medication matter?
This was inspired by the following reader comment:
- You forget that many of the studies showing no benefits from T4 plus T3 therapy use a very low dose of T3 ….(14:1 T4: T3 ratio). Look at the studies with a T4:T3 ratio around 4 to 1 and you see benefits in every single study. It is so simple.
This is a fair point. The level of confidence regarding the reader assertion is often a tell of only having a partial understanding of the issue, the Dunning-Kruger effect. Nevertheless, this is worth examining.
- There is no evidence from a review of 16 randomized controlled trials assessing various ratios of T4/T3 therapy for a clear benefit of a specific ratio of T4/T3 compared to T4 alone.
- While there is some evidence from patients preferring combination T4/T3 therapy over T4 alone, it is not correlated to any particular ratio of T4/T3.
A 2019 study titled: A Systematic Review and Meta-Analysis of Patient Preferences for Combination Thyroid Hormone Treatment for Hypothyroidism by Akirov et. al. examined a total of 348 hypothyroid individuals from 7 blinded randomized controlled trials assessing patient preference for combination therapy amidst many other indices of well-being and thyroid function and concluded that there was a signal of patient preference for T4/T3 therapy over T4 alone.
- “In conclusion, in RCTs in which patients and investigators were blinded to treatment allocation, approximately half of participants reported preferring combination L-T3 and L-T4 therapy compared to L-T4 alone; this finding was not distinguishable from chance.”
When the researchers investigated the potential mechanisms or reasons for this apparent preference for combination therapy they found that there was no correlation to a particular dose ratio.
- “In sensitivity analyses, combination treatment preference was explained in part by treatment effects on TSH concentration, mood, and symptoms, but not the quality of life nor body weight.
- In a secondary dose-response meta-regression analyses, a statistically significant association of treatment preference was identified for total daily L-T3 dose, but not L-T3:L-T4 dose ratio.”
- Most participants included in the meta-analysis were of younger age: <50
- Total study durations were actually rather short, usually no more than 3 months.
Deeper Dive into Combination T4/T3 studies
While the 2019 study appears to be the most rigorous and recent meta-analysis assessing patient preference and efficacy of combination therapy to date, there have been other randomized controlled studies assessing the role of combination therapy that were not included. In addition to this meta-analysis, we (the Ruscio Institute) examined a total of 16 randomized controlled studies comparing T4 therapy alone to combination therapy ranging from T4/T3 ratios of 2.5:1 to 15:1. 8 of the most prominent studies examined are listed below.
I have labeled the studies as
- Positive = supports hypothesis of a specific T4/T3 ratio being best
- Negative = directly refutes hypothesis
- No difference = ratio doesn’t matter
As you can clearly see:
- 2 of 8 studies suggest a specific ratio is best
- 1 of 8 studies suggest this ratio (4 to 1) is essentially worse
- 5 of 8 studies suggest ratio does not matter
|Smith et al, 1970
|87||LT4 or LT4:LT3 ratio 4:1||
|Nygaard et al, 2009
|59||LT4 or LT4:LT3 ratios from 2.5:1 to 8:1||
|Applehof et al, 2005
|130||LT4 or LT4:LT3 ratios 10:1 or 5:1||
|Sawka et al, 2003
NO CLINICAL DIFFERENCE
|40||LT4 or LT4:LT3 ratio mean 3:1||
|Rodriguez et al, 2005
NO CLINICAL DIFFERENCE
|27||LT4 or LT4:LT3 ratio 5:1||
|Saravanan et al, 2005
NO CLINICAL DIFFERENCE
|573||LT4 or LT4:LT3 ratios adjusted beginning at 5:1, some adjusted to 15:1||
|Kaminski et al, 2016
NO CLINICAL DIFFERENCE
|32||LT4 or LT4:LT3 ratio 5:1||
|Valizadeh et al, 2009
NO CLINICAL DIFFERENCE
|71||LT4 or LT4:LT3 ratio mean 4:1||
How do we account for our readers highly confident statement,
“You forget that many of the studies showing no benefits from T4 plus T3 therapy use a very low dose of T3 ….(14:1 T4: T3 ratio). Look at the studies with a T4:T3 ratio around 4 to 1 and you see benefits in every single study. It is so Simple.”
Sadly, this type of hubris is endemic in the field. I don’t blame the reader, I blame our educators from whom this temerity emanates. We, as a field and as clinicians, need to be more cautious, humble, and unsure of how much we know. This keeps us hungry, curious, and learning. If we aren’t… we wonder into Dunning-Kruger, the less one knows the more confident they are.
Combination Therapy Conclusions
- Combination therapy at any dose does not appear to be a clinical game changer. Addressing other areas of root imbalance such as gut health, nutritional status or environmental toxicity will likely yield greater patient benefit than manipulating T4/T3 ratios in medication.
- There does appear to be a small signal for patient preference for combination therapy although research has not readily identified a clinical causative factor. Supporting weight loss and improving QOL may be two domains leading to perceived patient preference.
Bonus: Thyroid Physiology Review
As I sought to more deeply examine the evidence around the potential efficacy of any particular ratio for thyroid combination therapy, I found this data about physiologic T4 and T3 production rather interesting.
- Central Thyroid Production – T4/T3 ratio ~ 15-17:1
- Total T4 / (Peripheral + Central T3) ratio ~ 4-5:1
A fascinating 1990 paper entitled: Thyroidal and peripheral production of 3,5,3′-triiodothyronine in humans by multicompartmental analysis showcased their findings about intrinsic thyroid hormone productions.
- Average daily production of T4 = 56 micrograms/day/m^2
- Average daily central production of T3 = 3.34 micrograms/day/m^2
- Average daily peripheral production of T3 = 12.7 micrograms/day/m^2
Thyroid Physiology Conclusions
- The normal central, thyroidal production of T4 and T3 appears to around a 15:1 ratio
- Taking total peripheral conversion of T4 to T3 into account, the total T4/T3 production ratio appears to be closer to 4:1.
- In healthy subjects, administration of combination thyroid hormone following a “natural” production methodology would perhaps be best served by the administration of a T4/T3 ratio closer to 15:1.
- “Slow plasma exchanging” tissues such as skeletal muscle and the GI tract are almost entirely dependent on intravascular or plasma T3 conversion/production rather than local tissue production once T4 has been delivered to the target tissue/cells.
Final Thoughts – Practice Guidelines
A 2012 practice guideline from the European Thyroid Association entitled: ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism
- Exercised caution for prescribers using T4/T3 therapy
- Encouraged utilizing T4 and T3 doses in a 13:1 to 20:1 ratio
- Encouraged the consideration of twice daily dosing for the total T3 amount and once daily dosing for T4
A combination consensus paper from professional medical societies including the American Thyroid Association and American Association of Clinical Endocrinologists published in 2014 entitled: Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement
- Stressed the importance of utilizing T4 only preparations
- Suggested/encouraged further study into desiccated or combination therapies
It is important to be aware of the practice guidelines as well as the evidence for T4/T3 combination therapies exercising appropriate clinical discernment and sharing evidence-based information about the use of any form of thyroid replacement therapy.
Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial
JAMA Psychiatry. 2020 Nov 4;e203285. doi: 10.1001/jamapsychiatry.2020.3285. Online ahead of print.
- The study involved 27 total participants (24 completing)
- 15 participants participated in immediate treatment with 2 sessions of psilocybin assisted psychotherapy
- 12 participants served received delayed treatment – waitlist control
- > 50% of the total participants (24) had rapid clinical improvements in depressive symptoms after just 1 treatment
- > 50% of the total participants were in clinical remission 4 weeks after the intervention.
- “Findings suggest that psilocybin with therapy is efficacious in treating MDD, thus extending the results of previous studies of this intervention in patients with cancer and depression and of a nonrandomized study in patients with treatment-resistant depression.”
Effects of a Fermented Dairy Drink Containing Lacticaseibacillus paracasei subsp. paracasei CNCM I-1518 (Lactobacillus casei CNCM I-1518) and the Standard Yogurt Cultures on the Incidence, Duration, and Severity of Common Infectious Diseases: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Nutrients. 2020 Nov 10;12(11):3443. doi: 10.3390/nu12113443.
- The meta-analysis included 9 study populations (2 children, 3 adult and 4 elderly) from 5 unique publications and found:
- Consumption of a fermented dairy drink resulted in statistically significant decreases in:
- The mean number of infectious disease episodes
- The likelihood of experiencing a common infectious disease
- Consumption of a fermented dairy drink resulted in statistically significant decreases in:
- “Compared to the control, the consumption of the FDD resulted in (1) a significant reduction in the odds of experiencing ≥1 CID (odds ratio (OR) (with a 95% confidence interval (CI)): 0.81 (0.66, 0.98); p = 0.029); (2) a significant reduction in mean CIDs per subject (−0.09 (−0.15, −0.04); p = 0.001)”
Patient Self Assessments
Consider how you are collecting patient data prior to the visit. The use of self-assessment questionnaires completed before patient visits that utilize basic Likert scales and other question formats to review current supplements/medications can be a huge time-saving tool for you as a busy clinician. This allows you to streamline your actual face to face time with the patient. Using electronic forms or self-created forms built into your EMR to collect this information will likely greatly enhance your clinical experience and even improve patient outcomes.