1. Clinical Update in Thyroid Disease Management
Michael D Morocco, MD
Endocrine Associates
Cleveland Clinic Akron General
April 2018

2. Outline Brief review of thyroid physiology
Biotin use and effects on lab results
Coffee and levothyroxine
Thyroid hormone replacement in the elderly

3. Hypothalamic-Pituitary-Thyroid Axis Physiology
Hypothalamus
TRH –
Pituitary – T4
TSH
Target Tissues T3
Heart
Thyroid Gland
Liver T4 TR T3
Bone
T4 ➔ T3
Liver
CNS

4. Outline Brief review of thyroid physiology
Biotin use and effects on lab results
Coffee and levothyroxine
Thyroid hormone replacement in the elderly

5. Biotin - Functions in metabolism Via biotin dependent enzymes
Involved in
Gluconeogenesis
Synthesis and oxidation of fatty acids
Degradation of some amino acids
Purine synthesis

6. Biotin - History 1936: Biotin first isolated 1943: Synthesis
Historically called:
Vitamin H, Coenzyme R, Factor S, Factor W, Vitamin Bw, Protective Factor X
Vitamin B7
Protected against dematosis and loss of hair in animals fed raw egg whites

7. Biotin - Deficiency
First noted in patients on long term TPN, prior to biotin supplementation
Consuming large amounts of raw egg whites
Avidin: binds biotin and prevents absorption
Long term anticonvulsants (carbamazepine, etc)
Clinical symptoms:
Dermatitis around the eyes, nose and mouth
Conjunctivitis
Alopecia
Neurologic symptoms: Change in mental status, lethargy, hallucination, paresthesias
Other: Myalgias, anorexia, nausea

8. Biotin RDA / Adequate intake 30 mcg daily in adults.
35 mcg daily in lactation

9. Biotin - Over the Counter Supplements
1000 mcg (1 mg), 5,000 mcg (5 mg), 10,000 mcg (10 mg)
Hair Skin Nail Vitamins
Biotin content typically mcg per daily dose
But can be lower, ~300 mcg per daily dose

10. Biotin - Over the Counter Supplements
B-Complex Vitamins
Biotin content varies

11. Biotin Clinical uses Multiple Sclerosis
100 mg three times daily (100,000 mcg TID) (one protocol)
Inherited Metabolic diseases
2-15 mg/kg/day

12. Biotin - A Review of the Use of Biotin for Hair Loss
Patel D.P. · Swink S.M. · Castelo-Soccio L. Skin Appendage Disord 2017;3:
18 reported cases of biotin use for hair and nail changes
In all cases, patients receiving biotin supplementation had an underlying pathology for poor hair or nail growth
All cases showed evidence of clinical improvement after receiving biotin
Conclusions:
Though its use as a hair and nail growth supplement is prevalent, research demonstrating the efficacy of biotin is limited.
In cases of acquired and inherited causes of biotin deficiency as well as pathologies, such as brittle nail syndrome or uncombable hair, biotin supplementation may be of benefit.
However, we propose these cases are uncommon and that there is lack of sufficient evidence for supplementation in healthy individuals.

13. Linus Pauling Institute (Oregon State Univ.)
Hair loss (alopecia)
Biotin administration was found to reverse alopecia in children treated with the anticonvulsant, valproic acid.
Yet, although hair loss is a symptom of severe biotin deficiency, there are no published scientific studies that support the claim that high-dose biotin supplements are effective in preventing or treating hair loss in men or women.

14. Biotin Supplementation Popularity Exceeds Evidence of Clinical Efficacy
J Drugs Dermatol 2017 May 01;16(5) , T Soleymani, KL Sicco, J Shapiro
Because of the lack of clinical evidence, its use to improve hair quantity or quality is not routinely recommended. However, societal infatuation with biotin supplementation is not only propagated by its glamorization in popular media, its popularity is vastly disproportionate to the insufficient clinical evidence supporting its efficacy in hair improvement. In other words, biotin supplements are quite “in vogue,” without there being any real reason to be so.

15. Biotin Treatment Mimicking Graves Disease
NEJM 375;7 Aug 18,2016
Series of 6 children on high-dose biotin for inherited metabolic diseases
All with low TSH, elevated free T4 and elevated total T3.
All with elevated anti-thyrotopin receptor antibodies.
All labs reversed / normalized after biotin stopped and labs rechecked

16. Streptavidin Biotin technology
Interference of Biotin in the Streptavidin - Biotin-Immunoassay-Technology
Streptavidin Biotin technology
Well established in several modern, automated immunoassays to fix antigens (e.g. hormones) or antibodies (e.g. thyrotropin receptor antibodies) to a solid phase.
Streptavidin coated tubes or microparticles respectively serve as a solid phase.
Streptavidin has the capture function, binding the biotinylated antibody or biotinylated antigen, respectively with a high degree of affinity and specificity.
The biotin-streptavidin complex is
one of the strongest non-covalent bonds observed in nature,
about 1,000 times the affinity of the most potent antibody-hapten interaction,
making it resistant not only to pH and temperature extremes but also solvents.

17. Interference of Biotin in the Streptavidin - Biotin-Immunoassay-Technology
If Biotin levels, due to a therapy regime, are highly increased in patient’s serum:
Biotin molecules interfere with the binding of biotinylated antibodies or biotinylated antigens to the streptavidin coated solid phase.
Whether concerning laboratory results are falsely increased or decreased depends on the immunoassay test principle.
(see diagram next slide)

19. Non-competitive immunoassay
Interference of Biotin in the Streptavidin - Biotin-Immunoassay-Technology
The TSH assay
Non-competitive immunoassay
monoclonal biotinylated TSH specific antibody
and a monoclonal ruthenium labelled TSH specific antibody
forming a sandwich complex with TSH.
After addition of Streptavidin coated microparticles,
the complex becomes bound to the solid phase via interaction of Biotin and Streptavidin.
The intensity of the chemiluminescent signal caused by the ruthenium molecule is directly proportional to the amount of TSH.
Highly increased biotin levels in patient’s serum compete with the binding of the TSH sandwich complex to Streptavidin coated microparticles resulting in falsely decreased TSH results.

20. The Free T4 is a competitive immunoassay.
Interference of Biotin in the Streptavidin - Biotin-Immunoassay-Technology
The Free T4 is a competitive immunoassay.
FT4 molecules in patient’s serum and biotinylated T4 compete with the binding to a ruthenium labelled T4 specific antibody.
After addition of Streptavidin coated microparticles,
The biotinylated T4 and ruthenium labelled T4 antibody complex becomes bound to the solid phase via interaction of Biotin and Streptavidin.
The intensity of the chemiluminescent signal caused by the ruthenium molecule is inversely proportional to the amount of FT4 in serum.
Highly increased Biotin levels lead to
a decreased binding of the biotinylated T4 ruthenium labelled antibody complex to the Streptavidin coated microparticles.
Therefore due to the competitive assay design decreased signal intensity result in falsely increased FT4 values.

21. Interference of Biotin in the Streptavidin - Biotin-Immunoassay-Technology
TSHR immunoassay is a competitive immunoassay.
The aTSHR immunoassay
contains solubilized porcine TSHR
which becomes immobilized to Streptavidin-coated microparticles by a biotinylated mouse monoclonal capture antibody.
Serum aTSHR bound to the TSH receptor
detected by their ability to inhibit the binding of ruthenium labelled human TSHR stimulating monoclonal antibody.
The intensity of the chemiluminescent signal caused by the ruthenium molecule is inversely proportional to the amount of aTSHR in serum.
Highly elevated Biotin levels lead to a decreased amount of captured porcine TSHR on Streptavidincoated microparticles. Therefore, binding of ruthenium labelled human TSHR antibody is decreased additionally and due to the competitive assay design falsely increased aTSHR test results were calculated.

22. JAMA. 2017;318(12):

23. Endocrine Practice: August 2017, Vol. 23, No. 8, pp. 989-998

24. Biotin interference (Not a complete list)
Sandwich Immunoassay
False low:
Thyroid stimulating hormone (TSH)
Thyroglobulin
LH and FSH
Creatinine phosphokinase
HCG
ACTH
Prolactin
Intact PTH
pro-BNP
Ferritin
Competitive Immunoassay
False elevation:
Free T4, Free T3, Total T3
Cortisol
25-Hydroxy Vitamin D
Thyroid receptor antibodies
Testosterone
Estradiol
Progesterone
DHEA-s
Vitamin B12

25. Biotin and Lab Testing Recommendations
American Thyroid Association (Thyroid. Oct 2016, 26(10): )
For patients who are taking biotin and are found to have low TSH and/or high T4,
the guidance recommends discontinuing the supplement and retesting in two days.
My personal protocol
If thyroid function tests (TSH, free T4, free T3 )
Hold biotin hours, then obtain labs
If antibody testing or thyroglobulin
Hold biotin 1 week, then obtain labs

26. Outline Brief review of thyroid physiology
Biotin use and effects on lab results
Coffee and levothyroxine
Thyroid hormone replacement in the elderly

27. Question
32 year old female with a history of thyroid cancer treated with total thyroidectomy and I-131 treatment. Her TSH has been properly suppressed x years, to a TSH goal range of uIU/mL. Her levothyroxine dose has been consistent at 137 mcg daily, providing 2.1 mcg/kg daily.

28. Question
She now presents for her yearly evaluation. Her new TSH is 6.5 ( uIU/mL) on the same dose of levothyroxine. You note her weight is the same, and her medicine/supplement list has not changed. She is not on an oral contraceptive pill. She states her compliance with her thyroid med is very good.

29. Question The next step would be to: A. Simply increase her dose 25%
B. Change to a dessicated thyroid product.
C. Add liothyronine (Cytomel) 5 mcg twice daily.
D. Take a complete diet history with emphasis of intake at time of levothyroxine administration.

30. Question
D. Take a complete diet history with emphasis of intake at time of levothyroxine administration.
Further history revealed that her job changed, and she started to consume coffee right after she took her levothyroxine in the morning, then rushed out the door to drive to work.

31. Coffee + levothyroxine = Bad
Benvenga S, et al: Altered intestinal absorption of levothyroxine cause by coffee. Thyroid 2008; 18:

32. Benvenga S, et al
Figure 1. T4 absorption in the acute loading test of 200 μg of oral T4 in four different methods of ingestion. Bran was ingested by only two patients. AUC is area under the curve for T4. *P<0.05 comparing patients with controls drinking water alone with L-T4. †P<0.001 compared with controls drinking water

33. Benvenga S, et al
Figure 2. Data for 9 volunteers. See Figure 1 explanation. *P<0.05 and †P<0.001 for result vs. water alone.

34. Benvenga S, et al
Results: espresso on levothyroxine (L-T4) absorption was variable, and was
present only if espresso was swallowed simultaneously with the L-T4, but not if 60 minutes later
Taking L-T4 with espresso
Lowered the average and peak incremental rise of serum T4 by 25% - 57%
Reduction in the maximal incremental rise in serum levels 14% - 49%
Overall reduction ranged from 23% - 55%.
Delayed the peak serum increase in serum T4 from 0 in one patient to 90 minutes in another.

35. Benvenga S, et al
The study clearly showed that drinking espresso or coffee may interfere with intestinal absorption of Levothyroxine
If one drinks it with, or shortly after levothyroxine is taken.
This pattern of taking espresso or coffee with L-T4 was highly consistent among the eight study patients.
The effect was significant,
but is not as severe as that produced by Maalox or by bran ingested at the time L-T4 is taken

36. Started 2012 Comparators Black coffee Coffee with milk Black tea Water
The Effect of Coffee on the Absorption of Thyroid Hormone in Patients With Thyroid Carcinoma
Started 2012
Comparators
Black coffee
Coffee with milk
Black tea
Water

37. Primary outcome measures
The Effect of Coffee on the Absorption of Thyroid Hormone in Patients With Thyroid Carcinoma
Primary outcome measures
Change in TSH (thyrotropin-stimulating-hormone) with each beverage type [ Time Frame: 6 hours ]
Secondary outcome measures
Change in TSH with various beverages [ Time Frame: 6 weeks ]
Change in total T4 with each beverage type [ Time Frame: 6 hours ]
Change in free T4 with each beverage type [ Time Frame: 6 hours ]
Change in total T3 with each beverage type [ Time Frame: 6 hours ]
(This data has yet to be published)

38. Soft gel capsule levothyroxine
Branded Tirosint
Not as affected by gastric pH (vs tablet form of levothyroxine
Can use in setting of proton pump inhibitors and coffee
Consistent dissolution regardless of gastric pH
Consistent absorption even when taken with black coffee
T4 with gelatin, glycerin and water
No sugars, dyes, alcohol, gluten or lactose

39. Tirosint with gastric pH

40. Levothyroxine - Interactions
Decreased absorption:
Aluminum and Magnesium containing antacids
Rolaids
Calcium carbonate, calcium citrate antacids/supplements
Tums, Os-Cal, Citracal
Phosphate binders / calcium acetate
Phoslo
Cholestryamine and colestipol (Colestid)
Effect of colesevelam (Welchol), and ezetimibe (Zetia) on thyroid absorption not as well established
Iron
Kayexalate
Proton pump inhibitors
Omeprazole, Lansoprazole
~35% L-T4 dose increased required after 2-6 months
Raloxifene (Evista)
Orlistat

41. Levothyroxine - Interactions
Increased metabolism of levothyroxine:
Phenytoin and other anticonvulsants
Levothyroxine can alter the effect of:
Digoxin; levels may be reduced in thyrotoxicosis, therapeutic effect may be reduced.
Theophylline; Deceased theophylline clearance in hypothyroid patients.
Tricyclic and tetracyclic antidepressants; Therapeutic and toxic effects of Levothyroxine and the antidepressant are increased.
Warfarin: hypoprothrombinemic response altered.

42. Levothyroxine Dosing Options
Morning
Upon awakening, with water. No coffee x 1 hour. No food or other meds x 1 hour
Bedtime
Needs to be 2+ hours after last food intake. No other meds at this time
Middle of the night
When wake up to urinate (~2-3 AM)
(These are my clinical options, not published recommendations)

43. Effects of Evening vs Morning Levothyroxine Intake
Randomized double blind crossover trial. Morning vs bedtime dosing of Levothyroxine
Bedtime dosing of levothyroxine
decrease in thyrotropin level of 1.25 mIU/L (95% confidence interval [CI], mIU/L; P < .001)
increase in free thyroxine level of 0.07 ng/dL ( ng/dL; P = .01)
increase in total triiodothyronine level of 6.5 ng/dL ( ng/dL; P = .02)
Secondary outcomes, including quality-of-life questionnaires (36-Item Short Form Health Survey, Hospital Anxiety and Depression Scale, 20-Item Multidimensional Fatigue Inventory, and a symptoms questionnaire),
showed no significant changes between morning vs bedtime intake of levothyroxine
Conclusions Levothyroxine taken at bedtime
significantly improved thyroid hormone levels.
Quality-of-life variables and plasma lipid levels showed no significant changes with bedtime vs morning intake.
Clinicians should consider prescribing levothyroxine intake at bedtime.
Arch Intern Med. 2010;170(22):

44. Outline Brief review of thyroid physiology
Biotin use and effects on lab results
Coffee and levothyroxine
Thyroid hormone replacement in the elderly

45. Subclinical Hypothyroidism in the Elderly
85 year old female
Past Medical History:
Coronary disease with CABG
Mild Diabetes Type 2
Hyperlipidemia
Hospitalized for chest pain
Labs show:
TSH 7.8 ( uIU/mL),
normal free T4

46. Subclinical Hypothyroidism in the Elderly
87 year old female
I-131 for toxic nodular goiter at age 65.
Hypothyroid, on levothyroxine 125 mcg daily
TSH with clinic labs, 0.88 ( uIU/mL), normal free T4

47. Subclinical Hypothyroidism in the Elderly
Common in the elderly
May not be associated with adverse outcomes in the oldest individuals when detected by screening alone

48. Hypothyroidism - Elderly
Gussekloo, et al (2004)
population-based, prospective study of 558
screened for hypothyroidism
At age 85
3 years later
Annual follow-up (for four years)
no association between baseline serum TSH concentration and cognitive function, depressive symptoms, or disability in ADLs
Higher baseline TSH was also associated with lower all-cause and cardiovascular mortality

49. Mood and Cognition in Elderly Subjects with Subclinical Hypothyroidism
The Birmingham Elderly Thyroid Study
(Roberts et al, 2006)
N=5865, age >65 yrs
No differences vs euthyroid subjects in:
Cognition
Anxiety
Depression

50. Thyroid Hormone Therapy for Adults with Hypothyroidism
N Engl J Med 2017; 376:
Double-blind, randomized, placebo-controlled, parallel-group trial.
n=737 adults, 65+ years old. All with TSH mIU/L, and normal free T4
Randomized Levothyroxine or placebo
The two primary outcomes were
the change in the Hypothyroid Symptoms score
Tiredness score on a thyroid-related quality-of-life questionnaire at 1 year
Conclusions: Levothyroxine provided no apparent benefits in older persons with subclinical hypothyroidism.

51. Treatment with Levothyroxine in Subclinical Hypothyroidism Is Associated with Increased Mortality in the Elderly
Alon Grossman, MD., Ilan Feldhamer, BSc, Joseph Meyerovitch, MD Eur J Intern Med Apr;50:65-68
A case-control study in which
Patients 65 years or older with TSH levels of mIU/L who died in the years ('cases')
Compared with matched individuals who did not die during this period ('controls').
Matching was based on
gender, age, Charlson comorbidity index,
date of TSH testing, duration of follow-up and TSH quartile.
Excluded
All cases of known thyroid disease
cases in which anti-thyroid medications or glucocorticoids were dispensed in the year preceding the TSH evaluation
Use of levothyroxine was compared between groups.

52. Treatment with Levothyroxine in Subclinical Hypothyroidism Is Associated with Increased Mortality in the Elderly
Alon Grossman, MD., Ilan Feldhamer, BSc, Joseph Meyerovitch, MD Eur J Intern Med Apr;50:65-68
RESULTS:
419 individuals died individuals who did not.
Factors found to be associated with mortality were
age, senile dementia, congestive heart failure, chronic renal failure and a history of cerebrovascular
disease.
On multivariate analysis, treatment with levothyroxine was associated with
significantly increased mortality (HR=1.19 CI ).
Femoral fractures and atrial fibrillation following initiation of levothyroxine therapy were not more prevalent in individuals who died during the follow-up period.
CONCLUSIONS:
Treatment with levothyroxine is associated with significantly increased mortality in individuals 65 years or older with subclinical hypothyroidism and TSH<10.

53. Redefining Ranges for Serum TSH
Reference range
Defined by values in normal population
mU/L
Individual’s range
Much narrower than reference range
+0.5 mU/L over time
Target range
Goals for thyroxine treatment of specific conditions
Hypothyroidism: mU/L
Thyroid cancer: undetectable to 0.5 mU/L
Eldest of Elderly (over ~80)- may need goal at upper end of ref range or with slightly elevated TSH .

54. Subclinical Hypothyroidism in the Elderly
Conclusions
Caution with use of levothyroxine for sub-clinical hypothyroidism in elderly
In sub-clinical hypothyroidism and advanced age
Monitoring, without any thyroid hormone treatment is valid option

55. Questions