• Credits
  • Section Writer: Dr. Om J Lakhani
  • Section Editor: Dr. Om J Lakhani

Support us:

1. Support us by purchasing our book - Click here for more details: Volume 1- THE BEST OF NOTES IN ENDOCRINOLOGY BOOK SERIES
2. Support you by Becoming a YouTube member (Click here)

• Note: for Hashimoto's encephalopathy 1 - please see separate notes (Coming soon)

• Q. Enlist the neurological manifestations of hypothyroidism in adults ?

  • Myxedema coma
  • Cognitive impairment (Dementia)
  • Cerebellar ataxia
  • Peripheral neuropathy – including Carpal tunnel syndrome
  • Hypothyroid myopathy
  • Sensorineural hearing loss

• Q. What are the neurological manifestation of Cretinism (congenital hypothyroidism) ?

  • Intellectual impairment
  • Delayed motor milestones
  • Kocher- Debre- Semelienge syndrome – hypothyroid myopathy
  • Sensio neural hearing loss
  • Strabismus

• Q. What is myxedema madness ?

  • Psychosis seen with severe hypothyroidism

• Q. Cognitive impairment (dementia)  in hypothyroidism is cortical or subcortical ?

  • It is mainly subcortical

• Q. Is Subclinical hypothyroidism associated with dementia ?

  • Results are conflicting

• Q. What other types of psychiatric manifestations are common in hypothyroidism?

  • Depression and anxiety are common features of hypothyroidism

• Q. Should cognitive impairment in elderly be screened for hypothyroidism?

  • Yes
  • Elderly with cognitive impairment must be screened for hypothyroidism based on AAN guidelines

• Q. Is there a link between Parkinsonism and Hypothyroidism ?

  • Again, conflicting data
  • However patient with Parkinsonism who does not respond to treatment must be screened for hypothyroidism
  • Also Levodopa reduces TSH and hence this care must be taken while screening

• Q. Is hypothyroidism commonly associated with cerebellar ataxia ?

  • Yes

Hypothyroidism and Depression

Q. What is the relation between Serotonin levels and hypothyroidism ?
- #Clinicalpearl
- Serotonin has a feedback loop with TRH. It suppresses TRH
- T3 in the brain increases serotonin levels

• Q. Do larger studies show any relation between depression and hypothyroidism?

  • According to a meta-analysis- some of the larger studies have shown no correlation between depression and hypothyroidism

• Q. What is the biggest bias with these studies ?

  • These studies by its nature, excludes patients already on LT4 and diagnosed to have hypothyroidism previously
  • The remaining people are those who probably did not have an indication for treatment in the first place

• Q. Is there a relationship between any thyroid-related polymorphism and depression?

  • Yes
  • A seminal study on this topic found a strong correlation between polymorphisms in Deiodinase type 2 (DIO2) and depression in hypothyroid Caucasian females

• Q. Can you elaborate more on this?

  • In the CNS- only type 2 deiodinase is present to convert T4 to T3
  • Subanalysis of various meta-analyses done for T3/T4 combination therapy has shown that a particular subset of patients having a polymorphism rs225014 in DIO2 have benefits in terms of T3 and T4 combination
  • This polymorphism was present in 12% of subjects
  • There is no biochemical test to identify this subset of a patient and can only be identified with genetic testing

• Q. Is there any other polymorphism that may have a potential association?

  • Polymorphism in OATP1C1, which helps transport T4 to the brain, may be associated with depressed mood and other psychological features

• Q. Is there a relationship between thyroid autoimmunity and depression?

  • some studies have shown a correlation between Anti TPO positivity and depression
  • This is especially true since Post partum thyroiditis is known to present as depression

• Q. Despite adequate control of TSH biochemically, do some patients with hypothyroidism continue to have a poor sense of well-being?

  • Yes
  • This has been shown in several studies in patients treated with LT4
  • In fact, some patients on LT4 may have worse psychological outcomes

• Q. What is cycle of misattribution?

  • This is one of the reasons why patients with hypothyroidism may not receive clinical response with Levothyroxine]] treatment
  • Patients having symptoms of depression- tested for hypothyroidism as per protocol - found to have Subclinical hypothyroidism- treatment started, but to start Subclinical hypothyroidism was NOT the reason for depression!
  • This is a cycle of misattribution

• Q. Does treatment with LT4 improve the mood?

  • There are no convincing placebo-controlled trials to show that there is a clear benefit in the mood with treatment with LT4
  • Only one placebo-controlled trial by Meier et al. have shown some benefit inpatient in whom TSH was >12

• Q. Is the combination of T3 and T4 having benefits?

  • This is an area of controversy
  • Large meta-analyses have shown no benefit, while some small studies have shown benefit
  • The exact dose and ratio of T3/T4 is different in different studies and hence making it difficult to interpret

• Q. Is overcorrection associated with adverse psychological outcomes?

  • Largely- trials have not shown this to be true

• Q. Does adding T3/T4 improve the effectiveness of anti-depressants?

  • Again, this is a controversial area with no clear consensus in either direction
  • Larger trials have shown mixed results- especially with T3
  • At present, there is no benefit of using LT4 or T3 for this purpose

• Q. What are the take-home messages from hypothyroidism and depression?

  • 1. There is no clear relation between LT4 replacement and improvement in mood with patients with hypothyroidism
  • 2. A lot of these patients may have a cycle of misattribution - a patient with depression having the symptoms attributed to hypothyroidism
  • 3. T3/T4 combination may or may not have the benefit
    • It is beneficial in patients having a functional polymorphism in the DIO2 (type 2 deiodinase) enzyme

• Evidence-Based Use of Levothyroxine/Liothyronine Combinations in Treating Hypothyroidism: A Consensus Document

• Q. What happens to the T3 when we treat hypothyroidism patients with LT4?

  • Studies in humans have shown that the use of LT4 for treating hypothyroidism leads to normalization of TSH, but abnormal FT4/FT3 ratio.
  • The FT3 is not normalized like it should be because of LT4

• Q. Where are the Type 1 deiodinase and Type 2 deiodinase found in the human body?

  • Type 1 deiodinase- Liver and Kidney
  • Type 2 - is found in the heart, skeletal muscle, CNS, fat, thyroid, and pituitary

• Q. Of the above 2 - which contributes most to the T3 levels?

  • Type 2 deiodinase contributes 80% of the T3 levels

• Q. So why does treatment with LT4 lead to pooer T4/T3 ratio?

  • LT4 given is taken up by the hypothalamus and pituitary - converted to T3 by the local D2, and then it normalizes TSH rapidly
  • However, the above correction occurs faster compared to the normalization of T3 levels in the peripheral circulation
  • Hence an adequate T3 level is never achieved before the TSH is normalized
  • 

• Q. Which specific Type 2 deiodinase polymorphism has produced this debate?

  • Thy92 Ala

• Q. What effects of the thyroid hormone are thought to occur via a non-canonical or non-thyroid receptor pathway?

  • Effect on cancer growth

• Q. What are the issues with the clinical trial with T3/T4 combination?

  • The suitable patients may not have been included
  • The suitable patients include those who are dissatisfied with the T4 replacement

• Q. What is the pharmacological equivalence between T3 and T4?

  • 1 T3 = 3 T4
  • i.e., 100 mcg of T4 = 33.3 mcg of T3
  • 40 mcg of T3 = 115 mcg of T4

• Q. What are the problems with T3 assays?

  • At low concentration, the T3 or FT3 immunoassays are less reliable
  • It is also affected by the patient factors
    • Patients on dietary restriction have lower levels
    • Patients with illness may have lower levels
    • Age
    • Time of the day

• Q. If given as monotherapy, how is T3 given?

  • it is given three times a day
  • Typically, 10 mcg TDS would be around 120 mcg of T4
  • Trials have used twice a day T3 generally because of patient compliance issue

• Q. What is the half-life of T3?

  • 22 hours

• Q. In our terms, how much thyroid hormone is produced by the thyroid gland?

  • 100 mcg of T4 is produced, and the normal thyroid gland produces about five mcg of T3
  • This is about a 14:1 ratio

• #Clinicalpearl: Slow release T3 preparations are required to solve the problem of the T3 and T4 combination

• Q. What happens to TSH with T3 monotherapy is given?

  • Studies have shown that with T3 monotherapy, the TSH levels tend to be a little lower
  • Fluctuations are also more
  • Lower TSH]] here may not represent overcorrection

• Q. Which are two critical psychological outcomes attributable to hypothyroidism?

  • Two outcomes attributable to hypothyroidism include
    • Emotional susceptibility
    • Tiredness
  • Depression and Anxiety are NOT attributable to thyroid dysfunction

• Q. What is the top psychological concern of patients with hypothyroidism?

  • Fatigue is the chief concern in patients with hypothyroidism
    • General fatigue
    • Physical fatigue
    • Mental fatigue

• #Clinicalpearl

  • Thyroid related QoL indices tend to perform better compared to general QoL indices like SF-36 etc
  • For fatigue specifically, thyroid-related fatigue may be different from other fatigues!

• Q. In hypothyroidism, what is the difference between patient-perceived symptoms and clinician-perceived symptoms ?

  • 

• Why are our hypothyroid patients unhappy? Is tissue hypothyroidism the answer?

  • Zulewski symptom score for hypothyroidism
    • 
    • Score ≥ strong correlation with hypothyroidism
    • <2 - less relation

• Q. Which two tests should be done to assess tissue level hypothyroidism and its correlation with hypothyroidism?

  • lipid profile]]
  • Creatine kinase]]
  • They have correlation with symptoms