More accurate repeat

[diogenes]

Some typos and jumbles have emerged. Here it is again in better shape I hope.

To the doctor

You and I are meeting to discuss my health problem that I suspect (know) is associated with hypothyroidism. I’m sure we both want to come to a conclusion and treatment that best suits my particular state of health. Therefore before we start, I’d like to put in front of you the ideas and concepts that modern thinking on thyroid function has developed. These have radically changed the understanding of the relationship of TSH with thyroid hormones T4 and T3, and the way in which these all interact together. At the moment, TSH alone is used initially to detect the onset of hypothyroidism. That this test is useful and highly sensitive is not denied, but the interpretation of the test is highly controversial when deciding on relevant action. An important part of this is a decision when, and at what TSH level, therapy by oral thyroid hormone is indicated. In this regard I put the following points to you:

1)The reference range for healthy subjects is generally accepted at 0.5-4 mIU/L. However unlike the symmetrical distribution of values for free thyroxine (FT4) and free triiodothyronine (FT3), the distribution of so-called healthy values for TSH is severely skewed towards the lower end of the scale, so that relatively few patients deemed euthyroid have TSH values above 2.5 mIU/L. It has been suggested that in such patients, the thyroid is showing the beginning of strains which may herald difficulties later on. TSH values above the top of the reference range up to 10 mIU/L are assigned to subclinical hypothyroid subjects, currently perceived not at the time to require medication.

2)Individuals maintain health through unique combinations of TSH, FT4 and FT3 applicable only to them. But for me, we do not know what these are, because I have not had these measured in health. Therefore, when thyroid disease strikes, it usually does so surreptitiously with only a gradual progressive change to overt hypothyroidism requiring treatment. Because of my individual makeup of thyroid hormones, the point at which indications of a thyroid under strain, but not yet obviously compromised, move into an overt state requiring treatment will be unique to me. However as I said, my start point from health is not known. Therefore diagnosing me by “shoehorning” TSH values into categories defined by ranges is not correct. It assumes that everyone will respond equivalently within that range, and that decisions to treat or not can be made purely on statistical, rather than on personal, grounds.

3)Diagnosing purely by TSH has to take account of a) my particular makeup as regards thyroid function and b) the symptoms I am displaying:

4)hair loss/limpness, loss of outer part of eyebrows, thickening facial skin, feeling cold, sluggish- THESE ARE JUST EXAMPLES –USE YOUR OWN HERE.

I realise that symptoms can be misleading, being nonspecific to thyroid problems, but combined with my results, it is more likely that they result from developing problems with my thyroid.

5)A TSH above the reference range but below 10 mIU/L therefore can have many meanings. For some individuals, given obvious symptoms of hypothyroidism, it can strongly indicate the need for treatment. For others with exactly the same value, it may not require treatment at present. However the magic number of 10 mIU/L should not be used as a decision point as to whether to treat or not. There cannot be a hard and fast cut-off point for treatment given patient individuality.

6)Are there any useful blood test pointers that can aid in deciding whether to treat or not that are independent of thyroid function tests? One useful test is blood cholesterol and triglycerides. If hypothyroidism is at a significant level, then these will be raised. On treatment with thyroxine, the levels should fall back to lower values if the treatment is appropriate. Thyroid antibody tests should also determine whether or not I have autoimmune thyroiditis.

7)Another useful approach is to measure FT4 and FT3 and obtain a FT4/FT3 ratio. If I am seriously on the path to hypothyroidism then my FT4/FT3 ratio will be significantly lower than 3/1, In health, this ratio is usually between 3/1 and 4/1, The reduction in the ratio is due to my thyroid failing to produce enough T4, while my body is trying to maintain T3 levels to a level normal for it in health.

8)I realise that deciding the exact point when and how to treat hypothyroidism is a difficult area, but decisions on my future based on hard diagnostic dividing lines cannot be the best way forward given my individuality. My individual presentation is at least as important as the biochemical numbers. The recently defined category of subclinical hypothyroidism (i.e. not requiring treatment) has been a retrograde step in diagnosis, as it has consigned individuality in disease progress into a statistically defined mass-based decision resulting in the arbitrary cut-off of 10 mIU/L. Incidentally, this situation seems not to be mirrored in other countries where treatment begins at a much lower TSH level.

9)It may possibly be that I display hypothyroid symptoms, when TSH is still within its reference range. In which case, FT4 should be measured to see if it is very low within this range or even below. If this turns out to be the case, it may be that I am suffering from central hypothyroidism (pituitary insufficiency rather than thyroid disease). In this case, unlike thyroid failure, both FT4 and FT3 will be reduced but the ratio will remain typical of health.

10) If in the event, treatment with T4 is indicated, 50 ug should be a starter dose (omit this if over 65 years when 25 ug might be a better more cautious start). When treatment is begun, FT3 should be used as a determinant of successful treatment, realising that neither TSH nor FT4 are adequate in this regard. This is because T3, not T4 or TSH is the determinant of health.

11)You will note that I have emphasised that TSH cannot be the only arbiter of diagnosis. Using it in the way done at present takes no regard of my individuality as to how my disease develops.

12) I hope by combining presentation with biochemical measurements in a considered and personal way, treatment can be begun. A problem with delaying treatment is that irreversible changes in the thyroid axis can occur which will be difficult to reverse in the future. This is the more problematic, the longer I am left without treatment as irreversible epigenetic effects can alter how I respond. This is another dilemma that we should discuss together.

Links:

1) TSH Measurement and Its Implications for Personalised Clinical Decision-Making December 2012 Journal of Thyroid Research 2012(2):438037

DOI: 10.1155/2012/438037

2) Recent Advances in Thyroid Hormone Regulation: Toward a New Paradigm for Optimal Diagnosis and Treatment

December 2017 Frontiers in Endocrinology DOI: 10.3389/fendo.2017.00364

[Jumbelina]

Thank you so much for this Diogenes. As I have had Hashimoto's for some years I particularly like 10) "FT3 should be used as a determinant of successful treatment" and I wish someone would thus advise the endocrinologist I saw at a London teaching hospital who was not prepared to test this.

[Musicmonkey]

diogenes You seem to have various random comments towards the end of this piece.....

[diogenes Remembering in reply to Musicmonkey]

These seem to infiltrated somehow. Ignore them

[SlowDragon Administrator in reply to diogenes]

I edited them out for you

[SilverAvocado in reply to SlowDragon]

I've got a bit confused about which is the final version. Looks like this one is, could it replace the current sticky we've got?

[diogenes Remembering in reply to SilverAvocado]

Yes

[MaryMary]

Thank you Diogenes - a really useful summary. I will take it to my doctor.

[Hidden]

I think it's great what you've done but my GP, being a misogynist who thinks he knows everything, would laugh at me .

[AliF]

Thank you Diogenes. Can you explain this a little more please ?

"A problem with delaying treatment is that irreversible changes in the thyroid axis can occur which will be difficult to reverse in the future. This is the more problematic, the longer I am left without treatment as irreversible epigenetic effects can alter how I respond.”

Thank you.

[diogenes Remembering]

The longer you are without adequate hormone treatment, the more changes in genes occur that are difficult to reverse back. What happens to genes is that they are "methylated" - this is a chemical addition that alters how genes are "read". Over a period, this becomes entrenched, so that reversal to normality becomes more and more difficult if indeed it is achievable at all. Therefore treatment becomes different and possibly difficult to optimise.

[Gigi216 in reply to diogenes]

I have never heard this! If you ever have time in the future I would love for you to write about this subject. I tried twice to go without thyroid medicine to try to restart my thyroid. It sounds like that was a big mistake. Is there a website or book I could read to learn more about this? Thank you!

[diogenes Remembering in reply to Gigi216]

The studies of course have been done on animals, rats and mice. It isn't ethical to use humans. Here is one review of epigenetic stress in rats. Only the abstract but it gives you the flavour:

Brain Research Reviews

Volume 57, Issue 2, 14 March 2008, Pages 571-585

Review

Epigenetic programming of the stress response in male and female rats by prenatal restraint stress

Muriel Darnaudéry, Stefania Maccariab.

doi.org/10.1016/j.brainresr...

[diogenes Remembering in reply to Gigi216]

Here is a report on mice with references:

Certain fears can be inherited through the generations, a provocative study of mice reports. The authors suggest that a similar phenomenon could influence anxiety and addiction in humans. But some researchers are sceptical of the findings because a biological mechanism that explains the phenomenon has not been identified.

According to convention, the genetic sequences contained in DNA are the only way to transmit biological information across generations. Random DNA mutations, when beneficial, enable organisms to adapt to changing conditions, but this process typically occurs slowly over many generations.

Yet some studies have hinted that environmental factors can influence biology more rapidly through 'epigenetic' modifications, which alter the expression of genes, but not their actual nucleotide sequence. For instance, children who were conceived during a harsh wartime famine in the Netherlands in the 1940s are at increased risk of diabetes, heart disease and other conditions — possibly because of epigenetic alterations to genes involved in these diseases2. Yet although epigenetic modifications are known to be important for processes such as development and the inactivation of one copy of the X-chromsome in females, their role in the inheritance of behaviour is still controversial.

Kerry Ressler, a neurobiologist and psychiatrist at Emory University in Atlanta, Georgia, and a co-author of the latest study, became interested in epigenetic inheritance after working with poor people living in inner cities, where cycles of drug addiction, neuropsychiatric illness and other problems often seem to recur in parents and their children. “There are a lot of anecdotes to suggest that there’s intergenerational transfer of risk, and that it’s hard to break that cycle,” he says.

Heritable traits

Studying the biological basis for those effects in humans would be difficult. So Ressler and his colleague Brian Dias opted to study epigenetic inheritance in laboratory mice trained to fear the smell of acetophenone, a chemical the scent of which has been compared to those of cherries and almonds. He and Dias wafted the scent around a small chamber, while giving small electric shocks to male mice. The animals eventually learned to associate the scent with pain, shuddering in the presence of acetophenone even without a shock.

This reaction was passed on to their pups, Dias and Ressler report today in Nature Neuroscience1. Despite never having encountered acetophenone in their lives, the offspring exhibited increased sensitivity when introduced to its smell, shuddering more markedly in its presence compared with the descendants of mice that had been conditioned to be startled by a different smell or that had gone through no such conditioning. A third generation of mice — the 'grandchildren' — also inherited this reaction, as did mice conceived through in vitro fertilization with sperm from males sensitized to acetophenone. Similar experiments showed that the response can also be transmitted down from the mother.

These responses were paired with changes to the brain structures that process odours. The mice sensitized to acetophenone, as well as their descendants, had more neurons that produce a receptor protein known to detect the odour compared with control mice and their progeny. Structures that receive signals from the acetophenone-detecting neurons and send smell signals to other parts of the brain (such as those involved in processing fear) were also bigger.

The researchers propose that DNA methylation — a reversible chemical modification to DNA that typically blocks transcription of a gene without altering its sequence — explains the inherited effect. In the fearful mice, the acetophenone-sensing gene of sperm cells had fewer methylation marks, which could have led to greater expression of the odorant-receptor gene during development.

But how the association of smell with pain influences sperm remains a mystery. Ressler notes that sperm cells themselves express odorant receptor proteins, and that some odorants find their way into the bloodstream, offering a potential mechanism, as do small, blood-borne fragments of RNA known as microRNAs, that control gene expression.

Contentious findings

Predictably, the study has divided researchers. “The overwhelming response has been 'Wow! But how the hell is it happening?'" says Dias. David Sweatt, a neurobiologist at the University of Alabama at Birmingham who was not involved in the work, calls it “the most rigorous and convincing set of studies published to date demonstrating acquired transgenerational epigenetic effects in a laboratory model".

However, Timothy Bestor, a molecular biologist at Columbia University in New York who studies epigenetic modifications, is incredulous. DNA methylation is unlikely to influence the production of the protein that detects acetophenone, he says. Most genes known to be controlled by methylation have these modifications in a region called the promoter, which precedes the gene in the DNA sequence. But the acetophenone-detecting gene does not contain nucleotides in this region that can be methylated, Bestor says. "The claims they make are so extreme they kind of violate the principle that extraordinary claims require extraordinary proof,” he adds.

Tracy Bale, a neuroscientist at the University of Pennsylvania in Philadelphia, says that researchers need to “determine the piece that links Dad's experience with specific signals capable of producing changes in epigenetic marks in the germ cell, and how these are maintained”.

“It's pretty unnerving to think that our germ cells could be so plastic and dynamic in response to changes in the environment,” she says.

Humans inherit epigenetic alterations that influence behaviour, too, Ressler suspects. A parent’s anxiety, he speculates, could influence later generations through epigenetic modifications to receptors for stress hormones. But Ressler and Dias are not sure how to prove the case, and they plan to focus on lab animals for the time being.

The researchers now want to determine for how many generations the sensitivity to acetophenone lasts, and whether that response can be eliminated. Scepticism that the inheritance mechanism is real will likely persist, Ressler says, “until someone can really explain it in a molecular way”, says Ressler. “Unfortunately, it’s probably going to be complicated and it’s probably going to take a while.”

Nature doi:10.1038/nature.2013.14272

References

Dias, B. G. & Ressler, K. J. Nature Neurosci. dx.doi.org/10.1038/nn.3594 (2013).

PubMed

Heijmans, B. T. et al. Proc. Natl Acad. Sci. USA 105, 17046–17049 (2008).

Pub Med Chem Port

[Gigi216 in reply to diogenes]

Truly fascinating! I’ve always loved epigenetics. Thank you so much for your reply. I developed anxiety when little because of difficult childhood and my grandchildren seem to have issues with anxiety even though they have been doted on wonder if they inherited a propensity for anxiety through me? As I said fascinating.

[diogenes Remembering]

This ratio doesn't really apply to T3 and NDT therapies but 3/1 will do you no harm if the actual quantities are OK.