THINK ABOUT NORMAL

Before we begin, remember that I am not a professorial-level expert on this subject. Therefore what I have to say here is merely my opinion, which I think is worth adding into the discussion of this complicated subject, “Normal”, but which, I must admit, cannot be the last word.

WHAT DOES “NORMAL” MEAN?

In health-related fields, “Normal” is not a single number. It is a reference range or reference interval, against which a health professional can compare urine, blood or other test results in order to decide whether they are within “normal limits”.

This dissertation is regarding “normal” and TSH is a good example.
This paper mentions, but does not discuss, Hypothyroidism.

Calculation of a “normal” curve is simple for mathematicians, but complicated for most of us: see Fig. 1:

Figure 1: “NORMAL” is the 95% in the middle.

The statement below is from a statistician’s explanation of “NORMAL”.
I have included it so that readers who are familiar with statistics won’t complain about me.

When we assume a normal distribution, the reference range is obtained by measuring the values in a reference group and subtracting a “standard deviation” on each side of the curve. This leaves the values found in ~ 95% of the test population.
The 95% interval can be estimated by assuming a normal distribution of the measured parameter, in which case it can be defined as the interval limited by 1.96 (often rounded up to 2), standard deviations from either side of the mean (the expected value).”
Be that as it may, in the real world neither the population mean nor the population standard deviation are known.
They both need to be estimated from a sample, of size designated n.
The population standard deviation is estimated by the sample standard deviation and the population mean is estimated by the sample mean (also called mean or arithmetic mean).
To account for these estimations, the 95% prediction interval (95% PI) is calculated as: 95% PI = mean ± t_0.975,n−1·√(n+1)/n·sd.”

  THE BOTTOM LINE, re. CALCULATING “NORMAL”

……… If that sounds complicated, don’t look at me: ask your favourite math genius for his/her usual facile explanation!
……… Suffice it that the reference range includes results found in 95% of a reference group from a healthy population.
……… There are also optimal ranges (ranges that we think indicate optimal health) and
……… There are ranges for particular conditions or situations (such as pregnancy reference ranges for hormone levels).
……… My preference is for optimal ranges. I have doubts about the accepted “normal” ranges of quite a few tests.
……… Caveat: the blithe idea that 95% of a “healthy” population will have “normal” levels for all test results is unrealistic unless the term “healthy” is rigorously defined and conscientiously applied. To assume otherwise is contrary to the principle of “a high index of suspicion” and will lead to under-diagnosis.

Therefore:
1] Reference groups should strictly include only candidates between 20 and 25 years of age.
2] Since our metabolic systems are interdependent and unpredictably variable in one way or another, an individual should be excluded from estimation of “normal” values unless his/her results are normal for all other available tests.
3] Thus, eligibility for an estimation of normal should be denied if the BMI is high or low, or if there is any physiological, metabolic, psychological*, sociological* or genetic abnormality.
4] Similarly, if the psychological balance is imperfect the candidate should be excluded from the reference group, because childhood PTSD, anxiety, depression and other psychological difficulties are associated with biochemical abnormalities which can make a surprising difference to blood test results.
* Regardless of racial origin, the highest and lowest echelons of society should be excluded, since both highest and lowest social groups are subject to significant stress.

DON’T CONFUSE “NATURAL” WITH “NORMAL”

NATURAL NORMAL: Many systems change over time and “gurus” have a tendency to modify “normal” according to age.

See Figure 2, depicting DHEA production from birth to adulthood and Figure 3, which shows the accepted “natural normal” of dehydroepiandrosterone (DHEA), in micro-moles / Litre
(from LifeLabs, in 2010):

Fig. 2: DHEA and cortisol levels, from conception to age 20

Figure 3: “AGE-ADJUSTED NORMALS” – DHEA

Age	Female	Male	COMMENT
Newborn	4.5-10	4.5-10	Mother gives her baby quite a lot, and baby makes some, too
01-12 Yr	< 5.0	< 5.0	We don’t make much DHEA when we are kids
13-29 Yr	< 11	< 11	Just before puberty, production spikes *
30-39 Yr	<7.3	<14	Females slow output, 1% per year, starting at age 25
40-49 Yr	<6.5	<14	Males usually continue high production through age 45, then lose 1%/Yr
50-59 Yr	<5.4	<8.4	By age 50, the ladies are in real trouble **
60-69 Yr	<3.5	<7.9	By age 65, the men are in the same boat **
70-79 Yr	<2.4	<4.7	At age 70, we are all over the hill
80-99 Yr	?? 0.0	?? 0.0	At age 80, only the brain makes DHEA ***

THIS SCHEDULE TELLS US SEVERAL THINGS:

[1] Males produce more DHEA than females.
[2] Women begin to reduce production by age 26 and men, in their 40s.
[3] Production is at infant levels or less by 60 and by 80, is close to zero.
[4] The researcher of the DHEA range didn’t know what the lower limits are.
[5] DHEA is important. No-one with a low DHEA should be a candidate for estimation of “Normal”.
[6] Falling production with age is natural, but not normal in terms of best function.

* Possibly, reduction of Melatonin just before puberty triggers the DHEA spike: this is not yet proven.
** Over 15 years, I observed that both genders begin low-DHEA symptoms when DHEA falls below 5.0 µMol/Litre.
*** The brain makes DHEA for its own use and is the only source of this all-important prohormone in lesser animals.
Only the great apes, including us, make DHEA in the adrenals as well as the brain.

Consider “natural normal” for Thyroid hormone (reported in picoMoles/Litre), as a second example:

(1) In 2005 Leonard Wartofsky and Richard A Dickey wrote, (paraphrased)

• “It has become clear that our reference ranges are no longer valid.“
• “We have more sensitive TSH tests and also, we now realise that previous reference populations included people with low-thyroid dysfunction, whose high TSH levels led to a spuriously wide reference range for TSH in the group.“
• “Recent laboratory guidelines from the National Academy of Clinical Biochemistry indicate that more than 95% of normal individuals have TSH levels below 2.5 mU/liter.”
  
  From this paper, many of us concluded that “normal” TSH should be less than 2.5.
  

(2) In 2007, Martin L Surks and Joseph G Hollowell said (paraphrased) as follows ……

• “The TSH median, 97.5 centile and prevalence of subclinical hypothyroidism (SCH) increase progressively with age. Age-adjusted reference ranges would include many people with TSH greater than 4.5 mIU/liter.”

They continued:

• ”Without thyroid disease, 10.6% of 20- to 29-yr-olds had TSH greater than 2.5 mIU/liter.” *
• “Without thyroid disease, in the 80+ year-old group 14.5% had TSH greater than 4.5 mIU/liter.“
• “Frequency distribution curves of the 80+ year-old group showed higher TSH.
• “The 97.5 centiles for 20–29 and 80+ year-old groups were 3.56 and 7.49 mIU/litre, respectively.”
• “70% of older patients with TSH >4.5 mIU/liter were within the age-specific reference range (up to 7.49)”. **

In spite of these findings, almost 100% of our medical doctors preferred to think like Surks and Hollowell and the reference range for TSH, “less than 4”, has remained unchanged. ***

NEW PARAMETER: Normal TSH range of 0.4–2.5

In support of a new “normal” TSH range of 0.4 – 2.5, the” “Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and Postpartum”, published via liebertpub.com in 2010, with respect to the management of thyroid function during pregnancy, reads as follows (copied text):
“The range of thyrotropin (TSH), under the impact of placental human chorionic gonadotropin (hCG), is decreased throughout pregnancy with the lower normal TSH level in the first trimester being poorly defined and an upper limit of 2.5 mIU/L. Ten percent to 20% of all pregnant women in the first trimester of pregnancy are thyroid peroxidase (TPO) or thyroglobulin (Tg) antibody positive and euthyroid. 16% of the women who are euthyroid and positive for TPO or Tg antibody in the first trimester will develop a TSH that exceeds 4.0 mIU/L by the third trimester, and 33%–50% of women who are positive for TPO or Tg antibody in the first trimester will develop postpartum thyroiditis. In essence, pregnancy is a stress test for the thyroid, resulting in hypothyroidism in women with limited thyroidal reserve or iodine deficiency, and postpartum thyroiditis in women with underlying Hashimoto’s disease who were euthyroid prior to conception.”

This recommendation of course is with specific reference to pregnancy: however a logical examination of the possible cause of deteriorating thyroid function during pregnancy, concludes that stress, with reduction, or limitation, of intracellular T4 conversion to T3 is at fault. I extrapolate therefore, that in the name of “safest possible practice”, the “2.5” upper limit of TSH it is reasonable for all (certainly, it TSH between 2.5 and 4.0 is suspicious).

HOWEVER TO ME, THE IMPLICATIONS ARE CLEAR:

(A) Wartofsky and Dickey were correct: the upper limit of normal TSH should be 2.5. However they should have realised that 10.6% of their 20-29-year-olds were hypothyroid and should have excluded their data from the calculations. ****
(B) Surks and Hollowell would have done better to label the older folks hypothyroid, rather than concluding that “high TSH is normal for the older population”. What their findings mean to me is that a large percentage of their 80+-year-olds were hypothyroid and should have been treated.
(C) “AGE-SPECIFIC NORMAL”, or “NATURAL NORMAL” makes no sense (review figure 3).
“Normal” should be understood to mean the status of healthy humans aged 20-25, because at 25+ years, we all begin reduction of our hormone output and by that token, anyone over 25 is subject to hormone deficiency-related metabolic aberration.
(C) Anxiety-related psychology, childhood PTSD, obesity, anorexia, chronic illness, or an abnormal finding for any test should disqualify the candidate for all estimates of “normal”.
(D) If the real normal for TSH is < 2.6 and not < 4.1, a whole lot of people are suffering from unsuspected, chronic, true hypothyroidism.
(E) Even Wartofsky and Dickey’s calculations are suspect: perhaps the opinion of some modern Metabolic Medicine practitioners is correct: maybe the upper limit of normal for TSH should be <1.6.

* This implies that 10.6% of the 20-29-year-olds were hypothyroid. They should have been excluded from the calculation.
** TSH >2.5 (??: some functional medicine practitioners say > 1.5?) indicates hypothyroidism, so this means that more than 14.5% of the over-80-year olds in Surks and Hollowell’s study were hypothyroid. Including them in the “normal” group means that 15+% of 80-yr-olds didn’t get treatment which they needed!
*** You should apply fair logic to every paper you read, to exclude errors and prejudices like these from your beliefs.
**** Think about it – if I am right, since thyroid hormone 3 controls the efficiency of every cell and system in the body, 10.6% of the younger thyroid test study population should have been excluded from the calculation of “normal” TSH.

Maybe the parameters for all our other tests are wrong and perhaps a lot of test reports are invalid !

COMMENTS

• DHEA goes down over time by 1-2 %/year, due to gradual loss of production.
  – Many other hormones suffer the same fate, including Melatonin, Progesterone, Allopregnanolone, Testosterone and Thyroid.
• Several hormones can “crash” simultaneously, causing various symptoms of deficiency depending on which hormones are involved. This can happen with Melatonin and DHEA in the “teens”, Progesterone and Allopregnanolone in the twenties, Testosterone in the thirties or earlier and particularly Oestrogen, which disappears in the early fifties but can fall to zero in the late thirties or early forties.
• Thyroid hormone goes down as we age: this deserves special attention because everything else depends on it.
• Precise assessment of “normal” is impossible if we call natural age-related hormone change “normal”.
• To give medical investigators their due, a concerted effort is always made to include only fit individuals in the group evaluated. However unknown or ignored factors can lead to a “curve ball” situation, causing an incorrect, or unreliable, “normal” range.
• Since Intracellular Hypothyroidism is the true cause of hypothyroid symptoms and since TSH is irrelevant to the diagnosis of Intracellular Hypothyroidism, the above discussion is purely with respect to “normal” and has no bearing on the management of Intracellular Hypothyroidism per se.
• Aberrations of hormonal production are pervasive and the interdependence of hormonal systems is delicate.
• Subjects selected for “reference range’ in the assessment of normal should be age 20-25 years.
• The present and past history, physical findings, sociology and psychology of candidates for test populations, for the estimation of “normal”, should be healthy.If there are candidates for inclusion in the estimation of “normal”, all their other test results should be normal.
• Please, also see “what our medical system ignores”: should thyroid hormone tests be reviewed?
  

REFERENCES

(1) The evidence for a narrower thyrotropin reference range is compelling, by Leonard Wartofsky ¹ , Richard A Dickey, J Clin Endocrinol Metab, 2005 Sep; 90(9):5483-8 PMID: 16148345 DOI: 10.1210/jc.2005-0455 .https://pubmed.ncbi.nlm.nih.gov/16148345/

(2) age-specific distribution of serum thyrotropin and antithyroid antibodies in the US population: implications for the prevalence of subclinical hypothyroidism, by Martin I Surks and Joseph G Hollowell, in the journal of clinical Endocrinology and metabolism, volume 92, issue 12, 12/1/07, 4575 – 4582.
https://doi.org/10.1210/jc.2007–1499 01 Dec. 2007.
Https://academic.oup.com/jcem/article/92/12/4575/2596923?login=true

(2) Age-Specific Distribution of Serum Thyrotropin and Antithyroid Antibodies in the U.S. Population: Implications for the Prevalence of Subclinical Hypothyroidism:

(3) Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and Postpartum, by Alex Stagnaro-Green, Marcos Abalovich, Erik Alexander, Fereidoun Azizi, Jorge Mestman, Roberto Negro, Angelita Nixon, Elizabeth N. Pearce, Offie P. Soldin, Scott Sullivan and Wilmar Wiersinga, in ThyroidVol. 21, No. 10 Pregnancy and Fetal Development, from
The American Thyroid Association Taskforce on Thyroid Disease During Pregnancy and Postpartum
Published Online: 23 Sep 2011: https://doi.org/10.1089/thy.2011.0087
https://www.liebertpub.com

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