An opinion re. pathogenesis, diagnosis and management Long Covid:
In 2021, I wrote a post entitled “Long Covid: a report from China” [1], in response to “Euthyroid Sick Syndrome (ESS), in Patients with COVID-19”, by Runmei Zou, et al [2].
Now, two years later, “long Covid” still affects approximately 10% of people who contract Covid 19, including a number of celebrities: so it is still a hot subject and I feel it imperative that I comment on it once more.
Note: here, the reference tags (#1 –10) are hyperlinked to the articles referenced.
Background
Since long Covid was first described, much effort has been put into its investigation, but no firm answers have been forthcoming: the enigma and the argument continue.
The condition has 2 aspects:
(1) continuing organ damage, which is variable as to site and severity and
(2) patient complaints, of symptoms including weakness, tiredness, muscle aches, intestinal upset, cognitive loss, ennui and unbearable fatigue, such that productive work becomes extremely difficult, or impossible.
Regarding the organs, the best guess to date is that the “spike protein” of the Covid virus causes inflammation of the lining (the “endothelium”) of the arteries and the inflammation excites the blood “platelets” (blood constituents which form blood clots in response to injury), resulting in the formation of microscopic clots.
However it may be that hyper-reactive platelets begin to stick together in the large blood vessels, forming micro-clots which then get stuck in the smallest vessels, producing inflammation of the endothelium.
Regardless of the mechanism, microscopic blood clots plug the capillaries in affected organs, reducing the blood flow, causing inflammation and adversely affecting function.
I can add little to the conversation regarding this “endothelialitis”*, excepting that a trial of low-dose aspirin, or (better, perhaps) Nattokinase, to prevent formation of micro-clots, might prove valuable.
However I do wish to comment on the symptoms, because there may be a solution (below).
*Re. Endothelialitis, go to an excellent article, published by Turner et al. on 4/23/23 [3]
For detail re. aspirin in Covid 19, see an explanation by Zareef et al., in 2021 [4].
The article by Zou et al., re. ESS in “Long Covid”
Zou et al reported that out of 149 Long-Covid cases, 41 (27.52%) had “Euthyroid Sick Syndrome” (ESS). Of the 41 affected patients, 34 (15%) were male and 65 (85 percent), female. The age range was 50–66Yrs and the median age was 58.
The sole criterion for diagnosing ESS was “Serum FT3 <2.3 pg/ml (3.5 pmol/L) with low or normal TSH”: rT3 values were not available. [5] Note that the accepted lower limit of normal for TSH, in Canada, is 3.1 pmol/L.
About ESS (IH)
“Euthyroid Sick Syndrome” (ESS) is also known as Functional Hypothyroidism, Nonthyroidal Illness, Subclinical Hypothyroidism and Low T3 Syndrome. Perhaps it should be called “Intracellular T3 Starvation”, but the best (certainly the most descriptive) term is “Intracellular Hypothyroidism” (IH), since the condition is due to elimination of T3 inside the cells. [6]
IH follows elevated cortisol, produced in response to stress, because cortisol blocks conversion of T4 to T3 and destroys any pre-existing T3. [6a]
The result is catastrophic, intracellular T3 starvation: T3 in the cells falls to zero because T4 is preferentially converted into nonfunctional “reverse T3” and pre-existing T3 is changed into T2. The serum T3 trends downward, since no T3 is ejected into the blood by the cells.
IH may be transient, if there is rapid elimination of the stressful factor. It may persist, as an ongoing response to a chronic condition, and it may self-perpetuate, because it contributes to and complicates stress, as with stress of psychological origin.
The important laboratory markers for IH are
– Low serum T3, because blood-borne T3 is made in the cells and exported to the blood, but conversion of T4 to T3 has stopped.
– Increased serum reverse T3, produced from the T4 which normally, would have been converted into T3.
– Reduction of the T3/rT3 ratio, to a value of less than 20: see Cameron Sutherland’s T3/rT3 ratio table, below.
– Normal T4 and TSH, because the thyroid gland is still making T4 and the pituitary gland is not affected by cortisol. An elevated serum cortisol also contributes to the diagnosis, but is of lesser diagnostic value, especially in chronic IH.
Sutherland’s table: “ratio of T3 (triiodothyronine) to rT3 (reverse T3)”
By permission from Cameron Sutherland:
T3 (picomoles/L) is in the light blue column.
T3 (nanograms/DL) occupies the yellow column.
Light blue horizontal numbers are reverse T3 values.
Normal T3/rT3 values are located in the pink area.
Subnormal T3/rT3 values are in the white area.
About the T3/rT3 table
T3 is represented vertically on the left, (picomoles/L in blue, nanograms/DL in yellow).
rT3 is shown in (horizontal) blue numbers on a yellow background.
Normal T3/rT3 ratios are on a pink background.
Low T3/rT3 ratio, diagnostic of IH, are on a white background.
About “Normal” rT3
The currently accepted normal range for rT3, “5 – 25 ng/DL”, is nonsensical:
(1) With a reverse T3 level of 21, IH will exist if the T3 is less than 6.4 Pm/L, which is in the hyperthyroid range: the accepted normal range for T3, 3.2 – 6.2, was adjusted to 2.8 – 5.8, in 2021.
(2) Therefore a serum rT3 level of >20, without a FT3 level, is sufficient to diagnose IH.
(3) There is no need to consider “normal” for rT3, since it is nonfunctional.
(4) There is a need for an approximate “desirable” rT3, which in my opinion should be 5 – 13, and a “desirable” level for T3, which should be 4 – 6.0 because an rT3 of <13 ng/DL indicates the absence of IH if the FT3 is 4.0 or more (check this, on the T3/rT3 table).
Caveat (1) The currently accepted normal levels for TSH, T4, T3 and rT3 are all suspect: [6b, 6c,]
– The TSH range should be 2.5 – 4.0. [6d]
– The T4 range, 12–30 pmol/L or 0.9 – 2.3 ng/DL, is too wide, but does not present a normal range of serum free T3 diagnostic difficulty.
– The low limit of the T3 range, originally 3.2 pmol/L, has been revised to 2.8 pmol/L in Canada and according to Google, 2.0 pmol/L in the USA.
Caveat (2) See Sutherland’s table:
When T3 is 3.2, the T3/rT3 ratio falls below 20 if rT3 >10 ng/DL and If FT3 = 2.0 and rT3 = 7, then T3/rT 3 = 18.55! The rT3 range, 5-25, is also unreasonable: if T3 is 2.8, IH exists if rT3 exceeds 10. Further, if T3 is 5.8, rT3 must not exceed 18. Therefore if we accept that “normal T3” = 3.2 – 6.2, “acceptable rT3” should be 5 – 13.
Differences between the two Long Covid patient groups, in Dr. Zou’s article
The patients were assigned to two groups according to serum FT3 values: an ESS group, whose FT3 was (arbitrarily) below 2.3 pg/ml and a non-ESS group, whose FT3 was greater.
The patients with ESS had stronger inflammatory responses (higher CRP, ESR and Procalcitonin), but lower lymphocyte counts, than those without ESS.
They had more fever, fatigue, shortness of breath, cough, expectoration, and anorexia.
They had similar TSH, with significantly lower T4 and FT4, as compared with non-IH patients, but T4 and FT4 parameters are not significant, when considering IH.
Caveat
Cortisol and rT3 levels had not been done during hospitalization, so the diagnosis of ESS was not absolute; but a serum FT3 of <2.3 Pg/ml, supports a logical, presumptive diagnosis of hypothyroidism.
Why is this report important?
(1) The authors proved that over 25% of their Long Covid patients had Intracellular Hypothyroidism and it is reasonable to apply at least that percentage to our patients.
(2) IH is a complication in all severe illness, so IH after Covid infection is not surprising.
(3) By applying a “cutoff” of T3 = <3.5 pmol/L, instead of the (admittedly arbitrary) <4.0 which I think is reasonable, to diagnose ESS, Zou et al. underestimated the prevalence of IH in the group.
If they had used 4.0 as the lower limit of normal for T3, and if the T3/rT3 ratio had been available, the percentage of patients diagnosed with IH would have been much higher.*
(4) IH responds well to oral T3, titrated to serum T3 of 5.0 – 6.2 [6]: therefore successful therapy with oral T3 is likely.
*A diagnosis of IH is confirmed when the T3/rT3 ratio is <20: in 7 years of metabolic medicine practice, a T3/rT3 ratio less than 20.0 was often found even when FT3 was as high as 3.9 or 4.0 Pm/L, because reverse T3 >19 is a fairly frequent finding (unpublished data).
The “workup”, for persons who have “long Covid” symptoms
Following routine history and physical examination, the following tests should be done:
Complete blood count and major-organ tests (renal, hepatic, cardiovascular etc.),
DHEA, free testosterone, estradiol, estrone, progesterone,
HS CRP, ESR, Homocysteine,
TSH, FT3, FT4 and reverse T3, for calculation of the T3/rT 3 ratio,
Thyroid Antibodies,
Vitamin D,
Other tests, specific to the presumptive diagnosis, as necessary.
Management of IH
IH should be diagnosed, assessed and treated by a healthcare professional trained in metabolic medicine, [8], [9] but a family physician with a full understanding of IH is perfectly competent.
Since T4 is being preferentially converted to rT3, T4 Therapy massively increases serum reverse T3, without changing intracellular T3. The correct therapy is oral T3, titrated upwards based on weekly testing, to a nominal therapeutic “target” serum FT3 of between 5.0 and 6.2 pm/L.
Desiccated thyroid (DT) is an attractive prescription and is effective sometimes: its T3 (30%) tends to improve the symptoms of intracellular hypothyroidism; but its T4 (70%) will be converted to rT3: one of my first few patients, who presented with an rT3 of 34 ng/DL and whom I treated with DT, had a reverse T3 of 54 ng/DL, after 2 weeks of treatment with DT 30 mg daily.
Slow-release capsules of T3 work rapidly and well: quick release tablets are prone to side-effects.
Treatment is started with a low dose, usually 5 µg daily, but occasionally 1-2 µg, daily: FT3 is monitored weekly and the dose is titrated upward until serum FT3 is 5.0 – 6.2 pm/L. [9]
Side effects are explained carefully, to the patient and the closest caregiver and at the first sign of side effects, the dose of T3 is reduced by 5 µg/day.
I encountered no significant adverse effects, during seven years practice in managing IH.
Therapy should also be directed towards correction, or elimination, of any associated disease and of the stressors responsible for increased cortisol secretion.
Caveats:
The above observations and opinions are based on my practice of BIHRT and management of intracellular hypothyroidism, from 2014 to 2020, but I discontinued practice in the early days of the Covid pandemic and had no cases of “Long Covid”.
Therefore the opinions above, while accurate in terms of the management of IH and presumably applicable to the management of Long Covid, do not reflect actual experience with the management of that condition.
IH occurring as an accompaniment to severe, brief acute illness or trauma, tends to settle and disappear with treatment of and recovery from the underlying condition.
However even in brief illness, immediate correction of IH will assist in the patient’s recovery; an FT3 test can be done quickly, to will justify a T3 prescription, pending rT3 results.
An FT3 result of <3.2 indicates probable IH, to be diagnosed if rT3 is >10. Therefore instead of awaiting the reverse T3 result, which is often delayed, oral T3 therapy should be started immediately and titrated to increase the serum FT3 to 5.0.
IH resulting from chronic stress will only subside with T3 therapy, or if the stressor is eliminated. Further, IH tends to self-perpetuate, due to psychological stress/cortisol release caused by the anxiety, inconfidence, confusion and depression which chronic, deep intracellular hypothyroidism produces.
The triiodothyronine prescription should be combined with therapy for the underlying condition and with support of other hormones, vitamins and minerals, following a full metabolic “workup”.
Diagnosis should be confirmed, and IH therapy supervised, by a physician trained in metabolic medicine, [7] defined by Dr. R. Klatz and Dr. R. Goldman, in 1992. [8] However management of the underlying condition should be at the discretion of the “MRP” (most responsible physician).
Online advice
A study of online information reveals many different attitudes to ESS (IH).
For example, an article saying that ESS is a self-correcting biochemical anomaly, occurring naturally in ICU cases, which does not require treatment [10] is to my mind, superficial.
Again, any article which does not mention, or discounts, rT3 cannot be applicable to a consideration of IH.
The idea that ESS (IH) will correct itself [10] may seem reasonable when IH results from transient illness. However, to apply a “hands-off” approach to the management IH associated with chronic conditions, is to sentence the patient to ongoing symptoms. This at best, would be an un-empathetic approach to a truly debilitating problem: at worst, the patient may progress to myxedema.
REFERENCES
[1] Long Covid: a report from China, by G. A. Harry, in CBHRT.ca,
https://cbhrt.ca/2021/08/17/long-covid-a-report-from-china/
[2] Euthyroid Sick Syndrome in Patients With COVID-19, Runmei Zou1†, Chenfang Wu2†, Siye Zhang2, Guyi Wang2, Quan Zhang3, Bo Yu2, Ying Wu2, Haiyun Dong2, Guobao Wu2, Shangjie Wu4 and Yanjun Zhong2*Front. Endocrinol., 07 October 2020, Sec. Thyroid Endocrinology, Volume 11 – 2020 | https://doi.org/10.3389/fendo.2020.566439 https://www.frontiersin.org/articles/10.3389/fendo.2020.566439/full
The original paper was published online, by Front Endocrinol (Lausanne), 2020 Oct 7;11:566439.
DOI: 10.3389/fendo.2020.566439.
I accessed it via https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575767/ DOI: 10.3389/fendo.2020.566439. PMCID: PMC7575767PMID: 33117282.
[3] “Long COVID: pathophysiological factors and abnormalities of coagulation” by Simone Turner, M Asad Khan, David Putrino, Ashley Woodcock, Douglas B Kell and Etheresia Pretorius, in “trends in Endocrinology and metabolism”, 4/19/23, at https://www.sciencedirect.com/science/article/pii/S1043276023000553#bb0040
[4] “Aspirin in COVID-19: Pros and Cons” by Rana Zareef1†, Marwa Diab1†, Tala Al Saleh2†, Adham Makarem2, Nour K. Younis3, Fadi Bitar1,2,4 and Mariam Arabi1,2,4* , in Front. Pharmacol., 10 March 2022, Sec. Pharmacology of Infectious Diseases, Volume 13 – 2022, https://doi.org/10.3389/fphar.2022.849628 https://www.frontiersin.org/articles/10.3389/fphar.2022.849628/full
[5] Euthyroid Sick Syndrome, by Serhat Aytug, MD Medscape, Updated: Oct 06, 2022 https://emedicine.medscape.com/article/118651-overview
[6] IH (intracellular hypothyroidism), by G. A. Harry, in cbhrt.ca,
https://cbhrt.ca/2023/04/27/intracellular-hypothyroidism-ih/
[6a] stress causes hypothyroidism, by G. A. Harry, in cbhrt.ca,
https://cbhrt.ca/2022/12/14/stress-causes-hypothyroidism/
[6b]Thyroid tests: should our thyroid hormonal assessment be reviewed?, by G. A. Harry, in cbhrt.ca,https://cbhrt.ca/2021/11/05/thyroid-tests/
[6c] Think about normal, by G. A. Harry, in cbhrt.ca,
https://cbhrt.ca/2021/10/23/thinking-about-normal/
[6d] 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/
[7] Specialty spotlight – metabolic medicine, Royal College of physicians, London, UK, https://www.rcplondon.ac.uk/education-practice/advice/specialty-spotlight-metabolic-medicine,
[8] A4 M/MMI, https://www.a4m.com/about-a4m-mmi.html
[9] T3 and intracellular hypothyroidism, by G. A. Harry, in CBHRT.ca,
https://www.researchgate.net/publication/370772568_INTRACELLULAR_HYPOTHYROIDISM
[10] Euthyroid Sick Syndrome, Kavitha Ganesan, Catherine Anastasopoulou, Khurram Wadud, In “Stat Pearls”, NIH,
https://www.ncbi.nlm.nih.gov/books/NBK482219/
