42 Matching Annotations
  1. May 2022
    1. DICER1 syndrome is a rare genetic condition predisposing to hereditary cancer and caused by variants in the DICER1

      GeneName: DICER1 PMCID: PMC7859642 HGNCID: Unavailable Inheritance Pattern: Autosomal dominant. Disease Entity: Familial pleuropulmonary blastoma (PPB), cervix embryonal rhabdomyosarcoma, multinodular goiter, nasal chondromesenchymal hemartoma, Ciliary body medulloepithelioma, Sertoli-Leydig Cell Tumor (SLCT), differentiated thyroid carcinoma, pituitary blastoma, pineoblastoma, cystic nephroma, Wilm's tumor and sarcomas of different sites including, amongst others, the uterine cervix, kidney and brain. Mutation: Germline Zygosity: Heterozygose Variant: No ClinVarID present. Family Information: No family outline Case: No specified information of patients included. CasePresentingHPO's: n/a CasePrevious Testing: n/a gnomAD: n/a Mutation Type: nonsense, frameshift, or splice affected.

  2. Apr 2022
    1. DICER1 syndrome is a rare genetic condition predisposing to hereditary cancer and caused by variants in the DICER1 gene.

      Gene Name: DICER1 PMID:33552988 HGNCID: Unavailable Inheritance Pattern:Autosomal Dominant Disease Entity: familial pleuropulmonary blastoma (PPB),cystic nephroma, ovarian Sertoli-Leydig cell tumor (SLCT), multinodular goiter, cervix embryonal rhabdomyosarcoma, Wilms’ tumor, nasal chondromesenchymal hamartoma, ciliary body medulloepithelioma, differentiated thyroid carcinoma, pituitary blastoma, pineoblastoma, and sarcomas of different sites. Mutation: Nonsense, Frameshift<br /> Zygosity: Heterosygosity Variant:No ClinVar ID present Family Information:no diseases mentioned in family Case: no specified case in this article gnomAD: n/a Mutation type: Nonsense. frameshift

    1. DICER1 Syndrome

      GeneName: DICER1 PMID: 28323992 PMCID: PMC5443331 *No HGNCID found Inheritance pattern: autosomal-dominant Disease Entity: multinodular goiter and thyroid cancer Mutation: Germline Zygosity: not listed Variant: c.3726C>A; p.Tyr1242a, c.3675C>G; p.Tyr1225a Family Information: 145 individuals with DICER1 germline mutations from 48 family controls (135 individuals) that lacked the DICER1 mutation Case: male and female carriers as well as family members were studied. Ages: 20, 30, and 40 for both populations (DICER1 carriers were significantly younger than controls}. Population from Great Britain, UK, and USA (no significant difference between race, ethnicity, or sex found). CasePresentingHPOs: no previous therapeutic radiation or chemotherapy. Thyroid cancer or MNG diagnoses were likely reported with the DICER1 mutation CasePreviousTesting: Sequencing performed with Sanger or next-generation sequencing assays. DICER1 carriers underwent testing to obtain thyroid-stimulating hormone, thyroxine, thyroxine-binding globulin, and serum albumin levels as well as medical history and physical examinations (+thyroid palpation). Participants were also given thyroid US examinations. gnomAD: n/a Mutation Type: missense

    1. Individuals who harbor germline pathogenic variants in DICER1 (MIM #601200) have an increased risk for a variety of benign and malignant tumors.


  3. Aug 2021
    1. No significant differences were found for HRV in SCHypo. No association was found between HRV and SCHyper or SCHypo compared to euthyroid subjects in this sample of apparently healthy subjects.

      This confirms that thyroid function probably lacks any (direct) effect sleep. Of course, not this evidence alone, but rather this combined with "Effects of Supraphysiological Doses of Levothyroxine on Sleep in Healthy Subjects: A Prospective Polysomnography Study"

  4. Apr 2021
    1. In seven out of the eleven subjects in whom core body temperature could be sampled, the nadir of body temperature was advanced during L-T4 intake by 15 minutes to 270 minutes.

      This supports my speculation from another study, found here.

  5. Apr 2020
    1. RESULTS: The rate of discontinuation due to side effects was significantly higher in the control group than for the patients (38% versus 0%). The severity of the side effects in the controls increased significantly during treatment with T(4). The side effect scores of the patients were higher than those of the controls prior to T(4) treatment, but did not change significantly during the treatment period. Although the serum concentrations of thyroid hormones rose significantly in both groups, concentrations of fT(3) and fT(4) were significantly higher in the controls.CONCLUSIONS: Healthy controls and depressed patients respond significantly differently to supraphysiological T(4). Healthy controls experience higher elevations of thyroid hormones in response to supraphysiological T(4), thus inducing significantly more side effects and discontinuation.LIMITATIONS: Open-label study; groups were studied at different times; in contrast to healthy controls, depressed patients were also taking antidepressants.

      Brilliant study. Astonishingly, ~500 mcg thyroxine only increased FT3 about 20% in depressed patients. In controls, it nearly doubled FT3 (about 80# increase), Thyroxine doubled total T4 and total T3 in both depressed and controls. That lines up with the FT3 rise in controls, but is still much lower than I'd expect from this dose.

      Note that the depressed patients had equal thyroid symptoms before taking thyroxine, so experienced no increase. The pre-treatment depressed patients, treated depressed patients, and treated controls all had an equal number of thyroid symptoms. Thus, only the pre-treatment healthy patients lacked hyperthyroid symptoms. This is interesting because the treatment was 500 mcg thyroxine (average 484 mcg), which you'd expect to cause more symptoms.

      This could mean either that the depressed patients had as many symptoms alleviated as they had caused by thyroxine, or that depressed patients simply had lower thyroidergic activity. The latter is supported by the fact that free T3 and free T4 rose 2 or 3 times less in treated depressed patients compared to treated controls (from full text).

      It's also possible that the pre-existence of symptoms masked their appearance (in which case increased severity might be expected). I doubt that this is the case. A few symptoms trended toward improvement.

    1. REE decreased approximately 15% when TSH increased between 0.1 and 10 mU/L.

      The individual change in REE to a given change in dose varied radically. The dose change was only 50 mcg, which seemed to change TSH about half what they've calculated for 15% REE change. That is to say, it looks like a 50 mcg dose reduction will only raise TSH from 1.0 to 5.0, not to 10.0. This is my personal guesstimate, and will need to be properly calculated from other studies. My point is merely that 50 mcg will not cause the full 15% REE increase. Additionally, the response to 50 mcg may depend on initial TSH.

      It looks like TSH changes that remained hyperthyroid (i.e. bellow 1.0) had little effect on REE. This might be because the body is maintaining thyroid status, or that REE is more like an on/off switch. However, this only covers relatively small changes in thyroxine dose.

      It is unclear how supraphysiological doses effect REE. It seems likely that the ten times greater dose (500 mcg) used for depression would significantly increase REE.

    1. Thyroxine treatment significantly lengthened TPX animals' cycles (average increase: 0.28 h) but did not affect intact rats' circadian rhythms.

      This suggests that hypothyroidism shortens the circadian cycle, while hyperthyroidism does nothing. This is disappointing, and also counter to what I expected. However, it could still be consistent with my expectations if these effects are behaviorally mediated. That is to say, it could be greater stimulation that keeps them awake longer (which in turn effects the body clock). If that is the case, the alertness/dullness effects could be countered by depressants/stimulants, which would reveal the direct circadian impact.

      Additionally, I'd like to know if T3 doses at wake time could provide any entrainment (or at night time). The half life of T3 is short enough that reveal phase effects. T4 only demonstrates net effects; like getting light exposure all day long, T4 may both delay and advance circadian phase.

      Also note that all conditions have a distinct rightward tilt when graphed. That is to say, they have a body clock longer than 24 hours. It's quite plausible that the thyroid hormone could interact with zeitgebers.

  6. Mar 2020
    1. l-thyroxine was added in the dose of 100 microm daily for 4 weeks.

      This is the same dosage that another study found to be indiscernible from placebo. I suspect a couple things are at play.

      The first is that these are treatment-resistant patients, meaning that we already know they are not susceptible to placebo; given that we are effectively comparing combination therapy to SSRIs alone, this means that the SSRI only stage is not experiencing placebo, thus making the therapeutic effect visible by comparison (retrospective comparison, given that there is no control group).

      The second is that this is combination therapy. It seems likely that thyroxine is more effective when combined with SSRIs.

      Note that this study uses much lower doses than similar studies I've seen, yet had similar results in terms of efficacy rate (roughly 50% responders). I'm not currently certain how the magnitude of effects compares with those studies. Namely, comparing with Pfeiffer et al (350 mcg), Rudas et al (235 mcg) and Bauer et al (482 mcg), and also Bauer et al from 2016 (300 mcg)

    1. The addition of supraphysiologic doses of L-T4 (300 mcg per day) to an otherwise stable medication regimen of standard treatments resulted in a significant decline in depression scores during the 6-week, double-blind treatment phase. At endpoint (week 6), the mean HamD score showed a group difference of 3.7 points in favor of L-T4. Such difference is generally considered to be clinically meaningful in a short-term treatment trial for major depression. NICE used a 3.0-point difference in HamD change scores as a criterion of clinical significance.27

      This is consistent with the open label data. The dose is also similar. Combining this placebo-controlled trial with the three open-label supraphysiological thyroxine studies that I've seen, that is sufficient for me to conclude efficacy. Namely, combining with Pfeiffer et al (350 mcg), Rudas et al (235 mcg) and Bauer et al (482 mcg)

      I would like to see if this study mentions nonresponders. Those three other studies found roughly a 50% response rate. Thus, the effect size in responders may be twice as significant.

    1. CONCLUSION: A 1.5- and 1.3-μg/kg dosage calculation based on actual weight is currently the best estimation for levothyroxine replacement therapy after thyroidectomy.

      1.5 mcg/kg comes to 102 mcg per 150 pounds. That's lower than I'd expected.

    1. L-thyroxine at an average dose of 350 micro g/die. Outcomes were moderate in 39.3% and very good in 21.5%, corresponding to 21-item HAMD scores of < or =16 and < or =8 and clinical judgement. Of all patients, 39.3% had to stop treatment due to nonresponse or side effects.

      This is another study consistent with the 50% remission figure. The dose is also similar: between 235 mcg (Rudas et al) and 482 mcg (Bauer et al).

    1. Fig. 2.

      These make good reference figures. Given that normal T3 values are around 100 ng/dL, Graves' patients had 2 to 7 times normal levels. This is good because it means the symptoms associated with hyperthyroidism may be only on the upper end. Supraphysiological therapeutic doses of T4 (500 mcg) are only 3 or so times the full replacement dose.

      T3 values in painless thyroiditis were only 1 to 3 times normal, except for 1 outlier. Thus, I would predict few symptoms in painless thyroiditis.Or, perhaps, symptoms only in few patients.

  7. Feb 2020
    1. Figure 1c. Temperature before and after T3 administration (T3 given at time 0 hours)

      It appears that the liothyronine could have advanced the phase of circadian temperature. However, since the study had no controls, it is impossible to confirm this hypothesis.

    2. Half-life22.04 hours

      It appears they are calculating based on total T3 rather than added T3. Assuming that the conversion of T4 to T3 remains constant, the half life of the liothyronine dose towards baseline is less than 10 hours (I'd estimate 5-7 hours). Given that this is short compared to other studies, it is likely that the conversion was slowed by the high thyroid status.

    1. At the end of the study neither group was able to identify accurately which treatment period was thyroxine or placebo (table ​(table4).4).

      Fascinating. At 100 mcg, I'd expect one to be able to tell the difference. This is especially surprising given the two groups. Namely, the symptomatic group and the healthy control group. I'd expect at least one group to be able to tell the difference. However, it's worth noting that the TSH between the two groups were virtually identical. The groups were selected based on hypothyroid symptoms rather than actual thyroid status.

      The fact that healthy controls could not tell the difference is odd. It is both not what I expected and cuts against what the related lesswrong article says about discernibility to healthy subjects (odd given that lesswrong mentions this specific study). What may be happening is that the question was not specific enough. If subjects interpreted reduced vitality as a sign that they were not receiving thyroxine, then many might get is wrong. I wish they has a more thorough questionnaire on perception of drug effects. Even an informal "describe the experience" question would be nice.

      All in all, I find it unlikely that this is accurate. There are at least two possibilities. It could indicate that the dose was not high enough, in which case the study is not testing what it thinks it's testing. That is supported the the fact that the TSH of the thyroxine group is barely out of the normal range. The other option, as mentioned above, is that they are not asking the right questions. If that is the case, that also seems to invalidate the findings.

      In conclusion, this result means that we can't trust the study. I'm certain higher doses would be discernable from placebo to subjects. It is likely that it was discernible at this dose (100 mcg) if the right questions were asked. I'm thankful they included this outcome.

      P.S. I found this study completely by accident, then found out it was related to that lesswrong article that I've always appreciated.

    2. Healthy participants had significantly lower scores for vitality when taking thyroxine compared to placebo

      This is very interesting to note. This is some of the most direct evidence that hyperthyroidism shares some symptoms with hypothyroidism. I'd still like to know if liothyronine (T3) would show the same results. I suspect T3 would be better, especially given that it may be less likely to disturb sleep (because of the half life).

    1. Surprisingly, treatment with supraphysiological doses of L-T4 did not cause significant effects on sleep architecture. However, the increase in body movements and REM density was close to reaching statistical significance.

      This is just as I expected, though I'd also be unsupervised by opposite findings. I'm yet to find why symptoms such as insomnia are so often cited for hyperthyroidism. I see a few possibilities. One is that it's very slow onset effect that takes more than 2 months to develop (personally, this seems unlikely). Another is that it only effects people with preexisting anxiety or hyper-arousal (strikes me as a likely partial explanation). A third is that it only effects people with the most extreme hyperthyroidism (also strikes me as partial explanation). Finally, it's possible that the entire thing is a myth. Authors of another study from 2011 noted that "[sleep] is being characterized as poor without further elaboration." I think it may be the case that people are just assuming patient's sleep issues are caused thyrotoxicosis because it seems like it would, when in fact only a small fraction actually are. Perhaps thyrotoxicosis even turns depressive insomnia into anxious insomnia, thereby confusing physicians.

      The next question is whether treating light to moderate hyperthyroidism would resolve insomnia. This would answer some of the above possibilities. However, I'm uninterested in severe hyperthyroidism because it is above the maximum treatment dose I commonly see, namely 500 mcg thyroxine.

    1. At the time of assessment, patients had been treated with supraphysiological T4 (mean dose 368 microg/d) for a mean of 54 months. The total subjective response score was +25.2.

      25.2 out of 33 is quite high (i.e. very positive results). In fact, those results seem too good to be true, and are likely due to the limitations of the study. In particular, by 54 months of treatment the non-responders or those with side effects would have already stopped taking thyroxine. Nonetheless, the data is consistent with other studies indicating that supraphysiological doses of levothyroxine has few and mild side effects (regardless of the sample population).

  8. Jan 2020
    1. RESULTS: Two patients dropped out of the study owing to side effects. The remaining 7 patients received a final mean dose of T4 of 235 +/- 58 micrograms/day (range: 150-300 micrograms/day). Their scores on the Hamilton Depression Rating Scale had fallen from a mean of 21.1 +/- 4.1 before inclusion in the study to a mean of 8.0 +/- 2.8 at the end of the 8th week. Five patients were full responders, 1 a partial responder, and 1 a nonresponder.CONCLUSIONS: Augmentation with high-dose T4 proved to have an antidepressant effect in more than 50% of the previously treatment-resistant patients with chronic depression and/or dysthymia.

      Thyroxine working in about 50% of patients was also found in Bauer et al. This dose was not quite as high as Bauer, but 235 mcg is still above a full replacement dose.

      I'd like to see results on minor depression. However, such studies are unlikely.

    1. 0.01 (0.006–0.028)

      It appears that even mild thyroid elevation radically cuts TSH. Makes sense.

    2. 15.72 ± 10.1

      Graves disease has a average free T3 at least 3 times the upper normal range. This implies that there is only a little bit of wiggle room between high thyroid status and thyrotoxicosis. However, free T4 is at about twice as high as upper normal, so the total thyroid activity may be closer to 3.5 or 4 times the upper normal (assuming that T4 is roughly 10 times less potent than T3)

    1. Fig. 2

      Most thyroiditis patients had total T3 in the upper reference range. Free T4, on the other hand, was nearly all above reference range. Graves' disease had half somewhat elevated and half extremely elevated levels for bot total T3 and free T4. I now just need data on free T3 (which in my recollection would be expected to scale tightly with total T3, so I may be able to predict the values).

    1. In an observational study of 14 patients, no subjects developed any cardiac or skeletal disease after receiving doses from 25- to 150mcg over a two-year period.41

      Note that the high dose was because they were increasing the dose based on symptoms. That is to say, as the thyroid gland produced less thyroid hormone, they increased liothyronine dose to compensate.

    1. RESULTS: In the hypothyroid state, the plasma volume measured by dilution of 125I-albumin (APV) was higher than the calculated plasma volume (CPV) from packed red cell mass, suggesting an extravascular escape of albumin. After substitutive therapy, the CPV showed a statistical increase (P < 0.05), whereas APV remained unchanged. Both ERPF and GFR increased after thyroxine therapy (p < 0.05). In the subclinical group, blood volumes and renal function were similar to those found in the other group of patients when in the euthyroid state.

      If this holds true, I'd expect rapid blood volume expansion from thyroid hormone. I'm also interested in whether thyroid hormone stimulates the production of albumin, given its anabolic properties.

    1. Because it is desirable to suppress TSH to less than normal levels in patients with TSH-dependent thyroid neoplasms, and because many patients tolerate 0.3 mg/day of levothyroxine sodium without clinical evidence of hyperthyroidism, it seems prudent to treat patients with thyroid cancer with higher replacement doses of thyroid hormone than is necessary for the treatment of hypothyroidism.3

      300 mcg is on the high side. Nevertheless, lack of hyperthyroid symptoms is not surprising. The highest dose administered in the Skinner study was 275 mcg, but that was merely for the elimination of hypothyroid symptoms.

      It seems like doses would need to be quite high in order to become symptomatic. The only counterevidence I'm aware of so far is anecdotes I've read online. Thus, it appears that high doses are well tolerated.

    1. Thyrotoxicosis creates a hyperdynamic circulatory state because of a marked fall in peripheral vascular resistance and associated increase in venous return, increased total blood volume, increased cardiac contractility and heart rate.

      If the mechanism is really the same as alpha blockers, then the blood volume expansion may be expected to be similar in constitution. However, I would expect more red blood cells in thyroid mediated volume expansion compared to alpha blockers. The reason, obviously, is because of the increased oxygen demand from thyroid hormone.

    1. The authors demonstrated an inverse correlation between TSH and REE with a change of 15% for a TSH ranging from 0.1 to 10 μIU/mL. Of interest, free T4 remained within the normal range in all of the study volunteers. Nonetheless, the changes in REE with different LT4 doses were demonstrated in every patient [46].

      Thus, a 15% expected increase would be reasonable for a euthyroid subject such as myself. However, since T3 reduces weight compared to T4, it is possible the weight loss indicates greater energy expenditure.

    1. In almost all cases the genetic basis of RTH lies in mutation of the carboxyl-terminus of the ß-thyroid hormone receptor. RTH is a dominant disorder, except in one family; most individuals are heterozygous for the mutant allele.

      So, given that thyroid hormone resistance does exist, the remaining question is whether it is common enough to explain some cases of CFS or similar conditions. Unfortunately this paper is not in english, but the abstract provides enough information to google more.

    1. altered thyroid gland function affects vasopressin and oxytocin release from the hypothalamo-neurohypophysial system in the state of equilibrated water metabolism

      I ought read the full study to see the proposed mechanism. The vasopressin effect is not surprising at all, but the oxytocin effect was unexpected for me. That may be because I know more about vasopressin than I do oxytocin.

    1. 0.19

      This is the only group with a TSH significantly below the reference range. The reason, of course, is that the patients with the most symptoms ended up getting the highest doses of thyroxine (T4) by the end of the study.

    1. At the final study visit, subjects were asked whether they thought their L-T4 doses at the end of the study were higher, lower, or unchanged from the start of the study and which of the two doses they preferred. Subjects were not able to accurately ascertain changes in L-T4 doses (P = 0.54)

      The study does not provide enough information to determine whether this is meaningful. It appears to be meaningless. If they had used a crossover design, then this might be useful.

    2. targeting one of three TSH ranges (0.34 to 2.50, 2.51 to 5.60, or 5.61 to 12.0 mU/L)

      Note that they did not have a mild hyperthyroidism group, whereas they did have a mild hypothyroidism group.

    1. The urticaria resolved upon treatment of the AITD. We also summarize the currently postulated pathophysiological links between the two diseases.

      Before reading the study, I'll state that my suspected mechanism is dry skin. Hyperthyroidism causes oily skin, while hypothyroidism causes dry skin. Thus, I'd expect hypothyroidism to have similar symptoms to using harsh detergents/soap and/or scrubbing too frequently or too hard.

  9. Dec 2019
    1. RESULTS: We observed that poor sleep quality was correlated to low total BMD and legs BMD in middle-aged women after adjusting for potential confounders. Furthermore, when we reran the regression models based on menopausal status in middle-aged women, significant associations between BMD and sleep quality were observed in premenopausal and early postmenopausal groups.

      This is exactly what I expected to find. This is why I doubt that there is significant risk to high dose T3 taken in the morning. In fact, given that hypothyroidism is also associated with increased fracture, I'm inclined to think that thyroid hormones per se play no role whatsoever, but rather the downstream effects. That is to say, hyperthyroidism disturbs sleep, thus harming bones. I conclude, then, that so long as sleep quality is maintained, hyperthyroidism is plausibly safe for the bones.

  10. Apr 2019
    1. “After trauma the world is experienced with a different nervous system. The survivor’s energy now becomes focused on suppressing inner chaos, at the expense of spontaneous involvement in their lives. These attempts to maintain control over unbearable physiological reactions can result in a whole range of physical symptoms, including fibromyalgia, chronic fatigue, and other autoimmune diseases. This explains why it is critical for trauma treatment to engage the entire organism, body, mind, and brain.”
  11. Mar 2019
    1. SBP, DBP, RR, and weight did not change following T3 administration

      Liothyronine does not raise blood pressure despite the rise in heart rate. The reason that respiratory rate (RR) was not changed may be because the increased cardiac output compensates for the increased oxygen demand.

    1. The peak T3 concentration after LT3 administration during week 6 was 292.8 ± 152.3 ng/dL, rising from a baseline value of 96.1 ± 7.6 ng/dL

      The T3 half-life, therefore, is only 14.25 hours (14 hours and 15 minutes). I calculated this based on taking the peak value and comparing it to the baseline value 22 hours later.

      Since they've been on the same dose during this study period, the baseline value is what's left from yesterday's peak, and can be assumed to be tomorrows trough. Since the drug took 2 hours to peak, there are 22 hours remaining to reach trough/baseline values.

  12. Aug 2018
    1. AbstractHigh dose thyroid hormone has been in use since the 1930s for the treatment of affective disorders. Despite numerous papers showing benefit, the lack of negative trials and its inclusion in multiple treatment guidelines, high dose thyroid has yet to find wide spread use. The major objection to the use of high dose thyroid is the myth that it causes osteoporosis. This paper reviews the literature surrounding the use of high dose thyroid, both in endocrinology and in psychiatry. High dose thyroid does not appear to be a significant risk factor for osteoporosis while other widely employed psychiatric medications do pose a risk. Psychiatrists are uniquely qualified to do the risk-benefit analyses of high dose thyroid for the treatment of the bipolar I, bipolar II and bipolar NOS. Other specialties do not have the requisite knowledge of the risks of alterative medications or of the mortality and morbidity of the bipolar disorders to do a full risk benefit analysis.

      This is all very interesting. It is also true that, in the treatment of depression, there is a relatively low dropout rate due to side effects from treatment with T3 (liothyronine).

      liothyronine (T3) augmentation in the treatment of depression

  13. Jun 2018
    1. Studies reported by Nicoloff and colleagues in 1972 calculated a half-life of T3 that varied with thyroid status (8). The mean half-life was 0.63 days in 7 hyperthyroid patients, 1.0 day in 8 euthyroid individuals, and 1.38 days in 9 hypothyroid patients.
  14. Apr 2018
    1. There was a boy who was born with congenital hypothyroidism and was raised on traditional T3 (Cytomel). He was never treated with a T4-containing medicine, and so essentially never had a molecule of T4 in his body. By age 26 he had developed normally with no problems.

      This is precisely the type of information I was looking for. Wikipedia implied T4 should be taken with long-term T3, but the reasoning was poorly explained. However, I'd like a more official source for this case report.

      This case would also express no rT3 (reverse-T3). Thus, it appears that neither T4 nor rT3 serve any vital functions.