På denne siden presenteres oversikt over forskningsrapporter som viser til behovet for behandlingsalternativer.

 

 

Acosta B, Bianco, A C (2010).New insights into thyroid hormone replacement therapyNew insights into thyroid hormone replacement therapy

Medicine Reports. 2010; 2: 34.

Abstract:

Physicians continue to report benefits from combined levothyroxine-triidothyronine therapy for some hypothyroid patients. Recently, a large prospective study reported that the benefit of the combined levothyroxine-triidothyronine therapy is associated with the Thr92Ala polymorphism in the type 2 deiodinase gene, which is present in about 15% of the general population. If confirmed, these findings indicate that personalized medicine is rapidly catching up with modern thyroidology.

 

 

Appelhof, B. C., Fliers, E., Wekking, E. M., Schene, A. H., Huyser, J., Tijssen, J. G., … & Wiersinga, W. M. (2005). Combined therapy with levothyroxine and liothyronine in two ratios, compared with levothyroxine monotherapy in primary hypothyroidism: a double-blind, randomized, controlled clinical trial. The Journal of Clinical Endocrinology & Metabolism, 90(5), 2666-2674.

Abstract: Patients preferred combined LT4/LT3 therapy to usual LT4 therapy, but changes in mood, fatigue, well-being, and neurocognitive functions could not satisfactorily explain why the primary outcome was in favor of LT4/LT3 combination therapy. Decrease in body weight was associated with satisfaction with study medication.

 

 

Dr. John C. Lowe, Thyroid Science 2009 Stability, Effectiveness, and Safety of Desiccated Thyroid vs Levothyroxine: A Rebuttal to the British Thyroid Association,

Forskningskritikk

Department of Endocrinology and Metabolism, Academic Medical Centre, University of Amsterdam, The Netherlands, 2001Thyroid Hormone Replacement Therapy

Utdrag: Third, recent animal experiments indicate that only the combination of T4 and T3 replacement, and not T4 alone, ensures euthyroidism in all tissues of thyroidectomized rats. It is indeed the experience of many physicians that there exists a small subset of hypothyroid patients who, despite biochemical euthyroidism, continue to complain of tiredness, lack of energy, discrete cognitive disorders and mood disturbances. As organs vary in the extent to T4 replacement dose by 12.5 µg T3. Confirmatory studies on this issue are urgently awaited. It could well be that a slow-release preparation containing both T4 and T3 might improve the quality of life, compared with T4 replacement alone, in some hypothyroid patients.

 

 

Baisier, W.V., Hertoghe, J., and Eeckhaut, W. (2001). Thyroid Insufficiency: Is Thyroxine the Only Valuable Drug? Journal of Nutritional and Environmental Medicine, 11:159-166, 2001.  

Results: A number of these patients were followed up during treatment with natural desiccated thyroid (NDT): 40 T4 treated patients and 278 untreated patients. Both groups responded equally favourably to NDT.

Conclusions: Combined T3 + T4 treatment seems to be more effective than treatment with T4 alone in hypothyroid patients.

 

 

Benevicius R, Kazanavicius G, Zalinkovicius R, Prange AJ (1999). Effects of thyroxine (T4) as compared with thyroxine (T4) plus triiodothyronine (T3) in patients with hypothyroidism. New England Journal of Medicine.1999; 340: 424-9.

Conclusions: In patients with hypothyroidism, partial substitution of triiodothyronine for thyroxine (medication) may improve mood and neuropsychological function; this finding suggests a specific effect of the triiodothyronine normally secreted by the thyroid gland.

Damiano Gullo,#* Adele Latina,# Francesco Frasca, Rosario Le Moli, Gabriella Pellegriti, and Riccardo Vigneri, PLOS one peer reviewed journal 2011 Levothyroxine Monotherapy Cannot Guarantee Euthyroidism in All Athyreotic Patients

Abstract

Context

Levothyroxine monotherapy is the treatment of choice for hypothyroid patients because peripheral T4 to T3 conversion is believed to account for the overall tissue requirement for thyroid hormones. However, there are indirect evidences that this may not be the case in all patients.

Objective

To evaluate in a large series of athyreotic patients whether levothyroxine monotherapy can normalize serum thyroid hormones and thyroid-pituitary feedback.

Conclusions

Athyreotic patients have a highly heterogeneous T3 production capacity from orally administered levothyroxine. More than 20% of these patients, despite normal TSH levels, do not maintain FT3 or FT4 values in the reference range, reflecting the inadequacy of peripheral deiodination to compensate for the absent T3 secretion. The long-term effects of chronic tissue exposure to abnormal T3/T4 ratio are unknown but a sensitive marker of target organ response to thyroid hormones (serum TSH) suggests that this condition causes an abnormal pituitary response. A more physiological treatment than levothyroxine monotherapy may be required in some hypothyroid patients.

 

 

Biondi, B., & Wartofsy, L. (2012). Combination Treatment with T4 and T3: Toward Personalized Replacement Therapy in Hypothyroidism?. The Journal of Clinical Endocrinology & Metabolism.

Conclusions: Further prospective randomized controlled studies are needed to clarify this important issue. Innovative formulations of the thyroid hormones will be required to mimic a more perfect thyroid hormone replacement therapy than is currently available.

Giorgio Iervasi, MD; Alessandro Pingitore, MD, PhD; Patrizia Landi, BSc; Mauro Raciti, BSc; Andrea Ripoli, PhD; Maria Scarlattini, BSc; Antonio L’Abbate, MD; Luigi Donato, MD

From C.N.R. Clinical Physiology Institute and Scuola Superiore di Studi Univeritari S. Anna (A.L.A.), Pisa, Italy .Low-T3 Syndrome: A Strong Prognostic Predictor of Death in Patients With Heart Disease American Heart Association, 2002.

Abstract

Background— Clinical and experimental data have suggested a potential negative impact of low-T3 state on the prognosis of cardiac diseases. The aim of the present prospective study was to assess the role of thyroid hormones in the prognosis of patient population with heart disease.

Methods and Results— A total of 573 consecutive cardiac patients underwent thyroid function profile evaluation. They were divided in two subgroups: group I, 173 patients with low T3, ie, with free T3 (fT3) <3.1 pmol/L, and group II, 400 patients with normal fT3 (≥3.1 pmol/L). We considered cumulative and cardiac death events. During the 1-year follow-up, there were 25 cumulative deaths in group I and 12 in group II (14.4% versus 3%, P<0.0001); cardiac deaths were 13 in group I and 6 in group II (7.5% versus 1.5%, P=0.0006). According to the Cox model, fT3 was the most important predictor of cumulative death (hazard ratio [HR] 3.582, P<0.0001), followed by dyslipidemia (HR 2.955, P=0.023), age (HR 1.051, P<0.005), and left ventricular ejection fraction (HR 1.037, P=0.006). At the logistic multivariate analysis, fT3 was the highest independent predictor of death (HR 0.395, P=0.003). A prevalence of low fT3 levels was found in patients with NYHA class III-IV illness compared with patients with NYHA class I-II (χ2 5.65, P=0.019).

Conclusions— Low-T3 syndrome is a strong predictor of death in cardiac patients and might be directly implicated in the poor prognosis of cardiac patients.

 

 

Alessandro Pingitore, Elena Galli, Andrea Barison, Annalisa Iervasi, Maria Scarlattini, Daniele Nucci, Antonio L’Abbate, Rita Mariotti, and Giorgio Iervasi Acute Effects of Triiodothyronine (T3) Replacement Therapy in Patients with Chronic Heart Failure and Low-T3 Syndrome: A Randomized, Placebo-Controlled Study

Received: October 02, 2007

Accepted: December 26, 2007

Published Online: July 02, 2013

Abstract

Context: Low-T3 syndrome is a predictor of poor outcome in patients with cardiac dysfunction. The study aimed to assess the short-term effects of synthetic l-T3 replacement therapy in patients with low-T3 syndrome and ischemic or nonischemic dilated cardiomyopathy (DC).

Conclusions: In DC patients, short-term synthetic l-T3 replacement therapy significantly improved neuroendocrine profile and ventricular performance. These data encourage further controlled trials with more patients and longer periods of synthetic l-T3 administration.

 

 

Celi, F. S., Zemskova, M., Linderman, J. D., Smith, S., Drinkard, B., Sachdev, V., … & Pucino, F. (2011). Metabolic effects of liothyronine therapy in hypothyroidism: a randomized, double-blind, crossover trial of liothyronine versus levothyroxine. The Journal of Clinical Endocrinology & Metabolism,96(11), 3466-3474.

 Results:   Liothyronine (l-T3) resulted in significant weight loss [l-T4, 70.6 ± 12.5, vs. l-T3, 68.5 ± 11.9 kg (P = 0.009)] and in a 10.9 ± 10.0% decrease in total cholesterol (P = 0.002), 13.3 ± 12.1% decrease in low-density lipoprotein-cholesterol (P = 0.002), and an 18.3 ± 28.6% decrease in apolipoprotein B (P = 0.018).  Conclusions:  The substitution of l-T3 for Levothyroxine (l-T4) at equivalent doses (relative to the pituitary) reduced body weight and resulted in greater thyroid hormone action on the lipid metabolism, without detected differences in cardiovascular function or insulin sensitivity.

 

 

Chakera, A.J., Pearce, S.H., Vaidya, B. (2012) Treatment for primary hypothyroidism: current approaches and future possibilities. Drug Des Devel Ther.; 6: 1-11.

Conclusion: Primary hypothyroidism is the most common endocrine disease. Although the diagnosis and treatment of hypothyroidism is often considered simple, there are large numbers of people with this condition who are suboptimally treated. Even in those people with hypothyroidism who are biochemically euthyroid on levothyroxine replacement there is a significant proportion who report poorer quality of life. This review explores the historical and current treatment options for hypothyroidism, reasons for and potential solutions to suboptimal treatment, and future possibilities in the treatment of hypothyroidism.

 

 

Chernow B, Burman KD, Johnson DL, McGuire RA, O’Brian JT, Wartofsky L, Georges LP (1983). T3 may be a better agent than T4 in the critically ill hypothyroid patient: evaluation of transport across the blood-brain barrier in a primate model. Critical Care Medicine. 1983 Feb;11(2):99-104.

Conclusions: These data suggest: (a) T4, T3, and reverse T3 are all capable of bidirectional transfer across the blood brain barrier, (b) T3 may be a better agent than T4 in treating patients with myxedema coma because T3 crosses more rapidly and more completely from serum to cerebrospinal fluid (CSF).

 

 

Cooper-Kazaz, R., Apter, J. T., Cohen, R., Karagichev, L., Muhammed-Moussa, S., Grupper, D., … & Lerer, B. (2007). Combined treatment with sertraline and liothyronine in major depression: a randomized, double-blind, placebo-controlled trial. Archives of general psychiatry, 64(6), 679-68

Conclusions:  These results demonstrate enhancement of the antidepressant effect of sertraline by concurrent treatment with liothyronine without a significant increase in adverse effects. The antidepressant effect of liothyronine may be directly linked to thyroid function.

 

 

The Journal of Clinical Investigation 2015

Joao Pedro Werneck de Castro1,2, Tatiana L. Fonseca1,2, Cintia B. Ueta1, Elizabeth A. McAninch1,2, Sherine Abdalla1, Gabor Wittmann3, Ronald M. Lechan3, Balazs Gereben4 and Antonio C. Bianco1,2 Differences in hypothalamic type 2 deiodinase ubiquitination explain localized sensitivity to thyroxine

Abstract: The current treatment for patients with hypothyroidism is levothyroxine (L-T4) along with normalization of serum thyroid-stimulating hormone (TSH). However, normalization of serum TSH with L-T4 monotherapy results in relatively low serum 3,5,3′-triiodothyronine (T3) and high serum thyroxine/T3 (T4/T3) ratio. In the hypothalamus-pituitary dyad as well as the rest of the brain, the majority of T3 present is generated locally by T4 deiodination via the type 2 deiodinase (D2); this pathway is self-limited by ubiquitination of D2 by the ubiquitin ligase WSB-1. Here, we determined that tissue-specific differences in D2 ubiquitination account for the high T4/T3 serum ratio in adult thyroidectomized (Tx) rats chronically implanted with subcutaneous L-T4 pellets. While L-T4 administration decreased whole-body D2-dependent T4 conversion to T3, D2 activity in the hypothalamus was only minimally affected by L-T4. In vivo studies in mice harboring an astrocyte-specific Wsb1 deletion as well as in vitro analysis of D2 ubiquitination driven by different tissue extracts indicated that D2 ubiquitination in the hypothalamus is relatively less. As a result, in contrast to other D2-expressing tissues, the hypothalamus is wired to have increased sensitivity to T4. These studies reveal that tissue-specific differences in D2 ubiquitination are an inherent property of the TRH/TSH feedback mechanism and indicate that only constant delivery of L-T4 and L-T3 fully normalizes T3-dependent metabolic markers and gene expression profiles in Tx rats.

MERK: God artikkel om denne studien på svensk

Utdrag: När forskarna jämförde obehandlade individer (råttor) med hypotyreos med hypotyreota levotyroxinbehandlade råttor, så fann de att råttorna med levotyroxinbehandling hade en minskad konvertering till det aktiva hormonet T3 jämfört med de obehandlade hypotyreota råttorna.

Og videre: Forskarna fann, att endast kombinationsbehandling där både T3-hormon och T4-hormon ingår ger normal koncentration av T3 i blodet och i studerade vävnader.

Intressant i studien är även att hypotalamus inte blev påverkad av förhöjda T4-halter.  Här fann man inte samma inaktivering av enzymet D2, varför konsekvensen blev att TSH var normalt i blodet.

 

 

Elizabeth A. McAninch, Sungro Jo, Nailliw Z. Preite, Erzsébet Farkas, Petra Mohácsik, Csaba Fekete,  Péter Egri, Balázs Gereben, Yan Li, Youping Deng, Mary Elizabeth Patti7, Chantal Zevenbergen, Robin P. Peeters, Deborah C. Mash, and Antonio C. Bianco

The Journal of Clinical Investigation 2014 Prevalent Polymorphism in Thyroid Hormone-Activating Enzyme Leaves a Genetic Fingerprint that Underlies Associated Clinical Syndromes

Abstract

Context:

A common polymorphism in the gene encoding the activating deiodinase (Thr92Ala-D2) is known to be associated with quality of life in millions of patients with hypothyroidism and with several organ-specific conditions. This polymorphism results in a single amino acid change within the D2 molecule where its susceptibility to ubiquitination and proteasomal degradation is regulated.

Conclusions:

Ala92-D2 accumulates in the Golgi, where its presence and/or ensuing oxidative stress disrupts basic cellular functions and increases pre-apoptosis. These findings are reminiscent to disease mechanisms observed in other neurodegenerative disorders such as Huntington’s disease, and could contribute to the unresolved neurocognitive symptoms of affected carriers.

 

 

Escobar-Morreale HF, del Rey FE, Obregon MJ, de Escobar GM (1996). Only the combined treatment with thyroxine and triiodothyronine ensures euthyroidism in all tissues of the thyroidectomized rat. Endocrinology. 1996 Jun;137(6):2490-502

Abstract: We have recently shown that it is not possible to restore euthyroidism completely in all tissues of thyroidectomized rats infused with T4 alone.

Results: Combined replacement therapy with T4 and T3 (in proportions similar to those secreted by the normal rat thyroid) completely restored euthyroidism in thyroidectomized rats at much lower doses of T4 than those needed to normalize T3 in most tissues when T4 alone was used. If pertinent to man, these results might well justify a change in the current therapy for hypothyroidism.

Gautam Das, Shweta Anand & Parijat De (2007).  Does synthetic thyroid extract work for everybody? Endocrine Abstracts (2007) 13 P316.

Introduction:  Synthetic levothyroxine (L-Thyroxine) is the treatment of choice for hypothyroidism. It is safe, effective and generally well tolerated. Some patients, however, cannot tolerate L-Thyroxine. There is still some controversy about the effectiveness of combination T4 & T3 therapy. We describe 3 patients who were successfully treated with Armour thyroid (pork extract of T4 & T3) after being intolerant to L-Thyroxine.  Although L-Thyroxine remains the treatment of choice in the majority, a trial of Armour could be considered in patients who have not responded to this conventional treatment and who remain symptomatic with raised serum TSH levels.

 

 

Gullo, D., Latina, A., Frasca, F., Le Moli, R., Pellegriti, G., & Vigneri, R. (2011). Levothyroxine monotherapy cannot guarantee euthyroidism in all athyreotic patients. PLoS One, 6(8), e22552.  

Conclusions: Athyreotic patients have a highly heterogeneous T3 production capacity from orally administered levothyroxine. More than 20% of these patients, despite normal TSH levels, do not maintain FT3 or FT4 values in the reference range, reflecting the inadequacy of peripheral deiodination to compensate for the absent T3 secretion. The long-term effects of chronic tissue exposure to abnormal T3/T4 ratio are unknown but a sensitive marker of target organ response to thyroid hormones (serum TSH) suggests that this condition causes an abnormal pituitary response. A more physiological treatment than levothyroxine monotherapy may be required in some hypothyroid patients.

 

 

Hoang, T., Olsen, C., Mai, V., Clyde, P., Shakir, M. (2013).  Desiccated Thyroid Extract Compared With Levothyroxine in the Treatment of Hypothyroidism: A Randomized, Double-Blind, Crossover Study.  The Journal of Clinical Endocrinology & Metabolism; May 1, 2013 vol. 98 no. 5 1982-1990.

Conclusion: Desiccated thyroid extract (DTE) therapy did not result in a significant improvement in quality of life (over levothyroxine); however, DTE caused modest weight loss and nearly half (48.6%) of the study patients expressed preference for DTE over l-T4. DTE therapy may be relevant for some hypothyroid patients.

Thyroidea Norge mener: Det som er bra med denne studien er selvsagt at den i det hele tatt har blitt utført. Den viste også klart at nær halvparten følte seg bedre på NDT og de hadde hele 70 pasienter som var med i studien (18-65 år), noe som gjør at man i større grad kan se generelle tendenser. Og det var en randomisert, dobbelblind studie.

Problemene med studien, slik vi ser det, er følgende; De var for fokusert på TSH og vi mener de holder seg til TSH-verdier som ikke holder mål. Svært mange av de som bruker NDT til vanlig går på en dose som gjør at TSH blir helt supprimert, altså at TSH blir ikke målbar. Endokrinologisk avdeling på Aker mener dette er helt normalt, og det virker ikke som om de har problemer med dette så lenge T4 og T3-verdiene ellers er nomale. De fleste leger som behandler stoffskiftepasienter vil ønske at TSH skal ligge i nedre del av normalområdet, ca 0,3-1,5. Men i studien har de operert med TSH-verdier helt opp til 3,6. En kan derfor tenke seg at en del flere av forsøkspersonene også ville følt seg bedre på NDT om de fikk riktig dose.

 

Merk at også overlege for endokrinologisk avdeling ved Aker mener at det er akseptabelt at de som bruker NDT har supprimert TSH

 

I tillegg har de kun brukt Armour Thyroid som eneste type NDT. Det er verdt å merke seg at produsenten, det amerikanske Forest Laboratories, plutelig og uten forvarsel i 2008/2009 endret formelen på denne medisinen, noe som fikk enorme konsekvenser for hundretusenvis av pasienter (ingen vet hvor mange det er snakk om). Hele internett var fullt av desperate pasienter som enten hadde fått alle hypothyreosesymptomer tilbake, eller som fikk hjerteproblemer, nyreproblemer eller at binyrene sviktet. Alle henvendelser til Forest Labs fra pasienter, media og leger har blitt møtt med total taushet.

Thyroidea Norge mener at denne studien er prinsipielt viktig, men at det er stort behov for å sammenligne flere typer NDT samt ha en mer oppdatert holding til TSH-verdier.

Merk at RELIS finner denne studien statistisk signifikant

 

 

Hoermann, R., Midgley, J. E., Giacobino, A., Eckl, W. A., Wahl, H. G., Dietrich, J. W., & Larisch, R. (2014). Homeostatic equilibria between free thyroid hormones and pituitary thyrotropin are modulated by various influences including age, body mass index and treatment. Clinical endocrinology.

Conclusions: TSH, FT4 and FT3 each have their individual, but also interlocking roles to play in defining the overall patterns of thyroidal expression, regulation and metabolic activity. Equilibria typical of the healthy state are not invariant, but profoundly altered, for example, by L-T4 treatment. Consequently, this suggests the revisitation of strategies for treatment optimization.

 

Stefan Sjöberg, Mats Eriksson, Sigbritt Werner, Per Bjellerup, and Conny Nordin

Department of Medicine, Karolinska Institutet, Februar 2011 L-thyroxine treatment in primary hypothyroidism does not increase the content of free triiodothyronine in cerebrospinal fluid: A pilot study

Abstract

The association between cerebrospinal fluid (CSF) and serum concentration of thyroid hormones and pituitary thyrotropin stimulating hormone (TSH) was studied in nine hypothyroid patients (HT) before and in seven after L-thyroxine treatment. With L-thyroxine, median free T4 increased 4-fold in serum (3.5 pmol/L vs 17.5 pmol/L) and 3-fold in CSF, (3.9pmol/L vs 11.5 pmol/L). Correspondingly, total T3 in serum increased two-fold (0.9 nmol/L vs 2.2 nmol/L). Unexpectedly, free T3 concentration in CSF was similar (1.5 pmol/L vs.1.5 pmol/L) before and during treatment. In HT, TSH in serum correlated with TSH in CSF as did free T4 in serum and in CSF. During L-thyroxine, the correlation with TSH in serum and CSF remained. Likewise, the free T4 concentration in serum correlated with that in CSF. However, no correlation was found between T3 in serum and free T3 in CSF. It seems evident that free T4 in serum equilibrates with that in the CSF both in the HT and during L-thyroxine. Despite a two-fold increase in total serum T3, free T3 in CSF remained unchanged, which agrees with previous results in rats showing that T3 is less exchangeable between serum and CSF. Alternatively, an accelerated conversion of T4 to T3 might have maintained the concentration of T3, due to strongly increased levels of TSH found in the hypothyroid state. The notion that free T4 in serum reflects the CSF concentration of free T4 is consistent with previous reports from studies in animals.

 

MERK: Artikkel på svensk om studien

Utdrag: Omvandlat T3 från Levaxin passerar inte blod/hjärnbarriären.

Studien visar att mängden fritt T3 inte ökade i spinalvätskan (hjärn-ryggmärgsvätska) på de sju hypotyreospatienterna (som inledningsvis hade ett mycket förhöjt TSH och sänkt T4), trots att T3 (totala mängden, dvs både fritt och bundet T3) mer än dubblades i blodet efter behandling med Levaxin.

 

 

Holtorf, K. (2014). Thyroid Hormone Transport into Cellular Tissue. Journal of Restorative Medicine, 3(1), 53-68. Chicago.

Abstract: New research is demonstrating that thyroid hormone transport across cellular membranes plays an important role in intracellular triiodothyronine (T3) levels of peripheral and pituitary tissues and is proving to have considerable clinical significance….A combination of both clinical and laboratory assessment, which may include a T3/reverse T3 ratio and the level of sex hormone binding globulin (SHBG), should be used to determine the likely overall thyroid status and if a therapeutic trail of straight T3 or a T4/T3 combination is indicated and not based solely on standard thyroid function tests

 

 

McDermott, M. (2012). Does Combination Therapy T3/T4 Make Sense? Endocrine Practice. American Association of Clinical Endocrinologists.

Conclusions: The majority of hypothyroid patients experience rapid symptomatic relief after institution of LT4 replacement therapy, but persistent symptoms remain in some despite what appears to be adequate LT4 therapy with normalization of the serum TSH level. A thorough investigation is warranted in these patients to detect and treat other responsible lifestyle issues, medical conditions and endocrine conditions. A subset of hypothyroid patients have a polymorphism of the D2 enzyme that may prevent full resolution of symptoms with LT4 therapy alone; these patients may benefit from combination LT4/LT3 therapy. When used, a physiological LT4 to LT3 ratio of about 10:1 to 14:1 is recommended and the serum TSH should be monitored carefully to ensure that euthyroidism is maintained.

 

 

Nygaard B, Jensen EW, Kvetny J, Jarlov A, Faber J (2009).  Effect of combination therapy with thyroxine (T4) and 3,5,3′-triiodothyronine versus T4 monotherapy in patients with hypothyroidism, a double-blind, randomised cross-over study. European Journal of Endocrinology.  December 161 895-902.

Objective: To compare the effect of combination therapy with thyroxine (T4) and T3 versus T4 monotherapy in patients with hypothyroidism on stable T4 substitution.

Conclusion: In a study design, where morning TSH levels were unaltered between groups combination therapy, (treated with T3 20 μg once daily) was superior to monotherapy by evaluating several QOL, depression and anxiety rating scales as well as patients own preference.

 

 

Pepper GM and Casanova-Romero PY (2014). Conversion to Armour Thyroid from Levothyroxine Improved Patient Satisfaction in the Treatment of Hypothyroidism.  Journal of Endocrinology, Diabetes & Obesity.  September, 11 2014.

Conclusion: AT treatment was preferred over LT4 replacement therapy by 78% of patients with hypothyroidism in the sub-group with persistent subjective complaints while on T4-only therapy. No serious adverse events were noted while on AT treatment including 30 subjects aged 65 yrs or older. AT could be a reasonable alternative choice for treating this sub-group of patients with hypothyroidism.

Thyroidea Norge mener: Også denne studien er statistisk signifikant. Merk at hele 78% av forsøkspersonene foretrakk NDT fremfor T4 etter bare fire uker på NDT. Problem: Man brukte kun Armour Thyroid. Vi viser igjen til problemene somkom etter formelendringen. Studien er foretatt etter denne formelendringen.
Pritchard, E.K. (2013).  Reducing the Scope of Guidelines and Policy Statements in Hypothyroidism.  Journal of Orthomolecular Medicine. Volume 28, Number 2, 2013.
Abstract:  
Although practice guidelines and policy statements on hypothyroidism are generally effective, many patients do not respond to the prescribed treatment. Significantly, clinicians routinely face the conundrum of either following the guidelines, which are ineffective, or ethically prescribing alternative (but proscribed) treatment, which might bring and has brought severe punishment by boards of medicine or medical councils.

 

 

Robertas Bunevičius, M.D., Ph.D., Gintautas Kažanavičius, M.D., Ph.D., Rimas Žalinkevičius, M.D., and Arthur J. Prange, Jr., M.D. (1999). Effects of Thyroxine as Compared with Thyroxine plus Triiodothyronine in Patents with Hypothyroidism. New England Journal of Medicine; 340:424-429.

Conclusions: In patients with hypothyroidism, partial substitution of triiodothyronine for thyroxine may improve mood and neuropsychological function; this finding suggests a specific effect of the triiodothyronine normally secreted by the thyroid gland.

 

 

Rosenthal, L. J., Goldner, W. S., & O’Reardon, J. P. (2011). T3 augmentation in major depressive disorder: safety considerations. American Journal of Psychiatry, 168(10), 1035-1040.

Conclusion:  Current textbooks and the 2010 APA guidelines agree that there is good evidence for the use of T3 in depressive syndromes, but largely do not mention monitoring of thyroid functioning. Schatzberg et al. suggest use of T3 in postmenopausal women or atypical depression and tapering augmentation after 60 days.

 

 

Saravanan P, Dayan C M. Understanding Thyroid Hormone Action and the Effects of Thyroid Hormone Replacement – Just the Beginning Not the End.  Hot Thyroidology.
Conclusions:
 Despite 100 years of thyroid hormone replacement, controversy still exists about the optimum replacement therapy for hypothyroid patients. Several recent studies have given insight in to the complex thyroid hormone metabolism. These support the hypothesis that serum and tissue levels of thyroid hormones may diverge significantly and vary between tissues. The dissatisfaction experienced by some individuals on thyroxine replacement despite normal TSH levels may in part relate to this.

 

 

Snyder, S., Listecki, R.E (2012) Bioidentical thyroid replacement therapy in practice: Delivering a physiologic T4:T3 ratio for improved patient outcomes with the Listecki-Snyder protocol. International Journal of Pharmaceutical Compound; 16(5): 376-378.

Conclusion: Bioidentical thyroid replacement therapy in practice: Delivering a physiologic T4:T3 ratio for improved patient outcomes with the Listecki-Snyder protocol

Effective thyroid replacement therapy may be elusive to some patients, and compounding pharmacists have an opportunity to deliver more effective therapy. Goodman & Gilman’s The Pharmacological Basis of Therapeutics 12th edition states that the body usually secretes T4:T3 in an 11:1 ratio but cautions against pursuing combined thyroid replacement due to the short halflife of T3 that necessitates multiple daily dosing; no commercial availability and lack of benefit were shown in trials.

 

 

Weltman, N. Y., Ojamaa, K., Schlenker, E. H., Chen, Y. F., Zucchi, R., Saba, A., … & Gerdes, A. M. (2014). Low-dose T3 replacement restores depressed cardiac T3 levels, preserves coronary microvasculature, and attenuates cardiac dysfunction in experimental diabetes mellitus. Molecular medicine (Cambridge, Mass.).

Abstract:  We conclude that cardiac dysfunction in chronic diabetes mellitus (DM) may be associated with tissue hypothyroidism despite normal serum thyroid hormone levels. Low-dose T3 replacement appears to be a safe and effective adjunct therapy to attenuate and/or reverse cardiac remodeling and dysfunction induced by experimental DM.

 

 

Wiersinga, W. M., & DeGroot, L. J. (2010). Adult hypothyroidism. Thyroid Disease Manager. Available at: www.thyroidmanager.org/chapter/adulthypothyroidism/#toc-9-2-definition-and-epidemiology-of-hypothyroidism . Accessed: Nov, 16, 2011.  See section 9.8 «Treatment of Hypothyroidism».

 

 

Woeber, K. A. (2002). Levothyroxine therapy and serum free thyroxine and free triiodothyronine concentrations. Journal of endocrinological investigation, 25(2), 106-109.

Abstract: These findings indicate that in hypothyroid patients L-T4-replacement, that is sufficient to maintain a normal serum TSH, is accompanied by a serum free T4 that is higher than that in untreated euthyroid patients or normal individuals and may not result in an appropriately normal serum free T3 concentration.

 

 

Dr John Lowe, Thyroid Science, 2009 Stability, Effectiveness, and Safety of Desiccated Thyroid vs Levothyroxine: A Rebuttal to the British Thyroid Association

Abstrakt: Legger frem studier som viser at NDT er tryggere eller like trygt å bruke som T4 og at The British Thyroid Association tar feil i en del av sine konklusjoner og bør revurdere sine antakelser om T4-monoterapi som eneste anbefalte behandlingsmetode.

 

 

Clinical Thyroidology 2013. Jerome M. Hershman.

Background:1991 was the centenary of the first use of a thyroid preparation to treat successfully a previously incurable disease, myxedema ” (1). Around then, thyroid hormone preparations made up over 1% of all prescriptions filled by retail pharmacies. In 1988, one fourth of all thyroid hormone prescriptions were for natural preparations, mainly thyroid USP

Og fra konklusjonen: Many endocrinologists refuse to prescribe DTE under any circumstances, even telling the patient to find another doctor who may do it. I think that the present study shows that the switch is not so dangerous, as long as the serum TSH remains in the normal range with careful titration of the DTE dose. The many years of satisfactory therapy with synthetic levothyroxine make it the vastly preferred substitution therapy, but for the patient who insists on continuing or trying DTE, I think that it is no more dangerous than adding some additional L-T3 in the hope that it will improve persistent “hypothyroid” symptoms in the patient taking L-T4. (desiccated thyroid) in the United States, even though synthetic T4 had gradually replaced the natural preparations for three fourths of patients during the previous 20 years (2). Now it is rare for physicians to prescribe desiccated thyroid extract (DTE) instead of levothyroxine (L-T4). However, many patients report that they “don’t feel normal” while taking L-T4, and they want the “natural preparation” that is advertised on the Web.

The current study is a careful comparison of desiccated thyroid extract and L-T4 in the treatment of hypothyroidism.

 

 

Gaby AR. MD, 2004 Sub-laboratory hypothyroidism and the empirical use of Armour thyroid

Abstract Evidence is presented that many people have hypothyroidism undetected by conventional laboratory thyroid-function tests, and cases are reported to support the empirical use of Armour thyroid. Clinical evaluation can identify individuals with sub-laboratory hypothyroidism who are likely to benefit from thyroid-replacement therapy. In a significant proportion of cases, treatment with thyroid hormone has resulted in marked improvement in chronic symptoms that had failed to respond to a wide array of conventional and alternative treatments. In some cases, treatment with desiccated thyroid has produced better clinical results than levothyroxine. Research supporting the existence of sub-laboratory hypothyroidism is reviewed, and the author’s clinical approach to the diagnosis and treatment of this condition is described.

 

Endocrine abstracts 2007 Gautam Das, Shweta Anand & Parijat De Does synthetic thyroid extract work for everybody?

Tre case studies der man med suksess behandlet pasienter med Armour Thyroid. Dette er pasienter som tidligere har hatt store problemer og mange symptomer på Levaxin

Escobar-Morreale HF1, Botella-Carretero JI, Gómez-Bueno M, Galán JM, Barrios V, Sancho J. 2005 Thyroid hormone replacement therapy in primary hypothyroidism: a randomized trial comparing L-thyroxine plus liothyronine with L-thyroxine alone.

Abstract
BACKGROUND:

Substituting part of the dose of l-thyroxine with small but supraphysiologic doses of liothyronine in hypothyroid patients has yielded conflicting results.

OBJECTIVE:

To evaluate combinations of L-thyroxine plus liothyronine in hypothyroid patients that match the proportions present in normal secretions of the human thyroid gland.

INTERVENTION:

Crossover trial comparing treatment with l-thyroxine, 100 microg/d (standard treatment), versus treatment with L-thyroxine, 75 microg/d, plus liothyronine, 5 microg/d (combination treatment), for 8-week periods. All patients also received L-thyroxine, 87.5 microg/d, plus liothyronine, 7.5 microg/d (add-on combination treatment), for a final 8-week add-on period.

RESULTS:

Compared with standard treatment, combination treatment led to lower free thyroxine levels (decrease, 3.9 pmol/L [95% CI, 2.5 to 5.3 pmol/L]), slightly higher serum levels of thyroid-stimulating hormone (increase, 0.62 mU/L [CI, 0.01 to 1.23 mU/L]), and unchanged free triiodothyronine levels. No improvement was observed in the other primary and secondary end points after combination treatment, with the exception of the Digit Span Test, in which the mean backward score and the mean total score increased slightly (0.6 digit [CI, 0.1 to 1.0 digit] and 0.8 digit [CI, 0.2 to 1.4 digits], respectively). The add-on combination treatment resulted in overreplacement. Levels of thyroid-stimulating hormone decreased by 0.85 mU/L (CI, 0.27 to 1.43 mU/L) and serum free triiodothyronine levels increased by 0.8 pmol/L (CI, 0.1 to 1.5 pmol/L) compared with standard treatment; 10 patients had levels of thyroid-stimulating hormone that were below the normal range. Twelve patients preferred combination treatment, 6 patients preferred the add-on combination treatment, 2 patients preferred standard treatment, and 6 patients had no preference (P = 0.015).

LIMITATIONS:

Treatment with L-thyroxine, 87.5 microg/d, plus liothyronine, 7.5 microg/d, was an add-on regimen and was not randomized.

CONCLUSIONS:

Physiologic combinations of L-thyroxine plus liothyronine do not offer any objective advantage over l-thyroxine alone, yet patients prefer combination treatment.

Thyroidea Norge mener:

Selv om 69% av de som var med i studien foretrakk kombinasjonsterapi T4+T3 foran utelukkende T4, konkluderte studien med at kombinasjonsterapien ikke har noen effekt og at man bør fortsette å ha kun T4 som behandlingsmetode for alle med hypothyreose

Det er flere problemer med studien.

Kun 28 personer var med, og to av dem droppet ut i løpet av studien. I tillegg var doseringen av T3 altfor liten i forhold til det mange erfaringsmessig trenger for å føle seg bra. Pasientene i gruppen fikk 5-7,5 mg Liothyronin, mens mange pasienter som bruker dette medikamentet må ta opptil 60 mg for å føle seg bra. I Norge får man Liothyronin kun i tabletter på 20 mg uansett. De som gikk på kombinasjonsterapi fikk også en ganske lav dose T4, maks 87,5 mg, mens vanlig dose for voksne mennesker som regel ligger fra 100-300 mg. I tillegg fikk alle den samme dosen, noe som er unormalt for ganske mange sykdommer, ikke bare stoffskiftesykdommer – det vanlige er å tilpasse dosen etter den individuelle pasient og ta høyde for vekt, alder, symptomer og ulike laboratorietester.

 

Studien ble likevel godkjent i Cochrane og har siden blitt referert til for å argumentere mot behandling med T3. Vi legger denne likevel med for å påpeke at ikke all forskning er god medisin.

 

 

MAURICE L. WELLBY, M.Sc., M.B., B.S.*, BRIAN F. GOOD, B.SC., JOHN S. CHARNOCK, B.SC.*, and BASIL S. HETZEL, M.D. THE EARLY METABOLIC EFFECTS OF DESICCATED THYROID, THYROXINE AND TRIIODOTHYRONINE IN MAN: COMPARISON WITH EARLY EFFECT OF THYROTROPIC HORMONE

Received: November 24, 1959

Published Online: July 01, 2013

ABSTRACT

In order to determine whether the early metabolic effect of thyrotropic hormone (as demonstrated previously in this laboratory) could be reproduced by certain known thyroid hormone preparations, triiodothyronine (T3), thyroxine (T4) and desiccated thyroid were administered orally on four occasions in single doses to 5 normal males, and the metabolic effects observed. The dose of T3 was 0.5 mg.; of T4 2.5–3.0 mg.; and of thyroid, 1.3–2.0 Gm. Observations were made over an eight-hour period after an overnight fast. It was confirmed that T3 produces a rise in metabolic rate and an increase in the levels of plasma and urinary phosphate within eight hours without significantly raising the level of plasma protein-bound iodine (PBI). There was a less marked rise in metabolic rate following administration of desiccated thyroid, with a significant rise in urinary phosphate within eight hours and a rise in the plasma PBI level to 10.2 μg. per 100 ml. within two hours. T4 produced no elevation in metabolic rate, pulse rate or phosphate excretion, although elevation of the plasma PBI level to 9.0 μg. per 100 ml. occurred within two hours. There were no consistent effects on urine flow and sodium, potassium or creatinine excretion, and no subjective symptoms during treatment with any of the preparations. The results indicate the similarity between the early metabolic effects of triiodothyronine and desiccated thyroid. Thyroxine had no effect over the eight-hour period of observation. None of the preparations reproduced the early metabolic effects of thyrotropic hormone.

 

 

Chernow B, Burman KD, Johnson DL, McGuire RA, O’Brian JT, Wartofsky L, Georges LP. T3 may be a better agent than T4 in the critically ill hypothyroid patient: evaluation of transport across the blood-brain barrier in a primate model. (1983)

Abstract: Thyroid hormone transport across the blood brain barrier in hypothyroid patients is clinically important yet poorly understood. To study this question, 200 micrograms of thyroxine (T4), 100 micrograms of 3,5,3′-triiodothyronine (T3) and 100 micrograms of 3,3′,5′-triiodothyronine (reverse T3) were administered separately to 3 baboons, first iv and at a later date intrathecally (IT). Six animals were used. Three received the iv injections and three received the IT injections. In each of the 18 experiments, cerebrospinal fluid (CSF) and serum specimens were collected serially for 6 h after injection. Mean maximal elevations from baseline in CSF iodothyronine levels were 100 +/- 10 ng/dl after iv T4, 3921 +/- 293 ng/dl after iv T3 and 31 +/- 17 ng/dl after iv reverse T3. When given IT in the same dosages, the mean maximal increases in serum iodothyronine concentrations were: 1670 +/- 600 ng/dl for T4, 806 +/- 405 ng/dl for T3, and 210 +/- 43 ng/dl for reverse T3. In every animal studied, rapid bidirectional transfer of T3 from serum to CSF and CSF to serum occurred, whereas iv T4 resulted in delayed minimal increments in CSF T4 concentration. Isotopic experiments were also performed and the results analyzed using a kinetic model. When 125I-T3 was given iv, the equilibrium point in CSF was observed within 90 min with 1.7% of the administered dose/L able to be counted in CSF at any moment in time. When labeled T4 was given iv, only 0.6% of the administered dose/L was counted in CSF and the equilibrium point was not reached until 360 min. These data suggest: (a) T4, T3, and reverse T3 are all capable of bidirectional transfer across the blood brain barrier, (b) T3 may be a better agent than T4 in treating patients with myxedema coma because T3 crosses more rapidly and more completely from serum to CSF.

 

 

 

Norsk Legetidsskrift 2000 P Gulbrandsen Trijodtyronin fysiologisk viktig?

Det er usikkert om trijodtyronin har fysiologisk betydning. Ved å erstatte deler av tyroksindosen til 33 pasienter med hypotyreose med trijodtyronin, kunne en forskergruppe i Litauen påvise bedring i stemningsleie og nevropsykologisk funksjonsnivå.

I undersøkelsen, som er publisert i New England Journal of Medicine , ble 33 pasienter som hadde stått på tyroksin i gjennomsnittlig 73 måneder behandlet enten med tyroksin alene eller med en kombinasjon av tyroksin og trijodtyronin (50 mg tyroksin erstattet med 12,5 mg trijodtyronin) i fem uker, dernest ble behandlingsregimene byttet om (1). Rekkefølgen av behandlingstypene for pasientene var tilfeldig. Ved enden av hver femukersperiode gjennomgikk pasientene en rekke fysiologiske og nevropsykologiske tester.

Doseringen ble reflektert i serumnivåene for tyroksin og trijodtyronin etter de respektive behandlingene, men man fant ikke forskjell i TSH-nivå. Etter kombinasjonsbehandlingen hadde pasientene statistisk signifikant høyere hvilepuls og nivå av kjønnshormonbindende protein (SHBG), men generelt var det beskjedne forskjeller i de fysiologiske variablene.

Resultatet av de nevropsykologiske testene var klart forskjellig. Etter kombinasjonsbehandlingen fant man bedre innlæringsevne, mental fleksibilitet og oppmerksomhetsnivå. Pasientene var mindre deprimert, utmattet og kjente mindre sinne enn etter perioden med ren tyroksinbehandling. Av de 33 pasientene foretrakk 20 kombinasjonsbehandlingen, to tyroksin alene og 11 hadde ingen preferanse. De to som foretrakk tyroksin alene, gav uttrykk for å føle seg mer nervøse under kombinasjonsbehandlingen.

Forfatterne konkluderer med at det synes som om trijodtyronin har en gunstig effekt i alle fall i hjernen og kanskje i annet vev, sammenliknet med en ekvivalent mengde tyroksin.

Litteratur

Bunevicius R, Kazanavicius G, Zalinkevicius R, Prange AJ. Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism. N Engl J Med 1999; 340: 424–9

 

 

Thyroid Science 2006 Four 2003 Studies of Thyroid Hormone Replacement Therapies: Logical Analysis and Ethical Implications

Dr John C. Lowe

Meget god kritikk av fire studier samt god forklaring på hvorfor disse har blitt feiltolket