T4/T3 kombinasjonsbehandling

I Norge er det  egentlig greit å få kombinasjonsbehandling.

I gamle dager, når man bare hadde skjoldkjertelekstrakt, fikk pasientene faktisk kombinasjonsbehandling..

Thyroxin ble registrert her i 1950 (kilde: www.legemiddelverket.no, www.legemiddelsiden.no , preparatomtaler)
Liothyronin ble registrert i 1958.
Obs, legemiddelverket har uavhengige preparatomtaler og kan skille seg fra omtalen i Felleskatalogen. I Legemiddelverkets omtale står det  at liothyronin kan brukes i kombinasjonsbehandling.

tilbake til historien til Armour og thyroxin
Artikkel i legetidsskriftet nr 9/2002 av Haug

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

flere studier:

A.M.Sawka et.al Kanada 2003pdf høyreklikk og velg last med

Her har mange pasienter med suksess brukt kombinasjonsbehandling, uten at det er stor debatt om det nå.

Stoffskifteforeningen (nå: thyreoideadoebundet) stod på for  å gjøre det kjent. 
Et problem som kan oppstå er at legen slår opp i felleskatalogen om doser, og at det står 2-3 tabletter som vanlig dose der.....Da blir pasienten vanligvis veldig overdosert.

Riktig dose å prøve er 10µg, som er en halv tablett, og den må man brekke i halv igjen og ta 5 µg i to omganger med fire-fem timers mellomrom.

Per Egil Haug har nevnt dosen liothyronin ved kombinasjonsbehandling i en av artiklene i serien om thyreoidea som kom i 2002 . Det står i nummer 9 og 10, og ligger ute på internett.

Det antydes 100µg levaxin pluss 10 µg liothyronin som et mulig sted å starte.

Pasienter melder også om at man etterpå må sjekke hvordan ft4 og ft3 oppfører seg, siden ft4 ofte går ganske mye ned og mange trenger den opp igjen ved en liten økning av levaxin-dosen (i samråd med legen, selvsagt).
TSH kan falle ganske mye, siden hypofysen er veldig følsom for liothyronin.
Da må man følge ft4 og ft3 i blodprøver, se Haugs artikkel om at mange trenger dem høyt og TSH lavt. Det er selvsagt individuelt. 

Mange beskriver virkningen av liothyronin som dramatisk, at tåken lettet innen noen timer og at de kunne konsentrere seg igjen.

De som pga. legens uvitenhet prøvde hele tabletter, til og med flere tabletter om dagen, opplevde hjertebank og overdose-symptomer.

I det store og hele er kombinasjonsbehandling  her i Norge ganske greit, bare man vet at man må følge opp med blodprøver fordi ft4 kan synke, samt at man ikke skal ta hele tabletter på 20 µg.

 

 

 

 

 

 

Utlandet:

Det ser ut som om de må gjøre forsøk i utlandet før de kan gå god for en type behandling. 

Dette er nok veldig vanskelig angående thyreoideasykdommer, siden dosene er så individuelle.

Hvis man tenker etter, så er dosene hos de aller  fleste andre medisiner like for alle voksne, med egne tabeller for barn.

I konklusjonene til noen medisinske forsøk skylder de på at liothyronin må være upålitelig. Jeg har lest et par av artiklene (Noen må man betale for å få lest) og jeg synes at de har underbehandlet pasientene, siden TSH gikk opp, og at forsøkene var dårlig planlagte siden de ikke kunne øke thyroxindosen slik som forsøket var planlagt. Jeg mener at man må innrømme at forsøket avdekket at planleggingen må forandres, istedenfor å konkludere med at "placeboeffekten holdt ikke lenge" eller at liothyronin er ustabil.

Utenlandske leger (fra land hvor andre preparater brukes) siteres ang. påstått upålitelighet i doser på t3 i Armour og påstått pålitelighet av levothyroxin. Amerikanske leger vet at det står i Federal Register at levothyroxin (og ikke Thyroid USP) er upålitelig. Derfor må man referere til skribenter utenfor USA.

Det har vært trykket flere artikler om forsøk med t4/t3 kombinasjonsbehandlig i JCEM.Det tar en stund til jcem artiklene er gratis.

Her er en australsk studie. Legg merke til at de tok vekk mer t4 enn som ville tilsvart dosen liothyronin, 10µg t3 er mer lik 36µg thyroxin. Da er det en stor risiko for at pasientene blir underbehandlet.

Jeg så etter denne når jeg fant en medscape-artikkel som sa at man foretrekker t4 alene fordi den er mer stabil  og er kjent for å være mer stabil enn t4. I medscape-artikkelen sies det at t3-behandlign og desiccated Thyroid gir svingninger i t3- nivåene med referanse til denne artikkelen her. Det menes formodentlig serum t3-nivåer siden levothyroxin er kjent for å være ustabil slik som dokumentert i Federal register i USA, og alle levothyroxinpreparater måtte gjennomgå en ny NDA New Drug Application. Mer om dette på en annen side her.

Combined Thyroxine/Liothyronine Treatment Does Not Improve Well-Being, Quality of Life, or Cognitive Function Compared to Thyroxine Alone: A Randomized Controlled Trial in Patients with Primary Hypothyroidism

John P. Walsh, Lauren Shiels, Ee Mun Lim, Chotoo I. Bhagat, Lynley C. Ward, Bronwyn G. A. Stuckey, Satvinder S. Dhaliwal, Gerard T. Chew, Minoti C. Bhagat and Andrea J. Cussons

http://intl-jcem.endojournals.org/cgi/content/full/88/10/4543

Kommentar: Pasientene på thyroid.about.com forumet vil angripe temaet fra en helt annen synsvinkel, ikke så fokusert på TSH, de går etter ft4 og ft3. Hvis man er ok med t4 alene, og man kan følge en viss TSH, altså hvis man vt hvilken TSH man er helt ok på, da gjør man ikke noen forandringer.

Hvis man er fremdeles dårlig, og ikke har lavt Ferritn, B-12 eller D-vitamininnhold i blodet, så ser men på ft4 og ft3. de fleste må ha ft4 i øvre halvdel av laboratoriets referanseområde, og mange veldig høyt.

Så er neste trinn å se på ft3. Veldig mange har blitt mye bedre når de tok tilskudd av t3 (Liothyronin, i amerika heter det cytomel) som hever ft3-nivået.

da er man på stadiet av de kliniske forsøk, de tar vekk 50µg t4 og tilfører 10 eller 12,5 µg t3.
Det som så skjer er at ft4 begynner veldig snart å gå ned fordi TSH går ned på t3. Da ender man opp med en lavere ft4, noe som gir symptomer hos mange.

Neste skritt er altså å måle ft4 og ft3 igjen og øke t4-dosen  til man har en bra ft4 igjen, vanligvis i øvre halvdel.

Noen få har det ok med en lav ft4 så lenge som ft3  er ganske høy, noen ganger litegrann over referanseområdet.

Det samme gjør man med kombinasjonen Armour og levaxin, man går etter ft4 og ft3.

Veldig mange pasienter har da en veldig lav TSH, fordi t3 senker TSH veldig mye.

Dette andre trinnet er alltid utelatt i studiene jeg har lest, å øke t4-dosen tilbake.

Her er beviset på at pasientene var underdosert i denne studien:

"Biochemistry results

During combined T4/T3 treatment, serum free T4 was significantly (P < 0.001) lower than during T4 treatment (Table 5Go), whereas there was no significant difference in serum free T3 concentrations. Serum TSH was significantly higher during combined therapy compared with T4 alone (1.5 ± 0.2 mU/liter for T4 vs. 3.1 ± 0.2 for combined T4/T3; P < 0.001). Serum SHBG was significantly (P < 0.01) lower, and plasma cholesterol higher (P = 0.015) during combined treatment compared with T4 alone."

TSH gikk altså opp til 3 og ft4 ned. Vi kunne fortalt dem dette hvis de hadde lest på forumene og lest hvordan pasienten må øke t4 tilbake  igjen.
Ft4 gikk ned fra 15 til 11. Ft3 gikk ned fra 3,7 til 3,5.
Og det var gjennomsnittet. Det var sikkert forskjeller. 

Og hvor står det noe om at t3 og desiccated thyroid er ustabilt, eller gir ustabile blodverdier?
Det er en referanse, nr. 6. . Wiersinga WM 2001 Thyroid hormone replacement therapy. Horm Res 56(Suppl 1):74–81 Ingen link gitt, så de fleste gir opp her.
et søk i google bringer en medline referanse: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11786691&dopt=Abstract
Den sier ikke at T3 gir ustabile blodverdier per se, men at man må ta t3 delt opptil to ganger daglig. Det er da noen annet ennå avskrive t3 og desiccatd thyroid fordi det gir "ustabile blodverdier"

"ustabile blodverdier" er også sitert av BTA i sitt Statement on Armour Thyroid . De gir ingen referanser, men det jeg antar er at de lener seg til de diverse Medscape artikler som henviser til artiklene ovenfor av Walsh et al som igjen gir en referanse til Wiersinga artikkelen. 

"Abstract

Thyroid hormone replacement has been used for more than 100 years in the treatment of hypothyroidism, and there is no doubt about its overall efficacy. Desiccated thyroid contains both thyroxine (T4) and triiodothyronine (T3); serum T3 frequently rises to supranormal values in the absorption phase, associated with palpitations. Liothyronine (T3) has the same drawback and requires twice-daily administration in view of its short half-life. Synthetic levothyroxine (L-T4) has many advantages: in view of its long half-life, once-daily administration suffices, the occasional missing of a tablet causes no harm, and the extrathyroidal conversion of T4 into T3 (normally providing 80% of the daily T3 production rate) remains fully operative, which may have some protective value during illness. Consequently, L-T4 is nowadays preferred, and its long-term use is not associated with excess mortality. The mean T4 dose required to normalize serum thyroid stimulating hormone (TSH) is 1.6 µg/kg per day, giving rise to serum free T4 (fT4) concentrations that are slightly elevated or in the upper half of the normal reference range. The higher fT4 values are probably due to the need to generate from T4 the 20% of the daily T3 production rate that otherwise is derived from the thyroid gland itself. The daily maintenance dose of T4 varies widely between 75 and 250 µg. Assessment of the appropriate T4 dose is by assay of TSH and fT4, preferably in a blood sample taken before ingestion of the subsequent T4 tablet. Dose adjustments can be necessary in pregnancy and when medications are used that are known to interfere with the absorption or metabolism of T4. A new equilibrium is reached after approximately 6 weeks, implying that laboratory tests should not be done earlier. With a stable maintenance dose, an annual check-up usually suffices. Accumulated experience with L-T4 replacement has identified some areas of concern. First, the bioequivalence sometimes differs among generics and brand names. Second, many patients on T4 replacement have a subnormal TSH. TSH values of le0.1 mU/l carry a risk of development of atrial fibrillation and are associated with bone loss although not with a higher fracture rate. It is thus advisable not to allow TSH to fall below - arbitrarily - 0.2 mU/l. 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 which their T3 content is derived from serum T3 or locally produced T3 from T4, these complaints may have a biologic substrate; for example, brain T3 content is largely determined by local deiodinase type II activity. Against this background it is of interest that a number of psychometric scores improved significantly in hypothyroid patients upon substitution of 50 µg of their 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.

Copyright © 2001 S. Karger AG, Basel"
 Author Contacts Dr. Wilmar Wiersinga
Department of Endocrinology and Metabolism
Academic Medical Centre, University of Amsterdam
NL-1105 AZ Amsterdam (The Netherlands)
Tel. +31 20 5666 071, Fax +31 20 6917 682, E-Mail  w.m.wiersinga @amc.uva.nl
 Article Information Number of Print Pages : 8
Number of Figures : 1, Number of Tables : 3, Number of References : 41
http://content.karger.com/produktedb/produkte.asp?typ=fulltext&file=hre6a074 Det koster å lese hele artikkelen.

Merk at man i holland bruker Thyreoïdum, et preparat av tørket svinekjertel fra Danmark, med varierende innhold av T4 og T4, og det inneholder en del mindre t4 enn Thyroid USP per 60 mg, nemlig ca 24µg mot Thyroid USP som har 38µg. Til gjengjeld er hver batch nøye analysert og varer i ett helt år. Det er dette som kan kalles varierende styrke på tørket-kjertel-preparater, men det varierer ikke fra tablett til tablett, men fra ett år til det neste året. Pasientene merker forresten ikke noe fordkjell når man spør på det hollandske forumet.

Dr. Lowe benekter at hjerteklapp er et problem ved behandling med Armour Thyroid. 
På forumene er det heller ikke rapportert om hjerteklapp.

Derimot har de som har lavt ferritin, under 50-70, en generell intoleranse mot stoffskiftemedisiner, altså at de reagerer med hypersymptomer ved økning mens TSH ennå er høy og ft4 ennå er lav og de har hyposymptomer. Det gjelder ikke bare Armour eller liothyronin , det gjelder generelt for alle, og de fleste klager over at de ikke tåler thyroxin. Grunnen er en hyperadrenerg reaksjon hvis man har lavt ferritin.
http://www.ithyroid.com/iron.htm 
  http://www.mayoclinicproceedings.com/inside.asp?AID=1372&UID=23777
http://www.aafp.org/afp/990315ap/1598.html
Anemia: a cause of intolerance to thyroxine sodium.Pubmed reference

En som har lest referansene som  det refereres til når man fraråder desiccated Thyroid er Gaby. Pdf her

Her er utdrag fra artikkelen hans om bruken av Armour Thyroid:

"

Objections to the Use of Armour

Thyroid

The main objections voiced in textbooks and editorials 1,73 regarding the use of desiccated

thyroid are: (1) its potency varies from batch to batch, and (2) the use of T3-containing preparations

causes the serum T3 concentration to rise to supraphysiological levels. Regarding between-batch

variability, there may have been some problems with quality control a half-century or more

ago, and in a 1980 study a number of generic versions of desiccated thyroid were still found to be

unreliable in their potency. The amounts of T4 and T3 in Armour thyroid, on the other hand, were

found to be constant.74 Moreover, two-year old tablets of Armour thyroid contained similar

amounts of T4 and T3 as did fresh tablets. Three studies are typically cited to support

the contention that T3-containing preparations should not be used. Smith et al reported a

levothyroxine-plus-T3 product caused adverse side effects in 46 percent of patients; whereas, side

effects occurred in only 10 percent of those receiving levothyroxine alone.75 In that study, however,

the combination product and the levothyroxine product differed substantially in

potency. For the combination treatment, each 100 mcg of levothyroxine was replaced by 80 mcg of

levothyroxine plus 20 mcg of T3. Considering 20 mcg of T3 is equivalent to 80 mcg of

levothyroxine, the total hormone dose in the combination product was 60-percent greater than that

in the levothyroxine preparation. Therefore, the high incidence of adverse side effects may not have

been due to the T3, but to the higher total dose of thyroid hormones.

In the second study, by Surks et al, the administration of T3-containing preparations to

hypothyroid patients caused the plasma T3 concentration to become markedly elevated for sev-eral

hours after ingestion of the medication.76 In most cases, however, the amount of T3 administered

(50-75 mcg) was considerably greater than that contained in a typical dose of desiccated thyroid

(9 mcg T3 per 60 mg),77 and/or the total dose of thyroid hormones given was excessive (180

mcg of levothyroxine plus 45 mcg of T3). By contrast, in a patient given 60 mg of desiccated thy-roid,

the plasma T3 concentration increased from a hypothyroid level to a euthyroid level. Of two

hypothyroid patients treated with 120 mg per day of desiccated thyroid, one showed a relatively

constant plasma concentration of T3. In the other patient, the T3 level increased by a maximum of

80 percent, to the bottom of the range seen in hyperthyroid patients, and returned to the baseline

value within 24 hours. In that patient, the pre-dose plasma T3 concentration was near the top of the

normal range, suggesting that this patient may have been receiving too high a dose of desiccated

thyroid.

Finally, Jackson and Cobb reported that the serum T3 concentration (measured 2-5 hours

after a dose) was above normal in most patients receiving desiccated thyroid.2 They concluded

there is little use for desiccated thyroid in clinical medicine. Most of the patients (87.5%) in that

study, however, were taking a relatively large dose of desiccated thyroid (120-180 mg daily). Moreover,

57.5 percent of the patients were not being treated for hypothyroidism, but rather to suppress

the thyroid gland. Nearly half of the patients continued to have an elevated serum T3 concentration

after they were switched to levothyroxine,

even though the equivalent dose was reduced in 62.5 percent of patients. Thus, the elevated serum

T3 concentrations found in this study can be explained in large part by the high doses used and

by the selection of patients, the majority of whom were not hypothyroid. What this study does suggest

is that desiccated thyroid should not be used for thyroid-suppression therapy.

Although the oral administration of T3 causes a transient increase in serum T3 concentrations,

that fact does not appear to be of significance for hypothyroid patients receiving usual

replacement doses of Armour thyroid. In this author’s experience, reports of post-dose symptoms

of hyperthyroidism are extremely rare, even among patients taking larger doses of desiccated

thyroid. An occasional patient reports feeling better when he or she takes Armour thyroid in two

divided doses daily. The nature of that improvement, however, is usually an increase in effectiveness,

rather than a reduction in side effects. For patients taking relatively large amounts of desiccated

thyroid (such as 120 mg daily or more), splitting the daily dose would obviate any potential

concern about transient elevations of T3 levels.

In practice, however, splitting the daily dose is rarely necessary.

"

Så konklusjonen må være at man alltid skal sjekke referansene og ikke umiddelbart ta dem for god fisk, spesielt når det ikke stemmer med hva man har erfart og hva pasientene har erfart.

For ordens skyld, her er hva BTF skriver:

"

THE BRITISH THYROID FOUNDATION

Our current views on Armour

The British Thyroid Foundation receives many queries about the use of desiccated thyroid extract. This statement aims to highlight our current position on this issue and inform people of the facts and uncertainties that relate to this treatment.

Armour thyroid is a brand of natural desiccated thyroid extract made by Forest Laboratories in the United States.

Natural desiccated thyroid tablets are made from raw pork thyroid glands collected at slaughterhouses, which are tested for absence of Salmonella and E. Coli, then held in a frozen state until they are delivered to the processing laboratory where they are minced, placed in a vacuum dryer, defatted, then milled to a fine powder before being packaged. Samples are tested for chemical and microbiological characteristics.

The manufacturers state that the following are the ingredients of Armour:

Active ingredients: T3 and T4
Inactive ingredients: calcium state, dextrose, microcrystalline cellulose, sodium starch and opadry white

We have written on several occasions to the manufacturers to ask for confirmation of their ingredients and for details of their quality control procedures but have received no reply to date.

Desiccated thyroid extract is not currently licensed in the UK and was withdrawn from use in the UK in the 1970s after synthetic thyroxine had been developed. At that time there was perceived to be a problem with the quality control of thyroid extract with large variations from batch to batch, due to the variation in T4 (thyroxine) and T3 (triiodothyronine) that it contained.

There is concern amongst some doctors over the substantial fluctuations in T3 levels in blood of patients treated with Armour and the potentially harmful effects on the heart (rapid irregular heart beat which predisposes to clots forming inside the heart and then causing strokes) and bones (osteoporosis).

It is difficult to monitor treatment containing a combination of T3/T4 because of peaks and troughs in T3. The long-term effects of T3, Armour, or combinations of T3 and T4 are not known. T3 has a short half-life of a few hours. Patients on T3 have fluctuating T3 levels and at times these may go beyond the upper limit of normal. By contrast T3 levels in patients on thyroxine are stable. Monitoring thyroid hormone replacement in patients on T4 is easy biochemically because of the stable levels. In someone on T3 or Armour it will depend on the time since the last dose.

The Medicine and Healthcare Products Regulatory Agency (MHRA), the licensing authority for pharmaceuticals in the UK and executive agency of the Department of Health, states that natural thyroid products including Armour are not currently licensed in the UK. Any hormone preparation would be classed as a medicine in the UK. As a result they can only be marketed if they have been fully assessed for safety, quality and efficacy by the MHRA and granted a marketing authorisation or product licence. The MHRA does not object to importation of desiccated thyroid extract products provided that they are approved by the United States' Food and Drugs Administration (FDA), standardised to the specification of the United States Pharmacopoeia (USP), and that they are authorised, prescription-only medicine for the treatment of patients with thyroid diseases for whom the UK-licensed synthetic thyroid hormones are not suitable. The MHRA says that it is the decision of each individual PCT as to whether an unlicensed product, in this case Armour, be available on NHS prescription or private prescription (MHRA, Jan 2005). If it is prescribed on an NHS prescription, the patient qualifies for medical exemption because the treatment is for hypothyroidism. Being unlicensed in this country, the doctor would be required to take full responsibility for any adverse effects of the treatment.

The Medicines Act makes provision for doctors to prescribe an unlicensed medicine to meet the needs of an individual patient, on their own responsibility, where they judge the benefit to the patient is justified and outweighs the risk of the unlicensed product. Therefore, the prescription of Armour is a question of clinical judgement on the part of each patient's GP. It is the responsibility of NHS Primary Care Trusts to fund supplies of medicines in their area, whether on a trial or permanent basis. Therefore the decision to provide Armour free from prescription charges would be taken by the GP in consultation with the local PCT.

The BTF sees synthetic thyroxine as the current first-line treatment of hypothyroidism. Current medical practice is governed by evidence. There is no known research showing that porcine thyroid extract is superior to synthetic thyroxine. On the contrary, there are good data that life-long treatment with synthetic thyroxine is safe.

The BTF understands that there are concerns about the use of Armour thyroid because of the rapid fluctuations in T3 levels, the difficulties in monitoring such treatment, uncertainties about the long-term health consequences and the considerably higher costs of such treatment.

The major professional thyroid organisations and published peer-reviewed guidelines on treatment of hypothyroidism recommend thyroxine as the treatment of choice for hypothyroidism and our position is in keeping with this view.

We believe that patients who feel unwell on thyroid hormone treatment merit assessment by a qualified, accredited endocrinologist. Such a management pathway will ensure that thyroid hormone replacement is optimal, other causes of symptoms are considered and a meaningful exploration of the potential risks and benefits of unproven therapies such as Armour can be explored.

We do not consider natural thyroid extract to be suitable for everyone but acknowledge that patients for whom synthetic thyroxine is judged not to be suitable on clinical grounds may, together with their doctor, wish to explore treatment with Armour.

We acknowledge that some doctors, acting out of the best possible interests in the well-being of their patients, and basing their judgement on current research evidence, may be reluctant to prescribe Armour.

Much of the debate about the use of Armour relates to individual accounts of patients who are convinced that switching from thyroxine to Armour has transformed their lives. Doctors are equally aware of patients who have found this treatment unhelpful and some have felt worse than on thyroxine. We feel that it is important to keep an open mind about alternative thyroid hormone replacement regimens to thyroxine, but these issues can only be addressed by a properly conducted prospective randomised controlled trial.


British Thyroid Foundation - www.btf-thyroid.org
Updated : Tuesday, 04 October 2005. [8:22:46]

"

------------------------------------

 

 

Dette er en privat hjemmeside. og ingen må ta dette som medisinske råd.