Denne artikkelen går detaljert gjennom rådene gitt til legene, for behandling av hypotyreose. Det viser seg at flere av rådene går mot forskningen som fins.

 

Behandlingsveilederen BMJ

Et utbredt problem for hypotyreosepasienter er at man gjerne blir holdt på for lave doser av tyroksin (Levaxin). Dosene blir holdt lave med argument om at langvarig overdosering vil gi økt risiko for osteoporose og hjerte-/kar-problemer senere.

Doseringen administreres i liten grad ut fra symptomer, men styres ut fra serumverdien på TSH (Thyreoidea Stimulerende Hormon). Behandlingsmålet er at denne er verdien skal være innenfor 0,4 – 1,5 og pasienten skal være eutyrot (uten symptomer). Men det er ofte her det svikter.

Mange pasienter opplever først bedring og fravær av symptomer ved mye lavere verdier av TSH, gjerne en helt supprimert (umålbar) TSH-verdi. Problemet blir da at legen holder pasienten underdosert, og ser bort fra ofte sterkt invalidiserende kliniske symptomer. Hovedargumentet er, som sagt, at en dosering som gir supprimert TSH gir økt risiko for osteoporose og hjerte- karproblemer.

British Medical Journal (BMJ) har utarbeidet behandlingsveiledere for leger innenfor en rekke sykdommer og tilstander.

En oversikt for hypotyreose finner du her

 

For pasienter under 60 år finner vi følgende veiledning for behandling:

Confirmed primary hypothyroidism

The goal of treatment is reduction of symptoms and prevention of long-term complications. [1] [5] [12] Treatment is given upon establishing the diagnosis and is lifelong.[B Evidence] Patients should be started on the full replacement dose of levothyroxine. [5]

The main complication of treatment is over-replacement of thyroid hormone, which increases the risk of osteoporosis[B Evidence] and atrial fibrillation. [1] [5]

Pregnancy increases thyroid hormone requirements and the required dose of levothyroxine may increase. TSH should be measured every 6 weeks in pregnant patients. [5] [19] Nephrotic syndrome and malabsorption (e.g., coeliac disease) can increase levothyroxine requirements. [5] Concomitant use of iron, cholestyramine, calcium, sucralfate, anticonvulsants (e.g., phenytoin, phenobarbital, and carbamazepine), rifampin, and sertraline may cause an increase in dosage requirements. [5] [12]

The dose is adjusted in small increments to normalise TSH, which is the chemical goal of therapy. Due to the long half-life of levothyroxine (1 week), TSH should be measured 4 to 6 weeks after initiation of therapy or dosage change. [1] [5] [12]

Primary Options: levothyroxine : 1.6 micrograms/kg/day orally adjust dose in increments of 12.5 to 25 micrograms to normalise TSH

 

 

For full referanseliste for veilederen, se her:

Påstanden om komplikasjoner ved overdosering inneholder flere referanser til studier:

The main complication of treatment is over-replacement of thyroid hormone, which increases the risk of osteoporosis[B Evidence] and atrial fibrillation. [1] [5]

Om «Evidence B» står det følgende:

Evidence Score Adverse effects: there is medium-quality evidence that prolonged therapy with levothyroxine causes more bone mass loss in post-menopausal women but not pre-menopausal women compared with control. Poor-quality evidence suggests that levothyroxine may be no different at reducing risk of fractures compared with control.

Evidence Level B Randomized controlled trials (RCTs) of <200 participants, methodologically flawed RCTs of >200 participants, methodologically flawed systematic reviews (SRs) or good quality observational (cohort) studies.

Altså, «medium-quality evidence» sier at man ved langvarig bruk av levotyroksin finner mer beinmassetap hos post-menopause kvinner, men ikke hos pre-menopause kvinner. Og «poor-quality evidence» antyder at behandling med levotyroksin ikke reduserer risiko for frakturer.

We found one longitudinal observational study,[7] one systematic review (search date not reported),[8] and one cohort study[9] that reported on adverse effects of levothyroxine.

 

For full referanseliste for «clinical evidence», se her:

Den første studien [7] tar for seg frakturer i bein:

Leese GP, Jung RT, Guthrie C, et al. Morbidity in patients on L-thyroxine: a comparison of those with a normal TSH to those with a suppressed TSH. Clin Endocrinol (Oxf) 1992;37:500–503. Her er lenke til abstract:

 

Abstract:

Patients on L-thyroxine with a ‘suppressed’ TSH (< 0.05 mU/l) were compared to those in whom TSH was detectable but not elevated (0.05-4.0 mU/l), with regard to morbidity data.

 

DESIGN: Biochemical data from Tayside Thyroid Register was matched to hospital admissions data obtained from Health Board Statistics.

 

PATIENTS: The patients were identified from those registered on the computerized Tayside Register.

 

MEASUREMENTS: Serum T4 and TSH assays, clinical assessment scores, and admission records with regard to ischaemic heart disease, overall fractures, fractured neck of femur and breast carcinoma.

 

RESULTS: Over one year, 1180 patients on thyroxine replacement had clinical and biochemical assessment; 59% had a suppressed TSH and 38% ‘normal’ TSH. Patients with a suppressed TSH exhibited higher median serum thyroxine levels (146 nmol/l, range 77-252 vs 119 nmol/l, 58-224; P < 0.001). Patients under the age of 65 years on L-thyroxine had an increased risk of ischaemic heart disease compared to the general population (female 2.7 vs 0.7%, P < 0.001; male 6.4 vs 1.7%, P < 0.01), but the risk was no different between those with suppressed and normal TSH. There was no increase in risk for overall fracture, fractured neck of femur or breast carcinoma in those on thyroxine with suppressed or normal TSH.

 

CONCLUSION: Patients under the age of 65 years on L-thyroxine had an increased risk of ischaemic heart disease. There was no excess of fractures in patients on L-thyroxine even if the TSH is suppressed.

 

Studien sier altså at det var ingen økt forekomst av frakturer hos pasienter med supprimert TSH. Pasienter under 65 år som behandles med levotyroksin, har en økt risiko for hjertesykdom i forhold til normalbefolkningen, men ingen større risiko for pasienter med supprimert TSH.

Den andre studien [8] tar for seg endringer i beinmasse hos pasienter med langvarig supprimert TSH:

Faber J, Galløe AM. Changes in bone mass during prolonged subclinical hyperthyroidism due to L-thyroxine treatment: a meta-analysis. Eur J Endocrinol 1994;130:350–356. Her er lenke til hele artikkelen

Abstract

l-Thyroxine (l-T4) in the treatment of thyroid disease resulting in reduced serum thyrotropin (TSH) has been associated with reduced bone mass and thus the potential risk of premature development of osteoporosis. However, several recent studies have failed to show such a detrimental effect. These disagreements are probably due to only a small number of patients taking part in each study, decreasing the change of finding significant differences and increasing the risk of missing a real difference (type 1 and 2 errors, respectively). We therefore performed a meta-analysis on the available papers (N = 13), in which bone mass was measured in the distal forearm, femoral neck or lumbar spine in a cross-sectional manner in women with suppressed serum TSH due to l-T4 treatment and in a control group. The women were divided according to their pre- and postmenopausal state, because preserved estrogen production plays a protective role against irreversible bone loss. Based on the number of measurements performed on the different sites of the skeleton, a theoretical bone composed of 30.4% distal forearm, 28.8% femoral neck and 40.8% lumbar spine could be constructed in premenopausal women (441 measurements). A premenopausal woman at an average age of 39.6 years and treated with 164 μg l-T4/day for 8.5 years, leading to suppressed serum TSH, had 2.67% less bone mass than controls (NS), corresponding to an excess annual bone loss of 0.31% after 8.5 years of treatment (NS). The risk of not detecting an excess bone loss of at least 1% per year (type 2 error) was p < 0.15. Similarly, a postmenopausal woman with a bone consisting of 11.3% distal forearm, 42.0% femoral neck and 46.7% lumbar spine (317 measurements) at an average age of 61.2 years and treated with 171 μg l-T4/day for 9.9 years had 9.02% less bone mass than controls (2p < 0.007), corresponding to a significant excess of annual loss of 0.91% after 9.9 years of treatment. Eighteen papers with a mean of 18 patients showing no difference between postmenopausal patients and controls would have to be published or found before this difference could turn into a non-significant finding (the file drawer problem).

In conclusion, the meta-analysis on the available crosssectional studies did not find any significant reduction in bone mass during prolonged l-T4 treatment resulting in reduced serum TSH in premenopausal women. The risk of the present meta-analysis missing a clinically relevant annual loss of at least 1% in premenopausal women was less than 15%. In contrast, l-T4 treatment in postmenopausal women in a dosis leading to reduced serum TSH resulted in a significant excess of annual bone loss of 0.91%/year after 9.9 years in comparison to control women.

 

Altså, ingen signifikant forskjell i beinmasse hos pre-menopause kvinner med supprimert TSH, sammenlignet med friske pre-menopause kvinner. For post-menopause kvinner viser artikkelforfatterne til østrogenmangel som en sannsynlig forklaring på redusert beinmasse, og at man i disse tilfellene må være mere forsiktig med overdosering, men at man også bør vurdere tilleggsbehandling med østrogen/gestagen.
Den siste studien [9] tar for seg risiko for hjerteproblemer ved lav TSH:
Sawin CT, Geller A, Wolf PA, et al. «Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons.» N Engl J Med 1994;331:1249–1252. Her er lenke til hele artikkelen

 

 

Abstract

BACKGROUND:

Low serum thyrotropin concentrations are a sensitive indicator of hyperthyroidism but can also occur in persons who have no clinical manifestations of the disorder. We studied whether low serum thyrotropin concentrations in clinically euthyroid older persons are a risk factor for subsequent atrial fibrillation.

 

METHODS:

We studied 2007 persons (814 men and 1193 women) 60 years of age or older who did not have atrial fibrillation in order to determine the frequency of this arrhythmia during a 10-year follow-up period. The subjects were classified according to their serum thyrotropin concentrations: those with low values (< or = 0.1 mU per liter; 61 subjects); those with slightly low values (> 0.1 to 0.4 mU per liter; 187 subjects); those with normal values (> 0.4 to 5.0 mU per liter; 1576 subjects); and those with high values (> 5.0 mU per liter; 183 subjects).

 

RESULTS:

During the 10-year follow-up period, atrial fibrillation occurred in 13 persons with low initial values for serum thyrotropin, 23 with slightly low values, 133 with normal values, and 23 with high values. The cumulative incidence of atrial fibrillation at 10 years was 28 percent among the subjects with low serum thyrotropin values (< or = 0.1 mU per liter), as compared with 11 percent among those with normal values; the age-adjusted incidence of atrial fibrillation was 28 per 1000 person-years among those with low values and 10 per 1000 person-years among those with normal values (P = 0.005). After adjustment for other known risk factors, the relative risk of atrial fibrillation in elderly subjects with low serum thyrotropin concentrations, as compared with those with normal concentrations, was 3.1 (95 percent confidence interval, 1.7 to 5.5; P < 0.001). The 10-year incidence of atrial fibrillation in the groups with slightly low and high serum thyrotropin values was not significantly different from that in the group with normal values.

 

CONCLUSIONS:

Among people 60 years of age or older, a low serum thyrotropin concentration is associated with a threefold higher risk that atrial fibrillation will develop in the subsequent decade.

Denne studien har flere svakheter i forhold til at den brukes som dokumentasjon for å utvise forsiktighet i dosering av levotyroksin generelt. For det første, så er det ikke en studie av pasienter under behandling av levotyroksin, men pasienter med «naturlig» supprimert TSH, altså såkalt subklinisk hypertyreose, definert som lav TSH, ingen hyper-symptomer og normale tyroid-hormon konsentrasjoner (T4). En annen svakhet er at utvalget er begrenset til personer over 60 år, og dermed er det kun denne aldersgruppen denne studien sier noe om. Allikevel bruker BMJ’s best practice dette som «bevis» i forhold til behandling av pasienter under 60 år.

Videre henviser bmj’s best pracice guide til referanser [1] og [5] i forhold til økt risiko for hjertearytmier:

[1]: Franklyn JA. Hypothyroidism. Medicine. 2005;33:27-29.

[5]: Roberts CG, Ladenson PW. Hypothyroidism. Lancet. 2004;363:793-803.

 

Det har ikke lykkes meg å finne den første referansen, som jeg antar er fra en grunnleggende lærebok i medisin. Den andre referansen er en seminar-artikkel fra The Lancet, som tar for seg flere sider rundt hypotyreose, både diagnostisering og behandling. Her er lenke til hele artikkelen

Hypothyroidism. Roberts CG, Ladenson PW. Division of Endocrinology and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Abstract

Hypothyroidism is common, potentially serious, often clinically overlooked, readily diagnosed by laboratory testing, and eminently treatable. The condition is particularly prevalent in older women, in whom autoimmune thyroiditis is common. Other important causes include congenital thyroid disorders, previous thyroid surgery and irradiation, drugs such as lithium carbonate and amiodarone, and pituitary and hypothalamic disorders. Worldwide, dietary iodine deficiency remains an important cause. Hypothyroidism can present with nonspecific constitutional and neuropsychiatric complaints, or with hypercholesterolaemia, hyponatraemia, hyperprolactinaemia, or hyperhomocysteinaemia. Severe untreated hypothyroidism can lead to heart failure, psychosis, and coma. Although these manifestations are neither specific nor sensitive, the diagnosis is confirmed or excluded by measurements of serum thyrotropin and free thyroxine. Thyroxine replacement therapy is highly effective and safe, but suboptimal dosing is common in clinical practice. Patient noncompliance, drug interactions, and pregnancy can lead to inadequate treatment. Iatrogenic thyrotoxicosis can cause symptoms, and, even when mild, provoke atrial fibrillation and osteoporosis. We summarise present understanding of the history, epidemiology, pathophysiology, and clinical diagnosis and management of hypothyroidism.

Også i denne artikkelen finner vi påstander om økt risiko for osteoporose og hjertearytmier:

Adverse reactions and problems:

Adverse reactions to thyroxine treatment are related to excessive or increased thyroid hormone action, and include symptomatic thyrotoxicosis, subclinical thyrotoxicosis with increased risks of bone loss,[132] and atrial tachyarrhythmias.[133]

Men legg merke til at her relaterer man ikke dette til en supprimert TSH-verdi, men heller til en for høy verdi av tyroid-hormoner (T4 og T3).

Den første referansen [132], som er relatert til økt risiko for redusert beinmasse, er denne:

May Lynn Quan, Janice L. Pasieka and Otto Rorstad: Bone mineral density in well-differentiated thyroid cancer patients treated with suppressive thyroxine: A systematic overview of the literature. Journal of Surgical Oncology 2002; 79: 62-69. Her er lenke til abstract.

 

Abstract:

Background:

The effects of subclinical hyperthyroidism on bone mineral density (BMD) induced by suppressive thyroxine therapy in patients with well-differentiated thyroid cancer (WDTC) remains unclear. An overview of the current literature was undertaken to evaluate studies to date.

 

Methods:

A systematic medline search yielded a total of 11 studies appropriate for review which included premenopausal women, postmenopausal women, and men on suppressive thyroxine post thyroidectomy for WDTC. Main outcome measures were bone mineral density and bone turnover markers.

 

Conclusions:

Although studies were limited by small numbers and varying degrees of control for confounding variables, results suggested no significant change in bone mineral density for premenopausal women or men. Findings for postmenopausal women remain unclear with two of the best controlled studies reporting opposing results. Further studies for this population are recommended to help guide clinical practice.

Studien sier faktiske det motsatte av det den blir brukt som belegg for!

Den andre refransen [133] er denne: Sawin CT, Geller A, Wolf PA, et al. Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons. N Engl J Med 1994;331:1249–1252.

Altså, den samme studien som bmj’s best practice guide refererer til …

Så for å gjøre en oppsummering:

BMJ’s Best Practice Guide for behandling av personer under 60 år maner til forsiktighet med dosering, med begrunnelse i forskjellige studier som gir «bevis» for at overdosering fører til økt risiko for osteoporose og hjertearytmi. Disse studiene sier det motsatte: at det ikke er noen signifikant forskjell i risiko for osteoporose hos yngre kvinner og menn. Og når det gjelder risiko for hjertearytmier, så henvises det kun til en studie gjort på eldre personer der ingen var under behandling med levotyroksin. Det må vel kunne sies å være en irrelevant studie i dette tilfellet, og ihvertfall alt for lite grunnlag til å trekke slike konklusjoner angående behandling av yngre pasienter.