About 5%–10% of hypothyroid patients on T4 replacement therapy have persistent symptoms, despite normal TSH levels. It was hoped that T4 + T3 combination therapy might provide better outcomes, but that was not observed according to a meta-analysis of 11 randomized clinical trials comparing T4 monotherapy with T4 + T3 combination therapy. However, the issue is still subject of much research because normal thyroid function tests in serum may not necessarily indicate an euthyroid state in all peripheral tissues. This review evaluates recent developments in the field of T4 + T3 combination therapy. T4 monotherapy is associated with higher serum FT4 levels than in healthy subjects, and subnormal serum FT3 and FT3/FT4 ratios are observed in about 15% and 30% respectively. T4 + T3 combination therapy may mimic more closely thyroid function tests of healthy subjects, but it has not been demonstrated that relatively low serum FT3 or FT3/FT4 ratios are linked to persistent symptoms. One study reports polymorphism Thr92Ala in DIO2 is related to lower serum FT3 levels after thyroidectomy, and that the D2-Ala mutant reduces T4 to T3 conversion in cell cultures. Peripheral tissue function tests such as serum cholesterol reflect thyroid hormone action in target tissues. Using such biochemical markers, patients who had a normal serum TSH during postoperative T4 monotherapy, were mildly hypothyroid, whereas those with a TSH 0.03–≤0.3 mU/L were closest to euthyroidism. Peripheral tissue function tests suggest euthyroidism more often in patients randomized to T4 + T3 rather than that to T4. Preference for T4 + T3 combination over T4 monotherapy was dose-dependently related to the presence of two polymorphisms in MCT10 and DIO2 in one small study. It is not known if persistent symptoms during T4 monotherapy disappear by switching to T4 + T3 combination therapy. The number of patients on T4 + T3 therapy has multiplied in the last decade, likely induced by indiscriminate statements on the internet. Patients are sometimes not just asking but rather demanding this treatment modality. It creates tensions between patients and physicians. Only continued research will answer the question whether or not T4 + T3 combination therapy has true benefits in some patients.
Wilmar M Wiersinga
Approximately 10% of hypothyroid patients are dissatisfied with the outcome of levothyroxine replacement. It is unlikely that slight over- or under-treatment with thyroxine (T4) explains remaining complaints. Meta-analysis of randomized clinical trials shows no advantage of T4/tri-iodothyronine (T3) combination therapy over T4 monotherapy. However, each of these trials can be criticized, and none is perfect: most of them failed to mimic the physiological ratio of serum free T4 (FT4) to free T3 (FT3) concentrations. Development of a sustained-release T3 preparation given as a single nighttime dose (together with levothyroxine once daily) might maintain physiological serum FT4–FT3 ratio's throughout 24 h. Genetic polymorphisms in deiodinase 2 and thyroid hormone transporters have been associated with well-being, fatigue, depression, and greater improvement on combination therapy. Future trials should target carriers of these polymorphisms to see whether they do better on T4/T3 combination therapy than on T4 monotherapy.
Gerasimos E Krassas and Wilmar Wiersinga
New studies have shown that smoking may protect against the development of thyroid peroxidase antibodies, which may result in a decreased risk of Hashimoto’s hypothyroidism (HH), whereas it stimulates the development of Graves’ hyperthyroidism (GH). According to the above-mentioned hypothesis, to stop smoking would decrease the risk of GH but increase the risk of HH. Also, smoking has been identified as one of the risk factors for the development or worsening of eye changes after 131I treatment of GH. Additionally, the outcome of medical treatment of Graves’ ophthalmopathy (GO) is less favourable in smokers as compared to non-smokers. There is concern also about the effect of passive smoking on autoimmune thyroid disease. In a recent study it has been shown that the latter may have a deleterious effect on childhood GO.
Grigoris Effraimidis and Wilmar M Wiersinga
The last 10 years have seen some progress in understanding the etiology of autoimmune thyroid disease (AITD). The female preponderance can now be explained – at least in part – by fetal microchimerism and X-chromosome inactivation. The number of identified susceptibility genes for AITD is increasing (among others now including TSHR, TG, HLA, CTLA4, PTPN22, CD40, FCRL3, IL2RA, and FOXP3), but these genes together probably do not explain more than about 10% of the heritability of AITD. As twin studies indicate that genes contribute for 70% of AITD, it follows that there must be many more loci, each of them contributing a little. While the genetic studies have clarified why various autoimmune diseases so often cluster in the same patient, the molecular mechanism of action of these genetic polymorphisms (frequently located in introns) has hardly been explained. Polymorphisms in AITD susceptibility genes may become helpful in clinical practice, e.g. in assessing risk of recurrent Graves' hyperthyroidism (GH) after a course of antithyroid drugs. Moderate alcohol intake decreases the risk on overt GH and overt Hashimoto's hypothyroidism. Current smokers – as well known – are at increased risk for Graves' disease, but – surprisingly – at diminished risk for Hashimoto's thyroiditis. Low selenium and low vitamin D levels might increase the risk of developing AITD, but data are still inconclusive. Current options for preventive interventions in subjects at risk to develop AITD are very limited.
Ria Adriaanse, Johannes A Romijn, Erik Endert and Wilmar M Wiersinga
The nocturnal TSH surge was studied in controls, in 34 patients with hypothalamic/pituitary disease and in 21 patients with primary hypothyroidism. It was absent in 5/12 hypothyroid patients and in 5/22 euthyroid patients with hypothalamic/pituitary disease (42% vs 23%. NS). Central hypothyroidism relative to euthyroidism was associated with a lower absolute (0.3±0.4 vs 0.9±1.0 mU/l, p<0.05) and relative (24±31 vs 63±51%, p<0.05) nocturnal rise in TSH. In primary hypothyroidism, the nocturnal TSH surge was absent in eight often patients with overt, in one of five patients with mild and in none of six patients with subclinical hypothyroidism. The relative nocturnal rise in TSH was normal in mild (54±33%) and subclinical (92±69%), but decreased in overt hypothyroidism (2±10%). Plasma T4 was positively and 09.00 plasma TSH negatively related to the relative nocturnal TSH surge in primary hypothyroidism, but not in central lesions. In both conditions, however, a positive relationship was observed between the relative nocturnal TSH surge and the relative increase of TSH to TRH. In conclusion: (a) The nocturnal TSH surge is usually absent in overt hypothyroidism but present in mild primary hypothyroidism and equivocal in central hypothyroidism. This limits its usefulness as an adjunct in the diagnosis of central hypothyroidism. (b) The magnitude of the nocturnal TSH surge in patients with hypothalamic/pituitary disease or primary hypothyroidism is directly related to the TSH response to TRH, and thus appears to be determined by the directly releasable TSH pool of the pituitary.
Anita Boelen, Marianne C Platvoet-ter Schiphorst, Nico van Rooijen and Wilmar M Wiersinga
Boelen A, Platvoet-ter Schiphorst MC, van Rooijen N, Wiersinga WM. Selective macrophage depletion in the liver does not prevent the development of the sick euthyroid syndrome in the mouse. Eur J Endocrinol 1996;134:513–8. ISSN 0804–4643
A decreased serum triiodothyronine (T3) level is one of the main characteristics of the sick euthyroid syndrome, caused mainly by a decreased 5′-deiodination of thyroxine (T4) in the liver. Cytokines have been implicated in the pathogenesis of the changes in thyroid hormone metabolism during illness. We therefore investigated the role of cytokines produced by the liver macrophages (Kupffer cells) in the development of the sick euthyroid syndrome, which was induced in mice by a single injection of bacterial endotoxin (lipopolysaccharide) or by 24-h starvation. Experiments were carried out with or without previous selective depletion of liver macrophages by intravenous administration of liposome-encapsulated dichloromethylene diphosphonate. Relative to saline-injected pair-fed controls, the administration of lipopolysaccharide caused a decrease of serum T3 and T4 and liver 5′-deiodinase mRNA. Selective depletion of liver macrophages did not affect these changes. Starvation for 24 h decreased serum T3 and T4, associated with a slight decrease of liver 5′-deiodinase mRNA. There were no differences between macrophage-depleted and non-depleted animals in this respect. In summary, selective depletion of liver macrophages did not affect the decrease in serum T3, T4 or liver 5′-deiodinase mRNA induced by lipopolysaccharide or 24-h starvation in mice. We conclude that cytokines produced by Kupffer cells are not involved in the pathogenesis of the sick euthyroid syndrome in this experimental model.
A Boelen, Department of Endocrinology, F5-171 Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
Xander G Vos, Natalie Smit, Erik Endert, Jan G P Tijssen and Wilmar M Wiersinga
Both genetic and environmental factors contribute to susceptibility of Graves' disease. In this study, we evaluated whether the duration of symptoms or a positive family history of autoimmune thyroid disease (AITD) are related to specific phenotypes in patients with a first episode of Graves' hyperthyroidism (GH).
Cross-sectional multicentre observational study.
Two hundred and sixty-three consecutive untreated patients (mean age (±s.d.) 42.6±12.4 years; range 16–79 years) with a first episode of GH were included. Biochemical and clinical severity of GH was evaluated. Participants were asked to complete questionnaires about environmental factors (smoking behavior, use of estrogens, stress etc.), the duration of symptoms (interval between start of symptoms and date of referral) and family history for AITD. We ascertained the autoimmune nature of thyroid disease in affected relatives. Family history scores (FHS; high score indicating a close genetic relationship and/or a large number of affected relatives) were calculated for patients with a positive family history for AITD.
The peak incidence for the diagnosis of GH was 2–3 months after onset of symptoms (32% of patients). Duration of symptoms was negatively associated with age (P for trend=0.04). A positive family history for AITD was present in 42.6% of patients. Patients with the highest FHS were more often male (P=0.01) while age at onset was lower (P=0.02) compared to patients with a lower FHS. Among patient groups with different FHS, no differences were found in exposure to environmental factors, nor in clinical or biochemical severity of hyperthyroidism.
Our study does not support the hypothesis that a short duration of thyrotoxic symptoms until diagnosis is related to more severe hyperthyroidism in Graves' disease. We have found supporting evidence for the existence of genetic anticipation in Graves' disease by means of a lower age of onset in the group with the highest FHS.
Xander G Vos, Erik Endert, Jan G P Tijssen and Wilmar M Wiersinga
Genetic polymorphisms and environmental factors are both involved in the pathogenesis of Graves' disease, but their interaction and effect on Graves' phenotypes have scarcely been investigated.
To test the hypothesis that subjects with susceptibility genotypes develop more severe Graves' hyperthyroidism at a younger age and after less exposure to environmental factors, with attention to gender differences.
A prospective observational multicenter study in 205 adult Caucasian patients with untreated first episode of Graves' hyperthyroidism.
Evaluation of genotypes (HLA DRB1*03, DQA1*05, DQB1*02; CTLA4 49A/G, CT60 A/G; PTPN22 C/T) in relation to phenotypes (age, sex, severity (clinical, biochemical, and immunological)) of hyperthyroidism and environmental factors (smoking, stress questionnaires).
G-alleles in CTLA4 single nucleotide polymorphisms were dose-dependently associated with younger age at the time of diagnosis and less exposure to daily hassles. In gender-specific analysis, this association is enhanced in men and attenuated in women. Males (but not females) in HLA linkage disequilibrium had more severe (biochemical and immunological) hyperthyroidism and a tendency to younger age at diagnosis, compared with those not in linkage disequilibrium.
Graves' hyperthyroidism occurs at a younger age with less exposure to environmental factors in subjects carrying susceptibility genotypes. The impact of genotypes seems to be greater in males than in females.
Ria Adriaanse, Georg Brabant, Erik Endert, Frederique J Bemelman and Wilmar M Wiersinga
Adriaanse R, Brabant G, Endert E, Bemelman FJ, Wiersinga WM. Pulsatile thyrotropin and prolactin secretion in a patient with mixed thyrotropin- and prolactin-secreting pituitary adenoma. Eur J Endocrinol 1994;130:113–20. ISSN 0804–4643
The circadian and pulsatile thyrotropin (TSH) and prolactin (PRL) release was investigated in a patient with slight hyperthyroidism due to a mixed TSH- and PRL-secreting pituitary adenoma. Blood was withdrawn every 10 min for 24 h (before and after medical treatment); pulse characteristics were analyzed by Desade and Cluster programs (values as mean±sd). The inappropriately high mean 24-h TSH concentration of 3.55 ±0.31 mU/l was associated with a higher mean 24-h TSH pulse amplitude but unaltered mean 24-h TSH pulse frequency relative to healthy controls. The nocturnal TSH surge (absolute surge 0.5 mU/l, relative surge 16%) was low, related to a loss of the usual nocturnal increase of TSH pulse amplitude and TSH pulse frequency. Chronic treatment with octreotide resulted in a modest clinical and biochemical improvement of the hyperthyroid state; addition of bromocriptine at a later stage had no further beneficial effect. At the end of the follow-up period the mean 24-h TSH paradoxically had increased to 5.33 ±0.81 mU/l. The nocturnal TSH surge also increased (absolute surge 1.9 mU/l, relative surge 42%), but circadian changes in TSH pulsatility remained absent. In the untreated period the increased mean 24-h PRL concentration of 234 ± 24 μg/l was associated with an increased mean 24-h PRL amplitude, whereas the 24-h PRL pulse frequency (N = 4) was lower relative to controls. No circadian PRL rhythm was present. After octreotide and bromocriptine treatment the mean 24-h PRL concentration and mean 24-h PRL pulse amplitude were unchanged, but a clear nocturnal increase of PRL now was observed. Analysis of the temporal coupling between TSH and PRL release by bivariate autoregressive modeling revealed significant cross-correlations in all three periods investigated (coefficients in the range 0.34–0.76, median 0.52; p<0.01) between TSH and PRL concentrations with a lag time of 10–20 min. We conclude that pulsatile TSH and PRL release in this mixed TSH- and PRL-secreting pituitary adenoma was autonomous in nature. The observed dampening of the nocturnal increase of TSH and PRL is putatively related to a lack of TRH receptors in these tumors. The observed co-secretion of TSH and PRL suggests synthesis of both hormones by the same cell.
R Adriaanse, Department of Endocrinology F5-171, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
Peter W Potgieser, Wilmar M Wiersinga, Noortje I Regensburg and Maarten P Mourits
To describe volumes of orbital fat (FV) and extraocular muscles (MV) in Graves' orbitopathy (GO) as a function of the duration of GO.
i) Cross-sectional survey among 95 consecutive patients with untreated GO who had been referred to the combined thyroid–eye clinics of our university hospital. ii) Longitudinal survey among 39 of the 95 patients who did not receive any therapeutic intervention and were followed for 1 year.
A computed tomography (CT)-based and well-validated method for calculating orbital soft tissues. In order to neutralize sex differences, results are expressed as ratios of FV:orbital volume (OV) and MV:OV.
i) Patients with GO duration of >1 year had greater FV:OV (0.65 vs 0.55, P=0.004), similar MV:OV (0.22 vs 0.21, not significant (NS)), and more proptosis (22 mm vs 21 mm, P=0.03) as compared to those with shorter duration. ii) As compared to baseline, after 1 year, FV:OV had increased (0.56 vs 0.63, P=0.000), MV:OV had not changed (0.19 vs 0.19, NS), proptosis was higher (20 mm vs 21 mm, P=0.003), and clinical activity scores had become lower (2 vs 1, P=0.02) (median values).
CT images show that a longer duration of GO is associated with a higher orbital FV. Extraocular MV, however, is not associated with GO duration; rather, it is related to the severity of GO.