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Wilmar M Wiersinga

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.

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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.

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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.

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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.

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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.

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Grigoris Effraimidis, Thea G A Strieder, Jan G P Tijssen and Wilmar M Wiersinga


To evaluate the progression in time from euthyroidism to overt autoimmune hypothyroidism or to overt autoimmune hyperthyroidism.

Subjects and methods

The design is that of a nested case–control study within the prospective Amsterdam autoimmune thyroid disease (AITD) cohort study in which 790 healthy euthyroid women with at least one first or second degree relative with documented AITD were followed for 5 years. Thyroid function tests were assessed annually. Contrast between cases (overt hypothyroidism – TSH>5.7 mU/l and free thyroxine (FT4)<9.3 pmol/l and overt hyperthyroidism – TSH<0.4 mU/l and FT4>20.1 pmol/l, also referred to as events) and controls (matched for age and duration of follow-up).


At baseline, the 38 hypothyroid cases had already higher TSH and lower FT4 concentrations than their 76 controls, and the difference between both the groups persisted 1 year before occurrence of the event. In contrast, neither TSH nor FT4 values differed between the 13 hyperthyroid cases and their 26 controls at baseline or 1 year before the event. The prevalence of thyroid peroxidase-Ab was higher in both hypothyroid and hyperthyroid cases than in controls. At the time of event, hypothyroid cases were less common among current smokers (P=0.083) and more common in the postpartum period (P=0.006) than their controls, whereas hyperthyroid cases were pregnant more frequently (P=0.063).


The data suggest that progression toward overt autoimmune hypothyroidism is a gradual process taking several years, but in contrast overt autoimmune hyperthyroidism develops faster in terms of months.

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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

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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.

Study design

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.

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Wilmar M. Wiersinga, Harrison J. L. Frank, Inder J. Chopra and David H. Solomon


The interrelationship between hepatic nuclear T3 receptors and glucose metabolism was studied in 8 diabetic rats and 8 paired control animals.

Serum glucose (mean ± sem, normal vs. diabetic, 167 ± 11 vs. 470 ± 41 mg/100 ml, P < 0.001) and plasma glucagon (183 ± 8.5 vs. 370 ± 29 pg/ml, P < 0.001) were higher in diabetic animals than in controls; serum insulin was lower but not significantly (59 ± 19 vs. 24 ± 12 μU/ml). Serum T4 (4.1 ± 0.53 vs. 0.8 ± 0.27 μg/100 ml, P < 0.005) and T3 (77.3 ± 3.2 vs. 41.7 ± 12.1 ng/100 ml, P < 0.05) were lower in diabetic rats than in controls. Hepatic concentration of non-protein sulfhydryl-groups was also moderately (∼ 19%) lower in diabetic rats than in controls (4.62 ± 0.11 vs. 3.75 ± 0.24 μmol/g, P < 0.02).

The maximal binding capacity (MBC) of the binding of [125I]T3 to isolated rat liver nuclei was significantly decreased in the diabetic rats (368 ± 37 vs. 232 ± 36 fmol/mg DNA, P < 0.01; mean decrease 38%); the affinity constant Ka) was also lower but not significantly (1.60 ± 0.13 vs. 1.25 ± 0.13 109 L/M, 0.05 < P < 0.1). Addition of 1 mm dithiothreitol (DTT) enhanced the Ka of nuclear binding of T3 similarly in the controls and the diabetics. However, it did not restore the decreased MBC of nuclear binding of T3 in diabetic rats to the level of the controls.

The decrease in MBC of hepatic nuclei for T3 did not correlate (P < 0.05) with the decrease in serum T3, serum T4, or hepatic non-protein sulfhydryl-groups. There was, however, a significant negative correlation of MBC of T3 with serum glucose and with plasma glucagon. These data suggest a regulatory role of glucose metabolism (or glucagon) in modulation of binding of T3 by hepatic nuclear T3 receptors.

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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