Thyroid Disorders: Diagnosis and Therapeutic Approaches 2015

J Lab Med 2016; aop

Endocrinology Edited by: M. Bidlingmaier/J. Kratzsch

Dagmar Führer* Thyroid disorders: diagnosis and therapeutic approaches 2015

DOI 10.1515/labmed-2016-0028 2. Graves’ orbitopathy is the most frequent extrathyroi- Received August 11, 2015; accepted November 16, 2015 dal manifestation and thus its prevention and adequate treatment is mandatory. Abstract: This review summarizes recent studies and 3. Treatment of Graves’ disease during pregnancy must evidence-based recommendations on management of take into account maternal and fetal aspects as well as thyroid disorders, including Graves’ disease and Graves’ the risk for neonatal hyperthyroidism. orbitopathy, laboratory and clinical issues on hypothyroidism and its treatment, risk assessment of thyroid nod- A recent survey among thyroid experts of American, ules and novel concepts for risk adapted management of European and Japanese thyroid associations [1] shows thyroid cancer. substantial regional variety in primary treatment regi- Keywords: Graves’ disease; Graves’s orbitopathy; hypo- mens for Graves’ disease. In Europe, primary treatment thyroidism; thyroid; thyroid cancer; thyroid nodules. involves thyrostatics (86%) radioiodine therapy is used in approx. 13% of patients, while 1% of patients undergo thyroid surgery. By contrast, radioiodine therapy is very common in the US (59%) and only 41% of US patients Graves’ disease and receive antithyroid drugs as primary treatment. Pre- thyroid-associated orbitopathy ferred antithyroid drugs were thiamazole or, less fre- quently carbimazole. Propylthiouracil was hardly used, because of reports on increased hepatotoxicity. The Differences in the primary treatment of preferred starting dose for thiamazole was 20–30 mg Graves’ disease once per day. After commencing thyrostatic treatment, most thyroid experts advised initial follow-up after 4–6 Graves’ disease is a systemic autoimmune disease. Its weeks. Upon reaching normal thyroid function, follow- disease course is determined by a complex network of still up intervals of 3 months were recommended. Follow-up not fully understood cellular and humoral factors. Medi- examinations usually included assessment of liver func- ated by TSH receptor antibodies, the condition results tion parameters and full blood count. If thyrostatics led in stimulation of thyroid function and often also thyroid to rashes, a regimen of antihistamines was commenced. proliferation. In countries with sufficient iodine intake, If there was no response to treatment, 55% of experts Graves’ disease represents the most common cause of recommended a change of antithyroid drug, while 38% hyperthyroidism. The treatment of Graves’ diseases poses would opt for thyroid ablation. Nineteen percent of several challenges: thyroid experts recommended thyrostatic treatment for 1. Hyperthyroidism often takes a variable course, and 24 months, 35% for 18 months, 30% for 12 months, and one must choose between conservative thyrostatic 14% for < 1 year up to the point where a decision must be management and thyroid ablation (radioiodine taken as to whether Graves’ disease could be expected to therapy or surgery). go into remission. The occurrence of Graves’ orbitopathy (GO) had a substantial influence on the therapeutic approach. In this *Correspondence: Prof. Dr. Dr. Dagmar Führer, Universitätsklinikum case, most experts were in favor of primary thyrostatic Essen (AöR), Klinik für Endokrinologie und Stoffwechselerkrankungen treatment (63%), followed by thyroid surgery (18.5%), und, Zentrallabor – Bereich Forschung und Lehre, Hufelandstr. 55, 45147 Essen, Germany, Tel.: +49 201/723-6401, Fax: +49 201/723- and radioiodine therapy (17%) together with steroid 5972, E-Mail: [email protected] prophylaxis [1]. 2 Führer: Update – Studies and evidence-based treatment recommendations regarding thyroid disorders

In summary and compared to previous surveys, this newborns of mothers with Graves’ disease (acute or recent questionnaire showed a significant increase in thy- former disease), one must expect neonatal hyper- rostatic primary treatment of Graves’ disease, which is thyroidism due to transplacental TRAb passage. It is already practice in Europe. therefore recommended that pregnant patients with Graves’ disease (known or determined from patient’s history) be tested for TRAb in the 22th to 28th weeks of Clinical significance of TSH receptor antibody pregnancy. Where TRAb levels are three times above determination reference range, a close monitoring of the fetus and neonatus is recommended. Hyperthyroidism in Graves’ disease is caused by direct stimulation of thyrocytes via the interaction of TSH recep- In summary, three indications for TRAb analysis can be tor antibodies (TRAb) with the G-Protein coupled TSH- defined: 1. differential diagnosis of hyperthyroidism, 2. receptor at the cell membrane. Assays for detection of TRAb prognostic estimation of remission at the end of thyro- rely on competitive binding of TRAb from patient sera vs. static therapy, and 3. assessment of risk for fetal and neo- monoclonal labeled TSHR antibodies to the porcine TSH natal hyperthyroidism in pregnancy [2]. receptor (so-called TBII assays). To assess the biological activity of TRAb (stimulating, blocking, neutral), the use of bioassays (TSI assays) is necessary, but these are not Graves orbitopathy (GO) widely available. In a review, Barbesino and Tomer discuss the diag- Graves orbitopathy (GO, syn. thyroid eye disease, nostic and prognostic significance of TRAb analysis [2]: endocrine orbitopathy) is the most common and often 1. Third-generation TBI assays have a specificity of up to the most troublesome complication of Graves’ disease, 99% and a sensitivity of up to 97% for the diagnosis with a severe negative impact on quality of life (including of Graves’ disease in patients with untreated hyper- capacity for work and driving; [3]). Thanks to EUGOGO thyroidism. TRAb analysis does not help, if Graves’ (European Group On Study of Graves’ Orbitopathy), cri- disease can be diagnosed clinically e.g. due to pres- teria have been developed and proposed for a standard- ence of Graves orbitopathy. But it does help in unclear ized evaluation of the activity and severity of GO (www. cases of hyperthyroidism (e.g. De Quervain’s thyroidi- eugogo.eu). tis, drug-induced thyroiditis, post-partum thyroiditis, hyperthyroidism during pregnancy). Furthermore, TRAb analysis is also helpful in cases of unexplained (euthyroid) exophthalmus. Prevalence and natural history of Graves’ orbitopathy in 2. TRAb analysis may have a prognostic significance in new onset Graves’ disease assessing the relapse risk for hyperthyroidism after discontinuation of thyrostatic treatment. According An Italian study examined 346 patients with newly to two studies, a TRAb level of > 3.8 IU/L or 5 IU/L diagnosed Graves’ disease with respect to presence and towards the end of thyrostatic treatment was predic- natural history of GO [4]. The survey was conducted at a tive of relapse of Graves’ disease. These studies, and university hospital acting as a primary referral center. At German ones too, have been the basis of recommen- the time of diagnosis of Graves’ disease, 74% of patients dations issued by the Thyroid Section of the DGE did not exhibit GO features, 20% showed mild, inactive (Deutsche Gesellschaft für Endokrinologie; German EO, 6% moderate to severe active GO requiring treatment, Society of Endocrinology) for determining TRAb and only one patient had an eyesight-threatening GO (dys- towards the end of thyrostatic treatment. Apart from thyroid optic neuropathy, DON). this, clinical factors (Graves orbitopathy, goiter, high Out of 237 patients who were treated with thyrostat- requirement for thyrostatics, smoking) may also influ- ics and received follow-up over 18 months, most did not ence the recommendation in favor of early thyroid develop GO. Moderate to severe GO occurred only in five ablation. Moreover, high TRAb levels also seem to cases (2.6%). Out of 43 patients who had a mild and inac- correlate with an unfavorable progression of thyroid tive GO at the time of initial manifestation of Graves’ orbitopathy. disease, only one patient developed moderate to severe 3. TRAb analysis has a prognostic value in pregnant GO and more than half of the patients experienced a full patients with Graves’ disease. In around 1–5% of all remission of GO. Führer: Update – Studies and evidence-based treatment recommendations regarding thyroid disorders 3

The authors conclude that, contrary to common This multicenter trial shows that intravenous methyl belief, most patients with new onset Graves’ disease do prednisolone leads to objective and subjective improve- not have GO and that the presence or relapse of moderate ment of moderate to severe GO only in a subset of patients to severe GO requiring treatment is rare. Furthermore in and that side effects must be expected. Even though high- most cases with (mild) GO, eye disease disappers when dose therapy may produce a better treatment response euthyroidism is achieved: this is why normalizing thyroid in the short term, this effect is temporary and associated function has top priority in a patient with GO. Patients with increased side-effects. The EUGOGO Group concludes with active moderate to severe EO, and even more so from their trial that a moderate dose regimen (total dosage: patients with dysthyroid optic neuropathy, require imme- 4.5–5 g) with weekly infusion intervals (treatment duration diate treatment at a specialist center. In Germany, for 12 weeks) should continue to be favored, that indication for example, the EUGOGO centers in Essen and Mainz can be treatment should be made according to EUGOGO recom- contacted. mendations and that better anti-inflammatory therapies of GO are urgently required (see below, [5]). With active moderate to severe GO, retrobulbar irra- Comparison of different protocols for intravenous steroid diation is an alternative or additional option besides intra- therapy with active moderate to severe GO venous steroid therapy. Tanda and Bartalena reviewed the published literature [6]. Retrobulbar irradiation seems According to the EUGOGO recommendations, patients promising, especially in connection with acute eye muscle should be treated by way of intravenous methylpredni- involvement, and probably has a favorable effect with soft solone rather than oral steroids in case of active mod- tissue involvement. By contrast, exophthalmus and pro- erate to severe GO. But the ideal protocol has not been longed eye muscle involvement respond poorly. clarified. As part of a multicenter EUGOGO study, a total Furthermore combination therapy (retrobulbar irra- of 159 patients were treated at eight centers and three diation with oral steroid therapy) is more effective than methylprednisolone dosages were compared: cumula- either treatment option alone. So far, studies on com- tive dose of 2.25 g vs. 4.98 g vs. 7.4 g methylpredniso- bined use of intravenous steroid therapy and retrobulbar lone [5]. This involved a weekly infusion of 250 mg vs. irradiation are lacking. On the basis of the published data 540 mg vs. 830 mg in the first 6 weeks, followed by half the authors recommend using retrobulbar irradiation as a the dose in the following 6 weeks. Efficacy of treatment second-line therapy for patients with active moderate to was investigated first after 12 weeks. Improvement of severe GO with insufficient response to intravenous glu- ophthalmological parameters was 52% in the high-dose cocorticoid therapy after the first treatment cycle (over a group, 35% in the medium-dose group, and 28% in the period of 6 weeks). Diabetic retinopathy and severe arte- low-dose group. Improvement was found particularly rial hypertension are seen as contraindications. While the in ocular motility and clinical activity score. However, risk of radiation-induced malignancies is low, lifelong dysthyroid optic neuropathy (DON) occurred in all three aftercare is recommended, so that a careful indication treatment groups and was the reason why, at the time of is advisable in younger patients (recommendation < 35 second follow-up (24 weeks), no significant differences years) [6]. were found between the three treatment arms. Quality of life improved in all three treatment arms (largest trend towards improvement in the high-dose group). Mild side effects (flushing, Cushing’s syndrome, Perspectives for the treatment moderate increase in blood pressure without treatment intervention) occurred in 21% of patients in the high-dose of Graves’ disease and Graves group, 30% in the medium-dose group, and 26% in the orbitopathy low-dose group. Serious side effects (diabetes requiring treatment, infection, psychosis, muscle weakness, Since the TSH receptor is the pivotal target in Graves’ myocardial infarction) occurred in 5 patients of the high- disease, and a crucial link in Graves orbitopathy, phar- dose group, 3 patients of the medium-dose group, and 2 macological modulation of TSH receptor activation patients of the low-dose group. Twenty-four weeks after seems logical. For this purpose, TSH receptor agonists initiation of treatment, 33% in the high-dose group, 21% and antagonists have been developed and explored by in the medium-dose group, and 40% in the low-dose various research groups. These small molecules interfere group experienced a deterioration of GO. with TSH receptor activity on thyroid cells and orbital 4 Führer: Update – Studies and evidence-based treatment recommendations regarding thyroid disorders fibroblasts. Orbital fibroblasts represent a starting point involves not only the patient’s medical history (includ- for uncontrolled adipogenesis and increased hyaluronic ing medication history!), but also thyroid ultrasound acid production contributing to soft tissue swelling and and determination of TPO antibodies, since Hashimoto’s exopthalmus in GO. Recently a US group showed that the disease is the most common cause of hypothyroidism. functional and biological activity (hyaluronic acid pro- The recommendations address in great detail the con- duction) of orbital fibroblasts can be inhibited by means troversy over the TSH reference range. Currently, there is of a neutral TSH receptor antagonist. It is therefore con- no evidence for the benefit of thyroid hormone replace- ceivable that small molecules may in the future be used to ment with only moderately elevated TSH levels. In addi- target Graves’ disease and/or Graves’ orbitopathy specifi- tion and importantly, approximately 50% of all patients cally with less side effects than current treatments [7]. with subclinical hypothyroidism exhibit-normalization of the TSH level at follow-up [8]. By contrast, if TSH levels > Conclusion: The data available on treatment optimization for are 10 mU/L, thyroid hormone replacement is recom- Graves’ disease and Graves’ orbitopathy are still heterogeneous mended. Pregnancy represents an exception. According and differ from country to country. The ultimate objective is to to updated guidelines by the the Endocrine Society and achieve a euthyroid state. In most cases, this is achieved efficiently the recent guidelines by the European Thyroid Associa- through thyrostatic therapy with thiamazole or carbimazole. In tion, replacement therapy should be initiated in pregnant Germany, this type of therapy over 12 to 18 months is common women if TSH levels are > 2.5 mU/L in the first trimester, practice. A determination of TSH receptor antibodies may be useful for estimating the risk of recurrence during thyrostatic therapy. even if TPO-antibodies are not detectable. TRAb analysis is also recommended for assessing the risk for fetal A British research group led by C. Dayan has looked hyperthyroidism in pregnant women with known or former Graves’ into the question of whether TSH levels within the “refer- disease. ence range” may be associated with a different metabolic Graves’ orbitopathy is present and develops only in a small read-out [9]. For this purpose, an extensive MedLine and proportion of patients with Graves’ disease. For assessment of Cochrane Database analysis was performed. The authors Graves’ orbitopathy (severity and activity), the recommendations of reach the conclusion that even within the reference range, EUGOGO (www.eugogo.eu) should be followed. Moderate to severe GO or DON are rare but require urgent therapy and should be treated higher TSH levels (or lower thyroid hormone levels) are at specialized centers. The development of TSH receptor antagonists associated with more unfavorable metabolic parameters offers perspectives for treatment of Graves’ disease and Graves’ (such as weight, lipids), while lower TSH levels (or higher orbitopathy. But current studies are still at the experimental stage. thyroid hormone levels within the reference range) tend to Very recently use of immunomodulatory drugs such as rituximab has be associated with decreased bone density and increased been explored in Graves’ orbitopathy, with very favorable response in one study and equivocal results in another. However, trial set-up risk of fracture. While the data for metabolic parameters between the two studies differed. appear to be sound, it is impossible – in the authors’ view – to draw reliable conclusions about an association with neurological or psychological endpoints. These results appear to be in contrast to the recommendations for treat- Hypothyroidism ment of hypothyroidism. It is however crucial, to note that published studies mostly describe associations, rather than Recommendations on the diagnosis and treatment of causal links. hypothyroidism were issued by the American Thyroid While the prognostic relevance of certain thyroid Association (ATA) and the American Association of Clini- hormone constellations could become part of risk assess- cal Endocrinologists (AACE) at the end of 2012. A total of 52 ment in the future (following the pattern of the low T3 syn- recommendations with evidence level were published [8]. drome in connection with severe systemic disease), this The most informative laboratory parameter for the is not automatically inferring an indication for treatment diagnosis of hypothyroidism is the TSH concentration. e.g. with thyroid hormones. The main exception here is central hypothyroidism (hypo- The same research group has also analyzed the pre- thalamic or pituitary disease), in which the diagnosis is scription practice for levothyroxine over the period 2001– made on the basis of decreased fT4 and normal/or low 2009. Data of 52,298 patients have been evaluated. It was TSH. found that LT4 was increasingly prescribed at lower TSH If the TSH level is above the reference range, the deter- levels and often only on the basis of a single TSH measure- mination of free T4 concentrations is recommended to dis- ment. Unwanted effects of this change in practice in the tinguish between subclinical and overt hypothyroidism. It UK, included TSH suppression, which was found in 5.8% is essential to clarify the cause of hypothyroidism. This of patients [10]. Führer: Update – Studies and evidence-based treatment recommendations regarding thyroid disorders 5

In a seminal review Biondi addresses the question in terms of symptoms and neurocognitive endpoints [13]. “The normal TSH reference range – what has changed in The patients received the medication for 16 weeks, which the last 10 years?” [11]. The controversy around the normal was then followed by a change in the treatment using a TSH reference range started with the NHANES III study: crossover design. In comparing the two treatment inter- Based on the US-American population, it was shown that vals, no significant differences in symptoms and neuro- 95% of test subjects without a previously known thyroid cognitive endpoints were identified. However, a moderate condition had TSH levels between 0.45 and 4.12 mU/L. weight loss (1.5–2 kg, n.s.) was observed in connection Further tests showed that TSH levels were not normally with the thyroid hormone extract, and almost one in two distributed and that the population also included patients patients preferred the thyroid hormone extract to levothy- with autoimmune thyroiditis (but negative TPO antibod- roxine therapy. ies). Then, in 2005, the National Academy of Clinical The authors conclude that treatment with a thyroid Biochemistry (NACB) announced that the upper TSH ref- hormone extract might be useful for some hypothyroid erence value should be 2.5 mU/L. Subsequently, however, patients [13]. it became clear that the situation was far more complex. The European Thyroid Association (ETA) has released TSH assays differ, for example, in terms of sensitivity new guidelines on thyroid hormone replacement therapy and specificity (and also in the detection of biologically (comparison between LT4 and LT4+LT3 combination inactive TSH isoforms). A further factor was the defini- therapy). Levothyroxine therapy continues, unchanged, to tion of the reference populations (reliable exclusion of be recommended as standard therapy, while combination autoimmunity, age distribution, ethnic origin, and iodine therapy is discussed as an individual treatment attempt intake). In addition, many epidemiological studies have even if sound evidence is lacking. The currently avail- demonstrated that TSH levels rise with age, which means able combinations (including Armor Thyroid®) comprise that there are age-dependent “TSH reference values”. In an unphysiological LT4/LT3 ratio (ratio recommended by the Leiden study, which looked at probands > 80 years of ETA guideline: LT4/LT3 20:1). A T3-slow-release prepara- age, elevated TSH levels were not associated with a worse tion is currently not available (www.eurothyroid.com). cognitive outcome, but actually indicated lower mortal- ity risk. Similar data are also available for other cohorts. The current evaluation of the Scottish Thyroid Epidemi- Are different levothyroxine preparations ology Audit and Research Study (TEARS) revealed a sig- equivalent? nificant increase both of the median and upper reference TSH values (97.5 percentile, from 3.98 to 5.94 mU/L) with For years, some manufacturers of thyroid hormone increasing age [12]. preparations have promoted “aut idem/“or the same” prescriptions, saying that the bioavailability of commer-

Practical consequences: The assessment of thyroid function and cially available LT4 preparations varies greatly. Clinical the decision for a treatment indication are not easy, especially experience confirms fluctuations in thyroid tests of some in the presence of subclinical hypothyroidism, an often purely patients undergoing LT4 substitution when levothyroxine biochemically defined condition. The previously available preparations are changed. One US study examined the evidence suggests a certain restraint when it comes to treatment stability of thyroid hormone replacement in children with of patients without a previous history of thyroid disease and congenital hypothyroidism, comparing Synthyroid® with with only moderately elevated TSH values ( > 4, < 10 mU/L) as well as, consideration of factors such as gender, co-medication, a generic LT4 preparation. This was a retrospective study comorbidity, or life circumstances. At the same time, more attention in 62 children with congenital hypothyroidism who had will have to be paid to the age-dependent TSH reference range in the been monitored over 5 years (age 0–36 months). Thirty-five future in order to avoid misdiagnosis and unwarranted treatment. patients only received Synthyroid®, and 27 patients were given a generic LT4 preparation. There were no significant differences in TSH concentrations between these two Are “natural thyroid hormones” superior to treatment groups. Instead, children given the generic LT4 levothyroxine? preparation exhibited smaller fluctuations in TSH levels than children in the Synthyroid® group. The frequency Some patients undergoing levothyroxine substitution of LT4 dose adjustments did not differ between the two complain of a reduced quality of life. A randomized dou- groups. On average, two dose adjustments were required ble-blind study compared the influence of LT4 substitution in the generic group versus three dose adjustments in the and that of a thyroid hormone extract (Armor Thyroid®) Synthyroid group. Another study examined children with 6 Führer: Update – Studies and evidence-based treatment recommendations regarding thyroid disorders hypothyroidism (several congenital hypothyroidism and Comment: The DanThyr study results, unfortunately, leave out a key acquired hypothyroidism) to compare a brand levothyrox- factor: the influence of age. It is perfectly normal to expect an age- ine preparation to a generic one. The brand preparation, based shift in TSH levels over an observation period of 11 years, overall, yielded lower TSH levels [14, 15]. especially when the cohort includes age groups from 20 to 65 years. What conclusions can be drawn from these two studies? Maybe the bioavailability of the generic prepara- In Britain, which has long been considered a country with tions has improved in quality in the meantime. None of adequate iodine supply the Avon-Longitudinal Study of the studies looked at the influence that a possibly involun- Parents and Children (ALSPAC) examined the influence tary change of different levothyroxine preparations might of iodine status during pregnancy on the neurocognitive have on the quality of adjusting thyroid function. Conse- outcome of children [17]. A total of 4,040 pregnant women quently, the ATA/ETA/AACE [8] recommendations should was examined, with urinary iodine excretion being ana- continue to be followed, and patients should be informed lyzed in the first trimester. Children were examined at the about the following aspects: age of 8 years in terms of IQ and at the age of 9 years in 1. The preparation must be taken on an empty stomach terms of reading skills. Possible confounding effects were where possible, that is, it should be taken with water also taken into account. On the basis of the WHO criteria, at least 30 min before breakfast. it was found that most pregnant women were iodine defi- 2. Patients should insist on using preparations from the cient: the median iodine urine level was 91 μg/L. Impor- same manufacturer. tantly children of women with low iodine excretion ( < 150 3. Whenever a preparation is changed, and definitely μg/g) exhibited lower verbal IQ scores, lower reading when doses are adjusted, TSH levels should be accuracy and lower reading comprehension compared checked (about 6–8 weeks after a change). to children of women with higher iodine excretion ( > 150 μg/g). A subgroup analysis showed that the results of neurocognitive testing in children were associated directly The importance of iodine intake for thyroid with the mother’s degree of ioduria in the first trimester. function The results of this analysis are important and wor- risome. They demonstrate that iodine deficiency is not Iodine deficiency is the most important exogenous taken seriously enough in our highly civilized industrial factor in the pathogenesis of thyroid pathologies. Iodine countries and that urgent action is needed. This also deficiency is closely correlated with the prevalence of includes implementing the long-established WHO recom- goiter, nodular thyroid changes and thyroid autonomy. mendation of iodine supplementation in pregnant and In the DanThyr cohort, a Danish population cohort, the breastfeeding women to achieve an iodine intake of at influence of improved iodine intake on thyroid function least 250 μg iodide per day. parameters has been examined [16]. Thus 2203 probands were studied longitudinally in 1997/1998 and with follow- up in 2008–2010. A change in iodine intake was observed Central hypothyroidism in 2000. The follow-up showed an increase in mean TSH levels from 1.27 mU/L to 1.83 mU/L in the study cohort. Central hypothyroidism results from insufficient TSH The biggest changes in TSH levels were observed in the stimulation of a normal functioning thyroid. The cause is population with the highest intake of iodine (TSH 1.30 an anatomical or functional disorder of the hypothalamus mU/L at start; 1.49 mU/L at follow-up). No significant and/or pituitary gland, such as neoplasia or impairment change in TSH levels was found in the region with low by neurosurgery or radiotherapy. Rarer causes include iodine intake. The change in TSH levels was associated vascular changes, trauma, autoimmune diseases, meta- with the presence of TPO antibodies at the start and cor- bolic diseases (hemochromatosis), inflammation, infec- related inversely with the presence of a goiter or multi- tious disease, and genetic defects (PROP-1 mutation, nodular thyroid. The authors conclude that even small TSH-beta mutation, etc.). Central hypothyroidism is very changes in iodine intake can change TSH levels and rare. The estimated prevalence is 1:1000 for hypothyroid may contribute to manifestation of thyroid disease in patients in the general population, and 1:116,000–160,000 the normal population. A multinodular thyroid disorder for newborns. Most patients with central hypothyroidism at baseline was associated with the lowest TSH change, have TSH levels within the reference range in spite of low possibly due to the presence of subclinical thyroid fT4 levels. This indicates the presence of biologically inac- autonomy [16]. tive TSH molecules [18]. Führer: Update – Studies and evidence-based treatment recommendations regarding thyroid disorders 7

Central hypothyroidism is treated with levothyroxine. cases, the first assessment of nodule risk involves thyroid Prior to starting treatment, adrenal failure should be ruled sonography and elastography [20]: In 2009 a French study out (particularly for patients with known hypothalamic- evaluated the then-newly proposed TI-RADS classifica- pituitary diseases) and in case of insufficiency, treatment tion with respect to interobserver variability and its use for should start with hydrocortisone substitution first. With selecting nodules for fine-needle aspiration (FNA) cytol- the exception of old patients and patients with previ- ogy. This was a prospective study that assessed a total ously known heart disease, a weight-adapted substitu- of 4550 thyroid nodules (n = 3543 patients) over 2 years tion (1.2–1.7 μg/kg body weight) is recommend. The TSH by way of a flow chart and six-point scale, followed by level cannot be used as a target parameter for monitor- ultrasound-controlled FNA. Nodules were additionally ing substitution. Thus the fT4 value is used to evaluate examined by means of elastography. FNA classification substitution therapy. For this purpose, and by way of an was based on the Bethesda criteria. Pathological find- exception, a blood sample is taken from the patient (but ings were available for 263 cases. Interobserver agreement never from patients with primary hypothyroidism!) prior with respect to the TI-RADS scale and FNA recommenda- to taking the morning dose of levothyroxine. When chang- tion was high. Furthermore it was possible to lower the ing the co-medication (in particular, growth hormone or number of FNA indications by one-third on the basis of estrogen replacement therapy), the levothyroxine substi- TI-RADS. The combination of elastography and ultra- tution must be checked and, if necessary, adjusted. With sound marginally improved sensitivity and specificity for TSH levels > 0.5 mU/L and/or fT4 levels in the lower refer- detecting thyroid cancer [21]. ence range, one must assume undersubstitution; with fT4 levels above the upper reference range, oversubstitution. How important is molecular analysis of thyroid aspirates? Thyroid nodules Recent years have seen a tremendous increase in know The prevalence of thyroid nodules in the general popula- ledge on the molecular pathogenesis of thyroid tumors, tion continues to be very high. Two population studies particularly thyroid cancer. More than 80% of all thyroid (SHIP and KORA cohort from Mecklenburg-Western carcinomas exhibit mutations in known oncogenes. Pomerania and the Augsburg region) found a nodule Furthermore, transcriptome and miRNA analysis have prevalence of 21% (SHIP) and/or 41% (KORA) in probands yielded a large number of so-called molecular markers. aged > 40 years, and 53% (SHIP) and/or 70% (KORA) in The relevance of a somatic BRAF mutation (BRAF V600E) probands aged > 65 years. Nodules were defined as sono- has been discussed extensively, since it represents the graphically determined thyroid lesions > 1 cm [19]. most common genetic alteration and hallmark of papil- The challenge in the differential diagnosis and treat- lary thyroid cancer. Currently, the analysis of the BRAF ment of nodular thyroid disease continues to revolve mutation is useful in situations of uncertain cytologi- around the question whether the patient has a clinically cal findings and for individualized targeted therapy in relevant nodule. This can include a number of different advanced radioiodine refractory thyroid cancers (even aspects (the presence of thyroid autonomy, thyroid malig- though drugs are currently not approved for this indica- nancy, compression signs and individual reasons such as tion). Cytology showing follicular neoplasia continues to fear of thyroid cancer). While presence of thyroid auton- be a problem. For such and other “indeterminate” cytolo- omy can be easily confirmed by determining the TSH gies, approx. 20–30% of all FNAs, commercial molecular levels, performing thyroid scintigraphy and possibly sup- tests have been developed and are increasingly applied pression scintigraphy, ruling out thyroid cancer is much in the US to direct which patients should undergo thyroid more challenging. Here one must distinguish between surgery. One of the first assays was the Veracyte Afirma prognostically significant thyroid carcinomas ( < 1% of all assay comprising a “gene expression classifier” which thyroid nodules) and mostly indolent microcarcinomas, was evaluated in fine-needle cytologies in a large mul- i.e. papillary microcarcinomas which can be found in up ticenter trial by Alexander et al. [22]. Samples taken to 30% in autopsy material. In the clinical setting, the from 265 nodules with “indeterminate” cytologies were patient’s history and clinical examination mostly do not analyzed and compared with results of the final histol- help, because both point to an already advanced thyroid ogy. Seventy-eight of the 85 thyroid cancers were cor- cancer in case of positive findings. Calcitonin is useful for rectly detected by the gene classifier, and 93 of the 180 early diagnosis of medullary thyroid cancer. In all other benign tumors were classified as benign. In summary, the 8 Führer: Update – Studies and evidence-based treatment recommendations regarding thyroid disorders number of “diagnostic thyroid surgeries” was halved by In recent years, therefore, a paradigm shift in the applying the Afirma test, however, the rate of false-nega- assessment and treatment of thyroid cancer has occurred. tive findings in the test was 10%. The focus is now on classifying carcinomas with a low, The same authors conducted further quality analy- intermediate or high risk of complications, with a second ses. One looked at the interobserver variability [23]. This prognostic assessment being made only after ablative revealed considerable discrepancies in classification (surgery or surgery plus radioiodine therapy). To this treat- of thyroid cytology based on Bethesda criteria by differ- ment one must add a critical appraisal of so-far irrefutable ent investigators! On the one hand, the sensitivity and doctrines concerning extent of thyroid surgery, type and specificity of any molecular method relies critically on necessity of radioiodine ablation, and TSH suppression the pre-selection of the material. On the other hand, the therapy in low-risk patients. use of reliable assessment criteria (cytological or if this Current controversies, particularly in the treatment of fails molecular markers) is utmost important to improve low-risk thyroid cancer patients, are discussed in detail in care of patients with thyroid nodules [24]. Meanwhile, an excellent review in Lancet [25]. In future, these patients several assays of other manufacturers are available in the will continue to be treated primarily by specialists in inter- United States, including detection of oncogene mutations nal medicine. and miRNA analysis in fine-needle aspirates (e.g. miRIn- Patients with radioiodine refractory thyroid cancer formThyroid® Asuragen Inc., Quest Diagnostics Thyroid will represent a further and new task for specialists in Cancer Mutation Panel etc.). Their proposed role is also internal medicine [26–28]. Radioiodine refractory cancer to influence decision on surgical treatment strategy i.e. occurs in 5–10% of all patients with a differentiated hemithyroidectomy or total thyroidectomy. All molecular thyroid carcinoma. In June 2014, the first tyrosine kinase assays are quite cost-intensive, which leaves their use for inhibitor (TKI) became available in the form of sorafenib patients with thyroid nodules in Germany in doubt at this to treat radioiodine refractory, non-medullary thyroid point. cancer. It was approved on the basis of the DECISION study, which included 417 patients with progressive radio iodine refractory thyroid cancer. The median progression- Conclusion: The identification of thyroid cancer still poses a free survival (PFS) was 10.8 months with sorafenib (800 challenge, particularly in light of the very high prevalence of mg/day) and 5.8 months for patients under placebo. In thyroid nodules in the general population. While the incidence of papillary microcarcinomas increases, which are usually indolent 2015 results of the phase III study for the TKI lenvatinib and therefore should not be subjected to diagnosis or therapy, were published: The SELECT study examined the effects studies are now focusing on identifying a clinically significant of lenvatinib (24 mg/day) in 392 patients with progressive thyroid malignancy as early as possible. Standardized ultrasound radioiodine refractory thyroid cancer [28]. The median PFS criteria should be employed in this context, ideally on the basis with lenvatinib was 18.3 months, compared to 3.6 months of a modified TI-RADS classification. Elastography may also prove for patients given a placebo. Lenvatinib was approved by helpful. The focus is thus on ultrasound-based selection and subsequent fine-needle aspiration of nodules at risk. Molecular the EMA at the end of May 2015 and has been available markers are part of commercially available assays, but will have to in Germany since July 2015. Phase I and II data are avail- be evaluated in the future both in terms of sensitivity and specificity able in connection with radioiodine refractory thyroid and cost-effectiveness in different countries. cancer for other oncological indications such as axitinib, cabozantinib, pazopanib, sunitinib and vandetanib, [26–28]. The molecularly targeted therapies are designed to antagonize specifically activated signaling pathways Thyroid carcinomas (MAPK and/or PI3K/AKT cascade) in the tumor. Most TKI inhibit also the VEGF signal transduction, thus conferring Thyroid carcinoma represents the most common endo- antiangiogenic effects ( = multi-kinase inhibitors). crine malignancy. The prevalence and incidence of thyroid cancer have risen significantly in recent decades. In particular, there has been a tremendous increase in papillary carcinomas. The causes for this are controversial, but one Outlook important reason is the widespread use of thyroid diagnostics as shown in several studies worldwide, which A highly innovative, but still purely experimental treat- correlates directly with the detection of papillary micro- ment approach is the redifferentiation of radioiodine carcinomas as incidental findings. refractory thyroid malignancy by inhibiting the Führer: Update – Studies and evidence-based treatment recommendations regarding thyroid disorders 9

MAP-kinase cascade. Ho et al. [29] showed in a pilot study Competing interests: The funding organization(s) played that it is possible to restore radioiodine uptake in thyroid no role in the study design; in the collection, analysis, and cancer metastases by means of selumetinib. By this it interpretation of data; in the writing of the report; or in the was possible to subject eight of 12 patients to radioiodine decision to submit the report for publication. therapy. Five patients showed partial response, while the disease was stabilized in a further three patients. As a matter of principle, the redifferentiation therapy should also work with other BRAF or MEK inhibitors – thus References genetically determined treatment may thus give rise to 1. Burch HB, Burman KD, Cooper DS. A 2011 survey of clinical interesting treatment options in the future. practice patterns in the management of Graves’ disease. J Clin Given their significant side effects, indication for TKI Endocrinol Metab 2012;97:4549–58. treatment of thyroid malignancy should be made by a 2. Barbesino G, Tomer Y. Clinical review: Clinical utility of TSH physician experienced in thyroid cancer and TKI therapy. receptor antibodies. J Clin Endocrinol Metab 2013;98:2247–55. Following the ETA recommendations regarding the start 3. Ponto KA, Merkesdal S, Hommel G, Pitz S, Pfeiffer N, Kahaly GJ. Public health relevance of Graves’ orbitopathy. J Clin Endocrinol of TKI therapy for advanced medullary thyroid cancer, Metab 2013;98:145–52. there ought to be radiological proof of progression and/or 4. Tanda ML, Piantanida E, Liparulo L, Veronesi G, Lai A, Sassi L, a symptomatically advanced disease also in case of radio et al. Prevalence and natural history of Graves’ orbitopathy in a iodine refractory cancer. large series of patients with newly diagnosed graves’ hyperthyroidism seen at a single center. J Clin Endocrinol Metab 2013;98:1443–9. Conclusion: Thyroid malignancies are now divided into three 5. Bartalena L, Krassas GE, Wiersinga W, Marcocci C, Salvi M, groups in terms of the risk of a poor outcome according to the ATA Daumerie C, et al. European Group on Graves’ Orbitopathy. recommendations (these have been updated in Oktober 2015). Efficacy and safety of three different cumulative doses of intra- Against the background of the overall extremely good prognosis of venous methylprednisolone for moderate to severe and active most thyroid carcinomas, a paradigm shift has occurred towards Graves’ orbitopathy. J Clin Endocrinol Metab 2012;97:4454–63. less aggressive therapy (surgery, nuclear medicine, thyroid 6. Tanda ML, Bartalena L. Efficacy and safety of orbital radio- hormone replacement therapy). The doctrines of radical surgery, therapy for graves’ orbitopathy. J Clin Endocrinol Metab radioiodine ablation and TSH suppression therapy apply, as before, 2012;97:3857–65. only to high-risk patients. The results of the first phase III trials 7. Turcu AF, Kumar S, Neumann S, Coenen M, Iyer S, Chiriboga P, on the use of TKI (sorafenib, lenvatinib) in radioiodine refractory, et al. A small molecule antagonist inhibits thyrotropin recep- metastatic, differentiated thyroid cancer were published in 2014 tor antibody-induced orbital fibroblast functions involved in and 2015. For both TKIs, which have meanwhile been approved for the pathogenesis of Graves ophthalmopathy. J Clin Endocrinol therapy, a longer progression-free survival has been demonstrated, Metab 2013;98:2153–9. but not an improved survival (the studies were not designed for 8. Garber JR, Cobin RH, Gharib H, Hennessey JV, Klein I, Mechanick this). Other TKI are available as off-label therapy, allowing for JI, et al. American Association of Clinical Endocrinologists and a broadening of palliative treatment options for patients with American Thyroid Association taskforce on hypothyroidism radioiodine refractory thyroid cancer. New perspectives may open in adults. Clinical practice guidelines for hypothyroidism in up with pharmacological redifferentiation therapy e.g. using adults: cosponsored by the American Association of Clinical MEK inhibitors, but in recent years no further studies have been Endocrinologists and the American Thyroid Association. Thyroid published. As a result of the sometimes significant side effects 2012;22:1200–35. of the individual substances and the special biology of thyroid 9. Taylor PN, Razvi S, Pearce SH, Dayan CM. A review of the clinical carcinomas, which differentiates them from other malignancies, consequences of variation in thyroid function within the refer- patients with advanced cancer should be treated at specialized ence range. J Clin Endocrinol Metab 2013;98:3562–71. centers whenever possible. For an overview of the current treatment 10. Taylor PN, Iqbal A, Minassian C, Sayers A, Draman MS, recommendations in connection with differentiated thyroid cancer, Greenwood R, et al. Falling threshold for treatment of border- reference is made to the ATA recommendations ([30], updated ATA line elevated thyrotropin levels-balancing benefits and risks: guidelines were published on 14 October 2015) and to the German evidence from a large community-based study. JAMA Intern Med Surgical Thyroid Cancer Guidelines [31]. 2014;174:32–9. 11. Biondi B. The normal TSH reference range: what has changed in the last decade? J Clin Endocrinol Metab 2013;98:3584–7. Author contributions: The author has accepted responsi- 12. Vadiveloo T, Donnan PT, Murphy MJ, Leese GP. Age- and gender- bility for the entire content of this submitted manuscript specific TSH reference intervals in people with no obvious thyroid disease in Tayside, Scotland: the Thyroid Epidemiology, and approved submission. Audit, and Research Study (TEARS). J Clin Endocrinol Metab Research funding: None declared. 2013;98:1147–53. Employment or leadership: None declared. 13. Hoang TD, Olsen CH, Mai VQ, Clyde PW, Shakir MK. Desiccated Honorarium: None declared. thyroid extract compared with levothyroxine in the treatment of 10 Führer: Update – Studies and evidence-based treatment recommendations regarding thyroid disorders

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