December 2007

Contributions by

 Furio Pacini (University of Siena, Italy)

Leslie DeGroot (Brown University, Providence, RI, USA)

 Manfred Blum (New York University, NY, USA)

TG assays for the follow-up of thyroid cancer 

TOPIC: Methodological issues with serum thyroglobulin measurements

Title: Comparison of seven serum thyroglobulin assays in the follow-up of papillary and follicular thyroid cancer patients.

Authors: Schlumberger M, Hitzel A, Toubert ME, Corone C, et al.

 SUMMARY

Objectives: Serum thyroglobulin (Tg) is the most sensitive and specific marker of differentiated thyroid cancer after initial treatment and TSH stimulation increases its sensitivity for the diagnosis of recurrent disease. Variability in the sensitivity and reproducibility of different commercial assays makes serum Tg measurement a delicate issue when interpreting the results. The goal of this study is to compare the diagnostic values of seven methods for serum Tg measurement for detecting recurrent disease both during L-T₄ treatment and after TSH stimulation.

 Methods: Thyroid cancer patients with no evidence of persistent disease after initial treatment were studied at 3 months on L-T₄ treatment (Tg1) and then at 9–12 months after withdrawal or recombinant human TSH stimulation (Tg2). Sera with anti-Tg antibodies or with an abnormal recovery test result were excluded from Tg analysis with the corresponding assay. The results of serum Tg determination were compared to the clinical status of the patient at the end of follow-up. All measurements were performed using seven commercial Tg assays with different functional sensitivity: 0.9 ng/ml (3 assays), 0.3-0.2-0.11-0.02 ng/ml (1 kit, respectively).

 Results: Thirty recurrences were detected among 944 patients. A control ¹³¹I total body scan had a low sensitivity, a low specificity, and a low clinical impact. Assuming a common cut-off for all Tg assays at 0.9 ng/ml, sensitivity ranged from 19–40% and 68–76% and specificity ranged from 92–97% and 81–91% for Tg 1 and Tg2, respectively. Using assays with a functional sensitivity at 0.2–0.3 ng/ml, sensitivity was 54–63% and specificity was 89% for Tg1. Using the two methods with a lowest functional sensitivity at 0.02 and 0.11 ng/ml resulted in a higher sensitivity for Tg1 (81% and 78%), but at the expense of a loss of specificity (42% and 63%); finally, for these two methods, using an optimized functional sensitivity according to receiver operating characteristic curves at 0.22 and 0.27 ng/ml resulted in a sensitivity at 65% and specificity at 85–87% for Tg1.

 Conclusions: Using an assay with a lower functional sensitivity may give an earlier indication of the presence of Tg in the serum on L-T₄ treatment and may be used to study the trend in serum Tg without performing any TSH stimulation. Serum Tg determination obtained after TSH stimulation still permits a more reliable assessment of cure and patient’s reassurance. 

COMMENTARY 

                  Serum Tg is recognized as the most sensitive and specific marker of residual disease in differentiated thyroid cancer patients treated with total thyroidectomy and 131-I ablation. Since suppressive l-T4 therapy may reduce serum Tg concentrations even to undetectable levels (false negative results), stimulation by endogenous or exogenous TSH may be required to increase the diagnostic value of serum Tg measurement. Such stimulation is particularly required in patients with undetectable basal serum Tg at the time of the first control (usually 8-12 months after initial treatment). 

                  The study by Schlumberger et al. compared the diagnostic accuracy of seven different commercial Tg kits both during l-T4 treatment and after TSH stimulation (endogenous or exogenous). Using different kits resulted in different sensitivity in detecting residual disease, both on l-T4 and after TSH stimulation, but with any kit, the results confirmed low sensitivity of serum Tg during l-T4 therapy and better sensitivity after TSH stimulation. The results also confirmed that many patients with detectable Tg concentrations are not associated with any detectable disease (false positive Tg? or disease that is to small to be localized?).                 

                  The novel and important finding of the study is that using new kits with a lower sensitivity (ultrasensitive assays) allowed an earlier discovery of detectable Tg in the serum and eventually the localization of persistent disease by imaging modalities, but, on the other hand, increased the number of patients with detectable Tg and no evidence of disease (lowering the specificity of the test). Thus, for the moment it is not possible to advocate the use of ultrasensitive Tg assays in alternative to TSH stimulation, which still permits a more reliable assessment of cure.
Summary and commentary prepared by Furio Pacini (related to Chapter 18 of TDM)

 

 

Is thyroxine administration the answer? 

TOPIC: Autoimmune thyroid disease during pregnancy

Title: Levothyroxine treatment in euthyroid pregnant women with autoimmune thyroid disease: effects on obstetrical complications.

Authors: Negro R, Formoso G, Mangieri T, Pezzarossa A, Dazzi D, & Hassan H.

 SUMMARY 

Background: Euthyroid women with autoimmune thyroid disease show impairment of thyroid function during gestation and seem to suffer from a higher rate of obstetrical complications.

Objective: The authors sought to determine whether these women suffer from a higher rate of obstetrical complications and whether levothyroxine (L-T4) treatment exerts beneficial effects. This was a prospective study conducted in a Department of Obstetrics and Gynecology. The literature on the impact of thyroid abnormalities on pregnancy and the postpartum has expanded rapidly over the last two decades. 

Methods: A total of 984 pregnant women were studied from November 2002 to October 2004; 11.7% were thyroid peroxidase antibody positive (TPO-Ab(+)). TPOAb(+) women were divided into two groups: Group A (n = 57) was treated with L-T4, and Group B (n = 58) was not treated. The 869 TPOAb(-) women (Group C) served as a normal population control group. Rates of obstetrical complications in treated and untreated groups were compared. 

Main Results: At baseline, TPOAb(+) had higher serum TSH compared with TPOAb(-); TSH remained higher in Group B compared with Groups A and C throughout gestation. Free T4 values were lower in Group B than Groups A and C after 30 weeks and after parturition. Groups A and C showed a similar rate of miscarriage (3.5% and 2.4%, respectively), which was lower than in Group B (13.8%) [P < 0.05; relative risk (RR) = 1.72; and P < 0.01; RR = 4.95]. Group B displayed a 22.4% rate of premature deliveries, which was significantly higher than Group A (7%) (P < 0.05; RR = 1.66) and group C (8.2%) (P < 0.01; RR = 12.18). 

Conclusions: Euthyroid pregnant women who are positive for TPOAb may develop impaired thyroid function during pregnancy. The presence of thyroid autoantibodies is associated with an increased risk of miscarriage and premature deliveries. In this study substitutive treatment with L-T4 was able to lower the chance of miscarriage and premature delivery among women who were positive for these antibodies in the first trimester of pregnancy.  

COMMENTARY

             This unique study has generated much interest, and also has presented physicians with a therapeutic quandary. Numerous retrospective studies have found a 3-6 fold increment in the incidence of miscarriage among women with positive anti-TPO antibody assays. The reason for this association is not entirely known. The association does not seem to be related to a generalized autoimmune process. One hypothesis is that thyroid autoimmunity may be associated with mild or subclinical hypothyroidism, which is known to develop in up to 40% of previously euthyroid antibody-positive women during the course of pregnancy. To date no reported prospective randomized study has examined this issue, although two studies are now underway that will (hopefully) be informative. 

            The study by Negro et al. was not specifically designed to examine the role of mild hypothyroidism in relation to miscarriage, but certainly offers suggestive data. The authors assayed serum TSH levels in the women to be given L-T4, and assigned doses of either 1.0, 0.75, or 0.5 µg/Kg b.w., depending on the initial TSH level. The women were followed throughout pregnancy. Serum TSH levels in the treated group paralleled those of the antibody-negative group during the last two trimesters, as did their free T4 levels, while serum TSH levels in the untreated but antibody-positive group climbed to the ‘top normal’ upper limit by the end of pregnancy. While these results are very interesting, it must be remembered that none of the treated patients had proven hypothyroidism. Perhaps more importantly, this is one observation, and has not yet been confirmed by other groups.  

                  What message should treating physicians take from the study? Should all antibody-positive women be treated with thyroid hormone? Obviously, this might risk complications including hyperthyroidism. From the opposite view, the possibility of nullifying the significant risk of miscarriage and prematurity by administering a safe dose of thyroid hormone seems quite attractive. This writer can not recommend such therapy as a general rule. But it is also clear that many antibody-positive pregnant women will be given thyroid hormone on an individual basis, while we await the results of other trials.                       

Summary and commentary prepared by Leslie DeGroot (related to Chapter 14 of TDM)

 

Thyroid volume and echostructure in children

TOPIC: Factors influencing thyroid volume in school-age children in an area with iodine sufficiency

Title: Thyroid volume and echo-structure in school children living in an iodine-replete area: relation to age, pubertal stage, and body mass index.

Authors: Kaloumenou I, Alevizaki M, Ladopoulos C, Antoniou A, Duntas LH, Mastorakos G, Chiotis D, Mengreli C, Livadas S, Xekouki P, & Dacou-Voutetakis C.

 SUMMARY

Background: Thyroid volume (TV) is not uniform among geographical regions, mainly because of differences in iodine intake. Age, gender, developmental status, and perhaps unknown factors may affect thyroid size and anatomy as well. Thus, in regions with long-standing iodine sufficiency, standards for TV that are specific for a defined geographical region and its populations may be more accurate than a single international reference. 

Purpose: The aim of the study was to determine TV and assess the prevalence of goiter and thyroid nodules in ethnically Greek school children aged 5–18 years living in Athens (Greece), an area considered to be iodine-sufficient. 

Patients: Four hundred and forty apparently healthy schoolchildren (200 boys and 240 girls), aged 5 to 18 years (mean ± SD: 10 ± 2.9; median: 9.7 years) were selected from schools in Athens (Greece) and were examined. The selection process was designed to secure a “representative” sample of students who were of “Greek ethnic origin” from regional schools to achieve ‘homogeneity of the study population’. Four hundred and thirty-one of the children were born in the Athens area and lived in Athens until the date of the examination. Nine of the subjects lived in another iodine-replete region of the country for the first years of their life and moved to Athens before attending school. 

Methods: All children included in the study had a questionnaire completed, underwent physical examination, and had ultrasonic examination of the thyroid. Vital statistics, body surface area (BSA), and body mass index (BMI) were recorded and urinary iodine excretion was measured. Pubertal status was defined using Tanner’s classification, in all cases by the same investigator. Children were classified as prepubertal if Tanner stage was I and pubertal if Tanner stage was II–V. The result of specific testing of thyroid function, antithyroid immunologic status, and profile of dietary intake were not reported.
Thyroid Ultrasound examination: TV was determined by real-time ultrasonography with each child lying supine with the neck hyper-extended. The same experienced radiologist performed the measurements with a General Electric Pro Series (Milwaukee, Wisconsin, USA) scanner with a 7.5 MHz linear transducer. The length (l), width (w), and depth (d) of each thyroid lobe (in cm) were measured on transverse and longitudinal scans. The volume (Vol) of each lobe (in mL) was estimated by the modified formula for an ellipsoid: Vol (mL) = (0.479 x d x w x l). TV was defined as the sum of the volumes of both lobes. The presence of nodules and diffusely or irregularly reduced echogenicity were recorded. The 50^th and 97 ^th percentiles for TV were calculated (P50 and P97).

Urinary iodine: Urinary iodine was determined spectrophotometrically on a morning spot urine sample in all children and calculated as the ratio of µg iodine/g creatinine (µgI/g cr).

Statistical analysis: For statistical analysis the Statistical Package for Social Sciences (SPSS, version 10.00) program for Windows was used. Pearson correlation was performed for univariate analysis; Spearman’s correlation was used when the distribution was not normal.  The chi-square test was employed followed by the Fisher’s exact test to compare categorical variables. One-factor analysis of variance (one-way ANOVA) was employed followed by the Scheffe post hoc test to compare quantitative variables. ANCOVA test was also used. All tests were two-sided. The limit of statistical significance was set at p < 0.05. 

Results: The thyroid gland was palpable in 13/440 subjects (Pan American Health Organization [PAHO] Ia in 9; PAHO II in 4). Otherwise, none of the subjects included in the study had obvious clinical signs or symptoms of thyroid disease. A questionnaire about date of birth and family history for thyroid disorders as well as any underlying chronic disease was completed for each subject. None of the subjects had any evidence of acute or chronic disease, and no previous known thyroid disorder was reported. There were no thyroid function or antibody data. Concerning urinary iodine excretion, the median urinary iodine concentration was 307.83 µg I/g cr (range: 44 – 1.105). There was no significant difference between boys and girls. Ninety-seven percent of the subjects had an iodine concentration above 100 µg I/g cr, which is considered normal. Concerning thyroid volume, mean TV was 4.99 ± 2.75 mL (boys: 4.94 ± 2.76 mL, girls: 5.03 ± 2.65 mL; P=0.797). The volume of the thyroid gland increased significantly with chronological age in both genders and TV was positively correlated to BSA in both genders. TV was weakly related to body mass index-standard deviation score in boys only (boys: P=0.023; girls: P=0.150). An inverse relationship was found between urinary iodine and TV (P < 0.0005). Mean TV increased significantly at puberty in both sexes. Mean TV in boys at Tanner stage I was 3.4 ± 1.3 mL and at Tanner stages II–V 7.3 ± 2.7 mL (P < 0.0005). In girls at Tanner stage I, mean TV was 3.7 ± 1.7 mL and at Tanner stages II–V 5.9 ± 2.8 mL (P < 0.0005). There was no significant difference in TV between boys and girls at Tanner stage I (3.4 ± 1.3 mL vs 3.7 ± 1.7 mL; P = 0.202), while mean TV at Tanner stages II–V was significantly greater in boys than in girls (7.3 ± 2.7 mL vs 5.9 ± 2.8 mL; P = 0.001). Concerning the prevalence of goiter, goiter was defined as a TV above the 97^th percentile of the study population. According to this criterion, 3.2% of the schoolchildren were goitrous. TV in these children ranged from 9.4 to 15.3 mL, with a mean TV of 12 ± 2.7 mL. Subjects with a goiter had a mean urinary iodine concentration of 217 ± 65 µg I/g cr, which did not differ significantly from that of children without a goiter. Finally concerning thyroid ultrasonographic characteristics, the echographic appearance of the thyroid lobes was altered from normal in 9.2% of the study group. In 5.1%, there were one or more nodules (sizes ranging from 5.4 x 4.5 x 3.2 mm to 13.5 x 10 x 9.5 mm). These children were treated with L- thyroxine and examined every six months with a new echography and thyroid function tests: during follow-up, the U/S findings remained stable in ten children and size of thyroid nodule(s) regressed in thirty children. 

Conclusions: TV was assessed in 440 selected, healthy, Athenian, ethnically Greek children living in an iodine-replete area. The observed influential factors on TV in both boys and girls were the age, BSA, and pubertal stage. The prevalence of goiter was 3.2% and of an abnormal echo-structure of the thyroid gland was 9.2%.

 
 
COMMENTARY

             This manuscript by Erion et al. describes a thyroid hormone (TH) agonist, MB-07834, that specifically targets the liver due to p450 conversion from a prodrug, MB-07811. The former has a high therapeutic index with respect to cardiac parameters, glucose, body weight, and suppression of HPT axis while significantly decreasing serum cholesterol and triglyceride levels in rodents. This study thus describes a new class of selective TH agonists that utilize tissue-specific metabolism, and offer a novel approach to therapeutic usage of such TH agonists, in addition to other compounds that have been developed which have tissue-selective uptake or thyroid hormone receptor (TR) isoform-specificity. 

            This is a well-written and well-conducted study that describes a novel approach to designing drugs that have a tissue-specific effect. MB-07834 is rapidly cleared by liver and biliary system, and also has very little enterohepatic recirculation, all of which contribute to low systemic levels, when the prodrug MB-07811 is administered either intravenously or orally. The high therapeutic index suggest that MB-07811 or similar drugs that are selectively extracted, metabolized, and excreted by the liver may have utility as novel anti-cholesterol and anti-obesity agents. A similar strategy could be employed by other drugs that are metabolically activated by the liver.
Summary and commentary prepared by Paul Yen (related to Chapter 3 of TDM)

 

 

Iron deficiency and maternal thyroid function

 TOPIC: Potential role of iron deficiency adversely affecting maternal thyroid function.

Title: Iron deficiency predicts poor maternal thyroid status during pregnancy.

Authors: Zimmerman MB, Burgi H, & Hurrell RF.

 SUMMARY

Background: Pregnant women are often iron deficient during the 2^nd and 3^rd trimesters of pregnancy. Iron deficiency has adverse effects on thyroid metabolism, for example it decreases circulating thyroid hormone concentrations and blunts the efficacy of iodine prophylaxis. As impaired thyroid function in pregnancy (increase in TSH and/or low T4)  has been shown to be associated with impaired childhood neurodevelopment, iron deficiency may be a determinant of TSH and/or TT4 in pregnancy.

Objective: To investigate whether maternal iron status is a determinant of TSH and/or TT4 concentrations during pregnancy.

Methods: Blood and urine samples were obtained from a representative national sample of Swiss pregnant women (N = 365) in the 2^nd and 3^rd trimesters. Maternal characteristics and supplement use were noted. TSH, TT4, Hb, MCV, ferritin, transferrin, transferrin receptor and urinary iodine were measured. Body iron stores were calculated and stepwise regression performed to look for associations.

Results: Median urinary iodine was 139 µg/L (borderline iodine deficient in pregnancy). Women with negative body iron stores (40%) had a higher TSH and lower TT4 (R.R.: 7.8 for TT4 <100 nmol/L). Ferritin, transferrin receptor and body iron stores were highly significant predictors of serum TSH.

COMMENTARY

             There are now substantial data to show that a high serum TSH and/or a low total T4/free T4 in pregnancy are associated with a risk for a reduced neurodevelopment of the offspring. The etiology of the impaired thyroid function in many - but certainly not all - cases is autoimmune thyroid disease. Iodine deficiency also plays an important role. The present study emphasises another factor, namely iron deficiency, possibly contributing to the impairment of thyroid function during gestation, at least in an area of borderline iodine deficiency. This cross-sectional study does not establish causation between iron status and thyroid function, but it is known that iron deficiency blunts the TSH response to TRH, thereby decreasing serum T4 and T3 in rats. Animal studies have shown that the heme dependent enzyme, TPO, is also adversely affected by iron deficiency, resulting in lower circulating TT3 and TT4.

            There may be other explanations for the findings reported in present study. Iron status may be an indicator of an unmeasured confounder; vitamin status was not specifically measured, nor were there any specific measures of overall nutrition, both of which may also influence thyroid status. Another possibility is that impairment of thyroid function could lower iron status. This is less likely to have occurred in the present study, as only 6% of the women were anaemic and the data did not suggest anemia due to hypothyroidism. Furthermore, the fact that iron status was determined both by measurements of transferrin and transferrin receptor strengthens the observed association between iron status and thyroid function. The exact relation of iron status to iodine status in this study is not clear and requires further evaluation. 

            Do these data have relevance to fetal and child neurodevelopment? Unfortunately, no measurements were performed during the first trimester when the influence of reduced maternal T4 is paramount. In addition, there were no estimates of maternal thyroid antibodies (TPO), which have also been noted to influence neurodevelopment even when the mothers remained euthyroid. Nevertheless, this well conducted study does suggest that iron status deserves further investigation as a contributory factor to low circulating maternal thyroid hormone concentrations in pregnancy, at least in mildly iodine deficient areas. The etiology of impaired gestational thyroid function is slowly being unravelled.
Summary and commentary prepared by John Lazarus
Related to Chapters 14 & 20 of TDM

 

October 2007       Contributions by

v  Jim Stockigt (Monash University, Melbourne, Australia)

v  Wilmar Wiersinga (University Amsterdam, The Netherlands)

v  Luigi Bartalena (University Insubria; Varese, Italy)

FNA in medullary thyroid carcinoma 

TOPIC:

Hormone determinations in wash-out fluid from FNA 

Title: Calcitonin measurement in wash-out fluid from fine needle aspiration of neck masses in patients with primary and metastatic medullary thyroid carcinoma. 

Authors: Boi F, Maurelli I, Pinna G, Atzeni F, Piga M, Lai ML, & Mariotti S.

 SUMMARY

Objective: The aim of the study was to evaluate the usefulness of calcitonin (CT) assay in fine-needle aspiration biopsy (FNAB) wash-out fluid alone or combined with cytology in the presurgical study of medullary thyroid carcinoma (MTC) patients with thyroid nodules (TNs) and of suspicious neck MTC recurrences/metastases. 

Subjects & Methods: A total of 36 ultrasound-guided FNABs were performed in neck masses from 23 patients with borderline or high basal and pentagastrin-stimulated serum CT. Cytology and CT-FNAB were performed on a total of 18 TNs and 3 neck lymph nodes (LNs) from 12 patients examined before thyroidectomy, and on 6 suspicious local recurrences (LRs) and 9 LNs from 9 totally thyroidectomized MTC patients. On the basis of CT-FNAB values found in 15 non-MTC lesions, CT-FNAB values more than 36 pg/ml were considered as indicative of MTC.

Results: All 21 positive CT-FNAB lesions (10 TNs, 6 LNS, & 5 LRs), 13 with positive cytology, were confirmed as MTC at histology. Of the 15 negative CT-FNAB suspicious masses (8 TNs, 6 LNs, & 1 LR), five displayed a benign lesion at histology. The remaining 10 cases, all with benign cytology, were not operated on, and no evidence of MTC was detected during follow-up. CT-FNAB reached 100% sensitivity and specificity for MTC, while cytology displayed 61.9% sensitivity and 80% specificity.

Conclusions: Ultrasound-guided CT-FNAB was the best tool to identify primary MTC and LRs/node metastases in MTC operated patients. This may have important implications in the management of MTC. 

COMMENTARY

             Two recent studies of medullary thyroid carcinoma (MTC) extend the technique reported by Pacini et al. in 1992, who showed that the assay of thyroglobulin in the needle/syringe wash-out from fine needle aspiration biopsy (FNAB) of neck lymph nodes could be definitive in demonstrating that neck lymph nodes were metastases from differentiated thyroid carcinoma (Pacini et al., JCEM 74:1401, 1992). This hormone assay application has also been validated for parathyroid hormone (Kiblut et al., World J Surg 28:1143, 2004; Maser et al., Ann Surg Oncol 13:1690, 2006). More recently, it was also shown that the assay of calcitonin (CT) can provide crucial information from ultrasound/FNAB studies (Present article, and Kudo et al., Thyroid 17:635, 2007).

             In the present article, Boi et al. reported 21 studies that were positive for CT on fine needle wash-out assays, with a better sensitivity & specificity than was obtained from cytology. Kudo et al. reported 5 thyroid nodules positive for medullary carcinoma, with only one of which identified by cytology. CT assay values in the needle wash-out were 300 to 10.000-fold higher than in other thyroid abnormalities that were biopsied.

             In this technique, the equipment used for FNAB is washed out with 1 ml of assay diluent after preparation of routine cytological samples. Precisely targeted surgery may be facilitated by answers to the following questions:
1. Does a newly recognized neck lymph node contain metastatic thyroid tissue?          2. Does a mass of doubtful significance, seen on ultrasound in differentiated thyroid         cancer or medullary carcinoma follow-up, contain metastatic or recurrent tissue? 3. Is a lump seen on ultrasound a parathyroid adenoma (if a rapid assay is available,         the technique may also be useful intra-operatively)?
 4. Is a thyroid nodule, lymph node or tissue mass, a focus of medullary thyroid      carcinoma?       

            The results are qualitative, but masses that are hormone-positive give results orders of magnitude higher than serum concentrations or hormone-negative lesions. To date, no false-negative results due to ‘hook effects’ have been reported, but this important possibility could be addressed by assaying samples in dilution (Lebouef et al., JCEM 91:361, 2006).
Summary and commentary prepared by Jim Stockigt (related to Chapters 6(d), 18, & 21 of TDM)

 

Mild hypo-/hyperthyroidism & mortality in cardiac patients

 TOPIC:Subclinical hypo- and hyperthyroidism and mortality

 Title: Association between increased mortality and mild thyroid dysfunction in cardiac patients.

 Authors: Ievarsie G, Molinaro S, Landi P, Taddei MC, Galli E, Mariani F, L’Abbate A, & Pingitore A.

 SUMMARY

Background: The clinical relevance of subclinical hypothyroidism (SCH) and subclinical hyperthyroidism (SCT) is not clear. There is a need for long-term outcome studies to gain more insight. 

Purpose: To evaluate if subclinical hypo-/hyperthyroidism is associated with a higher mortality in cardiac patients.

Methods: Included were all 4.368 patients hospitalized in 2000-2005 at the Department of Cardiology in Pisa. Exclusion criteria were acute coronary syndrome, pulmonary oedema, severe systemic diseases, hospital mortality, overt hyper-/hypothyroidism, medications influencing thyroid function, or atypical thyroid state (not fitting in any group described below): based on these criteria, 1.060 patients were excluded. Thyroid function was assessed in a blood sample withdrawn at 07.00 hrs at day 2-5 of the hospital admission. Patients were divided into 4 groups: Euthyroidism (TSH, FT4 & FT3 normal), SCH (TSH: 4.5-10 mU/L), SCT (TSH: <0.3 mU/L), and low T3 (FT3: < 3.2 pmol//L, TSH & FT4 normal). Thyroid function tests were repeated within 2 to 12 weeks and, if this resulted in another classification relative to the first blood sample, these patients were also excluded (N = 187). Finally, the study population comprised 3.121 patients (33% females; mean age: 61 years). The mean follow up period was 32 months.

Results: Cardiac and total mortality was 3.4% & 7.3% respectively in euthyroid patients, 7.2% & 13.0% respectively in SCH, 8.2% & 9.2% respectively in SCT, and finally 6.5% & 13.1% respectively in low T3. After correction for various risk factors, the hazard ratio for cardiac mortality was higher in SCH (RR: 2.40; 95% CI: 1.36-4.21), in SCT (RR: 2.32; 95% CI: 1.11-4.85), and in low T3 (RR: 1.63; 95% CI: 1.14-2.33) than in euthyroidism. Hazard ratio’s for total mortality were higher in SCH (RR: 2.01; 95% CI: 1.33-3.04) and in low T3 (RR: 1.57; 95% CI: 1.22-2.01), but not in SCT.

Conclusions: A mildly altered thyroid status is associated with an increased risk of mortality in patients with cardiac disease. 

COMMENTARY

             Limitations of the present study were the absence of thyroid function tests during the follow-up period, the absence of information on non-fatal cardiovascular events, and the lack of analysis of serum TSH levels.

             The author’s conclusion, however, seems to be valid from a methological point of view. One of the strengths of present study was that the investigators have classified the etiological diagnoses in all 208 patients with SCH: chronic autoimmune thyroiditis (75%), post-thyroidectomy or post-radioiodine (25%), and in all 98 patients with SCT: multinodular goiter (81%), Graves’ disease (15%), and thyroid adenoma (4%). Together with the 910 low T3 patients, this indicates that a slightly abnormal thyroid function was found in 39% of the cardiac patients.

             These results are of interest and present potentially a high clinical relevance, provided that it can be demonstrated (in further studies) that medical intervention might diminish the mortality. Such studies, however, on a preventive medical intervention aimed at correcting thyroid abnormalities, have not yet been performed, and would require a rather long follow-up period. Also, it is highly likely that any beneficial effect of medical intervention will be age-dependent, and in this respect a more detailed analysis of the data per decade in the present cohort study could illuminate further our insight.
Summary and commentary prepared by Wilmar Wiersinga (related to Chapters 9, 10, & 13 of TDM)

 

TSH receptor antibodies: risk of recurrence and orbitopathy

 TOPIC: Graves’ orbitopathy

 Title: Patients with severe Graves’ ophthalmopathy have a higher risk of relapsing hyperthyroidism and are unlikely to remain in remission.

 Authors: Ecktsein AK, Lax H, Losch C, Glowacka D, Plicht M, Mann K, Esser J

& Morgenthaler NG.

SUMMARY

Background: Graves’ hyperthyroidism and orbitopathy (GO) are frequently associated. This might be due to the putative pathogenic role of the TSH-receptor antibody (TRAb) in both conditions.

Purpose: The objective of this retrospective observational study was to investigate the possible relationship between the severity of GO and relapse/remission rate of hyperthyroidism after antithyroid drug (ATD) treatment.

Patients and Methods: One hund