non-HT Patients Research Articles

Abstract 10034: Digital Assessment of Peripheral Vascular Endothelial Function is Useful for the Risk Stratification in Patients With Hypertension

Introduction: Hypertension (HT) is the major risk factor of coronary artery disease (CAD), however all HT patients were not equally predisposed to CAD. Endothelial dysfunction has been implicated in atherogenesis, and digital assessment by reactive hyperemia peripheral arterial tonometry (RH-PAT) is a novel examination to evaluate endothelial function. Methods: In 1323 stable patients with suspected CAD including 1057 HT patients, we assessed peripheral endothelial function as fingertip RH-PAT index (RHI) and examined the presence and severity of CAD by coronary angiography. Results: Ln-RHI was significantly attenuated in HT patients (n=215) compared to risk-factor-matched non-HT patients (n=215) (0.538±0.224 vs. 0.664±0.248, p<0.001) after matching number of patients and coronary risk factors (CRFs). In HT patients, ln-RHI was further lower in CAD (n=786) than in non-CAD (n=271) (0.514±0.185 vs. 0.634±0.219, p<0.001). By multivariate-logistic-regression analysis, ln-RHI was independently associated with the presence of CAD in HT (per 0.1; odds ratio [OR]: 6.15, 95% confidence interval [CI]: 1.87-20.3, p<0.001). CAD with high-ln-RHI was significantly associated with the complication of multi-vessel disease (MVD) and B-type natriuretic peptide (both p<0.001). In receiver-operating-characteristic analysis, ln-RHI was a significant determinant for the presence of CAD (area under curve [AUC]: 0.650, 95% CI: 0.646-0.721, p<0.001), and adding ln-RHI to CRFs improved predictive values of CAD (AUC: 0.737, 95% CI: 0.701-0.773, p<0.001). The net reclassification index was significant with the inclusion of ln-RHI (13.8%, p<0.005). Furthermore, ln-RHI was significantly lower in CAD with MVD (n=464) than in those with single-vessel disease (n=322) (0.46 vs. 0.57, p<0.001). Multivariate-logistic-regression analysis suggested that ln-RHI was independently associated also with the presence of MVD in CAD (per 0.1; OR: 0.66, 95% CI: 0.60-0.73, p<0.001). Conclusions: Ln-RHI significantly correlated with the presence and severity of CAD in HT, and the combination with CRFs may be more powerful at predicting CAD. Identifying high-risk HT patients by RH-PAT might provide clinical benefits for risk stratification.

Hashimoto's thyroiditis, risk of coronary heart disease, and L-thyroxine treatment: a nationwide cohort study.

Our objective was to investigate the risk of coronary heart disease (CHD) in patients with Hashimoto's thyroiditis (HT). The Taiwan National Health Insurance Research Database was used to conduct a retrospective cohort analysis. The cohort study consisted of 1165 newly diagnosed HT patients and 4660 matched controls (non-HT patients) from 2000 to 2010. The median follow-up time was 5.46 years. The risk of developing CHD for HT patients was measured using the Cox proportional hazards model. The risk of developing CHD in HT patients was increased compared with the non-HT controls, with an adjusted hazard ratio (HR) of 1.44 (95% confidence interval [CI] = 1.05-1.99). The risk was significant in women but not in men, and restricted to subjects younger than 49 years. HT remained an independent risk factor after adjusting for comorbidities; however, combining with hypertension or hyperlipidemia further increased the risk of CHD (adjusted HR = 2.06, 95% CI = 1.46-2.92; and adjusted HR = 1.83, 95% CI = 1.31-2.55, respectively). Furthermore, HT without T4 treatment and HT with treatment for less than 1 year were associated with higher risk of CHD (adjusted HR = 1.55, 95% CI = 0.98-2.46; and adjusted HR = 2.42, 95% CI = 1.43-3.97, respectively). The risk of CHD decreased after treatment with T4 for more than 1 year and did not differ from the non-HT cohort (adjusted HR = 0.84, 95% CI = 0.0.47-1.52). Patients with HT, are at higher risk of developing CHD compared with the general population. Treatment with T4 reduces the risk of CHD.

Hypothermia in organ donation: a friend or foe?

Hypothermia is a known predictor of mortality in trauma patients; however, its impact on organ procurement has not been defined. The aim of this study was to assess the effect of hypothermia on organ procurement. We hypothesized that admission hypothermia impedes successful organ procurement. We performed a 5-year retrospective analysis of all trauma patients approached for organ donation. Hypothermia was defined as a core body temperature 36°C/97°F or less. The two groups (hypothermic [HT] vs. nonhypothermic [non-HT]) were matched in a 1:1 ratio using propensity score matching for age, sex, admission Glasgow Coma Scale (GCS) score, systolic blood pressure, international normalized ratio, and Injury Severity Score (ISS). Primary outcome measures were eligibility for organ donation and solid organ procurement. Secondary outcome measures were blood product and vasopressor requirements. This study was composed of 537 brain-dead patients, of whom 416 (HT, 208; non-HT, 208) were included in the analysis. The mean (SD) age was 40.5 (23.7) years, 75% were male, mean (SD) temperature was 36.6°C (1.7°C), and mean (SD) systolic blood pressure was 75.35 (68.7) mm Hg. Patients who were hypothermic on presentation were less likely to be eligible for organ donation (44.7% vs. 96%, p ≤ 0.001), and they donated fewer organs per donor (p = 0.04). HT patients required more units of fresh frozen plasma (p = 0.04) and greater mean dose of dopamine (p = 0.03) and vasopressin (p = 0.03) compared with the non-HT patients. Admission hypothermia is associated with decreased organ donation in potential organ donors independent of admission coagulopathy, hypotension, and injury severity. Early correction of hypothermia may improve organ donation in trauma patients. Epidemiologic/prognostic study, level III.

Thyro-gastric autoimmunity in patients with differentiated thyroid cancer: a prospective study.

Thyro-gastric autoimmunity has not been previously evaluated in patients with differentiated thyroid cancer (DTC), although its long-term complications may be relevant for the management of DTC patients. We assessed the prevalence of gastric autoimmunity and autoimmune gastritis (AG) in patients with Hashimoto's thyroiditis (HT) and concomitant DTC. Prevalence of parietal cell antibody (PCA) positivity, iron deficiency anemia (IDA), and pernicious anemia (PA) were prospectively assessed in 150 DTC patients referred for radioiodine ablation after total thyroidectomy. Patients were classified as HT (n = 31) and non-HT (n = 119) based on a combination of serological, ultrasonographic, and histological findings. Patients with PCA positivity were subsequently addressed to endoscopy for confirmation of atrophy body gastritis, required for the diagnosis of AG. For all the variables under study, a comparison between groups was made using Fisher's exact test and appropriate parametric and non-parametric tests. PCA positivity was significantly more prevalent in HT than in non-HT patients (12.9 vs 1.6 %, p = 0.017). After Hp eradication, a reversal of PCA positivity was observed in 3/4 patients in the HT group. IDA and PA did not differ significantly between groups. In the HT group, only one patient had endoscopical confirmation of mild gastric corporal atrophy. Gastric autoimmunity shows higher prevalence in patients with DTC and concomitant HT than in patients with DTC alone; however, in most cases, PCA positivity was associated with Hp infection. Furthermore, although previous reports found up to one-third of patients with HT to have associated AG, in our cohort AG was extremely rare.

Cancer risk in patients with Hashimoto’s thyroiditis: a nationwide cohort study

Background:This study examined the risk of cancer in patients with Hashimoto's thyroiditis (HT).Methods:The Taiwanese National Health Insurance Research Database (NHIRD) was used to identify 1521 newly diagnosed HT patients from 1998–2010, and 6084 frequency-matched non-HT patients. The risk of developing cancer for HT patients was measured using the Cox proportional hazard model.Results:The incidence of developing cancer in the HT cohort was 5.07 per 1000 person-years, which was 1.68-fold higher than that in the comparison cohort (P<0.001). Compared with patients aged 20–34 years, patients in older age groups had a higher risk of developing cancer (35–55 years: hazard ratio (HR)=5.96; >55 years: HR=9.66). After adjusting for sex, age, and comorbidities, the HT cohort had HRs of 4.76 and 11.8 for developing colorectal cancer and thyroid cancer, respectively, compared with non-HT cohort. Furthermore, the HT cohort to non-HT cohort incidence rate ratio (IRR) of thyroid cancer was higher in the first 3 years (48.4, 95% confidence interval (CI)=35.0–66.3), with an adjusted HR of 49.4 (95% CI=6.39–382.4).Conclusion:Hashimoto's thyroiditis patients have a higher risk of thyroid cancer and colorectal cancer. The thyroid cancer prevention effort should start soon after HT is diagnosed, while being cautious of colorectal cancer increases with time.

Dietary Supplementation Improves Blastocyst Number and Ongoing Pregnancy Rate of IVF Patients with Hashimoto Thyroiditis

In Assisted Reproduction Techniques (ART), autoimmune disorders of the thyroid gland present as common concomitant diseases. Hypothyroidism caused by autoimmune thyroiditis can impair fertility and pregnancy. Hashimoto thyroiditis (HT) is the most common autoimmune thyroid disease (AITD). Patients with HT undergoing IVF/ICSI using the long protocol are thought to benefit from a broad therapeutic concept. We compared the outcome of two different therapeutic schemes for HT patients presenting at our fertility clinic and compared the outcome to ART patients without thyroiditis. TSH level was adjusted to under 2 µIU/mL using L-thyroxine, as required. Concurrent medication from the time of oocyte puncture included daily administration of fragmin (dalteparin) and acetylsalicylic acid (ASA), as well as prednisolone in increasing dosage. One group of these HT patients (group1, n=56) had additionally highly-dosed folic acid, another group (group 2, n=50, referred to as the supplemented group) was alternatively supplemented with a micronutrient preparation containing selenium, high-dose folic acid, B-vitamins, antioxidants and iron. We compared the number of oocytes, fertilization rate, blastocyst formation rate, pregnancy- and ongoing pregnancy rate between the two groups. Also, the ART outcomes of both groups were compared to ART results of non-HT patients within the same age group. We observed a significant increase in the blastocyst rate and demonstrated a substantial rise in ongoing pregnancy rate of the supplemented patients. These also needed less L-thyroxine to achieve optimal TSH level. The outcome of the micronutrient supplemented patients corresponded to the average of healthy IVF patients without HT at our clinic.

Coexistence of papillary thyroid cancer with Hashimoto thyroiditis

AimsConflicting data have been reported with regard to Hashimoto thyroiditis (HT) and risk of malignancy. The aim of this study was to evaluate coexistence of papillary thyroid cancer (PTC) with HT.Patients and methodsThis is a retrospective cohort study in which HT was diagnosed in 452 (F/M ratio = 405:47, median age 53.5 ± 12.1 years) of 7,545 patients qualified for thyroidectomy throughout the years 2002 to 2010. Pathological reports were reviewed to identify prevalence of PTC in HT vs. non-HT patients.ResultsPTC was diagnosed in 106 of 452 (23.5 %) HT patients vs. 530 of 7,093 (7.5 %) non-HT patients (p < 0.001). Metastases to level VI lymph nodes were observed in 81 of 106 (76.4 %) patients with PTC in HT vs. 121 of 530 (22.8 %) patients with PTC in non-HT disease (p < 0.001).ConclusionsHT was associated with a threefold increase of PTC prevalence as compared to other non-HT thyroid diseases, and the spread of PTC to level VI lymph nodes was four times more frequent in HT than in non-HT patients.

Prediction of hemorrhagic transformation in acute ischemic stroke using texture analysis of postcontrast T1‐weighted MR images

To test the hypothesis that texture analysis of postcontrast T1-weighted MR images will predict hemorrhagic transformation (HT) in patients with acute ischemic stroke (AIS) with better accuracy than visual evidence of contrast-enhancement (VE). Thirty-four AIS patients were examined within 3.5 +/- 1.5 h after stroke. T1-weighted MR images were acquired 19 +/- 7 min postcontrast injection. HT was determined by follow-up imaging at 24-72 h. Postcontrast images were evaluated for VE. Four second-order textural features were extracted (f1, f2, f3, and f9) for each patient. Receiver operating characteristic (ROC) curves were constructed for VE and for textural features, with HT as the outcome measure. The f2 for HT patients (n = 12) was significantly lower than in non-HT patients (1058 +/- 356 versus 1568 +/- 527; P = 0.005); the converse was true for f3 (0.67 +/- 0.12 versus 0.54 +/- 0.13; P = 0.007). ROC analysis indicated that the f2 and f3 textural features were the only two significant predictors of HT (P = 0.0018 and P = 0.0042). The addition of VE to either f2 or f3 did not result in a significant improvement in accuracy. Texture analysis of postcontrast T1-weighted images may be superior to visual evidence of enhancement for the prediction of HT.

Relative Recirculation

To retrospectively evaluate the prognostic performance of a dynamic susceptibility contrast (DSC) MRI metric for permeability (relative recirculation or rR) for the prediction of hemorrhagic transformation (HT) in patients with acute ischemic stroke (AIS). To compare rR with dynamic contrast-enhanced (DCE) MRI estimates of blood-brain barrier permeability (KPS). Data obtained from 26 patients (age: 27-89 years) with a working diagnosis of AIS were examined retrospectively. Patients were examined within a mean of 3.5 hours of symptom onset. Eleven patients received intravenous recombinant tissue-plasminogen activator (rt-PA). HT was determined by follow-up computed tomography and/or magnetic resonance imaging 24 to 72 hours after initial imaging. Permeability (DCE) always preceded DSC imaging and consisted of a 3D gradient-recalled echo scan acquired in 4 minutes 48 s. DSC imaging consisted of a T2*-weighted single shot EPI scan acquired in 43 to 86 seconds. Gadodiamide (0.1 mmol/kg) was injected as a bolus for each scan. Permeability (KPS) and rR were calculated offline for regions of interest (ROI) defined within the core of the infarct, as well as within the homologous location in the contralateral hemisphere. The relationship between KPS and rR was investigated using linear regression and receiver operating characteristic (ROC) curves were computed for predicting HT from either rR or KPS. Eleven patients proceeded to HT (including 5 treated with rt-PA). Mean KPS values were significantly elevated in infarct relative to contralateral areas (0.84 +/- 0.57 vs. 0.42 +/- 0.34 mL/100 g/min; P = 0.0003). For infarct ROIs, KPS values were significantly greater in patients with HT compared with non-HT patients (1.25 +/- 0.63 vs. 0.53 +/- 0.23 mL/100 g/min; P = 0.0015). KPS values were higher in patients who received rt-PA than in untreated patients (1.09 +/- 0.61 vs. 0.65 +/- 0.47 mL/100 g/min; P = 0.0497). ROC analysis indicated a KPS threshold value of 0.67 mL/100 g/min for providing an optimal sensitivity and specificity for predicting HT of 91% and 80%, respectively. Mean rR values for infarct ROIs were significantly higher than those determined for contralateral regions (0.17 +/- 0.06 vs. 0.09 +/- 0.03; P < 0.0001). The mean rR for the HT group was significantly greater than for the non-HT group (0.22 +/- 0.05 vs. 0.14 +/- 0.05; P = 0.0002). As with KPS, the mean rR for patients who were treated with rt-PA was significantly greater than for untreated patients (0.21 +/- 0.07 vs. 0.15 +/- 0.05; P = 0.0112). ROC analysis indicated a threshold value of 0.17 for providing optimal sensitivity and specificity for predicting HT of 91% and 87%, respectively. There was a significant correlation between rR and KPS for infarct ROIs (r = 0.67; P < 0.001). Both KPS and rR are significantly elevated in infarcted, relative to uninfarcted tissue in the same AIS patient. Both parameters were also significantly elevated in HT, relative to non-HT infarcts. The strong correlation between rR and KPS, coupled with the high sensitivity and specificity of rR for the prediction of HT suggest that rR is related to blood-brain barrier integrity in AIS and may prove valuable in the prediction of HT.

Serum hepatocyte growth factor is increased in Hashimoto’s thyroiditis whether or not it is associated with nodular goiter as compared with healthy non-goitrous individuals

Some growth factors and cytokines are known to cooperate with TSH in thyroid nodular growth, but few data are available on their circulating levels in Hashimoto's thyroiditis (HT). To evaluate in HT patients whether thyroid nodules are associated with variations in serum levels of hepatocyte growth factor (HGF) and interleukin-6 (IL-6). Serum levels of HGF and IL-6 were measured by enzyme-linked immunosorbent assay in 176 euthyroid subjects, subdivided into 4 groups: A) HT patients with nodular goiter (no.=42); B) non-goitrous HT patients (no.=36); C) non-HT patients with nodular goiter (no.=48), and D) healthy subjects without thyroid disease (no.=50). The highest concentrations of serumHGF were found in patients with nodular goiter, irrespective of the presence of associated HT (groups A and C). Nevertheless, in group A serum HGF levels were significantly higher than in group C (860.8+/-333.6 pg/ml vs 691.5+/-156 pg/ml, p<0.01). Moreover, though serum HGF levels in group B (578.3+/-217 pg/ml) were lower than in group A, they were significantly higher than in healthy controls (group D, 512.7+/-170.4 pg/ml, p<0.001). Serum IL-6 levels were similar in the two HT groups (A and B), and increased with respect to groups C and D. Serum HGF is increased in HT, especially associated to thyroid nodules, as compared with healthy non-goitrous individuals.

Poor prognosis of heart transplant patients with end-stage renal failure

Chronic kidney disease (CKD) and end-stage renal failure (ESRF) are major complications after a heart transplant. The aim of this study is to compare survival in heart transplant (HT) vs non-heart transplant (non-HT) patients starting dialysis. Survival was studied among the 539 newly dialysed patients between 1 January 1995 and 31 December 2005 in our Department. All patients were prospectively followed from the date of first dialysis up to death or 31 December 2005. Multivariate survival analysis adjusted on baseline characteristics was performed with the Cox model. There were 21 HT patients and they were younger than non-HT patients at first dialysis: 58.6+/-11.6 vs 63.0+/-16.2 years (P=0.09). Calcineurin inhibitor nephrotoxicity was the main cause of ESRF in HT patients (47.6%). Crude 1, 3 and 5-year survival rates in HT and in non-HT patients were as follows: 76.2%, 57.1%, 28.6% and 79.1%, 58.7%, 46.7% (P=0.2). The adjusted hazard ratio of death in HT vs non-HT patients was 2.27 [1.33-3.87], P=0.003. Sudden death was the main cause of death in HT patients, in 33.3% vs 10.4% in non-HT patients (P=0.01). Five HT patients benefited from renal transplant. They were all alive at the end of the study period, while one patient among the 16 remaining on dialysis survived. HT patients with CKD who reached ESRF have a poor outcome after starting dialysis in comparison with other ESRF patients. Improvement in renal function management in the case of CKD is needed in these patients and non-nephrotoxic immunosuppressive regimens have to be evaluated. Renal transplant should be the ESRF treatment of choice in HT patients.

Evening–Morning Differences in Blood Pressure in Sleep Apnea Syndrome: Effect of Gender

Obstructive sleep apnea (OSA) is associated with hypertension. In the current study we sought to determine whether the evening-morning differences in blood pressure (BP) would correlate with the severity of OSA and whether there are gender-related differences. A total of 2009 consecutive patients referred to sleep examination because of suspected sleep apnea were retrospectively included. The patients comprised 1566 men, of whom 870 were nonhypertensive (non-HT) and 696 hypertensive (HT) and 443 women, of whom 258 were non-HT and 185 HT. Four BP measurements, two in the evening and two in the morning, were taken. The relationship between evening-morning differences in BP and the number of apneas/hypopneas divided by hours of sleep (AHI) were analyzed separately for HT and non-HT men and women. In men, increase in AHI was associated with increase in morning BP, and the evening-morning difference for both systolic and diastolic BP became negative. These trends were found to be significant by linear regression analyses both for HT (for systolic BP, r = 0.75, P < .05, for diastolic BP r = 0.96, P < .05) and non-HT patients (for systolic BP r = 0.93, P < .05, for diastolic BP r = 0.94, P < .05). In women (unlike in men), increasing AHI was not associated with a linear increase in the evening-morning BP differences. None of the regression lines fitted to the data was significant. Our results demonstrate that the evening to morning difference in BP in men with OSA is linearly related to the severity of OSA, both in patients with HT and in those with non-HT. These results may have practical relevance in screening for patients with OSA and may have prognostic clinical value in predicting future cardiovascular events.

Hypertension impairs post-operative regression of left ventricular hypertrophy and improvement in exercise capacity in patients operated for aortic valve stenosis

Previous studies have shown that regression of left ventricular (LV) hypertrophy represents the underlying determinant of event-free survival and LV function after aortic valve replacement (AVR) for aortic stenosis (AS). It is known that hypertension (HT) leads to LV hypertrophy and reduced exercise capacity. However, no data has been published about the influence of concomitant HT on LV hypertrophy regression and exercise capacity in patients operated for AS. We performed echocardiography and treadmill tests on 53 patients, mean age 72 (49–86) years, who received AVR with Medtronic Hall (17), Biocor (1), Carpentier-Edwards SAV (9) and Freestyle (26) prostheses for severe AS. 33 patients had a history of HT. Baseline echocardiography was performed 4–15 days post-AVR and follow-up, including treadmill tests with ergospirometry, took place at 6 (early evaluation) and 18 (late evaluation) months post-AVR, respectively. Blood pressure rose significantly more during follow up in HT patients (from 142/76 to 170/87 mmHg in HT patients and from 125/68 to 130/78 mmHg in nonHT patients, p<0.05). LV mass index was reduced by 45g/m2 in nonHT patients and 65g/m2 in HT patients at early evaluation and by 50g/m2 in nonHT patients and 89g/m2 in HT patients at late evaluation. HT patients maintained a higher LV mass index during the follow-up period (p<0.05). 30 patients (27% nonHT and 63% HT, p<0.05) had residual LV hypertrophy at late evaluation. In multiple regression analysis, controlling for initial LV mass index, LV hypertrophy reduction was inversely associated with age and concomitant HT, while no independent association was found with gender, prosthetic valve size or baseline systolic LV function (multiple R2=0.80, p<0.001). Exercise capacity assessed as peak oxygen uptake increased significantly from early to late evaluation in nonHT patients (VO2max 23.6 vs 26.3 ml/kg/min, p<0.01) while remained unchanged in HT patients (VO2max 22.1 vs 21.4 ml/kg/min). In multiple regression analysis, higher exercise capacity at late evaluation was predicted by male gender, younger age and absence of HT, while no independent association was found with prosthetic valve size (multiple R2=0.66, p<0.001). Concomitant HT is associated with less LV hypertrophy regression and lack of improvement in exercise capacity in patients having AVR due to aortic stenosis.

Doppler tissue imaging identifies altered activation sequences in stable heart transplant recipients

Introduction: Whether myocardial activation sequences in heart transplant (HT) recipients differ from non-transplanted structurally normal hearts is unknown. We performed a case control study to determine baseline myocardial activation sequences in stable heart transplant recipients utilizing Doppler tissue imaging (DTI) techniques. We then compared them to non-HT patients with structurally normal hearts to assess for potential differences between the two groups. Methods: We retrospectively reviewed our echocardiographic database and identified 11 HT recipients (8 males, 59±7 yrs) with normal LV systolic function. All transplants were performed>6 months from the time of the echocardiogram. We then analyzed DTI in these patients and compared them to 11 age matched controls (7 males, 64±10 yrs) with no evidence of structural heart disease. Patients with LV ejection fractions (LVEF)<55%, atrial fibrillation, permanent pacemakers, QRS duration>120 msec, or moderate or greater valvular heart disease were excluded. We analyzed DTI time intervals and peak velocities (GE Vivid 7). In DTI, onset of (ECG) Q wave to peak (DTI) S and E waves (Q-S, Q-E) was measured. An 8 segment global LV score was created by averaging 8 data points from the basal and mid-positions of the respective LV wall. Results: Baseline characteristics including age, sex, heart rate, LVEF, LV mass index, QRS duration and peak DTI velocities were not significantly different between the two groups. Conclusions: 1) DTI techniques allow detailed investigation into myocardial mechanics in HT recipients. 2) Stable HT recipients display altered patterns of ventricular activation sequences when compared to age matched non-HT recipients with normal LV systolic function. 3) Stable HT recipients demonstrated earlier activation and relaxation within the cardiac cycle as assessed by DTI. We speculate that the role of DTI in HT patients may expand, with potential applications including detection of rejection and allograft vasculopathy.ResultsHT (n=11)Control (n=11)p valueMean 4 chamber DTI Q-S (msec)145±26179±300.01Mean 2 chamber DTI Q-S (msec)126±14167±350.007Mean 4 chamber DTI Q-E (msec)448±26548±490.0002Mean 2 chamber DTI Q-E (msec)446±28550±490.00018 segment DTI Q-S(msec)136±18173±300.0068 segment DTI Q-E (msec)447±24549±560.0001

Heterogeneity of the thyroglobulin epitopes associated with circulating thyroid hormone autoantibodies in hashimoto's thyroiditis and non-autoimmune thyroid diseases.

We previously implicated TG leakage from fine-needle aspiration biopsy (FNAB) as responsible for circulating thyroid hormone autoantibodies (THAb). However, THAb were not always associated with TGAb. In the literature these negative findings have been interpreted against a role of TG as the antigen for THAb. To evaluate the TGAb status more fully and to gain information on TG epitopes involved in THAb development, we measured: 1) TGAb with an independent hemagglutination assay (HA), and 2) epitope specificity in a competitive ELISA using 2 monoclonal Abs (mAb) against TG: mAb 42C3 and mAb 134C2. MAb 42C3 recognizes a cross-reactive iodinated epitope, whereas 134C2 is specific for human TG. We tested 12 Hashimoto's thyroiditis (HT) and 35 non-HT patients sampled prior to, 1 and 3 months after FNAB. We found that, irrespective of thyroid disease or post-FNAB THAb status, certain patients previously classified as TGAb negative by IRMA tested TGAb positive by HA or by competition ELISA and vice versa. A post FNAB positive response to the 42C3 iodinated epitope in only one THAb IgM-T4+ve HT and a few THAb negative non-HT patients was observed. Furthermore, we observed that the 3 non-HT patients who expressed IgM-T3 THAb failed to bind either TG-mAb epitope. We conclude that a single TGAb assay is not sufficient to define the TGAb status, which can be achieved reliably only by using multiple TGAb assays. In addition, the TG-iodinated epitope recognized by 42C3 is not a major epitope in post-FNAB THAb, and the T3-epitope involved in THAb remains distinct from the mAb epitopes. In light of recent data in the literature, we further suggest that the responsible epitopes are more likely to be expressed in leaked TG fragments, rather than leaked intact TG.

Thyroid Hormone Autoantibodies Elicited by Diagnostic Fine Needle Biopsy1

Based on the knowledge that diagnostic fine needle biopsy of the thyroid (FNAB) results in a prompt increase in circulating thyroglobulin (Tg); we evaluated whether Tg is indeed the postulated antigen for circulating antibodies against thyroid hormones (THAb). Preliminarily, we verified that FNAB causes the release into the bloodstream of iodinated, heterologous, and thus potentially immunogenic, molecules of Tg. Of the initially enrolled 400 patients, 214 had a number of blood drawings sufficient to evaluate over time (before FNAB and 1-3 h, 3 days, 15 days, 30 days, 3 months, 6 months, and 12 months after FNAB) the following parameters: THAb of both IgM and IgG classes, Tg antibodies (TgAb; by a sensitive immunoradiometric assay), and Tg (in the 156 patients who were TgAb negative). We found the following. 1) Serum Tg most often peaks 1-3 h after FNAB (61 +/- 45% of the baseline level; mean +/- SD). 2) Only 7% of the initially TgAb-negative patients converted to positive, and only 12% of those initially positive had an increase in the levels of TgAb. 3) THAb were detected in 0 of 400 patients before FNAB, but were found in 9 of 214 (4.2%) after FNAB. This proportion is 2 orders of magnitude higher than that (149 of 369,000 or 0.04%) found in consecutive patients attending European thyroid clinics. Of the 9 cases, 6 had Hashimoto's thyroiditis (HT), 2 had euthyroid colloid goiter, and 1 had Hurthle cell carcinoma. In the 5 of 9 cases who were TgAb negative, the post-FNAB increment in Tg was 21-99%, i.e. lower than that of the majority of patients (101-12,500%). 4) THAb were of the IgM class in all 9 (6 against T3 and 3 against T4), and were accompanied and/or followed up to 3 months after FNAB by IgG-THAb of the same specificity (2 against T3 and 1 against T4) in 3 cases. In a fourth case, IgM-T3 were followed by a long-lasting synthesis of IgG-T3 (i.e. up to 1 yr post-FNAB). All 4 cases with IgG-THAb had HT and remained TgAb positive. 5) In the 2 HT and the 3 non-HT patients with undetectable TgAb, THAb were of the IgM class only. 6) In the HT group, 2 risk factors for the development of post-FNAB THAb appeared to be pre-FNAB TgAb levels below 400 U/mL that did not increase after FNAB and Tg released from a colloid nodule. We conclude that Tg release from the thyroid is sufficient to elicit THAb synthesis. In patients with autoimmune thyroid disease (HT), this synthesis occurs with a frequency 10-fold higher than that in patients with nonautoimmune thyroid diseases (21% vs. 2%). However, in only a fraction of patients with autoimmune disease, who need to be TgAb positive by a sensitive assay, the primary immune response (IgM) is followed by a secondary one (IgG). As, once present, this secondary response is long lasting in only a minority of our patients, we think that this could contribute to the rarity of naturally occurring THAb.