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Oxidative Stress and Advanced Glycation End Products in Hashimoto's Thyroiditis

BACKGROUND Oxidative stress, which occurs as a result of an imbalance between free-radical production and antioxidant defense mechanisms, has been implicated in the pathogenesis of several autoimmune disorders, including thyroid diseases. Importantly, it has been correlated to thyroid dysfunction. This study investigated the changes in oxidative balance in euthyroid Hashimotos thyroiditis (HT) by means of specific serum tests, such as derived reactive oxygen metabolites (d-ROMs) and the biological antioxidant potential (BAP) test. In addition, advanced glycation end products (AGEs) and advanced oxidation protein products (AOPPs)--compounds formed by the transformation of proteins--were evaluated as potential new markers of oxidative stress in this disease. METHODS This study included 134 euthyroid subject: 71 newly diagnosed HT patients (63 females; M age = 38 ± 13 years) and 63 age and sex-matched healthy controls. None of them were on thyroxine therapy. RESULTS Serum d-ROMs were elevated, and BAP decreased in HT patients compared with controls (p < 0.001), and the two parameters were inversely correlated (r = -0.211; p = 0.027), clearly indicating an enhanced oxidative stress. Furthermore, AGE levels were higher in HT patients (M = 223.18 AU/g prot) than in controls (M = 189.636 AU/g prot; p = 0.020) and inversely correlated with BAP levels (r = -0.196; p = 0.037). In uni- and multivariate analysis, serum antithyroperoxidase antibodies were the main predictors for d-ROMs (p = 0.006), BAP (p < 0.001), and AGEs (p = 0.014), irrespective of thyrotropin and/or free thyroxine values. No differences in AOPPs levels were found between patients and controls (p = 0.923). CONCLUSIONS Oxidants are increased and antioxidants decreased in euthyroid HT patients. As a result, the oxidative/antioxidative balance is shifted toward the oxidative side. Moreover, this study reports on a possible significant involvement of AGEs in HT, thus contributing to a better definition of the redox homoeostasis dysregulation in HT.

Serum interleukin-22 (IL-22) is increased in the early stage of Hashimoto's thyroiditis compared to non-autoimmune thyroid disease and healthy controls

OBJECTIVE: Hashimoto’s thyroiditis (HT) is considered to be a Th1-related autoimmune disease (AID). Recent studies revealed that Th17 lymphocytes (producing mostly IL-17, IL-21 and IL-22) play a major role in numerous AIDs commonly thought to be Th1 diseases. More recently, another subset of Th cells, which produce IL-22 and thus so-called Th-22, have been identified. Few data are available in the literature on the role of IL-22, the main soluble mediator of both Th17 and Th22 cells, in HT. DESIGN: Using IL-22 Quantikine ELISA Kit (lower limit of detection 0.7 pg/ml), we assayed serum levels of IL-22 in three groups of subjects: newly diagnosed HT patients (n=55, 5 males and 50 females, age 38 ± 17 years), non-HT patients with nodular goiter (n=30, 4 males and 26 females, age 43 ± 14 years) and an age- and sex-matched group of healthy individuals. HT patients were euthyroid and were not receiving any treatment. RESULTS: HT patients showed significantly higher levels of serum IL-22 (group A, 42 ± 34 pg/ml) as compared to non-HT-goitrous patients (18 ± 15 pg/ml; P < 0.001) and healthy controls (20 ± 13 pg/ml; P=0.014). Serum IL-22 levels did not differ between non-HT-goitrous patients and healthy controls (p=0.496). No significant correlation was found between serum levels of IL-22 and Tg-Ab, TPO-Ab or TSH in the HT patients. CONCLUSIONS: Serum IL-22 is increased in newly diagnosed, untreated HT patients, as compared to thyroid autoimmune disease-free individuals. Our data suggest that IL-22 could play some role in the development of HT.

AN ITALIAN SURVEY OF COMPLIANCE WITH MAJOR GUIDELINES FOR L-THYROXINE OF PRIMARY HYPOTHYROIDISM

OBJECTIVE The adherence by endocrinologists to guideline regarding levothyroxine (LT4) therapy and the compliance of patients may impact the management of hypothyroidism. The aim of this study was to compare the adherence of Italian endocrinologists to the ATA/AACE and ETA guidelines on the management of newly diagnosed primary hypothyroidism and to validate the Italian version of the Morisky-Green Medical Adherence Scale-8 (MMAS-8) questionnaire as applied to the evaluation of the adherence of patients with hypothyroidism to LT4 treatment. METHODS This was an observational, longitudinal, multicenter, cohort study, involving 12 Italian Units of Endocrinology. RESULTS The study enrolled 1,039 consecutive outpatients (mean age 48 years; 855 women, 184 men). The concordance of Italian endocrinologists with American Association of Clinical Endocrinologists/American Thyroid Association (AACE/ATA) and European Thyroid Association (ETA) recommendations was comparable (77.1% and 71.7%) and increased (86.7 and 88.6%) after the recommendations on LT4 dose were excluded, considering only the remaining recommendations on diagnosis, therapy, and follow-up. The MMAS-8 was filled out by 293 patients. The mean score was 6.71 with 23.9% low (score <6), 38.6% medium (6 to <8), 37.5% highly (= 8) adherers; the internal validation coefficient was 0.613. Highly adherent patients were not more likely to have good control of hypothyroidism compared with either medium (69% versus 72%, P = .878) or low (69% versus 43%, P = .861) adherers. CONCLUSION Clinical management of hypothyroidism in Italy demonstrated an observance of international guidelines by Italian endocrinologists. Validation of the Italian version of the MMAS-8 questionnaire provides clinicians with a reliable and simple tool for assessing the adherence of patients to LT4 treatment. ABBREVIATIONS AACE = American Association of Clinical Endocrinologists; ATA = American Thyroid Association; EDIPO = Endotrial SIE: DIagnosis and clinical management of Primitive hypothyrOidism in Italy; eCRF = electronic case report form; ETA = European Thyroid Association; fT3 = free triiodothyronine; fT4 = free thyroxine; LT4 = levothyroxine; MMAS-8 = Morisky-Green Medical Adherence Scale-8; PH = primary hypothyroidism; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; US = ultrasonography.

Hashimoto’s thyroiditis, hypoparathyroidism and coeliac disease: lessons from a rare association

We present the case of a 36 years old woman, affected by euthyroid Hashimoto’s thyroiditis (HT) from the age of 20. She reported the following symptoms for three years: weight reduction, abdominal pain, alternate constipation and diarrhoea, tiredness, paresthesias and cramps. Biochemical evaluation revealed low iron levels (21 ug/dl, with microcytic anemia) and hypocalcemia (6.6 mg/dl), first attributed to coeliac disease (EMA IgG, AGA IgG-A and tTG IgA positivity; Marsh-Oberhuber 3a/3b type at duodenal biopsy). TSH, PTH and 25-OHD3 were in the normal range. Although the patient was on a gluten-free diet for the second year, cramps persisted and facial spasms and tetanic crises appeared. One year later she came to our attention with severe hypocalcemia (Ca 5.1 mg/dl, Ca++ 0.6 nmol/L) and low PTH (2.5 pg/ml). A diagnosis of primary hypoparathyroidism was made and conventional treatment was started. In the following months, symptomatic hypocalcemia persisted (6.7 mg/dl, Ca++ 0.7 nmol/L), despite the gradual increase of calcium and calcitriol supplements. Gastro-intestinal re-evaluation demonstrated gluten contamination, so as to hypothesize that the scarce dietary compliance had caused persistent malabsorption and had made the hypocalcemia difficult to manage. The observation of these three disorders coexisting in a single patient, never reported by the literature, warns us about the virtually unlimited possibilities of autoimmune disease clustering. Clinicians should be aware of the increased risk of developing additional AIDs in patients with one autoimmune disorder.

Ovarian hyperthecosis coexisting with an incidental adrenal lesion: challenges in the diagnostic approach

Ovarian hyperthecosis is the most common cause of hyperandrogenism in women during postmenopausal age. However, its diagnosis is frequently challenging, since several causes must be ruled out, involving both adrenal glands and ovaries. Herein we describe the case of a 62 years old woman addressed to our Unit after the casual detection of an adrenal mass, compatible with an adenoma. Biochemical evaluation revealed gonadotropins in menopausal range, high testosterone and androstenedione, while the patient had been complaining of androgenetic alopecia and hirsutism for some years. Ultrasound imaging revealed only a small increase in ovarian volume, in relationship to the patient’s age. A GnRHa test was performed, demonstrating gonadotropins suppression and testosterone normalization, thus confirming the suspect of ovarian hyperthecosis. The administration of these agonists, together with the slow progression of symptoms over years, play a fundamental role into excluding an androgen-secreting neoplasia, also limiting the use of ovarian veins catheterization as second line test. Besides, they represent a valid therapeutical option, especially when surgery is contraindicated (or cannot be performed).