Giuseppe Giuffrida

Undetectable or low (<1 ng/ml) postsurgical thyroglobulin values do not rule out metastases in early stage differentiated thyroid cancer patients

Background Differentiated thyroid cancer (DTC) work-up is based on (near)total-thyroidectomy plus thyroid remnant ablation (TRA) with 131-radioiodine in many patients, and long-life follow-up. 131I-post therapy whole body scan (pT-WBS) and serum thyroglobulin (Tg) are used in identifying metastatic patients. Some authors have evaluated the possibility of using post-surgical Tg (ps-Tg) values in deciding for or against TRA. The aim of our study was to verify the diagnostic accuracy of 131I-pT-WBS and SPECT/CT imaging (post-therapeutic imaging) compared to serum Tg levels in detecting metastases in early stage of DTC patients. Results Post-therapeutic imaging revealed metastases in 82 out of 570 (14.4%) patients. Metastases were successively confirmed by other diagnostic tools or by histology (sensitivity and PPV = 100%). Seventy-three out of 82 patients (90.2%) showed ps-Tg levels ≤1 ng/ml. In fifty-four per cent of patients, serum Tg levels at TRA remained ≤1 ng/ml. Conclusion In conclusion, ps-Tg levels cannot be used in deciding for or against TRA. In early stage of DTC, post-therapeutic imaging (131I-pT-WBS and SPECT/CT) is an accurate method of detecting metastases, also in patients with stimulated serum Tg values ≤1 ng/ml Methods We retrospectively reviewed the records of 570 consecutive patients affected by pT1-pT3 DTC (F = 450, M = 120), referred to our Nuclear Medicine Units in the last five years to perform TRA after (near)-total-thyroidectomy.All patients underwent TRA 3-4 months after thyroid surgery either in euthyroid or in hypothyroid state. Serum Tg values evaluated in post-surgical period and at TRA were matched with post-therapeutic imaging results.

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.

An extremely rare association of TSH-secreting pituitary adenoma, metastatic neuroendocrine tumor and Cushing’s syndrome in a patient with MEN-1 gene mutation

Multiple endocrine neoplasia (MEN)-1 syndrome is a rare disorder, due to the loss of function of the tumor suppressor menin. It consists of the association of two or more endocrine tumors, often presenting in a familial setting, being inherited in an autosomal dominant fashion. The most frequent manifestations of MEN-1 syndrome are primary hyperparathyroidism, followed by pituitary adenomas (mainly prolactinomas) and gastrointestinal neuroendocrine tumors, but several other associated conditions have been reported. Herein we describe the case of a male patient, affected by sporadic MEN-1, diagnosed with primary hyperparathyroidism, TSH-secreting pituitary adenoma and bilateral adrenal hyperplasia causing Cushing’s syndrome, due to a de novo MEN-1 gene mutation. The patient has been successfully treated with first generation somatostatin analog Octreotide LAR (30 mg every 28 days) -with stabilization of the known neuroendocrine lesions and shrinkage of the pituitary adenoma- and with bilateral adrenalectomy. The patient is still regularly followed-up at our Endocrine Unit, and his clinical conditions are stable.

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.

Thyroid dysfunction in patients treated with the immune checkpoint inhibitor nivolumab: different clinical features

Rationale. Immune Checkpoint Inhibitors (ICIs) are approved for some advanced neoplasms, increasing survival. ICIs block inhibitor receptors cytotoxic T lymphocyte antigen 4 (CTLA4) and programmed death-1 (PD-1) and trigger T cell-mediated immunity against tumor. Their action is accompanied by several immunity-related adverse events (IRAEs), also involving the endocrine system (pituitary, thyroid, adrenals). We report two different cases of thyrotoxicosis following administration of the anti-PD-1 nivolumab. Patients. Patient 1, M, 75 years-old, treated for non-small cell lung carcinoma (NSCLC) since September 2016, with euthyroid multinodular goiter. In January 2017 (12 weeks from baseline), he developed frank hyperthyroidism, with positive TSH-receptor antibodies (TRAb) and thyroperoxidase antibodies (TPOAb). A Tc99m thyroid scintiscan showed diffuse uptake and “cold” areas. After nivolumab withdrawal, treatment with metimazole (MMI) 5 mg per day was started and euthyroidism was resumed, so to restart the drug in May 2017. Patient 2, M, 80 years-old, treated for a left-eye choroid melanoma since January 2017, with euthyroid nodular goiter. In April 2017 (6 weeks from baseline), thyrotoxicosis was detected, with positive thyroglobulin antibodies (Tg-Ab, 244 IU/ml, nv 4.5 µIU/ml (subclinical hypothyroidism). Patient was treated with replacement doses of levothyroxine (LT-4), and continued nivolumab infusions. Conclusions. Two forms of thyrotoxicosis were reported: the first with thyroid hyperfunction and positive TRAb, the latter as a destructive thyroiditis. In both cases (mean onset after 9 weeks), the moderate severity and the appropriate management of endocrine IRAEs allowed treatment continuation.

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).

Coexistence of diffuse large B-cell lymphoma and papillary thyroid carcinoma in a patient affected by Hashimoto's thyroiditis

Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. On the contrary, primary thyroid lymphoma (PTL) is a rare disease, accounting for 2% to 5% of all thyroid malignancies. Despite several cases in which both PTC and PTL arise in the setting of Hashimotos thyroiditis (HT), the coexistence of both tumors in HT patients is very rare. Herein we report the case of a 66-year-old woman with long-standing nodular HT under replacement therapy, who presented with a fast, painless enlargement in the right anterior side of the neck. Thyroid ultrasonography demonstrated increased growth of a hypoechoic nodule in the right lobe measuring 32 × 20 mm. A total thyroidectomy was performed, and histology revealed a diffuse large B-cell lymphoma (DLBCL) on a background of florid HT. Moreover, a unifocal papillary microcarcinoma, classical variant (7 mm, pT1aNxMx), was discovered. The patient was then treated with chemotherapy for the PTL, but she did not undergo radioactive iodine ablation treatment for the microPTC as per guidelines. Two years after surgery, the patient had no evidence of recurrence of either malignancy. This rare case highlights the importance of monitoring HT patients with nodular lesions, especially if they have long-standing disease. In addition, PTL should be considered for differential diagnosis in elder HT patients who present with sudden thyroid enlargement.