Difficult Diagnosis and Management of Concealed Cushing.

BACKGROUND: Adrenocorticotropic Hormone (ACTH)-secreting tumors account for 5- 10% of Cushing syndrome cases and are often difficult to diagnose and treat. CASE REPORT: A 44-year-old man presented with arterial hypertension and weight gain. On the physical examination, he exhibited central obesity, abdominal striae rubrae, and facial plethora. Due to the clinical suspicion of Cushing syndrome, the Nugent test and Liddle-1 test were performed, which showed a lack of cortisol suppression. ACTH levels were also high (138 pg/mL), so pituitary MRI and dynamic tests were performed, including the Corticotropin-releasing Hormone (CRH) stimulation test and Liddle-2. MRI showed a 3 mm pituitary microadenoma, but hormonal testing suggested ectopic ACTH production. Chest CT detected a 10-mm nodule in the upper lobe of the right lung, suspicious for a carcinoid tumor. However, the nodule did not exhibit any enhancement on 68-Gallium-DOTATOC PET-CT, and further, 18-FDG PET-CT was inconclusive. In addition, the nodule was deemed non-biopsiable due to its location. Meanwhile, the patient developed osteoporosis, resulting in two vertebral fractures and one rib fracture, which was treated with zoledronate. Furthermore, the patient developed acute aortic insufficiency. During bioprosthetic valve replacement, the thoracic surgeon performed wedge resection of the right upper lung lobe. The histological examination of the lesion revealed a typical lung carcinoid (1.2x0.9 cm, pT1bNXR0, Ki671%, ACTH positive in 95% of neoplastic elements). ACTH levels dropped to 4 pg/mL on the fourth postoperative day. CONCLUSION: ACTH-secreting tumors are particularly challenging diseases. A comprehensive hormonal and instrumental valuation is often required, necessitating a multidisciplinary approach.

Vertebral Fractures Associated with Spinal Sagittal Imbalance and Quality of Life in Acromegaly: A Radiographic Study with EOS 2D/3D Technology.

INTRODUCTION: Acromegaly is commonly complicated by arthropathy and skeletal fragility with high risk of vertebral fractures (VFs). OBJECTIVE: This study aimed to assess whether VFs may be associated with sagittal spine deformities, arthropathy, impaired quality of life (QoL), pain, and disability. METHODS: Thirty-eight patients with acromegaly (median age: 55 years, 20 males) and 38 matched control subjects were evaluated by a low-dose sagittal and coronal planes, X-ray imaging system (EOS®-2D/3D) for morphometric VFs, radiological signs of spine arthropathy, and spine deformities (Cobb thoracic index ≥40°, pelvic incidence minus lumbar lordosis ≥10°, pelvic tilt >20°, and sagittal vertical axis ≥4 cm) determining sagittal spine imbalance. Acromegalic patients were also evaluated by questionnaires for QoL (Acromegaly QoL Questionnaire [AcroQoL] and Short Form-36 [SF-36]) and pain and disability (Western Ontario and McMaster University [WOMAC]). RESULTS: Acromegalic patients showed higher prevalence of thoracic hyperkyphosis (i.e., Cobb thoracic index ≥40°; p = 0.04) and pelvic tilt >20° (p = 0.02) than control subjects. VFs were found in 34.2% of acromegalic patients (p = 0.003 vs. control subjects), in relationship with higher prevalence of hyperkyphosis (p = 0.03), pelvic tilt >20° (p = 0.04), sagittal vertical axis ≥4 cm (p = 0.03), and moderate/severe subchondral degeneration (p = 0.01). Moreover, patients with VFs had lower AcroQoL general health (p = 0.007) and SF-36 general health (p = 0.002) scores and higher WOMAC pain (p = 0.003) and global (p = 0.009) scores than patients who did not fracture. CONCLUSIONS: In acromegaly, VFs may be associated with spine deformities and sagittal imbalance, spine arthropathy, impaired QoL, and disability.

Thyrotoxicosis in patients with COVID-19: the THYRCOV study.

OBJECTIVE: This study assessed thyroid function in patients affected by the coronavirus disease-19 (COVID-19), based on the hypothesis that the cytokine storm associated with COVID-19 may influence thyroid function and/or the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may directly act on thyroid cells, such as previously demonstrated for SARS-CoV-1 infection. DESIGN AND METHODS: This single-center study was retrospective and consisted in evaluating thyroid function tests and serum interleukin-6 (IL-6) values in 287 consecutive patients (193 males, median age: 66 years, range: 27-92) hospitalized for COVID-19 in non-intensive care units. RESULTS: Fifty-eight patients (20.2%) were found with thyrotoxicosis (overt in 31 cases), 15 (5.2%) with hypothyroidism (overt in only 2 cases), and 214 (74.6%) with normal thyroid function. Serum thyrotropin (TSH) values were inversely correlated with age of patients (rho -0.27; P < 0.001) and IL-6 (rho -0.41; P < 0.001). In the multivariate analysis, thyrotoxicosis resulted to be significantly associated with higher IL-6 (odds ratio: 3.25, 95% confidence interval: 1.97-5.36; P < 0.001), whereas the association with age of patients was lost (P = 0.09). CONCLUSIONS: This study provides first evidence that COVID-19 may be associated with high risk of thyrotoxicosis in relationship with systemic immune activation induced by the SARS-CoV-2 infection.

Treatment of Acromegalic Osteopathy in Real-life Clinical Practice: The BAAC (Bone Active Drugs in Acromegaly) Study.

BACKGROUND: Vertebral fractures (VFs) are a frequent complication of acromegaly, but no studies have been so far published on effectiveness of antiosteoporotic drugs in this clinical setting. OBJECTIVE: To evaluate whether in real-life clinical practice bone active drugs may reduce the risk of VFs in patients with active or controlled acromegaly. STUDY DESIGN: Retrospective, longitudinal study including 9 tertiary care endocrine units. PATIENTS AND METHODS: Two hundred and forty-eight patients with acromegaly (104 males; mean age 56.00 ±â€…13.60 years) were evaluated for prevalent and incident VFs by quantitative morphometric approach. Bone active agents were used in 52 patients (20.97%) and the median period of follow-up was 48 months (range 12-132). RESULTS: During the follow-up, 65 patients (26.21%) developed incident VFs in relationship with pre-existing VFs (odds ratio [OR] 3.75; P < .001), duration of active acromegaly (OR 1.01; P = .04), active acromegaly at the study entry (OR 2.48; P = .007), and treated hypoadrenalism (OR 2.50; P = .005). In the entire population, treatment with bone active drugs did not have a significant effect on incident VFs (P = .82). However, in a sensitive analysis restricted to patients with active acromegaly at study entry (111 cases), treatment with bone active drugs was associated with a lower risk of incident VFs (OR 0.11; P = .004), independently of prevalent VFs (OR 7.65; P < .001) and treated hypoadrenalism (OR 3.86; P = .007). CONCLUSIONS: Bone active drugs may prevent VFs in patients with active acromegaly.

TNM 8th edition in thyroid cancer staging: is there an improvement in predicting recurrence?

TNM 8th edition introduces changes in the staging of patients with differentiated thyroid carcinoma (DTC). This study aims at assessing the value of TNM 8th edition in predicting response to therapy and structural recurrence of DTC. Four hundred and eighty DTC patients were retrospectively evaluated by 7th and 8th editions of TNM staging system in relationship with risk stratification, response to therapy and recurrence of disease as defined by 2015 ATA guidelines. As compared to the 7th edition, TNM 8th led to downstage 136 patients (28.3%), with 97.5% of patients falling into lower stages (I-II) and only 2.5% remaining in higher stages (III-IV) (P < 0.001). Patients who were downstaged in stages I-II by TNM 8th were classified more frequently at intermediate-high risk (P < 0.001), had more frequently structural incomplete response to therapy (P = 0.009) and had higher risk of structural recurrence (P = 0.002) as compared to patients who were in the same TNM stages but were not downstaged. Specifically, the risk of structural recurrence was significantly higher in patients in whom the downstaging was induced by changes in tumour classification (hazard ratio (HR) 6.18, 95% CI 2.20-17.40; P = 0.001) but not in those who were downstaged for the increase in age cut-off (HR 2.80, 95% CI 0.86-9.19; P = 0.09). In conclusion, TNM 8th edition did not show reliability in predicting aggressiveness of DTC. In fact, the downstaging of DTC patients especially when performed due to changes in tumour classification may overlook patients predisposed to structural recurrence, potentially causing uncertainty in the therapeutic decision-making at the time of disease's diagnosis.

Suboptimal medication adherence may favor the progression of vertebral fractures in women with post-menopausal osteoporosis treated with denosumab.

BACKGROUND: Medication adherence is a determinant of therapeutic outcomes in osteoporotic patients treated with bisphosphonates. In this monocentric study, we evaluated whether the regular drug administration may influence the effectiveness of denosumab in preventing vertebral fractures (VFs) in real-world clinical practice. METHODS: Two-hundred and four women (median age 75 years, range: 54-90 years) under treatment with denosumab for post-menopausal osteoporosis were longitudinally evaluated for incident radiological VFs and changes in lumbar spine bone mineral density (BMD) in relationship with medication adherence. All patients were persistent with denosumab treatment (i.e., maximum delay in administration of a single denosumab dose: 90 days). Patients were defined adherent to denosumab therapy when the drug was administered every 6 months ±28 days. RESULTS: One-hundred-seventy-three patients (84.4%) were adherent to denosumab therapy, whereas the remaining 31 patients (15.6%) received in delay one or more denosumab doses (cumulative delay: 52 days, range 29-183 days). Fourteen patients (6.9%) experienced incident VFs during the follow-up (median duration: 30 months, range: 18-48 months), in relationship with non-adherence to denosumab therapy (hazard ratio 4.44; 95% CI: 1.01-19.47) and smaller increase in lumbar spine BMD (hazard ratio 0.85, 95% CI: 0.76-0.94). CONCLUSIONS: In post-menopausal women at high risk of fractures, the small delay in the administration of denosumab (i.e., not uncommon in clinical practice) was associated with a significant increase in incidence of VFs. Preservation of standard dosing schedule appears to be an important determinant of denosumab effectiveness in the real-life clinical practice.

Recurrent Pregnancy Loss in Women with Hashimoto's Thyroiditis with Concurrent Non-Endocrine Autoimmune Disorders.

Background: An increased rate of recurrent miscarriage has been described in patients with autoimmune thyroid disease. However, there is a lack of studies that assess the rate of recurrent pregnancy loss (RPL) in patients with Hashimoto's thyroiditis (HT) isolated or with concurrent non-endocrine autoimmune disorders (NEAD). The objective of the study was to assess the rate of RPL in patients with HT isolated or accompanied with non-endocrine autoimmune diseases. Methods: This is a retrospective observational cohort study with a systematic review of the NEAD with concurrent HT in an outpatient Endocrinology Unit at a University Hospital. Among the 3480 consecutively examined women with HT, 87 patients met the criteria of RPL and represented the study group. Sixty-five of them had isolated HT and 22 women had HT+NEAD. Results: The rate of RPL in women with HT was 2.1% versus 5.64% observed in women with HT+NEAD (odds ratio = 2.78 [95% confidence interval 1.70-4.57]; p < 0.0001). On subdivision, this difference was still evident in euthyroid patients (p < 0.0001), while it disappeared in hypothyroid women (p = 0.21). The RPL did not correlate with the autoantibody concentrations nor in women with isolated HT nor in those with HT+NEAD. The presence of antiphospholipid syndrome (APS) explained RPL in 3 out of 22 (14%) patients with HT+NEAD, the remaining being related to different autoimmune disorders. Interestingly, even subtracting the patients with APS, RPL was more frequent in patients with poly-autoimmunity than in patients with isolated HT (p = 0.0013). Conclusions: The co-presence of NEAD is correlated with a higher risk of RPL in women with HT. The association with APS may explain only a fraction of RPL rate in patients with poly-autoimmunity.

Ulcerative Colitis as a Novel Cause of Increased Need for Levothyroxine.

Background: Thyroxine absorption takes place at the small intestine level and several disorders affecting this intestinal tract lead to thyroxine malabsorption. An increased need for thyroxine has also been observed in gastric disorders due to variations in drug dissolution and/or in its ionization status. Ulcerative colitis (UC) is an inflammatory bowel disease that has been postulated as a potential cause of the increased need for thyroxine, but there is a lack of evidence on this topic. This study is aimed at measuring the thyroxine requirement in hypothyroid patients with UC. Patients and Methods: Among 8,573 patients with thyroid disorders consecutively seen in our referral center from 2010 to 2017, we identified 34 patients with a definite diagnosis of UC. Thirteen of them were hypothyroid (12 F/1 M; median age = 53 years), bearing UC during the remission phase and in need for thyroxine treatment, thus representing the study group. The dose of T4 required by UC patients has been compared to the one observed in 51 similarly treated age- and weight-matched patients, compliant with treatment and clearly devoid of any gastrointestinal and /or pharmacological interference. Results: To reach the target serum TSH, the dose of thyroxine had to be increased in twelve out of thirteen (92%) hypothyroid patients with ulcerative colitis. The median thyroxine dose required by UC patients was 1.54 µg/kg weight/day, that is 26% higher than the control patients, to reach a similar TSH (1.23 µg/kg weight/day; p = 0.0002). Since half of our study group consisted of patients aged over 60 years old, we analyzed the effect of age on the subdivision in two classes. Six out of seven (86%) adult patients (<60 years) required more T4 than those in the respective control group (1.61 vs. 1.27 µg/kg weight/day; +27%; p < 0.0001). An increased dose (+17%; p = 0.0026) but to a lesser extent, was also observed in all patients over 60 years, as compared to the control group. Conclusions: In almost all hypothyroid patients with UC, the therapeutic dose of thyroxine is increased. Therefore, ulcerative colitis, even during clinical remission, should be included among the gastrointestinal causes of an increased need for oral thyroxine.

Infundibuloneurohypophysitis associated with autoimmune thrombocytopenia and chiasmal syndrome: a case report.

Lymphocytic hypophysitis is an uncommon autoimmune disease. It may involve the adenohypophysis, neurohypophysis and pituitary stalk. It is most often encountered in pregnant women. Its diagnosis and management pose a significant challenge, as its clinical manifestation and appearance in imaging studies are difficult to distinguish from more common lesion of the sellar region (e.g., pituitary adenomas). We present the case of a 42-year-old man who presented with a chiasmatic syndrome, diabetes insipidus and hypopituitarism. Brain MRI documented a sellar lesion with suprasellar extension and optic chiasm dislocation. He underwent an endoscopic endonasal transsphenoidal resection of the mass. Histopathological examination revealed a lymphocytic hypophysitis. Visual symptoms improved dramatically postoperatively with permanent diabetes insipidus and panhypopituitarism. We discuss the indication for surgical resection in patients with inflammatory lesions extending to the suprasellar region associated with visual impairment.

Hashimoto's Thyroiditis and Autoimmune Gastritis.

The term "thyrogastric syndrome" defines the association between autoimmune thyroid disease and chronic autoimmune gastritis (CAG), and it was first described in the early 1960s. More recently, this association has been included in polyglandular autoimmune syndrome type IIIb, in which autoimmune thyroiditis represents the pivotal disorder. Hashimoto's thyroiditis (HT) is the most frequent autoimmune disease, and it has been reported to be associated with gastric disorders in 10-40% of patients while about 40% of patients with autoimmune gastritis also present HT. Some intriguing similarities have been described about the pathogenic mechanism of these two disorders, involving a complex interaction among genetic, embryological, immunologic, and environmental factors. CAG is characterized by a partial or total disappearance of parietal cells implying the impairment of both hydrochloric acid and intrinsic factor production. The clinical outcome of this gastric damage is the occurrence of a hypochlorhydric-dependent iron-deficient anemia, followed by pernicious anemia concomitant with the progression to a severe gastric atrophy. Malabsorption of levothyroxine may occur as well. We have briefly summarized in this minireview the most recent achievements on this peculiar association of diseases that, in the last years, have been increasingly diagnosed.

Thyroxine softgel capsule in patients with gastric-related T4 malabsorption.

The key role of an intact gastric acid secretion for subsequent intestinal T4 absorption is supported by an increased requirement of thyroxine in patients with gastric disorders. A better pH-related dissolution profile has been described in vitro for softgel T4 preparation than for T4 tablets. Our study was aimed at comparing softgel and tablet T4 requirements in patients with gastric disorders. A total of 37 patients with gastric-related T4 malabsorption were enrolled, but only 31 (28F/3M; median age = 50 years; median T4 dose = 2.04 µg/kg/day) completed the study. All patients were in long-lasting treatment (>2 years) with the same dose of T4 tablets when treatment was switched to a lower dose of softgel T4 capsules (-17 %; p = 0.0002). Assessment of serum FT4 and TSH was carried out at baseline and after 3, 6, 12, and 18 months after the treatment switch. In more than 2/3 of patients (good-responders n = 21), despite the reduced dose of T4, median TSH values were similar at each time point (p = 0.3934) with no change in FT4 levels. In the remaining patients (poor-responders n = 10), TSH levels were significantly higher at each time point than at baseline (p < 0.0001). To note, in five of them intestinal comorbidity was subsequently detected. Comorbidity associated with poor-responders status was the only significant predictor in multivariate analysis (OR = 11.333). Doses of softgel T4 capsules lower than T4 tablet preparation are required to maintain the therapeutic goal in 2/3 of patients with impaired gastric acid secretion.

Systematic appraisal of lactose intolerance as cause of increased need for oral thyroxine.

CONTEXT: An increased need for T4 has been described in patients with different gastrointestinal disorders. However, there is a lack of systematic studies assessing the need for T4 in hypothyroid patients with lactose intolerance, a widespread and often occult disorder. OBJECTIVE: The objective of the study was to assess the replacement T4 dose required in hypothyroid patients with lactose intolerance. DESIGN: This was a cohort study. SETTING: The study was conducted at an outpatient endocrinology unit in a University Hospital. PATIENTS: The replacement T4 dose has been analyzed, from 2009 to 2012, in 34 hypothyroid patients due to Hashimoto's thyroiditis and lactose intolerance and being noncompliant with a lactose-free diet. MAIN OUTCOME MEASURE: An individually tailored T4 dose was measured. RESULTS: In all patients with isolated Hashimoto's thyroiditis, target TSH (median TSH 1.02 mU/L) was obtained at a median T4 dose of 1.31 µg/kg/d. In patients with lactose intolerance, only five of 34 patients reached the desired TSH (median TSH 0.83 mU/L) with a similar T4 dose (1.29 µg/kg/d). In the remaining 29 patients, the T4 dose was progressively increased and the target TSH (median TSH 1.21 mU/L) was attained at a median T4 dose of 1.81 µg/kg/d (+38%, P < .0001). In six of these patients, other gastrointestinal disorders were diagnosed, and their median T4 requirement was higher (2.04 µg/kg/d; +55%; P = .0032). In the remaining 23 patients with isolated lactose intolerance, a median T4 dose of 1.72 µg/kg/d (+31% P < .0001) has been required to attain pharmacological thyroid homeostasis. CONCLUSIONS: These findings show that lactose intolerance significantly increased the need for oral T4 in hypothyroid patients.