Graves' Disease in Hypopituitarism Due to Pituitary Apoplexy.

BACKGROUND: Central hypothyroidism and autoimmune hyperthyroidism are contrasting pathologies requiring careful hormone monitoring for restoring euthyroidism. Their coexistence is rare and challenging for clinicians [1, 2]. CASE REPORT: We have, herein, presented the case of a 41-year-old female patient with an unremarkable clinical history except for chronic autoimmune thyroiditis in euthyroidism. At the 21st week of gestation, she experienced a spontaneous abortion. The patient underwent an assessment of the uterine cavity, which was complicated by bleeding and hypotensive shock. In the postoperative course, the patient presented worsening headache, and after an MRI, the diagnosis of pituitary apoplexy due to an ischemic-hemorrhagic base was made. Laboratory tests showed anterior panhypopituitarism. Multiaxial replacement therapy was initiated with hydrocortisone, levothyroxine (LT4), and subsequently estrogen-progestin and GH. After two years of good recovery with stable LT4 dosage, the patient experienced palpitations and fine tremors; blood tests showed hyperthyroidism with suppressed Thyroid-stimulating Hormone (TSH) levels and elevated free thyroid fractions and anti-TSH receptor antibodies. Diagnosis of Graves' disease was made, and therapy with methimazole was initiated. During antithyroid therapy, TSH remained persistently suppressed, consistent with the underlying central hypothyroidism. This condition required close follow-up, with monitoring based solely on free thyroid hormone levels. After six months of antithyroid therapy, disease remission was achieved, with negative antibodies and mild hypothyroxinemia. Therefore, methimazole was discontinued and replacement therapy gradually resumed until optimal hormone levels were reached. CONCLUSION: This case is unique demonstrating autoimmune hyperthyroidism to coexist with central hypothyroidism, rendering TSH a misleading disease progression indicator. Consequently, managing Graves' disease has become more complex and challenging.

Parathyroid Carcinoma All-In-One, a Rare Life-Threatening Case With Multiple Systemic Manifestations: Case Report and Review of the Literature.

Parathyroid carcinoma (PC) is an extremely rare disease. Although it may occasionally occur in genetic syndromes, it is more often sporadic. It is usually associated with a consistent secretion of PTH, causing severe hypercalcemia and potentially all clinical conditions due to primary hyperparathyroidism. Management of PC can be challenging: some clinical, biochemical, and radiological features may be useful, but the final diagnosis of malignancy strictly relies on histological criteria. To date, radical surgery is the first-choice treatment and is the only effective therapy to control hypercalcemia and other clinical manifestations. On the other hand, chemo- or radiotherapy, local treatments, or novel drugs should be reserved for selected cases. We report an exceptionally unusual case of life-threatening PC, associated with several systemic manifestations: moderate pancreatitis, portal thrombosis, kidney stones, brown tumors, osteoporosis, hungry bone syndrome (HBS), chondrocalcinosis, neuropathy, and depression. The clinical case also represents an opportunity to provide a review of the recent literature, associated with a complete evaluation of the main diagnostic and therapeutic approaches.

The Volumetric Source Function: Looking Inside van der Waals Interactions.

The study of van der Waals interactions plays a central role in the understanding of bonding across a range of biological, chemical and physical phenomena. The presence of van der Waals interactions can be identified through analysis of the reduced density gradient, a fundamental parameter at the core of Density Functional Theory. An extension of Bader's Quantum Theory of Atoms in Molecules is developed here through combination with the analysis of the reduced density gradient. Through this development, a new quantum chemical topological tool is presented: the volumetric source function. This technique allows insight into the atomic composition of van der Waals interactions, offering the first route towards applying the highly successful source function to these disperse interactions. A new algorithm has been implemented in the open-source code, CRITIC2, and tested on acetone, adipic and maleic acids molecular crystals, each stabilized by van der Waals interactions. This novel technique for studying van der Waals interactions at an atomic level offers unprecedented opportunities in the fundamental study of intermolecular interactions and molecular design for crystal engineering, drug design and bio-macromolecular processes.

Follow-Up or Surgery for Indeterminate Thyroid Nodules: Could the CUT Score Application Be a Support for Decision-Making in the Preoperative Assessment?

Background: The CUT score is a thyroid nodule scoring system that has become recently available as a smartphone application. It has been created on the basis of a clinical (C) and ultrasonographic (U) meta-analysis of suspicious thyroid nodule features to help clinicians with the preoperative malignancy risk assessment of thyroid nodules. The aim of the present study was to analyze the C + U sum of the CUT score for cytologically indeterminate TIR3A and TIR3B thyroid nodules, comparing the results obtained from the two groups. Methods: The CUT score was applied to 201 cytologically indeterminate thyroid nodules, 78 categorized as TIR3A and 123 as TIR3B. The Mann-Whitney test was applied to compare the C + U score values of the two groups, and a receiver operating characteristic (ROC) curve analysis was performed to validate the C + U score as a diagnostic test. Results: In both groups, the median C + U value of all nodules was significantly higher in case of malignant (4.37 TIR3A, 4.50 TIR3B) versus benign nodules (2.75 TIR3A, 3.00 TIR3B). Through ROC curve analysis within the TIR3A group, a C + U value ≥4.00 was determined as diagnostic cutoff for the detection of malignant nodules (56% sensitivity, 77% specificity, area under the curve [AUC] = 0.714); and for the TIR3B group, a cutoff of C + U value of ≥3.75 was identified (65% sensitivity, 78% specificity, AUC = 0.744). Conclusion: The CUT score could represent a valid aid for the clinician in the management of indeterminate nodules with follicular proliferation.

Factors predicting the duration of adrenal insufficiency in patients successfully treated for Cushing disease and nonmalignant primary adrenal Cushing syndrome.

Successful treatment of Cushing syndrome causes transient or permanent adrenal insufficiency deriving from endogenous hypercortisolism-induced hypothalamus-pituitary-adrenal-axis suppression. We analyzed pre-treatment factors potentially affecting the duration of adrenal insufficiency. We conducted a retrospective analysis on patients successfully treated for Cushing disease (15 patients) who underwent transsphenoidal surgery, and nonmalignant primary adrenal Cushing syndrome (31 patients) who underwent unilateral adrenalectomy, divided into patients with overt primary adrenal Cushing syndrome (14 patients) and subclinical primary adrenal Cushing syndrome (17 patients). Epidemiological data, medical history, and hormonal parameters depending on the etiology of hypercortisolism were collected and compared to the duration of adrenal insufficiency. The median duration of follow-up after surgery for Cushing disease and primary adrenal Cushing syndrome was 70 and 48 months, respectively. In the Cushing disease group, the median duration of adrenal insufficiency after transsphenoidal surgery was 15 months: younger age at diagnosis and longer duration of signs and symptoms of hypercortisolism before diagnosis and surgery were associated with longer duration of adrenal insufficiency. The median duration of adrenal insufficiency was 6 months for subclinical primary adrenal Cushing syndrome and 18.5 months for overt primary adrenal Cushing syndrome. The biochemical severity of hypercortisolism, the grade of hypothalamus-pituitary-adrenal-axis suppression, and treatment with ketoconazole before surgery accounted for longer duration of adrenal insufficiency. In patients with Cushing disease, younger age and delayed diagnosis and treatment predict longer need for glucocorticoid replacement therapy after successful transsphenoidal surgery. In patients with primary adrenal Cushing syndrome, the severity of hypercortisolism plays a primary role in influencing the duration of adrenal insufficiency after unilateral adrenalectomy.

A meta-analysis-derived proposal for a clinical, ultrasonographic, and cytological scoring system to evaluate thyroid nodules: the "CUT" score.

The purpose of this study is to develop a new cancer risk score for preoperative assessment of thyroid nodules (TN) trying to reduce unnecessary thyroidectomies. On the basis of a recent meta-analysis of published literature, we assigned a matching value to the clinical (C) and ultrasonographic (U) features of TN with increased malignancy risk (MR). The created "CUT" score derived from "C+U" score, (CU[1-10] ), along with the five-tiered "T" (T[1-5] ), represents the cytologic result of the fine-needle aspiration. The C+U score was prospectively applied to 683 consecutive patients with 705 TN and validated through a ROC curve analysis. The CUT score was correlated with the histopathological diagnoses of 110 surgically resected TN. Fifty-five histologically benign TN had a mean C+U score of 2.4 versus 5.7 of 55 malignant TN (p < 0.001). Three categories were identified: low risk for C+U score ≤2.5 (MR: 9 %), intermediate risk for C+U score ≥2.75 and ≤5 (MR: 38 %), and high risk for C+U score ≥5.25 (MR: 95 %). Sensitivity and specificity were, respectively, 95 and 60 % for a cut-off value >2.5, and 69 and 96 % for >5. The "CUT" score can be easily applied, aiding clinicians in the evaluation of TN, especially in cases with indeterminate or repeated non-diagnostic FNA.

Quantification of cancer risk of each clinical and ultrasonographic suspicious feature of thyroid nodules: a systematic review and meta-analysis.

OBJECTIVE: In order to quantify the risk of malignancy of clinical and ultrasonographic features of thyroid nodules (TNs), we did a systematic review and meta-analysis of published studies. METHODS: We did a literature search in MEDLINE for studies published from 1st January 1989 until 31st December 2012. Studies were considered eligible if they investigated the association between at least one clinical/ultrasonographic feature and the risk of malignancy, did not have exclusion criteria for the detected nodules, had histologically confirmed the diagnoses of malignancy, and had a univariable analysis available. Two reviewers independently extracted data on study characteristics and outcomes. RESULTS: The meta-analysis included 41 studies, for a total of 29678 TN. A higher risk of malignancy expressed in odds ratio (OR) was found for the following: nodule height greater than width (OR: 10.15), absent halo sign (OR: 7.14), microcalcifications (OR: 6.76), irregular margins (OR: 6.12), hypoechogenicity (OR: 5.07), solid nodule structure (OR: 4.69), intranodular vascularization (OR: 3.76), family history of thyroid carcinoma (OR: 2.29), nodule size ≥4 cm (OR: 1.63), single nodule (OR: 1.43), history of head/neck irradiation (OR: 1.29), and male gender (OR: 1.22). Interestingly, meta-regression analysis showed a higher risk of malignancy for hypoechoic nodules in iodine-sufficient than in iodine-deficient geographical areas. CONCLUSIONS: The current meta-analysis verified and weighed out each suspicious clinical and ultrasonographic TN feature. The highest risk was found for nodule height greater than width, absent halo sign, and microcalcifications for ultrasonographic features and family history of thyroid carcinoma for clinical features. A meta-analysis-derived grading system of TN malignancy risk, validated on a large prospective cohort, could be a useful tool in TN diagnostic work-up.

Assessment of salivary free cortisol levels by liquid chromatography with tandem mass spectrometry (LC-MS/MS) in patients treated with mitotane.

OBJECTIVE: Mitotane is an adrenocytolytic agent used in adrenocortical carcinoma, inducing adrenal insufficiency, requiring replacement treatment. Such therapy is not easy to monitor because of mitotane interference. Salivary cortisol reflects a free fraction of plasma cortisol and may be useful in such patients. DESIGN: The aim of our study was to evaluate salivary cortisol by HPLC coupled to tandem-mass spectrometry (LC-MS/MS) and by an electrochemiluminescence immunoassay (ECLIA) in patients treated with mitotane. We enrolled 6 patients receiving mitotane and 2 Addison disease patients as negative controls and determined salivary cortisol rhythm. We also determined the salivary cortisol rhythm in 8 healthy subjects. Salivary samples (n=112) were assayed by ECLIA, using Roche Modular E170, and by LC-MS/MS. RESULTS: The mean values obtained by ECLIA were significantly higher than those obtained by LC-MS/MS in the mitotane group (p<0.001). In fact, in the group measured by LC-MS/MS, we observed several peaks eluting at a retention time different from the cortisol group, presumably due to cortisol-like analogues. In Addison disease, since steroidogenesis is absent, salivary cortisol values measured by the two methods did not show any significant difference (p=0.61). CONCLUSIONS: Salivary cortisol measured by LC-MS/MS is a selective method, excluding cortisol analogues accumulating in treated patients. Therefore, LC-MS/MS offers an effective system to monitor replacement therapy in mitotane treated patients.

Post-surgery severe hypocalcemia in primary hyperparathyroidism preoperatively treated with zoledronic acid.

Zoledronic acid is a newly FDA-approved bisphosphonate for the treatment of hypercalcemia of malignancy. Although the safety and efficacy of this drug in treating hypercalcemia associated with hyperparathyroidism have not yet been established in clinically controlled trials, its off-label use is not uncommon. We describe a patient with primary hyperparathyroidism treated with zoledronic acid who developed severe postoperative hypocalcemia. A 64-yr-old woman was admitted with severe hypercalcemia. She was treated with rehydration, calcitonin, methylprednisolone, furosemide as well as 4 mg/day of zoledronic acid for two consecutive days. Primary hyperparathyroidism caused by a right inferior parathyroid lesion was diagnosed. While awaiting surgery, she continued furosemide, methylprednisolone and hydration: after one week, serum calcium had fallen to such a low level that a short-term calcium carbonate supplementation was required. Three weeks after admission, the patient underwent selective right inferior parathyroidectomy, followed by reduction of PTH. During the postoperative period the patient presented severe hypocalcemia resistant to the usual treatment. Serum calcium levels returned to normal three months after surgery. The severity of hypocalcemia and the resistance to conventional treatments suggest that the effect of hungry bone syndrome could be worse in patients treated with bisphosphonates in the preoperative phase.