Reversibility of Acute Adrenal Insufficiency After Hip Replacement: A Case Series.

BACKGROUND: Acute adrenal insufficiency is a rare but potentially lethal condition, that is important to identify promptly and treat with replacement therapy. It can be consequent to adrenal hemorrhage that can occur after major orthopedic surgery. Few data are available about potential recovery of adrenal function, as well as both timing and modality of cortisone acetate withdrawal, probably due to the assumption that adrenal failure should be definitive. The extension of adrenal damage can be different, so justifying a partial, or potentially complete, recovery of adrenal function. The aim of our article is to highlight the opportunity of a periodical revaluation of adrenal reserve in order to identify those patients which are able to interrupt replacement therapy. CASE PRESENTATION: We had recently described one case of acute adrenal insufficiency, which developed short time after hip replacement; the patient was able to discontinue cortisone acetate treatment 46 months after the diagnosis and remained untreated up to five years later. We collected other two cases of acute adrenal insufficiency, developed about one week after major orthopedic surgery. We followed such patients for about three years, repeatedly reassessing adrenal imaging and cortisol response to 250 µg ACTH test, in order to ascertain the real need of lifetime substitutive treatment with cortisone acetate. Acute adrenal insufficiency partially reverted during the follow up for both patients. We observed a reduction in adrenal glands' volume and a progressive improvement of cortisol basal levels, without response (or with a poor one) to ACTH stimulation, as well as with ACTH basal levels persistently above the normal range after 36 and 28 months respectively spent from the acute event. CONCLUSION: The present finding suggests the opportunity that patients developing acute adrenal insufficiency after major orthopedic surgery undergo long-term surveillance, in order to establish if steroid replacement has to be continued, or it can be safely withdrawn.

Radiologic Manifestation of Bone Involvement in Primary Hyperparathyroidism: Prevalence and Clinical Significance in a Southern European Series.

OBJECTIVE: Clinically overt symptomatic bone disease in primary hyperparathyroidism (PHPT) is rarely seen today, and osteoporosis is the dominant finding. Subperiosteal bone resorption in the fingers and skull mottling are typical bone PHPT findings, the contemporary prevalence of which is unknown. We evaluated these mild lesions and investigated the impact of their occurrence on PHPT clinical management. METHODS: We evaluated retrospectively a monocentric series of 363 PHPT patients classified in Group 1 (n = 100) or Group 2 (n = 263) according to the presence or absence of bone involvement, respectively. Patients belonging to Group 1, in turn, were subdivided into Group 1A, with severe and symptomatic lesions (n = 48), and Group 1B, with milder signs of osteitis fibrosa cystica (OFC) without brown tumors or fractures (n = 52). RESULTS: Serum total and ionized calcium, parathyroid hormone, osteocalcin, alkaline phosphatase, and its bone fraction levels were higher in Group 1 than in Group 2, while no gender or age differences were observed between the groups. Osteoporosis prevalence was similar in Group 1B and Group 2 patients but lower than in Group 1A. Mild OFC findings did not modify the surgical indication in any patient of Group 1B. CONCLUSION: Minor radiologic signs of OFC are not uncommon in the modern PHPT phenotype and occur in patients with more active disease. These signs could identify PHPT patients in an earlier stage of typical bone involvement. However, these features do not seem to upgrade either the clinical classification of asymptomatic PHPT patients or the propensity toward surgical choice.

Lenvatinib Long-Term Responses in Refractory Thyroid Cancer: Our Mono-Institutional Real-Life Experience with the Multidisciplinary Approach and Review of Literature.

Lenvatinib (LEN) is a multikinase inhibitor with antiangiogenic properties recently approved in radioactive iodine-refractory differentiated thyroid cancer, hepatocellular carcinoma, and renal cell carcinoma in combination with everolimus. LEN-treated patients frequently have adverse events (AEs) that generally require such dose modifications, including drug discontinuation. Hypertension, diarrhea, weight loss, proteinuria, fatigue, and palmar-plantar erythrodysesthesia are reported among the most frequent AEs, often leading to discontinuations or dose modifications. This paper reports a case series focusing on the role of the immediate multidisciplinary approach to manage AEs.

INCREASED SERUM CALCITONIN IN SPORADIC PRIMARY HYPERPARATHYROIDISM IS AN UNCOMMON OCCURRENCE.

Objective: To evaluate calcitonin (CT) levels in sporadic primary hyperparathyroidism (PHPT), which has to date rarely been considered. Methods: We evaluated serum CT levels in 290 consecutive patients with sporadic PHPT at diagnosis. Results: Mild elevations in CT levels (hyperCT) were found in 25 patients (8.6%), with no correlation among the demographic, clinical, and biochemical findings. In addition, no differences were found between patients with and without hyperCT. Follow-up data were available for 19/25 patients, but CT values were only available for 10. CT normalized in all surgically cured patients regardless of the extent of the surgery (parathyroidectomy [PTX] only in 8 and associated with partial or total thyroidectomy for benign nodular goiters in 7). Conclusion: hyperCT is an uncommon feature of sporadic PHPT and not related to biochemical or clinical features of the disease. In addition, hyperCT is reversible after PTX, regardless of whether concomitant thyroidectomies have been conducted. Abbreviations: CT = calcitonin; eGFR = estimated glomerular filtration rate; hyperCT = hypercalcitoninemia; MEN = multiple endocrine neoplasm; MTC = medullary thyroid carcinoma; PHPT = primary hyperparathyroidism; PPI = proton pump inhibitor; PTH = parathyroid hormone; PTX = parathyroidectomy.

UNKNOWN AND ALREADY KNOWN THYROID ABNORMALITIES IN PRIMARY HYPERPARATHYROIDISM.

OBJECTIVE: Primary hyperparathyroidism (PHPT) and thyroid diseases are highly prevalent in the general population, but the putative link between the 2 conditions remains unclear. METHODS: A monocentric consecutive series of 434 patients with PHPT was retrospectively evaluated by lab and ultrasonography to look for thyroid abnormalities. Patients were classified in 3 groups: without thyroid abnormalities (group 1, n = 171), with thyroid diseases not previously known (group 2a, n = 69), and thyroid diseases previously known (group 2b, n = 194). RESULTS: In terms of thyroid disease, no significant difference was found between groups 2a and 2b, except for the significantly larger number of patients with toxic nodular goiter in group 2b. PHPT was more frequently symptomatic in group 2a than in group 2b, despite no differences in serum calcium, creatinine, parathyroid hormone (PTH), or 25-hydroxyvitamin D (25OHD) levels. CONCLUSION: A total of 60% of PHPT patients had a thyroid disease that was unknown prior to PHPT diagnosis in almost one-third of cases. The newly diagnosed and previously known thyroid diseases were similar, both mostly affecting postmenopausal females. ABBREVIATIONS: Ab = antibody; aPHPT = asymptomatic PHPT; 25OHD = 25-hydroxyvitamin D; PHPT = primary hyperparathyroidism; PTH = parathyroid hormone; Tg = thyroglobulin; TPO = thyroperoxidase; TSH = thyroid-stimulating hormone; US = ultrasound.

Acute Primary Adrenal Insufficiency after Hip Replacement in a Patient with Acute Intermittent Porphyria.

Adrenal insufficiency is a potentially life-threatening condition when it occurs acutely, as in adrenal hemorrhage. Generally it is not reversible and requires chronic replacement therapy. Acute intermittent porphyria (AIP) is a rare genetic disease characterized by alterations in heme biosynthesis that result in accumulation of precursors in tissues. A crisis can be triggered by many conditions such as surgery and infections. Symptoms are similar to those of acute hypoadrenalism. Moreover, both conditions are characterized by hyponatremia. We describe the case of a postmenopausal woman known to be affected by AIP who developed after surgery a primary adrenal insufficiency associated with adrenal enlargement; the latter completely reverted in six months.

Seasonal variations in TSH serum levels in athyreotic patients under L-thyroxine replacement monotherapy.

BACKGROUND: Whether serum TSH undergoes seasonal fluctuations in euthyroid and hypothyroid residents of temperate climates is controversial. METHODS: Monthly TSH and thyroid hormone levels were cross-sectionally analysed in a large cohort of euthyroid subjects (n=11 806) and L-thyroxine (L-T4)-treated athyreotic patients (n=3 934). Moreover, in a small group (n=119) of athyreotic patients treated with an unchanged dosage of L-T4 monotherapy, hormones were measured both in the coldest and in the hottest seasons of the same year (longitudinal study). RESULTS: No seasonal hormone change was observed in the euthyroid subjects except for a small FT3 increase in winter (+2.9%, P<.001). In contrast, the L-T4-treated athyreotic patients had significantly higher serum TSH values in the cold season when the FT4 values were significantly lower. The differences were more notable in the longitudinal series (TSH, 0.80 vs. 0.20 mU/L and FT4, 16.3 vs. 17.8 pmol/L in December-March vs. June-September, respectively). In these patients also serum FT3 values significantly decreased in winter (in the longitudinal series, 3.80 in winter vs 4.07 pmol/L in summer). Regression analysis showed that in athyreotic subjects, a greater FT4 change is required to obtain a TSH change similar to that of euthyroid controls and that this effect is more pronounced in the summer. CONCLUSION: Athyreotic patients undergoing L-T4 monotherapy have abnormal seasonal variations in TSH. These changes are secondary to the FT4 and FT3 serum decreases in winter, which occur in spite of the constant treatment. The underlying mechanisms are unclear, but in some cases, these changes may be clinically relevant.

NEPHROLITHIASIS IN PRIMARY HYPERPARATHYROIDISM: A COMPARISON BETWEEN SILENT AND SYMPTOMATIC PATIENTS.

OBJECTIVE: To characterize primary hyperparathyroidism (PHPT) patients with renal stones and to compare silent with symptomatic stone formers. METHODS: We reviewed clinical data from 234 patients with PHPT, comparing those with and without renal stones (n = 109 and 125, respectively), and among stone formers those symptomatic versus silent (n = 93 and 16, respectively). RESULTS: Stone formers were younger, had higher urinary calcium levels and higher estimated glomerular filtration rates (eGFRs) compared to patients without stones. Patients with silent stones had higher parathyroid hormone (PTH) and lower 25OH-vitamin D (25OHD) levels and more frequently experienced microlithiasis than patients with symptomatic renal stones. CONCLUSION: Nephrolithiasis is a common complication of PHPT. Most patients with silent renal stones have microlithiasis, associated to some features of more severe disease. Lower 25OHD levels in silent stone formers raise the hypothesis that vitamin D status can influence the clinical expression of nephrolithiasis in PHPT patients. ABBREVIATIONS: BMI = body mass index Ca = serum total calcium DM = diabetes mellitus eGFR = estimated glomerular filtration rate HOMA-IR = Homeostasis Model Assessment-Insulin Resistance 25OHD = 25OH-vitamin D PHPT = primary hyperparathyroidism PTH = parathyroid hormone UCa = 24-h urine for calcium US = ultrasound.

Chronic lymphocytic thyroiditis: could it be influenced by a petrochemical complex? Data from a cytological study in South-Eastern Sicily.

INTRODUCTION: In genetically predisposed individuals, exogenous factors (including pollution) influence the development of Hashimoto's thyroiditis/chronic lymphocytic thyroiditis (CLT). CLT may also be a risk factor for associated thyroid cancer. Few data are available on the role of pollution from petrochemical complexes, one of which is located in the Siracusa province (South-Eastern Sicily), in the pathogenesis of CLT. AIMS: i) To study the frequency of CLT in fine-needle aspiration cytology (FNAC)-interrogated thyroid nodules from patients who were stably resident in their zones, comparing it in patients living in the petrochemical complex area (zone A) with that of patients from a control area (zone B). ii) To study the frequency of CLT in the FNAC categories of malignancy risk, comparing the two zones. PATIENTS AND METHODS: We retrospectively evaluated cytologically adequate slides of 1323 nodules in 1013 outpatients who underwent ultrasound-guided FNAC from 2006 to 2012. We stratified by area of residence, gender, and FNAC categories of malignancy risk. RESULTS: CLT was detected with significantly greater frequency in either patients or nodules from zone A compared with zone B (32.0% vs 23.1%, P=0.002 or 28.2% vs 18.8%, P=0.0001), with a female preponderance (F=35.2% vs M=21.1% or 30.4% vs 20.4%, zone A and F=26.5% vs 12.3% or 21.6% vs 9.5%, zone B). Regardless of zone, CLT was approximately twofold more frequent in the suspiciously malignant+malignant classes (TH4+THY5=47.6%, zone A and 32.4%, zone B) compared with the benign+intermediate classes (THY2+THY3=27.3%, zone A and 18.2%, zone B), but with a clear stepwise THY2 through THY5 increase only in zone A (THY2=25.3%, THY5=66.7%; THY2=18.6%, THY5=28.6% in zone B). CONCLUSIONS: The petrochemical complex-related pollution is an environmental factor involved in the development of CLT and, likely, in the CLT association with thyroid neoplasms.

Intranuclear cytoplasmic inclusions in cytologically suspicious or malignant thyroid nodules: identification and correlation with echogenicity and size of the nodules.

Intranuclear inclusions (ICI) represent one cytological feature suggestive of malignancy. The aims of this study are (1) to correlate ICI with size and echogenicity of the thyroid nodules that, at fine-needle aspiration cytology (FNAC), are suspiciously malignant (THY4) or malignant (THY5); and (2) to ascertain whether ICI alone or combined with some ultrasonography (US) characteristics would help in predicting malignancy. We studied 90 consecutive thyroid nodules (THY4 n = 60 or THY5 n = 30) from 90 patients, who subsequently underwent thyroidectomy. Prior to thyroidectomy, all 90 nodules were examined by the US-guided FNAC. A cytology/histology correlation was performed. The results showed that 70 nodules were cancerous (82.2 %, THY4 = 73.3 %, THY5 = 100 %). ICI positive (ICI+) were 53/90 nodules (THY4 = 48.3 %, THY5 = 80.0 %), of which three (all THY4) were benign. The maximum diameter was smaller in the 53 ICI +ve than in the 37 ICI -ve nodules (14.2 ± 5.4 vs. 20.0 ± 9.4 mm, P = 0.0001; median volume 1.32 vs. 4.03 ml). In the THY4 smaller hypoechoic nodules, malignancy rate was 95 % with greater probability to detect ICI compared with non-hypoechoic nodules of >20 mm in maximum diameter (31 (75.6 %) vs. 4 (23.5 %), P = 0.0002). Based on the results, we conclude that ICI detection is associated with relatively smaller size and hypoechoic appearance in THY4 or THY5 nodules. In the THY4 nodules, when coupled with these US characteristics, ICI identification selects lesions with high chances of malignancy.

Hashimoto's thyroiditis: similar and dissimilar characteristics in neighboring areas. Possible implications for the epidemiology of thyroid cancer.

CONTEXT: Medical centers worldwide report an increased frequency of Hashimoto's thyroiditis (HT) and thyroid cancer (TC), two environmentally influenced diseases. In Sicily, data on HT are available for the province of Messina (1975-2005); data on TC are available for the whole island (2002-2004), with the volcanic province of Catania having the highest incidence. OBJECTIVE: To replicate in Catania, on comparable years, the HT data of Messina. DESIGN METHODS SETTING: Review of the clinical records of patients in years 1995-2005 to compare presentation and yearly changes of HT. During 1995-2005, records were computer stored in the Endocrine Divisions of the University Hospitals of Catania and Messina, two tertiary referral centers. RESULTS: Catania is outnumbered by Messina (742 vs. 3,409 HT patients). Similar were the linear increase in the yearly number of HT patients, rates of thyroid dysfunctions though with different proportions of subclinical and overt hypothyroidism, and rates of positiveness for TgAb or TPOAb. Different were age and its yearly trend; gender distribution and rates of the sonography variants, though yearly trends were similar. CONCLUSION: The HT epidemics is smaller in Catania, with changes in presentation overlapping partially those in Messina. Whatever environmental factors might be involved, they (and/or their intensity) were not necessarily the same in these provinces. Intriguingly, the expected number of TC in HT patients with thyroid nodules in Catania is congruent with that of the general population of this province, but it is far less than in the Messina province. Thus, TC and HT incidences could be influenced by distinct environmental factors.

Thyroid cancer in thyroglossal duct cysts requires a specific approach due to its unpredictable extension.

CONTEXT: Differentiated thyroid cancer (DTC) in thyroglossal duct cysts is uncommon. The requirement of total thyroidectomy and lymph node dissection is still controversial. SETTING: The study was performed in a referral thyroid cancer center at an academic hospital. PATIENTS: We conducted a single center retrospective study of a consecutive series of 26 patients with DTC in thyroglossal duct cyst, all having undergone cyst resection and total thyroidectomy. MAIN OUTCOME MEASURES: Diagnostic modalities, surgical treatment, histopathological features, and clinical outcome were included in the study. RESULTS: Thyroglossal duct cyst cancer histotype was papillary in 23 of 26 patients (88.5%) and follicular-Hurthle in 3 of 26 cases (11.5%). A concomitant papillary DTC in the thyroid gland was found in 16 of 26 cases (61.5%), and it was multifocal in 8 of 16 cases (50%). At presentation, the patients with cancer in both the thyroglossal duct cyst and the thyroid were older than the patients who only had cancer in the thyroglossal duct cyst (44.9 ± 7.6 vs 32.0 ± 12.7; P = .006). Lymph node dissection, performed in 17 of 26 patients (65.4%), indicated that the central compartment was involved in 6 patients (35.3%, all having cancer also in the thyroid), the laterocervical compartments in 10 patients (58.8%), and the submental in 4 (23.5%). Six patients (23.1%) had persistent disease at 6-year median follow-up. CONCLUSIONS: DTC in thyroglossal duct cysts occurs at a younger age and with more aggressive features at presentation. Concomitant cancer in the thyroid and lymph node metastases is present in most cases. Lymph node compartment involvement is different from that of cancers in the thyroid gland. Therefore, surgical treatment should include both thyroglossal duct cyst resection and total thyroidectomy, with individualized surgical nodal dissection. Subsequent management should follow current DTC guidelines.

Levothyroxine monotherapy cannot guarantee euthyroidism in all athyreotic patients.

CONTEXT: Levothyroxine monotherapy is the treatment of choice for hypothyroid patients because peripheral T4 to T3 conversion is believed to account for the overall tissue requirement for thyroid hormones. However, there are indirect evidences that this may not be the case in all patients. OBJECTIVE: To evaluate in a large series of athyreotic patients whether levothyroxine monotherapy can normalize serum thyroid hormones and thyroid-pituitary feedback. DESIGN: Retrospective study. SETTING: Academic hospital. PATIENTS: 1,811 athyreotic patients with normal TSH levels under levothyroxine monotherapy and 3,875 euthyroid controls. MEASUREMENTS: TSH, FT4 and FT3 concentrations by immunoassays. RESULTS: FT4 levels were significantly higher and FT3 levels were significantly lower (p<0.001 in both cases) in levothyroxine-treated athyreotic patients than in matched euthyroid controls. Among the levothyroxine-treated patients 15.2% had lower serum FT3 and 7.2% had higher serum FT4 compared to euthyroid controls. A wide range of FT3/FT4 ratios indicated a major heterogeneity in the peripheral T3 production capacity in different individuals. The correlation between thyroid hormones and serum TSH levels indicated an abnormal feedback mechanism in levothyroxine-treated patients. CONCLUSIONS: Athyreotic patients have a highly heterogeneous T3 production capacity from orally administered levothyroxine. More than 20% of these patients, despite normal TSH levels, do not maintain FT3 or FT4 values in the reference range, reflecting the inadequacy of peripheral deiodination to compensate for the absent T3 secretion. The long-term effects of chronic tissue exposure to abnormal T3/T4 ratio are unknown but a sensitive marker of target organ response to thyroid hormones (serum TSH) suggests that this condition causes an abnormal pituitary response. A more physiological treatment than levothyroxine monotherapy may be required in some hypothyroid patients.

Risk-adapted management of differentiated thyroid cancer assessed by a sensitive measurement of basal serum thyroglobulin.

CONTEXT: Treatment and follow-up of patients thyroidectomized for differentiated thyroid carcinoma (DTC) mainly depends on the identification of the patient's risk of recurrence. Thyroglobulin (Tg) is the most important marker of persistent/recurrent disease. The recent introduction of a new, more sensitive Tg measurement allows for the early detection of the disease by measuring the basal (under L-T(4) therapy) serum Tg level without TSH stimulation. OBJECTIVE: The goal of this study is to identify the basal serum Tg threshold value that indicates recurrent disease by using a second-generation Tg assay. DESIGN AND PATIENTS: A continuous series of 425 DTC patients, all thyroidectomized and treated with (131)I after surgery and having basal Tg of no more than 1.0 ng/ml, negative anti-Tg antibodies, and a recombinant human TSH-stimulated Tg measurement was retrospectively analyzed. SETTING: The study took place at an academic hospital. RESULTS: The most accurate basal Tg value for predicting the presence of recurrent/residual disease was more than 0.15 ng/ml (sensitivity 87%, specificity 91%, negative predictive value 98.6%, and positive predictive value 47.8%). When the basal Tg level was no more than 0.15 ng/ml, the risk of disease presence was very low, even in patients classified at an intermediate or high risk. In contrast, when the basal Tg level was more than 0.15 ng/ml, the percentage of recurrent disease was relatively high (12.5% or one in eight cases) in low-risk patients. CONCLUSIONS: Basal Tg, measured using a second-generation Tg assay allows for the identification of DTC patients who are likely to remain disease free with great accuracy. This simple measurement, therefore, may be sufficient to assess the risk-adapted management of DTC patients.