Papillary Thyroid Microcarcinoma: Differences between Lesions in Incidental and Nonincidental Settings-Considerations on These Clinical Entities and Personal Experience.

Papillary thyroid microcarcinoma (PTMC) represents 35-40% of all papillary cancers; it is defined as a nodule ≤ 10 mm at the time of histological diagnosis. The clinical significance of PTMC is still controversial, and it may be discovered in two settings: incidental PTMC (iPTMC), in which it is identified postoperatively upon histological examination of thyroid specimens following thyroid surgery for benign disease, and nonincidental PTMC (niPTMC), in which it is diagnosed before surgery. While iPTMC appears to be related to mild behavior and favorable clinical outcomes, niPTMC may exhibit markers of aggressiveness. We retrospectively review our experience, selecting 54 PTMCs: 28 classified as niPTMC (52%) and 26 classified as iPTMC (48%). Patients with niPTMC showed significant differences, such as younger age at diagnosis (p < 0.001); a lower male/female ratio (p < 0.01); a larger mean nodule diameter (p < 0.001); and a higher rate of aggressive pathological findings, such as multifocality, capsular invasion and/or lymphovascular invasion (p = 0.035). Other differences found in the niPTMC subgroup included a higher preoperative serum TSH level, higher hospital morbidity and a greater need for postoperative iodine ablation therapy (p < 0.05), while disease-free long-term survival did not differ between subgroups (p = 0.331) after a mean follow-up (FU) of 87 months, with one nodal recurrence among niPTMCs. The differences between iPTMC and niPTMC were consistent: patients operated on for total thyroidectomy and showing iPTMC can be considered healed after surgery, and follow-up should be designed to properly calibrate hormonal supplementation; conversely, niPTMC may sometimes exhibit aggressive behavior, and so the FU regimen should be closer and aimed at early detection of cancer recurrence.

Calcium Citrate Versus Calcium Carbonate in the Management of Chronic Hypoparathyroidism: A Randomized, Double-Blind, Crossover Clinical Trial.

In hypoparathyroidism (HypoPT), calcium supplementation is virtually always required, although the disease is likely to be associated with an increased risk of nephrolithiasis. The use of calcium citrate (Ca-Cit) theoretically could have a positive impact on the nephrolithiasis risk because citrate salts are used to reduce this risk. Our objective was to evaluate the potential therapeutic advantage of Ca-Cit in comparison with calcium carbonate (CaCO3 ) in HypoPT, on nephrolithiasis risk factors, as well as to their ability to maintain desirable serum calcium levels. We also evaluated these preparations on quality of life (QOL). This randomized, double-blind, crossover trial recruited 24 adults with postsurgical chronic hypoparathyroidism at Campus Bio-Medico University of Rome. Participants were randomized 1:1 to Ca-Cit or CaCO3 for 1 month and then crossed over to the other treatment for another month. The primary outcomes were changes in albumin-adjusted serum calcium and in ion activity product of calcium oxalate levels (AP[CaOx] index). Secondary efficacy outcomes included changes in SF-36 survey score, fatigue score, constipation, and adverse events. No difference in terms of AP(CaOx) index was observed between the two groups. However, Ca-Cit was associated with a significant reduction in the oxalate/creatinine ratio compared with CaCO3 (-2.46 mmol/mol [SD 11.93] versus 7.42 mmol/mol [SD 17.63], p = 0.029). Serum calcium and phosphorus concentration was not different between the two calcium preparations. Ca-Cit was associated with less constipation (p = 0.047). No difference was found in QOL scores. Although Ca-Cit did not modify the AP(CaOx) index when compared with CaCO3, it was associated with a reduction in urinary oxalate excretion that could have a potential beneficial effect on nephrolithiasis risk. These results are likely to have clinical implications in HypoPT, particularly those who do not tolerate CaCO3 and those affected by nephrolithiasis. A longer-term experience is needed to confirm these findings. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Cardiovascular autonomic neuropathy as a cause of fatigue in chronic hypoparathyroidism.

PURPOSE: Hypoparathyroidism (hypoPT) results in an impairment of quality of life (QoL), an increase in fatigue and a higher risk of mortality. Cardiovascular autonomic neuropathy (CAN) is an impairment of the cardiovascular autonomic system and is associated with increased mortality and fatigability. Patients with hypoPT show an increased risk of CAN. However, no previous studies have investigated the association between CAN and QoL in hypoPT. To test whether CAN is associated with fatigue and impaired QOL in hypoPT patients. METHODS: We enrolled 48 subjects with postsurgical hypoPT treated with calcium and calcitriol and 38 healthy subjects who underwent thyroidectomy. Subjects completed the RAND 36-Item Short Form (SF-36) Health Survey, evaluating physical (PCS) and mental (MCS) health, and fatigue score. CAN was assessed using cardiovascular autonomic reflex tests (CARTs). Participants were considered to have "early CAN" (EC) if they had one abnormal CART and "definite CAN" (DC) with two or more abnormal CARTs. RESULTS: Compared with controls, hypoPT population had lower fatigue scores (44.5 IQRː9 vs 38.5 IQRː12.3, P = 0.031). In the hypoPT group, only participants with DC had a lower fatigue score than subjects without CAN (DC: ß: -9.55, P = 0.005) after adjusting for age, duration of disease, calcium concentration, TSH, calcitriol and calcium supplementation. No differences were found in the PCS and MCS scores in the hypoPT group. CONCLUSIONS: CAN may explain fatigue, a common complaint of postsurgical hypoPT patients. Further larger and prospective investigations are needed to confirm our findings.

Clinical, Biochemical, and Radiological Profile of Normocalcemic Primary Hyperparathyroidism.

CONTEXT: The clinical and radiological aspects of normocalcemic hyperparathyroidism (NHPT) are confounded by the differing methods used to rule out secondary hyperparathyroidism and by the small sample size. OBJECTIVE: To assess the clinical, biochemical, and radiological profile of NHPT compared with primary hyperparathyroidism (PHPT) and control subjects. DESIGN: Multicentric cross-sectional study. SETTING: Outpatient clinic. PATIENTS: 47 NHPT, 41 PHPT, and 39 age- and sex-matched control subjects. MAIN OUTCOME MEASURES: Calcium metabolism and bone turnover markers (BTMs). Lumbar spine, total hip, femoral neck, one-third distal radius bone mineral density (BMD). Morphometric vertebral fracture (VF) assessed by dual-energy X-ray absorptiometry. RESULTS: NHPT patients had significantly higher parathyroid hormone, 25(OH)-vitamin D levels and lower calcium × phosphorus product than controls (P < .001). Compared with PHPT, the NHPT group had significantly higher 25(OH) vitamin D levels (P = .016). NHPT had BTM levels similar to controls and PHPT. NHPT, PHPT, and controls have similar lumbar spine and femoral neck BMD. NHPT and controls had a similar radial BMD, while patients with PHPT had a lower radial BMD than both patients with NHPT (P = .031) and controls (P < .05). Using the control group as the reference, after adjustment for interacting factors, there was no increase in risk of moderate-severe VF in NHPT (odds ratio [OR] 1.04, 95% confidence interval [CI] 0.25-4.55), while PHPT had an increased risk (OR 3.81,95% CI 1.15-15.12). Seventy-nine percent of NHPT and 59% of PHPT patients fulfilled the criteria for asymptomatic hyperparathyroidism. CONCLUSIONS: The biochemical phenotype of NHPT is intermediate between PHPT and controls. In contrast, the bone phenotype resembles controls with normal bone turnover, no significant BMD impairment, and no increased risk of VF.

Treatment of thyroid nodules with radiofrequency: a 1-year follow-up experience.

PURPOSE: The aim of this study is to assess the effectiveness and safety of radiofrequency ablation (RFA) in debulking benign solid thyroid nodules. MATERIALS AND METHODS: This is a retrospective review of 77 patients with predominantly solid thyroid nodules treated with RFA in a single center between 2013 and 2016. All patients declined or were not eligible for surgery. Benign proven thyroid nodules causing compressive symptoms and cosmetic concerns were considered for treatment. Nodule volume, thyroid nodule related compressive symptoms, cosmetic concerns and thyroid function were evaluated. RESULTS: All patients underwent a single treatment session. Mean nodule volume decreased from 17.9 ± 15.6 mL at baseline to 5.2 ± 7.4 after 12 months with a volume reduction ratio (VRR) of 70.9% ± 20.8%. There were no identifiable factors predictive of response to RFA. Median cosmetic and symptom scores of the entire population decreased from 3 [2-4] and 3 [0-10] to 1 [1-3] (p < 0.001) and 0 [0-5] (p < 0.001), respectively. No major complications occurred and RFA did not affect thyroid function when normal. CONCLUSION: RFA induces substantial volume reduction of predominantly solid thyroid nodules and improves compressive symptoms and cosmetic concerns. RFA does not impact normal thyroid function and has an acceptable safety profile.

Cardiovascular Autonomic Neuropathy as a New Complication of Postsurgical Chronic Hypoparathyroidism.

Postsurgical hypoparathyroidism (hypoPT) increases fatigue and seems to affect the risk of mortality. Cardiovascular autonomic neuropathy (CAN) is an impairment of the cardiovascular autonomic system, a cause of increased mortality, and associated with increased fatigability. The aim of this study is to evaluate CAN in hypoPT and its relationship with hypocalcemia, PTH levels, and hyperphosphatemia. This is a cross-sectional study comparing 51 postsurgical hypoPT patients treated with calcium and calcitriol and 43 control subjects without any PTH/calcium/phosphate disorders who underwent thyroidectomy. CAN was assessed by heart rate (HR) response to deep breathing, HR response to the lying-to-standing test, HR response to the Valsalva maneuver, and blood pressure response to standing. Participants were considered to have "early CAN" if they had one abnormal result in the HR tests and "definite CAN" with two or more abnormal results. The prevalence of CAN was 23% in the control group and 78% in the hypoPT group (OR 11.48; 95% CI, 4.48 to 32.17). Patients with hypoPT and serum calcium (sCa) ≥8.5 mg/dL had a prevalence of early CAN of 72.4% and the prevalence was 86.4% in those with sCa <8.5 mg/dL. Definite CAN was found in 2.3% of the control group, 24.1% of the hypoPT group without hypocalcemia, and 59.1% of the hypoPT group with hypocalcemia. In the hypoPT group, the OR for definite CAN in the patients with hypocalcemia compared to the patients with normocalcemia was 4.54 (95% CI, 1.36 to 15.11). The association between low sCa and definite CAN was confirmed after adjustment for confounders with OR 13.62 (95% CI, 2.12 to 149.84). No association was found between definite CAN and PTH levels or high phosphate levels. HypoPT is associated with CAN and hypocalcemia seems to affect its severity. Larger and prospective studies are needed to confirm our findings. © 2018 American Society for Bone and Mineral Research.

PTH(1-34) for Surgical Hypoparathyroidism: A 2-Year Prospective, Open-Label Investigation of Efficacy and Quality of Life.

Context: Daily parathyroid hormone (PTH) (1-34) administrations can reduce the required total daily dose of calcium and calcitriol and restore normocalcemia in refractory hypoparathyroidism. However, most PTH(1-34) trials have been conducted on small cohorts including subjects with hypoparathyroidism of various etiologies, and quality of life (QOL) was not investigated. Objective: To investigate the effects of 24-month PTH(1-34) treatment in a homogeneous cohort of adult subjects with postoperative hypoparathyroidism and to evaluate QOL changes. Design: Prospective open-label study. Setting: Italian multicenter study. Participants: 42 subjects. Intervention: Twice-daily PTH(1-34) 20 µg subcutaneous injection. Main Outcome Measures: Calcium and vitamin D supplementation requirements, serum calcium, phosphate, and urinary calcium excretion (3, 6, 12, 18, 24 months). At baseline and at 6 and 24 months, QOL was evaluated by the RAND 36-Item Short Form (SF-36) Health Survey, covering eight domains of physical and mental health. Results: Mean serum calcium concentration significantly increased from baseline to 3 months (7.6 ± 0.6 vs 8.9 ± 1.1 mg/dL, P < 0.001) and remained stable until the end of the study, despite reductions in calcium and vitamin D supplementation. Phosphate levels gradually decreased from baseline to 6 months (4.3 ± 1.1 vs 3.9 ± 0.6 mg/dL, P < 0.019), remaining stable until 24 months. Serum alkaline phosphatase and calcium excretion gradually increased from baseline to 24 months. Data from SF-36 showed a significant improvement in the mean scores of all eight domains (P < 0.001). Conclusion: This study demonstrates the efficacy and safety of PTH(1-34) to treat adult patients with postsurgical hypoparathyroidism. PTH(1-34) may improve their mental and physical health.

Italian Association of Clinical Endocrinologists (AME) and Italian Chapter of the American Association of Clinical Endocrinologists (AACE) Position Statement: Clinical Management of Vitamin D Deficiency in Adults.

Vitamin D deficiency is very common and prescriptions of both assay and supplementation are increasing more and more. Health expenditure is exponentially increasing, thus it is timely and appropriate to establish rules. The Italian Association of Clinical Endocrinologists appointed a task force to review literature about vitamin D deficiency in adults. Four topics were identified as worthy for the practicing clinicians. For each topic recommendations based on scientific evidence and clinical practice were issued according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) System. (1) What cut-off defines vitamin D deficiency: even though 20 ng/mL (50 nmol/L) can be considered appropriate in the general population, we recommend to maintain levels above 30 ng/mL (75 nmol/L) in categories at risk. (2) Whom, when, and how to perform screening for vitamin D deficiency: categories at risk (patients with bone, liver, kidney diseases, obesity, malabsorption, during pregnancy and lactation, some elderly) but not healthy people should be screened by the 25-hydroxy-vitamin D assay. (3) Whom and how to treat vitamin D deficiency: beyond healthy lifestyle (mostly sun exposure), we recommend oral vitamin D (vitamin D2 or vitamin D3) supplementation in patients treated with bone active drugs and in those with demonstrated deficiency. Dosages, molecules and modalities of administration can be profitably individually tailored. (4) How to monitor the efficacy of treatment with vitamin D: no routine monitoring is suggested during vitamin D treatment due to its large therapeutic index. In particular conditions, 25-hydroxy-vitamin D can be assayed after at least a 6-month treatment. We are confident that this document will help practicing clinicians in their daily clinical practice.

PTH(1-34) for Surgical Hypoparathyroidism: A Prospective, Open-Label Investigation of Efficacy and Quality of Life.

CONTEXT: Conventional therapy for hypoparathyroidism consists of calcium and calcitriol, but sometimes normal serum calcium cannot be maintained, and/or this approach might lead to nephrocalcinosis, nephrolithiasis, or renal insufficiency. OBJECTIVE: The objective of the study was to investigate the effects of 6 months of PTH(1-34) treatment in adult subjects with postoperative hypoparathyroidism and to evaluate quality-of-life changes. DESIGN: This was a 2-year prospective, open-label study. At baseline and after 6 months of PTH(1-34) treatment, calcium and vitamin D supplementation requirements, serum calcium, phosphate, creatinine, alkaline phosphatase, uric acid, and 24-hour urinary calcium excretion were evaluated. Quality of life was evaluated by the Rand 36-Item Short Form Health Survey covering eight domains of physical and mental health. SETTING: This was an Italian multicentric study. PARTICIPANTS: Participants included 42 subjects with surgical hypoparathyroidism (90% females, age range 34-77 y). INTERVENTION: The intervention included a twice-daily PTH(1-34) 20 µg sc injection. RESULTS: The mean serum calcium levels significantly increased from baseline to 15 days (7.6 ± 0.6 vs 9.1 ± 0.9 mg/dL, P < .001) and remained stable until the end of the observational period, despite a significant reduction in calcium and vitamin D supplementation. Phosphate levels gradually decreased from baseline to the sixth month (P = .005 for the trend), whereas the alkaline phosphatase increased (P < .001). Data from the Rand 36-Item Short Form Health Survey showed a significant improvement in the mean scores of all eight domains (P < .001). CONCLUSION: This is the largest study that demonstrates the effectiveness of PTH(1-34) in the treatment of adult patients with postsurgical hypoparathyroidism, and it shows that PTH(1-34) may improve the mental and physical health in hypoparathyroid subjects.