Consensus Statement on Vitamin D Status Assessment and Supplementation: Whys, Whens, and Hows.

The 6th International Conference, "Controversies in Vitamin D," was convened to discuss controversial topics, such as vitamin D metabolism, assessment, actions, and supplementation. Novel insights into vitamin D mechanisms of action suggest links with conditions that do not depend only on reduced solar exposure or diet intake and that can be detected with distinctive noncanonical vitamin D metabolites. Optimal 25-hydroxyvitamin D (25(OH)D) levels remain debated. Varying recommendations from different societies arise from evaluating different clinical or public health approaches. The lack of assay standardization also poses challenges in interpreting data from available studies, hindering rational data pooling and meta-analyses. Beyond the well-known skeletal features, interest in vitamin D's extraskeletal effects has led to clinical trials on cancer, cardiovascular risk, respiratory effects, autoimmune diseases, diabetes, and mortality. The initial negative results are likely due to enrollment of vitamin D-replete individuals. Subsequent post hoc analyses have suggested, nevertheless, potential benefits in reducing cancer incidence, autoimmune diseases, cardiovascular events, and diabetes. Oral administration of vitamin D is the preferred route. Parenteral administration is reserved for specific clinical situations. Cholecalciferol is favored due to safety and minimal monitoring requirements. Calcifediol may be used in certain conditions, while calcitriol should be limited to specific disorders in which the active metabolite is not readily produced in vivo. Further studies are needed to investigate vitamin D effects in relation to the different recommended 25(OH)D levels and the efficacy of the different supplementary formulations in achieving biochemical and clinical outcomes within the multifaced skeletal and extraskeletal potential effects of vitamin D.

New insights into the vitamin D/PTH axis in endocrine-driven metabolic bone diseases.

BACKGROUND: Endocrine regulation of bone metabolisms is the focus of the "Skeletal Endocrinology" series of meetings. AIMS: To report on the outcome of the discussion on the role of vitamin D/PTH axis in endocrine osteopathies held during the 10th Skeletal Endocrinology Meeting which took place in Stresa (Italy) in March 2023. OUTCOMES: Vitamin D/PTH axis has relevant influence on several outcomes in the general population and in patients affected by endocrinopathies such as hypoparathyroidism and secreting pituitary adenomas. CONCLUSIONS: Assessing the status of the vitamin D/PTH axis and using vitamin D and PTH as therapeutic agents is mandatory in several endocrine-related bone metabolic conditions.

Fat-to-blood recirculation of partially dysfunctional PD-1+CD4 Tconv cells is associated with dysglycemia in human obesity.

Obesity is characterized by the accumulation of T cells in insulin-sensitive tissues, including the visceral adipose tissue (VAT), that can interfere with the insulin signaling pathway eventually leading to insulin resistance (IR) and type 2 diabetes. Here, we found that PD-1+CD4 conventional T (Tconv) cells, endowed with a transcriptomic and functional profile of partially dysfunctional cells, are diminished in VAT of obese patients with dysglycemia (OB-Dys), without a concomitant increase in apoptosis. These cells showed enhanced capacity to recirculate into the bloodstream and had a non-restricted TCRß repertoire divergent from that of normoglycemic obese and lean individuals. PD-1+CD4 Tconv were reduced in the circulation of OB-Dys, exhibited an altered migration potential, and were detected in the liver of patients with non-alcoholic steatohepatitis. The findings suggest a potential role for partially dysfunctional PD-1+CD4 Tconv cells as inter-organ mediators of IR in obese patients with dysglycemic.

Use of vitamin D with anti-osteoporotic drugs: are available clinical trials telling us the whole story?

There is a strong rationale for using vitamin D in combination with anti-osteoporotic drugs. Still, available trials do not give clear indications in this setting, presenting a suboptimal and heavily inhomogeneous experimental design. Health authorities should revise requirements for using vitamin D in anti-osteoporotic drug trials to maximise their effect and produce reliable indications for clinical practice in this setting.

Ewing's sarcoma in a young man mimicking lateral elbow pain: A case report with 2 years follow-up.

BACKGROUND AND PURPOSE: Lateral elbow pain represents a common musculoskeletal disorder, mostly non-specific and benign. In rare cases, it can be the first symptom of a severe disease such as Ewing's sarcoma (ES). ES is the second most common primary malignant bone tumor in the young population, with a high probability of an unfavourable prognosis. CASE PRESENTATION: This case report presents the history of a young man presenting to the physical therapist with a diagnosis of "epicondylitis" in the right elbow, which was later revealed to be an aggressive ES of the ulna. Findings raising clinical doubts were (a) constant pain even at night and not dependent on load, (b) significant loss of function, (c) patient's young age, and (d) a palpable mass in the elbow. RESULTS: After diagnosis, the patient received medical (chemotherapy, radiotherapy and surgery) and a rehabilitation program. After treatment, the patient improved elbow function, decreased disability and returned to social participation, maintaining positive outcomes at the 2-year follow-up. DISCUSSION: In summary, this case report emphasizes the importance of differential diagnosis and screening for referral of red flags in physical therapy. Moreover, it describes the rehabilitation of a patient with ES, enriching the scientific literature in the field.

Transition from Hashimoto thyroiditis to Graves's Disease: an unpredictable change?

PURPOSE: Hashimoto thyroiditis and Graves's disease are two related autoimmune disorders, representing the leading causes of hypothyroidism and hyperthyroidism. Autoimmune hypothyroidism is generally irreversible but very rarely, some patients would shift to hyperthyroidism. The aim of the study was to seek for possible clinical predictors of the transition from hypo to hyperthyroidism in patients with Hashimoto thyroiditis and to outline their clinical phenotype. METHODS: Twelve patients with overt autoimmune hypothyroidism who had at least one transition from hypothyroidism to autoimmune hyperthyroidism were compared with 294 consecutive patients with autoimmune hypothyroidism and 69 consecutive patients with autoimmune hyperthyroidism that accessed the outpatient clinic over six months. Demographic, hormonal data and autoantibodies titers were compared. RESULTS: Prevalence of smoking habit was significantly higher in switchers compared to controls. Switchers showed a significantly higher prevalence of personal and familial history of non-thyroidal autoimmune disorders. TSH levels were significantly lower in the switcher group during the hypothyroid phase and levothyroxine dose required was lower. TSH concentrations were significantly lower while free fT4 and free fT3 values were higher in GD patients compared to switchers during the hyperthyroid phase despite comparable TRAb levels. Prevalence and type of hyperthyroid symptoms and orbitopathy were similar between switchers and GD group. Mean dose of anti-thyroid drugs was significantly higher in GD patients compared to switchers. No differences were observed in the remission rate from hyperthyroidism between the two groups, despite switchers showed a significantly lower time-to-remission. CONCLUSIONS: Conversion of Hashimoto Thyroiditis towards Graves' disease is a rare phenomenon which can occur almost at any time after the development of autoimmune hypothyroidism. Our findings suggest active surveillance of hypothyroid patients who require frequent reduction of levothyroxine during follow up and testing for TSHR antibodies in these patients.

Longitudinal Changes in Physical Function and Their Impact on Health Outcomes in COVID-19 Patients.

BACKGROUND: Coronavirus disease (COVID-19) is correlated with a variety of long-term sequelae that affect different aspects of health, including physical function. This study investigated the longitudinal changes in handgrip strength (HGS) over six months post-hospital discharge in COVID-19 patients and explores the associations between HGS, health-related quality of life, dyspnoea, exercise capacity, and body mass index (BMI). METHODS: Adult COVID-19 patients were followed up at one, three, and six months after hospital discharge. HGS, BMI, exercise capacity, and health-related quality of life were assessed. Data from patients with HGS measurements at all three time points were analysed. RESULTS: Low HGS was prevalent one month post-discharge (35%). Participants with low HGS exhibited more severe disease (30.5% vs. 5.9% were admitted to the intensive care unit, p < 0.01), longer hospital stays (median [IQR] 21 [10.0; 40.5] vs. 12.0 [8.0; 20.0] days, p < 0.01), greater weight loss (-5.7 [-9.1; -0.6] vs. -3.2 [-5.7; -0.0] kg, p = 0.004), and reduced exercise capacity (6 min walking test [6 MWT], 95.7 [84.0; 102.0] vs. 100.0 [92.9; 105.0]% predicted, p = 0.007). Those with persistently low HGS (40% of the initial low HGS group) had worse exercise capacity (6-MWT 93.3 [78.3; 101.0] vs. 101.0 [95.0; 107.0]% predicted, p < 0.001), more dyspnoea (29.0% vs. 2.0% of participants, p < 0.001), poorer quality of life (visual analogue scale score, 75 [50; 75] vs. 85 [75; 95], p < 0.001), and higher rates of problems in various health dimensions. HGS at 1 month was the only significant predictor of HGS improvement from 1 month to 6 months (odds ratio [95% CI] 1.11 [1.03; 1.20], p = 0.008). CONCLUSIONS: This study highlights the prevalence of reduced physical function among COVID-19 survivors and emphasises the importance of early identification and intervention to optimise their long-term health. Monitoring HGS, a simple and reliable tool, can provide valuable insights into patients' overall physical function, aiding in tailored care and improved outcomes.

Vitamin D status and supplementation before and after Bariatric Surgery: Recommendations based on a systematic review and meta-analysis.

Bariatric surgery is associated with a postoperative reduction of 25(OH) vitamin D levels (25(OH)D) and with skeletal complications. Currently, guidelines for 25(OH)D assessment and vitamin D supplementation in bariatric patients, pre- and post-surgery, are still lacking. The aim of this work is to analyse systematically the published experience on 25(OH)D status and vitamin D supplementation, pre- and post-surgery, and to propose, on this basis, recommendations for management. Preoperatively, 18 studies including 2,869 patients were evaluated. Prevalence of vitamin D insufficiency as defined by 25(OH)D < 30 ng/mL (75 nmol/L) was 85%, whereas when defined by 25(OH)D < 20 ng/mL (50 nmol/L) was 57%. The median preoperative 25(OH)D level was 19.75 ng/mL. After surgery, 39 studies including 5,296 patients were analysed and among those undergoing either malabsorptive or restrictive procedures, a lower rate of vitamin D insufficiency and higher 25(OH)D levels postoperatively were observed in patients treated with high-dose oral vitamin D supplementation, defined as ≥ 2,000 IU/daily (mostly D3-formulation), compared with low-doses (< 2,000 IU/daily). Our recommendations based on this systematic review and meta-analysis should help clinical practice in the assessment and management of vitamin D status before and after bariatric surgery. Assessment of vitamin D should be performed pre- and postoperatively in all patients undergoing bariatric surgery. Regardless of the type of procedure, high-dose supplementation is recommended in patients after bariatric surgery.

Cholecalciferol Use Is Associated With a Decreased Risk of Incident Morphometric Vertebral Fractures in Acromegaly.

CONTEXT: Skeletal fragility is observed in 30% to 60% of acromegaly patients, representing an emerging complication of the disease that increases disability. Despite several studies having investigated the clinical and hormonal prognostic factors for the occurrence of vertebral fractures (VFs) in acromegaly, very few data are available on their prevention/treatment including the effect of vitamin D (VD) supplementation, which has been reported to have a fracture-protective effect in several studies in patients with osteoporosis. OBJECTIVE: We aimed to investigate the role of cholecalciferol (D3) supplementation in the prevention of incident VFs (i-VFs) in acromegaly. METHODS: A longitudinal, retrospective and multicenter study was performed on 61 acromegaly patients treated and untreated with D3 supplementation. RESULTS: Twenty-six patients were treated with D3 supplementation according to clinical guidelines. The median D3 weekly dosage was 8500 IU (interquartile range [IQR]: 3900). The median duration of D3 supplementation was 94 months (IQR: 38). At last follow-up, i-VFs were diagnosed in 14 patients (23%). I-VFs were less prevalent in patients on D3 supplementation (14.3% of cases) compared to patients not treated with D3 (85.7%; P = .02). The final level of serum V25OH-D was significantly lower in patients who developed i-VFs (28.6 ng/mL, IQR: 4.1) compared to patients who did not develop i-VFs (34.2 ng/mL, IQR: 9.6; P = .05). The logistic regression confirmed the protective role of D3 supplementation on the occurrence of i-VFs (odds ratio: 0.16; 95% CI, 0.03-0.79; P = .01). CONCLUSION: It is likely that D3 supplementation could lead to a reduction in i-VFs in acromegaly.

Lack of vitamin D predicts impaired long-term immune response to COVID-19 vaccination.

PURPOSE: Low vitamin D levels were reported to negatively influence the outcome of acute COVID-19, as well as to be linked to Long-COVID. However, few studies have investigated, so far, its effects on humoral-response to anti-SARS-CoV-2 vaccination, reporting conflicting results. We aimed to evaluate the impact of baseline 25(OH)vitamin D (25(OH)D) levels on humoral-response to a two-dose cycle of Pfizer-BioNTech-vaccine up to 9-10 months after immunization. METHODS: We retrospectively included 119 consecutive healthcare-workers (median age 53 years) without a previous history of acute COVID-19 or anti-SARS-CoV-2 immunoglobulins presence immunized with two doses of Comirnaty-vaccine from January to February 2021. 25(OH)D was measured at time of first-immunization. Immune response was evaluated at: time 0 (T0), before the first-dose; T1, time of second-dose (21 days after T0); T2, T3, T4 at 1, 5 and 9 months after T1, respectively. RESULTS: Median 25(OH)D levels were 25.6 ng/mL, and vitamin D deficiency (25(OH)D <20 ng/mL) was observed in 29 subjects (24.8%). In those with vitamin D deficiency, we found a non-significant trend towards lower antibody-titers at T3, and significantly lower titers at T4 as compared to those not vitamin D-deficient, also observing a more pronounced antibody-titers negative drop from peak-T2 and T4 in those with vitamin D deficiency. A positive correlation between 25(OH)D levels and antibody-titers at T4 (p = 0.043) was found. In multiple linear-regression analysis, 25(OH)D deficiency and older-age resulted as negative independent factors associated with antibody titer at T4 (p = 0.026, p = 0.004; respectively). CONCLUSION: In our relatively young cohort presenting low prevalence of hypovitaminosis D, the long-term humoral response to anti-SARS-CoV-2 vaccination was negatively influenced by low baseline 25(OH)D. Vitamin D supplementation could be tested as a strategy to optimize the vaccination campaigns to prevent severe COVID-19.

Low Vitamin D Levels Are Associated With Long COVID Syndrome in COVID-19 Survivors.

CONTEXT: Long COVID is an emerging syndrome affecting 50% to 70% of COVID-19 survivors that still lacks predicting factors. OBJECTIVE: Due to the extraskeletal effects of vitamin D, we retrospectively assessed the association between 25(OH) vitamin D levels and long COVID in COVID-19 survivors 6 months after hospitalization. METHODS: Long COVID was defined according to NICE guidelines. Fifty long COVID and 50 non-long-COVID subjects matched on a 1:1 basis were enrolled from an outpatient clinic post-COVID cohort seen from August to November 2020. Therapies/comorbidities affecting calcium/vitamin D/bone metabolism, and/or admission to the intensive care unit during hospitalization were exclusion criteria. 25(OH) Vitamin D was measured at hospital admission and 6 months after discharge. RESULTS: We observed lower 25(OH) vitamin D levels, evaluated at follow-up, in subjects with long COVID than those without (20.1 vs 23.2 ng/mL, P = .03). Regarding the affected health areas evaluated in the entire cohort, we observed lower 25(OH) vitamin D levels in those with neurocognitive symptoms at follow-up (n = 7) than those without (n = 93) (14.6 vs 20.6 ng/mL, P = .042). In patients presenting vitamin D deficiency (<20 ng/mL), both at admission and at follow-up (n = 42), those affected by long COVID (n = 22) presented lower 25(OH) vitamin D levels at follow-up than those not affected (n = 20) (12.7 vs 15.2 ng/mL, P = .041). In multiple regression analyses, lower 25(OH) vitamin D levels at follow-up were the only variable significantly associated with long COVID in our cohort (P = .008, OR 1.09, CI 1.01-1.16). CONCLUSION: COVID-19 survivors with long COVID have lower 25(OH) vitamin D levels than matched patients without long COVID. Our data suggest that vitamin D levels should be evaluated in COVID-19 patients after hospital discharge. The role of vitamin D supplementation as a preventive strategy of COVID-19 sequelae should be tested in randomized controlled trials.

Low vitamin D levels predict outcomes of COVID-19 in patients with both severe and non-severe disease at hospitalization.

PURPOSE: Low vitamin D in COVID-19 have been related to worse outcomes. However, most of the studies conducted so far were not-controlled and retrospective, including biases potentially influencing this association. We evaluated 25(OH)vitamin D levels of patients with both severe and non-severe disease at hospital-admission, and in a cohort of control subjects. Moreover, we evaluated sACE-2 levels to investigate the mechanisms underlying the association between vitamin D and COVID-19. METHODS: COVID-19 patients were enrolled in a matched for age, sex and comorbidities 1:1-ratio based on the presence/or not of respiratory-distress/severe-disease at hospital-admission. Control matched subjects were enrolled from an outpatient-setting. RESULTS: Seventy-three COVID-19 patients (36 severe and 37 non-severe) and 30 control subjects were included. We observed a higher vitamin D deficiency (<20 ng/mL) prevalence in COVID-19 patients than control subjects (75% vs 43%). No differences were found regarding 25(OH)vitamin D and sACE-2 levels between patients with and without severe-disease at study entry. During the disease-course, in the severe group a life-threatening disease occurred in 17 patients (47.2%), and, in the non-severe group, a worsening disease occurred in 10 (27%). 25(OH)vitamin D levels, at admission, were negatively correlated with sACE-2 levels, and were lower in patients whose disease worsened as compared to those in whom it did not, independently from the disease severity at admission. In multivariate-analysis, lower 25(OH)vitamin D resulted as an independent risk factor for disease worsening. CONCLUSIONS: 25(OH)vitamin D levels at hospital-admission strongly predicted the occurrence of worsening outcomes in COVID-19 independently of the disease severity at presentation.

New tools for bone health assessment in secreting pituitary adenomas.

Pituitary hormones regulate skeletal physiology, and excess levels affect bone remodeling and alter bone microstructure. Vertebral fractures (VFs) are an early phenomenon of impaired bone health in secreting pituitary adenomas. However, they are not accurately predicted by areal bone mineral density (BMD). Emerging data demonstrate that a morphometric approach is essential for evaluating bone health in this clinical setting and is considered to be the gold standard method in acromegaly. Several novel tools have been proposed as alternative or additional methods for the prediction of fractures, particularly in pituitary-driven osteopathies. This review highlights the novel potential biomarkers and diagnostic methods for bone fragility, including their pathophysiological, clinical, radiological, and therapeutic implications in acromegaly, prolactinomas, and Cushing's disease.

Modern approach to resistant acromegaly.

BACKGROUND: Targets of acromegaly treatment are normalization of biochemical values, removal/reduction/stabilization of the pituitary mass, control of clinical activity and mortality with a multimodal/multidisciplinary approach. Despite significant technological and pharmacological progress, still several patients with acromegaly bear a resistant somatotroph adenoma and active disease may persist for many years with resultant poor clinical outcomes. AIM: To review briefly definition and pathophysiology of resistance to acromegaly treatment and the options of medical treatment in this context, exploring the role of novel clinical and molecular biomarkers in the personalization of therapy and proposing updates to the currently available guidelines for the treatment of resistant GH-secreting adenomas. CONCLUSIONS: In the last few years, in parallel with the increased number of medical options available for the therapy of acromegaly, relevant advances occurred in the understanding of the role of novel molecular and clinical biomarkers in predicting the responsiveness to second-line medical treatments, such as Pegvisomant and Pasireotide LAR, and helping clinicians in the personalization of the follow-up and treatment of resistant somatotroph adenomas. The integration of these findings into the existing guidelines may represent a possibly important step forward in the management of "difficult" acromegaly patients.

Vitamin D and malabsorptive gastrointestinal conditions: A bidirectional relationship?

This paper is one of the outcomes of the 5th International Conference "Controversies in Vitamin D" held in Stresa, Italy from 15 to 18 September 2021 as part of a series of annual meetings which was started in 2017. The scope of these meetings is to discuss controversial issues about vitamin D. Publication of the outcomes of the meeting in international journals allows a wide sharing of the most recent data with the medical and academic community. Vitamin D and malabsorptive gastrointestinal conditions was one of the topics discussed at the meeting and focus of this paper. Participants to the meeting were invited to review available literature on selected issues related to vitamin D and gastrointestinal system and to present their topic to all participants with the aim to initiate a discussion on the main outcomes of which are reported in this document. The presentations were focused on the possible bidirectional relationship between vitamin D and gastrointestinal malabsorptive conditions such as celiac disease, inflammatory bowel diseases (IBDs) and bariatric surgery. In fact, on one hand the impact of these conditions on vitamin D status was examined and on the other hand the possible role of hypovitaminosis D on pathophysiology and clinical course of these conditions was also evaluated. All examined malabsorptive conditions severely impair vitamin D status. Since vitamin D has known positive effects on bone this in turn may contribute to negative skeletal outcomes including reduced bone mineral density, and increased risk of fracture which may be mitigated by vitamin D supplementation. Due to the immune and metabolic extra-skeletal effects there is the possibility that low levels of vitamin D may negatively impact on the underlying gastrointestinal conditions worsening its clinical course or counteracting the effect of treatment. Therefore, vitamin D status assessment and supplementation should be routinely considered in all patients affected by these conditions. This concept is strengthened by the existence of a possible bidirectional relationship through which poor vitamin D status may negatively impact on clinical course of underlying disease. Sufficient elements are available to estimate the desired threshold vitamin D level above which a favourable impact on the skeleton in these conditions may be obtained. On the other hand, ad hoc controlled clinical trials are needed to better define this threshold for obtaining a positive effect of vitamin D supplementation on occurrence and clinical course of malabsorptive gastrointestinal diseases.

Distinct Clinical Features of Post-COVID-19 Vaccination Early-onset Graves' Disease.

CONTEXT: Several case reports of Graves' disease (GD) occurrence after COVID-19 vaccination that are possibly related to the autoimmune syndrome induced by adjuvants (ASIA) were published recently. OBJECTIVE: The aim of our study was to evaluate possible distinctive features in the presentation and clinical course of patients with GD occurring early (within 4 weeks) after COVID-19 vaccination who attended our Endocrine Unit in 2021. METHODS: Patients with a first episode of GD attending a tertiary endocrine center between January 1, 2021, and December 31, 2021, were included. RESULTS: Sixty-four patients with a first episode of GD were seen in 2021: 20 (31.2%) of them had onset within 4 weeks following vaccine administration. Compared with the other 44 patients, the 20 patients with postvaccine early-onset (PoVEO) GD were older (median age 51 years vs 35 years, P = .003) and more likely to be male (40.0% vs 13.6%, P = .018). At diagnosis, the biochemical and immune profiles were similar between the 2 groups. However, at 3 months after starting methimazole, patients with PoVEO GD had significantly lower thyrotropin receptor antibody titer and were taking lower doses of methimazole than the other patients with GD. None in the PoVEO group had sustained free triiodothyronine elevation. CONCLUSION: This relatively large series suggests that in 2021 PoVEO GD may be a new nosologic entity representing one-third of patients evaluated for new-onset GD in our center. Distinctive features included older age at onset, higher male prevalence, and a better initial biochemical and immunologic response to treatment. Further studies are warranted to clinically and biochemically differentiate these cases from sporadically occurring GD.

Ultrasound and FibroScan® Controlled Attenuation Parameter in patients with MAFLD: head to head comparison in assessing liver steatosis.

BACKGROUND: Controlled attenuation parameter (CAP) has been suggested as a new non-invasive measurement performed during transient elastography (TE) to assess liver steatosis. The aim of this study was to evaluate CAP values head to head with ultrasound (US) as reference standard. METHODS: A consecutive cohort of patients attending abdominal US in an outpatient liver unit was included in this study with simultaneous CAP determination using the FibroScan® M probe and fibrosis scored by TE. Patients were subdivided in four groups on the basis of risk factors for Metabolically Associated Fatty Liver Disease (MAFLD). RESULTS: Four hundred thirty-five patients were included in the analysis: 221 (51%) were male; 117 (26.9%) were in control group, 144 (33.1%) in group 2 with inactive HCV or HBV infection and at low-risk for MAFLD, 134 (30.8%) in group 3 at high-risk of MAFLD, 40 (9.2%) in group 4 at high-risk of MAFLD and concomitant inactive HCV or HBV infection. Liver steatosis detected with US evaluation was observed in the 41% of the entire cohort; in particular in the 3.4%, 20.1%, 83.6% and 87.4% of the group 1, 2, 3 and 4, respectively (p < 0.001). In patients at high-risk factor for MAFLD (group 3 and 4), CAP median levels were found statistically different among the severity-grading groups for US steatosis (S0 [n.27], ≥S1 [n.59], ≥S2 + S3 [n.89]), observing higher CAP levels in patients with a higher steatosis grade (≥S2 + S3 327.5 [±40.6] vs ≥S1 277.7 [±45.6] vs S0 245.1 [±47.4]; p < 0.001 for the whole cohort analysis) (p < 0.001 between ≥S2 + S3 and ≥S1) (p < 0.001 between ≥S2 + S3 and S0) (p = 0.004 between ≥S1 and S0). ROC analysis showed that the global performance of the CAP median level ≥ 258 to predict liver steatosis (S0 vs S1-3), was excellent with an Area Under the Curve (AUC) value of 0.87 [CI 95% 0. 835-0.904] with an 84% of sensitivity and a 78% of specificity, and a positive predictive value (PPV) of 73% and negative predictive value (NPV) of 88%. A TE-kPa median value <8.0 was detected in the 100%, 84%, 83.6% and 60% of patients in group 1, 2, 3 and 4, respectively. A TE-kPa median value >13.0 was detected in the 0%, 4.2%, 5.2% and 17.5% of patients in group 1, 2, 3 and 4, respectively. CONCLUSIONS: CAP values are strongly associated with the standard US criteria for different degree of steatosis. Integrating TE up to 5% of patients may be identified at risk for advanced fibrosis.

Novel approaches to bone comorbidity in Cushing's disease: an update.

Skeletal complications are frequent and clinically relevant findings in Cushing's disease (CD) since an uncoupled suppressed bone formation and enhanced bone resorption leads to a marked skeletal damage with a rapid increase of fracture risk. Reduced Bone Mineral Density (BMD) has been consistently reported and osteopenia or osteoporosis are typical findings in patients with CD. Vertebral Fractures (VFs) are frequently reported and may occur even in patients with an only mild reduction of BMD, representing nowadays a still under- or misdiagnosed comorbidity of these patients being frequently asymptomatic. A novel approach combining different available tools such as BMD evaluation and vertebral morphometry, in order to improve diagnosis, management, and follow-up of bone comorbidity in all patients affected by CD, is needed. This approach is foreseen to be a crucial part of management of patients with CD, particularly in Pituitary Tumor Center of Excellence since VFs, the landmark of the bone involvement, may occur early in the history of the disease and may represent a relevant risk factor for further fractures, reduced quality of life and survival and need for pharmacologic prevention and treatment.