Management of Adrenal Cortical Adenomas: Assessment of Bone Status in Patients with (Non-Functioning) Adrenal Incidentalomas.

Our aim is to analyse the bone profile in adults with (non-functioning) adrenal incidentalomas (AIs), specifically addressing the impact of autonomous cortisol secretion (ACS). This narrative review, based on a PubMed search from inception to February 2023 (case reports, non-ACS, and other secondary causes of osteoporosis were excluded), included 40 original studies, a total of 3046 patients with female prevalence (female:male ratio of 1921:1125), aged between 20.5 and 95.5 years old. This three decade-based analysis showed that 37 studies provided dual-energy X-ray absorptiometry (DXA) information; another five studies reports results on bone micro-architecture, including trabecular bone score (TBS), spinal deformity index, and high-resolution peripheral quantitative computed tomography; 20 cohorts included data on bone turnover markers (BTMs), while four longitudinal studies followed subjects between 1 and 10.5 years old (surgical versus non-adrenalectomy arms). Post-dexamethasone suppression test (DST) cortisol was inversely associated with bone mineral density (BMD). TBS predicted incidental vertebral fractures (VFx) regardless of BMD, being associated with post-DST cortisol independently of age and BMD. Low BTMs were identified in ACS, but not all studies agreed. An increased prevalence of ACS-related osteoporosis was confirmed in most studies (highest prevalence of 87.5%), as well as of VFx, including in pre-menopause (42.5%), post-menopause (78.6%), and male patients (72.7%) depending on the study, with a 10-fold increased incidental VFx risk up to a 12-fold increased risk after a 2-year follow-up. No specific medication against osteoporosis is indicated in ACS, but adrenalectomy (according to four studies) should be part of the long-term strategy. This bone profile case sample-based study (to our knowledge, one of the largest of its kind) showed that AIs, including the subgroup designated as having ACS, embraces a large panel of osseous complications. The level of evidence remains far from generous; there are still no homogenous results defining ACS and identifying skeletal involvement, which might be a consequence of different investigation clusters underling adrenal and bone assessments over time. However, bone status evaluations and associated therapy decisions remain an essential element of the management of adults with AIs-ACS.

New Entity-Thalassemic Endocrine Disease: Major Beta-Thalassemia and Endocrine Involvement.

Beta-thalassemia (BTH), a recessively inherited haemoglobin (Hb) disorder, causes iron overload (IO), extra-medullary haematopoiesis and bone marrow expansion with major clinical impact. The main objective of this review is to address endocrine components (including aspects of reproductive health as fertility potential and pregnancy outcome) in major beta-thalassemia patients, a complex panel known as thalassemic endocrine disease (TED). We included English, full-text articles based on PubMed research (January 2017-June 2022). TED includes hypogonadism (hypoGn), anomalies of GH/IGF1 axes with growth retardation, hypothyroidism (hypoT), hypoparathyroidism (hypoPT), glucose profile anomalies, adrenal insufficiency, reduced bone mineral density (BMD), and deterioration of microarchitecture with increased fracture risk (FR). The prevalence of each ED varies with population, criteria of definition, etc. At least one out of every three to four children below the age of 12 y have one ED. ED correlates with ferritin and poor compliance to therapy, but not all studies agree. Up to 86% of the adult population is affected by an ED. Age is a positive linear predictor for ED. Low IGF1 is found in 95% of the population with GH deficiency (GHD), but also in 93.6% of persons without GHD. HypoT is mostly pituitary-related; it is not clinically manifested in the majority of cases, hence the importance of TSH/FT4 screening. HypoT is found at any age, with the prevalence varying between 8.3% and 30%. Non-compliance to chelation increases the risk of hypoT, yet not all studies confirmed the correlation with chelation history (reversible hypoT under chelation is reported). The pitfalls of TSH interpretation due to hypophyseal IO should be taken into consideration. HypoPT prevalence varies from 6.66% (below the age of 12) to a maximum of 40% (depending on the study). Serum ferritin might act as a stimulator of FGF23. Associated hypocalcaemia transitions from asymptomatic to severe manifestations. HypoPT is mostly found in association with growth retardation and hypoGn. TED-associated adrenal dysfunction is typically mild; an index of suspicion should be considered due to potential life-threatening complications. Periodic check-up by ACTH stimulation test is advised. Adrenal insufficiency/hypocortisolism status is the rarest ED (but some reported a prevalence of up to one third of patients). Significantly, many studies did not routinely perform a dynamic test. Atypical EM sites might be found in adrenals, mimicking an incidentaloma. Between 7.5-10% of children with major BTH have DM; screening starts by the age of 10, and ferritin correlated with glycaemia. Larger studies found DM in up to 34%of cases. Many studies do not take into consideration IGF, IGT, or do not routinely include OGTT. Glucose anomalies are time dependent. Emerging new markers represent promising alternatives, such as insulin secretion-sensitivity index-2. The pitfalls of glucose profile interpretation include the levels of HbA1c and the particular risk of gestational DM. Thalassemia bone disease (TBD) is related to hypoGn-related osteoporosis, renal function anomalies, DM, GHD, malnutrition, chronic hypoxia-induced calcium malabsorption, and transplant-associated protocols. Low BMD was identified in both paediatric and adult population; the prevalence of osteoporosis/TBD in major BTH patients varies; the highest rate is 40-72% depending on age, studied parameters, DXA evaluation and corrections, and screening thoracic-lumbar spine X-ray. Lower TBS and abnormal dynamics of bone turnover markers are reported. The largest cohorts on transfusion-dependent BTH identified the prevalence of hypoGn to be between 44.5% and 82%. Ferritin positively correlates with pubertal delay, and negatively with pituitary volume. Some authors appreciate hypoGn as the most frequent ED below the age of 15. Long-term untreated hypoGn induces a high cardiovascular risk and increased FR. Hormonal replacement therapy is necessary in addition to specific BTH therapy. Infertility underlines TED-related hormonal elements (primary and secondary hypoGn) and IO-induced gonadal toxicity. Males with BTH are at risk of infertility due to germ cell loss. IO induces an excessive amount of free radicals which impair the quality of sperm, iron being a local catalyser of ROS. Adequate chelation might improve fertility issues. Due to the advances in current therapies, the reproductive health of females with major BTH is improving; a low level of statistical significance reflects the pregnancy status in major BTH (limited data on spontaneous pregnancies and growing evidence of the induction of ovulation/assisted reproductive techniques). Pregnancy outcome also depends on TED approach, including factors such as DM control, adequate replacement of hypoT and hypoPT, and vitamin D supplementation for bone health. Asymptomatic TED elements such as subclinical hypothyroidism or IFG/IGT might become overt during pregnancy. Endocrine glands are particularly sensitive to iron deposits, hence TED includes a complicated puzzle of EDs which massively impacts on the overall picture, including the quality of life in major BTH. The BTH prognostic has registered progress in the last decades due to modern therapy, but the medical and social burden remains elevated. Genetic counselling represents a major step in approaching TH individuals, including as part of the pre-conception assessment. A multidisciplinary surveillance team is mandatory.

Vitiligo and chronic autoimmune thyroiditis.

Vitiligo, the discoloration of the skin, has different autoimmune mechanisms reflected by many biomarkers as shown by skin histology, staining for CD4 and CD8 T lymphocytes, chemokine ligand 9 or circulating cytokines such as interleukin (IL)-1 beta, interferon (IFN)-gamma, transforming growth factor (TGF)-beta, antibodies, markers of oxidative stress, chemokines, and others. In this narrative review, we aim to overview vitiligo in relationship with chronic autoimmune thyroiditis. Regarding vitiligo, more than 50 different genetic loci have been associated with this disease, and the heritability is high. There is a 20% risk of an environmental connection which may also act as a trigger; moreover, the association with human leukocyte antigen (HLA) expression is well recognized. The specific lesions display CD8+ tissue-resident memory T cells as continuous key activators of melanocytes. The association with chronic thyroiditis is based on common autoimmune background and excessive reactive oxygen species that destroy melanocytes and thyrocytes (oxidative stress hypothesis) with thyroxine and melanin as target molecules, thus sharing a common origin: tyrosine. Moreover, common epigenetic anomalies or mutations of the Forkhead transcription factor D3 (FOXD3) have been described. Since vitiligo affects up to 1-2% of the population worldwide and 34% of patients have positive thyroid antibodies, apart from common autoimmunity background and oxidative stress toxicity, the association is clinically relevant for different practitioners.

Somatostatinoma: Beyond neurofibromatosis type 1 (Review).

Somatostatinoma is a tumour mainly originating from pancreas or duodenum; overall with an incidence of 1/40 million persons. We introduce a narrative review of literature of somatostatinoma including the relationship with neurofibromatosis type 1. Clinical presentation includes: Diabetes mellitus, cholelithiasis, steatorrhea, abdominal pain, and obstructive jaundice while papillary tumour may cause acute pancreatitis. The neoplasia may develop completely asymptomatic or it is detected as an incidental finding during an imaging or a surgical procedure. It may be sporadic or associated to genetic backgrounds especially for duodenal localisation as neurofibromatosis type 1 (NF1 gene with malfunction of RAS/MAPK pathway) or Pacak-Zhuang syndrome (EPAS1 gene encoding HIF). Surgery represents the central approach if feasible but the prognostic depends on location, and grading as indicated by WHO 2017 classification of neuroendocrine tumours. Previously known as Von Recklinghausen disease, neurofibromatosis type 1, the most frequent neurocutaneous syndrome, is an autosomal dominant disorder including: Café-au-lait spot, skin fold freckling on flexural zones, and neurofibromas as well as tumours such as gliomas of optic nerve, gastrointestinal stromal tumours (GISTs), iris hamartomas and brain tumours. Duodenal somatostatinoma is associated with the syndrome which actually involves more often a duodenal tumour of GIST type than a somatostatin secreting neoplasia. Other neuroendocrine tumours are reported: Gastrointestinal NENs at the level of rectum or jejunum and pheocromocytoma. Overall, one quarter of subjects have gastrointestinal tumours of different types. Somatostatinoma, when not located on pancreas but in duodenoum, may be registered in subjects with neurofibromatosis type 1 most probably in addition to other tumours. Overall, this type of neuroendocrine tumour with a challenging presentation has a poor prognosis unless adequate radical surgery is promptly offered to the patient.

Glucagonoma: From skin lesions to the neuroendocrine component (Review).

Glucagonoma is a hormonally active rare pancreatic neuroendocrine tumour causing an excess of glucagon. This is a narrative review based on a multidisciplinary approach of the tumour. Typically associated dermatosis is necrolytic migratory erythema (NME) which is most frequently seen at disease onset. Insulin-dependent diabetes mellitus, depression, diarrhoea, deep vein thrombosis are also identified, as parts of so-called 'D' syndrome. Early diagnosis is life saving due to potential aggressive profile and high risk of liver metastasis. NME as paraneoplastic syndrome may be present for months and even years until adequate recognition and therapy; it is remitted after successful pancreatic surgery. Thus the level of practitioners' awareness is essential. If surgery is not curative, debulking techniques may improve the clinical aspects and even the outcome in association with other procedures such as embolization of hepatic metastasis; ablation of radiofrequency type; medical therapy including chemotherapy, targeted therapy with mTOR inhibitors such as everolimus, PRRT (peptide receptor radiotherapy), and somatostatin analogues (including combinations of medical treatments). Increased awareness of the condition involves multidisciplinary practitioners.

Glucocorticoids and Trabecular Bone Score.

TBS (Trabecular Bone Score) is the latest tool for clinicians to evaluate bone micro-architecture based on a pixel greyscale, which is provided by lumbar dual-energy X-ray absorptiometry (DXA). Its use enhances fracture prediction in addition to DXA-BMD (Bone Mineral Density). This is independent of fracture risk assessment (FRAX) and DXA results. We present a narrative review regarding the connection between TBS and Glucocorticoids (GC), either as a drug used for different conditions or as a tumor-produced endogenous excess. TBS is a better discriminator for GC-induced vertebral fractures compared to DXA-BMD. This aspect is similarly available for patients with osteoporosis diagnosed by DXA. TBS is inversely correlated with the cumulative dose of GC (systemic or inhaled), with disease duration, and positively correlated with respiratory function in patients with asthma. Low TBS values are found in females with a T-score at the hip within the osteoporosis range, with diabetes mellitus, or who use GC. Lumbar TBS is a screening tool in menopausal women with type 2 diabetes mellitus. TBS is an independent parameter that provides information regarding skeleton deterioration in diabetic patients receiving GC therapy in a manner complementary to DXA-BMD. TBS might become an essential step regarding the adrenalectomy decision in patients with adrenal incidentaloma in whom autonomous cortisol secretion might damage bone micro-architecture. TBS currently represents a standard tool of fracture risk evaluation in patients receiving GC therapy or with endogenous Cushing's syndrome, a tool easy to be applied by different practitioners since GCs are largely used.

Current principles and practice of ethics and law in perinatal medicine.

One of the most controversial discussion topics in modern bioethics, science or philosophy is represented by the beginning of the individual human life. It is ethically, medically and scientifically correct that the human conception product to be born, so to gain personality and individuality, to be treated as a patient since the intrauterine life. Intrauterine foetal interventions, performed in various therapeutic purposes are still in the experimental stage even in centres with rich experience in perinatal medicine. Progresses truly outstanding are present especially in the prenatal diagnostic methods. Non invasive prenatal testing represents without a doubt a great progress in prenatal diagnosis, but from this point of view, the role of practitioners in the field of perinatal medicine, on counselling and addressing the indication of this test becomes essential. Beyond cultural, national, social or related differences, in perinatal medicine practice is particularly important to respect and permanently reassess the ethical codes. Our paper is targeting to spotlight the essential principles and practice of ethics and law in perinatal medicine nowadays on one hand, and to bring an update review on a controversial topic on the other hand.

The Place of the Ice Water Test (IWT) in the Evaluation of the Patients with Traumatic Spinal Cord Injury.

In the last decades, functional Urology developed itself as a subspecialty, and, although is strongly linked to Urology, it has its own language, devices and dedicated people. The ice water test (IWT) was first described in 1957 and gained its place in the armamentarium of functional urologists for the coming years. Now, when urodynamic devices are more and more complex and sensitive, when neuromodulation and neurostimulation are gaining popularity and with the terminology changes of the last decade, one can wonder if a 50 years old test may still be of some use. We performed a prospective study using the ice water test in 150 consecutive patients referred to us for urodynamics in order to identify if there is any improvement in the diagnostic process. The patients were referred for varied indications, but a large number of them were neurogenic, given the special profile of our unit. We classified the patients in four different groups and analyzed the data for each group. The results showed that, while there is no use of the IWT as a routine procedure, the test might prove extremely useful in selected cases.