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.

Hungry bone syndrome (HBS), severe hypocalcemia following parathyroidectomy (PTX) due to rapid drop of PTH (parathormone) after a previous long term elevated concentration in primary (PHPT) or renal hyperparathyroidism (RHPT), impairs the outcome of underlying parathyroid disease. Objective: overview HBS following PTx according to a dual perspective: pre- and post-operative outcome in PHPT and RHPT. This is a case- and study-based narrative review. Inclusion criteria: key research words “hungry bone syndrome” and “parathyroidectomy”; PubMed access; in extenso articles; publication timeline from Inception to April 2023. Exclusion criteria: non-PTx-related HBS; hypoparathyroidism following PTx. We identified 120 original studies covering different levels of statistical evidence. We are not aware of a larger analysis on published cases concerning HBS (N = 14,349). PHPT: 14 studies (N = 1545 patients, maximum 425 participants per study), and 36 case reports (N = 37), a total of 1582 adults, aged between 20 and 72. Pediatric PHPT: 3 studies (N = 232, maximum of 182 participants per study), and 15 case reports (N = 19), a total of 251 patients, aged between 6 and 18. RHPT: 27 studies (N = 12,468 individuals, the largest cohort of 7171) and 25 case reports/series (N = 48), a total of 12,516 persons, aged between 23 and 74. HBS involves an early post-operatory (emergency) phase (EP) followed by a recovery phase (RP). EP is due to severe hypocalcemia with various clinical elements (<8.4 mg/dL) with non-low PTH (to be differentiated from hypoparathyroidism), starting with day 3 (1 to 7) with a 3-day duration (up to 30) requiring prompt intravenous calcium (Ca) intervention and vitamin D (VD) (mostly calcitriol) replacement. Hypophosphatemia and hypomagnesiemia may be found. RP: mildly/asymptomatic hypocalcemia controlled under oral Ca+VD for maximum 12 months (protracted HBS is up to 42 months). RHPT associates a higher risk of developing HBS as compared to PHPT. HBS prevalence varied from 15% to 25% up to 75–92% in RHPT, while in PHPT, mostly one out of five adults, respectively, one out of three children and teenagers might be affected (if any, depending on study). In PHPT, there were four clusters of HBS indicators. The first (mostly important) is represented by pre-operatory biochemistry and hormonal panel, especially, increased PTH and alkaline phosphatase (additional indicators were elevated blood urea nitrogen, and a high serum calcium). The second category is the clinical presentation: an older age for adults (yet, not all authors agree); particular skeleton involvement (level of case reports) such as brown tumors and osteitis fibrosa cystica; insufficient evidence for the patients with osteoporosis or those admitted for a parathyroid crisis. The third category involves parathyroid tumor features (increased weight and diameter; giant, atypical, carcinomas, some ectopic adenomas). The fourth category relates to the intra-operatory and early post-surgery management, meaning an associated thyroid surgery and, maybe, a prolonged PTx time (but this is still an open issue) increases the risk, as opposite to prompt recognition of HBS based on calcium (and PTH) assays and rapid intervention (specific interventional protocols are rather used in RHPT than in PHPT). Two important aspects are not clarified yet: the use of pre-operatory bisphosphonates and the role of 25-hydroxyitamin D assay as pointer of HBS. In RHPT, we mentioned three types of evidence. Firstly, risk factors for HBS with a solid level of statistical evidence: younger age at PTx, pre-operatory elevated bone alkaline phosphatase, and PTH, respectively, normal/low serum calcium. The second group includes active interventional (hospital-based) protocols that either reduce the rate or improve the severity of HBS, in addition to an adequate use of dialysis following PTx. The third category involves data with inconsistent evidence that might be the objective of future studies to a better understanding; for instance, longer pre-surgery dialysis duration, obesity, an elevated pre-operatory calcitonin, prior use of cinalcet, the co-presence of brown tumors, and osteitis fibrosa cystica as seen in PHPT. HBS remains a rare complication following PTx, yet extremely severe and with a certain level of predictability; thus, the importance of being adequately identified and managed. The pre-operatory spectrum of assessments is based on biochemistry and hormonal panel in addition to a specific (mostly severe) clinical presentation while the parathyroid tumor itself might provide useful insights as potential risk factors. Particularly in RHPT, prompt interventional protocols of electrolytes surveillance and replacement, despite not being yet a matter of a unified, HBS-specific guideline, prevent symptomatic hypocalcemia, reduce the hospitalization stay, and the re-admission rates.

Bone fragility is a complication of type 2 diabetes mellitus (T2DM) that has been identified in recent decades. Trabecular bone score (TBS) appears to be more accurate than bone mineral density (BMD) in diabetic bone disease, particularly in menopausal women with T2DM, to independently capture the fracture risk. Our purpose was to provide the most recent overview on TBS-associated clinical data in T2DM. The core of this narrative review is based on original studies (PubMed-indexed journals, full-length, English articles). The sample-based analysis (n = 11, N = 4653) confirmed the use of TBS in T2DM particularly in females (females/males ratio of 1.9), with ages varying between 35 and 91 (mean 65.34) years. With concern to the study design, apart from the transversal studies, two others were prospective, while another two were case-control. These early-post-pandemic data included studies of various sample sizes, such as: males and females (N of 245, 361, 511, and 2294), only women (N of 80, 96, 104, 243, 493, and 887), and only men (N = 169). Overall, this 21-month study on published data confirmed the prior profile of BMD-TBS in T2DM, while the issue of whether checking the fracture risk is mandatory in adults with uncontrolled T2DM remains to be proven or whether, on the other hand, a reduced TBS might function as a surrogate marker of complicated/uncontrolled T2DM. The interventional approach with bisphosphonates for treating T2DM-associated osteoporosis remains a standard one (n = 2). One control study on 4 mg zoledronic acid showed after 1 year a statistically significant increase of lumbar BMD in both diabetic and non-diabetic groups (+3.6%, p = 0.01 and +6.2%, p = 0.01, respectively). Further studies will pinpoint additive benefits on glucose status of anti-osteoporotic drugs or will confirm if certain glucose-lowering regimes are supplementarily beneficial for fracture risk reduction. The novelty of this literature research: these insights showed once again that the patients with T2DM often have a lower TBS than those without diabetes or with normal glucose levels. Therefore, the decline in TBS may reflect an early stage of bone health impairment in T2DM. The novelty of the TBS as a handy, non-invasive method that proved to be an index of bone microarchitecture confirms its practicality as an easily applicable tool for assessing bone fragility in T2DM.

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.

Thyroid hormones are required for the physiological growth and maintenance of hair follicles. We aim to study the thyroid profile of patients with alopecia. This is a narrative review. PubMed literature was searched from 2013 to 2022. We followed different types of alopecia: alopecia areata (AA), androgenic alopecia in males and females, telogen effluvium (TE), frontal fibrosing alopecia (FFA), lichen planopilaris, and alopecia neoplastica (AN). AA shares a common autoimmune background with autoimmune thyroid diseases, either sporadic or belonging to autoimmune polyglandular syndromes. Some data suggested that AA is more severe if thyroid anomalies are confirmed, including subclinical dysfunction or positive antithyroid antibodies with normal hormone values. However, routine thyroid screening for patients with AA, if the patients are asymptomatic from a thyroid point of view and they have negative personal and family history of autoimmunity, remains controversial. TE, apart from the autoimmune type, associates thyroid anomalies of a hormonal assay (between 5.7% and 17%). FFA, mostly a postmenopausal entity (however, not exclusive), associates a higher prevalence of thyroid conditions (up to 50%) than the general population. However, these might have an age-dependent pattern, thus the association may be incidental since there are a limited number of studies. Overall, alopecia remains a very challenging condition for patients and physicians; a multidisciplinary team is required to improve the outcome and quality of life. The common autoimmune background is suggestive of some types of alopecia and thyroid disorders, yet, the underlying mechanisms are still a matter of debate. AA, TE, FFA, LPP, and, potentially, female pattern hair loss have been found to be connected with thyroid entities, thus a state of awareness from a dual perspective, of trichology and endocrinology, is helpful.

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