Search

Background: Data on the prevalence and type of endocrine disorders in β-thalassemia intermedia (β-TI) patients are scarce. This multicenter study was designed to determine the prevalence of endocrine complications and the associated risk factors in a large group of β-TI patients. Methods: In this cross-sectional multicenter study, 726 β-TI patients, aged 2.5–80 years, registered at 12 thalassemic centers, from nine countries, were enrolled during 2017. In a subgroup of 522 patients (mean age 30.8 ± 12.1; range: 2.5–80 years) from Qatar, Iran, Oman, Cyprus, and Jordan detailed data were available. Results: Overall, the most prevalent complications were osteopenia/osteoporosis (22.3%), hypogonadism (10.1%), and primary hypothyroidism (5.3%). In the subgroup multivariate analysis, older age was a risk factor for osteoporosis (Odds ratio: 7.870, 95% CI: 4.729–13.099, P< 0.001), hypogonadism (Odds ratio: 6.310, 95% CI: 2.944–13.521, P< 0.001), and non-insulin-dependent diabetes mellitus (NIDDM; Odds ratio: 17.67, 95% CI: 2.217–140.968, P= 0.007). Splenectomy was a risk factor for osteoporosis (Odds ratio: 1.736, 95% CI: 1.012–2.977, P= 0.045). Hydroxyurea was identified as a “protective factor” for NIDDM (Odds ratio: 0.259, 95% CI: 0.074–0.902, P= 0.034). Conclusions: To the best of our knowledge, this is the largest cohort of β-TI patients with endocrine disorders evaluated in extremely heterogenic thalassemic populations for age, clinical, hematological, and molecular composition. The study demonstrates that endocrine complications are less common in patients with β-TI compared with β-TM patients. However, regular monitoring with timely diagnosis and proper management is crucial to prevent endocrine complications in β-TI patients.

The syndrome of inappropriate antidiuresis (SIAD), the commonest cause of hyponatraemia, is associated with significant morbidity and mortality. Tolvaptan, an oral vasopressin V2-receptor antagonist, leads through aquaresis to an increase in serum sodium concentration and is the only medication licenced in Europe for the treatment of euvolaemic hyponatraemia. Randomised controlled trials have shown that tolvaptan is highly efficacious in correcting SIAD-related hyponatraemia. Real-world data have confirmed the marked efficacy of tolvaptan, but they have also reported a high risk of overly rapid sodium increase in patients with a very low baseline serum sodium. The lower the baseline serum sodium, the higher the tolvaptan-induced correction rate occurs. Therefore, a lower starting tolvaptan dose of 7.5 mg has been evaluated in small cohort studies, demonstrating its efficacy, but it still remains unclear as to whether it can reduce the risk of overcorrection. Most international guidelines, except for the European ones, recommend tolvaptan as second-line treatment for SIAD after fluid restriction. However, the risk of unduly rapid sodium correction in combination with its high cost have limited its routine use. Prospective controlled studies are warranted to evaluate whether tolvaptan-related sodium increase can improve patient-related clinical outcomes, such as mortality and length of hospital stay in the acute setting or neurocognitive symptoms and quality of life in the chronic setting. In addition, the potential role of a low tolvaptan starting dose needs to be further explored. Until then, tolvaptan should mainly be used as second-line treatment for SIAD, especially when there is a clinical need for prompt restoration of normonatraemia. Tolvaptan should be used with specialist input according to a structured clinical pathway, including rigorous monitoring of electrolyte and fluid balance and, if needed, implementation of appropriate measures to prevent, or when necessary reverse, overly rapid hyponatraemia correction.

Recent studies suggest a possible association of hyponatremia with osteoporosis, falls and bone fractures. The objectives of this narrative review were to further explore this association and the related pathophysiological mechanisms and to suggest a practical approach to patients with osteoporosis or chronic hyponatremia in clinical practice. We conducted an extensive PubMed search until October 2022 with the combination of the following keywords: ‘hyponatremia’ or ‘sodium’ or ‘SIADH’ and ‘fractures’ or ‘bone’ or ‘osteoporosis’, as MeSH Terms. Review of numerous observational studies confirms a significant independent association of, even mild, hyponatremia with two- to three-fold increase in the occurrence of bone fractures. Hyponatremia is a risk factor for osteoporosis with a predilection to affect the hip, while the magnitude of association depends on the severity and chronicity of hyponatremia. Chronic hyponatremia also increases the risk for falls by inducing gait instability and neurocognitive deficits. Besides the detrimental impact of hyponatremia on bone mineral density and risk of falls, it also induces changes in bone quality. Emerging evidence suggests that acute hyponatremia shifts bone turnover dynamics towards less bone formation, while hyponatremia correction increases bone formation. The key unanswered question whether treatment of hyponatremia could improve osteoporosis and lower fracture risk highlights the need for prospective studies, evaluating the impact of sodium normalization on bone metabolism and occurrence of fractures. Recommendations for clinical approach should include measurement of serum sodium in all individuals with fracture or osteoporosis. Also, hyponatremia, as an independent risk factor for fracture, should be taken into consideration when estimating the likelihood for future fragility fracture and in clinical decision-making about pharmacological therapy of osteoporosis. Until it is proven that normalization of sodium can lower fracture occurrence, correcting hyponatremia cannot be universally recommended on this basis, but should be decided on a case-by-case basis.

The syndrome of inappropriate antidiuresis is often undertreated with most patients discharged with persistent hyponatraemia. This study tested the hypothesis that an endocrine input is superior to routine care in correcting hyponatraemia and can improve patient outcomes. This single-centre prospective-controlled intervention study included inpatients admitted at a UK teaching hospital, with serum sodium ≤ 127 mmol/l, due to syndrome of inappropriate antidiuresis over a 6-month period. The prospective intervention group (18 subjects with mean serum sodium 120.7 mmol/l) received prompt endocrine input, while the historical control group (23 patients with mean serum sodium 124.1 mmol/l) received routine care. The time needed for serum sodium increase ≥ 5 mmol/l was the primary endpoint. The intervention group achieved serum sodium rise by ≥5 mmol/l in 3.5 vs. 7.1 days in the control group (P= 0.005). In the intervention group, the mean total serum sodium increase was 12 mmol/l with only 5.8 % of patients discharged with serum sodium < 130 vs. 6.3 mmol/l increase (P< 0.001) and 42.1 % of the subjects discharged with serum sodium < 130 mmol/l in the control group (P= 0.012). The mean length of hospital stay in the intervention group (10.9 days) was significantly shorter than in the control group (14.5 days; P= 0.004).The inpatient mortality rate was 5.5 % in intervention arm vs. 17.4 % in control arm, but this difference was not statistically significant. Since the endocrine input improved time for correction of hyponatraemia and shortened length of hospitalisation, widespread provision of endocrine input should be considered.

No relevant conflicts of interest to declare.

The diagnosis of beta thalassemia intermedia (BTI) is mainly based on the severity of clinical phenotype. It is associated with a wide range of specific complications including extramedullary hematopoiesis, leg ulcers, gallstones, hypercoagulable state, pulmonary hypertension (PHT), endocrine disorders and osteoporosis. The commonest endocrine complication in beta thalassemia major (TM) patients is hypogonadism followed by hypothyroidism and diabetesbut the data on endocrine disorders in BTI patients are scarce. The aim of this study is to determine the prevalence of endocrine complications in a large series of BTI patients.