Clinical utility of endocrine markers predicting myocardial siderosis in transfusion dependent thalassemia major

Ehsan, Lubaina; Rashid, Mariam; Alvi, Najveen; Awais, Khadija; Nadeem, Omair; Asghar, Aleezay; Sajjad, Fatimah; Fatima, Malika; Qidwai, Asim; Hussain, Shabneez; Hasan, Erum; Brown, Nick; Altaf, Sadaf; Hasan, Babar; Kirmani, Salman

doi:10.1002/pbc.27285

Cited by 5 publications

(11 citation statements)

References 29 publications

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“…The high prevalence of this endocrine disease in β-TM patients is well known, usually presenting as hypogonadotropic hypogonadism due to the hemosiderosis of the gonadotroph cells, which is directly connected to the iron-overload severity and rarely reversible [17,18]. It may have a strong influence on the development of metabolic syndrome, altering hormonal levels [19]; previous studies have shown how hypogonadism might be associated with more severe cardiac siderosis, representing not only a risk factor for but also a marker of established cardiac disease [12,15].…”

Section: Discussionmentioning

confidence: 99%

“…Cardiac disease still remains a major concern, with many efforts taking place to explore early cardiac dysfunction [8,9]. Furthermore, increased inflammation due to iron-overload pathophysiology could accelerate the atherosclerotic process, while juvenile diabetes and endocrine alterations may set in earlier than in non-thalassemic people [10][11][12]. In order to assess the cardiovascular risk of beta-thalassemic patients, we evaluated the distribution and prevalence of cardiovascular risk factors and their relationship with observed cardiovascular events and endocrine status.…”

Section: Introductionmentioning

confidence: 99%

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The Influence of Cardiovascular Risk Factors and Hypogonadism on Cardiac Outcomes in an Aging Population of Beta-Thalassemia Patients

Barbero

Ajassa

Gaglioti

et al. 2021

JCDD

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Beta-thalassemia major (β-TM) is a hereditary genetic disease worsened by many comorbidities due to transfusion-related iron despite chelation therapy. Since there has recently been an increase in life expectancy of patients to up to 50 years old, which influences the prevalence of these diseases and the time span for traditional cardiovascular risk factors to play their role, this study aims to evaluate their distribution and prevalence in a population of thalassemia major patients and their relationship with observed cardiovascular events and potential modifying factors. One hundred and fifty-nine β-TM patients with at least 15 years of follow-up were included in this study. The mean age was 40.9 ± 8.4 years; 28% had diabetes mellitus and 62% had hypogonadism. The cardiovascular risk assessed using algorithms (CUORE and Pooled Cohort Risk Equation—PCRE) was low, but 3.8% of patients had at least one episode of heart failure, 35.9% showed early signs of heart failure, 22% received a diagnosis of diastolic dysfunction, and 21.4% showed supraventricular arrhythmias. Hypogonadism was shown to be related to the occurrence of cardiovascular events. The chronic accumulation of iron in the heart and the specific metabolic profile, mainly observed in patients with hypogonadism, allows us to define β-TM as a condition with a high level of cardiovascular risk from many points of view (iron-related myopathy, atherosclerosis and arrhythmias), which requires better stratification tools and a specific follow-up program.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Influence of Cardiovascular Risk Factors and Hypogonadism on Cardiac Outcomes in an Aging Population of Beta-Thalassemia Patients

Barbero

Ajassa

Gaglioti

et al. 2021

JCDD

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“…Transfusion-related infections such as hepatitis C, hepatitis B and HIV (confirmed by serological testing) were reported to be highest in the group with severe disease. Details of the endocrine complications noted in this collaborative have been previously reported by Ehsan et al 19…”

Section: Resultsmentioning

confidence: 64%

“…Apart from cardiac complications, little work has been done in the Pakistani TDT population with regard to endocrine complications 31. As the presence of hypogonadism and stunting showed high sensitivity (90% and 80%, respectively) in predicting severe iron overload in our population, Tanner staging and basic anthropometry can be used as a cheap yet reliable alternative to predict severity of iron overload in resource-limited settings 19. The documentation of signs, symptoms, laboratory parameters and medications noted in this collaborative will provide us with the ability to make meaningful interpretations regarding surrogate indicators of management of patients with TDT in our population.…”

Section: Discussionmentioning

confidence: 92%

Establishment of a thalassaemia major quality improvement collaborative in Pakistan

et al. 2019

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ObjectivesThe aim of this study was to establish multidisciplinary care for patients with transfusion-dependent thalassaemia (TDT) by creating a TDT quality improvement (QI) collaborative in a resource-constrained setting. This study presents our initial experience of creating this collaborative, the baseline characteristics of the participants, the proposed QI interventions and the outcome metrics of the collaborative.Design and settingTDT QI collaborative is a database comprising patients with TDT from four centres in Karachi, Pakistan. Study variables included symptoms of cardiac or endocrine dysfunction, physical examination including anthropometry and Tanner staging, chelation therapy, results of echocardiography, T2* cardiac MRI (CMR) and serum ferritin. The main outcome of this collaborative was improvement in TDT-related morbidity and mortality. Interventions addressing the key drivers of outcome were designed and implemented.ResultsAt the time of reporting, the total number of patients in this database was 295. Most patients reported cardiac symptoms corresponding to New York Heart Association class 2. Approximately half (52%, n=153) of the patients demonstrated severe myocardial iron overload (T2* <10 ms). Majority of the patients (58%, n=175) were not on adequate chelation therapy. There was no difference in echocardiographic measures of systolic and diastolic left ventricle among the different spectrums of iron overloaded myocardium.ConclusionUsing T2* CMR and endocrine testing, we have identified significant burden of iron siderosis in our patients with TDT. Lack of adequate iron load assessment and standardised management was observed. Interventions designed to target these key drivers of outcome are the unique part of this QI-based TDT registry.

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“…The keywords of research are “beta-thalassemia” in combination with one of the following: “endocrine”, “fertility”, respective “pregnancy”; but, also, “hypogonadism”, “thyroid”, “TSH”, “parathyroid”, “parathormone”, “stature”, “puberty”, “pituitary”, “diabetes”, “glycaemia”, “fracture”, “TBS”, “DXA”, “ACTH”, “osteoporosis”, “osteopenia”, or “adrenal”. Core endocrine descriptive analysis as displayed in Table 1 was restricted to clinical studies with different levels of statistical evidence, in both paediatric and adult population with major BTH, including more than 40 participants/study aiming two types of data: the ratio of EDs among the general panel of complications; and correlations between EDs and other specific parameters of evaluation in BTH (we included 1 longitudinal study, 15 cross-sectional studies, 1 retrospective analysis, 1 cohort study, 2 meta-analysis, and 2 surveys) [ 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ] ( Table 1 ).…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2022

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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.

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Clinical utility of endocrine markers predicting myocardial siderosis in transfusion dependent thalassemia major

Cited by 5 publications

References 29 publications

The Influence of Cardiovascular Risk Factors and Hypogonadism on Cardiac Outcomes in an Aging Population of Beta-Thalassemia Patients

The Influence of Cardiovascular Risk Factors and Hypogonadism on Cardiac Outcomes in an Aging Population of Beta-Thalassemia Patients

Establishment of a thalassaemia major quality improvement collaborative in Pakistan

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

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