Endocrine dysfunction in homozygous beta-thalassemia: An underrecognized and undertreated consequence of prolonged survival

Abstract

The increasing longevity of patients with transfusion-dependent homozygous beta-thalassemia has brought endocrine complications to the forefront of long-term care. While iron overload remains a central mechanism, additional contributors such as hypothalamic dysfunction, neurosecretory disturbances, and chronic inflammation have been identified. Endocrine disorders including hypothyroidism, adrenal insufficiency, hypogonadotropic hypogonadism, hypoparathyroidism, osteoporosis, and growth axis impairment - are prevalent and often underdiagnosed. Diagnostic challenges include normal hormone levels in early stages, necessitating the use of dynamic endocrine testing and pituitary magnetic resonance imaging to detect subclinical dysfunction. Risk is modulated by sex, age, and chelation adherence. Early identification and proactive, multidisciplinary management of endocrine sequelae are essential in reducing morbidity and maintaining functional independence in this aging patient population.

Key Words: Thalassemia, Endocrine dysfunction; Iron overload; Hypogonadotropic hypogonadism; Adrenal insufficiency; Thyroid dysfunction; Bone disease

Core Tip: Endocrine dysfunction is a major source of long-term morbidity in transfusion-dependent beta-thalassemia. Subtle hypothalamic-pituitary axis abnormalities, such as neurosecretory growth hormone dysfunction and tertiary adrenal insufficiency, may precede overt clinical signs. Pituitary magnetic resonance imaging and dynamic hormone testing improve early detection. Integrating routine endocrine screening into thalassemia care enables timely interventions that can prevent irreversible complications and enhance quality of life.

TO THE EDITOR

We read with great interest the recent article by Dordevic et al[1], offering a valuable overview of the pathophysiology, diagnosis and the evolving therapeutic approaches in beta-thalassemia syndromes. As life expectancy improves, previously underrecognized complications - particularly of endocrine origin - are emerging as key determinants of long-term morbidity. Thus, following on the article by Dordevic et al[1], we would like to enrich this perspective by presenting an update on the spectrum of endocrine dysfunction in homozygous beta-thalassemia (hBT).

Thyroid dysfunction is one of the earliest recognized endocrine abnormalities in hBT. Both primary and central hypothyroidism are commonly reported, with an overall prevalence ranging from 15%-30% depending on age, transfusion burden, and adherence to chelation[2,3]. Iron-induced destruction of the thyroid gland can result in primary hypothyroidism, while hemosiderosis of the hypothalamic-pituitary axis contributes to central hypothyroidism. Notably, even in the absence of overt biochemical hypothyroidism, patients with serum ferritin > 2500 ng/mL often show subclinical abnormalities such as low-normal T4 and inappropriately low thyroid stimulating hormone, underscoring the need for sensitive screening protocols[3,4].

Although historically considered rare, adrenal insufficiency (AI) has been increasingly documented among patients with hBT. A recent meta-analysis demonstrated a pooled prevalence of 25.6%, with adult patients exceeding 51% positivity rates, particularly when using tetracosactrin stimulation[5]. Interestingly, testing methods significantly impact prevalence detection - glucagon stimulation and low-dose adrenocorticotropic hormone tests are more sensitive compared to single serum cortisol measurements. Huang et al[6] also reported that 92% of AI cases occurred in males, possibly due to differential hypothalamic sensitivity. Magnetic resonance imaging (MRI) data often show iron accumulation in the pituitary, yet patients exhibit normal adrenocorticotropic hormone responses to corticotropin-releasing hormone, suggesting hypothalamic dysfunction (tertiary AI) as a key pathogenic mechanism[6]. The implications are clinically relevant - undiagnosed AI may precipitate an adrenal crisis during surgery or infection. As such, annual dynamic testing should be strongly considered in adult patients or those with unexplained fatigue, hypotension, or poor stress tolerance.

Hypogonadotropic hypogonadism is the most prevalent endocrine complication in hBT, affecting up to 80% of adults and a significant proportion of adolescents[7,8]. Its pathophysiology includes iron deposition in the anterior pituitary, leading to reduced secretion of gonadotropins. Noetzli et al[9] demonstrated a strong inverse correlation between pituitary R2^× MRI values and volume with gonadotropin output, indicating early morphological and functional compromise. Clinically, patients present with delayed or arrested puberty, amenorrhea, infertility, or low libido. Notably, males appear to experience a more severe phenotype, with lower body mass index z-scores and bone density, suggesting a protective effect of estrogen in females[6]. Hormone replacement therapy, though effective, must be carefully individualized, especially in the presence of comorbidities such as cardiac iron overload or liver dysfunction.

Hypoparathyroidism is a rarer yet clinically significant complication in hBT, with reported prevalence between 4%-6%[10]. It results from iron toxicity to the parathyroid glands, while its clinical manifestations may be exacerbated by coexisting vitamin D deficiency and renal tubular dysfunction, both of which are not uncommon in transfusion-dependent patients. Hypocalcemia, tetany, perioral numbness, and seizures may occur. De Sanctis et al[10] noted that despite improved chelation, many adult patients still demonstrate latent hypocalcemia with low PTH levels, warranting lifelong surveillance. Correction of calcium-phosphate balance, adequate vitamin D repletion, and parathyroid hormone analogs are important management steps.

Bone complications remain a major cause of morbidity. More than 50% of hBT patients exhibit osteopenia or osteoporosis on dual-energy X-ray absorptiometry scan, driven by a multifactorial pathogenesis[11,12]. In addition to hypogonadism, chronic anemia causes marrow expansion and cortical thinning, while iron impairs osteoblast function. Notably, poor adherence to chelation therapy, reported in up to 43% of patients, has been strongly associated with more severe bone loss[13]. Sex differences are also notable - males exhibit more frequent and severe bone disease, potentially due to lower cumulative estrogen exposure. Clinical care should involve early screening, nutritional support, bisphosphonates in severe cases, and treatment of coexisting endocrine dysfunctions contributing to bone fragility.

Although not extensively studied, growth hormone (GH) deficiency and other anterior pituitary hormone deficits may occur in patients with transfusion-dependent thalassemia. Iron overload can affect the hypothalamus early, preceding overt pituitary dysfunction. GH axis impairment may manifest as persistently low serum insulin-like growth factor-1 (IGF-1) despite normal GH responses to stimulation tests - a pattern indicative of neurosecretory dysfunction, characterized by impaired spontaneous GH pulsatility despite preserved secretory reserve[14,15]. In such cases, 24-hour GH profiling or IGF-1 generation tests may reveal subclinical hypothalamic dysfunction[15,16]. Moreover, GH insensitivity, potentially related to chronic inflammation or hepatic siderosis, may further compromise IGF-1 synthesis[14]. These observations support a more comprehensive assessment of the somatotropic axis beyond conventional GH testing. Reduced growth velocity has been reported in pediatric patients with transfusion-dependent hBT, even in the presence of adequate transfusion and nutritional status, likely reflecting functional impairment of the somatotropic axis[14]. The potential role of MRI in early detection of hypothalamic-pituitary axis compromise should be further explored, as it may precede clinical hormone deficiencies[17-19].

The long-term endocrine sequelae in hBT are strongly influenced by therapeutic adherence, particularly to iron chelation. Table 1 summarizes the prevalence, pathophysiology, clinical features, diagnostics, and management considerations across endocrine axes affected in hBT. Locke et al[13] demonstrated adherence variability ranging from 57% to 98%, with non-adherence contributing to worse cardiac, hepatic, and endocrine outcomes[13]. Transitioning care from pediatric to adult clinics often results in fragmentation. We strongly support multidisciplinary teams including endocrinologists, hematologists, and reproductive specialists, with annual structured assessments covering thyroid, adrenal, gonadal, bone, and calcium metabolism. Moreover, early MRI screening of the pituitary and routine dynamic hormonal testing may allow pre-symptomatic intervention.

Table 1 Endocrine dysfunction in homozygous beta-thalassemia.

Endocrine axis	Prevalence key data	Pathophysiology	Clinical features	Diagnostic considerations	Management recommendations
Thyroid dysfunction	15%-30% (primary and central)	Iron-induced thyroid damage; pituitary hemosiderosis	Subclinical or overt hypothyroidism	Low-normal T4 and low/inappropriate TSH; ferritin > 2500 ng/mL	Annual screening; early detection protocols
AI	Pooled 25.6%; up to 51% in adults	Hypothalamic dysfunction (tertiary AI); pituitary iron deposition	Fatigue, hypotension, adrenal crisis risk	Dynamic testing (low-dose ACTH, glucagon > serum cortisol); males more affected (92%)	Annual testing in adults or symptomatic patients
Hypogonadotropic hypogonadism	Up to 80% in adults; common in adolescents	Pituitary iron overload leads to lower LH/FSH	Delayed puberty, amenorrhea, infertility, low libido	MRI pituitary R2× inverse correlation with function	Individualized HRT; monitor bone/cardiac/hepatic status
Hypoparathyroidism	4%-6%	Parathyroid iron toxicity; exacerbated by vitamin D deficiency and renal dysfunction	Hypocalcemia, tetany, perioral numbness, seizures	Low PTH; latent hypocalcemia despite chelation	Calcium-phosphate balance, vitamin D, PTH analogs
Bone disease (osteopenia/osteoporosis)	> 50%	Multifactorial: Anemia, hypogonadism, iron toxicity	Fragility fractures, bone pain	DXA scan; poor chelation linked to severity	Early DXA screening, bisphosphonates, endocrine optimization
GH axis dysfunction	Not well quantified; low IGF-1 with normal GH response to stimulation testing	Hypothalamic iron overload leads to neurosecretory dysfunction; GH insensitivity	Growth failure (children), low IGF-1	24 hours GH profile, MRI of hypothalamus-pituitary	Evaluate somatotropic axis; MRI for early changes
Contributing factors	Adherence to chelation therapy	Variability: 57%-98% adherence	Influences all endocrine outcomes	Fragmented care post-transition	Multidisciplinary annual assessment: Endocrine, hematology, reproductive care

AI: Adrenal insufficiency; TSH: Thyroid stimulating hormone; ACTH: Adrenocorticotropic hormone; LH: Luteinizing hormone; FSH: Follicular stimulating hormone; MRI: Magnetic resonance imaging; HRT: Hormone replacement therapy; PTH: Parathormone; DXA: Dual-energy X-ray absorptiometry; IGF-1: Insulin-like growth factor-1; GH: Growth hormone.

CONCLUSION

In conclusion, as survival in hBT improves, comprehensive endocrine care becomes indispensable. The article by Dordevic et al[1] offers a timely opportunity to re-emphasize the importance of structured screening and management of endocrine complications. Recognition of early subclinical dysfunction, adoption of dynamic testing protocols, and reinforcement of chelation adherence will help preserve quality of life in this unique population.