• Anaemia
• Paediatric hepatology
• Paediatric nephrology

• Humans
• Child
• Cross-Sectional Studies
• Female
• Sri Lanka/epidemiology
• Male
• Adolescent
• Child, Preschool
• beta-Thalassemia/complications
• beta-Thalassemia/physiopathology
• beta-Thalassemia/therapy
• Infant
• Hepatomegaly/etiology
• Hepatomegaly/epidemiology
• Liver/physiopathology
• Alanine Transaminase/blood
• Kidney/physiopathology

• Anaemia
• Haemoglobinopathy
• Iron deficiency
• Nutritional anaemia
• Thalassaemia

Hydroxyurea is an antimetabolite drug that induces fetal haemoglobin in sickle cell disease. However, its clinical usefulness in β-thalassaemia is unproven. We conducted a randomised, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of hydroxyurea in transfusion-dependent β-thalassaemia. Sixty patients were assigned 1:1 to oral hydroxyurea 10–20 mg/kg/day or placebo for 6 months by stratified block randomisation. Hydroxyurea treatment did not alter the blood transfusion volume overall. However, a significantly higher proportion of patients on hydroxyurea showed increases in fetal haemoglobin percentage (89% vs. 59%; p < 0.05) and reductions in erythropoietic stress as measured by soluble transferrin receptor concentration (79% vs. 40%; p < 0.05). Based on fetal haemoglobin induction (> 1.5%), 44% of patients were identified as hydroxyurea-responders. Hydroxyurea-responders, required significantly lower blood volume (77 ± SD27ml/kg) compared to hydroxyurea-non-responders (108 ± SD24ml/kg; p < 0.01) and placebo-receivers (102 ± 28ml/kg; p < 0.05). Response to hydroxyurea was significantly higher in patients with HbE β-thalassaemia genotype (50% vs. 0%; p < 0.01) and Xmn1 polymorphism of the γ-globin gene (67% vs. 27%; p < 0.05). We conclude that oral hydroxyurea increased fetal haemoglobin percentage and reduced erythropoietic stress of ineffective erythropoiesis in patients with transfusion-dependent β-thalassaemia. Hydroxyurea reduced the transfusion burden in approximately 40% of patients. Response to hydroxyurea was higher in patients with HbE β-thalassaemia genotype and Xmn1 polymorphism of the γ-globin gene.

Chelation is the mainstay of therapy in certain pediatric liver diseases. Copper and iron related disorders require chelation. Wilson’s disease (WD), one of the common causes of cirrhosis in children is treated primarily with copper chelating agents like D-penicillamine and trientine. D-Penicillamine though widely used due its high efficacy in hepatic WD is fraught with frequent adverse effects resulting discontinuation. Trientine, an alternative drug has comparable efficacy in hepatic WD but has lower frequency of adverse effects. The role of ammonium tetra-thiomolybdate is presently experimental in hepatic WD. Indian childhood cirrhosis is related to excessive copper ingestion, rarely seen in present era. D-Penicillamine is effective in the early part of this disease with reversal of clinical status. Iron chelators are commonly used in secondary hemochromatosis of liver in hemolytic anemias. There are strict chelation protocols during bone marrow transplant. The role of iron chelation in neonatal hemochromatosis is presently not in vogue due to its poor efficacy and availability of other modalities of therapy. Hereditary hemochromatosis is rare in children and the use of iron chelators in this condition is limited.

• Wilson’s disease
• D-Penicillamine
• Trientine
• Indian childhood cirrhosis
• Deferoxamine
• Deferasirox
• Hemochromatosis

• CRISPR/Cas9
• IOX1
• genome editing
• vorinostat
• α-globin
• α-thalassaemia
• β-thalassaemia

Hydroxyurea is one of the earliest drugs that showed promise in the management of haemoglobinopathies that include β-thalassaemia and sickle cell disease. Despite this, many aspects of hydroxyurea are either unknown or understudied; specifically, its usefulness in β-thalassaemia major and haemoglobin E β-thalassaemia is unclear. However, during COVID-19 pandemic, it has become a valuable adjunct to transfusion therapy in patients with β-haemoglobinopathies. In this review, we aim to explore the available in vitro and in vivo mechanistic data and the clinical utility of hydroxyurea in β-haemoglobinopathies with a special emphasis on its usefulness during the COVID-19 pandemic.

Hydroxyurea is an S-phase-specific drug that reversibly inhibits ribonucleoside diphosphate reductase enzyme which catalyses an essential step in the DNA biosynthesis. In human erythroid cells, it induces the expression of γ-globin, a fetal globin gene that is suppressed after birth. Through several molecular pathways described in this review, hydroxyurea exerts many favourable effects on the haemoglobin content, red blood cell indices, ineffective erythropoiesis, and blood rheology in patients with β-haemoglobinopathies. Currently, it is recommended for sickle cell disease and non-transfusion dependent β-thalassaemia. A number of clinical trials are ongoing to evaluate its usefulness in transfusion dependent β-thalassaemia. During the COVID-19 pandemic, it was widely used as an adjunct to transfusion therapy due to limitations in the availability of blood and logistical disturbances. Thus, it has become clear that hydroxyurea could play a remarkable role in reducing transfusion requirements of patients with haemoglobinopathies, especially when donor blood is a limited resource.

Hydroxyurea is a well-tolerated oral drug which has been in use for many decades. Through its actions of reversible inhibition of ribonucleoside diphosphate reductase enzyme and fetal haemoglobin induction, it exerts many favourable effects on patients with β-haemoglobinopathies. It is currently approved for the treatment of sickle cell disease and non-transfusion dependent β-thalassaemia. Also, there are various observations to suggest that hydroxyurea is an important adjunct in the treatment of transfusion dependent β-thalassaemia which should be confirmed by randomised clinical trials.

• Blood transfusion
• COVID-19
• Haemoglobinopathies
• Hydroxyurea
• Ribonucleoside diphosphate reductase
• Sickle cell disease
• Thalassaemia
• γ-Globin induction

• anaemia
• clinical trials
• genetics
• haematopathology

• Adolescent
• Adult
• Double-Blind Method
• Humans
• Hydroxyurea
• Quality of Life
• Randomized Controlled Trials as Topic
• Sri Lanka
• Thalassemia
• beta-Thalassemia/drug therapy

• National Research Council Sri Lanka

Thalassaemia is a chronic disease which requires lifelong treatment in a majority. Despite recent advances in the medical care, minimal attempts are made to improve psychological health in these patients. In this study, we aim to describe the psychological morbidity in patients with transfusion dependent β-thalassaemia and their mothers in Sri Lanka.

This case control study was conducted in the three largest thalassaemia centres of Sri Lanka. All patients with transfusion dependent β-thalassaemia aged 4–18 years were recruited as cases whilst a randomly selected group of children without chronic diseases were recruited as controls. Psychological morbidity of children was assessed using the Strengths and Difficulties Questionnaire and depressive symptoms of mothers was assessed by the Centre for Epidemiological Studies Depression Scale.

288 transfusion dependent β-thalassaemia patients and equal number of controls were recruited. Abnormal emotional, conduct, hyperactivity and peer relationship symptom scores were reported by 18%, 17%, 9% and 14% of patients with thalassaemia respectively. Prevalences of abnormal psychological symptom scores in all domains were significantly higher among patients compared to controls. Abnormal conduct symptoms were significantly more prevalent among patients with HbE β-thalassaemia and those with suboptimal pretransfusion haemoglobin levels, lower transfusion volumes, hypothyroidism and undernutrition. Short stature was associated with abnormal emotional and hyperactivity scores. Depressive symptoms were significantly higher among mothers of patients with thalassaemia. Higher depressive symptom scores in mothers were significantly associated with abnormal emotional, conduct and peer relationship symptom scores in children.

A higher proportion of patients with transfusion dependent β-thalassaemia had abnormal psychological symptom scores. Abnormal conduct symptoms were more prevalent among patients with HbE β-thalassaemia, those who were inadequately transfused and having hypothyroidism and undernutrition. Mothers of the children with transfusion dependent β-thalassaemia had significantly higher depressive symptoms which were significantly associated with psychological symptoms among children.

Thalassaemia is a chronic disease without an effective cure in a majority. The clinical management has improved considerably during recent years; however, minimal attempts are made to up lift the quality of life among patients, especially in developing countries. Here we aim to describe and compare and to determine factors associated with health related quality of life among patients with transfusion dependent β-thalassaemia major and haemoglobin E β-thalassemia in Sri Lanka.

A case control study was conducted in the three largest thalassaemia centres of Sri Lanka. All patients with transfusion dependent β-thalassaemia (β-thalassaemia major and haemoglobin E β-thalassaemia) aged 5–18 years were recruited as cases whilst a randomly selected group of children without chronic diseases were recruited as controls. Socio-demographic and clinical data were collected using an interviewer-administered questionnaire and health related quality of life was measured using the validated Paediatric Quality of Life Inventory Version 4.0.

Two hundred and seventy one patients with transfusion dependent β-thalassaemia (male-49.1%; mean age- 10.9 ± 3.6 years) and 254 controls (male-47.2%; mean age- 10.4 ± 3.5 years) were recruited. Mean health-related quality of life scores were significantly lower in patients compared to controls (72.9 vs. 91.5, p < 0.001). Of the patients, 224 (84%) had β-thalassaemia major and 43 (16%) had haemoglobin E β-thalassaemia. Quality of life scores in psychological health (p < 0.05), emotional functioning (p < 0.05) and social functioning (p < 0.05) were significantly lower in patients with haemoglobin E β-thalassaemia compared to β-thalassaemia major. Splenectomy (p < 0.05), short stature (p < 0.05), under nutrition (p < 0.05) and longer hospital stays (p < 0.05) were significantly associated with lower quality of life scores.

Despite improvements in management, the quality of life among patients with β-thalassaemia still remains low. This is more pronounced in the subset of patients with haemoglobin E β-thalassaemia. Splenectomy, short stature, undernutrition and longer hospital stays were significantly associated with poor quality of life. It is timely, even in developing countries, to direct emphasis and to take appropriate steps to improve standards of living and quality of life of patients with β-thalassaemia.

• Haemoglobin E β-thalassaemia
• Quality of life
• Thalassaemia
• Transfusion
• β-Thalassaemia major

• Beta-thalassemia major
• hemoglobinopathies
• thalassemia
• transfusion

This cross sectional study aims to describe the body iron status, trends of serum ferritin and associations of optimal body iron control in patients aged below 16 years with transfusion dependent β-thalassaemia attending Paediatric and Adolescent Thalassaemia Centres of the Colombo North Teaching Hospital of Sri Lanka.

Out of 54 children, 51% were males and a majority were aged 11–16 years; 83% had β-thalassaemia major while 13% had HbE β-thalassaemia. Mean serum ferritin was 1778(± 1458) µg/l and 29% had optimal serum ferritin (below 1000 µg/l). Trend of mean serum ferritin over time showed gradual decline between 2011 and 2017 and longitudinal trend of individual patients at yearly intervals showed gradual rise until 5 years of age and plateauing thereafter. All except two patients were receiving iron chelator medication of which the most commonly used was oral deferasirox (92%). The most common iron-related complications were short stature (24.1%) and pubertal delay (42.8% of > 14 years). None of the patients had hypothyroidism, hypoparathyroidism or diabetes. Optimal serum ferritin levels were significantly associated with the diagnosis of thalassaemia at a later age (23.6 vs 9.0 months) and higher family income (OR-4.81;95%CI 1.17–19.67) however was not associated with the age of the patient or duration of transfusion.

The online version of this article (10.1186/s13104-018-3634-9) contains supplementary material, which is available to authorized users.

• Chelation
• Iron overload
• Serum ferritin
• Transfusion dependent β-thalassaemia