Overview
Definition:
Thalassemia is a group of inherited blood disorders characterized by reduced or absent synthesis of globin chains, leading to ineffective erythropoiesis and hemolytic anemia
Thalassemia major (Cooley's anemia) is the most severe form, typically presenting in infancy with severe anemia requiring lifelong blood transfusions
Thalassemia intermedia is a milder form, with variable severity, often presenting later in childhood or adulthood and may not always require regular transfusions but can necessitate them with certain triggers or complications.
Epidemiology:
Thalassemia is prevalent worldwide, particularly in Mediterranean, Middle Eastern, South Asian, and Southeast Asian populations
India has a high burden of thalassemia carriers
Beta-thalassemia is more common than alpha-thalassemia
Thalassemia major is a significant cause of chronic anemia in children in endemic regions
The incidence of thalassemia major is estimated to be around 10,000-12,000 births annually in India
Thalassemia intermedia accounts for a substantial proportion of patients with milder phenotypes.
Clinical Significance:
Understanding the distinct clinical spectrum and management needs of thalassemia intermedia and major is critical for pediatricians
Inappropriate transfusion strategies can lead to severe complications such as iron overload, cardiac dysfunction, endocrine deficiencies, and bone disease
Early and accurate diagnosis, coupled with judicious use of transfusions and chelation therapy, significantly impacts long-term outcomes and quality of life for affected children, a key focus for DNB and NEET SS examinations.
Clinical Presentation
Symptoms:
Thalassemia Major: Severe pallor from early infancy
Poor feeding and failure to thrive
Jaundice
Abdominal distension due to hepatosplenomegaly
Skeletal deformities (e.g., frontal bossing, maxillary hypoplasia) developing by 6-12 months of age
Thalassemia Intermedia: Milder pallor, often presenting later in childhood or adolescence
Fatigue and reduced exercise tolerance
Splenomegaly
Possible mild skeletal changes
Increased susceptibility to infections.
Signs:
Thalassemia Major: Profound pallor
Icterus
Marked hepatosplenomegaly
Facial and long bone deformities
Growth retardation
Cardiac murmurs due to high-output failure
Thalassemia Intermedia: Moderate pallor
Palpable spleen and liver
Sometimes bony changes are less pronounced
May exhibit signs of extramedullary hematopoiesis (e.g., paraspinal masses).
Diagnostic Criteria:
Diagnosis is based on clinical suspicion, peripheral blood smear showing microcytic hypochromic anemia with target cells, poikilocytosis, and nucleated red blood cells
Confirmatory diagnosis is made by hemoglobin electrophoresis, demonstrating absent or reduced HbA and increased HbF and HbA2
Genetic testing can confirm specific mutations
A homozygous or compound heterozygous state for beta-globin gene mutations defines thalassemia major or intermedia based on phenotype.
Diagnostic Approach
History Taking:
Detailed family history of anemia or blood disorders
Age of onset of symptoms
History of blood transfusions and response
Nutritional history
Presence of symptoms suggestive of complications like bone pain, abdominal pain, or developmental delays
Recent infections or febrile episodes.
Physical Examination:
Assess for pallor, jaundice, and hepatosplenomegaly
Examine for skeletal abnormalities (e.g., Mongolian slant, malocclusion, prominent forehead)
Evaluate growth parameters (height, weight, head circumference)
Auscultate heart for murmurs and signs of heart failure
Palpate abdomen for liver and spleen size and consistency
Assess for signs of extramedullary hematopoiesis.
Investigations:
Complete Blood Count (CBC): Severe anemia (Hb < 7-8 g/dL in major, 7-10 g/dL in intermedia), microcytosis (MCV < 70 fL), hypochromia (MCH < 27 pg)
Peripheral smear: Target cells, anisopoikilocytosis, basophilic stippling, nucleated RBCs
Hemoglobin Electrophoresis: Crucial for diagnosis and differentiating subtypes
Shows elevated HbF, HbA2, and reduced/absent HbA
Serum ferritin: To assess iron stores and monitor iron overload
Liver function tests (LFTs) and Renal function tests (RFTs)
Echocardiography: To assess cardiac function and iron deposition in the heart
Endocrine evaluations (thyroid, pituitary, gonadal function)
Bone densitometry.
Differential Diagnosis:
Other causes of microcytic hypochromic anemia: Iron deficiency anemia (distinguished by low serum ferritin and normal Hb electrophoresis)
Anemia of chronic disease
Sideroblastic anemia
Alpha-thalassemia trait
Glucose-6-phosphate dehydrogenase (G6PD) deficiency.
Management
Transfusion Thresholds:
Thalassemia Major: The primary goal is to maintain a pre-transfusion hemoglobin level of at least 9-10.5 g/dL, typically aiming for a post-transfusion Hb of 12-14 g/dL
This usually involves regular transfusions every 2-4 weeks
This prevents chronic severe anemia, stimulates erythropoiesis, suppresses ineffective erythropoiesis, and mitigates extramedullary hematopoiesis and bone deformities
Thalassemia Intermedia: Transfusion thresholds are more individualized
Transfusions are generally indicated when pre-transfusion Hb drops below 7-8 g/dL, or in the presence of significant symptoms of anemia, poor growth, extramedullary hematopoiesis, leg ulcers, or if approaching puberty with inadequate Hb levels to support growth
Not all patients require regular transfusions.
Blood Product Selection:
Use packed red blood cells (PRBCs) to minimize volume
Leukoreduced PRBCs are preferred to reduce alloimmunization and febrile reactions
CMV-negative PRBCs may be considered for immunocompromised patients
Ensure units are crossmatched and compatible
Aim for units with a higher Hb concentration to reduce transfusion volume over time.
Iron Chelation Therapy:
Essential for all regularly transfused patients to prevent iron overload, a major cause of morbidity and mortality
Agents include deferoxamine (parenteral), deferasirox (oral), and deferiprone (oral)
Therapy is initiated when serum ferritin levels consistently exceed 500-1000 ng/mL
Regular monitoring of ferritin, cardiac MRI for iron quantification, and endocrine function is crucial
DNB and NEET SS often test knowledge of chelator choice, dosage, and monitoring.
Supportive Care:
Nutritional support is vital, focusing on adequate intake of vitamins and minerals, except iron
Folic acid supplementation is often recommended due to increased RBC turnover
Management of complications: infections, bone deformities, endocrine deficiencies, cardiac issues, and psychological support for the child and family.
Splenectomy:
Considered in patients with thalassemia intermedia or major who have massive splenomegaly causing discomfort, hypersplenism (requiring very frequent transfusions), or portal hypertension
However, splenectomy increases the risk of overwhelming post-splenectomy infection (OPSI), necessitating vaccinations (pneumococcal, meningococcal, Haemophilus influenzae type b) and prophylactic antibiotics
It is generally avoided in young children.
Hematopoietic Stem Cell Transplantation:
The only potential cure for thalassemia
Indicated for suitable patients with thalassemia major, typically those with a matched sibling donor
It carries significant risks and requires careful patient selection and pre-transplant conditioning.
Complications
Iron Overload:
The most significant long-term complication of chronic transfusions
Iron accumulates in the heart, liver, endocrine glands, and other organs, leading to cardiomyopathy, liver fibrosis, diabetes mellitus, hypothyroidism, hypogonadism, and growth failure
Prompt and adequate iron chelation is key.
Cardiac Dysfunction:
Iron deposition in the myocardium leads to arrhythmias, diastolic and systolic dysfunction, and eventually heart failure
Regular echocardiography and cardiac MRI for iron assessment are vital.
Endocrine Deficiencies:
Iron deposition in the pituitary, thyroid, pancreas, and gonads causes hypopituitarism, hypothyroidism, diabetes mellitus, and delayed puberty or hypogonadism
Regular endocrine screening is essential.
Bone Disease:
Osteopenia, osteoporosis, fractures, and extramedullary hematopoiesis can occur, leading to skeletal deformities and pain
Vitamin D and calcium supplementation may be beneficial.
Infections:
Increased susceptibility to infections, especially in splenectomized patients
Prompt treatment of infections is crucial.
Prognosis
Factors Affecting Prognosis:
Adherence to regular transfusions and iron chelation therapy
Age at diagnosis and initiation of treatment
Availability of effective chelation agents
Presence of comorbidities
Successful hematopoietic stem cell transplantation
Genetic background and severity of mutation.
Outcomes:
With optimal management, individuals with thalassemia major can live into adulthood with improved quality of life
Average lifespan has significantly increased
Thalassemia intermedia patients have a better prognosis but are at risk for complications that can impact quality of life and life expectancy
Regular monitoring and proactive management are crucial.
Follow Up:
Lifelong follow-up is required for all patients with thalassemia major and intermedia
This includes regular hematological monitoring, assessment of transfusion needs, iron status monitoring, cardiac and endocrine assessments, bone health evaluation, and management of any developing complications
Pediatric residents preparing for DNB/NEET SS must understand the comprehensive, multidisciplinary approach to managing these chronic conditions.
Key Points
Exam Focus:
Key transfusion targets: Pre-transfusion Hb ≥ 9-10.5 g/dL for major, and ≥ 7-8 g/dL (with symptoms) for intermedia
Indications for iron chelation: serum ferritin > 500-1000 ng/mL
Common iron chelators: Deferoxamine, Deferasirox, Deferiprone
Complications of iron overload: cardiac, hepatic, endocrine
Risk of OPSI post-splenectomy.
Clinical Pearls:
Individualize transfusion needs for thalassemia intermedia
Early initiation and adherence to iron chelation are paramount for long-term survival and quality of life
Screen for cardiac and endocrine complications regularly, even in well-managed patients
Consider bone health and psychological support.
Common Mistakes:
Underestimating the need for iron chelation or inadequately dosing chelators
Delayed transfusions leading to chronic anemia and its sequelae
Failure to screen for cardiac and endocrine complications
Over-reliance on Hb levels alone without considering patient symptoms and overall well-being
Not considering splenectomy complications or post-splenectomy prophylaxis.