What is thalassemia and how is it managed in individuals of Mediterranean, Middle Eastern, and South Asian descent?

Thalassemia: Comprehensive Overview and Management

Definition and Pathophysiology

Thalassemia is a genetic blood disorder characterized by reduced or absent production of globin chains that constitute hemoglobin, resulting in ineffective erythropoiesis, hemolytic anemia, and life-threatening complications from chronic transfusion-dependent iron overload. 1

Types of Thalassemia

β-Thalassemia Major (Transfusion-Dependent)

• Severe reduction or complete absence of β-globin chain production causing profound anemia that becomes life-threatening from approximately 1-2 years of age 1
• Requires lifelong blood transfusions, defined as >8 transfusion events per year in adults >16 years 1
• Each transfusion unit delivers approximately 200 mg of iron, combined with increased gastrointestinal iron absorption due to hepcidin suppression, necessitating lifelong iron chelation therapy 1

β-Thalassemia Intermedia (Non-Transfusion-Dependent)

• Moderate anemia presenting later in life without regular transfusion requirements 1
• Greater propensity for pulmonary hypertension, thrombosis, extramedullary hematopoiesis, osteoporosis, and leg ulcers 1
• May eventually require transfusions as patients age to prevent cardiovascular and other complications 1

β-Thalassemia Minor (Carrier State)

• Clinically asymptomatic with mild microcytic anemia 2, 3
• MCV <80 fL is the key screening parameter for carrier detection 4, 5

α-Thalassemia

• Results from deletion or dysfunction of one to four α-globin genes 4
• Four-gene deletion (Hemoglobin Bart's hydrops fetalis) is typically fatal in utero and represents the most common cause of non-immune hydrops fetalis in Southeast Asian populations (28-55% of cases) 4
• Three-gene deletion (Hemoglobin H disease) causes moderate hemolytic anemia requiring monitoring every 3-6 months 4

Geographic Distribution

Thalassemia is most prevalent in populations from the Mediterranean basin, Middle East, South Asia (Indian subcontinent), Southeast Asia, and regions with historical malaria exposure. 1, 4, 6

Clinical Manifestations and Complications

Untreated or Poorly Managed β-Thalassemia Major

• Growth retardation, severe pallor, jaundice, poor musculature 2
• Hepatosplenomegaly from extramedullary hematopoiesis 2
• Skeletal deformities and characteristic facial changes from bone marrow expansion 2
• Leg ulcers and masses from extramedullary hematopoiesis 2

Iron Overload Complications (Leading Cause of Morbidity and Mortality)

Cardiac complications represent the predominant cause of death in β-thalassemia major, but are reversible with intensive chelation therapy when detected early. 1, 5

Cardiac Iron Overload

• Cardiac T2* <6 ms on MRI confers 47% risk of developing heart failure within one year, with relative risk of 270 compared to patients with T2* >10 ms 5
• Iron cardiomyopathy is reversible with intensive combined chelation therapy if treated early 5
• Cardiac disease is easier and safer to treat at early stages rather than late stages when mortality hazard is high 1

Endocrine Complications

• Hypogonadotropic hypogonadism is the most common endocrinopathy 5
• Growth hormone deficiency, diabetes mellitus, thyroid dysfunction, parathyroid insufficiency, and pituitary dysfunction 5, 2

Hepatic Complications

• Liver fibrosis and cirrhosis from iron deposition 2
• Chronic viral hepatitis (HBV and HCV) from transfusions, with prevalence varying by region 7, 5

Diagnostic Approach

Screening and Initial Workup

Screen parents with MCV measurement; values <80 fL suggest possible thalassemia carrier status and warrant further investigation. 4, 5

• Consider ethnicity in diagnostic approach—failure to do so leads to missed diagnoses 4
• Complete blood count showing microcytic anemia with disproportionately low MCV relative to degree of anemia 5, 2
• Hemoglobin electrophoresis to identify abnormal hemoglobin patterns 2, 3

Definitive Diagnosis

• DNA testing for deletions or point mutations is the definitive diagnostic test to identify specific genetic defects 4, 3
• Over 200 disease-causing mutations have been identified in the β-globin gene on chromosome 11 3

Prenatal Diagnosis

• Recommended when both parents are carriers to detect severe forms like Hemoglobin Bart's hydrops fetalis 4
• Amniocentesis or fetal blood sampling for genetic testing 4
• Middle cerebral artery Doppler to assess for fetal anemia in suspected hydrops fetalis 4

Cascade Testing Strategy

• Test the affected family member first to identify the specific genetic mutation, followed by targeted testing of at-risk family members 4
• Pre-test counseling should discuss benefits (diagnosis confirmation, reproductive planning), family implications, and testing limitations 4

Management of β-Thalassemia Major

Transfusion Therapy

Initiate regular blood transfusions immediately to raise hemoglobin above 9 g/dL, then establish a regular transfusion schedule every 3-4 weeks. 7, 5

• Target pre-transfusion hemoglobin: 9-10 g/dL 7, 5
• Target post-transfusion hemoglobin: 13-14 g/dL to suppress ineffective erythropoiesis 7, 5
• Monitor hemoglobin levels every 2 weeks, especially during antiviral treatment if needed 7

Iron Chelation Therapy (Critical for Survival)

Start iron chelation therapy immediately upon diagnosis to prevent life-threatening complications from iron overload. 7, 5

Choice of Chelator Based on Clinical Status:

For patients WITHOUT cardiac complications:

• Deferiprone (oral) 75 mg/kg/day divided three times daily 8
• Deferoxamine (subcutaneous/IV) as alternative 1
• Deferasirox (oral) as alternative—equivalent efficacy to deferoxamine 1

For patients WITH cardiac T2 <6 ms or acute decompensated heart failure:*

• Continuous intravenous deferoxamine 50 mg/kg/day PLUS deferiprone 75 mg/kg/day for combined chelation therapy 7, 5
• This combination shows superior efficacy compared to monotherapy 1
• Transfer immediately to specialized thalassemia center with integrated cardiology and hematology expertise 7

Monitoring Iron Chelation:

• Target serum ferritin <1000 mcg/L, though MRI is more accurate than ferritin alone 7
• Monitor liver iron concentration (LIC) via MRI to guide chelation therapy intensity 7

Critical Warnings for Deferiprone:

• Risk of agranulocytosis and neutropenia—requires regular blood count monitoring 8
• Avoid during concurrent antiviral therapy due to increased neutropenia risk 7
• Patients must immediately interrupt therapy and report fever, sore throat, or flu-like symptoms 8
• Take with meals to reduce nausea 8

Comprehensive Monitoring Protocol

Cardiac Assessment:

• Echocardiography and cardiac MRI T2* annually to detect early iron-related cardiomyopathy 7, 5
• Continuous electrocardiographic and hemodynamic monitoring for patients with cardiac complications 7

Hepatic Assessment:

• Liver function tests every 3 months 7, 5
• Liver ultrasound every 6 months for hepatocellular carcinoma surveillance in patients with cirrhosis or chronic HBV 5

Endocrine Evaluation:

• Annual screening for diabetes, thyroid dysfunction, and hypogonadism 7, 5
• Evaluate for multiple endocrine deficiencies in any patient with decreased cardiac function 5

Infectious Disease Screening:

• Screen for hepatitis B and C at baseline and periodically 7, 5

Management of Cardiac Complications (Medical Emergency)

If patient presents with seizures or signs of heart failure, obtain immediate bedside echocardiography to exclude acute decompensated heart failure, as cardiac iron overload can present with seizures and has 50% one-year mortality if untreated. 7

Immediate Actions:

1. Initiate continuous IV deferoxamine 50 mg/kg/day PLUS deferiprone 75 mg/kg/day 7, 5
2. Transfer to specialized thalassemia center—this is a medical emergency where delay can be life-threatening 7
3. Maintain continuous cardiac monitoring 7
4. Use minimal diuretics only—avoid aggressive diuretic therapy as thalassemia patients require adequate preload 7
5. Do not delay cardiac assessment thinking symptoms are purely neurological 7

Management of Viral Hepatitis

For HCV Infection:

• Peg-interferon plus ribavirin for 24 weeks (genotypes 2/3) or 48 weeks (genotypes 1/4) 7, 5
• Expect 30-40% increase in transfusion requirements during antiviral treatment 7, 5
• Switch to deferoxamine during antiviral treatment (avoid deferiprone due to neutropenia risk) 7
• Exclude patients with decompensated myocardiopathy or severe arrhythmias from antiviral therapy 7

For HBV Infection:

• Peg-interferon or nucleoside/nucleotide analogs based on HBeAg status 7, 5

Curative Treatment Options

Hematopoietic Stem Cell Transplantation (HSCT):

• Remains the only definitive cure currently available 2, 3
• Optimize iron chelation before transplant to reduce non-relapse mortality 7
• Conditioning regimen uses intensive chemotherapy (busulfan, cyclophosphamide, fludarabine, ATG), not steroids 7

Gene Therapy and Gene Editing:

• Rapidly evolving field with strategies in pre-clinical and clinical evaluation 6
• Represents future curative treatment options 6

Management of Thalassemia Intermedia

• Folic acid supplementation 2
• Splenectomy may be required in some circumstances 2
• Treatment of extramedullary erythropoietic masses and leg ulcers 2
• Prevention and therapy of thromboembolic events 2
• Iron chelation if transfusions become necessary 1

Critical Pitfalls to Avoid

Do NOT use steroids as routine thalassemia management—they are not recommended in international guidelines for treatment of major or intermediate thalassemia. 7

• Avoid valproic acid for seizure management due to potential hepatotoxicity in patients with underlying liver disease from iron overload 7
• Do not use deferiprone during concurrent antiviral therapy due to compounded neutropenia risk 7
• Avoid inadequate monitoring during antiviral therapy—ribavirin causes hemolysis requiring 30-40% more transfusions 7
• Do not miss cardiac assessment in patients presenting with neurological symptoms—cardiac iron overload can present with seizures 7
• Failure to consider ethnicity in diagnostic approach leads to missed diagnoses 4

Prognosis

Prognosis for individuals with β-thalassemia has improved substantially in the last 20 years following advances in transfusion, iron chelation, and bone marrow transplantation therapy. 2

• Cardiac disease remains the main cause of death in patients with iron overload 2
• Evidence shows significant reduction in cardiac mortality with tailored chelation treatment and early cardiac monitoring 1
• Early detection and intensive treatment of cardiac iron overload is reversible and life-saving 5