Thalassemia

• Thalassemias are inherited blood disorders characterized by reduced or absent production of hemoglobin chains (alpha or beta), essential for oxygen transport in red blood cells.
• Genetics: Caused by mutations or deletions in hemoglobin genes. It is an autosomal recessive trait, requiring carrier status in one or both parents.

Hemoglobin Types

• Hemoglobin (Hb): Consists of an iron-containing heme ring and four globin chains (two alpha and two non-alpha chains).
• Fetal Hemoglobin (HbF): Composed of two alpha and two gamma chains (alpha2 gamma2).
• Adult Hemoglobin A (HbA): Made up of two alpha and two beta chains (alpha2 beta2).
• Hemoglobin A2 (HbA2): Contains two alpha and two delta chains (alpha2 delta2).
• Hemoglobin Transition: At birth, HbF accounts for 80% and HbA for 20%. The transition from HbF to HbA starts before birth and by six months, infants typically exhibit mostly HbA, some HbA2, and negligible HbF.

Alpha Thalassemia

• Cause: Deficient or absent synthesis of alpha globin chains, leading to excess beta chains. Controlled by two genes on chromosome 16.

• Types:
  • Silent Carrier: Single gene deletion, asymptomatic.
  • Alpha Thalassemia Trait (Minor): Two gene deletions, results in microcytosis, usually no anemia.
  • Alpha Thalassemia Intermedia (HbH Disease): Three gene deletions, causes moderate to severe hemolytic anemia, ineffective erythropoiesis, and splenomegaly.
  • Alpha Thalassemia Major (Hb Bart’s): Four gene deletions, usually results in fatal hydrops fetalis due to significant hemoglobin Bart’s production (gamma4)

Variant	Chromosome 16	Signs and symptoms
Alpha thalassemia silent carrier	One of four gene deletions	Asymptomatic
Alpha thalassemia trait	Two of four gene deletions	Asymptomatic
Hemoglobin Constant Spring	Reduced output of alpha globin	Silent or mildly symptomatic
Alpha thalassemia intermedia with significant hemoglobin H (hemoglobin H disease)	Three of four gene deletions	Moderate to severe hemolytic anemia, modest degree of ineffective erythropoiesis, splenomegaly, variable bone changes4
Alpha thalassemia major with significant hemoglobin Bart’s	Four of four gene deletions	Causes nonimmune hydrops fetalis, usually fatal5

Beta Thalassemia

• Cause: Deficient or absent synthesis of beta globin chains due to mutations or deletions of two genes on chromosome 11, leading to excess alpha chains.
• Types:
  • Beta Thalassemia Trait (Minor): One gene defect, asymptomatic, causes microcytosis and mild anemia.
  • Beta Thalassemia Intermedia: Two genes defective, symptoms less severe than beta thalassemia major, may not require lifelong transfusions.
  • Beta Thalassemia Major (Cooley Anemia): Severe decrease in beta chain synthesis from two genes, results in symptoms like abdominal swelling, growth retardation, and requires lifelong blood transfusions.

Variant	Chromosome 11	Signs and Symptoms
Beta thalassemia trait	One gene defect	Asymptomatic
Beta thalassemia intermedia	Two genes defective (mild to moderate decrease in beta globin synthesis)	Variable degrees of severity of symptoms of thalassemia major
Beta thalassemia major	Two genes defective (severe decrease in beta globin synthesis)	Abdominal swelling, growth retardation, irritability, jaundice, pallor, skeletal abnormalities, splenomegaly; requires lifelong blood transfusions6

History and Physical Examination

General Presentation

• Symptoms: Varies widely depending on type and severity of thalassemia. Common initial symptom is fatigue due to anemia.

Skin

• Pallor: Resulting from anemia.
• Jaundice: Due to hyperbilirubinemia from intravascular hemolysis.
• Ulcerations: May be present on extremities.
• Bronze Skin: Chronic iron deposition from multiple transfusions.

Musculoskeletal

• Facial and Skeletal Deformities: Extramedullary expansion of hematopoiesis may cause deformities like “chipmunk face.”

Cardiac

• Arrhythmias: Iron deposition in cardiac myocytes from chronic transfusions disrupts cardiac rhythm.
• Heart Failure: Overt heart failure may occur due to chronic anemia.

Abdominal

• Bilirubin Gallstones: Chronic hyperbilirubinemia can lead to gallstones, causing typical colicky pain of cholelithiasis.
• Hepatosplenomegaly: Resulting from chronic iron deposition and extramedullary hematopoiesis; may also see splenic infarcts or autophagy due to chronic hemolysis.

Hepatic

• Liver Involvement: Chronic liver failure or cirrhosis may develop from chronic iron deposition or transfusion-related viral hepatitis.

Growth and Development

• Slow Growth Rates: Anemia can inhibit growth and delay puberty.
• Developmental Monitoring: Important to track growth and developmental milestones according to age.

Endocrinopathies

• Iron Overload: Leads to deposition in various organs causing:
  • Diabetes Mellitus: From iron deposition in the pancreas.
  • Hypothyroidism and Hypoparathyroidism: Resulting from iron deposition in thyroid and parathyroid glands.
  • Chronic Arthropathies: Iron deposition in joints.
  • Neurological Impairments: Preferential iron accumulation in brain areas like the substantia nigra can cause early-onset Parkinson’s disease and other psychiatric issues.

Diagnostic Indicators for Thalassemia Trait

• Incidental Discovery: Thalassemia trait often discovered incidentally through routine blood tests showing mild microcytic anaemia.
• Common Causes of Microcytic Anaemia: Includes iron deficiency, thalassemia, lead poisoning, sideroblastic anaemia, and anaemia of chronic disease.
• Diagnostic Parameters:
  • Mean Corpuscular Volume (MCV): Key indicator in differentiating types of anaemia.
    • Thalassemia: MCV usually less than 75fl
    • Iron Deficiency: MCV rarely less than 80 fl unless hematocrit is below 30%.
  • Red Cell Distribution Width (RDW): Helps distinguish between iron deficiency, sideroblastic anaemia, and thalassemia.
    • Iron Deficiency: Elevated RDW in over 90% of cases.
    • Thalassemia: Elevated RDW in about 50% of cases.
    • Sideroblastic Anemia: Typically elevated RDW.
• Mentzer Index (MCV/red blood cell count): Useful for children to distinguish iron deficiency from thalassemia.
  • Iron Deficiency: Ratio usually greater than 13.
  • Thalassemia: Ratio less than 13.
  • A ratio of 13: Considered uncertain, necessitating further tests.
• Assessment: Normal RDW likely indicates thalassemia; elevated RDW suggests the need for additional diagnostic testing.

Hematologic Indices of Iron Deficiency and Alpha and Beta Thalassemia

Test	Iron deficiency	Beta thalassemia	Alpha thalassemia
MCV – abnormal if < 80 fl in adults < 70 fl in children six months to six years of age < 76 fl in children seven to 12 years of age	Low	Low	Low
Red blood cell distribution width	High	Normal; occasionally high	Normal
Ferritin	Low Thalassaemia may co-exist (treat iron deficiency then retest)	Normal	Normal
Mentzer index for children (MCV/red blood cell count)	> 13	< 13	< 13
Hb electrophoresis	Normal (may have reduced HbA2)	Increased HbA2 reduced HbA, and probably increased HbF	Adults: normal Newborns: may have HbH or Hb Bart’s

Hb = hemoglobin; HbF = fetal hemoglobin; MCV = mean corpuscular volume.

Iron Studies

• Purpose: Differentiate thalassemia from iron deficiency anemia.
• Tests Include:
  • Serum Iron: Measures iron in the blood.
  • Ferritin: Indicates total body iron stores.
  • Percent Saturation of Transferrin: Reflects how much iron is being carried by the transferrin protein.

Erythrocyte Porphyrin Levels

• Usage: Distinguish between beta-thalassemia minor and conditions like iron deficiency or lead poisoning.
• Indicator:
  • Normal porphyrin levels suggest beta-thalassemia.
  • Elevated porphyrin levels indicate iron deficiency or lead poisoning.

Hemoglobin Electrophoresis

• Function: Assess the type and quantity of hemoglobin.
• Findings:
  • Hemoglobin A (HbA): Predominant in adults (95% to 98%).
  • Hemoglobin A2 (HbA2): Normally 2% to 3%.
  • Hemoglobin F (HbF): Typically less than 2% in adults, but increased in some thalassemias.
  • Beta-Thalassemia: Altered proportions with more HbF and HbA2, and decreased or absent HbA.
  • Alpha-Thalassemia: May show Hemoglobin H (HbH).
• Application: Also used for prenatal screening and state-mandated newborn screening.

DNA Analysis

• Purpose: Confirm mutations in alpha and beta globin genes.
• Scope: Not routine, used for definitive diagnosis and assessing carrier status.
• Family Studies: May be required to determine carrier status and types of mutations in family members, especially if there’s a known history of thalassemia.

Complications of Thalassemia

• Beta Thalassemia Major/Intermedia:
  • Overstimulated bone marrow, ineffective erythropoiesis, iron overload from blood transfusions.
  • Complications include poor growth, skeletal abnormalities, jaundice, cardiac issues, endocrinopathies (e.g., diabetes, hypogonadism), and splenomegaly.
  • Increased risk of thromboembolic events, especially post-splenectomy.
  • Commonly develop osteoporosis; 51% of those over 12 years affected.
• Alpha Thalassemia:
  • Intermedia (HbH disease): Causes mild to moderate hemolysis; occasional transfusions needed.
  • Major (Hb Bart’s): Causes nonimmune hydrops fetalis, almost always fatal.

General Management

• Beta Thalassemia Major:
  • Requires lifelong blood transfusions to maintain hemoglobin above 9.5 g/dL.
  • Starts transfusions as early as six months old.
  • Bone marrow transplantation is the only curative therapy.
• Iron Chelation:
  • Necessary due to iron overload from transfusions.
  • Deferoxamine and oral deferasirox are common treatments.

Management of Specific Conditions

• Hypersplenism:
  • May need splenectomy; vaccine and antibiotics recommended pre and post-surgery.
• Endocrinopathies:
  • Growth hormone therapy variable; hormone therapy effective for hypogonadism.
• Pregnancy:
  • Genetic counseling recommended; risk of passing thalassemia to offspring.

Psychosocial and Nutritional Support

• Education on disease genetics and psychological therapy advised.
• Daily supplementation of 1 mg folic acid recommended for those with folate deficiency.

Prognosis

• Normal life expectancy for thalassemia trait carriers.
• Reduced lifespan for beta thalassemia major patients, with an average life expectancy until about 30 years due to cardiac complications from iron overload.

Considerations for carrier status and family planning:

1. Understanding Genetics and Inheritance:
   • Explain that thalassemia is an inherited blood disorder, involving autosomal recessive transmission.
   • Detail that two carrier parents have a 25% chance with each pregnancy of having a child with thalassemia major.
2. Importance of Carrier Identification:
   • Emphasize identifying carrier status due to often asymptomatic nature of thalassemia traits.
   • Discuss differences between alpha and beta thalassemia traits.
3. Family Planning Guidance:
   • Recommend genetic counseling for carriers or those with a family history.
   • Suggest genetic screening for partners to determine risk to offspring.
4. Diagnostic Testing Advocacy:
   • Encourage genetic testing for both the patient and their partner.
   • Utilize CBC, hemoglobin electrophoresis, and DNA analysis for accurate diagnosis.
5. Management Options:
   • Outline treatment and monitoring strategies for various thalassemia types.
   • Highlight importance of regular healthcare follow-ups, especially for severe forms.
6. Discussing Offspring Risks:
   • Explain the potential for children to inherit thalassemia, based on parental carrier status.
   • Describe the severity and symptoms of different thalassemia forms in potential offspring.
7. Support and Resources:
   • Provide contacts for support groups and informational resources.
   • Inform about ongoing research and potential clinical trials.
8. Promoting Family Communication:
   • Encourage patients to discuss genetic risks with extended family members who might also be carriers.