Disorders of Globin Synthesis Flashcards
List the protein chains (globins) found in hemoglobin and where they are found on the genome
Types of globins: o HbA: α2β2 = 98% in normal adults o HbF: α2γ2 = ~1% • Switch to HbA during first 6 months of life as bone marrow takes over from liver as major site of hematopoietic activity o HbA2: α2δ2 = <3.5%
Expression of human globin genes
o Chromosome 16 = 2 α genes
o Chromosome 11 = β gene, δ gene, and 2 γ genes
Define Hemoglobinopathy
Inherited mutation of globin genes leading to qualitative abnormality of globin synthesis
• Usually due to single nucleotide change → single amino acid change
• Ex: sickle cell anemia
Define Thalassemia
Inherited mutation of globin genes leading to quantitative abnormality of globin synthesis
• Imbalanced production (decrease in α or β globin; excess of unaffected chain)
• Heterogeneous group of mutations
Sickle Cell disease: Epidemiology
o Spectrum of disorders = autosomal recessive
o 1/600 African-Americans affected
o 1/8 African-Americans have sickle trait
o Hb βSβS accounts for ~60% of sickle cell disease
o Hb βSβC (compound heterozygosity for βS and hemoglobin C) and βSβ0 (compound heterozygosity for βS and β0 thalassemia) account for ~40%
Sickle Cell disease: Molecular basis of disease
o Mutation in codon 6 in β globin gene: adenine → thymidine
o Result: Glutamate → Valine at 6th position
o When deoxygenated → sickle Hb forms polymers
o Polymerized sickle Hb injures RBC membrane and distorts its shape = sickles
o Distorted RBC is hemolyzed
Sickle Cell disease: pathophysiology
Deoxygenation of mutant Hb leads to
↑ K+ efflux
↑ Cell density / dehydration
↑ Polymerization promoted by:
• Decreased oxygen
• Increased intracellular hemoglobin S concentration (SS > SC, S-thal)
• Increased 2,3-DPG
• Decreased pH
• Slowed transit time through the circulation
• Endothelial adhesion
Sickled cells adhere to endothelial cells
Endothelial factors ↑ vasoconstriction
Decreased blood flow promotes vaso-occlusion:
• Damaged RBCs hemolyze = release heme that scavenges NO
• Also release arginase = destroys L-arginine (NO substrate)
• Result: endothelial NO deficiency → vasoconstriction, endothelial activation, proliferation
Vicious cycle = decreased blood flow, hypoxemia / acidosis, increased sickling
Sickle Cell disease: clinical features
Associated with higher hemoglobin: Painful episodes • Dactylitis = painful swelling in hands and feet Acute chest syndrome • Tachypnea, hypoxia, fever, pain, cough, infiltrate on chest x-ray • Often associated with infection Osteonecrosis (of femoral head) Proliferative Retinopathy
Associated with lower hemoglobin:
• Stroke
• Priapism (can lead to impotence if recurrent)
• Leg ulcers
Others: • Pneumococcal disease (due to atrophic spleen) • Splenic infarction • Splenic sequestration • Gallstones • Renal abnormalities • Osteopenia • Nutritional deficiencies • Placental insufficiency • Pulmonary hypertension (increased risk if spleen removed)
Sickle Cell disease: treatment
o Opiates and hydration for painful crises
o Pneumococcal vaccination
o Retinal surveillance
o Transfusion for serious manifestations (stroke)
o Hydroxyurea = promotes fetal hemoglobin
o Stem cell transplant = curative
Overall management strategies: • Early Diagnosis • Comprehensive Care • Prophylactic Penicillin (for pneumococcal infection) • Pneumococcal Vaccine • Influenza Vaccine • Education and consistency
Sickle Cell Trait
1/8 African-Americans have sickle trait
• Heterozygous for HbS (βAβS)
• No serious clinical consequences
• Sudden death during intensive training (higher elevations)
• Usually asymptomatic; but can have hematuria, isosthenuria (renal papillary necrosis)
Beta vs. Alpha Thalassemia
o Beta thalassemia = reduced beta chain synthesis
o Alpha thalassemia = reduced alpha chain synthesis
Alpha Thalassemia (silent carrier)
-a/aa
Not sick
No treatment
Alpha Thalassemia minor
- a/-a
- -/aa
• Microcytosis, hypochromia, mild anisocytosis, poikilocytosis
• Mild or absent anemaia
• Newborns have increased Bart’s Hb (γ4)
No treatment needed (avoid unnecessary iron supplements)
Hemoglobin H disease
-a/–
- Chronic hemolytic anemia
- Hemoglobin usually ~8-10 g/dl
- Newborns have 20-40% Bart’s Hb
- Replaced as age by Hemoglobin H (β4)
- See HbH inclusion bodies in RBCs
- Microcytosis, hypochromia, target cells, anisocytosis, poikilocytosis
- Anemia = can become more severe after taking oxidant drugs (accelerate oxidation and precipitation of HbH)
Hydrops fetalis
–/–
- Lethal in utero
- Mostly Bart’s hemoglobin (high oxygen affinity so can’t deliver to tissues)
- Tissue hypoxia
- Extensive extramedullary hematopoiesis → engorges liver with nucleated RBCs → liver failure → death
Beta Thalassemia minor
(Hb >9 g/dl) • Usually β+/β or β/0β • Often asymptomatic • Diagnose: slightly elevated HbA2 and HbF; majority is normal HbA Treatment = none needed
