Sickle cell anemia
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Sickle cell anemia
Sickle cell anemia is the most severe common form of sickle cell disease (SCD). It is an inherited, autosomal-recessive blood disorder in which a person has two genes for hemoglobin S, called HbSS.
Cause and mechanism
A mutation in the beta-globin gene substitutes valine for glutamic acid at position 6 of the beta chain. When oxygen is low, hemoglobin S polymerizes, causing red cells to become rigid and sickle-shaped. Repeated sickling leads to:
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Hemolysis: premature destruction of red blood cells, causing chronic anemia.
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Vaso-occlusion: blockage of small blood vessels, causing severe pain and organ injury.
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Goldman-Cecil Medicine, p. 1718
Inheritance
If both parents have sickle cell trait (HbAS), each pregnancy has:
- 25% chance of sickle cell anemia (HbSS)
- 50% chance of sickle cell trait
- 25% chance of neither
Sickle cell trait is not the same as sickle cell anemia. Trait usually does not produce the chronic anemia and recurrent vaso-occlusive disease seen in HbSS.
Features
Symptoms often begin in infancy, after fetal hemoglobin declines. Important manifestations include:
- Chronic hemolytic anemia: fatigue, pallor, jaundice
- Painful vaso-occlusive episodes, often affecting bones, chest, abdomen, or limbs
- Dactylitis: painful swelling of hands and feet in young children
- Recurrent infections due to progressive loss of splenic function
- Acute chest syndrome: new respiratory symptoms with fever and a lung infiltrate
- Stroke, especially in children
- Splenic sequestration crisis, aplastic crisis, or sudden worsening of anemia
- Priapism, leg ulcers, avascular necrosis, kidney disease, and retinopathy
The CDC overview of SCD explains that rigid red cells can obstruct blood flow, causing pain, infection risk, acute chest syndrome, and stroke.
Diagnosis
- Newborn screening
- Hemoglobin electrophoresis or high-performance liquid chromatography
- Genetic testing when needed
- CBC commonly shows chronic anemia with reticulocytosis
- Peripheral smear may show sickled cells, target cells, and Howell-Jolly bodies due to functional asplenia
HbSS typically shows predominantly HbS with no HbA unless the patient has recently received a transfusion.
Management
Care should be coordinated with a hematology team. Common preventive and disease-modifying measures include:
- Vaccination and infection prevention
- Penicillin prophylaxis in young children, where indicated
- Hydroxyurea, which raises fetal hemoglobin (HbF) and reduces pain crises, acute chest syndrome, and transfusion requirements
- Regular transfusion programs for selected patients, such as stroke prevention
- Iron chelation if chronic transfusions cause iron overload
- Screening for complications, including transcranial Doppler screening in eligible children and regular eye evaluations
- Hematopoietic stem-cell transplant for selected patients, which can be curative
- Some people may be eligible for newer gene-based therapies through specialist centers
Hydroxyurea reduces sickling because HbF reduces HbS polymer formation. Fishman's Pulmonary Diseases and Disorders, section “Sickle Cell Disease.”
Acute problems that need urgent assessment
Seek emergency care immediately for:
- Fever of 38.5°C (101.3°F) or higher, particularly in a child
- Chest pain, shortness of breath, low oxygen level, or a new cough
- Sudden weakness, facial droop, confusion, seizure, or severe headache
- Marked pallor, fainting, unusual lethargy, or rapidly enlarging abdomen
- Severe pain not controlled by the person’s care plan
- Priapism lasting more than 4 hours
Fever can signal a rapidly serious bacterial infection because splenic function is commonly impaired. The CDC infection guidance advises immediate emergency assessment for possible infection.
Acute vaso-occlusive pain episode
Treatment is individualized but usually involves prompt analgesia, assessment for complications, careful hydration, oxygen only if hypoxemic, and treatment of triggers such as infection. Transfusion is not routine for uncomplicated pain but may be needed for severe anemia or complications. Acute chest syndrome and stroke may require urgent simple or exchange transfusion.
Key distinction
- Sickle cell anemia = usually HbSS, a severe disease.
- Sickle cell trait = HbAS carrier state, generally not chronic sickle cell disease.
This is a general overview, not a personal treatment plan. If you mean a specific patient, tell me their age, symptoms, test results, or whether you want exam-style notes, and I can tailor it.
Criggler najjar syndrome
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Crigler-Najjar syndrome
Crigler-Najjar syndrome (CNS) is a very rare, autosomal-recessive disorder that causes severe unconjugated (indirect) hyperbilirubinemia from birth.
It results from mutations in the UGT1A1 gene, which encodes bilirubin UDP-glucuronosyltransferase, the liver enzyme that conjugates bilirubin for excretion.
Pathophysiology
Unconjugated bilirubin cannot be efficiently converted into water-soluble conjugated bilirubin. It accumulates in blood and can enter the brain, causing bilirubin encephalopathy (kernicterus).
Liver enzymes and liver structure are generally normal, because this is a defect of bilirubin conjugation rather than hepatocellular injury.
- Goldman-Cecil Medicine, p. 1515
- Sleisenger and Fordtran's Gastrointestinal and Liver Disease, p. 336
Types
| Feature | Type I | Type II (Arias syndrome) |
|---|---|---|
| UGT1A1 activity | Virtually absent | Reduced, usually less than 10% of normal |
| Severity | Severe | Less severe |
| Typical unconjugated bilirubin | Usually >20 mg/dL, often 17-50 mg/dL | Usually <20 mg/dL, but can overlap |
| Onset | Neonatal period | Neonatal period or later |
| Risk of kernicterus | Very high | Much lower |
| Phenobarbital response | No meaningful response | Bilirubin falls with treatment |
| Prognosis untreated | Death or permanent neurologic injury can occur in infancy/childhood | Usually near-normal survival |
Type I
- Severe persistent jaundice begins soon after birth.
- There is no effective bilirubin conjugation.
- It is unresponsive to phenobarbital.
- Major danger: kernicterus, causing hypotonia, abnormal movements, hearing impairment, developmental disability, or death.
- Management involves intensive daily phototherapy from infancy, sometimes exchange transfusion or plasmapheresis for dangerous bilirubin rises, and early liver transplantation, which is the established curative treatment.
Type II
- Some enzyme activity remains.
- Jaundice and bilirubin levels are lower than in type I.
- Phenobarbital is effective, because it induces the remaining UGT1A1 activity.
- Kernicterus is uncommon but may occur during illness, fasting, dehydration, or other stressors that increase bilirubin.
A clinical review confirms that type II generally responds to phenobarbital, whereas type I does not, and that liver transplant remains the curative option for type I management review.
Diagnosis
Diagnosis includes:
- Predominantly indirect hyperbilirubinemia
- No evidence of hemolysis, significant liver disease, or biliary obstruction
- Normal or near-normal liver-function tests other than bilirubin
- Hemoglobin studies and hemolysis evaluation to exclude increased bilirubin production
- UGT1A1 genetic testing for confirmation
- Phenobarbital-response testing can help distinguish type II from type I, but genetic confirmation is preferred
Differentiation from Gilbert syndrome
Gilbert syndrome also involves UGT1A1, but it is common and mild:
- Mild intermittent unconjugated bilirubin elevation, often triggered by fasting, fever, or stress
- Normal health and no kernicterus risk in typical cases
- Enzyme activity is higher, approximately 10%-33% of normal, compared with near-zero in CNS type I and less than 10% in CNS type II
Exam points
- Gene: UGT1A1
- Inheritance: autosomal recessive
- Bilirubin: unconjugated
- Type I: absent enzyme, kernicterus, no phenobarbital response, transplant needed
- Type II: partial enzyme activity, responds to phenobarbital, better prognosis
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