Sickle Cell Disease, Epidemiology,Genetic History, complication and Management

Dr. Richard B. Fynn Dormaa Presby Hospital Dept. of Child Health

What Is Sickle Cell Disease?

An inherited disease of red blood cells Affects hemoglobin Polymerization of hemoglobin leads to a cascade of effects decreasing blood flow Tissue hypoxia causes acute and chronic damage

Prevalence/ Incidence of SCD

In African-Americans the incidence of SCD is 1 in 375 for HbSS, 1 in 835 for HbSC and 1 in 1,667 for Sickle beta-thalassemia. In addition, 1 in 12 African-Americans are carriers for the disorder In other U.S. populations, the prevalence of sickle cell disease is 1 in 58,000 Caucasians; 1 in 1,100 Hispanics (eastern states); 1 in 32,000 Hispanics (western states); 1 in 11,500 Asians; and 1 in 2,700 Native Americans

Sickle Cell Disease

SCD Genotype

Genotype

Genotype prevalence

Sickle cell anemia (SS) Sickle Hb C disease (SC) Sickle S beta plus (S+ thalassemia ) Sickle Beta zero (S thalassemia)

65% 25% 8% 2%

Who Is At Risk? The disease originated in at least 4 places in Africa,

Mediterranean countries (such as Turkey, Greece, and Italy), and in the Indian/Saudi Arabian subcontinent. It exists in all countries of Africa and in areas where Africans have migrated. It is most common in West and Central Africa where as many as 25% of the people have sickle cell trait and 12% of all babies are born with a form of the disease. In the United States with an estimated population of over 270 million, about 1,000 babies are born with sickle cell disease each year. In contrast, Nigeria, with an estimated 1997 population of 90 million, 45,000-90,000 babies with sickle cell disease are born each year.

Who Is At Risk?

Most common in people whose families come from Africa, South or Central America (especially Panama), Caribbean islands, Mediterranean countries (such as

Some Genetic History

The error in the hemoglobin gene results from a genetic mutation that occurred many thousands of years ago in people in parts of Africa, the Mediterranean basin, the Middle East, and India.
A deadly form of malaria was very common at that time Malaria epidemics caused the death of many In areas where malaria was a problem, children who inherited one sickle hemoglobin gene and who, therefore, carried the sickle cell trait - had a survival advantage. Unlike the children who had normal hemoglobin genes, they survived the malaria epidemics they grew up, had their own children, and passed on the gene- for sickle hemoglobin.

History
As populations migrated, the sickle cell-mutation spread to other Mediterranean areas, further into the Middle East and eventually into the Western Hemisphere.
In the United States and other countries where malaria is not a problem, the sickle hemoglobin gene no longer provides a survival advantage. Instead, it may be a serious threat to the carrier's children, who may inherit two abnormal sickle hemoglobin genes and have sickle cell anemia.

Inheritance of Sickle Cell Anemia

If one parent has sickle cell trait (HbAS) and the other does not carry the sickle hemoglobin at all (HbAA) then none of the children will have sickle cell anemia. There is a one in two (50%) chance that any given child will get one copy of the HbAS gene and therefore have the sickle cell trait. It is equally likely that any given child will get two HbAA genes and be completely unaffected.

Inheritance of Sickle Cell Anemia

If both parents have sickle cell trait (HbAS) there is a one in four (25%) chance that any given child could be born with sickle cell anemia. There is also a one in four chance that any given child could be completely unaffected. There is a one in two (50%) chance that any given child will get the sickle cell trait.

Inheritance of Sickle Cell Anemia

If one parent has sickle cell trait (HbAS) and the other has sickle cell anaemia (HbSS) there is a one in two (50%) chance that any given child will get sickle cell trait and a one in two (50%) chance that any given child will get sickle cell anemia. No children will be completely unaffected.

Inheritance of Sickle Cell Anemia

If one parent has sickle cell anaemia (HbSS) and the other is completely unaffected (HbAA) then all the children will have sickle cell trait. None will have sickle cell anemia. The parent who has sickle cell anemia (HbSS) can only pass the sickle hemoglobin gene to each of their children.

Signs and Symptoms

Individual signs and symptoms varies. Some have mild symptoms, others have very severe symptoms and may be hospitalized for treatment Present at birth, many infants doesnt show signs until after 4 months of age Anemia: Fatigue (tiredness), pale skin and nail beds, jaundice, and shortness of breath Pain (Sickle Cell Crisis): Sudden episode of pain throughout the body. Common sites: bones, lungs, abdomen, and joints. Lack of blood flow can cause pain and organ damage.

 First described in Chicago in 1910 by James Herrick as an inherited condition that results in a decrease in the ability of red blood cells to carry oxygen throughout the body Sickle red blood cells become hard and irregularly shaped (resembling a sickle) Become clogged in the small blood vessels and therefore do not deliver oxygen to the tissues. Lack of tissue oxygenation can cause excruciating pain,

Normal Vs. Sickle Red Cells

Normal
Disc-Shaped Deformable Life span of 120 days

Sickle
Sickle-Shaped Rigid Lives for 20 days or less

Complications
Fever/infection Acute chest syndrome Eye trauma (hyphema) Priapism Stroke Splenic sequestration Severe pain

Acute Chest Syndrome

A leading cause of death in sickle cell disease

Clinically: Acute onset of fever, respiratory symptoms, new infiltrate on chest x-ray Causes
Infection Fat emboli Lung infarct

Since you cannot distinguish between acute chest syndrome and pneumonia clinically there is no change in treatment.

Stroke
Any acute neurologic symptom other than mild headache, even if transient, requires urgent evaluation. Historically 8 to 10% of children with SS Silent Stroke in 22% of children with hemoglobin SS

Treatment: Chronic transfusion therapy to maintain sickle hemoglobin at or below 30%

Stroke
Intracranial hemorrhage
More common in adults

Sequela overt and silent strokes

Paralysis: overt stroke Neuropsychologic changes: both overt and silent strokes
Visual-spatial impairment Impaired memory Poor impulse control

Splenic Sequestration
Sudden trapping of blood within the spleen Usually occurs in infants under 2 years of age with SS Spleen enlarged on physical exam, may not be associated with fever, pain, respiratory, or other symptoms Circulatory collapse and death can occur in less than thirty minutes

Recurrence very common (50%) Associated with high mortality (20%)

Splenic Sequestration
Hemoglobin SS
Incidence increased: 6 and 36 months
Overall incidence about 15%

Hemoglobin SC
Incidence increased: 2 and 17 years
Mean age 8.9 years Can occur in adolescence and adulthood Incidence about 5%

Hand Foot Syndrome Dactylitis

Early complication of sickle cell disease Highest incidence 6 months to 2 years Painful swelling of hands and feet Treatment involves fluids and pain medication Fevers treated as medical emergency

Renal Disease
Renal findings
Decreased ability to concentrate urine Decreased ability to excrete potassium Inability to lower urine pH normally Hematuria / papillary necrosis

Risk factors for progressive renal failure

Anemia, proteinuria, hematuria

Renal Disease
Proteinuria/Nephrotic syndrome 40% of SCD patients with nephrotic syndrome develop end-stage renal disease Occurs in ~ 20% of all patients Occurs in 4.5% of all pediatric patients- increased in hemoglobin SS to 6.5%
Increased incidence with age Increased with anemia, increased MCV, and increased leukocyte count

Renal failure common in adults

Gall Bladder and Liver

Gall stones and biliary sludge
Monitor by ultrasound every 1-2 years

Cholestasis
May progress, leading to bleeding disorders or liver failure

Iron overload
Due to chronic transfusions

Chronic hepatitis

Hemolysis and Vaso-occlusion

Hemolysis:
The anemia in SCD is caused by red cell destruction, or hemolysis, and the degree of anemia varies widely between patients. The production of red cells by the bone marrow increases dramatically, but is unable to keep pace with the destruction.

Vaso-occlusion:
Occurs when the rigid sickle shaped cells fail to move through the small blood vessels, blocking local blood flow to a microscopic region of tissue. Amplified many times, these episodes produce tissue hypoxia. The result is pain, and often damage to organs.

Bone Disease Diagnosis and Treatment

Avascular necrosis of hips and shoulders
Index of suspicion
Persistent hip or shoulder pain Plain film or MRI

Treatment
Conservative
NSAIDs and 6 weeks of rest off affected limb Physical therapy

Chronic Complications
Anemia/Jaundice Brain Damage/Stroke Kidney failure Decreased lung function Eye disease (bleeding, retinal detachment) Leg ulcers Chronic pain management

Anemia Jaundice
Common and starting in the first year of life Decreased lifespan of sickle red cells
Hemolysis Anemia Hyperbilirubinemia Reticulocytosis

Leg Ulcers
Occurs in about 25% of all hemoglobin SS patients Predominantly males
Incidence increased with Age Decreased hemoglobin Incidence decreased with alpha thalassemia

Recurrence rate is ~ 75%

Chronic Pain
Pain lasting >3 to 6 months
Patients should receive comprehensive psychologic and clinical assessment

Treatment
Analgesics Hydroxyurea Relaxation techniques Physical and occupational therapy

Fever and Infection

Fever > 38.5 C (101F) is an EMERGENCY Basic laboratory evaluation:
CBC with differential and reticulocyte count, blood, urine, and throat cultures, urinalysis, chest x-ray

Indications for hospitalization & IV antibiotics: -Child appears ill -Any temperature > 40C -Abnormal laboratory values Start IV antibiotics IMMEDIATELY if child appears ill or temperature > 40C (DO NOT WAIT FOR LABS)

Management
Health maintenance Infection prevention Pain management Sickle emergencies Chronic disease management

Health Maintenance
Frequent visits: every 3 to 6 months Immunizations
Routine immunizations Hib- 6 months and older 23 valent Pneumovax at five years

Penicillin prophylaxis beginning no later than two months Nutrition and fluids
Folate supplementation is controversial

Health Maintenance
Physical exam with attention to:
Growth and development, jaundice, liver/spleen size, heart murmur of anemia, malocclusion from increased bone marrow activity, delayed puberty

Lab evaluations:
CBC with differential and reticulocyte count, urinalysis, renal & liver function

Health Maintenance
Special studies Brain- Transcranial doppler ultrasonography, MRI/MRA Lungs- Pulmonary function tests, Echo cardiogram for pulmonary hypertension Neurologic- neuropsychological testing

Current Recommendations
Penicillin Prophylaxis: SS, SbThalassemia
2 months to 3 years: 125 mg PO BID Over 3 years: 250 mg PO BID
When to discontinue is controversial

Penicillin Prophylaxis: SC and Sb+ Thalassemia

SC warrants penicillin prophylaxis similar to SS Sb+ Thalassemia: penicillin prophylaxis can be safely discontinued at 5 years
Routine use in infants and children is controversial

Special Circumstances
History of repeated sepsis, surgical splenectomy

Eye Examination
Retinal vessel disease
Incidence 33% in hemoglobin SC Incidence 3% in SS Sea Fan

Annual evaluation after age 10 years by ophthalmologist

Laser photocoagulation for vessel disease

Salmon Patch: SC

Priapism
Commonly occurs in children and adolescents with SS or SC Treatment is difficult
Opioid pain medication Intravenous fluids Aspiration and irrigation of the corpus cavernosum Surgery Blood Transfusions

Impotence with severe disease or recurrent episodes

Urethra Corpus cavernosum

Treatments For Splenic Sequestion

Intravenous fluids
Maintain vascular volume

Cautious blood transfusion

Treat anemia, sequestered blood can be released from spleen

Spleen removal or splenectomy

If indicated

Pain Management
Acute pain
Hand-foot syndrome (dactylitis) Painful episodes: vasoocculsion Splenic sequestration Acute chest syndrome Cholelithiasis Priapism Avascular necrosis Right upper quadrant syndrome

Pain Management
Pain is an emergency
Hospital evaluation: Hydration: 1.5 times maintenance unless acute chest syndrome suspected Assess pain level and treat
Do not withhold opioids Frequently reassess pain control

Assess for cause of pain/complications

Pain Management
Mild-moderate pain
Acetaminophen
Hepatotoxic

Non-steroidal anti-inflammatory agents (NSAIDs) -Contraindicated in patients with gastritis/ulcers and renal failure -Monitor renal function if used chronically

Pain Management
Moderate-severe pain
Opioids are first-line treatment Morphine sulfate or hydromorphone Meperidine NOT recommended
(Metabolite causes seizures & renal toxicity)

Moderate or less severe pain

Acetaminophen or NSAID's in combination with opioids Other adjuvant medications (sedatives, anxiolytics)
May increase efficacy of analgesics

Treatment
For respiratory distress
Antibiotic coverage Supplemental oxygen Partial exchange transfusion

For splenic sequestration

Repletion of intravascular volume Severe anemia, transfuse

Treatment
For suspicion of stroke
Exchange transfusion

For priapism
Analgesia, hydration Partial exchange transfusion

Treatment
Outpatient
Vaccinations
Pneumococcal, meningococcal, influenza vaccines

Penicillin prophylaxis Folic acid therapy Hydroxyurea for severe symptoms

Consideration for BMT for severe cases

Adolescents and Transition of Care

Young adults (>20 years) with frequent pain crises at greatest risk for early death
Barriers to care for young adults
Lack of adult SCD providers Loss of medical coverage Developmental (level of independence, denial of chronic illness) Ineffective coping skills (passive versus active)

Adolescents and Transition of Care

Develop explicit plan for transition
Team approach- pediatric and adult providers, social work, school/vocational staff, support groups Plan gradual transition (start 1 year before) Continue communication between pediatric & adult providers after transition

Genetic Counseling
Who should receive counseling?
-Parents of newborns with sickle disorders or traits -Pregnant women/ prenatal counseling

What is the purpose of counseling?

-Education -Informed decision-making

Content should include:

-Genetic basis, chances of disease or trait (potential pregnancy outcome), disease-related health problems, variability/unpredictability of disease, family planning, average life span

Thank You

References
www.nhlbi.nih.gov/health/prof/bl ood/sickle/sc_mngt.pdf
Nelsons Book of Medicine eMedicine