SICKLE CELL DISEASE/DISORDER

SICKLE CELL DISEASE/DISORDER
By Dr B. M. L. Yarima
INTRODUCTION
Sickle cell disease and its variants are genetic disorders resulting from the presence of a mutated form of haemoglobin, haemoglobin S (Hb S).
Sickle cell disease/disorder causes significant morbidity and mortality, particularly in people of African and Mediterranean ancestry.
Morbidity, frequency of crisis, degree of anaemia, and the organ systems involved vary considerably from individual to individual.

ETIOPATHOGENESIS
Sickle cell disease (SCD) is a group of inherited red blood cell disorders. Red blood cells contain haemoglobin, a protein that carries oxygen to tissues for normal cell function. Healthy red blood cells are round , and they move through small blood vessels to carry oxygen to all parts of the body.
In someone who has SCD, the haemoglobin is abnormal, which causes the red blood cells to become hard and sticky and look like a C-sharped farm tool called a “sickle.” The sickle cells die early, which causes a constant shortage of red blood cells. Also, when they travel through small blood vessels, they get stuck and clog the blood flow. This can cause pain and other serious complications (health problems) such as infection, acute chest syndrome and stroke.
NOTE- SCD is a genetic condition that is present at birth. It is inherited when a child receives two genes- one from each parent- that code for abnormal haemoglobin.

TYPES OF SCD
SCD denotes all genotypes containing at least one sickle gene, in which HbS makes up at least half the haemoglobin present.
There are several types of SCD. The specific type of SCD a person has depends on the genes they inherited from their parents. People with SCD inherit genes that contain instructions, or code, for abnormal haemoglobin.
Major sickle genotypes described so far include the following:
 HbSS disease
People who have this form of SCD inherit two genes, one from each parent, that code haemoglobin “S”. This is commonly called sickle cell anaemia and is usually the most severe form of the disease.
 HbSC
People who have this form of SCD inherit a haemoglobin “S” gene from one parent and a gene for a different type of abnormal haemoglobin called “C” from the other parent. This is usually a milder form a SCD.
 HbS beta thalassaemia
People who have this form of SCD inherit a haemoglobin “S” gene from one parent and a gene for beta thalassaemia, another type of haemoglobin abnormality, from the other parent. There are two types of beta thalassaemia:
– beta thalassaemia “zero” (HbS beta 0)
– beta thalassaemia “plus” (Hb beta +)
Those with HbS beta 0 thalassaemia usually have a severe form of SCD clinically indistintiguishable from SCA. People with HbS beta +-thalassaemia tend to have a milder form of SCD.

 HbS/hereditary persistence of fetal haemoglobin- very mild or asymptomatic phenotype.
 HbS/HbE syndrome- very rare with a phenotype similar to HbS/b+ thalassaemia
 Rare combinations of HbS with other abnormal haemoglobinopathies such as HbD Los Angeles, G-Philadelphia, HbO Arab, and others.
 Sickle cell trait (SCT) or carrier state, HbAS
People who have a sickle cell trait inherit a haemoglobin “S” from one parent and a normal gene (one that codes for haemoglobin “A”) from the other parent. People with SCT usually do not have any signs of the disease. However, in rare cases, a person with SCT may develop health problems; this occurs most often when there are other stresses on the body, such as when a person becomes dehydrated or exercises strenuously. Additionally, people who have SCT can pass the abnormal haemoglobin “S” gene on to their children.

SIGNS AND SYMPTOMS
Screening for HbS at birth is currently mandatory in the United States. For the first 6 months of life, infants are protected largely by elevated levels of foetal haemoglobin (Hb F). Sickle cell disease (SCD) usually manifests early in childhood, in the following ways:
 Acute and chronic pain: The most common clinical manifestation of SCD is vaso-occlusive crisis; pain crises are the most distinguishing clinical feature of SCD
 Bone pain: Often seen in long bones of extremities, primarily, due to bone marrow infarction.
 Anaemia: Usually present, chronic, and haemolytic in nature.
 Aplastic crisis: serious complication due to infection with parvovirus B19 (B19V).
 Splenic sequestion: Characterized by the onset of life-threatening anaemia with rapid enlargement of the spleen and high reticulocyte count.
 Infection: Organisms, that pose the greatest danger include encapsulated respiratory bacteria, particularly Streptococcus pneumoniae; adult infections are predominantly with gram-negative
organisms, especially Salmonella.
 Growth retardation, delayed sexual maturation, being underweight.
 Hand-foot-syndrome: This is a dactylitis presenting as bilateral painful and swollen hands and/or feet in children.
 Acute chest syndrome: Young children present with chest pain, fever, cough, tachypnoea, leukocytosis, and pulmonary infiltrates in the upper lobes; adults are usually afebrile, adults are usually afebrile, dyspnoiec with severe chest pain, with multilobar/lower lobe disease.
 Pulmonary hypertension: increasingly recognized as a serious complication of SCD.
 Avascular necrosis of the femoral or humeral head: Due to vascular occlusion
 Central nervous system (CNS) involvement: Most severe manifestation is stroke
 Opthalmic involvement: Ptosis, retinal vascular changes, proliferative retinitis
 Cardiac involvement: dilatation of both ventricles and the left atrium
 Gastrointestinal involvement: cholecystitis is common in children; liver may become involved
 Genitourinary involvement: kidneys lose concentration capacity; priapism is a well-recognized complication of SCD.
 Dermatologic involvement: leg ulcers are a chronic painful problem.
Appropriately half the individuals with homozygous Hb S disease experience vaso-occlusive crises. The frequency of crises is extremely variable. Some individuals have as many as 6 or more episodes annually, whereas others may have episodes only at great intervals or none at all. Each individual typically has a consistent pattern for crisis frequency.
Triggers of vaso-occlusive crises include the following:
– hypoxaemia/ hypoxia: may be due to acute chest syndrome or respiratory complications, or flying in unpressurized aircraft.
– dehydration: especially from exertion or warm weather or vomiting and diarrhoea
– Infection
– Cold weather due to vasospasm
– Emotional stress
– Pregnancy

DIAGNOSIS
SCD is suggested by the typical clinical picture of chronic haemolytic anaemia and vaso-occlusive crisis.
Laboratory tests used in patients with SCD include the following:
 Haemoglobin electrophoresis- electrophoresis confirms the diagnosis with the presence of homozygous HbS and can also document other haemoglobinothies (e.g. HbSC, HbS-beta+ thalassaemia)
 Complete Blood Count
 Serum electrolytes
 Peripheral blood smear
 Renal function (creatinine, BUN, urinalysis)
 Blood culture
Imaging Studies:
o Radiography- CXRs should be performed in patients with respiratory symptoms. Pelvic x-ray- for Avascular necrosis of mainly femoral head.
o Abdominal USS- to measure or assess spleen and liver sizes. It may be used to rule out cholecystitis or cholelithiasis.
o CT scanning: may demonstrate subtle regions of osteonecrosis not apparent on plain radiographs in patients who are unable to have MRI.
o Echocardiography: Identifies patients with portal hypertension
o Transcranial doppler ultrasonography: can identify children with SCD at risk for stroke.

TREATMENT
The goals of treatment in SCD are symptom control and management of disease complications. Treatment strategies include the following goals:
1) Management of vaso-occlusive crisis
2) Management of chronic pain syndromes
3) Management of chronic haemolytic anaemia
4) Prevention and treatment of infections
5) Management of the complications and the various organ damage syndromes associated with the disease
6) Prevention of stroke
7) Detection and treatment of pulmonary hypertension.
Pharmacotherapy:
SCD may be treated with the following medications:
 Opioid analgesics (eg, oxycodone/aspirin, methadone, morphine sulfate, oxycodone/acetaminophen, fentanyl, codeine, acetaminophen/codeine)
 Nonsteroidal analgesics (eg, ibuprofen, ketorolac, acetaminophen, aspirin)
 Antibiotics (eg, cefuroxime, amoxicillin/clavulanate, penicillin, ceftriazone, azithromycin, cefaclor)
 Antimetabolites: Hydroxyurea
 Vitamins (eg folic acid)
 Tricyclic antidepressants (eg amitriptyline)
 Vaccines (eg, pneumococcal, meningococcal, influenza, and recommended scheduled childhood/adult vaccinations)
 Others: haemoglobin oxygen-affinity modulators (eg, voxelotor), P-selectin inhibitors (eg, crizanlizumab), etc.
Other approaches to managing SCD include the following:
 Transfusions: For severe anaemia due to acute splenic sequestration, parvovirus, or hyperhaemolytic crises
 Wound debridement
 Physical therapy
 Heat and cold application
 Stem cell tranplantation: Can be curative
Combination pharmacotherapy and non-pharmacotherapy
 Vigorous hydration (plus analgesics): For vaso-occlusive crisis
 Oxygen, antibiotics, analgesics, transfusion, and bronchodilators: For treatment of acute chest syndrome.

PREVENTION
 Pre-marital screening and counselling
 Pre-conception screening and counselling
 Identifying and avoiding triggers
– dehydration: ensure adequate hydration
– fever: antipyretics, prompt treatment of cause
REFERENCES
 Medscape
 Cdc.gov/ncbddd/sicklecelldisease