Sickle cell disease is generally categorized into the following types:

1. Sickle Cell Anaemia (Homozygous): Individuals with this form of the disease have red blood cells containing only the abnormal beta globin chains, resulting in HbSS (SS) hemoglobin. This is commonly referred to as sickle-cell anaemia, and those affected exhibit the full range of signs and symptoms associated with the condition. A person with sickle cell anaemia inherits two copies of the mutated hemoglobin gene, one from each parent. This genetic makeup is represented as HbSS or SS. Other terms used to describe this condition include: HbSS, SS disease, Haemoglobin S.

2. Sickle Cell Trait (Heterozygous): In this case, a person’s red blood cells contain a mix of both normal beta globin chains (HbA) and abnormal beta globin chains (HbS). Consequently, their hemoglobin is a combination of both HbA and HbS (HbAS). Someone with sickle cell trait inherits a single copy of the normal hemoglobin gene from one parent and one copy of the faulty hemoglobin gene from the other parent. This genetic combination is denoted as HbAS. People with sickle cell trait are typically asymptomatic, meaning they usually do not show the characteristic symptoms of sickle cell disease. They are considered carriers of the mutated gene and have the potential to pass it on to their offspring.

To understand Homozygous and Heterozygous:

SCD (Sickle Cell Disease): Think of SCD as a problem arising from faulty genetic instructions for building red blood cells. Imagine it like a construction manual with errors that should guide the making of strong, healthy red blood cells (the “bricks” of your blood). These errors lead to red blood cells that are misshapen and don’t function properly.

Autosomal: This term relates to the autosomes, which are the chromosomes responsible for most of your traits, excluding those related to sex determination (male or female). Picture these chromosomes as the foundational structure of a house.

Heterozygous: Every individual has two copies of each autosome, inheriting one from each parent. Imagine receiving one instruction manual with correct instructions from one parent and another manual with errors from the other. This means you possess one normal copy and one faulty copy of the gene associated with sickle cell disease. As a result, you are a “carrier” of the faulty gene but do not have sickle cell disease itself.

Homozygous: This indicates that you’ve received the same version of the gene from both parents. There are two possibilities here:

• Homozygous dominant: You inherited two normal instruction manuals (one from each parent). Your red blood cells are built correctly, and you do not have sickle cell disease.

• Homozygous recessive: You inherited two faulty instruction manuals (one from each parent). This leads to significant problems with your red blood cells, and you have sickle cell disease.

Recessive: A recessive gene will only cause a disease if an individual has two copies of the faulty gene (as seen in the homozygous recessive scenario). Think of it as needing two incorrect instruction manuals to build a house with problems.

Dominant: A dominant gene will cause a disease even if only one faulty copy is present (as in the heterozygous case). Imagine the faulty instruction manual overriding the correct one.

Summary:

• SCD: Errors in the genetic instructions cause problems with red blood cells.

• Autosomal: Relates to the non-sex chromosomes that determine most traits (the house’s foundation).

• Heterozygous: Having one normal and one faulty copy of a gene (one correct and one faulty instruction manual).

• Homozygous: Having two identical copies of a gene (two correct or two faulty instruction manuals).

• Recessive: Two faulty copies of a gene are needed for the disease to be present (two faulty instruction manuals to build a bad house).

• Dominant: Only one faulty copy of a gene is needed for the disease to be present (one faulty instruction manual is enough to build a bad house).

• Red Blood Cells: These cells are responsible for carrying oxygen throughout the body.

• Haemoglobin: This is the protein within red blood cells that binds to oxygen.

• Haemoglobin Gene: This gene, located on chromosome 11, provides the instructions for making haemoglobin.

Possibility of Sickle cell Disease

Problems associated with sickle cell disease typically begin around 5 to 6 months of age. This timing is related to the decreasing levels of fetal hemoglobin in the infant’s blood. Sickle-cell disease develops when an individual inherits two copies of the abnormal haemoglobin gene, one from each parent. This gene is located on chromosome 11.

Cause of Sickle Cell Disease

The underlying cause of sickle cell disease is a defect in the beta globin chains of hemoglobin. Specifically, a particular amino acid is replaced by another (substitution of valine for glutamic acid) at position 6 of the chain. This substitution leads to the production of abnormal hemoglobin known as HbS.

In simpler terms, sickle cell disease arises from a genetic change, or mutation, in the gene responsible for producing haemoglobin, the protein in red blood cells that carries oxygen.

Normal Haemoglobin: Normal adult haemoglobin (HbA) is composed of two alpha globin chains and two beta globin chains.

Sickle Cell Haemoglobin: In sickle cell disease, a single change occurs within the genetic code for the beta globin chain. This is a point mutation where the instructions to include glutamic acid at position 6 are replaced with instructions to include valine. This altered haemoglobin is called HbS.

Pathophysiology of Sickle Cell Disease.

Normally, each haemoglobin molecule comprises four heme molecules (containing iron) attached to one molecule of globin (protein).

However, in sickle cell disease, this structure is altered, causing red blood cells to adopt a sickle shape. This shape change occurs because glutamic acid is replaced by valine in the hemoglobin molecule. These sickle-shaped cells become elongated when oxygen levels are low, in conditions of acidosis, or during dehydration.

When red blood cells (RBCs) containing only the abnormal HbS (homozygous HbS) are in environments with reduced oxygen, the sickling process is initiated. This process distorts the cell membranes, making the cells more likely to stick together. This clumping leads to increased blood viscosity, causing vessel occlusion (blockage) and subsequent tissue necrosis (tissue death due to lack of blood supply).

Importantly, these sickled cells often fail to return to their normal shape even when normal oxygen levels are restored. As a consequence, these rigid blood cells are unable to squeeze through narrow capillaries, leading to further blockage of blood vessels and ischemia (reduced blood flow) to tissues. The anaemia associated with sickle cell disease is a result of haemolysis, the premature destruction of these abnormally shaped red blood cells.

Although the bone marrow attempts to compensate for this destruction by producing new red blood cells, the rate of production cannot keep pace with the rate of destruction. While healthy red blood cells typically survive for 90–120 days, sickled cells only last for about 10–20 days. Additionally, increased trapping (sequestration) of red blood cells in the spleen also contributes to the development of anaemia.

Clinical Presentation of SCD

Children with sickle cell disease are often asymptomatic early in life, typically until later in the first year. This is because they still have higher levels of fetal haemoglobin, which protects red blood cells from sickling. The severity of symptoms can vary considerably among individuals with SCD. The disease can lead to a range of both acute and chronic complications, some of which can be life-threatening.

Common signs and symptoms include:

• Painful swelling of hands and feet (Hand-foot syndrome): This is a frequent early sign in children, resulting from vaso-occlusive crises affecting the small blood vessels in the hands and feet.

• Pain crisis (sickle crisis): A hallmark of the disease, characterized by episodes of intense pain caused by blocked blood flow to specific areas of the body. These crises can last for days or even weeks. Pain can be experienced in the chest, abdomen, limbs, and joints.

• Anaemia: A consistent feature of SCD due to the shortened lifespan of sickled red blood cells. This leads to persistent fatigue, weakness, and paleness.

• Jaundice: A yellowish discoloration of the skin and eyes, caused by the breakdown of red blood cells and the release of bilirubin.

• Haemoglobin levels: Typically low, ranging from 6 g/dL to 9 g/dL, reflecting the severity of the anaemia.

• Shortness of breath: Can arise from complications such as pneumonia, acute chest syndrome, and pulmonary hypertension.

• Fatigue and weakness: Common symptoms due to the reduced oxygen-carrying capacity of the blood.

• Priapism: A prolonged and painful erection, lasting for hours or days, caused by blocked blood flow in the penis. If not treated promptly, it can lead to impotence.

• Abdominal swelling and pain: Often associated with enlargement of the spleen (splenomegaly) or blockages in the blood vessels supplying the intestines.

• Unusual headache: May be a warning sign of stroke, as sickled cells can obstruct blood flow to the brain.

• Loss of appetite: A frequent symptom linked to anaemia and pain.

• Irritability: Can be a consequence of pain, fatigue, and other discomforts.

• Bossing of the bones of the skull: An indication of increased red blood cell production (erythropoiesis) in the bone marrow to compensate for the destruction of sickle cells.

• Intercurrent infections: Individuals with sickle cell disease are more susceptible to various infections, including pneumonia, acute respiratory infections, and malaria, which can be further complicated by severe anaemia.

• Splenomegaly: Enlargement of the spleen is common in younger children but often the spleen shrinks and becomes damaged (splenic infarction) in older children.

• Growth retardation: Can occur due to chronic illness, recurrent pain, and infections.

• Stroke: A severe complication resulting from blocked blood flow to the brain, potentially causing permanent brain damage.

• Newborns: May present with jaundice, delayed umbilical cord separation, and potential failure to thrive.

Clinical presentations at different ages:

• Children:

  • Dactylitis (Hand-foot Syndrome): Painful swelling of the hands and feet is a common early sign.

  • Splenomegaly: Often present in younger children but may be absent in older children due to splenic damage.

  • Delayed growth and development: Are common due to recurrent infections and pain episodes.

  • Delayed puberty: Can occur, particularly in males.

• Adults:

  • Chronic pain: A significant and often unpredictable feature of the disease.

  • Pulmonary complications: Pulmonary hypertension, acute chest syndrome, and pneumonia are frequent issues.

  • Osteonecrosis: Damage to bone tissue due to insufficient blood supply.

  • Avascular necrosis: Can affect bones, especially the hips and shoulders.

  • Chronic kidney disease: Can develop over time due to repeated damage to the kidneys.

Chronic Symptoms:

• Jaundice: Persistent yellowing of the skin and eyes due to red blood cell breakdown.

• Gallstones: Formation of stones in the gallbladder, often due to increased bilirubin from red blood cell destruction.

• Progressive kidney impairment: Damage to blood vessels in the kidneys can lead to reduced kidney function over time.

• Growth retardation: Slower growth of long bones and skeletal deformities, particularly in the spine, can occur.

• Delayed puberty: The chronic illness can delay the onset of puberty.

• Chronic painful leg ulcers: Related to chronic anaemia and poor blood flow to the extremities.

• Decreased lifespan: While medical advancements have improved life expectancy, individuals with sickle cell disease still tend to have a shorter lifespan compared to the general population.

• Altered body structures: These can include “bossing” of the skull (abnormal thickening of the skull bones) and septic necrosis (bone death due to infection) in the femur (thigh bone) and the head of the humerus (upper arm bone).

Sickle-cell crisis

A sickle cell crisis refers to episodes of sudden, severe pain that can last for several hours to several days.

The terms “sickle-cell crisis” or “sickling crisis” are often used to describe various acute conditions that can occur in individuals with Sickle Cell Disease. It happens when the misshapen red blood cells block small blood vessels that supply blood to the bones. Children experiencing a sickle cell crisis may complain of pain in the back, knees, legs, arms, chest, or stomach. The pain can be described as throbbing, sharp, dull, or stabbing.

Types of Sickle Cell Crisis.

(i) Vaso-occlusive Crisis: This is the most common type of sickle cell crisis. The sickle-shaped cells obstruct small blood vessels, leading to a lack of blood flow (ischemia) and tissue damage (infarction) in the affected area. This causes pain, swelling, and inflammation.

• Symptoms: Intense pain in the bones, joints, abdomen, chest, or head. Other symptoms may include fever, fatigue, and shortness of breath.

• Extremities: Bone damage can occur, leading to osteoporosis (weakening of bones) or ischaemic necrosis (bone death due to lack of blood supply).

• Foot and hand syndrome (Dactylitis): This is due to lack of blood flow (aseptic infarction) in the small bones of the hands and feet (metacarpals and metatarsals), causing swelling and pain. It is often seen in infants and toddlers.

• Triggers: Factors that can trigger a vaso-occlusive crisis include dehydration, infection, cold weather, high altitude, and strenuous physical activity.

• Treatment: Focuses on pain management with analgesics, providing intravenous fluids, and, in severe cases, blood transfusions.

(ii) Splenic sequestration Crisis: In this type of crisis, a large volume of blood becomes trapped within the spleen, leading to a significant decrease in circulating blood volume and a drop in blood pressure. The spleen becomes markedly enlarged.

• Symptoms: Abdominal pain, swelling, fever, and signs of shock. A rapid and significant decrease in red blood cell mass occurs within hours. Signs of circulatory collapse can develop quickly.

• This type of crisis is a leading cause of death in infants with sickle cell disease.

• Treatment: Requires immediate medical attention, including intravenous fluids, blood transfusions, and, in some cases, surgical removal of the spleen (splenectomy).

(iii) Aplastic Crisis: This occurs when the bone marrow temporarily stops producing red blood cells, leading to a sudden and severe drop in the red blood cell count (anaemia) and a worsening of symptoms.

• Cause: Aplastic crises are often triggered by viral infections, such as parvovirus B19. Other causes include folic acid deficiency and exposure to substances toxic to the bone marrow (e.g., phenylbutazone).

• Symptoms: Fatigue, weakness, paleness (pallor), and shortness of breath.

• Treatment: Primarily involves blood transfusions to increase the red blood cell count.

(iv) Haemolytic Crisis: A haemolytic crisis happens when red blood cells are destroyed at an accelerated rate, faster than the body can replace them.

• Cause: Often triggered by infections.

• Symptoms: Fatigue, pallor, jaundice, and dark urine.

• Treatment: Includes blood transfusions and treatment of any underlying infections.

• Causes of haemolysis (red blood cell destruction) can include:

  • A lack of specific proteins within red blood cells.

  • Autoimmune diseases.

  • Certain infections.

  • Defects in the haemoglobin molecules within red blood cells.

  • Defects in the proteins that form the internal structure of red blood cells.

  • Side effects of certain medications.

  • Reactions to blood transfusions.

(v) Acute chest syndrome: This is a serious complication affecting the lungs. It occurs when sickle-shaped red blood cells block blood flow to the lungs, causing inflammation and damage. It can be life-threatening. It often develops suddenly, especially when the body is under stress due to infection, fever, or dehydration.

• Symptoms: Chest pain, fever, shortness of breath, cough, and rapid breathing.

• Treatment: Involves oxygen therapy, antibiotics, pain management, and, in some cases, mechanical ventilation to support breathing.