Course:MEDG550/Student Activities/Sickle Cell Disease

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A) Normal red blood cells flowing through a blood vessel. The smaller image is a cross-section of a normal red blood cell with typical hemoglobin. B) Sickle shaped red blood cells blocking the blood flow in a blood vessel. The smaller image is a cross-section of a sickle cell with abnormal hemoglobin.

Sickle cell disease (SCD) is a term for a group of inherited blood disorders that are characterized by an altered red blood cell shape. Normally, red blood cells are disc-shaped. In sickle cell disease, the red blood cells are a crescent, or sickle, shape[1]. This abnormal red blood cell shape is most commonly occurring in individuals with African ancestry, and also more common in people with a Indian, Mediterranean, Middle Eastern, and Hispanic background[2][3].

The reason for their altered shape is a problem with the protein, hemoglobin. Hemoglobin is found within red blood cells, and its purpose is to capture oxygen in the lungs and deliver it to the different areas of the body[4].

Cause

Hemoglobin, made up of two alpha and two beta globin subunits and a heme molecule.

The cause of sickle cell disease is a genetic change that results in the abnormal formation of a protein called hemoglobin. Hemoglobin is found in red blood cells and functions to carry oxygen through the blood to various parts of the body[4]. Hemoglobin is made up of four subunits: two subunits called alpha-globin and two subunits called beta-globin. Each of these subunits carry an iron-containing molecule called heme, which is responsible for carrying an oxygen molecule.

In sickle cell disease, the structure of the beta-globin subunits are altered due to a change in the gene that provides instruction for creating the beta-globin molecule. This genetic change causes an abnormal version of beta-globin, known as hemoglobin S (HgbS), to be formed, which leads to the sickle-shape of the red blood cells[5]. The abnormal HgbS causes the protein to stick to other hemoglobins and create long, stiff rods. These rods cause the sickle red blood cell shape[4]. This sickle shape makes it difficult for the red blood cells to travel through the body, and therefore there are complications delivering oxygen to the organs and tissues of the body, possibly resulting in anemia and other health complications.

Clinical Features

In people with sickle cell disease, the malformed red blood cells rupture and die more quickly than usual. This results in a deficiency in red blood cells and hemoglobin and decrease in oxygen transport, and is called anemia.

Signs and symptoms of sickle cell disease and anemia usually begin in childhood or late infancy, and can include[6]:

  • Infections
  • Swelling of the hands and feet
  • Jaundice
  • Pale skin
  • Fatigue

Additionally, the sickle cell shape makes it difficult for the red blood cells to travel properly through the blood vessels, sometimes causing blocks in the vessels. In this situation, oxygen cannot reach some areas of the body. This can lead to episodes of severe pain some part of the body that can last up to a week, called a sickle cell crisis (also called sickling crisis)[1]. The blockages can lead to Acute Chest Syndrome, characterized by breathing difficulties and chest pain[3], and can also lead to an enlarged spleen, causing severe pain in the abdominal area[3]. The impaired travel and blockages can also lead to high blood pressure, and in severe cases, stroke[7].

The severity of the condition varies between individuals. Over time, the lack of oxygen in different areas of the body can cause organ damage, for example in the spleen, kidneys, lungs and brain.

Genetics

Genes are molecules in our cells that contain instructions for creating different proteins. These proteins are essential to human life, carrying out functions from digesting certain foods, to helping make up the colour of our eyes. There are over 25,000 genes within each cell of the human body. Each person has two copies of every gene, one inherited from mother and one inherited from father.

The hemoglobin S that characterizes sickle cell disease is a result of a change in the beta-globin gene, called the HBB gene[8]. A single letter change in the DNA code (a point mutation) leads to a change in the protein structure for the beta-globin protein, creating hemoglobin S and leading to sickle cell disease. For hemoglobin S specifically, a spelling mistake in the normal DNA code "GAG" causes it to become "GTG"; this mistake leads to a component of the protein called "glutamic acid" is replaced by a different component called "valine".[2]

Sickle cell disease is inherited in an autosomal recessive manner[8][3]. This means that an individual must have both copies of their beta-globin genes altered in order to be affected. One of their beta-globin gene copies must be the hemoglobin S variation, and the other can be hemoglobin S, C or a beta-thalassemia variant. Individuals with one hemoglobin S variation and one normal beta-globin gene are known as carriers; they have sickle cell trait, and do not have symptoms aside from the possibility of mild anemia[9].

Types of Sickle Cell Disease

The types of sickle cell disease depend on the specific changes in the HBB gene. At least one of the HBB genes must have the hemoglobin S variation, but the other may have a different variation that can cause a different type of sickle cell disease.[8]

Sickle Cell Anemia

When both copies of the beta-globin gene have the specific gene change that causes hemoglobin S to be formed[8], an individual is diagnosed with Sickle Cell Anemia.

Other Types

In other cases, one copy of the beta-globin gene results in hemoglobin S, and the other copy of the beta-globin gene has a different genetic change. There are a few different types of sickle cell disease resulting from this combination of hemoglobin S and various other alterations. As mentioned above, the other alterations can be hemoglobin C or beta-thalassemia variants. In each case, the other altered copy also affects the formation of hemoglobin, therefore also likely to result in anemia[8].

Prevalence and Incidence

Sickle cell disease includes some of the most common blood disorders that can be passed down in families. Globally, the estimated birth prevalence is approximately 1 in 900 for sickle cell disease (reported as 112 per 100,000). It is more common in individuals of African descent, where the birth prevalence is closer to 1 in 90 (reported as 1125 in 100,000)[8].

In the United States, the incidence of sickle cell trait was estimated to be approximately 1 in 65 (reported as 15.5 per 1,000)[9].

Diagnosis

Blood Test

Red blood cells, visualizing both normal and sickle shape.

Sickle Cell disease is diagnosed by a blood test. Doctors use a test to check what type of hemoglobin is in a person’s blood. In a person with Sickle Cell disease, nearly all of their blood cells will have hemoglobin S. In a person who has sickle cell trait, less than half of their blood cells will have hemoglobin S. People with two normal copies of the HBB gene will have no hemoglobin S.

In many countries, babies are checked for Sickle Cell disease at birth. This is done by pricking the baby’s heel, then collecting and examining the baby’s blood using the same tests used for adults. This may be repeated when the baby is 6 months old, or may be followed up by a genetic test depending on the results[3][10][11].

Genetic Testing

Doctors can sequence the beta-globin gene by taking another blood test. Based on the sequence of this gene, doctors can tell if someone has Sickle Cell disease. However, genetic tests are not common since Sickle Cell can be diagnosed just by running tests on the blood without sequencing the gene[11].

Treatment

There are various treatments that can help with the symptoms of sickle cell disease as well as a potential cure.

Transfusion

Sickle-shaped cells can be taken out of the body while normal-shaped cells are put back in. This is a process called transfusion. Since the sickle shape is what causes the symptoms of Sickle Cell disease, replacing the cells is an effective treatment.

However, not everybody responds well to transfusion. Adding new red blood cells also adds iron to the body. Since our bodies do not have many ways to get rid of extra iron, some people can get too much iron if they are receiving transfusions regularly. Some people’s bodies may reject the blood that is put into them, or may develop an infection after transfusion. Modern hospitals and blood banks are very careful about making sure blood types are compatible, so this is rare[7][3].

Hydroxyurea

Hydroxyurea is a medicine that is taken by mouth, which can stop the body from making hemoglobin S. It can make pain crises less common and reduces the need for transfusions. It does not stop a pain crisis that is already happening. It can also make a person more likely to get an infection[7][5].

Glutamine Therapy

Glutamine is another medicine taken by mouth and is a powerful antioxidant. Doctors do not know the exact mechanisms behind why glutamine helps, but they have found that taking glutamine can prevent pain crises. The drug has been approved by the FDA for this purpose[1].

Stem Cell Transplant

It is sometimes possible to cure Sickle Cell disease with a transplant of new bone marrow. This bone marrow comes from a donor who does not have Sickle Cell disease. The donor’s marrow makes normal hemoglobin, so hemoglobin S does not build up in blood.

However, this treatment can severely impact a person’s immune system. It is possible that the donor’s marrow will not be accepted by the patient’s body, and the patient can be made very sick. Because of the risks, this treatment is usually only offered to children who have severe symptoms that do not get better with any other treatments[5][10][12].

Management

Management of sickle cell disease is focused on alleviating specific problems that arise because of the condition. These include, but are not limited to, the following:

Sickle cell crisis (pain episodes)

  • At home remedies: staying hydrated, taking aspirin or ibuprofen, putting heat on the area, massage[3]
  • Hospitalization in severe episodes: IV fluids, pain medication (morphine)[3]

Fever & Infection

Acute Chest Syndrome

  • Oxygen treatment[3]
  • Antibiotics and pain medication[3]
  • Incentive Spirometry (device that teaches someone to take slow, deep breaths in order to keep lungs healthy)[13]

Enlarged Spleen & Abdominal Pain

  • Splenectomy (surgically removing the spleen)[3]

Stroke

  • Blood transfusion to reduce risk of future strokes[5]
  • Hydroxyurea (medication to increase hemoglobin) as alternative to reduce future risk of stroke[5]

Genetic Counselling

Sickle cell disease is a group of disorders with a genetic cause, and genetic counselling can help individuals and families affected by or at risk for SCD. Genetic counsellors help individuals understand how the disease may pass through their family, what their options are for genetic testing, and how to cope with a genetic condition in their family.

Genetic counselling involves understanding the patient and/or family's reason for seeking medical help, taking detailed medical and family histories, facilitating decision-making, and supporting the patient and/or family through emotional support and resources.

Family Planning Risks

The risk to future children depends on how many, and which, alterations are seen in the HBB gene of the parents.

When two people have a baby, each person randomly passes down one copy of each of their genes. When considering sickle cell disease, there are four possible outcomes for a pregnancy, depending on the genetic makeup of the parents. The following are a few possible scenarios:

Both parents have sickle cell disease.

In this scenario, both parents have both copies of the HBB gene affected. As a result, the child will have two altered copies of the beta-globin gene. If the child receives the HgbS variation from both parents, the result will be sickle cell anemia. If the fetus receives one HgbS and one of the other beta-globin gene alterations, the result will be one of the other sickle cell diseases. Otherwise, the fetus could receive both of the alternative beta-globin gene changes, and have a different blood disorder, such as beta-thalassemia.

One parent has sickle cell disease and the other has two normal copies.

Since one parent will be guaranteed to pass down a normal copy of the beta-globin gene, the fetus will be a carrier (sickle cell trait).

Both parents are carriers for HgbS.

In this situation, both parents can either pass on their normal beta-globin gene, or their HgbS gene. Therefore, the following outcomes are possible:

  • 25% chance of having sickle cell anemia (both HgbS copies are passed down)
  • 50% chance of being unaffected carriers (one HgbS and one normal copy passed down)
  • 25% chance of being unaffected and not a carrier (both normal copies are passed down)

Prenatal Diagnosis and Pre-Implantation Genetic Testing

For parents who have been identified as carriers of an abnormal HBB variation, prenatal testing is available for current pregnancies and pre-implantation genetic testing is available for future pregnancies[14].

Prenatal Diagnosis

The specific HBB gene variations identified in the parents can be tested for in a pregnancy, through invasive procedures called chorionic villus sampling or amniocentesis. Chorionic villus sampling (CVS) involves getting a sample of the placenta through the cervix or through the abdomen around 11-13 weeks in pregnancy, while amniocentesis involves inserting a needle through the abdomen to get amniotic fluid samples after 15 weeks in pregnancy. In both methods, the samples can be sent to a laboratory, where genetic testing can be performed to see if the baby carries any abnormal HBB gene variations. However, both methods come with a small risk (0.5-1%) of miscarriage or premature labour.

Pre-Implantation Genetic Testing for Monogenic Disorders (PGT-M)

Genetic testing can also be done before a pregnancy even begins. Couples who are identified as carriers and wish to have children without the abnormal HBB gene variation can choose to conceive through in vitro fertilization (IVF), where sperm and eggs are retrieved from the parents and are fertilized in the lab to create embryos. Some cells can be taken from each embryo, and a process called pre-implantation genetic testing for monogenic disorders (PGT-M) can be used to determine whether the embryo carries the abnormal gene variation. The couple can preferentially select for embryos that do not have the abnormal gene variation.

Psychosocial Considerations

Although most individuals with SCD now survive into adulthood, the majority of individuals usually experience other co-morbidities and require lifelong comprehensive care for these chronic complications. Similar to other chronic condition, individuals with SCD may have to adjust their life goals, employment and lifestyle. [15]This coupled with the unpredictable nature of pain and other unexpected complications associated with sickle cell disease can further add to stress and symptoms. It is common for individuals with SCD and their families to experience anxiety, depression or anger. [15]Talking to a health professional or genetic counsellor may help individuals and their families cope with this diagnosis better and learn about other available resources and clinical trials.

Patient Resources

For more information and support, the following resources are available:

https://www.sicklecellsociety.org/resources/

http://www.scdcoalition.org/

References

  1. 1.0 1.1 1.2 Riley, Tanya R.; Boss, Angelo; McClain, Dominique; Riley, Treavor T. "Review of Medication Therapy for the Prevention of Sickle Cell Crisis". Pharmacy and Therapeutics. 43 (7): 417–421.
  2. 2.0 2.1 Serjeant, Graham R. "The Natural History of Sickle Cell Disease". Cold Spring Harbor Perspectives in Medicine. 3: a011783.
  3. 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 Simon, Erica; Long, Brit; Koyfman, Alex. "Emergency Medicine Management of Sickle Cell Disease Complications: An Evidence-Based Update". Journal of Emergency Medicine. 51 (4): 370–381.
  4. 4.0 4.1 4.2 Maciaszek, Jamie L.; Lykotrafitis, Geirge. "Sickle cell trait human erythrocytes are significantly stiffer than normal". Journal of Biomechanics. 44 (4): 657–661.
  5. 5.0 5.1 5.2 5.3 5.4 Ware, Russell E; Montalembert, Mariane de; Tshilolo, León; Abbouud, Miguel R. "Sickle Cell Disease". The Lancet. 390 (10091): 311–323.
  6. Porter, Stanley; Thurman, William G. "Studies of Sickle Cell Disease: Diagnosis in Infancy". American Journal of Diseases of Children. 106: 69–76.
  7. 7.0 7.1 7.2 Yawn, BP; et al. "Management of sickle cell disease summary of the 2014 evidence-based report by expert panel members". JAMA. 312: 1033–1048. Explicit use of et al. in: |last= (help)
  8. 8.0 8.1 8.2 8.3 8.4 8.5 Wastnedge, Elizabeth; Waters, Donald; Patel, Smruti; Morrison, Kathleen; Goh, Mei Yi; Adeloye, Davies; Rudan, Igor. "The global burden of sickle cell disease in children under five years of age: a systematic review and meta-analysis". Journal of Global Health. 8: 021103.
  9. 9.0 9.1 Ojodu, Jelili; Hulihan, Mary M.; Pope, Shammara N.; Grant, Althea M. "Incidence of Sickle Cell Trait — United States, 2010". Morbidity and Mortality Weekly Report. 63 (49): 1155–1158.
  10. 10.0 10.1 Kavanagh, P.L., Fasipe, T.A. and Wun, T., 2022. Sickle cell disease: a review. JAMA, 328(1), pp.57-68.
  11. 11.0 11.1 Clarke, Gwendolyn M.; Higgins, Trefor N. "Laboratory Investigation of Hemoglobinopathies and Thalassemias: Review and Update". Clinical Chemistry. 46 (8): 1284–1290.
  12. Assal, Amer; George, Diane; Bhatia, Monica; Gordillo, Christian; Howard, Nicole; Reshef, Ranf; Mapara, Markus. "Curative Allogeneic Stem Cell Transplantation Is Safe and Feasible in Adult Patients with Sickle Cell Disease Despite Lack of Matched Sibling Donor and Presence of Sickle Cell-Related Co-Morbidities". Blood. 132: 5713.
  13. Glassberg, J. "Evidence-based management of sickle cell disease in the emergency department". Emergency Medicine Practice. 13 (8): 1–20.
  14. Bender MA. Sickle Cell Disease. 2003 Sep 15 [Updated 2017 Aug 17]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1377/
  15. 15.0 15.1 Pecker, L. H., & Darbari, D. S. (2019). Psychosocial and affective comorbidities in sickle cell disease. Neuroscience letters , 705, 1–6. https://doi.org/10.1016/j.neulet.2019.04.011