What is sickle cell disease?
Sickle cell disease (SCD) refers to a group of inherited health conditions characterized by the presence of atypical hemoglobin molecules. Hemoglobin is usually composed of four protein chains, two “alpha” and two “beta”. In some patients, one or both beta chains are replaced by abnormal proteins that affect their function. If a single beta chain is replaced, this is called sickle cell trait (SCT) and is not associated with health problems. Sickle cell disease results when both beta chains are affected.[1] The commonest beta chain mutation is called hemoglobin S. If both beta chains are hemoglobin S (referred to as HbSS), the condition is called sickle cell anemia.
These alterations in the hemoglobin structure cause some red blood cells to change into a sickle, or half-moon, shape.[2] Compared to normal red blood cells, sickled red blood cells have a significantly shorter lifespan of only 10 to 20 days, while normal ones live for 90 to 120 days. Additionally, the distorted shape of sickled red blood cells can lead to the blockage of blood vessels, resulting in reduced blood flow and oxygen supply to vital organs and tissues.
What are the main signs and symptoms of sickle cell disease?
Although newborns can be screened for sickle cell disease (SCD) from birth, signs and symptoms typically don’t appear until 5 or 6 months of age. The type and intensity of these signs and symptoms vary among individuals and may change over time, depending on which organs are affected.[3]
SCD is characterized by the accelerated breakdown of sickled red blood cells (hemolysis), which reduces the number of circulating red blood cells, causing anemia. This decreases the oxygen supply to organs and tissues. Common symptoms of anemia include fatigue, tiredness, irritability, and in more severe cases, shortness of breath. Accelerated hemolysis can also cause jaundice (yellowing of the skin), or icterus (yellowing of the white part of the eye, also called the sclera). These are among the earliest signs of SCD.[2]
Sickled red blood cells are rigid and adhesive, which can obstruct small blood vessels. This can cause episodes of pain, known as pain crises, of varying intensity and frequency. Pain crises can affect any part of the body, but most commonly the lower back and lower extremities.[4] Reduced blood flow can also result in swollen hands and feet.[1]
Children’s growth rate and development during puberty may be impacted due to inadequate delivery of oxygen and essential nutrients to the body. Children affected by SCD are also more susceptible to frequent infections.[2]
How is sickle cell disease diagnosed?
Both sickle cell disease (SCD) and sickle cell trait (SCT) can be diagnosed before birth, after birth, or during adulthood.[1]
Prenatal tests, such as chorionic villus sampling (CVS) and amniocentesis, can confirm whether the baby will have SCD or SCT, and are typically offered to women with a higher risk of having a baby affected by a genetic condition.[5]
Diagnosis of SCD or SCT in newborns or adults can be done through a simple blood test. In the US, all states conduct newborn screening for SCD to enable early intervention if deemed necessary. Additionally, parents who are planning on having a baby can undergo a blood test to check if they carry the sickle cell gene and to understand the likelihood of their children having SCT or SCD.[1]
What are some of the main medical treatments for sickle cell disease?
Bone marrow transplantation and stem cell transplantation are currently the only available cures for sickle cell disease (SCD). However, these procedures are risky, and to be successful they require a close match between the donor and recipient. Finding a suitable donor, even among relatives, can be challenging, and as a result, a bone marrow transplant is typically considered and offered only to children with severe SCD.[1]
Common medications prescribed for SCD include:[6]
- Antibiotics (e.g., penicillin), which are given daily to prevent infections, especially in young children. The treatment is usually continued up until the age of 5, but sometimes it may be prescribed for longer.
- Hydroxyurea reduces the likelihood of complications from severe cases of SCD. However, it is associated with a high risk of side effects and is therefore not suitable for milder cases.
- Voxelotor is an oral medication which reduces the likelihood of sickling of red blood cells. It is approved for patients 4 years or older.
- Crizanlizumab-tmc injections can be helpful in patients 16 years or older to reduce episodes of pain. Safety for younger patients has not been determined.
- L-glutamine powder and painkillers are used to reduce pain associated with sickle cell crises.[7]
Additionally, in severe cases of anemia, or in patients who have had a stroke or are at risk of developing one, blood transfusions and red blood cell transfusions may be recommended.[6]
Have any supplements been studied for sickle cell disease?
Folic acid has long been prescribed as a supplement for SCD, despite a lack of evidence supporting its effectiveness. Folate, also known as vitamin B9, is a water-soluble vitamin involved in the production of red blood cells. It is believed that adequate intake of folic acid can alleviate anemia symptoms caused by the rapid breakdown of red blood cells in SCD patients. However, recent data analysis indicates that while supplementation with folic acid increases folate levels, it does not significantly impact hemoglobin concentration, anemia symptoms, pain crises, rate of infections, or hospitalizations.[8]
Iron deficiency is common in individuals with SCD, but there are conflicting opinions regarding supplementation with iron. On one hand, low iron levels may reduce painful crises by decreasing hemoglobin concentration in sickled red blood cells.[9] On the other hand, iron deficiency can have a detrimental impact on both physical and mental growth, making adequate levels important. Until further studies are conducted, people with SCD should consult their doctor before starting any iron supplements.
Zinc sulfate may also be a promising supplement for SCD. Studies show that it may reduce the frequency of pain crises if taken for a year, and it may reduce the number of infections after just three months of use. However, these findings are based on a small group of trials, and more studies should be conducted to verify its efficacy and safety.[10]
Additionally, research is exploring the use of L-arginine as an adjunct therapy to reduce vaso-occlusion and associated pain crises. L-arginine is required to produce nitric oxide (NO), a vasodilator. Studies show that children who received L-arginine in addition to parenteral opioids experienced a 54% reduction in total opioid use throughout the study.[11]
How could diet affect sickle cell disease?
Children with SCD are more likely to have lower weight and body mass index (BMI). This is possibly caused by reduced appetite due to elevated inflammatory mediators, and a higher basal metabolic rate and resting energy expenditure. Inadequate nutrient intake or malnutrition may also worsen SCD signs and symptoms, so special attention to diet may be beneficial, especially during the growth phase in children and the development phase in teenagers.[12]
One study from 2016 on children between 6 months and 18 years old found that intakes of calcium, iron, vitamin C, and vitamin B1 were lower in children affected by SCD. Low intakes of proteins, lipids, and carbohydrates, and low levels of micronutrients such as calcium, vitamin B1, vitamin B2, vitamin B3, iron, and phosphorus are also correlated with more hospitalization days per year in children and teenagers.[12] Nutritional interventions, such as supplementation via nasogastric tube[13], have been studied relative to their impact on children's growth rate. Despite the positive outcomes, these procedures are not easily applicable in everyday life; more studies will hopefully be performed to find more practical interventions.
Are there any other treatments for sickle cell disease?
Some studies have looked into the potential of marijuana to relieve pain crises in people with SCD, although the results were not conclusive and more data is needed.[14]
Genetic therapies are also being explored, and some are being tested in clinical trials. They target the disease by either repairing a faulty gene or by adding a new genetic sequence that improves the way the cell works. No genetic therapy is currently approved by the Food and Drug Administration (FDA) for SCD, as no genetic therapy’s safety and efficacy for treatment of SCD has been established.[6]
People with SCD are encouraged to drink more and keep hydrated, as dehydration can exacerbate pain crises. Staying updated with all recommended vaccinations, including the flu vaccination, is also crucial to prevent infections.[6]
What causes sickle cell disease?
Sickle cell disease (SCD) is an inherited condition, so it’s present at birth. It occurs when a baby receives a copy of a specific mutated form of the HBB gene from both parents, which results in one or both beta globins (the beta chains of the hemoglobin molecules) being replaced by hemoglobin S. This type of gene inheritance pattern is called autosomal recessive, which means that disease happens only when both copies of the sickle cell gene are altered. This is possible only when both parents carry the mutation.[2] People born with only one copy of the altered gene don’t usually manifest any symptoms and live a healthy life, although they can still pass the defective gene to their children. This is called sickle cell trait (SCT).[reference|url=https://www.hematology.org/education/patients/anemia/sickle-cell-disease|title=Sickle Cell Disease: American Society
Examine Database: Sickle Cell Disease
Frequently asked questions
Sickle cell disease (SCD) refers to a group of inherited health conditions characterized by the presence of atypical hemoglobin molecules. Hemoglobin is usually composed of four protein chains, two “alpha” and two “beta”. In some patients, one or both beta chains are replaced by abnormal proteins that affect their function. If a single beta chain is replaced, this is called sickle cell trait (SCT) and is not associated with health problems. Sickle cell disease results when both beta chains are affected.[1] The commonest beta chain mutation is called hemoglobin S. If both beta chains are hemoglobin S (referred to as HbSS), the condition is called sickle cell anemia.
These alterations in the hemoglobin structure cause some red blood cells to change into a sickle, or half-moon, shape.[2] Compared to normal red blood cells, sickled red blood cells have a significantly shorter lifespan of only 10 to 20 days, while normal ones live for 90 to 120 days. Additionally, the distorted shape of sickled red blood cells can lead to the blockage of blood vessels, resulting in reduced blood flow and oxygen supply to vital organs and tissues.
Individuals with sickle cell disease have at least one of the two beta globins of their hemoglobin molecules replaced by hemoglobin S (HbS). The second beta subunit can be replaced by HbS or by a different variant. The combination of these variants (also called mutations) results in different types of SCD. The following table includes the most common forms of SCD, each characterized by a different combination of beta-globin variants.
| First hemoglobin beta chain mutation | Second hemoglobin beta chain mutation | Abnormal hemoglobin genotype | Disease name |
|---|---|---|---|
| HbS | HbS | HbSS | Sickle cell anemia |
| HbS | β0 thalassemia | HbS β0 | Sickle beta zero thalassemia |
| HbS | β+ thalassemia | HbS β+ | Sickle beta plus thalassemia |
| HbS | HbC | HbSC | Sickle C disease |
Sickle cell beta-plus thalassemia and sickle cell zero thalassemia are two specific types of SCD that result from two different genetic mutations. One mutation leads to the production of HbS instead of normal hemoglobin (HbA or adult hemoglobin), which characterizes all SCD. The other mutation (β0 thalassemia or β+thalassemia) affects the amount of normal beta chains produced, hence the amount of normal hemoglobin produced. People affected by sickle beta-plus thalassemia have both HbS and normal hemoglobin, but the latter is produced in lower-than-average amounts. On the other hand, people with sickle beta zero thalassemia are characterized by the presence of HbS, but they can’t produce normal hemoglobin.
Although newborns can be screened for sickle cell disease (SCD) from birth, signs and symptoms typically don’t appear until 5 or 6 months of age. The type and intensity of these signs and symptoms vary among individuals and may change over time, depending on which organs are affected.[3]
SCD is characterized by the accelerated breakdown of sickled red blood cells (hemolysis), which reduces the number of circulating red blood cells, causing anemia. This decreases the oxygen supply to organs and tissues. Common symptoms of anemia include fatigue, tiredness, irritability, and in more severe cases, shortness of breath. Accelerated hemolysis can also cause jaundice (yellowing of the skin), or icterus (yellowing of the white part of the eye, also called the sclera). These are among the earliest signs of SCD.[2]
Sickled red blood cells are rigid and adhesive, which can obstruct small blood vessels. This can cause episodes of pain, known as pain crises, of varying intensity and frequency. Pain crises can affect any part of the body, but most commonly the lower back and lower extremities.[4] Reduced blood flow can also result in swollen hands and feet.[1]
Children’s growth rate and development during puberty may be impacted due to inadequate delivery of oxygen and essential nutrients to the body. Children affected by SCD are also more susceptible to frequent infections.[2]
Sickle cell disease is a lifelong condition, which can significantly impact the quality of life of those affected. In a 2019 study, researchers assessed 73,225 adults hospitalized for SCD to understand the prevalence of depression among them. The findings revealed that comorbid depression was more common in females aged between 35 and 50, and was associated with a higher risk of major complications and a higher cost per hospital admission.[19] However, it is important to note that this study only looked at hospitalized patients, and did not evaluate a causal relationship between SCD and depression. Nonetheless, the data suggest that incorporating mental health assessments for individuals with SCD could improve patients’ outcomes.
Both sickle cell disease (SCD) and sickle cell trait (SCT) can be diagnosed before birth, after birth, or during adulthood.[1]
Prenatal tests, such as chorionic villus sampling (CVS) and amniocentesis, can confirm whether the baby will have SCD or SCT, and are typically offered to women with a higher risk of having a baby affected by a genetic condition.[5]
Diagnosis of SCD or SCT in newborns or adults can be done through a simple blood test. In the US, all states conduct newborn screening for SCD to enable early intervention if deemed necessary. Additionally, parents who are planning on having a baby can undergo a blood test to check if they carry the sickle cell gene and to understand the likelihood of their children having SCT or SCD.[1]
If both parents carry the sickle cell trait (SCT), then their child has a 25% chance of being born with sickle cell disease (SCD) and a 50% chance of having SCT.[15]
Sickle cell disease is a disease with global spread, although people of different ancestry are unequally affected. The incidence of SCD is higher among people of African, South American, Central American, Indian, Mediterranean, and Arabian Peninsular ancestry.[2]
Research has indicated that these regions, historically impacted by malaria or experiencing significant migration from malaria-endemic countries, often exhibit a higher prevalence of SCT in the population. It seems that SCT offers a protective effect against malaria, and the body developed this genetic mutation as a defense mechanism against the disease. Individuals with SCT can still contract malaria, but they have an increased likelihood of survival. In contrast, individuals with sickle cell disease experience more severe effects from the disease.[16][17]
Bone marrow transplantation and stem cell transplantation are currently the only available cures for sickle cell disease (SCD). However, these procedures are risky, and to be successful they require a close match between the donor and recipient. Finding a suitable donor, even among relatives, can be challenging, and as a result, a bone marrow transplant is typically considered and offered only to children with severe SCD.[1]
Common medications prescribed for SCD include:[6]
- Antibiotics (e.g., penicillin), which are given daily to prevent infections, especially in young children. The treatment is usually continued up until the age of 5, but sometimes it may be prescribed for longer.
- Hydroxyurea reduces the likelihood of complications from severe cases of SCD. However, it is associated with a high risk of side effects and is therefore not suitable for milder cases.
- Voxelotor is an oral medication which reduces the likelihood of sickling of red blood cells. It is approved for patients 4 years or older.
- Crizanlizumab-tmc injections can be helpful in patients 16 years or older to reduce episodes of pain. Safety for younger patients has not been determined.
- L-glutamine powder and painkillers are used to reduce pain associated with sickle cell crises.[7]
Additionally, in severe cases of anemia, or in patients who have had a stroke or are at risk of developing one, blood transfusions and red blood cell transfusions may be recommended.[6]
Folic acid has long been prescribed as a supplement for SCD, despite a lack of evidence supporting its effectiveness. Folate, also known as vitamin B9, is a water-soluble vitamin involved in the production of red blood cells. It is believed that adequate intake of folic acid can alleviate anemia symptoms caused by the rapid breakdown of red blood cells in SCD patients. However, recent data analysis indicates that while supplementation with folic acid increases folate levels, it does not significantly impact hemoglobin concentration, anemia symptoms, pain crises, rate of infections, or hospitalizations.[8]
Iron deficiency is common in individuals with SCD, but there are conflicting opinions regarding supplementation with iron. On one hand, low iron levels may reduce painful crises by decreasing hemoglobin concentration in sickled red blood cells.[9] On the other hand, iron deficiency can have a detrimental impact on both physical and mental growth, making adequate levels important. Until further studies are conducted, people with SCD should consult their doctor before starting any iron supplements.
Zinc sulfate may also be a promising supplement for SCD. Studies show that it may reduce the frequency of pain crises if taken for a year, and it may reduce the number of infections after just three months of use. However, these findings are based on a small group of trials, and more studies should be conducted to verify its efficacy and safety.[10]
Additionally, research is exploring the use of L-arginine as an adjunct therapy to reduce vaso-occlusion and associated pain crises. L-arginine is required to produce nitric oxide (NO), a vasodilator. Studies show that children who received L-arginine in addition to parenteral opioids experienced a 54% reduction in total opioid use throughout the study.[11]
Children with SCD are more likely to have lower weight and body mass index (BMI). This is possibly caused by reduced appetite due to elevated inflammatory mediators, and a higher basal metabolic rate and resting energy expenditure. Inadequate nutrient intake or malnutrition may also worsen SCD signs and symptoms, so special attention to diet may be beneficial, especially during the growth phase in children and the development phase in teenagers.[12]
One study from 2016 on children between 6 months and 18 years old found that intakes of calcium, iron, vitamin C, and vitamin B1 were lower in children affected by SCD. Low intakes of proteins, lipids, and carbohydrates, and low levels of micronutrients such as calcium, vitamin B1, vitamin B2, vitamin B3, iron, and phosphorus are also correlated with more hospitalization days per year in children and teenagers.[12] Nutritional interventions, such as supplementation via nasogastric tube[13], have been studied relative to their impact on children's growth rate. Despite the positive outcomes, these procedures are not easily applicable in everyday life; more studies will hopefully be performed to find more practical interventions.
Some studies have looked into the potential of marijuana to relieve pain crises in people with SCD, although the results were not conclusive and more data is needed.[14]
Genetic therapies are also being explored, and some are being tested in clinical trials. They target the disease by either repairing a faulty gene or by adding a new genetic sequence that improves the way the cell works. No genetic therapy is currently approved by the Food and Drug Administration (FDA) for SCD, as no genetic therapy’s safety and efficacy for treatment of SCD has been established.[6]
People with SCD are encouraged to drink more and keep hydrated, as dehydration can exacerbate pain crises. Staying updated with all recommended vaccinations, including the flu vaccination, is also crucial to prevent infections.[6]
Children and adults with SCD are often told to avoid strenuous exercise to prevent pain crises and further complications. However, it’s common knowledge that exercise has various benefits on both mental and physical health, and that it plays an important role in development. There are currently very few studies that look into the benefits versus the risks of exercising for people with SCD, and that compare the effect of various types of exercise on the disease.
Some studies found that acute exercise can trigger an inflammatory response and increase metabolic acidosis in both children and adults with SCD. On the other hand, consistent exercise has been shown to reduce inflammation and oxidative stress and to improve vascular health and general physical function in healthy individuals. There is limited data on the effect of regular exercise on SCD, compared to intense training. More research is required to compile evidence-based guidelines and allow pe
Sickle cell disease (SCD) is an inherited condition, so it’s present at birth. It occurs when a baby receives a copy of a specific mutated form of the HBB gene from both parents, which results in one or both beta globins (the beta chains of the hemoglobin molecules) being replaced by hemoglobin S. This type of gene inheritance pattern is called autosomal recessive, which means that disease happens only when both copies of the sickle cell gene are altered. This is possible only when both parents carry the mutation.[2] People born with only one copy of the altered gene don’t usually manifest any symptoms and live a healthy life, although they can still pass the defective gene to their children. This is called sickle cell trait (SCT).[reference|url=https://www.hematology.org/education/patients/anemia/sickle-cell-disease|title=Sickle Cell Disease: American Society
Sickle cell crises are caused by constriction of the blood vessels due to the half-moon and stiff shape of sickled red blood cells. Some events or physical conditions can exacerbate this constriction, and therefore trigger a pain crisis.
Cold weather, swimming in cold water, or sudden temperature changes may trigger a pain crisis, or exacerbate an existing one. Dehydration also plays an important role, so it’s best to drink plenty of water and reduce consumption of alcohol (a dehydrating substance).
For people with SCD, it’s safe to do low-to-moderate intensity physical exercise, but strenuous activities that cause shortness of breath should be avoided, as strenuous exercise can result in a pain crisis and other complications. High altitude may also trigger pain crises and other complications, due to reduced oxygen. However, by staying hydrated, taking breaks, and gradually building up exercise intensity, people with SCD can safely travel to, and train at, high altitudes.
Additionally, anxiety and mental stress can contribute to vasoconstriction and affect blood flow, which in turn may have a detrimental effect on people suffering from SCD.[18]
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References
- ^Sickle Cell Disease: MedlinePlus
- ^Sickle Cell Disease: MedlinePlus
- ^Sickle cell disease - Symptoms: NIH(July 14, 2022)
- ^McClish DK, Smith WR, Dahman BA, Levenson JL, Roberts JD, Penberthy LT, Aisiku IP, Roseff SD, Bovbjerg VEPain site frequency and location in sickle cell disease: the PiSCES project.Pain.(2009-Sep)
- ^Jain D, Atmapoojya P, Colah R, Lodha PSickle Cell Disease and Pregnancy.Mediterr J Hematol Infect Dis.(2019)
- ^Sickle cell disease - Treatment: NIH(July 15, 2022)
- ^Niihara Y, Miller ST, Kanter J, Lanzkron S, Smith WR, Hsu LL, Gordeuk VR, Viswanathan K, Sarnaik S, Osunkwo I, Guillaume E, Sadanandan S, Sieger L, Lasky JL, Panosyan EH, Blake OA, New TN, Bellevue R, Tran LT, Razon RL, Stark CW, Neumayr LD, Vichinsky EP,A Phase 3 Trial of l-Glutamine in Sickle Cell Disease.N Engl J Med.(2018-Jul-19)
- ^Dixit R, Nettem S, Madan SS, Soe HH, Abas AB, Vance LD, Stover PJFolate supplementation in people with sickle cell disease.Cochrane Database Syst Rev.(2016-Feb-16)
- ^KoduriIron in sickle cell disease: A review why less is betterAmerican Journal of Hematology.(2003)
- ^Swe KM, Abas AB, Bhardwaj A, Barua A, Nair NSZinc supplements for treating thalassaemia and sickle cell disease.Cochrane Database Syst Rev.(2013-Jun-28)
- ^Morris CR, Kuypers FA, Lavrisha L, Ansari M, Sweeters N, Stewart M, Gildengorin G, Neumayr L, Vichinsky EPA randomized, placebo-controlled trial of arginine therapy for the treatment of children with sickle cell disease hospitalized with vaso-occlusive pain episodes.Haematologica.(2013-Sep)
- ^Mandese et al.Effects of nutritional intake on disease severity in children with sickle cell diseaseNutrition Journal.(2016-04-30)
- ^Heyman et al.Growth retardation in sickle-cell disease treated by nutritional supportThe Lancet.(April 20, 1985)
- ^Paulsingh CN, Mohamed MB, Elhaj MS, Mohamed N, Ahmed TH, Singh T, Mohammed Z, Khan SThe Efficacy of Marijuana Use for Pain Relief in Adults With Sickle Cell Disease: A Systematic Review.Cureus.(2022-May)
- ^What is Sickle Cell Trait?: CDC(December 14, 2020)
- ^Piel FB, Patil AP, Howes RE, Nyangiri OA, Gething PW, Williams TN, Weatherall DJ, Hay SIGlobal distribution of the sickle cell gene and geographical confirmation of the malaria hypothesis.Nat Commun.(2010-Nov-02)
- ^Luzzatto LSickle cell anaemia and malaria.Mediterr J Hematol Infect Dis.(2012)
- ^Shah P, Khaleel M, Thuptimdang W, Sunwoo J, Veluswamy S, Chalacheva P, Kato RM, Detterich J, Wood JC, Zeltzer L, Sposto R, Khoo MCK, Coates TDMental stress causes vasoconstriction in subjects with sickle cell disease and in normal controls.Haematologica.(2020-Jan)
- ^Onyeaka HK, Queeneth U, Rashid W, Ahmad N, Rajan SK, Jaladi PR, Patel RSImpact of Depression in Sickle Cell Disease Hospitalization-Related Outcomes: An Analysis of the National Inpatient Sample (NIS).Medicina (Kaunas).(2019-Jul-17)
Examine Database References
- Sickle Cell Symptoms - Donald I Abrams, Paul Couey, Niharika Dixit, Varun Sagi, Ward Hagar, Elliott Vichinsky, Mary Ellen Kelly, John E Connett, Kalpna GuptaEffect of Inhaled Cannabis for Pain in Adults With Sickle Cell Disease: A Randomized Clinical TrialJAMA Netw Open.(2020 Jul 1)
- Anti-Oxidant Enzyme Profile - Martins VD, Manfredini V, Peralba MC, Benfato MSAlpha-lipoic acid modifies oxidative stress parameters in sickle cell trait subjects and sickle cell patientsClin Nutr.(2009 Apr)