Sickle Cell Disease Overview

Sickle cell disease (SCD) is an autosomal recessive haemoglobin disorder which produces abnormal haemoglobin (HbS). This results in the sickling of red blood cells in people who have inherited a mutated HBB gene from each parent. The prevalence of SCD varies worldwide with the World Health Organisation (2020) estimating that 5% of the world’s population are carriers of the mutated HBB gene for SCD. However, lower and middle income countries have higher rates of carriers and “in some parts of Uganda it is as high as 45%” (WHO, 2020). The average life expectancy for those with SCD in developed countries is 42-47 years due to red blood cells adopting a sickled shape, reducing their flexibility and stickiness. This causes a variety of life altering symptoms such as pain and infections but also blood clots, resulting in organ damage.

The symptoms of sickle cell disease are caused by abnormal haemoglobin S (HbS) produced by the mutated HBB gene. HbS consists of two normal alpha peptide chains and two distorted beta peptide chains caused by a non-conservative mutation. The 6th amino acid in each beta chain, valine, is hydrophobic and replaced by hydrophilic glutamic acid. HbS is capable of transporting oxygen however, when it becomes deoxygenated sickling occurs whereby, HbS molecules bind together creating long polymers which distort the cell wall causing red blood cells to become sickle shaped, more rigid and less sticky. Pressure on the cell wall results in sickle cell death after 10-20 days instead of the 120 day lifespan of normal red blood cells. This results in a reduced number of red blood cells able to transport oxygen and sufferers then develop sickle cell anaemia. The remaining cells capable of carrying oxygen are often prevented from reaching vital organs as vaso-occlusion occurs when a buildup of sickle cells block capillaries. The location of the blood clot results in excruciating pain and damage to nearby organs which are starved of oxygen. This can result in blindness, strokes, delayed growth and breathing difficulties such as acute chest syndrome from blood clots around the lungs. The spleen is also under extra pressure to break down red blood cells at a much faster rate, becoming inflamed and unable to support the immune system effectively. A reduced oxygen supply causes the spleen to reduce in size, becoming fibrous and unable to detect and destroy bacteria exposing the SCD sufferer to a number of infections such as meningitis, pneumonia, influenza and salmonella. Bones can also be weakened, misshapen and enlarged as they create more bone marrow to produce higher numbers of reticulocytes to compensate for the lower number of red blood cells, further contributing to prolonged periods of pain.

Sufferers of SCD are most likely given a lifelong treatment plan made up of a variety of medications and behavioural changes. Hydroxyurea is the main drug for treating SCD, which reduces the number of sickle cells the body produces allowing blood to flow with fewer or no clots, making oxygen transport more effective. A reduced number of blood cells however, still results in sickle cell anaemia which may need to be treated with blood transfusions in more severe cases. Vaccinations and antibiotics ensure protection against infections and folic acid supplements stimulate production of red blood cells. Behavioural changes such as avoiding sudden temperature or altitude changes and drinking more fluids have proven to reduce sickle cell crisis which often leads to hospitalisation with morphine administered for pain relief. Bone marrow transplants are currently considered the only cure for sickle cell disease however, it is a complicated, expensive procedure which requires an exact donor match and is not widely accessible. There have also been recent successful clinical trials carried out using CRISPR to replace the mutated gene resulting in the body being able to create normal adult haemoglobin. However, it is not yet known whether there are long term side effects, whether the body will continue producing normal adult haemoglobin or if additional treatments will be needed.

Preventative measures are also taken to reduce the number of people affected by SCD such as blood tests to inform people if they carry the mutated HBB gene responsible for sickle cell disease. Individuals can then make an informed decision knowing that if both parents are carriers there is a 1 in 4 chance their child will have SCD. A sample can also be taken when pregnant to determine whether the embryo will go onto develop SCD. Fetal haemoglobin (HbF) contains gamma peptide chains instead of beta chains which delays SCD symptoms for 6-12 months in newborn babies therefore, testing at birth ensures early diagnosis. This is done in many developed countries and enables a treatment plan to be put in place from birth.

These preventative measures are less accessible in countries with higher rates of SCD as they are often lower income countries with several societal and economic barriers preventing effective treatment and prevention. Anyone with SCD can “trace their ancestry to a country where malaria in endemic” (Ted-Ed, 2019) as the HBB gene mutation in carriers of SCD provides an evolutionary advantage, a partial immunity to malaria. Carriers have enough sickle shaped cells to prevent malaria maturing as they die after 10-20 days. Africa experiences 90% of malaria infections worldwide resulting in the continent having the highest rate of SCD which is still increasing. In the US treatment for SCD in costs $30,000 per person annually, making adequate treatment inaccessible in nations hit hardest by SCD. This results in high infant mortality rates with Nature (2019) stating “Between 50% and 90% of children in sub-Saharan Africa and India with the disease will die before their fifth birthday” from infections or blood loss due to limited access to healthcare, clean water, adequate living conditions and education.

SCD is a life-threatening genetic disorder affecting some of the poorest nations in the world without access to cost effective preventive solutions such as blood tests to identify couples likely to have children who will inherit either one of two of the mutated HBB genes. By 2050 the rate of babies born with SCD is predicted to increase by a third worldwide and “is expected to rise by half as much again” (Wellcome, 2013) in Nigeria. However, with increased awareness of SCD leading to education improving around prevention of the disease alongside programs with $200 million funding to “develop gene-based technologies to treat SCD and HIV in Africa” (Nature, 2013) there is hope that the prevalence of SCD will decrease with treatment becoming more affordable to all, improving the life expectancy and quality of life for sufferers worldwide.