By Ginevra Gini - Italy
This article gives an overview on sickle cell anaemia, a type of sickle cell disease. My exploration of this relevant topic has been inspired by my time volunteering in Kenya, where I witnessed several sickle cell disease cases. I decided to investigate sickle cell anaemia and its relationship with Malaria, as I found it an interesting discussion point, especially with regards to my volunteering experience.
Background
Hemoglobinopathies, including thalassemias and sickle cell disease (SCD), are the most common monogenic diseases worldwide, with a WHO report of 2008 estimating an annual birth of over 330,000 affected infants (83% SCD, 17% thalassemias). Haemoglobin (Hb) disorders account for about 3.4% of deaths in children less than 5 years of age. However, there are several areas where the burden of these diseases is significantly higher, such as SCD in Tanzania and Nigeria, where mortality for children under 5 years old reaches 6–10%.
Mutations and their consequences
Mutations are a change in the genetic make-up. The base substitution mutation occurs when one (nitrogenous) base is replaced by another. Therefore, a gene mutation is a change in the base sequence of a gene that alters the triplet code and modifies the mRNA during transcription. The different amino acid may be coded for a different polypeptide. The effect of mutation can then range from no effect or change in amino acid sequence to drastic and dangerous changes, that can also result in the change of the primary structure or in the sequence of amino acids.
Hb | HbA | |
HbA | Hb^2 HbA | HbA HbA |
HbA | Hb^s HbA | HbA HbA |
Development of this alteration in the DNA
Sickle-cell anaemia involves change in gene for one of the polypeptides in haemoglobin/ HBA/ Hb. Sickle cell disease is a genetic disease caused by a single point mutation within the gene (Hb) that codes for haemoglobin. Most humans have the normal allele HbA, however inheritance of the abnormal sickle cell gene from one parent, and a gene for normal HbA from the other parent results in the sickle cell trait HbS.
Figure 2: Shechter AN. Blood 2008;112:3927-3938; 2 . Habara A and Sterinberg MH. Exp Biol Med (Maywood).
In the haemoglobin gene a point mutation results in the DNA triplet GAG changing to GTG on the template strand. The resulting DNA triplet (CAC) on the coding strand is transcribed into the mRNA codon GUG, instead of GAG. During translation tRNA brings the amino acid to the ribosome: valine (VAL) replaces the original amino acid glutamic acid (GLU); this occurs on the sixth position of the polypeptide, the slightly different polypeptide results in a new allele, HbS.
The consequences of this mutation
During pregnancy the haemoglobin of the unborn child is mainly composed of foetal haemoglobin (HbF) that will switch from foetal (HbF) to adult (HbA) at birth. HbF has a higher oxygen affinity than HbA, helping to facilitate the transfer of oxygen across the placenta. At birth, 70–80% of total Hb is HbF, whereas at 6 months it decreases to a 4–5%, and by 12 months HbF reaches its final adult level of ~1% of total Hb.
As seen previously, the base substitution leads to the protein haemoglobin S being produced instead of haemoglobin. A different amino acid is placed in the polypeptide chain; this is significant as the two amino acids differ in solubility and have different properties: Valine causes HBS to be less soluble. This leads to changes in the shape of haemoglobin; it becomes less soluble and crystallises, impairing the transportation of oxygen by causing red blood cells to sickle, foreshadowing limited oxygen -carrying capacity. Other health problems can result including anaemia and tiredness as well as Vaso-occlusion: the blockage of the capillaries, limiting the flow of normal red blood cells.
The clinical severity of SCD can be unpredictable
SCD is a multi-system disease with acute and chronic components, primarily caused by poor blood flow and Vaso-occlusion.
Figure 3 Data taken by ppw. Recognizing and managing sickle cell disease.
It is estimated that 300,000 new cases of SCD occur globally each year, yet the sickle cell gene is more prominent in certain groups. HbS provides a genetic advantage against malaria; we can see that the highest frequencies are found where malaria is, or was. Homozygous HbS individuals carry a lethal genotype that kills many in infancy. Due to migration, frequencies have increased in other regions: In the USA, 15.5 per 1000 newborns have sickle cell trait (SCT). This increases to 73.1 per 1000 newborns among African-Americans.
Areas affected
According to the Nations Library of Medicine, “The frequency and severity of sickle cell disease varies markedly among genotypes and geographic regions”. The sickle cell trait is widespread throughout Africa, with low frequencies (<1%–2%) in the north and south of the continent. A way to prevent and recognize Sickle Cell Disease at an early stage is to do a screening at birth.
Figure 4: Spread of sickle cell disease
SCD screening at birth
Some countries, such as the USA and the UK, have mandatory screening for SCD at birth. SCD is diagnosed using heel prick test during routine newborn screening. A positive screening test should be confirmed using a second blood sample and a different diagnostic testing method. There should also be prompt referral to a provider of comprehensive care for disease management and treatment.
Figure 5: Telfer P et al. Haematologica 2007;92:905–912
What is the relationship with Malaria?
People with the sickle cell trait who have a relative resistance to falciparum malaria are less likely to get the disease, run lower parasite counts, and are less likely to die. This survival advantage is marked during early childhood between the loss of passively acquired maternal immunity and the development of active immunity. The length and timing of this window may vary between communities and it is influenced by the pattern of malarial transmission. The survival advantage relative to normal individuals with HbA has contributed to high frequencies of the sickle cell trait in areas with a history of malaria, such as East Africa and Kenya.
Treatments for sickle cell disease
Until recently, clinical interventions were mainly based on supportive care therapies, such as interventions to reduce infection risk, like prophylactic antibiotics and vaccinations against capsulated bacteria. Hydroxyurea, bone marrow transplantation, and chronic transfusion therapy for stroke prevention have been the only available modifying treatments for SCD.
Current and future therapies target different pathophysiological mechanisms of SCD: (a) the modulation of Hb polymerization, erythrocyte dehydration, and Hb oxygen affinity; (b) the prevention of Vaso-occlusion by inhibiting cells interactions; (c) the prevention of endothelial dysfunction, and (d) the modulation of inflammation.
In the past few decades, new curative strategies have been developed: gene addition and gene editing. Gene addition entails adding a copy of a gene into the genome of the cells in the target organ or tissue; this is achieved by altering the DNA sequence of a gene and thus modifying its expression. These are the great hope for the future.
My personal experience insight in the Kenyan pediatric ward
When volunteering in the paediatric ward, there was a 12 years old boy who suffered from sickle cell disease and was brought in with Jaundice. The mother of the patient was from another country, resulting in a language barrier between her and the nursing staff. Communication was difficult, as the mother did not understand the local language of Swahili or English, and translation software was inaccessible.
Jaundice is a common sign and symptom of sickle cell disease; it is a problem often related to the liver, gallbladder, pancreas. It occurs when sickle cells do not live as long as normal red blood cells, so they die at a rate too fast for the liver to sufficiently filter them out. Bilirubin (which causes the yellow color) from these broken-down cells builds up in the system, causing jaundice. To address the problem the MOI, medical officer, hydrated the patients and recommended a balanced diet. However, such a diet is very difficult to achieve due to widely spread malnutrition in Kenya.
I had an exceptional tutor known as Dr. Sharifaa during my time in CGTRH, the second largest hospital in Kenya. She taught me a remarkable amount about paediatric medicine and Kenyan medicine as a whole. They held weekly meetings that discussed how the mortality rate has changed over time, and they discovered that it has decreased between October and November, from a 11.8% to a 10%, 1.8% being an incredibly high percentage. The main reasons for deaths in the paediatric ward were birth asphyxia, prematurity, neonatal sepsis as well as gastroenteritis, pneumonia, severe acute malnutrition, neonatal jaundice, meningitis and malaria. The interns were repeatedly asked to introduce a patient and their patient history, present symptoms, and a diagnosis. Throughout this process Dr. Sharifaa would ask the student detailed questions and demand further clarification. The student would elaborate on the information, allowing me to expand my knowledge of their condition. I learned how to interact with patients and speak their local language, and in the paediatric ward I gained a greater understanding of tropical diseases, malnutrition, HIV/Aids, sickle cell anaemia, rheumatic fever, and communicable diseases.
The nurse staff went beyond what they were required to do in order to provide optimum health care to all the patients. It was also common practise in Kenya that the family of the patient had to buy the medicines in the pharmacy. The medication could only be administered to the patient once the relative had come back from the pharmacy having paid for the right dosage. This general requirement exists because medicines are limited; usually they are stolen and therefore must be reserved for critical patients. However, it is unpractical as it increases waiting time, and the patient’s illness could worsen in that frame of time.
What I learned about sickle cell disease during my experience in Kenya
Sickle cell Disease is a daunting and serious illness; I saw a lot of suffering in the paediatric ward with many children who felt very poorly. However, it is possible to alleviate the pain and doctors are trained to help patients find the right treatment for them to reduce the suffering of this condition.
Bibliography
Modell B, Darlison M (2008) Global epidemiology of haemoglobin disorders and derived service indicators. Bull World Health Organ 86:480–487.
Makani J, Soka D, Rwezaula S et al (2015) Health policy for sickle cell disease in Africa: experience from Tanzania on interventions to reduce under-five mortality. Trop Med Int Health 20:184–187.
Nnodu OE, Oron AP, Sopekan A et al (2021) Child mortality from sickle cell disease in Nigeria: a model-estimated, population-level analysis of data from the 2018 Demographic and Health Survey. Lancet Haematol 8:e723–e731.
(Manca L & Masala B. IUBMB Life 2008;60:94–111; 2. Akinsheye I et al. Blood 2011;118:19–27)
Schechter AN. Blood 2008;112:3927–3938; 2. Habara A & Steinberg MH. Exp Biol Med
(Maywood) 2016;241:689–696; 3. Bender MA & Seibel GD. Sickle Cell Disease. In: Pagon RA et al. GeneReviews; Seattle: University of Washington 1993–2017
Bakshi N, Sinha CB, Ross D et al (2017) Proponent or collaborative: physician perspectives and approaches to disease modifying therapies in sickle cell disease. PLoS ONE 12:e0178413.
Sundd P, Gladwin MT, Novelli EM (2019) Pathophysiology of sickle cell disease. Annu Rev Pathol 14:263–2
Comments