Barts and The London School of Medicine and Dentistry MBBS Year 1
Alessandro Conti, BSc November 17th, 2017
Problem Based Learning: Scenario Write Up
Sickle Cell Disease
Introduction
In this problem based learning (PBL) scenario, Daniel, a 2.5-year-old male child, is brought to an Accident and Emergency department. He presents with symptoms compatible with an acute sickle cell crisis (Lovett, Sule and Lopez, 2017). Initial investigations are performed and he is admitted to the hospital for further observation and treatment.
After reading the scenario out loud, our group appointed a chair to lead the discussion and a scribe to construct a mind map of the key issues.
The initial approach was to identify any unknown terms within the scenario. Subsequently, we defined the main problems that it presented and we brainstormed on these based on the previous knowledge each of us could contribute. At the end of the discussion, we formulated several learning objectives based on the points we could not fully explain within the session.
These learning objectives were then grouped into six clusters to aid our individual self-directed learning.
Learning Objectives from the PBL Session
The following learning objectives were formulated in a different order during the PBL session. I rearranged them to obtain a more sequential flow of information and to match my personal learning style.
1. Genetics of Sickle Cell Disease
This learning objective was generated to investigate the genetic causes that underpin the development of sickle cell disease.
The genetic mutation involved in sickle cell disease is a single nucleotide polymorphism (SNP) in the sequence of the β-globin gene at position 6 on chromosome 11. This consists in the adenine base (A) being substituted by thymine (T). When transcription and translation occur at this gene, the change in base results in an alteration of the amino acid sequence of the polypeptide being secreted. Specifically, glutamic acid (Glu) will be substituted by valine (Val) at the N terminus of the polypeptide (Hoffbrand, Moss and Pettit, 2006).
Under normal conditions, once secreted, two β-globin polypeptides will combine with two α-globin molecules to form adult haemoglobin (HbA1), the protein responsible for transporting oxygen through the blood. However, mutated β-globin molecules will have altered hydrophobic interactions once assembled into a tetrameric haemoglobin molecule. These interactions will make it insoluble and cause it to form crystals when exposed to low oxygen concentrations. These morphological changes distort the erythrocytes that carry the haemoglobin, causing them to assume a sickled shape. This type of haemoglobin is hence known as sickle haemoglobin (HbS).
This SNP mutation may occur either at one or at both alleles for the β-globin gene. Individuals who are heterozygous for this gene normally develop sickle cell trait, as they produce both HbA and HbS. Conversely, homozygous individuals will only produce HbS and therefore develop sickle cell disease. The mode of inheritance for this mutation is autosomal recessive (NHGRI, 2017).
2. Mechanisms of Sickle Cell Disease
The clinical presentation of sickle cell disease can be physiologically related to the effects of sickling erythrocytes in the circulation. Due to the morphological changes outlined above, affected erythrocytes tend to lose their elasticity and flexibility. While these characteristics allow them to pass through small capillaries in healthy conditions, abnormal red blood cells are unable to do so and often get stuck in the smaller vessels, causing painful vaso-occlusive crises and potential ischemia. In Daniel’s case, this phenomenon presents as dactylitis, a painful inflammation of the fingers which get swollen due to circulatory blockage and lack of venous drainage.
As the blood flows through the spleen, sickled erythrocytes get filtered. In the case of sickle cell disease, the amount of abnormal red blood cells exceeds the filtering capabilities of this organ. The consequent accumulation of sickled erythrocytes enlarges the spleen causing an acute splenic sequestration crisis, which accounts for Daniel’s hepatosplenomegaly, as noted upon initial examination (Brousse et al., 2012).
As Daniel’s red blood cells have a decreased ability to transport oxygen, his cardiovascular system tries to compensate by increasing its pulse rate in order to obtain more efficient circulation of oxygen. Similarly, his respiratory rate increases to try and provide the body with a larger amount of oxygen to supply its organs. This was also noted on examination, along with lung crackles and wheezing. Both of the above are signs of sickle cell anaemia, a condition closely associated with the development of sickle cell disease (Howard, Hamilton and Britton, 2013).
3. Timing and Development of Symptoms in Sickle Cell Disease
This learning objective was specifically aimed at understanding why Daniel only developed the symptoms of sickle cell disease at 2.5 years of age. This is partially explained by the fact that foetal haemoglobin (HbF), which is abundant throughout the first 5-6 months of life (Conran, 2015), has a higher oxygen binding capacity than adult haemoglobin. This mechanism, which favours oxygen diffusion across the placenta during pregnancy, can be demonstrated using the graph below:
Graph 1 – Haemoglobin oxygen saturation against partial pressure of oxygen.
Adapted from Themes, 2017
The higher oxygen binding capacity of HbF means that when exposed to the same partial pressure of oxygen, this haemoglobin variant will reach higher oxygen saturation than HbA (or HbS). This property will effectively mask the inability of HbS to carry oxygen around the circulatory system.
Additionally, HbF is not affected by SNP mutations in the β-globin gene because it only contains α and γ chains in its structure.
However, Daniel might have also been exposed to other factors which precipitated the occurrence of symptoms due to his underlying condition. These might include moving to a colder location, oxygen deprivation, exercise, infection, fever, dehydration and stress (Ilesanmi, 2010).
4. Types of Haemoglobin
Several variants of haemoglobin exist in humans. However, for the purposes of this discussion, four variants were taken into consideration. The most relevant characteristics of these are summarised in the table below:
Name Type Composition Relevance
HbA1 Adult haemoglobin 2 α, 2 β chains Most common in adults, makes up approximately 97% of all haemoglobin in healthy individuals.
HbA2 Adult haemoglobin 2 α, 2 δ chains Exists in low levels throughout life. Its physiological role is yet to be fully determined.
HbF Foetal haemoglobin 2 α, 2 γ chains High in foetuses, it decreases after 5-6 months of life. It has a higher oxygen binding capacity than HbA, which favours oxygen diffusion across the placenta.
HbS Sickle haemoglobin 2 α, 2 S chains Distorted heaemoglobin, unable to efficiently carry oxygen.
Table 1 – Types of haemoglobin (Manning et al., 2007; Hoffbrand, Moss and Pettit, 2006)
5. Diagnosis of Sickle Cell Disease
Diagnosis of sickle cell disease can occur at different stages throughout a patient’s lifetime. Some of the most common techniques are summarised below:
• Full blood count (FBC) – allows quantitative analysis of the different components of blood. In sickle cell disease, haemoglobin is reduced and the reticulocyte count is elevated. This is a measure of immature red blood cells which are secreted into the circulation in an attempt to compensate for the lack of functional mature erythrocytes.
• Erythrocye sedimentation rate (ESR) – a generic test for inflammation. In Daniel’s case, the elevated ESR indicates non specific inflammation within the circulatory system.
• Urinalysis – a urine analysis used to detect indications of urinary tract infection, which may have precipitated the symptoms of sickle cell disease.
• Chest radiography – used to detect signs of concurrent infection such as pneumonia. In Daniel’s case it revealed bilateral haziness, which may indicate such an infection, also in accordance with the crackles and wheezing noted on auscultation.
• Peripheral blood smear – a peripheral blood smear will show the characteristic sickle shaped red blood cells. Normal RBC’s will be hypochromic due to the associated anaemia.
• Hb electrophoresis – this technique allows separation of different proteins according to their respective electrical charge. The expected findings include a relatively large amount of HbS, some HbF depending on the patient’s age, and little to no HbA, like in Daniel’s case.
(Howard, Hamilton and Britton, 2013; Hillman and Ault, 2002)
A conceptually interesting point was raised during this phase of the group discussion. Having established the signs and symptoms of sickle cell disease, a student asked whether other diseases could present in a similar way. Hence, the question was phrased as: how can we diagnose sickle cell disease beyond any doubt, especially considering that several similar diseases exist, including for instance β-thalassemia? After some research, I was able to establish that the pathophysiology of sickle cell disease and β-thalassemia are similar and some sickle shaped red blood cells can be found in the blood smear for both diseases. However, blood from sickle cell disease patients will contain significantly more sickled erythrocytes than blood from a β-thalassemia patient. These diseases can be distinguished looking at the blood smear in question. If in doubt, haemoglobin electrophoresis will provide a definitive indication towards the correct diagnosis (Fanestil and Van Siclen, 2017).
Sickle cell disease can also be diagnosed antenatally by amniocentesis or chorionic villus sampling and at birth by performing a heel prick test (Singh, Shrivastava and Shrikhande, 2014; Sickle-thal.nwlh.nhs.uk, 2017). However these tests are only offered in some countries around the world, they are not mandatory and can still can be inconclusive as to whether the child has sickle cell disease.
6. Treatment of Sickle Cell Disease
Over the past decades, treatment for sickle cell disease has significantly improved, resulting in better outcomes for affected individuals. In any case of the disease, treatment is highly variable and depends on the specific symptoms that a patient presents with.
The treatments for acute sickle cell crises include:
• Analgesia with non-steroidal anti-inflammatory drugs (NSAID’s) or with opioids.
• Rehydration with magnesium and clotrimazole, an antifungal medication to prevent opportunistic infections.
• Antibiotics for existing infection or prophylaxis.
• Hydroxyurea, an antimetabolite that increases foetal haemoglobin in erythrocytes.
Long term supports include:
• All of the above
• Blood transfusion to increase normal adult haemoglobin concentrations.
• Exchange blood transfusion to filter out sickled erythrocytes and leave the healthy ones.
• Physical and psychological therapies to cope with the symptoms of the disease.
• Bone marrow transplant to eliminate the mutated genes.
• An additional form of support is provided by genetic counselling, a service that explains and analyses the risk of genetic disease within a family. This might also help with the implications of chronic disease on the family. These include issues of time and financial management, possible social stigma and the risk for offspring to develop the same or a different genetic disease. (Nhlbi.nih.gov, 2017; Hillman and Ault, 2002)
Personal Learning Objectives and Alternative Arguments
As a biomedical scientist, I had looked at sickle cell disease in a research context before this PBL session. Hence I was glad to contribute to our discussion by explaining the scientific principles behind the erythrocyte sedimentation rate (ESR) and haemoglobin electrophoresis. Being aware of the diagnostic value of these tests for sickle cell disease allowed me to focus more on the clinical aspects of the scenario, which I was less familiar with. By reflecting on these, I was able to construct a differential diagnosis and alternative arguments relating to this scenario.
The learning objectives outlined above reflect the knowledge gaps that emerged during this PBL scenario discussion. However, the information provided in the scenario itself is insufficient to come to a definitive conclusion on the precipitating cause of Daniel’s acute crisis. Therefore, any tentative explanation in this regard is merely speculative. For instance, one could base an argument on the following notions:
• Sickle cell disease is highly prevalent in the Afro-Caribbean populations all over the world. (Centers for Disease Control and Prevention, 2017).
• Known precipitating factors include moving to a colder location, oxygen deprivation, exercise, infection, fever, dehydration and stress (Ilesanmi, 2010).
• Foetal haemoglobin (HbF) protects sickle cell patients against the symptoms of disease in the first few (5-6) months of life (Conran, 2015).
• Diagnosis of sickle cell disease is often carried out antenatally or neonatally in developed countries with the appropriate resources (Singh, Shrivastava and Shrikhande, 2014; Sickle-thal.nwlh.nhs.uk, 2017).
By extrapolating information from all of the learning objectives above, the following speculations could be made:
• Daniel developed sickle cell disease symptoms due to a lung infection, which was duly noted using chest radiography and auscultation. However, no indication as to any specific pathogen was given in the scenario.
• The onset of Daniel’s symptoms could be due to his recent relocation to England from a conceivably warmer Afro-Caribbean location, where he was born. This would have subjected him to a considerably colder environment, stimulating the sickling of his red blood cells. Being born in a developing country, the local healthcare system might not have had the resources to test for sickle cell disease as described above. On the other hand, he might have been born in a developed country and not have been tested due to religious or personal reasons. Additionally, his test results might have been false negatives.
• A very similar argument to the one above could be made with oxygen content, as several locations in England are more polluted than the comparably more rural areas from which his family might have originated. These two explanations also coincide with the increased stress of moving, which may have prompted the sickling of his erythrocytes.
• Foetal haemoglobin persists to a small degree in adults. Therefore it might also be conceivable that the activation of the genes responsible for the production of this haemoglobin variant did not decrease until the age at which he presented to the hospital.
• Being a child, Daniel might have been exposed to a low oxygen tension whilst playing or exercising.
• Daniel might have been born in England or abroad and developed the symptoms due to an idiopathic cause not yet identified by research.
• Several or all of the factors above may have been concurrent in this case, as no single factor necessarily excludes the other.
All of the tentative explanations provided above could be true, although the relevance of these can be relegated to an intellectual interest more than a clinical perspective. However, the primary educational value of this scenario was to develop an awareness of sickle cell disease more than it was to identify the precipitating cause of his symptoms.
Conclusion
In order to complete this PBL process in a purposeful fashion, as outlined in Schmidt’s paper on the topic (1993), we shared the results from our private study during the feedback part of our following PBL session.
Sickle cell disease is a serious condition which affects vast populations across the world to different extents. There are several precipitating factors that stimulate the onset of the clinical symptoms of sickle cell disease. Research in this field is ongoing and the era of genomic medicine will offer interesting opportunities to tackle this disease and its symptoms. I was glad to learn more about the topic in this proactive environment and I look forward to discovering more about sickle cell disease and the process of problem based learning in my future studies.
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