Refeeding Syndrome – A Dangerous Complication of Anorexia Nervosa Treatment

Abstract:

Refeeding syndrome is one of the most dangerous and known complications from anorexia nervosa. This potentially lethal condition does not result in mortality itself – it is the electrolyte disturbances that occur secondary, resulting in organ failure and sometimes death.

Introduction:

In high income countries, obesity is becoming more prevalent, so it may seem paradoxical that Refeeding Syndrome (RFS) is also on the rise. RFS is a life-threatening condition characterised by the severe electrolyte and fluid shifts in response to the change from a catabolic to an anabolic state in the body. This occurs after the start of nutritional therapy and refeeding in malnourished patients during anorexia nervosa (AN) treatment, and the key prerequisite is the chronic nutritional deprivation regardless of the route of calorie administration. This is a serious condition with mortality of advanced RFS being as high as 70% cases. ^[1]

Pathogenesis of Refeeding Syndrome:

During prolonged starvation, insulin secretion is significantly suppressed and glucagon secretion increases. Hence there is an increased rate of conversion of glycogen into glucose, in addition to gluconeogenesis, which is the synthesis of glucose from lipid and protein breakdown products.^[2] As carbohydrate supplies are limited, the body adapts from carbohydrate to fatty acids and amino acids as the main energy source. This causes the typical clinical manifestation of anorexia nervosa – weight loss. There is breakdown of adipose and muscle tissues, resulting in a lean body mass. Basal metabolic rate also drastically decreases, and many intracellular minerals become severely depleted during this period without external supply. ^[3]

The reintroduction of nutrition to starved individuals during refeeding results in a fast decline in gluconeogenesis and anaerobic metabolism. The shift from fatty acids and ketone bodies to carbohydrate sources increases blood sugar, which, in response, results in an increase in insulin secretion. Hence, glycogen, fat, and protein synthesis increases. Since these processes require phosphates, magnesium, and potassium – stores of which were previously depleted – the remaining stores are rapidly utilised, leading to low extracellular levels by transport into the intracellular compartment. There is a steep concentration gradient between the high area of concentration in the extracellular compartment and the low area of concentration in the intracellular compartment, hence the depletion of extracellular ions occurs rapidly. ^[4]

Clinical Manifestations of Refeeding Syndrome:

Symptoms of RS vary greatly and are often unpredictable. Symptoms occur during to changes in electrolytes affecting the cell membrane potential, which impacts nerve, cardiac, renal and muscle function. With mild derangements in electrolytes, patients may be asymptomatic. However, more often, the spectrum of RS can vary from nausea and vomiting to more serious respiratory distress and cardiac failure. Deficiencies in certain electrolytes can have different clinical manifestations.^[5] Hypophosphatemia is most common and presents with arrythmias, hypotension, weakness, hyperglycaemia, and dysfunction of leukocytes.^[6] Whereas hyponatremia due to hyperglycaemia can present as respiratory failure, renal failure, and fluid retention. ^[7]Conditions secondary to RFS can have serious impacts of patient health and it is the complications that can cause death rather than RFS itself. If the cause of RFS and the electrolyte deficiencies are not established and appropriate measures are not instituted, clinical deterioration can occur rapidly. ^[8]

Prevention of Refeeding Syndrome: 

Prevention of RFS would involve the identification of high-risk patients. High-risk patients would include those with BMI lower than 16kg/m², little nutritional intake for more than 10 days, and/or low electrolyte levels prior to refeeding. A systematic assessment of each patient’s condition and their nutritional treatment should be taken regularly, particularly during the initial period of refeeding – most cases of RFS are observed within the first 72 hours of an increase in nutrition intake.^[9] The initial calorie supply should be low, and then increased slowly, typically by 10-20% per week. This is because too rapid introduction of caloric intake results in RS, hence the establishment of a safe level of caloric intake is key consideration. 

However, in contrast, many argue that a higher caloric intake and a faster increase in energy supply is therapeutically more effective, due to reduced initial weight loss and a potentially shortened hospitalisation period. A retrospective study identified that the increase in dietary intake in adolescents with AN does not significantly increase the probability of developing RFS, and in fact, improved the effectiveness of treatment with shorter duration of hospitalisation. The study suggested that perhaps RFS is more associated with an initial low level of malnutrition but not with caloric intake during nutritional treatment. Also, it was hypothesised that if carbohydrates initiate the sudden increase in insulin, then the development of RFS may depend more on carbohydrate than on total caloric intake.^[10] Hence, it is not clear enough whether increasing caloric intake is actually safe for people with extreme malnutrition. Though, whilst meeting the need to restore weight by increasing caloric intake, the systematic supplementation of electrolyte deficiencies could be a condition in prophylaxis of RFS. ^[11]

To monitor patients during refeeding, the regular assessments should cover numerous tests. This should include monitoring of body weight, heart rate and blood pressure, in addition to laboratory tests of fluid balance and electrolyte concentrations. Though if there are slight indications of RFS, nutrition should be stopped, and existing electrolyte imbalance should be aligned. ^[12]After serious complications and electrolyte levels have been treated, the patient should only be provided with half of the baseline caloric intake to reduce the risk of worsening electrolyte imbalances and reversing effects of treatment.^[13]  

Outlook:

Anorexia nervosa treatment should involve a multidisciplinary approach with correct nutritional, physical and psychological care, despite the severity of the disorder, since RFS can still arise in less serious anorexia nervosa cases as well as in atypical anorexia nervosa cases.^[15] Despite being potentially preventable, RFS is associated with high morbidity and mortality rates. It could be argued that, in some areas, RFS is still relatively poorly recognised when clinical manifestations begin. There should be an increased awareness of RFS in the public considering the increasing prevalence of eating disorders, and an extensive network of highly specialised units should be one of the main targets in the developments of psychiatric care for anorexia nervosa.^[16]

Conclusion:

RS is unfortunately encountered in modern clinical practice often and is still relatively poorly recognised or understood. Despite being potentially preventable, RFS is associated with high morbidity and mortality rate. These rates are continuing to increase as eating disorder services become more overwhelmed and less patients seek early treatment, resulting in severe malnutrition and drastically increasing the risk of RFS. RFS education in its prevention, recognition and treatment can be conducted and local treatments centres can facilitate this.

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^[1] Skowrońska, Anna, et al. “Refeeding Syndrome as Treatment Complication of Anorexia Nervosa.” Psychiatria Polska, vol. 53, no. 5, Oct. 2019, pp. 1113–23, psychiatriapolska.pl/uploads/images/PP_5_2019/ENGver1113Skowronska_PsychiatrPol2019v53i5.pdf.

^[2] Crook, M. A., et al. “The Importance of the Refeeding Syndrome.” Nutrition, vol. 17, no. 7-8, July 2001, pp. 632–37, http://www.hopkinsmedicine.org/gim/_pdf/consult/refeeding_syndrome.pdf.

^[3] Kohn, Michael, and Neville Golden. “Management of the Malnourished Patient: It’s Now Time to Revise the Guidelines.” J Eat Disord, vol. 10, no. 56, 2022, jeatdisord.biomedcentral.com/track/pdf/10.1186/s40337-022-00539-4.pdf.

^[4] Khan, L. U. R., et al. “Refeeding Syndrome: A Literature Review.” Gastroenterology Research and Practice, vol. 2011, 2011, pp. 1–6, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2945646/.

^[5] Khan, L. U. R., et al. “Refeeding Syndrome: A Literature Review.” Gastroenterology Research and Practice, vol. 2011, 2011, pp. 1–6, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2945646/.

^[6] Crook, M. A., et al. “The Importance of the Refeeding Syndrome.” Nutrition, vol. 17, no. 7-8, July 2001, pp. 632–37, http://www.hopkinsmedicine.org/gim/_pdf/consult/refeeding_syndrome.pdf.

^[7] Balci, Arif Kadri. “General Characteristics of Patients with Electrolyte Imbalance Admitted to Emergency Department.” World Journal of Emergency Medicine, vol. 4, no. 2, 2013, p. 113, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4129840/.

^[8] Khan, L. U. R., et al. “Refeeding Syndrome: A Literature Review.” Gastroenterology Research and Practice, vol. 2011, 2011, pp. 1–6, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2945646/.

^[9] Skowrońska, Anna, et al. “Refeeding Syndrome as Treatment Complication of Anorexia Nervosa.” Psychiatria Polska, vol. 53, no. 5, Oct. 2019, pp. 1113–23, psychiatriapolska.pl/uploads/images/PP_5_2019/ENGver1113Skowronska_PsychiatrPol2019v53i5.pdf.

^[10] Eating Disorders Hope. “Refeeding Patients with Anorexia Nervosa: What Does Research Show?” Eating Disorder Hope, 2015, http://www.eatingdisorderhope.com/information/anorexia/refeeding-patients-with-anorexia-nervosa-what-does-research-show.

^[11] Skowrońska, Anna, et al. “Refeeding Syndrome as Treatment Complication of Anorexia Nervosa.” Psychiatria Polska, vol. 53, no. 5, Oct. 2019, pp. 1113–23, psychiatriapolska.pl/uploads/images/PP_5_2019/ENGver1113Skowronska_PsychiatrPol2019v53i5.pdf.

^[12] Ponzo, Valentina, et al. “The Refeeding Syndrome: A Neglected but Potentially Serious Condition for Inpatients. A Narrative Review.” Internal and Emergency Medicine, vol. 16, no. 1, Oct. 2020, pp. 49–60, link.springer.com/article/10.1007/s11739-020-02525-7.

^[13] Skowrońska, Anna, et al. “Refeeding Syndrome as Treatment Complication of Anorexia Nervosa.” Psychiatria Polska, vol. 53, no. 5, Oct. 2019, pp. 1113–23, psychiatriapolska.pl/uploads/images/PP_5_2019/ENGver1113Skowronska_PsychiatrPol2019v53i5.pdf.

^[14] CancerConnect. “Electrolyte Imbalance Overview.” CancerConnect, 2018, news.cancerconnect.com/treatment-care/electrolyte-imbalance-overview.

^[15]Skowrońska, Anna, et al. “Refeeding Syndrome as Treatment Complication of Anorexia Nervosa.” Psychiatria Polska, vol. 53, no. 5, Oct. 2019, pp. 1113–23, psychiatriapolska.pl/uploads/images/PP_5_2019/ENGver1113Skowronska_PsychiatrPol2019v53i5.pdf.

^[16] Ponzo, Valentina, et al. “The Refeeding Syndrome: A Neglected but Potentially Serious Condition for Inpatients. A Narrative Review.” Internal and Emergency Medicine, vol. 16, no. 1, Oct. 2020, pp. 49–60, link.springer.com/article/10.1007/s11739-020-02525-7.

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Machine Learning in Medicine – The Next Revolutionary Technology?

Abstract

Machine Learning is increasingly becoming utilised in various sectors from engineering to psychology, and new successful developments of machine learning indicate that these technologies could be beneficial in medical settings. However, the viability of these technologies is questioned, given the ethical and logistical difficulties in medicine.

Introduction

On the surface, machine learning (ML) is one of many branches of artificial intelligence (AI), whereby AI refers broadly to the development of machine capabilities. Arthur Samuel – an American pioneer in machine intelligence – defined machine learning in 1959 as: 

 ‘a field of study that gives computers the ability to learn without being explicitly programmed.’ ^[1]

Here, the anthropomorphised term ‘learning’ in machine learning refers to the desire to create models that can learn like human beings, through experiences and evaluations, achieving objectives and creating outputs with minimal human assistance.

Structure of Machine Learning

In ML, unlike traditional computer programming technologies, there is no manual coding and once the framework is built for an ML model, it can learn patterns and rules independently, similarly to a human.

For example, to create a ML model to derive a differential diagnosis for abdominal pain, the series of decisions are not explicitly written into the computer. Instead, input-output data pairs (e.g., right lower quadrant pain is suggestive of appendicitis) are passed into the ML model, which learns the relationship between input and outputs. The feedback leads to a model that learns the important features automatically and generates the desired output. The result is the automated diagnosis of abdominal pain. The ability to adjust the function is the most notable aspect of ML models. The algorithm repeats evaluating and adapting its function and updates its rules autonomously until the required accuracy is met – this is how the automated learning occurs.

Previous Usage of Machine Learning

In the early 1970s, an ML system named MYCIN was developed to identify disease-causing bacteria and recommend antibiotics with dosages dependent on patients’ body weight. This was a significant breakthrough in medical ML, with higher accuracy and performance achieved than expected, however MYCIN was never used in practice.^[2] Despite the development of successful prototype systems, most clinicians were reluctant to use these systems. Contributing factors included general distrust, concerns around accountability, and the great effort needed to keep the ML knowledge updated and current with the relevant science and clinical practices. Furthermore, the AI winter in 1970-1980 resulted in reduced funding and interest and subsequently fewer significant developments.^[3]

Even after several innovations within other disciplines outside of medicine including the ‘first electronic person’ and the ‘first chatbot’, medicine was very slow to adopt AI. However, to establish the foundation for ML development, clinical information and medical records were first developed and digitalised.^[4] The development of other sophisticated medical technologies, such as various imaging machinery and constant patient monitoring, has also led to an increase in the quantity of data from each patient. Even though medical recording systems are in place, healthcare systems struggle to integrate and analyse these datasets due to the increasing global population, resource shortages, and the sheer size and complexity of healthcare datasets. This contributes to an increase in medical diagnostic errors which are significant source of morbidities and mortalities, and unnecessary costs.^[5]

Future Outlook

ML development has been markedly rapid in the recent years to aid medicine by analysing and classifying this clinical data, whilst outsourcing everyday tasks in medicine to technologies. ML technologies are driven by the expanding power of computer processing, the availability of large datasets and the financial input from private companies and governmental sources.^[6] However, although ML is currently developing rapidly, there remains numerous unresolved challenges – some which have been identified in previous ML developments, as well as possible new challenges, such as data privacy and public bias. 

It is important to identify the realistic potential of ML in medical diagnostics in modern clinical settings, as developments in the ML field have drastically progressed since the discovery of ML in the 1950s and challenges have not been thoroughly realised to date. Therefore, new studies should highlight the value of ML in diagnostics within the future and evaluate the true potential of ML benefits. With AI and ML becoming more available and capable, there is a need for further research into this topic, evaluating all aspects of ML in diagnostics in a broader viewpoint with acknowledgement of different stakeholders. The human and systematic effects are closely linked and identifying contributing factors will ensure that ML benefits can truly benefit patients and clinicians, whilst avoiding unnecessary costs and patient harm. The regulatory and ethical frameworks for ML must also be clarified so ML can reach clinical settings quickly and safely.

Swetha Babu, Youth Medical Journal 2022

References

[1] Samuel, A.L., (1959).

[2] Trivedi, M.C. (2014). 

[3] Kaul, V., Enslin, S. and Gross, S.A. (2020). 

[4] Kaul, V., Enslin, S. and Gross, S.A. (2020).

[5] Institute of Medicine (US) Committee on Data Standards for Patient Safety, et al. (2004). 

[6] Barber, J. (2012). 

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Current Difficulties in Medical Diagnostics

Abstract 

Medical diagnostics allow medical professionals to chart medical symptoms to other data and produce diagnoses and outcomes. However, difficulties in this medical field can result in diagnostic errors, causing detrimental costs to patients and healthcare systems. 

Introduction 

A significant source of mortalities and unnecessary costs is due to diagnostic errors in healthcare. The Institute of Medicine defines a diagnostic error as:

‘Failure of a planned action to be completed as intended (i.e., error of execution) and the use of a wrong plan to achieve an aim (i.e., error of planning)’

It is recognised that medical diagnostic errors are predominantly attributable to four main challenges within clinical settings – diagnostic uncertainty with time constraints, population trends and health disparities, limited resources, and cognitive biases. These challenges limit the ability to provide accurate medical diagnoses. These are particularly evident within Accident and Emergency Departments, where physicians must assess patients rapidly and either admit them to the inpatient wards or send them home. If the patient is diagnosed incorrectly and is not admitted into the hospital, this could result in the patient’s death after discharge. Alternatively, if the patient is diagnosed incorrectly and is admitted into the hospital, this would deplete medical testing and treatment resources as well as available staff, which could reduce the quantity and quality of care received by those who are critically ill, affecting the diagnosis/prognosis of such patients. With roughly 40,000 patients in the UK visiting an Accident and Emergency Department in the National Health Service (NHS) every day, the population at risk is extensive.

Diagnostic Uncertainty and Time 

Most diseases evolve over time so there is often a delay between the onset of the disease and the patient’s symptoms. During onset, it is difficult to determine which diagnosis is indicated by each unique combination of symptoms, especially if symptoms are non-specific, such as fatigue or loss of appetite. This raises the question of whether the harms of initiating immediate treatment to lesson symptoms exceed the harms of further diagnostic testing, including the impact of delaying treatment. Diagnoses can be delayed not only due to clinician uncertainty but due to patients delaying presenting to the clinicians for medical help – The generic symptoms of illness such as fever and fatigue may not be a cause for concern by the patient during early onset. A common situation where misdiagnosis often occurs due to atypical symptoms is the diagnosis of heart attack in women. Women are more likely than men to experience a missed diagnosis of a heart attack, a situation that has been partly attributed to gender biases, but which may also be the result of physiologic difference as women have a higher likelihood of presenting with atypical symptoms, including abdominal pain, shortness of breath and congestive heart failure. 

Furthermore, since diseases evolve, clinicians gain additional information over time, where available information during initial disease stages may support a wrong disease, and only later additional information allows the clinicians to diagnose correctly. Clinician delay also occurs when immediate diagnostic testing to obtain a definite diagnosis may be more harmful to the patient – invasive and harmful diagnostic testing may be detrimental to the patient’s diagnosis, or definite diagnosis may not alter the treatment received by the patient.

Population Trends 

Population trends, including increasing overall populations and the ageing of the populations add significant complexity to diagnostic processes, requiring clinicians to consider other factors in diagnosis as comorbidity and polypharmacy can result in ambiguous symptoms and provide greater differential diagnoses. Aging populations will likely result in more less common representations of diseases – for example, acute myocardial infarctions may onset will commonly with fatigue and confusion rather than more common chest or arm pains. Multiple comorbidities, medications, or cognitive and functional impairments, which are becoming increasingly prevalent, particularly in older patients, are more likely to have atypical disease presentations which can increase the risk of diagnostic errors.  

Frequent comorbidities often occurs when patients, typically ones with a compromised immune system such as elderly patients, suffer from multiple illnesses. Alongside atypical manifestations of disease, diagnostics are further complicated as diagnostic testing do not produce accurate results. Diagnostics tests can detect each of the underlying medial symptoms incorrectly. This can lead to an incorrect diagnosis and treatment due to the commonness of certain symptoms and the perceived overlapping of unconnected symptoms. Even if several machine testts are used, this would strain the supply of medical resources and the availability of medical testing for other patients.  

Increasing overall populations can put healthcare systems under strain, with numerous health issues arising from high population densities and the pollutant existing in such places. Squatter settlements in some of the world’s largest countries such as India and Brazil have significant effects on local healthcare systems. People who need to receive life-saving healthcare are deprived access to sufficient resources for diagnostic testing. Diagnostics are typically resource intensive processes, requiring both expert physicians and highly expensive and sensitive medical imaging/testing technology, which is not practical for developing world and industrialised nations. Furthermore, poor sanitation and deficient access to healthcare has increases the number of serious infections such as cholera and diarrhoea. In China, high population densities result in dangerous levels of air populations causing serious respiratory issues. As these infections and diseases increase, people with underlying chronic illnesses may not receive the care they need and may be left undiagnosed, increasing the risk of further complications. 

However, strain of resources, due to population trends, also affect high income countries. The National Health Service in the UK deals with over 1 million patients every 36 hours, and is evidently already under strain. With rising populations, this issue of lack of sufficient resources and infrastructures will increase along with it. Lack of staff can result in overworked medical staff who can make diagnostic decisions that could further jeopardise health. 

Cognitive Biases

The causes of diagnostic error can also be examined at the individual clinician level, where clinicians can provide misdiagnosis because of incorrect application of heuristics. A prevalent cognitive bias is the availability heuristic where the diagnosis of the current patient is biased by experience with past case – the clinician refers to what comes to mind most easily. Anchoring heuristic (also referred to premature closure) is where clinicians dismiss subsequent information (symptoms or diagnostic tests), relying on the initial diagnostic impression. An example of this bias is where repeated positive blood cultures can be dismissed as contaminants, resulting a misdiagnosis and the patient developing severe complication after an untreated infection. Framing bias often occurs when clinicians do not elicit different perspective by broadening the history, and make a diagnostic decision unduly biased by subtle cues and collateral information. This bias is often seen in Emergency Departments where quick diagnoses are made, despite the lack of through diagnostic tests, to increase the rate of clinical workflow. Misdiagnoses where medical history and demographic data are predominantly used as evidence are typically because of framing bias. For example, a patient with a previous history of heroin addiction displaying abdominal pain may be treated for opiate withdrawal but later may be identified to have a bowel perforation. 

Disparities in healthcare access and outcomes are well documented and persistent, often arising from cognitive bias – disparities by race, sex, gender, geographic location, and socioeconomic status are most common. The COVID-19 pandemic has also further unveiled these increasing disparities in health and healthcare. Before the COVID-19 pandemic, in 2011, diagnostic errors due to healthcare disparities in United States of America cost over USD$309 billion annually. A study in 2011 also revealed that racial and ethnic disparities in healthcare, particularly imposed costs on both direct medical costs, such as treating illness and complications, and indirect costs such as loss of productivity. Though there are very few studies that examine the relationships between diagnostic errors and healthcare disparities. 

Future Outlook and Conclusion

There is a dire need to reduce diagnostic error in medicine and diagnosis-related harm. Preventable diagnostic errors that lead to patient harm (mortality or morbidity) should be given priority in research. But, it is not clear how to determine preventability and which specific factors to intervene on first. 

However, technological advancements seem to be one of the most rapidly advancing solutions to aid medical diagnostics. The World Health Organisation suggests that worldwide populations numbering in the billions lack access to even basic healthcare, and this pent-up escalating demand has the potential  motivate advances in telemedicine and other technological advancements – these advancements may alleviate the issue with higher risks of diagnostic errors as a result of poor access to healthcare. Progress in AI imaging technology is also being driven by the rapidly expanding processing power of machines, the availability of large electronic health records and significant financial input from private technology corporations and government industries. 

Nevertheless, difficulties in medical diagnostics still exist and technological advancements may not be integrated into healthcare systems in the near future. Cognitive factors and systematic factors are still closely linked and untangling contributing factors is another challenge by itself. Other contextual information such as the certainty of the final diagnosis and the delay for diagnosis are also relevant considerations in understanding the complex interplay of factors in medical diagnostics. 

Image 2- 

Swetha Babu, Youth Medical Journal 2022

References

Baker, C. (2021). NHS Key Statistics: England, October 2021. [online] House of Commons Library. Available at: https://researchbriefings.files.parliament.uk/documents/CBP-7281/CBP-7281.pdf [Accessed 30 Jan. 2022].

Balogh, E.P., et al. (2015). Overview of Diagnostic Error in Health Care. [online] National Institute of Health. Available at: https://www.ncbi.nlm.nih.gov/books/NBK338594/ [Accessed 30 Jan. 2022].

Fletcher, D. (2017). How Will the Growing Population Affect Healthcare in the Future? [online] Socialist Health Association. Available at: https://www.sochealth.co.uk/2017/05/05/will-growing-population-affect-healthcare-future/ [Accessed 30 Jan. 2022].

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Ibrahim, S.A. and Pronovost, P.J. (2021). Diagnostic Errors, Health Disparities, and Artificial Intelligence. JAMA Health Forum, [online] 2(9), p.e212430. Available at: https://jamanetwork.com/journals/jama-health-forum/fullarticle/2784385[Accessed 30 Jan. 2022].

Image 1 – United Nations (2017). World Population Prospects Data Booklet 2017 REVISION. [online] Available at: https://www.un.org/development/desa/pd/sites/www.un.org.development.desa.pd/files/files/documents/2020/Jan/un_2017_world_population_prospects-2017_revision_databooklet.pdf [Accessed 30 Jan. 2022].

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Image 2 – Itri, J.N., et al. (2018). Fundamentals of Diagnostic Error in Imaging. RadioGraphics, [online] 38(6), pp.1845–1865. Available at: https://pubs.rsna.org/doi/full/10.1148/rg.2018180021 [Accessed 30 Jan. 2022].

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Institute of Medicine (US) Committee on Data Standards for Patient Safety, et al. (2004). Patient Safety: Achieving a New Standard for Care. [online] PubMed. Washington (DC): National Academies Press (US). Available at: https://pubmed.ncbi.nlm.nih.gov/25009854/ [Accessed 29 Jan. 2022].

 J. Flowers Health Institute (n.d.). Medical Diagnosis before Treatment Is Vital | Learn Why | J.Flowers Health. [online] J. Flowers Health Institute. Available at: https://jflowershealth.com/medical-diagnosis-before-treatment/ [Accessed 28 Feb. 2021].

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LaVeist, T.A., Gaskin, D. and Richard, P. (2011). Estimating the Economic Burden of Racial Health Inequalities in the United States. International Journal of Health Services, [online] 41(2), pp.231–238. Available at: https://pubmed.ncbi.nlm.nih.gov/21563622/ [Accessed 30 Jan. 2022].

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Zwaan, L. and Singh, H. (2015). The Challenges in Defining and Measuring Diagnostic Error. Diagnosis, [online] 2(2), pp.97–103. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4779119/ [Accessed 30 Jan. 2022].

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Management of Hypertensive Disorders in Pregnancy to Prevent Maternal and Foetal Mortality

Abstract

Hypertensive complications in pregnancy are increasing in prevalence and often cause significant impairments in maternal and foetal mortality and morbidity. Managing and treating these disorders aims to prevent serious cerebrovascular and cardiovascular effects in the mother without compromising foetal well-being.

Introduction

In the United States of America alone, hypertension occurs in roughly 6-8% of pregnancies among women ages 20-44. Associated complications of hypertension in pregnancies, including pre-eclampsia, eclampsia, and end-organ damage, are leading causes of maternal and foetal morbidity and mortality worldwide.  The main strategy in the treatment of hypertension in pregnancy is to prevent any cerebrovascular and cardiac complications for the mother whilst preserving the uteroplacental and foetal circulation and, limiting medication toxicity to the foetus.

Classification of Hypertension Disorders

These hypertensive pregnancy disorders are diagnosed using a variety of tests including blood pressure monitoring, PIGF (placental growth factor) test and urine tests for proteinuria (increased levels of protein in the urine). Blood pressure readings which are higher than 140/90 mm Hg must also be monitored closely.

–   Preeclampsia and Eclampsia

High blood pressure and proteinuria of over 300mg, after 20-week gestation, are both characteristics of these disorders. The difference between eclampsia and preeclampsia is that eclampsia is a convulsive, more life-threatening form of pre-eclampsia, which affects 0.1% of all pregnancies. The disorder is thought to be caused by placental malperfusion resulting from an abnormal modelling of the maternal spiral arteries.

–   Gestational Hypertension

This disorder is diagnosed by measuring high blood pressure for the first time from a patient, after 20-week gestation alongside the absence of proteinuria. Gestational hypertension is significantly less dangerous than preeclampsia/eclampsia since the patient has not developed renal impairment, hence the absence of proteinuria.

–   Chronic Hypertension

Chronic Hypertension in Pregnancy is defined as blood pressure greater than 140mm Hg systolic and/0r 90 mm Hg diastolic, before pregnancy – however many women seek care for chronic hypertension only after becoming pregnant, before 20 weeks of gestation. This disorder is estimated to be present in approximately 3 – 5% of pregnancy and is increasingly more commonly encountered.

The 2 main risk factors contributing to this increasing prevalence of chronic hypertension include obesity and old age, which are also of increasing prevalence in pregnancy. Although many women with chronic hypertension remain stable during pregnancy and delivery, they are at a greater risk of several pregnancy complications, particularly superimposed preeclampsia, placental abruption, and preterm birth.

–   Chronic Hypertension with superimposed preeclampsia

This hypertension disorder is the new onset of proteinuria in the setting of hypertension before 20 weeks of gestation. Although, similar to chronic hypertension, this disorder is categorised separately due to the onset of proteinuria which is drastically increases the patients’ risk of HELLP syndrome (Haemolysis, Elevated Liver Enzymes and Low Platelets – a rare liver and blood clotting disorder that can affect pregnancy women).

Overall, there are four main organ systems which can suffer from possible acute complications of hypertensive pregnancies: Cardiovascular, Renal, Hepatic and the Central Nervous System (CNS). For mild to moderate hypertension in pregnancy, maternal risks are small, although they may be adverse consequences of high blood pressure in foetal cerebrovascular development. In contrast, early-onset and severe preeclampsia have a significant risk of later cardiovascular and renal morbidity and mortality, particularly for the mother.

Managing Hypertensive Pregnancy Disorders

– Non-Pharmacological Approaches

In non-pregnant hypertensive patients, lifestyle changes and interventions, including weight loss and reducing salt intake, are often the course of treatment. However, currently, there is no evidence to show that these approaches, such as an exercise and diet programme, is effective in preventing and managing hypertension in pregnancy. A 2010 study concluded that exercise training could reduce preeclamptic features in animal models, both before and after gestation, however human randomised, double-blind trials have not had similar results. Similarly, although obesity is a contributing risk factor for gestational hypertension, no evidence institutes that weight loss interventions could prevent hypertensive disorders in pregnancy.

There are very few non-pharmacological approaches available for managing hypertensive pregnancy disorders, particularly the lack of evidence supporting such approaches. But, bed rest continued to be the most frequent advice for patients with preeclampsia, which has shown to lower blood pressure, promote renal function and, which all will prevent dire complications during delivery. Nevertheless, since the progression of preeclampsia to eclampsia is sudden and without prediction, patients with this condition will be admitted to hospital for observation, where pharmacological approaches are often used due to the severity of the condition.

The only definitive therapy for acute hypertensive syndromes (preeclampsia and eclampsia) is delivery. This is especially when urgent control of blood pressure is necessary, or when the risk of harm to the foetus and/or the mother is significantly high. Delivery must be postponed for as long as possible, to enable foetal maturation, particularly of the respiratory system – Premature babies often have underdeveloped lungs, where not enough surfactant has been produced, which can lead to lung collapse and respiratory distress. The decision for the time of delivery also determines the extent of preeclampsia and the risk of complications, dictated by the current gestational period, liver and renal function tests, coagulation tests, etc. Although delivery is seen as a definitive treatment, expectant management and close observation is appropriate, particularly for patients before 32 weeks gestation as the foetus will be underdeveloped and risk of mortality is high.

– Pharmacological Approaches

The aim of pharmacological approaches during pregnancy is to prevent progression to severe hypertension and maternal complications, and to improve foetal development by prolonging the pregnancy.

The two main pharmacological agents to treat hypertensive pregnancies include anti-hypertensive agents and beta blockers. Anti-hypertensive agents are a class of drugs that are used to treat hypertension, which can be vasodilators or inhibitors of noradrenaline release. However, these medications should be ceased if diastolic blood pressure falls too low, which can result in maternal ischemia and potentially heart failure: low diastolic BP can restrict foetal blood supply, threatening dangerously low oxygen saturation levels.  Anti-hypertensive drugs are successful in reducing blood pressure but must be monitored closely to prevent low diastolic BP and to limit the rate of foetal growth restriction. In comparison, beta blockers medications are most preferred for the treatment of hypertension in pregnancies due to its proven safety and efficacy, and no association to adverse maternal or foetal outcomes.

However, the pharmacological management of hypertension in pregnancies remains controversial and understudied, particularly due to the various and complex factors affecting maternal and foetal wellbeing. Furthermore, increases in diversity and variability across patients’ clinical responses to medications require individualised assessments for dosing.

Conclusion

Hypertensive disorders is a common complication of pregnancy and due to the significant risk of morbidities and mortalities, the main issue with managing these disorders is identifying a balance between the maternal benefits from BP control and the foetal risks caused by intrauterine mediation toxicity and potential growth restriction. The treatment of hypertension may improve the risk profile for the mother and baby, and therefore delay delivery to increase survival rates for the foetus, but it does not cure hypertension, and preeclampsia, nor does it delay the progression to preeclampsia.

Bibliography

Brown, M.A. (2018). Hypertensive Disorders of Pregnancy. Hypertension, [online] 72(1), pp.24–43. Available at: https://www.ahajournals.org/doi/10.1161/HYPERTENSIONAHA.117.10803 [Accessed 28 Oct. 2021].

CDC (2019). High Blood Pressure during Pregnancy. [online] Centers for Disease Control and Prevention. Available at: https://www.cdc.gov/bloodpressure/pregnancy.htm. [Accessed 28 Oct. 2021].

Deak, T.M. and Moskovitz, J.B. (2012). Hypertension and Pregnancy. Emergency Medicine Clinics of North America, [online] 30(4), pp.903–917. Available at: https://pubmed.ncbi.nlm.nih.gov/23137402/ [Accessed 28 Oct. 2021].

Easterling, T.R. (2014). Pharmacological management of hypertension in pregnancy. Seminars in Perinatology, [online] 38(8), pp.487–495. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4272602/ [Accessed 28 Oct. 2021].

Falcao, S. and Bisotto, S. (2010). Exercise training can attenuate preeclampsia-like features in an animal model. Journal of Hypertension, [online] 28(12), pp.2446–2453. Available at: https://pubmed.ncbi.nlm.nih.gov/20811291/ [Accessed 28 Oct. 2021].

Hladunewich, M., Karumanchi, S.A. and Lafayette, R. (2007). Pathophysiology of the Clinical Manifestations of Preeclampsia. Clinical Journal of the American Society of Nephrology, [online] 2(3), pp.543–549. Available at: https://cjasn.asnjournals.org/content/2/3/543 [Accessed 28 Oct. 2021].

Image 1 – https://www.wrh.ox.ac.uk/images/news/improving-the-prediction-of-preeclampsia/responsive_image?ratio=image&scale=w1140

Kattah, A.G. and Garovic, V.D. (2013). The Management of Hypertension in Pregnancy. Advances in Chronic Kidney Disease, [online] 20(3), pp.229–239. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3925675/ – R1 [Accessed 28 Oct. 2021].

NHS Choices (2019). Newborn Respiratory Distress Syndrome. [online] National Health Service. Available at: https://www.nhs.uk/conditions/neonatal-respiratory-distress-syndrome/ [Accessed 28 Oct. 2021].

NICE. (n.d.). BNF is only available in the UK. [online] Available at: https://bnf.nice.org.uk/treatment-summary/antihypertensive-drugs.html [Accessed 28 Oct. 2021].

Preeclampsia Foundation (2020). Signs and Symptoms. [online] Preeclampsia Foundation. Available at: https://www.preeclampsia.org/signs-and-symptoms [Accessed 28 Oct. 2021].Vatish, M. (2016). Improving the Prediction of Preeclampsia. [online] Nuffield Department of Women’s & Reproductive Health: Medical Sciences Division. Available at: https://www.wrh.ox.ac.uk/news/how-to-predict-which-pregnant-women-have-suspected-preeclampsia [Accessed 28 Oct. 2021].

Preventive Medicine – Does This Field of Medicine Have The Greatest Impact On Society?

Abstract:

Preventive medicine involves a combination of medical practices which are designed to avoid disease and illness, with the aims of improving quality and quantity of life. This proactive approach to patient care ensures sickness is minimised to enable patients to have the best chance of recovery to optimum health.

Introduction:

Throughout the years, medicine and healthcare have shown to be necessary for a society’s ability to function. Society’s functioning and stability suffer if there is a larger proportion of unhealthy people and, ill health hinders individuals’ productivity and prosperity in their roles in society. When illnesses and morbidities occur, societies rely upon trusted doctors and healthcare professionals to aid recovery – responsive actions taken to treat a sickness or disease. But what if there could be a medical field to prevent illness in the first instance?

Especially during the COVID-19 pandemic, preventive medicine has emerged to be one of the most important fields, focussing on promoting, protecting and maintaining health. Most medical fields are directed towards certain ages, illnesses or body systems – however, preventive medicine is not subject to these boundaries and, is a ubiquitous and relevant field in society. The three main aspects behind preventative medicine include health awareness, immunisations, and screening alongside testing. 

Health Awareness in Preventive Medicine:

Non-communicable diseases, such as Type 2 Diabetes mellitus and cardiovascular disease, have accounted for 89% of all deaths in the UK. This emphasises the significance of increased health awareness and preventive medicine required in society.  The risk factors of chronic diseases now are well-known and well-established – a set of lifestyle choices responsible for most of the main chronic diseases, including tobacco use, imbalanced diets and irregular physical activity. Clinical preventive care aids patients to alter lifestyle choices to reduce the onset of chronic disease and decrease the impact of the disease on patients. Awareness programmes, including mental health awareness, and non-communicable diseases awareness, permit ‘medicine [to bridge] the gap between society and science’ and reach out to individuals struggling with health, for support and improvement. 

Vaccinations in Preventive Medicine:

Continued and widespread vaccination programmes enable immunisation to infectious diseases, preventing illness, hospitalisation and mortality. For example, COVID-19 vaccines, such as the Pfizer, and Oxford-AstraZeneca vaccines, will help reduce the spread of the disease and are safer ways to provide protection, highlighting disease-control benefits of preventive medicine. Mortalities prevented also translate into long-term cost savings: between 2001-2020, immunisations since 2001 will have averted an estimated $350 billion in total global costs due to illness. This enables potential economic growth which can allow more investment in public services, particularly in healthcare, to further improve citizens’ quality of life.

Vaccination programmes greatly reduce the burden of infectious diseases, decreasing mortality and morbidity rates and enabling these resources and money to be used for other serious healthcare issues in countries.

Screening and Testing in Preventive Medicine:

Screening and testing benefit various fields in diagnosis and treatment. For example, developments of ultrasound, and other methods for prenatal diagnosis, enable obstetrician-gynaecologists to abort defective or unwanted pregnancies and create prenatal treatment plans. This increased birth rates globally and decreased maternal mortality ratios (MMR): previous studies show that MMR decreased by 38% between 2000 and 2017. These schemes also aid internal medicine physicians, who strive to discover diagnoses of complex medical issues in the care of chronic illness and comorbidities, by providing visual identification of damage in the body. Internists benefit from advanced testing schemes, which are effective for the emergence and evolution of new diseases. This enables the achievement of early, accurate diagnoses, improving patient outcomes. 

Future of Preventative Medicine:

Past medical research in preventive medicine has focussed predominantly on lengthening lifespan, however the resultant life extension, without reducing aging, has unsustainably increased the extent of aging alongside age-related diseases, plus social and medical costs. This suggests that the aim of preventive medicine should be re-focussed – preferably more towards ameliorating quality of life. 

Medical progress, particularly in the field of preventative medicine, will raise the questions of which aspect of healthcare should be invested in coming years and decades. Many may argue that a managed compression of morbidity should take place. This would entail switching the majority of medical research funding from the main causes of death/mortalities, such as cancer and heart disease, towards the main causes of morbidity, such as dementia, degenerative diseases and depression. This approach would preferably remain until the quality of life is sufficiently high to make it worth extending lifespan. 

This graph displays how, in Europe, life expectancy is continuing to increase more rapidly than healthy life expectancy (average number of years lived with good health and wellbeing), hence morbidity (average number of years lived with poor health and wellbeing) is slowly expanding.

If these approaches are successful, this would decrease the rate at which life expectancy is increasing and increase the rate at which healthy life expectancy is increasing, which will result in a compression of morbidity. This resultant compression of morbidity will benefit our health and the economy as social and medical costs will be reduced, and resources can eventually be switched back to expand life expectancy sustainably. 

Conclusion:

Preventative medicine can be perceived to have the greatest impact on society – It is a hub, linking other fields, to help see the outcome of the research in various fields come together. Technological advancements aid this field, influencing innovative solutions for disease prevention, diagnosis and clinical care, turning a tide on human disease – namely, to combat COVID-19.

Swetha Babu, Youth Medical Journal 2022

Bibliography:

World Health Organisation (2018) “Noncommunicable Diseases Country Profiles” https://apps.who.int/iris/handle/10665/274512

Working Party of the Royal College of Physicians (2005). “Doctors in society. Medical professionalism in a changing world.”  Clinical medicine (London, England), 5(6 Suppl 1)

World Health Organisation (2017). “Estimated economic impact of vaccinations in 73 low- and middle-income countries, 2001-2020.” Bulletin of the World Health Organization.  https://doi.org/10.2471/BLT.16.178475

Image 1 – https://www.afro.who.int/sites/default/files/2019-01/imnz.jpg

Britannica, T. Editors of Encyclopaedia (2018, December 7). Obstetrics and gynaecology. Encyclopaedia Britannica.https://www.britannica.com/science/obstetrics

UNICEF Data (2020). “Trends in estimates of maternal mortality ratio (MMR), maternal deaths and lifetime risk of maternal death, 2000-2017.” https://data.unicef.org/topic/maternal-health/maternal-mortality/

Brown G. C. (2015). Living too long: the current focus of medical research on increasing the quantity, rather than the quality, of life is damaging our health and harming the economy. EMBO reports, 16(2), 137–141. https://doi.org/10.15252/embr.201439518

Image 2 – embr0016-0137-f4.jpg

Xenotransplantation: Using Animal Organs to Relieve The Human Organ Crisis

By Swetha Babu

Published 2:35 EST, Sat November 20th, 2021

Abstract

The organ crisis is an ever-prominent issue as globally, the demand for healthy and well-functioning organs significantly exceeds the available supply. Xenotransplantation is a medical procedure whereby living cells, tissues or organs are transplanted from one species to another: a potential solution for the human organ crisis.

Introduction

In the United States of America alone, ten patients die each day while on the waiting list to receive life saving vital organ transplants.

Xenotransplantation can alleviate this issue, while also providing greater access of transplant organs to ethnic minorities and limiting rejection in grafts. The benefits and risks of this procedure will be evaluated to determine whether xenotransplantation is a potential solution to human organ shortages.

Potential for Xenotransplantation

 Organ Shortages 

Today, organ transplantation is mainly undertaken to treat severe failure of vital organs such as the heart, lungs, liver and kidneys. Population aging and increasing sedentary lifestyles will result in an increase of the prevalence of chronic diseases (such as Type 2 Diabetes Mellitus and Coronary Heart Disease) and, consequently, the demand for transplantation. The strain on transplant organ supplies will encourage advances in biomedical breakthroughs, particularly in diagnostics and genomics, to reduce the occurrence of diseases progressing to life-threatening stages where only organ transplantation is viable. However, currently, xenotransplantation is one of the most readily available options to lessen the organ transplant crisis.

Xenografts: Reducing Risk of Rejection

Xenotransplantation not only enables organ transplantation but also the transplantation of tissue and cells (known as xenografts). Various tissues such as animal bone, skin, and foetal neural tissues for xenotransplantation have been suggested to be viable. Animal-to-human transplantation of tissues is certainly less dangerous than organ xenotransplantation as the animal tissues do not have major blood supplies hence the immune response is less vigorous, and the surgical procedure is less risky. Meaning, less damage to the patient is expected due to the lower risk of rejection and infection.

Image 1

A common example of animal tissue xenotransplantation is biological heart valves. These valves are used since unlike mechanical valves, they are not associated with a higher risk of blood clots, so the intake of blood thinners is not required. Porcine (pig) valves, which are an example of successful xenografts in modern medicine, are frequently used to replace aortic and mitral valves in the heart to treat cardiac valve conditions such as valvular stenosis.

The benefit to Patients of Ethnic Minorities 

In addition, xenotransplantation could be hugely beneficial for patients of ethnic minorities, where locating a suitable organ match is difficult. To reduce the risk of rejection, donors and recipients are ‘matched’ – it is vital for the donor and the recipient to have a matching blood group and antigen tissues type which is generally difficult to coordinate with an ethnic minority group.

In 2017, figures revealed that 21 percent of people in the UK who died on the organ transplant waiting list were from a black, Asian, or ethnic minority background compared with 15 percent a decade ago. This problem is then heightened due to the fact that such ethnic minorities constitute a significantly larger proportion of the organ donation waitlist: patients of ethnic minorities are three to four times more likely to develop end-stage renal failure and therefore require a kidney transplant. The huge stress on the supply of organs for ethnic minority patients is clearly evident here, and xenotransplantation has the potential to curb this issue greatly.

Ethical Concerns Against The Procedure

Animal Mistreatment

Animal mistreatment and disobedience to animal rights is one of the most significant ethical concerns associated with xenotransplantation, and it is argued that xenotransplantation is a violation of nature to exploit animals for their organs.

The welfare of animals is of great concern as these animals will be subject to trials and experiments before xenotransplantation becomes an available medical procedure. In addition, since there is the possibility of virus transference from animal to human, these animals are raised with special diets and in supervised environments specified for their growth. This has resulted in ethical criticism, as keeping animals imprisoned in an area that is not similar to its natural habitat with synthetic food diets and without other animal interaction does not enable the animals to live naturally.

Xenotransplantation benefits humankind by potentially saving lives and elongating life expectancies to the detriment of animals.

Religious Concerns

From a religious perspective, a fundamental value is to protect and preserve human life.

Xenotransplantation could be difficult in some religious cultures, such as Judaism and Islam, as swine is prohibited to be consumed, and to receive an organ for transplant from this animal could be considered sinful, disobeying their religious ideologies. Hence, locating another appropriate animal species’ organs for transplantation into humans. However, according to some perspectives of Christianity, Judaism, and Islam, there are not any specific religious fundamental binding reasons which prohibit xenotransplantation to treat grave and life-threatening organ insufficiencies.

If a patient refuses xenotransplanted organs on religious or cultural grounds and still requires an organ to treat their condition, they may need to be prioritized for allotransplantation (human to human transplants), stimulating another ethical dilemma. In the event that xenotransplantation is a reality, the allocation of human and animal organs would have to be thoroughly evaluated, ensuring that allocation is based on clinical need and that the maximum number of people continue to receive transplant organs. 

Scientific Concerns Against The Procedure

Physiological Differences in Organs 

Size and longevity are two main issues regarding animal organs for xenotransplantation. For example, a pig heart or kidney, when of suitable size for donation, may still have the potential for rapid growth, and the rate of growth of animal organs compared to the growth of human organs is most likely to be significantly different. The differences in organ size will limit the range of potential recipients of xenotransplants. Furthermore, the natural lifestyle is roughly 15 years, and aging in xenotransplanted organs is unknown.

Introduction of Unknown Infections

Xenozoonosis is the transmission of infectious agents between species via xenotransplants and xenografts. Animal to human transmission of pathogens can be extremely rare but past occurrences include avian influenza.

The main reason for the increased likelihood of disease transmission in xenotransplantation is that the implantation of foreign tissues into the human body breaches the physical barriers that usually prevent the transmission of disease. This potentially leaves the recipient of the xenotransplant exposed to a myriad of unknown pathogens which will most likely leave the recipient severely immunosuppressed 

Impact on Psychological Well Being

It is possible for the transgenic animal organ transplantation into the human recipient to cause major psychological and personality issues for the recipient. In 2010, a study revealed that individuals can form certain perceptions about their physical shape and their identity, as they struggle with the acceptance of an animal organ transplant, providing controversies for both the patients and society.

Hyperacute Rejection

Hyperacute rejection occurs because the human antibodies in the blood recognize the foreign antigens on the cells of the xenograft/xenotransplant, which are cells of pigs and all other distantly related species, triggering a rapid immune response. These antibodies bind to the cells lining the blood vessels of the organs as blood flows through the animal tissues, which activates the complement system, attacking the xenograft/xenotransplant. White blood cells are also activated by the complement proteins, and within a few minutes, the animal tissues are reduced to a black, swollen mass: the xenograft/xenotransplant has been rejected.

Image 2
Example of hyperacute rejection after renal transplantation: Kidney is no longer able to function as tissues are destroyed.

Although hyperacute rejection can occur in allotransplantation, it is significantly more likely to occur in xenotransplant recipients as the tissues originate from an individual of a different species, resulting in notably different antigens on its cells’ surface. Hyperacute rejection is probably the most difficult scientific concern against xenotransplantation, however, many promising methods to tackle this issue have arisen. One method includes the genetic modification of pigs (transgenic pigs), where, when an organ of the modified pig is transplanted in a human, the human complement regulatory proteins on the cells of the pig organ to inhibit the activation of complement, inhibiting hyperacute rejection.

Application to Fundamentals of Medical Ethics

Autonomy

It is clear that the nature of informed consent is the permission of the patient about the procedure after receiving thorough information about the side effects, and in return, the patient will be safe from treatments that are incompatible with their beliefs or unwanted. Informed consent is infinitesimally significant when regarding medical procedures, particularly ethically and medically controversial procedures such as xenotransplantation.

Beneficence

With future scientific breakthroughs to reduce the risk of rejection and to alter the rate of aging of the tissues, xenotransplantation can become commercially available like allotransplantation, as the risk of further disease to the recipient will be much lower. However, in this age, xenotransplantation of organs remains extremely difficult as more harm to the patient will be done, even if the organ does not remain in the patient’s body on a long-term basis but just to elongate the patient’s life expectancy while they wait for a human transplant organ. 

Non-Maleficence

Currently, the risks associated with xenotransplantation potentially outweigh the benefits, mainly due to the lack of scientific uncertainty of whether the transplanted organ can function as desired in the recipient’s body. 

Justice

The physical risks of xenotransplantation can be life-threatening, hence,  the recipient should be under close follow-up for an indefinite period of time, which can affect many aspects of human life, including sexual relationships and nutrition. In addition, recipients may have compromised immune systems and an increased risk of contracting infections, resulting in complete isolation and quarantine from others. This situation is undoubtedly against the most basic human rights – freedom and the establishment of relationships with others.

Conclusion

Several solutions against medical issues concerning xenotransplantation have arisen in recent years, including genetic modification and using transgenic pigs. However, an abundance of research and funding for clinical trials is still required to ensure that the procedure is well understood for the safety of potential recipients.  

But currently, in the face of difficulties, such as the unmet balance between organ demand and supply, xenotransplantation may be an attractive option shortly as ethical concerns around anthropocentric views and animal mistreatment still remain. But, if society can accept the ethical obligations associated with xenotransplantation, this procedure undoubtedly has the potential to develop into a legitimate solution to organ shortages.

Swetha Babu, Youth Medical Journal 2021

References

US Food and Drug Administration. (2021, Mar 3.) “Xenotransplantation” https://www.fda.gov/vaccines-blood-biologics/xenotransplantation

Cascalho, M., & Platt, J. L. (2008). “Challenges and potentials of xenotransplantation” Clinical Immunology, 1215–1222. https://doi.org/10.1016/B978-0-323-04404-2.10081-8

Nuffield Council on Bioethics. (1996) “Animal-to-Human Transplants. The ethics of xenotransplantation” 5-6. https://www.who.int/ethics/en/ETH_Nuffiled_xenotransplantation.pdf

Morgan, M., Kenten, C., Deedat, S., Farsides, B., Newton, T., Randhawa, G., Sims, J., & Sque, M. (2016). “Increasing the acceptability and rates of organ donation among minority ethnic groups: a programme of observational and evaluative research on Donation, Transplantation and Ethnicity (DonaTE)” NIHR Journals Library.

NHS Blood and Transplant. Organ Donation. (2018, Jul 18.) “Government campaign will focus on urgent shortage of black, Asian and minority ethnic organ donors” https://www.organdonation.nhs.uk/get-involved/news/government-campaign-focus-on-bame-organ-shortage/

Behnam Manesh, S., Omani Samani, R., & Behnam Manesh, S. (2014). “Ethical issues of transplanting organs from transgenic animals into human beings” Cell journal, 16(3), 353–360.

Sautermeister, J., Mathieu, R., & Bogner, V. (2015). “Xenotransplantation-theological-ethical considerations in an interdisciplinary symposium” Xenotransplantation, 22(3), 174–182. https://doi.org/10.1111/xen.12163

Dooldeniya, M. D., & Warrens, A. N. (2003). “Xenotransplantation: where are we today?” Journal of the Royal Society of Medicine, 96(3), 111–117. https://doi.org/10.1258/jrsm.96.3.111

George J. F. (2006). Xenotransplantation: an ethical dilemma. Current opinion in cardiology, 21(2), 138–141. https://doi.org/10.1097/01.hco.0000203183.81534.f9

Image 1 – https://images.theconversation.com/files/196741/original/file-20171128-28856-5zra8q.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=668&h=324&fit=crop

Image 2 – https://static.cambridge.org/binary/version/id/urn:cambridge.org:id:binary:20181009125204364-0075:9781107281981:61398fig16_3.png?pub-status=live

The Increasing Prevalence of Autoimmune Diseases

By Swetha Babu

Published 11:16 PM EST, Mon August 16, 2021

Introduction

NIH (National Institutes of Health) have revealed that up to 23.5 million American citizens have an autoimmune disease and the prevalence is increasing. 80-100 various autoimmune diseases have been identified by scientists who also assume that at least 40 other diseases could potentially have an autoimmune basis.

Classifications of Autoimmune Diseases

No tissue or organ is exempt from autoimmune diseases: these diseases can affect various organs and organ systems, varying greatly among the individuals who have them, in terms of severity and responsiveness to therapy.

Autoimmune diseases can be either localized or systemic:

–       Systemic autoimmune diseases affect many organs and tissues simultaneously. Examples of systemic autoimmune diseases include scleroderma (affecting the skin, intestines, and less commonly lungs and kidneys) and Sjogren’s Syndrome (affecting salivary glands, tear glands, and joints.) 

–       Localised autoimmune diseases are organ-specific and remain in only a certain part of the body, but often can develop into systemic diseases. Examples of localized autoimmune diseases include Hashimoto’s disease (affecting the thyroid) and Discoid Lupus Erythematosus (affecting the skin). Discoid LE is an example of a localized disease that can progress into Systemic LE, affecting various organs such as the kidneys.

Increasing Prevalence

In the UK alone, the incidence of various autoimmune diseases is increasing at ranges between 3% and 9% year on year. This includes:

•       7.0% increase per year of rheumatic diseases such as rheumatoid arthritis

•       6.3% increase of endocrinological conditions such as type 1 diabetes

•       3.7% increase of neurological such as Multiple Sclerosis (MS)

•       4–9% increase per year of coeliac disease

In the United States of America, the prevalence of autoimmunity is also rising. According to researchers at the Allergy and Immunology section at Yale School of Medicine, in the last 25 years, there has been a 44% increase in ANA antibodies (antinuclear antibodies), which are antibodies that target themselves, with over 41 million people affected. These ANA antibodies presage autoimmune diseases such as lupus and autoimmune arthritis.

Image 1 –  ANA antibodies with fluorescent dye

Costs for hospitals to aid affected individuals continue to rise as the incidence of these diseases increases. Direct and indirect costs for just three autoimmune diseases alone (type 1 diabetes, rheumatoid arthritis, and multiple sclerosis) currently add up to more than £13 billion per year in the UK. The costs are significantly high due to the absence of treatments that cure autoimmune diseases and the likelihood for patients to develop major secondary diseases. Treatment of autoimmune disease focuses on controlling the autoimmune reaction with immunosuppressants: Corticosteroids are often used to control inflammation and suppress the immune response. Another medication such as pain medication is often prescribed to suppress symptoms of the disease.

Causes and Possible Reasons for Increasing Cases

The immune system is exceedingly complex, and research has revealed some potential triggers for excess immune responses.

Genetics, and Environmental Factors

The most simple theory is that as a result of a mutation, an individual inherited a faulty allele (a version of a gene, which codes for a specific protein). Hence, the protein does not form correctly and fails to function effectively. E.g., In Type I Diabetes mellitus, a mutation in particular protein results in the destruction of beta cells in the Islets of Langerhans, as the cells are wrongfully targeted and destroyed, which results in the inability to produce insulin.

Another genetic-related theory is that a certain genetic background makes an individual more likely to have a sensitive immune system, which, upon an encounter with a certain trigger (such as an infection or climate), sets off an autoimmune disease. Chilblain Lupus Erythematosus is an example of a disease that can be inherited but may only be expressed when an affected individual inhabits a colder climate.

Smoking and Drugs

Certain substances, particularly blood pressure medications or antibiotics, can trigger the onset of drug-induced lupus, which is a more benign form of the disease but can still greatly affect an individual’s daily activities. Statins can trigger the onset of statin-induced myopathy, which causes muscle weakness.

Weight and Obesity

Being overweight or obese raises the risk of developing autoimmune diseases such as rheumatoid arthritis or psoriatic arthritis. The greater fat content and greater weight put stress on the joints, particularly the knees, and intruding fat tissues encourage further inflammation. The increasing global epidemic of obesity can contribute to the rising incidence of autoimmune diseases.

Research Advances to Lower Number of Cases

Clinical Trials

Knowledge about various autoimmune diseases and new therapies can be gained from clinical research studies, conducted with volunteers who undergo various medical tests. Clinical trials for autoimmune diseases include studying “the Pathogenesis of Chronic Inflammatory Rheumatic Diseases’” and studying “Patients Undergoing Therapy for Immune-Mediated Inflammatory Skin Conditions.” The purpose of these clinical research trials can enable various worldwide healthcare professionals to assess the safety and effectiveness of current and future therapies and to study how the onset and severity of the diseases can be dependent on inherited or acquired traits.

Laboratory Research

Researchers in laboratories investigate the molecular mechanisms of the immune response to understand the disease progression further whilst uncovering new treatment approaches. This information can enable patients’ risk for certain diseases to be recognized earlier and to provide appropriate treatments.

Translational Research

This involves linking both laboratory and clinical research as materials and information are exchanged and shared between these two disciplines. For example, demographic data and medical data from clinical trials can be studied together with blood samples and tissue samples to understand the diseases’ pathogenesis and progression to better target treatments.

Swetha Babu, Youth Medical Journal 2021

Conclusion

The increasing prevalence of autoimmune diseases and immune-related diseases continues to exert pressure on hospitals and to increase the costs for hospital treatments, due to the chronic nature of the diseases and the regular requirement for medication.

The ultimate goal of early diagnosis and therapy is prevention – before autoimmune diseases become a clinical problem.

Swetha Babu, Youth Medical Journal 2021

References

Lovell, D., Huang, B., Chen, C., Angeles-Han, S., Simon, T., Brunner, H. (2021) Prevalence of autoimmune diseases and other associated conditions in children and young adults with juvenile idiopathic arthritis. National Centre for Biotechnology Information. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978075/

British Society for Immunology. (2018, Nov. 26) Report reveals the rising rates of autoimmune conditions. https://www.immunology.org/news/report-reveals-the-rising-rates-autoimmune-conditions

Yale School Of Medicine. (2021, May. 20) Understanding Autoimmune Diseases. https://medicine.yale.edu/news-article/understanding-autoimmune-diseases/

Image 1 – http://blog.mblintl.com/antinuclear-antibodies-and-the-ifa-test

Johns Hopkins Medicine, Johns Hopkins Arthritis Center. https://www.hopkinsmedicine.org/health/wellness-and-prevention/what-are-common-symptoms-of-autoimmune-disease

Mayo Clinic, Clinical Trials: Autoimmune Diseases. (2021) https://www.mayo.edu/research/clinical-trials/diseases-conditions/autoimmune-diseases

Benaroya Research Institute at Virginia Mason, Autoimmune Diseases.

https://www.benaroyaresearch.org/what-is-bri/disease-information/autoimmune-diseases

Phantom Limb: Perceiving the Invisible

By Swetha Babu

Published 3:02 PM EST, Sat July 10, 2021

Introduction

The incidence of phantom limb is reported to be as high as 60-80% in patients post-amputation. Phantom limb pain should be differentiated from residual limb pain (RLP), as the latter originates from the actual site of the amputation.

Unlike phantom limb, RLP is often a manifestation of an underlying source, such as nerve entrapment, skin infections, surgical trauma, etc.

Onset and Symptoms

The onset of phantom limb mostly occurs immediately after amputation, however, some are documented to onset after a few weeks, although, rarely months later. The rise towards maximal sensation and pain differs between patients, often due to the contrasting extent of trauma and amputation.

Phantom pains are often described as crushing, burning, tingling, and cramping. Phantom sensations can be categorised into three different types:

–   Kinetic (movement)

–   Kinaesthetic (position and shape)

–   Exteroceptive (other stimuli such as touch, temperature and irritations)

 Image 1

Pathophysiology Theories behind phantom pain

Peripheral Nerve Changes

Amputation can result in a great trauma to nerves and tissues surrounding the site of amputation. 

This damage disrupts the normal nervous signals involved with the missing limb. The proximal portions of severed nerves begin to form neuromas (benign growths of nerve tissue), and the nerves become hyper-excitable, resulting in spontaneous discharges of impulses – pain and other sensations are experienced. 

Brain Changes

There has been significant research into cortical reorganisation, and it is a commonly cited factor in phantom limb pain. Cortical reorganisation refers to how the brain ‘re-maps’ the sections of the brain, adapting to significant stimuli. This can result in stimulation of nerves in the residual limb and the surrounding areas, causing the experience of pain and sensation in the missing limb. There is also a correlation between the extent of cortical reorganisation and the amount of pain that the patient experiences. 

An example of Cortical Reorganisation in response to amputation:

Psychological Factors

Sensations and pain could be influenced by memory of the incident, memory of pain proceeding the amputation, mood state, and a variety of other social concerns. In addition, circulating epinephrine within the body resulting from emotional distress can contribute to the stimulations of the peripheral nervous system, which can develop into the perception of sensations and pain in the amputated section of the limb. 

Evaluating Symptoms

The diagnosis of this phantom limb phenomenon is primarily a diagnosis of exclusion and is greatly dependent on the patient’s history, hence laboratory tests are less required.  A complete blood count (CBC) can help rule out infection as the source of paraesthesia. An ultrasound can be ordered to look for neuromas as a possible pain stimulator. However, most importantly, a psychology evaluation may be indicative if the patient is having significant extrinsic triggers that may be contributing to the patient’s pain, which could signify the requirement of psychiatric therapy.

Treatment and Prognosis

Often, when phantom limb pain and sensations continue vigorously for more than six months, the prognosis for spontaneous improvement is poor: some patients will experience a lifelong struggle with chronic pain. Phantom limb is a very difficult and complex condition to treat, particularly due to the lack of understanding of the nature of the condition, and that the cause of the phenomenon varies between patients.

The first treatment is usually conservative and should include non-pharmacological and nonsurgical methods. Prosthetists should assess the stump – the site of amputation – and should encourage the patient to use a prosthetic device for improved mobility. Psychotherapists may help identify the psychological cause of the pain and sensations experienced by the patient with the aim to mitigate the experiences and to ease anxiety and depression. In the event that neither solution is successful, pharmacists will work to select appropriate pharmacological agents. The medication should be specific to the extent of pain and/or sensations, considering its debilitation and hindrance on everyday life, as well as the history of symptoms. The patient must be aware of why the medication is being administered and educated on the different pharmacological agents available and their effectiveness and adverse effects.

Treating phantom limbs tends to be for symptomatic control, and although no medications specifically for phantom limbs exist, some drugs designed to treat other conditions have been helpful in relieving nerve pain: 

• Antidepressants, especially Tricyclic antidepressants, help relieve the pain of phantom limb phenomena. 
• Receptor antagonist medications, specifically NMDA receptor antagonists, are anaesthetics which bind to specific receptors on nerve cells, blocking the binding of a protein called glutamate, which has a crucial role in relaying nerve signals.

Conclusion

Research about phantom limbs is still in early stages, hence currently nothing more can be done to prevent, reduce, and cure phantom limbs. With a variety of psychotherapy options, medication, and prosthetics, alongside occupational therapy, phantom limb pain and sensations can be relieved in some, but not all, cases. As mentioned before, there is no one treatment that works reliably or consistently in all patients; the outcomes for most patients are limited and the quality of life can be poor.

Swetha Babu, Youth Medical Journal 2021

References

BJA Education. (2016) 16(3): 107–112. Pain after amputation. https://doi.org/10.1093/bjaed/mkv028

Image 1: https://medicalxpress.com/news/2018-09-theory-phantom-limb-pain-effective. html

Hanya-Deutmeter, A., Cascella, A., Varacallo, A. (2021). Phantom Limb Pain. National Centre for Biotechnology Information. https://www.ncbi.nlm.nih.gov/books/NBK448188/

Mayo Clinic, Mayo Foundation for Medical Education and Research. (2020, Oct. 29) Phantom Pain. https://www.mayoclinic.org/diseases-conditions/phantom-pain/diagnosis-treatment/drc-20376278

Cleveland Clinic. (2016, Mar. 14). Phantom Limb Pain. https://my.clevelandclinic.org/health/diseases/12092-phantom-limb-pain