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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