Top Clin Nutr Vol. 36, No. 1, pp. 36–51 Copyright c 2021 Wolters Kluwer Health, Inc. All rights reserved. NARRATIVE REVIEW A Systematic Review of the Role of Thiamine Supplementation in Treatment of Refeeding Syndrome Lea Steiner, MS, RD, CSG; Susan Hewlings, PhD, RD The purpose of this systematic review is to identify studies where measurable thiamine supple- mentation was provided to patients at risk for or with refeeding syndrome to improve treatment guidelines. A systematic review of PubMed and CINAHL Plus databases was conducted using the terms refeeding syndrome, hypophosphatemia, thiamine, and vitamin B1. A total of 173 articles were retrieved and 11 case studies and 1 retrospective study met inclusion criteria. All studies identified symptoms of thiamine deficiency, and all studies indicated thiamine supplementation was associated with improved clinical symptoms and no harmful outcomes. Average dose provided was 173-mg thiamine/day. Key words: B1, hypophosphatemia, refeeding, refeeding syndrome, thiamine EFEEDING syndrome is defined as the case studies in eating disorders or prolonged R metabolic process in response to the voluntary fasts6 where refeeding syndrome is reintroduction of calories after starvation.1-3 self-induced because ethical barriers inhibit It is often diagnosed by electrolyte abnormal- controlled trials. Related to the paucity of ities and poor management can be fatal.1,2,4 studies and lack of comparability within the Refeeding syndrome was first recognized research available, evidence-based treatment in prisoners of war following the Second is not clearly defined.5 However, slow reintro- World War but continues to lack definitive duction of calories, electrolyte repletion, and criteria and remains poorly recognized vitamin supplementation including thiamine in the hospital setting despite significant is often recommended to manage refeeding incidence.2,3 For example, some sources sydrome.4,7,8 indicate that refeeding syndrome affects up to 25% of cancer patients and 14% of the geriatric population.4,5 The majority of PATHOPHYSIOLOGY OF REFEEDING evidence on refeeding syndrome is limited to SYNDROME Refeeding syndrome represents the shift Author Affiliation: Boise Veterans Affairs Medical to anabolic metabolism as nutrition is Center, Boise, Idaho. reinitiated.5 This metabolism shift contributes The authors have disclosed that they have no signif- to corresponding electrolyte abnormalities icant relationships with, or financial interest in, any especially abnormal potassium, magnesium, commercial companies pertaining to this article. and phosphorus.5 During starvation, fat and Correspondence: Lea Steiner, MS, RD, CSG (9steinl protein become the main source of energy @gmail.com). because glycogen stores are exhausted and DOI: 10.1097/TIN.0000000000000235 insulin is suppressed.7,9,10 Once eating is 36 Copyright © 2021 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Thiamine Supplementation in Treatment of Refeeding Syndrome 37 reinitiated, blood glucose increases promot- able thiamine stores are depleted.4,5 For ex- ing insulin secretion and contributes to a shift ample, thiamine pyrophosphate is needed in in electrolytes, as energy synthesis pathways synthesis of branched chain amino acids and are upregulated.4,5,10 Hypophosphatemia is fatty acids, anabolic pathways that are up- not exclusive in recognition of refeeding syn- regulated once subjects begin eating again drome but is often the hallmark feature.3,5,10 after starvation.5,14 Thiamine pyrophosphate Hypophosphatemia is precipitated from the is also a cofactor in carbohydrate metabolism insulin surge as eating restarts because serum associated with pyruvate dehydrogenase.12-16 phosphorus is depleted quickly.4,11 Phos- In this pathway, thiamine deficiency could phorus is depleted related to increased de- be rate limiting causing pyruvate to be used mand in phosphorylated intermediates such in anaerobic metabolism instead of aerobic as creation of adenosine triphosphate for resulting in lactic acidosis.12-16 Lactic acido- glucose phosphorylation.4,11 Hypokalemia is sis is frequently one of the clinical symp- likely caused by cellular uptake of potas- toms of refeeding syndrome, which could sium, as pathways like glycogen synthesis be explained by thiamine deficiency.12-16 are upregulated.4 It is also possible that the In protein and lipid metabolism, thiamine sodium/potassium adenosine triphosphatase is needed for adenosine triphosphate pro- pump, which generally maintains blood potas- duction and here thiamine deficiency limits sium, is overwhelmed with refeeding con- the ability of pyruvate to convert to acetyl tributing to increased urinary excretion and CoA.12-16 In amino and fatty acid synthesis, hypokalemia.12 Potassium abnormalities are thiamine is required in the pentose-phosphate often what can make refeeding syndrome shunt for nicotinamide adenine dinucleotide fatal, but any of the electrolyte abnormal- phosphate and thiamine deficiency limiting ities can contribute to symptoms.4,10 The the pentose-phosphate shunt could inhibit clinical features of refeeding syndrome in- myelin sheath repair and impair nucleic acid cluding delirium, seizures, edema and heart synthesis.12-17 In refeeding syndrome, these failure, metabolic alkalosis, and rhabdomy- metabolic pathways are upregulated increas- olysis can be attributed to these electrolyte ing thiamine needs and depleting thiamine if abnormalities.4,10,12 However, these symp- intake or stores are inadequate. toms could have causes besides electrolyte Inadequate thiamine is likely in refeed- abnormalities in refeeding syndrome such as ing syndrome for reasons in addition to in- thiamine deficiency.5,13 creased needs. Thiamine cannot be synthe- sized endogenously and storage is limited; therefore, inadequate exogenous intake can THIAMINE IN REFEEDING SYNDROME rapidly precipitate deficiency.4,5 Inadequate thiamine intake independent of refeeding syn- Wernicke-Korsakoff syndrome or symp- drome can contribute to deficiency in as toms associated with wet or dry beriberi such little as 2 weeks.13 Prolonged starvation is as ophthalmoplegia, ataxia, paralysis, con- one of the key risk factors in refeeding syn- fusion, congestive heart failure (CHF), and drome, predisposing patients for thiamine de- edema are often identified in refeeding syn- ficiency in addition to refeeding induced in- drome and could be explained by thiamine creased metabolic demand for thiamine and deficiency.5,14 Thiamine deficiency is likely increased cellular thiamine use.4,5 Malnutri- in refeeding syndrome because of increased tion and alcohol intake are additional risk metabolic needs. Thiamine is required as a co- factors for refeeding syndrome that predis- factor in many of the metabolic pathways that pose patients for poor thiamine intake or de- are upregulated once feeding is reinitiated.4,5 ficiency at baseline.4,5 For example, thiamine This could contribute to thiamine deficiency supplementation is frequently recommended if there is a deficiency at baseline or avail- as part of treatment in alcohol withdrawal Copyright © 2021 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. 38 TOPIC IN CLINICAL NUTRITION/JANUARY–MARCH 2021 often to avoid Wernicke’s encephalopathy but malities with thiamine supplementation.13 also because thiamine use is impaired in alco- Cases also identify the concept that supple- holic patients because of changes in gluco- mentation prior to initiating feeding may neogenesis or decreased intestinal absorption be beneficial in avoiding clinical symptoms making deficiency likely.18 from precipitating because thiamine avail- It is not conclusive whether thiamine defi- ability would be adequate for the increased ciency is present at baseline in refeeding syn- metabolic needs.14 This theory explains why drome or caused by refeeding syndrome.14,15 National Institute for Health and Care Ex- Lack of evidence differentiating this can be cellence (NICE) criteria recommend starting attributed to limited thiamine measurement thiamine supplementation prior to reintro- in the research because some measures ducing calories. NICE guidelines recommend are not accurate and others are difficult to thiamine supplementation 200 to 300 mg/day measure. Serum thiamine is not an accurate orally or 200 to 300 mg/day intravenously (IV) measurement because it only identifies a as part of an undefined B vitamin preparation portion of total body thiamine and concentra- if needed, initiated before refeeding and for tions are not indicative of thiamine stores.5,18 the first 10 days of calorie reintroduction.8 Thiamine is a cofactor for transketolase, an The NICE guidelines do not define when to enzyme involved in many metabolism path- use IV supplementation instead of oral.8 NICE ways and its activity increased in response to guidelines were selected for comparison increased thiamine.5 Erythrocyte transketo- in this review because multiple treatment lase activity and a thiamine loading test are the guidelines for refeeding syndrome base thi- best measure to identify thiamine deficiency amine recommendations on them or have the because enzyme activity increases after same recommendations as these guidelines thiamine pyrophosphate loading.5 However, for thiamine supplementation in refeeding erythrocyte transketolase activity requires syndrome including Friedli et al,4 the Irish high-performance liquid chromatography for Society for Clinical Nutrition and Metabolism, measurement, which