Journal of Clinical Medicine Article A Retrospective Case Series of Thiamine Deficiency in Non-Alcoholic Hospitalized Veterans: An Important Cause of Delirium and Falling? Elisabeth Mates 1,2,* , Deepti Alluri 3, Tailer Artis 2 and Mark S. Riddle 1,2 1 Medicine Department, Veterans Affairs Sierra Nevada Healthcare System, Reno, NV 89502, USA; [email protected] 2 School of Medicine, University of Nevada, Reno, NV 89502, USA; [email protected] 3 Sound Physicians, Lutheran Hospital, Fort Wayne, IN 46804, USA; [email protected] * Correspondence: [email protected] Abstract: Thiamine deficiency (TD) in non-alcoholic hospitalized patients causes a variety of non- specific symptoms. Studies suggest it is not rare in acutely and chronically ill individuals in high income countries and is underdiagnosed. Our aim is to demonstrate data which help define the risk factors and constellation of symptoms of TD in this population. We describe 36 cases of TD in hospitalized non-alcoholic veterans over 5 years. Clinical and laboratory data were extracted by chart review +/− 4 weeks of plasma thiamine level 7 nmol/L or less. Ninety-seven percent had two or more chronic inflammatory conditions (CICs) and 83% had one or more acute inflammatory conditions (AICs). Of possible etiologies of TD 97% had two or more of: insufficient intake, inflammatory stress, or increased losses. Seventy-five percent experienced 5% or more weight loss. Ninety-two percent had symptoms with the most common being weakness or falling (75%) followed by neuropsychiatric Citation: Mates, E.; Alluri, D.; Artis, manifestations (72%), gastrointestinal dysfunction (53%), and ataxia (42%). We conclude that TD is T.; Riddle, M.S. A Retrospective Case underdiagnosed in this population with consequent morbidity and mortality. TD likely develops Series of Thiamine Deficiency in because of inflammatory stress from CIC’s compounded by AIC’s combined with decreased energy Non-Alcoholic Hospitalized Veterans: intake or increased nutrient losses. An Important Cause of Delirium and Falling?. J. Clin. Med. 2021, 10, 1449. https://doi.org/ Keywords: thiamine deficiency; delirium; falls; thiamine deficiency symptoms; encephalopathy; 10.3390/jcm10071449 inpatient; vitamin B1; beriberi; gastrointestinal dysfunction Academic Editor: H. Christian Weber Received: 9 March 2021 1. Introduction Accepted: 24 March 2021 Thiamine micronutrient deficiency (TD) can cause a variety of non-specific symptoms Published: 1 April 2021 and leads to a variety of thiamine deficiency disorders (TDDs) [1,2] such as heart failure, type 2 lactic acidosis, polyneuropathy, Wernicke’s Encephalopathy (WE) and Korsakoff Publisher’s Note: MDPI stays neutral syndrome [1–3]. Left untreated, more severe disorders can lead to permanent disability with regard to jurisdictional claims in or death. TD and TDDs are reportedly rare in high income countries except in alcohol published maps and institutional affil- abusers (2.8% or less) although there is a lack of prevalence data [4]. Symptoms are often iations. vague and non-specific such as fatigue, leg edema, imbalance, confusion, mood disorders, gastrointestinal (GI) upset, and muscle weakness [1] which likely contributes to under diagnosis of TDDs in non-alcoholics. There is literature to suggest it is not rare in the acutely and chronically ill in developed countries where food security is common [3,5–8]. Copyright: © 2021 by the authors. The body’s supply of thiamine depends entirely on dietary intake, there is no endoge- Licensee MDPI, Basel, Switzerland. nous synthesis [1,3]. Thiamine diphosphate is an essential cofactor for the metabolism of This article is an open access article carbohydrates and amino acids [1,3]. TD can develop quickly, within 18 days on a thiamine distributed under the terms and deficient diet or within 72 h in critically ill patients [9]. Any disease that adversely affects conditions of the Creative Commons intake or absorption, accentuates loss of nutrients, or causes acute inflammatory stress can Attribution (CC BY) license (https:// lead to development of TD in a matter of days. There are many restrictive diets which creativecommons.org/licenses/by/ minimize the intake of thiamine fortified foods such as wheat flour (a gluten free diet 4.0/). J. Clin. Med. 2021, 10, 1449. https://doi.org/10.3390/jcm10071449 https://www.mdpi.com/journal/jcm J. Clin. Med. 2021, 10, 1449 2 of 11 for example) that could lead to TD. The high prevalence of TD in obese patients who are dieting suggests even typical weight loss diets predispose to its development [10]. There have been many published accounts of TD in acutely and chronically ill patients with conditions such as end stage renal disease [11], cancer [12–14], heart failure [15–18], dementia [19,20], acute psychiatric illness [21], stroke [22], diabetic ketoacidosis [23], critical illness [2], and medically complicated obesity [10,24]. Acute Illnesses which increase metabolic demands can lead to TD more quickly including severe sepsis [2,9]. Elderly patients admitted to hospital seem particularly vulnerable [5,7,8]. Despite a preponderance of evidence that TD is not rare in these populations, it is still under-diagnosed and under- treated [4]. We hypothesize that TD is not rare in hospitalized patients who generally have higher chronic disease burden [25] and an incidence of malnutrition of 24% or more [26–28]. The etiologies of TD can be broadly categorized as insufficient intake (including malabsorp- tion and toxin interference), increased need due to inflammatory stress (e.g., sepsis), and increased losses (such as vomiting, diarrhea, dialysis [29], or chronic diuretic use [16]). Hos- pitalized patients often have increased inflammatory stress due to acute and chronic forms of inflammation with concomitant cachexia [30,31]. Many use diuretics for hypertension and heart failure treatment. The purpose of this study is to describe a series of 36 cases of TD in hospitalized non-alcoholic patients in a Veterans Affairs (VA) hospital, defined by plasma thiamine level less than or equal to 7 nmol/L. We describe their symptoms of TDD’s as well as possible underlying factors leading to TD. Our overall goal is to generate data which help to define the problem of TD in hospitalized veterans and lead to future efforts on mitigation. 2. Materials and Methods This is a retrospective case series of hospitalized non-alcoholics at the VA hospital in Reno, NV who were identified as having TD defined as abnormally low plasma thiamine concentration. In most cases the thiamine level was ordered because of suggestive symp- toms. Cases were identified in two ways: by personal knowledge of author EM, and by querying the laboratory database of the VA Sierra Nevada Healthcare System (VASNHCS) from 9 December 2014 to 3 September 2020 for values of 7 nmol/L or less. Plasma thiamine measurements were performed at Quest Diagnostics in Valencia, California using Liquid Chromatography/Tandem Mass Spectrometry with a normal range of 8–30 nmol/L. Cases were excluded if there was a history of unhealthy alcohol use as described by The National Institute on Alcohol Abuse and Alcoholism (more than 14 standard drinks per week for men less than age 65, or more than 7 per week for women or men 65 years or older). Additionally, cases were excluded if they were not hospitalized within +/− 4 weeks of the result. Exclusions were determined by chart review. The laboratory database query returned 84 individuals with low thiamine levels. Of those, sixteen were excluded due to excess alcohol intake and thirty-five were excluded for not having been hospitalized within four weeks of the result. Three additional cases were identified in the clinical practice of author EM for a total of thirty-six cases. All patient data including demographics, medical history, and laboratory values were extracted from their electronic medical records at VASNHCS. This study was reviewed by the University of Nevada, Reno Institutional Review Board (IRB) and determined to be exempt from IRB review under Category 4, secondary research utilizing identifiable private information recorded by the investigator in such a manner that the identity of the human subjects cannot be readily ascertained. Clinical and laboratory data were extracted within +/− 4 weeks of the abnormally low thiamine result. For non-thiamine tests with multiple results within that timeframe, the value closest to the date and time of the thiamine test was chosen. Demographic data included age on the date of the thiamine result, sex assigned at birth, race, and date of death where applicable. Anthropometric data include actual standing or bed weight on admission, trend in weight in the preceding weeks or months (within 1 year) J. Clin. Med. 2021, 10, 1449 3 of 11 as a percentage of their baseline weight (average weight before the onset of weight loss), and body mass index (BMI) at the time of admission. We extracted albumin (g/dL) and prealbumin (mg/dL) as biomarkers of malnutrition and acute inflammation [32]. We noted magnesium deficiency, lactic acid (mmol/L), alcohol level (mg/dL) and urine drug screens where available. We recorded other micronutrient deficiencies including vitamin C, D, B12, folate, and iron. Chart notes were reviewed for acute medical conditions diagnosed during hospital- ization and chronic medical conditions present before admission. Causes of increased thiamine loss (IL) were defined as nausea, vomiting, diarrhea, diuretic use, or dialysis. Inflammatory stress (IS) was defined as any acute or chronic inflammatory