Thiamine deficiency unrelated to alcohol consumption in high‐income countries: a literature review

Abstract Thiamine deficiency has been typically associated with alcoholism or as a prevalent problem in low‐ and middle‐income countries (LMICs) whose populations rely on staple foods with a low content of thiamine. We conducted a literature review of published and unpublished data to identify relevant adult cases with confirmed thiamine deficiency of nonalcoholic cause in developed countries. We selected 17 reports with 81 adult cases of confirmed thiamine deficiency affecting adult patients with a wide range of ages and underlying conditions (e.g., cancer, gastrointestinal diseases, heart failure, and obesity). Thiamine deficiency may have been caused by disease‐related malnutrition, bariatric surgery, chronic use of diuretics, repeated vomiting, lack of thiamine in parenteral nutrition formulas, food insecurity, and reliance on monotonous or restrictive diets. Treatment with intravenous thiamine resulted in partial or complete recovery from the symptoms (cardiac, neurologic, and metabolic disorders) for most patients. The number and variety of symptomatic thiamine‐deficient adults identified in this review demonstrates that thiamine deficiency is not exclusive to LMICs and, in high‐income settings, is not exclusive to alcoholic patients. In developed countries, this serious but treatable condition can be expected in patients suffering from various medical conditions or following certain dietary patterns.


Introduction
Thiamine (a B-complex vitamin) plays a key role in energy metabolism and in the proper functioning of the multiple organ systems, such as the nervous, musculoskeletal, and cardiovascular systems. 1,2 Thiamine deficiency has been increasingly recognized as an important problem in lowand middle-income countries (LMICs). In these settings, populations that rely on staple crops with low thiamine content (such as polished rice or cassava), consume antithiamine factors (such as betel nuts and fermented fish), or follow postpartum restrictive diets have suffered from thiamine deficiency disorders. The pediatric population is known to be particularly susceptible to thiamine deficiency. Infantile beriberi mostly affects exclusively breast-fed infants whose mothers are thiamine deficient, and it results in death within hours of clinical presentation if not promptly treated. 1 All of these facts are discussed in other articles of this special issue. 3,4 While food fortification with thiamine is less common in LMICs, in some high-income countries, fortified foods (e.g., breads and breakfast cereals) contribute to about half of the total amount of thiamine consumed. 5 In highly resourced countries, thiamine deficiency is considered to be very rare because of food fortification and access to a varied diet, and is most commonly associated with alcoholism. 6 The excessive chronic consumption of alcohol is a well-known cause of thiamine deficiency and the consequent Wernicke encephalopathy (due to impaired intestinal absorption and utilization of thiamine); thus, when facing a patient with a history of alcoholism, clinicians tend to look for symptoms of thiamine deficiency. 7,8 However, in the absence of a medical history of alcoholism, the variable symptoms of thiamine deficiency (which affects multiple organ systems) may be attributed to other conditions and can be easily misdiagnosed. 2,6,9 With this literature review, we aim to provide an overview of adult cases of confirmed thiamine deficiency of nonalcoholic origin that have been reported in high-income countries. In particular, we aim to capture the variety of clinical manifestations of thiamine deficiency disorders.

Materials and methods
Using the electronic bibliographic database Medline, via PubMed, we conducted literature searches to identify relevant reports of adult cases with confirmed thiamine deficiency of nonalcoholic cause in high-income countries. We used the search terms "thiamine deficiency" or "beriberi," in combination with one or more of the following keywords: "adult," "report," "case report," "case series," "nonalcoholic," "polyneuropathy," "encephalopathy," "neuropathy," and "metabolic/lactic acidosis." In addition to searching published material, we also identified abstracts from conferences and unpublished data. We considered confirmation of thiamine deficiency as per the judgment of the authors of each report/case study, which were based on improvement of symptoms after the administration of thiamine, and/or on laboratory assessment of thiamine blood levels, and/or on clinical history/assessment (e.g., neuroimaging findings). Cases reported in the pediatric population, in adults with a current history of excessive alcohol consumption, or from LMICs were excluded. The definition of countries with high-income economies was based on the most recent World Bank classification. 10 We described the overall characteristics of each identified case, the likely cause of thiamine deficiency, how it was treated, whether treatment resulted in the resolution of symptoms, the identified delays in diagnosis (when reported), and potential associations with infections.

Results
We included 17 selected relevant reports with 81 adult cases (or clusters of cases) of confirmed thiamine deficiency of nonalcoholic origin that were observed in high-income countries (Table 1). These cases were described in published papers, conference abstracts, and in a personal communication (i.e., shared via email, within our network of thiamine experts). Most reports (nine) were identified in the United States; three were observed in Japan, one in Italy, one in France, one in the United Kingdom, one in Korea, and one in Saudi Arabia, between 1999 and 2020. The 81 patients included in this analysis were between 19 and 75 years old and 69% were males. Most of the cases (94%) had an underlying health condition (such as cancer, gallstone, pancreatitis, heart failure, or a recent surgery or medical treatment that caused weight loss); a smaller number of cases (6%) did not present with a background disease but experienced some level of food insecurity, followed a particular dietary pattern according to personal preferences (e.g., ate mostly white rice and disliked meat and vegetables), or ate a restrictive diet to encourage weight loss. Thus, there was a wide range of likely causes of thiamine deficiency, including diseaserelated malnutrition (usually accompanied by a significant, unintentional weight loss), gastrointestinal symptoms and surgical complications following bariatric surgery, food insecurity, chronic use of diuretics (to manage heart failure), repeated vomiting, lack of thiamine in parenteral nutrition formulas, and reliance on monotonous or restrictive diets. Body mass indexes, when reported, varied from underweight (13 kg/m 2 ) to obese (43 kg/m 2 ). Blood thiamine levels were measured in the majority of the patients (94%), with most presenting low levels compared with the laboratory reference ranges. The symptoms and clinical presentation varied significantly from case to case, with a wide range of neurologic and cardiac manifestations typical of thiamine deficiency (e.g., muscle weakness, peripheral neuropathy, confusion, edema, tachycardia, dyspnea, and metabolic acidosis), in agreement with the existing literature. The initial treatment of thiamine deficiency in the various cases was mostly intravenous, and when reported, the dose varied from 75 mg once daily to 500 mg three times a day. Despite this variability in the dose of thiamine administered, treatment resulted in partial or complete recovery from the symptoms for most of the patients, except in three cases that resulted in death. 11,12 Infections were present in 11 cases: one with a septic state, 13       intra-abdominal infections, 14 and nine that did not specify the type of infection. 15

Discussion
The present work provides an overview of the variety of conditions or dietary modifications that can lead to thiamine deficiency and are not linked to excessive chronic consumption of alcohol. It demonstrates that thiamine deficiency is not a resolved problem and is not exclusive to LMICs; it is still present even in areas where it is not expected. It highlights that, in high-income countries, thiamine deficiency affects many more patients beyond the expected cases caused by alcoholism. These may include patients with cancer, heart failure, gastrointestinal diseases, or surgeries in the gastrointestinal tract that lead to reduced intake and absorption of nutrients (e.g., gastrectomy to treat cancer   43,44 or gastric bypass to promote weight loss). Other causes of nonalcoholic thiamine deficiency include the inappropriate formulation of parenteral nutrition (even when used for only a few weeks) and the chronic use of diuretics, which are used to manage fluid and sodium levels in heart failure (among other health conditions) but can cause hyperexcretion of thiamine. 16 Thus, the clinical community should consider thiamine deficiency in these patient populations that present with cardiac and neurologic symptoms, as well as metabolic acidosis and muscular symptoms. The pathophysiologic mechanisms that can lead to thiamine deficiency are summarized in Table 2.
Healthcare professionals are relatively unaware of thiamine deficiency as a possible cause of polyneuropathy, particularly in patients without Wernicke encephalopathy or heart failure in the initial phase, and some of the thiamine deficiency cases we identified were initially diagnosed as Guillain-Barré syndrome. 13,17 Even in patients with Wernicke encephalopathy, it is estimated that 80% of the cases do not receive a diagnosis, with some cases only being diagnosed postmortem. 18 A delayed diagnosis of thiamine deficiency is a serious problem because, if intravenous thiamine is not administered soon after the onset of symptoms, the patient's clinical condition can deteriorate very quickly and even result in death. 17,19 Early symptoms of thiamine deficiency, such as nausea, vomiting, fatigue, weakness, and milder neurological manifestations, are often not attributed to thiamine deficiency by clinicians. 20 It usually takes a few days to obtain the results of a laboratory assessment of blood thiamine levels. Some authors recommend obtaining a thiamine level before thiamine replacement (to help confirm the diagnosis), without delaying the treatment, that is, beginning the thiamine administration immediately after the blood is collected for analysis. 2,14 Thiamine has no tolerable upper intake level (there is no established toxic level) and is safe and inexpensive, justifying the prompt treatment. It is also recommended that the thiamine infusion should precede or be given along with intravenous glucose, as glucose (alone) can precipitate Wernicke encephalopathy in thiamine-deficient individuals due to increased utilization of thiamine. 14,21,22 Infections can increase the use of thiamine and precipitate Wernicke encephalopathy in patients with a suboptimal thiamine status; in addition, infections have been shown to lead to worse neuropsychological outcomes in thiamine-deficient patients. 23 In the present study, severe infections were reported in only two cases, and another nine cases did not specify the type of infection, although it should be noted that infections may have been present in other patients but not reported in the description of the case study.
Body mass index, when reported in the case study, varied from 13 to 43 kg/m 2   weight, overweight, and even obese patients. The history of a significant unintentional weight loss (which can be as high as 20 kg in 2 months 11 ) is, however, a sign that the patient is malnourished or at risk of malnutrition, even in the presence of abundant fat reserves. When unintentional weight loss is coupled with the presence of neurological or cardiac symptoms, it should alert the clinician to the suspicion of thiamine deficiency. This literature review revealed a significant number of obese individuals who became thiamine deficient after undergoing weight-loss surgery-a phenomenon that has been called "bariatric beriberi." 24 Bariatric surgery can lead to thiamine deficiency because postoperative vomiting is common and because the area of the gut available for nutrient absorption is reduced in certain procedures (e.g., Roux-en-Y gastric bypass), resulting in decreased thiamine absorption. Patients with a history of bariatric surgery are, therefore, recommended to take daily thiamine supplements indefinitely. 18 In addition, thiamine deficiency seems to affect a significant proportion (15-29%) of preoperative bariatric surgery patients. This suggests that obese patients are a group at risk of thiamine deficiency, which may be explained by the typical dietary pattern of high consumption of simple sugars (which contain very little thiamine and require relatively high amounts of this vitamin for their metabolism) and low consumption of foods high in thiamine (such as whole grains, legumes, and seeds). 25 Other previously published studies have looked at specific manifestations of thiamine deficiency, that is, Wernicke-Korsakoff syndrome not related to alcohol use, 26 Wernicke encephalopathy in schizophrenia, 27 Wernicke encephalopathy in patients with depression, 27 Wernicke encephalopathy following gastrointestinal surgeries, 28 Wernicke encephalopathy in hyperemesis gravidarum, 29 and Wernicke encephalopathy after bariatric surgery. 24 The present work, despite not being an exhaustive nor a comprehensive list of cases found in the literature, includes a variety of cardiac, neurologic, muscular, and metabolic manifestations of thiamine deficiency not associated with excessive alcohol consumption. This is a major strength of our review and an approach that, to our knowledge, has not been used before. For example, the thiaminedeficient oncologic patients identified in our literature review presented with a wide range of clinical manifestations, from Wernicke encephalopathy 11 and Wernicke-Korsakoff syndrome 15 to polyneuropathy and cardiomyopathy. 2 In these cancer patients, thiamine deficiency can be caused by several mechanisms, including decreased thiamine availability/intake (e.g., low oral intake, low appetite, nausea, and oral thrush), accelerated usage (e.g., the presence of infection and fever), impaired functioning (e.g., use of medications, including metronidazole and fluorouracil, which inactivate thiamine), and excessive loss (e.g., due to vomiting and diarrhea). 15 In summary, our work suggests that thiamine deficiency associated with certain underlying diseases can have diverse clinical manifestations.
Hopefully, this article will raise awareness about the need for early recognition and appropriate treatment of thiamine deficiency in a variety of conditions not associated with alcoholism. While thiamine deficiency can result in serious consequences, prompt treatment can lead to a full recovery of the affected patient.