An Overview of Beriberi

Abstract

Beriberi is a nutritional disorder caused by thiamine deficiency. Classically, Beriberi presents in two primary clinical forms: “wet” Beriberi, which features heart and circulatory system impairment, and “dry” Beriberi, which causes polyneuropathy. Although it is an easily treatable condition, it is often misdiagnosed and can be life-threatening if not promptly recognized and managed. The diagnosis of Beriberi is performed by the signs and symptoms of the disease and can be confirmed by thiamine deficiency identification or by therapeutic testing. However, considering the costs and the limitations of the assays to evaluate thiamine deficiency, the diagnosis based on the evaluation of clinical signs and symptoms and the therapeutic test could eliminate the need for measuring serum thiamine levels. Regarding treatment, immediate thiamine administration in the presence of clinical manifestations of the disease is recommended. Overall, 100–300 mg daily doses are enough to improve symptoms. In this review, we aim to (1) provide a clinical update about how to identify and treat the Beriberi and (2) describe the historical perspective, pathophysiological mechanisms, and other relevant aspects which may have applications in clinical management of Beriberi.

Highlights of the Study

• Beriberi is rare in developed countries but remains prevalent in some regions.

• Diagnosis is based on symptoms and response to thiamine due to the cost of testing.

• Food fortification, education, and early action are key to preventing Beriberi.

Introduction

Beriberi is a nutritional disorder caused by thiamine (vitamin B1) deficiency [1]. When left untreated or if the diagnosis is delayed, it can result in cardiovascular damage and motor changes, increasing the risk of mortality [2]. Classically, Beriberi presents two major clinical forms: “wet” Beriberi, which features heart and circulatory system impairment, and “dry” Beriberi, which causes damage to the nervous system, leading to polyneuropathy [3]. Long-term alcohol drinking is the most common cause of Beriberi. Still, etiologic factors are also related to food insecurity, increased demand for thiamine, medication use, and impaired absorption and metabolism of this vitamin [3, 4]. Beriberi is not a worldwide disease concern, occurring predominantly in outbreaks and isolated cases among susceptible groups [4].

From a worldwide perspective, thiamine deficiency is prevalent in many communities in Southeast Asia, South Asia, and West Africa. However, the assays’ limitations in measuring thiamine levels, their high costs, and the limited number of clinical studies make it difficult to determine the global prevalence of thiamine deficiency [5–8]. Considering these limitations, the presence of Beriberi’s signs and symptoms could eliminate the need for thiamine measurement to confirm its diagnosis and initiate treatment. In addition, there is still controversy regarding the need and dose of thiamine supplementation to improve clinical outcomes [9–11]. Although it is an easily treatable condition, it is often misdiagnosed and can be life-threatening if not promptly recognized and managed [12, 13]. In this review, we aim to (1) provide a clinical update about how to identify and treat the Beriberi and (2) describe the historical perspective, pathophysiological mechanisms, and relevant aspects that could have applications in the clinical management of Beriberi.

Historical Perspective

The etymology of the term beriberi is unclear, but it has been proposed that it is derived from the Sinhalese word “Bharyee,” which means “extreme weakness.” The earliest description of a condition supposed to be beriberi dates to the Huangdi Neijing, an ancient Chinese medical text compiled between the 5th and 3rd centuries BC [14, 15]. Later, a disease affecting the nervous system and causing symptoms such as edema, breathlessness, and unusual gait, was reported in Japan during the 17th century, named as Kak’ke, meaning “disease of the legs” [14]. In the late 19th century, the cause of Beriberi was initially attributed to an unknown infectious organism [15]. This theory was supported by the fact that the incidence of Beriberi seemed to be higher in specific populations, such as prisoners and soldiers, who were living in crowded and unsanitary conditions [15–17]. However, the physician Christiaan Eijkman’s pioneering experiments in the Dutch East Indies (now Indonesia) demonstrated that chickens fed with polished rice experienced leg paralysis or “polyneuritis.” In contrast, chickens given brown (unpolished) rice did not suffer from this condition. Concomitantly, in the early 20th century, a national epidemic of Beriberi in Japan coincided with the introduction of mechanical polishing of rice, establishing a clear connection between the rice brand and its specific dietary component against this condition known as the “anti-beriberi factor” [18, 19].

Only in the 1920s, a substance that cured polyneuritis in pigeons was isolated and crystallized from rice polishings and named thiamine, based on its chemical structure, which includes a thiazole ring containing a sulfur atom (represented by “thia-”) that is similar to the sulfur-containing amino acid cysteine (represented by “-amine”) [18].

To date, reports of Beriberi are relatively rare due to the widespread availability of thiamine-enriched foods and supplements, particularly in high‐risk regions. Although accurate estimates of its prevalence are unknown, thiamine deficiency remains a public health issue across South and Southeast Asia. It still happens because the population has a high consumption of polished white rice as a dietary staple, along with the frequent consumption of raw or fermented fish that contains anti-thiamine compounds, which inhibits thiamine bioavailability. Additionally, Asian cultural food restrictions during the perinatal period can lead to insufficient breast milk thiamine and, consequently, inadequate supply of thiamine to infantile [19, 20].

Also, many parts of Latin America and Africa still suffer from occasional outbreaks of Beriberi, related frequently to inadequate food consumption and preparation, poverty, malnutrition, and widely overlapping with other disease conditions, such as HIV/AIDS, malaria, and tuberculosis, which can increase the risk of thiamine deficiency [19, 21].

In the early 2000s, two sizeable outbreaks of Beriberi were recorded in Brazil. First, the Northeast region involved 1,207 cases and 40 deaths, potentially linked to alcohol abuse, mycotoxin contamination of rice, and extremely physically demanding [21, 22]. Soon after this, 10 cases and 3 deaths emerged within indigenous populations residing in a remote area of the Amazon Basin, a community subsisting mainly from fishing and daily consumption of caxiri, a local traditional alcoholic drink [21, 23]. Data obtained from the Ministry of Health through FormSUS revealed that between 2014 and 2020, 542 cases of Beriberi were identified in Brazil, resulting in 117 deaths. The majority of cases in the country are found within the indigenous community, primarily attributed to issues related to food insecurity and physically strenuous labor [24].

In the African continent, a large outbreak of Beriberi was reported in 2009 among 241 soldiers in Mogadishu, exposed to a severely restricted diet during the humanitarian crisis in Somalia. The clinical symptoms included the acute onset of peripheral edema, difficulty breathing, palpitations, and fever, evolving to heart failure and death in 4 patients [25].

Beyond social and cultural determinants, thiamine deficiency has also re-emerged in developed countries as a relevant complication following bariatric surgery, typically after procedures such as Roux-en-Y gastric bypass and sleeve gastrectomy. This procedure-related deficiency often arises within weeks due to limited body thiamine stores and reduced absorption, frequently manifesting as Wernicke’s encephalopathy or wet beriberi if not promptly treated [26, 27]. In this sense, Beriberi is still an emerging disease today, especially in developing countries. Ongoing vigilance and intervention through public policies are necessary to address thiamine deficiency, particularly in vulnerable populations, and provide clinical updates on identifying and treating this disease.

Functions of Thiamine and Pathophysiology of Beriberi

Thiamine is naturally present in various foods, including most animal sources, yeast, wheat germ, and unrefined cereal grains [28]. The recommended daily intake of thiamine for children depends on age, ranging from 0.5 mg/day for 1- to 3-year-olds to 0.9 mg/day for 9- to 13-year-olds. Typically, thiamine requirements are around 1.1–1.2 mg/day for adults and older people. During pregnancy and lactation, the requirement increases to 1.4 and 1.5 mg/day, respectively. Nevertheless, the intake of this nutrient should be constant, as body reserves are relatively small and can only last about 18 days. Also, the use of medications, especially diuretics, is linked to increased excretion [3, 28, 29]. Thiamine is absorbed in the upper part of the small intestine through a saturable process mediated by two transporters: THTR2 on the luminal surface and THTR1 on the basal surface, releasing thiamine in its free form into the circulation. The biologically active form, thiamine pyrophosphate (TPP), also known as thiamine diphosphate, is generated in cells from free thiamine by the enzyme thiamine pyrophosphokinase [30]. TPP then acts as a cofactor for enzyme activity in several metabolic pathways, including glucose metabolism, energy production, and nucleic acid synthesis. Enzymes such as transketolase, α-ketoglutarate dehydrogenase, pyruvate dehydrogenase complex, and 2-hydroxyacyl-CoA lyase depend on TPP for proper functioning [28, 30]. In this sense, nutritional deficiency by thiamine can lead to the impairment of these enzymes, resulting in metabolic alterations that compromise adenosine triphosphate synthesis, which depends on TPP, as well as predisposing to metabolic acidosis, due to the high concentration of lactate [31].

Thiamine deficiency is still often an under-recognized condition; however, the presence of signs and symptoms of Beriberi indicates thiamine deficiency without the need for laboratory confirmation [32]. Beriberi is categorized as either dry or wet [2].

Dry Beriberi is distinguished by psychomotor alterations stemming from disruptions in the neurotransmission pathways of the glutamatergic and GABAergic systems, leading to neurotoxicity. Additionally, a reduction in myelin sheath formation occurs due to pentose phosphate pathway disturbances [2]. The other clinical form is wet Beriberi, which includes cardiovascular alterations through the stimulation of peripheral vasodilation [33, 34]. This vasodilation triggers compensatory mechanisms, including activating the sympathetic and renin-angiotensin systems. Consequently, this leads to increased renal sodium and water absorption. The reduction in afterload, in conjunction with hypervolemia, culminates in a clinical presentation characteristic of heart failure, characterized by elevated cardiac output aimed at sustaining blood pressure. However, in the most severe cases, where acute and often fatal manifestations occur, it is referred to as “Shoshin beriberi” [35, 36]. In the context of “Shoshin Beriberi,” individuals commonly present with cardiogenic shock [35]. Thiamine deficiency also contributes to increased lactate production and subsequent metabolic acidosis. In turn, the subsequent accumulation of hydrogen ions results in depression of myocardial contractility and additional vasodilation, exacerbating systemic hypotension [10, 35, 37]. However, the pathophysiological manifestation of Beriberi is not completely understood, as it is still unclear whether genetic and epigenetic factors influence its development. Furthermore, even following the confirmation of thiamine deficiency, some individuals do not progress to the clinical presentation of the disease. In addition, no conclusive evidence is available to discern which individuals are more predisposed to cardiac as opposed to psychomotor complications. Additional studies are imperative to elucidate and address these knowledge gaps.

Clinical Features

Diagnosis

The diagnosis of Beriberi is performed by the signs and symptoms of the disease and can be confirmed by identification of thiamine deficiency or by therapeutic testing. The assessment of serum thiamine level is commonly used for this purpose.

However, it only provides an inadequate evaluation of the body’s thiamine status due to the short-term thiamine intake representation [38]. Alternative methods used for thiamine measurement include urine thiamine levels, which is not considered a reliable indicator of overall body thiamine store, and the thiamine pyrophosphate (TPP) analysis, which is characterized considered highly sensitivity and specific [39]. However, small studies suggest that TPP levels alone may not effectively distinguish clinical beriberi from subclinical deficiency. In populations with chronically low thiamine intake, both symptomatic and asymptomatic individuals often present relatively low TPP concentrations [40–42].

The gold standard method is the test for activating erythrocyte transketolase by TPP since it can indirectly measure the biologically active form of thiamine. Nevertheless, this method also remains less accessible in clinical practice due to its high cost [43]. Considering the costs and limitations of the assays to evaluate thiamine deficiency, a diagnosis based on the evaluation of clinical signs and symptoms and the therapeutic test could eliminate the need for measuring serum thiamine levels [28].

The main clinical manifestations of wet Beriberi are linked to changes in the cardiovascular system, mainly high-output heart failure. The impairment of the vascular endothelium in response to reduced nitric oxide synthesis that is thiamine-dependent and could also lead to pulmonary hypertension and right-sided heart failure [33, 34]. These alterations are detected by symptoms such as lower limb edema, dyspnea, tachycardia, and hepatic and splenic congestion (Figure 1) [13, 34]. However, in more severe cases of wet Beriberi, the clinical manifestations may resemble cardiogenic shock, i.e., ventricular failure, metabolic acidosis, changes in cardiac output, and vascular changes. As previously mentioned, this particular condition is referred to as “Shoshin beriberi,” which frequently presents with indications of generalized fatigue, loss of appetite, and abdominal pain. However, when left undiagnosed in its early stages, it can lead to a fatal outcome [36, 44]. On the other hand, dry Beriberi is based on signs and symptoms related to peripheral polyneuropathy and the presence of muscle weakness [2].

Fig. 1.

Clinical features of Beriberi.

Diagnosing Beriberi can be difficult due to diverse clinical manifestations and similar symptomatology with other illnesses, which may mask its diagnosis. Vulnerable populations such as malnourished individuals, alcoholics, infants, the indigenous community, and individuals with malabsorptive syndromes, are at a higher risk of thiamine deficiency and, subsequently, beriberi development. Signs and symptoms of Beriberi were also observed in individuals following bariatric and gastrointestinal surgery, as well as in patients with cancer and pancreatitis [14, 45]. Table 1 shows the signs and symptoms of Beriberi.

Table 1.

Signs and symptoms of Beriberi

Wet Beriberi

High-output heart failure

Tachycardia

Pulmonary hypertension

Predominantly right-sided heart failure

Lower limb edema

Dyspnea

Liver and spleen congestion

“Shoshin beriberi”

Cardiogenic shock

Increased serum lactate

Metabolic acidosis

Generalized fatigue

Loss of appetite

Abdominal pain

Heart failure

Reduced cardiac output

Dry Beriberi

Peripheral polyneuropathy

Muscle weakness

Treatment

Early diagnosis of Beriberi is essential for therapeutic success. Thus, the recommendations are based on immediate treatment with thiamine administration in the presence of clinical manifestations of the disease [29]. The thiamine is usually administered for a minimum period of 6 weeks and may be provided orally. Overall, 100–300 mg daily doses are enough to improve the symptoms [3, 29].

After diagnosis, the thiamine administration regimen is based on the type of Beriberi. In cases where the manifestations align with wet Beriberi, the recommendations suggest thiamine supplementation orally, along with hemodynamic support. In more severe cases, where the clinical presentation indicates “Shoshin beriberi,” some authors recommend parenteral administration of higher thiamine doses until the signs and symptoms subside. The most commonly employed dose ranges between 100 and 300 mg per day [28, 29]. For dry Beriberi, thiamine recommendations are generally lower, with variations in administration time, depending on psychomotor impairment. Also, in cases of moderate to severe neuropathy, physical rehabilitation is recommended [39, 46].

The recommendations for thiamine administration (Table 2) reinforce that when the intravenous method is chosen; the dilution should be performed using a saline solution without adding glucose. This approach is recommended as carbohydrate metabolism can elevate the thiamine requirement, potentially exacerbating the clinical condition and increasing mortality risk [2]. To summarize, the recommendations are based on thiamine administration for an extended period until the risk factor for thiamine deficiency is removed. In addition, it is important to assess and replace other micronutrients besides thiamine that may be deficient [47].

Table 2.

Recommendations for thiamine administration for Beriberi treatment

Condition	Recommendation
Wet Beriberi	Orally, 100–300 mg daily for at least 6 weeks, accompanied by hemodynamic support [26]
“Shoshin beriberi”	100–300 mg per day, parenterally, for at least 6 weeks, accompanied by hemodynamic support [26]
Dry Beriberi	25–100 mg per day, orally, for at least 2 weeks, accompanied by psychomotor therapy [19]

Health Education Activities to Prevent Beriberi

Beriberi is considered a prevalent disease in developing countries [21]. Thus, global cooperation strategies and knowledge translation are essential to implementing scientific evidence [48]. In Brazil, where the disease persists, particularly within indigenous lands, the Ministry of Health, in collaboration with the Pan American Health Organization (PAHO) and the World Health Organization (WHO), has established a partnership under the “Country Cooperation Strategy 2022–2027” program. This collaboration aims to strengthen the commitment to addressing both communicable and non-communicable diseases that continue to affect Brazil and to guarantee control and eradication within the realm of public health. Beriberi stands as one of the priority diseases to be targeted in this endeavor [49]. On a worldwide scale, since 1999, the WHO has put forth global strategies regarding thiamine deficiency that can be implemented, such as the development of food products fortified with thiamine, food and nutrition education for individuals and communities, continuing education for health professionals, and easier methods of diagnosing nutritional deficiencies [50]. This body of information highlights the need for short-term, medium-term, and long-term solutions to prevent thiamine deficiency and address potential repercussions stemming from thiamine deficiency and Beriberi.

Conclusion

Beriberi is a clinical condition that still exists. Although it is a readily treatable disease, the challenges associated with diagnosis make it potentially fatal, particularly within vulnerable populations. The certainty of beriberi symptoms renders measurement of serum thiamine levels unnecessary, considering the limitations and costs associated with these methods. Refined epidemiological screening can contribute to the timely identification of at-risk populations, fostering proactive intervention strategies, and improving patient outcomes and effective public health management.

Statement of Ethics

This article is a narrative review and did not involve any studies with human or animal subjects performed by any of the authors. Therefore, ethical approval was not required.

Conflict of Interest Statement

None of the authors have any conflict of interest to declare.

Funding Sources

The authors received no financial support for the research, authorship, and publication of this article.

Author Contributions

Marcos Ferreira Minicucci and Leonardo Antônio Mamede Zornoff: study conception and critical review for intellectual improvement. Amanda Gomes Pereira, Nara Aline Costa, and Letycia Netto de Paula Cunha: study design; acquisition, analysis, interpretation of data for the work, and drafting. Paula Schmidt Azevedo, Bertha Furlan Polegato, and Sergio Alberto Rupp Paiva: critical review for intellectual improvement. All authors critically revised the article for important intellectual content and approved the final version of the manuscript.

Funding Statement

The authors received no financial support for the research, authorship, and publication of this article.