Analysis of ThDP in whole blood or erythrocytes can be a useful biomarker of thiamine status.14 The majority (∼80%) of the total thiamine content of whole blood is present in erythrocytes as ThDP. Whole blood or erythrocyte ThDP (eThDP) concentration is reflective of body stores and provides a better measure of thiamine status than total thiamine. However, direct measurement of ThDP does not assess thiamine metabolic function.

The expected concentration of ThDP in whole blood is approximately 70−180 nmol/L for healthy individuals, though there is no universally accepted cutoff value for thiamine deficiency, and a wide range of cutoffs have been used.14, 16 Thiamine metabolites can be determined by high‐performance liquid chromatography (HPLC) with ultraviolet‐visible spectroscopy (UV/VIS) or fluorescence detection.14, 17, 18 Thiamine is excreted in urine, chiefly as free thiamine and ThMP, with smaller amounts of ThDP and more than 20 other metabolites, including the oxidation product thiochrome. Urinary losses of thiamine metabolites vary with plasma thiamine concentrations, increasing markedly when renal tubular reabsorption is saturated, which occurs in healthy adults at intakes of 0.3−0.4 mg thiamine per 1000 kcal.19 Above that threshold, excretion of the vitamin exceeds 100 μg/day, whereas urinary excretion in deficient individuals is <25 μg/day. Increased concentrations of both pyruvate and α‐ketoglutarate in whole blood or plasma, and of methylglyoxal in the urine and cerebrospinal fluid, also occur in thiamine deficiency.

The functional assessment of thiamine status was developed more than 50 years ago, using the response of the ThDP‐dependent enzyme transketolase in erythrocyte hemolysates to exogenous ThDP.15 Erythrocyte transketolase (ETK) activity is suboptimal when thiamine intake, and hence, ThDP supply, is low. Therefore, the change in ETK activity upon the addition of exogenous saturating amounts of ThDP is indicative of thiamine functional status.

Threshold ETKAC values indicative of thiamine deficiency or adequacy are based largely on results of dated studies in animal models. No cutoff values are available for erythrocyte or whole blood ThDP concentrations, which to date have been studied predominantly in thiamine‐adequate adults from high‐income countries.16 Limited data are available from two different clinical series of European patients with either chronic alcoholism28 or other illnesses17 to compare blood ThDP levels and ETKAC values in the same individuals. For example, one study of 63 medical and surgical patients at risk of thiamine deficiency (e.g., with chronic renal failure) found that the inflection point in the ETKAC−ThDP curve occurred at an ETKAC value of approximately 1.25 (i.e., 25% activation over baseline), which corresponded to a blood ThDP concentration of 280 ng/g hemoglobin (Fig. 4). Similar results were reported from the study of patients with chronic alcoholism.28 However, it is not certain if the same results would occur in populations with endemic thiamine deficiency.

Therefore, there is a need to generate cutoff values for erythrocyte or whole blood ThDP concentrations indicative of both clinical thiamine deficiency and adequacy in at‐risk populations, such as pediatric populations—who are especially vulnerable—in countries where beriberi is reported. Such studies should assess the relationships of ETKAC values and whole blood or eThDP concentrations and compare both to measures of thiamine intake and clinical parameters of health.

The assessment of biomarkers of thiamine status is not widely practiced, particularly in LMIC. It appears that only one laboratory, in Cambridge, UK, currently determines ETKAC, and that only a few laboratories currently measure ThDP and/or ThMP in erythrocytes. The cold chain required to transport the samples to laboratories adds costs and challenges to assessment of thiamine status. As clinical thiamine deficiency may present suddenly and be rapidly fatal, especially in infants, clinicians are advised to treat suspected beriberi patients empirically with thiamine. A rapid, positive response to thiamine is conventionally interpreted as confirmation of deficient thiamine status. A rapid test of thiamine status that avoids the need for a cold chain would be useful both in clinical practice and for nutritional surveillance.

Point‐of‐care (PoC) diagnostics have recently emerged as an analytical alternative for remote settings. Microfluidic devices are attractive candidates for use with PoC applications for diagnostics.29, 30 Alternatively, a PoC device could detect ThDP (or chemical analogs) based on electrochemical properties. Portable electrochemical analyzers have been recently developed by the Plaxco,31 Whitesides,32 and Wheeler laboratories.33 New methods are also being developed using a modified thiamine binding protein, which recognizes ThDP and ThMP, produced in Escherichia coli. Based on the initial report, this fluorescence‐based assay has a lower limit of detection of 0.5 nM, and range between 1 and 370 nM, which puts it well within the physiological concentrations of thiamine in human blood and provides a relatively rapid (∼30 min) and high throughput method for thiamine analysis.34

Dried blood spot (DBS) samples, which are already used worldwide for newborn screening, coupled with a microfluidic paper‐based analytical device (μPAD) could potentially make population assessment easier, more cost‐effective, and faster for the detection of thiamine deficiency. Shih et al. have demonstrated DBS analysis by digital microfluidics.35 Two companies, Diagnostics For All (DfA) and MC10, have also developed a μPAD for the detection of vitamin A.36 The device has been used to detect vitamin A colorimetrically using a competitive assay for retinol‐binding protein at a cost of $1 per test (including the integrated reader). Developing DBS‐based techniques to analyze thiamine content could potentially simplify the cold‐chain and make assessment more readily available. The above‐mentioned devices, as well as a myriad of low‐cost PoC solutions presented by other groups and organizations, are still under development. Extensive field testing and evaluation against gold standards will be required before applying these devises for routine use in thiamine status assessment.

Thiamine deficiency is rare in healthy individuals in food‐secure settings, where access to thiamine‐rich foods ensures adequate intakes.9 Regions where diets are monotonous and the primary sources of energy are starchy, low‐thiamine staples, such as polished rice or cassava, are likely to be at high risk of thiamine deficiency.37, 38, 39 Regular consumption of foods containing thiamine antagonists, such as betel nut or tea leaves, and thiaminases in foods such as raw fish and African silkworm larvae, have also been implicated as precipitants of thiamine deficiency.9, 12, 40 Some bacteria (e.g., Clostridium botulinum) are also capable of producing thiaminases.41 Conditions that lead to food insecurity, including drought, conflict, displacement due to war, famine, or natural disaster, as well as severe acute malnutrition (SAM), raise the risk of deficiency.42, 43, 44, 45 Abnormal gut microbiota, as occurs in SAM, may also play a role in reduced thiamine uptake.46, 47

Infants are particularly vulnerable to the effects of thiamine deficiency in the first months of life, and exclusively breastfed infants of thiamine‐deficient mothers are at highest risk.16, 48 Thiamine deficiency is also frequently observed in patients who are critically ill or in intensive care because of increased demand for thiamine (hypermetabolism).49, 50, 51, 52, 53, 54 In clinical practice, associated comorbidities and other risk factors, such as SAM with fever and shock and use of dextrose‐based intravenous fluid, further increase the risk of thiamine deficiency.42 Most other cases of thiamine deficiency occur among alcoholics,28 postoperative bariatric surgery patients,55 or patients with advanced HIV infection/AIDS,56, 57 who tend to have low thiamine intakes or absorption and impaired thiamine utilization.

Children with SAM often have multiple risk factors for thiamine deficiency. Upon admission to a hospital, these patients often receive several days of a low‐protein 75 kcal/100 mL refeeding milk formula (F75), which provides a possibly insufficient amount of thiamine (0.5–1.7 mg/day depending on the total daily F75 intake). Several experts have recently recommended increasing the thiamine content of this formula to align with therapeutic amounts.58

Overt thiamine deficiency syndromes represent a spectrum of clinical presentations that have been historically divided into two categories based on symptomology: (1) beriberi, which can be “wet” if it predominantly affects the cardiovascular system and is accompanied by edema, or “dry” if it predominantly affects the peripheral nervous system; and (2) Wernicke's encephalopathy or Wernicke‐Korsakoff syndrome.5, 59 Beriberi affects the cardiovascular system (e.g., acute cardiologic form), nervous system (e.g., pseudo meningitic form), or both; whereas Wernicke's encephalopathy primarily presents with neurological signs (e.g., encephalopathy and peripheral neuropathy forms),39 as described in more detail in Figure 5. The most important pediatric presentation—usually referred to as infantile beriberi—has a wide range of nonspecific clinical features and organ involvement, including central nervous system abnormalities, mainly characterized by heart failure. Infantile beriberi sometimes presents in the context of an acute infectious illness, further complicating the diagnosis.39, 42 The consultation group suggested adopting the umbrella term thiamine deficiency disorders (TDDs) to describe the spectrum of overlapping clinical presentations attributable to thiamine deficiency across the life course. However, the term beriberi (without wet/dry subtype disaggregation) remains commonly used in clinical pediatrics, so it is retained here to refer generally to TDD presenting in infancy.

TDDs primarily occur in low‐income countries as a result of low dietary thiamine intake. The risk of TDD is highest in the first year of life, especially during the period of exclusive breastfeeding, as mothers in regions where the disease is prevalent are thiamine deficient and thiamine content of breastmilk is related to maternal thiamine status.48 Infantile beriberi is rare in the first 2 months of life, as thiamine levels are higher in newborns, and then falls rapidly in the third month of life, likely due to changes in metabolic activity.60 It has been recognized in areas of Central and Southeast Asia,61 especially in Myanmar,44, 62 Laos,63, 64, 65 and Cambodia;13, 66 but, TDDs have also been observed in West Africa,67 Angola,45 Mayotte Island,68 Kiribati,69 Cuba,70 and parts of the Caribbean, and may go unrecognized in other settings.221

Infantile beriberi in children younger than 4 months of age typically presents first with nonspecific signs, including irritability, refusal to breastfeed, tachycardia and tachypnea, vomiting and incessant crying that is often described as “loud” or “piercing” and in some cases evolves into a “silent cry,” or aphonia.39 As the disease progresses, signs and symptoms of congestive heart failure begin to appear, such as tachypnea, tachycardia, pulmonary edema, hepatomegaly, and, sometimes, cyanosis; at this point, deterioration of the clinical condition is often rapid. As beriberi may be misdiagnosed as a viral infection, pneumonia, typhus, or malaria, beriberi patients may die before the correct diagnosis of thiamine deficiency is made.42, 44, 71 Prompt recognition of beriberi and immediate administration of thiamine produces rapid recovery. Within hours, even infants with advanced beriberi return to breastfeeding and, within days, their cardiac function returns to normal. Shoshin beriberi is a fulminant form of wet beriberi (acute cardiogenic shock with lactic acidosis multiorgan failure and no edema) and can easily mimic sepsis.72, 73, 74, 75, 76 Because of uncertainties regarding the diagnostic criteria of TDDs, it may only be possible to diagnosis beriberi after a patient demonstrates significant improvement following treatment with thiamine.

Beriberi in older infants and children may present with predominant neurological symptoms, including loss of appetite, nystagmus, ophthalmoplegia, bulging fontanelle, and loss of consciousness.59, 77, 78, 79 In areas with low awareness of thiamine deficiency, symptoms are easily mistaken for meningitis. In some cases, these signs may overlap with cardiac symptoms of beriberi. Older children, adolescents, and adults with TDD may present only with peripheral neuropathy—tingling or loss of sensation in the feet and hands, pain, and abnormal tendon reflexes—or with more severe signs of peripheral nervous system involvement, such as paralysis or sensory deficits.45, 80

Wernicke's encephalopathy, the most common form of thiamine deficiency in adults and older children, is characterized by a triad of signs and symptoms: abnormal eye movement, gait ataxia, and cognitive impairment. In younger children, though, the triad may not include ataxia.81, 82 The most severe form of Wernicke's encephalopathy can include a condition called Korsakoff's psychosis, in which patients are amnesiac, profoundly confused, and display confabulation with little or no working memory.83 This condition is more common in individuals with hereditary anomalies of transketolase in which its binding to ThDP is weak. In higher income countries, Wernicke's encephalopathy is most common in alcoholics, as chronic alcoholism impairs both intestinal thiamine absorption and increases thiamine requirements for metabolism. Wernicke's encephalopathy can also occur in HIV‐infected patients, pregnant women suffering from hyperemesis gravidarum, and postoperative bariatric patients.84, 85 If thiamine deficiency is corrected before the development of significant brain damage, the neurological symptoms may be completely reversible. However, if thiamine deficiency persists, it can result in permanent brain damage.83, 86 As Wernicke's encephalopathy in adults—especially in the nonalcoholic or chronically ill population—is less often fatal than infantile beriberi, it will not be extensively discussed here; readers interested in Wernicke's encephalopathy are referred to several excellent reviews of the disease.59, 81, 83, 85, 86

Some children with beriberi and adults with Wernicke's encephalopathy display similar brain changes on magnetic resonance imaging, specifically, bilateral, symmetric hyperintensity signals in the mammillary bodies, thalamic, and periaqueductal areas; however, pediatric brain neuroimaging may also show lesions in the basal ganglia and the frontal lobes. In a recent study of infants with thiamine deficiency encephalopathies, cranial ultrasound revealed hyperechoic lesions of the basal ganglia.73, 77, 79, 87

As mentioned above, thiamine is a cofactor of several key cellular enzyme complexes found in mitochondria; thiamine deficiency, therefore, may be considered to be an acquired mitochondrial disease, which explains the multiple organ involvement, including the nervous and cardiac systems.42 Owing to the highly variable clinical presentations of TDD (Fig. 5) and the lack of consensus on clinical case definitions or biomarkers, these conditions are often misdiagnosed, possibly leading to gross underestimation of the prevalence of TDDs in many parts of the world. It is not clear why some thiamine‐deficient children present with only cardiac signs, while others present only with neurological signs. However, it is suspected that overall nutritional status and the presence or absence of comorbidities and multiple micronutrient deficiencies may contribute to the variable clinical presentations of thiamine deficiency.

As thiamine administration rapidly alleviates signs and symptoms of deficiency, patients with TDD can apparently make a full physical recovery if treated early. It was long believed that subclinical thiamine deficiency had no long‐term sequelae. However, persistent cognitive and motor deficits are now being recognized among children who experienced infantile thiamine deficiency. Longitudinal studies of Israeli children who survived a 2003 outbreak of thiamine deficiency after consuming an infant formula in which thiamine was erroneously omitted have shown long‐term medical, neurodevelopmental, and gross motor impairments.94, 95

The most severely affected survivors demonstrated marked intellectual disabilities, seizures, motor disabilities, microcephaly, auditory dysfunction, and complete heart block.94 Not all infants who received thiamine‐deficient formula were initially symptomatic; but even those who initially appeared unaffected subsequently displayed delayed language acquisition, persistent lexical and syntactical language impairments,96 gross motor delays,95 poor fine motor and coordination skills,97 dyslexia, and learning disabilities (unpublished data). It is assumed that these effects are the result of neuronal insult during a critical period in brain development. Considering the Israeli experience, one could hypothesize that it is possible that negative cognitive and developmental outcomes resulting from early and/or lifelong subclinical thiamine deficiency may also occur in regions where dietary thiamine intake is low.

More research is needed to understand the long‐term developmental effects of subclinical thiamine deficiency and to identify the factors that may trigger overt clinical disease in both infants and adults. Studies of Cambodian children have shown that blood ThDP levels of beriberi patients are often the same as their asymptomatic peers, which has led experts to believe that asymptomatic or subclinical thiamine deficiency may quickly shift to acute beriberi in the presence of other physiological stressors (e.g., acute infection, diarrhea, and parasitic infection).13 Additionally, there have been no long‐term intervention trials examining the impacts of maternal/infant thiamine supplementation on developmental outcomes—a critical research gap that the consultation group suggests should be urgently filled.

Cohorts of children treated for thiamine deficiency should also be followed in longitudinal prospective studies and evaluated for possible short‐ and long‐term sequelae of thiamine deficiency with serial neuropsychological testing and neurophysiological tests, such as nerve conduction studies, electroencephalography, and visual evoked potential testing. To facilitate neuropsychological studies in resource‐poor settings, simple, neurocognitive and neurodevelopmental‐testing instruments need to be developed and validated for use in local communities.

Despite a lack of consensus on the case definition of thiamine deficiency, clinical experiences have led experts to believe that many individuals in populations where thiamine intake is low teeter on the brink of clinical deficiency, and can be quickly pushed into overt deficiency by factors such as acute infections or other illnesses. The case studies of Israeli children exposed to a thiamine‐deficient formula diet are among the only studies of beriberi in children who were otherwise well nourished.98 The long‐term follow‐up of that cohort will be important for understanding the delayed effects of isolated thiamine insufficiency on neurobehavioral development.

Although TDDs are well documented in case studies, epidemiological studies linking thiamine deficiency to specific clinical scenarios are rare. This may be attributable to the heterogeneities in disease presentation and difficulty of assessing thiamine status.

The consultation group agreed that developing case definitions of the various TDDs may reduce some of the confusion surrounding diagnosis, and that this endeavor is a worthwhile subject for future research. Prospective cohort studies of children with clinically suspected beriberi would be valuable in identifying which combinations of clinical features are most predictive of confirmed thiamine deficiency. Such studies may enable the development of consensus case definitions for thiamine deficiency that are based on presenting clinical findings without requiring biochemical testing and could be used effectively by researchers and clinicians.

Suboptimal thiamine status and TDDs have been recently documented in Cambodia.16 Verbal autopsy review suggests that approximately half of children dying after the neonatal weeks but during the first 6 months of life might have had beriberi.54 In 2012, Coats et al. published the results of a case–control study in which 27 infants presenting with clinical symptoms of beriberi (and their mothers) were compared with 27 infants and mothers without beriberi who also presented at a health clinic in Mesang District, Prey Veng, and 20 healthy American control dyads.13 Interestingly, there was no significant difference in the whole blood ThDP of Cambodian mothers and infants with or without beriberi.13 However, both sets of Cambodian mothers and infants had significantly lower ThDP than the Americans.13 Other cases of infantile beriberi have been reported in this same clinic in Mesang District in Prey Veng,66 as well as at a clinic in Siem Reap province.71

In 2013, Whitfield and colleagues conducted an exploratory cross‐sectional study to assess the thiamine status among women of reproductive age in rural and urban Cambodia, compared with women in Canada. Not surprisingly, they found significantly lower eThDP among nonpregnant, nonlactating women of reproductive age in both rural Prey Veng (mean ± SD, 149 ± 36 nmol/L RBC; n = 121) and urban Phnom Penh (156 ± 32 nmol/L RBC; n = 117), compared with women from Vancouver, Canada (179 ± 37 nmol/L RBC; n = 47; P < 0.05).37, 100 Although statistically significant, the authors note the relatively small absolute difference between women in Cambodia and Canada, which may be attributed to the small sample size and/or convenience sample of Vancouver women, the majority of whom were young university students.

The first‐ever Cambodian National Micronutrient Survey was conducted in conjunction with the 2014 Cambodian Demographic and Health Survey.101 This was a nationally representative survey of adults 15−49 years of age and their children (6–59 months) from 24 Cambodian provinces; eThDP was measured in 719 women and 761 children. The women's mean (95% CI) eThDP was 150 nmol/L RBC (146−153); the children's was 174 nmol/L RBC (171−179). As noted above, there are no widely accepted interpretative criteria for the classification of thiamine deficiency based on eThDP; nearly all of the cutoffs that have been used previously were derived from healthy populations, and most were calculated with fewer than the best practice of a minimum of 120 individuals.102 Two of the most extreme cutoffs from the literature define thiamine deficiency as <118.5 and <180 nmol/L RBC. The cutoff of <118.5 nmol/L RBC is the 95th percentile reference range among healthy black South African adults103 and was used in Bailey et al.;104 <180 nmol/L RBC is the 25th percentile of 103 healthy, asymptomatic adult employees of University “La Sapienza” Hospital in Rome.105 With a cutoff of eThDP <120 nmol/L RBC,104, 106, 107 27% of mothers and 15% of children in the Cambodian survey would be considered thiamine deficient; however, prevalence rates of deficiency were as high as 78% for mothers and 58% for children using the higher cutoff of <180 nmol/L RBC, highlighting the difficulties with establishing prevalence rates in the absence of clear cutoffs for thiamine deficiency.105

Finally, Cambodians have been responsive to increased thiamine intakes, both through diet, as from randomized controlled trials by Whitfield et al. of thiamine‐fortified fish sauce showing increases in eThDP100, 108 and breastmilk thiamine,100 and through thiamine supplementation, as shown in a recent pharmacokinetics study by Coats et al.109 Improvements to thiamine status upon supplementation are indicative of initial suboptimal status, as similar increases have not been observed among thiamine‐replete individuals. In part, this stems from the differential thiamine absorption depending on concentration: below 1 μmol/L, thiamine is transported through an active, carrier‐mediated, sodium‐dependent mechanism, whereas at higher concentrations thiamine is absorbed via passive diffusion.110 An experimental thiamine supplementation study among six healthy, thiamine‐replete Canadian males in the 1960s found 21% absorption of a 2.5‐mg thiamine dose, but decreased absorption of 9% and 4% at doses of 5 and 20 mg, respectively.111 Also, little thiamine is retained among thiamine‐replete individuals;112 for example, Australian researchers found rapid urinary excretion of thiamine among six volunteers (22−43 years; n = 3 men and 3 women) who consumed an 11‐mg dose of thiamine.110, 111, 112 In the study of thiamine‐fortified fish sauce, there was a statistically significant response between baseline and endline regardless of baseline thiamine status, except for the women who received the most heavily fortified fish sauce (where there was only a significant increase from baseline to endline among those women in the lowest tertile at baseline).108

There are several recent case reports of beriberi and suboptimal thiamine status among infants in Laos. A survey of 22 villages in northern Laos (various ethnic groups) reported a high infant (<6 months of age) mortality rate of 50 deaths among 468 live births.63 Of these 50 infant deaths, 36 occurred when infants were 1−3 months of age, and 17 were suspected to be caused by infantile beriberi.63 In the capital city of Vientiane, 13% of a cohort of 778 sick infants <1 year were found to have biochemical evidence of thiamine deficiency (defined as basal ETK activity <0.59, without clinical signs of beriberi).12

Another study of hospital records in Laos offered retrospective data on beriberi cases. Based on reports from 51 hospitals (including central, provincial, and district hospitals), about 60 infants under 12 months of age were treated with thiamine for beriberi each month, but biochemical measures were unavailable. In the catchment areas of these hospitals, there are an estimated 71,696 infants under 12 months old. Adult beriberi cases were much lower—an average of 20 men and 16 women were treated for thiamine deficiency per month. There was no seasonality associated with the caseload. In population centers like Luang Prabang, where health workers are reportedly more aware of the symptoms of beriberi, infant prevalence is highest at an estimated 2.5 per 1000 infants (Lao PDR Ministry of Health, unpublished data).

As described above, beriberi is the second leading cause of postneonatal death of children 29 to 365 days old in Myanmar. On a national level, this equates to 17% of infant (29 to 365 days old) deaths, but is more common in rural areas.113 Currently, Myanmar is combatting thiamine deficiency by providing 10 mg/day thiamine supplements to pregnant and lactating women up to 3 months postpartum.

A number of reports of infantile beriberi have emerged from the northern region of India, where the diet consists largely of polished, unfortified rice.75, 77, 79, 114 Cases all occurred in infants who were exclusively breastfed, and the majority of mothers followed a customary dietary restriction. Postpartum food avoidances in this region lead to especially thiamine‐deficient diets consisting of polished rice and chicken soup.74 Nearly, 100 infants documented in these papers had either pulmonary hypertension or encephalopathy and nearly all responded to thiamine at the Government Medical College in Srinagar.

Aside from the areas described above where thiamine deficiency is endemic, there have been a number of outbreaks reported in specific subpopulations within LMIC. Table 4 presents a list of the published outbreaks of TDDs in LMIC since 1980. As is the case in endemic areas, most of these cases of thiamine deficiency were caused by a limited diet that was high in polished rice. These recent outbreaks from LMIC suggest that thiamine deficiency can occur anywhere and under a number of circumstances. They also highlight the need for greater awareness of the clinical presentation of TDD in order to promptly diagnose and treat thiamine deficiency and prevent mortality associated with it.

There have also been clinical case reports of suboptimal thiamine status in various high‐income countries where beriberi was previously thought to be nonexistent or eradicated. Such reports include, for instance, a 24‐year‐old Japanese man presenting with beriberi after subsisting on rice balls for 4 years,76 and a 38‐year‐old Scottish man on an extreme weight‐loss diet.115 These isolated cases, where individual dietary or lifestyle habits were likely responsible for the case presentation, should not be considered as evidence for instigating a national public health intervention.

The best indicators of risk of thiamine deficiency in a population are (1) clinical signs of beriberi that respond to thiamine treatment, and (2) a high prevalence of the population with biomarkers indicative of deficiency. While a definition of high prevalence currently does not exist, a cutoff of 20% has been used by the World Health Organization (WHO) for anemia. However, few countries have produced representative data on the population's thiamine status, and the interpretation of erythrocyte or whole blood ThDP remains uncertain (as discussed above). Several approaches using food availability or intake data and month‐specific infant mortality rates have been proposed to fill the gaps in population‐level indicators of thiamine status.

For the purposes of this technical consultation, two preliminary analyses were performed to assess the population risk of thiamine deficiency using these proxy measures. It should be noted that these provide a cursory overview of what could be done in greater detail to identify areas at risk of TDD. Because elevated ETKAC represents a functional abnormality due to thiamine deficiency, we suggest that this is currently the best biochemical evidence of deficiency. If more than 10% of the population has an ETKAC >1.2, this should be considered evidence of an elevated risk of thiamine deficiency in the population. When more than 20% of the population has an ETKAC above this threshold, this should be considered a public health problem and a large‐scale intervention should be considered. Once information is available on the whole‐blood or eThDP concentration that corresponds to elevated ETKAC, ThDP can be used as an alternative biomarker for population assessment, using the same prevalence cutoffs to indicate whether there is a problem of public health concern.

Suboptimal thiamine status has been called the “forgotten disease of Asia,”12 as reports of TDDs in the region are common despite the known etiology and relatively straightforward approaches to prevention and treatment.117 There is current evidence of suboptimal thiamine intake or status in Southeast Asia, notably in Cambodia,13, 37, 66, 71, 100, 108 Laos,12, 63, 118, 119 and Myanmar,113 parts of India,75, 79 and in recent reports of Karen refugees upon their arrival in the Mae La Camp on the Thai‐Myanmar border.44, 62

What is not currently clear is how widespread suboptimal thiamine status is and whether countries should be prioritizing thiamine as a micronutrient of concern for public health intervention programs. For instance, while there have been several reports of infantile beriberi in Laos, it is unclear whether the issue is localized or widespread, and whether it is a major contributor to the burden of infant mortality in the country. The consultation group has developed a decision tree to help guide countries on the best course of action for investigating thiamine status and/or implementing interventions to improve thiamine intake.

The decision tree consists of two paths: one for those countries where there is a known high risk of thiamine deficiency, based on beriberi or TDD case reports, and another for those where there may be some risk of thiamine deficiency in the absence of beriberi reports. For the former, the group suggests countries confirm with biomarkers if possible and engage with stakeholders to discuss possible interventions and monitoring programs. For the latter, we suggest both several methods for analyzing existing data to better understand the risk (prevalence and severity) of suboptimal dietary thiamine intake and implementing surveys and/or clinical surveillance of thiamine status. This roadmap is based on the current state of knowledge, and it serves as a guide for public health action: rapid assessment, diagnosis, and treatment should continue for any individual presenting at a health facility with clinical signs consistent with TDD. Figure 10 provides a decision tree for countries to consider when assessing the potential for thiamine deficiency.

Large‐scale, mandatory food fortification has several advantages: it has potential to be a sustainable and cost‐effective intervention,38, 127, 128, 129 and it requires little or no behavior change on the part of the consumer, as the fortificant is added to a commonly consumed food vehicle (i.e., staple food or condiment). Moreover, food fortification can restore nutrients such as thiamine, riboflavin, and iron lost during processing.130 As a population‐wide intervention, fortification offers the potential to reach large sections of the population with relatively low cost and effort.131 Large‐scale fortification holds considerable promise for increasing thiamine status in women (and thus in breastfeeding infants). Fortification is a sustainable, long‐term solution for combating suboptimal thiamine status and related TDDs. Thus, the consultation group suggests that countries with cases of TDD consider developing a mandatory thiamine fortification program in situations where the food system is compatible with this approach. Most often this has been done successfully in combination with other fortification efforts, such as cofortification of thiamine along with other micronutrients in wheat flour in several countries, but it has also been done as a sole fortificant in experimental fish sauce.108, 132, 133

Two forms of thiamine are used in fortification: thiamine hydrochloride, which is the fortificant of choice for liquid vehicles, and thiamine mononitrate, which is preferred for dry applications. When fortifying with thiamine, it is important to consider that both forms of thiamine are heat labile, are destabilized in the presence of sulfites, and are somewhat light sensitive. The WHO has estimated that thiamine is one of the lowest cost fortificants; for example, $0.018 (USD) provides 100% of the EAR for a male per day for 1 year.38

Thiamine supplementation guidelines have focused on emergency situations, most often when conflict or famine results in food insecurity for large numbers of refugees or displaced persons. Infantile beriberi outbreaks are well documented in such populations, for example, in the Karen refugee population in Thailand.44 In these cases, the addition of thiamine‐rich foods to emergency aid rations or the delivery of thiamine supplements is recommended and has proven effective in reducing or eliminating cases of infantile beriberi.44 In the clinical setting, patients treated for beriberi are given thiamine supplements for approximately 1 month following recovery. Few nonemergency thiamine supplementation programs have been implemented. One such program, the Infantile Beriberi Project in Myanmar, offers 10 mg of daily thiamine supplements to pregnant and lactating women from the final month of pregnancy through the first 3 months of lactation. It is essential to monitor and evaluate the programs on an ongoing basis, both for program coverage and recipient adherence to the supplementation regimen.

Changing dietary patterns to increase the consumption of thiamine‐rich foods, and limit the intake of known thiamine antagonists and thiamine‐poor foods, could improve thiamine intake. Nutrition education and behavioral change communication on promoting dietary diversity with nutrient‐rich foods are essential to changing dietary patterns. In some countries like Myanmar, ideas about avoiding specific foods are still common for pregnant and lactating women that result in limited intake of nutrient‐rich foods and increase the risk of deficiencies. In a cross‐sectional survey in Vientiane, Lao, Barennes et al. found that 93% of women (n = 274/300) practiced postpartum food restriction (phit kam). It was common for women to consume only a traditional herbal tea for the first 15 days postpartum (n = 285/300; 95%), which translated to an estimated mean (95% CI) thiamine intake of 0.4 (0.1−0.7 mg/day) intake during this period (dietary intake n = 31, days 1−15, 24 h recall).163 Raising awareness of the consequences of local food avoidances in pregnant and lactating women and promoting thiamine‐rich alternatives can improve maternal thiamine intake.

As noted above, in populations where white, polished rice is the main dietary staple, thiamine is lacking not only because white rice is thiamine poor, but also because the sheer volume consumed limits the consumption of thiamine‐rich foods. Parboiling rice can increase thiamine content of polished rice by leeching thiamine from the bran into the endosperm. Additionally, traditional food processing techniques such as fermentation can also be promoted in the nutrition education message, as it can increase the level of thiamine and other B vitamins in the plant‐based diets.164

Providing nonspecific nutrition education messages will likely not have a significant effect on the population's thiamine intake or status. Rather in LMIC, the promotion of locally available nutrient‐rich foods could be considered as an alternative to optimize thiamine intake as well as to tackle the coexistence of multiple micronutrient deficiencies. Identifying context‐specific nutrient‐rich foods and supporting their intake may be useful, especially in resource‐poor countries as a long‐term and sustainable strategy. An approach known as Linear Programming is available to identify the problem nutrients in the diet of the population, to formulate the food‐based recommendations that resemble the current dietary practices, and to fill the nutrient gaps. This approach considers multiple factors, such as existing dietary pattern, nutrient content of foods, food cost, and cultural factors, and hence reduces the challenge for the population to totally change their current dietary practices.165, 166, 167

Food processing changes also have the potential to affect the thiamine content of various foods. Rice processing and consumption is particularly important because, as detailed above, TDD often appears in regions where polished rice is a dietary staple.

In most rice‐consuming countries, well‐polished white rice is preferred for various reasons, including cultural (e.g., white rice is a status symbol,61 it has optimal organoleptic properties) and economic (e.g., removal of the lipid‐rich outer bran increases shelf‐life,168 and less fuel and water is required for cooking).168, 169 There are also economic incentives for rice millers to polish rice thoroughly, as rice bran is a major animal feed product in Southeast Asia.170, 171 Anecdotal evidence from rural Cambodia suggests that local rice millers do not charge famers to mill rice, but rather are allowed to keep the rice polishings, which they sell as animal feed. With this model, it is in the best interest of the rice miller to fully mill the husk and bran of the rice to maximize the weight of animal feed they can sell.

As noted above, TDDs are often under‐recognized by clinicians, leading to missed or delayed diagnosis. In addition, it is not uncommon for infants to present with beriberi while their mothers remain asymptomatic.13, 119, 156

We suggest that countries with known cases of TDD consider developing culturally relevant healthcare provider education tools to help identify, treat, and prevent suboptimal thiamine status. A recent trial in Cambodia employed a local artist to develop a poster outlining the common signs of infantile beriberi for study participants and to raise awareness of infantile beriberi symptoms (Fig. 11). While this tool was originally designed to educate study participants about the signs of thiamine deficiency, it was also shared with local village health volunteers and village chiefs to increase awareness of infantile beriberi. Alternatively, video clips showing the appropriate assessment, diagnoses, treatment, and importantly the recovery of infants presenting with beriberi may be extremely helpful training tools for healthcare practitioners. Professional training and in‐service refresher courses for health‐care providers in settings where thiamine deficiency occurs should provide information on promoting appropriate dietary habits and counseling pregnant and lactating women not to avoid thiamine‐rich foods.