18.1: Thiamine (20a.1)

The isolation and synthesis of thiamine was carried out in 1933 by Williams and Cline (1936). The structure of thiamine consists of a pyrimidine and thiazole ring linked by a methylene bridge (Figure 20a.1). Phosphorylated forms of thiamine include thiamine monophosphate (ThMP), thiamine diphosphate (ThDP) and thiamine triphosphate (ThTP), all of which can be interconverted in the tissues. Of these, ThDP is the biologically active form and accounts for nearly 90% of total thiamine in tissues (Rindi & Laforenza, 2000).

Figure 20a.1: Structure of thiamine and the coenzyme thiamine diphosphate

20a.1.1 Functions of thiamine

Thiamine, when converted to ThDP (shown in Figure 20a.1.1), has a major role in carbo­hydrate metabolism. As a co-enzyme in the pyruvate dehydro­genase complex, α‑ketoglutarate dehydrogenase complex and the branched chain α‑keto acid dehydro­ genase complex, ThDP is required in both the Kreb's cycle and pentose phosphate pathway (Whitfield et al., 2018). ThDP is also involved in amino acid and fatty acid metabolism. Thiamine is required for the biosynthesis of neurotransmitters (Fattal-Valevski, 2011) and in early life, thiamine has a vital role in normal cognitive development (Mimouni-Bloch et al., 2014).

20a.1.2 Deficiency of thiamine in humans

Thiamine deficiency has been classically defined as either Wernicke-Korsakoff syndrome among chronic alcoholics, or beriberi: wet beriberi for cardiac presentation, dry beriberi for neurological symptoms, Shoshin beriberi for rapid onset, or infantile beriberi for pediatric presentation. However, the broad and overlapping clinical symptoms of beriberi have recently prompted use of the terms “thiamine deficiency disorders”, or “thiamine-responsive disorders” to describe patients with symptoms or disorders that improve with thiamine treatment (Whitfield et al., 2018). Thiamine deficiency disorders have a broad clinical presentation (see examples in Table 20a.1), often leaving the disorder unrecognized, or causing mis-diagnoses (Smith et al., 2020).

Table 20a.1: Thiamine deficiency disorders (TDD) have a broad clinical presentation, with often overlapping signs and symptoms. A selection of clinical presentations of TDD is summarized here. (Smith et al., 2020; Whitfield et al., 2018).

Organ system	Select manifestations of thiamine deficiency
Cardiorespiratory	* lower extremity edema (adults) or generalized edema (infants) * pulmonary hypertension * right-sided heart failure * tachycardia * tachypnea
Gastrointestinal	* anorexia * constipation * diarrhea * vomiting
Musculoskeletal	* muscle atrophy * peripheral neuropathy * weakness
Nervous	* ataxia * encephalitic presentations (brain inflammation) * impaired cognitive development (language, motor delays) * nystagmus * ophthalmoplegia

Thiamine deficiency has three general pathophysiologic mechanisms (Gomes et al., 2021):

• increased thiamine requirements, caused by fever, sepsis, malignancy, etc.;
• increased thiamine losses, caused by hemodialysis and peritoneal dialysis, chronic diuretic use, prolonged vomiting or diarrhea, etc.; and/or
• decreased thiamine intake and/or absorption, caused by malnutrition, alcoholism, hyperemesis gravidarum, consumption of thiamine antagonists or thiaminases, etc.

Thiamine deficiency often presents in low- and middle-income countries where thiamine-poor foods like white, polished rice or cassava are staples. Although historically thought to be confined to Southeast Asia, more recent reports indicate that thiamine deficiency may be a growing concern in South Asia and in other regions, such as Pacific Island nations, where white rice is increasingly consumed as a staple (Johnson et al., 2019).

It is well-established that thiamine requirements increase with higher carbo­hydrate intakes and greater energy expenditures (Elmadfa et al.,2001). For example, periodic outbreaks of thiamine deficiency have been reported among populations consuming monotonous rice-based diets such as illegal gold miners in French Guiana (Mosnier et al., 2017), Thai commercial fishermen (Doung-ngern et al., 2007), and Gambian farmers (Thurnham et al., 2011).

Given the role of thiamine and mechanisms of deficiency highlighted above, individuals with clinical conditions such as patients with chronic renal failure (Talwar et al., 2000), malnutrition (Hiffler et al., 2016), people living with HIV (Müri et al., 1999) and those with critical illnesses (Mates et al., 2021) may be at risk of deficiency.

The most common clinical presentation of thiamine deficiency in high-income settings is among chronic alcoholics due to general malnutrition and alcohol-induced increases in thiamine requirements and impaired thiamine absorption (Latt & Dore, 2014). Wernicke's encephalopathy is an acute, reversible presentation of thiamine deficiency that can lead to Korsakoff syndrome; the often-overlapping presentation is known as Wernicke-Korsakoff syndrome (Latt & Dore, 2014). Treatment of Wernicke-Korsakoff syndrome with both thiamine and magnesium has been recommended by Peake et al.(2013) because magnesium is also required for the full activation of the transketolase enzyme in the pentose phosphate pathway.

Another key risk group is post-operative bariatric surgery patients, in whom thiamine deficiency is caused either by lower dietary intakes or thiamine malabsorption due to the bypass or removal of the proximal small intestine (Frank, 2015). In addition, Mates et al. (2021) recently hypothesized that thiamine deficiency may be more common, yet unrecognized, among older adults in high-income settings presenting with weakness, falling, delirium, and gastro­intestinal symptoms. Thiamine deficiency in older adults could be caused by the co-existence of chronic disease burden (i.e. inflammation), insufficient thiamine intake due to age-related malnutrition, and increased thiamine losses (i.e., higher diuretic use in this population) (Mates et al., 2021). Two ongoing areas of clinical research include use of thiamine, or the highly bio­available analogue benfotiamine, in the treatment of both Alzheimer's Disease and/or dementia (Gibson et al., 2016; Pan et al., 2016; Sambon et al., 2021) and diabetic polyneuropathy (Stracke et al., 2008).

Another growing area of interest is the impact of early life thiamine intake on cognitive development. An unfortunate “natural experiment” took place in Israel in 2003 when thiamine was erroneously excluded from infant formula, resulting in otherwise well-nourished infants presenting with symptoms of thiamine deficiency (Fattal-Valevski et al., 2005). Infants with sub-clinical infantile beriberi were followed up and later experienced delays in language(Fattal-Valevski et al., 2009) and motor skills development (Harel et al., 2017). This is relevant as the thiamine content of human milk depends on maternal thiamine intake (Dror & Allen, 2018). Thus, exclusively breastfed infants of mothers with low thiamine intakes could be at risk of either mortality via infantile beriberi, or impaired cognitive development, despite no signs of clinical deficiency. Empirical studies are currently underway to better understand the impact of thiamine exposure during the first six months of life on various aspects of cognitive and neurological development(Whitfield et al., 2019). Results thus far support that thiamine is integral to normal expressive and receptive language development (Measelle et al., 2021).

20a.1.3 Food sources and dietary intakes

Whole grain cereals, pork, and legumes are the richest food sources of thiamine, followed by other meats, fish, green vegetables, fruits and milk. Polished rice, sugar, alcohol, fat and other refined foods are poor sources of thiamine. Thiamine is thought to be highly bio­available; notable losses would occur only with concurrent consumption of known thiamine antagonists such as betel nuts or tea, or thiaminase-containing raw fish, ferns, or African silkworm larvae (Vimokesant et al., 1982; Whitfield et al., 2018).

While whole grains are a good source of thiamine, milling induces substantial losses because most thiamine is stored in the bran; up to 50% of thiamine in wheat is lost during milling (Oghbaei & Prakash, 2016). Consequently, thiamine enrichment or fortification programs contribute greatly to thiamine intakes globally (Whitfield et al., 2021). Besides mandatory fortification of wheat flour and rice, which have been in place in Canada, the United States, and the Philippines since the 1940s (Aykroyd et al., 1945; Salcedo & Pedroche, 1949), the voluntary fortification of ready-to-eat breakfast cereals also contributes meaningfully to thiamine intakes (Fulgoni (III) & Buckley, 2015). Thiamine-rich yeast in leavened products also contributes to thiamine intake, in addition to fortified flour: Australian researchers reported that despite heat-induced baking losses, baked bread contained more thiamine than the fortified wheat flour from which it was made (Tiong et al., 2015).

Thiamine is prone to degradation by exposure to UV light, heat, oxygen and moisture (Camire et al., 1990). Of these factors, pH has the greatest effect on thiamine stability, with even weak alkaline conditions leading to thiamine degradation (Lešková et al., 2006). Thiamine is rapidly destroyed at elevated temp­eratures unless the pH is below 5. Hence, the addition of sodium bicarbonate to green vegetables to retain their green color destroys thiamine (Aughey and Daniel, 1940). Thiamine is lost when cooking water is discarded because it is a water-soluble vitamin. In meat thiamine is leeched into cooking juices, although losses are generally lower in dark muscles, possibly due to a protective effect from their fat content (Lešková et al., 2006). In alkaline solution, thiamine may be oxidized to the fluorescent compound thiochrome. This reaction is widely used for measuring thiamine in biological tissues and fluids.

20a.1.4 Effects of high intakes of thiamine

No adverse effects of excessive thiamine intakes have been described, except some minor transient local irritation or generalized pruritus at high treatment doses (100mg intravenous administration) (Wrenn et al., 1989). The relatively few studies conducted on the adverse effects of large doses of thiamine were insufficient to allow a Tolerable Upper Intake Level (UL) to be set by the National Academy of Medicine, formerly the Institute of Medicine (Institute of Medicine, 1998). Likewise, the European Food Safety Authority (EFSA) did not set a UL for thiamine, and concluded that the current levels of intake from thimaine from all sources do not represent a health risk for the population (EFSA 2016).

20a.1.5 Pharmacokinetics of thiamine supplementation

Oral thiamine supplementation results in a rapid increase in blood thiamine markers (Smithline et al., 2012). Thiamine is absorbed in the proximal small intestine via passive diffusion, or with an active, carrier-mediated transport mechanism at low concentrations. Some researchers have reported that, in a single dose, no more than between 2.5 to 8.3mg is absorbed (Morrison & Campbell, 1960; Thomson & Leevy, 1972). A more recent pharmacokinetics study with 12 healthy American participants found that the thiamine absorption mechanism was not saturable with a single high oral dose of 1,500mg thiamine hydrochloride (Smithline et al., 2012). However, most hospitals would be unlikely to prescribe such a high dose; 100mg thiamine supplements are much more common (Smith et al., 2021). In a population at high-risk to thiamine deficiency in Cambodia, Coats et al. (2013)found that 16 lactating women also showed a rapid blood (and breastmilk) thiamine response to both a single 100mg dose, as well as 5 consecutive days of 100mg doses of thiamine hydrochloride.