Causes of Thiamine Deficiency


Thiamine deficiencies are caused by restricted dietary intake, poor absorption from dietary sources, or factors that cause thiamine breakdown. Additionally, the symptoms of thiamine deficiency may manifest due to conditions causing limited conversion to its active form (thiamine diphosphate (TDP)) or deficiencies in enzymes which utilize this form of thiamine as a cofactor in their normal physiological function.

Dietary insufficiency

As thiamine is highly water soluble, it is not stored in the body and must be continually obtained from dietary sources. The total amount of thiamine in a person is approximately 30 mg, an amount which can be depleted within 2-3 weeks. Thiamine deficiency due to inadequate intake is prevalent in people who have diets rich in carbohydrates, but lean in proteins. People most likely to suffer from inadequate intake of thiamine include those in developing nations, prison camps, and refugee populations where rice is often a dietary staple1. The refining process for various foods, including rice and wheat flour, results in loss of thiamine (among other nutrients). For example, after removal of the outer hull of the rice seed post harvesting, during the processing of brown rice to white rice, the bran layer and germ components that have moderate levels of thiamine are removed (Figure 1). In fact, the widespread outbreaks of beriberi in the late 1800's were associated with the widespread distribution of milling machines which made rice polishing more efficient.2

rice seed
Figure 1. Intact rice seed showing bran and germ components that are rich in thiamine

The processing of rice to remove these constituents is done to improve its shelf life by removing layers that contain fats that can become rancid as well as to change its appearance from brown to white which often improves its acceptability by consumers. Within the bran layer are enzymes known as lipases that break down the oils in the whole grain rice.

Further, given the labile and hydrophilic nature of thiamine, much of this essential vitamin that remains can be lost during food manufacturing and cooking. Thus, thiamine, in its less hygroscopic mononitrate form, is often added to enrich flour, white rice, and beer to compensate for losses. As an alternative, by parboiling, or partially cooking, rice while it is still in its hull, the enzymes are inactivated and some of the thiamine in the aleurone layer is forced into the endosperm. This improves both the nutritional value of rice as well as its shelf life.

As thiamine is involved in carbohydrate metabolism, the amount of thiamine required depends on caloric intake. The amount of thiamine needed also is dependent on the composition of the diet, with foods containing fats and proteins having a thiamine-sparing effect versus those dominant in carbohydrates.3 In fact, in healthcare settings, thiamine is concurrently administered in hypoglycemic patients receiving high dose glucose to ensure that ramifications associated with high carbohydrates and limited thiamine do not manifest, most notably Wernicke Encephalopathy.

Chemical Degradation and Complexation

Various physical and chemical conditions can cause the breakdown of thiamine. Conditions of high pH, elevated temperatures, and the presence of sulfites (Figure 2), which are used as preservatives of meat products, are common causes of thiamine loss. Sulfiting agents used for food preservation include bisulfites, sulfites, metabisulfites, and sulfur dioxide.

Figure 2. Sulfite-induced cleavage of thiamine

These preservatives serve to prevent the oxidation of oxymyoglobin to metmyoglobin in meat, which causes its discoloration from red to brown upon exposure to air. Aside from their use as anti-oxidants, they also have anti-microbial properties, delaying the onset and rate of growth of bacteria. In the United States, the use of sulfiting agents as meat preservatives, as well as in other foods recognized as a source of thiamine, is prohibited.4 Aside from causing allergic reactions in sensitive people, sulfites cleave thiamine at its methylene bridge (Figure 2), causing its destruction.

Foods and beverages that contain high concentrations of polyphenolic compounds can also cause thiamine deficiency. Polyphenolic compounds are plant extracts including tannins and catechins (Figure 3), that are commonly found in coffee and tea.

tannic acid
Figure 3. Structure of (+)-catechin (top) and tannic acid (bottom).

These compounds are composed of multiple hydroxyl-substituted aromatic rings which can undergo oxidation to their quinone counterparts (Figure 4). Under basic conditions, the oxidized form of these compounds is believed to cause the conversion of the thiol form of thiamine to thiamine disulfide from thiamine.5

Figure 4. Oxidation of polyphenolic compounds to quinone forms.

Another dietary cause of thiamine deficiency are cyanogenic glycosides. Cyanogenic glycosides are sugar-based molecules with a nitrile substitution. Examples of these compounds include linamarin and lotaustralin (Figure 5), which are present at high concentrations in the cassava plant (Manihot esculenta).2

cyanogenic glycosides
Figure 5. Linamarin (right) and lotaustralin (left).

Upon chewing of plant parts containing these compounds, the sugar portion is enzymatically cleaved, thus freeing hydrogen cyanide which can cause toxicity if eaten without proper preparation. Most of the hydrogen cyanide is typically removed through thorough grinding and washing, allowing plants containing these compounds to be edible. Further, with a balanced diet containing sufficient cysteine and methionine, the sulfur in these amino acids serves as a cosubstrate for the enzyme rhodanese to detoxify residual cyanide. (Figure 6)

Figure 6. Detoxification of cyanide via cysteine amino acids in rhodanese with the conversion of thiosulfite to sulfite.

However, in many populations, cassava which is high in carbohydrates and low in proteins, provides the bulk of the diet. While there are preparation methods to decrease the content of the cyanogenic glycosides, those that are successful are laborious, time-consuming, and vary by culture.

Ingestion of inadequately processed cassava roots has been implicated in Konzo, a syndrome prevalent in Africa which results in irreversible partial paralysis of the lower limbs.6 The mechanism postulated is that in the absence of dietary sulfur-containing amino acids, that cyanide present in the cassava roots interacts with the sulfur in thiazole and inactivates thiamine. These amino acids themselves are lacking in the cassava plant, exacerbating the risks of a primarily single source diet. Further, many of the approaches to process cassava reduces its own natural thiamine content, causing further risk of deficiency.2

A condition affecting hearing, sight, and gait also attributed to thiamine deficiency, is tropical ataxic neuropathy (TAN).7 This condition has most notably affected populations in Western Nigeria, Tanzania, Sierra Leone, India, and Cuba.8 Unlike populations affected by Konzo, some of the populations affected by TAN do not have a high dietary cassava intake and instead their thiamine deficiency stems from a rice-based diet.

Enzymatic degradation

Thiaminase enzymes break down thiamine into its pyrimidine and thiazole moieties. There are two known types of thiaminases: thiaminase I (EC and thiaminase II (EC Thiaminase I can use a number of different nucleophiles including heterocyclic amines and sulfhydryl groups, whereas thiaminase II uses water as its nucleophile (Figure 7).9

Figure 7. Enzymatic cleavage of thiamine by thiaminases

Nucleophiles are species that have a formal negative charge, contain π bonds, or contain lone pairs of electrons and can donate this pair of electrons towards the formation of a covalent bond. These substances include aromatic amines, heterocyclic molecules, and sulfhydryl compounds. Specific examples of nucleophiles that serve in thiaminase I induced exchange reactions include sulfhydryl compounds such as β-mercaptoethanol and dithiothreitol (DTT); nicotinic acid; amino acids and derivatives including lysine, cysteine, and taurine; and organic bases such as pyridine, aniline, m-nitroaniline, veratrylamine, and quinoline.

Thiaminase I is present in certain plants, microorganisms, insects, and fish, whereas thiaminase II is reportedly present only in microorganisms. An excellent overview of thiaminases is available at this website.

Plants containing high levels of thiaminases include Rock fern, Bracken fern, and Nardoo fern. The latter was held responsible for an unfortunate turn of events for Europeon explorers of Australia. In 1860-1861, the explorers Burke and Wills led a team of men across Australia. A shortage of supplies led them to consume Nardoo fern, which was a dietary staple of the local aborigines. When prepared properly by soaking in water followed by cooking, this plant can provide a good source of nutrition, however when consumed raw, its high content of thiaminases can cause the breakdown of thiamine otherwise present. Unfortunately, in the case of the Burke-Wills expedition, the large amount of Nardoo consumed to provide sufficient caloric intake was counteracted by the thiaminases it contained, leading to tremors, muscle weakness, and ultimately death of many of the explorers. Even with cooking, given the high temperature resistance of these enzymes, intended deactivation is sometimes ineffective to inner structures not reaching the necessary inactivation temperature.

Bacteria noted to produce thiaminase I include Paenibacillus thiaminolyticus and Clostridium sporogenes, while species that produce thiaminase II include Staphylococcus aureus and Bacillus aneurinolyticus.10 The ingestion of large quantities of carbohydrates can yield conditions promoting an overgrowth of these thiaminase-producing bacteria in the gut which can cause thiamine deficiency.

In certain cultures, the consumption of insects as a protein source is common. The thiaminase content of some insects, such as African silkworm (Anaphe venata), consumed by people as food is high and has been associated with thiamine deficiency in people. For example, there has been noted a seasonal correlation in symptoms including confusion, impaired conciousness, and tremors collectively termed African Seasonal Ataxia (ASA) with the development cycle of the African silkworm.11 Coupled with an otherwise monodisperse diet high in carbohydrates, the consumption of the larvae of these thiaminase-containing insects has resulted in epidemics of ASA in Western Nigeria.

Interferences with thiamine absorption and metabolism

Section under construction

Other conditions are not caused by thiamine deficiency, but rather by a lack of or dysfunction of transporters responsible for thiamine transport, enzymes needed for conversion to TDP, or those relying on TDP for function. This section will cover conditions that cause thiamine deficiency by way of an inability to uptake this vitamin.


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