Thiamin consists of a molecule of pyrimidine and a molecule of thiazole linked by a methylene bridge. It contains both nitrogen and sulfur atoms (Illus. 7-1). Thiamin is isolated in pure form as the white thiamin hydrochloride. The vitamin has a characteristic sulfurous odor and a slightly bitter taste. Thiamin is very soluble in water, sparingly so in alcohol, and insoluble in fat solvents. It is very sensitive to alkali, in which the thiazole ring opens at room temperature when pH is above 7. In a dry state, thiamin is stable at 100°C for several hours, but moisture greatly accelerates destruction, and thus it is much less stable to heat in fresh than in dry foods. Under ordinary conditions, thiamin hydrochloride takes up moisture and therefore should be kept in a sealed container.
Substances with an antithiamin activity are fairly common in nature. They include structurally similar antagonists and structure-altering antagonists. The synthetic compounds pyrithiamin, oxythiamin and amprolium are structurally similar antagonists whose mode of action is competitive inhibition. They interfere with thiamin at different points in metabolism. Pyrithiamin blocks chiefly the esterification of thiamin with phosphoric acid, resulting in inhibition of the thiamin coenzyme cocarboxylase. Oxythiamin likewise displaces cocarboxylase from important metabolic reactions. Amprolium inhibits the absorption of thiamin from the intestine and also blocks the phosphorylation of the vitamin (McDowell, 2000). Sulfur has been shown to be antagonistic to thiamin enzymes. The sulfite ion has been shown to cleave thiamin from enzymes at the methylene bridge and analytically, will imitate thiaminase. Sulfate increases thiamin-destroying activity in the rumen contents and the destructive mechanism involves thermolabile factor(s). However, the ruminal synthesis of thiamin is not affected by sulfate (Olkowski et al., 1993). Tall fescue (Festuca arundinacea Schreb.) toxicosis resembles diseases caused by elevated rumen thiaminase activity (Lauriault et al., 1990).
Two types of thiaminase enzymes have been described—I and II. Thiaminase I substitues a new base for the thiazole ring. This leads to less thiamin, but it also results in thiamin analogs consisting of the pyrimidine ring of the original thiamin and another ring from the “cosubstrate”. This thiamin analog may then be absorbed and possibly inhibit thiamin-requiring reactions (Frye et al., 1991). Thiaminase II simply cleaves the vitamin at the methylene bridge between the thiazole and the pyrimidine rings.
Thiaminase activity destroys thiamin by altering the structure of the vitamin. The disease Chastek paralysis in foxes and other animals fed certain types of raw fish results from a thiaminase that splits the thiamin molecule into two components and thus renders it inactive. Since thiaminase is heat labile, the problem can be avoided by cooking the fish at 83°C for at least five minutes. Certain microorganisms (bacteria and molds) and plants (bracken fern) have been shown to produce thiaminases.
Thiamin appears to be readily digested and released from natural sources. A precondition for normal absorption of thiamin is sufficient production of stomach hydrochloric acid. Phosphoric acid esters of thiamin are split in the intestine. Free thiamin is soluble in water and is easily absorbed, especially in the duodenum. The mechanism of thiamin absorption is not yet fully understood, but apparently both active transport and simple diffusion are involved (Braunlich and Zintzen, 1976). At low concentrations there is an active sodium-dependent transport against the electrochemical potential, whereas at high concentrations thiamin diffuses passively through the intestinal wall. Specific proteins (transporters and carriers) in the cell membrane have binding sites for thiamin, allowing it to be solubilized within the cell membrane. This permits the vitamin to pass through the membrane and ultimately reach the aqueous environment on the other side (Rose, 1990; Bates, 2006). Absorbed thiamin is transported via the portal vein to the liver with a carrier plasma protein.
Thiamin phosphorylation can take place in most tissues, but particularly in the liver. Four-fifths of thiamin in animals is phosphorylated in liver under the action of ATP to form the metabolically active enzyme form, thiamin pyrophosphate (TPP, or cocarboxylase). Of total body thiamin, about 80% is TPP, about 10% is thiamin triphosphate (TTP), and the remainder is thiamin monophosphate (TMP) and free thiamin.
Although thiamin is readily absorbed and transported to cells throughout the body, it is not stored to any great extent. Thiamin content in individual organs varies considerably, with the vitamin preferentially retained in organs with a high metabolic activity. During deficiencies, thiamin is retained in greatest quantities in important organs, such as the heart, brain, liver and kidney. Intakes in excess of current needs are rapidly excreted. This means that the body needs a regular supply and also that unneeded intakes are excreted. The pig is somewhat of an exception, however. For some unknown reason its tissues contain several times as much thiamin as is the case with other species studied, and thus it has a store that can meet body needs on a thiamin deficient diet for as long as two months (Heinemann et al., 1946).
Absorbed thiamin is excreted in both urine and feces, with small quantities excreted in sweat. Fecal thiamin may originate from feed, synthesis by microorganisms, or endogenous synthesis (i.e., via bile or excretion through the mucosa of the large intestine). When thiamin is administered in large doses, urinary excretion first increases, then reaches a saturation level, and with additional thiamin the fecal concentration increases considerably (Braunlich and Zintzen, 1976). Roth-Maier and Kirchgessner (1993, 1994) determined in two separate investigations that more than 90% to 95% of excess thiamin is excreted via feces.
A principal function of thiamin in all cells is as the coenzyme cocarboxylase or thiamin pyrophosphate (TPP). The tricarboxylic acid cycle (TCA), citric acid cycle, or Krebs cycle is responsible for production of energy in the body. In this cycle, breakdown products of carbohydrates, fats and proteins are brought together for further breakdown and for synthesis. The vitamins riboflavin, pantothenic acid and niacin, as well as thiamin, play roles in the cycle. Thiamin is the coenzyme for all enzymatic carboxylations of alpha-keto acids. Thus it functions in the oxidative decarboxylation of pyruvate to acetate, which in turn is combined with coenzyme A (CoA) for entrance into the TCA cycle. Thiamin is essential in two oxidative decarboxylation reactions in the TCA cycle that take place in cell mitochondria and one reaction in the cytoplasm of the cells (Figure 7-1). These are essential reactions for utilization of carbohydrates to provide energy. Decarboxylation in the TCA cycle removes carbon dioxide, and the substrate is converted into the compound having the next lower number of carbon atoms:
Pyruvate→acetyl-CoA + CO2Alpha-ketoglutaric acid→succinyl-CoA + CO2
Thiamin pyrophosphate is a coenzyme in the transketolase reaction that is part of the direct oxidative pathway (pentose phosphate cycle) of glucose metabolism. It occurs not in mitochondria but in the cell cytoplasm of the liver, brain, adrenal cortex and kidney. It does not occur in skeletal muscle. Transketolase catalyzes transfer of two-carbon fragments, hence with ribulose 5-phosphate as donor and ribose 5-phosphate as acceptor, sedoheptulose 7-phosphate and triose phosphate are formed. The pentose phosphate cycle is the only mechanism known for synthesis of ribose, which is needed for nucleotide formation and also results in formulation of nicotinamide adenine dinucleotide phosphate (NADP), which is essential for reducing intermediates from carbohydrate metabolism to form fatty acids. Little is known of thiamin functions in nervous tissue. However, evidence has accumulated for a specific role of thiamin in neurophysiology that is independent of its coenzyme function. Possible mechanisms of action of thiamin in nervous tissue include the following (Muralt, 1962; Bates, 2006): (1) thiamin is involved in the synthesis of acetylcholine, which transmits neural impulses; (2) thiamin participates in the passive transport of sodium to excitable membranes, which is important for the transmission of impulses at the membrane of ganglionic cells; (3) the reduction in the activity of transketolase in the pentose phosphate pathway that follows a deficiency of thiamin reduces the synthesis of fatty acids and the metabolism of energy in the nervous system.
Recently, the detailed pathophysiology and biochemistry of thiamin deficiency-induced problems in the brain have been studied in human subjects, animal models, and cultured cells (Gibson and Zhang, 2002; Martin et al., 2003; Ke and Gibson 2004). Neurodegeneration becomes apparent, initially as a reversible lesion and later irreversibly, in very specific areas of the brain, notably the submedial thalamic nucleus and parts of the cerebellum, especially the superior cerebellar vermis (Bates, 2006).
Thiamin requirements in most species are difficult to establish due to endogenous vitamin synthesis by intestinal microflora. For swine, it is doubtful whether the amount of thiamin produced by intestinal synthesis and absorbed is large enough to make a significant contribution to body needs. Hughes (1940) reported that the daily minimum requirement of thiamin for the growing pig (weighing between 27.3 and 29.5 kg or 60 and 65 lb at initiation of the experiment) was approximately 1 mg thiamin per 45.5 kg (100 lb) body weight. Other early researchers (Van Etten et al., 1940) attempted to determine the thiamin requirement of young swine (approximately 3 weeks of age initially) by using basal diets that were made thiamin-free by either autoclaving or by sodium sulfite-sulfur dioxide treatment of the basal diets and subsequent supplementary feeding of specific amounts of crystalline thiamin hydrochloride. Van Etten et al. (1940) estimated that the requirement for thiamin hydrochloride was between 106 and 120 mg per 100 g of carbohydrate and protein consumed. For today’s situations, swine thiamin requirements generally range between 1 and 1.5 mg per kg (0.45 and 0.68 mg per lb) of feed (NRC, 1998). Based on data from an experiment with high health status pigs with a high genetic capacity for lean tissue growth, Stahly and Cook (1996) concluded that 2.2 ppm thiamin was adequate to support growth performance of pigs weighing 10 to 40 kg (22 to 88 lb). Other researchers (Woodworth et al., 1997) have confirmed these findings with younger pigs. They indicated that supplementation of thiamin beyond what is present in typical grain-soybean meal diets is not required for maximum growth of weanling pigs. Woodworth et al.(1997) found that average daily gain was identical for pigs fed the control ration to that for those receiving additional thiamin at the rate of 5 g thiamin per ton of diet. Overall growth performance was not improved by the addition of thiamin. Roth-Maier and Kirchgessner (1994) concluded from biochemical analyses that thiamin maintenance requirements of sows could be met by the addition of 1.2 mg thiamin per day. Thiamin requirements for swine have been shown to increase as environmental temperature increased from 20° to 35°C (Peng and Heitman, 1974). In addition, diet composition can dramatically influence thiamin requirements. Since thiamin is specifically involved in carbohydrate metabolism, level of dietary carbohydrate relative to other energy-supplying components influences thiamin requirement. The need for thiamin increases as consumption of carbohydrate increases. This was illustrated by Ellis and Madsen (1944). Where the survival time of thiamin-deficient pigs was increased by increasing fat levels to 28% of the diet at the expense of carbohydrates. When thiamin is deficient, body reserves become depleted more rapidly when animals are being maintained on a feed rich in carbohydrates than when they are receiving a diet rich in fat and protein. The thiamin-sparing effect of fats and protein has long been known (McDowell, 2000). Thiamin requirements are obviously higher if feeds contain raw materials (i.e., fish) or additives with antithiamin activity. Spoiled and moldy feeds may contain such antagonists or thiaminases. Chicks kept on a feed infected with Fusarium moniliform developed polyneuritis that could be cured with thiamin injections (Fritz et al., 1973). Analysis of moldy feeds showed a thiamin content of less than 0.1 mg per kg (0.05 mg per lb), whereas the same feed not contaminated with Fusarium had a thiamin content of 5.3 mg per kg (2.4 mg per lb). The antagonistic factor could be destroyed by treatment with steam.
Disease conditions also increase thiamin requirements. When dietary thiamin is marginal, typical deficiency signs of thiamin are more likely to develop in infected animals than in normal animals. Endoparasites such as strongyloides and coccidia compete with the host for thiamin in food. It has been shown experimentally that infection with coccidia results in considerable reduction in thiamin blood levels. Thiamin levels found were directly correlated to infection severity (McManus and Judith, 1972). Likewise, conditions such as diarrhea and malabsorption may negatively affect thiamin status and increase the dietary requirement for the vitamin.
Brewer’s yeast is the richest known natural source of thiamin. Cereal grains and their by-products, soybean meal, cottonseed meal and peanut meal are relatively rich sources of thiamin. Since the vitamin is present primarily in the germ and seed coats, by-products containing the latter are richer than the whole kernel, while highly milled flour is very deficient. Whole rice may contain 5 mg per kg (2.3 mg per lb) thiamin, with much lower concentrations for polished rice (0.3 mg per kg; 0.14 mg per lb) and higher concentrations for rice bran (23 mg per kg; 10.5 mg per lb) (Marks, 1975). Wheat germ ranks next to yeast in thiamin concentration. Using nongravid sows fed a low-thiamin compound feed supplemented with 0, 225 or 675 g wheat bran per day and 0, 575 or 1150 g alfalfa meal per day, the availability of wheat-bran thiamin was found to be better than that of alfalfa-meal thiamin (Roth-Maier and Kirchgessner, 1994). Roth-Maier and Kirchgessner (1994) also reported “the bacterially fermentable substances from wheat bran and alfalfa meal included a higher bacterial thiamin synthesis than with pectin.” Roth-Maier and Kirchgessner (1993) indicated that high pectin supplementation (400 g daily) did not affect thiamin bioavailability for sows.
The presence of mold in feeds can result in substantial nutrient loss, including thiamin (Cook, 1990). The content of thiamin was reduced from 43 to 50% for two cultivars of wheat infested with Aspergillus flavus compared to the uncontaminated sound wheat (Kao and Robinson, 1973). Analyses of moldy feed showed thiamin content of less than 0.1 ppm, whereas the same feed not contaminated had a thiamin content of 5.33 ppm.
Reddy and Pushpamma (1986) studied the effects of one year of storage and insect infestation on thiamin content of feeds. Thiamin losses were high in different varieties of sorghum and pigeonpea (40% to 70%) and lower in rice and chickpea (10% to 40%), with insect infestation causing further loss.
The level of thiamin in grain rises as the level of protein rises. Grain levels depend on species, strain, and use of nitrogenous fertilizers (Zintzen, 1974). Since thiamin is water-soluble as well as unstable to heat, large losses in certain cooking operations result (McDowell, 2000).
Thiamin sources available for addition to feed are the hydrochloride and mononitrate forms. Because of its lower solubility in water, the mononitrate form has somewhat better stability characteristics in dry products than the hydrochloride (Bauernfeind, 1969).
Thiamin deficiency in swine reveals itself particularly in a decrease of appetite and body weight, vomiting, a slow pulse, subnormal body temperature, nervous signs, postmortem heart changes and sudden death because of heart failure. Animals consuming a low-thiamin diet soon show severe anorexia, lose all interest in food and will not resume eating unless given thiamin (Illus. 7-2). If the deficiency is severe, thiamin must be force-fed or injected to induce animals to resume eating.
Pig fed normal diet with thiamin on left.
Pig fed diet lacking thiamin on right.
Heinemann et al. (1946) reported that the pig can utilize stored thiamin over a long time, as 56 days was required for the pigs to lose their appetites after beginning a thiamin-deficient diet. Death has been reported 74 days after pigs began a thiamin-free, but otherwise adequate diet (Loew, 1978). For young pigs, severe thiamin deficiency has resulted in death at the age of three to four weeks. First signs of thiamin deficiency in pigs are reduced feed consumption and vomiting, with a sharp reduction in weight gains (Van Etten et al., 1940; Miller et al., 1955; Peng and Heitman, 1973). Functional and structural cardiac changes are the main findings in experimentally deficient swine; in contrast to clinical reports, nervous system lesions were not detected (Follis et al., 1943). Electrocardiographically demonstrable changes in heart tissue are also seen, with enlarged hearts obtained from pigs receiving thiamin-deficient diets (Illus. 7-3). The heart can be flabby, as reported by Van Etten et al. (1940), with myocardial degeneration. On microscopic examination, it is possible to recognize inflammations and necrotic changes in the myocardial fibers.
Courtesy of T.J. Cunha and Washington State University
Thiamin-deficient animals have elevated plasma pyruvate concentrations (Miller et al., 1955), since with this vitamin deficiency there is an accumulation of intermediates of carbohydrate metabolism. The red blood cell enzyme transketolase is lowered in thiamin-deficient pigs. This enzyme is used as an indicator of thiamin status (McDowell, 2000). Peng and Heitman (1973) determined that erythrocyte transketolase and TPP stimulation were very useful, sensitive and specific methods to study thiamin status of growing-finishing pigs.
The thiamin content of most common feeds should be three to four times greater than requirements for most species (Brent, 1985). For swine consuming typical diets (e.g., corn-soybean meal), thiamin is one of the vitamins least likely to be deficient. Thiamin concentration of corn, soybean meal and dried whey, the principal ingredients in most diets of weanling pigs, range from 3.2 to 4.1 mg per kg (1.45 to 1.86 mg per lb) (NRC, 1998). This compares to a thiamin requirement (NRC, 1998) for 5 to 20 kg (11 to 44 lb) pigs of 1 mg per kg (0.45 mg per lb) of feed. Woodworth et al.(2000) fed weanling pigs, that were receiving a corn, whey and soybean meal diet, supplemental thiamin for 35 days. There was no difference in growth performance, indicating no need for supplemental thiamin under the diet conditions. Although thiamin levels supplied by feedstuffs in the diet are generally considered adequate for swine, thiamin deficiency and inadequacy have been observed in swine under commercial production conditions. Utilization of available thiamin in feedstuffs may be limited and may also be impaired by thiamin antagonists; therefore, it is common practice to add supplemental thiamin to swine diets to replace thiamin lost during processing and storage. For example, it has been reported that use of high-moisture barley treated with sulfur dioxide resulted in destruction of 61% of dietary thiamin for pigs (Gibson et al., 1987). Treatment of feed ingredients with sulfur dioxide inactivates thiamin. This process was used to produce deficient diets in early studies to determine the pig’s thiamin requirement (NRC, 1998).
Drying and processing can lower the concentration of available thiamin in feedstuffs because thiamin is heat labile.
Based on thiamin status indicators, reduced pig weight gains were attributed to thiamin deficiency. Thiamin supplementation should be greatly modified if diets contain antithiamin substances, such as thiaminases from raw fish and moldy feeds. As an example, in free-range farming, pigs may occasionally suffer from bracken fern poisoning, as the roots contain anti-thiamin substances. The animals can be saved by timely thiamin injections. Anti-thiamin substances present in some feedstuffs and weeds, such as oxythiamin, should likewise be considered. Other thiamin antagonists, such as free bisulfite, may be present in feeds and reduce free thiamin activity.
Under certain conditions a thiamin inadequacy for swine feed may be created. Thiamin is very unstable in heat under neutral and alkaline pH conditions. Tests show that while no destruction occurs in 1% HCl during 7 hours at 100°C, over 90% destruction occurs under the same conditions at pH 7, and 100% destruction in 15 minutes at pH 9. Swine diets, and especially pelleted diets, should not contain alkaline salts in sufficient quantities to produce an alkaline reaction in the feed (McDowell, 2000; Leeson and Summers, 2001). In recent years, feed manufacturers have increased pelleting temperatures for all animal feeds in order to control Salmonella organisms and increase digestibility and are using steam pelleting, pre-pelleting conditioners and feed expanders, which lead to increased vitamin degradation (Ward, 2005).
Stability of thiamin (hydrochloride and mononitrate forms) in feed premixes can be a problem. More than 50% of the thiamin was destroyed in premixes after one month at room temperature (Verbeeck, 1975). Thiamin in premixes without minerals showed no losses when the premixes were at room temperature for six months. When the minerals were supplied as sulfates, the losses of thiamin were also greatly lowered. After six months only 27% of the activity of thiamin hydrochloride remained in a vitamin premix that also contained choline and trace minerals (Coelho, 1991).
As recent genetic and technologic advances have allowed the production of pigs with accelerated rates of lean tissue growth, the nutrient fortification optimal for growth must be considered so that adequate energy is available. Thiamin is vital as the coenzyme involved in the energy-producing TCA cycle. Therefore, it would be logical to consider whether or not thiamin concentration would affect rate and efficiency of gain in pigs with high lean growth potential and high health status. However, Stahly and Cook (1996) did not find any significant improvement in pig performance when higher dietary concentrations (200% and 720% of NRC  recommendations) were supplied to growing pigs 10 kg (22 lbs) initially through 40 kg (88 lbs) body weight. Stahly and Cook (1996) indicated that the lack of response to thiamin may likely be related to the pig’s apparent and unique ability to store thiamin for as long as two months on a thiamin-deficient diet. Thus, Stahly and Cook (1996) suggested that although there may have been an increased demand for thiamin, body stores were sufficient to meet the need. These authors concluded that 2.2 ppm, the dietary thiamin value of a corn-soy-based diet, would be adequate for optimal growth performance in high lean growth pigs.
Thiamin ingested in large amounts orally is not toxic, and usually the same is true of parenteral doses. Dietary intakes of thiamin up to 1,000 times the requirement are apparently safe for most animal species (NRC, 1998). The effects of excessive intakes of thiamin have not been studied in swine (NRC, 1998). Lethal doses with intravenous injections were 125, 250, 300 and 350 mg per kg (56.8, 113.6, 136.4, and 159.1 mg per lb) of bodyweight for mice, rats, rabbits and dogs, respectively (Bates, 2006).
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