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Nutrition in Clinical Practice
http://ncp.sagepub.com/
Thiamine in Nutrition Therapy
Krishnan Sriram, William Manzanares and Kimberly Joseph
Nutr Clin Pract 2012 27: 41 originally published online 4 January 2012
DOI: 10.1177/0884533611426149
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Invited Review
Nutrition in Clinical Practice
Thiamine in Nutrition Therapy Volume 27 Number 1
February 2012 41-50
© 2012 American Society
for Parenteral and Enteral Nutrition
DOI: 10.1177/0884533611426149
http://ncp.sagepub.com
1 2 hosted at
Krishnan Sriram, MBBS, FACS, FRCS(C) ; William Manzanares, MD, PhD ; http://online.sagepub.com
and Kimberly Joseph, MD, FACS, FCCM3
Abstract
Clinicians involved with nutrition therapy traditionally concentrated on macronutrients and have generally neglected the importance of
micronutrients, both vitamins and trace elements. Micronutrients, which work in unison, are important for fundamental biological pro-
cesses and enzymatic reactions, and deficiencies may lead to disastrous consequences. This review concentrates on vitamin B , or thia-
1
mine. Alcoholism is not the only risk factor for thiamine deficiency, and thiamine deficiency is often not suspected in seemingly
well-nourished or even overnourished patients. Deficiency of thiamine has historically been described as beriberi but may often be seen in
current-day practice, manifesting as neurologic abnormalities, mental changes, congestive heart failure, unexplained metabolic acidosis,
and so on. This review explains the importance of thiamine in nutrition therapy and offers practical tips on prevention and management
of deficiency states. (Nutr Clin Pract. 2012;27:41-50)
Keywords
thiamine; vitamin B ; beriberi; metabolic acidosis; critical illness; micronutrients; enteral nutrition; parenteral nutrition; refeeding
1
syndrome; congestive heart failure
Clinicians have traditionally concentrated on macronutrients 1881. However, it took many more decades to establish a rela-
in nutrition therapy. For example, there is wide debate on the tionship between consumption of milled or polished rice and
actual caloric requirement of a critically ill patient or the the development of beriberi due to thiamine deficiency in
4
carbohydrate-to-fat ratios. The importance of micronutrients humans. It was only after the 1950s that enrichment of rice and
is often neglected. The attitude that “one size fits all” is not other grains became common practice.
applicable to vitamin and trace element supplementation. The After the advent of nutrition therapy in the mid- to late 1970s,
practical use of micronutrient supplementation in nutrition thiamine deficiency was no longer a historic curiosity, especially
1
therapy in general has been recently reviewed. The present in developed countries. It began to be recognized during or after
review focuses on the specific role of thiamine (vitamin B ) in nutrition therapy, both enteral and parenteral, even in patients
1 who were seemingly well nourished or overnourished and not
nutrition therapy and in certain disease states, with a focus on
practical aspects of clinical management. Early suspicion and necessarily in the expected patient population—for example,
recognition of thiamine deficiency are needed so that therapy alcoholics.5
This was especially true when a high carbohydrate
can be immediately initiated, as thiamine reserves are depleted intake is provided, as in parenteral nutrition with a high glucose
2,3 6
as early as 20 days of inadequate oral intake. A simple inex- content. We now also speak of gastrointestinal beriberi and
pensive treatment modality may make the difference between bariatric beriberi, to be discussed later.
life and death, thus avoiding unnecessary, invasive, and costly
investigations to determine the cause of the various hemody-
1
namic, neurologic, and metabolic manifestations of thiamine From Division of Surgical Critical Care, Department of Surgery, Stroger
2
deficiency. Preventive measures and treatment are both Hospital of Cook County, Chicago, Illinois, Department of Critical
discussed. Care, Hospital de Clinicas (University Hospital), Faculty of Medicine,
3
Universidad de la Republica, Montevideo, Uruguay, Department of
Trauma, Stroger Hospital of Cook County, Chicago, Illinois
Historical Facts Financial disclosure: none declared.
The term beriberi is often associated with thiamine deficiency, Received for publication September 5, 2011; accepted for publication
although the origin of the word is not clear. It has been sug- September 16, 2011.
gested that it might come from Sinhalese meaning “I cannot” Corresponding Author: K. Sriram, Department of Surgery, Room 3350,
or from Arabic (“sailor’s asthma”). Carl Wernicke described the Stroger Hospital, 1901 West Harrison St, Chicago, IL 60612; e-mail:
eponymous syndrome—Wernicke encephalopathy (WE)—in ksriram@cookcountyhhs.org
Downloaded from ncp.sagepub.com at BIOLOGICAL LABS LIBRARY on November 22, 2013
42 Nutrition in Clinical Practice 27(1)
Absorption of Thiamine enzyme complexes α-ketoglutarate dehydrogenase and pyru-
vate dehydrogenase. Therefore, TPP is required for the conver-
Thiamine is rapidly absorbed in the jejunum and ileum by an sion of pyruvate to acetyl CoA and entry to Krebs cycle, as well
active, carrier-mediated, and rate-limited process, but at higher as the conversion of α-ketoglutarate to succinyl CoA (Figure 1).
concentrations, the uptake is by passive diffusion. However, the Both enzymes decrease its activity during thiamine deficiency
clinical relevance of passive diffusion remains questionable. states, but in general α-ketoglutarate dehydrogenase is more
14
The intestine is exposed to 2 sources of thiamine: a dietary severely affected than the pyruvate dehydrogenase complex
source and a bacterial source in which the vitamin is generated and is one of the earliest biochemical changes observed in thia-
7,8 15
by the normal intestinal microbiota. After hydrolysis of the mine deficiency. It is well known that TPP activates decarbox-
phosphorylated forms of thiamine in the intestinal lumen, free ylation of pyruvate dehydrogenase complex. This complex is a
thiamine enters the absorptive cells via a specialized sodium- group of enzymes and cofactors that form acetyl CoA, which
independent, pH-dependent, and amiloride-sensitive carrier- then condenses with oxaloacetate to form citrate, the first com-
mediated mechanism. Two thiamine intestinal transporters ponent of the Krebs cycle.12 Thiamine’s important role in tricar-
have been indentified: the human thiamine transporter–1 boxylic acid cycle is explained in Figure 1.
(hTHTR-1; the product of SLC19A2 transporters) and the Basically, thiamine is important for the conversion of
hTHTR-2 (the product of SLC19A3). Both hTHTR-1 and lactate to pyruvate; in its absence, lactic acid accumulates.
hTHTR-2 are expressed in the small and large intestines.7,9 The acidosis is manifested both systemically and locally. An
However, hTHTR-1 shows its maximal expression in the liver, example of focal damage due to lactic acidosis is its effect on
followed in order by stomach, duodenum, jejunum, colon, and vulnerable brain structures (mamillary bodies and posterome-
10 dial thalamus) detectable by magnetic resonance imaging
ileum.
The intestinal thiamine uptake process appears to be under scanning. Apoptotic cell death due to N-methyl-D-aspartate
the regulation of an intracellular calcium/calmodulin mediated toxicity is responsible for neurologic symptoms in thiamine
7,8 16
pathway. Also, thiamine absorption is adaptively regulated deficiency.
by the extracellular thiamine level. In fact, thiamine deficiency Another important enzyme requiring TPP is erythrocyte
was found to lead to an induction in intestinal carrier-mediated transketolase, an enzyme of the pentose phosphate pathways.
uptake. This effect was associated with a significant induction The functions of this pathway are to provide pentose phos-
7
in the level of expression of THTR-2 (but not THTR-1). phate for nucleotide synthesis and to supply reduced nicotin-
Furthermore, chronic alcohol use leads to thiamine defi- amide adenine dinucleotide phosphate for various synthetic
12
ciency, and inhibition in intestinal thiamine absorption plays a pathways.
role in causing this deficiency. This inhibition was associated
with a marked decrease in the level of expression of THTR-1
(but not THTR-2). In addition, a similar mechanism of inhibi- Risk Factors
tion in thiamine uptake was demonstrated in kidneys. Thus,
chronic alcoholism is characterized by inhibition in the intesti- Thiamine deficiency occurs due to poor oral intake, inadequate
nal absorption and in the reabsorption by the kidneys, which provision of thiamine in enteral or parenteral nutrition therapy,
determine a negative impact on the thiamine balance in the reduced gastrointestinal absorption due to disease or surgery,
7
body. or increased metabolic requirements. Increased gastrointesti-
In summary, current knowledge indicates that active nal or renal losses should also be considered. Often, multiple
absorption of thiamine is the most important and significant. factors exist, predisposing the patient to thiamine deficiency,
Thiamine transport seems to be at different capacities along the in addition to deficiencies of other micronutrients. Patients
gastrointestinal tract: duodenum and jejunum > colon > with a history of alcoholism, AIDS, and malignancies form a
11 substantial group of patients in whom thiamine deficiency
stomach.
should be suspected. Although thiamine deficiency is often
Biochemical Actions associated with alcohol abuse, it is being increasingly recog-
nized that it can occur in patients without this history. Preg-
Following absorption, thiamine is initially phosphorylated to nancy and lactation, hyperthyroidism, renal failure especially
thiamine diphosphate, also known as thiamine pyrophosphate on hemodialysis, systemic infections, advanced age, diabetes
4
(TPP), by a specific enzyme: thiamine pyro(di)phosphokinase. mellitus, and any critical illness are other major risk factors.
TPP is the active form involved in several enzyme functions Obese patients, candidates for bariatric surgery, and postbariat-
associated with metabolism of carbohydrates, lipids, and ric surgery patients are not exempt from developing thiamine
branched chain amino acids. TPP is a cofactor for multiple steps deficiency even if routine multivitamin supplements are being
in the glycolysis and oxidative decarboxylation of carbohy- taken. Because of its short half-life and poor stores, a continu-
drates.12,13 ous supply of thiamine is needed for optimal metabolism.
TPP is required as a coenzyme for the mitochondrial
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Thiamine in Nutrition Therapy / Sriram et al 43
Glucose
Glucose-6-phosphate
Ribose-5-phosphate
Fructose-6-phosphate
Transketolase-TPP
Fructose-1-6-biphosphate
Glycerylaldheyde-3-phosphate CYTOSOL
+ + MITOCHONDRION
NAD+H NAD
Pyruvate Lactate
Pyruvate Lactic dehydrogenase
dehydrogenase-TPP
Acetyl-CoA
Malate Oxalacetate
Fumarate Citrate
Krebs cycle
Succinate Isocitrate
Succinyl-CoA α-ketoglutarate
α-ketoglutarate
dehydrogenase-TPP
Figure 1. The glycolytic pathway and Krebs cycle pathways. TPP, thiamine pyrophosphate. Modified from Klooster A et al, Medical
Hypothesis 2007; 69:873-878, and used with permission from Elsevier Ltd, Oxford, UK.
Some of these specific conditions are discussed in further However, the current preferred test is measurement of thia-
detail in this review. mine diphosphate in erythrocyte (ie, red blood cell) hemoly-
sates using high-performance liquid chromatography. It is
Laboratory Diagnosis more reproducible than the other tests and suitable for research
and clinical purposes.17
Serum thiamine level represents only a small portion of the Considering the expense of these sophisticated tests and the
total body thiamine and is not a reliable indicator of thiamine delay in obtaining the results from a reference laboratory, the
4
status. However, in clinical practice, serum and red blood cell clinician should depend on clinical judgment and initiate treat-
thiamine levels are the only tests that can be ordered and ment without waiting for a laboratory confirmation.
obtained easily. A normal level does not exclude the diagnosis Additionally, serum tests normalize rapidly after thiamine
of thiamine deficiency. Erythrocyte transketolase activation administration and must be obtained prior to treatment. We do
assay, a functional test, is also mentioned in the literature. not recommend routine testing. A high index of suspicion
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