Did You Know Just That Many Cancers Are Linked To A Vitamin Deficiency?
vitamin
B1
Thiamin
Thiamin (also spelled thiamine) is a water-soluble B-complex
vitamin, previously known as vitamin B1 or aneurine (1).
Isolated and characterized in the 1930's, thiamin was one
of the first organic compounds to be recognized as a vitamin
(2). Thiamin occurs in the human body as free thiamin and
its phosphorylated forms: thiamin monophosphate (TMP), thiamin
triphosphate (TTP), and thiamin pyrophosphate (TPP), which
is also known as thiamin diphosphate.
Function
Coenzyme
function
Thiamin
pyrophosphate (TPP) is a required coenzyme for a small number
of very important enzymes. The synthesis of TPP from free
thiamin requires magnesium, adenosine triphosphate (ATP),
and the enzyme, thiamin pyrophosphokinase.
Pyruvate
dehydrogenase, a-ketoglutarate dehydrogenase, and branched
chain ketoacid (BCKA) dehydrogenase each comprise a different
enzyme complex found within cellular organelles called mitochondria.
They catalyze the decarboxylation of pyruvate, a-ketoglutarate,
and branched-chain amino acids to form acetyl-coenzyme A,
succinyl-coenzyme A, and derivatives of branched chain amino
acids, respectively, all of which play critical roles in
the production of energy from food (2). In addition to the
thiamin coenzyme (TPP), each dehydrogenase complex requires
a niacin-containing coenzyme (NAD), a riboflavin-containing
coenzyme (FAD), and lipoic acid.
Transketolase
catalyzes critical reactions in another metabolic pathway
known as the pentose phosphate pathway. One of the most
important intermediates of this pathway is ribose-5-phosphate,
a phosphorylated 5-carbon sugar, required for the synthesis
of the high-energy ribonucleotides, ATP and guanosine triphosphate
(GTP), the nucleic acids, DNA and RNA, and the niacin-containing
coenzyme NADPH, which is essential for a number of biosynthetic
reactions (1, 3). Because transketolase decreases early
in thiamin deficiency, measurement of its activity in red
blood cells has been used to assess thiamin nutritional
status (2).
Non-coenzyme
function
Thiamin
triphosphate (TTP) is concentrated in nerve and muscle cells.
Research in animals indicates that TTP activates membrane
ion channels, possibly by phosphorylating them (4). The
flow of electrolytes like sodium or potassium in or out
of nerve and muscle cells through membrane ion channels
plays a role in nerve impulse conduction and voluntary muscle
action. Impaired formation of TTP may play a role in the
neurologic symptoms of severe thiamin deficiency.
Deficiency
Beriberi,
the disease resulting from severe thiamin deficiency, was
described in Chinese literature as early as 2600 B.C. Thiamin
deficiency affects the cardiovascular, nervous, muscular,
and gastrointestinal systems (2). Beriberi has been termed
dry, wet, and cerebral, depending on the systems affected
by severe thiamin deficiency (1).
Dry
berberi
The main
feature of dry (paralytic or nervous) beriberi is peripheral
neuropathy. Early in the course of the neuropathy "burning
feet syndrome" may occur. Other symptoms include abnormal
(exaggerated) reflexes, diminished sensation and weakness
in the legs and arms. Muscle pain and tenderness and difficulty
rising from a squatting position have also been observed.
Severely thiamin deficient individuals may experience seizures.
Wet
beriberi
In addition
to neurologic symptoms, wet (cardiac) beriberi is characterized
by cardiovascular manifestations of thiamin deficiency,
which include rapid heart rate, enlargement of the heart,
severe swelling (edema), difficulty breathing, and ultimately
congestive heart failure.
Cerebral
beriberi
Cerebral
beriberi may lead to Wernicke's encephalopathy and Korsakoff's
psychosis. The diagnosis of Wernicke's encephalopathy is
based on a "triad" of signs, which include abnormal
eye movements, stance and gait abnormalities, and abnormalities
in mental function, which may include a confused apathetic
state or a profound memory disorder termed Korsakoff's amnesia
or Korsakoff's psychosis. Thiamin deficiency affecting the
central nervous system is referred to as Wernicke's disease
when the amnesic state is not present and Wernicke-Korsakoff
syndrome (WKS) when the amnesic symptoms are present along
with the eye movement and gait disorders. Most WKS sufferers
are alcoholics, although it has been observed in other disorders
of gross malnutrition, including stomach cancer and AIDS.
Administration of intravenous thiamin to WKS patients generally
results in prompt improvement of the eye symptoms, but improvements
in motor coordination and memory may be less, depending
on how long the symptoms have been present. Recent evidence
of increased immune cell activation and increased free radical
production in the areas of the brain that are selectively
damaged suggests that oxidative stress plays an important
role in the neurologic pathology of thiamin deficiency (5).
Causes
of thiamin deficiency
Thiamin
deficiency may result from inadequate thiamin intake, an
increased requirement for thiamin, excessive loss of thiamin
from the body, consumption of anti-thiamin factors in food,
or a combination of factors.
Inadequate
intake
Inadequate
consumption of thiamin is the main cause of thiamin deficiency
in underdeveloped countries (2). Thiamin deficiency is common
in low-income populations whose diets are high in carbohydrate
and low in thiamin (e.g., milled or polished rice). Breast
fed infants whose mothers are thiamin deficient are vulnerable
to developing infantile beriberi. Alcoholism, which is associated
with low intake of thiamin among other nutrients, is the
primary cause of thiamin deficiency in industrialized countries.
Increased
requirement
Conditions
resulting in an increased requirement for thiamin include
strenuous physical exertion, fever, pregnancy, breastfeeding,
and adolescent growth. Such conditions place individuals
with marginal thiamin intake at risk for developing symptomatic
thiamin deficiency. Recently, malaria patients in Thailand
were found to be severely thiamin deficient more frequently
than non-infected individuals. Malarial infection leads
to a large increase in the metabolic demand for glucose,
as well as increased demand for the disposal of lactate.
The stresses induced by malarial infection could exacerbate
thiamin deficiency in individuals already predisposed (6).
HIV-infected individuals, whether or not they had developed
AIDS, were also found to be at increased risk for thiamin
deficiency (7). The lack of association between thiamin
intake and evidence of deficiency in these HIV-infected
individuals suggested they had an increased requirement
for thiamin.
Excessive
loss
Excessive
loss of thiamin may precipitate thiamin deficiency. Individuals
with kidney failure requiring hemodialysis lose thiamin
at an increased rate, and are at risk for thiamin deficiency
(8). By increasing urinary flow, diuretics may prevent reabsorption
of thiamin by the kidney and increase its excretion in the
urine (9, 10). Alcoholics who maintain a high fluid intake
and urine flow rate may also experience increased loss of
thiamin, exacerbating the effects of low thiamin intake
(11).
Anti-thiamin
factors (ATF)
The presence
of anti-thiamin factors (ATF) in foods also contributes
to the risk of thiamin deficiency. Certain plants contain
ATF, which react with thiamin to form a product that is
oxidized in the body, rendering it inactive. Consuming large
amounts of tea and coffee (including decaffeinated), as
well as chewing tea leaves and betel nut have been associated
with thiamin depletion in humans due to the presence of
ATF. Vitamin C and other antioxidants can protect thiamin
in some foods by preventing its oxidation to an inactive
form (1). Thiaminases are enzymes that break down thiamin
in food. Individuals who habitually eat certain raw freshwater
fish, raw shellfish, and ferns are at higher risk of thiamin
deficiency because these foods contain a thiaminase, which
would normally be inactivated by the heat used for cooking.
An acute neurologic syndrome (seasonal ataxia) in Nigeria
has been associated with thiamin deficiency precipitated
by a thiaminase in African silkworms, a traditional high-protein
food for some Nigerians (12).
Recommended
Dietary Allowance (RDA) for ThiaminLife Stage Age Males
(mg/day) Females (mg/day) Infants 0-6 months 0.2 (AI) 0.2
(AI) Infants 7-12 months 0.3 (AI) 0.3 (AI) Children 1-3
years 0.5 0.5 Children 4-8 years 0.6 0.6 Children 9-13 years
0.9 0.9 Adolescents 14-18 years 1.2 1.0 Adults 19 years
and older 1.2 1.1 Pregnancy all ages- 1.4 Breastfeeding
all ages - 1.4
The Recommended
Dietary Allowance (RDA)
The RDA
for thiamin, revised in 1998, was based on the prevention
of deficiency in generally healthy individuals (13).
Disease
Treatment
Alzheimer's
disease
Because
thiamin deficiency can result in a form of dementia (Wernicke-Korsakoff
syndrome), its relationship to Alzheimer's disease and other
forms of dementia have been investigated. Several investigators
found evidence of decreased activity of the thiamin pyrophosphate-dependent
enzymes, a-ketoglutarate dehydrogenase and transketolase,
in the brains of patients who died of Alzheimer's disease
(4). Such findings are consistent with evidence of reduced
glucose metabolism found on PET scans of the brains of Alzheimer's
disease patients (14). The finding of decreased brain levels
of thiamin pyrophophosphate (TPP) in the presence of normal
levels of free thiamin and thiamin monophosphate (TMP) suggests
that the decreased enzyme activity is not likely to be the
result of thiamin deficiency, but rather of impaired synthesis
of TPP (15, 16). Presently, there is only slight evidence
that thiamin supplements are of benefit in Alzheimer's disease.
A double blind placebo-controlled study of 15 patients (10
completed the study) reported no beneficial effect of 3
grams of thiamin/day on cognitive decline over a 12-month
period. A preliminary report from another study claimed
a mild benefit of 3 to 8 grams of thiamin/day in dementia
of Alzheimer's type in 1993, but no additional data from
that study are available (17). A mild beneficial effect
in patients with Alzheimer's disease was reported after
12 weeks of treatment with 100 milligrams/day of a thiamin
derivative (thiamin tetrahydrofurfuryl disulfide), but this
study was not placebo-controlled (18). A recent systematic
review of randomized, double blind, placebo-controlled trials
of thiamin in patients with dementia of Alzheimer's type
found no evidence that thiamin was a useful treatment for
the symptoms of Alzheimer's disease (19).
Congestive
heart failure (CHF)
Severe thiamin
deficiency (wet beriberi) can lead to impaired cardiac function
and ultimately congestive heart failure (CHF). Although
cardiac manifestations of beriberi are rarely encountered
in industrialized countries, CHF due to other causes is
common, especially in the elderly. Diuretics used in the
treatment of CHF, notably furosemide (Lasix), have been
found to increase thiamin excretion, potentially leading
to marginal thiamin deficiency. A number of studies have
examined thiamin nutritional status in CHF patients and
most found a fairly low incidence of thiamin deficiency,
as measured by assays of transketolase activity. As in the
general population, older CHF patients were found to be
at higher risk of thiamin deficiency (20). An important
measure of cardiac function in CHF is the left ventricular
ejection fraction (LVEF), which can be assessed by echocardiography.
In a randomized double-blind study of 30 CHF patients, all
of whom had been taking furosemide for at least 3 months,
intravenous (IV) thiamin therapy (200 mg/day) for 7 days
resulted in an improved LVEF compared to IV placebo (21).
When all 30 of the CHF patients in that study subsequently
received 6 weeks of oral thiamin therapy (200 mg/day) the
average LVEF improved by 22%. This finding may be significant
because improvements in LVEF have been associated with improved
survival in CHF patients (22). Conclusions that can be drawn
from the studies published to date are limited due to small
sample sizes, lack of randomization in some studies, and
a need for more precise assays of thiamin nutritional status.
Presently, the role of thiamin supplementation in maintaining
cardiac function in CHF patients remains controversial.
Cancer
Thiamin
deficiency has been observed in some cancer patients with
rapidly growing tumors. Recent research in cell culture
and animal models indicates that rapidly dividing cancer
cells have a high requirement for thiamin (23). All rapidly
dividing cells require nucleic acids at an increased rate,
but some cancer cells appear to rely heavily on the TPP-dependent
enzyme, transketolase, to provide the ribose-5-phosphate
necessary for nucleic acid synthesis. Thiamin supplementation
in cancer patients is common to prevent thiamin deficiency,
but some investigators caution that too much thiamin may
fuel the growth of some malignant tumors. These investigators
suggest that thiamin supplementation be reserved for those
cancer patients that are actually thiamin deficient (24).
Presently, there is no evidence available from studies in
humans to support or refute this theory. However, it would
be prudent for individuals with cancer who are considering
thiamin supplementation to discuss this issue with the clinician
managing their cancer therapy.
Sources
Food
sources
A varied
diet should provide most individuals with adequate thiamin
to prevent deficiency. In the U.S. the average dietary thiamin
intake for young adult men is about 2 mg/day and 1.2 mg/day
for young adult women. A survey of people over the age of
60 found an average dietary thiamin intake of 1.4 mg/day
for men and 1.1 mg/day for women (13). However, institutionalization
and poverty increase the likelihood of inadequate thiamin
intake in the elderly (25).Whole grain cereals, legumes
(e.g., beans and lentils), nuts, lean pork, and yeast are
rich sources of thiamin (1). Because most of the thiamin
is lost during the production of white flour and polished
(milled) rice, white rice and foods made from white flour
(e.g., bread and pasta) are fortified with thiamin. A number
of thiamin-rich foods are listed in the table below along
with their thiamin content in milligrams (mg). For more
information on the nutrient content of foods you eat frequently,
search the USDA food composition database.
