Thiamine and Neuritis

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Thiamine and Neuritis

• Presentation by
• Jonathan Chiu, Mary Fahmy,
• Maria Grabowski, Jessica Lam

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What is thiamine?

• Small, water soluble molecule
• Functions solely to form thiamine diphosphate,
  also referred to as thiamine pyrophosphate (TPP)
• TPP cofactor also referred to as vitamin B1
• Not produced endogenously, must be ingested

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Thiamine Requirement Sources

• 1 1.5 mg/day for healthy adult (see RDA slide
  below)
• Found in
• Whole grains, seeds, nuts, legumes, beef,
  uncooked green vegetables
• Not found in significant quantities in food that
  has been cooked/heated for a long time
• Flour, bread, cereals have been fortified since
  the 1940s
• Uptake is inhibited by thyroid hormone, diabetes,
  alcohol, and old age

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Absorption Body Stores

• GI absorption of nutritional thiamine via lumen
  of small intestine (mainly jejunum) via
  Na-dependent active transport mechanism
• For levels 2µmol/L, passive diffusion plays an
  additional role
• Occurs in body as both free thiamine and
  phosphorylated forms
• High turnover rate/biological half-life (10-20
  days) and not appreciably stored in body
  (1mg/day used up in tissues)
• Hence, daily supply required limited stores may
  be depleted within 2 weeks or less on
  thiamine-free diet, with clinical signs of
  deficiency beginning shortly after
• Heart, kidney, liver and brain have highest
  concentrations, followed by leukocytes and RBCs

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Biochemical Pathway
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Thiamine
Thiamine Pyrophosphate
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Reaction Site of TPP

• Proton on the C2 of TPP is acidic
• Proton dissociates to form a carbanion (y-lide)
• Carbanion acts is the active form of TPP ?
  nucleophilic addition to carbonyl groups

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Biochemical Pathway of Thiamine
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(No Transcript)
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Biochemical Pathway of Thiamine
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Thiamine in the Krebs Cycle
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Thiamine in the Pentose Phosphate Shunt
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Why does it matter?

• Thiamine plays role in glucose metabolism to
  produce energy for brain hence, absence of
  thiamine results in inadequate supply of energy
  to brain
• Brain pathology observed is partly due to build
  up of reactive oxygen species as result of
  impairment of mitochondrial function, which can
  ultimately lead to cell damage
• Accumulation of pyruvate due to impairment of
  function of pyruvate dehydrogenase, which
  requires thiamine as a coenzyme, leads to
  metabolic acidosis
• Thiamine deficiency produces cascade of events,
  including impairment of oxidative metabolism,
  activation of microglia, astrocytes and
  endothelial cells that leads to neuronal loss in
  select brain regions
• Thiamine deficiency induces quantitative,
  distinct inflammatory responses and oxidative
  stress
• Without adequate levels of thiamine,
  thiamine-dependent enzymes, such as pyruvate
  dehydrogenase and a-ketoglutarate dehydrogenase,
  cannot perform their enzymatic functions in the
  Krebs Cycle deficiency manifests as marked
  reduction of enzyme activity followed by decrease
  in neuronal mitochondrial transmembrane potential
  and ATP prior to cortical neuronal death

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Thiamine Deficiencies
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Thiamine Deficiency Pathologies

• Decreased glucose utilization causes lactic
  acidosis, which results in neuritis - this
  manifests as the neuropathy characteristic of
• Dry Beriberi
• Wernickes encephalopathy leading to Korsakoff
  Syndrome
• Thiamine deficiency also affects the
  cardiovascular system, leading to Wet Beriberi

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Dry Beriberi

• Thiamine depletion leads to tachycardia, weakness
  and decreased deep tendon reflex
• When the nervous system becomes involved, it is
  termed Dry Beriberi, which includes above
  symptoms plus peripheral neuropathy
• Peripheral neuropathy is characterized by
  impairment of sensory, motor, and reflex
  functions in extremities (in particular, the
  distal lower limbs)

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Wet Beriberi - Chronic

• Cardiovascular involvement of thiamine deficiency
  is termed Wet Beriberi
• First stage patients exhibit peripheral
  vasodilation ? high cardiac output ? salt and
  water retention (renin-angiotensin-aldosterone
  system in kidneys) ? fluid overload leading to
  edema of extremities
• High cardiac output leads to muscle overuse
  injury in the heart resulting in tachycardia,
  high arterial and venous pressure, chest pain

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Wet Beriberi - Acute

• This rare form of Wet Beriberi is also termed
  Shoshin Beriberi or acute fulminant
  cardiovascular Beriberi
• The predominant injury is to the heart, leading
  to inability to meet bodys demands (in this
  case, edema may not be present)
• Cells are rapidly injured, possibly leading to
  sudden death of the individual
• Cyanosis of hands and feet, tachycardia, anxiety,
  restlessness are observed

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Wernickes Encephalopathy Korsakoff Syndrome

• Vomiting, horizontal nystagmus, palsies of the
  eye movements, fever, ataxia, and progressive
  mental impairment leading to Korsakoff syndrome
• Once patients at Korsakoff stage, only half of
  the treated ones recover significantly
• Damage to multiple nerves in CNS and PNS due to
  decreased glucose utilization
• Korsakoff Syndrome nerve damage in areas
  involved in memory ? psychosis, made-up stories
  to cover up poor memory

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Wernicke-Korsakoff Syndrome

• Wernicke-Korsakoff Syndrome
• Diagnosis requires the inclusion of 2 of the
  following 4 symptoms
• Dietary deficiencies
• Oculomotor abnormalities
• Cerebellar dysfunction
• Altered mental state OR mild amnesia

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People At Risk

• Alcoholics
• Malnutrition (ie diet, starvation, high carb
  diet)
• Heavy consumers of tea/coffee (tannin
  antithiamin)
• High energy consumers (ie pregnant lactating,
  heavy physical exertion, adolescent growth)
• Diseases (dysentery, diarrhea, hyperemesis,
  hyperthyroidism)
• Peritoneal Dialysis without thiamine replacement
• Severe liver disease impairs thiamine use

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Diagnostics and Treatment
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Diagnostic Testing

• Serum thiamine
• Normal range 1.5-5.5 nM/ml
• Bioassay or high performance
• chromatography
• Transketolase
• Measure RBC content (a-ETK) both with and without
  stimulation of this enzyme by the addition of TDP
  cofactor
• Measurement of urinary thiamine excretion
• Wernickes Encephalopathy
• No specific tests
• Magnetic Resonance Imaging can show lesions in
  dorsal and medial nuclei of thalamus,
  periaqueductal grey matter, and cerebellar vermis

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Treatment of Thiamine Deficiency

• Disease Prevention Therapeutic Use
• Cornerstone of treatment is timely administration
  of thiamine 100mg/day (not RCT tested contested)
• Thiamine used in the specific prevention and
  treatment of beriberi and other manifestations
  e.g. Wernicke-Korsakoff, peripheral neuritis
• Thiamine administration beneficial in neuritis
  accompanied by excessive alcohol consumption or
  pregnancy
• Dosage 100mg daily in mild deficiency states to
  200-300mg in severe cases
• Alcoholic diabetic polyneuropathies
  10-100mg/day
• Should be administered parenterally (preferably
  IV) (why?)
• Patients without active disease receiving
  prophylaxis with discharge can continue oral
  thiamine to supplement compromised nutritional
  status

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Treatment of Thiamine Deficiency

• Optimal treatment regimen remains unknown, but
  may be BID/TID rather than conventional once
  daily treatment (why?)
• Duration of treatment continues to be debated
• Data insufficient to make definitive dosage
  recommendations professional judgment should be
  exercised when dosage, frequency, duration
  determined
• Glucose loading reported to precipitate/worsen
  Wernicke encephalopathy (why?)
• Patients with alcoholism occasionally given Mg2
  an K supplements

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Pharmaceutical Relevance
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Recommended Dietary Allowance (RDA)

• Adults 0.5mg/1000kcal (based on average caloric
  intake)
• Women 1.0-1.1mg/day
• Men 1.2-1.5mg/day
• Pregnancy and Lactation Additional 0.4-0.5mg/day
• Childrensneeds are lower, but depend on age and
  caloric intake
• Infants 0.3-0.4mg/day
• Children 0.7-1.0mg/day
• Note Since thiamine facilitates energy
  utilization, its requirements are tied to energy
  intake, which can be dependent on activity levels

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Drug/Herbal Interactions

• Positive Interactions
• Other B-vitamins e.g. B6 (pyridoxine), B12
  (cyanocobalamin), B3 (niacin), pantothenic acid
  induce action of thiamine
• Antioxidant vitamins e.g. E and C, protect
  thiamine by preventing oxidation to its inactive
  form

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Drug/Herbal Interactions

• Negative Interactions
• Foods coffee, tea, betel nuts (SE Asia), some
  cereals antagonize action of thiamine
• Some tropical fish African silkworms contain
  thiaminase enzymes that metabolize thiamine
• Drugs that cause nausea and lack of appetite, or
  increase intestinal function or urinary excretion
  decrease availability of thiamine
• Heavy metal poisoning

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Drugs/Herbal Interactions

• Phenytoin (Dilantin)
• Antacids Barbiturates
• Diuretics (particularly furosemide (Lasix))
• Tobacco
• Some Antibiotics
• Oral Contraceptives
• Fluorouracil-containing chemotherapy
• Metformin
• Betel Nuts
• Horsetail (wound-healing inflammation)

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Stability issues of thiamine that patients should
be aware of

• Thiamine unstable when exposed to heat, alkali
  conditions, oxygen, radiation
• Water solubility also factor in loss of thiamine
  from foods
• Suggestions to preserve thiamine in food relate
  to method of preparation
• Recommended to reuse juices and cooking water in
  stews and sauces

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Safety Counseling

• Treatment is well-tolerated in healthy
  individuals even at high oral doses (up to
  200mg/day)
• Rare cases of hypersensitivity reported
• England Anaphylaxis reported at rate of 4 of 1
  million pairs of ampules of vitamin complex with
  thiamine
• UK Guidelines Thiamine given during 15-30min
  interval in mixture of saline/dextrose solution
  to avert potential adverse reactions

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Summary Slide

• Thiamine (vitamin B1) is present in the active
  form as thiamine pyrophosphate (TPP)
• TPP functions as a coenzyme for many important
  carbohydrate metabolising enzymes
• We need to get thiamine from our diet nuts,
  seeds, legumes, beef and uncooked vegetables
  destroyed by heat, alkali conditions, oxygen and
  radiation
• Water soluble, little storage therefore, regular
  ingestion necessary
• Deprotonation of the thiozole ring on TPP will
  lead to formation of a carbanion (y-lide) which
  readily undergoes nucleophilic addition onto
  carbonyl groups
• Without adequate levels of thiamine and
  thiamine-dependent enzymes, such as pyruvate
  dehydrogenase and a-ketoglutarate dehydrogenase,
  you cannot perform their enzymatic functions in
  the Krebs Cycle
• Accumulation of pyruvate due to impairment of
  function of pyruvate dehydrogenase, which
  requires thiamine as a coenzyme, leads to
  metabolic acidosis
• Decreased glucose utilization and lactic acidosis
  cause neuritis and nerve degeneration, which
  leads to symptoms associated with neuropathy
• Neuropathy is common to Dry Beriberi as well as
  Wernicke-korsakoff encephalopathy
• Cardiovascular damage as a result of thiamine
  deficiency is characteristic of Wet Beriberi
• Those at risk of becoming thiamine deficient
  include alcoholics, dialysis patients, high
  energy consumers, malnourished, those who ingest
  high levels of coffee/tea, and those with various
  disease states such as liver disease
• The most common diagnostic test is that which
  test for serum thiamine levels
• Treatment is parenteral thiamine
• 0.5mg/1000kcal thiamine needed demands increase
  in pregnancy
• Vitamin B3, 6, and 12 induce the effects of
  thiamine structure protected by antioxidants
• Some cereals, coffee/tea can antagonize the
  effects of thiamine some foods contain
  thiaminase (tropical fish) which can break down
  thiamin

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