Vitamin B1 (Thiamine)

Structure and Active Form

Thiamine was the first B vitamin to be identified, hence the name B1. It consists of a pyrimidine ring and a thiazole ring linked by a methylene bridge. The biologically active form is thiamine pyrophosphate (TPP), formed when a pyrophosphate group is transferred from ATP to thiamine. TPP is the most abundant form in mammals.

Biochemistry, 8th ed. Lippincott Illustrated Reviews, p. 1064
Harrison's Principles of Internal Medicine 22E, p. 2649

Biochemical Functions

TPP serves as a coenzyme for several key enzymatic reactions:

Reaction	Enzyme	Pathway
Pyruvate → Acetyl-CoA	Pyruvate dehydrogenase complex	Glycolysis → TCA cycle
α-Ketoglutarate → Succinyl-CoA	α-Ketoglutarate dehydrogenase	TCA cycle
Branched-chain keto acid oxidation	BCKA dehydrogenase	Amino acid catabolism
Transketolase reactions	Transketolase	Pentose phosphate pathway

TPP is especially critical in the CNS, where energy dependence on glucose oxidation is highest. Impaired TPP activity leads to reduced ATP production and oxidative stress, causing mitochondrial dysfunction.

Thiamine triphosphate, another form, also influences membrane chloride channel regulation.

Sleisenger & Fordtran's GI and Liver Disease, p. 3561
Lippincott Biochemistry, p. 1064

Dietary Sources and Requirements

Rich sources: yeast, organ meats, pork, legumes, beef, whole grains, nuts
Poor sources: milled/polished rice, heavily processed grains
Anti-thiamine factors:
- Heat-labile thiaminases in raw fish and shellfish - destroy thiamine
- Heat-stable polyhydroxyphenols (tannins) in tea, coffee, betel nuts, Brussels sprouts - inactivate thiamine
Recommended daily intake: ~1.1-1.2 mg/day for adults
Dietary level associated with overt deficiency: <0.3 mg/1000 kcal
Harrison's Principles of Internal Medicine 22E, p. 2649

Causes of Deficiency

Setting	Mechanism
Alcohol use disorder	Impairs intestinal absorption, inhibits TPP synthesis, increases urinary excretion
Polished rice-based diets	Milling removes thiamine
Hyperemesis gravidarum	Vomiting + poor intake
Chronic diuretic use	Urinary thiamine losses
Parenteral glucose without thiamine	Carbohydrate repletion drives demand
Bariatric surgery	Malabsorption
Drugs	Metformin, verapamil inhibit intestinal thiamine transporters (ThTR-2)
Renal dialysis	Losses during dialysis
Cancer, IBD, celiac disease	Malabsorption / increased demand

Important: Carbohydrate refeeding without thiamine in a deficient patient can precipitate acute deficiency with lactic acidosis - thiamine must always be given before glucose in at-risk patients.

Harrison's 22E, p. 2649; Sleisenger & Fordtran's, p. 3562

Clinical Syndromes of Deficiency

1. Beriberi (three phenotypes)

Dry beriberi

Symmetrical ascending peripheral polyneuropathy, mainly affecting legs
Muscle weakness and wasting
Occurs more in older individuals

Wet beriberi

Involves the heart: dilated cardiomyopathy, high-output cardiac failure
Lower extremity edema, cardiomegaly
Increased cardiac output due to vasodilation from energy failure in peripheral tissues

Shoshin (Acute fulminating) beriberi

Occurs mainly in infants
Acute heart failure + metabolic abnormalities
Can be rapidly fatal

2. Wernicke-Korsakoff Syndrome

Most common in chronic alcohol use disorder. The two components often overlap:

Wernicke Encephalopathy (acute, reversible if treated quickly):

Classic triad: ophthalmoplegia, gait ataxia, mental confusion
Also: nystagmus, convulsions, coma
Anatomic lesions: hemorrhagic lesions in the thalamus, mammillary bodies, and pontine tegmentum; damage to astrocytes, neuronal dendrites, and myelin sheaths

Korsakoff Psychosis (develops as Wernicke symptoms resolve):

Anterograde and retrograde amnesia
Confabulation, hallucinations
Often leads to permanent brain damage - memory recovery typically incomplete

3. Gastrointestinal Manifestations

Indigestion, severe constipation, anorexia
Gastric atony, hypochlorhydria
Result from failure of smooth muscle/glands to generate sufficient energy
Lippincott Biochemistry, p. 1064; Sleisenger & Fordtran's, p. 3561; Guyton & Hall Physiology

Genetic / Transporter Disorders

Disorder	Gene Mutation	Clinical Features
Thiamine-responsive megaloblastic anemia (TRMA)	SLC19A2 (hTHTR-1) - autosomal recessive	Megaloblastic anemia, sensorineural deafness, insulin-requiring diabetes
Thiamine-responsive Wernicke-like encephalopathy	SLC19A3 (hTHTR-2)	Seizures, ophthalmoplegia, nystagmus, ataxia

Both respond to high-dose oral thiamine supplementation.

Sleisenger & Fordtran's, p. 3562

Diagnosis

Erythrocyte transketolase activity: baseline low; increases significantly after TPP addition (TPP effect >25% = deficiency)
Blood thiamine concentration: direct measurement
Erythrocyte transketolase is considered the more reliable diagnostic test
Lippincott Biochemistry, p. 1064; Fitzpatrick's Dermatology

Treatment

Wernicke encephalopathy: IV thiamine 500 mg three times daily x 2-3 days, then oral supplementation - must be given before any glucose infusion
Beriberi: oral or parenteral thiamine replacement
TRMA / genetic disorders: high-dose oral thiamine improves most clinical symptoms

Summary Table

Feature	Detail
Water solubility	Water-soluble; no fat storage
Active form	Thiamine pyrophosphate (TPP)
Key enzymes	Pyruvate dehydrogenase, α-KG dehydrogenase, transketolase, BCKA dehydrogenase
Best dietary sources	Pork, yeast, organ meats, legumes, whole grains
Deficiency disease	Beriberi (wet/dry/shoshin), Wernicke-Korsakoff syndrome
At-risk groups	Alcoholics, malnourished, bariatric surgery, hyperemesis patients
Diagnostic test	Erythrocyte transketolase + TPP stimulation
RDA (adults)	~1.1-1.2 mg/day

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