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Q. 1- What is the active form of thiamine? Explain the coenzyme role of thiamine.

Answer- Thiamine is also known as vitamin B1. Thiamine occurs in the human body as free thiamine and in various phosphorylated forms: thiamine monophosphate (TMP), thiamine triphosphate (TTP), and thiamine  pyrophosphate (TPP), which is also known as thiamine diphosphate. Thiamine pyro phosphate is the active form of Thiamine. It is rapidly converted to its active form, in the brain and liver by a specific enzyme, TPP synthetase. The synthesis of TPP from free thiamine also requires the presence of magnesium and adenosine triphosphate (ATP)-(Figure-1)









Figure-1- reaction showing the  activation of thiamine

Coenzyme functions

Thiamin has a central role in energy-yielding metabolism, and especially the metabolism of carbohydrates. Pyruvate dehydrogenase, Alpha-ketoglutarate dehydrogenase, and branched chain ketoacids (BCKA) dehydrogenase each comprise a different enzyme complex found within mitochondria. They catalyze the decarboxylation of pyruvate, Alpha-ketoglutarate, and branched-chain amino acids to form acetyl-coenzyme A , succinyl-coenzyme A, and derivatives of branched chain amino acids, respectively; all products play critical roles in the production of energy from food. In addition to the thiamine coenzyme (TPP), each dehydrogenase complex requires a niacin-containing coenzyme (NAD), a riboflavin-containing coenzyme (FAD), and lipoic acid.

Transketolase catalyzes critical reactions in 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). It is also required for the synthesis of the nucleic acids, DNA and RNA, and the niacin-containing coenzyme NADPH, which is essential for a number of biosynthetic reactions. Because transketolase decreases early in thiamine deficiency, measurement of its activity in red blood cells has been used to assess thiamine nutritional status.

Certain non-coenzyme functions of thiamine are important for nervous tissues and muscles.  It has an important role in the metabolism of neurotransmitters like acetylcholine, adrenaline, and serotonin. Its triphosphate form (TTP) in particular plays a role in the conduction of nerve impulses. TTP phosphorylates, and so activates, a chloride channel in the nerve membrane.

 Q.2- Why is it said that the requirement of thiamine increases with the increasing carbohydrate load ?

Answer- Because thiamine is required for enzymes involved in glucose metabolism such as Pyruvate dehydrogenase complex, Alpha keto glutarate dehydrogenase complex and transketolase, so its requirement also increases with the increasing carbohydrate load for the proper functioning of these enzymes. The severe thiamine deficiency disease known as Beriberi is the result of a diet that is carbohydrate rich and thiamine deficient. In subjects on a relatively high carbohydrate diet, this results in increased plasma concentrations of lactate and pyruvate which may cause life-threatening lactic acidosis.

 Q.3- What is the cause of lactic acidosis in thiamine deficiency?

Answer- Lactate, a product of anaerobic glucose metabolism, is generated from pyruvate with lactate dehydrogenase as a catalyst. Pyruvate is normally aerobically metabolized to CO2 and H2 O in the mitochondrion. Initially pyruvate is converted to Acetyl co A with pyruvate dehydrogenase complex acting as a catalyst requiring thiamine, niacin, riboflavin, pantothenic acid and lipoic acid as coenzymes. Acetyl co A is completely oxidized in the Krebs cycle.

Normally, pyruvate is in a state of equilibrium with lactate and under condition like thiamine deficiency, when PDH complex becomes less active, the equilibrium is shifted towards production of lactate. Lactate is cleared from blood, primarily by the liver, with the kidneys (10-20%) and skeletal muscles to a lesser degree.  Lactic acidosis results from an increase in blood lactate levels when lactate production exceeds consumption and body buffer systems become overburdened. (See Figure-2)

Acute thiamine deficiency, an uncommon cause of hemodynamic instability in Western countries, is manifested by acute heart failure and neurological deficits. Severe metabolic acidosis is one of its least recognized features. Empiric treatment with thiamine is initiated immediately. Delaying thiamine administration in patients with deficiency can cause severe life-threatening metabolic acidosis and affect recovery.















Figure-2- showing the role of thiamine in the conversion of pyruvate to Acetyl co A and in the conversion of Alpha keto glutarate to Succinyl co A. The block in the conversion of Pyruvate to Acetyl co A due to non availability of thiamine leads to lactic acidosis.

 Q.4-Explain how a deficiency of thiamine in the diet will produce serious effects on health?


Describe the link in chemical and metabolic terms between polished rice and sudden cardiac failure.


thiamine deficiency (causing beriberi) is most common among people subsisting on white rice or highly refined carbohydrates in developing countries and among alcoholics. Symptoms include diffuse polyneuropathy, high-output heart failure, and Wernicke-Korsakoff syndrome.


Primary thiamine deficiency is caused by inadequate intake of thiamine. It is commonly due to a diet of highly refined carbohydrates (eg, polished rice, white flour, and white sugar). It also develops when intake of other nutrients is inadequate or it can occur with other B vitamin deficiencies.

Secondary thiamine deficiency is caused by increased demand (eg, due to hyperthyroidism, pregnancy, lactation, strenuous exercise, or fever), impaired absorption (eg, due to prolonged diarrhea), or impaired metabolism (eg, due to hepatic insufficiency). In alcoholics, many mechanisms contribute to thiamine deficiency; they include decreased intake, impaired absorption and use, increased demand, and possibly an apoenzyme defect.


Deficiency causes degeneration of peripheral nerves, thalamus, mammillary bodies, and cerebellum. Cerebral blood flow is markedly reduced, and vascular resistance is increased.

The heart may become dilated; muscle fibers become swollen, fragmented, and vacuolized, with interstitial spaces dilated by fluid. Vasodilation occurs and can result in edema in the feet and legs. Arteriovenous shunting of blood increases. Eventually, high-output heart failure may occur.

Symptoms and Signs

Early symptoms are nonspecific: fatigue, irritability, poor memory, sleep disturbances, precordial pain, anorexia, and abdominal discomfort.

Dry beriberi refers to peripheral neurologic deficits due to thiamine deficiency. These deficits are bilateral and roughly symmetric, occurring in a stocking-glove distribution. They affect predominantly the lower extremities, beginning with paresthesias in the toes, burning in the feet (particularly severe at night), muscle cramps in the calves, pains in the legs, and plantar dysesthesias. Calf muscle tenderness, difficulty rising from a squatting position, and decreased vibratory sensation in the toes are early signs. Muscle wasting occurs. Continued deficiency worsens polyneuropathy, which can eventually affect the arms.

Wernicke-Korsakoff syndrome, which combines Wernicke’s encephalopathy and Korsakoff’s psychosis, occurs in some alcoholics who do not consume foods fortified with thiamine. Wernicke’s encephalopathy consists of psychomotor slowing or apathy, nystagmus, ataxia, ophthalmoplegia, impaired consciousness, and, if untreated, coma and death. It probably results from severe acute deficiency superimposed on chronic deficiency. Korsakoff’s psychosis consists of mental confusion, dysphonia, and confabulation with impaired memory of recent events. It probably results from chronic deficiency and may develop after repeated episodes of Wernicke’s encephalopathy.

Cardiovascular (wet) beriberi is myocardial disease due to thiamine deficiency. The first effects are vasodilation, tachycardia, a wide pulse pressure, sweating, warm skin, and lactic acidosis. Later, heart failure develops, causing orthopnea and pulmonary and peripheral edema. Vasodilation can continue, sometimes resulting in shock.

Infantile beriberi occurs in infants (usually by age 3 to 4 wk) who are breastfed by thiamine-deficient mothers. Heart failure (which may occur suddenly), aphonia, and absent deep tendon reflexes are characteristic.

Because thiamine is necessary for glucose metabolism, glucose infusions may precipitate or worsen symptoms of deficiency in thiamine-deficient people.


  • Favorable response to thiamine

Diagnosis is usually based on a favorable response to treatment with thiamine in a patient with symptoms or signs of deficiency. Similar bilateral lower extremity polyneuropathies due to other disorders (eg, diabetes, alcoholism, vitamin B12 deficiency, heavy metal poisoning) do not respond to thiamine.

  • In conjunction with whole blood or erythrocyte transketolase activity a thiamine loading test (preloading and post loading, ) is the best indicator of thiamine deficiency. An increase of more than 15% in enzyme activity is a definitive marker of deficiency.
  • If laboratory confirmation is needed, blood thiamine, pyruvate, alpha-ketoglutarate, and lactate can be measured. Also, urinary excretion of thiamine and its metabolites can be measured. A rise in blood lactate level is indicative of thiamine deficiency.


Supplemental thiamine, with dose based on clinical manifestations


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