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B Vitamins and Energy Metabolism

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Mechanisms of Function & Deficiency

  1. eliminate chronic deficiency

    • marginal/chronic deficiency​

      • subtle, takes a while to appear​

    • severe/acute deficiency

      • symptoms in a few weeks​

  2. enhancement of healthy pathways of cells metabolism

    • trace elements as cofactors of enzymes​

  3. at levels far greater than those in usual diets, certain micronutrients develop beneficial new actions

micronutrient deficiencies are widespread due to: 

  • food refining, processing and storage

    • fortification ​and enrichment help

  • depletion of minerals and trace minerals from agricultural methods

  • poor diet choice

  • dietary limitations

  • increase requirements due to pollution

  • malabsorption due to drugs alcohol, caffeine, etc.  â€‹

Units

  • international units (I.U.s)

    • measurement of biological activity​

  • mg or μg

    • measurement of weight​

study question:

  • why are measurements for vitamins required?

DRIs

  • reference values

    • quantitive estimates of nutrient intakes​

    • to be used for planning and assessing diets for healthy people

  • refer to average daily nutrient intake of individuals over time

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  • The FDA sets DRIs - the highest amounts of daily vitamins that are needed by 95% of the population

  • difference between DRI and RDA

  • DRIs are a set of 4 reference values

    • estimated daily average (EAR)​

    • recommended dietary allowance (RDA)

    • adequate intake (AI)

    • tolerable upper intake levels (UL)

study question:

  • explain the difference between EAR, RDA, AI and UL

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Fat vs Water Soluble

  • vitamins are not chemically related and differ in physiological roles

  • based on solubility in different solvents, vitamins are classified as fat or water soluble

    • differ in digestion and absorption, transport and storage, and likelihood of developing toxicity​

study questions:

  • which vitamins are water soluble? fat soluble?

  • what are the differences between fat and water soluble?

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Fat-Soluble

  • vitamin A, D, E, K

  • importance of fat solubility

    • absorption similar to dietary lipids​

      • absorbed when other fat absorption is taking place​

      • need bile salts to emulsify

      • anything that interferes with lipid absorption interferes with absorption of fat soluble vitamins

      • must have dietary fats in diet to properly absorb these vitamins

  • after being absorbed: 

    • transported like other non-polar lipids​

      • lipoproteins​

    • extraction from blood and analysis requires solvents

    • storage: in lipid fraction (ex. liver)

    • with high consumption, fat-soluble vitamins can accumulate in the body and cause toxicity

Water-Soluble

  • B vitamins and vitamin C

  • absorbed into the blood portal

  • cannot be retained by the body for long periods of time

  • storage occurs when binding to enzymes or proteins

  • excess excreted in urine, hard to reach UL

  • diverse functions

    • B enzymes often need coenzymes to function​

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Thiamin (B1)

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Thiamin Food Sources

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  • wide distribution in foods

  • has several forms

    • plants​

      • free thiamin​

    • animal products

      • TPP/TDP​

    • supplements

      • thiamin hydrochloride​

      • thiamine mononitrate

study question:

  • what are the differences between the different forms of thiamin?

Digestion, Absorption, and Storage

  • Phosphate groups in TPP have to be hydrolyzed before thiamin can be absorbed

    • ​`phosphatases/pyrophosphatases in duodenum

Absorption mainly occurs in jejunum

  • may be controlled by corticosteroids

  • passive diffusion at high intake (2.5mg)

    • active transport occurs in duodenum when concentration is low (<2uM)​

    • active transport at basolateral surface into blood is Na+ linked

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Factors that interfere with thiamin availability

  • absorption inhibited by alcohol and pyrithiamine (antibiotic)

  • pH >8, heat, cooking with water

  • thiaminases in raw fish destroys thiamin

    • cooking fish inactivates the enzymes​

  • polyphenols  in coffee and tea

  • thiamin can be protected by vitamin C and citric acid

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  • Thiamin in blood is either in it's free form, as thiamin monophosphate (TMP) or bound to albumin

  • uptake is by tissues

    • facilitated diffusion in RBCs​

      • needs carrier, but no energy​

      • requires energy in other tissues

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Storage: approx 30-50mg in body

  • approx 10-20 days, depletion occurs in a few weeks

    • approx 80% in form of TPP/TDP

    • 10% TTP

    • 10% TMP

  • mainly in skeletal muscle (50%), liver, heart, kidneys and brain

    • aka metabolically active organs and tissues​

    • rephosphorylation occurs in the cytosol of tissues

Conversion and Activation

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Thiamin Functions

Non-coenzyme Roles​

  • membrane and nerve conduction​

    • dependant on TTP​

      • TTP activates inon transports in nerve membranes​

      • TTP may be involved in nerve impulse transmission by regulation of Na+ channels and acetylcholine receptors

  • found in brain​

  • synaptosomal membranes

    • regulation of Na+ permeability​

  • cholinergic nerves

    • synthesis of GABA​

  • possibly a role in synthesis of myelin

study question:

  • explain the differences in coenzyme vs non-coenzyme functions of thiamin

Coenzyme Roles​

  • synthesis of pentose and NADPH in PPPs

    • TPP is a coenzyme necessary for transketolase in PPP​

  • energy transformation

    • macronutrients are oxidized when we need to release stored energy to support physiological and biochemical processes in our body​

    • decarboxylation

  • TPP is a coenzyme in the PDH complex​​

    • ​necessary for oxidative decarboxylation of: 

      • pyruvate​​

      • a-kg​​

      • BCAA​s

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Thiamin Deficiency

Risk Factors

  • chronically low intake

Increased Need

  • pregnancy and lactation

  • strenuous PA and sports

  • alcoholism

  • HIV/AIDS

  • cancers

  • malaria

  • dialysis/loop dietetics

Beriberi - disease caused by thiamin deficiency

  • causes muscle weakness, which leads to weak contraction and vasodilation

  • one of the symptoms is anorexia --> weight loss

  • untreated cases can lead to: 

    • hypertrophy, altered heart rate​

    • apathy, confusion, irritability, short term memory

Dry Beriberi

  • caused by chronic low intake coupled with increase CHO intake

    • more thiamin is needed to run glycolysis and TCA to oxidize increased CHO​

  • muscle weakness, muscle wasting, peripheral neuropathy

    • "burning feet syndrome"​

    • exaggerated reflexes & diminished sensation and weakness in limbs

    • muscle pain and tenderness and difficulty rising from a squatting position

    • seizures

Wet Beriberi

  • characterized by more extensive cardiovascular manifestations

    • rapid HR​

    • enlargement of the heart

    • edema, especially in lower body

    • difficulty breathing

    • congestive heart failure

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study question:

  • what are the physiological differences between wet and dry beriberi?

    • What about acute and cerebral?​

Acute Beriberi

  • anorexia, vomiting, weight loss

  • caused by parenteral nutrition

    • nutrition delivered outside the digestive tract​

Cerebral Beriberi

  • can cause wernicke's encephalopathy and wernicke-korsakoff's syndrome

    • ophthalmoplegia​

    • nystagmus

    • ataxia

  • risk factors: 

    • alcoholism​

    • gross malnutrition

    • parenteral nutrition

Thiamin Toxicity

  • No established UL

  • excessive intravenous and intramuscular dose may cause: 

    • headache​

    • convulsions

    • arrhythmia

    • anaphylactic shock

Clinical Application

  • congestive heart failure

    • increases CO and left ventricular ejection​

    • vasodilator

  • lactic acidosis

  • alzheimers

    • ​thiamin deficiency leads to one type of dementia, Wernicke-Korsakoff syndrome

  • parkinson's disease

    • may be protective against​

  • nerve disorders

  • cataracts

Assessment

  • transketolase activity in RBCs

    • is an enzyme in the PPP that is thiamin dependent​

    • if deficient, adding thiamin will lead to increase in transketolase activity

      • increase <15% = adequate​

      • increase 15-25% = marginal

      • increase >25% = deficient

Riboflavin (B2)

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Riboflavin Food Sources

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  • Found in a wide variety of foods

    • free riboflavin, FAD, FMN

    • most is found as FAD (67%)

​

milk and dairy (riboflavin)

eggs (riboflavin)

meat (FAD/FMN)

legumes (FAD/FMN)

green veggies (FAD/FMN)

study question:

  • what are the differences between the different forms of riboflavin?

Digestion, Absorption, Storage

  • riboflavin bonded non-covalently with proteins in food can be released by gastric acid and enzymes in the intestine that hydrolyze proteins

    • riboflavin as FMN and FAD needs to be freed​

    • riboflavin from animal products are better absorbed

  • high absorption rate of 95%

    • Intake ∞ absorption up to 27 mg in a single dose, no further absorption after 27mg

    • absorption increased by deficiency, bile salts and psyllium, absorption is down regulated by high doses​

  • main form is free riboflavin, bound the plasma proteins such as albumin and globulin

  • total body reserve is equivalent to meet metabolic demands for 2-6 weeks

  • after assimilation, riboflavin is converted into coenzyme forms

  • wide tissue distribution especially in liver, small intestine, kidneys, heart

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Riboflavin Functions

  • FAD and FMN function as coenzymes for a wide variety of oxidative enzyme systems and remain bound to the enzymes during redox reactions

  • able to accept or lose 1-2 H atoms

    • 1 e- transferred through radical semiquinone structure​

    • 2 e- transferred through fully reduced hydroquinone structure

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  • Coenzyme for many sits of redox in energy producing pathways

    • TCA cycle​

    • beta-oxidation

    • antioxidant enzymes

    • helps convert other B vitamins into coenzymes

study question:

  • how do the riboflavin coenzymes assist these pathways?

Riboflavin Deficiency

Ariboflavinosis

  • rarely occurs alone, usually accompanied by other nutrient deficiencies

  • risk factors: 

    • alcoholism​

    • thyroid disease

    • DM

    • trauma

    • stress

Deficiency can also cause: 

  • glossitis

  • seborrheic dermatitis

  • angular stomatitis

  • cheilosis

  • photophobia

Riboflavin Toxicity

  • No established UL

  • No toxic or adverse affects of high riboflavin intake in humans are known

  • large dose can lead to harmless yellow color in urine

Clinical Application

  • detoxification

  • antioxidant functions

  • fatigue

  • depression

  • migraine

    • low mitochondrial energy reserves increases migraine frequency​

    • riboflavin influences mitochondrial dysfunction and thus reduces migraine frequency

  • skin and mucous tissues

Riboflavin Application

  • the most sensitive method is to measure the activity of RBC glutathione reductase which requires FAD as coenzyme

  • activity coefficients (AC) are determined with and without adding FAD to RBC culture medium

  • when FAD is added:

    • AC < 1.2 = adequate​

    • AC 1.2 - 1.4 = low

    • AC >1.4 = deficient

Niacin (B3)

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study question:

  • what are the differences between the different forms of niacin?

Niacin Food Sources

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  • in corn, wheat and some other cereal products, niacin may be bound to

    • complex CHO --> niacytins​

    • small peptides --> niacinogens

    • treatment with bases such as lime water (CaOH) can improve availability of bound niacin

  • NAD can be synthesized in the liver from tryptophan

    • not an efficient source​

      • 60mg tryptophan = 1mg niacin​

    • other micronutrients needed to support this pathway as well: FAD, iron, B6

Digestion, Absorption, Storage

  • can be absorbed in stomach, main absorption site is small intestine

  • nicotinamide is the main form in the blood

    • most readily absorbed​

    • nicotinamide is the primary precursor for NAD

    • in liver, nicotinic acid can be used to synthesize NAD

  • niacin is trapped inside cells as NAD or NADP (coenzymes)

Niacin Functions

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  • main role of NAD+/NADH is to transfer electrons from metabolic intermediates through ETC to generate ATP

    • major coenzyme in redox​

    • glycolysis

    • oxidative decarboxylation of pyruvate

    • TCA

    • beta oxidation

  • NADPH acts as a reducing agent in many biosynthetic pathways

    • fatty acid de novo synthesis​

    • cholesterol synthesis

    • steroid hormones synthesis

Niacin Equivalent (NE)

  • 1g of high quality (complete protein)

    • 10mg tryptophan​

    • 60mg tryptophan = 1mg niacin

    • therefore, 6g complete protein = 1 mg niacin = 1 NE

  • typical US diet contains 900mg tryptophan

    • tryptophan provides approx 50% of NE​

study question:

  • describe the relationship between niacin and tryptophan

Niacin Deficiency

  • Pellagra in humans

  • causes 4 Ds

    • dermatitis​

    • dementia

    • diarrhea

    • death

  • risk factors/causes

    • inadequate dietary intake​​​

    • alcoholism

    • diseases that interfere with niacin absorption

    • prolonged treatment with the anti-tuberculosis drug: isoniazid

    • diseases that increase use of niacin

study question:

  • how does alcoholism cause deficiency for thiamin, riboflavin and niacin?

Niacin Toxicity

  • Niacin from food is not known to cause toxic effects

  • nicotinamide is generally better tolerated

  • large dose of nicotinic acid, >1g/day

    • vasodilation effects​

    • GI problems

    • liver injury

    • hyperuricemia

    • glucose intolerance

study question:

  • thiamin, riboflavin, and niacin do not have ULs. why are none of these vitamins toxic?

Clinical Application

  • pharmacological doses of nicotinic acid are 2-4g/day, lowers plasma cholesterol

  • shown to be useful in treating hypercholesterolemia

  • mostly acts by reducing fatty acid mobilization from adipose tissue

  • also depletes glycogen stores and fat reserves in skeletal muscle and cardiac muscle

  • elevation in blood glucose and uric acid production, therefore not recommended in patients with diabetes or gout

  • high doses of nicotinamide (3g/day) are used to protect beta-cells in the pancreas of those newly diagnosed with T1DM

    • delay independence on insulin​

    • could also delay neuropathy of neuropathy in diabetes

©2023 by Syracuse University Dr.Margaret Voss

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