Water-Soluble Vitamins
Andrew Ukleja, M.D., C.N.S.P.
Assistant Professor of Medicine
Director of Nutrition Support Team
Department of Gastroenterology
Cleveland Clinic
Weston, FL
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Objectives
• To review
• Functions of water-soluble vitamins
• Symptoms and signs of vitamin deficiencies
• Treatment of the vitamin deficiencies
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The Location of Vitamin
Absorption
Preferentially
absorbed in jejunum
Fat-soluble
vitamins
Thiamin
Riboflavin
Niacin
Biotin
Folate
(Jejunum only)
Colon
Vitamin B12
(Ileum only)
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B Vitamins
• Coenzymes in the same energy metabolic
pathways
• Overlap in clinical symptoms of deficiency
between B vitamins
• Cheilosis
• Glossitis
• Dermatitis
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Vitamin B1 (Thiamine)
• Thiamine was named "the antiberiberi factor“ (1926)
• Absorption: jejunum/ileum
• Biologic half-life: ~10-20 days
• Limited tissue storage
• Continuous supplementation is required
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Thiamine
• Functions: Cofactor for enzymes in AA and CHO metabolism
• Dietary sources: yeast, legumes, rice, cereals, pork
• RDI: 1.2-1.5 mg/d; parenteral dose - 3 mg/d
• Thiamine requirement:
– based on the total caloric intake
– 0.5 mg of vit. B1 daily /1000 Kcal for adults
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Individuals at Risk for
Thiamine Deficiency
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Alcoholics
Calorie-protein poor diet
Severe malnutrition
Malabsorption
Gastric bypass
Chronic renal failure on HD
Prolonged febrile illness
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Thiamine Deficiency
• Beriberi
• Wernicke-Korsakoff syndrome
• Leigh's syndrome
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Beriberi
Adult beriberi:
• Dry beriberi: distal symmetrical peripheral neuropathy of
the extremities (sensory and motor impairment)
• Wet beriberi: neuropathy / cardiac involvement – high
output CHF (cardiomegaly, cardiomyopathy, tachycardia,
pitting peripheral edema)
• Other symptoms: anorexia, weight loss, confusion, muscle
wasting, weakness
Infantile beriberi (infants, 2-3 months of age)
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Wernicke-Korsakoff Syndrome
• Almost exclusively described in chronic alcoholics
• Wernicke’s encephalopathy: horizontal nystagmus,
ophthalmoplegia, gait ataxia, confusion, weakness
• Korsakoff's psychosis
• Impaired short-term memory and confabulation
• ? genetic predisposition - impaired synthesis of erythrocyte
transketolase
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Thiamine Deficiency
Detection:
• Erythrocyte thiamine transketolase activity (ETKA)
• Serum thiamine concentration
• Urinary thiamine/transketolase excretion
Treatment:
– Vitamin B1: 50-100 mg/d (IV. or IM.) for 7-14 days, then
5-10 mg/d orally until full recovery
Sensitivity to thiamine I.V. has been reported:
– Tingling, pruritus, nausea, sweating, anaphylactic
reaction (IgE-mediated)
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Vitamin B2 (Riboflavin)
• Stored in the body as flavoproteins
• Poorly soluble in water
• Functions:
– Involved in cellular metabolism, oxidation - reduction
reactions; electron transporter
– Essential component of coenzymes
• flavin mononucleotide (FMN)
• flavin-adenine dinucleotide (FAD)
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RIBOFLAVIN
• Dietary sources
– Milk, green vegetables
– Yeast, enriched foods
– Liver, meats, fish, eggs
• Daily values: 0.6 mg/1000 kcal
– Adults 1.2-1.7 mg/d
– Infants 0.4 mg/d
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Deficiency of Vitamin B2
• Pure deficiency of vit. B2 is rare
• Often accompanied by other water-soluble vitamin
deficiencies
– Alcoholics
– Malabsorption
• Detection of deficiency:
– Urinary riboflavin excretion
– Erythrocyte glutathione reductase assay
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Patients at Risk for Vit. B2 Deficiency
• Avoidance of dairy products
– lactose intolerance
• Anorexia nervosa
• Malabsorptive syndromes
– Celiac sprue
– Malignancies
– Short bowel syndrome
• Inborn errors of metabolism
– defect in riboflavin synthesis
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Manifestations of Vit. B2 Deficiency
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Angular stomatitis
Cheilosis
Glossitis
Sore throat
Hyperemia, pharyngeal mucous membranes
Seborrheic dermatitis
Pruritus
Photophobia
Normocytic, normochromic anemia
• Treatment: Vit. B2
– 5 mg bid for a few weeks
– 3 mg/d - prophylaxis in malabsorption syndrome
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NIACIN (Vitamin B3)
Forms
• Nicotinic acid
• Nicotinamide
Functions:
• Component of NAD/NADP - essential for redox
reactions and hydrogen transport, metabolism of
carbohydrates, fatty acids, and proteins
Dietary sources:
– Meats (liver), milk, fish, whole-grain, nuts
RDI: 17-20 mg/d
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Niacin Deficiency
Pellagra
• Pellagra - meaning "raw skin"
• First described in Spain/Italy in the mid 18th century
• Epidemic amongst the corn eating population of
southeastern US in the early 1900s
• Seen mainly in alcoholics
• Reported in carcinoid syndrome, Hartnup disease,
Isoniazid therapy
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Pellagra
Symptoms (three D’s)
• Dermatitis
• Photosensitive symmetric
pigmented in sun-exposed areas
• Diarrhea
• Dementia
Glossitis/red tongue
Neurologic symptoms
– insomnia, anxiety, disorientation,
delusions, encephalopathy, seizures
•
Detection: serum niacin level
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Treatment of Pellagra
• Niacin: Oral 100 mg tid. until symptoms resolved
• Nicotinamide:
• 100mg IM if needed
• Only available IV form
• Clinical response:
• GI and neurologic symptoms resolve rapidly
• Dermatitis subsides over a few months after treatment
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Vitamin B6 (PYRIDOXINE)
• Forms
– Pyridoxine (plant foods)
– Pyridoxal (animal foods)
– Pyridoxamine
active form
Pyridoxal phosphate
(PLP)
• Functions
– Transamination and decarboxylation of AA
– Gluconeogenesis
– Formation of niacin/serotonin from tryptophan
– Synthesis of lecithin, RNA, sphingolipids, heme
– Immune function (IL-2, lymphocyte proliferation)
– Steroid hormone modulation
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PYRIDOXINE
• Dietary sources:
– Meats, fish
– Whole grains
– Vegetables
– Nuts
• Recommended daily requirements
– Children 0.6 mg
– Female 1.6 mg
– Pregnancy
1.9 mg
– Male
2.0 mg
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Vitamin B6 Deficiency
• Overt deficiencies are rare
• Manifestations
– Stomatitis, glossitis, cheilosis
– Seborrheic dermatitis
– Irritability, confusion, depression
– Sideroblastic anemia
•  serum homocysteine with deficiency
– risk factor for atherosclerosis / DVT
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Detection of Vitamin B6 Deficiency
• Plasma pyridoxal-5-phophate (PLP)
– Males
27-75 nmol/L
– Females 26-93 nmol/L
• Erythrocyte transaminase activity
• Urinary excretion of 4-pyridoxic acid > 3.0 mmol/d
– indicates adequate short-term vit. B6 status
• Urinary excretion of xanthurenic acid (< 65 mmol/d)
after a 2 g tryptophan load
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PYRIDOXINE
• Treatment:
– Oral 50-150 mg/d
– 50 mg/d prophylactic dose with Isoniazide Rx
• Toxicity (long-term megadoses > 250 mg/d)
– Peripheral neuropathy/paresthesias
– Dermatoses
– Photosensitivity
– Dizziness
– Nausea
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Vitamin B12 (Cobalamin)
• Functions
– A carrier for methyl group and hydrogen
– Synthesis of nucleic acids, porphyrins, methionine,
and fatty acids
• Dietary source
– Meat
– Dairy products
• Daily requirement: 4-5 mcg/d
• Total body stores: 2-5 mg (½ stored in the liver)
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Factors Affecting Vitamin B12 Absorption
– Dietary intake
– Acid-pepsin in the stomach
– Secretion of IF by gastric
parietal cells
– Pancreatic proteases
– Presence of ileum
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Causes of Vitamin B12 Deficiency
• Diet
– Strict vegetarians
– Vegetarian diet in pregnancy
• Gastric abnormalities
– Pernicious anemia*
– Gastritis, Helicobacter pylori infection
– Gastrectomy/gastric bypass
– Atrophic gastritis (autoimmune)
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Causes of Vitamin B12 Deficiency
• Small bowel disease
– Malabsorption syndromes
– Ileal resection/ bypass*
• Crohn’s disease, tuberculous ileitis, lymphoma,
radiation enteritis
– Blind loops/bacterial overgrowth
– Fish tapeworm (Diphyllobothrium latum)
• Pancreatic exocrine failure
– Chronic alcoholism
• Drugs
– Antibiotic, Biguanides, PPI, Neomycin
• HIV infection
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Vitamin B12 Deficiency
Pernicious Anemia
• Common in whites (northern European)
– Older patients > 50years
– Associated with autoimmune diseases under the
age of 30
• Lack of intrinsic factor
• The classic description of patient with PA
– Lemon colored skin (anemia/icterus)
– Shiny tongue (atrophic glossitis)
– Mentally sluggish
– Shuffling broad gait
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Hematologic Manifestations of
Vitamin B12 Deficiency
• Macrocytic anemia
–  serum bilirubin / LDH levels
– Low-normal WBC/platelet count
• Peripheral blood smear
– Megaloblasts
– Hypersegmented neutrophils
>5% with 5 +more lobes
• Bone marrow aspiration
– hypercellular marrow: megaloblastic
erythroid hyperplasia, giant
metamyelocytes
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Neurologic Manifestations
of Vitamin B12 Deficiency
• Subacute combined degeneration of the
posterior/lateral spinal columns
– Defect in myelin formation
• Symmetrical neuropathy (legs >> arms)
– Paresthesias (stocking/glove distribution)
–  vibratory and position sense
– severe weakness, ataxia, spasticity, clonus,
paraplegia, fecal and urinary incontinence
• Dementia, memory loss, irritability
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Manifestations
of Vitamin B12 Deficiency
• Glossitis
– Beefy red tongue
– Loss of taste
• Diarrhea, dyspepsia, anorexia
• Impotence
• Vaginal atrophy
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Detection of Vitamin B12 Deficiency
• Serum level of Vitamin B12
– Normal >400 pg/ml
– Low <210 pg/ml
•  serum methylmalonic acid
• Schilling test
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Schilling Test
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Treatment of Vitamin B12 Deficiency
• Rx: 100-1000 mcg IM x 5-10 days, then 1000 mcg/monthly
• Vegetarians: 3-6 mcg/d orally
• Supplements
1) Sublingual tablet: 350 mcg/day
2) Intramuscular injection: 1000mcg/month
3) Nasal spray (Nascobal): 500mcg weekly
one nostril
4) MVI (1-15mcg)
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Folic Acid
• Functions
– A carrier of one-carbon groups
– Synthesis of nucleic acids and protein
• Dietary source
– Animal products (liver)
– Leafy green vegetables
• Small body stores (5-10 mg)
• Daily requirements:
– Pregnancy/lactation
0.2-0.4 mg/d
0.5-0.8 mg/d
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Causes of Folate Deficiency
Nutritional deficiency
Poor dietary intake
Alcoholism (37% of ETOH users)
Elderly (10% in pts >75 years)
Malabsorption
Sprue
IBD
Gastric bypass
Short bowel
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Causes of Folic Acid Deficiency
• Increased requirements
– Pregnancy
– Hemolytic anemia (chronic hemolysis)
– Exfoliative skin disease
* Pregnancy – prophylaxis with FA at 0.8-1.0 mg/d to
prevent neural tube defects
• Drugs (sulfasalazine)
– Interference with folate metabolism
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Symptoms of Folate Deficiency
• Macrocytic or megaloblastic anemia
• Glossitis, fatigue, diarrhea
• Progressive neurologic deterioration
– Neuropathy, ataxia, seizures, mental retardation
• Failure to thrive
• Detection
– Serum or RBC folate
–  Homocysteine level
• Rx:
– Folate 1mg/d orally x 2-3 weeks
– Maintenance 0.4 mg (in MVI) with malabsorption
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VITAMIN C
• Functions: Antioxidant (biologic reductant)
– Provides electrons to reduce molecular oxygen
– Involved in iron/copper reactions
• RDA:
– Adult 75-90 mg/d
– Elderly 125 mg/d
– Smokers -  requirement by ~ 40%
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Vitamin C
ASCORBIC ACID
• Dietary source:
– Citrus fruit
– Fresh fruit
– Vegetables
• Absorption: distal small intestine
– Intake up to 100 mg/d - 100% absorbed
– Intake >1000 mg/d - <50% absorbed
• Excess of vit. C removed by kidneys
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Functions of Vitamin C
• Collagen synthesis
– Formation of hydroxyproline/ hydroxylysine
–  synthesis: impaired wound healing, defective tooth
formation, osteoblast and fibroblast dysfunction
• Neurotransmitters
– Cofactor in synthesis of norepinephrine, thyroxin
• Prostaglandin metabolism
• Immune functions: chemotaxis and phagocytosis
modulation
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Vitamin C Deficiency
Scurvy
• Described in Egyptian, Greek, and Roman literature
• A major cause of morbidity and death in the US
during Civil War and the California gold rush
• Ascorbate is an essential nutrient derived from the
diet
• Scurvy develops 2-3 months with diet deficient in
ascorbic acid
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Vitamin C Deficiency
Groups at Risk
Poor dietary intake
– Severely malnourished individuals
– Drug and alcohol abusers
– Poverty
– Elderly, institutionalized pts.
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Symptoms of Vitamin C Deficiency
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Swollen and bleeding gums
Loosened teeth
Arthralgias and joint effusions
Lower extremities weakness
Petechiae and periungual hemorrhage
Ecchymoses
Corkscrew hair
Slow wound healing
Anemia
Death
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Vitamin C
Rx: Ascorbic acid 250 mg qid. x 1 week, then
100-200 mg/ day + rich Vit. C diet
Toxicity
• Seen with large doses of vit. C (grams)
– diarrhea/abdominal bloating
– calcium oxalate nephrolithiasis
– cardiac arrhythmias if iron overload (oxidative
injury)
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PANTOTHENIC ACID
Vitamin B5
• Functions: precursor of coenzyme A (CoA)
– Essential cofactor in acetylation reactions
– Synthesis of vitamins A, D, cholesterol, fatty acids,
proteins, steroids, porphyrins
• Dietary sources:
– Egg yolk, liver, kidney, milk, broccoli
• Adequate daily intake 4-7mg/d
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Deficiency of Pantothenic Acid
• It is rare
• Manifestations
– Paresthesias and dysesthesias (burning feet syndrome)
– Gastrointestinal: nausea, vomiting, cramping
• Growth failure, hemorrhage and necrosis of adrenal cortex,
dermatitis, and achromotrichia (gray hair) in rats
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BIOTIN
• Growth factor found in yeast, called "bios“
• Called vitamin H, coenzyme R, protective factor X
• Functions:
– Cofactor for the carboxylases involved in CHO and lipid
metabolism
– Essential in protein and DNA synthesis and cell
replication (CO2 carrier)
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Biotin
• Dietary sources:
– Liver, meats, egg yolk, soybean, yeast
• Adequate dietary intake: 0.03-0.1mg/d
• Biotin deficiency was first noted in patients on long-term
parenteral nutrition
• Associated with consumption of large amounts of raw egg
whites which contain glycoprotein – avidin (binds to biotin
and prevents its absorption)
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Biotin Deficiency
• Symptoms
– Seborrheic dermatitis /maculosquamous/
– Alopecia
– Anorexia
– Lethargy, dysesthesias, seizure
– Hypotonia, myoclonus, myalgia
– Metabolic acidosis/ organic aciduria
• Detection
– Serum biotin level; normal ~1500 pmol/L
– Radioligand assays labeled avidin
• Treatment: biotin
– oral 0.2-10 mg/d, i.v. 0.15-0.3 mg
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Biotin Deficiency
• Biotin deficiency - defect in metabolism of long-chain fatty acids
- seborrheic dermatitis and alopecia
RAT
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Conclusions
• Diagnosis of deficiency can be difficult
• History is a key to diagnosis of vitamin deficiency
• Blood tests are important in diagnosis
• The majority of patients with unclear diagnosis should
receive vitamin supplementation
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