JSS092000

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 The Location of Vitamin AbsorptionAbsorption

Preferentially absorbed in jejunum Fat-soluble

vitamins

Folate (Jejunum only)

Vitamin B12(Ileum only)

Colon

ThiaminRiboflavinNiacinBiotin

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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 Individuals at Risk for Thiamine DeficiencyThiamine Deficiency

• Alcoholics• Calorie-protein poor diet• Severe malnutrition • Malabsorption• Gastric bypass• Chronic renal failure on HD• Prolonged febrile illness

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Thiamine DeficiencyThiamine Deficiency

• Beriberi

• Wernicke-Korsakoff syndrome                        • Leigh's syndrome

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Beriberi 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 Wernicke-Korsakoff SyndromeSyndrome

• 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 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 Patients at Risk for Vit. B2 Deficiency 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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ManifestationsManifestations of Vit. B2 Deficiency

• 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 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) active form– Pyridoxal (animal foods) Pyridoxal phosphate– Pyridoxamine (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 DeficiencyDetection 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)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 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 DeficiencyCauses 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 DeficiencyCauses 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 Vitamin B12 Deficiency Pernicious AnemiaPernicious 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 ofHematologic Manifestations of

Vitamin B12 DeficiencyVitamin 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 Neurologic Manifestations of Vitamin B12 Deficiency 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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ManifestationsManifestations

of Vitamin B12 Deficiencyof Vitamin B12 Deficiency

• Glossitis– Beefy red tongue– Loss of taste

• Diarrhea, dyspepsia, anorexia• Impotence• Vaginal atrophy

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Detection of Vitamin B12 DeficiencyDetection 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 TestSchilling Test

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Treatment of Vitamin B12 DeficiencyTreatment 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 AcidFolic 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: 0.2-0.4 mg/d– Pregnancy/lactation 0.5-0.8 mg/d

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Causes of Folate DeficiencyCauses of Folate Deficiency

Nutritional deficiency Poor dietary intake Alcoholism (37% of ETOH users)Elderly (10% in pts >75 years)

MalabsorptionSprueIBDGastric bypassShort bowel

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Causes of Folic Acid DeficiencyCauses 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 DeficiencySymptoms 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 CVITAMIN 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 Vitamin C ASCORBIC ACIDASCORBIC 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 CFunctions 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 DeficiencyVitamin C Deficiency Scurvy 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 Vitamin C Deficiency Groups at RiskGroups at Risk

Poor dietary intake– Severely malnourished individuals– Drug and alcohol abusers– Poverty– Elderly, institutionalized pts.

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Symptoms of Vitamin C DeficiencySymptoms of Vitamin C Deficiency

– 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 CVitamin 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 PANTOTHENIC ACID Vitamin B5 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 AcidDeficiency 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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BIOTINBIOTIN

• 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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BiotinBiotin

• 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 DeficiencyBiotin 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

• Biotin deficiency - defect in metabolism of long-chain fatty acids - seborrheic dermatitis and alopecia

RAT

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ConclusionsConclusions

• 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