1. 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

2. 2 JSS092000 Objectives To review Functions of water-soluble vitamins Symptoms and signs of vitamin deficiencies Treatment of the vitamin deficiencies

3. 3 JSS092000 The Location of Vitamin Absorption Preferentially absorbed in jejunum Fat-soluble vitamins Folate (Jejunum only) Vitamin B12 (Ileum only) Colon Thiamin Riboflavin Niacin Biotin

4. 4 JSS092000 B Vitamins Coenzymes in the same energy metabolic pathways Overlap in clinical symptoms of deficiency between B vitamins Cheilosis Glossitis Dermatitis

5. 5 JSS092000 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

6. 6 JSS092000 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

7. 7 JSS092000 Individuals at Risk for Thiamine Deficiency Alcoholics Calorie-protein poor diet Severe malnutrition Malabsorption Gastric bypass Chronic renal failure on HD Prolonged febrile illness

8. 8 JSS092000 Thiamine Deficiency Beriberi Wernicke-Korsakoff syndrome Leigh's syndrome

9. 9 JSS092000 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)

10. 1010 JSS092000 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

11. 1 JSS092000 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)

12. 1212 JSS092000 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)

13. 1313 JSS092000 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

14. 1414 JSS092000 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

15. 1515 JSS092000 Patients at Risk for Deficiency 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

16. 1616 JSS092000 Manifestations Manifestations 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

17. 1717 JSS092000 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

18. 1818 JSS092000 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

19. 1919 JSS092000 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

20. 2020 JSS092000 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

21. 2121 JSS092000 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

22. 2 JSS092000 PYRIDOXINE Dietary sources: –Meats, fish –Whole grains –Vegetables –Nuts Recommended daily requirements –Children0.6 mg –Female 1.6 mg –Pregnancy 1.9 mg –Male 2.0 mg

23. 2323 JSS092000 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

24. 2424 JSS092000 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

25. 2525 JSS092000 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

26. 2626 JSS092000 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)

27. 2727 JSS092000 Factors Affecting Vitamin B12 Absorption – Dietary intake – Acid-pepsin in the stomach – Secretion of IF by gastric parietal cells – Pancreatic proteases – Presence of ileum

28. 2828 JSS092000 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)

29. 2929 JSS092000 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

30. 3030 JSS092000 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

31. 3131 JSS092000 Hematologic Manifestations of Vitamin B12 Deficiency 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

32. 3232 JSS092000 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

33. 3 JSS092000 Manifestations of Vitamin B12 Deficiency Manifestations of Vitamin B12 Deficiency Glossitis –Beefy red tongue –Loss of taste Diarrhea, dyspepsia, anorexia Impotence Vaginal atrophy

34. 3434 JSS092000 Detection of Vitamin B12 Deficiency Detection of Vitamin B12 Deficiency Serum level of Vitamin B12 –Normal >400 pg/ml –Low <210 pg/ml  serum methylmalonic acid Schilling test

35. 3535 JSS092000 Schilling Test

36. 3636 JSS092000 Treatment of Vitamin B12 Deficiency 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)

37. 3737 JSS092000 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: 0.2-0.4 mg/d –Pregnancy/lactation 0.5-0.8 mg/d

38. 3838 JSS092000 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

39. 3939 JSS092000 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

40. 4040 JSS092000 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

41. 4141 JSS092000 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 %

42. 4242 JSS092000 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

43. 4343 JSS092000 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

44. 4 JSS092000 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

45. 4545 JSS092000 Vitamin C Deficiency Groups at Risk Poor dietary intake –Severely malnourished individuals –Drug and alcohol abusers –Poverty –Elderly, institutionalized pts.

46. 4646 JSS092000 Symptoms 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

47. 4747 JSS092000 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)

48. 4848 JSS092000 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

49. 4949 JSS092000 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

50. 5050 JSS092000 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)

51. 5151 JSS092000 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)

52. 5252 JSS092000 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

53. 5353 JSS092000 Biotin Deficiency Biotin Deficiency Biotin deficiency - defect in metabolism of long-chain fatty acids - seborrheic dermatitis and alopecia RAT

54. 5454 JSS092000 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