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Minerals ,trace elements and vitamins Karel Kotaska Minerals 1. Macronutrients building of the systems (water, proteins, fats, sacharides, lipids) C, H, O, N, S 2. Dietary important minerals (More than 100 mg /day) Ca, P, Mg, Na, K, Cl 3. Trace elements Cr, Co, Cu, Fe, Mn, Mo, Zn, Se, I, F 4. Added elements (not essential for human) Ni, Si, Sn, V, B, Li 5. Toxic ELEMENTS Pb, Hg, Cd Minerals TRACE ELEMENTS AND MINERALS • Transport mechanisms of trace elements – – – – – albumin - Cu, Zn transferin - Fe, Cr, Mn, Zn aminoacids - Cu, (Fe in small amount) transcobalamin - Co globulins - Mn TRACE ELEMENTS AND MINERALS • Elimination of minerals and trace elements – – – – – Bile – Cr, Cu, Mn, Zn Urine – Co, Cr, Mo, Zn pancreatic juice - Zn sweat - Zn mucotic tissue – Fe, Zn Trace elements Main biological functions - catalysers of various chemical reaction, parts of metalloproteins - modulation of enyzmatic activities in inermedial metabolism of aminoacids, lipids and sacharides - Structural function in various cell components (nuclear proteins, DNA, membranes) Trace elements - RDA RDA per os (men) Zn Fe Cu Se Mn Cr Mo J F Parenteral RDA USA UK EU 11 9,5 9,5 3,2 - 6,5 168 145 145 50 - 100 8 8,7 9,0 1,2 µmol 143 155 161 20 mg 0,9 1,2 1,1 0,3 - 1,3 µmol 14 19 17 5 - 20 µg 55 75 55 30 - 60 µmol 0,7 1,0 0,7 0,4 - 0,8 mg 2,3 1,4 1-10 0,2 - 0,3 µmol 42 25 18-182 3-5 µg 35 > 25 10 - 20 1-4 > 0,5 0,2 - 0,4 µg 45 50 - 400 19 µmol 0,5 0,5 - 4,2 0,2 µg 150 140 130 131 µmol 1,2 1,1 1,0 1 mg 4,0 0,05/kg (children) 0 - 0,95 µmol 210 2,6/kg (children) 0 - 50 mg µmol mg µmol Preanalytical aspects of trace elements investigation Sample storage and collection Blood -Avoid contamimation -Commonly used syringes can contamine sample with Fe, Mn, Ni, Cr and K - Special collecting systeme with silicone coated syringes - Zinc contamination if rubber cups are used - Zn is about 5 to 15 % elevated in serum - is released from erythrocytes during clotting -hemolysis, elevation of Fe, Zn and Mn Preanalytical aspects of trace elements assays Urine - collection into polyethylene (PE) tubes (including PE caps) - tubes are before use added 24 h in 10% nitric acid, immediately before use tubes are washed by deionised water Hair - hair are collected from the top of the head (0,5 g) into PE bags or paper envelopes - Before assays are hair are washed according to the WHO guidelines (acetone, water 3x, acetone). Preanalytical aspects of trace elements assays Sample storage - Urine, blood 3 days in 4C, 1 year at -20C, - hair, nails after drying in closed PE tubes at room temperature - Stabilization of samples by using HCl or HNO3 absolute (1% v/v) in some assays Sample contamination - is inevitable to use superclean reagents and water Most important analytical procedures for investigattion of trace elements ● ● ● ● ● ● ● ● ● ● ● ● Atomic absorption spectrometry with electrotermic atomization (ETA-AAS) Flame atomic absorption spectrometry (FAAS) AAS ICP-AES P-AFS ICP-MS NAA XRFS Voltammetry Polarography Immunochemistry ISE Copper Copper Copper • Absorption in gut – metallothionein (Cu2+ is insoluble). Intracelular protein involved in Cu metabolism (distribution and cellular utilization of Cu). • Ceruloplasmin (CP) - glycoprotein, Cu-dependent feroxidase – bond 6 – 7 Cu atoms – 80 - 95% total plasma Cu , – oxidation of Fe2+ to Fe3+ during iron absorption in GIT Copper Wilson disease – autosomal recesive disease – Cu is not bind to apoceruloplasmin • Low serum or plasma Cu • Loss of Cu - liver impairment, mental retardation • Ceruloplasmin where Cu is missed does not acts as feroxidase. Menkes disease – X-linked disease –impaired Cu absorption in intestine. Signs: – decreased Cu absorption, – increased concentration of Cu in urine and abnormal cellular transporttwisted of the hair, arterial wall defect, delayed development, spasms Childhood, early death (3 years of age) Copper Iron Iron metabolism Iron Hemochromatosis – genetic disease • Increased Fe absorption (2 – 3 mg/day instead of 1 mg) increased Fe accumulation in tissues • Middle aged men, in women signs occur 10 -15 years later Symptoms Liver cirrhosis, hepatomegaly, DM 2. type, arthropaties, bronze skin Iron Hemosiderosis • Hemosiderin - micelar form of Fe after feritine degradation • Thalasemia and erythrocyte impairment • Prolonged alveolar bleeding - Fe is accumulated in macrophages • Lung fibrosis Iron Reference values 0 - 6 weeks 6 weeks - 1 year 1 - 15 years 11,0 - 36,0 µmol/l 6,0 - 28,0 µmol/l 4,0 - 24,0 µmol/l males 15 - 60 years 90 - 150 years 7,2 - 29,0 µmol/l 7,0 - 23,0 µmol/l Females 15 - 60 years 90 - 150 years 9,0 - 28,0 µmol/l 6,0 - 24,0 µmol/l Molybdene Important for various metalloenzymes : – xantinoxidases – aldehydoxidases – sulfitoxidases Molybden cofactor • Dietary molybden intake interferes with Cu – less utilization of CU in organism). Manganese • Increased concentration in mitochondria • Activation of glycosyltransferases • Inevitable for superoxiddismutases and also other enzymes : – – – – hydrolases kinases dekarboxylases transferases Mn deficiency increases concentration of glycoproteins and proteoglycans Zinc Zinc Zinc • Important for nucleic acid synthesis • Zn/Cu-superoxiddismutase – antioxidation processess • Immunity – T lymfphocytes differentiation • Correct gonadal function • Deficiency – decreased intake – systemic disorders Zinc • Acrodermatitis enterohpeatica Reference values: 0 - 6 weeks 6 weeks - 60 years 60 - 90 years 90 - 150 years 9,1 - 13,7 µmol/l 9 - 16 µmol/l 9,6 - 16,4 µmol/l 8 - 15,1 µmol/l Zinc Reference values in various biological materials Cobalt • Part of cobalamine – vitamin B12 (pyrrolic core). • Absorption in gut and incorporated in B12 Selenium • Important part of glutathionperoxidase – protection against peroxidation, oxidative stress, UV light, important for metabolism of xenobiotics Selenium • Thyronine deiodinase - metabolic regulation of thyroid hormones 3 types of deiodinase Type I – 5´ deiodination Type II - T4 toT3 deiodination Type III – deiodination of T4 toT3 and T3 to T2 Selenium • Translation tRNA – proteins - lenghthening of polypeptide chain Selenium Importance of Se in immune systeme – Lack of Se decrease T-lymfocytes function – Decrease ability of antibody formation Se poisoning – hemolytic anemia, degenerative changes in parenchyme, hemosiderosis Selenium Reference values 6 months - 1 year 1 - 15 years 15 - 60 years 18 - 101 µg/l 58 - 121 µg/l 74 - 170 µg/l Chromium Regulation of glucose and lipid metabolism Glucose factor (GTF) – control of glycemia, complex of Cr with nicotinic acid and Gly,Glu, Cys - binding of glucose to receptors Fluoride •Anorganic matrix teets and bones •Lack - osteoporosis, karies Iodine thyreoid hormons Lack of iodine - goiter Borone utilization of Ca, Cu, Mn, N, glucose and triacylglycerols stabilization of biomembranes – inhibition of energetic metabolism and immune system burning) (respiration Vitamins Vitamins RDA -vitamins Vitamin Males Females A Retinol (mg) 1,00 0,80 pregnancy (after 4. month) 1,10 Elderly 1,50 Parenteral intake/24 hrs 1,00 B1 Thiamin (mg) < 50 years 1,5 1,1 > 50 years 1,2 1,1 Parenteral intake/24 hrs 100 µg/100 kcal of diet B2 Riboflavin (mg) < 50 years 1,7 1,3 > 50 years 1,3 1,1 Parenteral intake/24 hrs 3,6 RDA -vitamins Vitamin Males Females B3 Niacin (mg) < 50 years 19 16 > 50 years 15 14 Parenteral intake/24 hrs 40 B6 Pyridoxin (mg) 0,016 - 0,020 mg of B6/g of protein < 50 let 2,0 1,6 > 50 let 1,7 1,7 Parenteral intake/24 hrs 4,0 B7 Biotin (µg) < 50 let 30 - 100 > 50 let 30 Parenteral intake/24 hrs 60 RDA -vitamins Vitamin Males Females B12 CN-kobalamin (µg) < 50 years 2,0 > 50 years 2,4 Parenteral intake/24 hrs 5,0 vitamin C (mg) < 50 years 100 60 > 50 years 90 75 Parenteral intake/24 hrs 100 D vitamin D3 (mg) < 50 years 0,005 0,005 > 50 years 0,015 0,010 Pregnancy Parenteral intake/24 hrs 0,005 0,005 RDA -vitamins Vitamin Males Females E Tocopherols (mg) < 50 years 10 8 - 10 > 50 years 15 15 pregnancy 13 Parenteral intake/24 hrs 10 K vitamin K1 (mg) < 50 years 0,080 0,065 > 50 years 0,060 0,060 Pregnancy Parenteral intake/24 hrs 0,060 0,150 RDA -vitamins Vitamin Males Females Carotenoids beta-carotene (mg) 1,6 Folic acid (mg) < 50 years 0,20 0,18 > 50 years 0,40 0,40 pregnancy Parenteral intake/24 hrs 0,60 0,40 Pantothenic acid (mg) < 50 years 4–7 > 50 years 5 Parenteral intake/24 hrs 15 Reference values Males Females Vitamin A Retinol Serum - adults 1,05 – 2,27 µmol/l 0,83 – 1,75 µmol/l Serum - newborns 1,22 – 2,60 µmol/l Serum - choldren 1,05 – 2,80 µmol/l B1 Thiamin Serum < 0,075 µmol/l B2 Riboflavin Whole blood 0,361 – 1,770 µmol/l serum 0,133 – 0,478 µmol/l B3 Niacin Serum 2 – 12 mol/l Whole blood 16 – 73 mol/l Reference values Males Females Vitamin B6 Pyridoxin Serum 0,106 - 0,638 µmol/l Plazma > 0,243 µmol/l Erytrocytes 0,266 -1,330 µmol/l Urine > 0,320 µmol/l/d B7 Biotin Serum/plazma 0,15 - 0,37 µmol/l Urine 0,03 - 0,25 µmol/l B12 CN-kobalamin Serum - newborns 0,118 – 0,959 nmol/l Serum - adults 0,162 – 0,694 nmol/l Serum - pregnancy < 0,125 nmol/l vitamin C Plazma Leukocytes 34 - 114 µmo/l 8 20 – 53 µg/10 leukocytes (1,14 – 3,00 fmol/leukocyte) Reference values Males Females Vitamin D vitamin D3 Serum - children: 1,25 (OH)2 0,075 – 0,175 nmol/l Serum - adults: 1,25 (OH)2 0,050 – 0,200 nmol/l Serum - summer - adults: 25–OH 50 – 300 nmol/l Serum - winter - adults: 25–OH 25 – 125 nmol/l Serum - summer – healthy (95% CI): 25–OH 41,6 - 192,4 nmol/l E Tocoferol Serum - 0 – 1 month 8 – 28 µmol/l Serum - 1 – 6 months 10 – 31 µmol/l Serum - 6 months – 6 years 20 – 30 µmol/l Serum - adults 19 - 35 µmol/l Reference values Males Females Vitamin K vitamin K1 Serum 0,3 – 2,64 nmo/l Carotenoids beta-carotene serum: beta-carotene 0,93 - 3,72 µmol/l Folic acid Serum - adults > 0,0135 µmol/l Erythrocytes - adults > 0,360 µmol/l Serum - newborns 0,016 – 0,072 µmol/l Panthotenic acid Serum 4,7 – 8,4 µmol/l Vitamin A and carotenoids retinol, all-trans-3,7-Dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)2,4,6,8-nonatetraen-1-ol C20H30O Mh: 286,4 Sources – liver, milk products and fat fishes, yolk, yellow and orange vegatable, dried apricots, leafy vegetable - in plazma bind to retinol binding protein (RBP). -Carotenoids are bind coupled with LDL, HDL and lipoproteins - 80-90 % stored in liver -beta-carotene is converted to vitamin A by enzymatic oxidation (A) all-trans retinol, (B) all-trans retinaldehyde, (C) all-trans retinoic acid, (D) retinylphosphate Vitamin A and carotenoids Vitamin A and carotenoids Vitamin A and carotenoids Functions ● retinal fotoreception ● epitelial dysfunction ● lipoprotein and subcellurar integrity ● lysosomal stability ● Act on the steroid and glykoprotein syntehsis ● Main component of reproductions and embryogenesis ● Tissue proliferation and diferetiation ● Imunological integrity ● Gene expression, cancerogenesis ● Bone growth ● antioxidants Target organs - Liver tissue (fyziological storages for 2 years). - capacity is decreased in liver diseases, zinc defficiency (inevitable for Zn mobilization) and alcoholism. Vitamin A and carotenoids Resorption - in duodenum relevant to amount of fats, proteins, bile acids and pancreatic lipase - Esters dissolved in fats and emulgated in bile are hydrolyzed in intestine to retinol and are absorbetd to intestinal epitelia where retinal is formed - Incorporated into LDL and HDL and stored in liver adipocytes. Deficiency symptomes - gloomy, xerophtalmia tongue inflammation, folicular hyperkeratosis or ichtyosis, Keratinization of epitelial cells in respiratory, gastrointestinal and genitourenal tract xerodermia, karies, lack of appetite. Impaired immunity (low activity of T lymphocytes) Vitamin A and carotenoids Toxicity Doses above 20x normal values for children and more 100x for adults. Signs of toxicity - Alopecia, anemia, head aches, dermatitis, diplopia, hepatomegalia, hypercalcemia, hyperlipidemia, irregular menstruation, insomnia, patological births, bone disorders, liver dysfunction, spontaneous abortions, vomitting. Elevated levels Diabetes mellitus, hepatomegaly, idiopathic hypercalcemia in children, hypercholesterolemia, hyperlipidemia, hypervitaminosis A, vitamin A intoxication, chronic renal diseases, pregnancy. Decreased values cystic fibrosis, hepatitis, hypothyreosis, kwashiorkor, malabsorption, malnutrition, nefritis, fat absorption diseases, growth impairment, sprue, carcinoid, gloomy, xerophtalmia, tuberculosis. Vitamin A and carotenoids Interfering factors causing decreased values Alcohol, drugs (allopurinol, cholestyramin, diethylstilbestrol, neomycin). Biochemical interactions of vitamin A intake In serum In urine 2+ ↑ ALP, bilirubin, Ca , glucose, prothrombin ↑ urine volume time ↓ erythrocyte count, hemoglobin, hematocrit, leucocyte count, parathyrine Therapeutic dosing ● ● ● Gloomy Acne Oncological diseases prevention and therapy (i. e. promyelocytic leukemia) Vitamin D vitamin D3 - cholecalciferol Two equivalent forms C27H44O Mh: 384,6 CAS: 67-97-0 vitamin D2 vitamin D3 synonymum ergocalciferol cholecalciferol precursor ergosterol 7-dehydrocholesterol synthesis syntetic (UV) Skin (UV) ergokalciferol contains double bond between C22-23 and additional methylic group on side chain Vitamin D Vitamin D metabolism Vitamin D Vitamin D regulation Sources -Fishes (mackerel, tuna, herring), yolk, liver, milk, butter - Concentrations of vitamin D and metabolites in serum oscillate according to the season (UV light) and dietary intake Vitamin D Other vitamin D regulation Vitamin D3 (active) Vitamin D2 (inactive) Vitamin D vitamin D3 and gut -Stimulation of calcium excretion without relationship to PTH. -Synthesis and phosphorylation of (CaBP) by proteinkinases and calcium transport activation in enterocytes vitamin D3 and bones - Colagen matrix induction and proliferation - if Ca level is decreased, then vit D3 stimulates bone rsorption and osteoclast and mobilizes Ca without relationship to PTH - Vit D deficiency in childhood and adult results in rachitis and osteomalatia - Therapeutic dosing of vitamin D during parathyreoideal impairment could lead due to decreased calcium reabsoprtion in kidney to elevated concentrations of calcium in urine and high risk of nephrolitiases and nephrocalcinosis. Vitamin D Vitamin D3 and kidney - increase of 24-hydroxylase activity. - increase of syntesis less active 24,25(OH)2 vitamin D3 and loss of 1,25(OH)2 vitamin D3 production -Stimulation of CaBP expression – increased Ca and P reabsorption in dist al and proximal tubule Vitamin D3 and parathyreoid glands -1,25(OH)2 vitamin D3 decreases PTH synthesis Vitamin D Other functions of 1,25(OH)2 vitamin D3 - Control of proliferaton and diferentiation of normal and tumor cells - Induction of production and maturation of IL-1 - Deficiency elevated the prevalence and severity of autoimmune diseases (multiple sclerosis, arthritis, juvenile diabetes), increased risk of tuberculosis - Inhibition of proliferation and stimulation fibroblast and kearatinocytes differentiation - Importance in maturity and function of hair folicules - Regulation of muscle contractility . - Increased acumulation of Ca2+ - Important in reproductive function - Neuroprotective efect - Decreases calcitonin production, increase of insulin secretion and synthesis - Activation of adenohypophyseal hormones Vitamin D Elevated 25-OH-D levels with s hypercalcemia - iatrogenic vitamin D intoxication Decreased 25-OH-D levels Depletion cause (= indication to 25-OH-D investigation) low offer Low diet, UV light insufficiency Impaired absorption malabsorption low hydroxylation chronic hepatocelular lesion and cholestasis Renal loss Nephrotic syndroma complex iatrogenic anticonvulsives loss of vit D-binding protein Vitamin E (tocopherol) alfa-tocopherol, 2,5,7,8-Tetramethyl-2-(4',8',12'-trimethyltridecyl)-6-chromanol tocol R1 R2 R3 Mh Tocopherol alpha 5,7,8-trimethyl CH3 CH3 CH3 C29H50O2 430,7 beta 5,8-dimethyl CH3 H CH3 C28H48O2 416,7 gama 7,8-dimetyl H CH3 CH3 C28H48O2 416,7 delta 8-methyl H H CH3 C27H46O2 402,7 - tocol H H H - - Vitamin E reabsorbed in small intestine (35 %), then s incorporated to chylomicrons and transported to tissuues contains lipoporitein lipases - - Stored in fats (in mitochondrial phospholipides, endoplasmic reticulum and plasmatic membrane of erythrocytes and respiratory tract cells) - Excreted in liver (70 – 80 %) during 7 days, 20 – 30 % in urine (tocoferic acid and gama lacturonides) Vitamin E Functions ● Organism protection against the free oxygen radicals leading to vit A oxidation and DNA damage ● Synergistic function with Selenium ● Mutagenic inhibition in GIT ● Membrane integritiy of neurological cells ● Erytrocyte protection against hemolysis ● Deficiency leads to increased concentration of lipoperoxidic substances and to the cell membrane damage with cell death ● Therapeutic dosing before cardiovascular and reperfusion procedures Vitamin E Antioxidant functions Vitamin E Deficiency ● ● ● ● anaemia, short life of erythrocytes increased thrombocytal agregability morphological changes of peripheral neurons decreased of serum creatinine concetration with increase of renal creatinine excretion Prolonged deficiency ● ● ● ● ● ● muscle myopathy and necrosis inclusion in reticuloendothelial cells in bone marrow Hypo- aand areflexia Spinocereberal ataxia Myopathy Retinopathy Vitamin E Elevated serum vitamin E concentrations - Hyperlipidemia, liver fibrosis, increased dietary vit E intake , pregnancy, renal failure Decreased serum vitamin E concentrations - Abetalipoproteinemia, hemolytic anemia, celrebellar ataxia, bile tract atresia, coeliac disease, chronic cholestasis, liver cirrhosis, enecefalomalatia, enteritis, gluten enteropathy, cystic fibrosis, hemolysis, malabsorption, pancreatic tumors, peripheral neuropathy, chronic pancreatitis, premature delivery, imbalances in lipid resorption Vitamin E Interfering factors decreased serum vitamin E concentrations ● drugs (anticonvulsives, ethanol, phenobarbital, phenytoin, cholestyramin, carbamazepine, clofibrate). Biochemical interaction of vitamin E - Urine aminolevulic acid, uroporphyrin Sources Sprouting corn (wheat) cotton oil , poppy, nuts, yolk Toxicity gastrointestinal problems, fatigue, headache, muscle weakness , coagulation defects (together with Vitamin K deficiency). Vitamin K vitamin K1 C31H46O2 Mh: 450,7 vitamin K3 (menadione) Esential cofactor acts in posttranslational carboxylation of glutamic acid -Important in coagulation factors (II, VII, IX a X ) and other important proteins (protein C, protein S (Protein S free, Protein S total) -Reaction is inhibited by anticoagulant substances (warfarin) For this reason is Vitamin K1 specific antidotum of oral anticoagulants (dicumarols). vitamin K1 (phyloquinone) Vitamin K Vitamin K -Resorption in intestine (10 – 80 %), bile, pancreatic enzymes and correct fat absorption is necessary - Absorption in lymph, late is transported to liver and other tissues. Liver stored phylocinones (10 % ) and menachinones (90 %) -Excretion – bile, urine (60 - 70 % of phyloochinones is excreted in urine and faeces during several days) Symptoma of defficiency Petecchia, bleeding Vitamin K Sources - green leaves vegetable, vegatable oils. - Menachinones are in ferrmented diets (cheese, yoghurts) and ruminant livers Therapeutic indications ● ● warfarine intoxication anticonvulsives (phenobarbitalu, diphenylhydantoin) in pregnancy Deficiences ● ● ● ● lipid malabsorption drug interaction high doses of vitamin A and E liver fibrosis Signs of defficiency ● bleeding (from petecchia to infaust hematemesis, melena, hematuria, hematoma) Vitamin K Prolonged deficiency ● ● ● ● ● ● ● liver diseases chronic pancreatitis sprue bile diseases, cholestasis coeliac disease inflammatory gut diseases antibiotic therapy of gut infection Possible reasons of decreased serum values ● ● ● ● ● ● ● ● ● ● diarrhoea, cystic fibrosis, hypoprothrombinaemia, chronic diseases treated by antibiotics chronic lipid malabsorption breast milk poor to vitamin K, hemorhagic disease of newborns, obstructive hepatitis, gastrointestinal tract diseases pancreatic diseases, liver, hemorrhagic diseases Vitamin K Interfering factors decreasing serum concentrations drugs – (vitaminu K antagonists, antibiotics, anticoagulants, cholestyramin, hydantoins). Vitamin K supplementation can affect various biochemical parameters: in serum In urine bilirubin (newborns), catecholamines proteins 17-hydroxycortikosteroids, erytrocytes porphyrins Vitamin C L-ascorbic acid, L-Threoascorbic acid, vitamin C C6H8O6 Mh: 176,1 (A) Ascorbic acid, (B) Dehydroascorbic acid Source Orange fruits and juices, strawberries, wild roses, parsley tops, black currant, horsereadish, vegetables, potatoes. Vitamin C Storage in organism are to 35 – 40 days Reference values vitamin C in serum: 34 - 114 µmo/l vitamin C in leukocytes: 20 – 53 µg/108 leukocytes (1,14 – 3,00 fmol/leukocyte) Daily changes in serum is around 25 %, higher concentration – early morning, during day slight decrease, maximal elevation – summer, minimal – winter, in women – maximal elevation during ovulation Low concentrations in serum Alcoholism, anemia, febrilia, hemodialysis, hyperthyreoidism, smoking, malabsorption, Tumors, obesity, acute and chronic inflammatory diseases, rheumatoid diseases, lead Poisoning, high diet intake of Fe, scurvy, steatorhea, stress, pregnancy Low concentrations in leukocytes: Gastroduodenal diseases, post operations Vitamin C Elevated demand of vitamin C ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● pregnancy, breast feeding (vitamin C is transported to breast milk) surgical treatment, polytrauma, burns tumors, x ray parenteral diet high vitamin E dosage smoking prolonged stress chronic infection prolonged expozition to cold hyperthyreosis hemodialysis HIV alcoholism poisning skin diseases atherosclerosis Vitamin C Vitamin C in diet can effect several biochemical parametres In serum ↑ oxalate ↓ TG ↓ uric acid In urine ↑ glucose (false elevation) ↑ hemoglobin ↑ uric acid crystals – cystin, oxalaty, urates In faeces ↑ blood Vitamin C Drug interaction high vitamin C could decrease pH in urine and affect renal tubular reabsorption of acid and basic drugs high doses intract with disulphiram –alcohol interaction Doses more than 10 g of vitamin C can decrease coumarin anticoagulants in GIT Plasma concentration of vit C is decreased by acetylsalicylate, aminopyrine, barbiturates,.p.o. kontracepties with estrogene. Toxic effects Extremely high doses (5 – 15 g/day) - sleeplessness, diarhoea, nausea, stomach spasms, eczema long time – osmotic diuresis Vitamin B1 (Thiamin) vitamin B1 x HCl, thiaminpyrophosphate (TPP) is cofactor C12H17ON4S× HCl Mh: 337,3 -Act in saccharide metabolism (glycolysis, pentosa-phosphate cycle, pyruvate – alpha oxo glutarate change) -Transketolase/transaldolase oxidative carboxylation affect periferal and central nervous systeme functions and heart cells function - Absorption in upper part of small intestine Vitamin B1 (Thiamin) Deficiency symptoms Polyneuritis (beri-beri) -Dried form of beri-beri –neurological impairment (peripheral nerves, sensoric and motoric impairment in legs, parestezia, weaknesses) -Wet form of beri-beri – dyspnoea, hepatomegaly, heart ailment, tachycardia, generalized oedema, oliguria, ketone accumulation, lactate acidosis due to hypoxia, metabolic acidosis -Alcoholism - Wernicke encephalopathy (confusedness, ataxia, nystagm, ophthalmoplegia) Vitamin B1 (Thiamin) Decreased serum levels Alcoholism, megaloblastic anemia, beri-beri, dementia, diabetes mellitus, subacute necrotic encephaloalopathy, prolonged hyperalimentation, lactation, dialysis, periferal neuropathy, diarrhoea, feever, chronic liver diseases, impaired pyruvate oxidase activity, heart ailment, hyperthyreosis, pregnancy,tumors, impaired dietary intake, excessive tea drinking. Interfering factors decreasing serum concentrations Drugs (barbiturates). Elevated serum levels Hodgkin disease, leukemia polycythemia vera. Sources Yeast, bran, liver, rolled oats, rice, nuts, buckwheat, asparagus, black bread, wheat sprouts, potatoes, beans. Vitamin H (Biotine) Biotin, vitamin B7 C10H16O3N2S Mh: 244,3 Sources yolk, liver, soya, chocolade,cauliflower, wheat, pea, yeast, sea fishes. Basic metabolic functions -Carboxylation - Carboxyl bond to N1 biotin is forming active intermediate carboxybiotin-enzym (HCO3-, ATP, Mg2+ and acetyl-CoA). Vitamin H (Biotin) Function - carboxylation ● ● ● ● ● ● ● ● ● acetyl-CoA, propionyl-CoA, pyruvate, fatty acid synthesis, PUFA metabolism propionic acid oxidation, leucine oxidation gluconeogenesis, catabolism of branched aminoacides cholesterol metabolism cell growth - decreased of muscle pain, ihibits hair greying and falling, improve nail quality, helps in skin diseses Vitamin H (Biotin) Deficiency symptomes rare anorexia nausea, vomiting paleness muscle pains dried skin, hair falling elevated cholesterol and bile acids concentrations ● depression ● ● ● ● ● ● Important demand ● ● ● ● alcoholism patients after gastrectomia burns pregnancy and breast-feeding Low serum values ● inborn metabolic disorders (-methylkrotonate, -hydroxyisovalerate, -hydroxypropionate), ● prolonged parenteral diet Pyridoxin (Vitamin B6) Pyridoxin pyridoxal, vitamin B6, pyridoxalphosphate (PLP) C8H9O3N Mh: 167,2 (A) pyridoxin, (B) pyridoxal, (C) pyridoxamine, (D) pyridoxic acid Pyridoxin (Vitamin B6) Active vitamin B6 forms and metabolites Water soluble vitamin, syntetized in pllants and microorganisms, termal unstable Pyridoxin (Vitamin B6) Transport and metabolism Pyridoxin (Vitamin B6) Function ● ● ● ● ● ● ● ● ● ● ● enzymatic reactions tryptophane conversion to nicotinic acid and sfingosin synthesis glykogenphosphorylase activation in delta aminolevulic acid synthesis DNA and heme synthesis niacin synthesis (from tryptophan) synthesis of neurotransmitters (serotonine, dopamine, noradrenaline, GABA) taurine synthesis myelin synthesis hormone modulation effects heme synthesis immune functions Pyridoxin (Vitamin B6) Pyridoxin (Vitamin B6) Sources yeast, wheat sprouts, black bread, bananas, potatoes, nuts, sunflower seeds, buckwheat,bran, harsh rye flower, meat (chocken, fish, liver), legumes Deficiency symptoms - sideroblastic anaemia, - inborn apoenzyme abnormalities coupled with pyridoxal phosphate (newborn mental retardations, skelet deformities, thrombosis, osteoporosis, aminoacidurias, vision impairment) - elevated homocysteine levels in adults - eye corners and mind corner infections, folicular hyperkeratosis (= increased keratin production and increased growth of skin cells around the hair pouches) Pyridoxin (Vitamin B6) Increased utility: hyperthyreosis, chronic infections Indications to suplementation (doses up 300 mg during 6 months): ● vitamin B6 deficiency ● isoniazid therapy prophylaxion (10 – 20 mg/100 mg of isoniazide) to suppress neurotoxicity ● homocystinuria, homocysteinemia ● sideroblastic anemia due to vitamin B6 deficiency ● adjuvant therapy of vomiting during gestation (50 – 80 mg/day). ● carpal tunnel syndroma Decreased serum concentrations - chronic alkoholism, sideroblastic anemia, asthma bronchiale, diabetes mellitus in gestation, dialysis, acute myocardial infarction, smoking, lactation, leukemia, malabsorption and malnutrition, pelagra, preeklampsia,renal failure, pregnancy, uremia Pyridoxin (Vitamin B6) Interfering factors decreased serum pyridoxine concentrations: Amiodarone, anticonvulsives, carbamazepine, cyclosporiny, disulfiram, ethanol, hydralazine, isoniazide, L-dopa, oral contraceptives, penicilamine, phenobarbital, phenytoin, primidon, teophylin, tricyclická antidepressants Excess Sensoric neuropathy Pantothenic acid Coenzyme A (CoA), CoASH - hydrolyzed in intestine and reabsorbed by gut C9H16O5NNa Mh: 241,2 - 70 % is eliminated in urine - coenzyme A and esters - essential in lipid and sacharide metabolism Sources -Animal products, grains, vegetables, syntetized in human intestinal mucosa Pantothenic acid Pantothenic acid Function ● ● ● ● energy release from saccharides, lipides and ketonic aminoacids heme and sterol synthesis acetylation and gluconeogenesis importance in lipid synthesis Deficiency symptoms (rare) ● ● ● ● ● ● ● ● burning foot syndroma (impaired acetylation capacity) hearing impairment fatigue, and depression sleep disorders neurocirculation diseases renal impairment worsened wound healing immune disorders, relevance to infections Pantothenic acid Therapeutic importance ● chromic malnutrition ● prolonged catabolism ● ethanol intoxication Low serum levels occur in: ● ● ● ● ● mental anorexia, immunodeficiency sepsis malabsorption syndroma prolonged parenteral nutrition Niacin (Vitamin B3) Nicotinic acid, nicotinamide, vitamin B3, NAD+, NADP+, NADH, NADPH C6H5O2N Mh: 123,1 - absorbed from stomach and small intestine - oxidation metabolism, coenzymes,H+ transportation - target tissues – muscles and liver svalovina. Sources (A) nicotinic acid, (B) nicotinamide, (C) nicotinamide adenine dinukleotide phosphate - Meat (liver, tuna fish, poultry), - Sunflower seeds, peanuts, black bread, legumes, yeast Niacin Niacin cofactors Functions oxidation-reduction reaction citrate cycle saccharide metabolism synthesis and oxidation of fatty acids cellular metabolism vasodilatation NAD and NADPH coenzymes hydrolyzed NAD takes part in DNA replication ● total cholesterol to LDL transformation ● DNA reparation ● apoptosis ● ● ● ● ● ● ● ● Niacin Niacin excretion NAD synthesis Niacin Niacin defidciency Pelagra - „three D disease": dermatitis, diarrhoea, dementia. ● gastrointestinal signs due to inflammation in vomititng and diarrhea ● pigment rash in UV light impact ● depresion, irritability, deyorientation, halucination, catatonia Elevated niacine levels (overdosing): ● ● ● ● ● ● vasodilatation (headache, nausea, vomitting) fulminant liver failure severe forms of hepatitis thrombocytopathia myopathy impaired sacharide tolerance during high dose treatment in diabetics Niacin Decreased serum levels -alcoholism, liver cirrhosis, dietary defficiency of niacin, Hartnup disease, leucine overdose, pelagra. Increased serum levels - pregnancy Interfering factors causing decrease of serum concentrations drugs - isoniazide increase - oral contraceptives Biochemical interactions: vitamin B3 dosing can affect some biochemic values: Serum ALP, ALT, apolipoprotein A-I, glucose, GGT, HDL-cholesterol, histamin, insulin, catecholamines, uric acid, growth hormone beta-lipoprotein, total cholesterol, LDL-cholesterol, P, phospholipids, pre-beta LP, TAG, VLDL cholesterol, FFA urine glucose, ketones, Na K Riboflavin vitamin B2, coenzymes FMN (flavinmononukleotide, riboflavinmonophosphate ), FAD (flavinadenindinukleotid, riboflavinadenosindifosfát) C17H20O6N4 Mh: 376,4 -flavinmononukleotide (FMN) or flavinadendinukleotide (FAD) are active forms - dehydrogenases and oxidases - redox processes (oxidative phosphorylation, synthesis and degradation of FA) - part of important enzymes (xantin oxidases, gluthathionreductases, amino acid oxidases Sources Cheese, egg, liver, meat, broccoli, parsley, yeast, milk products Riboflavin Riboflavin metabolism Riboflavin Riboflavin as cofactor Riboflavin Function - electrone transport in Krebs cycle oxido-redukction processes in aminoacids, sachcarides, purines and pyrimidines integrity of cell membrane and erythrocytes antioxidant function (glutathionreductase cofactor) detoxication of drugs and xenobiotics Deficiency symptoms corneal and conjunctival inflammation, neurologic diseases, ariboflavinosis – delayed growth and high risk of epitelial inflammation Decreased serum levels Chronic alcoholism, anorexia nervosa, coeliac disease, dermatosis, hypothyreosis, stress, infectious enteritis, conjunctivitis, malabsorption, tumors, low protein diet with high sacharide intake, bile duct obstruction, liver diseases, chronic diarrhoea, gut resection, dermatitis, pregnancy, sprue. Vitamin B12 alpha-(5,6-Dimethylbenzimidazolyl)cyanocobamide, CN-kobalamin, adenosylkobalamin (AdoCbl) a metylkobalamin (MeCbl) C63H88O14N14PCo Mh: 1355,4 -syntetized in microorganisms - target organs - liver (ca 50 %; 3 – 5 mg), muscles and kidney Sources - meat, liver, milk products, yeast droždí. - Cooking significantly eliminate B12 activity Vitamin B12 Active metabolites R Me- B12 CH3 Metylcobalamine AdoB12 5´deoxyadenosine Deoxyadenosylkobalamine OHB12 OH Hydroxykobalamine CN- B12 CN cyanokobalamine Active cofactors Therapeutic forms Deficiency Deficiency in diet or malabsorption, drug and alcohol interaction 4 stages ● ● ● ● decrease of plazma concentration decrease of intracelular concentrations metabolic impairment clinical manifestation of deficiency Vitamin B12 Signs of deficiency ● megaloblastic anemia ● pernicious anemia ● methionine metabolism disorders (impaired DNA synthesis with abnormal formation of nuclear erythrocytes – storage of megaloblasts in bone marrow) ● impaired purine and pyrimidine synthesis ● homocystinuria ● methylmaloate aciduria ● parestesia, orientation disorders due to impaired myelin synthesis ● confuseness, bradypsychie ● depression ● memory weakness Vitamin B12 Therapeutical efects ● parenteral application is not approved (anaphylactic reactions). ● in elderly substituion is questionable ● during substitutional therapy control of serum K, Fe, folate, hemoglobin, MCV, retikulocytes levels is necessary. ● thromboembolic complication in patients with heart ailment ● interpretace of vitaminu B12 concentration is related to folate concentration in erythrocytes • Schilling test is performed in cases of impaired vitamin B12 resorption (chronic gastritis, intestinal deficiency). ● Suspect defficiency is associated with increased methylmalonate and homocysteine excretion Vitamin B12 Functions ● ● ● ● ● ● ● ● ● ● ● antipernicious effect erythrocyte maturation neuronal function DNA/RNA synthesis cofactor cellular proliferation hemathopoiesis myeline synthesis nucleoprotein formation enzymatic reaction (metylmalonyl-CoA mutase, methylation) valine metabolism folate coenzyme recyclation Vitamin B12 Why investigate vitamin B12 levels? ● diferential diagnosis of megaloblastic anemias to avoid: CNS disorders, chronic stomach insuficiency with mucous athrophy after resection, intestinal parasitie diseases, chronic liver and kidney failure, in vegetarians Decreased serum levels Achlorhydria, alphaa-thalasemia, chronic alkoholism, anemia, dementia, divertikulotitis of the jejunum, cystická fibrosis, gastrectomy, chronic atrophic gastritis, delirium, hemodialysis, hypermetabolic states, hyperthyreosis, primary hypothyreosis, chronic pancreatitis, pankreatic insufficience, smoking, leukemia, malnutrition, multiple myeloma, intestinal tumors, drugs Vitamin B12 Elevated serum levels Liver cirrhosis, diabetes mellitus, liver dystrophia, acute and chronic hepatitis, induced cholestasis, leukemia, leukocytosis, protein malnutrition, myeloproliferative disorders, chronic renal failure, congestive heart failure, elevated erythrocyte count, tumors with liver metastases, uremia. Interfering factors increased serum concentrations drugs- anticonvulsives, estrogens, vitamin A, vitamin C. Intrinsic factor and vitamin B12 IF is secreted by parietal cells in upper part of the stomach - Inevitable role in vitamin B12 absorption from diet Macrocytic anemia Folate determination Vitamin B12 determination low B12 Normal B12 IF Ab investigatio n Pernicious Algorithm of B12 investigation Plasma tHcy tHcy > URL tHcy < URL Folate and vitaminu B12 in serum Folate > 7.5 nmol/l and B12 > 200 pmol/l No deficiency URL – upper reference limit Folate < 7,5 nmol/l Folate deficiency B12 < 200 pmol/l Vitamin B12 deficiency Folic acid Pteroyl-L-glutamic aqcid, vitamin M, tetrahydrofolate, 10-formyltetrahydrofolate, 5metyltetrahydrofolate C19H19O6N7 Mh: 441,4 -Active resorption in proximal part of small intestine - transport as free form or coupled with albumin -Resorption is associated with inteatinal mucose - target organ - liver Sources Yeast, leaf vegetable, nuts, liver, kidney, orange juice Structural forms Folic acid Folic acid Folic acid metabolism Folic acid Function ● methionin synthesis (synergy with B12) ● normal function of erythrocytes and leukocytes ● coenzyme in purine synthesis ● DNA synthesis ● conversion of homocysteine to methionine ● conversion of serine and glycine ● histidine degradation ● cellular growth and differentiation ● important role in lipid metabolism ● anticancerous efect ● neural tube deffects prevention (1 month before conception 4 – 5 mg of folic acid until the end of thirt month of gestation). Folic acid Deficiency symptoms -megaloblastic anemia -pernicious anemia in pregnancy -neural tube defects in pregnancy -cardiovascular diseases Signs of deficiency Macrocytic anemia, trombocytopenia, defects of digestion (tongue burn, mucosal inflammation, diarrhoea, ulceration), depression, psychic instability Folic acid Increased utility of folates ● ● ● ● alcoholism, wound healing and regeneration pregnancy energetic metabolism Therapeutic dosing of folate ● ● ● ● ● megaloblastic anemia malnutrition malabsorption alcoholism neurological diseases Folic acid Decreased serum levels Alcoholism, amyloidosis, anemia, anorexia nervosa, liver cirrhosis, coeliac disease, Crohn disease, vitamin B and C deficiency, dermatitis herpetiformis, diabetes mellitus, peritoneal dialysis, diabetic enteropaty, partial gastrektomy, hemodialysis, chronic hemolysis, hepatoma, starving, homocystinuria, hyperthyreosis, hypothyreosis, infectious diseases, breast feeding, leukemia, lymphoma, folate malabsorption, smoking,dermatitis, chronic heart disease Increased serum levels Vitamin B12 deficiency, transfusion vegetarianism Interfering factors decreasing derum concentrations Alcohol, aminopterine, ampicoilin, antiepileptics, antimalarics, azulfadin, barbiturates, cycloserin, erythromycin, estrogens,phenobarbital, fphenytoin, chloramfenicol, isoniazid, karbamazepin, oral contraceptives, acetylsalicilate, metformin, methotrexat, nitrofurantoin, penicillin, pentamidin, sulfasalazin, tetracyklin, triamteren.