11.10.2009 tracen.ppt 1
Trace elements
Lecture from pathological physiology
Oliver Rácz
2009
11.10.2009 tracen.ppt 2
Trace elements - overview
• The elements of life
• Current knowledge and unanswered questions
• Iron metabolism
• Zinc and copper
• Vanadium, nickel, molybdenium, cobalt
• Selenium
• Iodine and fluorine
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Elements of life
• Main biogenic elements - 6
– C, H, N, O, & P, S
• Electrolytes
– Na+, K+, Mg++, Ca++ against Cl- (?)
• Trace, < 1 g with two exceptions
– metals: Fe, Zn, Cu, Mn, Mo, Cr, Co, V, Sn
– most of them transition metals (complexes)
– nonmetals: F, I, Se, Si, B
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Elements of life - be careful!
• Not the same as the elements found in human body:
– As, Au, Pb, Hg….(contaminations)
• Strong selection:
– Earth crust - O, Si, Al, Fe, Ca
– Sea water ? Sea when life was arising ?
– Element composition of plants resembles that of soil
• Life is „easy“ - first half of Mendelejev table,
only 4 with atomic No > 30: 34Se (79) ,42Mo (96), 50Sn (119), 53I (127)
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Trace elements - current
knowledge - 1
• Composition of body, tissues, cells, O.K.
• Form - metals only as complexes!
– Stable complexes are well known (heme,
molybdopterin, etc.)
– Less stable complexes are hard to study
– Added to biochemical structures after their
synthesis - with exception of Se
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Trace elements - current
knowledge - 2
• Cycles in biosphere - natural & influenced by
human activity (ecology) ⇒ influence on health
• Cycles in human body - many unanswered
questions
• Clinical chemistry
– Only iron status is routinely assessed
– Plasmatic levels do not reflect metabolism
– Indirect markers - e.g. GPX for Se
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Essential or toxic ?
+-------------------------------------------------- -------------------+¦ ¦ BIOGÉNNE PRVKY ¦ ¦¦ +-----------------------------------------+-- -------------------¦¦ ¦ HLAVNÉ ¦ELEKTROLYTY¦ STOPOVÉ ¦ TOXICKÉ ¦¦ ¦ ¦ ¦ a ¦b ¦ ¦+-----+--------+-----------+-------------+------+-- -------------------¦
¦ I ¦ 1H ¦ 11Na 19K ¦ 29Cu ¦ ¦ 47Ag 79Au ¦
¦ II ¦ ¦ 12Mg 20Ca ¦ 30Zn ¦ ¦ 4Be 48Cd 56Ba 80Hg ¦
¦ III ¦ ¦ ¦ ¦ 5B ¦ 5B 13Al ¦
¦ IV ¦ 6C ¦ ¦ 50Sn ¦ 14Si ¦ 82Pb ¦
¦ V ¦ 7N 15P ¦ ¦ 23V ¦ ¦ 33As 73Ta 83Bi ¦
¦ VI ¦ 8O 16S ¦ ¦ 24Cr 42Mo ¦ 34Se ¦ 24Cr 34Se 42Mo ¦
¦ VII ¦ ¦ 17Cl ¦ 25Mn ¦ 9F 53I¦ 9F 35Br ¦
¦ VIII¦ ¦ ¦ 26Fe27Co28Ni¦ ¦ 26Fe 27Co 28Ni ¦+-------------------------------------------------- -------------------+
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Supplementaion ?
• RDA = recommended daily allowance
• Enough for deficiency prevention
• New system - DRI = daily recommended intake– Estimated average requirement
– RDA
– Adequate intake
– Upper limit
• YES - Fe, Zn, Cr, Se, I, F (if indicated)
• NO - Cu, V, Mn, Ni, Co, Sn, Si
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Iron distribution
Total amount 4000 mg 100 %
Haemoglobin 2500 63
Myoglobin 160 4
Enzymes (catalase) 8 0,2
Stores (ferritin) 1350 33
Transport(transferrin)
5 0,12
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Iron balance
• Destruction of red
cells
(0,8 % /day ≅ 20 ml)
20 - 25 mg Fe/ day
• 90 - 95 % recycled!
• Losses only 1 - 2 mg/d
• Average diet
10 - 15 mg/ day
controlled resorbtion
1 - 2 mg/d
Physiologic increased losses: Menstruation: 30 mg, gravidity 300 mg, lactation 180 mg
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Diagnosis ?
• Anemia - suspected sideropenia
• Serum iron (m: 14 - 29, w: 12 - 23 µµµµmol/l)
is not sufficient for dg. !!!
• TIBS, total iron binding capacity is a simple and
not expensive assay
• Ferritin assay ? if you are rich, it is an excellent
marker of total stores (plasma: 40 - 50 ng/l)
• Transferrin assay ? (2 - 3 mg/l), fluctuating
• Soluble transferrin receptor assay
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Iron binding capacity (TIBC)
• 1. Iron assay from serum (16)
• Excess iron added to the sample -
saturation of transferrin to 100 %
• Removal on non bound iron
• 2. Iron assay (64)
• Saturation index = 16/64 = 0,25 (25 %)
• < 0,2 = sideropenia; > 0,55 = iron excess
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Iron deficiency and excess
• Sideropenia is common in women living in poorcoun tries – repeated gravidities, infections, poornutrition
• In rich countries - achlorhydria & diseases associated with chronic blood loss - kidney, gynecologic diseases, peptic ulcer
• Strict vegetarians - children
• 3 stages, microcytic hypochromic anemia is thelast
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Iron deficiency and excess
• Popeye, the brave seaman and the spinach
• Mistake - spinach is not a good source of iron
(meat)
• Bigger mistake - iron excess is a risk factor of
coronary heart disease
• Hereditary haemochromatosis - our european
heritage (10 - 15 thousand years ago)
• Secondary haemochromatosis (Sickle cell
disease and transfusions)
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Clinical manifestation of haemochromatosis
• Bronze-colored skin
• Hepatomegalia, later liver cirrhosis
• Painful damage of joints
• Disorders of endocrine glands (e.g. diabetes bronze).
• Cardiomyopathy
• Chronic fatigue syndrome
• Loss of libido, impotency
• OxidativeOxidativeOxidativeOxidative stress stress stress stress and accelerated atherosclerosis already and accelerated atherosclerosis already and accelerated atherosclerosis already and accelerated atherosclerosis already
in latent stagein latent stagein latent stagein latent stage
❀ Factors of manifestation: sex (m>w), nutrition (meat),
excess alcohol consumption
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Hemochromatosis
and the regulation of iron resorbtion
♥ OMIM *235200; carrier frequency 0,045 - 0,071 (!)
♥ Homozygotes 2 - 5/1000
♥ HFE gene in HLA region, 1 common mutation
♠ 1999 HFE2 - long arm, ch. 1
♠ 2000 HFE3 - 7q22, transferrin receptor 2
♠ 2001 HFE4 - ch 2; SCL40A1 gene for ferroportin
♠ 2003 HAMP gene; ch 1 for hepcidin
♠ 2004 HJV gene for hemojuvelin
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Hemochromatosis
and the regulation of iron resorbtion
♥ For general practice these extremely rare
conditions are not important but
♥ they are important to understand the
physiological regulation of iron resorbtion
♥ The main regulator is the hepcidin from liver
♥ increased expression in experiment - Fe deficiency
♥ mutation or decreased expression – Fe excess
♥ and also hemojuvelin
And iron accumulation in substantia nigra -Parkinsonism
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Zinc, Zn
2 - 3 g; RDA 12 - 15 mg
• Constituent of enzymes (cca 300) and other
proteins ( insulin crystalls)
• Smell and taste receptors, ion channels
• Not a catalyst
• Stabilisation of proper spatial structure of
domains - zinc fingers, regulating gene expression
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Zn - history
• Nihil album (ZnO) as a použivali už v stredoveku na
liečbu očných chorôb
• 1746 A.S. Margaff, Germany
• 1869 - 1957 essential micronutrient for plants and
domestic animals, deficiency described
• 1940 - 1961 essential for man, Zn-proteins
described
• 1974 RDA
• Now intensive research about marginal deficiency
not only in human but also in veterinary medicine
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Zn-metalloenzymes and proteins
• DNA polymerase
• Zn-Cu SOD
• Retinol
dehydrogenase
• Collagenase
• Metallothionein
• Zn fingers
• Thymulin
• Steroid receptors
• NA synthesis, cell division
• Antioxidant defense
• Regeneration of visual pigment
• Connective tissue, vessel wall
• Transport
• Gene expression
• T lymfocyte differentiation !
• Endocrine functions
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Zinc, Zn - deficiency
2 - 3 g; RDA 12 - 15 mg
• Sources, liver, kidney, mushrooms, red beet
• Small stores, phytates from cereals block resorbtion
• Marginal deficiency is probably common -repeated infections, growth retardation
• Severe deficiency– Middle East - cereals
– Alcoholism, cirrhosis, nefrotic & malabosrbtion sy.
• Hereditary disturbance of absorbtion -acrodermatitis enteropathica
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Copper, Cu 100 - 150 mg; RDA 2 - 5 mg
• Muscles, bones, liver
• Active centre of many enzymes, mainlyoxidoreductases
• Cu++ + e- ⇔ ⇔ ⇔ ⇔ Cu+
• Superoxddismutase, lysyloxidase, cytochromoxidase and others
• Ceruloplasmin is the main transporter ofcopper
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Cu metabolism, deficiency and excess
• Sources: nuts, oysters, sea fish
• Binding to albumin, transcuprein and in the liver to
ceruloplasmin
• Excretion through bile
• Deficiency - experimental and severe malnutrition -
anemia, leukopenia, brittle bones
• Accumulation in obstructive icterus,
• Intoxication - diarrhoe, liver damage
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Hereditary pathological conditions
• m. Wilson is a hereditary deficiency ofcoeruloplasmin - hepatolenticular degeneration
– Autosomal recessive, 1/30 000 newborns
– Free copper induces oxidative damage
– ATP7B 13q14; 200 different mutation, 1 common
– Different clinical manifestation, from mild (only higher transaminases and Kayser-Fleischer ring to serious liver damage, hemolysis and neurological/psychiatric spts.
• KF ring = green/brown ring in cornea = deposit of Cu
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Hereditary pathological conditions
• Menkes’ kinky hair syndrome
– X chromosome related, ATP7A (1/250 000)
– disorder of intracellular transport of Cu
– Low activity of key copper enzymes (SOD, Cytochromoxidase, etc.)
– Severe fatal disease with progressive neurological spts., connective tissue, skin, digestion
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m. Wilson
IndexIndexIndexIndex NormNormNormNorm m. m. m. m. WilsonWilsonWilsonWilson
CeruloplazminCeruloplazminCeruloplazminCeruloplazmin 1,8 – 2,5 µmol/l < 1,8 µmol/l
Cu – plasmaCu – plasmaCu – plasmaCu – plasma 16 – 31 µmol/l < 16 µmol/l
Cu – Cu – Cu – Cu – liverliverliverliver 30 – 50 µg/g 100 – 150 µg/g
Cu – urineCu – urineCu – urineCu – urine traces 100 µg/d
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Chromium, Cr 1 mg, decrease with age
• Very toxic
• In complex form (picolinate) increases insulin
sensitivity
• Prevention of impaired glucose tolerance
• Adjuvant therapy in Type 2 diabetes
• Cr activates a step in insulin induced signal
pathway (2003)
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Vanadium, manganese, nickel cobalt, a
molybdenium• Vanadium
– No deficiency in humans, intoxication is possible
– Insulin like effect in vitro ?
• Manganese, nickel
– No deficiency syndromes
• Cobalt
– very toxic - additive to beer - cardiomypathy
– only as the constituent of vitamin B12
• Molybdenium (molybdopterin)
– No deficiency in humans, intoxication is possible
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Selenium, Se
• Toxic compound (semi-condcuctors)
• m. Keshan (China), cardiomyopathy
• No selenium in soil, plants, food
• Active center of glutathione peroxidase (GPX), key enzyme of antioxidant defense
• Involved also in iodine metabolism
• Selenocysteine is incorporated to peptide chain
during synthesis
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Selenium, Se• Sources: garlic, yeast, sea fish
• Marginal deficiency in many countries of Europe
(SK, H, PL, CZ)
• RDA m: 70 µg; w: 50 µg,
• Recently up to 200 µg
• Supplementation is recommended in
atherosclerosis and cancer prevention
• In 2001 after 10 years of supplementation
significantly less prostata and colon cancer
• Not a panacea
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Iodine, I Metabolism, differentiation, CNS development
• Thyroid gland and hormones (TG, T3, T4)
• RDA: 100 - 200 µµµµg/d
• Deficiency threatens cca 1 billion people living in mountains but also in lowlands (far from sea),
• This country: In the past high incidence ofendemic goiter
• Sources: seafood, egg yolk / salt iodidation
• Strumigens (cabbage) block thyroid metabolism
• Normal urine excretion > 100 µµµµg/d
• USG volume measurement of thyroid
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Requirements
Group RDA, µg/d Ioduria µg/l
adults and adolescents
150 100 – 200
gravidity 200 200 – 300
newborns 90 > 150
children, 6mo – 6y 90 180 – 220
children, 6 – 12y 120 100 – 200
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Consequences of iodine deficiency
Embryo abort, malformations
Newborn increased mortality goiter, hypothyreosis psychosomatic retardation cretenism
Child goiter, hypothyreosis psychosomatic retardation cretenism
Adult goiter, hypothyreosis low IQ cretenism
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Markers of iodine metabolism
Ioduria, µµµµg/l Deficiency
< 20 severe
20 – 50 significant
50 – 100 mild
100 – 200 no
Volume of thyroid
ml (USG)
men < 22 ml
women < 18 ml
children according to body surface
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Fluorine, F - metabolic toxin/caries
prevention
• Already 0,1 mmol/l fluoride blocks bacterial enolase
• Fluoroapatite, forming 10 % tooth enamel is more resistant as hydroxyapatite
• Fluorine helps convert amorph calciumphosphate into crystallic apatite
� Tooth pasta, mouthwash, KF pills, 1 - 2 mg/d
� Fluoridation of tap water
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