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Trace elements

Lecture from pathological physiology

Oliver Rácz

2009

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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