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Institut für Experimentelle Endokrinologie IEÉ
Endokrinologisches Forschungs Centrum Charité
&
Hormon-Centrum Charité, Berlin
EnForCé
Josef Köhrle
Köhrle Charité
http://www.charite.de/enforce
http://www.charite.de/expendo
Institut Experimentelle EndokrinologieAscheim-Zondeck Haus
Die essentiellen Spurenelemente Selen & Jod: gezielte Prävention oder individuelle Selbstmedikation
mit Freiheit zur Mangel- oder Überversorgung ?
IEÉ ENFORCÉ
Topics
Trace Elements
Minerals
Iodine, Selenium and Thyroid
Mechanisms
Clinical Implications
Perspectives
Periodic Table
Twenty-five elements are essential to life
–Four of these make up about 96% of the weight of the human body
–Trace elements occur in smaller amounts
http://faculty.dbcc.cc.fl.us/viscoma/BSC1005Survey/notes/SurveyCH2.ppt
Standbild der Prinzessinnen Luise und Friederike. Luise war die Ehefrau Friedrich Wilhelms III., König von Preußen.
Ihre Schilddrüsenerkrankung verdeckte Sie mit Hilfe eines Schals
Schadow 1795
Goitre – Iodine Deficiency
V. Shashidar, Fiji School of Medicine
Iodine Deficiency
Enlarged Thyroids in GermanyIEÉ EnForCé
Including nodules
Direkte und Folgekosten für das deutsche Gesundheitswesen: 1.5 Milliarden € pro Jahr !
World-wide Iodine SupplyIEÉ EnForCé
Germany: at stage of developping countries
Adequate: Bahrain, South Africa (Cape town), Peru (coastal region), Switzerland)(> 100 to < 200 µg/d)
Moderate to mild deficiency: Germany, New Zealand, Australia, parts of USA(> 50 to < 100 µg/d)
Excess: coastal Hokkaido (> 500 µg/d)
Zimmermann et al. Am J Clin Nutr (2005) 81.840-4
Consequences of the world wide Iodine Deficiency
6 Million: Kretins
26 Million: Brain damage
655 Million: Goiters
1,6 Billion : Risk of impaired mental development
Quelle: WHO/UNICEF 1995
Iodine Deficient Populations
• Intelligence reduced
• by 13.5 IQ points
source: 18 studies (other countries)
Permanent!
Permanent!
The iodine nutrition status…. too little, enough, probably too much ...
Inpregnantwomen200- 250 µg/dis the
goal toachieve
In normal adults
< 50 µg/d overt ID50-100 µg/d relative restriction
100-150 µg/d probably OK150-200 µg/d certainly OK200-350 µg/d “grey zone”
> 350 µg/d iodine excess
Iodine supplementation programmes require prior assess-ment (and continuous monitoring) of the actual iodinenutrition situation to know « what needs to be implemented »
MIMVirchows Opinions on Cretinism
Goiter & Cretinism not relatedto iodine deficiencybut caused by 'Miasm':Adverse, bad, volatile influence of the environment and inadequateSocioeconomic status
Virchows Studies on Kretinism in Frankonian Spessart Region
Die Zwerge von Lhasa
Kashin-Beck Disease: Combined Iodine and Selenium Deficiency
Ein Leben lang nicht fähig zu arbeiten: Der 50-Jährige Bukchun (links) und eine Nachbarin. - Foto: maa Harald Maass 2007 TS
Kashin Beck Erkrankung
big joint disease
Osteoarthropathie, Störung der Knorpel- und Knochen-Differenzierung
Nahrungskontamination durch Pilzgifte (Getreide)
Nord-Ost-Asien
SELENIUM and the THYROID
•Thyroid: highest selenium content per mass unit
• expression of many selenoproteins
•Thyrocytes: life-long H202 production under control of TSH from fetal week 12 to death
• combined iodine and selenium deficiency leads to myxedematous cretinism in Central Africa
• association low serum Se and thyroid cancer
• Low serum Se associated with increased thyroid volume in females (SuViMax-study) Derumeaux et al EJE (2003)148:309
• selenite treatment reduces titers of thyroid auto-antibodies in Hashimoto‘s and postpartum thyroiditis
SELENIUM, THE THYROID GLAND & CLINICS
SELENIUM CONTENT OF HUMAN TISSUES[µg/g tissue]
Dickson and Tomlinson, 1967
infant1.5 y (pneumonia)
0.050.460.640.160.310.190.920.34
adult52 y (aneurisma)
0.130.471.240.270.220.170.630.39
pancreasgonadthyroidbrainintestinestomachkidneyliver
tissue
highest retentionof Se duringSe deficiency
in CNS and thyroid gland
EnForCé
Selenium in medicine and biology - or:a long way to overcome the first impression ...
1817 - Berzelius discovers Se 1957 - Schwarz & Foltz: Se - essential trace element1973 - Se: constituent of GSH-Peroxidase (GPx)1990 - an active residue in 5‘-deiodinase2003 – human selenogenome : 25 genes
Breite Varianz der täglichen Se-Aufnahme
Land Se [µg/day]Venezuela 200-350Kanada 113-220U.S.A. 60-160Japan 128Mexiko 61-73Germany 38-47UK, Scotland 31-43Finnland, -‘80 12-23““ , since –‘86 69-82
China, low 2-36““ , high 240-6990
Berzelius
RDA 2006:1 µg/kg BW
Low - lower - lowest
capillaryThyrocyteC-cell
Colloid-lumen
Capillary network Arteriole
NerveThyrocyte
C-cell
Organisation of Thyroid FolliclesEnForCéIEÉ
Köhrle, IEÉ, Charité
Thyroid gland – Iodide – TH Biosynthesis
TTF1/2, Pax8, AP1,NF-kB
Iodide
ThOx TPO
TSH
cAMP
NIS
Iodide
Dehal1Pendrin ?
Tg
Tg
2 Na+ Iodide
Thyroid Hormone BiosynthesisIEÉ EnForCé
3
5’
3’
5
DIT
DIT + DIT = THYROXINE (T4)3, 5, 3’, 5’-TETRAIODOTHYRONINE
MIT + DIT = TRIIODOTHYRONINE (T3)3, 5, 3’-TRIIODOTHYRONINE
Dohan et al. Endocr Rev 24 (2003) 48-77
Continuing, TSH-stimulated production of thyroid hormone during life depends on regulated H2O2generation and therefore requires antioxidativedefense mechanisms of thyrocytes.
Thyroid Hormone Biosynthesis
IEÉ ENFORCÉ
H2O2
GPx3
IEEEnForCé
Thyroid hormonesThyroid hormonesT4 (Thyroxine,
3,3′,5,5′-Tetraiodothyronine)
5´Deiodinases
T3 (3,3´,5-Triiodothyronine)
HO
I
O
I
I
OH
O
H2N
I
HO
I
O
I
I
OH
O
H2N
active hormone
Animation: Peter Hofmann, IEÉ
EnForCéIEÉ Selenium in proteins
seleno-cysteine
CH2 CNH3
+
HC
O
OSe
H
seleno-methionine
Se CH2 CH2 CNH3
+
HC
OOH3C
Functionally active & relevantRegulated biosynthesis21st codon
Not directly available,No specific function,Oxidized form Regenerated by MsrB(a selenoprotein) ?
2 H2Se
SeCys-tRNA
Seleno-Proteins
SeCys Se0
essential
3
(CH3)2Se
(CH3)3Se+
Seleno-sugars
Excretion
Steps in selenium (Se) metabolism I
seleno-methionine
Se CH2 CH2 CNH3
+
HC
OOH3C
SeMet
SeCys
Nutrient-Proteins
without special function
SeMet
SeMet-Proteine
1
SelenoproteineEnForCé
Selenoproteine stellen eine Erweiterung des klassischen genetischen Codes dar.Sie enthalten die 21te proteinogene Aminosäure Se-Cysteine (Sec).Der Einbau erfolgt co-translational:
UGA
eEFsecSECIS-BP
SeCys-tRNA
AUG 3´UGA5´
Sec eEFsec: Sec-spezifischer Elongations-Faktor SECIS: Sec-Insertions-Sequenz
Animation, Kostja Renko, IEÉ
The New World of Selenoproteins
Selenogenome:Human 25 genes, rodents 24C. elegans 1Drosophila 4
2003
selenoproteins withknown enzyme functions:GPx, TrxR, Dio
1973-2002
selenoproteome: 30-70:splicing, alternative start sites, posttranslationalmodification
2007-???
http://www.jb.man.ac.uk/~drl/
Selenoproteins25 genes encoding Se-proteins in the human genome
• 5 glutathione peroxidases• 3 deiodinases• 3 thioredoxin reductases• Selenoprotein P (SePP)• selenophosphate synthetase 2• methionine sulfoxide reductase• selenoproteins H, I, K, M, N, O, P, S, T, U, V, W
Se deficiency impairs the expression of Se proteins and is associated with increased vulnerability to "toxins " and changed thyroid hormone levels
Human Defect in Selenoprotein Biosynthesis –First Mutations in SBP2
IEÉ EnForCé
Two families with unknown cause of disturbed TH Feedback
Mildly elevated TSH and T4, elevated rT3; low T3
Inadequate T4- but normal T3-supression of TSH
Low Plasma GPx activity
Low Plasma Se
Low Plasma SePP
Impaired Type II 5'-Deiodinase activity in fibroblasts
Dumitrescu, …, Schomburg et al., Nature Genetics 16. Oct. 2005 aol
EnForCéMIMIEÉ SBP2 Mutation affects Selenoproteins
SBP2 mutation human: T4⇑ rT3⇑TSH ⇑;T3 ⇒
Dumitrescu, …., Schomburg et al, Nature Genetics 16. Oct. 2005 aol
Patients with hereditary SBP2-Defect
normal
defectnormal
defectl
A low SePP-concentration under normal nutrtion indicates a disturbed Selenium metabolism
Dumitrescu,A … Schomburg,L … Refetoff,S: Nature Genetics 2005.
EnForCéTissue-specific aspects of the hierarchical Se metabolism in mice
Relation between serum glutathione peroxidase activity (GPX) and serum selenium concentration after selenium supplementation in unsupplemented subjects ({blacktriangleup}), placebo-iodine-supplemented subjects ({circ}), and selenium-iodine-supplemented subjects (*)
Moreno-Reyes, R. et al. Am J Clin Nutr 2003;78:137-144
Copyright ©2003 The American Society for Nutrition
Selenium Excretion, Leipzig
Brauer VFH et al. European Journal of Endocrinology (2006) 155 807–812
TPOAb concentrations at the beginning of the study and 3 months after treatment with 200 mg L-selenomethionine/day
Turker O, Kumanlioglu K, Karapolat I, Dogan I. J Endocrinol. 2006 Jul;190(1):151-6
Percentage of patients who had PPTD (left) and hypothyroidism (right) develop in TPOAb(+) women who received Se (group S1) or placebo (group
S0), and in TPOAb(-) women (group C)
Negro, R. et al. J Clin Endocrinol Metab 2007;92:1263-1268
Copyright ©2007 The Endocrine Society
IEÉ EnForCéTreatment of AITD with Selenium
K.J. Schmidt, (1998) VitAminSpur 13:33-39100 µg selenium (yeast) for 6 weeks: M. Hashimoto, TSHdecrease, trend towards decreased thyroid volume, TPOAb, TRAK
R. Gärtner, JCEM 2002500 µg selenite for 3 to 6 months; M. Hashimotodecreased TPOAb, improved subjective feeling
L. Duntas, EJE 2003500 µg selenomethionine, 6 monthsdecreased TPOAb, improved subjective feeling
L. Duntas et al. ITC 2005, O 76200 µg selenomethionine, 6 monthsTRAB decreased, more rapid euthyroidism, mood effects
Turker et al. 2006: dose dependent effects in AITD, TPO-AbItalian Study 2007: benefit in postpartum thyroiditis
0
20
40
60
80
100
120
140
placebo Se
case
s
total cancerlung cancercolorectal cancerprostate cancer
Clark, Combs, et al. JAMA 1996
mean serum Se in USA: 125 µg/L(Kafai MR and Ganji V, J Trace Elem Med Biol 2003, 17, 13-18)
whereas mean serum Se in Germany: 67 µg/L(Oster O et al. Biol. Trace Elem. Res. 1998, 15, 47-81)… and mean serum in mice (C57BL/6): 320 µg/L (own data).
Reduction of Cancer Risk by Se
SELECT (Selenium and Vitamin E Clinical Trial)
• Double-blind, placebo-controlled, randomized, population-based trial in 32,400 men age ≥ 55.
• 2 x 2 factorial design: 200 µg Se (SeMet) x 400 mg α-tocopherol acetate daily for 7 years.
• 99% statistical power to detect 10% decrease in prostate cancer incidence.
• $180,000,000 for 12 years.
Cumulative incidence of type 2 diabetesCumulative Incidence Type II
Diabetes
Stranges, S. et. al. Ann Intern Med 2007;147:217-223
Sepsis
Selenbedarf bei Schwerkranken erhöht
Forceville et al, 1998 Crit. Care Med.
Plasmaselen bei schwerer Sepsis signifikant erniedrigt
Selenspiegel negativ mit Schwere der Erkrankung assoziiert
Selenium Deficiency Syndromes• Exudative diathesis in poultry (& Vit E).• Mulberry heart disease in swine (& Vit E).• Gizzard myopathy in turkeys (& Vit E).• White muscle disease (NMD) in sheep.• Pancreatic atrophy in poultry.• Liver necrosis in rats.• Keshan disease in humans (coxsackie B virus cofactor).• Kaschin-Beck Disease (osteoarthropathy) in humans (I?,
Mo?, B?, fungal toxins?).• Myxedematous cretinism in humans (iodine co-
deficiency).• Skeletal myopathy in TPN patients w/o added Se.
C. Hawkes et al.
IEÉ EnForCéAre There Reliable Indicators of Selenium Supply?
• blood selenium– erythrocytes– platelets
• plasma selenium• plasma selenoproteins
– pGPx– SePP
• tissue selenium content and selenoproteins
EnForCéNew Assay for SePP
SePP
Festphasen AB (CT)
Detektions AB (Tracer)
SePP
Schematische Darstellung des Sandwich-ELISAsim Coated-Tube Format zur SePP-Bestimmung.
hν
IEÉ EnForCé
Organ meats are another good source of the element.
From http://www.sciencenews.org/20030503/food.asp
The seafood in this bowl of sushi can be a rich source of selenium (and iodine, too! )
IEÉ EnForCé
Brazil Nuts are rich in Selenium
IEÉ EnForCéSummary & OutlookIEÉ
The trace element Selenium (Se)essential micronutrient for normal thyroid functionsignificant health benefits attributed to Sepromising cancer chemopreventive agentprevention of autoimmune thyroid disease
Active in Hashimoto‘s, Graves‘ and postpartum thyroiditisMechanism ???
Downregulation of expression of some selenoproteinsin (thyroid) cancer tissue
Mechanism ? DNA methylation (Dio1 promoter)
Biomarkers and indicators of adequate supply ? SePP
Interaction Se, Iodine, Iron?Köhrle Charité
IEÉ EnForCéSome Open IssuesIEÉ
Function of novel selenoproteinsThyroidal Se uptakeDifferent bioavailability & functions of various forms of SeSelenoprotein-specific drugs
Se & endocrine systemSe & immune system
Se in (chemo-)prevention & therapy of cancer
Mechanisms of Se toxicity
Köhrle Charité
Selenoproteins, ROS and DNA-damageIEÉ EnForCé
DNA-repair
defectiveDNA-repair enzymes or
cell cycle control-systems
Impaired antioxidativedefense systems e.g. Se-dependent GPx
Increased production of ROS: hydrogen peroxide, lipid- and phospholipid hydroperoxides
DNA-damage
IEÉ EnForCé
“The dose makes the poison”
Paracelsus
(1493-1541)
–“It is the task of chemistry to produce medicines for the treatment of disease since the vital functions are basically chemical in nature. All things are poisons, for there is nothing without poisonous qualities. It is only the dose, which makes things a poison.”
EnForCéIEÉ
Especially to the Deutsche Forschungsgemeinschaft DFG& Dt. Krebshilfe Dr. Mildred Scheel Stiftung & EnForCé
Institut für Experimentelle EndokrinologieMIMIEÉ EnForCé
Ulrich Schweizer
Lutz Schomburg
Florian Streckfuss
Marten Michaelis
Conny Riese
Kostya Renko
Jazmin Chiu
Vartiter Seher
Silke Kappler
Anita KinneDFG, Dt. Krebshilfe, Charité
IEÉ EnForCé
&
Institut Experimentelle Endokrinologie
Endokrinologisches Forschungs-Centrum der Charité EnForCé
IEÉ
IEÉ EnForCé
Fluorimetric Se-determination
HClSample HNO3/HClO4
Se IV
190° 150°
2 h 0,5 hSe xy Se VI
364 nm
Se IV-DAN
Se IV-DAN
2,3-DiAmino-Naphtalene
Cyclo-
hexan520 nm
Synthesis of thyroid hormones by follicular thyrocyte epithelial cells, storage of iodinated thyroglobulin in colloidal space and secretion of thyroid hormones
2I- + H2O2 2I0 + H2O + ½ O2O2 + 2e- +2H+ H2O2nI0 + Tg + nH2O2 Tg-DIT,Tg-MIT, Tg-T4,Tg-T3 + nH+ + H2O
DUOX
TPO
iodide
iodide
TgTg
T4 T3
NIS
PDS
1
2
3
5
6
4
Tg Tg
Tg Tg
7
MIT+NADPHI-+NADP+
8
TSHr
MCT8
pGPx
pGPx
9
1. basolateral iodide uptake by NIS
2. apical export by pendrin (PDS)
3. synthesis and apical secretion of thyroglobulin (Tg)
4. synthesis and apical insertion of thyroperoxidase (TPO) and dual oxidase (DUOX)
NADPH-dependent production of H2O2 by DUOX
5. iodide oxidation, iodination of Tg-tyrosyl residues and coupling of Tg iodtyrosine residues to iodothyronines iscatalyzed by TPO using H2O2 as cosubstrate
6. polymerisation and deposition of iodinated Tg in colloid
7. micropinocytosis, reduction and cathepsin catalyzedproteoloysis of Tg in secondary lysosomes
release of thyroid hormones T4 and T3 into the bloodby the transporter MCT8
8. dehalogenation of DIT and MIT and re-utilization of iodide for thyroid hormone biosynthesis
9. Secretion of pGPx (GPx-3) into the colloidal space fordegradation of excess H2O2
Enzymatic Deiodination of Thyroid Hormones by Deiodinase Selenoenzymes
T4
O
C O 2-H
N H3
I
I
I
I
-O
+
rT3
O
C O 2-H
N H 3
H
I
I
I
- O
+T3
O
C O 2-H
N H 3
I
I
H
I
HO
+
Dio1Dio2
5'-Deiodination 5-Deiodination
Dio3Dio1
Activation of prohormone T4 to active T3: Dio1 and Dio2Termination of T3 and T4 action: Dio3 and Dio1
Köhrle Charité
IEÉ EnForCéInstitut für Experimentelle Endokrinologie, Charité
Lutz Schomburg Ulrich SchweizerConny SchmutzlerBirgit MentrupBane RadovicFlorian StreckfussMarten MichaelisInka HamannConny RieseKostya RenkoPeter HofmannBirgit HollenbachSusi PiehlEva WirthStefan Roth
Vartiter SeherSilke KapplerAnita KinneAntje KunzeKatja SchreiberMetin YenilmezRosi GrossklausDFG, Charité, Dt. Krebshilfe, TSB & Zukunftsfonds Berlin
IEÉ EnForCé
Clark, Combs & Follow-upIEÉ
Se reduces incidence of lung cancer in persons with relatively low baseline plasma Se levels
Duffield-Lillico et al. 2002; Reid et al. 2002
Serum Se inversely related with risk of prostate cancerand a-tocopherol is higher in men with Serum Se in highest quartile
Vogt et al. Int J Cancer 2003 103:664
Se as chemopreventive agent for recurrent colon polyps(Se yeast alone and in combination with COX-2 inhibitor celeocoxib)
Organized by Alberts et al.
Köhrle Charité
Selenium & Iodine Status, Leipzig
Brauer VFH et al. European Journal of Endocrinology (2006) 155 807–812
Dietary Se Intake in Children New Sealand
n Infants (6–11.9 mo) n Toddlers (12–24 mo) P-value
Serum Se, µmol/L
Breast-fed 22
0.69 ± 0.27 7 0.61 ± 0.19 0.180
Nonbreast-fed 16
0.70 ± 0.34 91 0.57 ± 0.17 0.115
Se intake, µg/d 42
7.9 ± 6.2 188
13.7 ± 8.4 <0.001
Se density, µg/(MJ · d) 42
2.4 ± 1.7 188
3.2 ± 1.7 0.003
Energy intake, kJ/d 42
3227 ± 521 188
4162 ± 1099 <0.001
Protein intake, g/d 42
26 ± 7 188
36 ± 11 <0.001
1 Dietary selenium intakes exclude infants and toddlers currently breast-fed. 2 Values are means ± SD.
McLachlan SK et al. J. Nutr. 134:3290-3295, December 2004
Epidemiological criteria for assessing iodine nutrition based on median UI concentrations in school-age children
Median UI (µg/l) Iodine intake Iodine nutrition
< 20 Insufficient Severe iodine deficiency
20–49 Insufficient Moderate iodine deficiency
50–99 Insufficient Mild iodine deficiency
100–199 Adequate Optimal iodine nutrition
200–299 More than adequate Risk of iodine-induced hyperthyroidism within 5–10 years following introduction of iodized salt in susceptible groups
≥ 300 Excessive Risk of adverse health consequences(iodine induced hyperthyroidism,auto-immunethyroid diseases)
Source: WHO et al.
Population coveragea by UI surveys carried out between 1993 and 2003, by WHO region
Total number School-age Coverage of school-age children
children covered
WHO regionb (millions)c (millions) (%)
Africa 128.9 116.9 90.7
Americas 109.0 98.8 90.6
South-East Asia 242.4 239.4 98.8
Europe 81.2 70.5 86.8
Eastern Mediterranean 87.1 72.6 83.4
Western Pacific 199.4 183.0 91.8
Total 848.0 781.2 92.1a School-age children (6–12 years).
b 192 WHO Member States.
c Based on population estimates for the year 2002 (23).