Epidemiologi, patogenese og immunologi
Transcript of Epidemiologi, patogenese og immunologi
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Marte Lie HøivikOverlege/FørsteamanuensisGastromedisinsk avdeling OUS/UiO
INFLAMMATORISK TARMSYKDOMEpidemiologi, patogenese og immunologi
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Figure 1
Ng et al. Gastroenterology 2017
1st case of
Crohn’s disease
reported by
Dr. Burril Crohn
1932
«Nye» sykdommer
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Crohn’s diseaseUlcerative colitis
Constatinos et al Gut 2007
Geografisk gradient
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Prevalens CD 2014
>230
190-230
150-190
<150
Prevalens UC 2014
>320
270-320
220-270
<220
Høivik et al, abstrakt Lillehammer 2016
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Gjennomsnittlig insidens (vestlige land)
Kaplan G, Nature Reviews 2020
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Lirhus et al, Clin Epid 2021
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Lirhus et al, Clin Epid 2021Kaplan G, Nature Reviews 2020
Norske insidenstall - basert registerdata(norsk pasientregister og reseptregisteret)
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Insidens - prevalens
Kaplan G, Nature Reviews 2020
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Fire stadier for «sykdomsbyrde»
Kaplan G, Nature Reviews 2020
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Fire stadier for sykdomsbyrde
Kaplan G, Nature Reviews 2020
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Kaplan G, Nature Reviews 2020
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Lirhus et al, Clin Epid 2021
Norske prevalenstall- basert på registerdata(norsk pasientregister og reseptregisteret)
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Fleremenn
Flerekvinner
Kjønnsforskjeller i forekomst UC
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Fleremenn
Flerekvinner
Kjønnsforskjeller i forekomst CD
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Oppsummering - epidemiologi
• Pågående endringer i IBD-epidemiologi
– Økende insidens særlig i nyindustrialiserte land
– Økende prevalens – på vei til å stabiliseres i vestlige land?
• Høy og økende forekomst (prevalens) også i Norge
økt byrde på helsevesenet
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Patogenese og immunologi
Although still not completely clear, scientific evidences support a multifactorial pathogenesis characterized by a dysregulated immune response to gut microbiota which leads to progressive destructive damage and defective repair of the gastrointestinal tract, in genetically susceptible individuals exposed to environmental factors….
….. ok, men
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Patogenese og immunologi
Although still not completely clear, scientific evidences support a multifactorial pathogenesis characterized by a dysregulated immune response to gut microbiota which leads to progressive destructive damage and defective repair of the gastrointestinal tract, in genetically susceptible individuals exposed to environmental factors….
….. ok, da går vi igang
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19
Genetikk Miljø
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Etniske forskjeller i forekomst
Familiær opphopning: ↑ risiko hos 1.gradsslektninger
Tvillingstudier – konkordans raterEneggede (CD 37%; UC 10%)
Toeggede (CD 7%; UC 3%)
Genetikk
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Genetikk GWAS studier: 240 ++ genetiske loci (alleler)Forklarer ca. 8-13 % av arveligheten
Diaz Obrero et al, JCC 2021deLange et al, Nat Genetics 2017Lees et al, Gut 2011
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Genetikk Miljø
240 ++ genetiske loci
8-13% av arveligheten
Infeksjoner
Diett
Røyking
Stress
Bakterieflora
Medisinbruk
Pre og periantalefaktorer
Fysisk aktivitet
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Miljø
Pre- og periantale faktorer
• Forløsningsmetode: Ikke økt risiko ved keisersnitt
• Amming: Mulig beskyttende effekt, men heterogene studier
• Intrauterin eksponering tungmetaller: Økt risiko for CD (melketenner, bly, kopper, sink, krom)
Torres et al, JCC 2021
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Miljø
Medisinbruk • Antibiotika: Assosiert med økt risiko for CD men ikke UC
- dose respons, høyere risiko for pediatric onset enn adult onset- antibiotika under svangerskap – økt risiko for CD hos barna
• P-piller: Assosiert med økt risiko for CD
Torres et al, JCC 2021
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Miljø
Livsstil • Røyking: Påvirker barriereintegritet, immunrespons, diversitet av mikrobiota,
epigenetiske effekter og kan påvirke genekspresjon. Røykere: 2-4 økt risiko for CD , røykestopp øker risiko for UC
Torres et al, JCC 2021
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Miljø
Livsstil
• Fysisk aktivitet: Redusert risiko for CD
• Diet: Økning av forekomst i land som går over til mer vestlig diett
Torres et al, JCC 2021
www.helsedirektoratet.no
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Stress?
Bernstein C, Gastroenterol Clin N Am 2017
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Immunologisk dysregulering ved IBD karakteriseres av:
1. Forstyrret barrierefunksjon
-epitelskade, ødelagte tight junctions og abnorm slimproduksjon (årsak eller virkning?)
2. Ukontrollert inflammasjonsrespons
-drevet av tarmfloraen (?)
-aktivering av store mengder celler som infiltrerer lamina propria (T-celler, B-celler, makrofager, dendritiske celler, neutrofile)
-produksjon av store mengder proinflammatoriske cytokiner i vevet (feks: TNF, IL1beta, INF gamma, IL23/th17 pathway)
3. Svikt i immunreguleringsmekanismer som skal kontrollere responsen
Torres et al, JCC 2021
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Ulc
erø
s ko
litt
Ungaro et al, Lancet 2017
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Mb
Cro
hn
Torres et al, Lancet 2017
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JAK/STAT -intracellulære signalsystemer som bla overfører cytokinmedierte signaler fra reseptor og inn i cellen
Salas et al, Nature Reviews 2020
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Mikrobiomets rolle
Mange case kontroll studier
IBD mikrobiota karakterisert ved:
• Nedsatt diversitet
• Økt ustabilitet
• Reduksjon av phyla med anti-inflammatoriske egenskaper (feksbutyrate produsenter (Firmicutes).
- årsak eller konsekvens?
Glasner et al, J Allergy clin immunol 2019
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Lee et al, Gastroenterology 2021
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Torres et al, JCC 2021
Mulighet for å forebygge IBD?
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Oppsummering patogenese og immunologi
• Mye mer komplekst enn for ti år siden….men hovedlinjene er ganske like
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Aktuelle referanser
• The four epidemiological stages in the global evolution of inflammatory bowel diseaseGilaad G. Kaplan and Joseph W. Windsor, Nature reviews Gastroenterology and Hepatology 2020
• Ulcerative colitis Ryan Ungaro, Saurabh Mehandru, Patrick B Allen, Laurent Peyrin-Biroulet, Jean-FrédéricColombel, Lancet 2017; 389: 1756–70
• Crohn’s disease Joana Torres, Saurabh Mehandru, Jean-Frédéric Colombel, Laurent Peyrin-Biroulet, Lancet2017; 389: 1741–55
• Precision medicine in IBD- prediction and prevention of inflammatory bowel disease JoanaTorresa,b, Jonas Halfvarson , Iago Rodríguez-Lagod , Charlotte RH Hedine,f, Tine Jessg,h, Marla Dubinskyi , Kenneth Croitoruj , Jean-Frédéric Colombelk , on behalf of the Scientific Workshop Steering Committee*, JCC 2021
• Incidence and Prevalence of Inflammatory Bowel Disease in Norway and the Impact of Different Case Definitions: A Nationwide Registry Study Sandre Svatun Lirhus, Marte Lie Høivik, Bjørn Moum, Karoline Anisdahl, Hans Olav Melberg, J Clin Epidemiology 2021
• JAK–STAT pathway targeting for the treatment of inflammatory bowel disease Azucena Salas, Cristian Hernandez-Rocha, Marjolijn Duijvestein , William Faubion, Dermot McGovern, Severine Vermeire , Stefania Vetrano, and Niels Vande Casteele Nature reviews Gastroenterology and Hepatology 2020