Crohnova choroba

Symptomy

Obecně

• Spíše kontinuální
• Progresivní
• Stacionárním
• Regresivním [1]

Začátek onemocnění

• Akutní průběh
• Imitující akutní apendicitidu [1]
• Nenápadně nespecificky
• Začíná asi u 1/3 [1]
• U starších
• Spíše segmentární postižení tlustého střeva [1]
• U mladších
• Spíše celé colon
• Rektum může a nemusí být postiženo [1]
• Ve sliznici v postiženém místě střevní stěny
• se tvoří vředy [1]
• často jsou
• Dlouhotrvající průjmy
• Zvracením
• Nález krve ve stolici
• Bolesti břicha
• Hubnutí, únava [1]
• Další projevy dle na lokalizace zánětu:
• Ileocekální
• Bolest v pravém podbřišku
• Někdy hmatný infiltrát imitující apendicitidu [1]
• Tenké střevo
• Nejsou průjmy
• Je plynatost, říhání a škroukání 1–2 hod po jídle
• Stenózy – až subileus [1]
• Tlusté střevo
• Mírná enterorhagie
• Na rozdíl od ulcerosní kolitidy, kdy je krev ve stolici pravidlem [1]
• Anorektální
• Fisury, stenózy, píštěle [1]
• U dětí
• Opoždění růstu (u 50 %)
• Porucha sexuálního vyzrávání [1]
• Ulcerace v ústech
• Artritidy
• Iritidy
• Paličkovité prsty aj. [1]

Symptomy přímé a asociované

• Vital signs
• Normal
• Tachycardia in anemic or dehydrated patients
• Chronic intermittent fever [3]
• Gastrointestinal
• From normal to those of an acute abdomen
• Rectal sphincter tone
• Gross rectal mucosal abnormalities
• Hematochezia [3]
• Genitourinary
• Skin tags, fistulae, ulcers, abscesses,
• Scarring in the perianal region [3]
• Urological-
• Nephrolithiasis
• Hydronephrosis
• Enterovesical fistulae [3]
• Musculoskeletal
• Arthritis and arthralgia
• Particularly of the large joints [3]
• Dermatologic
• Pallor or jaundice
• Mucocutaneous or aphthous ulcers
• Erythema nodosum
• Pyoderma gangrenosum [3]
• Ophthalmologic
• Episcleritis
• Possible uveitis [3]
• Growth delay
• Decreased growth velocity (eg, height)
• Pubertal delay [3]
• Hematologic
• Hypercoagulable state [3]

Rizikové faktory pro vznik Crohnovy choroby

• Age
• At any age
• častěji v mládí do 30 let [2]

• Ethnicity
• Whites
• Eastern European (Ashkenazi) Jewish descent
• The highest risk [2]

• Family history
• Close relative
• 1 in 5 people with Crohn's disease has a family member with the disease [2]

• Cigarette smoking
• Most important controllable risk factor
• Also leads to more severe disease
• Greater risk of having surgery [2]

• Nonsteroidal anti-inflammatory medications
• Ibuprofen (Advil, Motrin IB, others)
• Naproxen sodium (Aleve, Anaprox)
• Diclofenac sodium (Voltaren, Solaraze) etc
• Can lead to inflammation of the bowel that makes Crohn's disease worse [2]

• Urban area or in an industrialized country
• More likely to develop Crohn's disease [2]

• Diet
• High in fat
• Refined foods [2]

• Northern climates
• Seem to be at greater risk [2]

• Zvýšená střevní propustnost

Patofyziologie

Mycobacterium avium subspecies paratuberculosis

• Granulomatous inflammation of Crohn's disease resembles that of intestinal tuberculosis
• Spontaneous enteritis caused by Mycobacterium avium subspecies paratuberculosis (MAP) in ruminants
• Johne's disease [3]
• Up to 84% of patients respond to treatment with combinations of antibiotics effective against MAP
• Intensified when MAP was reported to be present in commercial pasteurized milk and in human breast milk
• Viable MAP can be cultured from the blood of patients
• In Crohn's disease (55%)
• In ulcerative colitis (22%)
• Not from controls [3]
• MAP DNA insertion sequence (IS)900 in resected gut tissue of
• 52% of Crohn's disease patients
• 2% of ulcerative colitis patients
• 5% of controls [3]
• MAP more frequently in Crohn's disease patients
• Mycobacterial disease would be expected to intensify with immunosuppression caused by
• Corticosteroids
• Anti-TNF treatment
• Concomitant HIV infection [3]
• Crohn's disease patients clinically improve with immunosuppression rather than worsen
• Possible that a subset of genetically susceptible Crohn's disease patients may have persistent MAP infection
• Those with a defect in their ability to clear an intracellular infection
• CARD15 polymorphisms
• Causes their disease
• Organism potentiates cellular immune responses to commensal enteric bacteria [3]
• It is more likely that
• Relatively common environmental agent
• Selectively colonizes or lodges in the ulcerated mucosa of Crohn's disease patients
• But does not cause disease [3]

Enteroadherent and invasive E. coli

• Virulent strain of E. coli from 22% of mucosal biopsies from Crohn's disease patients
• Chronic, postoperative, recurrent inflammation in the neoterminal ileum
• 36% of those with early recurrence
• Only 6% of controls [3]
• adhere to epithelial cells via type 1 pilli
• Invade macrophages by an active, monofilament-dependent and microtubule-dependent mechanism
• persist and replicate within phagocytes
• Infection of macrophages induces TNF production, but no cellular apoptosis
• Following infection with this E. coli strain
• Monocytes of patients with CARD15 polymorphisms had decreased TNF and IL-10 production
• Increased E. coli mucosal adherence, invasion of ulcers and fistulae
• Their presence within lamina propria macrophages in Crohn's disease patients
• Defective clearance of intracellular infections of patients with CARD15 polymorphisms [3]

Dysbiosis

• Altered balance of beneficial versus aggressive microbial species
• Proinflammatory luminal milieu in a susceptible host
• E. coli
• X intestin. bariéry
• Bacteroides
• Enterococcus
• Klebsiella species
• Protektivní
• Various Lactobacillus and Bifidobacterium species
• Used therapeutically as probiotics
• Enteroadherent and invasive E. coli
• In the neoterminal ileum of patients with postoperative recurrence of Crohn's disease
• Flagellin from Clostridium subphylum cluster XIVa organisms
• Dominant antigen in experimental colitis
• Elicit serologic responses in approximately 50% of Crohn's disease patients
• E. faecalis
• Superoxide dismutase activity alters the pathogenicity

Aeroby

• Collitida
• TGFbeta
• + kolagenní depozita ve střevě

Anaeroby

• Crohnova choroba

Dietary components can alter

• Composition and virulence of enteric commensal bacteria
• Increase in the incidence of IBD in Western countries

Nonabsorbed carbohydrates (prebiotics)

• inulin
• fructose oligosaccharides
• Enhance the growth of Bifidobacterium and Lactobacillus species
• Substrate for the production of short-chain fatty acids by these bacterial species
• Especially butyrate
• Preferred metabolic substrates of colonocytes
• Stimulate various mucosal barrier functions

Iron

• Stimulates growth and virulence of intracellular bacteria

Aluminum

• Adjuvant for bacterial stimulation of immune responses
• Ubiquitous food additives in Western diets
• Processed identically by mammalian and bacterial acquisition and storage proteins
• Dietary iron and aluminum can potentiate experimental colitis

Hygiene hypothesis

• Increased incidence of IBD, asthma and autoimmune disorders such as rheumatoid arthritis and type I diabetes in Western society
• Exposure to pathogens or parasites, especially early in life, stimulates protective immunity that prevents later aggressive immunologic processes
• Elimination of helminths by public health measures has increased the incidence of IBD
• Have demonstrated a therapeutic effect of Tricuris suis, the pig whipworm, in ulcerative colitis, Crohn's disease and experimental colitis models [3]

Defect in mucosal barrier integrity

• Increased uptake of luminal antigens and/or adjuvants
• Overwhelm the net suppressive tone of the mucosal immune system [3]
• Defect in epithelial repair
• Potentiate damage by environmental triggers
• NSAIDs
• Infections [3]
• Constant stimulation of innate and acquired mucosal immune responses by
• Luminal adjuvants
• Antigens [3]
• Each of the genes associated with IBD are involved in epithelial function:
• CARD15
• Might mediate bacterial clearance
• Production of antimicrobial alpha-defensins by Paneth cells [3]
• OCTN1 and OCTN2
• DLG5
• MDR1
• Mediate excretion of xenobiotic, possibly bacterial, molecules from epithelial cells [3]
• Vyšší incidence protilátek v séru proti různým antigenům z potravin [5]

Imbalance between proinflammatory and anti-inflammatory mediators

• Activated innate (macrophage, neutrophil) and acquired (T and B cell) immune responses
• Loss of tolerance to enteric commensal bacteria
• Tolerance, in normal hosts, is mediated by:
• regulatory T cells
• B lymphocytes
• Natural killer T cells
• Dendritic cells that secrete
• Transforming growth factor (TGF)-beta
• Interleukin (IL)-10
• Interferon (IFN)-alpha/beta
• Prostaglandin J2 [3]
• In the pathogenesis of Crohn's disease
• tumor necrosis factor (TNF)
• IL-12 [3]
• Linked to ulcerative colitis
• T cells
• T-cell-ablative therapies
• ciclosporin
• tacrolimus [3]

Activation of NFkappaB

Prozánětlivé

• IL-1beta
• TNF
• IL-6
• IL-8
• ICAM1
• Adhesion molecules
• Co-stimulatory molecules
• CD40, CD80, CD86
• Inducible T-cell co-stimulator ICOS [3]
• Cytokines that induce TH1 and TH17 responses are selectively upregulated in active Crohn's disease
• But not ulcerative colitis [3]
• blockade of TNF
• Neutralizing monoclonal antibodies
• Treats active Crohn's disease and ulcerative colitis
• antibodies to IL-12 p40
• Treat Crohn's disease [3]

Protizánětlivé vlivy NFkappaB

• Simultaneously stimulates the expression of various protective molecules:
• TNF-induced protein 3 (formerly A20)
• CARD15
• cyclo-oxygenase 2
• Beta defensins
• PPARgamma
• Its own inhibitor, IkappaBalpha, that inhibit inflammatory responses [3]

• Deletion of Myd88
• Exacerbates the colitis induced by dextran sodium sulfate
• By blocking epithelial NFkappaB activation by commensal enteric bacteria [3]

• Chronic intestinal inflammation can result from
• Defective immunosuppression
• Hyperactive TH1 cell function
• Cytokine hypersecretion [3]

• The primary mediators of immunosuppression are:
• IL-10
• TGF-beta [3]
• Immune activation is driven by aggressive innate or T-cell responses
• Rather than defective immunoregulatory function [3]

• Induction of SMAD7 expression in patients with active disease
• Blocks TGF-beta activity
• By inhibiting SMAD 2/4 phosphorylation [3]

• Overexpression of proinflammatory
• In Crohn's disease TH1 and TH17 cytokines:
• TNF, IL-6, IL-12, IL-17, IL-23
• IFN-gamma [3]
• In ulcerative colitis TH2 cytokines
• IL-4
• IL-13
• Innate immune products IL-1beta, TNF, IL-6 and chemokines [3]

• T regulatory and TR1 cells
• Can prevent the onset of intestinal inflammation [3]
• CD4+CD25+ T regulatory cells
• Can reverse established experimental colitis [3]

• TH1 products such as interferon-gamma stimulate
• IL-12 p40
• MHC class II expression [3]

• Regulatory T cells secrete
• IL-10
• Transforming growth factor beta
• Suppress antigen-presenting cell activity [3]

• CARD15 can inhibit cellular NFkappaB activation and IL-12 p40 secretion
• Following stimulation by a TLR2 ligand
• Potential mechanism for the observed activation of NFkappaB in Crohn's disease [3]

• Overexpression of truncated Card15 in mice
• Enhanced NFkappaB activation
• Associated with a Crohn's disease phenotype [3]

• Bacterial DNA (CpG motif)- prevents and treats experimental colitis in numerous models
• Inhibits NFkappaB activation
• By inducing IFN-alpha/beta in dendritic cells [3]

• Defective APC function
• Decreased innate responses to bacterial ligands
• Implicated in enhanced pathogenic TH1 responses
• Possibly through genetic alterations in NFkappaB function [3]

Imunitní buňky in Crohn's disease

B-buňky

• B-cell responses to enteric microbial constituents are exaggerated in
• Crohn's disease
• Ulcerative colitis
• Experimental intestinal inflammation [3]
• Antibodies are not necessary to transmit disease in experimental colitis
• B-lymphocytes seem to be regulatory rather than pathogenic
• Antibodies to bacteria
• Part of diagnostic tests [3]

T-buňky

• Aggressive T-cell responses to luminal commensal bacteria
• Flagellin-specific T-cell clones can transfer colitis to SCID mice [3]

• TH1 cytokine profile dominant in patients with Crohn's disease
• IFN-gamma
• IL-12 p40 [3]
• Traditional TH1 responses are mediated by IFN-gamma
• Stimulated by IL-12
• By antigen-presenting cells (APCs) [3]

• IL-17 mediates TH17 responses
• Stimulated by the production of
• IL-6
• TGFB
• IL-23 by innate immune cells and APCs
• Especially dendritic cells [3]
• IFN-gamma suppresses IL-17 [3]

• Bacterial colonization
• Stimulates IL-23 expression by ileal dendritic cells
• Levels of IL-23 and IL-17 are increased in Crohn's disease and most forms of experimental colitis [3]

• IL-12-related protein, IL-27
• Increased in patients with Crohn's disease [3]

• Production of IL-21 is induced by IL-12
• Selectively increased in Crohn's disease [3]

• IL-12 and IL-21 stimulates T-bet
• Intracellular transcription factor
• Key to TH1 cell differentiation and activation [3]

• Inflamed ileum contains CD4+ T cells
• Express the chemokine receptor CCR2
• Binds to CCL2 (formerly known as macrophage chemotactic factor 1) [3]

• Innate immune cells:
• TNF, IL-1beta and IL-6 upregulate local
• Endothelial expression of vascular cell adhesion molecule 1 (VCAM1)
• Very late antigen 4 (VLA4)
• ICAM1 [3]
• Cause circulating neutrophils and monocytes to adhere to the inflamed endothelium [3]
• Potentiate the inflammatory response
• Newly recruited innate immune cells
• Particularly sensitive to activation by bacterial adjuvants like
• Lipopolysaccharide
• Peptidoglycan
• Flagellin [3]

• Anti - integrin-alpha4 (natalizumab) effective in treating Crohn's disease binds:
• Intergrin-alpha 4 beta 7 (the MAdCAM1 ligand)
• Integrin-alpha 4 beta 1 (the VLA4 ligand) [3]

• T cells in Crohn's disease patients are resistant to apoptosis
• Lead to an expanded population of activated effector TH1 cells
• By altered activity of proapoptotic and antiapoptotic molecules
• By the binding of IL-6 and soluble IL-6 receptor complexes to membrane-bound glycoprotein 130
• Trans-signaling by IL-6 induces the antiapoptotic genes
• BCL2
• BCL2L1 (formerly BCL-XL)
• Anti-IL-6-receptor antibody, or glycoprotein 130 fusion protein
• Induce apoptosis
• Attenuate colitis [3]
• Therapies that are effective in the treatment of IBD
• Induce apoptosis of activated T cells and in some cases monocytes:
• Corticosteroids
• Sulfasalazine
• Azathioprine
• 6-mercaptopurine
• Infliximab
• Anti-IL-12 antibody [3]

Defective microbial clearance

• CARD15 ass. with Crohn's disease
• Constitutively expressed in small-intestinal Paneth cells
• Stimulate alpha-defensin
• Stim. cryptdin expression
• Might mediate intracellular bacterial killing [3]
• Therapeutic activity of granulocyte-macrophage colony-stimulating factor (GM-CSF)
• Crohn's disease as a result of defective bacterial killing
• Dramatic increases in mucosally adherent enteric bacteria in patients with active Crohn's disease and ulcerative colitis
• Defective alpha-defensin and beta-defensin expression in Crohn's disease patients
• Maximal alterations in patients with CARD15 polymorphisms [3]
• Defective killing of bacteria by the innate immune system
• Pathogenic similarities of Crohn's disease and
• Enterocolitis associated with chronic granulomatous disease [3]
• glycogen-storage disease type IIb [3]
• Persistence of bacteria in tissues of patients with Crohn's disease has been detected by
• Immunohistochemistry
• Culturing mesenteric lymph nodes [3]
• Daily administration of recombinant GM-CSF induced
• Remission in 40% of patients with moderate-to-severe Crohn's disease
• By activating microbial killing by macrophages, monocytes and neutrophils
• GM-CSF might affect the functions of plasmacytoid dendritic cells, Paneth cells and epithelial cells
• Express receptors for this growth factor [3]

Bacterial adjuvants

• lipopolysaccharide
• peptidoglycan
• flagellin
• nonmethylated DNA (CpG motif) [3]

• Bind selectively to various TLRs on
• Innate immune cells
• Intestinal epithelial cells
• Mesenchymal cells [3]

• Ligation of these TLRs activates
• NFkappaB
• Mitogen-activated protein kinases
• Stimulate the transcription of a host of proinflammatory and regulatory genes [3]

• Activation of macrophages from susceptible individuals stimulates:
• IL-1beta
• TNF
• IL-6
• IL-8
• Other chemokines
• IL-12 p40
• And thus IL-12 and IL-23 [3]
• Adhesion molecules
• IL-18
• Reactive oxygen species
• nitric oxide
• Leukotrienes [3]

• NFkappaB activation of APCs (including dendritic cells) by microbial adjuvants induces:
• Expression of MHC class II antigens
• Co-stimulatory molecules
• IL-12
• IL-23
• Can activate TH1 and TH17 cells [3]

• Lipopolysaccharide can stimulate:
• IL-12 p40 production by bone-marrow-derived dendritic cells in IL-10-deficient mice [3]

• Colonization of previously germ-free rodents with various commensal bacterial species can induce:
• ICAM1
• IL-6 by intestinal epithelial cells [3]

• Commensal bacteria selectively activate
• IL-12 p40 in dendritic cells of the distal ileum [3]

• Bacterial flagellin
• Antigen
• Adjuvant
• A form of flagellin
• Dominant antigen in experimental colitis
• Induce serum antibody production in 50% of Crohn's disease patients [3]
• binds to TLR5 to activate NFkappaB [3]

Antiinflammatory

• Lipopolysaccharide
• Stimulates IL-10 production in dendritic cells from normal mice
• Can prevent the onset of experimental colitis
• By inducing the production of type 1 IFN (IFN-alpha/beta) in plasmacytoid dendritic cells
• Via TLR9 ligation [3]

Different genetic abnormalities

• Similar disease phenotypes
• Overly aggressive T-cell responses to a subset of commensal enteric bacteria [3]
• defects in mucosal barrier function
• Immunoregulation or bacterial clearance [3]

CARD15 (caspase recruitment domain family member 15, formerly known as NOD2)

• Three mutations—causing amino-acid substitutions Arg702Trp and Gly908Arg and the frameshift 1007fs—found
• Within the region of CARD15
• Encodes a leucine-rich repeat
• Responsible for bacterial recognition
• 1 of these mutations is present in 25–35% of Crohn's disease patients of European ancestry
• Not in Asian or African American Crohn's disease patients [3]

• Distal ileal Crohn's disease in particular
• In some patients with stricturing disease
• leucine-rich repeat region of CARD15
• binds muramyl dipeptide (MDP)
• Active moiety of peptidoglycan
• Ubiquitous cell-wall polymer found in almost all bacteria [3]
• Binding of MDP by dimerized CARD15 activates nuclear factor (NF)kappaB
• Forms part of a central signaling pathway that stimulates the transcription of multiple genes
• Proinflammatory and protective molecules [3]
• Delelci distální části CARD15 vede k aktivaci NKfB

Arg702Trp, Gly908Arg and 1007fs

• Defective MDP binding
• Conflicting consequences [3]

CARD15 mutation

• fails to clear Salmonella from epithelial cells
• Clearance of invasive bacteria is dependent on NFkappaB activation
• Via the cell-death regulatory protein GRIM-19.9 [3]
• increased luminal bacterial populations
• Particularly within the crypts [3]
• CARD15 is constitutively expressed in Paneth cells
• Source of secreted antimicrobial peptides such as the alpha-defensins
• Targeted deletion of Card15 in mice
• Decreases alpha-defensin production
• Enhances susceptibility to experimental Listeria monocytogenes infection
• After oral, but not systemic (intraperitoneal) [3]
• decrease in alpha-defensin production seen in Crohn's disease patients
• Particularly those with CARD15 mutations [3]
• Paneth cells are selectively expressed in the ileum
• Perhaps accounting for the distal ileal involvement of Crohn's disease in patients with CARD15 mutations [3]
• In patients:
• activation of NFkappaB in patients with active Crohn's disease, rather than decreased activity
• CARD15-defective cells, Toll-like receptor 2 (TLR2) was unable to downregulate NFkappaB activation [3]
• Defective downregulation of the innate immune response to bacterial adjuvant stimulation
• Ineffective clearance of intracellular bacterial infection
• Proliferation of both luminal and mucosally adherent commensal bacteria
• Each of these situations has been documented in Crohn's disease patients [3]

SLC22A4 and SLC22A5

• SLC22A4, which encodes OCTN1
• Promoter region of SLC22A5, which encodes OCTN2
• Organic cation transporters OCTN1 and OCTN2
• Associated with Crohn's disease in association with CARD15 mutations
• Mutations affect the transcription and function of these carnitine and organic cation transporters
• Expressed in the
• Intestinal epithelium
• Macrophages
• T cells [3]
• Cause decreased carnitine transport [3]

The DLG5 gene

• Two haplotypes of DLG5
• Encodes a scaffolding protein
• Helps to maintain epithelial integrity
• Associated with Crohn's disease
• Combined ulcerative colitis and Crohn's disease populations
• 113G>A substitution in DLG5
• Associated with CARD15 mutations in patients with Crohn's disease [3]

MDR1 gene

• Multidrug resistance gene encodes P-glycoprotein 170
• A transporter
• Efflux of drugs and possibly xenobiotic compounds from cells
• Also function as a 'flippase'
• Moves amphipathic substrates from the inner to the outer leaflet of the cell membrane
• Associated with ulcerative colitis and Crohn's disease
• Associated with treatment-refractory IBD
• Mice in which Mdr1 has been deleted develop colitis
• Bone-marrow-transplantation studies have implicated
• Epithelial and/or mesenchymal cells in the pathogenesis of colitis in Mdr1-deficient mice [3]

PPARG gene - peroxisome proliferative-activated receptor gamma

• Variants have been linked with susceptibility in the SAMP1/YitFc mouse model of spontaneous chronic ileitis
• PPARG polymorphisms were found to be associated with human Crohn's disease [3]
• Nuclear receptor that inhibits NFkappaB activity [3]
• Expression is decreased in patients with active ulcerative colitis [3]
• Expression is upregulated by 5-aminosalicylic acid [3]
• Potential role in protecting against intestinal inflammation [3]
• Treatment with the PPARgamma ligand rosiglitazone [3]
• Was effective in an open-label trial involving ulcerative colitis patients [3]
• As well as in mouse experimental colitis [3]

Diagnostika

Laboratorně

Aktivní stadium

• často anémie (70 %) [1]
• Zvýšená sedimentace (80 %) [1]
• Hypoalbuminémie (60 %) [1]
• Pozitivní okultní krvácení (35 %) [1]
• trombocytóza
• Zvýšené CRP
• Známky malnutrice
• ASCA (protilátky proti pivovarským kvasnicím) [1]
• Elevace calprotectinu ve stolici [1]

Zobrazovací metody,

• Endoskopie
• Koloskopie
• Enteroskopie [1]
• Biopsie
• RTG
• Pasáž střevní, enteroklysa, fistulografie [1]
• UZ
• CT
• Posouzení tloušťky střevní stěny
• Abscesy
• Infiltrace v okolí střeva [1]
• Scintigrafie 99Tc-leu
• Rozsah, aktivita, lokální komplikace, ev. screening [1]

Medikamentózní terapie

• Pouze symptomatická, pouze oddaluje chirurgický výkon

Aminosalicyláty

• Inhibují cyklooxygenasu a lipooxygenasu (tvorbu eikosanoidů)
• Snižují aktivitu T i B lymfocytů (tvorbu protilátek)
• Snižují odpověď neutrofilů a makrofágů na chemotaktické signály
• Chrání střevní sliznici před působením kyslíkových radikálů
• Podávání
• P.o.
• V klysmatech
• čípcích [1]

Mesalazin - kys. 5-aminosalicylová - 5-ASA

• 30–50 mg/kg/den
• Z luminální strany
• Vstřebává se už v jejunu [1]

Sulfasalazin

• Ester kys. 5-aminosalycilové
• 5-ASA se z něho uvolňuje až v tlustém střevě činností bakterií [1]

Olsalazin

• Dvě molekuly 5-ASA spojené
• Uvolňují se v tlustém střevě bakteriemi [1]

Azathioprin

Merkaptopurin

• Analoga purinových basí
• Tlumí aktivitu NK-buněk [1]

Cyklosporin A

• Selektivní inhibice CD4 lymfocytů
• Hlavní imunosupresivum u transplantací [1]

Metotrexát

• Antagonista kys. listové [1]

Kortikoidy

• Tlumí zánětlivou aktivitu u 79–92 % dospělých
• U dětí se doporučuje přechod na alternující způsob podávání (neruší růst pacienta)
• čípky
• Dramaticky potlačí příznaky (horečky, průjmy, bolesti břicha, zlepšují chuť k jídlu a celkový pocit zdraví),
• Po dosažení relapsu obecně není rozhodnuto, zda v podávání pokračovat,
• Děti mají časté relapsy při snížení dávky kortikoidů
• často se pak užívají dlouhodobě (prednizon 0,2–0,5 mg/kg/den) [1]
• Nutnost doplňovat vápník a vitaminu D !!!
• Provádět denzitometrii kostí
• Pravidelně i oční vyšetření na kataraktu [1]

Antibiotika při komplikacích

• Rezistence na kortikoidy a aminosalicyláty
• chinolony + metronidazol [5]

Metronidazol

• Perianální komplikace, píštěle a abscesy
• 15 mg/kg/den (max. 800 mg/den) [1]

Ciprofloxacin

• Antibiotics are effective for Crohn's colitis
• But not isolated ileitis
• Except in the postoperative state
• Loss of the ileocecal valve probably changes the luminal microenvironment
• Antibiotics are not effective in ulcerative colitis
• Reproducibly treat pouchitis

Probiotics

• Can prevent the relapse of chronic, relapsing pouchitis and ulcerative colitis
• Not useful in treatment of active disease
• Dominant bacterial stimuli are different in ileal and colonic Crohn's disease
• Commensal bacteria probably have a more important role in Crohn's disease and pouchitis

Antidiarrheal agents

• Loperamide
• Diphenoxylate-atropine [3]

Bile acid sequestrants

• Cholestyramine
• Colestipol [3]

Anticholinergic agents

• Dicyclomine
• Hyoscyamine
• Propantheline [3]

Nutriční terapie vhodná

Parenterální výživa

• Bowl rest v autkním stavu

Enterální výživa

• Terapie první volby při akutním vzplanutí zánětu
• Pomáhá navodit remisi choroby
• Vhodné kombinovat s léky

Sipping

• Protifar
• Mléčná bílkovina
• Fantomalt
• Maltodextriny

Strava v autkní fázi zánětu

Ano

• Lehce stravitelné
• Bílá masa
• Drůbež
• Ryby
• Vejce
• Lecithin působí hojivě na střevní stěnu
• Mléko a ml. výrobky
• Pokud není intolerance laktózy
• Ta bývá u silnějších zánětů v GIT
• Omezení nasycených tuků
• Doplňovat minerály a tekutiny
• Ztráty stolicí kompenzovat
• Porce menší, ale častější
• 5-6xd
• Mixovat
• Dobře kousat
• Oddělit jídlo a pití časově min. 1h
• 2,5 l vody/d
• Přírodní kvalitní vína jsou povoleny
• šetrná tepelná úprava
• 0 přepálených tuků
• Pohanka
• Hlavně sliz z vymáčené pohanky působí protizánětlivě na střeva
• Oleje jako jediný tuk a jenom za syrova
• Koření
• Nedráždivé, nepálivé
• Ideálně čerstvé bylinky a hodně
• Působí protizánětlivě a potlačí přerůstání bakterií
• Vnitřnosti
• Tvaroh
• Mrkev, špenát, mladé kedlubny,...
• Zeleninové šťávy, kaše, strouhané saláty aj.
• Ovocné kaše, šťávy, mixy, shaky, pyré, rosoly

Protektivní prvky v jídelníčku obecně

Probiotika

• Nepatogenní bakterie, které zredukují množství patogenních

E.coli subspec. Nissle 1917

• Izolován Dr. Niesslem ze stolice vojáka, který neonemocněl střevními epidemiemi kolem něho
• Terapeutický efekt v léčbě Crohnovy choroby, ulc. kolitidy, ekzému, revmatoidní artritidy aj.
• Umí navodit a udržet remisi Crohnovy choroby

Kysané mléčné výrobky

Omega - 3 MK

• Aktivuji rec. PPARgamma - snižuje se zánět
• Rybí tuk
• Lněný olej
• Konopný olej

Krátké mastné kyseliny

• K. máselná
• Snižuje propustnost střeva
• Vzniká činností probitických bakterií při trávení vlákniny

Vláknina

• Alespoň rozpustná
• Nerozpustná může dráždit střevo, které je narušené / se zánětem / stenozou

Omega- 6 - MK

• Mohly by zhoršovat zánět

Byliny, které umí potlačit NFkappaB

Obecně protizánětlivé byliny

Kurkumin ?

Ovoce a zelenina

• Snižují riziko Crohnovy choroby i ulcerozní kolitidy !!!

Zinek

• Snižuje střevní propustnost tenkého střeva [3]

Vitamín A

• Inhibuje transkripci NKfB a sekreci zánětlivých cytokinů
• Zesilují zánětlivou odpověd vedenou T - buňkami
• Deicit vit. A zesiluje zánětlivou odpověď, atrofii klků, infiltraci, hyperplazii, fibróze aj.

Vitamín E

• Snižuje TNFa
• Snižuje aktivaci NKfB

Často chybí - potřeba dodávat

• vit. B12
• Vit. A
• Fe
• Podávat společně s vit. E aj. protizáněltivými prvky stravy
• Ne v akutním zánětu
• Mg
• Ca
• Zn
• vit. D
• B9 - kyselina listová - folát
• U 25% pac. s Cronovhou chorobou je deficit [5]
• Res. v prox. č. tenk. střeva
• Nechybí u syndromu přerůstání bakterií [5]
• Sulfasalazin a metotrexát mohou působit deficit [5]
• Prevence osteoporozy
• selen

Další rozsáhlý seznam tipů, jak snížit úroveň zánětu ve střevě zde

Prozánětlivé prvky stravy

V akutní fái zánětu ne

• Omezení vlákniny nerozpustné
• Slupičky !!
• Celuloza
• Slupky zeleniny a ovoce
• Luštěniny - slupičky
• Oříšky a semena na hrubo také omezit
• Mechanické dráždění
• 0 aditiv v potravinách
• 0 uzenin
• Max. jenom šunka kvalitní bez chemie, glutamátu a braviv
• 0 alkoholu
• 0 tučných mas
• 0 nadýmavých pokrmů
• V zánětu působí bolest
• 0 jížky
• žádné nesmysly v podobě přepálených škrobů a lepku nebo dokonce s tukem
• 0 brambor
• Solanin také zhoršuje hoejní střevní sliznice
• Ryže ok
• 0 burizony
• Pufované škroby jsou kancerogenní a zcela jistě nepřispějí k hojení zánětu ve střevě
• 0 rajčat
• Tomatin zvyšuje střevní propustnost
• 0 konzerv
• 0 jídla z plastu
• 0 celozrnných pečiv a kynutých těst
• 0 plísňové sýry
• 0 káva

Železo

• Potřebují ho do sebe dostat, ale může podpororvat růst patogenních baterií a zhoršovat zánět

Hliník

• Zhoršuje zánět
• Aditiva !!

Curky

• Růst bakterií, zhoršení zánětu
• Rafinované cukry
• Vztah i s častějším výskytem zubního kazu u pac. s Crohnovou chorobou [5]

Lepek

• Zvýšení střevní propustnosti a zánětu
• Pšenice, ječmen, žito
• Nesouhlasím s autory publikace [5] že tato strava je vhodná, protože může zvyšovat střevní propustnost i u zdravých lidí a zpomalovat hojení střeva

Živočišné tuky

• Spíše méně

Kouření

• Zhoršuje Crohnovu chorobu

Dextran sodium sulfate

Margariny

• Ztužené tuky

Kravské mléko

• Nebývá tolerováno

Biologická léčba

• Adalimumab (Humira)
• Certolizumab pegol (Cimzia)
• Infliximab (Remicade)
• Anti-TNF-alpha [2]
• Infliximab-dyyb (Inflectra) [2]

• Anti alpha-4 integrin
• Natalizumab (Tysabri)
• Vedolizumab (Entyvio) [2]

Chirurgická terapie

Indikace

• Komplikace
• Akutní či chronická obstrukce
• Krvácení
• Toxické megakolon
• Fulminantní kolitida
• Perforační peritonitida
• Píštěle
• Abscesy

Prováděné výkony

• Resekce s anastomózami nebo stomiemi,
• Co nejmenšího rozsahu
• Riziko nutnosti opakovaných resekcí při recidivách
• Nutnost zachovat alespoň 60 cm tenkého střeva

• Segmentární resekce tenkého a tlustého střeva,
• Ileocekální resekce s ileo-acendentoanastomózou,
• Pravostranná hemikolektomie s ileo-transversoanastomózou,
• Subtotální kolektomie s ileo-rektoanastomózou,
• Proktokolektomie s ileostomií,
• Abdominoperineální amputace s kolostomií,
• Strikturoplastiky a balónkové dilatace stenóz,
• Spíše než resekcím se dává přednost strikturoplastikám
• Drainage abscesů,
• Fistulotomie,
• Anastomosy end–to–end
• Nevytvářet pouch
• Stomie u akutních stavů
• Nejde-li rekonstruovat oblast rekta

• Není-li rektum postiženo, je výhodnější jej ponechat i při trvalé ileostomii
• šetření nervových pánevních pletení
• Sexuální funkce
• Nutnost opakovaných kontrol rekta

Literatura:

[1] www.wikiskripta.eu/index.php/Crohnova_choroba
[2] www.mayoclinic.org/diseases-conditions/crohns-disease/basics/risk-factors/con-20032061
[3] emedicine.medscape.com/article/172940-overview
[4] www.nature.com/nrgastro/journal/v3/n7/full/ncpgasthep0528.html
[5] Výživa u pacientů s idiopatickým střevním zánětem, Pavel Kohout a kol., Jessenius Maxdorf, ISBN 80-7345-023-2, 2004
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