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Lower GI-Bleed Michael J. Lentze Children‘s Hospital Medical Center University Hospitals Bonn/Germany • Clinical Spectrum • Diagnostics and Differe...
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Lower GI-Bleed

Michael J. Lentze Children‘s Hospital Medical Center University Hospitals Bonn/Germany

• Clinical Spectrum • Diagnostics and Differential Diagnosis • Therapy

Clinical Case : B., Arzu, 5 months History: At 7 weeks start of bloody- slimy stools, but only a little blood each time, when changing diapers Mother is peadiatrician, has allergic rhinitis, penicillin allergy, the 4 year old sister atopic dermatitis. Normal pregnancy, delivery by caesarian section because of birth arrest. BW 3160 g, BH 51 cm. The child is fully breast fed Clinical Examination: Weight 7210 g, height 64 cm. Normal clinical status. Next steps?

Nutrition of the Mother Nutrition of the mother: she eats „normal“ food, does not drink milk, but has to eat every day 300 g of icecream and ½ bar of milk chocolate. Typical: Extraordinary nutrition habits during pregnancy are transfered into the breast feeding period Therefore: Inquiering the nutrition of a whole day including drinks and extras like other milk products, sweets etc. Treatment: Elimination of the suspected nutrition

Infectious Enterocolitis with bloody Stools in Childhood Virus

Bacteria

Parasiten

Rotavirus (rarely bloody in young infants) Astrovirus? Norovirus? CMV, HIV Salmonella Shigella Campylobacter jejuni Toxin + Yersinia Invasion E.Coli (EPEC,EHEC) C. difficile (AAD) M. Tuberculosis Giardia lamblia Invasion Entamoeba Cryptosporidia

Invasion of the gut by Bacteria

Cossart P, Sansonetti PJ Science, 304: 242-248 , 2004

„Zipper-“ and „Trigger“-Mechanisme

Salmonella typhi murium Listeria, Yersinia

Dramsi S, Cossart P Ann Rev CellDev Biol 14:137-66,1998

„Zipper-“ und „Trigger“- Mechanism of Uptake of Bacteria into the Cells

Cossart P, Sansonetti PJ Science, 304: 242-248 , 2004

Invasion of Parasites

Sibley LD, Science 304: 248-53,2004

„Gliding“ Parasite Plasmodium berghei Gametozytes on Insect Intestinal Epithelia

Without Movement no Invasion!

Sibley LD, Science 304: 248-253, 2004

Invasion of the Parasite Toxoplasma gondii

Lovett JL, Sibley LD, JSC 116:3009-16, 2003

Clinical Examination Besides the examination of the whole body always do the examination of the abdomen: • Pain by palpitation in the four quadrants? • Bubbely sounds? • Inspection of the anus: leasions, fissures, marisks? • Rectale digital palpation not immediately! Wait depending on the anxioness of the child. Easist before endoscopy, if necessary

Open or occult Bleeding? • Occult Blood: 3 x from different stool samples withit the Guajac-Test • False positive: raw meat, cauliflower, radish. False negative: Vitamine C

Initial Diagnostic Procedures in bloody Diarrhea • Blood count: Hb, MCV, RBC, WBC, differential, platelets, sedimentation rate, CRP • Virological (HIV, CMV), bacteriological and parasitological investigation of stools, inclusive C. difficile (Toxin A), tuberculosis (quantiferon test or MendelMantoux test • 3 x Guajac-test in Stool • Lactoferrin or Calprotectin in stool (cannot distinguish between infectious and IBD!) Therefore after the bacteriol.-virol.-parasitol. investigation. • Sonography of the abdomen: fluid containing loops or thickened intestinal walls • Rectoscopie or colonoscopy: Biopsis for histology and virology

Diagnostics in IBD • Clinical examination (inspection of the anus!) height, weight. Percentiles, pubertal state, • Lab: Sed.-rate, RBC,WBC, differential, CRP, GPT, GGT, IgG, iron, ferritine, 3 x guajactest in stool, lactoferrin, calprotectin i. stool • Sonograpohy lower abdomen • Colonoscopy, in older children MRI • Esophago-gastro-duodenoscopy • No general recommendation for: NOD2 or other genetic markers, ANCA, ASCA i. serum

Differential Diagnosis Depending on age: Infants and toddlers: usually infectious enterocolitis: sudden beginning out of good health with vomiting, fever and diarrhea, more rare allergic colitis, colitis with coeliac disease Children and adolescents: the longer the history the more suspicious it is for IBD or tuberculosis

Differential diagnosis – Infants when Infections including Tb are excluded • Allergic Colitis (milk, egg) • Rhagades: locally visible and palpable. Usually no diarrhea • Intussusception: sudden beginning with severe abdomial pain, shock-like symptoms, sometimes small amounts of jelly-like blood in stool • Fissures: more in older children (IBD?)

Severe Fissures in a Toddler

Severe Fissures in a Toddler

Colonoscopy of this Girl

DD: Bloody Stools without Pain: • Blood on the surface of stool or after defecation with blood on the toilet paper • Painless Bleeding • Common in 2 – 8 year old children • Almost always juvenile benign polyps • Rarely several Polyps • Complete Colonoscopy necessary • DD: Meckel-Diverticulum

Typical Juvenile Polyps

Age Distribution of IBD (CEDATA) (n=1629) 250

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Diagnostical Latency (n=1629) Patienten

25%

gesamt

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M.Crohn Colitis ulcerosa 15%

10%

5%

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>12 Monate

Anal Changes in Crohn‘s Disease

Anal Changes CD

Anal lesions in a 11 year old boy with steroid depending Crohn‘s

Sonography of Crohn‘s: Thickened Intestinal Walls

Typical Mucosal Lesions in Crohn‘s: Aphtae

Ulcers in Crohn‘s

Ulcers in deeper mucosal Layers in Crohn‘s

Pebble Stone like Lesions in Crohn‘s

Stenosis in the coecum in Crohn‘s

Microerosions in Ulcerative Colitis (UC)

Typical radiological Changes in Crohn‘s

Normal

MRI‘s of the Colon Milde Colitis

Ajai WM et al Gut 54: 257-63, 2005

MRI of a Patient with Crohn‘s

Schreyer AG et al. Gut 54: 250-56, 2006

What to do in unclear bloody Diarrhea? If: • Esophago-Gastro-Duodenoscopy is normal • Colonoscopy is normal What then? Capsule Endoscopy: rather expensive (500€) Push-Endoscopy

Capsule Endoscopy

Can only used once Costs: ca. 500 Euro / Capsule

Capsule Endoscopy

Typical Findings with Capsule Endoscopy in Children Esophagus: Stomach:

Duodenum: Small Intestine:

Terminal Ileum: Colon:

Capsule

Endoscopy

None Erythema Erosive Gastritis Pebble Stones Erythema Erosions Erythema Erosions Ulcers Nodul. Hyperplasia Inflammation Enterobiasis Cecal Inflammation

Esophagitis Nodularity Gastritis

Shamir R JPGN 44: 45-50, 2007

Capsule Endoscopy Coeliac Disease

Fissure i. Ileum

Crohn‘s

Bleeding i. Duodenum

Nematodes

Push-Endoscopy

Indications for Drug Therapy in infectious bloody Diarrhea Most impostant is the oral Rehydratation and Relalimentation. Antibiotics are indicated in Salmonella typhi: Ciprofloxacin i.v Dysentery, Giardiasis: Metronidazol p.o Cryptosporidium: Nitazoxanide Clostridium difficile Toxin pos. (if >1 year): Vancomycin i.v., and Saccharomyces boulardii p.o Antibiotics in other Enteritis Bacteria: young infants with severe course of the Disease, or in immunsuppression (HIV)

Therapy: Crohn‘s Disease 1. Nutrition Therapy: balanced fluid diet over 4-6 weeks 2. Sulphasalazine: 50-75 mg /kg/ day in 2 doses (maximal 2-3 g/ day) 2. 5-ASA: 50 - (100) mg/ kg/ day p.o. 3. Metronidazol: 10-20 mg/ kg/ Tag Duration? 4. Prednisolone: 1-2 mg/kg/ Tag (maximal 40-60 mg/Tag) in 2 doses, after 3-4 weeks start tapering 5. Azathioprine:1,5 - 2 mg/ kg/ day, Methotrexate 6. Budenoside: 9 mg/ Tag Einzeldosis,or 2 x 4,5 mg/ day p.o in adults is effective in remission. Children? 7. Biologica: TNF-α Antibodies u.a., Probiotics, lyophilised bakteria (E.coli Nissle)

Activation and Effect on NFκB by TNFα TNF-RI α β

Activator: TNFα

IκB-Kinase-Complex IκB

DNA

NF κB

IKK

NF κB P

Promotor

Transcription

P

Translocation

IκB

NF κB Degradation

New Protein: Cange of Cell function Translation

100

120

80

100

% Luciferase

% Luciferase

Effect of Sulfasalazine on NFκB

60 40 20

80 60 40 20

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0

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Sulfasalazine (mM)

5

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5-ASA(mM) Sulfapyridine (mM)

Wahl C, Liptay S et al. JCI 101: 1163-1174, 1998

Reduktion of PCDAI by Infliximab 60 50

PCDAI

40 Day 0 Day 7-10

30 20 10 0 Pat 1

Pat 2

Pat3

Pat 4

Pat 5

Buderus S et al. Dig Dis Sci 49: 1036-39,2004

Lactoferrin in Stool before and after Infliximab Lactoferrin im Stuhl (µg/g Stuhl

600 500 400 Day 0 Day 7-10

300 200 100 0 Pat 1 Pat 2 Pat 3 Pat 4 Pat 5 Mittel Buderus S et al. Dig Dis Sci 49: 1036-39,2004

24 at present used Biologics in IBD

Rutgers et al. Gastroenterology 136: 1182-97, 2009

Risks of Therapy with Infliximab in IBD • Infections: Reactivation of Tuberculosis • Malignant tumors: α/β and γ/δLymphomas of spleen/liver when at the same time treated with immunsuppressivs (thiopurine: azathioprine,mercaptopurine) • 1998-2008 at the FDA registered: 15 cases, 12-39 years, 13 with CD, 2 with UC (Mackey AC, JPGN 48: 386-88, 2009)

Efficiency of Probiotics in IBD • VSL#3: (Lactobacillus acidophilus, L. casei, L. plantarum, L. bulgaricum, Bifidobakterium longum, B. breve, B. infantis und Streptococcus thermophilus):

Induction and Remission of UC • E. coli Nissle: effective in UC for remission, pouchitis (adults)

VSL#3 in Ulcerative Colitis of Children Randomised, placebo controlled double blind study

Dose: depending on age 0,5 Sachets (450 Billionen Bact) to 2 Sachets (1800 Bill) per day Miele E et al. Am J Gastroenterol 104:437-43,2009

Therapy of Crohn‘s with Trichiuris suis Eggs

Randomised double blind Study with Trichiuris suis – Eggs in ulcerative Colitis

Summers RW et al. Gastroenterology 128: 825-32, 2005

Randomised double blind Study with Trichiuris suis – Eggs in ulcerative Colitis

Summers RW et al. Gut 54:87-90, 2005

12 year old Girls with UC

With Enterobius vermicularis Infection

After anti-helminthic Therapy

Büning J et al, Gut, epub March 2008