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
200
150
100
50
0 0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
Diagnostical Latency (n=1629) Patienten
25%
gesamt
20%
M.Crohn Colitis ulcerosa 15%
10%
5%
0% 1
2
3
4
5
6
7
8
9
10
11
12
>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
0
0
0,1
0,2
0,5
1
2
Sulfasalazine (mM)
5
1
2
5
1
2
5
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