DOLORE ADDOMINALE RICORRENTE Annamaria Staiano Dipartimento di Scienze Mediche Traslazionali Università di Napoli “Federico II”, Italia

RECURRENT ABDOMINAL PAIN In 75% of children in secondary schools at least one episode of AP in previous years In 10-25% the pain is recurrent Age of onset: 4-15 years, with a peak around 10 yrs Organic cause in only about 10% of them

Quality of Life For Children With Functional Abdominal Pain: A Comparison Study of Patients’ and Parents’ Perceptions School absences Increased psychological distress Reduced quality of life Youssef NN et al. Pediatrics 2006; 117: 54-59

RECURRENT ABDOMINAL PAIN Functional disorders Functional abdominal pain Functional abdominal pain syndrome Irritable bowel syndrome Abdominal migraine Aerophagia Genitourinary tract Urinary tract infection Hydronephrosis Urolithiasis Dysmenorrhea Pelvic inflammatory disease GI tract Gastroesophageal reflux disease Helicobacter pylori gastritis Peptic ulcer Esophagitis Lactose intolerance Celiac disease Parasitic infection (Giardia, Blastocystis hominis) Inflammatory bowel disease Meckel diverticulum Malrotation with intermittent volvulus Chronic appendicitis Miscellaneous causes Gilbert’s syndrome Familial Mediterranean fever Malignancies Sickle cell crisis Lead poisoning Vasculitis (especially Henoch Schonlein Purpura) Angioneurotic edema Acute intermittent porphyria Galbladder, liver and pancreas Cholelithiasis Choledochal cyst Hepatitis Liver abcess Recurrent pancreatitis

RECURRENT ABDOMINAL PAIN 227 children with RAP Age>5 years 171 (75%) No Cause 46 (20.3%) Lactose malabsorption 1 (0.5%) Celiac disease 9 (4%) Inflammatory bowel disease 117 (68.4%) Irritable Bowel syndrome Hyams, J Pediatr Gastroenterol Nutr, 1995

RECURRENT ABDOMINAL PAIN FUNCTIONAL GI DISORDERS Functional Dyspepsia Irritable Bowel Syndrome Abdominal Migraine Childhood Functional abdominal pain - Childhood functional abdominal pain syndrome Gastroenterology 2006; 130: 1527-37

IRRITABLE BOWEL SYNDROME (IBS) DIAGNOSTIC CRITERIA Rasquin A, et al. Gastroenterology 2006;130:1527–1537

FUNCTIONAL DYSPEPSIA (FD) DIAGNOSTIC CRITERIA Rasquin A, et al. Gastroenterology 2006;130:1527–1537

RECURRENT ABDOMINAL PAIN A diagnosis of functional AP should be made in a positive fashion Negative tests do not reassure the patient, but rather reinforce a medical model of disease Minimal diagnostic investigations  

IRRITABLE BOWEL SYNDROME (IBS) Disorders which may mimic IBS: Inflammatory bowel disease Celiac Disease Carbohydrate Malabsorption Infection (e.g. giardia) Intestinal malformation Neoplasias Genito-urinary tract alteration Allergic Bowel Disease

DISEASES ASSOCIATED WITH DYSPEPSIA IN CHILDREN Gastroesophageal Reflux Eosinophilic Esophagitis Gastritis Gastric or Duodenal Ulcer Duodenitis Gall bladder disease Hepatic Disease Pancreatic Disease 11

RECURRENT ABDOMINAL PAIN Medical History Psychosocial History Physical Examination Limited tests

POST-INFECTIOUS FUNCTIONAL GASTROINTESTINAL DISORDERS IN CHILDREN 36% of exposed children Abdominal Pain 87% Irritable Bowel Syndrome 24% Functional Dyspepsia 56% reported onset of pain following Acute Gastroenteritis (AGE) LOOK FOR PRAEVIOUS AGE Saps M, Staiano A et al. J Pediatr. 2008

Abdominal Pain-Related Functional Gastrointestinal Disorders WARNING SIGNS “RED FLAGS” Rasquin A. et al. Gastroenterology 2006;130:1527–1537

Objective To compare history and symptoms at initial presentation of patients with chronic abdominal pain (CAP) and Crohn’s disease (CD). Study design:Patients with abdominal pain for at least 1 month and no evidence of organic disease were compared with patients diagnosed with CD. Results Patients with functional gastrointestinal disorders had more stressors (P<0.001), were more likely to have a positive family history of irritable bowel syndrome, reflux, vomiting or constipation (P < .05); Anemia, hematochezia, and weight loss were most predictive of CD (cumulative sensitivity of 94%). J Pediatr 2013;162:783-7

IBS IN CHILDREN: PSYCHOSOCIAL HISTORY Evidence for stressful psychological stimuli Marital-Financial problems Death or illnesses Family history for IBS, IBD, PUD, Migraine Reinforcement of pain behavior by environmental factors Attention at time of pain Absence from school on days of pain

the group of parents of children with FGIDs: 64% “FAMILIAL AGGREGATION IN CHILDREN AFFECTED BY FUNCTIONAL GASTROINTESTINAL DISORDERS” Prevalence of FGIDs in the group of parents of children with FGIDs: 64% the group of parents of children without FGIDs: 30.7% Association between the children’s type of GI disorder and their parents’disorder in 35/103 (33.9%) Anxiety was significally higher in the group of children with FGIDs (27.0%, vs 3, 8.3%) Buonavolontà R. JPGN 2010; 50(5):500-505

“FAMILIAL AGGREGATION IN CHILDREN AFFECTED BY FUNCTIONAL GASTROINTESTINAL DISORDERS” Having a mother with FGID was a stronger predictor (OR=3.5%) of FGID than having a father with FGIDs Buonavolontà R. JPGN 2010; 50(5):500-505

RECURRENT ABDOMINAL PAIN PHYSICAL EXAMINATION Abdominal pressure tenderness Chronic constipation ???

Occult constipation defined as ‘abdominal pain disappearing with laxative treatment and not reappearing within a 6 month follow up Period was found in 92 patients (46 %) affectedd by RAP. Of these, 18 had considerable relief of pain when treated for a somatic cause but experienced complete relief only after laxative measures; Eur J Pediatr. 2014 Jan 3. [Epub ahead of print]

Sixty-six % (28/42) children with functional dyspepsia were affected by functional constipation associated with delayed gastric emptying Normalization of bowel habit improved gastric emptying as well as dyspeptic symptoms Boccia et al. Clinical Gastroenterol Hepatol 2008

Total gastric emptying time evaluated at entry (T0) and at 3 months of follow-up (T3) in dyspeptic patients with functional constipation (FC yes) who received lactulose and in dyspeptic patients without functional constipation (FC no) Boccia et al. Clinical Gastroenterol Hepatol 2008

In boys, diarrhea-IBS is the most common subtype. Constipation-IBS is the prevalent subtype in children, with a higher frequency in girls. In boys, diarrhea-IBS is the most common subtype. It is important to acquire knowledge about IBS subtypes to design clinical trials that may eventually shed new light on suptype-specific approaches to this condition. Giannetti E. J Pediatr 2014 Jan 31[Epub ahead of print]

RECURRENT ABDOMINAL PAIN LABORATORY TESTS Complete blood count C-reactive protein Erythrocyte sedimentation rate Comprehensive Metabolic Panel Urinalysis Stool studies for bacteria and parasites Breath hydrogen test or trial lactose-free diet Antitransglutaminase antibodies Fecal calprotectin

RECURRENT ABDOMINAL PAIN ESR altered in 90% of children affected by IBD Boyle JT, Pediatr Rev, 1997 Rectal bleeding >ESR, <Hg identify 86% of patients affected by IBD before endoscopy Khan k et al. Inflamm Bowel Dis, 2002 I level investigations

Sensibility and Specificity “Intestinal ESR” for the screening of IBD FECAL CALPROTECTIN Patients affected by IBD had high levels of fecal calprotectin compared with healthy children (p < 0.0001) and children presenting with recurrent abdominal pain (p < 0.0001) Acta Paediatr. 2002;91(1):45-50. Sensibility and Specificity “Intestinal ESR” for the screening of IBD Eur J Gastroenterol Hepatol 2002;14 (8):841-5 Conclusions: Fecal calprotectin could be useful in differentiating the functional recurrent abdominal pain from the organic recurrent abdominal pain Canani RB, Miele E, Staiano A et al. Dig Liver Dis 2008; 40 (7): 547-53

On the predictive value of blood tests with or without alarm signs J Pediatr Gastroenterol Nutr 2005; 40 (3): 245-8 There is no evidence: On the predictive value of blood tests with or without alarm signs To suggest that the use of US examination of the abdomen and pelvis in the absence of alarm symptoms has a significant yields of organic disease Evidence Quality C

In children with AP with alarm symptoms: abnormalities in 11% Value Of Abdominal Sonography In The Assessment Of Children With Abdominal Pain (AP) In children with AP without alarm symptoms: abnormalities in less than 1% In children with AP with alarm symptoms: abnormalities in 11% J Clin Ultrasound 1998; 26: 397-400

J Pediatr Gastroenterol Nutr 2005; 40 (3): 245-8 There is little evidence that the use of endoscopy with biopsy or esophageal pH monitoring has a significant yield of organic disease in the absence of alarm symptoms Evidence Quality C

Of the 1624 procedures, 26% were considered inappropriate. Based on the symptoms, endoscopic procedures were considered inappropriate if the Rome criteria had been met and appropriate if they had not been met. Of the 1624 procedures, 26% were considered inappropriate. Inappropriate procedures decreased significantly after publication of the Rome II criteria. Miele E et al. Aliment Pharmacol Ther 2010; 32:582–590

Persistent right upper or right lower quadrant pain predicted a negative diagnostic yield of OGD. As regards colonoscopy, persistent right upper or right lower quadrant pain and gastrointestinal blood loss (haematochezia, occult lower GI bleeding) remained independently associated with an increased diagnostic yield The use of the criteria for functional gastrointestinal disorders makes a significant positive impact, they should reduce unnecessary paediatric GI endoscopy. Miele E et al. Aliment Pharmacol Ther 2010; 32:582–590

Yuk Him Tam et al. JPGN 2011;52: 387–391

Meta-analysis including 14 cross-sectional studies ASSOCIATION BETWEEN HELICOBACTER PYLORI AND GASTROINTESTINAL SYMPTOMS IN CHILDREN Meta-analysis including 14 cross-sectional studies No association was found between RAP and H pylori infection and conflicting evidence for an association between epigastric pain and H pylori infection Evidence for an association between unspecified abdominal pain was found, but this finding could not be confirmed in children seen in primary care Spee LA et al. Pediatrics 2010;125(3):e651-69

Pediatric Patients With Dyspepsia Have Chronic Symptoms, Anxiety, and Lower Quality of Life as Adolescents and Adults  Pediatric patients (ages 8-16 yrs) with dyspeptic symptoms, re-evaluated 5-15 yrs later, both with and without abnormal esophageal histology, had more dyspeptic symptoms, greater functional disability, and poorer health-related quality of life compared with controls, in adolescence and young adulthood Histology alone is not adequate to discriminate between organic and functional dyspepsia Anxiety and depression could develop as a consequence of living with chronic dyspeptic symptoms. Rippel SW et al. Gastroenterology. 2012 Apr;142(4):754-61

DYSPEPSIA IN CHILDREN AND ADOLESCENTS: A PROSPECTIVE STUDY 127 children with dyspepsia 56 Upper GI Endoscopy 21(38%) 35 (62%) Mucosal inflammation Normal mucosa (5HP+) Functional dyspepsia Hyams et al. J Pediatr Gastroenterol Nutr 2000 ;30 : 413-418

DYSPEPSIA IN CHILDREN AND ADOLESCENTS: A PROSPECTIVE STUDY SUGGESTIONS: In absence of alarming symptoms short trial with antisecretory drugs If persistent symptoms upper GI endoscopy Hyams et al. J Pediatr Gastroenterol Nutr 2000 ;30 : 413-418

Chronic abdominal pain “CHRONIC ABDOMINAL PAIN INCLUDING FUNCTIONAL ABDOMINAL PAIN, IRRITABLE BOWEL SYNDROME AND ABDOMINAL MIGRAINE” Involuntary weight loss Growth retardation Delayed puberty Significant vomiting Significant diarrhea GI blood loss Extra intestinal symptoms Unexplained fever Family history of IBD Consistent RUQ or RLQ abdominal pain Abdominal physical examination Chronic abdominal pain History and Physical exam Presence of alarm signals Yes Evaluate further No CBC with differential ESR CMP Celiac Disease Urinalysis Stool O&P Stool HP antigen/13C UBT Lactose breath test Fulfills criteria of constipation Yes Treat constipation No Working diagnosis of pain-related FGIDs Diagnostic testing Make subtype diagnosis according to Rome III Criteria Tests abnormal Pain alone: Call functional abdominal pain Pain + associated symptoms: Call FAPS Pain in upper abdomen: Call Functional Dyspepsia Pain + altered bowel movements: Call IBS Paroxysmal episodes of pain: Call abdomen migraine Yes No Evaluate further Initiate appropriate treatment Vlieger AM, Benninga MA. In Walker textbook of Pediatric GI Disease 5; Vol 1: 715-727