DOLORI ADDOMINALI: Quando il sintomo è veramente importante Annamaria Staiano Dipartimento di Scienze Mediche Traslazionali Sezione di Pediatria Università di Napoli “Federico II”, Italia

CLASSIFICAZIONE DEL DOLORE ADDOMINALE Dolore addominale acuto Dolore addominale ricorrente/cronico

Dolore addominale acuto: Caratteristiche cliniche Intensità e durata del dolore Sintomi associati (vomito, febbre, etc) Condizioni generali Esame obiettivo completo con palpazione addome Dolore addominale viscerale, somatoparietale e riflesso

Color Analog Scale (CAS) Faces Pain Scale - Revised (FPS-R), 2001, International Association for the Study of Pain Color Analog Scale (CAS) Tsze DS et al Pediatrics 2013;132:e971–e979

Differential Diagnosis of Acute Abdominal Pain by Predominant Age Joon Sung KimPediatr Gastroenterol Hepatol Nutr 2013; 16(4):219-224

Algorithmic approach to the children with acute abdominal pain requiring urgent management Joon Sung KimPediatr Gastroenterol Hepatol Nutr 2013; 16(4):219-224

305 children aged 4 – 17 years consulting for abdominal pain 89.2% of children were diagnosed with general practice as functional abdominal pain (GPFAP). Headaches and bloating were positively associated with GPFAP whereas fever and 3 red flag symptoms were inversely associated. Additional diagnostic tests were performed in 26.8% of children. Spee LA et al. Scand J Prim Health Care. 2013 Dec;31(4):197-202.

DOLORE ADDOMINALE RICORRENTE Nel 75% dei bambini in età scolare almeno un episodio di dolore addominale negli anni precedenti Nel 10-25% il dolore è ricorrente Età di insorgenza: 4-15 anni, con un picco intorno ai 10 anni Cause organiche in solo il circa 10% di essi

Prevalence of Functional Abdominal Pain in Children Sweden 13% Norway 6% Finland 8% United Kingdom 12% Germany 2.5% Prevalence of Functional Abdominal Pain in Children Countries where chronic or recurrent functional abdominal pain has been studied are shown in orange. Published studies in children demonstrate a higher prevalence of chronic or recurrent abdominal pain without obvious organic etiology in females, with the highest prevalence of symptoms between 4 and 6 years and early adolescence. Chitkara DK, Rawat DJ, Talley NJ. The epidemiology of childhood recurrent abdominal pain in Western countries: a systematic review. Am J Gastroenterol. 2005;100:1868-1875. USA 13% Italy 10% Chitkara DK et al. Am J Gastroenterol 2005; 100:1868 9

DOLORE ADDOMINALE RICORRENTE Disordini Funzionali Gastrointestinali Dispepsia Funzionale Sindrome del Colon Irritabile Emicrania Addominale Dolore addominale funzionale aspecifico Gastroenterology 2006; 130: 1527-37

SIDNDROME DEL COLON IRRITABILE: CRITERI DIAGNOSTICI Deve includere tutti I seguenti criteri, soddisfatti almeno una volta a settimana per almeno due mesi precedenti la diagnosi: Dolore addominale associato a due o più dei seguenti criteri per almeno il 25% del tempo Miglioramento con la defecazione Insorgenza associata con un cambiamento della frequenza evacuativa Insorgenza associata con un cambiamento della consistenza delle feci Nessuna evidenza di condizione infiammatoria, anatomica, metabolica o neoplastic ache possa spigare i sintomi del soggetto Rasquin A, et al. Gastroenterology 2006;130:1527–1537

DISPEPSIA FUNZIONALE CRITERI DIAGNOSTICI Deve includere tutti I seguenti criteri, soddisfatti almeno una volta a settimana per almeno due mesi precedent la diagnosi: Dolore addominale localizzato ai quadranti addominali superiori Assenza di miglioramento con l’evacuazione o di associazione con un cambiamento della frequenza evacuativa o della consistenza delle feci Nessuna evidenza di condizione infiammatoria, anatomica, metabolica o neoplastic ache possa spigare i sintomi del soggetto Rasquin A, et al. Gastroenterology 2006;130:1527–1537

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

Pain Predominant FGIDs Sensitizing medical events: Inflammation (infection, allergies) Distension Trauma Stress Motility disorder Disability Genetic predisposition Visceral hyperalgesia This slide depicts visceral hyperalgesia as the final outcome of a variety of sensitizing medical events superimposed on a background of genetic predisposition and sensitizing medical events. Environmental factors that may act as precipitating events include intestinal infections, allergies, distention, stressors that exceed the child’s coping abilities, have the potential to disturb the homeostasis of the brain-gut axis and abdominal pain may result. Sensitizing psychosocial events, such as mood disorders and anxiety, the child’s appraising and coping style and, significantly, the family‘s coping style, psychological morbidities in the mother, and the presence of potential secondary gains for the patient may lead to loss of function and increased disability. Anxious parents tend to be overprotective in a harmful way, by keeping the child at home from school and other activities and showing excessively solicitous behaviour centered on the child’s symptoms. These protective parental actions are prone to increase the child’s dependency and apprehensive anticipation of pain or other symptoms, bringing about an avoidance of school and other potentially problematic situations. On the other hand, if the child’s and/or the family’s coping styles proceed by encouraging the child to maintain his or her activities despite pain, and boost independent coping behavior, these children preserve a normal level of functioning. Early life events Sensitizing psychosocial events: Depression Anxiety Family stress Coping style Secondary gains

Do Noxious Early Life Events Predispose to FGID? Pediatrics Do Noxious Early Life Events Predispose to FGID? 40 Controls (siblings) Cases (hospitalized for FGID) 30 Odds ratio: 2.99; P<0.009 % of subjects with FGID 20 Do Noxious Early Life Events Predispose to FGID? This study tested the hypothesis that noxious stimulation at birth may increase the risk of developing functional gastrointestinal disorders (FGIDs) later in life.1 By employing a matched case-control study using sibling controls, birth records were retrieved for 494 mothers who had 2 or more children with birth weights 2500 g. Among the offspring (n=1110), 108 children were eventually hospitalized for a functional intestinal disorder. Of these, 96 were compared with 116 unaffected sibling controls. Gastric suction at birth occurred more frequently among the cases compared with their siblings (23% vs 11%); there were no differences in the number of cases or controls exposed to perinatal trauma or birth asphyxia. Gastric suction at birth was associated with a 3-fold greater risk of a severe functional intestinal disorder later in life, whereas maternal and perinatal variables were not. The authors speculated that noxious stimulation at birth caused by gastric suction might promote the development of long-term visceral hypersensitivity and cognitive hypervigilance leading to functional intestinal disorders. The role of early life events in causing FGID later in life is still controversial.2 Anand KJ, Runeson B, Jacobson B. Gastric suction at birth associated with long-term risk for functional intestinal disorders in later life. J Pediatr. 2004;144:449-454. Di Lorenzo C, Saps M. Gastric suction in newborns: guilty as charged or innocent bystander? J Pediatr. 2004;144:417-420. Di Lorenzo C, Saps M. Gastric suction in newborns: guilty as charged or innocent bystander? J Pediatr. 2004;144:417-20. 10 Gastric suction Trauma score > 0 Asphyxia score > 0 Anand KJ et al. J Pediatr 2004; 144:449

Evidence for Social Learning over Genetics in Twin Study Chance of one dizygotic twin having IBS if other does MZ DZ Chance of mother of twins having IBS if a twin has IBS 15.2% 6.7% 17.1% 5 10 15 20 % Evidence for Social Learning over Genetics in Twin Study Rates of IBS among dizygotic twins are significantly less than rates of IBS in mothers of twins. If genetics, rather than learning, were dominant we would expect these rates to be comparable. DZ = dizygotic; IBS = irritable bowel syndrome; monozygotic Levy RL, Jones KR, Whitehead WE, Feld SI, Talley NJ, Corey LJ. Irritable bowel syndrome in twins: Heredity and social learning both contribute to etiology. Gastroenterology. 2001;121:799-804. Levy RL et al. Gastroenterology 2001;121:799 P62

Parent Attention vs. Distraction Pediatrics Parent Attention vs. Distraction Questionnaire-Reported GI Symptom Ratings (range 0-20) 20 P< 0.01 Pain induced by water-load test Parents randomized to using distraction or attention in their interaction with children in pain All mothers felt distraction was inappropriate response to pain Pain Patients 15 Well Children 10 Parent Attention vs Distraction The object of this study was to assess the impact of parent attention and distraction on symptom complaints by children with and without chronic functional abdominal pain. Subjects and controls were asked to drink water through a tube from a hidden reservoir until they felt “completely full” (water load test). Parents were trained to interact with their children in one of three ways: attention, distraction, or no instruction. Compared to the no-instruction subgroup, symptom complaints by either children with chronic abdominal pain or well children nearly doubled in the attention subgroup and were reduced by half in the distraction subgroup. The effect of attention was greater for the female chronic abdominal pain subjects than it was for both the male subjects with pain and for the healthy controls. Parent response to a child’s symptom complaint can have significant effects in increasing or decreasing those complaints, especially in females. GI = gastrointestinal. Walker LS, Williams SE, Smith CA, Garber J, Van Slyke DA, Lipani TA. Parent attention versus distraction: impact on symptom complaints by children with and without chronic functional abdominal pain. Pain. 2006;122:43-52. 5 Distraction No Instruction Attention Walker LS et al. Pain 2006, 122:43 Youssef NN 2007©

DOLORE ADDOMINALE RICORRENTE La diagnosi di dolore addominale funzionale deve essere effettuata in positivo Test negativi non rassicurano il paziente, ma piuttosto rinforzano il modello medico di malattia Minime indagini diagnostiche

DOLORE ADDOMINALE RICORRENTE Anamnesi/Storia Psicosociale Esame obiettivo Indagini limitate

DOLORE ADDOMINALE RICORRENTE Anamnesi/Storia Psicosociale

Sintomi di allarme Artrite Dolore notturno Malattia perianale Disfagia Dolore persistente al quadrante superiore destro o inferiore destro   Artrite   Dolore notturno   Malattia perianale   Disfagia   Vomito persistente   Perdita di peso involontaria   Decelerazione della crescita lineare   Pubertà ritardata   Sanguinamento gastrointestinale   Diarrea notturna   Febbre inspiegabile   Storia familiare di MICI, malattia celiaca o Malattia Ulceroso-Peptica

SINDROME DEL COLON IRRITABILE (SCI) Disordini che possono mimare la SCI: Malattie Infiammatorie croniche intestinali Malattia Celiaca Malassorbimento di Carboidrati Infezioni (es. giardia) Malformazioni Intestinali Neoplasie Alterazioni del tratto Genito-urinario Malattie Intestinali Allergiche

MALATTIE ASSOCIATE ALLA DISPEPSIA IN ETA’ PEDIATRICA Reflusso Gastroesofageo Esofagite Eosinofila Gastrite Eosinofilica Ulcera Gastrica o Duodenale Duodenite Malattie della colecisti Malattia Epatica Malattia Pancreatica 23

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

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

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

DOLORE ADDOMINALE RICORRENTE: ESAME OBIETTIVO 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

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 164(5):1099-1103.e1

DOLORE ADDOMINALE RICORRENTE: INDAGINI DI LABORATORIO Emocromo completo con formula Proteina C-reattiva Velocità di eritrosedimentazione Pannello metabolico completo Analisi urine Coprocoltura ed esame parassitologico delle feci Breath test idrogeno o trial con dieta priva di lattosio Anticorpi antitransglutaminasi Calprotectina fecale

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 2004; 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

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

Approach to diagnostic testing Diagnosis/findings Basic laboratory tests Complete blood cell count Anemia, thrombocytosis, leukocytosis Erythrocyte sedimentation rate or C-reactive protein Systemic inflammation (e.g., inflammatory bowel disease) Albumin and total protein Nutrition and inflammation Tissue transglutaminase IgA, total IgA Celiac disease Urinalysis and urine culture Hematuria, urinary tract infection Stool guaiac, Calprotectin Inflammation Additional laboratory tests/imaging/other testing to consider Basic metabolic panel, including blood urea nitrogen/creatinine Electrolyte disturbance, renal insufficiency Aspartate aminotransferase/alanine aminotransferase, γ-glutamyl transpeptidase Hepatobiliary inflammation or obstruction Amylase, lipase Pancreatitis Stool culture and staining for ova and parasites Infectious colitis, giardiasis Breath testing for carbohydrate malabsorption Lactose or fructose intolerance Other symptom-guided diagnostic testing: abdominal ultrasound; contrast and other imaging studies; endoscopy/colonoscopy To be performed only if indicated by history, physicial examination findings or screening laboratory tests Eric Chiou and Samuel Nurko. Therapy. 2011 May 1; 8(3): 315–331.