Malattie da acido gastrico

Sedi primarie delle malattie acido-correlate Reflusso acido Esofagite Stenosi Esofago di Barrett Adenocarcinoma Gastrite Malattia ulcerosa peptica (Incluse le ulcere da FANS) Dispepsia All of the diseases on this slide are related to inappropriate amounts of acid/levels of acid secretion in the various regions of the upper gastrointestinal (GI) tract. These are the primary areas dealt with in this slide kit. Duodenite Ulcera duodenale

Malattie acido-correlate dell’esofago

Giunzione squamo-colonnare normale o linea Z

Definizioni Esofagite: Malattia da reflusso gastro-esofageo (GERD): Lesione della mucosa esofagea rilevabile endoscopicamente Malattia da reflusso gastro-esofageo (GERD): Reflusso gastro-esofageo patologico che può causare lesioni (dalla erosione semplice al Barrett) Malattia da reflusso non-erosiva (NERD): Reflusso gastro-esofageo patologico che non causa lesioni The primary symptom of acid-related diseases of the oesophagus is heartburn. The pain of heartburn can be severe and frightening for the patient. It can mimic the pain of a heart attack, so it is important to take seriously any symptoms with sudden onset. On examination, many patients with heartburn have oesophagitis – inflammation of the oesophagus that can be seen on endoscopy. Gastro-oesophageal reflux disease (GORD) is the pathological mechanism by which acid arrives in the oesophagus to cause inflammation/erosion of the oesophageal mucosa. Many patients do not have evidence of oesophagitis and are classified as having non-erosive reflux disease (NERD) – also referred to as endoscopy-negative reflux disease (ENRD) or symptomatic GORD. Barrett’s oesophagus is a pre-cancerous lesion. Talley et al., BMJ 2001; 323: 1294–7. de Caestecker, BMJ 2001; 323: 736–9. Nathoo, Int J Clin Pract 2001; 55: 465–9. Quigley, Eur J Gastroenterol Hepatol 2001; 13(Suppl 1): S13–18. Throughout this presentation, GORD is equivalent to gastro-esophageal reflux disease, GERD.

Epidemiologia Una delle più frequenti patologie del tratto g.i. IL 15% della popolazione ha almeno una volta la settimana pirosi e/o rigurgito L’incidenza è in aumento (obesità?) Maschi, > 50 anni

Patogenesi multifattoriale Fattori esofagei Fattori gastrici Rilasciamenti transitori ed inappropriati del LES Ipotonia del LES Ridotta clearance esofagea Diminuita resistenza della mucosa esofagea Ritardato svuotamento gastrico Incoordinazione motoria gastro-duodenale (reflusso biliare)

Vuotamento gastrico (grassi) Fisopatologia HCO3 salivare Ridotta difesa mucosa Ridotta clearance LES difettoso (fumo, grassi, alcool) – rilasciamenti transitori – tono basale Ernia hiatale secrezione acida (fumo, caffè) H+ Pepsina Bile ed enzimi pancreatici There are several possible mechanisms that can account for increased gastro-oesophageal reflux. These include: reduced salivary bicarbonate impairs neutralisation of gastric acid (may be caused by reduced secretion or impaired peristalsis and reduced saliva transport) impaired mucosal defence/acid clearance in the oesophagus (normal peristaltic activity in the oesophagus causes acid to be cleared back into the stomach – lying flat and agents such as alcohol and caffeine impair this mechanism increased reflux of acid from the stomach due to impaired pressure at the lower oesophageal sphincter, to increased back pressure from the stomach or to delayed gastric emptying (which allows acid to stay longer in the stomach and hence have more opportunity to reflux into the oesophagus). Many lifestyle factors, such as smoking, alcohol intake, fat intake and obesity can cause GORD. LOS = lower oesophageal sphincter. pressione intragastrica (obesità, lying flat) Reflusso biliare Vuotamento gastrico (grassi) de Caestecker, BMJ 2001; 323:736–9. Johanson, Am J Med 2000; 108(Suppl 4A): S99–103.

Fattori di rischio per la GERD Età avanzata Obesità/ sovrappeso Familliarità1 Ernia hiatale? 1 Sclerodermia Uso di FANS1 Danno da farmaci3 It is important to investigate the presence of possible risk factors for GORD. A German study among patients in general practice found that axial hiatus hernia, positive family history, advancing age, being overweight, female gender and treatment with NSAIDs or aspirin were significant risk factors in the development of GORD. Evidence also shows that smoking and psychological stress are risk factors for GORD symptoms. Some data suggest that caffeine consumption can aggravate symptoms of GORD but the evidence is inconclusive. A common cause of oesophagitis is drug-induced injury – particularly when medications are taken at bedtime or without fluids. Fumo2 Stress psicologico 2 1. Hollenz et al., Dtsch Med Wochenschr 2002; 127: 1007–12. 2. Stanghellini, Scand J Gastroenterol 1999; (Suppl 231): 29–37. 3. Jaspersen, Drug Safety 2000; 22: 237-49.

Farmaci che possono indurre la comparsa di sintomi esofagei Altri farmaci e.g. alendronato glibenclamide captopril nifedipina teofillina diazepam alprenololo warfarin nitroderivati FANS e.g. aspirina indometacina piroxicam ibuprofene naproxene diclofenac Sintomi Drugs that are responsible for inducing oesophageal disorders include: NSAIDs: aspirin, indomethacin, piroxicam, ibuprofen, naproxen, diclofenac Antibacterials: doxycycline, tetracycline, oxytetracycline, minocycline, penicillins, amoxicillin, ampicillin, erythromycin, tinidazole Other drugs: potassium chloride, quinidine, alendronate, calcium dobesilate, ascorbic acid, ferrous sulphate, glibenclamide, mexiletine, captopril, nifedipine, estramustine phosphate sodium, theophylline, diazepam, emepronium bromide, thiazinamium, thioridazine, alprenolol, warfarin, phenytoin, phenobarbital, tryptophan, clomethiazole, naftidrofuryl. Antibatterici e.g. tetraciclina minociclina penicilline amoxicillina eritromicina tinidazolo Jaspersen, Drug Safety 2000; 22: 237-49.

Classificazione delle malattie esofagee acido-correlate

Esofagite Classificazione di Los Angeles Grado A Grado B Una o più lesioni della mucosa, non superiori a 5 mm, che non si estendono tra gli apici di due pliche mucose Una o più lesioni della mucosa, superiori a 5 mm, che non si estendono tra gli apici di due pliche mucose Grado C Grado D Una o più lesioni della mucosa, continue tra gli apici di due o più pliche mucose, ma che si estendono per meno del 75% della circonferenza Una o più lesioni mucose, che si estendono per almeno il 75% della circonferenza The Los Angeles classification system can be used to describe varying severities of reflux oesophagitis. The Savary-Miller classification can also be used to classify oesophagitis (see next slide) and is more commonly used in Europe. Lundell et al., Gut 1999; 45: 172–80.

Classificazione di Los Angeles Grado A Grado B Grado C Grado D

Esofagite di grado A

Esofagite di grado C

Esofagite di grado D

Presentazione della GERD Sintomi tipici e atipici e complicazioni

Modalità di presentazione della GERD Sintomi tipici Sintomi atipici Complicazioni Pirosi Dolore toracico Disfagia Erosioni esofagee e/o ulcere Rigurgiti Raucedine (“laringite da reflusso”) Stenosi The classic symptom of GORD is heartburn, with or without regurgitation. Patients may or may not have evidence of oesophagitis. There are also atypical symptoms, including chest pain, hoarseness and asthma, so it is important to consider GORD when patients present with these symptoms. Patients with GORD may develop complications, some of which are very serious. Background information on some of these symptoms is given in the next few slides. Esofago di Barrett Asma, tosse cronica, dispnea Adenocarcinoma esofageo Erosioni dei denti Nathoo, Int J Clin Pract 2001; 55: 465–9.

Definizione di pirosi Sensazione di bruciore o di fastidio retrosternale con irradiazione verso l’alto e talvolta posteriormente E’ scatenata da: Postura: posizione supina, piegamenti del tronco Alimenti ipotonizzanti del LES: menta, cioccolata, caffè Alimenti irritanti: alcool, agrumi Pasti abbondanti o ricchi in grassi

Definizione di rigurgiti Risalita di materiale endoesofageo nella cavità buccale Non sono preceduti da nausea Non si accompagnano a contrazione della muscolatura gastrica e della parete addominale

Sintomi atipici respiratori

Sintomi d’asma con reflusso esofageo Meccanismi alla base dei sintomi asmatici conseguenti al reflusso esofageo acido Sintomi d’asma con reflusso esofageo Broncocostrizione indotta dalla presenza di acido in esofago : Riflesso esofageo-bronchiale vago-mediato Aumento reattività bronchiale Microaspirazioni Oesophageal acid has two major effects on respiratory symptoms: bronchoconstriction increasing minute ventilation and respiratory rate. This results in a worsening of the symptoms of asthma. Reproduced with permission. Aumento: ventilazione frequenza respiratoria Harding & Sontag, Am J Gastroenterol 2000; 95(Suppl): S23–32.

Effetti dei PPI sui sintomi polmonari e GI in pazienti con asma 14 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Sintomi polmonari Sintomi gastrici (n=25) 12 Score dei sintomi 10 8 6 4 2 A double-blind, placebo-controlled, crossover study conducted with omeprazole 40 mg/day in 107 asthma patients with GORD. Weekly pulmonary (cough, dyspnoea and wheezing) and gastric (regurgitation, heartburn and chest pain) symptoms scores fell during omeprazole therapy. There was a significant improvement in the gastric symptom score with omeprazole compared to placebo (p=0.0001). While pulmonary symptom scores also improved with omeprazole compared to placebo, this improvement was not significant (p=0.14). There was a small but statistically significant improvement in night-time asthma (p=0.04). Note: Asthma is not an approved indication for omeprazole. Reproduced with permission. PPI (omeprazolo) Settimane Placebo Kiljander et al., Chest 1999; 16: 1257–64.

Complicazioni di un reflusso severo e prolungato

Complicazioni di un reflusso severo e prolungato Grado IV di Savary-Miller Stenosi esofagea Esofago di Barrett Adenocarcinoma esofageo Emorragia Perforazione Anemia Most patients present to the GP with heartburn or other symptoms of GORD. Relatively few will present for the first time with the more serious complications of GORD. Serious complications of GORD are generally managed by a specialist. Nathoo, Int J Clin Pract 2001; 55: 465–9.

Stenosi esofagea di tipo peptico

Stenosi esofagea di tipo peptico

Diagnosi e incidenza della stenosi esofagea Sintomi Disfagia Odinofagia Calo ponderale Pirosi Test diagnostici Esofago baritato Endoscopia Incidenza Prevalenza della GERD: 20–40% nella popolazione La stenosi si verifica in circa l’11% dei pazienti con GERD La stenosi è più frequente nel sesso maschile Patients with oesophageal stricture present with difficulty in eating and swallowing and this generally results in reduced food intake and hence weight loss. Reduced capacity at the level of the lower oesophageal sphincter may also lead to increased reflux of gastric acid. The diagnosis of stricture requires visualisation of the oesophagus. Stricture occurs in a relatively low percentage of people with GORD. However, as the prevalence of GORD is 20–40% in the general population, there is the potential for a relatively high number of people to progress to stricture if GORD is not managed appropriately in the long term. Spechler, Digestion 1992; 51(Suppl 1): 24–9. Johanson, Am J Med 2000; 108(Suppl 4A): S99–103.

Esofago di Barrett Sostituzione dell’epitelio squamoso esofageo con mucosa di tipo colonnare, al di sopra del cardias anatomico (metaplasia intestinale con epitelio specializzato) Fenomeno di adattamento della mucosa esofagea allo stimolo cloridro-peptico cronico secondario al reflusso gastro-esofageo

Esofago di Barrett

Prevalenza e rischio dell’ esofago di Barrett in Europa/USA Riscontro endoscopico di Barrett : 0.5–2%1 Riscontro di Barrett in corso di diagnosi di GERD: 10–15%2,3 Il Barrett è frequente nei maschi di razza bianca Il Barrett incrementa il rischio di cancro esofageo da 50 a 100 volte4 Barrett’s oesophagus is a condition in which the normal squamous epithelium of the oesophagus is replaced by metaplastic columnar epithelium. This is a pre-malignant condition with a 50– to 100-fold (possibly even higher) increased risk of oesophageal cancer. About 10–15% of patients with GORD will have Barrett’s oesophagus. The condition is most common in white men. 20–40% of the adult population experiences heartburn, the primary symptom of GORD. Barrett’s oesophagitis, along with stricture, is one of the complications of GORD. Due to the increased risk of developing oesophageal adenocarcinoma, many gastroenterologists recommend regular (yearly or biennial) endoscopic screening with multiple biopsies to detect dysplasia in patients with Barrett’s oesophagus. 1. Jankowski et al., The Lancet 2000; 356: 2079–85. 2. Gore et al., Aliment Pharmacol Ther 1993; 7: 623–8. 3. Spechler, Digestion 1992; 51(Suppl 1): 24–9. 4. Peters et al., Gut 1999; 45: 489–94.

Mortalità per adenocarcinoma esofageo (Inghilterra e Galles) 4000 3500 3000 2500 Mortalià annua 2000 1500 1000 The number of patients developing adenocarcinoma of the oesophagus is increasing year on year. 500 79 84 89 94 97 Anno Office of National Statistics, 1999.

Adenocarcinoma esofageo

Adenocarcinoma esofageo

Diagnosi e terapia della GERD

Diagnosi strumentale Endoscopia Esame Rx con mezzo di contrasto dell’esofago e dello stomaco pH-metria di 24 ore Manometria

Tracciato pH-metrico patologico

Sintomi d’allarme Odinofagia Disfagia Sanguinamento Allarme Vomito Alarm features for GORD include: Dysphagia – difficulty swallowing Odynophagia – pain on swallowing Bleeding, which may present as melaena or haematemesis or result in anaemia. Weight loss can also include anorexia. The presence of one or more of these symptoms might indicate: underlying cardiac disease that is presenting as heartburn blockage of the oesophagus, possibly due to stricture or adenocarcinoma of the oesophagus. Vomito Calo ponderale Nathoo, Int J Clin Pract 2001; 55: 465–9.

Linee-guida ACG per la GERD: Iniziale terapia sintomatica se presenti sintomi tipici Indagini diagnostiche in caso di fallimento della terapia o di sintomi atipici L’endoscopia è l’indagine di prima scelta Endoscopia con biopsie indispensabile per la diagnosi di esofago di Barrett Nella stragrande maggioranza dei pazienti i PPI promuovono un rapido sollievo dei sintomi e la guarigione dell’esofagite Nelle forme meno severe anche gli anti-H2 sono efficaci a dosi frazionate Current American College of Gastroenterology guidelines recommend first-line empirical therapy with a PPI or other antisecretory agent for the majority of patients with a typical disease profile. ACG: American College of Gastroenterology DeVault & Castell, Am J Gastroenterol 1999; 94: 1434–42.

Endoscopia nella GERD Non necessaria per la diagnosi di GERD tipica Indispensabile per l’esofago di Barrett Principale indicazione per l’endoscopia Verifica il grado dell’esofagite Controversie: Quando Disponibilità Costo- efficacia Endoscopy is not recommended for the routine management of GORD, which is usually treated effectively in general practice. Most guidelines recommend a trial of antisecretory agents, such as PPIs, as first-line therapy in suspected GORD. If a diagnosis of GORD is established, treatment with a PPI or other antisecretory agent is generally appropriate, regardless of the grade of oesophagitis found on endoscopy. There are differences in practice in countries across Europe. National guidelines may indicate an early endoscopy to definitively establish the cause of symptoms. DeVault & Castell, Am J Gastroenterol 1999; 94: 1434–42. Dent et al., BMJ 2001; 322: 344–7.

Diagnosi differenziale Ernia hiatale Stenosi Cancro Dolore toracico cardiaco Dispepsia funzionale Patients presenting with symptoms of GORD may have a range of underlying conditions, so it is important to take a careful history, including the duration, location and severity of symptoms. If a simple trial of acid suppression is not successful in treating the symptoms, endoscopy will probably be required to establish a firm diagnosis. Nathoo, Int J Clin Pract 2001; 55: 465–9.

Ernia hiatale: endoscopia

Terapia della GERD

Modifiche dello stile di vita Procinetici farmaci della motilità Terapia Modifiche dello stile di vita Antacidi e alginato PPI Opzioni Anti-H2 For patients with typical GORD there are a number of long-term treatment approaches. In most patients the disease can be managed by lifestyle modifications and through the choice of appropriate antisecretory drug treatment (e.g. a PPI). Surgery is a last resort in GORD. Procinetici farmaci della motilità Chirurgia Hatlebakk & Berstad, Clin Pharmacokinet 1996; 31: 386–406.

Modifiche dello stile di vita Riduzione dl peso Sollevamento della testata del letto Stop al fumo Modifiche Basso consumo di sostanze pro-reflusso (es. alcool, caffè, cioccolata, menta) Uso di farmaci alternativi a quelli pro-reflusso (es. Teoflllina, anticolinergici) As in all fields of medicine, lifestyle modifications are effective in the short term, but in the long term they require the patient to be highly motivated. Changing diet, stopping smoking and losing weight are all difficult for patients to achieve long term. Often patients will require counselling support and the use of antisecretory agents to remove symptoms while the lifestyle changes take effect. Pasti piccoli, non mettersi a letto subito dopo I pasti, ridurre I cibi grassi

Antiacidi Innalzano il pH del contenuto gastrico Utili ad un rapido sollievo dei sintomi di lieve entità Non utili per la terapia della GERD o dell’esofagite perchè poco efficaci Effetti collaterali: Accumulo nei pazienti con insuficienza renale Sindrome alcalinizzante (ad alte dosi) Stipsi Diarrea Antacids are effective for short-term relief of GORD symptoms, although their effectiveness has not been confirmed in controlled trials. Many patients, particularly those who have not consulted their GP, rely on self-medication with antacids to control their symptoms. Sonnenberg, Pharmacoeconomics 2000; 17: 391–401. de Caestecker, BMJ 2001; 323: 736–9. Hatlebakk & Berstad, Clin Pharmacokinet 1996; 31: 386–406. Scott & Gelhot, Am Fam Physic 1999; 59: 1161–9.

Procinetici Incrementano il tono del LES e accelerano lo svuotamento gastrico Agiscono sulla pirosi ma non guariscono l’esofagite La Cisapride è il più efficace ma: PPI hanno una superiore efficacia Il rischio di effetti collaterali di tipo cardiaco attualmente ne impedisce l’uso Motility-modifying agents relieve the symptoms of heartburn to a similar degree to H2RAs, but do not heal oesophagitis. Some agents have troublesome cardiac or CNS side effects. Cisapride has been withdrawn in some markets. Prokinetic motility agents can be useful in patients with GORD and other dyspeptic symptoms such as nausea or early satiety. Vicari et al., Acta Endoscopica 1999; 5: 607-11. van Rensburg et al., Gastroenterology 2000; 118(Suppl 2): A1318. de Caestecher, Eur J Gastroenterol Hepatol 2002; 14: 5–7. de Caestecker, BMJ 2001; 323: 736–9. Dent et al., BMJ 2001; 322: 344–7.

Antagonisti dei recettori H2 (Anti-H2) Inibiscono la stimolazione istaminica della cellula parietale gastrica, riducendo la secrezione acida Inizio d’azione ritardato ma di più lunga durata rispetto agli antacidi Meno efficaci dei PPI sia sui sintomi che sulle lesioni Before the development of the PPIs, the H2RAs were the mainstay of antisecretory therapy. Ranitidine is still extensively used by GPs in many countries, and remains on formularies and in local and national guidelines. However, there is good evidence that H2RAs provide poorer acid suppression than PPIs, and thus are less desirable for short- or long-term treatment. de Caestecker, BMJ 2001; 323: 736–9. Sonnenberg, Pharmacoeconomics 2000; 17: 391–401.

Inibitori della pompa protonica (PPI) Omeprazolo Lansoprazolo Pantoprazolo Rabeprazolo Esomeprazolo These are the main PPIs currently available in Europe

% di guarigione dell’esofagite con diversi PPI L = lansoprazolo P = pantoprazolo O = omeprazolo R = rabeprazoleo 30 = 30 mg/die, 20 = 20 mg/die, 40 = 40 mg/die Petite et al. L30/O20 Castell et al. L30/O20 Mee et al. L30/O20 Mulder et al. L30/O40 Mossneret al. P40/O20 Corinaldesi et al. P40/O20 Hotz et al. P40/O20 Vicari et al. P40/O20 Data from double-blind, randomised, multicentre controlled trials show that PPIs achieve good healing rates in GORD after 8 weeks of therapy. There are no significant differences in healing rates or symptom relief with pantoprazole and omeprazole, and rabeprazole and omeprazole. Healing rates are generally comparable for lansoprazole and omeprazole. Thjodleifsson et al. R20/O20 Dekkers et al. R20/O20 0 20 40 60 80 100 Pazienti guariti a 8 settimane (%) Thomson, Curr Gastroenterol Rep 2000; 2: 482–93.

Terapia di mantenimento

Terapia di mantenimento della GERD Obiettivi: Controllo dei sintomi Assenza di lesioni esofagee Prevenzione delle complicanze Possibili scelte: PPI Anti-H2 a dosi standard o ad alte dosi Chirurgia o tecniche endoscopiche (ancora in fase sperimentale) The options for pharmacological treatment of GORD do not change in the longer term – PPIs and H2RAs remain the antisecretory agents of choice. Effective long-term therapy is essential to prevent the development of complications. Anti-reflux surgery eliminates the need for lifelong drug therapy, and may be preferred by some patients. Open anti-reflux surgery and long-term PPI therapy have been shown to be equally effective over 5-year follow up, although there is a small (0.2%) risk of mortality associated with surgery. Laparoscopic surgery is now popular, but maintenance of special surgical skills is required for consistent results. New endoscopic techniques, such as high frequency radiotherapy and the formulation of pliccae by sucking and stitching folds into the mucosa (Stretta method) aim to narrow the gastro-oesophageal junction and hence reduce the reflux of acid. Experience with these methods is still very limited and thus restricted to clinical research. Dent et al., BMJ 2001; 322: 344–7. Nathoo, Int J Clin Pract 2001; 55: 465–9.

Mantenimento nell’esofagite con PPI: % di remissione a 12 mesi Lansoprazolo 15mg qd Lansoprazolo 30mg qd Omeprazolo 20mg qd Ranitidina 300mg daily Ranitidina 600mg daily Placebo 100 80 60 40 20 * 90 89 90 91 85 87 86 87 * 79 * 79 72 73 * 65 * 66 Remissioni (%) 31 The slide summarises the results of seven trials studying lansoprazole and other therapies for healed erosive oesophagitis maintenance therapy. All trials showed that daily doses of 15 or 30 mg lansoprazole are associated with low rates of relapse after 6 months and a year. Lansoprazole was significantly more effective than ranitidine in maintaining remissions. 24 15 50 53 99 85 59 56 55 295 309 302 124 120 100 106 96 89 81 Hatlebakk Poynard Robinson Baldi Carling Hirschowitz Gough 1997 1995 1996 1996 1996 1999 1996 *p0.001 Freston et al., Drugs 2000; 62: 1173.

Gestione delle complicanze The complications of GORD are: oesophageal stricture Barrett’s oesophagus ulceration or bleeding oesophageal adenocarcinoma.

Stenosi Dilatazione endoscopica: necessarie più sedute per alto tasso di recidive Soppressione della secrezione acida con PPI Oesophageal stricture is one of the complications of GORD. This complication can be treated by: dilatation of the oesophagus, which may need to be repeated as the recurrence of stricture following dilatation is high acid suppression with PPI therapy. Note: PPIs are not indicated for stricture in all countries. 1. de Caestecker, BMJ 2001; 323: 736–9.

Esofago di Barrett Soppressione acida con PPI1 Sorveglianza endoscopico/istologica Ablazione (elettrocauterizzazione, laser o terapia fotodinamica) in combinazione con terapia di soppressione Resezione esofagea distale Barrett’s oesophagus is one of the complications of GORD. It can be managed in a number of ways, as listed here. Some of these management options are discussed in more detail in the following slides. Note: PPIs are not indicated for Barrett’s oesophagus in all countries. 1. de Caestecker, BMJ 2001; 323: 736–9.