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DRUG INDUCED INJURY OF THE G.I. TRACT David A. Owen University of British Columbia NON STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs) These are the most common drugs causing intestinal injury. In the majority of cases these agents are not physician prescribed but are obtained “over the counter” from drug stores and supermarkets etc. Their use is so widespread that patients may be assumed to be taking them until proved otherwise. Unfortunately, information about their use is seldom provided on patient pathology requisitions. Advertisers’ claims that their NSAIDs are safer than the other companies NSAIDs may or may not be correct and it is safe to assume that any NSAID may cause GI problems The pathologic findings do not differ among the various brands available. Low-dose preparations may also cause problems although as a general rule higher doses and prolonged periods of administration result in greater problems. It has been estimated that low-dose aspirin administration increases the risk of upper gastro-intestinal bleeding by 2-4%. In the UK it has been estimated that there are 12,000 hospital admissions annually that are attributable to NSAID use. 2230 of these patients died. Mechanisms of action: 1) Many NSAIDs are acidic in nature (e.g. aspirin) and are capable of directly interfering with the mucus that covers the gastrointestinal mucosa. This may lead to breaks in the mucous barrier. In addition, the chemical nature of the NSAIDs themselves can directly irritate the exposed mucosa. 2) Cyclooxygenase (COX) produces prostaglandins that are important for maintaining mucosal integrity in gastrointestinal mucosa, particularly in the stomach where they mediate blood flow and epithelial repair. NSAIDs inhibit COX1 and consequently prostaglandin production resulting in neutrophil mediated damage to mucosal endothelium and ulceration. Esophagus: NSAID damage in the esophagus produces a syndrome known as “pill esophagitis”. Other drugs including tetracyclines, clindamycin, ascorbic acid, iron supplements and bisphosphonates (e.g. alendronate) may also cause pill esophagitis and the histologic changes produced are similar. The basic disease mechanism of mucosal damage is poor swallowing and lodgement of pills at the level of the aortic arch or in the distal esophagus. Ineffective swallowing may be promoted by ingestion of pills when the patient is in a horizontal position or by taking inadequate amounts of water. The contents of the pills are caustic and release of drugs from the core produces inflammation and eventually ulceration. Endoscopically, lesions present as discrete “punched out” ulcers with relatively little damage to adjacent mucosa. Histologically there is neutrophil infiltration, erosions or deep ulcers. Occasionally polarizable crystalline pill remnants can be identified. There is some evidence that NSAIDs given in standard doses is harmful to the esophagus and promotes esophagitis, esophageal ulcers and stricture formation. Stomach and Duodenum: A number of gastric lesions are described in patients that are taking NSAIDs. These include erosive gastritis, erosive duodenitis, deep ulcers (stomach and duodenum) and reactive gastropathy. Erosive gastritis may be hemorrhagic or non-hemorrhagic. Ulcers secondary to NSAIDs tend to be deeper and larger than the usual type of peptic ulceration. Reactive gastropathy (also known as chemical gastritis) probably occurs in between one third and one half of patients taking NSAIDs. Endoscopically, it is characterized by mucosal redness. Histologically, there is foveolar hyperplasia resulting in a corkscrew appearance. The individual cells show cytoplasmic mucin depletion with enlarged nuclei and prominent nucleoli. The lamina propria is congested and edematous. Small tongues of muscle from the muscularis mucosae may extend into the lamina propria as far as the surface epithelium. The lamina propria shows no increase in inflammatory cells. Reactive gastropathy secondary to NSAIDs is often patchy because the pills break up into small fragments. A more diffuse antral distribution of reactive gastropathy suggests the possibility of duodenal reflux and increased mucosal surface cell lost secondary to the cytotoxic properties of bile. The underlying pathogenesis of reactive gastropathy is increased exfoliation of cells from the mucosal surface and the mucosal hyperplasia is a compensatory reaction. If the rate of exfoliation exceeds the rate of epithelial regeneration then an erosion will develop. Continued use of NSAIDs will result in frank ulceration and expose the patient to the possibility of complications such as bleeding and perforation. Lower gastro-intestinal tract: NSAIDs may also produce ulcers in the distal small bowel and proximal colon. The pathogenesis of small bowel ulcers is similar to that of esophageal ulceration: local irritative effect. Bile has the effect of promoting this damage and suppression of prostaglandins does not seem to be involved. It is interesting to note that ligation of the bile duct prevents small intestinal damage by NSAIDs. Multiple colonic lesions have been attributed to NSAIDs. The list includes: non-specific colitis, erosions, ulcers, diaphragm disease, collagenous colitis, lymphocytic colitis, pseudomembranous colitis, eosinophilic colitis and apoptotic colonopathy. They may also exacerbate ulcerative colitis and diverticular disease. Ulceration in the colon may be due to direct mucosal irritation by the drugs or it may be secondary to suppression of prostaglandin production. Colonic ulcers are “non-specific” histologically and resemble the NSAIDs induced ulcers in the stomach and esophagus. Typically they are sharply circumscribed with dense fibrosis at the base. Inflammation is usually scanty and confined to the immediate ulcer edge. They have some features similar to ischemic ulceration. In older literature NSAIDs ulcers were often referred to as “solitary ulcer of the cecum” and considered to be ischemic in etiology. This was an inappropriate designation as the ulcers are commonly multiple and not confined to the cecum. Diaphragm disease is a rare complication of NSAID therapy. It mainly involves the small bowel but occasionally my affect the proximal large bowel. Histologically diaphragms consist of a thin incomplete membrane composed of a central fibrous core and covered by normal or attenuated mucosa. At the inner edge of the membrane there is often nonspecific ulceration. Fibrosis may extend into the submucosa of the adjacent tubular bowel but generally the muscular component of the bowel wall is unaffected. One common effect of NSAIDs is to promote epithelial apoptosis. In turn this leads to increased epithelial turnover with loss of cells that could contain pre-cancerous mutations. This is one of the proposed benefits of taking low-dose aspirin on a daily basis. It follows therefore that biopsies from patients taking this medication may demonstrate increased apoptosis. This change has been demonstrated in gastric and colo-rectal biopsies. PROTON PUMP INHIBITORS (PPIs) Patients treated with PPIs will inevitably develop hypoclorhydria. This leads to antral G cell hyperplasia and hypergastrinemia which in turn leads to hyperplasia and hypertrophy of parietal cells and hyperplasia of ECL cells in the gastric body. Initially hyperplasia of the ECL cells (histamine producing) is linear but with continued stimulation nodularity may develop. Unlike ECL stimulation in cases of pernicious anemia it is unusual for neuroendocrine neoplasms (micro carcinoids) to develop. Gastrin stimulation of parietal cells leads to cytoplasmic expansion and proliferation. Parietal cells may extend downwards to deeper levels of the mucosa where they appear to crowd out chief cells. They may also expand upwards into the gastric foveolae. Morphologic changes consist of gland dilatation with swelling and bulging of individual cells (parietal cell profusion). The cells lining the gland therefore produce a serrated rather than a smooth outline. The cytoplasm of the parietal cells becomes paler and may ultimately become vacuolated as the canalicular system expands. PPIs have also been associated with the development of fundic gland polyps. Polyps are present in 17% of individuals after three months treatment and in 35% after five months treatment. Reports suggest that the polyps will regress after PPI treatment is stopped but will reappear when treatment is re-started. Histologically, the polyps themselves are an exaggerated version of PPI changes in flat mucosa with parietal cell overgrowth and cyst formation. It is rare to be able to identify Helicobacter pylori organisms in patients who are taking PPIs long-term. However, some authors have identified overgrowth of non-specific cocci and bacilli. This presumable represents oral contamination with growth in the absence of stomach acid. INTESTINAL DISEASE SECONDARY TO CHEMOTHERAPY AND RADIOTHERAPY The effects of cancer chemotherapy and radiotherapy on tissues are similar. Low doses produce degenerative changes within epithelial cells that are accompanied by nonspecific lamina propria inflammation. These changes persist for about four months following treatment after which they gradually resolve. Intermediate doses will result in permanent damage usually in the form of atrophy. This includes loss of glands (particularly oxyntic glands), intestinal metaplasia and crypt shortening and distortion (small and large intestine). Larger doses may produce deep, non-healing ulcers. Epithelial cytologic changes that accompany epithelial regeneration have to be distinguished from dysplasia. Chemo-radiotherapy changes are characterized by: 1) Enlarged vesicular nuclei with prominent but irregular nucleoli, 2) Cytoplasmic degenerative changes with vacuolation and eosinophilia. 3) Syncytial change in the surface epithelium. 4) Atypia of fibroblasts and endothelial cells. 5) Absence of atypical mitoses, 6) Changes affect the glands and foveolae of the stomach. In the stomach chemotherapy changes are most frequent following hepatic arterial 5FU infusion for the treatment of primary and secondary liver cancer. In the colon radiotherapy changes are commonly seen alongside recto-sigmoid carcinomas that have been treated prior to total mesenteric excision. Radiotherapy changes that are seen closely mimic chronic ulcerative colitis with dysplasia. However, the main distinguishing feature is uniformity of changes following radiation versus patchy dysplasia in inflammatory bowel disease. ANTIBIOTICS Some antibiotic tablets are large (e.g. tetracycline, doxycycline) and difficult to swallow. They may lodge in the esophagus and cause localized inflammation with erosion and ulceration (pill esophagitis). Antibiotics are associated with the development of pseudomembranous colitis. However, this is not a direct toxic effect of the drug. The normal colonic flora may be destroyed leading to an overgrowth of cytotoxin producing Clostridium difficile. Blood volume depletion in patients with pseudomembranous colitis may produce ischemic changes in addition to the pseudomembranes. Antibiotic associated hemorrhagic colitis (AAHC) may produce a clinical and pathologic picture resembling colonic ischemia. The pathogenesis is unknown. Antibiotics primarily implicated in causing this condition include penicillin derivatives such as ampicillin and amoxicillin. Rarely macrolides, cephalosporin, chloramphenicol, fluroquinalones, and tetracycline have been implicated. This condition is more commonly recognized in Japan than in North America. This may relate to differences in normal bowel microflora. POTASSIUM CHLORIDE Potassium replacement may be prescribed for patients on diuretics. Many pharmacologic preparations are designed for “slow-release” of the drug. If this does not occur, localized damage to gastrointestinal mucosa may occur and the effects can be very similar to those of NSAIDs. Specifically, lesions that have been identified include: 1) Pill esophagitis with or without fibrous strictures. 2) Gastric, small and large bowel erosions, erosions, ulcers and fibrous strictures. DRUG MEDIATED ISCHEMIC COLITIS A wide variety of drugs have been implicated. These include: antibiotics, appetite suppressants (phentermine), chemotherapeutic agents (taxanes and vinca alkaloids), constipating agents (mechanism of action may be via fecal impaction), decongestants (pseudoephedrine), digitalis (vasoconstriction of splanchnic circulation), diuretics (lower circulating blood volume), ergot alkaloids (vasoconstriction), steroid hormones (thrombosis), amphetamines, cocaine, interleukins, tricyclic antidepressants and phenothiazines, (See reference Hass AJ et al for detailed information). SODIUM PHOSPHATE ENEMAS AND LAXATIVES Preparations used for bowel preparation prior to colonoscopy can themselves be a cause of colitis. This is particularly true where purgatives based on sodium phosphate are used. They may cause low-grade focal colitis and increase epithelial apoptosis (apoptotic colopathy). Laxatives may also increase apoptosis and there is an association between this finding and melanosis coli. ALENDRONATE This drug is used for treating osteoporosis and other bone disorders. Its use has been associated with pill esophagitis and gastro-duodenal ulceration. Crystals may sometimes be seen in the base of the ulcers. IRON Orally ingested iron may cause damage to the upper GI tract. Two patterns of injury are noted: 1) Pill esophagitis with ulceration. Blackish crystalline material may be demonstrated in the base of ulcers. 2) Gastric iron deposition within foveolae, glands and lamina propria. In both instances histochemical stains for iron (Perl’s Prussian blue reaction) will be positive. KAYEXALATE Kayexelate is an ion exchange resin which is active in the small bowel where it exchanges sodium ions for potassium ions in the treatment of hyperkalemia. It may cause erosions and ulcers within the esophagus, stomach and duodenum. In the base of the ulcers non-polarizable rhomboid or triangular crystals are present. These crystals stain red with PAS/D and acid fast stains. COLCHICINE AND TAXOL Taxol is an anti-cancer agent. Colchicine is used in the treatment of gout. Both drugs interfere with tubulin and inhibit its polymerization. This causes mitotic arrest. Histologically ring-shaped mitotic figures may be seen in the proliferation zones of the esophagus, stomach and duodenum. MYCOPHENOLATE Mycophenolate is used in organ transplant patients for prevention and suppression of acute rejection. Colonic biopsies from patients taking these drugs show changes in up to 70% of cases. A variety of changes have been described and these may occur as isolated findings or in combination. These include apoptosis, architectural distortion and crypt atrophy, IBD-like changes, GVHD-like changes, ischemia-like changes and selflimited colitis-like changes. PANCREATIC ENZYME REPLACEMENTS This topic is of historic interest only as the drugs responsible for fibrosing colonopathy have now been withdrawn from use. Formerly, high-strength pancreatic enzymes were combined with methacrylic acid and caused segmental fibrous strictures particularly in the proximal colon. Biopsies of the strictures showed increased intramucosal eosinophils. REFERENCES: Cappell MS. Colonic toxicity of administered drugs and chemicals. Am J Gastroenterol 2004;99:1175-90 Wallace JL. Non-steroidal anti-inflammatory drugs and gastroenteropathy: the second hundred years. Gastroenterology 1997:112:1000-1016. Maguire A, Sheahan K. Pathology of oesophagitis. Histopathology 2011; Misdraji J. Drug-induced pathology of the upper gastrointestinal tract. Diagn Histopathol 2010;14:411-417. Mason JC. NSAIDs and the esophagus. Eur J Gastroenterol Hepatol 1999;11:369-373 Boyce Jr. HW. Drug-induced esophageal damage: diseases of medical progress. Gastrointest Endosc 1998;47:547-550 Lewis JH. Gastrointestinal injury due to medicinal agents. Am J Gastroenterol 1986;81;819-834. Parfitt JR, Driman DK. Pathological effects of drugs on the gastrointestinal tract: a review. Hum Pathol 2007;38:527-536 Lanas A, Hirschowitz Toxicity of NSAIDs in the stomach and duodenum. Eur J Gastroenterol Hepatol 1999;11:375-381. Sherman A, Bini EJ. Pill-induced gastric injury. Am J Gastroenterol 1999;94; 511-513 Puspok A, Kiener H-P, Oberhuber G. Clinical, endoscopic and histologic spectrum of nonsteroidal anti-inflammatory drug-induced lesions in the colon. Dis Colon Rectum 2000;43:685-691 Faucheron J-L. Toxicity of non-steroidal anti-inflammatory drugs in the large bowel. Eur J Gastroenterol Hepatol 1999;11:389-392. Bjarnson I, Hayllar J MacPherson AJ, Russell AS. Side effects of Nonsteroidal anti-inflammatory drugs on the small and large intestine in humans. Gastroenterology 1993;104;1832-1847. Fortun PJ, Hawkey CJ. Nonsteroidal anti-inflammatory drugs and the small intestine. Curr Opin Gastroenterol 2005;21:516-526. Goldstein NS, Cinenza AN. The histopathology of Nonsteroidal anti-inflammatory drugassociated colitis. Am J Clin Pathol 1998;110:622-628. Lang J, Price AB, Levi AJ, et al. Diaphragm disease: pathology of disease of the small intestine induced by non-steroidal anti-inflammatory drugs. J Clin Pathol 1988;41:516-26. Giardiello FM, Hansen III C, Lazenby AJ. Collagenous colitis in the setting of Nonsteroidal antiinflammatory drugs and antibiotics. Dig Dis Sci 1990;35:257-260. Riddell RH, Tanaka M, Mazzoleni G. Non-steroidal antiinflammatory drugs as a possible cause of collagenous colitis. Gut 1992;33:683-687. Wilson RG, Smith AN, Macintyre M. Complications of diverticular disease and non-steroidal anti-inflammatory drugs: a prospective study. Br J Surg 1990;77:1103-1104. Gleeson M, Ramsay D, Hutchinson S, Spencer D, Monteith G. Colitis associated with nonsteroidal anti-inflammatory drugs. Lancet 1994;344:1028. Gentric A, Pennec YL. Dicolfenac-induced pseudo-membranous colitis. Lancet 1992;340:126127. Driman DK, Wright C, Tougas G, Riddell RH. Omeprazole produces parietal cell hypertrophy and hyperplasia in humans. Dig Dis Sci 1996;41:2039-2047. Hassell E, Owen D, Kerr W, et al. Gastric histology in children treated with proton pump inhibitors long-term with emphasis on enterochromaffin like-cell hyperplasia. Aliment Pharmacol Ther 2011;33:829-836. El Zimaity HM, Jackson FW, Graham DY. Fundic gland polyps developing during omeprazole therapy. Am J Gastroenterol 1997;92:1858-1860. Cats A, Schenk BE, Bloemena E, et al. Parietal cell protrusions and fundic gland cysts during omeprazole maintenance treatment. Hum Pathol 2000;31:684-690. Chondury U, Boyce HW Jr, Coppola D. Proton pump inhibitor-associated gastric polyps. Am J Clin Pathol 1998;110:615-621 Chande N, Driman DK. Microscopic colitis associated with lansoprazole: report of two cases and review of the literature. Scand J Gastroenterol 2007;42: 530-533. Brien TP, Farraye FA, Odze RD. Gastric dysplasia-like epithelial atypia associated with chemo radiotherapy for esophageal cancer: a clinicopathologic and immunohistochemical study of 15 cases. Mod Pathol 2001;14;389-396. Lim L, Gibbs P, Yip D, et al. A prospective evaluation of treatment with selective internal radiation therapy (SIR-spheres) in patients with unresectable liver metastases from colorectal cancer previously treated with 5-FU based chemotherapy. BMC Cancer 2005;6:132-138. Hass, Kozuch P, Brandt LJ. Pharmacologically mediated colon ischemia. Am J Gastroenterol 2007;102:1765-1780 Barcewicz PA, Welch JP. Ischemic colitis in young adult patients. Dis Colon Rectum 1980;23:109-114 Leriche M, Devroede G, Sanchez G, Rossano J. Changes in the rectal mucosa induced by hypertonic enemas. Dis Colon Rectum 1978; :227-236. Moulis H, Vender RJ. Antibiotic related colitis. J Clin Gastroenterol 1994;18:227-231. Gould PC, Khawaj FI, Rosenthal WS. Antibiotic associated hemorrhagic colitis. Am J Gastroenterol 1982;77:491-493. Welch DC, Wirth PS, Goldenring JR, et al. Gastric graft versus host disease re-visited: does proton pump inhibitor therapy affect endoscopic gastric biopsy interpretation. Am J Surg Pathol 2006;30:444-449. Lee FD. Importance of apoptosis in the histopathology of drug related lesions in the large bowel. J Clin Pathol 1993;46:118-122. Abraham SC, Cruz-Correa M, Lee LA, et al. Alendronate-associated esophageal injury: pathologic and endoscopic features. Mod Pathol 1999;12:1152-1157. Haig A, Driman DK. Iron-induced injury to the upper gastrointestinal tract. Histopathology 2006;48:808-812. Abraham SC, Bhagavan BS, Lee LA, et al. Upper gastrointestinal tract injury in patients receiving Kayexelate (sodium polystyrene sulfonate) in sorbitol: clinical, endoscopic and histopathologic findings. Am J Surg Pathol 2001;25:637-644. Iacobuzio-Donahue CA, Lee EL, Abraham SC, et al. Colchicine toxicity: distinct morphologic findings in gastrointestinal biopsies. Am J Surg Pathol 2001;25:1067-1073. Selbst MK, Ahrens WA, Robert ME, et al. Spectrum of histologic changes in colonic biopsies in patients treated with mycophenolate mofetil. Hum Pathol 2009;22:737-743. Al-Absi AI, Cooke CR, Wall BM, et al. Patterns of injury in mycophenolate mofetil-related colitis. Transplant Proc 2010;42:3591-3593. Pawel B, de Chadarevian JP, Franco ME. The pathology of fibrosing colonopathy of cystic fibrosis: a study of 12 cases and review of the literature. Hum Pathol 1997;28:395-399. DRUG INDUCED INJURY OF THE G.I. TRACT David A Owen University of British Columbia 10/02/2012 NSAIDs INDUCED GI INJURY • • • • • • • • • Pill esophagitis, ulcers and strictures Erosive gastritis and duodenitis Gastric and duodenal ulcers Reactive gastropathy Distal ileal ulcers Proximal colonic ulcers and focal colitis Diaphragm disease Collagenous and lymphocytic colitis Increased apoptosis 10/02/2012 10/02/2012 10/02/2012 10/02/2012 10/02/2012 10/02/2012 10/02/2012 10/02/2012 10/02/2012 10/02/2012 10/02/2012 10/02/2012 PROTON PUMP INHIBITORS (PPIs) • • • • • • Hypertrophy and hyperplasia of parietal cells Hyperplasia of ECL cells Gland dilatation Parietal cell “snouting” Parietal cell cytoplasmic vacuolation Fundic gland polyps 10/02/2012 10/02/2012 10/02/2012 10/02/2012 10/02/2012 10/02/2012 10/02/2012 10/02/2012 CHEMOTHERAPY AND RADIOTHERAPY • Early changes: Non-specific inflammation and cytologic changes consisting of 1) Syncytial change in surface epithelium 2) Enlarged vesicular nuclei and irregular nucleoli 3) Cytoplasmic eosinophilia and vacuolation • Chronic changes: Mucosal atrophy and intestinal metaplasia, non-healing ulcers, stricture formation 10/02/2012 10/02/2012 10/02/2012 10/02/2012 10/02/2012 10/02/2012 10/02/2012 10/02/2012 ANTIBIOTICS • Pill esophagitis (tetracycline, doxycycline) • Pseudomembranous colitis • Antibiotic associated hemorrhagic colitis (AAHC) (ampicillin, amoxicillin, macrolides, cephalosporin, chloramphenicol, fluoroquinolones, tetracycline. • Histologically and clinically AAHC resembles acute colonic ischemia 10/02/2012 POTASSIUM CHLORIDE • Pill esophagitis with or without fibrous strictures • Gastric, small bowel, large bowel erosions, ulcers and fibrous strictures 10/02/2012 DRUG MEDIATED ISCHEMIC COLITIS • • • • • • • • Antibiotics Phentermine Chemotherapeutic agents (Taxol, vinca alkaloids) Constipating agents (fecal impaction) Decongestants (pseudoephedrine) Digitalis, ergotamine, cocaine (vasoconstriction) Diuretics (lower blood volume) Steroid hormones (thrombosis) 10/02/2012 ENEMAS AND LAXATIVES • Melanosis coli • Apoptotic colopathy 10/02/2012 10/02/2012 10/02/2012 10/02/2012 ALENDRONATE • Alendronate is use for treating patients with osteoporosis or other bone disease • May cause esophageal, gastric and duodenal ulceration. Crystals (non-specific) may be present in the base of the ulcers 10/02/2012 IRON • Localized inflammation with ulceration especially in esophagus, stomach and duodenum (crystalline material present in the base of the ulcers) • Gastric and small bowel deposition within epithelium, glands and lamina propria • Ingested iron, hemosiderin and iron in hemochromatosis will all be Prussian blue positive 10/02/2012 10/02/2012 10/02/2012 10/02/2012 COLCHICINE AND TAXOL • Ischemic colitis • Ring shaped mitotic figures may be seen in proliferation zones in all areas of the gastrointestinal tract 10/02/2012 MYCOPHENOLATE • Mycophenolate is used to prevent and suppress acute rejection • Produces a colitis characterized by apoptosis, architectural distortion, crypt atrophy, IBD-like changes, GVHD-like changes and ischemia-like changes 10/02/2012 10/02/2012 10/02/2012 10/02/2012 KAYEXELATE • Kayexalate is an ion exchange resin that is active in the small bowel where it exchanges sodium ions for potassium ions in the treatment of hyperkalemia • Kayexalate crystals are triangular or rhomboid in configuration and are basophilic on routine sections. They are PAS/D positive • Apart from the presence of crystals the ulcers are non-specific in type 10/02/2012 10/02/2012 10/02/2012 10/02/2012 PANCREATIC ENZYME REPLACEMENTS • Of historical interest only: Thought to be related to high dose enzyme therapy and methacrylic acid in the formulation (this medication is now withdrawn) • Changes consist of localized fibrous strictures in the proximal colon with increased numbers of eosinophils in overlying mucosa (fibrosing colonopathy) 10/02/2012 10/02/2012