Klinični primer Metabolne in hormonske motnje

Metabolne in hormonske motnje

Collagenous : A case report Kolagenozni gastritis – Prikaz primera

Marija Malgaj, Nina Zidar,1 Nejc Sever2

1 Inštitut za patologijo, Abstract Medicinska fakulteta Background: Collagenous gastritis is a rare disease defined histologically by the subepithelial de- Ljubljana position of collagen bands thicker than 10 μm and the infiltration of inflammatory mononuclear 2 Klinični oddelek za cells in the . There are approximately 60 reported cases of collagenous gastritis in the gastroenterologijo, English literature. Univerzitetni klinični center Ljubljana Case report: We present a 41-year-old female patient with weight loss, postprandial abdominal dis- comfort, early satiety, flatulence and a change in bowel habits. Her current laboratory investigation Korespondenca/ reports showed mild sideropenic anemia. Esophagogastroduodenoscopy and the corresponding his- Correspondence: tological examination showed findings, typical for collagenous gastritis. Gastric emptying scintigra- Marija Malgaj, phy and SPECT/CT of the abdomen revealed . e: [email protected] Conclusion: Collagenous gastritis is a diagnostically challenging disease and its exact etiology re- Ključne besede: mains unclear. Even though collagenous gastritis is a histological diagnosis, the combination of other odlaganje kolagena; key clinical and endoscopic findings should prompt consideration of this entity. No safe and effective hujšanje; dispepsija; treatment has been established. Therefore, better understanding of the disease and study of a larger anemija; nodularna number of patients will help to establish diagnostic criteria and therapeutic strategies. želodčna sluznica Key words: Izvleček collagen deposition; weight loss; dyspepsia; Izhodišča: Kolagenozni gastritis je redka bolezen, pri kateri najdemo v histološki sliki pomnoženo anemia; nodular gastric kolagenizirano vezivo pod epitelom (debeline vsaj 10 μm) in monojedrnocelični infiltrat v lamini mucosa propriji. V angleški literaturi je do sedaj opisanih približno 60 primerov kolagenoznega gastritisa. Citirajte kot/Cite as: Prikaz primera: V prispevku je prikazan primer 41-letne bolnice, obravnavane zaradi hujšanja, ne- Zdrav Vestn. 2016; lagodja po jedi, prezgodnjega občutka sitosti, napenjanja in sprememb v odvajanju blata. Laborato- 85: 296–302 rijski izvidi so razkrili sideropenično anemijo. Izvida ezofagogastroduodenoskopije in pripadajoče histološke preiskave sta bila značilna za kolagenozni gastritis. Scintigrafija hitrosti praznjenja želod- Prispelo: 24. mar. 2016, ca in SPECT/CT trebuha sta pri bolnici odkrili še gastroparezo. Sprejeto: 12. maj 2016 Zaključek: Kolagenozni gastritis je diagnostično zahtevna bolezen, njegova etiologija pa ostaja ne- pojasnjena. Čeprav je diagnoza kolagenoznega gastritisa histološka, moramo nanjo pomisliti, če od- krijemo ključne klinične in endoskopske znake. Zaenkrat še ne poznamo varnega in učinkovitega zdravljenja. Za oblikovanje diagnostičnih meril in razvoj učinkovitega zdravljenja bi bilo potrebno boljše razumevanje bolezni in raziskave na večjem številu bolnikov.

Background

Collagenous gastritis (CG) is a rare of inflammatory mononuclear cells in disease defined histologically by the su- the lamina propria.1,2 CG has similar bepithelial deposition of collagen bands histological characteristics as collageno- thicker than 10 μm and the infiltration us and collagenous sprue and are

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cal therapy so far. She was referred to a gastroenterologist for further evaluation. On examination a decreased body mass index of 16.8 was found. Her la- boratory values showed a mild sidero- penic anemia. We diagnosed (low lactase levels in duode- nal mucosa and a positive blood lactose tolerance test) and she was given proper diet counseling. We excluded celiac dise- ase and other immune-related disorders. Previously reported elevated total IgE levels were now normal. She underwent esophagogastroduodenoscopy, which showed nodularity (Fig. 1) and oedema of the gastric corpus and antrum. Duo- denal bulb mucosa exhibited a diffuse cobblestone appearance. Biopsies were taken from the stomach according to Figure 1: Nodular thought to be part of the same disease the Sydney protocol and from the duo- appearance of the stomach mucosa on entity – collagenous gastroenteritides.1 denum. Histological examination of ga- gastroscopy. While there are many published cases of stric biopsies showed a thickened sube- , there are only 60 re- pithelial layer in the corporal and antral ported cases of CG in the English litera- mucosa (Fig. 2) with associated gastritis. ture since the disease was first identified The inflammatory infiltrate was predo- by Colletti and Trainer in 1989.1,3 In con- minantly lymphoplasmacytic. The sube- trast to collagenous colitis, the course of pithelial collagenous layer stained blue CG is unpredictable and the optimal tre- with Masson trichrome stain (Fig. 3) and atment has yet to be defined. We present was more than 20 μm thick, suggesting a patient with CG. the diagnosis of CG. Immunohistoche- mistry for Helicobacter pylori was negati- Case report ve. Histological examination of the duo- denal biopsies showed a non-specific A 41-year-old Caucasian woman chronic inflammation, but staining with presented with a history of progressive Masson trichrome stain did not show a weight loss, postprandial abdominal di- thickened subepithelial layer of connec- scomfort, early satiety, flatulence and a tive tissue. In addition to esophagoga- change in bowel habits. She has previo- stroduodenoscopy, she also underwent usly been diagnosed with an eating di- : macroscopic appearance sorder (anorexia nervosa) and has been of the mucosa was normal, however, treated by a psychiatrist with cognitive histological examination of the biopsy behavioral therapy. While her treatment samples showed mild inflammation, but was reported successful and she mana- it was not diagnostic for collagenous co- ged to gain some weight and menstru- litis. Furthermore, we performed gastric al cycle (although irregular) her other emptying scintigraphy and SPECT/CT symptoms mainly persisted. She has not of the abdomen, which revealed delayed been maintained on any pharmacologi- emptying from the fundus and corpus of

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mens before starting a more aggressive therapeutic approach (e.g. steroids). We plan to do the first follow-up endosco- pic investigation in about one year after the initial diagnosis. The lack of possi- ble etiopathogenic factors remains the main problem, which disables us to start causal treatment (e.g. treatment of concurrent immune-related disorders, discontinuation of certain drugs). Our current conclusion is that the patient’s symptoms and clinical findings are most likely multifactorial – a combi- nation of the relapsing eating disorder, functional gastrointestinal disorder (ir- ritable bowel syndrome), gastroparesis and CG. The correlation and causality between these entities, if any at all, is unclear and will be hard to prove. Mul- Figure 2: Increased the stomach, thus suggesting gastropare- tidisciplinary approach will be needed collagenous fibrous tissue beneath the sis. in the future to form a proper treatment surface epithelium in After reviewing the literature and strategy. the biopsy sample from excluding all potentially reversible fac- the antral mucosa. Hematoxylin and eosin, tors, which might influence and/or ca- Discussion orig. magn. 20x. use CG (e.g. immune-related disorders, specific drugs), we have decided to start Etiology and pathogenesis of CG a trial with a proton pump inhibitor is unknown, but autoimmune mecha- for symptom relief. Treatment of side- nisms, drugs and infection have been ropenic anemia with oral iron supple- postulated as possible etiopathoge- ments was ineffective, but was resolved nic factors.2,4,5 CG has been descri- after parenteral iron supplementation. bed in patients with immune-related Because of suspected gastroparesis she disorders, including celiac disease,6,7 was also started on a short-term the- Sjögren syndrome,8 systemic lupus rapy with a prokinetic agent: first with erythematosus,9 common variable im- metoclopramide and later with dom- mune deficiency (CVID),10 lymphocytic peridone. She discontinued the use gastritis, lymphocytic colitis and ulcera- of both shortly after receiving each of tive colitis,2 Hashimoto thyroiditis and them because of adverse effects. Over a polymyositis,11 juvenile arthritis, rheu- few weeks of follow-up, her symptoms matoid arthritis, Graves disease and dia- have not improved. She still complains betes mellitus type 1.12 Collectively, these of postprandial abdominal discomfort, associations support the hypothesis that while her weight is now stable. Because collagenous gastroenteritides might be of the unclear natural history of CG and related to immune mechanisms.13,14 A no standard therapy regimens, we have subset of CG cases may be attributed to decided to do follow-up esophagoga- drugs, such as olmesartan, an angioten- stroduodenoscopies with a histological sin II receptor blocker,15 and venlaflaxi- examination of corresponding speci- ne, an antidepressant.12

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Interestingly, the nodular lesions repre- sent the undamaged mucosa, and the depressed areas surrounding the nodu- les are the result of inflammation with atrophic changes and collagen deposi- tion.18 The other endoscopic findings include mucosal erythema, erosions and exudate.1,12 The diagnosis of CG is made by hi- stology – in order to make a diagnosis it is necessary to take biopsy specimens according to the updated Sydney pro- tocol: two specimens from the antrum, two specimens from the corpus and one specimen from the incisura angularis. Especially in the early stages, the disea- se can be unevenly distributed over the gastric mucosa, thus it is important to take at least five specimens. Furthermo- Figure 3: Blue staining of Patients of a wide age range present re, additional biopsy samples must be the subepithelial fibrous tissue by Masson’s with epigastric and/or abdominal pain, taken from any macroscopically unusu- trichrome stain, orig. anemia, gastrointestinal bleeding, diar- al regions. Histology shows distinctive magn. 20x. rhea, and vomiting, perforated findings: infiltration of chronic inflam- ulcer, weight loss, abdominal distenti- matory cells in the lamina propria, and on, fatigue, dyspepsia, retrosternal pain, the deposition of collagen bands thicker and dysphagia.1,12,16. Previ- than 10 μm.2,19 The inflammatory cells ous studies have proposed two clinico- include lymphocytes, plasma cells, and pathologic types of CG on the basis of eosinophils. A recent study7 identified patient’s age at disease onset:6,8,11 (a) pe- 3 distinct histological patterns of colla- diatric type (18 years of age or younger) genous gastritis: (a) an eosinophil-rich presenting with severe anemia, nodular pattern (more than 30 lamina propria gastric mucosa and isolated gastric di- eosinophils per high-power field), (b) sease;17 and (b) adult type with chronic a lymphocytic gastritis-like pattern (at watery that is associated with least 25 intraepithelial lymphocytes per diffuse collagenous involvement of the 100 surface epithelial cells) and (c) an .6 However, nota- atrophic pattern (involves the gastric ble exceptions exist and a broad varia- corpus with marked loss of the oxyntic bility in clinical presentation, etiology, glands, pyloric metaplasia and minimal treatment and disease course has been ECL cell hyperplasia).12 Clinically, the reported.12 Within the most recent pu- lymphocytic gastritis-like pattern is beli- blished papers, no statistically signifi- eved to be associated with celiac disease, cant differences in clinical presentation collagenous sprue, and/or collagenous or endoscopic findings among children colitis.7 and adults were seen.7,12 CG, collagenous colitis and collage- The characteristic endoscopic finding nous sprue are thought to be part of the in CG is nodularity of the gastric cor- same disease entity – collagenous ga- pus,1,12,18 but it is not seen in all cases. stroenteritides. Especially in adult type

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of CG, it is important to rule out the and parenteral nutrition6,16,33 have also possible concurrent collagenous sprue been tested. A few patients have shown or collagenous colitis, which can be done improvement of the clinical symptoms by histological examination of the duo- but no randomized, controlled trials denal biopsies and colon biopsies obtai- have been performed.1 In addition, the ned during esophagogastroduodenosco- lack of symptoms does not necessarily py and colonoscopy, respectively. Both correlate with the negative follow-up bi- were done in our patient and the histo- opsies or vice versa.12 Also, the eradicati- logic changes were not diagnostic for on of Helicobacter pylori did not produce collagenous sprue or collagenous colitis. any therapeutic benefit.1 Further cases Inflammation causes gland atrophy are needed to establish a standard thera- and leads to the depressed mucosal pat- peutic strategy. tern found on endoscopy.18 The diagno- The natural history of CG is also un- stic pathological features are less marked clear. Although regarded by many in- in the nodular lesions.18 Several mucosal vestigators as a chronic but benign di- biopsies are therefore needed for correct sorder, a 12-year follow up study of the diagnosis and careful mapping is requi- first patient diagnosed with CG revealed red for the follow-up of mucosal inflam- progressive glandular atrophy, intesti- mation and the thickness of collagen nal metaplasia, linear neuroendocrine deposits.1 Collagen deposition can be vi- hyperplasia and surface epithelial chan- sualized with Masson trichrome staining ges interpreted as indefinite for dyspla- and tenascin immunohistochemistry.7 sia.21 This raises the possibility that CG Collagen analysis has been performed in may be a predisposing factor for gastric a few patients with CG and revealed the neuroendocrine tumors and adenocarci- presence of collagen types III and VI.6,20- noma. Although the course of CG rema- 23 Type III collagen is released by subepi- ins uncertain, none of the patients de- thelial fibroblasts to repair damage cau- scribed in the recent studies developed sed by inflammation. Therefore, collagen dysplasia and/or invasive adenocarcino- synthesis in CG is probably a reparative ma.7,12 Moreover, there are known cases response.20 The thickness of the collagen of CG which showed complete absence deposits may increase with disease dura- of collagen deposits,6,17 improvement of tion; however, it may also be influenced inflammation,6 or a moderate decrease by the location of the biopsy rather than in the thickness of subepithelial collagen the severity of the disease.2,6,11,24,25 deposits17 on biopsies obtained a few Because of the small number of cases years after the initial diagnosis. Patients and the unknown etiology, no standard who recovered had been treated with: therapy has been established. Anti-sec- (a) steroid, sulfasalazine, and parenteral retory agents including proton pump alimentation;6 (b) oral iron supplemen- inhibitors,4,9,11,17,19-22,25-32 and H2- tation and proton-pump inhibitors.17 -receptor antagonists,3,20,21,31,32 stero- However, in most cases, the collagen ids,2,6,11,16,19,23,25,27,29,33 iron supplemen- deposits remain unchanged or become tation14,17,19,20,24-26,34 and hypoallergenic thicker as a result of continued inflam- diets8,11,20 have been tried with limited mation.1 success. Other treatment modalities, There are number of potential pitfalls such as sucralfate,3,11,21,27 mesalazi- in diagnosing CG. Considering the rari- ne,2,19,29 bismuth subsalicylate,29 furazo- ty of this condition with respect to col- lidone,3 sulfasalazine,6,35 azathioprine,16 lagenous deposition at other gastrointe-

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stinal sites, CG may be underdiagnosed. as CG.12 Additional stains for collagen, Indeed, reassessment of prior biopsies in such as Masson trichrome or immuno- a recent study showed misdiagnosed or histochemistry for tenascin, are of great overlooked cases of CG.12 In these cases, use in these situations. a prominent subepithelial collagen layer was overlooked, but associated symp- Conclusion toms, such as diarrhea and anemia, and gastric nodularity on endoscopy were Collagenous gastritis is a rare and present.12 Although CG is a histological diagnostically challenging disease. Ga- diagnosis, the combination of other key stroenterologists and pathologists need clinical and endoscopic findings should to be aware of this condition, otherwise prompt consideration of this entity. The it can be easily overlooked. Even thou- other problem that can lead to misdia- gh CG is a histological diagnosis, the gnosis is the fact that collagen deposition combination of clinical and endoscopic within the lamina propria can be seen in findings should prompt consideration other conditions, such as ischemia and of this entity. No safe and effective tre- radiation-induced injury. However, in atments have been identified. Therefore, these cases the distribution of collagen better understanding of the disease and is typically diffuse rather than subepi- analysis of larger number of patients is thelial.36 Moreover, fibrin in the setting needed to establish diagnostic criteria of an erosion or amyloid deposits aro- and to develop therapeutic strategies. und blood vessels may be misdiagnosed

Literature 1. Kamimura K, Kobayashi M, Sato Y, Aoyagi Y, Te- lupus erythromatosis: a case report. J Med Case rai S. Collagenous gastritis: Review. World J Ga- Rep 2014; 8: 278. strointest Endosc 2015; 7: 265–73. 10. Daniels JA, Lederman HM, Maitra A, Montgo- 2. Vesoulis Z, Lozanski G, Ravichandran P, Esber E. mery EA. Gastrointestinal tract pathology in pa- Collagenous gastritis: a case report, morpholo- tients with common variable immunodeficiency gic evaluation, and review. Mod Pathol 2000; 13: (CVID): a clinicopathologic study and review. Am 591–6. J Surg Pathol 2007; 31: 1800–12. 3. Colletti RB, Trainer TD. Collagenous gastritis. Ga- 11. Leung ST, Chandan VS, Murray JA, Wu TT. Col- stroenterology 1989; 97: 1552–5. lagenous gastritis: histopathologic features and as- 4. Kori M, Cohen S, Levine A, Givony S, Sokolovska- sociation with other gastrointestinal diseases. Am ia-Ziv N, Melzer E, et al. Collagenous gastritis: a J Surg Pathol 2009; 33: 788–98. rare cause of abdominal pain and iron-deficiency 12. Ma C, Park JY, Montgomery EA, Arnold CA, Mc- anemia. J Pediatr Gastroenterol Nutr 2007; 45: Donald OG, Liu TC, et al. A Comparative Clini- 603–6. copathologic Study of Collagenous Gastritis in 5. Jain R, Chetty R. Collagenous gastritis. Int J Surg Children and Adults: The Same Disorder With As- Pathol 2010; 18: 534–6. sociated Immune-mediated Diseases. Am J Surg 6. Lagorce-Pages C, Fabiani B, Bouvier R, Scoazec Pathol 2015; 39: 802–12. JY, Durand L, Flejou JF. Collagenous gastritis: a re- 13. Gillett HR, Freeman HJ. Prevalence of celiac dise- port of six cases. Am J Surg Pathol 2001; 25: 1174–9. ase in collagenous and lymphocytic colitis. Can J 7. Arnason T, Brown IS, Goldsmith JD, Anderson W, Gastroenterol 2000; 14: 919–21. O’Brien BH, Wilson C, et al. Collagenous gastritis: 14. Park S, Kim DH, Choe YH, Suh YL. Collagenous a morphologic and immunohistochemical study gastritis in a Korean child: a case report. J Korean of 40 patients. Mod Pathol 2015; 28: 533–44. Med Sci 2005; 20: 146–9. 8. Stancu M, De Petris G, Palumbo TP, Lev R. Col- 15. Rubio-Tapia A, Herman ML, Ludvigsson JF, Kel- lagenous gastritis associated with lymphocytic ly DG, Mangan TF, Wu TT, et al. Severe spruelike gastritis and celiac disease. Arch Pathol Lab Med associated with olmesartan. Mayo 2001; 125: 1579–84. Clin Proc 2012; 87: 732–8. 9. Al-Kandari A, Al-Alardati H, Sayadi H, Al-Judai- 16. Wang HL, Shah AG, Yerian LM, Cohen RD, Hart bi B, Mawardi M. An unusual case of collagenous J. Collagenous gastritis: an unusual association gastritis in a middle- aged woman with systemic with profound weight loss. Arch Pathol Lab Med 2004; 128: 229–32.

Collagenous gastritis: A case report 301 Metabolne in hormonske motnje PRILOGAODMEVI

17. Hijaz NM, Septer SS, Degaetano J, Attard TM. vealed by severe anemia in a child. Hum Pathol Clinical outcome of pediatric collagenous gastri- 1998; 29: 883–6. tis: case series and review of literature. World J 28. Freeman HJ. Topographic mapping of collagenous Gastroenterol 2013; 19: 1478–84. gastritis. Can J Gastroenterol 2001; 15: 475–8. 18. Kamimura K, Kobayashi M, Narisawa R, Watana- 29. Leiby A, Khan S, Corao D. Clinical challenges and be H, Sato Y, Honma T, et al. Collagenous gastritis: images in GI. Collagenous gastroduodenocolitis. endoscopic and pathologic evaluation of the no- 2008; 135: 17, 327. dularity of gastric mucosa. Dig Dis Sci 2007; 52: 30. Jin X, Koike T, Chiba T, Kondo Y, Ara N, Uno K, 995–1000. et al. Collagenous gastritis. Dig Endosc 2013; 25: 19. Suskind D, Wahbeh G, Murray K, Christie D, Ka- 547–9. pur RP. Collagenous gastritis, a new spectrum of 31. Tanabe J, Yasumaru M, Tsujimoto M, Iijima H, disease in pediatric patients: two case reports. Ca- Hiyama S, Nishio A, et al. A case of collagenous ses J 2009; 2: 7511. gastritis resembling nodular gastritis in endos- 20. Brain O, Rajaguru C, Warren B, Booth J, Travis S. copic appearance. Clin J Gastroenterol 2013; 6: Collagenous gastritis: reports and systematic revi- 442–6. ew. Eur J Gastroenterol Hepatol 2009; 21: 1419–24. 32. Soeda A, Mamiya T, Hiroshima Y, Sugiyama H, 21. Winslow JL, Trainer TD, Colletti RB. Collageno- Shidara S, Dai Y, et al. Collagenous gastroduode- us gastritis: a long-term follow-up with the deve- nitis coexisting repeated Dieulafoy ulcer: A case lopment of endocrine cell hyperplasia, intestinal report and review of collagenous gastritis and ga- metaplasia, and epithelial changes indeterminate stroduodenitis without colonic involvement. Clin for dysplasia. Am J Clin Pathol 2001; 116: 753–8. J Gastroenterol 2014; 7: 402–9. 22. Kajino Y, Kushima R, Koyama S, Fujiyama Y, Oka- 33. Billiémaz K, Robles-Medranda C, Le Gall C, Gay be H. Collagenous gastritis in a young Japanese C, Mory O, Clémenson A, et al. A first report woman. Pathol Int 2003; 53: 174–8. of collagenous gastritis, sprue, and colitis in a 23. Castellano VM, Muñoz MT, Colina F, Nevado M, 9-month-old infant: 14 years of clinical, endosco- Casis B, Solís-Herruzo JA. Collagenous gastrobul- pic, and histologic follow-up. Endoscopy 2009; 41 bitis and collagenous colitis. Case report and re- Suppl 2: S233–4. view of the literature. Scand J Gastroenterol 1999; 34. Ravikumara M, Ramani P, Spray CH. Collageno- 34: 632–8. us gastritis: a case report and review. Eur J Pediatr 24. Wilson C, Thompson K, Hunter C. Nodular col- 2007; 166: 769–73. lagenous gastritis. J Pediatr Gastroenterol Nutr 35. Groisman GM, Meyers S, Harpaz N. Collagenous 2009; 49: 157. gastritis associated with lymphocytic colitis. J Clin 25. Dray X, Reignier S, Vahedi K, Lavergne-Slove A, Gastroenterol 1996; 22: 134–7. Marteau P. Collagenous gastritis. Endoscopy 2007; 36. Crowder CD, Grabowski C, Inampudi S, Sielaff T, 39 Suppl 1: E292–3. Sherman CA, Batts KP. Selective internal radiati- 26. Rustagi T, Rai M, Scholes JV. Collagenous gastro- on therapy-induced extrahepatic injury: an emer- . J Clin Gastroenterol 2011; 45: 794–9. ging cause of iatrogenic organ damage. Am J Surg 27. Côté JF, Hankard GF, Faure C, Mougenot JF, Hol- Pathol 2009; 33: 963–75. voet L, Cézard JP, et al. Collagenous gastritis re-

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