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Gastritis and gastropathy: More than meets the eye This paper discusses the different types of gastritides and gastropathies, focusing on their wide range of aetiologies.

W Nel, MB ChB, M Med (Anat Path) Anatomical pathologist, Ampath Laboratories, Pretoria Willie Nel did his undergraduate training at the University of the Free State and postgraduate training at the University of Pretoria. He joined the private practice of doctors Du Buisson and partners (Ampath) after two years as a consultant at the Institute of Pathology in Pretoria. Amongst his special interests are motorcycling and cattle breeding.

Correspondence to: W Nel ([email protected])

Gastrointestinal symptoms such as conjunction with bicarbonate-secreting Acute in Helicobacter pylori dyspepsia, heartburn, epigastric pain, nausea surface epithelial cells and local prosta- infection and vomiting are extremely common and glandin production, as a protective barrier The initial phase of Helicobacter infection have been experienced by the majority against autodigestion and noxious agents. causes an acute inflammatory reaction of people at some stage in their lifetime. The gastric mucosa also has the ability to and degenerative changes in the surface These complaints are often as a result of proliferate and replace damaged epithe- epithelial cells of the gastric mucosa. pathology in the upper . lium very rapidly. Symptoms may include epigastric pain, a Correlation between the clinical presentation bloated feeling and nausea; these most often (symptoms, signs and endoscopic findings) In 1990 the Sydney system was developed as resolve within a week. After approximately and pathology, including the degree and a guideline for the classification and grading two weeks the reaction evolves into an precise localisation of the disease process, of gastritis by a group of international active chronic gastritis. is unfortunately notoriously poor. This is experts in Sydney, Australia. This system mainly due to the absence of a somatic combines topographical, morphological Acute bacterial or phlegmonous nerve supply to the gut wall. The is and aetiological information into a scheme gastritis a common site of pathology responsible for that helps generate a reproducible and This is exceedingly rare and in many upper gastrointestinal symptoms, which may clinically useful diagnosis. Four years later cases only identified at postmortem have an extremely wide range of causes. this system was updated and subsequently examination. Predisposing factors include modified to improve the criteria for immunosuppression, disability and chronic In pathological terms, gastritis is defined as evaluating atrophy. It recommends that at . The most common infective of the gastric mucosa. It is, least five specimens (two from the organism is Streptococcus, but Staphylococcus, however, a term often used loosely for clini- greater and lesser curvatures of the corpus, Haemophilus influenzae, Escherichia coli cal conditions associated with any upper one from the incisura angularis and two and Proteus spp have also been implicated. gastrointestinal symptoms without clinical from the larger and lesser curvatures of These bacteria cause an intense acute or radiological signs. Gastropathy, on the the antrum) with mucosa and muscularis inflammatory response with ulceration other hand, refers to a nonspecific micro- mucosae represented in each biopsy be and abscess formation involving the full scopic injury pattern of stomach mucosa, evaluated. In practice, however, pathologists thickness of the gastric wall. Patients present with minimal or no inflammatory cell infil- are usually asked to make a diagnosis on one with nausea, vomiting, upper abdominal tration. Both gastritis and gastropathy may or two biopsy specimens as most types of pain and tenderness, usually associated with be clinically asymptomatic. gastritis can be diagnosed without extensive a neutrophilic . The condition tissue sampling. has a high mortality, but patients treated Acute gastritis is an acute mucosal surgically have a better chance of survival. inflammatory process, usually of transient The different types of gastritides and nature, while chronic gastritis refers to gastropathies and their wide range of Chronic gastritis chronic inflammatory changes which aetiologies will now be discussed. Helicobacter pylori (HP) gastritis may eventually lead to mucosal atrophy These tiny spiral-shaped bacilli in the and epithelial metaplasia. Gastritis is a Acute gastritis stomach were described for decades by dynamic process, which can vary from Acute haemorrhagic gastritis pathologists, but were dismissed as irrelevant acute to chronic (active or inactive), Acute haemorrhagic gastritis is characterised contaminants. In 1984 Warren and Marshall present in different stages of recovery or by the presence of hyperaemic, oedematous proposed their aetiological role in chronic atrophy and may lead to complications. mucosa, erosions/ulcers and active bleeding, idiopathic gastritis due to toxins released by The inflammation may be diffuse, or affect and is usually seen in stress situations (e.g. the organisms directly affecting the gastric predominantly the antrum or corpus. severe burns), patients in ICU and after epithelium and local microcirculation. ingestion of large doses of aspirin, and The mucosa of the stomach is covered other types of NSAID or large quantities of HP gastritis has a high prevalence in by a thin surface mucus layer serving, in . developing countries, but has been declining

37 CME February 2013 Vol. 31 No. 2

Composite Gastritis and gastropathy

in areas due to improved sanitary conditions and histological examination of gastric and the widespread use of antibiotics. (Fig. 2). Th ese have the advantage Your consulting pathologists Natural acquisition of HP infection usually of allowing direct evaluation the upper GI occurs in childhood and may persist for life. tract for any superimposed complications. However, transient infections oft en occur. Th e number of organisms in biopsy material Direct person-to-person spread is the most may be markedly reduced (even absent) likely mode of transmission, as no signifi cant due to antibiotic treatment prior to biopsy, reservoir has been shown to exist outside the use of proton pump inhibitors (PPIs) or the human stomach. Ingestion appears to in chronic . Noninvasive be the most common means of acquiring Fig. 1. A biopsy demonstrating chronic diagnostic tests include the C-urea breath HP. Routes of transmission include gastric- active gastritis — a background of chronic test (only performed in certain centres), oral (by refl uxed gastric juice or vomitus), infl ammation, with present detection of serum IgG antibodies directed and the faecal-oral route (during episodes between the glandular epithelium. against HP and stool HP antigen tests, some of diarrhoea). Poor hygiene standards, of which can also be used for follow-up. crowded households, defi cient sanitation As a method to evaluate HP eradication, and the absence of running water in the the C-urea breath test should preferably be home are associated with a high prevalence performed 4 weeks aft er the end of therapy, of HP infection. as the test may produce a false-negative result with persistent infection due to temporary Th e endoscopist may fi nd mucosal inactivation of the pathogen shortly aft er hyperaemia, erosions, hypertrophy and treatment. HP serology is relatively sensitive even atrophy, but there are no distinctive and specifi c with no interference due to the endoscopic patterns of chronic HP gastritis. intake of bismuth, antibiotics and PPIs. Th ere is no correlation between the IgG antibody In the early phase an acute infl ammatory Fig. 2. Curved Helicobacter pylori bacilli titres and the severity of the HP gastritis, www.ampath.co.za response is elicited, which usually progresses adjacent to the gastric epithelium on a however, and a decrease in titres less than 6 to an active chronic gastritis. Th is may be methylene blue stain. months aft er therapy is of no diagnostic value antral-predominant, corpus-predominant or in verifying successful eradication. diff usely aff ect the stomach as a pangastritis Cystic fibrosis (CF) is an Clinical Findings: Sweat testing should always be (Fig. 1). Aft er treatment, neutrophils More than 50 species of Helicobacter have autosomal recessive disease • Prenatal Screening – Amniocentesis repeated on 2 separate occasions, and disappear rapidly; their continued presence been described, but only a few have been affecting all South African (SA) when both parents are identified sweat chloride testing may be negative shown to cause gastritis. In about 0.1 - 2.7% population groups. carriers (Identifying specific mutations in a small number of confirmed CF cases. of cases H. heilmannii is identifi ed. Th ese in parents), or restriction fragment C M Y CM MY CY CMY K The incidence of live births in South organisms are twice as long as HP and length polymorphism (RFLP) analysis Africa is 1 in 2800 for Whites, 1 in the case of one parent having Other laboratory tests in CF usually cause a milder and patchier gastritis. in 10000 for Coloureds and 1 in identified mutation but the couple evaluation include: Treatment is similar to that for HP infections. 52000 for Blacks. The defect is have a previously affected child . • For pancreatic insufficiency: Faecal caused by mutations in the CFTR (cystic Diagnostic accuracy is nearly 100%. steatocrit (Children and infants) Some patients with HP are asymptomatic fibrosis transmembrane conductance • Newborn Screening – Bloodspot • Random faecal specimen for regulator) gene resulting in thickened, Fig. 3. Macroscopic appearance of a gastric and go undetected, but all patients in whom immunoreactive trypsin (IRT), which is Sudan staining viscous secretions in many organs, elevated in CF infants. Detection rate • Oral Fat loading test chronic peptic ulcer (courtesy of Dr M Louw, HP infection is identifi ed should undergo including sweat glands. CF patients are is 95%. A second IRT testing and • 72 hour faecal fat Department of Anatomical Pathology, treatment. If untreated, HP gastritis confers homozygous (2 identical mutations) or DNA testing should be performed. • Faecal pancreatic elastase University of Pretoria). a 15 - 20% lifetime risk of developing peptic compound heterozygous (two different • Sweat testing- Sweat chloride testing ulcer disease (Fig. 3). Eradication of HP mutations) and unaffected carriers carry is the gold standard in CF diagnosis. • Genetic testing: DNA mutation only one mutation. in biopsies is considered a valuable facilitates healing of these ulcers and prevents Sweat conductivity testing is analysis should be performed performed as a screening test, and especially in case of negative or indicator of unsuccessful HP eradication. their recurrence. More than 90% of primary Many affected patients present with results should be confirmed by sweat intermediate sweatchloride levels. Aft er successful treatment the intensity gastric mucosa-associated lymphoid tissue mild or atypical symptoms; therefore chloride testing. • Respiratory tract culture for CF- of the chronic infl ammation declines, but (MALT) lymphomas are seen in patients a high index of suspicion is required. Sweat testing can be performed from associated pathogens and broncho patients may show persistence of chronic with HP gastritis, and more than 75% will A final diagnosis is made if there 48 hours after birth (preferably from alveolar lavage for cytology and are characteristic clinical features, a inactive gastritis for several years. Persistent regress for extended periods upon successful 2 weeks and >2 kg), provided the microbial cultures. history of CF in a sibling, or a positive infant is not oedematous nor • Evidence of azoospermia in sexually infections may eventually lead to atrophic eradication of the infection. Atrophic gastritis newborn screen (NBS) test, plus receiving steroids. mature males. gastritis, which may be antrum-restricted or is also a risk factor for dysplasia and intestinal laboratory evidence of an abnormality involve the stomach more extensively. type adenocarcinoma. in the CFTR gene ( i.e. diagnostic sweat Indications for sweat testing: Should evaluation fail to provide tests on two occasions; or presence of convincing evidence of CF, and two disease-causing mutations in CFTR Diagnosis of HP infection can be rendered Triple therapy with either amoxicillin • Clinical symptoms suggestive of CF – the sweat chloride results are in the gene). infants, children and adults intermediate range, the patients using invasive and noninvasive tests. or metronidazole, clarithromycin and a • Positive CF newborn screening test should be monitored regularly for the Invasive tests are based on endoscopy PPI given twice daily for 7 - 14 days is Early diagnosis of patients with CF • Siblings of a patient with confirmed appearance of symptoms. improves the final outcome. The CF diagnosis of CF requires a multi-level 38 CME February 2013 Vol. 31 No. 2 approach and includes: Gastritis and gastropathy

recommended as first-line therapy. As second with destruction of the oxyntic glands. Eosinophilic gastritis line therapy levofloxacin, amoxicillin and PPI As atrophy sets in, the mucosa shows a Eosinophilic gastritis and for 10 -14 days or bismuth-based quadruple marked reduction of these glands, reduced may affect all age groups and present with therapy are recommended. Increasing inflammation and increasing degrees of failure to thrive (in children), abdominal HP resistance to various antibiotics is a intestinal and pyloric metaplasia. Metaplasia pain, irritability, gastric dysmotility, vomiting, significant concern, however. refers to replacement of normal gastric diarrhoea, dysphagia and (in severe cases) epithelium by modified cells of intestinal protein-losing . Many patients are Autoimmune gastritis or pyloric variety. The hypo-/ atopic and have increased serum total IgE and This corpus-restricted gastritis is associated cause physiological hypergastrinaemia, food-specific IgE, as well as blood eosinophilia. with circulating autoantibodies against which in turn stimulates proliferation This entity is characterised by eosinophil-rich the microsomes of parietal cells as well as of neuroendocrine cells and can lead to inflammation of all or a portion of the GI tract intrinsic factor. Intrinsic factor plays a key development of neuroendocrine tumours wall. Gastroscopy may reveal antral mucosal role in the absorption of vitamin B12, and (‘carcinoids’). These tumours are relatively swelling and redness with narrowing of the gastric acid is important for absorption of innocuous, in contrast to the less common pylorus and diminished peristalsis. iron. Destruction of the cells producing solitary, sporadic type which is more hydrochloric acid and intrinsic factor, aggressive. Improvement after elimination of certain respectively, results in hypochlorhydria foods from the diet supports an allergic and a reduction in pepsin activity within Lymphocytic gastritis aetiology. Parasites and drug reactions are a gastric juices and may lead to pernicious or A diagnosis of lymphocytic gastritis can much less common cause. iron deficiency anemia. The finding of a low only be made on , but many pepsinogen I level in the serum is a sensitive patients have the endoscopic features of Granulomatous gastritis and specific indicator of gastric atrophy. varioliform gastritis with mucosal nodules, This group of conditions is characterised by chronic persistent erosions and thickened multiple in the gastric mucosa Endoscopically, the mucosa of the corpus is mucosal folds. The disease is characterised and has a long list of possible causes. This thinner than normal. Often a reduction or by an infiltrate of lymphocytes in the lamina includes infections such as tuberculosis and absence of rugal folds and small mucosal propria with large numbers of lymphocytes histoplasmosis, foreign body reaction directed elevations due to the presence of islands of among the epithelial cells lining the surface against postoperative sutures or food trapped intestinal metaplasia are seen. In the florid and foveolae. in ulcers, tumours such as mucus-producing phase microscopy reveals a dense infiltrate adenocarcinomas and lymphomas, as well of lymphocytes and plasma cells involving The aetiology remains uncertain, although as systemic granulomatous diseases such as the entire thickness of the corpus mucosa an allergic or autoimmune pathogenesis is sarcoidosis, Crohn’s disease and Wegener’s proposed. Lymphocytic gastritis may be found granulomatosis.

C M Y CM MY CY CMYin associationK with (gluten- sensitive enteropathy), Menetrier’s disease Opportunistic infections of the (hypertrophic gastropathy characterised by a stomach hypertrophic gastric mucosa with convoluted, Immunocompromised patients are at risk thickened mucosal folds and protein-losing for opportunistic GI infections, with the enteropathy), as an abnormal response to HP stomach relatively rarely affected in com- infection or NSAID use, or in association with parison to the rest of the gut. lymphocytic/collagenous . Treatment is steroids and management of any underlying Fungal infections include gastric cause. candidiasis, which may appear as a white

Collagenous gastritis This is a rare entity characterised by a thickened subepithelial band of collagen and chronic inflammatory infiltrate in the gastric mucosa, similar to that seen in . The disease may be limited to the stomach, then usually in children and young adults presenting with anaemia due to gastric bleeding, and demonstrate focal nodularity of the gastric Fig. 4. Gastric biopsy showing Cryptospo- mucosa on endoscopy. It may also be found ridium spp. infection, with large numbers of in adults with collagenous colitis and present small spherical parasitic organisms adjacent with a chronic watery diarrhoea. to the epithelium.

39 CME February 2013 Vol. 31 No. 2 Gastritis and gastropathy

4) are protozoal infections which may affect vessels and a paucity or absence of Table 1. Aetiology of gastritis and the stomach. inflammation. gastropathy • Gastric antral vascular ectasia (GAVE or Gastritis Gastropathy ‘watermelon stomach’) is a rare condition • Acute Chemical (reactive) gastropathy of unknown aetiology. Endoscopy shows Stress Chemical gastropathy was recommended longitudinal mucosal folds with ectatic NSAIDs as the preferred term to synonyms such vessels converging from the proximal Alcohol as chemical gastritis, type C gastritis antrum into the pylorus. Histology reveals Helicobacter (early phase) and reactive gastropathy, and refers to marked dilated mucosal capillaries, some Bacteria (phlegmonous) endoscopic and histological changes caused of which may be thrombosed, and features • Chronic by chemical injury to the gastric mucosa. of reactive gastropathy. Patients may Helicobacter present with occult bleeding, melaena, Autoimmune Chemical agents commonly associated haematemesis and anaemia. Allergy with mucosal damage include: • Portal hypertensive gastropathy is seen Tuberculosis • Medications, particularly NSAIDs, but in patients with who Opportunistic infections also drugs such as PPIs, iron, kayexalate, may present with gastric haemorrhage Idiopathic colchicine, antineoplastics and corticos- due to dilatation, congestion and Gastropathy teroids. NSAIDs cause mucosal dam- proliferation of mucosal blood vessels, • Chemical age by reducing synthesis. most prominent in the proximal stomach. Medications Second-generation and selective NSAIDs The endoscopic appearance may resemble reflux and COX-2 inhibitors are better tolerated snake skin, cherry red spots or have a Acids, alkalis, alcohol by the gastric mucosa. Endoscopically, mosaic pattern. Decompression of the • Vascular long-term users of NSAIDs may show portal hypertension by means of bypass Portal hypertension mucosal erythema, congestion, erosions surgery reduces the risk of haemorrhage. Vascular ectasia (idiopathic) and ulcers. Histologically the mucosa The varied aetiologies of gastritis and reveals oedema, foveolar hyperplasia, gastropathy are summarised in Table I. smooth-muscle proliferation, regenera- plaque which can be removed to reveal tion and, on occasion, erosion with a rela- Conclusion a reddened underlying mucosa, or as tively mild inflammatory cell response. Gastritis and gastropathy may be clinically a saprophyte colonising the necrotic • Duodenopancreatic (bile) reflux is seen silent or present with central upper abdominal debris in an ulcer base, aggravating the particularly in patients with a Billroth II symptoms, and have a wide range of causes. disease. GI phycomycosis (zygomycosis, partial gastrectomy. A chronic gastritis H. pylori infection is common worldwide mucormycosis) is rare, may be associated with marked foveolar hyperplasia, which and, if left untreated, is associated with with diabetes mellitus and results in may be cystic or polypoid, develops complications including , ulceration and invasion of blood vessels by proximal to the stoma. atrophic gastritis and gastric neoplasms. the fungus. Cryptococcus and Histoplasma • Acids, alkalis and large quantities of Chemical injury to the gastric mucosa due to gastric infections are seen in conjunction alcohol. Most of these cause extensive medications such as NSAIDs, bile reflux and with disseminated disease. Viral infections severe, necrotising lesions. the intake of large quantities of alcohol is well such as cytomegalovirus and herpes known, as are autoimmune reactions causing simplex virus more commonly affect the Vascular gastropathy atrophic gastritis and allergies to food which oesophagus, but may also demonstrate Vascular gastropathy refers to a group may result in an eosinophilic gastritis. gastric involvement with ulceration. of disorders characterised by distinct Toxoplasmosis and cryptosporidiosis (Fig. alterations in the gastric mucosal blood Further reading available at www.cmej.org.za

IN A NUTSHELL • Gastritis and gastropathy are common causes of upper gastrointestinal symptoms. • Correlation between clinical presentation, endoscopic features and biopsy findings is poor. • Gastritis refers to inflammation of the gastric mucosa, whereas gastropathy is a nonspecific microscopic injury pattern with little or no inflam- matory cell infiltration. • Gastritis and gastropathy are associated with a wide range of aetiologies (causes). • Gastritis is divided into acute and chronic forms. • The commonest form of acute gastritis is acute haemorrhagic gastritis. • Helicobacter-associated and autoimmune gastritis are the commonest types of chronic gastritis. • Less common and more unusual forms of gastritis include eosinophilic, lymphocytic, collagenous and granulomatous gastritis. • Opportunistic gastric infections may be caused by numerous fungi, parasites and viruses. • Gastropathy is most often due to chemical irritation of the gastric mucosa.

40 CME February 2013 Vol. 31 No. 2 References

Further reading 1. Costa F, D’Elios MM. Management of Helicobacter pylori infection. 4. Mitchell HM. Epidemiology of infection. In: Mobley HLT, Mendz GL, Expert Rev Anti Infect Ther 2010;8(8):887-892. Hazell SL, eds. Helicobacter pylori: Physiology and Genetics.Washington 2. Day DW, Jass JR, Price AB, et al. Morson and Dawson’s Gastrointestinal DC: ASM Press, 2001. Pathology. 4th ed. Oxford, UK: Blackwell Publishing, 2003. 5. Odze RD, Goldblum JR, eds. Surgical Pathology of the GI Tract, Liver, 3. Dixon MF, Genta RM, Yardley JH, Correa P. Classification and grading and Pancreas. 2nd ed. Philadelphia: Saunders Elsevier, 2009. of gastritis. The updated Sydney System. International Workshop 6. Thomas L. Clinical Laboratory Diagnostics. Use and Assessment of Clinical on the Histopathology of Gastritis, Houston 1994. Am J Surg Pathol Laboratory Results. 1st ed. Frankfurt: TH-Books Verlagsgesellschaft 1996;20(10):1161-1181. mbH, 1998.