Sepsis and elevated liver enzymes in a patient with inflammatory bowel disease: think of portal vein thrombosis.

A 42-year old man, 1 year previously diagnosed with ulcerative colitis after an emergency subtotal colectomy with formation of an ileostomy because of severe colitis with perforation, was admitted with sepsis and jaundice. The liver enzymes were elevated and blood cultures were positive for Streptococcus milleri. Magnetic resonance imaging showed a complete thrombosis of the main stem of the portal vein with occlusion of the left branch. Intravenous antibiotic therapy combined with heparinisation led to complete recanalisation of the thrombus. Portal vein thrombosis is a rare complication of inflammatory bowel disease and has been described in only 10 patients thus far. Multiple aetiologic factors may be responsible in relation to inflammatory bowel disease, such as hypercoagulability, thrombocytosis and abdominal sepsis. In patients with inflammatory bowel disease, unexplained sepsis and abnormal liver function tests, the possibility of an acute portal vein thrombosis should be considered and investigated, because unrecognised it may have serious long-term complications.

Genome wide array comparative genomic hybridisation analysis of premalignant lesions of the stomach.

BACKGROUND: Gastric cancer is one of the most frequent malignancies in the world, ranking fifth in the Netherlands as a cause of cancer death. Surgery is the only curative treatment for advanced cases, but results of gastrectomy largely depend on the stage of the disease. A better understanding of the mechanisms of progression from a preneoplastic condition through intraepithelial neoplasia to invasive cancer may provide information relevant to designing focused prevention strategies. METHODS: Because the pattern of chromosomal aberrations in precursors of gastric cancer is unclear, 11 gastric polyps with intraepithelial neoplasia (three hyperplastic polyps and eight adenomas) were analysed by microarray comparative genomic hybridisation to study chromosomal instability in precursors of gastric cancer. RESULTS: Chromosomal aberrations were detected in all specimens. Adenomas showed no more chromosomal aberrations than did the hyperplastic polyps. The most frequent aberrations were gain of 7q36 and 20q12, and loss of 5q14-q21 in the adenomas, and loss of 15q11-14, 1p21-31, and 21q11-21.2 in the hyperplastic polyps. The most frequent chromosomal aberration in common to both types was loss of 9p21.3. CONCLUSION: Hyperplastic polyps showed many chromosomal aberrations, confirming that neoplastic transformation can occur in these lesions. These observations are consistent with the existence of two morphologically and genetically distinct pathways to gastric cancer-the hyperplastic polyp pathway and the (intestinal type) adenoma pathway. The relative contribution of each to gastric carcinogenesis in general, and how they compare to patterns of chromosomal aberrations in the more prevalent flat foci of intraepithelial neoplasia remain to be determined.

Comparative genomic hybridisation as a supportive tool in diagnostic pathology.

AIMS: Patients with multiple tumour localisations pose a particular problem to the pathologist when the traditional combination of clinical data, morphology, and immunohistochemistry does not provide conclusive evidence to differentiate between metastasis or second primary, or does not identify the primary location in cases of metastases and two primary tumours. Because this is crucial to decide on further treatment, molecular techniques are increasingly being used as ancillary tools. METHODS: The value of comparative genomic hybridisation (CGH) to differentiate between metastasis and second primary, or to identify the primary location in cases of metastases and two primary tumours was studied in seven patients. CGH is a cytogenetic technique that allows the analysis of genome wide amplifications, gains, and losses (deletions) in a tumour within a single experiment. The patterns of these chromosomal aberrations at the different tumour localisations were compared. RESULTS: In all seven cases, CGH patterns of gains and losses supported the differentiation between metastasis and second primary, or the identification of the primary location in cases of metastases and two primary tumours. CONCLUSION: The results illustrate the diagnostic value of CGH in patients with multiple tumours.

Increased apoptosis in gastric mucosa adjacent to intestinal metaplasia.

BACKGROUND: The biological processes involved in the development of gastric mucosal atrophy and intestinal metaplasia are still incompletely understood. Reports testing the hypothesis that apoptosis leads to atrophy have yielded conflicting results. The availability of new antibodies for the detection of apoptotic cells in tissue sections has facilitated the analysis of the role of apoptosis in the gastritis-atrophy-intestinal metaplasia sequence. METHODS: Archival material from 40 gastric resection specimens with normal mucosa (n = 5), chronic active gastritis (n = 17), or intestinal metaplasia (n = 18) was studied. Immunohistochemistry was performed using antibodies directed against cleaved cytokeratin 18 and active caspase 3. Slides were scored on a 0-3 scale for the presence of apoptotic cells. RESULTS: Normal gastric mucosa contained low numbers of apoptotic cells at the surface epithelium (mean score, 0.20). This number was significantly increased in cases with chronic gastritis (mean score, 1.06) and in those with intestinal metaplasia (mean score, 2.56). Within the intestinal metaplasia cases, 44 different foci of intestinal metaplasia were identified. In 39 of these 44 areas, concentrations of apoptotic cells were seen immediately adjacent to the foci of intestinal metaplasia, but not in the metaplastic epithelium itself. CONCLUSIONS: Apoptosis is uncommon in normal gastric mucosa. Chronic inflammation and intestinal metaplasia are associated with increased apoptosis, but occur mainly at the mucosal surface and not in the deeper layers. These findings do not support the concept that apoptosis underlies the loss of gastric glands and leads to atrophy, but the observed concentration of apoptotic epithelial cells adjacent to foci of intestinal metaplasia could be related to heterogeneity of epithelial damage, causing apoptosis, to which intestinal metaplasia is a response.

Surveillance in Barrett's oesophagus: a critical reappraisal.

BACKGROUND: Current recommendations are for endoscopic surveillance of patients with Barrett's oesophagus to detect dysplasia and to diagnose carcinoma at an early and possibly treatable stage. However, observations suggest that these current practice guidelines are thwarted by many factors often not taken into account. These observations stem from general surveillance aspects as well from specific data on Barrett's oesophagus. This review therefore aims at discussing data on the current surveillance strategy in conjunction with general surveillance aspects relevant for their interpretation. METHODS: Literature survey of published articles. RESULTS: A critical reappraisal of the literature shows that the current surveillance strategy is hampered by multiple problems with the marker dysplasia, cost-ineffectiveness, an overrated cancer risk and an astonishing lack of prospective, randomized data showing a clear benefit in terms of a greater life expectancy. Moreover, the decisive study is unlikely ever to be performed because of the large number of patients needed and the required length of follow-up. As a result, protocols are being carried out that have never been critically tested prior to large-scale clinical implementation. CONCLUSIONS: Although these findings should not lead to therapeutic nihilism, the data raise the issue of whether or not surveillance protocols should be restricted to specialized referral centres with particular research efforts aimed at improving existing and developing new techniques that lack most of the described pitfalls and problems. Since it is foreseen that matters will not change rapidly in the (near) future, the clinician has no other choice than to rely on individually tailored arguments to survey taking into account for example family history, age and anxiety about potential long-term effects.

Effects of prucalopride on colonic transit, anorectal function and bowel habits in patients with chronic constipation.

BACKGROUND: There is a need for better tolerated drugs to normalize bowel function in chronic constipation. Prucalopride is a highly selective, specific, serotonin4 receptor agonist with enterokinetic properties. AIM: To evaluate the effects of prucalopride on bowel function, colonic transit and anorectal function in patients with chronic constipation. METHODS: Twenty-eight patients were enrolled in this double-blind, placebo-controlled, crossover study (prucalopride: 1 mg, n=12; 2 mg, n=16). Patients kept a bowel function diary. Colonic transit times and anorectal function (anal manometry, rectal sensitivity and rectal compliance) were assessed. RESULTS: Prucalopride (1 mg) compared to placebo significantly increased the mean number of spontaneous complete, spontaneous and all bowel movements per week. Prucalopride (1 mg) significantly decreased the percentage of bowel movements with hard/lumpy stools and straining and increased the urge to defecate. Prucalopride (1 and 2 mg) decreased the mean total colonic transit time by 12.0 h (prucalopride 42.8 h vs. placebo 54.8 h; P=0.074). No statistically significant effects were found in any of the anorectal function parameters. Prucalopride was well tolerated. There were no clinically relevant changes in standard safety parameters. CONCLUSIONS: Prucalopride significantly improves stool frequency and consistency, and the urge to defecate, and may decrease colonic transit times in patients with chronic constipation.

Lipoprotein (a), thrombophilia and inflammatory bowel disease.

Thrombophilia in inflammatory bowel disease may be due to several risk factors, such as a dysbalanced haemostasis with a hypercoagulative state, thrombocytosis, hyperfibrinogenaemia and hyperhomocysteinaemia. In addition, increased concentrations of lipoprotein (a), a modified form of low-density lipoprotein particles, have been associated with a higher risk of thrombotic vascular disease, probably due to inhibition of (local and endothelial) fibrinolysis. The mechanisms regulating the plasma concentration of lipoprotein (a) have not yet been elucidated completely, but genetic factors are involved. Dietary factors seem to play a minor role. In this issue of the journal, Koutroubakis et al. report that lipoprotein (a) concentration is elevated in patients with Crohn's disease, but not in patients with ulcerative colitis. Several other (apo)lipoproteins have a different pattern in patients with inflammatory bowel disease than in a control population of healthy subjects from Crete. These findings add up to the multifactorial nature of thrombophilia in inflammatory bowel disease patients, especially in patients with Crohn's disease, and give rise to speculations about the clinical significance of the observed different lipoprotein metabolism in patients with inflammatory bowel disease.

Quantitative assessment of gastric corpus atrophy in subjects using omeprazole: a randomized follow-up study.

OBJECTIVES: Atrophy of the gastric mucosa most frequently results from chronic Helicobacter pylori infection and is a risk factor for the development of gastric cancer. Profound acid suppression has been suggested to accelerate the onset of gastric mucosal atrophy. The aim of the present study was to evaluate the effects of H. pylori eradication and acid inhibition by omeprazole on gastric atrophy by means of quantitative analysis of tissue morphology. METHODS: Corpus biopsy specimens were obtained during endoscopy in 71 gastroesophageal reflux disease (GERD) patients at baseline and after 3 and 12 months. A total of 48 subjects were H. pylori positive and 23 were H. pylori negative. All subjects received omeprazole 40 mg once daily after the first endoscopy for 12 months. After randomization, 27 of the 48 H. pylori-positive patients also received eradication therapy. In hematoxylin and eosin-stained slides the volume percentages of glands (VPGL), volume percentages of stroma (VPS), and volume percentages of infiltrate (VPI) were measured in the glandular zone of the mucosa. The results were evaluated by computerized morphometric analysis. RESULTS: In the eradication group, the mean VPGL increased from 63.0% to 67.7% and 71.5% after 3 and 12 months (p < 0.001), respectively. The mean VPS and VPI decreased from 33.1% and 4.0% to 29.3% and 3.0% and to 26.4% and 2.1% (p < 0.001 and p = 0.04), respectively. Patients with the lowest VPGL at baseline showed the largest increases of VPGL after eradication treatment as compared to patients with high a VPGL at baseline. In the H. pylori-persistent group the VPI showed a significant increase (p = 0.01), and in the H. pylori-negative group VPGL increased significantly from 71.9% to 75.2% (p = 0.03) after 12 months. CONCLUSIONS: Eradication of H. pylori leads to restitution of the volume percentage of glandular epithelium to normal levels, even during treatment with proton pump inhibitors. Whether this effect can also be seen in patients with marked atrophy needs further investigation.

Assessment and classification of fistula-in-ano in patients with Crohn's disease by hydrogen peroxide enhanced transanal ultrasound.

Crohn's disease is well known for its perianal complications, among which fistulas-in-ano are the most common abnormalities. Fistulas-in-ano in Crohn's disease tend to be complex and have a high recurrence rate. Therefore the role of surgery is generally more conservative. Hydrogen peroxide enhanced transanal ultrasound has proven superior to physical examination, fistulography, computed tomography, and conventional ultrasound in demonstrating the fistula tract. This study examined the fistula tracks in patients with Crohn's disease. Forty-one patients with Crohn's disease and fistula-in-ano were investigated using physical examination, sondage of the fistula, proctoscopy and transanal ultrasound. Hydrogen peroxide was infused via a small catheter into the fistula. The main track and the ramification of the fistula were classified according to the anatomical Parks' classification. Only 9 (22%) patients had a single inter- or transsphincteric fistula. In 5 (12%) patients a single supra- or extrasphincteric fistula (high fistula) was found, in 14 (34%) more than one fistula track (ramified), and in 13 (32%) an anovaginal fistula. Thus 78% of patients had a surgically difficult to treat fistula. In the ramified fistula the main track follows the Parks' classification, but ramifications can have a bizarre pattern which is not in agreement with this classification. Optimal documentation by means of hydrogen peroxide enhanced transanal ultrasound is therefore mandatory before surgery or before other therapies such as anti-tumor necrosis factor treatment.

[Gastrointestinal surgery and gastroenterology. XIII. Classification and diagnosis of perianal fistulas]. / Gastro-intestinale chirurgie en gastro-enterologie. XIII. Classificatie en diagnostiek van perianale fistels.

Intersphincteric abscesses due to inflammation of an anal gland are the origin of most perianal fistulas. Perianal fistulas are classified into four types. Intersphincteric and transsphincteric fistulas are the most common. The appropriate surgical treatment of perianal fistulas is dependent upon their correct classification. Despite new imaging-techniques, physical examination of the perianal region remains of paramount importance for the preoperative classification of perianal fistulas. At present, endoanal ultrasound with the injection of hydrogen peroxide into the fistulous tract, is advocated as the most suitable method for the preoperative imaging of perianal fistulas.

Distinct chromosomal aberrations in Epstein-Barr virus-carrying gastric carcinomas tested by comparative genomic hybridization.

BACKGROUND & AIMS: Approximately 10% of gastric adenocarcinomas carry the human pathogenic Epstein-Barr virus (EBV). The role of EBV in the pathogenesis of these carcinomas remains to be established. METHODS: To obtain a comprehensive overview of chromosomal aberrations in EBV-carrying and EBV-negative gastric carcinomas we performed comparative genomic hybridization (CGH) on 44 gastric carcinomas, 10 EBV-positive, and 34 EBV-negative. Additionally, DNA flow cytometry was done. RESULTS: Loss of chromosome 4p (P < 0.001) and of 11p (P < 0.02) was exclusively restricted to EBV-carrying gastric carcinomas. In addition, loss of 18q (P < 0.02) was significantly more frequent in EBV-carrying gastric carcinomas. The latter involves loci, which have already been linked to gastric carcinogenesis such as the DCC and SMAD4 gene. In contrast, the losses on chromosome 4 and 11 do not yet harbor a gene related to gastric carcinogenesis. No significant correlation was found between DNA-ploidy and the EBV-status. A number of chromosomal aberrations were found at comparable frequencies in both groups, i.e., losses of chromosome 17, 12q, and loss of 1p. Interestingly, gains of 13q (10/34) and 3q (5/34) and loss of 1q (5/34) were solely observed in EBV-negative gastric carcinomas. CONCLUSIONS: These data indicate that EBV-carrying and EBV-negative gastric carcinomas have different pathogenetic pathways in which EBV might play a crucial role.

Absence of tpr-met and expression of c-met in human gastric mucosa and carcinoma.

The c-met proto-oncogene, encoding the hepatocyte growth factor receptor, can be activated by various mechanisms. These include, among others, gene amplification with concomitant overexpression and the tpr-met oncogenic rearrangement. In the case of gastric cancer, contradictory results on the presence of the tpr-met oncogenic rearrangement have been published. The current study aimed therefore to assess the prevalence of tpr-met expression in Caucasian gastric adenocarcinomas, to evaluate the importance of this oncogene in their carcinogenesis. In addition, the level of c-met expression was determined, to evaluate the role of this alternative mode of activation of the proto-oncogene. A series of Caucasian gastric adenocarcinomas (n=43) and normal gastric mucosal samples (n=14) was analysed for tpr-met and c-met expression. Expression of tpr-met mRNA in the samples was performed by two reverse transcriptase polymerase chain reaction (RT-PCR) assays, with excellent correlation. The specificity of both methods was confirmed by direct sequencing of the PCR products of the MNNG-HOS cell line, which is known to contain the rearrangement. The level of c-met expression was assessed using semi-quantitative RT-PCR assays and immunohistochemistry (IHC). None of the normal gastric mucosal or gastric adenocarcinoma samples expressed tpr-met mRNA, as determined by both RT-PCR assays. Seventy per cent of the adenocarcinomas showed overexpression of c-met, according to elevated c-met mRNA levels, compared with the expression level of normal gastric mucosa. A significant correlation was found between the level of c-met mRNA and protein expression. In conclusion, these results strongly suggest that tpr-met activation does not play a role in Caucasian gastric carcinogenesis, while overexpression of the c-met gene occurs in the majority of Caucasian gastric adenocarcinomas.

Selective gene delivery toward gastric and esophageal adenocarcinoma cells via EpCAM-targeted adenoviral vectors.

Application of recombinant adenoviral vectors for cancer gene therapy is currently limited due to lack of specificity for tumor cells. For gastric and esophageal adenocarcinoma, we present here that the relative abundant expression of the primary adenovirus receptor, coxsackie/adenovirus receptor (CAR), on normal epithelium compared to carcinoma favors the transduction of the epithelium. As such, to achieve specific transduction of cancer cells, targeting approaches are required that ablate the binding of the virus to CAR and redirect the virus to tumor-specific receptors. By immunohistochemistry and reverse transcriptase polymerase chain reaction assays, we demonstrate a marked difference in expression of the human epithelial cell adhesion molecule (EpCAM) between normal and (pre)malignant lesions of the stomach and esophagus. Based on this, we explored the feasibility of using EpCAM to achieve gastric and esophageal adenocarcinoma selective gene transfer. Adenoviral vectors redirected to EpCAM using bispecific antibodies against the adenovirus fiber-knob protein and EpCAM specifically infected gastric and esophageal cancer cell lines. Using primary human cells, an improved ratio of tumor transduction over normal epithelium transduction was accomplished by the EpCAM-targeted vectors. This study thus indicates that EpCAM-targeted adenoviral vectors may be useful for gastric and esophageal cancer-specific gene therapy in patients.

Percutaneous endoscopic gastrostomy: complications and suggestions to avoid them.

OBJECTIVES: Percutaneous endoscopic gastrostomy (PEG) tubes have become an excellent alternative for the long-term management of patients with proximal obstructions of the gastrointestinal tract. However, their use has limitations and can be associated with serious complications. We therefore studied the frequency and severity of complications related to the use of PEG tubes in our clinic. DESIGN: All adults (aged 18 years and above) in whom a PEG tube was placed between January 1 1994 and January 1 1999 at the Free University Hospital in Amsterdam were included in this study. In initial cases, the indication and procedure were individually judged according to a liberal protocol. However, after several major complications, a strict procedure protocol was implemented in September 1996. RESULTS: During the study period, 263 PEG tubes were placed in 254 patients with head and neck cancer (n = 183; 70%), neurological disorders (n = 52; 20%) or severe upper gastrointestinal motility disorders (n = 28; 11%). In period I, 167 PEG tubes were placed and in period II, 96 PEG tubes were inserted. Patients were followed for a median 111 days. Minor complications occurred in 13% of the patients. Major complications occurred in 8% of the patients. In period I, the percentage of major complications was higher than in period II (9.5% versus 6%). CONCLUSION: PEG tube placement is a safe procedure when performed according to strict guidelines. By doing so, PEG tubes allow optimal feeding for prolonged periods with the occasional need for replacement of the tube. PEG tubes should not be introduced in acutely ill patients, patients with a short life expectancy and preferably not to patients with severe coughing.

The prevalence of constipation in institutionalized people with intellectual disability.

Constipation is a common problem in people with intellectual disability (ID). Laxatives are frequently prescribed with disappointing results. The prevalence of constipation was investigated in a random population of 215 people with ID (IQ < 50) and constipation was correlated with clinical symptoms. All subjects were scored for bowel habits. Constipation was defined as having a bowel movement less than three times a week or the necessity of using laxatives more than three times a week. Further possible accompanying factors were evaluated. The control subjects were defined as individuals who did not use laxatives. Subjects with constipation were defined as patients and were compared to subjects without constipation (controls). One hundred and forty-nine out of 215 cases (69.3%) showed constipation. Constipation was significantly correlated with non-ambulancy, cerebral palsy, the use of anticonvulsive medication or benzodiazepines, H2-receptor antagonists or proton pump inhibitors, food refusal, and an IQ < 35. Fifty-eight per cent of the patients used bisacodyl or magnesium oxide, 39% lactulose, 13% sodiumlaurylsulphoacetate/sodium citrate/sorbitol and only 10% were given sodium phosphate enemas. Faecal soiling was found in 15% of subjects, while manual evacuation of faeces was performed in nearly 7% of cases. Constipation was randomly demonstrated in almost 70% of the population with ID. Subjects with the above-mentioned accompanying factors are especially at risk for constipation. Contrary to the general population, constipation in people with ID is associated with little use of phosphate enemas, microlax, a low incidence of faecal soiling and manual evacuation of faeces, suggesting an aetiology without distal faecal impaction. The regimen and effect of therapy has to be studied to define adequate treatment schedules.

Gastric mucosal morphological consequences of acid suppression: a balanced view.

In the chapter, an analysis of the literature on the relationship between Helicobacter pylori, the use of proton pump inhibitors and the development of atrophic gastritis is presented, and the difficulties of classifying gastritis and the new possibilities of quantifying chronic inflammation by morphometric analysis are discussed. The issue surrounding the necessity of eradicating H. pylori in H. pylori-positive patients has still not been solved. Most studies have now accepted that proton pump inhibitors indeed accelerate the onset of atrophic gastritis in H. pylori-positive patients, but evidence against such an association was published in one recent (Scandinavian) study; conclusions from this study have, however, been challenged by several groups. Some data are available on the efficacy of H. pylori eradication with regard to the prevention of atrophy. The limited significance of the development of parietal cell protrusions and fundic gland cysts is better understood, but much less is known of the development and long-term consequence of H. pylori-induced autoimmune gastritis. Finally, recent studies in H. pylori-positive patients indicate that treatment with proton pump inhibitors may promote bacterial N-nitrosation formation. These data taken together suggest that the eradication of H. pylori may be based not only on morphological arguments, but also on bacterial alterations in the gastric milieu.

The role of Helicobacter pylori virulence factors in interleukin production by monocytic cells.

Helicobacter pylori infection results in chronic gastritis, which is initiated by the release of cytokines like interleukin (IL)-12 and IL-8 from mononuclear cells, and IL-8 from gastric epithelial cells. The severity of gastritis is influenced both by host factors and by bacterial factors such as the Cag proteins and the vacuolating cytotoxin VacA. Amounts of IL-12 and IL-8 produced by monocytic THP-1 cells differed considerably between the eight H. pylori isolates tested, but in contrast to H. pylori-induced IL-8 production by gastric epithelial cells, did not correlate to the Cag and VacA types of the strains. Apparently, in addition to Cag and VacA, other bacterial factors determine the extent in which H. pylori induced IL production in monocytes.

Rapid quantitative assessment of gastric corpus atrophy in tissue sections.

BACKGROUND/AIMS: Grading of Helicobacter pylori induced atrophic gastritis using the updated Sydney system is severely limited by high interobserver variability. The aim of this study was to set up a quantitative test of gastric corpus mucosal atrophy in tissue sections and test its reproducibility and correlation with the Sydney scores of atrophy. METHOD: Mucosal atrophy was assessed in 124 haematoxylin and eosin stained corpus biopsy specimens by two experienced gastrointestinal pathologists (EB, JL) according to the updated Sydney system as none (n = 33), mild (n = 33), moderate (n = 33), or pronounced (n = 25). In each specimen, the proportions of glands, stroma, infiltrate, and intestinal metaplasia in the glandular zone were measured as volume percentages using a point counting method. The optimal point sample size, intra-observer and interobserver reproducibility, discriminative power for degrees of atrophy, and correlations with H pylori status were evaluated. RESULTS: Counting 400 points in 200 fields of vision provided the smallest sample size that still had excellent intra-observer and interobserver reproducibility (r > or = 0.96). Overall, the volume percentage of glands (VPGL), infiltrate (VPI), and stroma (VPS) correlated well with the Sydney scores for atrophy (p < or = 0.003). However, no differences were found between non-atrophic mucosa and mild atrophy. No correlation was found between age and either the Sydney grade of atrophy or the VPGL or VPS. In non-atrophic mucosa and mild atrophy, H pylori positive cases showed a significantly higher VPI than did H pylori negative cases. A lower VPGL was seen in H pylori positive cases than in H pylori negative cases in the mild atrophy group. VPS did not correlate with H pylori status within each grade of atrophy. CONCLUSION: Point counting is a powerful and reproducible tool for the quantitative analysis of mucosal corpus atrophy in tissue sections. These data favour the combination of "none" and "mild" atrophy into one category, resulting in a three class grading system for corpus atrophy, when using the updated Sydney system.