Barbara J. McKenna

Magnetization Transfer Helps Detect Intestinal Fibrosis in an Animal Model of Crohn Disease

PURPOSE To determine the utility of magnetization transfer (MT) in the identification and quantification of intestinal fibrosis in a rat model of Crohn disease. MATERIALS AND METHODS The university committee on the use and care of animals approved this study (UCUCA 08592). Lewis rats injected subserosally with peptidoglycan-polysaccharide (PG-PS) develop bowel inflammation 1 day after laparotomy (early phase) and fibrosis starting 14 days after laparotomy (late phase). The authors performed 2.0-T magnetic resonance (MR) imaging in 25 rats injected with PG-PS and 13 injected with human serum albumin (HSA) (control animals). Imaging was performed before laparotomy and on a weekly basis thereafter for up to 28 days. The MT ratio in the bowel wall was calculated. Resected cecal tissue was scored for inflammation and fibrosis. Tissue fibrosis was determined with colorimetric analysis of trichrome-stained specimens. Collagen content was measured with Western blot analysis. Statistical analyses were performed with the Student t test for continuous bivariate comparisons, the Pearson correlation for continuous variables, and the Spearman correlation for ordinal variables. RESULTS All rats developed early inflammation, which subsided over time. Rats injected with PG-PS developed increased fibrosis in the late phase, whereas control rats did not. The mean MT ratio of rats injected with PG-PS with late-phase fibrosis was higher than that in rats with early phase inflammation (P = .017). In addition, the MT ratio of rats injected with PG-PS with late-phase fibrosis was higher than that of control animals that did not develop fibrosis in the late phase (P = .0001). The MT ratio of control animals remained unchanged over time as inflammation subsided. The MT ratio in rats injected with PG-PS showed correlation with tissue fibrosis (ρ = 0.63). The MT ratio showed correlation with tissue collagen (R = 0.74). The positive and negative predictive values of the MT ratio in the prediction of fibrosis were 92% (12 of 13 rats) and 83% (five of six rats), respectively. CONCLUSION These results indicate that MT is sensitive to bowel wall fibrosis as occurs in Crohn strictures.

Computed tomography enterography findings correlate with tissue inflammation, not fibrosis in resected small bowel Crohn's disease

Background: It has become commonplace to categorize small intestinal Crohns disease (CD) as “active” vs. “inactive” or “inflammatory” vs. “fibrotic” based on computed tomography enterography (CTE) findings. Data on histologic correlates of CTE findings are lacking. We aimed to compare CTE findings with histology from surgically resected specimens. We tested the hypothesis that CTE findings can distinguish tissue inflammation from fibrosis. Methods: Patients who underwent CTE within 3 months before intestinal resection for CD were retrospectively studied. Radiologists blinded to history and histology scored findings on CTE. Pathologists blinded to history and imaging scored resected histology. We compared histology with CTE findings and radiologists assessment of whether the stricture was likely “active” or “inactive.” Results: In all, 22 patients met inclusion criteria. Inflammatory CTE findings correlated with histologic inflammation (rho = 0.52). Strictures believed to be “active” on CTE were more inflamed at histology (P = 0.0002). Strictures lacking inflammatory findings on CTE or considered “inactive” were not associated with greater histologic fibrosis or significant histologic inflammation. Upstream dilation was associated with greater tissue fibrosis in univariate (P = 0.014) but not in multivariate analysis (P = 0.53). Overall, histologic fibrosis correlated best with histologic inflammation (rho = 0.52). Strictures on CTE with the most active disease activity also had the most fibrosis on histology. Conclusions: CTE findings of mesenteric hypervascularity, mucosal hyperenhancement, and mesenteric fat stranding predict tissue inflammation. However, small bowel stricture without CTE findings of inflammation does not predict the presence of tissue fibrosis. Therefore, caution should be used when using CTE criteria to predict the presence of scar tissue. (Inflamm Bowel Dis 2011;)

Ultrasound Elasticity Imaging for Detecting Intestinal Fibrosis and Inflammation in Rats and Humans With Crohn's Disease

BACKGROUND Intestinal fibrosis causes many complications of Crohns disease (CD). Available biomarkers and imaging modalities lack sufficient accuracy to distinguish intestinal inflammation from fibrosis. Transcutaneous ultrasound elasticity imaging (UEI) is a promising, noninvasive approach for measuring tissue mechanical properties. We hypothesized that UEI could differentiate inflammatory from fibrotic bowel wall changes in both animal models of colitis and humans with CD. METHODS Female Lewis rats underwent weekly trinitrobenzene sulfonic acid enemas yielding models of acute inflammatory colitis (n = 5) and chronic intestinal fibrosis (n = 6). UEI scanning used a novel speckle-tracking algorithm to estimate tissue strain. Resected bowel segments were evaluated for evidence of inflammation and fibrosis. Seven consecutive patients with stenotic CD were studied with UEI and their resected stenotic and normal bowel segments were evaluated by ex vivo elastometry and histopathology. RESULTS Transcutaneous UEI normalized strain was able to differentiate acutely inflamed (-2.07) versus chronic fibrotic (-1.10) colon in rat models of inflammatory bowel disease (IBD; P = .037). Transcutaneous UEI normalized strain also differentiated stenotic (-0.87) versus adjacent normal small bowel (-1.99) in human CD (P = .0008), and this measurement also correlated well with ex vivo elastometry (r = -0.81). CONCLUSIONS UEI can differentiate inflammatory from fibrotic intestine in rat models of IBD and can differentiate between fibrotic and unaffected intestine in a pilot study in humans with CD. UEI represents a novel technology with potential to become a new objective measure of progression of intestinal fibrosis. Prospective clinical studies in CD are needed.

The diagnostic value of endoscopic terminal ileum biopsies

OBJECTIVES:Biopsy of the terminal ileum (TI) is commonly performed during colonoscopy. The primary utility of this is to diagnose or rule out Crohns disease in patients with symptoms and/or radiographic findings suggesting this diagnosis. We see many such biopsies in our gastrointestinal pathology service and have been impressed by the subjectively low yield of TI biopsies. Therefore, we studied this to obtain objective data.METHODS:We retrospectively reviewed 414 consecutive patients with terminal ileal biopsies. Histologic parameters evaluated were primarily those changes diagnostic of chronic inflammation or its sequelae. Histologic findings were then compared with the indication(s) and endoscopic findings.RESULTS:The TI was histologically normal in 82% and endoscopically normal in 81% with most endoscopic abnormals having “ileitis” (13%). Known or strongly suspected inflammatory bowel disease was the most common indication (38%) with Crohns disease accounting for 20% and ulcerative colitis 16% followed by diarrhea (33%), anemia/hematochezia (15%), abdominal pain (6%), and abnormal imaging (5%). Diagnostic yield varied, with indication and endoscopic findings being highest with known suspected Crohns disease (40%), abnormal imaging (32%), and with endoscopic “ileitis” (84%) or ulcers/erosions (69%).CONCLUSIONS:Diagnostic yield of TI biopsy varied with indication and endoscopic findings. Our study indicates that biopsy is of greatest value in patients undergoing endoscopy for known or strongly suspected Crohns disease, or with an abnormal imaging study of the TI. Biopsy of endoscopically normal mucosa is unlikely to yield diagnostically useful information, and is not encouraged as routine. However, when “ileitis,” ulcers, or erosions are identified, biopsies can be very helpful.

Morphologic Findings in Upper Gastrointestinal Biopsies of Patients With Ulcerative Colitis: A Controlled Study

IntroductionUpper gastrointestinal involvement, both gastric and duodenal, is known to occur in both Crohn disease and ulcerative colitis (UC). However, the frequency and types of inflammation in upper gastrointestinal biopsies in patients with UC has not been well studied, especially in a controlled study. MethodsTwenty-four esophageal, 59 gastric, and 40 duodenal biopsies from 69 UC patients were reviewed. These were compared with 35 esophageal, 66 gastric, and 46 duodenal biopsies from a control group of 97 consecutive patients of similar age and sex distribution. The pattern and extent of inflammation were noted in each biopsy. ResultsThere were 3 types of gastric inflammation that occurred more in UC patients than in controls, and the differences were statistically significant. The most common was an intense focal gastritis, present in 29% of UC gastric biospies, compared with 9% of controls. Twenty-two percent of UC patients had a basal mixed inflammation compared with 8% of controls, and 20% of the UC patients had superficial plasmacytosis compared with 6% of controls. There were no esophageal inflammations that occurred more commonly in UC than controls. Four UC patients and no controls had diffuse chronic duodenitis, also a statistically significant difference. All 4 UC-duodenitis patients were among the 10 with previous colectomies, and all 4 patients had pouchitis. Only 1 of the 4 UC-colectomy patients without duodenitis developed pouchitis. ConclusionsMost UC patients have no upper gastrointestinal inflammation in biopsies, and most of the inflammations they have are not unique. The most common upper gastrointestinal inflammatory pattern in patients with UC is focal gastritis, followed by gastric basal mixed inflammation and superficial plasmacytosis. The one unique upper gastrointestinal inflammation in UC patients is diffuse chronic duodenitis, present in 10% of patients who had duodenal biopsies, and in 40% of UC patients who had colectomy and all of these patients had pouchitis. This association strongly suggests that diffuse chronic duodenitis in UC patients who have colectomy is a strong predictor of pouchitis.

Lymphocytic esophagitis: a chronic or recurring pattern of esophagitis resembling allergic contact dermatitis.

Lymphocytic esophagitis (LE) is characterized by intraepithelial lymphocytes (IELs) and spongiosis, resembling contact dermatitis. LE has been defined as high numbers of IELs and no or rare granulocytes and was found in young patients and in association with Crohn disease (CD). We reviewed the medical records of 42 LE cases. Cases were divided into severe (IELs in interpapillary and peripapillary fields) and mild (IELs in peripapillary fields) LE. The control group included specimens from 34 consecutive esophageal biopsy cases. Mean ages were similar (LE, 44 years; control subjects, 43 years). CD was present in 5 LE cases (12%) and 1 control case, an insignificant difference. Of patients with LE, 14 (33%) had an allergy; 11 (26%), gastroesophageal reflux disease (GERD); 4 (10%), Helicobacter pylori gastritis; and 18 (43%), dysphagia. No differences were found in clinical features between LE and control cases, except GERD was less common in severe LE (6/30 [20%]) than in control cases (17 [50%]). No patient with LE had celiac disease. No medications were common among LE cases. Patients with LE are statistically no more likely than control subjects to have CD. We found no association between LE and any clinical condition or symptom. Based on sequential biopsies in 7 patients, LE seems to be a chronic disease.

Resveratrol has antiinflammatory and antifibrotic effects in the peptidoglycan-polysaccharide rat model of Crohn's disease†

Background: Resveratrol has antiinflammatory and antifibrotic effects. Resveratrol decreases proliferation and collagen synthesis by intestinal smooth muscle cells. We hypothesized that resveratrol would decrease inflammation and fibrosis in an animal model of Crohns disease. Methods: Peptidoglycan‐polysaccharide (PG‐PS) or human serum albumin (HSA) was injected into the bowel wall of Lewis rats at laparotomy. Resveratrol or vehicle was administered daily by gavage 1–27 days postinjection. On day 28, gross abdominal and histologic findings were scored. Cecal collagen content was measured by colorimetric analysis of digital images of trichrome‐stained sections. Cecal levels of procollagen, cytokine, and growth factor mRNAs were determined. Results: PG‐PS‐injected rats (vehicle‐treated) developed more fibrosis than HSA‐injected rats by all measurements: gross abdominal score (P < 0.001), cecal collagen content (P = 0.04), and procollagen I and III mRNAs (P ≤ 0.0007). PG‐PS‐injected rats treated with 40 mg/kg resveratrol showed a trend toward decreased gross abdominal score, inflammatory cytokine mRNAs, and procollagen mRNAs. PG‐PS‐injected rats treated with 100 mg/kg resveratrol had lower inflammatory cytokine mRNAs (IL‐1&bgr; [3.50 ± 1.08 vs. 10.79 ± 1.88, P = 0.005], IL‐6 [17.11 ± 9.22 vs. 45.64 ± 8.83, P = 0.03], tumor necrosis factor alpha (TNF‐&agr;) [0.80 ± 0.14 vs. 1.89 ± 0.22, P = 0.002]), transforming growth factor beta 1 (TGF‐&bgr;1) mRNA (2.24 ± 0.37 vs. 4.06 ± 0.58, P = 0.01), and histologic fibrosis score (6.4 ± 1.1 vs. 9.8 ± 1.0; P = 0.035) than those treated with vehicle. There were trends toward decreased gross abdominal score and decreased cecal collagen content. Procollagen I, procollagen III, and IGF‐I mRNAs also trended downward. Conclusions: Resveratrol decreases inflammatory cytokines and TGF‐&bgr;1 in the PG‐PS model of Crohns disease and demonstrates a promising trend in decreasing tissue fibrosis. These findings may have therapeutic applications in inflammatory bowel disease. (Inflamm Bowel Dis 2011;)

Sloughing esophagitis is associated with chronic debilitation and medications that injure the esophageal mucosa

Sloughing esophagitis is characterized by superficial necrotic squamous epithelium and endoscopic plaques or membranes. According to abstract reports SE affects older, debilitated patients on multiple medications. This study seeks to evaluate the clinical findings in patients with SE. Thirty-one patients with necrotic superficial squamous epithelium, with endoscopic white plaques or membranes, but without fungi, were compared with 34 patients having esophageal biopsies done for any purpose other than Barretts surveillance. Sloughing esophagits patients were older than controls (56 vs 43.5 years) and were more likely to be taking five or more medications (77 vs 32%), especially central nervous system depressants (65 vs 32%) and medications associated with esophageal injury (55 vs 18%). In 69% the plaques were in the distal and/or mid-esophagus; 23% involved the entire esophagus; 8% were limited to the proximal esophagus. There was no correlation between medication history and site. Sloughing esophagitis patients were likely to be debilitated based on evidence such as being on home oxygen, in nursing homes, bedridden, hospitalized, or malnourished, having metastatic cancer, organ transplantation, and/or being immunosuppressed. Sloughing esophagitis patients were more likely to have died since the biopsy (23 vs 3%), have peptic ulcer disease (55 vs 24%), or renal insufficiency (16% vs none), but no more likely to have dysmotility disorders, irritable bowel disease, or atherosclerosis. SE patients were less likely to have gastroesophageal reflux disease (45 vs 74%). No specific cause for sloughing esophagitis was identified, but the association with multiple drugs and conditions that may lead to esophageal stasis and/or injury, suggest that this is a local, perhaps contact injury, rather than an ischemic injury.

Lymphocytic esophagitis: A diagnosis of increasing frequency

Background: Despite being found with increasing frequency on esophageal biopsies, the clinical significance of lymphocytic esophagitis (LE) remains poorly understood. Goals: The primary aim of our study was to characterize the clinical presentation and natural history of LE among adult patients. Study: We retrospectively reviewed records for all 81 adult patients at the University of Michigan Medical Center who had a histopathologic diagnosis of LE between January 1998 and November 2009. Patient demographics, clinical history, laboratory data, and imaging results from the time of diagnosis were obtained through review of computerized medical records. A telephone survey was conducted to collect natural history data. Results: The number of LE diagnoses increased over time, with 81.5% (n=66) of patients being diagnosed in the last 3 years. The most frequent symptoms at the time of presentation were dysphagia (n=54), chest/abdominal pain (n=36), and heartburn (n=38). The majority (58.6%) of patients reported improvement in their initial gastrointestinal symptoms—most commonly associated with initiation of a proton pump inhibitor. Upon follow-up, most patients reported a good quality of life and satisfaction with their current health status. Conclusions: LE is a new clinical entity with an increasing incidence. LE seems to have a benign natural history, with most patients reporting an improvement in symptoms and satisfaction with their health-related quality of life. Prospective studies are needed to better characterize the natural history and potential treatments for this clinical entity.

Hepatic Mesenchymal Hamartoma: A Short Review

Hepatic mesenchymal hamartoma is a hamartomatous growth of mesenchymal tissue in the liver of uncertain etiology. It is a space-occupying lesion that can potentially compress adjacent organs resulting in various complications including death. Hepatic mesenchymal hamartoma is characterized by proliferation of variably myxomatous mesenchyme and malformed bile ducts. The differential diagnosis includes other pediatric hepatic masses. The diagnosis is typically made during infancy, and complete resection is invariably curative.