Christopher D. Lind

Possible role of transforming growth factor α in the pathogenesis of Ménétrier's disease: Supportive evidence from humans and transgenic mice

Ménétriers disease is an uncommon disorder of unknown etiology characterized by enlarged gastric folds with foveolar hyperplasia and cystic dilatation of gastric glands. Biochemical features that are seen frequently include hypoproteinemia, hypochlorhydria, and increased gastric mucus. Because transforming growth factor alpha (TGF alpha) is an epithelial cell mitogen that inhibits gastric acid secretion and increases gastric mucin content, we hypothesized that its altered expression might be involved in the pathogenesis of this disease. Therefore, we characterized TGF alpha immunoreactivity in the gastric mucosa of 4 patients with Ménétriers disease. In contrast to the normal pattern of TGF alpha immunostaining in which TGF alpha appears most concentrated in parietal cells, there was intense staining in the majority of mucous cells in the gastric mucosa of patients with Ménétriers disease. In one patient from whom sufficient fresh tissue was obtained to isolate RNA, expression of TGF alpha and the epidermal growth factor receptor was higher in the gastric mucosa relative to a normal control. In addition, metallothionein-TGF alpha transgenic mice, which overexpress TGF alpha in gastric mucosa, show a number of features characteristic of Ménétriers disease. These include foveolar hyperplasia and glandular cystic dilatation, increased gastric neutral mucin staining, and reduced basal and histamine-stimulated rates of acid production. Taken together, observations derived from the human material and correlation with data from a transgenic mouse model support an important role for TGF alpha in the pathogenesis of Ménétriers disease.

Incidence of shunt occlusion or stenosis following transjugular intrahepatic portosystemic shunt placement

BACKGROUND/AIMS Transjugular intrahepatic portosystemic shunt (TIPS) placement has been used for the treatment of recurrent variceal hemorrhage. The 1-year incidence of shunt stenosis or occlusion after TIPS placement was prospectively assessed, and the accuracy of Doppler ultrasonography to predict TIPS stenosis was evaluated. METHODS Twenty-two patients with recurrent variceal hemorrhage were selected for TIPS placement between April 1991 and May 1992. Preoperative and postoperative evaluation included clinical assessment, upper gastrointestinal endoscopy, portal angiography with pressure measurements, and Doppler ultrasonography. Follow-up was performed at 3 and 12 months post-TIPS and when patients developed recurrent bleeding. RESULTS Twenty-one of 22 patients (Child-Pugh class A-1, B-11, C-9) had successful TIPS placement. Seventeen of 21 patients have completed follow-up for at least 12 months. Of these 17 patients, 2 of 17 (12%) developed TIPS occlusion, 7 of 17 (41%) developed shunt stenosis, and 8 of 17 (47%) showed no stenosis on follow-up angiography. Doppler ultrasonographic assessment of the TIPS predicted shunt stenosis or occlusion with 100% sensitivity, 98% specificity, and 90% positive predictive value. CONCLUSIONS Shunt occlusion or stenosis develops frequently within 12 months after TIPS placement, and Doppler ultrasonography is accurate in the noninvasive assessment of shunt stenosis. TIPS placement without careful follow-up and shunt revision cannot be considered a long-term treatment of variceal hemorrhage.

Dysphagia: evaluation and treatment

The evaluation of dysphagia begins with a careful history, which usually points to the underlying cause in up to 80% of cases. The goals of the history are to distinguish oropharyngeal causes from esophageal causes of dysphagia and to distinguish mechanical from motor disorders of the esophagus in those patients with esophageal dysphagia. Evaluation typically begins with a videofluoroscopic examination in patients with oropharyngeal dysphagia and begins with a routine barium swallow or upper GI endoscopy in patients with esophageal dysphagia. Esophageal manometry may be an adjunct to the evaluation of patients with esophageal dysphagia, particularly to confirm specific motor disorders, such as achalasia. The management of functional causes of dysphagia is supportive and empiric given the lack of well-controlled treatment studies in this heterogenous group of patients.

Prevalence of gastroesophageal reflux after laparoscopic Heller myotomy

AbstractBackground: There is still some controversy over the need for antireflux procedures with Heller myotomy in the treatment of achalasia. This study was undertaken in an effort to clarify this question. Methods: To determine whether Heller myotomy alone would cause significant gastroesophageal reflux (GER), we studied 16 patients who had undergone laparoscopic Heller myotomy without concomitant antireflux procedures. Patients were asked to return for esophageal manometry and 24-h pH studies after giving informed consent for the Institutional Review Board (IRB)-approved study at a median follow-up time of 8.3 months (range, 3–51). Results are expressed as the mean ± SEM. Results: Fourteen of the 16 patients reported good to excellent relief of dysphagia after myotomy. They were subsequently studied with a 24-h pH probe and esophageal manometry. These 14 patients had a significant fall in lower esophageal sphincter (LES) pressure from 41.4 ± 4.2 mmHg to 14.2 ± 1.3 mmHg, after the myotomy (p < 0.01, Students t-test). The two patients who reported more dysphagia postoperatively had LES pressures of 20 and 25 mmHg, respectively. Two of 14 patients had DeMeester scores of >22 (scores = 61.8, 29.4), while only one patient had a pathologic total time of reflux (percent time of reflux, 8%). The mean percent time of reflux in the other 13 patients was 1.9 ± 0.6% (range, 0.1–4%), and the mean DeMeester score was 11.7 ± 4.6 (range, 0.48–19.7). Conclusions: Laparoscopic Heller myotomy is effective for the relief of dysphagia in achalasia if the myotomy lowers the LES pressure to <17 mmHg. If performed without dissection of the entire esophagus, the laparoscopic Heller myotomy does not create significant GER in the postoperative period. Clearance of acid refluxate from the aperistaltic esophagus is an important component of the pathologic gastroesophageal reflux disease (GERD) seen after Heller myotomy for achalasia. Furthermore, GERD symptoms do not correlate with objective measurement of GE reflux in patients with achalasia. Objective measurement of GERD with 24 h pH probes may be indicated to identify those patients with pathologic acid reflux who need additional medical treatment.

Distinguishing Ménétrier's disease from its mimics

Objective Ménétriers disease (MD) is a rare hypertrophic gastropathy characterised by giant rugal folds, hypochlorhydria, protein loss and a classic constellation of symptoms (nausea, vomiting, abdominal pain and peripheral oedema). It is considered a clinical diagnosis that may at times be difficult to establish. Firm diagnostic criteria for MD are proposed by delineating the clinicopathological features that best differentiate MD from its mimics. Method 48 patients referred to Vanderbilt University Medical Center for consideration of enrolment in a clinical trial of treatment of patients with MD with cetuximab were evaluated for a definitive diagnosis by assessing the clinical presentation, pertinent laboratory values and histopathological features. Results MD was confirmed in 25 of the 48 patients (52%). The remaining 23 patients were considered to be mimics of MD, the most common diagnoses being gastric polyps or polyposis syndromes (13/23, 57%). Gastric slides were available from 40 of the 48 patients for detailed histological analysis (22/25 MD and 18/23 non-MD). Foveolar hyperplasia, glandular tortuosity and dilation, and a marked reduction in parietal cell number were present in all 22 cases of MD. Lamina propria smooth muscle hyperplasia and oedema characterised most cases (18/22 and 19/22, respectively). More than half had prominent eosinophils (11/22) and/or plasma cells (12/22) in the lamina propria. The clinical presentation of patients with MD was characterised by significantly younger age of onset, male predominance and increased vomiting compared with non-MD patients, and a lower prevalence of anaemia compared with MD patients with polyps. There was a trend towards increased frequency of peripheral oedema in patients with MD compared with non-MD patients. Conclusions MD is most accurately diagnosed by clinicohistopathological analysis including oesophagogastroduodenoscopy with gastric pH, appropriate laboratory tests (complete blood count, serum albumin, serum gastrin, Helicobacter pylori and cytomegalovirus serology) and full-thickness mucosal biopsy of the involved gastric mucosa.

Efficacy of Cetuximab in the Treatment of Ménétrier’s Disease

An antibody to the epidermal growth factor receptor successfully treats nine patients with a disease in which the lining of the stomach abnormally proliferates. Smoothing the Ménétrier’s Stomach The inner surface of the stomach might be viewed as uneven terrain—it’s covered with millions of pits that contain gastric glands and is folded into a series of ridges called rugae. This topography seems mild, however, in comparison to what’s seen in Ménétrier’s disease, a rare, chronic disorder in adults. In this condition, because of overgrowth of the mucous cells that line the inside of the stomach, the rugal folds become so massively enlarged that the stomach interior almost resembles the convoluted surface of the brain, as first noted by Pierre Ménétrier in 1888. The gland cells, in contrast, are reduced in number. These changes result in production of too much mucus and too little stomach acid, along with protein loss across the stomach lining, which leads to the accumulation of fluid in the feet and ankles and malnutrition. Patients suffer from severe vomiting and abdominal pain and have an increased risk of stomach cancer. With no effective drugs for treating this disease, the last line of defense has been removal of part or all of the stomach. Now, Coffey and colleagues describe nearly complete remission of this disease in several patients after a clinical trial testing a new therapy. Ménétrier’s disease symptoms appear to result from excess stimulation of the epidermal growth factor receptor (EGFR) by one of its ligands, transforming growth factor–α, which is overproduced in the stomach of patients with this condition. This too-active EGFR has been linked to several cancers, including lung, brain, and colon cancer, and as a result, a number of EGFR inhibitors have been developed as cancer therapeutics. Cetuximab, a monoclonal antibody that binds to the extracellular region of EGFR and blocks signaling, is used to treat colorectal and head and neck cancer. Because of the link between EGFR and Ménétrier’s disease, and the lack of any effective drugs for this disease, a number of years ago Coffey’s group received approval to treat an individual with Ménétrier’s disease with cetuximab. This treatment led to substantial improvement in the patient’s symptoms and biochemical indicators of the disease. On the strength of that result, Coffey’s group then undertook a trial of cetuximab in nine other patients with Ménétrier’s disease. Because the disease is so rare, it took 8 years to gather these patients. Seven patients completed the 1-month trial, during which cetuximab was delivered intravenously once a week, and all showed marked improvement in clinical, biochemical, and histological features of the disease. All seven patients chose to continue treatment and four of them later showed almost complete remission, indicating that cetuximab is an effective treatment for Ménétrier’s disease. Ménétrier’s disease is a rare premalignant disorder of the stomach with no proven effective medical therapy. Increased epidermal growth factor receptor signaling has been implicated in the pathogenesis of Ménétrier’s disease. We conducted a single-arm clinical trial with cetuximab, a monoclonal antibody that blocks epidermal growth factor receptor signaling, in nine individuals with clinically and histologically documented severe Ménétrier’s disease that impaired quality of life to the extent that gastrectomy was being considered. Of the seven patients who completed the 1-month course of treatment, all showed statistically significant improvement both clinically (quality-of-life indices) and biochemically (increased parietal cell mass and gastric acidity). Furthermore, all seven patients who completed the 1-month trial elected to continue treatment, and four subsequently showed near-complete histological remission. Cetuximab should be considered as first-line therapy for Ménétrier’s disease.

Chronic Treatment of Ménétrier’s Disease With Erbitux: Clinical Efficacy and Insight Into Pathophysiology

BACKGROUND & AIMS Ménétriers disease is a rare premalignant hypertrophic gastropathy characterized by large rugal folds, foveolar hyperplasia with glandular atrophy, hypochlorhydria, and hypoalbuminemia. Patients with severe disease often exhibit refractory nausea and vomiting and require gastrectomy. Evidence from both mice and human beings suggests a critical role for epidermal growth factor receptor (EGFR) signaling in the pathogenesis of this disease. We previously reported significant clinical and biochemical improvement of a single patient treated for 1 month with Erbitux, a monoclonal antibody that blocks ligand binding to EGFR. METHODS/RESULTS We describe 2 patients who were given longer-term treatment with Erbitux as an alternative to gastrectomy. The first patient presented with nausea, hypoalbuminemia, and peripheral edema that required total parenteral nutrition (TPN) and infusions of albumin. On institution of Erbitux, there was rapid improvement in nausea and vomiting and stabilization of serum albumin with discontinuation of TPN and albumin infusions. Serum albumin remained stable during a 1-year course of Erbitux without supplemental protein. Application before and after Erbitux of the radiopaque dye ruthenium red to biopsies of the gastric oxyntic gland mucosa demonstrated prompt and persistent closure of tight junctions by electron microscopy. The second patient presented with chronic gastric bleeding that required bimonthly blood transfusions. During a 4-month course of Erbitux, his hematocrit stabilized, and transfusion requirements were eliminated. CONCLUSIONS The present report demonstrates the efficacy of prolonged Erbitux therapy in patients with different presentations of severe Ménétriers disease and also provides insight into the pathophysiology of the protein-losing gastropathy.

Effects of Vibrio cholerae recombinant strains on rabbit ileum in vivo

Previous studies have identified the effects of Vibrio cholerae and its enterotoxin, choleragen (CT A+B+), on the myoelectric activity of rabbit ileal loops in vivo. The response was defined as the migrating action potential complex, the single ring contraction that propels luminal contents aborad. In this study the same rabbit model is used to assess whether migrating action potential complex activity or fluid output is induced by recombinant strains of V. cholerae that produce no subunit of cholera toxin (CT A-B-) or only by the inactive binding subunit (CT A-B+). Three live strains were studied: El Tor wild-type N16961 (CT A+B+) and recombinant strains CVD106 (CT A-B+) and JBK70 (CT A-B-). Controls received sterile culture broth. Migrating action potential complex frequency in animals inoculated with CT A+B+ was significantly increased compared with that in all other experimental groups (P less than 0.01). Fluid output was also increased in animals inoculated with CT A+B+ compared with fluid output in all other groups (P less than 0.05). Migrating action potential complex frequency and fluid output in rabbits given CT A-B+ or CT A-B- did not differ from activity in controls. How these recombinant strains induce diarrhea is unknown, but the mechanism may involve bacterial colonization or production of an unknown toxin.