Digestive Diseases and Sciences

, Volume 54, Issue 7, pp 1403–1407

Successful Use of Octreotide to Treat Ménétrier’s Disease: A Rare Cause of Abdominal Pain, Weight Loss, Edema, and Hypoalbuminemia

Authors

    • Division of Gastroenterology and HepatologyStanford University Medical Center
  • Reetesh Pai
    • Department of Pathology and Laboratory MedicineStanford University Medical Center
  • Kevin Stuart
Stanford Multidisciplinary Seminars

DOI: 10.1007/s10620-009-0754-z

Cite this article as:
Rothenberg, M., Pai, R. & Stuart, K. Dig Dis Sci (2009) 54: 1403. doi:10.1007/s10620-009-0754-z

Case Presentation and Evolution

A 75-year-old man presented with steadily increasing upper abdominal pain, worse after meals, over 6 weeks. He also described anorexia, early satiety, intermittent post-prandial nausea and bilious vomiting, as well as bilateral ankle edema and an unintentional 10-lb weight loss, despite daily use of lansoprazole and furosemide. He described no heartburn, dysphagia, melena, hematemesis, diarrhea, fevers, night sweats, or other cardiopulmonary or urinary symptoms. His past medical history was notable for mild gastroesophageal reflux, hypertension, depression, and benign prostatic hyperplasia. Current medications included lansoprazole, valsartan, furosemide, and escitalopram. He had a negative family history and did not smoke or drink alcohol. Physical examination was normal except for 2+ bilateral pitting edema to the knees.

Laboratory studies were notable mainly for an albumin level of 1.5 g/dl. His white blood cell count was 10,800/mm3 (54% neutrophils, 22% lymphocytes, 22% eosinophils), hematocrit 42%, and platelets 338,000/mm3. Other liver function tests and serum chemistries were normal except for calcium of 6.9 mg/dl. Urinalysis was normal. Chest X-ray was normal, as was his electrocardiogram. IgA and IgG for Helicobacter pylori were positive. Abdominal computed tomography (CT) after intravenous and oral contrast showed significant thickening of the proximal gastric body and fundus with associated engorgement of the perigastric vessels and no mass (Fig. 1). The distal stomach wall was normal.
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Fig. 1

Computed tomography (CT) scan of the abdomen after intravenous and oral contrast shows ill-defined wall thickening in the gastric body and fundus (both panels) and engorgement of perigastric vessels (right panel, red asterisks)

Endoscopy revealed markedly thickened gastric folds with nodularity, erythema, and exudate involving the proximal stomach (Fig. 2a, b), but sparing the antrum and pylorus. The stomach was poorly distensible, and a small hiatal hernia was seen. Multiple superficial cold forceps biopsies revealed no evidence for active H. pylori infection and failed to show eosinophilia, viral inclusions, epithelial malignancy, or lymphoma. Interestingly, there were elongated gastric foveolae, many of which exhibited a corkscrew-like appearance. These hyperplastic foveolae were lined by gastric epithelium without regenerative features or mucin depletion. Atrophy of the parietal cell layer and mild lamina propria chronic inflammation were also noted.
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Fig. 2

Serial endoscopies show gradual resolution of the thickened gastric folds of Ménétrier’s disease after treatment with octreotide. a, b Initial study shows markedly thickened gastric folds with nodularity, erythema, and exudate involving the majority of the proximal stomach. The antrum and pylorus are relatively spared (not shown). c, d Repeat esophagogastroduodenoscopy (EGD) shows some improvement, with less exudate and moderately (but not markedly) thickened gastric folds. e, f Endoscopy performed 4 months post-octreotide therapy shows normalization of the gastric mucosa

The patient was treated empirically for H. pylori with a 14-day course of amoxicillin, clarithromycin, and lansoprazole based on the positive H. pylori serologies. After treatment, he continued taking a proton pump inhibitor twice daily but his symptoms did not change. He was also prescribed a brief course of prednisone that improved his peripheral eosinophilia; however, his symptoms continued to worsen.

Full-thickness gastric biopsies, obtained using a jumbo forceps during a repeat endoscopy, showed foveolar hyperplasia with tortuous, corkscrew shapes and dilated mucin-filled gastric pits, atrophy of the parietal cell layer, and mild chronic inflammation of the lamina propria (Fig. 3). Some foveolar cells exhibited mucin depletion. There were no H. pylori organisms or cytomegalovirus (CMV) viral inclusions seen. Overall, the clinical and pathological findings were most consistent with Ménétrier’s disease.
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Fig. 3

Histopathology from routine (a and b) and full-thickness snare (c and d) gastric biopsies show shows elongated, cystically-dilated gastric foveolae, many of which exhibit a corkscrew-like appearance. The hyperplastic foveolae are lined by gastric epithelium without regenerative features or mucin depletion. In addition, there is atrophy of the parietal cell layer. The lamina propria contains only mild chronic inflammation

Based on preliminary reports of octreotide being used to successfully treat Ménétrier’s disease [13], the patient was given several doses of octreotide (150 µg subcutaneously every 8 h), which he tolerated well. He then began monthly 20-mg depot octreotide injections. After 3 months, his albumin increased to 3.4 g/dl, his edema resolved, his abdominal symptoms improved, and he gained back much of the weight he had lost. Significant endoscopic improvement was seen on follow-up endoscopy four months later (Fig. 2c, d). He was able to stop the octreotide injections, and most recently—12 months since his third and last octreotide injection—he has been asymptomatic with a normal albumin of 3.9 g/dl and no eosinophilia. Repeat endoscopy showed normalization of the gastric mucosa (Fig. 2e, f).

Discussion

Ménétrier’s disease, first described in 1888 by Pierre Ménétrier, is a rare, acquired disease of markedly hypertrophied gastric mucosal folds, often with associated achlorhydria and increased mucus production [4, 5]. Due to protein losses across the diseased gastric mucosa, profound hypoproteinemia with resultant edema or anasarca are often seen. The condition predominantly affects the gastric body and fundus, with relative sparing of the antrum; however, in children, it can involve the entire stomach. The disease carries an increased risk of subsequent gastric cancer, as high as a 2–15% lifetime risk; however, because of its rarity, the exact gastric cancer risk is unknown and there is no general consensus on endoscopic screening [5]. Although usually progressive, it may be self-limited, particularly in children, where it has been associated with CMV infection (as well as H. pylori). Cases refractory to medical therapy may require subtotal gastrectomy, which leads to rapid improvement.

Patients with Ménétrier’s disease may be debilitated from epigastric pain, vomiting, weakness, fatigue, anorexia, weight loss, hypoalbuminemia, and edema [5] that are occasionally severe. In addition, patients may develop iron deficiency anemia from gastric blood loss. The symptoms and degree of hypoalbuminemia can be profound. Endoscopically, massively thickened irregular ‘cerebriform’ gastric folds are found in the proximal stomach amidst edematous mucosa. Histologically, the main finding is foveolar hyperplasia, i.e., massive overproliferation of the surface mucous-producing cells, with cystic dilation of pits. Frequently, a reduction in the number of parietal and chief cells is observed. Inflammation is variably present [4, 5].

The cause of Ménétrier’s disease remains uncertain, but transforming growth factor alpha (TGF-α), one of several ligands for the epidermal growth factor receptor (EGF-R), may play a role. TGF-α is a soluble, secreted mitogenic signaling molecule normally found in the gastric body and fundus, the regions of the stomach most often involved in Ménétrier’s disease. The molecule causes dose-dependent in vitro proliferation of gastric epithelial cells and dose-dependent reduction of acid secretion, both of which are hallmarks of the disease. Interestingly, TGF-α immunoreactivity is highly upregulated in Ménétrier’s disease [6, 7]. In mice, the over-expression of TGF-α causes a striking phenocopy of Ménétrier’s disease. Features seen in these mice include massively thickened gastric rugae, severe foveolar hyperplasia with cystic dilation, increased mucin production, reduced numbers of chief and parietal cells, reduced basal and histamine-stimulated acid secretion (achlorhydria), and hypoalbuminemia [7, 8].

Recent molecular evidence suggests that octreotide (a somatostatin analog) may modulate EGF-R signaling on several possible levels. First, in some circumstances, somatostatin has been shown to decrease the number of EGF binding sites at the cell surface and coincidentally slow cell growth, suggesting an interplay between the two pathways [9]. Next, at least some of the downstream effectors of the somatostatin receptors are shared by the EGF-R (e.g., the MAPK [mitogen-activated protein kinase] pathway, a key regulator of cellular proliferation), so octreotide may act on these effectors and mitigate the abnormally high activity seen in excess EGF-R signaling [10]. Finally, recent data suggests that one of the somatostatin receptor (SST) subtypes (SST5) that binds to octreotide with high affinity may hetero-dimerize with EGF-R, an interaction which could allow the alteration of EGF-R/TGF-α signaling by octreotide [11].

In 2000, a group described the use of a monoclonal antibody against EGF-R (cetuximab) to successfully treat a severe case of Ménétrier’s disease unresponsive to numerous medications, including octreotide, associated with advanced primary pulmonary hypertension [12]. Intriguingly, primary pulmonary hypertension has also been linked to aberrant EGF-R signaling, and EGF-R blockade can ameliorate TGF-α-induced pulmonary fibrosis and hypertension [13]. Whether this patient’s Ménétrier’s disease and pulmonary hypertension were attributable to aberrant EGF-R signaling is unknown. In that report, soon after cetuximab, symptoms remarkably improved, as did the hypoalbuminemia; subsequently, the abnormally high gastric proliferative index decreased 8-fold, and parietal cells reappeared. Active (phosphorylated) MAPK, a downstream effector of the EGF-R, decreased markedly, as predicted. This case provided further evidence for the role of EGF-R signaling in the pathogenesis of Ménétrier’s disease. Two more cases of Ménétrier’s disease successfully treated with cetuximab were reported in 2005 [14].

Key Messages

  • Though rare, Ménétrier’s disease should be considered in patients with post-prandial abdominal pain, weight loss, edema, and hypoalbuminemia. The hallmark of the disease is markedly thickened gastric folds with relative antral sparing. Gastric biopsies exhibit foveolar hyperplasia, i.e., massive overproliferation of the surface mucous-producing cells, with cystic dilation of pits, which are best seen on full-thickness (rather than routine pinch) biopsies. The condition likely carries an increased risk of subsequent gastric cancer (2–15% lifetime risk), though the role of surveillance endoscopy is unclear.

  • Transforming growth factor alpha (TGF-α) and epidermal growth factor receptor (EGF-R) signaling may play a role in the pathogenesis of Ménétrier’s disease. Cetuximab, an EGF-R blocker, may help some patients.

  • Octreotide, a somatostatin analog, may also be an effective treatment in some patients, perhaps due to the modulation of EGF-R signaling by octreotide that may interface with EGF-R signaling by one or more plausible molecular mechanisms.

  • When the condition does not respond to medical therapy, gastrectomy may be required. This ameliorates the hypoalbuminemia, improves the quality of life, and eliminates the risk of subsequent gastric cancer.

Copyright information

© Springer Science+Business Media, LLC 2009