Ménétrier Disease: Rare Manifestations and Mechanistic Insights From 2 Adult Cases

Introduction

Ménétrier disease is a rare, hypertrophic, hyperplastic gastropathy characterized by extensive foveolar epithelium hyperplasia in the body and fundus of the stomach, thickening and hypertrophy of the mucosal folds, and hypoproteinemia, which usually occurs in males 40–60 years of age, with less than 1000 cases reported worldwide [1,2]. The main symptoms are abdominal pain, diarrhea, nausea, vomiting, anemia (secondary to gastric hemorrhage), hypoacidity (due to marked reduction of parietal cells), and edema of the peripheral tissues (due to leakage of proteins from the gastric mucosa) [1,3–6], secondary gastric outlet obstruction, and weight loss [3,7]. Ménétrier disease is usually suspected in cases of hypoproteinemia of unknown etiology and special gastroscopic manifestations. We report 2 cases of Ménétrier disease with markedly different clinical manifestations and treatment courses, and introduce 99mTc-DTPA-human serum albumin scintigraphy as a method to enhance the sensitivity and specificity of clinical diagnosis by confirming gastric protein leakage. Furthermore, based on recent literature, we discuss the potential association between H. pylori and Ménétrier disease.

Case Reports

CASE1:

A 35-year-old man had intermittent epigastric abdominal pain, vomiting, melena, and anemia for 2 months. Two weeks before presentation at our center, he was transfused with 400 ml of plasma and 2 units of suspended red blood cells to treat his anemia. He denied smoking and alcohol abuse. Notably, his mother died due to rectal cancer. His medical history was otherwise unremarkable.

Labs on admission: total protein 51.2 g/L (normal range 65–85 g/L), albumin 30.5 g/L (normal range 40–55 g/L), hemoglobin 59 g/L (normal range 115–150 g/L), erythrocytes 2.97×1012/L (normal range 4.3–5.8×1012/L), MCV 71.4 fl (normal range 82–100 fl), MCHC 278g/L (normal range 316–354 g/L), and a positive fecal occult blood test. He underwent a 13C-urea breath test and serum H. pylori antibody testing after admission, both of which were negative. Reassuringly, tumor markers were in the normal range. An abdominal CT scan showed cerebriform thickening of the gastric wall (Figure 1A), with a large mass measuring 5.6×6.8 cm in the duodenal bulb (Figure 1B), exhibiting heterogeneous enhancement and signs of cystic degeneration. Esophagogastroduodenoscopy provided visual evidence of mucosal roughness in the gastric fundus and corpus (Figure 1C), characterized by granular hyperplasia and edema. A large polypoid protrusion in the anterior wall of the gastric corpus was observed, which extended to the antrum, resulting in chronic gastric outlet obstruction (Figure 1D–1G).

To ascertain the depth of the lesion, endoscopic ultrasonography (EUS) was conducted, demonstrating lesions confined to the mucosa and submucosa, with heterogeneous echogenicity, yet the muscularis propria remained intact (Figure 1H). Biopsies from the gastric corpus showed epithelial hyperplasia in the gastric pits, with chronic inflammatory cell infiltration. Colonoscopy showed no abnormalities. The patient, who had chronic gastric outlet obstruction and uncertain malignancy, underwent laparoscopic total gastrectomy and lymphadenectomy of the stomach. The surgical intervention revealed a mass within the duodenal lumen, identified as a giant hyperplastic gastric polyp, without plasma membrane involvement or infiltration into the lymph nodes.

Pathological examination revealed hypertrophy of the gastric wall, especially significant thickening of the mucosal layer, marked hyperplasia of the gastric epithelium, lengthening of the glands with partial cystic dilatation, and reduction of the parietal cells (Figure 2A, 2B), which aligned with the diagnosis of hyperplastic polyps. Further immunohistochemical analysis yielded the following results: P53 (scattered+), Ki-67 (partially+), AB-PAS (+), mucin-1 (+), mucin-2 (+), mucin-6 (partially+), mucin-5ac (+), CD10 (−), CD56 (−), CgA and Syn (scattered+), gastrin (slightly+), Pep-I/II (scattered+), and ATPase (partially+).

Pathology assessment showed no evidence of gastric malignancy, and serum gastrin levels were within the normal range, ruling out Zollinger-Ellison syndrome. Given the presence of multiple polyps in the fundus and corpus of the stomach, along with significant anemia and protein loss, he was diagnosed with Ménétrier disease.

After surgery, the anemia gradually resolved. By 2 months postoperatively, a repeat laboratory test showed hemoglobin 144 g/L and total plasma protein 72.5 g/L (albumin 44.9 g/L).

CASE 2:

A 44-year-old man was referred to the clinic for evaluation of epigastric fullness and belching, which had been persistent for 6 years. He had received eradication treatment for H. pylori 3 years ago. Notably, his father had cardial carcinoma and is currently undergoing conventional chemotherapy.

Vital signs were normal and stable, except for mild bilateral eyelid and anterior tibial edema in the lower limbs. Laboratory tests were normal, except for total protein 50.9 g/L (normal range 65–85 g/L), albumin 32.2 g/L (normal range 40–55 g/L), and globulin 18.7 g/L (normal range 20–40 g/L), and serum cytomegalovirus IgG (+). Gastrin and pepsinogen levels were within normal range, and the 13C urea breath test result for H. pylori was negative. An abdominal CT scan revealed the presence of multiple solid nodules within the gastric lumen (Figure 3A, 3B). Esophagogastroduodenoscopy uncovered substantial cerebriform enlargement of the rugal folds in the fundus and corpus, accompanied by multiple polyps measuring 1–4 cm in diameter (Figure 3C, 3D). The stomach was limited to dilation. The epithelium of these lesions appeared mildly indurated and edematous, covered with a substantial amount of mucus, and exhibited redness with congestion; however, the mucosa of the gastric antrum was smooth and slightly reddish, without any swelling, erosion, or ulceration, and demonstrated normal peristaltic activity. Endoscopic ultrasonography indicated mucosal thickening in the fundus and corpus of the stomach with hyperechoic segregation, while the submucosal layer was intact, with hypoechoic changes (Figure 3E, 3F). 99mTc-DTPA-human serum albumin scintigraphy confirmed the loss of protein from the stomach (Figure 3G).

Endoscopic mucosal resection (EMR) was carried out to obtain deep mucosal biopsies, showing chronic inflammation affecting the fundic glands, significant hyperplasia of the foveolar epithelium, small focal erosions, interstitial edema within the mucosal lamina propria, and a slight disruption of the muscular layer of the mucosa, all of which are consistent with the characteristics of hyperplastic polyps (Figure 4A, 4B). The patient underwent further genetic testing for hereditary polyposis syndromes, which did not identify any genetic mutations. Given the lack of significant symptoms and the absence of evidence supporting a neoplastic change, surgical treatment was not performed at this stage. He was treated with proton pump inhibitors, gastrointestinal prokinetic drugs, and probiotics, and was temporarily discharged for observation.

Discussion

Ménétrier disease is a complex disorder characterized by dysregulated EGFR signaling, primarily driven by transforming growth factor-alpha (TGF-α) overexpression, which induces foveolar hyperplasia and parietal cell loss [8–10]. While pediatric cases are strongly associated with CMV infection and often resolve after viral clearance [11–13], the pathogenesis in adults remains unclear. Emerging evidence suggests a potential role for H. pylori in modulating EGFR activity, but this is a matter of dispute [14–16]. Similarly, our second case also received H. pylori eradication treatment 3 years ago, but it is unclear whether there is an association between H. pylori and Ménétrier disease. A Mayo Clinic study stated that the impact of H. pylori infection on the prognosis of Ménétrier disease has not been evaluated [17].

To elucidate this matter, we fully reviewed the literature. Proteomic analysis of H. pylori-infected mice showed increased EGFR signaling [18], and Sierra et al [19] found that epithelial EGFR activation persists in both humans and mice, even if H. pylori is eradicated. Ashktorab et al [20] analyzed the expression of EGFR by immunohistochemistry in tissue microarrays of 44 gastric biopsy samples from H. pylori-positive patients. After H. pylori exposure, the binding of c-Jun and c-Fos to the EGFR promoter region increased by 8-fold and 6-fold, respectively [20]. Compared to the controls, staining for EGFR activity of the gastric mucosa was significantly increased in H. pylori-infected individuals [20].

Oxidative DNA damage and mutagenicity of gastric cells have been demonstrated in Ménétrier disease patients colonized by H. pylori [8]. In 2016, Slomiany et al [21] found that infection of the gastric mucosa by H. pylori triggers a pattern of inflammatory response characterized by increased secretion of pro-inflammatory cytokines, upregulation of the mitogen-activated protein kinase (MAPK) cascade, and EGFR activation. They reported the role of MAPK/p38 and Rac1 in H. pylori-induced TGF-α ectodomain shedding and EGFR transcriptional activation [21]. It was found that stimulation of gastric mucosal cells by H. pylori is accompanied by activation of membrane-associated metalloproteinase (also known as ADAM17), which leads to release of soluble TGF-α [21]. McClurg et al [22] further found that H. pylori-induced phosphorylation of ADAM17 in gastric epithelial cells may be an essential trigger for the induction of ADAM17 activation and EGFR transcription. These findings provide strong evidence that H. pylori can similarly increase TGF-a expression, causing activation of the EGFR by CMV, and suggests that H. pylori infection may lead to an increased risk of Ménétrier disease development. More research is needed to assess the possible association between Ménétrier disease and gastric cancer.

The diagnosis of Ménétrier disease is mainly exclusionary due to the lack of specific symptoms and non-specific laboratory results, which may contribute to misdiagnosis and underdiagnosis. Most laboratory findings in Ménétrier disease include decreased gastric acid secretion with a normal serum gastrin level, marked hypoproteinemia, and varying degrees of anemia [3]. CT scans can show mucosal folds from the gastric body and fundus protruding into the gastric lumen, resulting in reduced gastric volume and limited filling [3]. Esophagogastroduodenoscopy (EGD) reveals large mucosal folds shaped like the cerebral gyrus, with irregular surfaces, nodular, polypoid, or cobblestone-like [5,7]. Endoscopic ultrasonography reveals hypertrophy of the mucosa layer, with no significant structural changes in the submucosal or intrinsic muscular layer, a feature that help distinguishes it from malignant progressing tumors. Full-thickness biopsy specimens of the gastric mucosa are characterized by elongation of the epithelium of the gastric, edema on the surface, capillary congestion, and chronic inflammatory cell infiltration [1,3,5,23]. PET/CT scans often show an increased metabolic activity of the lesion, but it is still markedly lower than most lymphomas and gastric carcinomas. 99mTc-labelled radionuclide imaging of human serum albumin can assess protein loss from the stomach [24].

Gastric outlet obstruction is relatively rare in adults with Ménétrier disease, as reported by Chen et al [3]. Macroscopically, Ménétrier disease often presents as thickening of the gastric wall, which restricts the filling and peristalsis of the stomach. The stomach plays a crucial role in grinding food under normal physiological conditions. However, this active peristalsis may provide an opportunity for polypoid protrusion into the duodenum in pathological conditions, thereby causing gastric outlet obstruction.

Our 2 cases further emphasize the importance of integrating clinical, endoscopic, and molecular data to avoid misdiagnosis, particularly in atypical presentations with severe anemia or obstruction. Therapeutic strategies remain limited. Monoclonal antibodies targeting EGFR have shown promise in reducing mucosal hyperplasia and protein loss [22], while surgical resection may be necessary for obstructive complications [7,11]. However, the long-term risk of gastric cancer in Ménétrier disease patients warrants vigilance. Although no direct carcinogenic link is proven, chronic mucosal inflammation and oxidative DNA damage in H. pylori-colonized patients may elevate the malignancy risk [13]. Further studies are needed to elucidate whether TGF-α/EGFR dysregulation itself or secondary inflammatory cascades drive the oncogenic transformation.

Conclusions

In conclusion, Ménétrier disease is a multifactorial disorder in which infectious, genetic, and signaling aberrations converge. Even if Ménétrier disease is suspected, cases with severe anemia and gastric outlet obstruction as the main presentations are uncommon. Our case highlights the importance of integrating various imaging and histopathological examinations for diagnosis, while also emphasizing that the association between H. pylori and Menteri’s disease warrants further investigation. Future research should prioritize longitudinal studies to clarify the roles of EGFR modifiers and infectious cofactors in disease progression and malignant potential.