INTRODUCTION — Enlarged or giant mucosal folds in the stomach (diffuse mucosal hypertrophy) are attributable to a variety of proliferative, inflammatory, and infiltrative conditions of the stomach. These conditions may primarily involve the mucosa, submucosa, or both but have a similar endoscopic appearance, and the underlying etiology cannot be determined without additional evaluation. This topic reviews the epidemiology, etiology, and evaluation of large gastric folds.
HISTOPATHOLOGY — The normal gastric mucosa is composed of two compartments: the superficial mucosa, which includes the surface mucous cells and foveolar cells, and the deep compartment, which is composed of the specialized epithelium [1]. Surface cells and foveolar cells line the upper portion of the gastric glands. Slightly deeper in the gland is the isthmus, which contains the mucous neck cells. The base of the oxyntic gland contains the specialized epithelium, which includes the enterochromaffin cell (serotonin), the enterochromaffin-like cell (histamine), the chief cell (pepsinogen), the D cell (somatostatin), and the parietal cell (acid and intrinsic factor).
Enlarged or giant gastric folds are due to diffuse mucosal hypertrophy, which may be due to a hyperplastic or nonhyperplastic gastropathy.
●Hyperplastic gastropathy – The gastric epithelial cells that compose the oxyntic glands become hyperplastic and give rise to giant mucosal folds. Hyperplastic gastropathies include Ménétrier's disease and its rare variant, hyperplastic hypersecretory gastropathy, and Zollinger-Ellison syndrome. (See 'Hyperplastic gastropathies' below.)
●Nonhyperplastic gastropathy – The gastric mucosa may contain other (non-intrinsic) cell types that result in enlargement of the gastric folds. Nonhyperplastic gastropathy may be due to Helicobacter pylori gastritis, infiltrative diseases, infections, and malignancy. (See 'Nonhyperplastic gastropathies' below.)
In one series, endoscopic snare biopsy was performed in 52 patients with large gastric folds (greater than 1.0 cm in width and persisting after air insufflation) [2]. The diagnoses included the following:
●Chronic gastritis/lymphoid hyperplasia – 40 percent
●Benign tumors – 16 percent
●Gastric malignancy (adenocarcinoma, B cell lymphoma) – 12 percent
●Zollinger-Ellison syndrome – 10 percent
●Ménétrier's disease – 8 percent
ETIOLOGY OF ENLARGED GASTRIC FOLDS
Hyperplastic gastropathies
Ménétrier's disease — Ménétrier's disease (also called protein-losing hypertrophic gastropathy) is a rare acquired condition of the stomach that is characterized by the following features:
●Giant mucosal folds in the gastric fundus and body (picture 1)
●Diminished acid secretory capacity
●A protein-losing state resulting in hypoalbuminemia
Epidemiology — Ménétrier's disease is most common in middle-aged males and cases have been reported in both adults and in children. In contrast to children, Ménétrier's disease is usually progressive in adults. There are rare reports of spontaneous regression in adults, and virtually none in adults with symptoms longer than six months' duration [3]. An association with ulcerative colitis has been reported [4].
Pathogenesis — The pathogenesis of Ménétrier's disease is not well understood. It is thought to involve increased signaling of the epidermal growth factor receptor (EGFR), which results in proliferation of epithelial cells of the surface mucous cell compartment [1,5-7]. The enhanced signaling of EGFR in Ménétrier's disease is driven by overproduction of transforming growth factor-alpha (TGF-alpha), a ligand that can bind and activate EGFR. TGF-alpha is produced by the oxyntic mucosa, predominantly by the parietal cells; however, the molecular defect that results in the localized upregulation of TGF-alpha is not known [1,6,7]. TGF-alpha is known to stimulate growth of epithelial cells and to inhibit gastric acid secretion. The decreased acid production may be due to both direct effects on the parietal cells and indirectly via stimulation of somatostatin release.
Gastric infection with cytomegalovirus (CMV) is postulated to be an important cause of Ménétrier's disease in children. One-third of the children with Ménétrier's reportedly have CMV-associated Ménétrier's disease, which usually spontaneously resolves in two to four weeks. It has been difficult to prove that an actual infection with CMV is present in these pediatric cases due to the high prevalence of CMV infection in children. CMV may infect epithelial cells by interacting with EGFR, thereby activating a tyrosine kinase, a requirement for viral particle entry [8,9]. TGF-alpha was found to be increased by immunohistochemistry in one childhood and one adult case of CMV-associated Ménétrier's disease [8,10]. As CMV is cleared from the stomach, the stimulus to the EGFR is decreased, thus resulting in less TGF-alpha production, lessened cell proliferation, and a return to normal anatomy.
Clinical manifestations
●Signs and symptoms – Patients with Ménétrier's disease can present with a variety of clinical features including epigastric pain, nausea, vomiting, diarrhea, weight loss, and more rarely, gastrointestinal bleeding [11-14]. In addition, patients with Ménétrier's disease also have manifestations of protein-losing gastroenteropathy. These include peripheral edema, ascites, pleural and pericardial effusions. Patients with the hypertrophic, hypersecretory variant of Ménétrier's disease may have peptic ulcers due to high rates of gastric acid secretion. Otherwise, the clinical features are similar to the more common form of Ménétrier's disease [13,15-19]. (See "Protein-losing gastroenteropathy".)
In one series of 40 patients, the main complaints were epigastric pain (65 percent), weakness (60 percent), anorexia (45 percent), weight loss (45 percent), edema (38 percent), and vomiting (38 percent) [14]. In addition, approximately 80 percent of patients had hypoalbuminemia and increased enteric protein loss.
●Laboratory findings – Hypoalbuminemia is present in 20 to 100 percent of patients with Ménétrier's disease [11-13,20,21]. Other laboratory abnormalities include lymphopenia, hypochlorhydria, and reduced serum levels of globulins, cholesterol, alpha-1 antitrypsin, fibrinogen, and ceruloplasmin; these reductions are similar to patients with other forms of protein-losing gastroenteropathy.
Small to moderate elevation of serum gastrin levels may be present [22]. Intragastric pH is usually high (median pH of 6). Basal and stimulated gastric acid secretion is usually low or normal in Ménétrier's disease, but varies depending upon the point in the disease course when such measurements are made [11,13,21,23]. Patients with the rare hypertrophic, hypersecretory variant of Ménétrier's disease have elevated gastric acid secretion without significant hypergastrinemia.
Cancer risk — There may be an increased risk of gastric neoplasia (dysplasia or adenocarcinoma) in patients with Ménétrier's disease. However, there are few studies that have evaluated the risk of gastric cancer in Ménétrier's disease [24]. Risk estimates vary from 2 to 15 percent [11,13,21,25-27]. In many studies that have reported an increased risk of gastric cancer in patients with Ménétrier's disease, adequate histologic confirmation of the two conditions is lacking.
Zollinger-Ellison syndrome — Zollinger-Ellison syndrome (gastric acid hypersecretion due to hypergastrinemia from a gastrinoma, either sporadic or as a component of multiple endocrine neoplasia type 1 [MEN1]) is a hyperplastic gastropathy involving the body and fundus of the stomach. One hyperplastic cell type in Zollinger-Ellison syndrome is the parietal cell that results in the hypersecretion of gastric acid. The high levels of circulating gastrin seen in patients with gastrinoma lead to parietal cell hyperplasia via increased expression of parathyroid hormone-related peptide (PTHrP), also known as parathyroid hormone-like hormone (PTHLH), expression by parietal cells [28]. There is also an increase in histamine-secreting enterochromaffin-like cells, as gastrin is trophic for these cells. (See "Zollinger-Ellison syndrome (gastrinoma): Clinical manifestations and diagnosis".)
Nonhyperplastic gastropathies
Helicobacter pylori gastritis — Acute gastritis due to H. pylori can be associated with striking acute inflammation and enlarged gastric folds, giving the impression of a gastric malignancy [29]. Chronic H. pylori gastritis may also be associated with enlarged gastric folds [30,31]. In a report of 48 patients biopsied with isolated thickened gastric folds, chronic active gastritis was identified most frequently on biopsy (81 percent), with evidence of H. pylori in 92 percent of those biopsied [32]. (See "Acute and chronic gastritis due to Helicobacter pylori".)
Other observations have suggested an association between H. pylori gastritis and enlarged gastric folds [15-17,33-36]. In one such series, 18 of 32 patients with thickened gastric folds were infected with H. pylori [34]. H. pylori eradication therapy led to normalization of gastric fold size.
The pathogenesis of diffuse mucosal hypertrophy in H. pylori gastritis is uncertain. One case report suggested that production of an enteroendocrine mucosal growth factor, glucagon-like peptide (GLP)-2, is upregulated in H. pylori infection. It is hypothesized that the increase in this trophic hormone may result in the formation of giant folds, which then recede along with the serum GLP-2 levels with resolution of infection [37].
Another study demonstrated different levels of cytokine production associated with different strains of H. pylori [38]. They found that the H. pylori isolated from a patient with Ménétrier's disease induced the production of high levels of hepatocyte growth factor (HGF) mRNA expression. HGF has been reported to alter the tight junctions of gastric epithelial cells, which would lead to protein loss.
Gastric neoplasia — Neoplasms, particularly adenocarcinoma and lymphoma or even lymphoblastic leukemia [39], and carcinoid tumors, should be excluded in patients with enlarged gastric folds [2]. Endoscopic ultrasonography may be helpful in this setting [40,41]; however, a biopsy is needed to make the diagnosis. (See "Clinical presentation and diagnosis of primary gastrointestinal lymphomas" and "Clinical features, diagnosis, and staging of gastric cancer" and "Clinical characteristics of well-differentiated neuroendocrine (carcinoid) tumors arising in the gastrointestinal and genitourinary tracts".)
Other causes — Other diseases that may be associated with large gastric folds include lymphocytic gastritis (picture 2) (which may be related in some cases to H. pylori [33,42]), sarcoidosis, eosinophilic gastroenteritis, HIV-associated hypertrophic gastritis, and very rarely, Cronkhite-Canada syndrome [43]. (See "Gastrointestinal, hepatic, pancreatic, and peritoneal sarcoidosis" and "Eosinophilic gastrointestinal diseases" and "Overview of colon polyps".)
EVALUATION
History and examination — The patient's medical history and physical examination may provide valuable clues as to the possible etiology of enlarged gastric folds. For example, patients with pronounced constitutional symptoms (eg, persistent fevers, night sweats, weight loss, fatigue) should be evaluated for systemic diseases such as gastric lymphoma. Patients with Cronkhite-Canada syndrome have alopecia, cutaneous hyperpigmentation, gastrointestinal polyposis, onychodystrophy, diarrhea, weight loss, and abdominal pain. Patients with Zollinger-Ellison syndrome have a history of multiple or refractory peptic ulcers; ulcers distal to the duodenum; peptic ulcer disease and diarrhea; or multiple endocrine neoplasia type 1 (MEN1). (See "Overview of colon polyps", section on 'Cronkhite-Canada syndrome'.)
In some cases, the presence of an underlying condition is already known (eg, H. pylori, sarcoidosis, or eosinophilic gastroenteritis).
Upper endoscopy — The underlying etiology cannot be determined without additional evaluation (eg, gastric biopsy). In patients with Ménétrier's disease, the enlarged folds are usually confined to the oxyntic mucosa (body and fundus), with sparing of the antrum (picture 1), and may reach several centimeters in thickness. Although gastric folds are usually enlarged symmetrically, the appearance may be asymmetric and polypoid. Gastric rugal folds may fill the lumen, and often have surface erosions, and are accompanied by copious amounts of thick mucus that may form bridges across the gastric lumen and obscure visualization.
Patients with Zollinger-Ellison syndrome and eosinophilic gastroenteritis may have concurrent ulcers in the stomach or small intestine. The endoscopic appearance of polyposis syndromes (familial adenomatous polyposis, Peutz-Jeghers syndrome) and, rarely, proton pump inhibitor-induced fundal gland polyposis can mimic Ménétrier's disease when polyposis is profuse [44,45]. However, these are distinguished by histology. (See "Gastric polyps" and "Clinical manifestations and diagnosis of familial adenomatous polyposis" and "Peutz-Jeghers syndrome: Clinical manifestations, diagnosis, and management".)
Rarely, gastric varices in the fundus can give the appearance of enlarged folds on imaging or on upper endoscopy. If gastric varices are suspected, gastric biopsies should be avoided, and endoscopic ultrasonography should be performed to distinguish between the two [46]. Varices are round anechoic structures arising from the lamina propria or submucosa. Benign causes of giant gastric folds (eg, gastritis) tend to thicken the second and third of the five layers of the stomach, whereas malignancies tend to involve the fourth layer. Gastric lymphoma may be hypoechoic, whereas gastric adenocarcinoma can show thick noncompressible folds [41]. (See "Endoscopic ultrasound for the characterization of subepithelial lesions of the upper gastrointestinal tract", section on 'Varices'.)
Gastric biopsy — Determining the etiology of large gastric folds is often possible based on histopathology. A full-thickness gastric biopsy (or endoscopic snare or suction biopsy) is usually required to evaluate for the loss of the deep glandular component [21,47]. The diagnosis of Ménétrier's disease is established on biopsy by the demonstration of extreme foveolar hyperplasia with glandular atrophy, involving loss of parietal and chief cells. Ménétrier's disease usually is associated with a marked reduction in parietal cell mass. The diagnosis of gastric sarcoidosis rests upon histologic evidence of non-necrotizing granulomas in the biopsy specimens, exclusion of other causes of granulomatous inflammation (eg, some infections), and clinical and pathologic evidence of sarcoidosis affecting other organ systems. Additional stains for H. pylori and cytomegalovirus should be performed to rule out concurrent infection.
Laboratory tests — In patients with Zollinger-Ellison syndrome, a serum gastrin value greater than 10 times the upper limit of normal (1000 pg/mL) in the presence of a gastric pH below 2 is diagnostic. In patients with Ménétrier's disease, intragastric pH is usually high and small to moderate elevation of fasting serum gastrin levels may be present [22].
We also obtain a complete blood count to evaluate for anemia and total protein and serum albumin levels to screen for a protein-losing enteropathy. In patients with edema and hypoalbuminemia, additional evaluation to confirm the presence of a protein-losing gastroenteropathy is discussed in detail separately. (See "Protein-losing gastroenteropathy", section on 'Laboratory studies'.)
MANAGEMENT
Treatment of underlying diseases — The mainstay of management is to treat the underlying disease. The treatments used for specific disorders are described in detail separately.
●Zollinger-Ellison (See "Zollinger-Ellison syndrome (gastrinoma): Clinical manifestations and diagnosis".)
●Sarcoidosis (See "Gastrointestinal, hepatic, pancreatic, and peritoneal sarcoidosis", section on 'Gastric'.)
●Eosinophilic gastroenteritis (See "Eosinophilic gastrointestinal diseases", section on 'Clinical manifestations'.)
●Cronkhite-Canada syndrome (See "Overview of colon polyps", section on 'Cronkhite-Canada syndrome'.)
●Lymphocytic gastritis (See "Gastritis: Etiology and diagnosis", section on 'Etiology and classification'.)
●H. pylori (See "Treatment regimens for Helicobacter pylori in adults".)
Ménétrier's disease
Initial management — The treatment of Ménétrier's disease is challenging and the best approach to treatment is unclear. Randomized controlled trials are lacking and data on treatment efficacy are limited to small case series and case reports.
●General measures – Supportive care in patients with a protein-losing enteropathy is with a low-fat, high-protein, high medium-chain triglyceride diet to reduce protein loss. The diet should be low in long-chain fatty acids, generally present as long-chain triglycerides. (See "Protein-losing gastroenteropathy", section on 'Dietary therapy'.)
Patients with evidence of cytomegalovirus or H. pylori infections on gastric biopsy should undergo treatment. Treatment of these infections has been associated with resolution of Ménétrier's disease in case reports [33-36,42,48-50]. (See 'Helicobacter pylori gastritis' above and "Epidemiology, clinical manifestations, and treatment of cytomegalovirus infection in immunocompetent adults", section on 'Organ-specific complications'.)
The management of gastrointestinal bleeding in patients with Ménétrier's disease is similar to other causes of GI bleeding and is discussed in detail separately. (See "Approach to acute upper gastrointestinal bleeding in adults".)
●Gastric antisecretory agents – In patients with persistent symptoms despite supportive measures, we perform a one- to three-month trial of an antisecretory agent (histamine 2 receptor antagonist or proton pump inhibitor) in order to reduce gastric acid secretion and gastric protein loss while monitoring the patient for a reduction in symptoms and signs (eg, edema) and improvement in serum protein levels. However, studies supporting the effectiveness of these agents are lacking.
Persistent symptoms — There are limited data to guide treatment in patients with persistent symptoms despite antisecretory therapy, and the choice of treatment is based on the nature and severity of symptoms, ease of administration, individual preference, and insurance considerations.
●Octreotide – Multiple case reports of the use of octreotide, a somatostatin analogue, for 3 to 12 months in patients with Ménétrier's disease suggest that its use is associated with improvement of serum protein levels and in clinical symptoms [51-54]. Molecular evidence suggests that octreotide may reduce epidermal growth factor receptor (EGFR) signaling downstream [7]. However, octreotide does not appear to consistently reverse the underlying gastric rugal hypertrophy, and long-term outcome data are lacking [53-55]. In addition, octreotide and its analogues require subcutaneous administration. Although an oral preparation is now available, it has not been evaluated in patients with Ménétrier's disease.
●Cetuximab – Cetuximab is a monoclonal antibody to EGFR that has been used to treat Ménétrier's disease. In one case series that included nine patients with Ménétrier's disease, seven patients completed treatment with cetuximab for one month [4]. All seven patients demonstrated statistically significant improvement in quality-of-life indices as well as in biochemical measures (gastric acidity). Four patients also had almost complete reversal of foveolar hyperplasia. However, four of the seven eventually required total gastrectomy [4]. In another case series of two patients who were treated for four months and one year, respectively, both had resolution of symptoms while on treatment with cetuximab [56]. In the United States, the Food and Drug Administration (FDA) has allowed cetuximab to be used on a compassionate need basis in some patients with Ménétrier's disease.
●Gastrectomy – Gastrectomy is reserved for those patients with intractable symptoms and signs refractory to medical therapy. In rare cases with massive or unrelenting bleeding that is uncontrollable endoscopically, gastrectomy is required. Even though Ménétrier's disease is primarily a disease of the gastric fundus and body, a total gastrectomy is the surgery of choice due to fewer surgical complications and better quality of life as compared with partial proximal gastrectomy.
Gastric cancer screening — In patients with Ménétrier's disease who have not undergone gastrectomy, we perform endoscopic surveillance every one to two years for early detection of dysplasia or carcinoma [8,57].
SUMMARY AND RECOMMENDATIONS
●Enlarged or giant mucosal folds in the stomach (diffuse mucosal hypertrophy) are attributable to a variety of proliferative, inflammatory, and infiltrative conditions of the stomach, which can cause a hyperplastic or nonhyperplastic gastropathy. In hyperplastic gastropathies, gastric epithelial cells that compose the oxyntic glands become hyperplastic and give rise to giant mucosal folds. Hyperplastic gastropathies include Ménétrier's disease and its rare variant, hyperplastic hypersecretory gastropathy, and Zollinger-Ellison syndrome. Large gastric folds are associated with other non-hyperplastic gastropathies including infections (eg, H. pylori, cytomegalovirus [CMV]), infiltrative diseases, and neoplasms. (See 'Histopathology' above and 'Etiology of enlarged gastric folds' above.)
●Ménétrier's disease is a rare acquired condition of the stomach. Patients with Ménétrier's disease can present with a variety of clinical features including epigastric pain, weight loss, nausea, vomiting, diarrhea, peripheral edema due to protein-losing gastroenteropathy, and gastrointestinal bleeding. (See 'Ménétrier's disease' above.)
●The underlying etiology of large gastric folds cannot be determined based on endoscopic imaging alone. Although the patient's medical history and physical examination may provide valuable clues as to the underlying etiology of enlarged gastric folds, a full-thickness gastric biopsy (or endoscopic snare or suction biopsy) is usually required. The diagnosis of Ménétrier's disease is established by a deep gastric biopsy showing extreme foveolar hyperplasia with glandular atrophy in a patient with striking enlargement of gastric folds or rugae seen on endoscopy or abdominal imaging. (See 'Upper endoscopy' above.)
●In patients with large gastric folds, we also obtain a complete blood count to evaluate for anemia and total protein and serum albumin levels to screen for a protein-losing enteropathy. (See 'Laboratory tests' above.)
●The mainstay of management is to treat the underlying disease. The treatment of Ménétrier's disease is challenging and the best approach to treatment is unclear. (See 'Ménétrier's disease' above.)
•In addition to a low-fat, high-protein, high medium-chain triglyceride diet to reduce protein loss, initial management includes treatment of H. pylori or CMV infection, if present, and a one- to three-month trial of acid suppressive therapy.
•For those with persistent symptoms in spite of antisecretory therapy, options include octreotide or cetuximab, an epidermal growth factor receptor inhibitor. However, data on the efficacy of both options are limited in this population.
•Gastrectomy is reserved for those patients with intractable symptoms and signs refractory to medical therapy. In rare cases with massive or unrelenting bleeding that is uncontrollable endoscopically, gastrectomy is required. (See 'Ménétrier's disease' above.)
●In patients with Ménétrier's disease who have not had total gastrectomy, we perform endoscopic surveillance every one to two years because of the possible increase in risk of gastric cancer. (See 'Cancer risk' above.)
ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge Beverly Dickson, MD, who contributed to an earlier version of this topic review.