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Menetrier’s Disease (MD) is a rare hypertrophic gas tropathy associated with protein loss, first described by Pierre Menetrier in 1888, whose incidence and mortality rates remain unclear.
The clinical condition is characterized histologically by enlarged gastric folds with massive foveolar hyperplasia and primarily affects adult males (mean age at diagnosis 55 years). Classic symptoms at presentation include: abdominal pain, nausea, vomiting, anemia, hypochlor hydria and peripheral edema due to protein loss across the gastric mucosa. The natural course of the disease varies significantly between adults and children. In child hood, the disorder typically presents with abrupt onset and resolves spontaneously, and has been associated with cytomegalovirus (CMV) infection1. In adults, onset is insidious and progression slow2 .MD aetiology remains unknown, although previous studies have shown it to be associated with infection by pathogens such as Helico bacter pylori and CMV1,3,4. Some authors suggest MD pathogenesis may be linked to upregulation of transform ing growth factor (TGF)5, however targeted therapies such as H. pylori eradication and treatment with antibiotics, prednisone, octreotide and monoclonal antibodies have yielded inconsistent results in clinical trials6,7. Notably, a number of patients with MD have presented gastric cancer, which may imply increase oncologic risk in such cases2,8.
Case report
We describe the case of a 35-year-old man, with a medical history of insulin-requiring diabetes and 1-year history of bowel habit changes of constipation alternating with steat orrheic diarrhea, postprandial abdominal pain and disten sion associated to generalized edema. Seven days prior to consultation at our hospital, patient referred functional class III dyspnea.
Blood biochemistry results at admission showed: hema tocrit 24%; Hb 6.7g; Mean corpuscular volume (MCV):69 fl; white blood cells count (WBC) 6900 cells/ml; platelet 434000 cells/ml; glycemia 303 mg/dl; blood ureic N (BUN) 36 mg/dl; creatinine 0.69mg/dl; sodium 135 mEq/l; potassium 4.5 mEq/l; aspartate transaminase 25UI/l; alanine transaminase 33 UI/l; total bilirubin: 0.1 g/dl, protein total 6 g/dl, albumin 2.5 g/dl. The 24-hour proteinuria was 0.08 g. Protein electrophoresis showed marked hypoalbuminemia and hypo-gammaglobu linemia. Serology results: HBsAg negative; Anti-HCV nega tive; CMV IgG reactive > 250; CMV IgM non-reactive; HIV non-reactive; TSH 2.31 μUI/ml, T4l 0.8 ng/dl, TPO < 10; and steatocrit 7% (normal values < 2%); and HbA1c 9.1%. The patient presented iron deficiency anemia with ferritin levels of 5 ng/ml; serum iron: 11μ/ml; transferrin 310 mg/dl; TIBC 394 μg/dl. Stool analysis (bacteria, parasites and ova) was negative. Serology for celiac disease and IgA levels were normal. Fecal elastase and serum gastrin were also normal and alpha-1-antitrypsin stool clearance was high 22.7 ml/24 hours (normal values < 12.5 ml /24 hours)
Abdominal ultrasound revealed an enlarged liver with well-preserved shape and internal echo pattern, minimal perito neal fluid and severe bowel loop distention. CT enterography showed diffuse concentric thickening of the gastric wall in the fundus and corpus, with no signs of pathological reinforce ment, and presence of enlarged lymph nodes (10 mm) within the lesser omentum and three round lymph nodes along the gastrocolic ligament (Fig. 1 A).
Fig. 1 A: CT enterography shows concentric thickening of the gastric wall in the fundus and corpus. B: Digestive endoscopy with thickened gastric folds with diffuse shape
An upper gastrointestinal endoscopy (UGE) revealed abun dant thick mucus, giant gastric folds resembling cerebral gyri, friable cobblestone mucosa and a preserved antrum (Fig. 1 B). Endoscopic ultrasound (EUS) showed parietal thickening with preserved architecture of gastric wall layers (Fig. 2 A). Multiple biopsies were taken with the objective of obtaining full-thickness mucosal samples. Those from gastric corpus showed marked foveolar hyperplasia, tortuosity and dilatation of the glands, and significant parietal cell loss. Other features include deep lateral branching, lamina propria edema, surface erosion and smooth muscle hyperplasia. The normal gastric pit to gland ratio is 1:4, but in our case, this ratio is reversed, as depicted by Dr. Menetrier in the original description of the disease. Antral biopsies showed normal architectural features. CMV was negative morphologically and by immunohistochem istry and Helicobacter pylori was absent (Fig. 2 B).
Fig. 2 A: Endoscopic ultrasonography shows thickness of gastric wall and preservation of five-layered structure. B: Hyperplasia of the foveolar component and tortuous and dilated glands
MD was diagnosed and treatment instituted with high-protein diet and cetuximab. The patient received intravenous cetuximab once weekly with an initial loading dose of 400 mg/m2 of body surface area, followed by three weekly doses of 250 mg/m2 until completing twelve months of treatment.
During follow-up, significant clinical and biochemical im provement was observed. Diarrhea episodes, generalized edema and bloating resolved. Albumin levels returned to nor mal (3.5 g/dl). UGE performed after twelve months to monitor treatment response, showed improvement.
Biopsies assaying Ki-67, a marker of cell proliferation, were obtained to monitor treatment response. Tissue levels were 15% on pre-treatment biopsy, decreasing to 10% and later to 3%, after twelve months on cetuximab.
Discussion
Menetrier´s is a disease predominantly affecting adult patients, causing marked hypertrophy of gastric mucosal folds, typically associated with hypoalbuminemia and anemia9. The disease is associated with considerable morbidity and even mortality in this age group, linked to surgical resection as well as a potential risk of malignant transformation2,8. Targeted therapies such as H. pylori eradication, antibiotics, prednisone, octreotide and mono clonal antibodies have yielded varied results in previous studies6,7. This case presented all the typical clinical features of MD including epigastric pain, weight loss, hypoalbuminemia, edema and symptomatic anemia, but no nausea or vomiting7.
The etiology of MD remains largely unknown. Some reports indicate over 90% presence of H. pylori in biop sies from patients with hypertrophic gastropathy7. In this patient however, results were negative. Some authors recommend to confirm the absence of infection through non-invasive tests such as the 13C urea breath test or serology, because the modification of the intragastric environment, and the patchy distribution of the infection in the gastric mucosa may decrease the diagnostic sensitiv ity of invasive tests10. In our case the limitation was the lack of availability of other diagnostic tests to confirm the absence of H. pylori infection.
Infection, or other as yet unknown causes may trigger an immunologic reaction involving cytokines, such as TGF-α, and sustained antigenic stimulation may ultimately cause development of MD. Overproduction of TGF-α, one of several EGF-R ligands in the stomach, has been proposed to explain several of the clinical characteristics of MD, including decreased acid production, increased hyperplasia of surface mucous cells, oxyntic atrophy and increased mucin production5.
There are no pathognomonic features to diagnose Menetrier’s disease, and it continues to be a clinic-path ological diagnosis. It is essential to obtain a full-thickness biopsy of the involved gastric mucosa when entertaining the diagnosis of Menetrier’s disease11.
Disease diagnosis is based on clinical suspicion, presence of thickened gastric folds on endoscopy and characteristic histological alterations, including: foveolar hyperplasia, tortuous and dilated glands, reduction in parietal cell numbers and inflammatory infiltrate. In this case because the multiple biopsies taken were negative for carcinoma, USE was performed. It is the most cost-effective diagnostic method to rule out malignancy and useful for differential diagnosis since it allows adequate evaluation of thickened gastric folds (TGF) characteristics, thus supporting Menetrier disease diagnosis, particularly when thickening originates in the deep mucosa. Thicken ing of the deeper layers (third and fourth) is associated with malignancy, while thickening of the superficial mu cosa (first and second layers) is associated with benign disease12,13.
Although MD has been linked to increased risk of gas tric cancer (GC), the magnitude of this risk is not known, varying between 0-10% in published cases13. Patients should therefore be followed for a substantial period, with current recommendations suggesting endoscopic control evaluations every 1 to 2 years14.
Differential diagnoses include infectious gastritis secondary to H. pylori, CMV, histoplasmosis, TB, myco plasma, syphilis, cryptococcosis or aspergillosis; tumors such as lymphoma, adenocarcinoma, Zollinger-Ellison syndrome, infiltrative pathologies such as sarcoidosis, amyloidosis, or other causes such as eosinophilic gas troenteritis or gastric varices, making MD a diagnostic challenge.
Treatment is controversial. On this occasion, we pre scribed the immunoglobulin cetuximab, a G1 (IgG1) mono clonal antibody specifically binding to the extracellular segment of the epidermal growth factor receptor (EGFR), inhibiting ligand binding of transforming growth factor alpha (TGFa), thus preventing gastric mucosa cell prolif eration. Although this treatment is approved by the FDA, with 7 cases reported in the literature showing favorable response15, indication is still limited to “compassionate” use. Current treatment of choice for MD continues to be total or partial gastrectomy depending on degree of gastric involvement and clinical symptom severity. In this case, patient’s symptoms, Ki-67 serum and gastric biopsy levels improved following completion of cetuximab treatment.
