Giant Hypertrophic Gastritis (Ménétrier’s-like Disease) in an Old English Sheepdog

Introduction

Giant hypertrophic gastritis is a rare disease in the dog and is characterized by pronounced mucosal proliferation of the gastric body, which usually spares the pyloric antrum.¹ Breed-associated giant hypertrophic gastritis includes the immunoproliferative enteropathy of basenji dogs, in which gastritis is invariably associated with lymphocytic-plasmacytic enteritis, and the familial stomatocytosis-hypertrophic gastritis of Drentse Patrijshond dogs.^2,3 Only a single case of giant hypertrophic gastritis has been reported in breeds other than the basenji or Drentse Patrijshond.⁴ Hypertrophic gastritis has been compared to Ménétrier’s disease in humans, which is characterized by giant gastric folds, hypoalbuminemia, hypochlorhydria, and mucosal epithelial cell hyperplasia.^5,6 The present report describes a case of giant hypertrophic gastritis in an Old English sheepdog. The condition bore a strong resemblance to Ménétrier’s disease, especially with regard to the clinicopathological, imaging, gastroscopic, and histopathological findings.

Case Report

An 11-year-old, 28-kg, male Old English sheepdog was admitted for a 1-month duration of marked weight loss, anorexia, intermittent vomiting, and tarry stools. On physical examination, the only abnormalities detected were pale mucous membranes and a large, football-sized, nonpainful mass in the cranioventral abdomen.

A complete blood count (CBC) revealed a nonregenerative, normocytic, normochromic anemia [see Table]. No abnormal erythrocyte morphology was noted in Giemsa^a-stained peripheral blood smears, and a saline agglutination test was negative. Blood serum biochemical abnormalities included hypoproteinemia, hypoalbuminemia, and hypoglobulinemia [see Table]. Complete urinalysis and routine coagulation profile (i.e., prothrombin time, activated partial thromboplastin time) were unremarkable. The dog tested negative for Leishmania infantum antibodies^b and Dirofilaria immitis antigens.^c

Survey abdominal radiography revealed an opaque mass in the cranial part of the abdomen, caudal to the liver and displacing the intestinal loops caudodorsally. Thoracic radiographs appeared normal. Barium contrast radiography demonstrated mild enlargement of the stomach, absence of the normal pattern of gastric rugal folds, and multiple variably sized filling defects extending across the gastric body [Figure 1]. Abdominal ultrasonography revealed a remarkably thickened gastric wall that ranged between 10 and 60 mm (reference range 3 to 5 mm).⁷ Multilobulated, thickened gastric folds protruded into the gastric lumen [Figure 2]. No blood flow could be detected by color and pulsed Doppler ultrasonography in the multiple anechoic areas that appeared like cystic lesions within the thickened folds.

Gastroscopy with a flexible endoscope revealed a restricted gastric cavity from the presence of multiple giant folds throughout the fundus and the body [Figure 3]. The folds did not shrink even after stomach overinflation. The antrum was spared. Mucosal friability and a moderate amount of gastric fluid were also noted. A gastrotomy performed immediately following gastroscopy revealed giant cerebriform rugal folds protruding from the fundus and body but sparing the antrum [Figure 4]. No regional lymphadenopathy was observed, and no gross lesions of the liver, pancreas, duodenum, kidneys, or omentum were identified. Incisional wedge biopsies were obtained from the gastric fundus and body, along with a mesenteric lymph node, and they were submitted in 10% neutral-buffered formalin for histopathology.

Sections from the gastric fundus and body had similar histological appearances. The overlying epithelium was intact, with pronounced glandular hyperplasia [Figures 5A, 5B]. The mucosal tissue was markedly expanded and composed of a loosely packed connective tissue matrix with muscle fiber bundles, within which numerous variably sized and cystically dilated glandular elements were embedded. There was no evidence of cellular atypia. The glandular lumena contained no secretions. Low numbers of mixed mononuclear cells (i.e., plasma cells, lymphocytes, and macrophages) were scattered throughout the stromal tissue. Lymph node histopathology and Giemsa-stained imprint smears from the gastric specimens were unremarkable.

During the 6-day hospitalization period, the dog was treated with intravenous (IV) crystalloid solutions and metoclopramide^d (0.5 mg/kg IV q 8 hours). A blood-typed and cross-matched whole blood transfusion was also given. A post-transfusion hematocrit was 34% (reference range =37%). Intermittent vomiting, hematemesis, hemorrhagic diarrhea, and melena continued through day 4 of hospitalization; but on day 6, the dog appeared much better. Its appetite was fully restored, and the vomiting, diarrhea, and melena had resolved. The dog was discharged on prednisolone^e (0.5 mg/kg per os [PO] q 12 hours), hyoscine butylbromide^f (0.25 mg/kg PO q 12 hours), and cimetidine^g (10 mg/kg PO q 12 hours); administration of these medications was intended to continue for the next 3 months.

Forty-five days after initial admission, the dog was still in clinical remission, and a CBC revealed a moderate non-regenerative, microcytic, and normochromic anemia, as well as a mature neutrophilia, lymphopenia, eosinopenia, and thrombocytosis [see Table]. Serum biochemical profile was unremarkable apart from slightly elevated alanine aminotransferase (ALT) and alkaline phosphatase (ALP) [see Table]. At the same time, ultrasonography revealed a decrease in the gastric wall thickness (10 to 30 mm), and gastroscopy revealed an approximate 30% reduction in the rugal folds. Histopathology of multiple endoscopic pinch biopsies obtained from the gastric body did not differ from that of the original biopsies. The dog was discharged on the original treatment protocol, with the addition of ferrous sulphate^h (300 mg PO q 24 hours for 3 months).

On day 105 after the initial admission, the general condition of the dog was very good, including a substantial increase in body weight (32 kg). Laboratory investigation showed a moderate nonregenerative normochromic/normocytic anemia, along with mature neutrophilia, thrombocytosis, and marginal hypoalbuminemia [see Table]. One month later (day 135 from the admission) and while still in remission, the dog unexpectedly died. Permission for necropsy was declined by the owner.

Discussion

The presence of giant gastric folds, hypoalbuminemia, and the unique histopathological lesions that constitute the major features of human Ménétrier’s disease were all met in the case reported here.^1,5 Documentation of hypochlorhydria (another typical feature of Ménétrier’s disease) was not pursued in this case, but it has not been established as a component of giant hypertrophic gastritis in dogs.⁵ Importantly, Ménétrier’s disease is clearly distinguished from Zollinger-Ellison syndrome, because the enlarged gastric folds of the latter disease are gastrin-induced secondary to pancreatic gastrinoma. In Ménétrier’s disease, gastrin levels are generally normal.⁸ In the case reported here, a thorough surgical exploration of the pancreas and adjacent structures ruled out the possibility of gastrinoma. More than 85% of gastrinomas have evidence of metastasis to the liver at the time of diagnosis, and no such lesions were seen in this case.⁹

The majority of dogs reported with giant hypertrophic gastritis have belonged to the Drentse Patrijshond and basenji breeds.^2,10 No stomatocytosis, evidence of neurological deficits, hemolytic anemia, or liver disease were documented in the dog of this study, as opposed to a significant proportion of Drentse Patrijshond dogs with familial stomatocytosis-hypertrophic gastritis.^3,10 Also, giant hypertrophic gastritis of basenji dogs is characterized by chronic intractable diarrhea secondary to severe lymphocytic-plasmacytic enteritis, and most affected dogs have consistent hypoalbuminemia and hyperglobulinemia.^2,11 Although no intestinal biopsies were procured, the diarrhea exhibited by the dog in this report was transient and was accompanied by panhypoproteinemia rather than combined hypoalbuminemia and hyperglobulinemia.

Although the cause of giant hypertrophic gastritis/Ménétrier’s disease is poorly understood, over-representation of certain canine breeds and the occasional appearance of Ménétrier’s disease in human twins indicate potential influence of hereditary factors.^1,12 Immune-mediated mechanisms have also been incriminated in both dogs and humans.¹ An association between Helicobacter pylori infection and Ménétrier’s disease has been reported in man, and cytomegalovirus infection may be implicated in the juvenile form of Ménétrier’s disease.^6,13 However, a familial occurrence was not documented in this dog, and no Helicobacter-like organisms were observed on either cytological or histopathological examination of the gastric mucosa.

Hypertrophic gastritis usually affects older male animals, as was the case in this dog.¹ Chronic vomiting and weight loss are common historical and clinical manifestations of giant hypertrophic gastritis/Ménétrier’s disease, while melena is uncommon unless the friability of the gastric mucosa leads to spontaneous bleeding.^1,4 Diarrhea is rarely observed in giant hypertrophic gastritis, unless concurrent lymphocytic/plasmacytic enteritis is present (e.g., in basenji dogs).² Interestingly, in a case described by van der Gaag et al., the observed diarrhea was not associated with intestinal inflammation or biochemical abnormalities suggestive of systemic disease.⁴ Since full-thickness intestinal biopsies were not obtained in that case, the possibility of intestinal inflammation could not be excluded.⁴

The nonregenerative anemia identified in the case reported here was attributed to the chronic nature of the disease process and possibly to iron deficiency following persistent gastrointestinal blood loss. The latter factor was supported by the microcytic, normochromic anemia documented during the follow-up period (day 45) and the response to iron supplementation (day 105). The changes that occurred in the differential leukocyte count (i.e., mature neutrophilic leukocytosis, lymphopenia, and eosinopenia) after treatment were most likely the result of glucocorticoid administration. Glucocorticoid therapy may have accounted for the thrombocytosis and the increased activity of liver enzymes.¹⁴ Since no proteinuria, liver insufficiency, or bleeding tendencies were documented in this dog, hypoalbuminemia and hypoglobulinemia were attributed to gastric bleeding. In Ménétrier’s disease, profuse protein losses from increased vascular permeability may explain the severe hypoproteinemia (protein-losing gastropathy).¹⁵ Increased gastrointestinal protein loss without concurrent bleeding was documented in another canine case reported in the literature.⁴

Ultrasonography revealed diffuse thickening of the gastric wall with enlarged folds containing multiple cystic-like lesions that probably represented dilated mucosal glands. These findings were confirmed by gastroscopy and exploratory gastrotomy, which indicated that ultrasonography was a useful, noninvasive tool in the diagnosis of giant hypertrophic gastritis.¹⁶ Although neoplasia is a highly ranked differential diagnosis in humans with enlarged gastric folds, most gastric neoplasms in the dog produce localized or diffuse thickening and/or ulceration of the gastric wall, and occasionally a substantial decrease in the number of rugae on imaging and gastroscopy.^4,5,17 Therefore, the diagnosis of gastric neoplasia in the dog should not be made upon the basis of the gross appearance of the lesions, as a variety of potentially treatable diseases (e.g., granulomatous gastropathy) may have a similar appearance.¹⁷

Histopathology is crucial to ruling out neoplasia. Wedge and pinch biopsies were apparently of the same value in the present case, although surgical biopsies should be obtained whenever a significant thickening of the gastric wall is demonstrated by radiography and/or ultrasonography.¹ The histopathological features that met the criteria of Ménétrier’s disease in this dog were the excessive hyperplasia and cystic dilatation of mucosal glands.^5,8,18 The mononuclear cell infiltrate is also a common finding in Ménétrier’s disease.⁸ Other investigators have questioned the importance of this inflammatory infiltrate, suggesting that Ménétrier’s disease simply represents a noninflammatory gastropathy.¹⁹

The efficacy of therapeutic measures in giant hypertrophic gastritis is unclear because the condition is rare, controlled trials are lacking, and spontaneous remission occurs in some cases.⁶ The rationale for the treatment instituted in the present case was that histamine (H₂)-receptor antagonists and anticholinergic agents would decrease gastric protein loss by strengthening the intercellular tight junctions or by reducing hydrogen ion production and, hence, its potential damaging effect to the mucosa.^6,20 The concurrent use of glucocorticoids was based on the assumption of an immune-mediated etiology. A significant reduction in the size of the gastric folds and an increase in serum protein concentration were documented approximately 40 days after the initiation of the treatment. The same response was also observed in a human patient following intensive treatment with propantheline bromide.²⁰ Subtotal or total gastrectomy is reserved for refractory cases in humans.⁶

The cause of death in the dog reported here remained elusive, since postmortem examination was denied by the owner. Massive gastric bleeding and thromboembolic disease secondary to protein-losing gastropathy are considered life-threatening complications in Ménétrier’s disease and may have developed in this dog.^5,6

Conclusion

An 11-year-old, Old English sheepdog demonstrated clinical, laboratory, and histopathological evidence of giant hypertrophic gastritis, a disease that is comparable to Ménétrier’s disease in humans. Giant gastric folds, low serum albumin concentration, and mucosal epithelial cell hyperplasia were the main features of the disease in this dog. A combination of glucocorticoids, a histamine-receptor antagonist, and an anticholinergic agent resulted in short-term clinical remission.