NLH of the gastrointestinal tract is a rare disorder, often reported with immune deficiency disorders and/or recurrent giardiasis [11–13, 15, 17–19]. The disease may be localized to a segment or may affect longer segments of bowel . In contrast to reported disease in literature, the cohort of patients described in this study had significant differences. Firstly the disease was often encountered and report of 40 cases from one centre in 5 years period is a testimony to that. Second the disease involvement was limited to postbulbar duodenum, second and third part and duodeno-jejunal junction. Duodenal bulb was spared and there was no involvement of jejunum and ileum. Third none of the patients included in this study had immune deficiency or giardiasis. There are several reports of large cohort of patients similar to described by us from Mexico [16, 29]. However, around half of such patients had hypogammaglobinemia.
Diarrhea and weight loss secondary to malabsorption has been the dominant symptom of NLH of small bowel as reported in the literature [1, 15, 30, 31]. Malabsorption is a common symptom in patients with immune deficiency with or without superadded recurrent giardiasis . In contrast our patients with DDNLH presented with epigastric pain and vomiting, clinically suggesting gastric stasis and obstruction. Only 6 of our patients presented with diarrhea which may suggest co-existent malabsorption. Weight loss, gastric symptoms, iron lack anemia, and hypoalbuminemia in our patients were mostly caused by selective and dominant involvement of the duodenal mucosa .
The pathogenesis of nodular lymphoid hyperplasia has been a matter of debate for long. Histology of these lesions demonstrates hyperplasic lymphoid follicles with mitotically active germinal centres. In immune deficiency states, the lymphoid hyperplasia is likely the result of an accumulation of plasma-cell precursors due to maturational defect in the development of B-lymphocytes [2, 29]. These cells attempt to compensate for functionally inadequate intestinal lymphoid function. Bacterial contamination of small intestines is often mentioned as an etiological factor for NLH . This is supported by regression of nodules following oral antibiotic therapy in some cases . Some investigators suggest that coeliac disease may be associated with NLH . However, NLH may occur in a whole spectrum of disorders without any abnormalities in immunoglobulins [33–35]. It is believed that NLH in absence of immune deficiency disorders may be related to immune stimulation of the gut lymphoid tissue.
H. pylori infection is etiologically associated with a number of gastroduodenal disorders. Acute infection causes neutrophilic gastritis with transient hypochlorhydria and subjects complain of epigastric pain and nausea . Chronic infection causes a wide variety of gastritis including chronic superficial gastritis, nodular gastritis and chronic atrophic corpus gastritis with metaplasia [37, 38]. H. pylori infection is strongly associated with peptic ulceration of duodenum and stomach [39, 40]. Chronic corpus atrophic gastritis with intestinal metaplasia caused by H. pylori infection is an initiating event in most cases of intestinal type adenocarcinomas stomach. In fact H. pylori infection is associated with both diffuse-type and intestinal-type gastric adenocarcinoma [40, 41]. Another entity which is etiologically related to H. pylori infection is gastric MALT lymphoma. The disease evolves through H. Pylori gastritis with mucosa associated lymphoid tissue (MALT), lymphoepithelial lesions, low grade B cell lymphoma and finally diffuse large B cell lymphoma [42–44]. There are no published reports of association of diffuse duodenal nodular lymphoid hyperplasia (DDNLH) with H. pylori infection.
A number of findings strongly pointed to H. pylori to be etiologically associated with DDNLH in our patients. All patients were infected with H. pylori infection. Patients in whom H. pylori were eradicated showed significant clinical response and regression/resolution of duodenal events. In contrast patients in whom H. pylori could not be eradicated showed persistence of clinical symptoms and persistence of duodenal nodular lesions. A number of earlier studies have suggested H. pylori as a possible cause of NLH [16, 29], but none has followed this lead and none has substantiated this association.
What could be the pathogenesis of DDNLH in our patients? All patients had heavy H. pylori infection with advanced changes in the stomach as evidenced by gastroscopic and histological findings. In fact 2 of our patients had low grade MALT lymphoma. However, the duodenal changes seen were not as a result of direct involvement by H. pylori, as the organisms were not consistently present in the duodenal biopsies. A number of nongastrointestinal tract diseases are possibly associated with H. pylori infection. Many of these associations are suggested to be related to the effects of H. pylori on coagulation and markers of systemic inflammation. We believe the duodenal lesions were as a result of immune stimulation of prolonged and heavy H. pylori infection . This was supported by elevated immunoglobulins in a number of patients in our series. Some extragastric disease states are particularly associated with H. pylori CagA-positive infections [46, 47]. DDNLH seen in our community may be related to high prevalence of such H. pylori infections in our community and this need to be explored further. We believe careful examination of post-bulbar and second part of duodenum at EGD and liberal use of duodenal biopsies in patients with heavy H. pylori infection in tropical countries is needed to define the impact of this disease.
Two of our patients who failed to eradicate H. pylori infection had disease progression. However, biopsies showed prominent lymphoid follicles with active germinal centres located in the mucosa and there was no suspicion of disease evolving in to lymphoma. NLH has special relationship with lymphoma [7–9]. The disease needs to be differentiated from lymphoma. The presence of highly reactive germinal centres, numerous cell types, prominent vascularity, and polyclonality as determined immunohistochemically are the most important features in the differential diagnosis with lymphoma. Lymphoid hyperplasia may be differentiated from follicular lymphoma presenting as lymphomatous polyposis by Bcl-2 immunostaining of follicular germinal centres. NLH may be a manifestation of extraintestinal lymphoma and disease regresses after extraintestinal lymphoma undergoes remission under chemotherapy . May patients with gastrointestinal lymphoma may present with NLH. Moreover, studies have shown that NLH itself may evolve in to lymphoma on long term follow up. The study period in our patients was not enough to define whether disease can evolve in to lymphoma. Long term follow up of these patients needs to be done to evaluate the malignant potential of this entity.