Gastrointestinal complications after renal transplantation are frequent and can cause significant morbidity and mortality (1,2). Uremia (before transplantation) and immunosuppressive drugs used after transplantation increase the susceptibility to peptic ulcer disease, gastritis, and esophagitis (3-5).
Dyspeptic symptoms can also be associated with lymphoproliferative disorders (6). The incidence of lymphoproliferative disease in renal transplant recipients is approximately 1.2% in a large series of patients observed for 15 years (7). The site of lymphoproliferative disease is variable, with the small intestine involved in as many as a third of patients (7). Benign intestinal masses can also be found, particularly hyperplasia of Brunner's glands, in chronic renal failure (8-10).
Given the overall poor outcome of advanced lymphoproliferative disease despite reduction of immunosuppressive therapy, a high index of suspicion should be raised in patients who have undergone solid organ transplant and have gastrointestinal symptoms. This report describes a case of Brunner's gland hyperplasia in a child with dyspeptic symptoms after renal transplant.
A 12-year-old boy who had undergone a second kidney transplant 4 months earlier was readmitted to the hospital with nonbilious vomiting, epigastric pain, and bloating. He had Joubert's syndrome (hypoplasia of the cerebellar vermis and associated progressive renal failure) (11). He had received a cadaveric kidney transplant in 1992, but the initial graft was lost 2 years later because of lymphoproliferative disease involving the liver, spleen, and brain. The lymphoproliferative disease was treated with withdrawal of immunosuppression, interferon-α, intravenous γ-globulin and cranial irradiation. He returned to hemodialysis until he underwent a living, related-donor kidney transplant in July 1995. Medications on admission included azathioprine, cyclosporin A, prednisone, nystatin, amlodipine, and ranitidine.
On physical examination, he was noted to be a well-nourished child with Cushingoid facies and alopecia. There were no enlarged lymph nodes. Abdominal examination was remarkable for mild epigastric and periumbilical tenderness without guarding or rebound tenderness. There were multiple scars and a kidney graft palpable in the right lower quadrant. No other masses were palpable.
Initial laboratory investigations included (normal range or value) hemoglobin, 111 g/l (120-160 g/l) and a white cell count of 7.5 × 109/1 (4-10 × 109/1), with a normal differential. Liver enzyme tests showed aspartate aminotransferase, 34 U/l (<36 U/l); alanine aminotransferase, 33 U/l (<40 U/l); alkaline phosphatase, 75 U/l (200-630 U/l); and γ-glutamyl transferase, 69 U/l (<45 U/l). Liver function tests included albumin level, 33 g/l (33-58 g/l) and prothrombin time, 11 seconds (10.5-13.5 seconds). Other laboratory tests included: urea, 3.1 (2.9-7.1 mmol/l); creatinine, 54 (<106 µmol/l); sodium, 137 mmol/l (135-143 mmol/l); potassium, 3.9 mmol/l (3.5-5.2 mmol/l); calcium, 2.27 mmol/l (2.25-2.62 mmol/l); phosphate, 1.4 mmol/l (1.07-1.71 mmol/l); pH, 7.39 (7.35-7.45); PCO2, 42 mmHg (33-46 mmHg); and bicarbonate, 25 mmol/l (20-28 mmol/l). Fasting serum gastrin was 229 ng/l (<90 ng/l).
A barium contrast study revealed a normal esophagus and delayed gastric emptying with few peristaltic waves. A focal area of concentric wall thickening was present in the second portion of the duodenum, causing luminal narrowing. There was no evidence of mucosal ulceration.
The patient underwent a diagnostic upper endoscopy under general anesthesia. There was esophageal erythema with linear ulcerations. The body and antrum of the stomach appeared normal. Multiple polypoid lesions were present in the first portion of the duodenum (Fig. 1). Multiple biopsies of the mass lesions were taken for histopathologic study, which revealed normal duodenal mucosa. A computed tomographic scan of the abdomen showed duodenal wall thickening but no masses (Fig. 2).
The history of lymphoproliferative disease and the radiologic and endoscopic findings in the duodenum raised a strong suspicion that these duodenal nodules represented small bowel lymphoma as a recurrence of lymphoproliferative disease in this patient. For these reasons, a full-thickness biopsy of the duodenum was undertaken through laparotomy. Analysis of the biopsy specimen showed normal mucosal architecture without ulceration or erosion, but with evidence of hyperplasia of the underlying Brunner's glands (Fig. 3). The architecture of the glands was normal. No inflammatory infiltrates or cytologic abnormalities were identified. Epstein-Barr virus DNA was determined to be negative by polymerase chain reaction.
To consider the pathogenesis of the Brunner's gland hyperplasia, several immunohistochemical staining analyses were performed. MIB-1 antibody (Ki-67), a proliferative marker (12), was negative in the Brunner's glands in both this patient and in matched control subjects (Fig. 4). Stains for chromogranin A were highly positive in our patient's Brunner's glands and negative in those of matched control subjects (Fig. 5). Stains for serotonin and gastrin showed the same findings (data not shown).
The patient recovered from the laparotomy uneventfully and was discharged home with improved gastrointestinal symptoms and receiving cisapride and omeprazole for peptic esophagitis.
MATERIALS AND METHODS
Biopsy specimens were fixed in 10% formalin, embedded in paraffin, and stained with hematoxylin and eosin. Immunostaining to detect chromogranin A, gastrin, serotonin, and MIB-1 were performed using an indirect immunoperoxidase method (13). An antigen retrieval technique by microwaving in 0.01 mol/l sodium citrate (pH 6) was used for MIB-1. This technique was standardized for the microwave in our pathology laboratory (14). The sections for serotonin and gastrin were digested with 0.5% pepsin (Sigma, St. Louis, MO, U.S.A.). Endogenous peroxidase was blocked with 1.5% H2O2 in methanol for 30 minutes. The sections were first blocked in 5% normal goat (chromogranin A and gastrin), rabbit (serotonin), or horse (MIB-1) serum and then incubated for an hour at room temperature with 1:800 primary antibody chromogranin A (Harlon Sera Lab, Leicester, England), 1:4000 gastrin (Dako, Santa Barbara, CA, U.S.A.), and 1:80 serotonin (Harlon Sera Lab, Leicester, England) or with 1:50 MIB-1 (Immunotech, Miami, FL, U.S.A.) overnight at 4°C. The slides were then washed three times with phosphate-buffered saline-bovine serum albumin, incubated for 30 minutes at room temperature with biotinylated horse anti-mouse IgG (MIB-1), rabbit anti-rat IgG (serotonin), or goat anti-rabbit IgG (chromogranin and gastrin; Molecular Probes, Eugene, OR, U.S.A.); washed three times as above; and incubated with avidin peroxidase (Elite ABC) for 35 minutes at room temperature, followed by final washes in Tris-buffered saline. Bound antibody complex was visualized by reaction in 3,3′-diaminobenzidine (DAB) substrate (Vector, Burlingame, CA, U.S.A.) and counterstained with Harris hematoxylin.
This is the first report in the pediatric literature of duodenal Brunner's glands nodules mimicking small bowel lymphoma. Allograft recipients who undergo the required immunosuppression are at an increased risk of development of malignant lymphoma and other lymphoproliferative disorders (15). The single most common site for the development of lymphoproliferative disease in kidney transplant recipients is the gastrointestinal tract (6,16). Both the small bowel and large intestine can be involved, and patients can have symptoms including epigastric tenderness, vomiting, intestinal perforation, or intussusception (6,17).
Branched acinar (Brunner's) glands are located in the submucosa and the deep layers of the mucosa, mostly in the first part of the duodenum. The incidence of benign tumors of the small intestine in autopsy series is 0.16% (18). Of these, 25% are located in the duodenum, and 10% are lesions of the Brunner's glands (19).
The incidence of Brunner's gland hyperplasia is increased in subjects with chronic renal failure (8,20). Paimela et al. (8) cited a series of 2800 consecutive autopsies in which 40 cases of hyperplasia of Brunner's glands were identified. In 22 of these 40 cases, patients had been uremic before death. In that report, 5 cases of multiple duodenal polyps, caused by hyperplasia of Brunner's glands were observed among 33 consecutive uremic patients (15%), compared with only 1 case in 300 control subjects (0.7%) (8).
The pathogenesis of Brunner's gland hyperplasia is still not well understood. The increased prevalence in uremia suggests that a state of hyperstimulation exists in chronic renal failure. Proliferation of the Brunner's glands could occur in response to the gastric acid hypersecretion that occurs in chronic renal failure (21). Increased gastrin levels, as seen in the child presented in this case report, have been reported previously in patients with Brunner's gland hyperplasia (22,23). However, in another study, less than one half of patients with hyperplasia of Brunner's glands had an increase in gastric acid secretion (18). Basal-and pentagastrin-stimulated acid output and serum concentrations of gastrin did not distinguish patients with Brunner's gland hyperplasia and chronic renal failure from patients with chronic renal failure alone (8).
Chronic renal failure affects neuroendocrine cell populations in the gastric mucosa (24,25). Rantala et al. (24) showed that the number of serotonin-containing enterochromaffin cells is lower in patients with chronic renal failure than in control subjects. The appearance of neuroendocrine cells in the hyperplastic Brunner's glands of our patient may be a compensation in response to an alteration in the normal gastric neuroendocrine cell population. This abnormal presence of enteroendocrine cells may lead to Brunner's gland hyperplasia by local secretion of proliferation factors such as epidermal growth factor, insulin-like growth factor-1, and transforming growth factor-α (26). The MIB-1 staining results in our case report suggest that this proliferation, which is also controlled by counterregulatory peptides, had reached a steady state.
Clinical manifestations of Brunner's gland hyperplasia are caused by the large size of the intraluminal tumor, circumferential hyperplasia, or duodenal intussusception (27). Symptoms that have been attributed to the lesion include abdominal pain and vomiting caused by intestinal obstruction (8,18). Melena, unexplained anemia, and hematemesis can also develop (18). However, most patients are asymptomatic (8), and evidence of Brunner's gland hyperplasia is generally found incidentally during endoscopic examination undertaken to exclude known causes of abdominal pain.
Treatment is generally conservative, because hyperplasia of Brunner's glands is considered a benign condition. However, lesions complicated by obstruction or gastrointestinal bleeding can be excised endoscopically or surgically (28).
In summary, we describe a case of Brunner's gland hyperplasia in a child with dyspeptic symptoms after renal transplant. Given the possibility of lymphoproliferative disease in this patient population, a diagnostic biopsy-either deep endoscopic biopsy (i.e., biopsy on biopsy) or laparoscopic biopsy-should be obtained. Brunner's gland hyperplasia is a common occurrence in renal patients that can have a range of clinical symptoms. The present case report indicates that hyperplasia of Brunner's glands must now be included in the differential diagnosis of duodenal hypernodularity observed radiographically or endoscopically in children with chronic renal failure.
Acknowledgment: Dr. Shaoul is a Canadian Cystic Fibrosis Foundation Research Fellow. He is also supported by grants from the American Physicians Fellowship for Medicine in Israel program, Janssen/Ortho Inc., North York, Ontario, Canada and the Postgraduate Dyson Fellowship award from the University of Toronto, Canada.
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