Case Report
NESIDIOBLASTOSIS IN AN ADULT WITH SHORT GUT SYNDROME AND TYPE 2 DIABETES
Mimi Wong, BSc, MBBS(Hons)1,2; Luke Conway, MBBS, FRACP1; Caroline Cooper, MBBS(Hons), FRCPA2,3; Ashim Sinha, MD, FRACP, FACE1,4; Nirjhar Nandi, FRACP1
ABSTRACT
Abbreviations: BSL = blood sugar level; GLP-1 = glucagon-like peptide 1; MMT = mixed meal test; RYGB = Roux- en-Y gastric bypass; T2DM = type 2 diabetes mellitus
INTRODUCTION
Objective: Adult nesidioblastosis is characterized by endogenous hyperinsulinemia typically causing post-pran- dial hypoglycemia, and most commonly occurs post-Roux- en-Y gastric bypass. Methods: We report a unique case of nesidioblastosis occurring in a 67-year-old female. Results: A 5-year history of symptomatic hypoglyce- mia occurred in a patient with short bowel syndrome and type 2 diabetes mellitus (T2DM) managed previously with a glucagon-like peptide 1 (GLP-1) agonist, which achieved significant weight loss. Continuous glucose monitoring captured 42 hypoglycemia episodes in a 2-week period, and following an oral glucose tolerance test there was the suggestion of a hyperinsulinemia state. She was managed with an open distal pancreatectomy, and subsequently required medical therapy to maintain euglycemia. Conclusion: We present the first case of nesidioblas- tosis occurring in a patient with short bowel syndrome, pre-existing T2DM managed with a GLP-1 agonist which achieved significant weight loss, all of which we specu- late could have predisposed to hypoglycemia and devel- opment of nesidioblastosis. (AACE Clinical Case Rep. 2019;5:e375-e379)
Adult nesidioblastosis is a rare hyperinsulinemic state, classically associated with post-prandial hypoglycemia (1). Typically, hypoglycemia is provoked with a mixed- meal test (MMT) and localizing studies are invariably negative (2). It is not possible to diagnose nesidioblastosis clinically, with imaging, or biochemically. Histopathologic features of adult nesidioblastosis are more variable than the more common newborn setting, and include exclusion of an insulinoma, the presence of conspicuous islet cells with enlarged, hyperchromatic nuclei, and islet hypertrophy and hyperplasia. Formation of ductuloinsular complexes is not a distinctive feature in adults but is well reported. In some cases the histopathologic changes are minimal and distinc- tion from normal pancreas is difficult (3,4). The pathophysiology of adult nesidioblastosis remains to be elucidated. Genetic factors, trophic factors, and receptor expression on islet cells have been suggested to be involved. Roux-en-Y gastric bypass (RYGB) has been linked to nesidioblastosis, and it is thought that elevated glucagon-like peptide 1 (GLP-1) and gastric inhibitory peptide may unmask a b-cell defect (1,3).
CASE REPORT
Submitted for publication May 26, 2019 Accepted for publication August 2, 2019 From 1Department of Diabetes and Endocrinology, Cairns Hospital, Queensland, Australia, 2School of Medicine, University of Queensland, 3Pathology Queensland, Princess Alexandra Hospital, Australia, Queensland, Australia, and 4Department of Medicine, James Cook University, Queensland, Australia. Address correspondence to Dr. Mimi Wong, Department of Medicine, 165 Esplanade, Cairns City, QLD, 4870 Australia. E-mail: mimi.wong@uqconnect.edu.au. DOI: 10.4158/ACCR-2019-0243 To purchase reprints of this article, please visit: www.aace.com/reprints. Copyright © 2019 AACE.
A 67-year-old female was referred to our institution in 2018. In 2009, she had a motor vehicle accident which led to total colectomy, resection of 75% of her small bowel, and formation of an end ileostomy. This was complicated
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by high-output stoma and malnutrition. She was referred to a dietician, and dietary advice included having small and frequent meals with high fiber. In addition, she had trailed multiple pharmacologic therapies which had limited effects, including loperamide and buscopan. Enteral feed- ing had never been used. In 2013, she was diagnosed with type 2 diabetes mellitus (T2DM) which coincided with weight gain, from a baseline of 45 to 50 kg (body mass index [BMI] 19), to 75 kg (BMI 29.7). Hemoglobin A1c (HbA1c) and oral glucose tolerance test (OGTT) at diagnosis were not avail- able, though blood sugar levels (BSLs) through glucom- eter peaked to 23 mmol/L. Initially she was managed with metformin for a month, and subsequently with a GLP-1 agonist (exenatide, 10 mcg twice a day) in 2013 for 18 months, which led to a dramatic weight reduction to 45 kg. Lifestyle optimization and malabsorption also likely
contributed to this significant weight loss. Following this, exenatide was ceased. Her diabetes has since been managed with lifestyle measures with good glycemic control (HbA1c 5.3%, 34 mmol/mol), and her weight has been between 55 to 59 kg in the past few years. Since 2013 she reported having episodes of symp- tomatic hypoglycemia, with BSLs less than 4 mmol/L, which consisted of sweating, tremor, light-headedness and lethargy. Initial BSL monitoring revealed fasting and post- prandial hypoglycemia to as low as 2.3 mmol/L. These episodes resolved within 5 to 10 minutes of correction. Initially hypoglycemia occurred once every 2 months; however, in the last 12 months she had increased episodes, and in 2018, an episode resulted in loss of consciousness which was complicated by a tibial fracture. At the time her BSL was 3.6 mmol/L, and occurred 30 minutes following a meal.
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A
B
Fig. 1. Flash glucose monitor readings. Episodes of symptomatic hypoglycemia occurred with BSL less than 4 mmol/L, and each hypoglycemic episode was treated. A, Readings prior to subtotal pancreatectomy. B, Readings following subtotal pancreatectomy and commencement of 50 mg octreotide 3 times a day. BSL = blood sugar level; M = Main meals of breakfast, lunch, and dinner.
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Table 1 Preoperative Evaluation of Hypoglycemia Fasting sample Serum glucose (mmol/L) 8.1 Insulin (<25 mU/L) 210 C-peptide (0.2-1.2 nmol/L) 3.8 Other Sulphonylurea screen Negative Insulin antibody (<0.7 units) 0.4 75 g oral glucose tolerance test Baseline 2.5 hours post 75 g glucose Serum glucose (mmol/L) 4.8 1.6 Insulin (mU/L) 6.6 C-peptide (0.3-1.4 nmol/L) 0.3 1.0
Diagnostic Evaluation
bowel syndrome they were ceased and she was commenced on octreotide. She has responded well to octreotide (Fig. 1), and it has been uptitrated to 100 mg 3 times a day subcutaneously.
DISCUSSION
Flash glucose monitoring (FreeStyle Libre, Abbott Laboratories Ltd.) was used and captured 42 episodes of symptomatic hypoglycemia in a 2-week period (Fig. 1). Simultaneous BSL recording via a glucometer yielded similar readings. There was no suggestion of a medical illness or medication contributing to her hypoglycemia, though there was suspicion of a hyperinsulinemia state (Table 1). A 24-hour fast did not induce BSLs less than 4.3 mmol/L. Localizing studies including magnetic resonance imaging, fluorine-18 dihydroxyphenylalanine positron emission tomography, and endoscopic ultrasound did not identify a focal pancreatic lesion.
Management
The patient was provided with dietary advice which included avoiding short-acting carbohydrates, and consum- ing a high protein and fiber diet, and limiting complex carbohydrates and fat. Oral therapy to manage hyperin- sulinemia was deemed to be likely ineffective due to her short bowel syndrome. Prior to her open distal pancreatec- tomy, she was provided with a trial of octreotide; however, she preferred to pursue surgical management. Histology of her operative specimen confirmed the diagnosis of nesidioblastosis. Findings included retained lobular architecture of the exocrine pancreas, normal pancreatic ducts, an increased number of islets, enlarged islets, formation of ductuloinsular complexes, and islet cells with enlarged and hyperchromatic nuclei and abun- dant clear cytoplasm (Fig. 2).
Progress
Following her distal pancreatectomy, she contin- ued to have episodes of symptomatic hypoglycemia. The frequency, however, was less; she had 17 episodes in a 2-week period. Subsequently, acarbose and diazoxide were commenced; however, due to limited absorption from short
Here we present a case of nesidioblastosis occurring in a patient with short bowel syndrome, pre-existing T2DM managed with a GLP-1 agonist, which we speculate could have predisposed to nesidioblastosis. This is the first report of nesidioblastosis occurring in the context of short bowel syndrome. There have been cases of hyperinsulinemic hypoglycemia in patients with intestinal failure, though these patients were managed with parenteral nutrition and had a high infusion of glucose which may have altered insulin secretion (5). Short bowel syndrome induced in mouse models is associated with increased pancreatic islet size, number, and proliferation (6,7). The upper intestinal hypothesis where glycemic control improves if ingested contents avoid contact with the proximal small intestine, namely the duodenum, has been suggested to have a role, though its exact mechanism is yet to be defined (6). Additionally, increased secretion of growth factors and cytokines for intestinal adaptation may play a role (8). Perez-Arana et al (6) postulated that the pancreatic islet cell change could reflect a stage of development of nesidioblastosis. However, Barron et al (7) have shown in mouse models following intestinal resection, evidence of metabolic consequences including glucose intolerance, hepatic steatosis, and abnor- mal body composition with less lean mass (7). Though, the underlying pathophysiology of a paradoxical decrease in b-cell function following short bowel syndrome remains to be defined (7). Another unique feature is of pre-existing T2DM. We identified only 5 prior cases of nesidioblastosis occurring in patients with T2DM (9-13). Although the association
including that of glucagon, possibly predisposes patients to hypoglycemia (14). It is possible these mechanisms may have predisposed our patient to hypoglycemia following her significant weight loss. Continuous glucose monitoring use has been described with insulinoma (15), and has been recom- mended as a hypoglycemia screening tool post-RYGB, as it is more effective in detecting hypoglycemia than MMT (16). A flash glucometer was used for evaluation, along with an OGTT, though it is acknowledged that a MMT is the gold standard test for evaluating nesidioblastosis. The limitation of using a flash glucometer is that lower BSLs are often recorded. BSLs obtained from Freestyle Libre were compared to HemoCue, and the mean absolute rela- tive difference was 13.2%; with BSLs less than 4 it was 20.3% (17). We acknowledge the issue of Libre monitor- ing for hypoglycemia, though given the frequent hypo- glycemia episodes, it was believed it would be the most practical approach.
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CONCLUSION
We present a rare case of nesidioblastosis occur- ring in a patient with short bowel syndrome, pre-existing T2DM managed with a GLP-1 agonist, all of which may have been a predisposing factor for islet cell hyperplasia. Significant weight loss could have also heightened the risk of hypoglycemia.
DISCLOSURE
The authors have no multiplicity of interest to disclose.
REFERENCES
Fig. 2. Histology from distal pancreatectomy. Top image: Low power showing an increase in numbers of enlarged and irregularly shaped islets, many in close approximation to ducts (Hematoxylin and eosin stain, x40). Bottom image: High power showing formation of ductuloinsular units and occasional enlarged, hyperchromatic nuclei (arrows) (Hematoxylin and eosin stain, x400).
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