Diagnostic and Surgical Management of Nesidioblastosis in a 42-Year-Old Man with Refractory Hypoglycemia

Introduction

Hypoglycemia is considered a clinical and laboratory condition that can be a consequence of various diseases or the use of medications [1,3]. It is a common condition in people with diabetes who use some oral hypoglycemic agents or insulin therapy [1,2]. It is less common in non-diabetic patients and many causes are challenging for doctors to diagnose [3]. The diagnosis of hypoglycemia is based on Whipple’s triad, which consists of symptoms of hypoglycemia, low serum glucose concentration, and resolution of symptoms after an increase in plasma glucose [4].

Clinical history and physical examination are fundamental to identifying the etiological causes of hypoglycemia. A common cause of hypoglycemia is gastric bypass surgery [5,6]. Other common causes that should be investigated carefully include hormonal deficiency/adrenal insufficiency, critical illness with organ dysfunction, sepsis, starvation, non-beta cell tumors, and beta cell tumors [7].

In healthy patients, the possibility of endogenous hyperinsulinism or accidental or factitious hypoglycemia should be considered [8]. The main cause of persistent endogenous hyperinsulinemic hypoglycemia or endogenous hyperinsulinism in adults is insulinoma, a benign tumor of the pancreatic beta cells responsible for producing insulin. These tumors can cause excessive insulin production, leading to episodes of hypoglycemia (low blood glucose levels) [2,9]. However, a rare cause of functional hyperinsulinemia is hyperplasia of the pancreatic beta cells, known as nesidioblastosis [10]. In 1938, Laidlaw [11] coined the term “nesidioblastosis” to define the proliferation of endocrine cells originating from the pancreatic duct epithelium culminating in the inadequate hypersecretion of insulin [12–14]. Nesidioblastosis can present in various clinical forms ranging from mild and transient hypoglycemia to more severe and refractory forms, resulting in severe hypoglycemic conditions and hypoglycemic or ischemic encephalopathies [5]. Surgical treatment consisting of partial or total pancreatectomy is indicated for patients with severe and refractory hypoglycemia that is difficult to control [5].

We report a case of persistent hyperinsulinemic hypoglycemia in an adult whose initial diagnosis, an insulinoma, was not detected by imaging methods. He underwent extensive diagnostic investigation but refractoriness to drug and nutritional therapy culminated in the need for aggressive surgical treatment. We hope that this discussion of the diagnostic and therapeutic management of this rare case of hypoglycemia contributes to increasing knowledge on the topic.

The study was approved by the Research Ethics Committee of the Faculty of Medicine of Jundiaí, CAAE: 63588022.0.0000.5412.

Case Report

FIRST HOSPITALIZATION:

Two years ago, the patient presented to the emergency department of a general hospital with a chief concern of syncope.

After an initial investigation into potential cardiovascular etiologies, hypoglycemia was identified, accompanied by diaphoresis, tachycardia, and partial loss of consciousness. His blood pressure was 130/88 mmHg and his heart rate was 80 beats per minute. An electrocardiogram was performed, revealing no acute ischemic changes or evidence of arrhythmias. Myocardial necrosis markers were also evaluated, and no changes were identified. A chest X-ray and laboratory tests (complete blood count, urea, creatinine, serum sodium, potassium) also showed no abnormalities. However, blood glucose levels (capillary blood glucose) were low at 48 mg/dL (reference range [RR]: 70–100 mg/dL) (Figure 1). There was subsequent improvement following the bolus administration of 50 g of intravenous hypertonic glucose solution, characteristic of Whipple’s triad.

During the 17-day hospitalization, he underwent laboratory tests, including cortisol, serum insulin, and glucagon measurements, and all results were within normal limits. Contrast-enhanced CT of the abdomen revealed renal lithiasis and signs of hepatic steatosis. The Internal Medicine team provided continuous care to the patient during his hospitalization, although the underlying cause of hypoglycemia remained undefined. Glycemic control was achieved with diet therapy and glucose-containing solutions, with satisfactory glycemic control (blood glucose level 80–180 mg/dl) (Figure 1) at discharge. He was referred to endocrinology, and during this period, attended only 1 medical appointment; he remained euglycemic and asymptomatic until his return to the hospital.

SECOND HOSPITALIZATION:

Ten months later, he required rehospitalization due to hypoglycemia. He was hospitalized for 4 months, during which an extensive investigation was conducted to establish the etiological diagnosis of hypoglycemia, including laboratory and imaging tests (Table 1). Laboratory tests showed elevated serum insulin levels and low blood glucose. Based on these results, abdominal ultrasound, a new CT scan of the whole abdomen, MRI, echoendoscopy, and positron emission tomography (PET) imaging with a somatostatin analog were requested, which did not identify pancreatic abnormalities (Table 1). The patient also underwent an assisted fasting protocol to investigate insulinoma (Table 2), which revealed normal insulin and C-peptide levels (Figure 2). Autoimmune disease antibodies and hormonal profiles were also investigated, but no abnormalities were found.

Due to recurrence of severe hypoglycemia, he required hospitalization and monitoring in the Intensive Care Unit (ICU), being subjected to a nutritional plan with a high energy value (>40 Kcal/Kg/day), orally (accompanied by the nutrition team, always aiming to balance macronutrients [low carb] and micronutrients [5,15]) associated with intravenous glucose infusion (10% glucose serum, with continuous infusion of 150 g glucose per day).

Given these findings, the suggested diagnosis was persistent hyperinsulinemic hypoglycemia in adults. Selective arteriography of the pancreatic artery to measure insulin levels revealed results within the reference range (Table 3). Transhepatic pancreatic catheterization was performed, and pancreatic venous blood samples were collected to identify the site of focal hyperinsulinism. Additionally, the glucagon reversal test result was negative. The hospitalization was exclusively due to recurrent episodes of hypoglycemia despite the therapy being implemented.

The intensive care team prescribed octreotide, which inhibits the release of insulin and several other hormones. Reports in the literature recommend subcutaneous administration of 100–600 µg of octreotide per day [16,17]. Initially, we administered 300 µg per day subcutaneously (divided into 3 doses), which were later increased to 600 µg per day, to maintain blood glucose levels within normal limits and obviate the need for intravenous glucose.

At the end of these 4 months of hospitalization, he was discharged with a prescription for octreotide, nutritional guidance, and recommendations for follow-up with the endocrinology team, as the etiological diagnosis was not definitive.

THIRD HOSPITALIZATION:

Five months after hospital discharge, he was readmitted due to hypoglycemia. He was admitted to the Intensive Care Unit due to hypoglycemia refractory to nutritional therapy, again requiring continuous intravenous glucose infusion. Octreotide medication was maintained. With the consensus of the medical team, upper echo-endoscopy and CT/PET with gallium-labeled somatostatin analog (Table 1) were repeated, showing no abnormalities.

Given this presentation, the case was discussed among clinical and surgical specialties. The hospital’s clinical teams (general practitioners, intensivists, and endocrinologists) and surgical team (general surgery) agreed on surgical treatment consisting of total pancreatectomy with splenectomy. The possibility of performing a pancreatic biopsy was discussed. However, the use of antiplatelet agents, the absence of focal lesions on imaging, the refractoriness of severe and potentially fatal hypoglycemia resulted in the choice of aggressive surgical treatment and not performing a biopsy. To ensure optimal conditions for the procedure, the patient was prepared for surgery by administration of anti-pneumococcal vaccine (1^st dose), conjugated with Hemophilus type B and meningococcal C.

The surgery was performed without complications. The patient showed good evolution in the ICU, with postoperative hyperglycemia. There was a need for the introduction of insulin therapy. The Clinical Nutrition and Nutrology team monitored nutritional therapy. The intake of pancreatic enzymes during meals was necessary after starting the oral diet.

The material collected during the total pancreatectomy and splenectomy was sent for anatomopathological/immunohistochemical examination, which revealed a pancreatic parenchyma with enlarged and irregular Langerhans islets, some close to a duct. Occasional neuroendocrine cells with karyomegaly were positive for insulin. These findings are consistent with nesidioblastosis (Figure 3).

FOLLOW-UP:

The Clinical Endocrinology team is currently following the patient. The treatment consists of insulin therapy and nutritional therapy combined with ingestion of pancreatic enzymes. The patient’s pre-existing medical conditions, including systemic arterial hypertension, heart failure, and coronary artery disease, are being managed. Currently, he is adapting to the need for new medications and trying to regain his previous quality of life (Figure 4).

Discussion

This case report contributes to the medical literature by highlighting a rare and complex instance of nesidioblastosis in an adult patient with multiple cardiovascular comorbidities. By discussing the diagnostic and therapeutic approach for this specific case, we provide valuable insights into managing persistent hyperinsulinemic hypoglycemia in adults, particularly when the etiology is not readily identified by conventional imaging methods. Similar to other case reports [9,10], we discuss the diagnostic challenges due to the low sensitivity of conventional imaging techniques. Nesidioblastosis is a rare disease [10,14] with a broad spectrum of clinical presentations, ranging from mild and transient hypoglycemia to severe forms that can lead to brain damage and death due to difficult-to-control hypoglycemia [15,18].

The present case concerns a non-diabetic man with a history of systemic arterial hypertension, heart failure, and coronary artery disease admitted to the hospital for hypoglycemia. The patient was evaluated with laboratory and imaging tests to establish the diagnosis. The initial assessment to determine the etiology of hypoglycemia based on Whipple’s triad excluded causes such as adrenal insufficiency, medication use, and alcohol consumption, as well as some alternative causes such as bariatric surgery [19,20], critical illness/organ dysfunction, use of insulin or other glucose-lowering agents, and a history of malignancy [21]. These steps are essential for a comprehensive differential diagnosis, as described by Cryer et al [2].

Given the high level of serum insulin, the first diagnostic hypothesis was insulinoma. Imaging studies, such as CT, MRI, upper endoscopy, and PET/CT are commonly used to investigate the presence of insulinoma, despite their low preoperative sensitivity (approximately 50%). Endoscopic ultrasound increases the sensitivity to 80% and scintigraphy with somatostatin analog has a diagnostic sensitivity of 60% [22]. However, the imaging studies results did not confirm the diagnosis of insulinoma in this case. This aligns with the findings of Doppnam et al, who discussed the limitations of conventional imaging methods in detecting insulinomas [23]. Selective pancreatic arteriography allows for the precise localization of an insulinoma in 30% to 85% of patients [22]. Our patient underwent selective arteriography of the gastroduodenal, proximal splenic, distal splenic, and superior mesenteric arteries. In the presence of pancreatic tumors, pancreatic arterial embolization can control refractory hypoglycemia [24–26]. The fact that the results were within the normal range made the diagnosis more difficult.

Based on the clinical presentation of persistent hyperinsulinemic hypoglycemia in adults, associated with the results of the complementary investigation, the most likely diagnosis was nesidioblastosis. Hypoglycemia has a broad differential diagnosis, requiring a systematic investigation of the etiology. Coordination of the medical and multidisciplinary teams is essential to define an etiological diagnosis and an assertive treatment, as reported by Service et al [13].

Studies show recurrence of persistent hypoglycemia in approximately 30% of cases where partial pancreatectomy is performed. This is due to the probable coexistence of hyperplasia of beta cell islet hyperplasia in the remaining pancreatic tissue [27]. Many patients with this condition undergo a new surgical procedure with its associated complications. Case reports suggest that subtotal pancreatectomy may be a treatment option, but hypoglycemia recurrence is frequent [28]. We opted for total pancreatectomy with splenectomy, considering the risks and benefits of this approach, a decision supported by reports such as that of Analauf et al [14]. We also considered the history of hospitalizations affecting psychological well-being, cardiovascular comorbidities, the surgical team’s opinion based on the patient’s anatomical condition, and extensive multidisciplinary discussions.

The decision to perform a total pancreatectomy, which is an aggressive procedure, was not easy for the doctors or the patient. The multidisciplinary team talked to the patient, advising him about the surgery, its consequences, and the need for lifelong treatment with insulin and pancreatic enzymes. The patient’s agreement with the medical team reflects a consensus on the best possible treatment given the particularities of the clinical case. This type of shared decision-making is vital in complex cases, as highlighted in the systematic review by Stacey et al [29].

Our patient showed good postoperative evolution, including glycemic control and adequate nutritional support, associated with the intake of pancreatic enzymes and administration of insulin therapy. The endocrinological and multidisciplinary follow-up indicates that, despite a new reality and new medications, the patient is trying to recover the quality of life lost due to prolonged hospitalizations and the risks that severe hypoglycemia represents. New treatment options to preserve exocrine and endocrine pancreatic function are needed.

The significance of this case report lies in the risks and dangers of nesidioblastosis or NIPHS for the patient, the diagnostic challenges, and the responsibility of proposing aggressive surgical treatment. The diagnostic assertiveness and the restoration of the patient’s quality of life have been satisfactory for the health professionals involved in the treatment so far.

Conclusion

The diagnosis of nesidioblastosis in adults is complex and time-consuming, being a diagnosis of exclusion. A multidisciplinary approach proved crucial in ensuring comprehensive and effective treatment. Knowledge about diagnosis, precise investigation, and targeted treatment are needed to increase understanding of the disease, direct new treatments, and reduce morbidity and mortality in affected patients.