Insulinoma after sleeve gastrectomy: A case report

lNTRODUCTlON

The obesity pandemic has become a great topic of interest due to its implications for quality of life,comorbidities, increasing mortality, and the economic impact on health services worldwide[1]. Bariatric surgery (BS) is an effective and durable treatment for severe obesity and glucose metabolism disorders,with laparoscopic Roux-Y gastric bypass surgery (RYGB) being the most common procedure[2,3].Nevertheless, laparoscopic sleeve gastrectomy (LSG) has been proposed as a procedure capable of achieving the same goals, but with fewer complications[4].

A common complication in BS is the development of a postprandial hyperinsulinemic hypoglycemic state[5]. Hypoglycemia is defined as a glucose level below 70 mg/dL according to the American Diabetes Association guidelines[6]. The possible causes of hypoglycemia in patients who had undergone BS include late dumping syndrome, nesidioblastosis and, rarely, insulinoma[5,7]. Up to 40 cases of nesidioblastosis have been reported after RYGB, and only one case has been reported after sleeve gastrectomy[8,9]. To our knowledge, there are few reports of insulinoma after BS[10] but no reports after LSG. The purpose of these case reports is to inform clinicians that patients with neuroglycopenic symptoms during the fasting state could have hypoglycemia caused by insulinoma, which is not only due to late dumping syndrome.

座椅处振动的均方根值较大,使得驾驶室的驾乘舒适性较差.将此测点处降噪后的信号进行频响分析,找出该处的振动特性.通过将其进行快速傅立叶变换(Fast Fourier Transformation,FFT)后,得出座椅处的频响特性,如图10所示.由图10可得座椅处在4种不同车速下,其主要振动频段在0～10 Hz的范围内,刚好与人体敏感频段重叠.故该类矿用自卸车在任何速度下的驾乘舒适性均不太理想,且车速为30 km/h时的舒适性最差.因此,后续需要对车辆的簧载悬架系统、驾驶室悬置系统和座椅减振系统进行优化,以降低振动幅度提升驾乘舒适性.

CASE PRESENTATlON

Chief complaints

A 43-year-old woman was referred to the obesity clinic due to neuroglycopenic symptoms caused by an insulinoma 2 years after a sleeve gastrectomy.

记录传统形心算法和窗宽自适应形心修正算法对同一波形的仿真结果，再将其与真值的差作为误差.仿真基于10 ns脉冲宽度，ADC采样率为2G SPS，ADC的量化输入范围是0～400 mV，两种算法对饱和度在50%～1 000%的波形在不同的信噪比(Signal-to-Noise Ratio, SNR)条件下分别进行5 000次仿真，分析算法的精度，统计在不同饱和度和SNR条件下的最大误差，SNR指ADC输入量化范围和噪声比值.

History of present illness

Hypoglycemia is a well-documented complication after BS. Papamargaritis[12,13] recorded a study where 33% of patients experienced severe hypoglycemia a year after LSG due to late dumping symptomswhich usually occurs 1-3 h after a high-carbohydrate meal triggering a hyperinsulinemic response. Since 2005, up to 40 cases of nesidioblastosis after RYGB have been reported[8], and only one case after LSG was documented in 2019 by Kim[9]. While rare, insulinomas have been reported after BS. Mulla[10] described seven cases of insulinoma, one patient with pancreatic neuroendocrine tumor, and one patient with insulinoma and pancreatic neuroendocrine tumor after BS, 78% of whom were women. In these cases, hypoglycemia was more common in the fasting state.

History of past illness

The patient had no specific personal or family history.

Personal and family history

In 2002, the patient was diagnosed with obesity and dyslipidemia (high triglycerides and cholesterol with low HDL) and treated with improvements in diet, physical activity, and statins without weight control. In 2016, a gastric balloon was placed, and although her body mass index (BMI) in 2018 was 34.4 kg/m, LSG was performed.

对相同变量进行访问的过程中，对线程进行并行执行时，若线程A赋值变量X的过程中，线程B应对该变量数值进行读取，线程A没有赋值变量X时，B无法对数值进行读取，怎样解决这样的问题？由此针对访问变量X的方式，需要借助syn⁃chronized关键词进行一定的修饰。该方式一旦被线程A所调用，其余线程就要经历等待的过程，线程A结束之后即可运用[5]。同步方式就是借助synchronized进行说明，在设计多线程程序中有着广泛的应用，能够确保单个线程在相同时间对方法进行访问，将线程间的同步变为了现实。协商、共享不同资源的关键就在于同步。

出口去向方面,中国甘薯出口目标市场集中度非常高．ITC官方网站公布的数据显示,2017年我国甘薯出口的主要市场包括中国香港,占中国甘薯出口额总量的85%以上，如表3所示．

Physical examination

After LSG, the patient weighed 74 kg, and her BMI was 32 kg/m. The physical examination showed no obvious cardiovascular or respiratory abnormalities. The abdomen was soft, and the only sign was the presence of postsurgery scars.

Laboratory examinations

Upon hospitalization prior to the surgery, the patient’s hemoglobin A1c level was 4.8% (normal range: ＜5.7%). The C-peptide value was normal at 3.64 ng/mL (1.1-4.4 ng/mL), and insulin was mildly elevated at 16.40 μUI/mL (3.21-16.30 μUI/mL). Lipid levels indicated dyslipidemia with total cholesterol of 224 mg/dL and LDL-c of 142.8 mg/dL. Other biochemical parameters were normal and only an iron deficiency anemia was documented. Thyroid function was normal, with TSH 2.46 μUI/mL (0.27-4.20 μUI/mL), FT41.06 ng/dL (0.93-1.70 ng/dL), and cortisol level 15.04 ug/dL (3.70-19.40 μg/dL), all within the normal range.

Imaging examinations

Histopathological findings revealed a well-differentiated neuroendocrine grade 2 tumor with free edges. Immunohistochemical studies confirmed positive chromogranin and synaptophysin as well as a proliferative activity (Ki67) in 4% of neoplastic cells.

An increase in ghrelin levels has been observed a year after BS[15]. Ghrelin and the type 1a ghrelin receptor (GHS-R1A) are expressed in different types of neuroendocrine tumors. Recently, Wu[16]found that GHS-R1a was found in 60% of insulinomas, suggesting that ghrelin may act through autocrine or paracrine pathways. The proliferative effects of ghrelin and its association with insulinoma have not been studied, although there is a clinical case report where a ghrelin-producing neuroendocrine tumor was transformed into an insulinoma[17].

洋桔梗适合的土壤EC值为1.0～1.3[1]。栽苗后第10 d可施第1次肥，以浓度约为0.1%～0.2%的高磷肥为主，以促进植株根系的生长；生长前期主要施用高N肥，如N∶P∶K=30∶10∶10的水溶肥促进叶片、茎秆生长；在中期每隔10 d左右施用1次平衡肥，如N∶P∶K=20∶20∶20的水溶肥或N∶P∶K=17∶17∶17的复合肥；大约定植后50 d生长到第7节位时，进入花蕾期要施高钾肥，如K2SO4；中后期土壤施肥的同时要结合叶面肥，如KH2PO4喷施，每隔7 d喷1次。在花芽形成前随着苗正常生长而慢慢上调肥料EC值。

FlNAL DlAGNOSlS

The final diagnosis was insulinoma. This was confirmed by histology and immunohistochemistry of the tumor (Figure 2).

TREATMENT

After a surgery consultation, a laparoscopic insulinoma enucleation was performed without complications. No other tumors were identified in the upper abdomen.

1.1 资料来源 选取2016年1-12月在德阳市人民医院门诊进行体检的健康学龄前儿童1 452例为研究对象，经血常规检查确诊，排除其他类型的贫血、其他疾病导致的贫血、合并感染、肝肾功能不全、心脑血管疾病、内分泌疾病、1个月内无消化道或呼吸道感染、3个月内使用过糖皮质激素及免疫制剂者、正在接受缺铁性贫血治疗者。所有研究对象均为健康体检儿童，非因疾病原因接受检查。研究对象男815例，女637例；年龄6个月～6岁，平均 (3.14±0.57)岁，其中<1岁378例、1～3岁595例、4～6岁479例。本研究经医院伦理委员会批准，所有研究对象家属对本研究知情并签署知情同意书。

OUTCOME AND FOLLOW-UP

Computed tomography (CT) demonstrated the presence of a focal asymmetric reinforcement area in the head of the pancreas (Figure 1A). Endoscopic ultrasound showed the presence of a tumoral lesion in the pancreas in close proximity to the main pancreatic duct and splenomesenteric confluence without evidence of invasion (Figure 1B and C).

After surgery, the neuroglycopenic symptoms were relieved, and the patient had no hypoglycemic events. Her current treatment is diet and physical activity, targeting a BMI of 31.1 kg/m.

DlSCUSSlON

Since 2013, 468609 BSs have been performed worldwide[2]. LSG was initially introduced as a first-stage restrictive procedure to a more complex definitive one. At present, it is performed as a stand-alone BS[7]. Since 2008, the prevalence of the LSG procedure has increased from 5% to 37% worldwide[2], but in Mexico, it is performed only in 13% of patients, whereas LRYGB is performed in 85.8%, with a bypass/sleeve ratio of 7:1. In our center, LSG accounts for 20% of total BSs (200 procedures since 2010).

LSG comprises vertical longitudinal resection of the greater gastric curve that includes the fundus,body, and antrum as well as the formation of a tubular conduit with a capacity of ＜ 100 mL. Weight loss is achieved by restrictive and humoral effects[8,11].

In March 2020, 2 years after LSG was performed, the patient developed neuroglycopenic symptoms including short-term memory loss, lingual nerve paresthesia, and nonspecific visual alterations predominantly during the morning in a fasting state. These symptoms were suppressed with food intake. Two months later, she visited a physician who documented fasting plasma glucose of 27 mg/dL, and in June 2020, the symptoms occurred more frequently, and she gained 14 kg. In the beginning, late dumping symptoms were suspected, but in September 2020, fasting plasma glucose of 30 mg/dL was documented, so she was hospitalized for the evaluation of hypoglycemia in a 72-h supervised fast test. She had baseline plasma glucose of 67 mg/dL, nonsuppressed insulin of 16.4 IU/mL, and C-peptide of 3.64 ng/mL. In the first hour after initiation, she developed Whipple’s triad symptoms, and her lab results detected plasma glucose of 38 mg/dL, insulin of 25.9 IU/mL, and C-peptide of 4.31 ng/mL. Thus, it was decided to stop the protocol and initiate 1000 mL of 20% glucose solution in 12 h.

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The mechanism of the post-BS hyperinsulinemic hypoglycemic state and the changes in beta cell proliferation are not fully understood. In the LSG, the faster transit of undigested nutrients to the distal gastrointestinal tract due to rapid gastric emptying upregulates the production of GLP-1 secreted by enteroendocrine L cells in the distal intestine. This increase can normalize blood glucose and regulate insulin synthesis and proinsulin gene expression, as well as glucagon and somatostatin secretion[3].GLP-1 has multiple beneficial effects on β cells, including an increase in their number by inhibiting apoptosis and enhancing neogenesis as well as promoting its proliferation. In a study carried out in 2016 by Xu[14], it was found that a chemically modified GLP-1 (mGLP-1) analog promotes the proliferation of pancreatic mouse β cells, upregulating the expression of cyclin E, CDK2, Bcl-2, Bax, and p21.The cyclin E-CDK2 complex plays an important role in the regulation of the G1 phase of the G1/S cell cycle, while p21 is a universal cyclin-dependent kinase (CKI) inhibitor. Meanwhile, the-andgenes, two important members of the-gene family, have opposite functions, inhibiting or promoting cell apoptosis, respectively[14].

4.4 构建传播力是武术对外教材“走出去”的必要措施传播力，实质就是实现有效传播的能力[6]。教材“走出去”的关键，实际上就是要提升自身的有效传播能力。当前，对于中国武术对外教材“走出去”战略的实现，最重要的就是构建自身的传播力，让其具备强硬的竞争实力，才能走的更加长远。

The diagnosis of hypoglycemia after BS is challenging. The first step after identifying the presence of symptoms is to verify their relationship to hypoglycemia. A detailed clinical history must be performed to identify family or personal history of neuroendocrine tumors, if patients are taking any hypoglycemic medication such as sulfonylureas or if the symptoms are more common in fasting state, as in our case.

In a stepwise manner, biochemical analysis must be performed to rule out other causes[18]. Plasma glucose, insulin, C-peptide, proinsulin, beta-hydroxybutyrate, and cortisol levels should be measured.The development of provocative studies such as a 72-h fasting test is also recommended[10,18]. The goal is to determine whether beta-cell peptides are appropriately suppressed during hypoglycemia. If autonomous insulin secretion is identified, insulinoma should be suspected[10,18]. The next step is to determine the anatomical localization and to exclude other tumors. Multidetector contrast-enhanced imaging CT or dual phase helical CT with thin sections are the preferred initial imaging options. In patients in whom noninvasive radiologic techniques are negative or to improve the sensitivity for identifying an insulinoma, endoscopic ultrasound (EUS) must be performed. EUS has 80%-92%sensitivity for detecting tumors as small as 5 mm. Additionally, EUS-guided fine needle aspiration allows pathologic confirmation in 57% of patients. If the techniques mentioned above fail to detect the tumor, selective arteriography and intra-arterial calcium stimulation tests with hepatic venous sampling can be performed. They should be used only as a last resort because they are invasive techniques[5,10].In our case, we performed CT and EUS that allowed us to identify insulinoma.

Finally, histopathologic and immunohistochemical confirmation is necessary to classify the type of tumor and to determine the patient’s follow-up[19].

The definitive treatment for insulinoma comprises complete surgical resection. However, there are other treatment options such as octreotide or EUS-guided alcohol tumor ablation, radiofrequency ablation (RFA), or embolization[20]. There is superior short-term recovery, shorter length of stay,decreased hemorrhage, and improved cosmesis when performing minimally invasive pancreatic resection compared to open pancreatic surgery[10]. However, the technique used depends on the size,extension, localization, and type of lesion. Atypical resection, including enucleation and partial or middle pancreatectomy, has the advantage of pancreatic parenchyma preservation, thereby reducing the risk of late exocrine and/or endocrine insufficiency[20]. As in the case of our patient, when the lesion was small, benign, solitary, and superficial and when the pancreatic duct was not involved, the best surgical approach was laparoscopic enucleation[21]. It is important to note that positive resection margins are not associated with increased recurrence rates[10].

CONCLUSlON

This is the first case of insulinoma after sleeve gastrectomy. Although this is a very rare case, clinicians must be aware of it, especially if the patient has hypoglycemic symptoms during the fasting state.

FOOTNOTES

Lobaton-Ginsberg M participated in the conception and design of the report and wrote the paper; Sotelo-González MP made substantial contributions to the acquisition, analysis, and interpretation of the patient data and helped write the paper; Juárez-Aguilar FG performed the histopathological and immunohistochemical report; Ramírez-Rentería C and Ferreira-Hermosillo A were involved in the coordination and design of the report and the revision of the manuscript; all authors read and approved the final manuscript.

Informed written consent was obtained from the patient for the publication of this report and any accompanying images.

The authors declare that they have no conflict of interest to disclose.

The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).

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Mexico

Miry Lobaton-Ginsberg 0000-0001-8227-087X; Pilar Sotelo-González 0000-0002-4132-5093; Claudia Ramirez-Renteria 0000-0003-3025-8339; Fany Gabriela Juárez-Aguilar 0000-0002-6204-3677; Aldo Ferreira-Hermosillo 0000-0002-5159-9856.

Chen YL

Wang TQ

Chen YL