代謝因子於胃腸道疾病之臨床意義及病態生理學研究

Abstract

背景及目的 在台灣，包括糖尿病及肥胖在內的代謝症候群的盛行率逐年上升。許多糖尿病患者常會出現胃腸併發症，包括胃食道逆流、胃輕癱、腹瀉、便祕等，常會影響患者之生活品質及血糖控制。糖尿病患者之自律神經病變，如何造成胃腸道運動功能失調及胃腸道症狀，目前仍不清楚。此外，流行病學研究發現，胃食道逆流症進展之自然史及大腸息肉的發生與代謝症候群有密切的關係。然而，其間詳細之病理生理機轉目前亦不完全明瞭。氟-18氟化葡萄糖，可蓄積於發炎部位，具有與發炎細胞代謝活性成正相關的特性，因此，氟-18氟化葡萄糖正子斷層掃描不但可以評估解剖結構上的異常，也可以同時評估局部葡萄糖代謝或是發炎的程度，似乎可以作為評估食道發炎與肥胖之間複雜關係之創新工具。因此，本研究結合臨床與基礎動物實驗，建立跨科目的研究模式，探討以糖尿病及肥胖為主之代謝因子對胃腸道臨床表現之影響，此結果將有助於釐清代謝危險因子與胃腸疾病的發生或病程進展間的關係，找出這些可能的致病途徑及中間因子並予以移除或治療，以避免嚴重之胃腸道併發症的發生。 研究對象與方法 本研究第一部分，利用台大醫院建立之完整健康檢查資料庫，藉由與一般非糖尿病族群之對照比較，分析糖尿病患者各種主觀胃腸道症狀及客觀之上下消化道內視鏡病灶之盛行率及獨特臨床表現，並進一步探討其與血糖控制狀況及各種糖尿病併發症的交互關係。本研究第二部分進一步延伸，利用健康檢查資料庫中同時接受氟-18氟化葡萄糖的全身正子斷層掃描及上消化道內視鏡檢查的個案，同步定量食道發炎程度、皮下及內臟脂肪量，據以探討肥胖、發炎與胃食道逆流症主觀症狀(問卷計分高低)及客觀食道發炎糜爛情形(洛杉磯分類)之關聯。本研究之第三部分則是前瞻性招募60名志願之健康受試者，建立起以即沖即食之大燕麥片為試驗餐包及流程簡化的胃排空時間造影術，提供運用在華人所需的正常標準值，包括排空一半所需時間，第0.5、1、2、3小時胃殘存同位素活性比例。此外，我們將此正常值應用於有上腹不適症狀，如噁心、嘔吐、打呃或餐後飽脹等之糖尿病及功能性消化不良患者，藉以評估胃排空速率。最後，我們利用第二型糖尿病的動物模式C57BLKS/J db/db小鼠，建立以樹脂珠子為基礎之固體胃排空測定方法，並配合胰島素或藥物之血糖控制，探討血糖控制與胃排空功能之關聯。 結果 本研究第一部分發現，糖尿病患者各種主觀胃腸道症狀相較於一般非糖尿病族群顯著較低 (30.3% vs. 35.4%, P = 0.006)；相反地，各種客觀之上下消化道內視鏡病灶盛行率則顯著較高，包括糜爛性食道炎 (34.3% vs. 28.6%, P = 0.002), 巴瑞特氏食道 (0.6% vs. 0.1%, P = 0.001), 消化性潰瘍 (14.8% vs. 8.5%, P < 0.001), 胃息肉 (1.8% vs. 0.7%, P = 0.003) 以及大腸息肉 (26.6% vs. 16.5%, P < 0.001)。較高的血中糖化血紅素濃度也與較少的胃腸道症狀及較多的胃腸道內視鏡異常有關。有糖尿病併發症的患者也有較高比例患有大腸息肉(39.2% vs. 24.5%, P = 0.002)。 本研究之第二部分發現，糜爛性食道炎個案的氟-18氟化葡萄糖最大標準攝入值(SUVmax)在食道上、中、下各段均顯著較高，胃或十二指腸則沒有顯著差異。巴瑞特氏食道的個案在食道中段（3.18 ± 1.06）和食道胃交界（3.95 ± 1.35）有最高的SUVmax。胃食道逆流症狀方面，胸口灼熱分項計分和逆流症狀問卷總計分與中間食道較高的SUVmax呈現正相關。利用多元逐步回歸分析，總膽固醇濃度（P = 0.003）和皮下脂肪組織（P < 0.001）與上食道括約肌較高之SUVmax值有關，而飲酒（P = 0.03）和身體質量指數（P < 0.001）與食道中段較高SUVmax相關，年齡（P = 0.027）及腰圍（P < 0.001）則與食道胃交界處較高的SUVmax相關。 本研究之第三部分發現，有症狀的患者之3小時胃殘留值顯著大於健康志願者的（3.7 ± 5.8 % vs. 2.0 ± 2.4%，P = 0.04）。有症狀的患者中，分別有4位（13%）和3位（10%）的糖尿病患者被診斷為延遲和快速胃排空；而功能性消化不良患者中有4位（13%）為延遲胃排空。此外，胃排空參數與多項胃輕癱症狀呈現正相關，此相關性在糖尿病患者中比在功能性消化不良患者中為強。年齡、性別和停經前後並無顯著影響胃排空結果。雖然身體質量指數並不影響胃排空參數，腰圍與1小時的胃殘留比例則是呈現負相關（r =-0.329，P = 0.013）。 動物研究方面，八週齡之db/db小鼠(糖尿病組)，相較於同齡之db/m小鼠(血糖正常對照組)，體重顯著較重(36.5 ± 3.2 vs. 21.5 ± 1.5 公克，P < 0.001)，空腹血糖顯著較高(388 ± 49 vs. 131 ± 14 mg/dL，P < 0.001)，胃排空速率則是顯著較快(80 ± 18 vs.48 ± 16 %，P = 0.018)。十二週齡及十六週齡之db/db小鼠胃排空速率減慢，接受胰島素及類昇醣激素胜肽類似物liraglutide之治療則觀察到胃排空速率增快。 結論 本研究發現，糖尿病及偏高的糖化血紅素值與較低的胃腸道症狀盛行率及較高的內視鏡病灶盛行率相關，這可能造成糖尿病病患之胃腸道問題被低估或忽視，進而引發更嚴重之併發症。正子斷層掃描顯示之食道發炎程度與胃食道逆流症之內視鏡表現及症狀學有關，本研究進一步證實，肥胖指標，包括身體質量指數，腰圍，內臟和皮下脂肪量與糜爛性食道炎的產生及食道發炎程度的增加有關。此外，本研究建立以即沖即食大燕麥片為試驗餐包及簡化流程之胃排空時間造影術及華人之正常標準值，將有助於未來對胃排空障礙疾病的診斷與評估。最後，本研究建立第二型糖尿病db/db小鼠之固體胃排空測定方法，此動物模式方便可行，未來將可廣泛應用於探討代謝因子與自律神經病變之因果關聯性及相關機制。

Background and objective Metabolic syndrome, especially diabetes mellitus (DM) and obesity, has been associated a myriad of gastrointestinal (GI) complications, including gastroesophageal reflux disease (GERD), gastroparesis, constipation and diarrhea. The pathogenesis of GI complications in patients with metabolic derangement is complex and multi-factorial. Epidemiological studies have shown a close relationship between obesity and GERD-related complications. 18F-Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) assesses not only anatomical structures, but also the degree of local glucose metabolism and provides us a unique opportunity to explore the complex relationship of GERD, esophageal inflammation and obesity. With the integrated approaches with both clinical and animal studies, we aim to investigate the clinical implication and underlying pathophysiology of metabolic factors of the various GI diseases. Materials and methods First, we analyzed the prevalence and severity of GI symptoms and endoscopic findings in diabetic subjects from a general population undergoing upper endoscopy/colonoscopy as part of a medical examination at the National Taiwan University Hospital. Second, we studied 458 subjects who underwent both an upper gastrointestinal endoscopy and FDG PET/CT during health check-ups. GERD symptoms were evaluated with Reflux Disease Questionnaire. Inflammatory activity, represented by standardized uptake values (SUVmax) of FDG at pre-determined locations of esophagus, stomach and duodenum, were compared. Third, to establish normal oatmeal-based gastric emptying scintigraphy reference values and test its correlation with gastroparesis symptoms in the Chinese population, we prospectively enrolled 60 healthy volunteers and 60 symptomatic patients (30 functional dyspepsia and 30 diabetes patients with gastroparesis symptoms). All participants were evaluated using the Gastroparesis Cardinal Symptom Index. Finally, we established the solid gastric emptying measurement with “beads method” in murine models of type 2 DM, C57BLKS/J db/db mice. We investigated the effect of glycemic control with insulin and GLP-1 analogue treatment on the gastric emptying of db/db mice.. Results In the first part, among the 7770 study subjects, 722 (9.3%) were diagnosed with DM. The overall prevalence of GI symptoms was lower in DM subjects (30.3% vs. 35.4%, P = 0.006). In contrast, the prevalence of erosive esophagitis, Barrett’s esophagus, peptic ulcer disease, gastric neoplasms, and colonic neoplasms were higher in diabetic subjects. Higher HbA1c levels were associated with a decrease of GI symptoms and an increase of endoscopic abnormalities. Second, subjects with erosive esophagitis on endoscopy had significantly higher SUVmax at esophagus, but not in stomach or duodenum. The severity of erosive esophagitis correlated with SUVmax and subjects with Barrett’s esophagus had the highest SUVmax at middle esophagus and esophagogastric junction. Heartburn positively correlated with higher SUVmax at middle esophagus. Using multivariate regression analyses, age, total cholesterol level, alcohol drinking, subcutaneous adipose tissue, BMI and waist circumference were independently associated with higher SUVmax at respective esophageal locations. Third, all participants finished the oatmeal-based test meal and tolerated the scintigraphy procedure well. All gastric emptying parameters were not significantly affected by age or gender. Waist circumference inversely correlated with gastric retention at 1 h. There were 4 (13.3%) diabetic patients found to have delayed emptying and 3 patients (10%) found to have rapid emptying, respectively. Gastric emptying parameters correlated best with vomiting severity in diabetic patients. For the animal studies, body weight (36.5 ± 3.2 vs. 21.5 ± 1.5 gm，P < 0.001) and fasting blood glucose (388 ± 49 vs. 131 ± 14 mg/dL，P < 0.001) were significantly higher in db/db mice than in db/m mice of the same age of 8 weeks. Solid gastric emptying measured with beads method was also faster in the db/db group (80 ± 18 vs. 48 ± 16 %，P = 0.018). Gastric emptying was slower in db/db mice of 12 and 16 weeks of age, while treatment with insulin or liraglutide accelerated the gastric emptying. Conclusion In conclusion, the present study shows that DM and higher levels of HbA1c are associated with lower prevalence of GI symptoms but higher prevalence of endoscopic abnormalities. Esophageal inflammation demonstrated by FDG PET/CT correlates with endoscopic findings and symptomatology of GERD. Obesity markers, both visceral and general, are independent determinants of esophageal inflammation. Furthermore, we established normal values of a simplified oatmeal-based gastric emptying scintigraphy and observe good correlation with various gastroparesis symptoms in the Chinese population. Finally, our animal model of measuring solid gastric emptying in db/db mice may be applied to further studies and may help to clarify the temporal relationship between metabolic factors and autonomic neuropathy in GI motility disorders.