| Small bowel bleeding(SBB),also known as middle gastrointestinal bleeding,refers to bleeding between duodenal papilla and ileocecal valve,which accounts for 5%-10%of clinical gastrointestinal bleeding.Because of the special anatomy,bleeding in this part has always been the focus and difficulty of gastroenterology department.The most common cause of small bowel bleeding is small bowel angioectasias(SBA),accounting for about 50%,which is also the leading cause of gastrointestinal bleeding in patients over 40 years of age.Clinical manifestations of SB A can be either melena,hematochezia,positive fecal occult blood,and even massive bleeding that require emergency endoscopic intervention.Patients often need long-term iron supplementation and blood transfusion,which seriously affect and threaten the quality of life and life safety of patients,and increase the pressure on medical and health resources,especially the precious blood resources.The overall mortality from SBA bleeding has been reported to be up to 3.5%.Because of the harm and complexity of the clinical manifestations of SBA,it is important to analyze the clinical characteristics of SBA to improve the understanding of the disease and the efficiency of diagnosis and treatment.The pathogenesis of small bowel angioectasias has not been elucidated.The mechanical theory suggests that enhanced intestinal wall muscle contraction leads to chronic and intermittent obstruction of intestinal mucosa and submucosal blood vessels,precapillary sphincter failure,and constant vascular dilation.According to the angiogenesis theory,chronic ischemia,hypoxia and other factors destroy the balance between pro-angiogenesis factors and angiogenesis inhibitors,and the PI3K/AKT/mTOR and the ANG/TIE2 signaling pathways may play an important role in the occurrence and development of SBA.As more and more small bowel angioectasias has been diagnosed,the treatment of SBA has become an urgent clinical problem to be solved.At present,various clinical treatment methods are not satisfactory.It has become an urgent clinical need to find drugs to treat and prevent SBA bleeding.Studies have shown that abnormal activation of PI3K/AKT/mTOR signaling pathway plays an important role in small bowel angioectasias.Sirolimus is an mTOR inhibitor,and thus has a pharmacological effect of treating small bowel angioectasias by inhibiting PI3K/AKT/mTOR signaling pathway.Current studies have confirmed that sirolimus has an inhibitory effect on abnormal angiogenesis in various tissues and organs such as skin,cornea and tumor,but there is no research on the treatment of bleeding from small bowel angioectasias.This study is carried out in the following three aspects:the clinical features of small bowel angioectasias and the expression levels of peripheral blood angiogenesis factors were analyzed;The efficacy and safety of sirolimus in the treatment of bleeding from small bowel angioectasias were preliminarily explored through elf-controlled study,and the molecular mechanism of sirolimus in the treatment of bleeding from small bowel angioectasias were preliminary analyzed.1.Analysis of the clinical characteristics of small bowel hemorrhage caused by small bowel angioectasias and the expression levels of serum VEGF,HIF-1α,ANG-1 and ANG-2This study collected 121 patients who underwent capsule endoscopy or double-balloon enteroscopy because of suspected small bowel bleeding(gastrointestinal bleeding whose cause remained still unknown after gastroscopy and colonoscopy)at the Gastroenterology Department of the Air Force Medical Center from January 2021 to December 2022.After inclusion and exclusion criteria,101 patients were finally enrolled.According to the etiology of bleeding,the patients were divided into two groups:small bowel angioectasias group(SBA group)and other causes group(control group).The clinical characteristics of small bowel angioectasias were analyzed.The serum levels of hypoxia inducible factor1α(HIF-1α),angiopoietin-1(ANG-1),angiopoietin-2(ANG-2)and vascular endothelial growth factor(VEGF)in peripheral venous blood were compared between the two groups.This study was approved by the Ethics Committee of Air Force Medical Center.The results showed that small bowel angioectasias accounted for 36.63%(37/101)of the etiology of small intestinal bleeding.Among the 37 patients with SBA,there were 16 males and 21 females,with an average age of(67.95±11.10)years,ranged from 39 to 85 years of age.There was no significant difference between male and female prevalence(P=0.411).Compared with patients ≤60 years old(n=10),the prevalence of patients>60 years old(n=27)was significantly higher(P=0.005).The mean hemoglobin was(78.44± 19.83)g/L.The median course of disease was 11(0.4,192)months.Among the patients with SBA,16 cases(43.24%)had hypertension,9 cases(24.32%)had valvular heart disease,8 cases(21.62%)had chronic obstructive pulmonary disease,7 cases(18.92%)had diabetes mellitus,7 cases(18.92%)had coronary heart disease,6 cases(16.22%)had atrial fibrillation,4 cases(10.81%)had chronic kidney disease,and 4 cases(10.81%)had aortic stenosis.Multiple small bowel angioectasias occurred in 26 patients(70.27%),and single lesion were found in 11 patients(29.73%).The incidence of multiple lesions was significantly higher than that of single lesion(P=0.014).Twenty-two cases(59.46%)were confined to jejunum,9 cases(24.32%)were confined to ileum,and 6 cases(16.22%)were involved in both jejunum and ileum.The detection rate of SBA in jejunum was highest(75.68%).Of the 37 patients with SB A,2(5.41%)had occult bleeding(iron deficiency anemia with positive fecal occult blood);and 35 cases(94.59%)had overt bleeding,including 31 cases(83.78%)of melena and 4 cases(10.81%)of hematochezia.The incidence of melena was significantly higher than that of(hematochezia and occult hemorrhage)(P<0.001).In the course of the disease,4 of the 37 patients(10.81%)had hemodynamic instability due to short-term heavy bleeding.Thirty-four patients(91.89%)needed long-term or intermittent iron supplementation,and 32 patients(86.49%)needed blood transfusion during the course of the disease.There were 4 patients who underwent endoscopic Argon plasma coagulation(APC),2 patients who underwent surgical treatment,2 patients who underwent vascular embolization and 2 patients who underwent thalidomide treatment still experienced recurrent bleeding after the treatment,respectively.Compared with the control group,the age of patients in SBA group was significantly higher(P<0.001);mean hemoglobin levels were significantly lower(P=0.001);the prevalence of valvular heart disease(P=0.001),aortic stenosis(P=0.031),atrial fibrillation(P=0.004)and chronic obstructive pulmonary disease(P=0.002)were significantly increased;the rate of anticoagulant/antiplatelet drugs use(P<0.001)was significantly higher;and serum HIF-1α and ANG-2 concentrations were significantly increased(P<0.001 and P<0.001).The above results showed that SBA accounted for 36.63%of the etiology of small bowel bleeding in this study.It is mainly seen in patients in middle-aged and elderly patients over 60 years old,with no gender difference in incidence.The prevalence of valvular heart disease,aortic stenosis,atrial fibrillation,chronic obstructive pulmonary disease is higher in SBA patients.SBA lesions mainly located in jejunum,and the incidence of multiple lesions are higher than that of single lesion.The most common form of bleeding with small bowel angioectasias is melena but it can also present occult or hematochezia or even short-term heavy bleeding that leads to hemodynamic instability.Small bowel angioectasias is a great hazard to the health and life safety of patients that patients often need long-term iron supplementation and blood transfusion.Recurrent bleeding can occur even after endoscopic APC,vascular embolization or surgical treatment.HIF-1αand ANG-2 may be involved in the occurrence and development of small bowel angioectasias.2.Preliminary study on the efficacy and safety of sirolimus in the treatment of bleeding from small bowel angioectasiasIn this part,we mainly explore the preliminary efficacy and safety of sirolimus in the treatment of bleeding from small bowel angioectasias.A total of 9 patients diagnosed with SBA and treated with oral sirolimus in the gastroenterology Department of Air Force Medical Center from March 2021 to December 2022 were collected.The total clinical score of clinical symptoms,average number of bleeding episodes,average volume of blood transfusion and mean haemoglobin concentration in patients with gastrointestinal bleeding from small bowel angioectasias were compared before and after sirolimus treatment,and the complications were analyzed.This study was approved by the Ethics Committee of Air Force Medical Center[(Scientific Research)No.2021-97-PJ01].All subjects had signed informed consent.A total of 9 patients were recruited,including 3 males and 6 females,with an average age of 58.0 ±11.2(39,73)years.The median course of the disease was 26(0.5,168)months,and the mean follow-up was 9.86 12.97(6,14)months.The therapeutic effect could be seen after taking sirolimus for 3 months:the mean total score of clinical symptoms was significantly lower(5.78 ± 4.41 vs.11.89 ± 3.79,P=0.002);the number of bleeding episodes was significantly decreased[1.33 ± 1.12 vs.2(1,4)times,P=0.020];median blood transfusion volume was significantly decreased[0(0,1200)ml vs.800(200,5000)ml,P=0.027],and the mean haemoglobin concentration was significantly increased(105.63±12.27g/L vs.76.82±16.26g/L,P=0.003).The mean total score of clinical symptoms,mean number of bleeding episodes,median blood transfusion volume and average haemoglobin level were still significantly improved after 6 months of medication compared with the same period before taking sirolimus.Six patients(66.7%)had side effects after taking sirolimus orally,among whom four(44.4%)had oral ulcers,two(22.2%)had mild abdominal discomfort with increased stool frequency,one(11.1%)had scattered rash of trunk and one(11.1%)developed mild to moderate serum Triglyceride elevation.The side effects of the drug were generally mild and self-limited,most of which disappeared or were apparently alleviated within 1 week to 1 month without additional treatment.The above results indicated that oral sirolimus is effective in the treatment of bleeding from small bowel angioectasias,which can reduce the total clinical symptom score,increase haemoglobin concentration,decrease the number of bleeding episodes and blood transfusion dependence in patients with gastrointestinal bleeding from small bowel angiodysplasias.Most side effects are mild,including oral ulcers,rashes,slight abdominal discomfort,increased stool frequency,hyperlipidemia,etc.3.Preliminary molecular mechanism of sirolimus in the treatment of bleeding from small bowel angioectasiasFive patients who participated in oral sirolimus clinical trial from March 2021 to December 2022 in gastroenterology Department of Air Force Medical Center and had complete serum angiogenesis factor data(before the treatment,3 months after and 6 months after taking sirolimus)were enrolled.Serum concentrations of VEGF,HIF-1α,ANG-1 and ANG-2 were compared after 3 and 6 months of treatment with those before treatment,respectively.This study was approved by the Ethics Committee of the Air Force Medical Center.The results showed that serum ANG-2 concentration decreased significantly after 3 months(P=0.034),and after taking the medicine for 6 months,it decreased but there was no significant difference after 6 months compared with that before the treatment.After 3 months and 6 months,the level of HIF-1α,ANG-1 and VEGF decreased but there were no significant differences observed.These findings suggest that oral sirolimus may play a therapeutic role in the treatment of bleeding from small bowel angioectasias via reducing HIF-1α/VEGF and ANG-2 expression. |
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