慢性胰腺炎研究进展

慢性胰腺炎以胰腺慢性纤维化、钙化、胰管慢性炎症和胰管结石为主要病理改变,其发病率在国内外有逐年升高的趋势.虽然内镜治疗技术的飞速发展、胰酶替代药物的广泛应用、影像学和实验室技术的发展使慢性胰腺炎的内科诊断和治疗措施有了较大的进展。但确切的病因和发病机制尚不清楚,其诊断和治疗也尚未达成共识.因此,迫切需要开展慢性胰腺炎的流行病学、病因学、诊断学和治疗学等相关基础与,临床研究,为慢性胰腺炎的诊治提供理论和实践依据,并尽快制定出科学、客观的慢性胰腺炎诊治规范,指导其诊断和治疗.     

Serum cytokine profiles in patients with pancreatic cancer and chronic pancreatitis

BackgroundChronic pancreatitis (CP) may cause tumor-like lesions, creating a challenge in distinguishing between CP and pancreatic ductal adenocarcinoma (PDAC) in a patient. Given that invasive surgery is a standard cancer treatment, we aimed to examine whether a noninvasive diagnostic tool utilizing serum cytokines could safely differentiate between PDAC and CP.MethodsA pre-operative serum panel comprising 48 inflammatory cytokines, CA19-9, and C-reactive protein (CRP) was analyzed, consisting of 231 patients, 186 with stage I–III PDAC and 45 with CP. We excluded PDAC patients who underwent neoadjuvant therapy and those CP patients with other active malignancies. The laboratory variables most associated with PDAC diagnosis were assessed using logistic regression and selected using the lasso method.ResultsThe cytokines CTACK, GRO-α, and β-NGF were selected alongside CA19-9 and CRP for our differential diagnostic model. The area under the curve (AUC) for our differential diagnostic model was 0.809 (95% confidence interval [CI] 0.738–0.880), compared with 0.791 (95% CI 0.728–0.854) for CA19-9 alone (not significant).ConclusionsWe found that inflammatory cytokines CTACK, GRO-α, and β-NGF alongside CA19-9 and CRP may help distinguish PDAC from CP.     

类风湿关节炎患者血清滑液和滑膜组织白细胞介素-18的水平及意义

目的 研究类风湿关节炎（RA）患者血清、滑液中白细胞介素－18（IL－18）蛋白及滑膜组织IL－18mRNA表达水平，探讨其在RA致病中的作用。方法 应用双抗夹心酶免疫吸附（ELISA）法和细胞生物法分别测定RA患者血清、滑液中IL－28蛋白水平和生物活性，同时还检测NO、前列腺素E2的含量；有用半定量RT－PCR法检测膜组织IL－18m RNAG表达水平。以骨关节炎（OA）病人及因外伤截肢的正常人作对照。结果 RA患者血清、滑液中IL－18蛋白水平和生物活性均显著高于对照组，滑液中量及活化性比血清高；RA滑膜组织IL－18mRNA表达水平也明显高于对照组。结论 过度表达的IL－18参与了RA的致病过程,；选择性地抑制IL－18生物活性，将是RA治疗的新途径。     

Significant elevation of serum interleukin-18 levels in patients with acute pancreatitis

Background We have reported that peripheral lymphocyte reduction due to apoptosis is linked to the development of subsequent infectious complications in patients with severe acute pancreatitis and that Th1 (helper T cell type 1)/Th2 (helper T cell type 2) balance tends to cause Th1 suppression in experimental severe acute pancreatitis. It has been reported that interleukin (IL)-18 is a cytokine produced from Kupffer cells and activated macrophages, and that IL-18 acts on Th1 cells and in combination with IL-12 strongly induces production of interferon-γ. However, the role of IL-18 in acute pancreatitis has not yet been fully understood. Methods Serum IL-18 concentrations were determined by an enzyme-linked immunosorbent assay in 43 patients with acute pancreatitis at the time of admission. The relationships with etiology, pancreatic necrosis, severity, blood biochemical parameters on admission, infection, and organ dysfunction during the clinical course and prognosis were analyzed. Results Serum IL-18 levels in patients with acute pancreatitis (656 ± 11pg/ml) were significantly higher than those in healthy volunteers (126 ± pg/ml). Serum IL-18 levels were significantly positively correlated with the Ranson score and Japanese severity score. Among the blood biochemical parameters on admission, base excess and total protein were significantly negatively correlated with serum IL-18 levels. Moreover, the CD4/CD8 rate of lymphocytes, serum IL-6 levels, and serum IL-8 levels were significantly positively correlated with serum IL-18 levels. On day 7 after admission, the CD4/CD8 rate of lymphocytes and the rate of CD4-positive lymphocytes were significantly positively correlated with serum IL-18 levels. Furthermore, serum IL-18 levels in patients with hepatic dysfunction (980 ± 25pg/ml) were significantly higher than those without hepatic dysfunction (464 ± 8pg/ml). Serum IL-18 levels were not related to infection or prognosis. Elevation of serum IL-18 levels continued during 4 weeks after admission. Conclusions These results suggest that serum IL-18 levels are significantly elevated and are correlated with severity in patients with acute pancreatitis and that IL-18 may be closely related to helper T cell response and hepatic dysfunction in this disease.     

Zinc deficiency in patients with chronic pancreatitis

BACKGROUND Zinc is a key element in numerous proteins and plays an important role in essential cell functions such as defense against free radicals and DNA damage repair. Chronic pancreatitis(CP) is a chronic inflammation with progressive fibrosis of pancreas ultimately resulting in pancreatic exocrine insufficiency(PEI),which is associated with malnutrition. Studies analyzing zinc levels in patients with CP are sparse and lead to conflicting results.AIM To investigate serum zinc levels in patients with CP of various etiologies.METHODS Between October 2015 and March 2018, patients with a diagnosis of CP were identified and recruited from the Pancreatic Outpatient Clinic at the Karolinska University Hospital in Stockholm, Sweden. Demographic, clinical and laboratory data were analyzed. Etiology of CP was determined according to the MANNHEIM classification system into the following etiological subcategories:alcohol consumption, nicotine consumption, hereditary factors, efferent pancreatic duct factors and immunological factors. Pancreatic exocrine function was defined as normal(fecal elastase 1 > 200 μg/g), mildly reduced(100-200μg/g) and severely reduced(fecal elastase 1 < 100 μg/g).RESULTS A total of 150 patients were included in the analysis. Zinc deficiency(< 11μmol/L) was present in 39(26.0%) of patients: 22 females and 17 males. In the group of patients with zinc deficiency, 76.7% of patients had an exocrine pancreatic insufficiency(FE-1 < 200 μg/g). Older age was significantly associated with low zinc levels. Following a univariate analysis, patients aged 60-69 and patients ≥ 70 years of age had a significantly higher prevalence of zinc deficiencies compared to patients < 40 years of age [OR: 3.8, 95%CI(1.08-13.4); P= 0.04]; [OR 6.26, 95%CI(1.94-20.2), P > 0.002]. Smoking and number of packyears were additionally associated with low zinc levels. The risk of zinc deficiency in current smokers and smokers with ≥ 20 pack-years was approximately three times higher compared to those who had never smoked.Gender, body mass index, etiology of CP, presence of diabetes mellitus, levels of glycated hemoglobin(HbA1 c), bone mineral density, alcohol intake and presence of PEI were not associated with low zinc levels.CONCLUSION Zinc deficiency is common in patients with CP and is significantly associated with age ≥ 60, smoking and the number of pack-years, but not with PEI.     

胰管内支架治疗慢性胰腺炎

目的 探讨胰管内支架引流术治疗慢性胰腺炎的临床疗效。方法 对１４例临床及影像学检查确诊的慢性胰腺炎伴胰管狭窄患者在内镜下进行了胰管内支架引流术,并对术后腹痛缓解率、胃纳、脂肪泻、体重变化及并发症发生率作了近期及远期了随访观察。结果 １４例患者均在内镜下内支架一次性置入成功,支架规格为５～１０Ｆ,术后随访２８～５２０ｄ,平均２１０ｄ,１４例患者术后近期（〈３个月）腹痛缓解率为９２．９％（１３／１４）     

Pancreatic volume does not correlate with histologic fibrosis in adult patients with recurrent acute and chronic pancreatitis

ObjectivesReduced pancreatic volume, often referred to as atrophy, is a commonly reported imaging feature of chronic pancreatitis (CP). This study evaluated whether there is an association between pancreatic volume and fibrosis, the criterion standard of CP, in patients undergoing total pancreatectomy with islet autotransplantation (TPIAT) for recurrent acute pancreatitis (RAP) and CP.MethodsAll adult patients who underwent TPIAT between 2010 and 2019 were categorized into 3 groups: RAP, definite CP and indeterminate CP. Pancreatic volume was calculated by summing up the areas from each thin section of the pancreas on 3D CT imaging. Excisional biopsies of the pancreatic head as well as body/tail region were obtained at the time of TPIAT. Two different fibrosis scores were used for histologic assessment.ResultsA total of 16, 29 and 15 patients underwent TPIAT for RAP, definite CP and indeterminate CP, respectively. The mean pancreatic volumes for patients with RAP, definite CP and indeterminate CP were 65.7 ± 28.5 cc, 54.9 ± 22.9 cc and 61.8 ± 23.6 cc, respectively (p = 0.3). The mean fibrosis scores were significantly higher in patients with definite CP compared to RAP (p < 0.001) and indeterminate CP (p < 0.001). Pancreatic volume was not associated with either fibrosis score after adjusting for age, gender, duration of disease, BMI and diabetes in the multivariable analysis.ConclusionsWhile the fibrosis scores were higher in definite CP compared to both RAP and indeterminate CP, there was no correlation between pancreatic volume and fibrosis. This suggests that atrophy alone cannot be used to diagnose CP.     

Enhanced lipoperoxidation products in pure pancreatic juice: evidence for organ-specific oxidative stress in chronic pancreatitis

Background. Oxygen-free radicals can play a role in the development of chronic pancreatitis, altering the redox state with damage of cell constituents and decrease in antioxidant defences.

Aims. To measure levels of lipoperoxidation products, conjugated dienes and lipid hydroperoxides, in pure pancreatic juice and serum of chronic pancreatitis patients and compare them to that in controls. To investigate a possible correlation with serum indexes of pancreatic inflammation (amylase and lipase).

Patients. Pancreatic juice was collected during ERCP, after secretin stimulation, in 20 patients with chronic pancreatitis and 11 controls with biliary diseases.

Methods. Lipid hydroperoxide levels were determined with FOX2 method and measured as absorbance at 560 nm. Conjugated diene levels were measured using second-derivative spectroscopy.

Results. No substantial difference was present in serum levels of lipid hydroperoxides, conjugated dienes (in both isomeric forms) and isomer-ratio values between those of patients with chronic pancreatitis and controls.

In pancreatic juice, there was a significant increase in lipid hydroperoxides and conjugated dienes levels (especially trans–trans isomers) in chronic pancreatitis patients compared with controls, with a decrease in cis–trans isomers and a significant difference in isomer-ratio values.

Conclusions. Increased levels of lipid hydroperoxides and conjugated dienes in the pancreatic juice of chronic pancreatitis patients is indicative of an enhanced lipoperoxidation and antioxidants consumption in pancreatic tissue, confirmed by the decreased isomer-ratio values as an indirect index of decreased antioxidant capacity. The lack of significant difference in conjugated diene and lipid hydroperoxide levels in the serum of chronic pancreatitis patients versus that of controls suggests an oxidative stress limited to pancreatic tissue and indicative of an organ-specific pathology, confirmed by the parallel behaviour of oxidative parameters (lipid hydroperoxides and conjugated dienes) and indexes of pancreatic inflammation (amylase and lipase).     

Pharmacological management of pain in chronic pancreatitis

Pain is the major presenting symptom of chronic pancreatitis. Patients with chronic pancreatitis experience substantial impairments in health-related quality of life. Pain may be considered as the most important factor affecting the quality of life. The pathogenesis of pancreatic pain is poorly understood. The cause of pain in chronic pancreatitis is probably multifactorial. This article discusses the various hypotheses that have been suggested to underlie pain. Special attention is paid to the concept of autonomous central sensitisation and hyperalgesia as a cause of pain. Strict abstinence from alcohol is the first step of chronic pancreatic pain management. As a second step, it is important to exclude treatable complications of chronic pancreatitis, such as pseudocysts. Symptomatic treatment with analgesics is often unavoidable in patients with chronic pancreatitis. Acetaminophen, non-steroidal anti-inflammatory drugs and eventually opioids are suitable. Several trials have been performed with pancreatic enzymes, but a meta-analysis demonstrated no significant benefit in terms of pain relief. The treatment of chronic pancreatic pain requires a multidisciplinary approach that tailors the various therapeutic options to meet the need of the individual patient.     

狼疮肾炎患者肾组织白细胞介素-18表达的研究

目的　初步探讨白细胞介素 18(IL 18)在人类狼疮肾炎 (LN)肾组织炎症损伤中的作用。方法　应用免疫组织化学和原位杂交技术观察 6例正常肾组织和 18例LN患者肾组织IL 18的蛋白和基因表达量 ,并用酶联免疫吸附测定 (ELISA)法对该组患者尿IL 18水平进行检测。结果　正常肾组织有弱的IL 18mRNA及蛋白表达 ;LN患者肾组织IL 18mRNA及蛋白表达量均较正常肾组织显著增高 (IL 18mRNA :8 9± 3 4比 2 2± 0 6 ;IL 18蛋白 :8 8± 3 7比 1 4± 0 4 ) ,而且WHOⅣ型LN患者肾组织IL 18表达量显著高于非WHOⅣ型LN患者 (IL 18mRNA :10 8± 3 2比6 6± 1 7;IL 18蛋白 :11 2± 2 7比 5 6± 2 0 ) ;Spearman相关分析提示肾组织IL 18蛋白表达量与狼疮肾炎肾组织活动指数 (AI)、尿IL 18水平及肾组织损伤程度均呈正相关 (P均 <0 0 5 )。结论　肾内IL 18表达上调参与LN肾组织炎症损伤过程 ,尿IL 18水平可能作为衡量LN肾组织炎症活动程度的评估指标。     

内镜下诊治伴发胰管结石慢性胰腺炎的价值

目的探讨ERCP在胰管结石诊断和治疗中的临床价值及其安全性评估。方法分析2008年2月～2008年10月期间共20例接受ERCP诊断和治疗的伴发胰腺结石慢性胰腺炎患者的临床资料。结果20例病例中,16例（80％）胰管结石位于胰头处,3例（15％）位于胰头及胰体处,1例（5％）累及全程胰管。14例（70％）患者一次性取石完全,5例患者术后接受体外震波碎石（ESWL）,1例患者未能完成取石,建议其外科手术治疗．18例表现为腹痛的病例,在接受内镜下治疗结石后,腹痛症状均消失,在接受治疗后2～10d内出院,平均（5．3±2．43）d。术后2例（10％）出现一过性的血淀粉酶升高。结论对于伴有胰管结石的慢性胰腺炎病例而青,内镜下取石是安全有效的方法,同时应川支架及鼻胰管引流,不仅对胰管结石的治疗有效,而且充分的胰液引流对于缓解腹痛症状、减少术后的胰腺炎、高淀粉酶m症的发乍有着重要的作用。     

Surgical decompression of Wirsung duct reduces serum concentration of SPINK1 in patients with chronic pancreatitis

Objectives

The primary aim of this study was to determine the blood levels of SPINK1 in patients with chronic pancreatitis (CP) submitted to surgical or endoscopic decompression of pancreatic duct (PD). Additionally, we measured trypsin activity levels.

Corticosteroids prevent the progression of autoimmune pancreatitis to chronic pancreatitis

Background/objectivesPatients with autoimmune pancreatitis (AIP) sometimes progress to chronic pancreatitis (CP). We evaluated the ability of corticosteroids to prevent the progression to CP.MethodsWe defined patients with definitive findings of CP (stones in the main pancreatic duct [MPD] or multiple pancreatic calcifications) as having severe calcification (SC). A total of 145 AIP patients were enrolled. We measured the duration between AIP diagnosis and SC development and retrospectively compared the time to SC development between patients with and without steroids. Multivariate analysis for factors associated with SC were performed.ResultsNineteen (13%) patients progressed to SC. Since 95 patients had pancreatic head swelling and SC was found in these patients only, our analysis focused mainly on these at-risk populations. In Kaplan-Meier analysis limited to patients with pancreatic head swelling, the incidence of SC was significantly lower in patients with steroids than in those without (hazard ratio [HR] 0.18, 95% confidence interval [CI] 0.07–0.52; p < 0.001). Multivariate testing of patients with pancreatic head swelling confirmed that steroid therapy was significantly associated with a lower incidence of SC (HR 0.11, 95% CI 0.03–0.34; p < 0.001), while MPD dilation at AIP diagnosis was related to a higher incidence of SC (HR 4.02, 95% CI 1.43–11.7; p = 0.009).ConclusionsCorticosteroids appeared to prevent progression to CP in AIP patients, especially in those with pancreatic head swelling. Patients with both pancreatic head swelling and MPD dilation at diagnosis have a higher incidence of progression to CP. Steroid therapy is suggested for these high-risk cases.     

Pressure of papillary sphincter zone and pancreatic main duct in patients with alcoholic and idiopathic chronic pancreatitis

Summary To determine the significance of manometric pressure of the pancreatic duct in patients with alcoholic and idiopathic chronic pancreatitis, we used a microtransducer inserted through a duodenoscope to measure pressures in the papillary sphincter zone and pancreatic main duct in 20 control subjects and 31 patients with chronic pancreatitis without papillary stenosis including 10 cases of alcoholic chronic pancreatitis (ALCP) and 21 cases of idiopathic chronic pancreatitis (ICP). The pancreatic main ductal pressure was significantly higher in the patients with ALCP (55.7±28.9 mm Hg) or ICP (44.5±25.8 mm Hg) than in the controls (16.2±8.7 mm Hg), but there was no significant difference between ALCP and ICP. There was no significant difference between control subjects and ICP in the motility of the sphincter of Oddi. In ICP there no were correlationships between pancreatic ductal pressure and the motility of papillary sphincter zone. In ALCP, the frequency of the papillary sphincter waves was significantly higher than in normal subjects and there was a correlation between the pancreatic ductal pressure and the motility of the papillary sphincter zone. These data suggest that increased pancreatic ductal pressure in ALCP may be in part due to papillary dysfunction, but not in ICP.     

Morphological advantages of endoscopic treatment in obstructive chronic pancreatitis

Backgroundand study aims: Chronic pancreatitis is associated with recurrent or persistent abdominal pain over the course of the disease. Ductal hypertension showing obstructed and dilated pancreatic duct has been suggested as a major factor in the mechanism of pain in chronic pancreatitis. Many studies investigating pain relief after endoscopic treatment of pancreatic duct (PD) are available, but the number of studies regarding the morphological changes to pancreas such as changes in PD caliber, pancreatic parenchyma, and especially pancreatic volume is far fewer. As such, we analyzed the changes of ductal caliber and parenchymal volume after endoscopic treatment of PD in patients with obstructive chronic pancreatitis.Patients and methodsIn this retrospective study, we compared two groups of patients with obstructive chronic pancreatitis that either received endoscopic management of PD or conservative treatment without such endoscopic management. After we obtained age, sex, etiology of chronic pancreatitis, diabetic status, smoking and alcohol abuse status from the database, we compared the incidence for changes in pancreatic parenchymal volume and PD caliber between two groups.ResultIn our study population, total of 480 patients was diagnosed with chronic pancreatitis between January 2006 and December 2016, and 166 (34.5%) of these patients were diagnosed with obstructive chronic pancreatitis with obstructed and dilated PD. After reviewing the population with the exclusion criteria, 71 patients were available for the final analysis. 28 of those patient received endoscopic treatment of pancreatic duct and 43 received conservative treatment without any endoscopic treatment of PD. Statistical analysis with Cox proportional hazards models showed that diabetes and endoscopic PD management were significant predictors for progression of PD caliber and in pancreatic parenchyma, and that only PD management influenced the pancreatic volume loss.ConclusionEndoscopic management of PD in obstructive chronic pancreatitis have advantages on morphologic change such as pancreatic volume loss and progression of PD caliber in long follow-up period.     

Pancreatic cancer after surgery for chronic pancreatitis

BACKGROUND: Chronic pancreatitis is known to be a risk factor for pancreatic cancer. AIMS: To identify patients who were diagnosed with pancreatic cancer after undergoing surgery for histologically documented chronic pancreatitis. PATIENTS/METHODS: Records of 484 consecutive patients who underwent surgery for chronic pancreatitis from 1976 to 1997 were reviewed. RESULTS: Pancreatic cancer was diagnosed after a mean of 3.4 years (range: 2 months-1 years) in 14 patients (2.9%). In four patients, pancreatic cancer became evident within 12 months of surgery for chronic pancreatitis, suggesting cancer was present at the original surgery. Cancer presented with recurrent or persistent pain, jaundice, and/or weight loss. Pancreatic resection was possible in eight patients, but in the others, the cancer was inoperable. There was one long-term survivor (alive 14 years postoperatively), but for theothers mean survival was 10 months (16 months after resection vs. 4 months for inoperable cancer). CONCLUSION: Pancreatic malignancy should be suspected in patients who have had surgery for chronic pancreatitis when symptoms (such as recurrent pain, jaundice, weight loss, or anorexia) recur. Attempts at curative pancreatic resection are indicated and can offer palliation and the potential for a cure.     

Incidence of and risk factors for pancreatic cancer in chronic pancreatitis: A cohort of 1656 patients

BackgroundRisk of pancreatic cancer may increase in chronic pancreatitis patients.AimsThis study aimed to identify the incidence of and risk factors for pancreatic cancer in chronic pancreatitis patients.MethodsChronic pancreatitis patients admitted to our center from January 2000 to December 2013 were enrolled. Cumulative rates of pancreatic cancer and survival rates were calculated. The standardized incidence ratio was calculated based on the pancreatic cancer incidence in general population of China. Risk factors for pancreatic cancer were identified.ResultsIn a total of 1656 patients, the median follow-up duration was 8.0 years. Pancreatic cancer was detected in 21 patients (1.3%). The expected number of cases of pancreatic cancer was 1.039, yielding a standardized incidence ratio of 20.22. The standardized incidence ratios for patients with a >60 pack-year smoking history were much higher (145.82). Two risk factors for pancreatic cancer were identified: age at the onset of chronic pancreatitis (hazard ratio, 1.05) and a >60 pack-year smoking history (hazard ratio, 11.83).ConclusionThe risk of pancreatic cancer is markedly increased in chronic pancreatitis patients compared with the general population, especially in patients with an older age at onset and a >60 pack-year smoking history. The high-risk populations were suggested to be followed up closely.     

胰管内支架治疗慢性胰腺炎18例临床分析

目的　探讨慢性胰腺炎胰管内支架治疗的临床疗效。方法　取沈阳军区总医院 2 0 0 2 - 0 7～ 2 0 0 4 -17经临床、化验及检查明确诊断为慢性胰腺炎的 18例患者 ,分别接受胰管内支架治疗 ,术后观察随访临床症状及化验检查等指标变化情况。结果　所有患者胰管内支架置放成功 ,腹痛症状在术后 1个月内均基本缓解 ,腹痛缓解率 10 0 % ,消瘦、脂肪泻等症状得到改善 ,除 1例因有胰腺外分泌障碍血清淀粉酶下降慢外 ,其他患者血清淀粉酶均于术后 1～ 14d内降至正常 ,1例患者术后第 10天因支架阻塞更换支架。结论　慢性胰腺炎内镜下置放胰管内支架治疗是一种较安全、低创伤、低费用、见效快的首选方法 ,极具临床应用价值。