【经验】复发性急性胰腺炎的诊断和治疗

南卡罗莱纳医科大学Gregory A. Coté 博士

复发性急性胰腺炎(RAP)是一种急性胰腺炎复发性发作的综合症，其特征是长达几个月到几年不等的、间断性出现的无症状或轻微症状。为了清晰起见，由于胰腺炎导致的慢性和迁延性症状被归类为 “迁延性急性胰腺炎”或者慢性胰腺炎；诊断后者时需要确凿的证据，横断面影像或者超声内镜检查证实存在纤维化。慢性胰腺炎患者可能会出现RAP的表现，而那些伴有RAP者，随着时间推移，存在发展为慢性胰腺炎的潜在风险。因此，临床医师在诊疗RAP患者时，应尽一切努力减少复发的可能性。

考虑胆源性胰腺炎

在西方国家，胆结石和酒精是两种最常见的急性胰腺炎病因。当患者先前没有进行胆囊切除术，或者他的或她的临床表现存在一个或更多的急性胰腺炎相关症状、同时伴有血清肝化学指标升高超过两倍时，除非获得十分充分的酒精摄入病史，应该重点考虑胆结石可能。症状发作时如果横断面影像没有发现胆囊结石，且肝脏化学检查正常或接近正常水平，那么此时行胆囊切除术用于防止反复发作是存在争议的。否则，出院前进行胆囊切除术是适当的。

检查胆囊结石的最佳影像学方法是MRI和内镜超声(EUS)。鉴于其较低的成本和风险，腹部超声是一种合理的初始检测手段；然而，急性胰腺炎或者体型较大者会降低其诊断的灵敏度。

考虑其他的病因

如果排除了胆结石和酒精病因，然后鉴别诊断需要扩大考虑一些不太常见的因素，如阻塞性病因(例如，导管内乳头状粘液瘤、胰腺实体瘤、壶腹部肿瘤、胰腺分裂症，以及其他)、药物(也许最常见的罪魁祸首是利尿剂、抗艾滋病毒药物和硫唑嘌呤)、吸烟、高钙血症、高甘油三酯血症、遗传畸形，以及自身免疫性胰腺炎。待完善历史收集、体格检查、基本的实验室检查、对比剂增强CT或磁共振胰胆管造影(MRCP)之后，这些病因应该是不言而喻的。基因突变包括囊性纤维化跨膜传导调节蛋白(CFTR)、丝氨酸蛋白酶1(PRSS1)、Kazal型丝氨酸蛋白酶抑制剂1(SPINK1)，以及胰凝乳蛋白酶C(CTRC)可能出现在RAP成年患者中，即使不存在家族病史。当患者新近出现糖尿病且年龄大于50岁，应怀疑胰腺癌可能。对于小于2cm的肿瘤，EUS优于MRI和CT；这还需要进一步证实，因为前期评估尚不确定。

有争议的部分

内镜逆行胆管造影(ERCP)很少用于诊断检查，由于EUS和MRCP侵袭性更小、可以识别慢性胰腺炎、导管畸形(如狭窄)以及隐匿性阻塞病因。因此，在明确病因之后ERCP通常被认为是一种治疗手段；典型的例子是胆总管结石或者主胰管狭窄。

专家推荐常规检查应考虑包括胰腺分裂症和Oddi氏括约肌功能障碍(SOD)在内的RAP潜在病因，尽管相应的治疗会存在本质上的争议。当伴有导管扩张或者梗阻性疾病(如石头或狭窄)时，内镜下括约肌切开术是最为广泛接受的方式。ERCP是识别胰腺分裂症的金标准，而EUS或者MRCP可能会在很小的一部分病例中带来误诊。然而，乳头括约肌小切开术用于“治疗”胰腺分裂症的获益尚存在争议。批评者认为，RAP患者出现胰腺分裂症的发病率与健康人群相似(8% -10%)。有一项随机临床试验评价了期对RAP患者(N = 19)的影响，且随访是多变的。然而，引人注目的是许多回顾性队列研究表明了其获益，因此大多数ERCP提供者主张对RAP患者和胰腺分裂症患者进行ERCP检查。

Oddi氏括约肌功能障碍(SOD)，其经典定义为基底括约肌压力病理性升高> 40毫米汞柱，专家们对此的看法仍存在较大分歧。虽然生理上似是而非，SOD可能通过升高胰腺导管内压力(类似于导致胆总管结石的机制)而引发急性胰腺炎，有一些小规模的数据支持使用胰腺括约肌切开术治疗RAP。类似于胰腺分裂症，文献研究一般限于非随机化、非盲队列、随访多变且成功的定义存在差异。一项最大的临床试验(N = 69)比较了胆管括约肌切开术与胆管并胰管括约肌切开术治疗RAP和SOD的作用，结果显示在急性胰腺炎复发方面二者没有差异。胰管括约肌切开术是有潜在危险的，因为存在穿孔风险，且ERCP术后胰腺炎发生率更高，远期风险可导致括约肌狭窄(显然这会造成胰液流出受阻)。

经验性胆管括约肌切开术治疗隐匿性胆总管结石或者微石症时的益处尚未证实。虽然胆管括约肌切开术比胰管括约肌切开术安全，其对RAP自然病史的作用尚不清楚。在缺乏客观证据证明胆源性胰腺炎时，同经验性行胆囊切除术相似，胆管括约肌切开术治疗RAP患者需要进行对照研究。

总结

1. 确认不存在胆石病需要使用先进的成像方式，比如MRI和EUS。

2. 考虑基因突变的存在，即使是成年患病者和无家族史者。

3. 排除隐匿性胰腺肿瘤，特别是最近新发糖尿病的老年患者。

4. 尽量减少使用诊断性ERCP，应与患者系统的讨论存在争议的部分，比如胰腺分裂症、胆管括约肌切开术以及胰管括约肌切开术。

独家授权，未经许可请勿转载！

Recurrent acute pancreatitis (RAP) is a syndrome of relapsing bouts of acute pancreatitis marked by variable asymptomatic or minimally symptomatic intervals ranging from months to years. For clarity, patients with chronic and smoldering symptoms attributable to pancreatitis are better classified as having “smoldering acute pancreatitis” or chronic pancreatitis; the latter is applied when definitive evidence of fibrosis is present on cross-sectional imaging or endoscopic ultrasound. Patients with chronic pancreatitis may present with RAP, and those with RAP are at substantial risk for developing chronic pancreatitis over time. Therefore, clinicians should make every effort to minimize the likelihood of relapse when evaluating a patient with RAP.

Consider gallstone pancreatitis

Gallstones and alcohol represent the two most common etiologies for acute pancreatitis in Western countries. In addition to obtaining a thorough alcohol history, gallstones should be strongly considered when the patient has not previously undergone a cholecystectomy or when one or more of his or her clinical presentations with acute pancreatitis is associated with a greater than twofold elevation in serum liver chemistries. If no gallbladder stones are identified on cross-sectional imaging and liver chemistries are normal or near-normal with attacks, the benefit of cholecystectomy to prevent recurrent bouts is controversial. Otherwise, proceeding with cholecystectomy prior to discharge from the hospital is appropriate.

The best imaging tests for gallbladder stones are MRI and endoscopic ultrasound (EUS). Transabdominal ultrasound is a reasonable initial test given its favorable cost and risk profile; however, its sensitivity is reduced in the setting of acute pancreatitis or large body habitus.

Consider alternative etiologies

If gallstones and alcohol etiologies are ruled out, then the differential diagnosis broadens to include less common factors such as obstructive etiologies (eg, intraductal papillary mucinous neoplasm, solid pancreatic tumors, ampullary tumors, and pancreas divisum, among others), medications (perhaps the most common culprits being diuretics, HIV medications, and azathioprine), smoking, hypercalcemia, hypertriglyceridemia, genetic abnormalities, and autoimmune pancreatitis. Many of these should be self-evident following a complete history, physical examination, basic laboratory testing, and contrast-enhanced CT or magnetic resonance cholangiopancreatography (MRCP). Genetic mutations in cystic fibrosis transmembrane conductance regulator (CFTR), protease, serine, 1 (PRSS1), serine protease inhibitor kazal type 1 (SPINK1), and chymotrypsin C (CTRC) may be present in patients who present with RAP during adulthood, even in the absence of a family history. Pancreatic cancer should be suspected in patients with recent-onset diabetes mellitus and those >50 years of age. EUS is superior to MRI and CT for tumors <2 cm in size; this should be pursued if the antecedent evaluation is inconclusive.

Controversial entities

Endoscopic retrograde cholangiopancreatography (ERCP) is rarely required as a diagnostic test, as EUS and MRCP are less invasive alternatives for identifying chronic pancreatitis, ductal abnormalities (eg, strictures), and occult obstructive etiologies. Therefore, ERCP is usually considered for treatment after a discrete etiology has been identified; classic examples would be choledocholithiasis or a main pancreatic duct stricture.

Experts routinely include pancreas divisum and sphincter of Oddi dysfunction (SOD) as etiologies of RAP despite substantial controversy pertaining to their treatment. Endoscopic sphincterotomy is most widely accepted when there is concomitant duct dilation or obstructing pathology (eg, stone or stricture). ERCP is the gold standard for identifying pancreas divisum, which may be missed by EUS or MRCP in a minority of cases. However, the benefit of minor papilla sphincterotomy for the “treatment” of pancreas divisum is questionable. Critics argue that the prevalence of pancreas divisum in the setting of RAP is comparable to that in the healthy population (8%–10%). There is one randomized clinical trial of patients (N = 19) with RAP evaluating its impact, and the follow-up was variable. Nevertheless, there are compelling retrospective cohort studies suggesting its benefit, so most high-volume ERCP providers offer this for patients with RAP and pancreas divisum.

SOD, classically defined as a pathologic elevation in basal sphincter pressure >40 mmHg, garners even greater disagreement among experts. While it is biologically plausible that SOD may trigger acute pancreatitis by causing an increase in pancreatic intraductal pressure (akin to the mechanism attributed to choledocholithiasis), there are little data supporting the practice of pancreatic sphincterotomy for the treatment of RAP. Similar to the divisum literature, studies are generally limited to nonrandomized, open-label cohorts, with variable follow-up and definitions of success. The largest clinical trial (N = 69) comparing biliary to dual (biliary + pancreatic) sphincterotomy for patients with RAP and SOD revealed no difference in time to recurrent acute pancreatitis. Pancreatic sphincterotomy is potentially hazardous because the risks for perforation and post-ERCP pancreatitis are higher and there is a long-term risk for sphincter stenosis (causing indisputable obstruction of pancreatic juice outflow).

The benefit of empiric biliary sphincterotomy for the treatment of occult choledocholithiasis or microlithiasis is also unproven. While biliary sphincterotomy is safer than pancreatic sphincterotomy, its impact on the natural history of RAP remains unclear. Like empiric cholecystectomy in the absence of objective evidence to suggest gallstone pancreatitis, biliary sphincterotomy needs to be compared with sham for patients with RAP.

Summary

Confirm the absence of gallstone disease using advanced imaging modalities such as MRI and EUS.

Consider genetic mutations, even in patients with adult-onset disease and without a family history.

Rule out occult pancreatic tumors, particularly in older adults with recent-onset diabetes mellitus.

Minimize the use of diagnostic ERCP, and systematically discuss the controversies surrounding pancreas divisum, biliary sphincterotomy, and pancreatic sphincterotomy with your patients.

Copyright © 2015 Elsevier Inc. All rights reserved.