Chronic pancreatitis: pathogenesis and molecular aspects

Chronic pancreatitis (CP) is characterized by irreversible morphological and functional alterations of the pancreas presenting clinically with upper abdominal pain as well as exocrine and endocrine insufficiencies. CP is morphologically characterized by pancreatic head enlargement, calcifications of the parenchyma, cysts, and pancreatic stones. The most common etiological factor of CP in Western industrialized countries is alcohol abuse; less common factors include hereditary pancreatitis, CP due to metabolic disturbances, CP due to pancreas divisum or duodenal wall cysts, and idiopathic CP. The molecular alterations leading to the chronic inflammatory process are nor completely understood. Research during the last years, however, has elucidated that a number of growth factors and their receptors are overexpressed in CP, which is thought to contribute to the high degree of pancreatic fibrosis and to the proliferative potential of ductular cells in this disorder. In addition, gene mutations have been detected in a subgroup of CP samples underscoring the pre-malignant potential of CP. In this review we will summarize our current knowledge about pathogenic and molecular aspects of CP.     

Mechanisms of pain in chronic pancreatitis

Pain is a leading symptom in chronic pancreatitis (CP) and often its management necessitates surgical intervention. Nevertheless the presence of different hypotheses, the pathophysiology of pain is not understood, thus the indications for therapy remain controversial. Increased pressure within the ductal system and/or the parenchyma has been suggested to be one of the causes of pain. This controversial theory has been substantiated by the demonstration of a relationship between intrapancreatic pressure and intensity of pain. On the other hand, recent studies have shown the inflammatory involvement of intrapancreatic nerve fibres in a so called "neuroimmune interaction". In fact, infiltration of inflammatory cells around the nerves together with an increase in the number of nerve fibres in the fibrotic pancreatic tissue have been proposed as a possible cause of pain in chronic pancreatitis. Moreover, immunohistological studies have shown that the amount of neurotransmitters, such as substance P and calcitonin gene related peptide, is increased in afferent pancreatic nerves and a close interrelationship between pain and immune cell infiltration of the nerves has been reported in CP. In addition to these hypothesis, extrapancreatic causes such as common bile duct obstruction and duodenal stenosis are discussed. This article review points to the different pathogenic mechanisms of pancreatic pain in CP.     

Islet cell dysfunction in patients with chronic pancreatitis

Chronic pancreatitis(CP) is characterized by progressive inflammation and fibrosis of the pancreas that eventually leads to pancreatic exocrine and endocrine insufficiency. Diabetes in the background of CP is very difficult to manage due to high glycemic variability and concomitant malabsorption. Progressive beta cell loss leading to insulin deficiency is the cardinal mechanism underlying diabetes development in CP. Alpha cell dysfunction leading to deranged glucagon secretion has been described in different studies using a variety of stimuli in CP. However, the emerging evidence is varied probably because of dependence on the study procedure, the study population as well as on the stage of the disease. The mechanism behind islet cell dysfunction in CP is multifactorial. The intra-islet alpha and beta cell regulation of each other is often lost. Moreover, secretion of the incretin hormones such as glucagon like peptide-1 and glucose-dependent insulinotropic polypeptide is dysregulated. This significantly contributes to islet cell disturbances. Persistent and progressive inflammation with changes in the function of other cells such as islet delta cells and pancreatic polypeptide cells are also implicated in CP. In addition, the different surgical procedures performed in patients with CP and antihyperglycemic drugs used to treat diabetes associated with CP also affect islet cell function. Hence, different factors such as chronic inflammation, dysregulated incretin axis, surgical interventions and anti-diabetic drugs all affect islet cell function in patients with CP. Newer therapies targeting alpha cell function and beta cell regeneration would be useful in the management of pancreatic diabetes in the near future.     

Chronic pancreatitis: relation to acute pancreatitis and pancreatic cancer

The relationship between chronic pancreatitis (CP) and other pancreatic diseases, such as acute pancreatitis (AP) and pancreatic cancer (PK), remains a fairly debated question. The progression from alcoholic AP to CP is controversial, and some long-term epidemiological studies suggest that alcoholic CP might be the result of recurrent alcoholic AP (necrosis-fibrosis sequence) and a subgroup of alcoholics may present recurrent AP without progression to CP. Other predisposing factors (genetic, nutritional, environmental) seems to be important in inducing different outcomes of pancreatic damage due to alcohol. However, recurrent episodes of AP are clearly involved in pathophysiology of CP in patients with hereditary pancreatitis. A relationship between CP and subsequent PK development has long been suspected, but we actually don't know whether this association is direct or is the result of confounding factors, such as alcohol intake or cigarette smoking. Many issues should be considered as indicators of a causal association, and several of them are not fulfilled. Nonetheless, epidemiological studies (case-control or cohort studies) showed that the risk of PK is increased in patients with CP; the risk is significantly higher in tropical calcifying CP and hereditary pancreatitis. Studies on growth factors, oncogenes, tumor-suppressor genes, and angiogenesis suggest that the sequence PC-KP is plausible from the biological standpoint.     

胰头肿块型慢性胰腺炎的治疗

胰头肿块型慢性胰腺炎已被视为胰腺癌的癌前病变,并且可以导致胰管、胆管及十二指肠梗阻,其与胰头癌的鉴别诊断困难,然而二者的预后截然不同。因此,胰头肿块型慢性胰腺炎一旦诊断明确即应积极手术治疗,以切除病变,缓解疼痛症状,改善病人的生活质量。胰头部肿块型慢性胰腺炎的手术方式是直接针对胰头的,不同的手术方法包括胰十二指肠切除术（保留或不保留幽门的Whipple 手术）和保留十二指肠的胰头切除术（Beger手术及其改良术式）。手术方式尽可能采用胰十二指肠切除术,不仅切除了胰头部肿块、解除了胆道、胰管及十二指肠的梗阻,而且也去除了胰头癌的潜在病因;如胰头肿块巨大,行胰十二指肠切除术有极大风险,可考虑行保留十二指肠的胰头切除术。     

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??Treatment of Chronic pancreatitis(CP) with an inflammatory mass ZHANG Zhong-tao,YIN Jie. Beijing Friendship Hospital,Capital Medical University,Beijing100050,China
Corresponding author: ZHANG Zhong-tao,E-mail: zhangzht@medmail.com.cn
Abstract Chronic pancreatitis(CP) with an inflammatory mass has been thought of as a precancerous lesion of pancreatic cancer, and it can lead to obstruction of the pancreatic duct, bile duct and duodenum. The CP with mass and pancreatic cancer are difficult to identify from clinical performance, and their prognosis are very different. Once CP with mass has been diagnosed it should be clear that surgical treatment is necessary in order to remove the focus, ease pain, and improve the patient's quality of life. Surgical strategy in CP with mass has been directed at the pancreatic head with a variety of tactics including pancreatoduodenectomy (Whipple procedure with or without pylorus preservation) and duodenum-preserving resection of the pancreatic head (Beger operation and other operations). Pancreatoduodenectomy is preformed in the treatment of CP with mass, not only resection of the pancreatic head mass, lifting the obstruction of the pancreatic duct, bile duct and duodenum, but also removing the potential causes of pancreatic cancer. Pancreatoduodenectomy is a great risk When the pancreatic head mass is large, but the partial head resection can be accomplished with relative safety.     

Chronic pancreatitis

Chronic pancreatitis (CP) is a complex progressive fibro-inflammatory disease of the pancreas with a variable clinical course often progressing to a permanent loss of exocrine and endocrine function. Over the last 20 years the incidence has continued to increase. CP has multifactorial aetiological risk factors with chronic alcoholism being the most common. The updated TIGAR-O_V2 classification identifies the pertinent risk factors and aetiology. The most susceptible patients to develop CP have a sentinel acute pancreatitis event which initiates the chronic progressive inflammation, scarring and fibrosis of the pancreas. Symptomatically CP presents as intractable abdominal pain, with weight loss and functional loss (steatorrhoea and type 3c diabetes mellitus) being late manifestations of the disease. Diagnosis is made by a combination of clinical history, examination and cross sectional imaging, combined with pancreatic function tests (only in equivocal cases). Complications include gastric and biliary obstruction, pseudocyst formation, pancreatic ascites, pseudoaneurysms, venous thrombosis and an increased risk of developing pancreatic adenocarcinoma. Management includes: diagnosis and identifying the aetiology, instituting life-style changes to abstain from alcohol and smoking, and involving the specialist multidisciplinary team (including pain team, dietician, clinical psychologist, endoscopist, GI physician and pancreatic surgeon) in patients with on-going symptoms or when there is doubt in the diagnosis.     

Choroid plexus transplants in the treatment of brain diseases

The choroid plexus (CP) produces and secretes numerous biologically active neurotrophic factors into the cerebrospinal fluid (CSF). These circulate throughout the brain and spinal cord, maintaining neuronal networks and associated cells. In neurodegenerative disease and in acute brain injury there is local up-regulation of neurotrophin production close to the site of the lesion. Treatment by direct injection of neurotrophins and growth factors close to these lesion sites has repeatedly been demonstrated to improve recovery. It has therefore been proposed that transplanting viable choroid plexus cells close to the lesion might provide a novel means for continuous delivery of these molecules directly to the site of injury. Recent publications describe how transplanted CP, either free or in an immunoprotected encapsulated form, deliver therapeutic molecules to the desired site. This review briefly describes the accumulated evidence that CP cells support neuronal cells in vitro and have therapeutic properties when transplanted to treat acute and chronic brain disease and injury in animal models.     

Chronic Pancreatitis and Bone Disease

Patients with chronic pancreatitis (CP) may have a higher prevalence of osteoporosis than the general population thereby increasing the risk of bone fracture. The pathophysiology of bone disease in CP is multifactorial. Their risk factors for secondary osteoporosis include increasing age, low body mass index from sitophobia, maldigestion due to exocrine pancreatic insufficiency (EPI) with resulting low vitamin D, as well as smoking and alcohol abuse. An obvious association of bone disease with CP is from EPI with maldigestion of fat-soluble vitamins including vitamin-D, which has a significant role in the process of bone formation. Vitamin-D deficiency may be higher in CP patients vs controls, and it is especially so in CP patients with EPI. Screening for CP-associated osteopathy, including osteopenia and osteoporosis, should be initiated early in the course of CP, as the overall prevalence of bone disease is approximately two-thirds of CP patients. Our initial approach in the treatment of osteoporosis should include correction of maldigestion resulting from EPI with use of pancreatic enzyme replacement therapy (PERT). PERT, which is the treatment for EPI is associated with improvement in Dual energy X-ray absorptiometry (DXA) values and vitamin-D levels compared to those who are not treated. This should improve, in addition to body mass index, vitamin-D deficiency and calcium absorption as well as improve overall nutritional status. Osteopathy is common in CP patients, has significant associated morbidity, should be screened for regularly, and corrected with fat soluble vitamin supplementation and PERT to prevent clinical sequelae. In this article, we review the epidemiology, pathophysiology, and treatment of bone disease in patients with CP.     

Management of pain in small duct chronic pancreatitis

Small duct chronic pancreatitis (CP) is defined by a nondilated main pancreatic duct, and the morphological and clinical features of chronic pancreatitis with pain are the most prominent symptoms. Current treatment strategies are based on pain history and the location and extent of disease. Traditionally, radical pancreatic resectional procedures have been carried out for small duct CP, especially with an associated head mass of uncertain aetiology. Based on the information from five randomized trials, the duodenum-preserving pancreatic head resection and its modifications have proven to provide excellent long-term pain relief and to be superior to more radical operations. Therefore, these procedures can be considered the standard for small duct CP with head dominant disease. The longitudinal V-shaped excision of the ventral pancreas combines extensive drainage and a limited resection and offers good pain relief in diffuse small duct CP. However, long-term results and larger series are awaited for definite conclusions. Thoracoscopic splanchnicectomy and endosonography-guided celiac plexus blocks require controlled trials before their routine use. This article provides an overview about the current and evidence-based pain management in small duct CP. Presented at the 2005 American Hepato-Pancreato-Biliary Association Congress, Hollywood, Florida, April 14–17, 2005.     

Inflammatory mechanisms contributing to pancreatic cancer development

OBJECTIVE: Pancreatic cancer is the most deadly of all gastrointestinal (GI) malignancies, yet relatively little is known regarding mechanisms of tumor development including the role of inflammation. SUMMARY BACKGROUND DATA: Chronic pancreatitis (CP) increases the risk of developing cancer by 10- to 20-fold; mediators of the chronic inflammatory process and the surrounding fibrotic stroma likely support a transformation to malignancy, yet the exact mechanisms remain undefined. The purpose of our present study was to determine potential inflammatory components in epithelial and stromal cells that may contribute to both CP and pancreatic cancers. METHODS: Specimens of normal pancreas, CP, and pancreatic cancer were examined using laser-capture microdissection (LCM), gene array, and immunohistochemistry. RESULTS: Gene array analysis from LCM-dissected tissues demonstrated: (i) increased expression of interleukin-8 (IL-8), an activator of the inflammatory factor nuclear factor-kappaB (NF-kappaB), and (ii) decreased expression of IkappaB (an inhibitor of NF-kappaB) in CP ductal cells compared with normal ducts. Compared with CP, cancers demonstrated: (i) increased expression of tumor related genes including S100A4, cyclin E1, and epidermal growth factor (EGF) receptor, and (ii) expression of matrix metalloproteinase 2, a pro-invasive factor for tumor cells, which was not present in the CP stroma. Increased staining of both the p50 NF-kappaB subunit and IKKalpha kinase (a protein that allows activation of NF-kappaB) was noted in CP and cancers. CONCLUSIONS: Our results demonstrate that similar inflammatory components and downstream effectors are present in CP and pancreatic cancers. Importantly, these findings suggest that a common pathway for pancreatic cancer development may be through a chronic inflammatory process including stroma formation. These findings may lead to novel strategies for pancreatic cancer prophylaxis based on inhibition of inflammatory mediators.     

内镜治疗慢性胰腺炎的优势与局限性

慢性胰腺炎的特征性病理改变为胰腺组织进行性纤维化,临床治疗目标包括缓解腹痛症状及延缓胰腺内、外分泌功能减退。内镜治疗慢性胰腺炎（逆行胰胆管造影术、体外震波碎石术和超声内镜等）创伤小,对慢性胰腺炎并发胰管结石、狭窄、胰腺假性囊肿及继发胆道梗阻安全有效,已部分替代外科手术,成为首选治疗方式之一。无论单纯内镜或是外科治疗慢性胰腺炎均有其局限性,因此,需要内科、外科、内镜、麻醉以及营养等多学科合作,制订最佳方案,提高患者生命质量。     

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??Etiology and pathogenesis of chronic pancreatitis WANG Xing-peng*, ZHANG Ru-ling. *Tenth People’s Hospital of Tongji University, Shanghai 200072, China
Corresponding author: WANG Xing-peng, E-mail: wangxp1965@yahoo.com.cn
Abstract Chronic pancreatitis (CP) is the progressive and permanent destruction of the pancreas resulting in exocrine and endocrine insufficiency. The typical pathological change of CP is pancreatic fibrosis, which could cause persistent or recurrent abdominal pain as well as loss of pancreatic endo- and exocrine function. The etiology and pathogenesis of CP are multifactorial, including cholelithiasis, alcoholism, genetic predisposition and autoimmune factors. However, the incidence of CP should be a result of multiple etiological factors, and the individual pathogenesis remains unclear. Further researches of individual etiology and pathogenesis of CP would be helpful to the prevention and treatment of this disease.     

23例胰头肿块型胰腺炎的诊治分析

目的 总结分析胰头肿块型胰腺炎的诊断和治疗方法。方法 回顾性分析我院1983年5月至2001年10月收治的245例慢性胰腺炎病例，总结其中23例因胰头上位术前难以与胰腺癌进行鉴别而行胰十二指肠切除术病人的病例资料。结果 本组中有饮酒史者16例，慢性胆囊炎史5例，特发性1例，工作中长期接触有毒气体者1例。因梗阻性黄疸入院者14例，另9例因主诉腹痛入院，病程小于2年者19例，大于2年者14例。诊断方法包括肿瘤标记物，B超，CT，ERCP和血管造影。23例病人术中探查均显示肿物位于胰头，与周围组织粘连严重，其中3例与门静脉有粘连，但尚能剥离，而术后病理均为慢性胰腺炎。结论 目前尚无特异性好和敏感性高的有效鉴别诊断方法区分慢性胰腺炎与胰腺癌，分子生物学进展对此有一定帮助，增强CT结合ERCP对大部分病例的鉴别诊断具有较高的价值。由于酒精性胰腺炎已经被认为是癌前病变，对于胰头肿块型胰腺炎行胰十二指肠切除术已经逐渐被接受。     

Chronic pancreatitis

Chronic pancreatitis (CP) is a progressive, disabling, fibro-inflammatory disease of the pancreas of variable clinical course and is usually associated with permanent loss of exocrine and endocrine function over a period of time. The incidence is increasing. There are various aetiological risk factors that cause CP, chronic alcoholism being the most common risk factor. The TIGAR-O classification identifies all the risk factors and aetiology. Most susceptible patients have a sentinel acute pancreatitis event which initiates chronic progressive inflammation, scarring and fibrosis, though some may present insidiously with symptoms of functional loss – diabetes or steatorrhoea. Intractable abdominal pain, steatorrhoea, weight loss and (type 3c) diabetes mellitus are late manifestations of the disease. Diagnosis is made with a combination of clinical history, examination, cross sectional imaging combined with pancreatic function tests (in equivocal cases). Complications include gastric and biliary obstruction, pseudocyst formation, pancreatic ascites, pseudoaneurysms and venous thrombosis. Patients with CP have increased risk of developing pancreatic adenocarcinoma. Management includes making the diagnosis, identifying the aetiology, instituting life-style changes to abstain from alcohol and smoking, and involving the specialist multidisciplinary team (including pain team, dietician, clinical psychologist, endoscopist, gastrointestinal physician and pancreatic surgeon) if initial steps do not control the symptoms.     

软骨寡聚基质蛋白在慢性胰腺炎损伤中退变腺泡细胞内的表达

目的 研究正常胰腺、慢性胰腺炎与胰腺癌组织中软骨寡聚基质蛋白(cartilage oligomeric matrix protein,COMP)mRNA和蛋白表达水平的差异,揭示COMP在慢性胰腺炎样损伤中的意义。方法 采用Northern印迹法、Western印迹法、原位杂交法与免疫组化方法对14例慢性胰腺炎、14例胰腺癌及15例正常胰腺组织进行分析。结果 在慢性胰腺炎组织中和胰腺癌组织中类似慢性胰腺炎损伤的退变腺泡细胞胞浆内,存在高水平的COMP mRNA信号与免疫反应;而在胰腺癌细胞、正常胰腺组织的导管细胞与胰岛细胞的胞浆内,COMP mRNA信号与免疫反应微弱或缺如。结论 COMP在慢性胰腺炎及胰腺癌中类似慢性胰腺炎损伤的退变腺泡细胞内高表达,可能与慢性胰腺炎中腺泡细胞功能异常有关。     

慢性胰腺炎的治疗策略:内镜治疗与外科干预

慢性胰腺炎是由多种病因导致的胰腺慢性炎症性和纤维化病变,其基本治疗原则为去除病因、缓解症状、改善胰腺分泌功能不足及防治并发症等。目前,对于慢性胰腺炎治疗策略的探讨日趋增多,创伤递进式策略与早期外科手术干预是共性治疗理念。临床实践中,对于出现胰腺假性囊肿、胰管结石、胆管狭窄等并发症,内镜干预可作为优选治疗方式;无胰头部病变的主胰管扩张,可首选Partington术;合并胰头部病变,可行Beger术或Frey术;无主胰管扩张,应根据具体病变部位行胰腺切除术;全胰炎性病变或多发部位病变,可行全胰腺切除术。外科医师在诸多手术方式的选择中,应遵循个体化与多学科化的整体治疗理念与策略,尤其对于干预指征、时机及方式的掌控。笔者综合分析国内外研究进展,阐述慢性胰腺炎的内镜治疗与外科干预策略,以期进一步优化慢性胰腺炎病人的整体疗效。     

Autoimmune pancreatitis: frequency, IgG4 expression, and clonality of T and B cells

Autoimmune pancreatitis (AIP) is a newly recognized disease. The presence of IgG4 positive plasma cells is thought to be of diagnostic help. In a surgical series of chronic pancreatitis cases, we determined the relative frequency of AIP before and after 1990, analyzed the diagnostic significance of IgG4 expression and examined the presence of oligoclonal T or B-cell populations. The histopathology of 202 surgical specimens of chronic pancreatitis removed between 1975 and 2004 was reviewed and 2 groups were distinguished, 1 of AIP cases and the other of nonautoimmune chronic pancreatitis (non-AIP CP). The intensity of infiltration of pancreatic tissue by IgG4 positive plasma cells and other immune cells was studied immunohistochemically. Finally, T and B-cell clonality was tested by polymerase chain reaction-based analysis. Except for 1 case in 1978, all cases of AIP were observed after 1990. IgG4 positive plasma cells were detected in 72.5% of AIP cases and in 63.1% of non-AIP CP cases. More than 20 cells per high power field were only seen in AIP (sensitivity 43%, specificity 100%). This finding was associated with higher age and grade. Polyclonal T and B-cell populations were found in both AIP and non-AIP CP except for 1 AIP case showing an oligoclonal IgGH-FR3 gene rearrangement. AIP seems to have increased considerably in frequency in the last 2 decades. High density infiltrates of IgG4 positive plasma cells are diagnostic for AIP, but are seen in less than half of the cases. T or B-cell oligoclonality could not be established as a feature of AIP.     

胰头肿块型胰腺炎的诊断与治疗

胰头肿块型慢性胰腺炎从临床表现上很难与胰头癌相鉴别,影像学检查在肿块型慢性胰腺炎诊断中起重要作用,对于手术指征的掌握、胰头部肿块的可切除性、手术方式的选择以及手术困难程度的估计很有帮助.目前已将发生于胰头的肿块型慢性胰腺炎视为胰腺癌发生的癌前病变.胰头肿块型慢性胰腺炎的手术方式是直接针对胰头的,不同的手术方法包括:胰十二指肠切除术(保留或不保留幽门)和胰头部分切除(Beger手术)加胰管引流术(Frey手术).胰头肿块型慢性胰腺炎一旦诊断明确即应积极手术治疗,手术方式尽可能采用胰十二指肠切除术,因为它不仅切除了胰头肿块、解除了胆道和胰管及十二指肠的梗阻,而且也去除了胰头癌的潜在病因;若胰头肿块巨大胰十二指肠切除有极大风险,可考虑保留十二指肠的胰头切除术.     

慢性胰腺炎138例分析

目的：探讨慢性胰腺炎（CP）的发病因素及诊治特征。方法：回顾性分析138例CP患者一般资料、临床表现、治疗方法,探讨主要危险因素与临床特征的关系,根据2012年中华医学会CP诊治指南对进行患者临床分型、分期,用M-ANNHEIM的评分系统分析患者治疗（手术治疗与保守治疗）前后CP病情变化。结果：138例CP患者中,116例（84.1%）以腹痛为主要表现;长期饮酒者44.2%（61/138）,长期吸烟42.8%（59/138）、高脂血症39.9%（55/138）、胆道疾病20.2%（28/138）;I型11例,II型58例,III型47例,IV型22例;1期69例,2期47例,3期22例。大量饮酒患者胰腺钙化比例高于非饮酒患者,而长期吸烟患者胰腺钙化比例与糖尿病比例均高于非吸烟患者（均P<0.05）。1期患者保守治疗与手术治疗效果差异无统计学意义（P=0.744）,2期患者手术治疗效果优于保守治疗（P<0.05）,3期患者保守治疗治疗效果优于手术治疗（P<0.05）。结论：饮酒、吸烟、高脂血症、胆道疾病依然是CP的主要致病危险因素,不同因素所致CP的特征有所不同,应该根据CP诊治指南并结合患者具体情况,制定合理的治疗方案。