Treatment of alcoholic pancreatitis

Chronic pancreatitis is characterized by progressive and irreversible loss of pancreatic exocrine and endocrine function. The majority of cases in the Western world are related to alcohol consumption. Treatment of alcoholic chronic pancreatitis has been difficult, since the mechanisms of disease progression and the causes of pain are poorly understood. The conservative management of chronic pancreatitis focuses on (a) avoidance of precipitating factors such as alcohol and smoking; (b) treatment of pain, and (c) replacement of exocrine and endocrine function. There is a lack of good controlled, randomized treatment trials in alcoholic pancreatitis. However, there is good evidence that lifestyle changes, such as alcohol cessation, hamper progression of the disease. Conservative treatment of pain should be based on a stepwise approach; however, underlying causes such as pseudocysts may require endoscopic or surgical therapy. Treatment of exocrine insufficiency requires pancreatic enzyme supplementation and adjustment to several smaller meals per day, while treatment of endocrine insufficiency requires insulin treatment.     

Hereditary chronic pancreatitis

Hereditary chronic pancreatitis (HCP) is a very rare form of early-onset chronic pancreatitis. Apart from young age at diagnosis and a slower progression, the clinical course, morphological features and laboratory findings of HCP do not differ from those of patients with alcoholic chronic pancreatitis. Diagnostic criteria and treatment of HCP also resemble those of chronic pancreatitis of other causes. The clinical presentation is highly variable and includes chronic abdominal pain, impairment of endocrine and exocrine pancreatic function, nausea and vomiting, maldigestion, diabetes, pseudocysts, bile-duct and duodenal obstruction, and rarely pancreatic cancer. Fortunately, the disease is mild in most patients. Mutations in the PRSS1 gene, encoding cationic trypsinogen, play a causative role in chronic pancreatitis. It has been shown that the PRSS1 mutations increase autocatalytic conversion of trypsinogen to active trypsin, and thus probably cause premature, intrapancreatic trypsinogen activation, disturbing the intrapancreatic balance of proteases and their inhibitors. Other genes--such as the anionic trypsinogen (PRSS2), the serine protease inhibitor Kazal type 1 (SPINK1), and the cystic fibrosis transmembrane conductance regulator (CFTR)--have also been found to be associated with chronic pancreatitis (idiopathic and hereditary). Genetic testing should only be performed in carefully selected patients by direct DNA sequencing, and antenatal diagnosis should not be encouraged. Treatment focuses on enzyme and nutritional supplementation, pain management, pancreatic diabetes, and local organ complications such as pseudocysts and bile-duct or duodenal obstruction. The disease course and prognosis of patients with HCP is unpredictable. The risk of pancreatic cancer is elevated. Therefore, HCP patients should strongly avoid environmental risk factors for pancreatic cancer.     

Recent Advances in the Epidemiology of Alcoholic Pancreatitis

Clinical observation has defined the medical profile of alcoholic pancreatitis, but its low incidence and prevalence has limited characterizing the disease at a population level, the contribution of environmental exposures, and a clear picture of its natural history. Recent studies have defined the impact of alcohol use and smoking on disease risk, and a threshold for alcohol consumption has been identified. Recurrent attacks of acute pancreatitis have been linked with continued alcohol consumption, and aggressive alcohol intervention has been shown to decrease recurrence. Progression from alcoholic acute pancreatitis to chronic pancreatitis is now believed to occur infrequently, and factors associated with progression have been identified. Alcoholic pancreatitis reduces lifespan in these patients, and the economic impact of pancreatitis is substantial. Efforts are needed to increase awareness of the impact of alcohol consumption and smoking on risk for pancreatitis and the benefits of cessation for primary and secondary prevention.     

Últimos avances en pancreatitis crónica

This article summarizes some of the recent and clinically relevant advances in chronic pancreatitis. These advances mainly concern knowledge of the etiopathogenesis of the disease, the pharmacological treatment of pain, and knowledge of the natural history of autoimmune pancreatitis. New evidence supports the relatively low prevalence of chronic alcoholic pancreatitis, and the role of tobacco in triggering the etiopathogenic mechanisms of chronic pancreatitis is better understood. Some studies have identified certain factors that are associated with having a positive genetic test in adults with chronic idiopathic pancreatitis, which should help to select those patients who should undergo genetic studies. Antioxidant therapy has been shown to be effective in reducing pain secondary to chronic pancreatitis, although the type and optimal dose of antioxidants remains to be elucidated. Finally, the development of exocrine and endocrine pancreatic insufficiency is a very common finding during the long-term follow-up of patients with autoimmune pancreatitis. Smoking also seems to play a role in this type of pancreatitis.     

Natural course and medical treatment of chronic pancreatitis]

Chronic pancreatitis is a progressive disease without curative treatment. Abdominal pain is the most predominant symptom of chronic pancreatitis that initially brings most of the patients to the physician's attention. Some studies have correlated the course of pain in chronic pancreatitis in comparison with the duration of the disease, progressing exocrine and endocrine pancreatic insufficiency, and morphological changes such as pancreatic calcification and duct abnormalities. Furthermore, the course of pain has been studied after alcohol abstinence or surgery in some groups. However, there are only few well-performed and valid studies, and some of them even have produced diversing results, in part. Further controlled studies harboring a large number of patients in a multicenter setting should be considered. Therapeutic efforts on chronic pancreatitis have focused on palliative treatment of pain which is present in about 80% of cases. Endoscopic treatment of pain in chronic pancreatitis is useful and feasible in many patients. Selecting candidate for endotherapy is mandatory. Main indication of pancreatic stent insertion in chronic pancreatitis is the presence of an obvious ductal stricture. Complications of chronic pancreatitis are also indications of endoscopic intervention. Exocrine and endocrine insufficiencies should be meticulously managed to prevent complications and to maintain good quality of life.     

The natural history and physiopathology of chronic pancreatitis

Recent longitudinal studies have improved the knowledge of the natural history of chronic pancreatitis. This disease is mainly induced by alcohol abuse. Mean age at onset of the disease is 40 years. First symptoms are generally pain, often related to acute pancreatitis. Over the first five years of course, complications as pseudocysts or common bile duct stenoses can occur, often necessitating surgical treatment. In the late course, the disease becomes less symptomatic but the risk of diabetes mellitus increases. Occurrence of pancreatic calcifications is observed with time in the majority of patients. Chronic pancreatitis is associated with overmortality but the causes of death are mainly extrapancreatic (alcoholic liver disease and cancers). Abnormalities of pancreatic secretion induced by alcohol abuse play an important role in the pathophysiology of the disease: it is possible that the decrease of concentration of the "pancreatic stone protein" promotes formation of calcifications. Direct toxicity of alcohol is another possible factor.     

The Problem of Classification and Staging of Chronic Pancreatitis: Proposals Based on Current Knowledge of Its Natural History

Chari ST, Singer MV. The problem of classification and staging of chronic pancreatitis. Proposals based on current knowledge of its natural history. Scand J Gastroenterol 1994;29:949-960.

Background: Even though the four international meetings held so far on classification of pancreatitis have helped considerably to further our understanding of the disease, all have serious drawbacks that limit their clinical utility. The main problem with the Marseille classifications is the need for histologic proof, and the Cambridge classification relies on imaging modalities that are not sensitive or specific enough. Results: Chronic pancreatic inflammation (CP) has been observed in association with several systemic diseases (such as autoimmune diseases), and since the natural history of the pancreatic affliction in these conditions is clearly distinct from that seen in other forms of CP, these need to be classified separately. Furthermore, many clinical/aetiologic forms of chronic calcifying pancreatitis (CCP) exist which differ sufficiently in their clinical features and management to deserve individual recognition. Proposal: A subclassification of CCP into alcoholic, tropical, hereditary, hypercalcaemic, hyper-lipoproteinaemic, drug-induced, and idiopathic is proposed. The staging of chronic alcoholic pancreatitis has been a controversial issue, mainly because of the apparent unpredictability of the course of pain. However, several large follow-up studies in the past decade suggest that recurrent acute exacerbations dominate the clinical picture in the first few years after onset of symptoms, and progressive pancreatic insufficiency is the predominant feature in the late stages of the disease. On the basis of the results of these studies it is proposed that alcoholic chronic pancreatitis be divided into four stages: I) latent or subclinical, II) early, or stage of inflammatory complications, III) late, or stage of severe pancreatic insufficiency, and IV) advanced, or stage of secondary painless pancreatitis.     

Conservative treatment of chronic pancreatitis

Chronic pancreatitis has been difficult to treat because the origin, pathophysiologic mechanisms and causes of unrelenting pain are so poorly understood. Furthermore, the pharmacologic agents often employed in other diseases with pain appear to be ineffective in many cases. The conservative management of chronic pancreatitis aims at (1) limiting progression and complications of the disease; (2) replacing lost exocrine and endocrine function; and (3) pain control. Thus, life style changes such as cessation of alcohol consumption and tobacco smoking, trials of pancreatic enzymes, treatment of duct obstruction and pseudocysts, and surgical therapies are currently employed. The good news is that the understanding of the underlying pathophysiological mechanisms is now advancing rapidly, and hopefully patient-specific and highly effective therapies will become available in the near future.     

Surgical Approaches to Chronic Pancreatitis: Indications and Techniques

There are a number of surgical strategies for the treatment of chronic pancreatitis. The optimal intervention should provide effective pain relief, improve/maintain quality of life, preserve exocrine and endocrine function, and manage local complications. Pancreaticoduodenectomy was once the standard operation for patients with chronic pancreatitis; however, other procedures such as the duodenum-preserving pancreatic head resections and its variants have been introduced with good long-term results. Pancreatic duct drainage via a lateral pancreaticojejunostomy continues to be effective in ameliorating symptoms and expediting return to normal lifestyle in many patients. This review summarizes operative indications and gives an overview of the different surgical strategies in treating chronic pancreatitis.     

Systematic mechanism-orientated approach to chronic pancreatitis pain

Pain in chronic pancreatitis(CP) shows similarities with other visceral pain syndromes(i.e.,inflammatory bowel disease and esophagitis),which should thus be managed in a similar fashion.Typical causes of CP pain include increased intrapancreatic pressure,pancreatic inflammation and pancreatic/extrapancreatic complications.Unfortunately,CP pain continues to be a major clinical challenge.It is recognized that ongoing pain may induce altered central pain processing,e.g.,central sensitization or pro-nociceptive pain modulation.When this is present conventional pain treatment targeting the nociceptive focus,e.g.,opioid analgesia or surgical/endoscopic intervention,often fails even if technically successful.If central nervous system pain processing is altered,specific treatment targeting these changes should be instituted(e.g.,gabapentinoids,ketamine or tricyclic antidepressants).Suitable tools are now available to make altered central processing visible,including quantitative sensory testing,electroencephalograpy and(functional) magnetic resonance imaging.These techniques are potentially clinically useful diagnostic tools to analyze central pain processing and thus define optimum management approaches for pain in CP and other visceral pain syndromes.The present review proposes a systematic mechanism-orientated approach to pain management in CP based on a holistic view of the mechanisms involved.Future research should address the circumstances under which central nervous system pain processing changes in CP,and how this is influenced by ongoing nociceptive input and therapies.Thus we hope to predict which patients are at risk for developing chronic pain or not responding to therapy,leading to improved treatment of chronic pain in CP and other visceral pain disorders.     

Genetic predisposition to alcoholic chronic pancreatitis

The mechanisms leading to alcoholic chronic pancreatitis in humans have remained elusive. Numerous questions surround the apparent random nature of the disease in which 1 person is hit with alcoholic chronic pancreatitis while the next is spared. Why do fewer than 10% of chronic, heavy alcohol users ever develop pancreatitis, while others develop alcoholic liver disease, neuropathy, or other alcohol-associated problems? Why do laboratory animals, fed large amounts of alcohol for prolonged periods of time, fail to develop typical chronic pancreatitis? Why are heavy alcohol users from a black African background more likely to develop pancreatic diseases than Caucasians, whereas the opposite is true for the development of liver disease? The answers underlying these questions appear to reflect the differences in underlying genetic susceptibility, environmental exposure, and the interaction between these factors. Thus, even cases of "typical" alcoholic chronic pancreatitis or other forms of pancreatitis appear to be complex diseases. Recently, several genetic mutations have been identified that increase the susceptibility to pancreatitis. However, the major common gene mutations in CFTR, PRSS1, and SPINK1 only slightly increase the risk of alcoholic chronic pancreatitis. New genetic, environmental, and triggering factors must be considered to gain further insight into the mechanisms leading to alcoholic chronic pancreatitis so that strategies for treatment and prevention can be developed.     

The natural history of alcoholic chronic pancreatitis

An improved knowledge of the natural history is the indispensible basis for a rational concept in regard to the diagnosis, classification, understanding and management of pain in chronic pancreatitis. Unfortunately, data on the natural history of CP are scarce and conflicting. Some relevant observations of our prospective long-term study of a mixed medical-surgical cohort comprising 207 patients with alcoholic CP (mean follow-up 17 years from onset) are summarized. In early-stage CP, episodes of recurrent pancreatitis were predominant. Severe persistent pain was typically associated with local complications (mainly postnecrotic cysts in 54%; symptomatic cholestasis in 24%) relieved definitely by a drainage procedure. Lasting pain remission was documented in >80% of the whole cohort within 10 years from onset in association with marked pancreatic dysfunction. From our experience, the relief of "chronic" pain regularly follows selective surgery tailored to the presumptive pain cause or it occurs spontaneously in uncomplicated advanced CP (excluding narcotic addiction).     

Associated liver disease in alcoholic pancreatitis

Two studies investigating the association of liver disease with acute and chronic pancreatitis in alcoholics are presented. In a retrospective study of 50 patients, no clinical liver disease was found in 9 patients with acute pancreatitis, while 23 (56%) of 41 patients with chronic pancreatitis had liver disease by clinical criteria. Of this latter group, 8 were confirmed histologically; thus 19% of patients with chronic pancreatitis had biopsy-proven cirrhosis. Fifty alcoholic patients with pancreatitis were prospectively evaluated. All who had clinical evidence of liver disease were biopsied. No cases of liver disease were encountered in the 4 patients with acute pancreatitis. Although 28 (60%) cases of clinically diagnosed liver disease were present in 46 patients with chronic pancreatitis, only 20 of these seemed significant (cirrhosis, alcoholic hepatitis, severe fatty liver), for an incidence of 43%. Thus, clinically significant alcoholic liver disease occurs quite frequently in association with alcoholic pancreatitis. This association is meaningful in more effective management of these patients in general and in preoperative assessment of the risk of surgery in particular.Presented in part, at the Annual Meeting of American Pancreatic Study Group held on November 7, 1975, in Chicage, Illinois.     

Pancreas divisum does not modify the natural course of chronic pancreatitis

Background Pancreas divisum is the most common congenital variant of the pancreas; however, its clinical significance remains controversial. The purpose of our study was to determine the role of pancreas divisum in the development of chronic pancreatitis. Methods We compared the clinical presentation, morphological findings, and course of disease of 30 patients with chronic pancreatitis associated with pancreas divisum (there was coexisting chronic alcohol abuse in 18 cases) to those of 57 patients with chronic pancreatitis and no evidence of pancreas divisum (15 with nonalcoholic pancreatitis and 42 with alcoholic pancreatitis). Results Sex distribution, age at onset of disease, clinical presentation, course of disease, and frequency of complications were not affected by the presence of pancreas divisum. Although the etiology of pancreatitis in patients with pancreas divisum may be attributed to impaired drainage of the majority of the gland through the minor papilla, we observed a relatively low frequency of isolated dorsal duct involvement in our patients irrespective of alcohol use (25% and 28% in patients with and without a history of alcohol abuse, respectively). However, involvement of the ventral duct was commonly observed (75% and 72%, respectively). Conclusions The presence of pancreas divisum in our study did not modify the natural course of chronic nonalcoholic or alcoholic pancreatitis. Pancreas divisum is not likely to play a dominant role in the etiopathogenesis of chronic pancreatitis.     

Alcohol-induced pancreatic injury

Alcoholic pancreatitis is a major complication of alcohol abuse. Until recently, it was generally accepted that alcoholic pancreatitis was a chronic disease from the outset. However, evidence is now emerging in support of the 'necrosis-fibrosis' hypothesis that alcoholic pancreatitis begins as an acute process and that repeated episodes of acute injury lead to the changes of chronic pancreatitis (acinar atrophy and fibrosis) resulting in exocrine and endocrine dysfunction. The treatment of acute pancreatitis follows the regimen of bed rest, nasogastric suction, analgesia and intravenous support. The role of additional therapeutic measures such as prophylactic antibiotics, antioxidants and enteral nutrition in severe cases has not yet been precisely defined. The treatment of chronic pancreatitis involves attention to its three cardinal features: pain, maldigestion and diabetes. With respect to the pathogenesis of alcoholic pancreatitis, the focus of research over the past 30 years has shifted from the sphincter of Oddi and ductular abnormalities to the acinar cell itself. It has now been established that the acinar cell is capable of metabolizing alcohol and that direct toxic effects of alcohol and/or its metabolites on acinar cells may predispose the gland to injury in the presence of an appropriate trigger factor. A significant recent development relates to the characterization of pancreatic stellate cells, increasingly implicated in alcoholic pancreatic fibrosis. This chapter summarizes the natural history, clinical features, current trends in treatment as well as recent advances in our understanding of the pathogenesis of alcoholic pancreatitis.     

Mechanisms and natural history of pain in chronic pancreatitis: a surgical perspective

Pain is a major clinical manifestation of chronic pancreatitis (CP) and a common indication for surgery in these patients. Pathogenesis of pain in CP is multifactorial and the mechanisms of pain may differ from patient to patient. This can explain why one therapeutic method of treatment of pain does not work in all patients and in different stages of the disease. Two main complimentary pathogenetic theories have been proposed to explain the mechanisms of pain in CP, the neurogenic theory and the theory of increased intraductal/intraparenchymal pressures. According to the neurogenic theory, in CP there are alterations of pancreatic/peripancreatic nerves, exposing them to noxious substances and/or activated immune cells, thereby generating pain ("neuroimmune interaction"). The other theory of intraductal/intraparenchymal hypertension suggests that pain in CP is generated as a result of increased pressures within the pancreatic ductal system and/or pancreatic parenchyma, like the pain in the classic compartment syndrome. The theory of intraductal/intraparenchymal hypertension is strongly supported by the good results of drainage procedures in the surgical management of CP. Pancreatic ischemia, oxygen-free radicals, centrally sensitized pain state, acute exacerbations of CP, development of complications from the pancreas (most commonly, pseudocysts) or adjacent organs (usually, duodenal and/or common bile duct stenosis), etc. are other possible contributing factors. Different patterns of pain have been described in idiopathic (early vs. late onset) and in alcoholic CP. Interestingly, pain is automatically relieved during the natural course of the disease in some patients (the "burn-out" phenomenon), after a relatively long time (from a few years to up to 3 decades). However, this is an unpredictable evolution for the individual patient. Therefore, surgery should be offered when pain is intense and after failure of conservative treatment. Surgical management should be individualized, depending on the particular findings of each patient. The knowledge of the pathophysiologic basis and of natural course of pain in CP is of paramount importance for the surgeon to select appropriate therapy for the individual patient with CP.     

Effect of cessation of alcohol use on the course of pancreatic dysfunction in alcoholic pancreatitis

Exocrine pancreatic function was studied sequentially by means of the secretin-cerulein test in 32 patients with alcoholic chronic pancreatitis to elucidate the long-term course of pancreatic dysfunction, and to determine whether the cessation of alcohol use had any influence on the natural history of pancreatic functional changes caused by this disease. At initial studies, 5 patients had normal pancreatic function, and the remaining 27 had pancreatic insufficiency, which was mild to moderate in most subjects. The final studies, carried out at an average of 7.3 yr (range, 4-11 yr) after the first, showed a significant deterioration in pancreatic function, both in patients who stopped alcohol after the initial study (n = 18) and in those who did not (n = 14). The deterioration, however, was significantly less marked in patients who stopped drinking alcohol than in those who continued. These data indicate that pancreatic functional changes caused by alcoholic pancreatitis progress even after cessation of alcohol use; however, the progression is slower and less severe when alcohol intake is stopped.     

慢性胰腺炎的相关因素及诊治分析

目的研究我国慢性胰腺炎（CP）的相关因素及诊治特点。方法回顾分析我国近10年21所综合医院确诊为CP的1700例住院患者，调查其相关因素、诊断方法及治疗措施。结果近年我国CP的发病有增多趋势，男性多于女性。相关因素中以慢性乙醇中毒为主，1700例患者中，酒精性601例（35．4％），胆源性576例（33．9％），其他相关因素包括自身免疫性疾病、胰腺外伤等。反复发作的腹痛为最常见症状，少数患者表现为脂肪泻或体重减轻等。组织学检查是CP诊断的金标准，但大部分患者经由影像学检查及胰腺外分泌试验（BTPABA试验）诊断。85.9％的患者经非手术治疗获得症状缓解。结论重度饮酒已成为我国CP的主要致病因素，影像学检查在CP诊断中具有重要作用，非手术治疗是目前治疗慢性胰腺炎的主要方法。     

Chronic pancreatitis. Long-term pain relief with or without surgery,cancer risk,and mortality

To determine the natural history of chronic pancreatitis (CP), we retrospectively studied 193 consecutive patients who had at least one hospitalization for the control of pain or a complication of CP by examining the hospital records and by using a standard questionnaire. Alcohol (66%) was the major cause of CP and the cause was unknown in 21%. Pain was the presenting symptom in 93%. Pancreatic calcification was observed in 41% (alcoholic 54% vs. nonalcoholic 19%; OR = 6.7, CI = 2.7, 14.3; p < 0.0001). Diabetes (28%), malabsorption (16%), pseudocysts (21%) and pancreatic (3%) or extrapancreatic malignancy (5%) were the main complications. 43% had surgical intervention for pain relief, 10% had either endoscopic sphincterotomy or surgical sphincteroplasty and 16% had surgery for complications. Surgical or endoscopic intervention was more commonly performed in nonalcoholics compared with alcoholics (OR = 12.8, CI = 3.6, 53.9; p < 0.0001). However, if sphincterotomy and sphincteroplasty were excluded, the total number of surgical procedures for pain relief was similar in both groups. Complete follow-up information was available in 107 patients with a mean duration of follow-up of 10 years (range, 1-28 years); 27 patients died during the follow-up; 5, 10 and 15 year mortality was 14%, 18% and 20% respectively. The mortality was significantly higher in patients with alcoholic CP than in nonalcoholic CP (35% vs. 10%; OR = 1.4, 18.7; p = 0.005). Of the 80 patients who were alive and had complete long-term follow-up, pain improved in 62 patients, remained unchanged in 17 and worsened in one. Pain improved in 34 of 41 (83%) patients who had surgical intervention for pain, 7 of 9 patients (78%) who had surgery for complications, 4 of 7 (57%) who had sphincter ablation and 17 of 23 patients (74%) who had nonprocedural treatment. Long-term pain relief was similar in patients with alcoholic and nonalcoholic pancreatitis.     

Clinical evidence of pathogenesis in chronic pancreatitis

Chronic pancreatitis is a continuing inflammatory disease characterized by irreversible morphological change and, typically, by pain and permanent impairment of function. The pathogenesis of pancreatitis, either acute or chronic, is still controversial. There have been no widely accepted concepts to provide a reasonable explanation linking the known etiological factors and the pathophysiological aspects of the disease. Alcohol is undoubtedly the major etiological factor in most countries, and the relative importance of alcohol as a cause of chronic pancreatitis ranges from 40% to 90% in various countries. As fewer than 10% of alcoholics develop chronic pancreatitis, other nutritional or genetic influences are likely to be involved in the pathogenesis of alcoholic pancreatitis. Accessory pancreas incidentally found in patients with chronic alcoholic pancreatitis does not always have the pathological findings seen in the main pancreas. Integrity of the pancreatic duct seems to be another important factor for chronic alcoholic pancreatitis. Gene mutations of the cystic fibrosis transmembrane conductance regulator (CFTR), cationic trypsinogen, and pancreatic secretory trypsin inhibitor have been investigated in idiopathic chronic pancreatitis. Molecular and cell biology research during the past few years has elucidated pathophysiological factors that are involved in the pathogenesis of chronic pancreatitis, but cannot demonstrate a common pathway between etiological factors and the pathogenesis or development of the disease.