Chronic pancreatitis

Symptomatic pancreatitis can be associated with pancreatic cell death and/or with ductal fibrosis and calcification. Acute pancreatitis, such as that induced by passage of a gallstone, is thought to be pathogenetically and morphologically different from chronic pancreatitis19 and generally resolves without permanent structural abnormalities. Chronic pancreatitis is associated with permanent abnormalities, but may present with an acute necrotic episode. Excessive alcohol consumption is the primary etiology in 70-80 percent of the cases of chronic pancreatitis in developed nations, although the precise mechanism of action of alcohol has not been determined. First described in 1788 by Cawley in his description of "a free living young man'' who developed severe pancreatic disease, it has been described as a "drunkard's pancreas'' since 1878. Only 5-10 percent of heavy drinkers develop symptomatic chronic pancreatitis and so there are likely genetic, infectious, and/or nutritional factors that also contribute to its development. The other 20-30 percent of cases of chronic pancreatitis are predominantly idiopathic in origin, although other etiologies include a pancreas divisum, genetic causes (hereditary-type), previous trauma, previous obstructive episodes, hyperparathyr-oidism, hyperlipidemia, statin use,20 and a 1-antitrypsin deficiency. In certain Third World nations, a tropical variety of chronic pancreatitis is common and has been associated with specific dietary patterns.

Various theories have been put forward related to the precise pathophysiology of chronic pancreatitis. Experimentally, chronic pancreatitis may be induced in animals by the administration of toxins but similar links have not been conclusively identified in humans. Alterations in the protein components of pancreatic fluids have been noted which may result in the formation of "sludge" or intraductal "plugs" that become calcified into "stones" which produce inflammatory and fibrotic reactions.21 It has been proposed that oxidative stress underlies chronic pancreatitis with periodic bursts of free radical formation leading to chronic injury. Genetic factors have been clearly identified in hereditary pancreatitis and in association with such diseases as cystic fibrosis, but no specific marker has been identified in association with other etiologies. Intraductal hypertension is a common sequel of stone formation/fibrosis and has been proposed as a source of the continuous pain that may develop in chronic pancreatitis. However, relief of ductal obstruction and hypertension does not invariably result in pain relief. Similarly, pancreatic intraparenchymal pressure, a correlate to myofascial compartment syndromes with associated ischemia and neural compression, has also been proposed as the source of pain. As stated before, for most cases of chronic pancreatitis a common finding is a high level of chronic alcohol ingestion. The average latent period is 18 years and a comorbidity is cirrhosis of the liver (to complement "cirrhosis" of the pancreas.)

Cigarette smoking is associated with increased incidence of chronic pancreatitis22 and diets with too much or too little fat and/or protein have been implicated.

Histopathologically, chronic pancreatitis is identified by the presence of intraductal calcification (stones), aci-nar cell loss, fibrosis, and inflammation. Proliferation of unmyelinated nerve fibers and mononuclear cell infiltrates around nerve sheathes has been noted and elevated levels of the neuropeptides have been identified23 but, unfortunately, identifiable pathology does not firmly correlate with reports of pain.

The primary presenting complaint is pain. Classically, it is deep, boring, and epigastric with frequent radiation through to the back. It may be episodic in nature but may advance until it is continuous and may be precipitated by eating. Sitting upright or leaning forward may decrease the pain. It is often coupled with nausea and vomiting which may lead to dehydration, malnutrition, and an inability to take oral analgesics. Steatorrhea due to pancreatic insufficiency may result with advanced disease as may glucose intolerance and eventual diabetes mellitus with associated clinical history. Subjects with alcoholic chronic pancreatitis are generally thin individuals (often emaciated) and may have stigmata associated with extensive alcohol use and associated liver failure. An inflammatory mass may be palpable but typically abdominal guarding precludes adequate deep palpation. There are no definitive findings on physical exam.

Diffuse intraductal calcium deposition is pathogno-monic of chronic pancreatitis and this may be demonstrated by plain abdominal radiographs in 30 percent of cases. Ultrasonagraphic evaluation is 60-70 percent sensitive for intraductal abnormalities and computed tomography is 90 percent sensitive. Endoscopic retrograde cholangiopancreatography (ERCP) is the "gold standard'' for chronic pancreatitis based on ductal abnormalities which are graded by severity. Newer, non-invasive imaging studies include magnetic resonance cholangio-pancreatography. Elevated serum amylase and lipase levels indicate a pancreatic exocrine cell damaging process. Pancreatic function tests have found less utility with improved sensitivity of other diagnostic modalities.

A system of stratification or subgroupings of patients by morphological or functional criteria has never been agreed upon.19 Differential diagnoses must include pancreatic cancer but also include peptic ulcer disease, irritable bowel syndrome, gallstones, and endometriosis. An initial first step in the management of pain in patients with chronic pancreatitis is the exclusion of complications that can be the cause of the pain such as pseudocysts or compression of adjacent visceral structures.24

The literature related to the treatment of pain in chronic pancreatitis consists of numerous retrospective collections of patients subjected to treatments determined by interest in applying a certain method.19 Until recently, few studies of chronic pancreatitis pain have employed placebo-controlled methodologies. Those that have, generally demonstrated limited effects of the studied treatment. Interventional/procedural studies have generally not had controls performed. The symptomatology of chronic pancreatitis is episodic in nature with frequent exacerbations and spontaneous resolution. Hence, any "open" study which is initiated during an exacerbation (when the patient presents to the study physician for treatment) is likely to be deemed effective in some patients due to the natural course of the disease. Therapeutic options for chronic pancreatitis are listed in Box 40.4 and a suggested treatment pathway given in Figure 40.1.

For alcoholic chronic pancreatitis, the initial treatment is abstinence from alcohol. If the patient continues to drink, their five-year mortality rate approaches 50 percent; if they do not drink, it takes 25 years to achieve a mortality rate of 50 percent. Psychological therapies directed toward developing alternative coping mechanisms and abstaining from alcohol are considered vitally necessary, but outcomes related to substance abuse treatment are mixed and not limited to this specific population. It has been commonly reported that total abstinence from alcohol achieves pain relief in up to 50 percent of patients, particularly those with mild to moderate disease,24'26 but even this tenet of care has been questioned.33

The endoscopic placement of stents, sphincterotomy, dilatation, and/or stone removal are well-established alternatives to surgery in the treatment of biliary tract diseases, and similar techniques for the relief of chronic pancreatic pain have developed.28 However, recent randomized comparisons of endoscopic versus surgical management of ductal obstruction have suggested superiority of surgical intervention.29,32 Extracorporeal shock-wave lithotripsy with or without associated endo-scopic procedures to remove stones from pancreatic ducts has been effective at reducing pain.30,34

Opioids are the primary analgesic therapy of advanced chronic pancreatitis,25 although some have suggested use of "adjuvants" such as antidepressants. There is the unfortunate but common experience of clinicians that patients who have alcoholic pancreatitis may exchange their alcohol addiction for an opioid addiction. Patients with substance abuse histories develop painful diseases and ethically require treatment, but clinicians still experience significant angst in association with their patients' symptomatic treatment. Both corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs) would seem logical choices in the treatment of a chronic inflammatory process. However, case reports35,36 of pancreatitis induced by these agents has temporized their use.

Based on the oxidative stress hypothesis, placebo-controlled medical trials of antioxidants and micro-nutrients such as vitamins C and E, p-carotene, S-ade-nosylmethionine, and selenium have produced favorable results.2527 Oral pancreatic enzyme treatments have been utilized as inhibitors of pancreatic enzyme secretion with a resultant decrease in intraductal pressure. This negative feedback strategy has been effective at reducing pain and improving quality of life in some studies37 but results overall have been mixed.25 Negative feedback inhibition of pancreatic secretion can also be provided by soma-tostatin or its analogue octreotide and have similarly had mixed results related to pain, but they clearly affect some of the processes thought to be associated with complications of pancreatitis thought to be involved in the generation of pain (pseudocysts and fistulas).25 Other pharmacological therapies that have undergone clinical trials with some measure of success related to pain include kappa opioid receptor agonists,38 loxiglumide (a CCK-A receptor antagonist), and secretin which also improved pancreatic secretion viscosity25 A notable failure in clinical trial was use of montelukast, a leukotriene receptor antagonist, which failed to have any effect on

pain.39

Celiac plexus blocks with local anesthetics have been used for diagnostic purposes,40 as part of protocols for the determination of eligibility for surgical treatment41 and as primary therapies when coupled with steroids.31,40 It is notable that series reporting the efficacy of intraceliac plexus steroids did not compare their treatment with systemic steroids, although significant central nervous system effects of the steroids (i.e. acute mania) have been repor-ted.42 NCPBs have been performed using alcohol or phenol. NCPB for the treatment of nonmalignant pancreatic pain has both proponents43 and opponents.44 Fugere and Lewis45 reviewed 20 series in which NCPBs were utilized for chronic pancreatitis and concluded that there were deficiencies in every report stating that most of the studies were not prospective, randomized, or controlled. They also noted that results of NCPB on chronic pancreatitis pain were not as good as those for cancer-related pain. Enthusiasm for NCPB for chronic pancreatitis has also been tempered by

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