In Brief

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Chronic pancreatitis is an ongoing inflammatory disorder characterized by irreversible destruction of the pancreas associated with disabling chronic pain and permanent loss of exocrine and endocrine function. The apparent incidence of chronic pancreatitis has nearly quadrupled in the past 30 years, although this likely represents increased recognition due to broader definitions and improvements in pancreatic imaging (with consequent inclusion of earlier stage patients) rather than a true increase in occurrence. Because of our limited understanding of disease pathogenesis, the unpredictability of the clinical course in a given individual, and controversies in both diagnostic criteria and therapeutic options, management of patients with suspected chronic pancreatitis remains a challenge. Recent years have seen several important scientific and clinical advances, and therefore a review of some of these developments in the context of our current strategies for diagnosis and management of chronic pancreatitis at the University of Cincinnati Pancreatic Disease Center is timely.

The distinction between acute and chronic forms of pancreatitis may be difficult to make on clinical grounds alone, since each may manifest as an initial episode of abdominal pain, nausea, and vomiting associated with elevation of the serum amylase and lipase and with similar nonspecific inflammatory changes on noninvasive pancreatic imaging studies (at least in the early phases of chronic pancreatitis). Acute and chronic forms of pancreatitis are characterized by overlapping risk factors and are thought to share a common pathogenetic origin as a pancreatic autodigestive process. Certain forms of pancreatitis do appear to have the potential to evolve into chronic pancreatitis, but it is far from universally accepted that acute pancreatitis is a precursor to the chronic form. Several attempts have been made to standardize terminology and draw distinctions between acute and chronic disease. Currently, the best available approach to etiology/risk factor categorization is the TIGAR-O classification system developed by the Midwest Multicenter Pancreatic Study Group. TIGAR-O introduces the concept of risk modifiers, not etiologies, which interact in a given patient to induce pancreatitis. Each of the risk factors identified in the TIGAR-O system predisposes an individual to the development of chronic pancreatitis, but these risk factors are likely to operate through different mechanisms.

The natural history of chronic pancreatitis is not well-defined and tends to vary with respect to etiologic factors, genetic predisposition, and the presence of anatomic complications such as pseudocyst, biliary stricture, and duodenal obstruction. The factors that account for the pace and extent of disease progression are ill-defined, although more is known about alcohol-associated chronic pancreatitis than about other etiologies. Studies that have followed patients with chronic pancreatitis have demonstrated a mean age of disease between 30 and 36 years. The mean age at the time of death was 54 years for alcohol-associated disease and 67 years for the remaining patients, with death directly related to complications of pancreatitis in only 19%. The major causes of death were malignancy (predominantly adenocarcinoma of pancreas and aerodigestive tract origin), cardiovascular events, cirrhosis, or severe infections. Fifty percent survival appeared to be 20 to 24 years after onset of chronic pancreatitis. Nearly one third of the patients underwent pancreatic operations for the indication of severe pain during this time, largely decompressive procedures, with 50% experiencing lasting pain relief.

Over the past several decades, several theories have emerged to explain the pathogenesis and evolution of pancreatitis. Four have received particular attention: (1) toxic-metabolic, (2) oxidative stress, (3) stone and duct obstruction, and (4) necrosis-fibrosis. These models provide conceptual frameworks that are not mutually exclusive but at times are mutually contradictory. Each theory is undermined by oversimplification and a tendency to gloss over persistent gaps in the chain of causality. Moreover, none of the existing theories accounts for the heterogeneity of clinical phenotypes. One of the fundamental barriers to the development of a comprehensive model of chronic pancreatitis pathogenesis has been the absence of a suitable experimental model that recapitulates the human disease. More recently, the SAPE (sentinel acute pancreatitis event) hypothesis, introduced by Whitcomb, has been proposed and integrates several of the foregoing concepts into a unified pathway that accounts for disease progression. The hypothesis was based initially on observations of the evolution of patients with hereditary forms of pancreatitis. The 2 central tenets of the SAPE hypothesis are, first, that progression to chronic pancreatitis requires an initiating event that “primes” the pancreas for fibrogenesis and, second, that fibrosis is driven by anti-inflammatory (rather than proinflammatory) cellular responses. According to this model, exposure of the normal pancreas to alcohol or other factors (particularly in the setting of acinar cell hyperstimulation) leads to toxic-metabolic and oxidative stresses that induce the release of cytokines and other mediators from acinar cells, yet because the normal gland contains few inflammatory effector cells, acute inflammatory infiltrates do not develop and fibrosis does not occur. If a critical (undefined) threshold is reached, acute pancreatitis is triggered and results in local infiltration of leukocytes, lymphocytes, and circulating macrophages. The SAPE hypothesis is an attractive explanation for the progression of pancreatic fibrosis and is consistent with elements of the necrosis-fibrosis hypothesis, the toxic-metabolic hypothesis, the oxidative stress hypothesis, and the duct obstruction hypothesis.

Over the past decade, molecular insights into hereditary and idiopathic pancreatitis have been made that carry important implications for the pathogenesis of alcohol-associated and other forms of chronic pancreatitis. Genetic defects have been identified that originate in acinar cells (related to digestive enzyme activity and stability) and ductal cells (related to the characteristics of pancreatic secretions). These mutations have both autosomal dominant and recessive patterns of inheritance with variable penetration and may be influenced by certain modifier genes and environmental factors. Since the discovery of specific genes linked to chronic pancreatitis, it has become clear that these defects alone are not sufficient for the development of the disease. Chronic pancreatitis appears to require the combination of genetic predisposition and a second environmental, structural, or toxic insult. Improved understanding of this disease will no doubt derive from the more focused application of genomic and proteomic techniques in susceptible populations. What has become abundantly clear, however, is that chronic pancreatitis is far from merely a “drunkard’s disease.”

The diagnosis of chronic pancreatitis in the majority of patients is usually straightforward, based on the constellation of clinical history, supporting laboratory investigations, and imaging studies. However, in certain instances, establishing the diagnosis can be surprisingly difficult. This is particularly true for patients with early or mild small-duct or so-called minimal change variants. Particularly challenging are patients who report pancreatic-type pain but who have normal biochemical and imaging studies. Chronic pancreatitis should be considered in all patients with unexplained abdominal pain. The pain of chronic pancreatitis can be intermittent or continuous and variable in severity. It is typically triggered by pancreatic stimulation, particularly after a meal rich in fat or proteins, which may lead to fear of eating with consequent weight loss. The diagnostic evaluation should begin with simple, noninvasive, and relatively inexpensive tests and followed by more complicated testing if the diagnosis remains uncertain. The current available diagnostic tests are divided into tests to assess pancreatic structure and function. Serum markers such as amylase and lipase are typically elevated during attacks of pain early in the course of the disease, although these may be entirely normal in the later phases with progressive destruction of the gland. On imaging, findings that are associated with chronic pancreatitis include parenchymal atrophy and focal enlargement, ductal calcification, pancreatic and biliary ductal dilation, and pseudocysts. Over the last 15 years, significant advances in noninvasive imaging techniques have provided additional methods in the assessment of patients with chronic pancreatitis. Newer techniques in computed tomography (CT) and magnetic resonance (MR) imaging have greatly increased our ability to diagnose chronic pancreatitis.

Patients with chronic pancreatitis generally seek medical treatment because of chronic unrelenting abdominal pain or frequent flare-ups. As the disease progresses, pancreatic exocrine and endocrine dysfunction may require treatment. The aim of medical therapy is to ameliorate pain without interfering with work and family life. Although the pain of chronic pancreatitis may “burn out” over time, particularly in alcohol-associated disease, the duration over which this may occur is highly variable (6 to 8 years in 50% of the patients and in most cases after 10 years), if it occurs at all. As a general rule, pain management should proceed in a stepwise approach beginning with elimination of exogenous toxic factors such as alcohol, followed by pancreatic enzyme supplementation, and then judicious use of analgesics. Patients with continued symptoms may be candidates for more invasive options, which should probably be performed only in specialized centers.

Unfortunately, more than 50% of patients develop progressive or intractable symptoms and become candidates for surgical intervention. Operative intervention may be required for complications of pancreatitis such as pseudocyst or fistula formation, stricture of neighboring structure, or suspicion of neoplasia. However, the primary indication for surgery is intractable abdominal pain. The etiology of pain in chronic pancreatitis is unclear. It is believed to be multifactorial caused by a combination of perineural inflammation, obstruction of the pancreatic duct causing increased ductal pressure, or due to chronic changes in the pancreas parenchyma. A variety of surgical options are available. Operations to relieve pain involve resection, decompression, or a combination of the 2. Resective procedures include pancreatic head resection (ie, Whipple procedure), pancreatic tail resection (distal pancreatectomy), and total pancreatectomy. Decompressive procedures include lateral pancreaticojejunostomy, cyst-enterostomy, and sphincterotomy/sphincterplasty.

More recently, at the University of Cincinnati, we have been performing total pancreatectomy and autologous islet cell transplantation for patients with chronic pancreatitis. In our experience with 54 patients, an insulin independence rate of 40% and narcotic independence rate of 70% can be achieved in properly selected patients. Although longitudinal studies are needed to assess long-term graft function more fully, this procedure should be considered for patients who undergo partial or total pancreatectomy for chronic pancreatitis.