Overview

The most common etiology of chronic pancreatitis (CP) in adults in Western societies is long-term alcohol abuse, which accounts for 70% of cases. Although many of the etiologies of CP are well known, as are the clinical and morphologic characteristics, the pathogenic mechanisms of CP have remained elusive. Major scientific progress has been made in the understanding of the underlying genetic, cellular, and molecular aspects of CP, but ongoing debate continues regarding the initiating events of the various factors of CP. Multiple hypotheses have been proposed to explain the pathophysiology in subgroups of patients with CP, but to date no single, unifying theory exists. The best known hypotheses about the pathogenesis of CP include necrosis-fibrosis, toxic-metabolic causes, oxidative stress, plug and stone formation with duct obstruction, primary duct obstruction, and the sentinel acute pancreatitis event (SAPE).

CP is a well-defined disease on histopathologic grounds, but histology is rarely available for diagnosis; therefore the diagnosis is reached by using a combination of clinical, laboratory, and imaging criteria. The correct diagnosis of CP is easy in late stages but difficult in early stages of the disease. Several imaging methods are available for patients with known or suspected CP. In early stages of the disease, both endoscopic retrograde pancreatography (ERP; see Chapter 18) and endoscopic ultrasonography (EUS; see Chapter 14) are methods with reliable diagnostic accuracy. Initial studies have shown superiority of EUS over ERP for the diagnosis of CP in its early stages. Transabdominal ultrasonography (US) is less sensitive for diagnosis of CP and is limited only to patients with advanced disease. In patients with an early stage of disease, we believe that EUS is the method of choice. In the absence of EUS, the combination of ERP and computed tomography (CT; see Chapter 16) provides the most reliable morphologic information. Among all imaging methods, magnetic resonance imaging (MRI), includingmagnetic resonance cholangiopancreatography (MRCP), has seen the most rapid development over the last years (see Chapter 17). With further improvement of hardware and software, it is likely that these methods will be capable of visualizing even early stages of the disease in the near future. The most common pancreatic function tests do not detect mild to moderate exocrine pancreatic insufficiency with adequate accuracy, therefore functional investigation techniques of the pancreas play only a complementary role in the routine clinical evaluation of CP but are important methods used in clinical research and in specialized pancreatic disease centers.

This chapter is divided into three sections. The first part presents the known etiologies of CP; the second part is a discussion of the most important pathogenic mechanisms of CP. The etiology and pathogenesis of CP are presented based on the TIGAR-O classification (toxic–metabolic, idiopathic, genetic, autoimmune, recurrent severe, obstructive) proposed by Etemad and Whitcomb (2001) and elegantly delineated by Stevens and colleagues (2004). It is inevitable that data must be provided on the pathogenesis of CP while presenting its etiology and vice versa; in this manner, the reader will have a better comprehension of the disease process. The third part of this chapter discusses an approach to the diagnosis of CP, with emphasis on the use of radiologic diagnostic methods, and a brief discussion of the most commonly used pancreatic function tests.

Etiology Of Chronic Pancreatitis

The classification of CP has evolved during the last several decades, and the basis for such classification stems from three consensus conferences: Marseille in 1963, Marseille-Rome in 1986, and Cambridge in 1984 (Axon et al, 1984; Sarles, 1986, 1991; Singer et al, 1985). Subdivisions of CP are based mainly on imaging characteristics, but newer classification systems such as the TIGAR-O categorize CP based on the various known etiologic factors and mechanisms jointly considered to be risk modifiers (Chari & Singer, 1994; Etemad & Whitcomb, 2001). It is likely that these risk modifiers, as well as multiple genetic and environmental cofactors, interact to produce expression of the disease in a given individual (Bourliere et al, 1991; Cavallini et al, 1994; Cavestro et al, 2003; Cohn et al, 1998; Ichimura et al, 2002; Whitcomb, 2001). It is clear that an individual, whose genetic composition is unique, will respond or not respond to an insult of similar etiology in a different morphologic pattern (inflammation or no inflammation) giving rise to disease. Response to an insult results in presence or absence of disease and progression or regression of the disease. Progression is likely to be closely related to the individual’s genetic characteristics and to ongoing environmental toxic or infectious insults. This general concept explains why individuals respond differently to the same amounts of a toxin, such as alcohol, or why less amounts of the same toxin produce disease in a susceptible individual. Furthermore, the low prevalence of CP among alcoholics would seem to suggest other cofactors at play in many with diagnosed “alcoholic” pancreatitis. In fact, the presence of multiple risk factors may be required for progression to fibrosis. The various etiologies of CP based on the TIGAR-O system (Stevens et al, 2004) provide a further advancement in the etiologic and mechanistic classification of CP, although we anticipate it will likely require revision in the future. For example, the category of “idiopathic” will tend to decrease or even disappear as other etiologies are being discovered (Jansen et al, 2002; Mahlke et al, 2005; Teich et al, 2005; Whitcomb, 2001; Whitcomb et al, 1996a; Whitcomb & Schneider, 2002; Witt et al, 2000, 2001).

AIP, autoimmune pancreatitis; PD, pancreas divisum

In the past it was believed that at the time of the initial attack, most patients with alcohol-induced CP already had underlying fibrosis and calcifications of the pancreas, but the Zürich group has demonstrated that acute attacks preceded the development of chronic disease (Ammann & Muellhaupt, 1994). Because only a fraction of alcoholics develop CP, involvements of other factors are actively being investigated. Several lines of evidence have shown that in addition to the direct effects of alcohol, various predisposing factors, such as genetics, smoking, intestinal infection, high-fat diet, compromised immune function, gallstones, gender, hormonal factors, and drinking patterns, may render the pancreas more susceptible to alcohol-induced tissue injury (Angelini et al, 1993; Lankisch et al, 2002; Levy et al, 1995; Lowenfels et al, 1994; Sahel et al, 1986). Many patients thought to have CP as a result of alcohol abuse, may indeed have a higher inherited susceptibility to alcohol-induced pancreatic damage or genetic defects that cause pancreatitis independent of alcohol exposure (Malats et al, 2001; Stevens et al, 2004).

There is convincing evidence that smoking is also independently associated with increased risk for CP, with odds ratios as high as 17.3 (Talamini et al, 1996). CP induced by smoking is particularly associated with pancreatic calcifications. By mechanisms similar to alcohol, tobacco produces alterations in the secretion and composition of pancreatic juice mainly as a result of decreased pancreatic juice and bicarbonate secretion and induction of oxidative stress (Bynum et al, 1972; Cavallini et al, 1994; Crowley-Weber et al, 2003; Stevens et al, 2004). In a large study involving 146 patients with CP, 52 patients with pancreatic cancer, and 235 healthy controls, Ockenga and colleagues (2003) analyzed the genomic DNA for expression of uridine 5′-diphospho (UDP) glucuronosyltransferase (UGT1A7) genes. These proteins are vital biochemical factors for detoxification and cell defense. The incidence of this mutation was much more common in patients with CP and tobacco abuse but not in patients with nonalcoholic CP. This study establishes the possible connection between genetic predisposition and external triggering factors. It is possible that smoking is the main factor of CP in some patients, whereas in others smoking may increase the damage induced by alcohol, and in another group it might potentiate an as yet unidentified factor or pathogen (Crowley-Weber, 2003).

Calcium plays a central role in trypsinogen secretion and trypsin stabilization. Hypercalcemia as a result of primary or secondary hyperparathyroidism results in recurrent acute pancreatitis, which progresses to CP, likely due to trypsinogen activation, which in turn results in necrosis and fibrosis of the parenchyma (Goebell, 1976; Noël-Jorand et al, 1981). Increased serum calcium concentration is believed to induce direct damage to acinar cells, and increased secretion of calcium results in intraductal stone formation. It also appears that hypercalcemia modifies pancreatic secretion and leads to protein plug formation (Goebell, 1976; Noël-Jorand et al, 1981), in turn resulting in varying degrees of pancreatic fibrosis with calcifications. This is likely due to hypercalcemia related to secondary hyperparathyroidism, but other mechanisms msy nr involved, including toxicity of uremic substances to the pancreatic parenchyma (Karanjia et al, 1992; Owyang et al, 1982).

Idiopathic

Up to 30% of patients with CP have no known risk factors; therefore the CP they have is called idiopathic. It is likely that many of these patients are mislabeled because of underreported alcohol abuse, an underlying genetic abnormality, or other unknown factors (Truninger et al, 2002; Witt, 2000). Pfützer and colleagues (2000) and Witt and colleagues (2000) have described mutations of the serine protease inhibitor Kazal type 1 (SPINK1 gene) in up to 25% of patients with idiopathic CP. Based on the bimodal age of onset of the clinical symptoms, idiopathic pancreatitis is separated into two distinct entities: Early idiopathic CP is seen during the first 2 decades of life, with abdominal pain being the predominant clinical feature, whereas pancreatic calcifications and exocrine and endocrine pancreatic insufficiency are very rare at the time of first diagnosis (Layer et al, 1994). In contrast, the clinical presentation of late-onset idiopathic CP is in patients during their fifth decade of life, usually following a rather painless course but associated with significant exocrine and endocrine pancreatic insufficiency and pancreatic calcifications (Layer et al, 1994; Papachristou & Whitcomb, 2004). Histologically, many cases of idiopathic chronic pancreatitis have T-lymphocyte infiltration, ductal obstruction, acinar atrophy, and fibrosis, raising the possibility of autoimmune etiology.

Tropical or nutritional pancreatitis is considered a form of idiopathic CP. It is the most common form of CP in certain parts of the world, such as India, sub-Saharan Africa, and Brazil, where it is a disease of youth and young adulthood (Schneider et al, 2002). The disease is subdivided into tropical calcific pancreatitis, characterized by severe recurrent and chronic abdominal pain and extensive pancreatic calcifications and fibrocalculous pancreatic diabetes with significant pancreatic endocrine insufficiency. This form of CP is clearly related to mutations in the SPINK1 gene (Chandak et al, 2002). Based on this important fact, this form of CP is likely going to be categorized as genetic. The SPINK1 pancreatic secretory trypsin inhibitory (PSTI) gene, is responsible for the encoding of SPINK1 (Chandak et al, 2002; Schneider et al, 2002). PSTI has the main function of inhibiting activated trypsin. SPINK1 is the major intrapancreatic “deactivator” of activated trypsinogen (Kukor et al, 2002; Teich et al, 2005). Trypsin has a central role in the digestion of dietary proteins and in the activation of other digestive enzymes. If the trypsin inhibitory protein malfunctions or cannot bind itself to trypsin, then trypsin is not properly deactivated or destroyed, and it remains active for a longer period of time. This is called a gain of function of trypsin (Gorry et al, 1997; Kukor et al, 2002; Pfützer et al, 2000; Sahin-Tóth, 2000; Stevens et al, 2004; Whitcomb et al, 1996a). Other genetic alterations have been described in patients with idiopathic CP. Cohn and colleagues (1998) and Durie (1998) independently demonstrated the strong association between cystic fibrosis transmembrane regulator (CFTR) mutations and idiopathic CP. In patients without evidence of cystic fibrosis, the frequency of CFTR mutations was six times that of patients without mutations. Subsequently, Cavestro and colleagues (2003) reported that one third of all patients with idiopathic CP have CFTR mutations. In the future, many patients categorized under idiopathic CP will fall into the categories of the other risk factor groups, specifically in the genetic category. In fact, leading pancreatologists speculate that most CP might be a genetic disease with multifactorial triggering factors (Papachristou & Whitcomb, 2004; Stevens et al, 2004; Whitcomb et al, 1996b).

Genetic

Until a few years ago, data on the genetic basis of CP were scarce. The only well-studied hereditary form of chronic pancreatic insufficiency was cystic fibrosis (Cohn et al, 1998; Durie, 1998). Many cases of CP represent a variable part of the cystic fibrosis syndrome, which is caused by mutations in the gene coding for the cystic fibrosis transmembrane conductance regulator. Several groups have reported an increased prevalence of CFTR mutations in patients with chronic pancreatitis of different etiologies. Later studies demonstrated that the mutations associated with cystic fibrosis (CFTR mutations) were also found with increased frequency in patients with CP (Teich et al, 2005). Interestingly, this mutation was also found to be more frequent in patients with CP thought to be secondary to pancreas divisum (Gelrud et al, 2004).

Other genetic variants predispose for CP. Research has focused on the SPINK1–N34S gene mutation, which is also closely associated with tropical (50%), alcoholic (6%), or idiopathic (20%) CP (Schneider et al, 2002; Sahin-Tóth & Tóth, 2000). One of the major discoveries in CP was the description of the point mutation in patients with autosomal dominant hereditary pancreatitis (HP) (Gorry et al, 1997). Several variants of the mutation of the cationic trypsinogen gene exist, all of which lead to a malfunction of trypsinogen (Chandak et al, 2002; Chen et al, 2000; Kukor et al, 2002; Sahin-Tóth, 2000; Teich et al, 2004). Consequently, premature intracellular activation of trypsinogen within the pancreatic acinar cell leads to activation of other enzymes, which may ultimately result in autodigestion (Kukor et al, 2002). Genetic abnormalities have been described more commonly in HP, which present typically in a bimodal pattern of childhood and adulthood (Teich et al, 2004, 2005). Associated with trypsinogen gene mutations, HP is an autosomal dominant disease that carries an 80% penetrance (Howes et al, 2004; Keim et al, 2001; Sossenheimer et al, 1997). HP is characterized by recurrent episodes of acute pancreatitis or familiar aggregation of CP, but most patients with this genetic mutation are asymptomatic (Teich et al, 2005). The progression of CP is faster in patients with SPINK-N34S mutation than in patients with cationic trypsinogen mutations (Howes et al, 2004; Keim et al, 2003). Patients with HP have a more than 50-fold increased risk of pancreatic ductal cancer compared with the general population (Howes et al, 2004; Lowenfels et al, 1987). Despite great advances in the knowledge of genetics in pancreatitis, currently it is only advised to evaluate for mutations in patients with HP. The genetic-phenotyping correlation of SPINK1 or CFTR mutations has not been studied well enough to allow for guidelines and recommendations to be established regarding its use in general clinical practice (Ellis et al, 2001; Teich et al, 2005).

Autoimmune

Autoimmune pancreatitis (AIP) is a rare but distinct form of CP characterized by specific histopathologic and immunologic features (Klöppel et al, 2005; Külling et al, 2003; Montefusco et al, 1984). In recent years, it has been established as a special type of CP whose morphologic hallmarks are periductal infiltration by lymphocytes and plasma cells and granulocytic epithelial lesions with consequent destruction of the duct epithelium and venulitis (Klöppel et al, 2003).

The pathogenesis of AIP involves both a cellular (CD4+ and CD8+ T cells) and humoral immune-mediated attack to the ductal cells and pancreatic ducts that results in cytokine-mediated inflammation and periductular fibrosis with subsequent obstruction of the pancreatic ducts (see primary duct hypothesis) (Okazaki, 2002). AIP is commonly associated with other autoimmune diseases such as Sjögren syndrome, primary sclerosing cholangitis, and inflammatory bowel disease (Külling et al, 2003; Montefusco et al, 1984). Nevertheless, more than a third of patients with AIP do not have other extrapancreatic autoimmune disorders.

AIP is clinically characterized by minimal abdominal pain and diffuse enlargement of the pancreas without calcifications or pseudocysts, and it most commonly involves the head of the pancreas and the distal bile duct. On occassion, masses have been described as inflammatory myofibroblastic tumors (Klöppel et al, 2005). On laboratory examination patients have hypergammaglobulinemia and autoantibodies, such as antinuclear and anti–smooth muscle antibodies (Bovo et al, 1987; Okazaki et al, 2000). Histopathologic examination of the pancreas reveals inflammatory infiltration of lymphocytes and plasma cells around the pancreatic duct, as well as fibrosis, in a pattern similar to primary sclerosing cholangitis (Montefusco et al, 1984; Okazaki et al, 2000).

In 2002, the Japan Pancreas Society was the first in the world to propose diagnostic criteria for autoimmune pancreatitis. These criteria were revised by an Asian consensus conference a few years later (Otsuki et al, 2008).

Recurrent and Severe Acute Pancreatitis

Recurrent acute pancreatitis can result in CP. This form of pancreatitis is discussed in more detail in the chapter on acute pancreatitis, but it is mentioned here as part of the TIGAR-O classification, in which the R is for recurrent and severe acute pancreatitis.

Obstructive

Obstruction of the main pancreatic duct is well known to result in CP. The most common etiologies causing CP as a result of obstruction of the pancreatic duct include scars of the pancreatic duct, tumors of the ampulla of Vater and head of the pancreas, and trauma (see Table 55A.1). Other disorders, such as sphincter of Oddi dysfunction and pancreas divisum, have a more tenuous connection with CP. Obstruction of the main pancreatic duct produces changes of CP within weeks in several animal models (Boerma et al, 2003; Reber et al, 1999). Main pancreatic duct obstruction may lead to stagnation and stone formation of pancreatic juice (stone and duct obstruction theory) or acute recurrent pancreatitis and periductular fibrosis (necrosis-fibrosis theory). Histopathologic characteristics of human CP as a result of obstruction include uniform distribution of interlobular and intralobular fibrosis and marked destruction of the exocrine parenchyma in the territory of obstruction, without significant protein plugs and calcifications (Suda et al, 1990). Experiments in cats with obstructive chronic pancreatitis have demonstrated impaired pancreatic blood flow in addition to elevated tissue pressure (Karanjia et al, 1992; Reber et al, 1992). In contrast to the normal hyperemic response, these cats show a decrease in blood flow after secretin injection that constitutes a form of compartment syndrome, as the normal postprandial augmentation of blood flow and oxygen supply is prevented because of decreased tissue compliance and increased interstitial pressures.

Pathogenesis Of Chronic Pancreatitis

In the past 50 years, several hypotheses have been postulated to explain the pathogenesis of CP. Debate is ongoing as to which of these hypotheses bests explains the origins of CP, and although each proposes a specific mechanism to explain the pathophysiology, none of them explains the entire pathogenic process in all cases. Thus far, no hypothesis or theory has been able to unify the concepts of the known pathways of CP, and no reported hypothesis convincingly demonstrates the first molecular steps in the development of CP. Six major theories are described, and the reader will no doubt notice that many of the hypotheses share similarities, especially later in the disease process, once the initiating factors of each mechanism have “opened the flood gates” for the amplification and continuation of the process of CP. A close interaction is known to exist between underlying genetic predisposition, triggering factors, inflammatory processes mediated through cytokines, the immunologic process, oxidative and toxic-metabolic stress, changes in the consistency and flow of pancreatic juice, and fibrosis and obstruction of the ducts that play a role in almost every case of CP. Furthermore, every year, new information on cellular, genetic, and molecular mechanisms of pancreatic inflammation and fibrosis emerge, and it is likely that other pathogenic models or the unification of existing models will come into existence.