Etiology, pathogenesis, and diagnosis of chronic pancreatitis

Toxic and metabolic (A, N = alcohol and nicotine in MANNHEIM)

Alcohol is the most common cause of chronic pancreatitis in most developed countries, and this association was first described by Comfort and colleagues (1946). Notably, clinically apparent chronic pancreatitis develops in only 5% to 10% of patients with alcoholism, pointing to the multifactorial pathophysiology. Although the cumulative toxin dose required for alcohol to cause chronic pancreatitis varies, 60% to 90% of patients will have 10 to 15 years of heavy alcohol consumption before development of clinical disease. The critical threshold of daily alcohol intake has been estimated to be approximately 40 g daily for women and 80 g daily for men (four to five drinks a day). The type of alcoholic beverage does not appear to be a modifying factor, but early age of alcoholism may result in shorter duration before onset of symptoms. ^{, , ,} In the past it was believed that at the time of the initial attack, most patients with alcohol-induced chronic pancreatitis already had underlying fibrosis and calcifications of the pancreas, but the Zurich group has demonstrated that acute attacks preceded the development of chronic disease. ^, Of patients with chronic pancreatitis, those with alcohol-induced disease may be more likely to develop necrosis and pseudocysts ( Fig. 57.1 ; see Chapter 58 ).

As only a minority of alcoholic individuals develop symptoms, cofactors in the evolution of clinical chronic pancreatitis have been 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. ^, Many patients thought to have chronic pancreatitis 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. ^,

Tobacco smoke is a common cofactor in the development of alcoholic pancreatitis, and there is convincing evidence that smoking is independently associated with an increased risk for chronic pancreatitis, with an odds ratio (OR) as high as 17.3. ^, Smoking increases the risk of chronic pancreatitis in a dose-dependent manner, and the risk for chronic pancreatitis in individuals smoking less than 1 pack of cigarettes per day is 2.4, increasing to 3.3 in individuals who smoke more than 1 pack per day. In smokers with alcoholic chronic pancreatitis, the course was accelerated and a major threshold effect is seen at 20 pack-years. Just as abstinence from alcohol after an episode of acute pancreatitis can significantly decrease the risk of progression to chronic pancreatitis, smoking cessation reduces the risk ratio estimate for chronic pancreatitis. ^, In a large cohort of US Veterans Administration (VA) patients, including almost one-half million individuals, Munigala and colleagues also found that smoking is an independent risk factor for acute pancreatitis and augmented the effect of alcohol on the risk, age of onset, and recurrence of pancreatitis.

Tobacco induces oxidative stress and alters the secretion and composition of pancreatic juice, resulting in decreased juice and bicarbonate secretion and inflammation. ^{, , ,} In a large study involving 146 patients with chronic pancreatitis, 52 patients with pancreatic cancer, and 235 healthy controls, the genomic DNA for expression of uridine 5′-diphosphate (UDP) glucuronosyltransferase (UGT1A7) genes was analyzed by Ockenga and colleagues (2003). These proteins are vital biochemical factors for detoxification and cell defense. The incidence of this mutation was much more common in patients with chronic pancreatitis and tobacco abuse, but not in patients with nonalcoholic chronic pancreatitis. This study established the possible connection between genetic predisposition and external triggering factors. It is possible that smoking is the main factor of chronic pancreatitis in some patients, whereas in others smoking may increase the damage induced by alcohol, and in another group it might potentiate another yet unidentified factor or pathogen (see Chapter 9D ).

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 chronic pancreatitis, likely from trypsinogen activation, which in turn results in necrosis and fibrosis of the parenchyma. Increased serum calcium concentration is also 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, in turn resulting in varying degrees of pancreatic fibrosis with calcifications.

Nutritional factors (N = nutritional in M-ANNHEIM)

Evidence for the role of diets rich in fat and protein in the development of chronic pancreatitis come predominantly from animal studies, in which it has been found to induce pancreatic injury and alcohol induced damage. ^, There are limited data in humans that high-fat diets may result in more pain symptoms and earlier age of onset. ^, As will be discussed later in this chapter, the availability of excess substrate in the form of lipid and protein is thought to be an important catalyst for cytochrome P-450 activation and subsequent induction of oxidative stress. Additional support comes from the association between hyperlipidemia and recurrent acute pancreatitis, and in some cases, chronic pancreatitis. In sum, however, the evidence for the causative effect of nutritional factors in the pathogenesis of chronic pancreatitis is limited mostly because of the challenges of retrospectively collecting accurate dietary data.

Idiopathic (I = idiopathic in M-ANNHEIM)

Based on the bimodal age of onset of the clinical symptoms, idiopathic pancreatitis is traditionally separated into two distinct entities. Early idiopathic chronic pancreatitis is seen during the first 2 decades of life, with abdominal pain the predominant clinical feature, whereas pancreatic calcifications and exocrine and endocrine pancreatic insufficiency are rare at the first diagnosis. In contrast, the clinical presentation of late-onset idiopathic chronic pancreatitis typically occurs in patients during their fifth decade of life, and is marked by greater incidence of exocrine and endocrine pancreatic insufficiency and pancreatic calcifications rather than pain. ^, A more modern prospective study performed by Lewis and colleagues demonstrated that the median age for early-onset idiopathic pancreatitis was 20, whereas late-onset symptoms started at a median age of 58. Both groups were predominantly women (62% and 81%, respectively, for early and late onset). As in earlier studies, pain was a more prominent feature in early-onset disease (96% vs. 69%), and exocrine insufficiency was more typical in the late-onset group (85%). Histologically, many cases of idiopathic chronic pancreatitis have T-lymphocyte infiltration, ductal obstruction, acinar atrophy, and fibrosis, raising the possibility of autoimmune etiology.

As the understanding of chronic pancreatitis matures and diagnostic tools become more sophisticated, the category of idiopathic pancreatitis will likely continue to shrink. Approximately 30% of patients with chronic pancreatitis have been labeled as having an idiopathic cause in the past, but in many cases risk factors ranging from underreported alcohol and tobacco abuse, undiscovered underlying genetic or hereditary abnormalities, or currently undiscovered factors are the actual stimulants of disease. ^, Mutations of the serine protease inhibitor Kazal type 1 ( SPINK1 gene) have been described in up to 25% of patients with “idiopathic” chronic pancreatitis. ^, Other genetic alterations have been described in patients with idiopathic chronic pancreatitis. In a series published by Jalaly and colleagues, 47.8% of patients with acute recurrent or chronic idiopathic pancreatitis had variants in PRSS1 , CFTR , SPINK1 , or CTRC . Similarly, nearly 50% of patients with early-onset idiopathic pancreatitis were found to have a mutation in cystic fibrosis transmembrane regulator (CFTR), chymotrypsin C (CTRC), or SPINK1 by Lewis and colleagues. A strong association between CFTR mutations and idiopathic chronic pancreatitis has also been demonstrated. ^{, ,} In patients without evidence of cystic fibrosis, the frequency of CFTR mutations was six times that of patients without mutations. Subsequently, Cavestro and colleagues reported that one-third of all patients with idiopathic chronic pancreatitis have CFTR mutations. Mutations in the SPINK1 gene are associated with familial patterns of idiopathic pancreatitis.

Until recently, tropical pancreatitis or nutritional pancreatitis was considered a form of idiopathic chronic pancreatitis and up to 60% to 70% of chronic pancreatitis in India and China have been labeled idiopathic. Initial attempts to understand the disease implicated malnutrition and excess consumption of cyanogenic glycosides in cassava. This conception of tropical pancreatitis has been the subject of significant debate, however, and several studies have confirmed that many of these patients have gene mutations that are associated with acute and chronic pancreatitis. Several studies have shown that variants in SPINK1 , cathepsin B, CTRC , CFTR , and carboxypeptidase A1 predict the risk for tropical calcific pancreatitis. ^, Therefore many of these patients, once labeled as having idiopathic pancreatitis, would be more accurately categorized as genetic.

Genetic (H = hereditary in M-ANNHEIM)

Several genetic variations have been associated with pancreatitis, including cationic trypsinogen (PRSS1), anionic trypsinogen (PRSS2), SPINK1, CTRC, calcium-sensing receptor (CASR), and CFTR, all of which are closely linked with the trypsin pathway, either through early activation or failure to inhibit the activated enzyme. Until recently, data on the genetic basis of chronic pancreatitis were scarce. Cystic fibrosis is the classic example of chronic pancreatic insufficiency and probably the best studied. ^, Many cases of chronic pancreatitis represent a variable part of the cystic fibrosis syndrome, which is caused by mutations in the gene coding for the CFTR. 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 chronic pancreatitis. Interestingly, this mutation was also found to be more frequent in patients with chronic pancreatitis thought to be secondary to pancreas divisum.

Other genetic variants predispose for chronic pancreatitis. Research has focused on the SPINK1 - N34S gene mutation, which is also closely associated with tropical (50%), alcoholic (6%), or idiopathic (20%) chronic pancreatitis. ^, Dysregulated calcium homeostasis has been associated with development of pancreatitis, and mutations in the calcium ion channel gene TRPV6 have been associated with development of chronic pancreatitis. As noted previously, emerging evidence supports an important role for genetic risk factors in tropical pancreatitis. Therefore “classic” tropical pancreatitis may indeed be a form of hereditary pancreatitis related to SPINK1 mutations, similar to forms of chronic pancreatitis seen in Western countries. ^, The SPINK1 pancreatic secretory trypsin inhibitory (PSTI) gene is responsible for the encoding of SPINK1 . ^, PSTI has the main function of inhibiting activated trypsin. SPINK1 is the major intrapancreatic “deactivator” of activated trypsinogen. Trypsin has a central role in the digestion of dietary proteins and 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 time. This is called a gain of function of trypsin. ^{, ,}

One of the major discoveries in chronic pancreatitis was the description of the point mutation in patients with autosomal dominant hereditary pancreatitis. Several variants of PRSS1 exist, all of which lead to a malfunction of trypsinogen. ^{, ,} Consequently, premature intracellular activation of trypsinogen within the pancreatic acinar cell leads to activation of other enzymes, which may ultimately result in autodigestion. Genetic abnormalities have been described more frequently in hereditary pancreatitis, which typically present in a bimodal pattern of childhood and adulthood. Associated with trypsinogen gene mutations, hereditary chronic pancreatitis is an autosomal dominant disease that carries an 80% penetrance. It is characterized by recurrent episodes of acute pancreatitis or familial aggregation of chronic pancreatitis, but most patients with this genetic mutation are asymptomatic. The progression of chronic pancreatitis is faster in patients with SPINK-N34S mutation than in patients with PRSS1 mutations. ^, Patients with hereditary pancreatitis have a more than 50-fold increased risk of pancreatic ductal cancer compared with the general population ^, (see Chapter 9D ).

Autoimmune (I = immunologic in M-ANNHEIM)

Autoimmune pancreatitis (AIP) is a rare but distinct form of chronic pancreatitis characterized by specific histopathologic, immunologic, and imaging features ( Fig. 57.2 ) (see Chapters 10 , 54 , 55 , and 59 ). Its morphologic hallmarks are periductal infiltration by lymphocytes and plasma cells and granulocytic epithelial lesions, with consequent destruction of the duct epithelium and venulitis. Based on etiology, serum markers, histology, and systemic involvement, AIP is classified into two distinct subtypes: type 1, related to immunoglobulin G4 (IgG4) (lymphoplasmacytic sclerosing pancreatitis), and type 2, related to a granulocytic epithelial lesion (idiopathic duct-centric chronic pancreatitis).

The pathogenesis of AIP involves both a cellular (CD4 ⁺ and CD8 ⁺ T cells) and a humoral immune-mediated attack on the ductal cells that results in cytokine-mediated inflammation and periductular fibrosis, with subsequent obstruction of the pancreatic ducts (see primary duct hypothesis ). Unlike type 2 AIP, type 1 AIP is characteristically associated with increasing levels of serum IgG4 and positive serum autoantibodies, abundant infiltration of IgG4-positive plasmacytes, frequent extrapancreatic lesions, and clinical recurrence. ^, AIP, especially type 1, is often associated with other autoimmune diseases, such as Sjögren’s syndrome, primary sclerosing cholangitis (PSC), and inflammatory bowel disease. ^, Nevertheless, more than one-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 frequently involves the head of the pancreas and the distal bile duct. On occasion, masses have been described as inflammatory myofibroblastic tumors . The presentation and imaging findings of AIP sometimes resemble those of pancreatic malignancy, but the therapeutic approach differs significantly.

On laboratory examination, patients may have hypergammaglobulinemia and autoantibodies, such as antinuclear and anti–smooth muscle antibodies. ^, 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 PSC. ^, In 2002 the Japan Pancreas Society was the first in the world to propose diagnostic criteria for AIP, and a number of diagnostic criteria have been proposed since that time. The Unifying-Autoimmune-Pancreatitis-Criteria for diagnosis are listed in in Box 57.1 . ^,

Obstructive (E = efferent duct factors in M-ANNHEIM)

Pancreatic fusion or migration anomalies may result in anatomic variants that predispose patients to specific pancreatic or peripancreatic diseases, such as recurrent acute or chronic pancreatitis, cystic dystrophy of the duodenum, duodenal obstruction, cholangiocarcinoma, and gallbladder carcinoma (see Chapters 46 , 53 , and 62 ). Obstruction of the main pancreatic duct is well known to result in chronic pancreatitis. The most common causes of pancreatic duct obstruction resulting in chronic pancreatitis include scars of the pancreatic duct, tumors of the ampulla of Vater, mucinous duct ectasia, tumors of head of the pancreas, and trauma ( Fig. 57.3 ). Other disorders, such as sphincter of Oddi dysfunction and pancreas divisum, have a more tenuous connection with recurrent acute and chronic pancreatitis ( Fig. 57.4 ).

Obstruction of the main pancreatic duct produces changes of chronic pancreatitis within weeks in several animal models. ^, Main pancreatic duct obstruction leads 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 chronic pancreatitis 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 or calcifications.

Miscellaneous (M = miscellaneous in MANNHEIM)

The TIGAR-O system does not contain a letter for miscellaneous forms of chronic pancreatitis, such as primary hypercalcemia, hyperlipidemia, or hyperthyroidism. These etiologic factors are summarized under the second M of MANNHEIM. In addition, tropical calcific pancreatitis is included here in the MANNHEIM classification, whereas it is considered “idiopathic” in the TIGAR-O classification. As previously mentioned, tropical pancreatitis is likely a genetic (hereditary) form of pancreatitis likely triggered by lack of micronutrients or toxins, including alcohol and tobacco.