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Chronic Pancreatitis
Chronic pancreatitis is a progressive inflammatory disorder that leads to irreversible destruction of the exocrine and endocrine tissue of the pancreas. Fibrotic replacement of the normal pancreas may be associated with persistent abdominal pain, the development of exocrine insufficiency, and ultimately, diabetes mellitus. Inflammation may lead to local complications, including biliary and gastrointestinal obstruction, ascites, mesoportal-splenic thrombosis, pseudocyst formation, hemorrhage, and sepsis. In its advanced stages, chronic pancreatitis is readily apparent clinically, typically associated with pancreatic duct stricture and ductal dilation, stones and diffuse parenchymal calcification, and the digestive and metabolic effects of organ insufficiency. However, recognition of patients with early and mild disease remains a difficult challenge. The absence of a clinically relevant classification system for chronic pancreatitis contributes to inconsistencies in the treatment of the disease. Treatment decisions are better made in the context of individual circumstances such as patient symptoms and anatomic findings rather than classification systems based on etiology or morphologic severity.
Definition
Acute pancreatitis generally refers to a single episode of acute inflammation of the organ, typically associated with histopathologic changes that may include edema, fat necrosis, and hemorrhage. Although often fully reversible, the acute injury may be so severe as to result in permanent parenchymal damage, local or remote complications, or death. Chronic pancreatitis generally refers to an ongoing inflammatory and fibrosing disorder characterized by irreversible morphologic changes, progressive and permanent loss of exocrine and endocrine function, and a clinical pattern of recurrent acute exacerbation or persistent pain. In reality, however, acute and chronic pancreatitis represent more of a spectrum of inflammatory and fibrosing conditions of the pancreas than the two dichotomous terms would otherwise imply. Recurrent episodes (or even a single episode) of acute pancreatitis may lead to chronic changes within the pancreas, although the timing and extent to which such changes merit a change in nomenclature to chronic pancreatitis is somewhat arbitrary. The histopathologic changes of chronic pancreatitis comprise fibrosis, a reduced number of acinar cells and islets of Langerhans, and development of strictures and dilation of pancreatic ducts as well as calcium calculi (pancreatic duct stones). The morphologic/structural changes of chronic pancreatitis can occur years before any clinical symptoms are present. One hypothesis envisions the activation of pancreatic stellate cells, which induce desmoplasia, as the key pathogenetic “switch” that leads to the transition to chronic pancreatitis.
Efforts to establish consensus for uniform terminology of pancreatitis began with an international conference held in Marseille in 1963, during which participants agreed that chronic pancreatitis was distinguished by irreversible focal, segmental, or diffuse destruction of the exocrine tissue along with dilation or focal strictures of the main pancreatic duct. At a second meeting in Marseille held in 1984, chronic pancreatitis was subclassified as chronic pancreatitis with focal or segmental or diffuse fibrosis, and chronic pancreatitis with or without stones, and obstructive chronic pancreatitis was listed as a distinct form. To help define changes associated with clinical risk factors, a 1988 meeting in Rome added the morphologic distinction of chronic calcifying pancreatitis, which is characterized by intraductal calcifications and protein plugs, and chronic inflammatory pancreatitis, which is characterized by dense infiltration of mononuclear inflammatory cells. A consensus conference in Cambridge in 1984 defined the distinction between acute and chronic pancreatitis as the reversibility of the morphologic and functional changes of inflammation. The Cambridge meeting proposed a classification system of chronic pancreatitis based on radiographic findings on endoscopic retrograde cholangiopancreatography (ERCP) ( Table 92.1 ) and ultrasonography (US) or computed tomography (CT). Criteria for chronic pancreatitis from the Japan Pancreas Society focused on findings from an array of diagnostic approaches including US, CT, ERCP, secretin stimulation, and histologic examination of pancreatic tissue. The presence of certain criteria such as pancreatic stones on CT or US is considered definitive evidence of chronic pancreatitis, whereas other criteria such as pancreatic deformity with irregular contour are considered only probable or possible evidence in support of the disease. The shortcoming of all of these consensus approaches has been the inability to establish a definitive diagnosis in the earliest stages of disease. Moreover, no classification system has proven practical applicability in guiding decisions for therapy.
TABLE 92.1
Cambridge Conference Classification of Chronic Pancreatitis: Endoscopic Retrograde Cholangiopancreatography
Modified from Sarner M, Cotton PB. Classification of pancreatitis. Gut. 1984;25:756.
| Terminology | Main Duct | Abnormal Side Ducts | Additional Features |
|---|---|---|---|
| Normal | Normal | None | — |
| Equivocal | Normal | <3 | — |
| Mild changes | Normal | ≥3 | — |
| Moderate changes | Abnormal | >3 | — |
| Marked changes | Abnormal | >3 | 1 or more of large cavity, obstruction, filling defects, severe dilation, or irregularity |
Risk Factors
An association between alcohol and acute and chronic pancreatitis has been noted for over half a century. Sarles et al. demonstrated that the relative risk of chronic pancreatitis increases directly with mean daily alcohol consumption. However, even relatively moderate alcohol intake can cause chronic pancreatitis, and the duration of alcohol consumption can be relatively short before the onset of disease. In chronic pancreatitis, alcohol is thought to increase the protein concentration in pancreatic juice, which causes intraductal calcium stone formation, ductal epithelial ulceration, inflammation, and fibrosis. Yet it is only a small percentage (5% to 10%) of alcoholics that develop pancreatic disease, suggesting that alcohol is more of a risk factor than a causative agent for pancreatitis in patients who are susceptible for various unknown or poorly defined reasons. Different disease processes causing similar-appearing injury to the pancreas may follow different clinical courses. Thus, rather than classifying pancreatitis based on the presumed causative agent, Whitcomb et al. proposed a system to classify risk factors that may interact to predispose an individual patient to produce pancreatitis. According to this framework, risk factors are grouped as toxic/metabolic, idiopathic, genetic, autoimmune, recurrent acute, or obstructive (TIGAR-O) ( Table 92.2 ). An additional classification system uses the M-ANNHEIM paradigm: M ultiple risk factors of A lcohol consumption (excessive >80 g/day, increased 20 to 80 g/day, moderate <20 g/day), N icotine consumption, N utritional factors (high calorie proportion of fat and protein, hyperlipidemia), H ereditary factors, E fferent duct factors (pancreas divisum, annular pancreas, tumors, posttraumatic, sphincter of Oddi dysfunction), I mmunologic factors and M iscellaneous and rare metabolic disorders (hypercalcemia, hyperparathyroidism, chronic renal failure, drugs, toxins).
TABLE 92.2
Etiologic Risk Factors Associated With Chronic Pancreatitis
Modified from Etemad B, Whitcomb DC. Chronic pancreatitis: diagnosis, classification, and new genetic developments. Gastroenterology. 2001;120:682.
| Toxic/metabolic |
|
| Idiopathic | Tropical |
| Genetic |
|
| Autoimmune | Isolated or associated with autoimmune disorders |
| Recurrent acute and severe |
|
| Obstructive |
|
Toxic/Metabolic
Almost 70% of chronic pancreatitis cases are associated with chronic alcoholic intake in Western countries. Tobacco use is associated with the early presentation of alcoholic chronic pancreatitis and is associated with the presentation of calcifications and the development of diabetes. It is unknown if tobacco initiates the disease ; however, tobacco is thought to potentiate the progression. In a preclinical model, investigators demonstrated that tobacco exposure increases the risk of pancreatic cancer in chronic pancreatitis patients. Hyperparathyroidism and hypercalcemia are also associated with chronic pancreatitis. Patients with chronic renal failure have a higher risk.
Idiopathic
Historically, no environmental or metabolic risk factor can be identified in approximately 20% of patients who are therefore categorized as having idiopathic acute, recurrent acute, or chronic pancreatitis. Patients with idiopathic disease typically fall into a bimodal age distribution, presenting between the ages of 10 and 20 or after age 50 years. However, many of these patients are increasingly recognized to have underlying genetic mutations and polymorphisms and may be more appropriately recategorized into the genetic subgroup. To better understand the interactions among genetic, environmental, and metabolic factors predisposing to chronic pancreatitis, a consortium (North American Pancreatitis Study 2) has been established to collect patient questionnaires and blood for genomic DNA and biomarker studies.
Genetic
Although hereditary pancreatitis was recognized as a distinct clinical entity in the 1950s, it was not until 1996 that its genetic basis began to be understood. The inheritance pattern of hereditary chronic pancreatitis is autosomal dominant and has roughly a 78% penetrance rate. Genetic linkage analysis established a locus for hereditary chronic pancreatitis on chromosome 7q, a region that encodes eight different zymogen genes including various trypsins and carboxypeptidase A. Whitcomb et al. performed mutational screening analyses for each of the encoding regions of the cationic and anionic trypsinogen genes and discovered a single G-to-A transition mutation in the cationic trypsinogen gene (PRSS1) . This transition mutation resulted in an Arg (CGC)-to-His (CAC) (R122H) substitution that did not change the structure or catalytic activity of the enzyme but led to an unusually stable protein. The R122H mutation produces a proteolytic-resistant trypsinogen favoring inappropriate activation within the pancreas, leading to autodigestion. Other mutations in PRSS1 have been identified in various kindreds, although these are less well studied. Patients with hereditary pancreatitis, especially those bearing the R122H mutation of PRSS1 , have an estimated 35% lifetime risk of developing pancreatic cancer, a risk that is roughly doubled by smoking.
Variations in a number of other genes have been associated with chronic pancreatitis. Witt et al. studied 96 unrelated children and adolescents with idiopathic chronic pancreatitis and identified frequent mutations in the serine protease inhibitor, Kazal type 1 (SPINK1) , a pancreatic trypsin inhibitor. SPINK1 is colocalized with trypsinogen within zymogen granules and is believed to prevent inappropriate intrapancreatic protease activation. The most frequent mutation associated with chronic pancreatitis is an N34S amino acid substitution in exon 3. Mutations in SPINK1 or in PRSS1 lead to an imbalance toward intrapancreatic trypsin activation, thereby leading to autodigestion of the pancreas and inflammation. It is postulated that the SPINK1 mutations are not directly responsible for pancreatitis but may lower the threshold for the disease from other risk factors.
Chronic pancreatitis is also associated with mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR) . Cystic fibrosis is an autosomal recessive disorder that has been linked to mutation of the CFTR gene, which encodes a cyclic adenosine monophosphate–regulated chloride channel located in the apical domain of epithelial cells lining the proximal ducts of the pancreas. More than 1000 mutations have been characterized with a wide range of impact on the characteristics of the channel function. The most common mutation results in a deletion of the single amino acid, phenylalanine, at position 508 (DF508) . The clinical manifestations are dependent on the specific mutation and the impact on the functional characteristic of the chloride channel. Sharer et al. found that CFTR mutations were more common in patients with idiopathic rather than alcoholic chronic pancreatitis. The CFTR mutation is not a direct cause of chronic pancreatitis but may contribute to the disease. Mutation of the CFTR may lead to a decrease in bicarbonate secretion, impaired fluid secretion and formation of protein plugs, and pancreatic insufficiency. Alternatively, the CFTR mutation may alter vesicular sorting and granule trafficking or cause membrane lipid imbalance. Chronic pancreatitis has also been associated with mutations in the anionic trypsinogen (PRSS2) and chymotrypsin C (CTRC) . PRSS2 has a lower incidence of mutations in chronic pancreatitis; a variant of PRSS2 with a glycine-to-arginine change at codon 191 appears to have a protective effect against chronic pancreatitis. Chymotrypsin C gene mutation may increase the risk and encourage progression of chronic pancreatitis in patients with CFTR and SPINK1 mutations with tobacco and alcohol abuse. Calcium-sensing receptor (CSR) , X-linked claudin-2 (CLDN2) , carboxypeptidase A1 (CPA1) , and additional genetic and nongenetic alterations are also associated with chronic pancreatitis.
Autoimmune
Autoimmune pancreatitis, also known as lymphoplasmacytic sclerosing pancreatitis, is a rare cause (1%) of chronic pancreatitis. Gland enlargement, diffuse duct narrowing, and stenosis of the intrapancreatic portion of the bile duct characterize the disease. Histologic examination of the tissue demonstrates pancreas parenchyma infiltrated by both CD4 + and CD8 + lymphocytes and IgG4 plasma cells, with interstitial fibrosis and acinar cell atrophy. Patients with autoimmune pancreatitis have antibodies directed against a peptide that is homologous with the sequence of the plasminogen-binding protein (PBP) of Helicobacter pylori and with the ubiquitin-protein ligase E3 component n-recognin 2, which is expressed in the acinar cells of the pancreas. Autoimmune pancreatitis can be associated with other autoimmune diseases including Sjögren syndrome, primary sclerosing cholangitis (PSC), and inflammatory bowel disease. Primary treatment for autoimmune pancreatitis is steroid treatment. Focal inflammation seen with this disease can often mimic a pancreatic mass, which may be difficult to differentiate from a pancreatic malignancy on imaging studies.
Recurrent Acute
Recurrent episodes of acute pancreatitis of any etiology can cause chronic pancreatitis. This mechanism is poorly understood but likely involves the accumulated effects of postinflammatory scarring and necrosis as well as the priming of pancreatic stellate cells to induce fibrosis. In addition, radiation and ischemia may contribute to irreversible histopathologic changes and inflammation characteristic of chronic pancreatitis. However, the term recurrent acute pancreatitis (RAP) refers specifically to episodes of acute pancreatitis that do not lead to chronic pancreatitis if the underlying inciting factors are treated.
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