Although several risk factors for the development of chronic pancreatitis have been identified, the cause of pancreatitis in some instances remains uncertain. Among established risk factors, alcohol ingestion is associated with up to 60–70% of cases of chronic pancreatitis. In addition, ductal obstruction, autoimmune disease, tropical disease, and an association with further systemic illnesses such as scleroderma and hypertriglyceridemia have been described. Recently new insights have been gained into the genetic and molecular basis associated with hereditary forms of chronic pancreatitis. Recent epidemiologic studies clearly demonstrate that smoking is emerging as an independent risk factor for chronic pancreatitis development. The most widely accepted system of etiologic classification for chronic pancreatitis is the TIGAR-O system, which categorizes risk factors according to mechanism and prevalence (Table 27–1). A more recent M-ANNHEIM multiple risk factor classification system incorporates etiology, different stages of the disease, and various degrees of clinical severity. This system will be helpful for research studies investigating the impact and interaction of various risk factors on the course of the disease and will facilitate the comparison and combination of interinstitutional data.

Morphologic changes associated with chronic pancreatitis include ductal, parenchymal, and nerve changes. Pancreatic ducts may become dilated, irregular, or strictured. Meanwhile, the glandular tissue itself is often characterized by irregular and patchy replacement of normal acinar cell architecture with fibrosis. Morphologic features of neuritis and hypertrophy may account for part of the pain syndrome.

Several hypotheses have been proposed to explain the mechanisms underlying the pathogenesis of chronic pancreatitis. These focus on (1) the role of oxidative stress, (2) toxic-metabolic causes, (3) obstructive causes, and (4) necrosis-fibrosis (also referred to as the Sentinel Acute Pancreatitis Event [SAPE] hypothesis) (Table 27–2). The oxidative-stress hypothesis attributes pancreatic damage to reflux of bile rich in reactive oxidation byproducts. The toxic-metabolic theory involves direct damage to pancreatic acinar cells from noxious stimuli such as alcohol. The obstructive theory attributes the majority of injury to pancreatic ductal injury resulting from obstruction related to increased lithogenicity, the latter, in turn, caused by either genetic or environmental exposures (eg, alcohol). Finally, the necrosis-fibrosis hypothesis describes chronic pancreatitis as a continuum that is initiated early by an attack of acute pancreatitis; the subsequent recurrent injury and remodeling lead to pancreatic fibrosis. This hypothesis has gained further support with the observation of progression to chronic pancreatitis from childhood through adulthood of patients with a rare disorder known as hereditary pancreatitis. This disorder, which is caused by a gain of function mutation in cationic trypsinogen, leads to recurrent bouts of acute pancreatitis with later onset of chronic pancreatitis. These explanations are not necessarily mutually exclusive, and a unifying model explaining the precise mechanisms leading to impaired ductal bicarbonate secretion and the patchy inflammatory changes seen on histopathologic examination remains to be further elucidated.

Recent characterization of pancreatic stellate cells (PSC) has added insight to the underlying cellular responses behind development of chronic pancreatitis. Specifically, PSCs are believed to play a role in maintaining normal pancreatic architecture, which can shift toward fibrogenesis in the case of chronic pancreatitis. It is believed that alcohol or additional stimuli lead to matrix metalloproteinase–mediated destruction of normal collagen in pancreatic parenchyma that later allows for pancreatic remodeling. Proinflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin (IL)-1, and IL-6, as well as oxidant complexes, are able to induce PSC activity with subsequent new collagen synthesis. In addition to being stimulated by cytokines, oxidants, or growth factors, PSCs also possess transforming growth factor-β (TGFβ)–mediated self-activating autocrine pathways, which may explain disease progression in chronic pancreatitis even after removal of noxious stimuli.

A. Symptoms and Signs

The hallmark features of chronic pancreatitis are abdominal pain and pancreatic insufficiency. Advanced disease can also be associated with weight loss and diabetes. The possibility of chronic pancreatitis should be entertained in any patient with symptoms of chronic abdominal pain. Further supporting features on history include postprandial pain triggered by high-fat or protein-rich meals. In addition, predisposing etiologic factors according to the TIGAR-O classification should be actively sought with attention paid to indicators of possible inherited pancreatic disease such as family history of pancreatitis, pancreatic cancer, or cystic fibrosis.

1. Abdominal pain

The pain associated with chronic pancreatitis is described as epigastric, often with radiation to the back. Pain is often unrelenting and difficult to treat. Pain may be postprandial, associated with nausea and vomiting. Early in the disease course, pain is described as occurring in discrete episodes (type A pain). However, as the disease progresses pain may become continuous (type B pain). Ultimately, the pattern and course of pain symptoms is highly variable among patients with chronic pancreatitis. Up to 20–45% of patients having objective evidence of pancreatic endocrine or exocrine dysfunction may not have pain. Thus, pain is not a prerequisite for the diagnosis of chronic pancreatitis.

2. Pancreatic insufficiency

The second cardinal feature of chronic pancreatitis is the development of pancreatic exocrine and endocrine dysfunction with advanced disease. By comparison to the pain of chronic pancreatitis, the symptoms of pancreatic insufficiency are relatively easily managed. Clinically significant protein malabsorption and fat deficiency does not occur until over 90% of pancreatic function is lost. Typically steatorrhea precedes the onset of protein malabsorption. Fat malabsorption can manifest clinically as poorly formed greasy, malodorous stools. Although absorption of fat-soluble vitamins may be reduced, clinically significant vitamin deficiency is rarely reported. There have been numerous small reports of metabolic bone disease in patients with pancreas insufficiency. A recent epidemiologic study reported a high prevalence of low-trauma fracture in chronic pancreatitis when compared to age- and gender-matched controls. In fact, the odds of fracture in chronic pancreatitis approached that of other high-risk gastrointestinal illnesses such as inflammatory bowel disease for which osteoporosis screening guidelines exist. Further studies are needed to explore the strength of this association.

Pancreatic endocrine insufficiency presenting as diabetes is a distinctly late occurrence. Patients with chronic calcific pancreatitis or with a family history of diabetes have been observed to be at increased risk of developing this complication. Although diabetes associated with chronic pancreatitis is insulin-requiring and patients are also at increased risk of hypoglycemia due to impaired glucagon synthesis resulting from pancreatic α-cell destruction.