Encyclopedia of Cancer, 2015


Pancreatitis is a disease characterized by the inflammation of exocrine pancreas that is initiated by the premature activation and intracellular release of the digestive enzymes produced in pancreatic acinar cells. The release of these enzymes causes destruction of acinar cells and a subsequent robust inflammatory response, resulting in a significant injury to the pancreas.


Pancreatitis was first described as a disease of autodigestion in 1896 by pathologist Hans Chiari. Common symptoms include searing upper abdominal pain that radiates into the back; nausea and vomiting, especially after eating; fever; rapid heartbeat; and jaundice (the yellowing of the skin, the whites of the eyes (conjunctiva), and mucous membranes caused by increased levels of bilirubin in the blood that may be due to liver damage as well as other diseases) – discoloration is the result of increased levels of bilirubin in the blood due to obstruction of the biliary drainage from the liver through the biliary tree into the small intestine. Over the period of time, indigestion due to lack of sufficient pancreatic enzymes also causes weight loss.

Causes and diagnosis

Among various factors known to cause pancreatitis, the most common factors are alcohol abuse andpresence of gallstones (80%). Pancreatitis associated with prolonged alcohol abuse is known as alcoholic pancreatitis. Recognized for well over 100 years, it remains one of the least understood alcohol-associated human diseases. Other triggers include trauma, steroids (such as prednisolone), mumps, autoimmune pancreatitis, scorpion sting, hyperlipidemia (elevated blood triglycerides), hypothermia, high blood calcium, ERCP (endoscopic retrograde cholangiopancreatography), and drugs (azathioprine, didanosine, pentamidine, valproic acid, statins, metformin, gliptins, etc.). These causative factors are also referred by a mnemonic GETSMASHED. Other causes are type 2 diabetes, pancreatic cancer, pancreatic duct stones, microbial infections, etc.

Diagnosis is largely centered on the characteristic of abdominal pain, abdominal ultrasound or endoscopic ultrasound (EUS) accompanied by biopsy, CT scan (computed tomography scan), and ERCP. Pancreatic function test and glucose tolerance tests are also used to assess the normal functionality of pancreas. Elevated blood amylase and lipase are also considered indicators for pancreatitis although controversial.

Types of pancreatitis

Pancreatitis is generally classified as either acute (sudden occurrence and lasting few days) or chronic (persisting for a long time or constantly recurring).

Acute pancreatitis

Acute pancreatitis is a condition that develops when the pancreas is damaged by an inflammation that leads to swelling and sometimes to necrosis (death) of parts of the pancreas. The digestive enzymes from damaged pancreas cause breakdown of fatty tissue in the abdomen. The most common risk factor for acute pancreatitis is the presence of gallstones. The pathophysiology of gallstone-induced pancreatitis was first described by pathologist Eugene Opie in 1901. In about 85% of patients, acute pancreatitis is a mild disease and is associated with a rapid recovery within a few days of onset of the illness. In about 15–20% of patients, acute pancreatitis can lead to severe damage of the pancreas, often leading to a severe illness associated with extended hospital stay, multiple surgical procedures, and occasionally death in some patients. Patients with severe acute pancreatitis are at risk for developing the following complications:

  • Parts of the pancreas get destroyed causing the release of digestive enzymes and subsequent death in the pancreas (pancreatic necrosis) and the surrounding abdominal areas (peripancreatic necrosis). Treatment involves surgical removal of the dead tissue in extreme cases.
  • Failure of multiple body organ systems such as the heart, lungs, liver, and kidney due to damage from toxins released in the bloodstream from the dead pancreatic tissue.
  • More than 80% of death among pancreatitis patients is due to infected pancreatic necrosis. Treatment involves urgent and often multiple surgeries to remove all the dead tissue.
  • Pseudocysts: a collection of fluid around the pancreas. The fluid in the cyst is usually pancreatic juice that has leaked out of a damaged pancreatic duct. Characterized by abdominal pain and bloating due to indigestion, it is usually diagnosed by a CTscan. Although not commonly required, treatment includes surgical, endoscopic, or radiological intervention.
  • Pancreatic abscess occurs in around 3%of acute pancreatitis patients, after more than a month of initial attack. It often develops from infected pancreatic pseudocysts and primarily treated through surgical or endoscopic drainage. Left untreated, it can lead to sepsis, fistula formation, or chronic pancreatitis.
  • Pancreatic fistula: leakage of pancreatic juice in the abdomen from an injury to the pancreas. As a common occurrence after surgery, fistula forms from the portion of the pancreas left behind after removal of the dead pancreas. Although it heals in the vast majority of patients without any further surgery, some patients require additional surgery to remove the part of the pancreas that is contributing to the fi
  • Damage to surrounding organs such as the small bowel, colon, and duodenum due to the infl

Intracellular trypsinogen activation and NF[kappa]B activation are two important and independent molecular events consistently observed during the early stages of pancreatitis and capable of inducing acute pancreatitis in experimental models. Mouse models shows that intra-acinar NF[kappa]B activation is required as well as sufficient to induce inflammatory response of pancreatitis including local inflammation and systemic inflammatory response while acinar death due to pathologic trypsinogen activation leads to about half of all pancreatic cell necrosis during pancreatitis.

Chronic pancreatitis

Chronic pancreatitis (CP) is characterized by a widespread scarring and inflammatory destruction of pancreatic tissue over many years. Although the most common etiological factor in chronic pancreatitis is prolonged alcohol abuse (70%), in many patients, this condition may develop without any apparent cause (20%). It also occurs most commonly after an episode of acute pancreatitis, as the result of ongoing inflammation of the pancreas. Smoking increases the risk of non-gallstone acute pancreatitis twofold in non-alcoholics and fourfold in alcoholics. Smoking is also the most important factor influencing progression of acute to chronic pancreatitis. Other minor causes which constitute 10% of cases include tropical pancreatitis, hereditary pancreatitis, cystic fibrosis, pancreas divisum, and hyperparathyroidism.

Risks posed by CP include:

  • Diabetes mellitus due to damaged insulin-secreting endocrine cells of the pancreas. The overall prevalence of diabetes is 47% in CP patients. The incidence of diabetes increases over time, ranging from 0% to 22% at the onset of symptoms and more than 80% 25 years after the onset of CP. The independent predictors of diabetes are distal pancreatectomy, smoking in patients with prior surgery, pancreatic calcifications, age at the onset of CP, smoking, and chronic pain in patients without surgery.
  • Pancreatic cancer.
  • Severe chronic pain.
  • Malsorption of nutrients from the digestive tract leading to weight loss.
  • Stomach bleeding.

Treatment often involves pain medications and supplementation with pancreatic enzymes or insulin with meals to aid in nutrient absorption. The pancreatic enzyme product (PEP) approved by the US Food and Drug Administration (FDA) contains pancrelipase, a mixture of porcine lipase, amylase, and proteases.

Around 50% of patients require surgical intervention which produces superior results to conservative and endoscopic treatment approaches. Management includes a low-fat diet and alcohol abstinence.

Autoimmune pancreatitis

It is an idiopathic chronic inflammatory disease that produces pancreatic masses and ductal strictures. Although considered a type of chronic pancreatitis, autoimmune pancreatitis is distinct from conventional chronic pancreatitis but bears more resemblance to pancreatic cancer, both clinically and radiographically.

Most patients are more than 50 years old at diagnosis and twice as many men as women are affected. The most common clinical features are painless obstructive jaundice, new-onset diabetes mellitus (endocrine dysfunction in 67%of cases), and weight loss from impaired digestion and decreased appetite (pancreatic exocrine insufficiency in 88% of cases). Most patients have no history of alcohol abuse or other traditional risk factors for chronic pancreatitis. Diagnosis of autoimmune pancreatitis involves combination of serological, radiographic, and histopathological analyses. Gamma globulin, total IgG, and IgG4 are usually elevated in autoimmune pancreatitis with serum IgG4 considered the most sensitive and specific marker, elevated in 63–94% of patients. Antilactoferrin and anti-carbonic anhydrase II autoantibodies are also elevated in autoimmune pancreatitis. The most common radiographic feature is diffuse enlargement of the entire pancreas. The “sausage-like” appearance of the gland is a feature best seen with CT and magnetic resonance imaging (MRI). Histological evaluation is the gold standard for diagnosis with the following characteristic features:

  • Parenchymal and often periductal lymphoplasmacytic infiltration (CD4+ and CD8+ lymphocytes, IgG4-positive plasmacytes), which is typically florid in intensity.
  • Storiform fibrosis: characterized by ductal luminal destruction, acinar atrophy, and arrangement of myofibroblasts in a storiform pattern resembling an inflammatory pseudotumor.
  • Obliterative phlebitis: Venulitis is seen mainly in small and medium-size pancreatic and peripancreatic veins. The inflammatory response and fibrosis disrupt the venous endothelium and often result in obliterative phlebitis.

Corticosteroids (prednisone) are very effective in treating autoimmune pancreatitis. In fact, a poor response to steroid therapy raises suspicion of pancreatic cancer, necessitating reevaluation of the diagnosis.

Genetic basis of pancreatitis

Pancreatitis results from a complex interaction of multiple genetic and environmental factors. Genetic studies for hereditary, idiopathic, and tropical forms of pancreatitis have established at least the following five pancreatitis susceptibility genes:


Expressed in acinar cells, it encodes cationic trypsinogen, which is the most abundant isoform of trypsinogen in human pancreatic juice. Most of the bona fide disease-causing missense mutations in the PRSS1 gene led to enhanced trypsinogen autoactivation and/or increased trypsin stability resulting in autosomal dominant or hereditary pancreatitis.


Expressed in acinar cells, the serum protease inhibitor, Kazal type 1 gene (SPINK1), encodes pancreatic secretory trypsin inhibitor (PSTI), one of the key defensive mechanisms against prematurely activated trypsin within the pancreatic acinar cells during ongoing inflammation. Multiple loss-of-function variations in the SPINK1 gene have been found in patients with idiopathic chronic pancreatitis.


It encodes cystic fibrosis transmembrane conductance regulator and is expressed in the ductal and  centroacinar cells. As an anion channel, it allows movement of chloride or bicarbonate across the duct cell luminal membrane into the duct, increasing the pH, as well as initiating and driving pancreatic juice flow. By diluting and alkalinizing the protein-rich acinar secretions, CFTR prevents the formation of protein plugs that predispose to pancreatic injury. Various loss-of-function mutations have been reported to be associated with idiopathic and alcoholic chronic pancreatitis.


Expressed in acinar cells, it encodes the chymotrypsinogen C gene. Multiple mutations associated with chronic pancreatitis are believed to cause impaired trypsinogen, trypsin degradation, and induction of endoplasmic reticulum stress.


Expressed in both acinar and duct cells of the pancreas, it encodes a plasma membrane-bound G-proteincoupled calcium-sensing receptor. As a monitor and regulator of pancreatic juice calcium concentration, it triggers ductal electrolyte and fluid secretion when Ca2+ levels are elevated, which otherwise could increase the risk of trypsinogen activation and trypsin stabilization causing acute pancreatitis. Multiple mutations and SNPs have been associated with hereditary pancreatitis.

Experimentally induced pancreatitis

To better understand the pathophysiology of pancreatitis for the development of targeted treatment options, various experimental animal models have been developed which resemble the human pancreatitis to various degrees. It includes the noninvasive models of acute pancreatitis such as hormone-induced, alcohol-induced, immune-mediated, diet-induced, gene knockout, and L-arginine and invasive models including closed duodenal loop, antegrade pancreatic duct perfusion, biliopancreatic duct injection, combination of secretory hyperstimulation with minimal intraductal bile acid exposure, vascular-induced, ischemia/reperfusion, and duct ligation.

Caerulein, a cholecystokinin-pancreozymin analogue, has been widely used for the induction of acute pancreatitis in laboratory animals. Caerulein administration causes intracellular proteolytic enzyme activation resulting in pancreatic acinar autolysis. Increased concentrations of pancreatic enzymes in blood plasma, acinar cell necrosis, and pancreatic inflammation are the common observations.

A relatively simple and inexpensive model, it has been frequently used to study the cell biology and pathophysiology of acute pancreatitis and regeneration of damaged tissue, as its effects are reversed after being discontinued.

In a diet-induced model of acute pancreatitis, young female mice are fed with a choline-deficient diet containing ethionine (CDE diet) which induces severe acute necrotizing pancreatitis. It is the simplest system to establish for the investigation of acute hemorrhagic pancreatitis.

L-arginine-induced necrotizing acute pancreatitis: Intraperitoneal (i.p.) administration of excessive doses of L-arginine (500 mg/100 g body weight) in rats selectively damages pancreatic acinar cells without any morphological change in islets of Langerhans or other organs. Although the exact mechanism of L-arginine pancreatitis is not clear, it is proposed that its metabolites, oxidative stress, and metabolic acidosis contribute to the pancreatic injury in this model.

Pancreatic cancer and pancreatitis

Meta-analysis of various epidemiological studies revealed the association of pancreatic cancer with several risk factors among which chronic pancreatitis is the most considerate risk factor. It has been reported that among patients with hereditary pancreatitis, 40%develop pancreatic cancer in their lifetime.

The chronic inflammation incurred during pancreatitis results in pancreatic cancer development over a period of time increasing the risk by 10- to 20-folds. Chronic pancreatitis is accompanied by a series of events including fibrosis, tumor-stromal interaction, loss of immune surveillance, and DNA repair response, leading to the development of pancreatic tumor. It is known that numerous inflammatory mediators induced due to smoking, obesity, diabetes, alcohol abuse, and chronic pancreatitis are capable of causing genomic damage, altered gene expression, and induction of oncogenic signaling pathways leading to the development of precancerous precursor lesions called pancreatic intraepithelial neoplasias (PanINs) and further growth and progression of pancreatic cancer. In adult mice models, brief bouts of experimentally induced pancreatitis lead to PanINs and pancreatic cancer when acinar cells express mutant K-Ras oncogene.


DiMagno MJ, DiMagno EP (2012) Chronic pancreatitis. Curr Opin Gastroenterol 28:523–531

LaRusch J, Whitcomb DC (2011) Genetics of pancreatitis. Curr Opin Gastroenterol 27:467–474

Momi N, Kaur S, Krishn SR, Batra SK (2012) Discovering the route from inflammation to pancreatic cancer. Minerva Gastroenterol Dietol 58:283–297

Sah RP, Garg P, Saluja AK (2012) Pathogenic mechanisms of acute pancreatitis. Curr Opin Gastroenterol 28:507–515

Su KH, Cuthbertson C, Christophi C (2006) Review of experimental animal models of acute pancreatitis. HPB (Oxford) 8:264–286