Introduction
Background
The pancreas is a gland located in the upper, posterior abdomen and is responsible for insulin production (endocrine pancreas) and the manufacture and secretion of digestive enzymes (exocrine pancreas) leading to carbohydrate, fat, and protein metabolism. Approximately 80% of the gross weight of the pancreas supports exocrine function, while the remaining 20% is involved with endocrine function. The focus of this article is on the exocrine function of the pancreas.
As mentioned, the principal function of the exocrine pancreas is to make food-digesting enzymes. The pancreas, comprising only 0.1% of total body weight, has 13 times the protein-producing capacity of the liver and the reticuloendothelial system combined, which make up 4% of total body weight. Enzymes are produced within the pancreatic acinar cells, packaged into storage vesicles called zymogens, and then released via the pancreatic ductal cells into the pancreatic duct, where they are secreted into the small intestine to begin the metabolic process.
In normal pancreatic function, up to 15 different types of digestive enzymes are manufactured in the rough endoplasmic reticulum, targeted in the golgi apparatus and packaged into zymogens as pro-enzymes. When a meal is ingested, the vagal nerves, VIP, GRP, secretin, CCK, and encephalins stimulate enzymatic release into the pancreatic duct. The pro-enzymes travel to the brush border of the duodenum, where trypsinogen, the pro-enzyme for trypsin, is activated via hydrolysis of an N-terminal hexapeptide fragment by the brush border enzyme enterokinase. Trypsin then facilitates the conversion of the other pro-enzymes to their active form.
A feedback mechanism exists to limit pancreatic enzyme activation after appropriate metabolism has occurred. It is hypothesized that elevated levels of trypsin, having become unbound from digesting food, lead to decreased CCK and secretin levels, thus limiting further pancreatic secretion.
Because premature activation of pancreatic enzymes within the pancreas leads to organ injury and pancreatitis, several mechanisms exist to limit this occurrence. First, proteins are translated into the inactive pro-enzymes. Later, posttranslational modification of the Golgi cells allows their segregation into the unique subcellular zymogen compartments. The pro-enzymes are packaged in a paracrystalline arrangement with protease inhibitors.
Zymogen granules have an acidic pH and a low calcium concentration, which are factors that guard against premature activation until after secretion occurs and extracellular factors trigger the activation cascade. Under various conditions, these protective mechanisms are disrupted, resulting in intracellular enzyme activation and pancreatic autodigestion, leading to acute pancreatitis.
Pathophysiology
Acute pancreatitis may occur when factors involved in maintaining cellular homeostasis are out of balance. The initiating event may be anything that injures the acinar cell and impairs the secretion of zymogen granules, such as alcohol use, gallstones, and certain drugs. At this time, it is unclear mechanistically exactly what pathophysiologic event triggers the onset of acute pancreatitis. However, it is believed that both extracellular factors (eg, neural response, vascular response) and intracellular factors (eg, intracellular digestive enzyme activation, increased calcium signaling, heat shock protein activation) play a role. In addition, acute pancreatitis can develop when ductal cell injury leads to delayed or absent enzymatic secretion, such as with the CFTR gene mutation.
Once a cellular injury pattern has been initiated, cellular membrane trafficking becomes chaotic, with the following deleterious effects: (1) lysosomal and zymogen granule compartments fuse, enabling activation of trypsinogen to trypsin; (2) intracellular trypsin triggers the entire zymogen activation cascade; and (3) secretory vesicles are extruded across the basolateral membrane into the interstitium, where molecular fragments act as chemoattractants for inflammatory cells. Activated neutrophils then exacerbate the problem by releasing superoxide (the respiratory burst) or proteolytic enzymes (cathepsins B, D, and G; collagenase; and elastase). Finally, macrophages release cytokines that further mediate local (and, in severe cases, systemic) inflammatory responses. The early mediators defined to date are tumor necrosis factor-alpha, interleukin-6, and interleukin-8.
These mediators of inflammation cause an increased pancreatic vascular permeability, leading to hemorrhage, edema, and eventually pancreatic necrosis. As the mediators are excreted into the circulation, systemic complications can arise, such as bacteremia due to gut flora translocation, acute respiratory distress syndrome, pleural effusions, gastrointestinal hemorrhage, and renal failure. The systemic inflammatory response syndrome can also develop, leading to the development of systemic shock. Eventually, the mediators of inflammation can become so overwhelming to the body that hemodynamic instability and death ensue.
Li et al compared 2 set of patients with severe acute pancreatitis—those with acute renal failure and those without it—in order to determine the risk factors for acute renal failure in these patients.1 Data collected included age, history of renal disease, Acute Physiology and Chronic Health Evaluation (APACHE) II scores, hypoxemia, and abdominal compartment syndrome. The authors concluded that a history of renal disease, hypoxemia, and abdominal compartment syndrome are significant risk factors for acute renal failure in patients with severe acute pancreatitis. In addition, compared with the other patients in the study, those with acute renal failure were found to have a significantly greater average length of stay in the hospital and in the intensive care unit, as well as higher rates of pancreatic infection and mortality.
Frequency
United States
In 2007, nearly 220,000 patients with acute pancreatitis are expected to be admitted to non-federally funded hospitals. In 1998, 183,000 patients with acute pancreatitis were admitted. This trend in rising incidence has been recognized over the past several decades.2
International
In Luneburg, Germany, the incidence is 17.5 cases per 100,000 people. In Finland, the incidence is 73.4 cases per 100,000 people. Similar incidence rates have been reported in Australia. The incidence of disease is less well known outside of North America, Europe, and Australia.
In Europe and other developed nations, such as Hong Kong, more patients tend to have gallstone pancreatitis, whereas in the United States, alcoholic pancreatitis is most common.Mortality/Morbidity
- The overall mortality rate of patients with acute pancreatitis is 10-15%. Patients with biliary pancreatitis tend to have a higher mortality rate than patients with alcoholic pancreatitis. This rate has been falling over the last two decades as improvements in supportive care have been initiated.
- In patients with severe disease (organ failure), the mortality rate is approximately 30%. This rate in mortality has not dropped in the last 10 years.
- In patients with necrosis without organ failure, the mortality rate approaches zero.
- In the first week of illness, most deaths result from multiorgan system failure. In subsequent weeks, infection plays a more significant role, but organ failure still constitutes a major cause of mortality.
Race
The hospitalization rates of patients with acute pancreatitis per 100,000 population are 3 times higher for blacks than whites. These racial differences are more pronounced for males than females.
Sex
- In general, acute pancreatitis affects males more often than females.
- The etiology in males is more often related to alcohol; in females, to biliary tract disease.
- Idiopathic pancreatitis has no clear predilection for either sex.
Age
- The median age at onset depends on the etiology.3
- The following are median ages of onset for various etiologies:
- Alcohol-related - 39 years
- Biliary tract–related - 69 years
- Trauma-related - 66 years
- Drug-induced etiology - 42 years
- Endoscopic retrograde cholangiopancreatography (ERCP)–related - 58 years
- AIDS-related - 31 years
- Vasculitis-related - 36 years
- Hospitalization rates increase with age. For people aged 35-75 years, the rate doubles for males and quadruples for females.
Clinical
History
The cardinal symptom of acute pancreatitis is abdominal pain, which is characteristically dull, boring, and steady. Usually, the pain is sudden in onset and gradually intensifies in severity until reaching a constant ache. Most often, it is located in the upper abdomen, usually in the epigastric region, but it may be perceived more on the left or right side, depending on which portion of the pancreas is involved. The pain radiates directly through the abdomen to the back in approximately one half of cases. Nausea and vomiting are often present along with accompanying anorexia. Diarrhea can also occur. Positioning can be important, because the discomfort frequently improves with the patient in the supine position. The duration of pain varies but typically lasts more than a day. It is the intensity and persistence of the pain that usually causes patients to seek medical attention.
Atypical acute pancreatitis may be misdiagnosed. In a study of patients with pancreatitis discovered at autopsy, 13% presented with abdominal pain, 19% had disease that occurred in the postoperative setting, and 68% presented with various cardiac, pulmonary, hepatic, renal, abdominal, and metabolic disturbances.
Physical
The following physical examination findings vary with the severity of the disease.
- Fever (76%) and tachycardia (65%) are common abnormal vital signs.
- Abdominal tenderness, muscular guarding (68%), and distension (65%) are observed in most patients. Bowel sounds are often hypoactive due to gastric and transverse colonic ileus. Guarding tends to be more pronounced in the upper abdomen.
- A minority of patients exhibit jaundice (28%).
- Some patients experience dyspnea (10%), which may be caused by irritation of the diaphragm (resulting from inflammation), pleural effusion, or a more serious condition, such as acute respiratory distress syndrome.
- In severe cases, hemodynamic instability is evident (10%) and hematemesis or melena sometimes develops (5%). In addition, patients with severe acute pancreatitis are often pale, diaphoretic, and listless.
A few uncommon physical findings are associated with severe necrotizing pancreatitis
- The Cullen sign is a bluish discoloration around the umbilicus resulting from hemoperitoneum.
- The Grey-Turner sign is a reddish-brown discoloration along the flanks resulting from retroperitoneal blood dissecting along tissue planes. More commonly, patients may have a ruddy erythema in the flanks secondary to extravasated pancreatic exudate.
- Erythematous skin nodules may result from focal subcutaneous fat necrosis. These are usually not more than 1 cm in size and are typically located on extensor skin surfaces. In addition, polyarthritis is occasionally seen.
- Rarely, abnormalities on funduscopic examination may be seen in severe pancreatitis. Termed Purtscher retinopathy, this ischemic injury to the retina appears to be caused by activation of complement and agglutination of blood cells within retinal vessels. It may cause temporary or permanent blindness.
Causes
Pancreatitis has numerous etiologies, but alcohol exposure and biliary tract disease cause most cases. In 10-30% of cases, the cause is unknown, although studies have suggested that up to 70% of cases of idiopathic pancreatitis are secondary to biliary microlithiasis.
- Biliary tract disease (approximately 40%): The most common cause of acute pancreatitis in most developed countries is gallstones passing into the bile duct and temporarily lodging at the sphincter of Oddi. The risk of a stone causing pancreatitis is inversely proportional to its size. It is thought that acinar cell injury occurs secondary to increasing pancreatic duct pressures caused by obstructive biliary stones at the ampulla of Vater, although this has not been definitively proven in humans. Occult microlithiasis is probably responsible for most cases of idiopathic acute pancreatitis.
- Alcohol (approximately 35%): Alcohol use is a major cause of acute pancreatitis. Most commonly, the disease develops in patients whose alcohol ingestion is habitual over 5-15 years. Alcoholics are usually admitted with an acute exacerbation of chronic pancreatitis. Occasionally, however, pancreatitis can develop in a patient with a weekend binging habit, and several case reports have described a sole large alcohol load precipitating a first attack. Nevertheless, the alcoholic who imbibes routinely remains the rule rather than the exception. Currently, there is no universally accepted explanation for why certain alcoholics are more predisposed to developing acute pancreatitis than others who ingest similar quantities.
- Post-ERCP (approximately 4%)
- Post-ERCP pancreatitis is probably the third most common cause of pancreatitis. While retrospective surveys indicate the risk is only 1%, prospective studies have shown the risk is at least 5%.
- The risk is increased if the endoscopist is inexperienced, the patient is thought to have sphincter of Oddi dysfunction (SOD), or manometry is performed on the sphincter of Oddi.
- No medications, with the exception of aggressive preintervention intravenous hydration, have been durably shown to prevent post-ERCP pancreatitis in randomized studies.
- Trauma (approximately 1.5%)
- Abdominal trauma causes an elevation of amylase and lipase levels in 17% of cases and clinical pancreatitis in 5% of cases.
- Pancreatic injury, as shown below, occurs more often in penetrating injuries (eg, from knives, bullets) than in blunt abdominal trauma (eg, from steering wheels, horses, bicycles). Blunt injury may crush the gland across the spine, leading to a ductal injury in that location.
CT scan of the abdomen in a child with traumatic pancreatitis. The fluid collection adjacent to the pancreas will become a pseudocyst. Note that the pancreas is lacerated, nearly cut in half, by the force of the abdominal trauma. Also, note the typical location of this injury in relation to the vertebral column.
- Drugs (approximately 2%)
- Considering the small number of patients who develop pancreatitis compared to the relatively large number who receive potentially toxic drugs, drug-induced pancreatitis is a relatively rare occurrence probably related to an unknown predisposition. Fortunately, drug-induced pancreatitis is usually mild.
- Drugs definitely associated with acute pancreatitis include azathioprine, sulfonamides, sulindac, tetracycline, valproic acid, didanosine, methyldopa, estrogens, furosemide, 6-mercaptopurine, pentamidine, 5-aminosalicylic acid compounds, corticosteroids, and octreotide.
- Drugs probably associated with acute pancreatitis include chlorothiazide and hydrochlorothiazide, methandienone, metronidazole, nitrofurantoin, phenformin, piroxicam, procainamide, colaspase, chlorthalidone, combination cancer chemotherapy drugs (especially asparaginase), cimetidine, cisplatin, cytosine arabinoside, diphenoxylate, and ethacrynic acid.
- There are many drugs that have been reported to cause acute pancreatitis in isolated or sporadic cases.
- Infection (<1%)
- Several infectious diseases may cause pancreatitis, especially in children. These cases of acute pancreatitis tend to be milder when compared to biliary or alcohol-induced pancreatitis.
- Viral causes include mumps, Epstein-Barr, coxsackievirus, echovirus, varicella-zoster, and measles.
- Bacterial causes include Mycoplasma pneumoniae, Salmonella, Campylobacter, and Mycobacterium tuberculosis.
- Worldwide, ascariasis is a recognized cause of pancreatitis resulting from the migration of worms in and out of the duodenal papillae.
- Pancreatitis has been associated with AIDS; however, this may be the result of opportunistic infections, neoplasms, lipodystrophy, or drug therapies.
- Hereditary pancreatitis (<1%)
- Hereditary pancreatitis is an autosomal dominant gain-of-function disorder related to mutations of the cationic trypsinogen gene (PRSS1), which has an 80% penetrance. Mutations in this gene cause premature activation of trypsinogen to trypsin.
- In addition, the CFTR mutation plays a role in predisposing patients to acute pancreatitis by causing abnormalities of ductal secretion. However, the phenotypic variability of patients with the CFTR mutation is not well understood at this time. Certainly, patients homozygous for the CFTR mutation are at risk for pancreatic disease; however, which of the more than 800 mutations carries the most significant risk is not known at this time. In addition, the role of CFTR heterozygotes in pancreatic disease is unknown.
- Mutations in the SPINK1 protein, which blocks the active binding site of trypsin, rendering it inactive, also likely play a role in causing a predisposition toward acute pancreatitis.
- This probably explains the predisposition, rather than the cause, of acute pancreatitis in these patients. If enough mutant enzymes become activated intracellularly, they can overwhelm the first line of defense (ie, pancreatic secretory trypsin inhibitor) and resist backup defenses (ie, proteolytic degradation by mesotrypsin, enzyme Y, and trypsin itself). Activated mutant cationic trypsin can then trigger the entire zymogen activation cascade.
- Hypercalcemia (<1%)
- Hypercalcemia from any cause can lead to acute pancreatitis. Causes include hyperparathyroidism, excessive doses of vitamin D, familial hypocalciuric hypercalcemia, and total parenteral nutrition (TPN).
- The routine use of automated serum chemistries has allowed earlier detection and reduced the frequency of hypercalcemia manifesting as pancreatitis.
- Developmental abnormalities of the pancreas (<1%)
- The pancreas develops from two buds stemming from the alimentary tract of the developing embryo. Two developmental abnormalities are associated with pancreatitis: pancreas divisum and annular pancreas.
- Pancreas divisum is a failure of the dorsal and ventral pancreatic ducts to fuse during embryogenesis. Probably a variant of normal anatomy, it occurs in approximately 5% of the population. In most cases, this variant may actually protect against gallstone pancreatitis. Although controversial, the presence of stenotic minor papillae and an atretic duct of Santorini are additional risk factors that together contribute to the development of acute pancreatitis through an obstructive mechanism. (See the images below.)
Pancreas divisum associated with minor papilla stenosis causing recurrent pancreatitis. Because pancreas divisum is relatively common in the general population, it is best regarded as a variant of normal anatomy and not necessarily as a cause of pancreatitis. In this case, note the bulbous contour of the duct adjacent to the cannula. This appearance has been termed a Santorinicele. A dorsal duct outflow obstruction is the probable cause of pancreatitis when a Santorinicele is present and associated with a minor papilla that accommodates only a guidewire.
Recurrent pancreatitis associated with pancreas divisum in an elderly man. This pancreatogram of the dorsal duct shows a distal stenosis with upstream chronic pancreatitis. After the stenosis was dilated and stented, the pain resolved, and the patient improved clinically during 1 year of stent exchanges on a quarterly basis. Follow-up CT scans showed resolution of an inflammatory mass. Although ductal biopsies and cytology were repeatedly negative, pain and pancreatitis returned when the stents were removed. The patient developed duodenal outflow obstruction and was sent to surgery; a Whipple procedure revealed a periampullary adenocarcinoma (of the minor papilla).
- Anular pancreas is an uncommon congenital anomaly in which a band of pancreatic tissue surrounds the second part of the duodenum. Usually, it does not cause symptoms until later in life. This condition is a rare cause of acute pancreatitis, probably through an obstructive mechanism.
- Sphincter of Oddi dysfunction can lead to acute pancreatitis by causing increased pancreatic ductal pressures. However, the role of SOD-induced pancreatitis in patients without elevated sphincter pressures on manometry remains controversial.
- Hypertriglyceridemia (<1%)
- Clinically significant pancreatitis usually does not occur until a person's serum triglyceride level reaches 1000 mg/dL. It is associated with type I and type V hyperlipidemia.
- While somewhat controversial, most authorities believe that the association is caused by the underlying derangement in lipid metabolism rather than by pancreatitis causing hyperlipidemia. This type of pancreatitis tends to be more severe than alcohol- or gallstone-induced disease.
- Tumor (<1%)
- Obstruction of the pancreatic ductal system by a pancreatic ductal carcinoma, ampullary carcinoma, islet cell tumor, solid pseudotumor of the pancreas, sarcoma, lymphoma, cholangiocarcinoma, or metastatic tumor can cause acute pancreatitis.
- The chance of pancreatitis occurring when a tumor is present is approximately 14%.
- Pancreatic cystic neoplasm, such as intraductal papillary-mucinous neoplasm (IPMN), mucinous cystadenoma, or serous cystadenoma, can also cause pancreatitis.
- Toxins (<1%)
- Exposure to organophosphate insecticide can cause acute pancreatitis.
- In Trinidad, the sting of the scorpion Tityus trinitatis is the most common cause of acute pancreatitis.
- Hyperstimulation of pancreas exocrine secretion appears to be the mechanism of action in both instances.
- Postoperative (<1%)
- Acute pancreatitis may occur in the postoperative period of various surgical procedures.
- Postoperative acute pancreatitis is often a difficult diagnosis to confirm, and it has a higher complication rate than pancreatitis associated with other etiologies. The mechanism is unclear.
- Vascular abnormalities (<1%): Vasculitis can predispose patients to pancreatic ischemia, especially in those with polyarteritis nodosa and systemic lupus erythematosus.
- Autoimmune pancreatitis (<1%): This relatively newly described entity is an extremely rare cause of acute pancreatitis. If it does cause acute pancreatitis, it is usually in young people (approximately 40 y) who also suffer from inflammatory bowel disease.
- In up to 10% of cases, the cause of pancreatitis remains unknown (idiopathic).
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Further Reading
Clinical guidelines
AGA Institute medical position statement on acute pancreatitis.
American Gastroenterological Association Institute - Medical Specialty Society. 2007 May. 3 pages. NGC:005792
Role of EUS.
American Society for Gastrointestinal Endoscopy - Medical Specialty Society. 2000 (revised 2007 Sep). 10 pages. NGC:006206
ACR Appropriateness Criteria® acute pancreatitis.
American College of Radiology - Medical Specialty Society. 1998 (revised 2006). 5 pages. NGC:005114
Clinical trials
Diagnostic and Interventional Therapy in Acute Pancreatitis
Early Goal-Directed Volume Resuscitation in Severe Acute Pancreatitis (EAGLE)
Goal-directed Fluid Resuscitation in Acute Pancreatitis
Related eMedicine topics
Pancreatitis
Pancreatitis, Acute (Radiology)
Pancreatic Necrosis and Pancreatic Abscess
Pancreatic Pseudocysts
Acute Renal Failure
Keywords
acute pancreatitis, pancreas, pancreatitis, chronic pancreatitis, pancreatic enzymes, endoscopic retrograde cholangiopancreatography, ERCP, magnetic resonance cholangiopancreatography, zymogen, biliary disease, biliary tract disease, elevated pancreatic enzymes, inflammation of the pancreas, pancreatitis diet, pancreatitis treatment, autoimmune pancreatitis, pancreatic disease, alcohol pancreatitis, alcoholic pancreatitis, pancreas inflammation
