Epidemiology
Acute pancreatitis is one of the most common diseases of the gastrointestinal tract leading to hospital admission.[7] For reasons not completely understood, the incidence is increasing, with higher levels of alcohol consumption and obesity (and associated increased risk of gallstones) likely to be among the causative factors. Overall incidence varies from 3.4 to 73.4 per 100,000 per year in different countries.[8] This variation is due to different diagnostic criteria, geographic factors, and changes over time.[9][10] Global age-standardized incidence was estimated at 34.8 per 100,000 in 2019.[11] A 10-fold increase in its incidence from 1960 to 1980, with a mortality rate from 1% to 9%, was noted.[12] Approximately 300,000 patients are admitted to hospitals in the US each year with acute pancreatitis.[13] The mortality rate is influenced by the severity of the disease, and several prognostic factors have been investigated and described. In contrast to the milder form of the disease, which has a mortality rate of 1%, the mortality associated with severe acute pancreatitis is 10% with sterile and 25% with infected pancreatic necrosis.[1] Gallstone pancreatitis is more common in women >60 years of age, especially among patients with microlithiasis. Alcoholic pancreatitis is seen more frequently in men.[14]
Risk factors
Women between 50 and 70 years of age are more likely to have gallbladder disease and may present with pancreatitis at later age than men with alcoholic pancreatitis (40-55 years of age).
Mostly associated with high alcohol intake.
Gallstone pancreatitis accounts for 45% to 50% of acute pancreatitis in the US.[26] It is seen more frequently in older women and those with a history of gallstone disease. Impaction of a stone within the common bile duct causes reflux of biliohepatic secretions and intrapancreatic enzymatic activation. Stones may cause inflammation and edema of the ducts, causing some degree of flow restriction and backflow of activated enzymes into the pancreas.[26]
Alcohol is the most common cause of acute pancreatitis in many regions. Although patients with alcohol-induced pancreatitis present acutely, the underlying pathology is caused by chronic exposure to alcohol. A dose-related destruction of the pancreatic parenchyma has been described. This form of pancreatitis is more common in men than in women and is usually seen after periods of binge drinking against a background of chronic alcohol misuse. The average amount of alcohol intake in patients with acute pancreatitis is 150-175 g per day.[12][26] There is no threshold for the development of acute pancreatitis. Individuals who do not have a long previous history of excessive alcohol intake are unlikely to present with alcohol-induced acute pancreatitis.
The mechanism for hypertriglyceridemia causing acute pancreatitis has not been elucidated. It has been suggested that the pancreatic lipase can produce toxic fatty acids that are secreted into the pancreatic microcirculation, leading to endothelial injury and ischemic insult to the acinar cell.[19] Many patients with acute pancreatitis demonstrate an acute increase in circulating triglycerides in the range of a few hundred mg/dL. However, patients with true hypertriglyceridemia-induced acute pancreatitis manifest a substantial increase in circulating triglycerides, commonly over 1000 mg/dL and as high as 9000 mg/dL.[27][28] Acute pancreatitis caused by hypertriglyceridemia may be more severe than disease from other causes.[29]
There is good quality evidence from randomized trials that 6-mercaptopurine and azathioprine may cause acute pancreatitis.[24] However, most other drugs implicated in acute pancreatitis are unlikely to have a causative role; much of the evidence is based only on speculative case reports (e.g., furosemide, estrogens, thiazide diuretics, sulfonamides, tetracyclines, sulindac, mercaptopurine, valproate, and asparaginase). Before labeling a drug as the cause, clinicians should rule out other common causes or consider the possibility of idiopathic pancreatitis.[23]
Patients undergoing ERCP experience a risk of acute pancreatitis ranging up to approximately 15%, depending on the underlying patient profile and prior use of prophylaxis.[33] The risk can be reduced by use of peri-ERCP rectal indomethacin suppositories, peri-ERCP intravenous hydration with Ringer lactate (Hartmann solution), and the use of pancreatic duct stents for selected high risk patients.[33][34][35]
Traumatic pancreatitis can be caused by therapeutic or diagnostic procedures or during external trauma. Blunt trauma is the most common cause of pancreatic injury and can be associated with parenchymal inflammation and hyperamylasemia. Given that the pancreas is a retroperitoneal organ, trauma is not a common etiologic factor but its incidence may be underreported, because patients may not have a clear clinical manifestation.[19]
Causal mechanisms are still not completely understood. Animal studies have shown that calcium has a direct toxic effect on the pancreatic acinar cell. Other proposed pathophysiologic mechanisms include accumulation of zymogen granules in the cytoplasm, cytoplasmic vacuolization, focal acinar depolarization, acinar necrosis, increased amylase secretion, and formation of calcified stones intraductally.[19][30][31]
Pancreas divisum is the most common anatomic anomaly of the gastrointestinal tract. During organogenesis, the pancreas derives from the foregut after the fusion of the larger dorsal bud and the smaller ventral bud. The smaller accessory duct of Santorini drains the pancreatic structures that derive from the dorsal bud (upper half of the head, neck, body, and tail), whereas the larger duct of Wirsung drains the ventral bud (lower part of the head and uncinate process). It has been proposed that failure of the rotation of the ventral bud prevents fusion of both ducts, leading to insufficient drainage of the dorsal bud derivatives, which can lead to acute pancreatitis.[26] Endoscopic sphincterotomy of the minor papilla and stenting of the dorsal duct may decrease the recurrence of pancreatitis but its role for pain control has not been demonstrated.[36][37]
While there does not appear to be an increased risk of acute pancreatitis in large observational studies of patients with pancreas divisum, other factors may explain why some patients with pancreas divisum are susceptible. Genetic anomalies in the CFTR gene in such patients may lead to sludging of pancreatic secretions, similar to that seen in patients with cystic fibrosis, contributing to a higher risk of acute pancreatitis in some individuals.[21]
The most common primary malignancy of the pancreas is the adenocarcinoma. Cancer has been implicated as a potential risk factor for the development of pancreatitis if it causes duct obstruction. It has been reported that 1% to 2% of acute pancreatitis may be attributed to periampullary tumors.[19]
There are different types of sphincter of Oddi dysfunction (SOD). SOD can be primary (idiopathic) or secondary (trauma during ERCP), and can lead to obstruction of bile and retrograde flow into the pancreatic parenchyma, causing inflammation.[38] SOD may cause recurrent pain, pancreatitis, abnormal pancreaticobiliary tree on imaging, and/or abnormal liver function tests (aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and bilirubin). While ERCP with a sphincterotomy may relieve the mechanical obstruction responsible for pain and pancreatitis, conversely it may precipitate acute pancreatitis, and its use in individuals with idiopathic pancreatitis (and/or chronic pain) should be limited to those with a high likelihood of SOD (e.g., abnormal imaging and abnormal liver function tests).[39]
Patients with the familial form of pancreatitis present with a variety of diseases of the pancreas, including acute and chronic pancreatitis, and pancreatic cancer. Some patients present with chronic abdominal pain early in childhood. The genetic defects vary. The most common seems to be transmitted as a non-X-linked dominant with variable penetrance and progress to chronic pancreatitis. Other conditions may be associated, such as diabetes mellitus or aminoaciduria.[5] Hereditary pancreatitis accounts for 1% of all cases, and several mutations have been described as possible inducers of the disease. The strongest correlations are with the cationic trypsinogen gene (PRSS1) on chromosome 7q35 and SPINK1 and CRTF gene mutations.[40][41][42] PRSS1 and chymotrypsin C mutations are strongly associated with early-onset pancreatitis.[43] In general, genetic evaluation of patients with acute pancreatitis is inappropriate and offers little practical benefit to clinicians managing the condition. Any patients with a strong family history of pancreatic disease should be evaluated at a center of excellence for potential genetic traits.
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