Epidemiology
Acute pancreatitis is one of the most common diseases of the gastrointestinal tract leading to hospital admission.[7] Incidence varies from 4.5 to 79.8 per 100,000 per year in different countries, with incidence in the UK reported at approximately 56 per 100,000 per year.[8] The variation in incidence between different countries is due to different diagnostic criteria, geographical factors, and changes over time.[9][10] Global age-standardised incidence was estimated at 20.6 per 100,000 in 2017.[11] A 10-fold increase in its incidence from 1960 to 1980, with a mortality rate from 1% to 9%, was noted.[12] The overall mortality rate in the UK is reported as around 5%, rising to 25% for patients with severe disease.[8] In the UK, around 50% of cases are caused by gallstones, 25% by alcohol, and 25% by other factors.[8] Gallstone pancreatitis is more common in women >60 years of age, especially among patients with microlithiasis. Alcoholic pancreatitis is seen more frequently in men.[13]
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 to 55 years of age).
Mostly associated with high alcohol intake.
Gallstone pancreatitis accounts for 45% to 50% of acute pancreatitis in the US.[27] 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 intra-pancreatic enzymatic activation. Stones may cause inflammation and oedema of the ducts, causing some degree of flow restriction and backflow of activated enzymes into the pancreas.[27]
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 to 175 g per day.[12][27] 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 hypertriglyceridaemia 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 micro-circulation, leading to endothelial injury and ischaemic insult to the acinar cell.[17] Many patients with acute pancreatitis demonstrate an acute increase in circulating triglycerides in the range of 5 or 6 mmol/L (a few hundred mg/dL). However, patients with true hypertriglyceridaemia-induced acute pancreatitis manifest a substantial increase in circulating triglycerides, commonly over 12 mmol/L (1000 mg/dL) and as high as 100 mmol/L (9000 mg/dL).[28][29] Acute pancreatitis caused by hypertriglyceridaemia may be more severe than disease from other causes.[30]
There is evidence from randomised trials that mercaptopurine and azathioprine may cause acute pancreatitis. There are limited data to support a causative role for other drugs that have been implicated (e.g., furosemide, oestrogens, thiazide diuretics, sulfonamides, tetracyclines, sulindac, valproate, and L-asparaginase). Before labelling a drug as the cause, rule out other common causes or consider the possibility of idiopathic pancreatitis.[25]
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.[31] Studies show risk reduction from the use of a peri-ERCP non-steroidal anti-inflammatory agent such as rectal indomethacin, aggressive hydration with lactated Ringer’s solution, and pancreatic stents for selected patients.[31][32][33][34][35][36]
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 hyperamylasaemia. Given that the pancreas is a retroperitoneal organ, trauma is not a common aetiological factor but its incidence may be under-reported, because patients may not have a clear clinical manifestation.[17]
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 pathophysiological mechanisms include accumulation of zymogen granules in the cytoplasm, cytoplasmic vacuolisation, focal acinar depolarisation, acinar necrosis, increased amylase secretion, and formation of calcified stones intraductally.[17][37][38]
Pancreas divisum is the most common anatomical 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 derivates, which can lead to acute pancreatitis.[27] 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.[41]
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.[23]
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 peri-ampullary tumours.[17] Chronic pancreatitis significantly increases the risk of pancreatic cancer.[8]
Oddi's dysfunction can be primary (idiopathic) or secondary (trauma during endoscopic retrograde cholangiopancreatography [ERCP]), and can lead to obstruction of bile and retrograde flow into the pancreatic parenchyma, causing inflammation.[42] Oddi dysfunction 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 sphincter of Oddi dysfunction (e.g., abnormal imaging and abnormal liver function tests).[43]
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 abdominal pain early in childhood. The genetic defects vary. The most common appears 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.[44][45][46] PRSS1 and chymotrypsin C mutations are strongly associated with early-onset pancreatitis.[47]
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