What is The Most Common Cause of Pancreatitis

What is The Most Common Cause of Pancreatitis
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What is The Most Common Cause of Pancreatitis / Pancreatitis is common and is the leading cause of hospitalization amongst gastrointestinal disorders in the United States. The severity of the disease varies widely, from mild disease needing conservative treatment to severe and complicated disease with high morbidity and mortality. The diagnosis of acute presentation is easy, but the major challenge is predicting the progression of disease course and outcome. This is important to determine the level of care. 

Pancreatitis is a condition characterized by inflammation of the pancreas.[rx] The pancreas is a large organ behind the stomach that produces digestive enzymes and a number of hormones.[rx] There are two main types, acute pancreatitis, and chronic pancreatitis.[rx] Signs and symptoms of pancreatitis include pain in the upper abdomen, nausea, and vomiting.[rx] The pain often goes into the back and is usually severe.[rx] In acute pancreatitis, a fever may occur and symptoms typically resolve in a few days.[rx] In chronic pancreatitis weight loss, fatty stool, and diarrhea may occur.[rx] Complications may include infection, bleeding, diabetes mellitus, or problems with other organs.[rx]

Causes of Autoimmune Pancreatitis

In the majority of cases, alcohol use, gallstones, and hypertriglyceridemia cause acute pancreatitis. The rate of occurrence of each etiology of acute pancreatitis varies across geographic regions and socio-economic strata. Common etiologies of acute pancreatitis are listed below.

  • Alcohol use
  • Gallstones
  • Hypertriglyceridemia
  • Idiopathic
  • Drug-induced pancreatitis
  • Post-procedural (ERCP or abdominal surgery)
  • Ampullary stenosis is formerly known as sphincter of Oddi dysfunction type I
  • Autoimmune pancreatitis, type I (systemic IgG4 disease-related) and type II
  • Viral infection (Coxsackie, Cytomegalovirus, Echovirus, Epstein-Barr virus, Hepatitis A/B/C, HIV, Mumps, Rubella, Varicella)
  • Bacterial infection (Campylobacter jejuni, Legionella, Leptospirosis, Mycobacterium avium, Mycobacterium tuberculosis, Mycoplasma)
  • Trauma
  • Congenital anomalies (annular pancreas)
  • Genetic disorders (hereditary pancreatitis, cystic fibrosis, alpha 1-antitrypsin deficiency)
  • Hypercalcemia
  • Parasitic infections (Ascaris lumbricoides, Cryptosporidium, Clonorchis sinensis, Microsporidia)
  • Renal disease (Hemodialysis)
  • Toxins (Scorpion bites, organophosphate poisoning)
  • Vasculitis (Polyarteritis nodosa, Systemic lupus erythematosus)

Acute Pancreatitis

There are many potential causes of acute pancreatitis, the two major ones being gallstones and alcohol. The majority of recent studies, detailed in the following section, have employed experimental models of acute pancreatitis to explore the molecular basis of subsequent cellular responses. Recent studies have identified potential mechanisms for several of the common causes of acute pancreatitis.

Bile Acids

  • Exposure of pancreatic acinar cells to bile during biliary acute pancreatitis may contribute to the disease. Many past studies have shown that pathologic increases in acinar cell cytosolic calcium ([Ca2+]i) are linked to the early events in acute pancreatitis.
  • Fischer et al. [] found that bile acids induced pathologic increases in the acinar cell [Ca2+]i through a phosphatidylinositol-3 kinase (PI3K)-dependent mechanism by preventing reuptake of Ca2+ into the endoplasmic reticulum. It was also shown by Barrow et al. [] that bile-mediated Ca2+ responses are enhanced by cellular ATP depletion, suggesting that elevations in bile acids and ischemia may synergize to cause pancreatic injury.


  • Disordered secretion, including inhibition of apical secretion and enhanced basolateral exocytosis, are early features of acute pancreatitis and may be central to disease pathogenesis.
  • Lam et al. [] and Cosen-Binker et al. [,] have now shown that acute ethanol exposure sensitizes the acinar cell to the effects of physiologic concentrations of cholecystokinin (CCK) by causing both inhibitions of apical inhibition and basolateral exocytosis through the same mechanism.


  • The mechanism of hypertriglyceridemic pancreatitis may involve the release of free fatty acids (FFA) through the hydrolysis of triglycerides by pancreatic lipase. Pancreatitis-associated ascitic fluid plays a critical role in acute pancreatitis. Gutierrez et al. [] have now shown ascites to contain high concentrations of oxidized FFA, which interferes with the endogenous regulation of inflammation and may promote macrophage activation in acute pancreatitis.
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  • Clinical evidence suggests that acute pancreatitis can arise as a complication of massive hemolysis; a recent study by Saruc et al. [] supports this hypothesis using an experimental model.
  • Hemolysis induced in rats by intraperitoneal (i.p.) injection of acetylphenylhydrazine (APH) caused increased pancreatic cytokine levels and histological signs of acute pancreatitis. Furthermore, free vascular heme seems to act as the signaling molecule for triggering inflammation, though the mechanism remains undetermined.

Experimental Models of Pancreatitis

  • A limiting feature of the commonly used caerulein-hyperstimulation model of acute pancreatitis is that it causes only mild disease. Several new in-vivo mouse models now generate severe acute pancreatitis.
  • This includes mouse models of acute pancreatitis that use retrograde pancreatic duct infusion of the bile salt, sodium taurocholate by Laukkarinen et al. [], and i.p. injection of L-arginine by Dawra et al. []. These models may prove useful for studying therapeutic interventions and examining disease mechanisms in transgenic mice.

Cellular Responses

  • A series of the acinar cell and inflammatory cell responses underlie the pathogenesis of acute pancreatitis. Some of these have been explored in publications during the last year.

Membrane Permeability

  • One of the earliest events in acute pancreatitis may be the disruption of the acinar cell plasma membrane. Muller et al. [] used both caerulein and taurocholate-induced models of acute pancreatitis in rats to demonstrate that endogenous albumin and immunoglobulin G (IgG) entered acinar cell cytosol.
  • Such defects could contribute to pathologic increases in [Ca2+] and allow cytoplasmic proteins to leak from the cell. It will be of interest to determine how these defects occur, whether they might be related to the plasma membrane blebbing that has been observed in acute pancreatitis or to defects in the complex process of membrane resealing and if such defects are found in human acute pancreatitis.

Zymogen Activation

  • Premature intracellular activation of trypsinogen by the lysosomal hydrolase cathepsin B has generally been considered a pivotal event in the initiation of acute pancreatitis. However, using a cathepsin B inhibitor, CA074Me, Van Acker et al. [] showed that enzyme colocalization and other acute pancreatitis events, such as actin redistribution and inflammation, were cathepsin B independent.
  • Other mechanisms, such as those mediated by [Ca2+]and its protein targets, might mediate these responses. The Ca2+-dependent protein phosphatase calcineurin (PP2B) might serve this role. Husain et al. [] showed that the calcineurin inhibitor FK506 or a cell-permeable calcineurin inhibitory peptide reduced zymogen activation without affecting initial elevations in [Ca2+]or enzyme secretion. Thus, PP2B may be down-stream to the pathologic [Ca2+] that typifies acute pancreatitis. The effects of elevating cAMP on acute pancreatitis are complex, but the most important response might be to enhance the secretion of active enzymes.


  • Two recent studies have focused on the neuropeptide, substance P and its role in pancreatic inflammation. Ramnath et al. [] reported that expression of the substance P gene (preprotachykinin-A, PPT-A) and neurokinin-1 receptor (NK-1R), the primary receptor for substance P, were increased in caerulein-treated mouse pancreatic acinar cells. Furthermore, the messenger hydrogen sulphide was shown to provoke inflammation through a substance P, NK-1R related pathway by Tamizhselvi et al. [].

Endoplasmic reticulum stress

  • Endoplasmic reticulum stress can lead to accumulation of unfolded proteins, initiation of the unfolded protein response (UPR), inflammation and cell death. Kubisch and Logsdon [] reported that stimulation of rat pancreatic acini with three secretagogues, CCK8, CCK-JVM-180 or bombesin, resulted in distinct UPR responses that included increased chaperone BiP levels, PKR-like endoplasmic reticulum kinase (PERK) phosphorylation, X box-binding protein 1 (XBP1) splicing, and CCAAT/enhancer binding protein homologous protein (CHOP) expression.
  • Treatment with caerulein and lipopolysaccharide (LPS), a more severe model of acute pancreatitis, resulted in less expression of inflammation-associated caspases (caspase-11 and caspase-1) in CHOP−/− mice. These studies indicate a pivotal role for the endoplasmic reticulum stress-CHOP pathway in accelerating pancreatitis through induction of inflammation-linked caspases.
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  • The severity of pancreatitis may depend on the mechanism of cell death; greater levels of apoptosis over necrosis favor milder disease. To examine the mechanisms of apoptosis, Baumgartner et al. [] used the oxidative stressor menadione and identified two independent apoptotic pathways in pancreatic acinar cells.
  • The first is the classical caspase-9-mediated pathway that is Ca2+-dependent, mediated by mitochondria and is rapidly initiated. The second is much slower, mediated by caspase-8, depends on the lysosomal activities of cathepsins and is used when the caspase-9 pathway is disabled.
  • This information might be used to develop strategies for shifting cell death pathways to favor apoptosis during acute pancreatitis.

Protective Mechanisms

  • A number of protective and restorative mechanisms in acute pancreatitis have been characterized over the past year. Singh et al. [] used protease-activated receptor-2 (PAR-2) deficient mice in a caerulein acute pancreatitis model to demonstrate that PAR-2 stimulation caused exocrine secretion, thus protecting acinar cells from the damaging effects of activated enzymes. The study by Bhagat et al. [] explored the protective role played by heat shock proteins (HSPs), particularly HSP 70, using both caerulein and L-arginine models of acute pancreatitis. Sodium arsenite pretreatment was used to upregulate HSP 70 expression and significantly reduced the severity of pancreatitis in both models.
  • The pancreas is a rich source of the polyamine spermidine, and a study by Hyvonen et al. [] showed that depletion of these polyamines led to acute necrotizing pancreatitis. Replacement of depleted polyamines using methylated polyamine analogs prior to induction of acute pancreatitis prevented the development of the disease, strongly supporting an endogenous protective role for these compounds.

Genetic Factors

  • Two studies from the last year have highlighted the importance of genetic factors in predisposing patients to acute pancreatitis []. Gao et al. [] investigated why some patients are more prone to pancreatic infection during acute pancreatitis. LPS or endotoxin may cross leaky paracellular barriers in the colon or be released into the bloodstream by circulating Gram-negative bacteria during acute pancreatitis.
  • LPS can then bind to Toll-like receptors (TLRs) on the surface of the acinar cell, producing a host defense response. However, in some patients, a polymorphism in TLR-4 led to impaired signaling and lack of a defensive response, rendering them more prone to infection.
  • In another genetic study, Chang et al. [] found that mutations on the cystic fibrosis transmembrane conductance regulator (CFTR) predisposed patients with elevated lipids to developing hypertriglyceridemic pancreatitis. Further studies that use newer genome-wide analysis will likely reveal additional genetic factors that affect the risk of developing acute pancreatitis or its severity.

Miscellaneous Mechanisms

  • Ghrelin is a ligand of the growth hormone secretagogue receptor (GHSR) and has been shown to affect exocrine pancreatic secretion. Previous studies have suggested that ghrelin may modulate the severity of acute pancreatitis and that serum ghrelin levels predict severity in acute pancreatitis.
  • Lai et al. [] reported that both ghrelin and its receptor are present in pancreatic acinar cells and that the receptor was downregulated in acute pancreatitis. The data indicate that a ghrelin-dependent system is present in the exocrine pancreas. However, its function in normal pancreatic physiology and pancreatitis requires further study.

Chronic Pancreatitis

Chronic pancreatitis is characterized by chronic inflammation, progressive fibrosis, pain and loss of exocrine and endocrine function. The molecular basis of these responses is addressed by many of the studies detailed in the following section.

Inflammation and Fibrosis

  • Pancreatic stellate cells (PSCs) play a key role in pancreatic fibrosis. Masamune et al. [] reported that the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in PSCs generated reactive oxygen species that modulate their activation and the subsequent deposition of extracellular matrix (ECM), leading to pancreatic fibrosis.
  • Coculture experiments with PSCs and peripheral blood mononuclear cells (PBMCs) reported by Michalski et al. [] demonstrated increased fibronectin secretion from the PBMCs as well as increased levels of IL-6, MCP-1, transforming growth factor (TGF)-β, and ECM from the PSCs. Thus, increased infiltration of mononuclear cells, as seen in chronic pancreatitis, might be a trigger for PSCs to initiate fibrosis and inflammation.
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Inflammation and Pain

  • They reported that pain levels in patients with chronic pancreatitis correlated with neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) levels. PBMCs from patients with chronic pancreatitis were more responsive to the effects of PACAP. Xu et al. [] reported that pancreatic hyperalgesia is mediated by upregulation of the transient receptor potential vanilloid 1 (TRPV1) in a model of chronic pancreatitis. As pharmacologic TRPV1 inhibition reduced visceral pain responses in this model, this might be a target for pain treatment in chronic pancreatitis.

Alcohol Use and Chronic Pancreatitis

  • Fortunato et al. [] reported that chronic alcohol exposure in rats increased the pancreatic activity of an anti-inflammatory nuclear receptor, peroxisome proliferator-activated receptor gamma (PPARγ). Although PPARγ activity was associated with the reduced immune cell and inflammatory responses, damage to acinar cell mitochondria and lysosomes and pericellular fibrosis and protease activation occurred. These results could explain how chronic alcohol use might predispose the pancreas to chronic pancreatitis without causing intense inflammation.


There are seven classes of medications associated with acute pancreatitis

  • Statins,
  • ACE inhibitors
  • Oral contraceptives/hormone replacement therapy (HRT)
  • Diuretics
  • Antiretroviral therapy
  • Valproic acid, and
  • Oral hypoglycemic agents
  • ACE inhibitors cause angioedema of the pancreas through the accumulation of bradykinin.
  • Oral contraceptives/HRT cause arterial thrombosis of the pancreas through the accumulation of fat (hypertriglyceridemia). Diuretics such as furosemide have a direct toxic effect on the pancreas. Meanwhile, thiazide diuretics cause hypertriglyceridemia and hypercalcemia, where the latter is the risk factor for pancreatic stones.
  • HIV infection itself can cause a person to be more likely to get pancreatitis. Meanwhile, antiretroviral drugs may cause metabolic disturbances such as hyperglycemia and hypercholesterolemia, which predisposes to pancreatitis.
  • Valproic acid may have a direct toxic effect on the pancreas.[rx] There are various oral hypoglycemic agents that contribute to pancreatitis including metformin. But, glucagon-like peptide-1 (GLP-1) is more strongly associated with pancreatitis by promoting inflammation.[rx]
  • Atypical antipsychotics such as clozapine, risperidone, and olanzapine can also cause pancreatitis.[rx]


A number of infectious agents have been recognized as causes of pancreatitis including:[rx][rx]


  • Coxsackievirus
  • Cytomegalovirus
  • Hepatitis B
  • Herpes simplex virus
  • Mumps
  • Varicella-zoster virus


  • Legionella
  • Leptospira
  • Mycoplasma
  • Salmonella


  • Aspergillus


  • Ascaris
  • Cryptosporidium
  • Toxoplasma

Other/What is The Most Common Cause of Pancreatitis

  • Other common causes include trauma, autoimmune disease, high blood calcium, hypothermia, and endoscopic retrograde cholangiopancreatography (ERCP). Pancreas divisum is a common congenital malformation of the pancreas that may underlie some recurrent cases. Diabetes mellitus type 2 is associated with a 2.8-fold higher risk.[rx]
  • Less common causes include pancreatic cancer, pancreatic duct stones,[rx] vasculitis (inflammation of the small blood vessels in the pancreas), and porphyria—particularly acute intermittent porphyria and erythropoietic protoporphyria.
  • There is an inherited form that results in the activation of trypsinogen within the pancreas, leading to autodigestion. Involved genes may include trypsin 1, which codes for trypsinogen, SPINK1, which codes for a trypsin inhibitor, or cystic fibrosis transmembrane conductance regulator.[rx]
  • The mnemonic GETSMASHED is often used to remember the common causes of pancreatitis: G—gallstones, E—ethanol, T—trauma, S—steroids, M—mumps, A—autoimmune pancreatitis, S—scorpion sting, H—hyperlipidemia, hypothermia, hyperparathyroidism, E—endoscopic retrograde cholangiopancreatography, D—drugs (commonly azathioprine, valproic acid, liraglutide)



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