Pathobiology of Alcoholic Pancreatitis

Pandol, Stephen J.; Raraty, Michael

doi:10.1159/000104235

Cited by 77 publications

(58 citation statements)

References 117 publications

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“…Although fat necrosis has been associated with severe cases of pancreatitis for more than a century, 1,2 and alcohol consumption is a well-known risk factor for acute pancreatitis (AP), 3 only recently have we started understanding the mechanistic basis of these observations. 4e7 High amounts of unsaturated fatty acids (UFAs) have been noted in the pancreatic necrosis and sera of severe AP (SAP) patients by multiple groups.…”

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“…8e12 These high UFAs seem pathogenically relevant because several studies show UFAs can cause pancreatic acinar injury or can worsen AP. 11e14 Ethanol may play a role in AP by distinct mechanisms, 3 including a worse inflammatory response to cholecystokinin, 4 increased zymogen activation, 15 basolateral enzyme release, 16 sensitization to stress, 7 FA ethyl esters (FAEEs), 17 cytosolic calcium, 18 and cell death. 19 Because the nonoxidative ethanol metabolite of fatty acids (FAs), FAEEs, were first noted to be elevated in the pancreata of dying alcoholics, they have been thought to play a role in AP.…”

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Fatty Acid Ethyl Esters Are Less Toxic Than Their Parent Fatty Acids Generated during Acute Pancreatitis

Patel

Durgampudi

Noel

et al. 2016

The American Journal of Pathology

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Although ethanol causes acute pancreatitis (AP) and lipolytic fatty acid (FA) generation worsens AP, the contribution of ethanol metabolites of FAs, ie, FA ethyl esters (FAEEs), to AP outcomes is unclear. Previously, pancreata of dying alcoholics and pancreatic necrosis in severe AP, respectively, showed high FAEEs and FAs, with oleic acid (OA) and its ethyl esters being the most abundant. We thus compared the toxicities of FAEEs and their parent FAs in severe AP. Pancreatic acini and peripheral blood mononuclear cells were exposed to FAs or FAEEs in vitro. The triglyceride of OA (i.e., glyceryl tri-oleate) or OAEE was injected into the pancreatic ducts of rats, and local and systemic severities were studied. Unsaturated FAs at equimolar concentrations to FAEEs induced a larger increase in cytosolic calcium, mitochondrial depolarization, and necro-apoptotic cell death. Glyceryl tri-oleate but not OAEE resulted in 70% mortality with increased serum OA, a severe inflammatory response, worse pancreatic necrosis, and multisystem organ failure. Our data show that FAs are more likely to worsen AP than FAEEs. Our observations correlate well with the high pancreatic FAEE concentrations in alcoholics without pancreatitis and high FA concentrations in pancreatic necrosis. Thus, conversion of FAs to FAEE may ameliorate AP in alcoholics. (Am J Pathol 2016, 186: 874e884; http://dx.doi.org/10.1016/j.ajpath.2015 Although fat necrosis has been associated with severe cases of pancreatitis for more than a century, 1,2 and alcohol consumption is a well-known risk factor for acute pancreatitis (AP), 3 only recently have we started understanding the mechanistic basis of these observations. 4e7 High amounts of unsaturated fatty acids (UFAs) have been noted in the pancreatic necrosis and sera of severe AP (SAP) patients by multiple groups. 8e12 These high UFAs seem pathogenically relevant because several studies show UFAs can cause pancreatic acinar injury or can worsen AP. 11e14 Ethanol may play a role in AP by distinct mechanisms, 3 including a worse inflammatory response to cholecystokinin, 4 increased zymogen activation, 15 basolateral enzyme release, 16 sensitization to stress, 7 FA ethyl esters (FAEEs), 17 cytosolic calcium, 18 and cell death. 19 Because the nonoxidative ethanol metabolite of fatty acids (FAs), FAEEs, were first noted to be elevated in the pancreata of dying alcoholics, they have been thought to play a role in AP. 17,19À22 Conclusive proof of the role of FAEEs in AP in comparison with their parent UFAs is lacking. Uncontrolled release of lipases into fat, whether in the pancreas or in the peritoneal cavity, may result in fat necrosis, UFA generation, which has been associated with SAP. 11,12 Pancreatic homogenates were also noted to have an ability to synthesize FAEEs from FAs and ethanol,20,23 and the putative enzyme for this was thought to be a lipase. 24,25 It has been shown that the FAEE synthase activity of the putative enzyme exceeds its lipolytic capacity by several fold. 25 Triglyceride (TG) forms >80% ...

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Fatty Acid Ethyl Esters Are Less Toxic Than Their Parent Fatty Acids Generated during Acute Pancreatitis

Patel

Durgampudi

Noel

et al. 2016

The American Journal of Pathology

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“…In the majority of alcohol abusers there are no clinical manifestations of pancreatic disease. In those who develop pancreatic disease findings there are findings of both acute and chronic pancreatitis [1,2] . In general, early after the onset of pancreatic disease the pancreas shows inflammation and necrosis of tissue and a minimum of chronic inflammation and fibrosis.…”

Section: Pathobiology Of Alcoholic Pancreatitismentioning

confidence: 99%

Alcohol Abuse, Endoplasmic Reticulum Stress and Pancreatitis

Pandol¹,

Gorelick

Gerloff³

et al. 2010

Dig Dis

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Alcohol abuse is a common cause of both acute and chronic pancreatitis. There is a wide spectrum of pancreatic manifestations in heavy drinkers from no apparent disease in most individuals to acute inflammatory and necrotizing pancreatitis in a minority of individuals with some progressing to chronic pancreatitis characterized by replacement of the gland by fibrosis and chronic inflammation. Both smoking and African-American ethnicity are associated with increased risk of alcoholic pancreatitis. In this review we describe how our recent studies demonstrate that ethanol feeding in rodents causes oxidative stress in the endoplasmic reticulum (ER) of the digestive enzyme synthesizing acinar cell of the exocrine pancreas. This ER stress is attenuated by a robust unfolded protein response (UPR) involving X-box binding protein-1 (XBP1) in the acinar cell. When the UPR activation is prevented by genetic reduction in XBP1, ethanol feeding causes significant pathological responses in the pancreas. These results suggest that the reason most individuals who drink alcohol heavily do not get significant pancreatic disease is because the pancreas mounts an adaptive UPR to attenuate the ER stress that ethanol causes. We hypothesize that disease in the pancreas results when the UPR is insufficiently robust to alleviate the ER stress caused by alcohol abuse.

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“…3 Most theories suggest a direct toxic effect of the ethanol upon the pancreatic parenchyma or its neurovascular supply. 4 There are many other less common causes of acute pancreatitis including toxins, drugs, infections, trauma, vascular insults, anatomic abnormalities, and metabolic derangements. Hypertriglyceridemia and hypercalcemia are both implicated in acute pancreatitis.…”

Section: Etiologymentioning

confidence: 99%

Acute pancreatitis

Munsell

Buscaglia

2010

Journal of Hospital Medicine

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Acute pancreatitis is a common disease most frequently caused by gallstone disease or excess alcohol ingestion. Diagnosis is usually based on characteristic symptoms, often in conjunction with elevated serum pancreatic enzymes. Imaging is not always necessary, but may be performed for many reasons, such as to confirm a diagnosis of pancreatitis, rule out other causes of abdominal pain, elucidate the cause of pancreatitis, or to evaluate for complications such as necrosis or pseudocysts. Though the majority of patients will have mild, self‐limiting disease, some will develop severe disease associated with organ failure. These patients are at risk to develop complications from ongoing pancreatic inflammation such as pancreatic necrosis, fluid collections, pseudocysts, and pancreatic duct disruption. Validated scoring systems can help predict the severity of pancreatitis, and thus, guide monitoring and intervention.Treatment of acute pancreatitis involves supportive care with fluid replacement, pain control, and controlled initiation of regular food intake. Prophylactic antibiotics are not recommended in acute pancreatitis if there is no evidence of pancreatic infection. In patients who fail to improve, further evaluation is necessary to assess for complications that require intervention such as pseudocysts or pancreatic necrosis. Endoscopy, including ERCP and EUS, and/or cholecystectomy may be indicated in the appropriate clinical setting. Ultimately, the management of the patient with severe acute pancreatitis will require a multidisciplinary approach. Journal of Hospital Medicine 2010;5:241–250. © 2010 Society of Hospital Medicine.

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Pathobiology of Alcoholic Pancreatitis

Cited by 77 publications

References 117 publications

Fatty Acid Ethyl Esters Are Less Toxic Than Their Parent Fatty Acids Generated during Acute Pancreatitis

Fatty Acid Ethyl Esters Are Less Toxic Than Their Parent Fatty Acids Generated during Acute Pancreatitis

Alcohol Abuse, Endoplasmic Reticulum Stress and Pancreatitis

Acute pancreatitis

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