Pathophysiology of alcoholic pancreatitis: An overview

The UPR is activated by accumulation of unfolded proteins in the ER lumen, a condition termed “ER stress” [9, 10]. In response to chronic alcohol misuse and oxidative stress, this mechanism causes upregulation of spliced X box-binding protein (sXBP1) which limits alcohol damage [9]. SXBP1 regulates a broad spectrum of UPR genes involved https://rehabliving.net/ in protein folding [10, 20, 21]. The effects of sXBP1 generally adapt to ER stressors and enhance normal function in many cells but play an especially important supportive role in secretory cells. Interestingly, it was demonstrated that cigarette smoke reduces sXBP1 levels and inreases ER stress and cell death in acinar cells [22].

Oxidant stress has been implicated as a possible mechanism of pancreatitis. Metabolism of alcohol by an enzyme in the liver called cytochrome P450 2E1 leads to the generation of free radicals. Normally functioning at a low level, this enzyme system can be activated (i.e., induced) by heavy alcohol consumption and is a major pathway for alcohol metabolism in the liver in heavy drinkers (Lieber 1992).

Understanding Alcohol-Induced Pancreatitis and its Risks

Heavy smokers who drink more than 400 g of alcohol per month are four times more likely to develop acute pancreatitis [2]. On the other hand, less than 5% of heavy drinkers (defined by most authors as drinking of ≥4–5 drinks on 5 or more days a month; a standard drink is approx. 8–14 g of pure alcohol – depending on country) will develop an episode of pancreatitis [4]. The underlying explanation of this phenomenon is that alcohol toxicity requires additional risk factors, either environmental or genetic, for disease to occur (Fig. 1) [5, 6]. In addition, in animal models alcohol by itself does not cause pancreatitis but rather sensitizes the pancreas to damage caused by a number of other pancreatic costressors [7, 8]. A favored hypothesis regarding the mechanism of action of chronic alcohol consumption on the pancreas is the observation that ethanol increases the protein content of pancreatic juice, with a concomitant decrease in water and electrolytes.

However, in a categorical analysis the lower drinking categories were not significantly elevated, with an apparent threshold of 4 drinks daily. Conclusions As the available evidence also indicates that the relationship is biologically plausible, these results support the existence of a link between alcohol consumption and the risk of pancreatitis. Due to inability to explain the pathogenesis of alcoholic pancreatitis by theories as mentioned above the focus was directed to pancreatic acinar cells. It is now believed that acinar cells are capable of metabolizing alcohol and the toxic effect may predispose the gland to injury in the presence of an appropriate triggering factor.

Treatment of Chronic Pancreatitis

A block of apical secretion causes activation of proteases within acinar cells, as well as basolateral exocytosis through the basolateral plasma membrane in the acinar cell releasing active zymogens into the interstitial space. The authors postulated that this may be a crucial process involving acinar cell damage caused by alcohol [27]. High alcohol intake also increases levels of circulating TNF-α – a factor which directly induces premature protease activation and necrosis in pancreatic acinar cells [29]. Among the environmental factors studied, smoking has garnered the most interest.

• Most physicians will recommend an alcohol treatment program to help the patient recover in order to slow the damage to the Pancreas.
• During oxidation of ethanol, hydrogen ions and reducing equivalents are released[74]; increase NADH, thereby leading to an imbalance between free radicals and antioxidant defense mechanism.
• Protective genetic variants decreasing the risk of disease have recently been described.
• One complication of pancreatitis is localized masses of dead tissue and old blood walled off between the pancreas and surrounding organs (i.e., pseudocysts).
• Ca2+ and PKC contribute to NF-κB activation induced by CCK-8 in acinar cells.

Data coming from animal models have shown that CFTR knockout mice given ethanol developed more severe pancreatitis than control CFTR knockout mice [33]. In patients with chronic alcoholic pancreatitis an estimated 15% displayed a CFTR mutation [43]. This prevalence is comparable to the prevalence of CFTR mutations in other forms of chronic pancreatitis when the entire coding region of the CFTR gene is sequenced [54]. Moreover, so far almost all studies investigating the association of CFTR mutations with an increased risk of alcoholic pancreatitis showed a distribution comparable to that of the normal population [55, 56]. When it comes to other dietary factors which are suggested to contribute to the development of alcoholic pancreatitis, vitamin deficiency – common among severe alcoholics – is also disputed. So far data on this issue are scarce, and this matter needs further evaluation.

Pancreatitis Episodes

The complete pathophysiology of this disease is not entirely understood but likely results from alcohol’s effects on the small pancreatic ducts and acinar cells. Cigarette smoking is a known risk factor for alcoholic and chronic pancreatitis. About 80%-95% of people who abuse alcohol also smoke while 25%-30% of smokers do not drink alcohol[94]. The incidence of alcoholism is 10 times more likely in smokers than nonsmokers.

Chronic pancreatitis as a result of long-term alcohol misuse is identified in nearly 70 percent of the cases, whereas about 20 percent of cases of chronic pancreatitis have no discernible cause and may result from numerous interacting issues. For example, for gallstones causing acute pancreatitis, a cholecystectomy (gallbladder removal) is advised. Patients with alcohol-induced pancreatitis usually need attention from many specialists, including pain specialists, dietitians, mental health nurses, and pharmacists. At each refill for medications, the pharmacist should educate the patient about the harms of alcohol and the importance of abstaining from this beverage. If the patient is non-compliant, the pharmacist should inform the clinician of concerns [16]. Chronic pancreatitis pain can be managed with analgesics (avoiding high-potency opioids) and/or pancreatic enzyme replacement therapy.

Damage to the pancreas as a result of pancreatitis or some other issue occurs when digestive enzymes that are normally released by the pancreas are activated before they are released into the small intestine. Other risk factors may include smoking and a family history of pancreatitis. Excessive alcohol use is one of the two leading causes of acute pancreatitis, and a recent report from the Centers for Disease Control and Prevention (CDC) says deaths from alcohol-induced acute pancreatitis increased by 50% between 2019 and 2020. The cause of a case of pancreatitis can be attributed to alcohol based on a patient’s history of alcohol abuse. Attempts are under way to find a biochemical marker that would help distinguish alcoholic from nonalcoholic pancreatitis.

Pain Management

Those who develop pancreatitis should also be sure to monitor their blood sugar levels closely. Alcoholic pancreatitis tends to be recurrent and progressive and to result in pancreatic exocrine insufficiency. This complication can be quite severe, with violent epigastric pain, nausea, and vomiting. “In this study, using an established alcoholic pancreatitis mice model, we have addressed two of the major unanswered questions with regards to the pathogenesis of pancreatitis. If you or a loved one is struggling with alcohol addiction or alcoholic pancreatitis, it’s important to know that you are not alone. Once you’ve decided to seek help, you’ll need to go about finding an alcohol addiction rehab center.

Methods We searched Ovid MEDLINE, EMBASE, CINAHL, Web of Science, ETOH and AIM. Studies were included if they reported quantifiable information on risk and related confidence intervals with respect to at least three different levels of alcohol intake. Results Six studies, including 146,517 individuals with 1,671 cases of pancreatitis, met the inclusion criteria. We found a monotonic and approximately exponential dose-response relationship between average volume of alcohol consumption and pancreatitis.

What Is Pancreatitis?

This induces a precipitation of protein plugs within the pancreatic ducts, followed by retraction and calcification, resulting in pancreatic stones, atrophy of the duct epithelium, and proliferation of the connective tissue. The consequences are stenosis or dilatations of the ducts, cysts and pseudocysts, and progressive disappearance of the pancreatic exocrine tissue which is replaced by fibrosis. Besides chronic overconsumption of alcohol, both a high-fat, high-protein diet and, paradoxically, malnutrition have been implicated in the pathogenesis of the disorder. Context Epidemiologic studies have suggested an association between alcohol consumption and pancreatitis, although the exact dose-response relationship is unknown. Objective To conduct a systematic review and meta-analysis of epidemiologic studies on the association between alcohol consumption and the risk of pancreatitis.

Heavy drinkers (defined as those who consume more than three alcoholic drinks per day) are at the greatest risk of developing the condition. Alcohol-induced pancreatitis is a complicated disease with many remaining unknowns. Because of such complexity, patients suffering from this disease greatly benefit from a multidisciplinary approach to treatment. Patients often need special attention from pain specialists, psychotherapists, and dieticians, as well as pharmacists. Primarily, patients receiving chronic therapy with narcotics should be evaluated for appropriate use of the medication with each refill, as well as educated about the commonly reported adverse affects such as constipation and respiratory suppression.

Experiments show that repeated episodes of acute pancreatitis in rats produce chronic changes in the pancreas, including fat deposits, atrophy, and fibrosis (Elsasser et al. 1992). Abstinence from alcohol reduces the frequency of acute attacks as well as decreases pain. The pain of chronic pancreatitis can be controlled by medication (preferably nonnarcotics). The clinician first must rule out other possible causes of pain in these patients, such as pseudocysts, tumors, or ulcers. In some cases, intractable pain can be temporarily relieved by chemically blocking the nerves that supply sensation to the pancreas.

Although tobacco smoke contains more than 4,000 chemical compounds, experimental studies have mainly studied the role of nicotine and nicotine-derived substrates in relation to pancreatitis. It was suggested that smoking induces an inflammatory process in pancreatic tissue, as it stimulates expression of pancreatic procollagen 1 gene, interleukin-1ß and TGF-ß in acinar cells [67, 68]. Moreover, it has been shown that cigarette smoking extract as well as nicotine and one of its major metabolites cause activation of PSCs via nicotinic acetylcholine receptors. This effect may contribute to activation of fibrosis and progression of chronic pancreatitis [69]. The direct effect of alcohol on the pancreas has been studied in its effects on the pancreatic duct and the acinar cells.

• The underlying explanation of this phenomenon is that alcohol toxicity requires additional risk factors, either environmental or genetic, for disease to occur (Fig. 1) [5, 6].
• These changes occur in the absence of overt pancreatic damage, suggesting that an additional trigger factor may be required to initiate injury.
• There are single preliminary studies which deal with vitamin deficiency as a possible factor in disease onset.

The metabolic effects of alcohol on pancreatic cells may lead to digestion of the cell. (1) Chronic alcohol consumption increases cholesteryl esters and fatty acid ethyl esters in organelle membranes, altering eco sober house price the fragility of enzyme storage structures within the cell (i.e., lysosomes [L] and zymogen granules [Z]). (3) Chronic alcohol consumption blocks the release of digestive enzymes from the cell.

Treatment for chronic pancreatitis may involve medications to control pain, nutrition therapy, and the administration of insulin or other enzymes. «Pancreatitis, by definition, means inflammation of the pancreas,» says Dr. Santhi Swaroop Vege, a gastroenterologist with the Mayo Clinic Pancreas Clinic. «They are broadly divided into two types — acute and chronic pancreatitis.» Additionally, alcohol can harm the pancreas by causing oxidative stress, a process where chemical formation can damage the area around the pancreas.

If you have chronic alcoholic pancreatitis, it’s important to get treatment as soon as possible. The earlier you get treatment, the better your chances are of reversing the damage and preventing further complications. Chronic pancreatitis is often the result of chronic alcohol consumption, resulting in around 40% to 70% of all cases. Those already struggling with acute pancreatitis who are also chronic alcohol abusers, may experience recurrent bouts leading to chronic pancreatitis. «Diabetes happens both in people with acute as well as chronic pancreatitis. In acute pancreatitis, in 10% of where you have severe forms where a part of pancreatic tissue dies, is what we call necrosis,» he says. «Obviously, because of loss of pancreatic tissue, your capacity to secrete insulin has come down, and you develop diabetes.»

The characteristics of pancreatic stellate cells showing the involvement of acinar cells in pancreatic fibrosis may be another possible link[71] . It is speculated that metabolites of ethanol like acetaldehyde and FAEEs have direct effects on acinar cells/or induce metabolic alterations within cells indirectly. Acetaldehyde is believed to interfere with the binding of secretagogue to their receptors[72] and thereby inhibit stimulated secretion from isolated pancreatic acini[72]. It also causes microtubule dysfunction thereby affecting exocytosis from acinar cells[73]. The pancreas uses oxidative and non-oxidative metabolism to process alcohol. Necrosis and resorption of damaged cells by macrophages could be the initial event that induces fibrogenesis [39].

Cigarette smoke potentiates pancreatic microcirculatory impairment by ethanol and also induces leukocyte aggregation and adhesion. FAEEs, products of non-oxidative ethanol metabolism, have been shown to induce pancreatic injury in vivo[77] and in vitro[78]. FAEE undergo hydrolysis to FFA which impairs mitochondrial function by uncoupling of mitochondrial and oxidative phosphorylation[79]. Also its direct binding to the intracellular membrane leads to alteration in function and permeability of cell membrane[80]. The generation of cholestryl esters is responsible for the increase in lysosomal fragility releasing hydrolase’s which act on the zymogen granule membrane and increase release of trypsin[81,82].