Pancreas: Alcoholic Pancreatitis—It's the Alcohol, Stupid

Minoti V. Apte; Romano C. Pirola; Jeremy S. Wilson

Disclosures

The management of alcoholic pancreatitis is mostly reactive; little is done to prevent disease progression. It is time for physicians to pay attention to the root cause of the condition—that is, alcohol—rather than just responding to its effects. This article discusses an important paper that describes the first prospective, randomized, controlled, clinical trial to investigate the effect of brief interventions for alcohol abuse on the progression of alcoholic pancreatitis.

Overuse of alcohol is a major cause of acute and chronic pancreatitis in both developed and developing countries. The disease usually presents as an acute episode of pancreatitis and progresses with further attacks that can lead to chronic pancreatitis, which is characterized by a sequence of necrotic and fibrotic events. The initial cellular events that lead to an episode of necroinflammation have been the subject of great scrutiny and are believed to include premature intracellular activation of digestive enzymes, which leads to autodigestion.

Prolonged overconsumption of alcohol for 5–10 years typically precedes the initial attack of acute alcoholic pancreatitis. Isolated alcoholic binges rarely, if ever, cause pancreatitis.

Two major clinical observations have driven research into the pathogenesis of alcoholic pancreatitis. The first is that the risk of developing the disease increases with the amount of alcohol consumed, which suggests a direct toxic effect of alcohol on the gland. This observation led to research on the metabolic effects of alcohol on the pancreas with use of animal models and in vitro methods. Alcohol is metabolized by the pancreas and causes oxidative stress in the gland; it also promotes the synthesis of pancreatic digestive enzymes and destabilizes intracellular membranes, which predisposes the gland to autodigestion.[1]

Pancreatic stellate cells have been identified as the key effector cells in the regulation of pancreatic fibrosis. Activation of these cells by cytokines released during necroinflammation or directly by alcohol results in the production of excess collagen.[2]

The second major observation that has driven research on the pathogenesis of alcoholic pancreatitis is that only a minority (around 5%) of alcoholics develop pancreatitis. This finding suggests the presence of specific susceptibility or trigger factors in some individuals. However, no single, clear-cut susceptibility factor has yet been identified, despite numerous studies into the roles that putative lifestyle and genetic factors may have.[1] The role of smoking in the etiology of alcoholic pancreatitis is controversial, although researchers agree that this factor is a major cause of mortality for patients with this disease through the development of cancers of the aerodigestive tract and cardiovascular disease.[3] Evidence also suggests that smoking may accelerate the progression of established alcoholic pancreatitis.[4] Studies in humans have indicated that variants of the genes that encode anionic trypsinogen and cholesteryl ester lipase, an enzyme that metabolizes ethanol to fatty-acid ethyl esters, may influence an individual's susceptibility to development of pancreatitis.[2] Findings from another experimental study suggested a role for bacterial endotoxin in some individuals.[5] However, despite these promising findings, the identification of factors that influence individual susceptibility to alcoholic pancreatitis remains a field that is ripe for study.[6]

Given these considerations, what can physicians offer the patient with alcoholic pancreatitis? We can offer medical, endoscopic and surgical therapies for acute attacks. When the patient develops chronic pancreatitis with maldigestion, diabetes and pain, we can offer enzyme-replacement therapy, insulin and analgesics. Various surgical and endoscopic procedures have been devised to treat the pain of chronic pancreatitis and these are offered to patients; however, none has been compared with medical therapy alone in randomized trials. Evidence from a double-blind, randomized, controlled trial published this year suggests that antioxidant therapy consisting of a cocktail of common antioxidants may be of benefit to ameliorate pain associated with chronic pancreatitis.[6]

Thus, the extraordinary situation exists that the major factor responsible for the illness, namely excessive alcohol intake, receives little attention in its routine medical management. Measures to reduce alcohol consumption are not even mentioned in many published guidelines for management of alcoholic pancreatitis. The current approach to treatment of alcoholic pancreatitis is, therefore, largely symptomatic. Admittedly, there is some controversy within the literature in relation to the benefit of abstinence on the natural history of the disease—some reports suggest that destruction of the pancreatic parenchyma continues in these patients despite cessation of alcohol intake;[7] however, evidence that abstinence decreases the frequency and severity of attacks also exists.[8] Yet little is done in routine clinical practice to prevent subsequent attacks of pancreatitis in alcoholics by reducing their consumption of (and dependence on) alcohol.

This somewhat nihilistic stance on measures to reduce alcohol intake may reflect a deep-seated negative bias among doctors about the success of such approaches in these patients. This bias may also explain the lack of any robust studies (whether retrospective or prospective) that have investigated the effects of interventions for alcohol abuse on alcoholic pancreatitis. Fortunately, Nordback and colleagues[9] have now taken up this challenge with their prospective study of controlled interventions in patients with alcoholic pancreatitis.

These researchers from Finland randomly allocated 120 patients who had been admitted to hospital with their first attack of acute alcoholic pancreatitis to one of two groups: one group received a single 30 min motivational intervention against alcohol consumption before discharge from hospital, while the other received several such interventions at the gastroenterology clinic, repeated at 6-month intervals for 2 years. Each intervention was performed by a registered nurse and consisted of a discussion of the relevance of alcohol consumption to pancreatitis, the consequent need for a change in the patient's drinking habits, the personal responsibility of the patient for their condition, and counseling and assistance for associated psychosocial issues. Significantly fewer patients who received repeated interventions were readmitted to hospital with acute alcoholic pancreatitis than those who received a single intervention. Differences in alcohol consumption and alcohol dependency between the groups were difficult to elicit, but perhaps not surprisingly, a trend for decreased daily alcohol consumption and a superior decrease in alcohol dependency scores were observed in the group of patients who received repeated interventions. The findings from this study support the concept that, at least in the short to medium term, specific interventions and/or counseling measures result in a demonstrable reduction in attacks of alcoholic pancreatitis. Importantly, this study reveals the need for large, prospective, long-term studies in this area.

One would hope that what this study has really done is focus a spotlight on a feature of treatment for alcoholic pancreatitis that has long been neglected by pancreatologists, yet one that may be a critical factor in the reduction or prevention of recurrent attacks. Nordback and colleagues have shown that brief interventions can have a positive effect on the reduction of alcohol consumption. While this observation may seem rather surprising, it concurs with previous reports of short interventions that resulted in sustained decreases in alcohol consumption. In 2007, a meta-analysis of 21 randomized, controlled trials (with a total of 7,300 individuals) that used interventions to reduce alcohol consumption reported a significant decrease in alcohol consumption after 1–4 brief interventions.[10] Of note, these counseling sessions were straightforward, simple and involved very limited investments of time, but gave significant returns. In view of these findings, a therapeutic imperative is that the routine approach to alcoholic pancreatitis is expanded to include measures to emphasize the importance of abstinence and to support the patient in their efforts to minimize their drinking. As such, we envisage that these interventions will be performed not only by the specialist, but perhaps more importantly, by general practitioners, nursing or allied health staff who would be likely to see the patient on a regular basis.


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