Alcohol Related Pancreatitis

[Guest guest]

Colin,

That is a good question. Unfortunately, despite decades of research on how

alcohol damage occurs, it remains elusive. There are several theories which

center on the alcohol's direct affect on the acinar cells of the pancreas.

1) Alcohol & the Large Pancreatic Duct:

One early theory postulated that pancreatic injury is caused by alcohol induced

spasms of the sphincter of Oddi, leading to the backup of pancreatic enzymes

into the unprotected tissues of the pancreas.

2) Alcohol & the Small Pancreatic Ducts:

An early theory in 1970 postulated that alcohol induces pancreatitis by causing

small pancreatic ducts to be blocked with protein plugs. Accordingly, the acini

that secrete into the blocked ducts would then undergo fibrosis, while the plugs

would enlarge and calcify. Proteins plugs are composed of pancreatic digestive

enzymes and two other pancreatic secretory proteins, lithostathine and GP2,

which posses unique properties important to the formation of protein plugs.

3. Pancreatic Lithostathine:

A recent study shows that long term alcohol ingestion significantly increases

one of the factors that regulate lithostathine synthesis. The consequent

increase in synthesis could result in increased concentration of lithostathine

in pancreatic digestive juice. The action of enzymes on lithostathine may

promote protein deposits in ducts.

4. Pancreatic GP2:

This theory shows when the pancreas is stimulated, the protein GP2 is also

discharged along with pancreatic enzymes from the acinar cells. In patients who

consume alcohol are at a higher risk as to GP2 tends to aggregate in pancreatic

juice, may encourage further protein precipitation, thus favoring protein plug

formation.

5. Direct Toxic Effect of Alcohol on Acinar Cells:

Long term, alcohol may cause premature activation of digestive enzymes in the

acinar cells. In this regard it has been shown that alcohol does increase the

synthesis of digestive enzymes in the pancreas and increases the fragility of

the zymogen granules, potentially allowing zymogens to leak into the cell.

Alcohol also increases the fragility of lysosomes, similar structures affecting

enzymes.

6. Alcohol Related Stress:

Reactive oxygen species, or free radicals, are unstable molecules generated by

normal metabolic processes. These molecules damage cell membranes through the

process of oxidation. The cells are normally protected from damage by chemical

antioxidant systems. An imbalance leads to oxidant stress within the cell.

Metabolism of alcohol by an enzyme in the liver called cytochrome P450 2E1 leads

to the generation of free radicals. Recent evidence demonstrates that cytochrome

P450 2E1 is also present in the pancreas. In addition, the alcohol increases

levels of compounds formed by the reaction of free radicals with the membrane

components, indicative of oxidant stress.

7. Effects of Toxic Metabolites of Alcohol:

Metabolism of alcohol by the liver results in the production of toxic

metabolites, such as acetaldehyde and FAEE's, and has been shown to play a

central role in alcohol liver damage. Acetaldehyde binds to liver proteins,

altering their function and inducing a damaging immune response. FAEE's can

disrupt membranes within the cell. Similar metabolic events have been shown to

occur in the pancreas.

In summary:

An apparent clinical paradox exists with respect to the occurrence of

pancreatitis related to alcohol consumption. Although, it is well established

that the risk of developing pancreatitis rises with increasing alcohol

consumption, it is also clear that only a small proportion of heavy drinkers

develop pancreatitis. The percentage of persons with alcohol related

pancreatitis, on the other hand, seems considerably large. This observation

raises the possibility that a factor other than alcohol influences the

susceptibility of a person who consumes large amounts of alcohol to

pancreatitis.

A number of actors that may distinguish those that develop pancreatitis from

those that do not have been investigated. These factors include diet, amount and

type of alcohol consumed, the pattern of alcohol consumption, hereditary

factors, fat tolerance, and smoking. There have been many conflicting factors in

this research.

It is likely that a combination of the postulated mechanisms is responsible for

the manifestations of alcohol related pancreatitis. Though there is no

supporting research, it is apparent that any consumption of alcohol, whether as

a drink, in food, perfumes, mouthwash, etc., would pose a detriment to anyone

with pancreatitis.

Karyn E. , RN

Executive Director, PAI

http://www.pancassociation.org

Pancreatitis Association International

PS. There is nothing better than a refreshing herbal spritzer :-)

[Guest guest]

There are tons of pics with this article which can be found at

http://www.top5plus5.com/Pancreas/Alcoholic%20pancreatisis/Alcoholic%20pancreati\

tis.htm

Alcohol-Related Pancreatic Damage

Mechanisms and Treatment

MINOTI V. APTE, M.D., M. MED. SCI.; JEREMY S. WILSON, M.D., PH.D.; AND MARK

A. KORSTEN, M.D.

Pancreatitis is a potentially fatal inflammation of the pancreas often

associated with long-term alcohol consumption. Symptoms may result from

blockage of small pancreatic ducts as well as from destruction of pancreatic

tissue by digestive enzymes. In addition, by-products of alcohol metabolism

within the pancreas may damage cell membranes. Research on the causes of

pancreatitis may support more effective disease management and provide hope

for a potential cure. KEY WORDS: alcoholic pancreatitis; prevalence;

pathogenesis; diagnosis; treatment

An association between alcohol abuse and pancreatic injury was reported as

early as 1878 (Friedreich 1878). Alcoholic pancreatitis is a potentially

fatal illness that may be short term (i.e., acute) or long term (i.e.,

chronic). The relationship between acute and chronic pancreatitis is

complex. Symptoms shared by acute and chronic pancreatitis include disabling

abdominal pain and interference with normal pancreatic functions. Although

the prevalence of alcoholic pancreatitis in the population is unknown,

clinicians usually agree that both acute and chronic alcoholic pancreatitis

are responsible for a significant amount of illness and death in the United

States. This article discusses the extent of the problem, clinical aspects,

diagnosis, development (i.e., pathogenesis), and treatment of both acute and

chronic alcohol-related pancreatitis.

THE HEALTHY PANCREAS

The pancreas lies deep within the abdomen, behind the stomach. The pancreas

serves two major functions (figure 1). First, certain cells (i.e., islet

cells) dispersed throughout the pancreas play the role of an endocrine gland

by producing two crucial hormones that regulate blood-sugar (i.e., glucose)

levels: insulin and glucagon. Poorly regulated blood glucose can produce

symptoms associated with diabetes. The hormones produced by these cells are

released directly into the bloodstream. Second, another specialized group of

cells (i.e., acinar cells) secrete digestive enzymes into the small

intestine through tubes (i.e., ducts). In support of its digestive function,

the pancreas also secretes bicarbonate through these same ducts. Pancreatic

bicarbonate, a chemical similar to household baking soda, helps adjust and

maintain the relatively weak acidity required for the action of intestinal

digestive enzymes. Pancreatitis arises in the acinar cells. However,

inflammatory damage can destroy all parts of the pancreas- the islet cells

as well as the acinar cells. Any disorder that affects the digestion of food

or the subsequent metabolism of digested food in the bloodstream is likely

to have serious consequences for the entire body.

THE EXTENT OF THE PROBLEM

Since Friedreich's initial observation, many studies have confirmed that

excessive alcohol intake is associated with pancreatic damage. However, the

proportion of cases of pancreatitis attributed to alcohol varies widely

among countries and even among different studies in the same country. In the

United States, for instance, the reported incidence of pancreatitis

attributed to alcohol ranges from 5 to 90 percent. This huge variation may

be related to the difficulties in accurately identifying alcohol abuse and

to differences in the populations studied. For example, in a Veterans

Affairs hospital (where the prevalence of alcoholism among patients is high)

(Steinberg and Tenner 1994), the number of cases of alcohol-related

pancreatitis is likely to be higher than that in a rural community hospital.

The mortality rate of patients with alcoholic pancreatitis is about 36

percent higher than that of the general population. Approximately 50 percent

of patients with alcoholic pancreatitis die within 20 years of onset of the

disease. Only 20 percent of deaths occurring before a patient's life

expectancy are attributed to pancreatitis or its complications; most of

these deaths are attributed to the effects of alcohol or smoking on other

organs such as the liver.

The increased risk of pancreatic cancer reported in heavy alcohol users

(i.e., people who consume 10 to 12 standard drinks per day)1 by earlier

studies has not been confirmed by more recent investigations. One

complicating factor in some of the studies is cigarette smoking, which is

commonly associated with alcohol abuse. When the effect of cigarette smoking

was controlled for statistically, no association was found between alcohol

abuse and pancreatic cancer. It has been suggested that the specific risk of

pancreatic cancer among alcoholics may be limited to those alcoholics who

develop chronic pancreatitis (Ahlgren 1996). This notion is not

unreasonable, given that an excess relative risk of pancreatic cancer has

been found in nonalcoholic types of pancreatitis, including a hereditary

form of the disease (Andren-Sandberg and Lowenfels 1997). The relationship

of alcohol-related pancreatitis to pancreatic cancer, however, is less

clear, again because of possible contributing factors, such as malnutrition

and smoking.

MEDICAL ASPECTS

Alcoholic pancreatitis usually occurs in men in their forties. Initial

symptoms include vomiting as well as acute abdominal pain, which may be

localized to the back and upper abdomen and is relieved by leaning forward.

In mild cases, the pain may last 2 to 3 days; the short-term prognosis in

such cases is very good. In severe cases, however, the pain may persist for

several weeks and the risk of death rises to about 30 percent. Less

commonly, pancreatitis can be completely painless and is only diagnosed from

symptoms of insufficient pancreatic function, such as diabetes and

steatorrhea (excess fat in feces)

..1A standard drink is roughly equivalent to the amount of alcohol contained

in 12 ounces of beer, 5 ounces of wine, or one and a half ounces of 80-proof

distilled spirits.

One complication of pancreatitis is localized masses of dead tissue and old

blood walled off between the pancreas and surrounding organs (i.e.,

pseudocysts). If a pseudocyst becomes infected, it can invade the pancreas

and become an abscess.

Approximately 5 to 6 years after the onset of the disease (especially in

patients who continue to drink), evidence of chronic pancreatic disease

develops as a result of progressive destruction of pancreatic tissue (i.e.,

parenchyma). Patients seek medical attention for persistent pain (which

often leads to narcotic addiction from excessive use of pain medication),

weight loss, diabetes, and maldigestion of food (a result of inadequate

production of digestive enzymes by the pancreas). Abstinence from alcohol

has been shown to slow the rate of progression of the disease and decrease

the severity of abdominal pain.

Until recently, it was generally accepted that alcoholic pancreatitis began

as a chronic disease with occasional episodes, or acute " flareups. " This

notion was based on results of tissue analyses and x-ray studies taken from

alcoholics during their first attack of pancreatitis that seemed to reveal

signs of already existing chronic pancreatitis. Among these signs were

shrinkage of tissue (i.e., atrophy), replacement of healthy tissue by scar

tissue (i.e., fibrosis), and hardening of tissue caused by calcium deposits

(i.e., calcification) (figure 2). Furthermore, autopsy studies demonstrated

evidence of pancreatic fibrosis in alcoholics who had no history of clinical

pancreatitis.

In recent years, the view that alcoholic pancreatitis is a form of chronic

pancreatitis has been challenged. Opinion is now reverting to the hypothesis

first put forward in 1946 by Comfort and colleagues, who suggested that

repeated attacks of acute pancreatic inflammation resulted in chronic

pancreatitis (Comfort et al. 1946). This hypothesis is supported by both

clinical and experimental studies. A large prospective study has reported

that changes in the pancreas related to chronic pancreatitis were more

likely to occur in alcoholics who had recurrent acute inflammation of the

pancreas (Ammann and Muellhaupt 1994). In addition, a post mortem study of

247 patients with fatal alcoholic pancreatitis demonstrated that in 53

percent of the patients, no evidence existed of chronic changes in the

pancreas. 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).

DIAGNOSIS OF ALCOHOLIC PANCREATITIS

A clinical diagnosis of pancreatitis is usually made on the basis of an

attack of severe abdominal pain and tenderness, accompanied by a rise in the

blood level of a pancreatic enzyme that digests starch (i.e., amylase) to

more than three times the normal limit. Increased amylase in the blood has

been the " gold-standard " diagnostic test for acute pancreatitis for more

than 50 years. However, recent studies indicate that up to one-third of

patients with alcoholic pancreatitis may fail to show any significant rise

in amylase levels. In such circumstances, measurement of blood levels of a

pancreatic enzyme that digests fats (i.e., lipase) can be helpful, because

serum lipase levels remain elevated for a longer period than do amylase

levels.

The diagnosis of pancreatitis may be confirmed using imaging techniques,

such as X ray of the pancreas (which may reveal calcification); ultrasound

examination (which provides a two-dimensional image of the pancreas); and

computed tomography (CT) to detect calcification and pseudocysts. The latest

development in imaging techniques for pancreatic disorders is magnetic

resonance cholangiopancreatography (MRCP). This technique involves

subjecting the body to a magnetic field and radiofrequency signals and

provides excellent cross-sectional images of the pancreas and its main duct.

It has the potential to become the diagnostic technique of choice for

patients with suspected pancreatic disorders.

All the investigations described above provide structural, but not

functional, information about the pancreas. To determine pancreatic

function, other investigations-whether invasive or noninvasive-are

necessary. Invasive methods involve stimulating the pancreas to secrete its

enzymes and other fluids, collecting the fluids, and analyzing them for

enzyme and bicarbonate concentration. Pancreatic insufficiency is indicated

by a low secretion rate of pancreatic fluids and/or decreased enzyme and

bicarbonate levels in the fluids.

One noninvasive method for testing pancreatic function is by testing for the

presence of steatorrhoea. Still another, more recent, method involves oral

administration of a substance that requires pancreatic enzymes for its

breakdown. The amount of the breakdown product subsequently detected in

breath or urine is compared with values found in people with normal

pancreatic function. The main disadvantage of functional tests, however, is

that they often yield false-normal results in cases with mild pancreatic

dysfunction and false-abnormal results in the presence of diseases of other

organs, such as the liver, lungs, and kidneys.

Despite decades of research, the pathogenesis of alcoholic pancreatitis

remains elusive.

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. One report has suggested that the ratio of serum lipase to

serum amylase levels may be helpful in this regard (Gumaste et al. 1991).

Subsequent investigations, however, have found that this ratio is not

sufficiently sensitive or specific for determining the cause of pancreatitis

(King et al. 1995).

Another potentially useful biochemical test has been described recently. A

Belgian study demonstrated that elevated activity of trypsin, a pancreatic

enzyme that digests protein, is specifically associated with acute alcoholic

pancreatitis (Le Moine et al. 1994). These researchers found that activity

of trypsin in the blood increased in every study subject with alcoholic

pancreatitis, even when the amylase and lipase levels were normal.

Conversely, serum trypsin activity did not differ between healthy controls,

alcoholic controls, and patients with nonalcoholic pancreatitis. However,

this was a small study, with only 32 patients in the experimental group.

Larger studies are needed to confirm the usefulness of serum trypsin as a

specific marker of alcohol-related pancreatic disease.

TREATMENT OF ALCOHOLIC PANCREATITIS

The mainstays of treatment for an acute attack of alcoholic pancreatitis are

bed rest, pain relief, fasting, and administration of intravenous fluids.

Other treatment measures, such as the administration of enzyme inhibitors

(to reduce the corrosive effects of digestive enzymes on the pancreas) and

the administration of chemicals that protect against dangerously reactive

molecular fragments (i.e., antioxidants) are not yet of proven benefit.

Similarly, it is not yet known whether protective (i.e., prophylactic)

antibiotics have any place in the routine treatment of acute pancreatitis.

Two controlled trials of prophylactic antibiotic treatment in severe

pancreatitis have demonstrated a significant reduction in secondary systemic

infection (i.e., septic episodes), although the treatment did not alter the

death rate or the need for surgery in these patients (Pederzoli et al. 1993;

Delcenserie et al. 1996). Surgery is required to manage complications such

as pseudocysts and pancreatic abscesses and is sometimes needed for the

treatment of chronic pain.

The treatment of chronic alcoholic pancreatitis is difficult. 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. Poor pancreatic

function (e.g., impaired enzyme excretion) is often treated by administering

pancreatic enzyme preparations in tablets or capsules, whereas diabetes is

treated with oral hypoglycemic agents or insulin.

HOW ALCOHOLIC PANCREATITIS MAY DEVELOP

Despite decades of research, the pathogenesis of alcoholic pancreatitis

remains elusive. Studies have been hampered because little is known about

the earliest effects of alcohol on the human pancreas and because obtaining

human pancreatic tissue for examination during life is difficult, because of

its relatively inaccessible position within the abdomen. The slow progress

in this field also can be attributed to the lack of a suitable animal model.

Nonetheless, significant advances have been made, particularly with respect

to the direct toxic effects of alcohol on acinar cells.

Early theories regarding the development of alcoholic pancreatitis focused

on the main pancreatic duct, which carries pancreatic juices to the small

intestine, and a muscular structure where the pancreatic duct opens into the

small intestine (i.e., the sphincter of Oddi). In the 1970's, the research

emphasis shifted to the small ducts that lead to the main pancreatic duct.

In recent years, however, the focus has changed again, with most research

centering on the alcohol's direct effects on acinar cells. These theories

are discussed below.

Alcohol and the Large Pancreatic Duct

One early theory postulated that pancreatic injury is caused by

alcoholinduced spasm of the sphincter of Oddi, leading to backup of

pancreatic enzymes into the unprotected tissues of the pancreas. Therefore,

instead of entering the intestine to digest food, the enzymes " digest " the

pancreatic cells themselves. Another theory postulated that backflow of bile

or the contents of the duodenum into the pancreatic duct led to pancreatic

damage. However, studies to date have failed to provide convincing data to

support these theories.

Effects of Alcohol on Small Ducts Small pancreatic ducts begin at the acini

and drain into the large pancreatic duct. In the early 1970's researchers

hypothesized that alcohol induces pancreatitis by causing small pancreatic

ducts to be blocked by protein plugs. According to this hypothesis, the

acini that secrete into the blocked ducts would then undergo fibrosis, while

the plugs would eventually enlarge and calcify. Research has not clearly

demonstrated that protein deposition within pancreatic ducts precedes acinar

damage. It is therefore uncertain whether protein plugs are a cause or an

effect of pancreatic injury. Nonetheless, it is generally accepted that

protein plugs may play an important role in the progression, if not the

initiation, of the disease.

Protein plugs are composed of pancreatic digestive enzymes and two other

pancreatic secretory proteins, lithostathine and GP2 (Freedman et al. 1993).

These two proteins possess unique properties that may be important to the

process of protein-plug formation.

Pancreatic Lithostathine. Lithostathine is a proteinlike substance that

forms 5 to 10 percent of the protein in pancreatic secretions. Lithostathine

has two properties that make it relevant to the protein plug theory. First,

lithostathine inhibits the deposition of calcium from pancreatic juice

(Bernard et al. 1992). Therefore, a decrease in the level of lithostathine

could promote calcification of protein plugs. Second, enzymes may convert

lithostathine to lithostathine S1, which forms deposits spontaneously in

pancreatic juice, possibly forming a starting point for further protein plug

formation.

Reports conflict on the levels of lithostathine in the pancreatic fluids or

tissue of patients with alcoholic pancreatitis. A recent study (Apte et al.

1996) has shown that long-term alcohol administration significantly

increases one of the factors that regulate lithostathine synthesis (i.e.,

lithostathine mRNA levels). The consequent increase in synthesis of

lithostathine could, in turn, lead to increased concentrations of

lithostathine in pancreatic juice. The action of enzymes on lithostathine in

the juice may promote protein deposition in ducts.

Pancreatic GP2. The protein GP2 is another protein consistently found in

protein plugs and in calcifications from the pancreatic ducts of patients

with alcoholic pancreatitis. When the pancreas is stimulated (as by

consuming a meal), GP2 is discharged, along with digestive enzymes from the

acinar cells. GP2 tends to aggregate in pancreatic juice (Freedman et al.

1993) and may encourage further protein precipitation. An increase in GP2

concentration in pancreatic juice would therefore favor protein plug

formation.

Direct Toxic Effects of Alcohol on Acinar Cells

Most recent research into the pathogenesis of alcoholic pancreatitis has

centered on the direct toxic effects of alcohol on acinar cells. This

direction of research is not unreasonable given that the acinar cell

synthesizes large amounts of digestive enzymes, which have the potential to

cause cell injury when activated (see below).

Role of Digestive Enzymes in Pancreatic Injury. A single pancreatic acinar

cell can synthesize and secrete up to 10 million enzyme molecules per day.

The acinar cell is normally protected from digesting itself by synthesizing

most digestive enzymes as inactive precursors (i.e., zymogens), by

segregating zymogens within membranous compartments (i.e., zymogen

granules), and by producing protective enzymes that destroy digestive

enzymes. Any disruption of these normal protective mechanisms could result

in premature activation of zymogens and subsequent " autodigestive " injury.

Substantial evidence supports a role for active digestive enzymes, such as

trypsin, in pancreatic injury. Perhaps the most compelling evidence that

active trypsin plays a role in pancreatitis is the recent discovery of a

mutant gene in patients with hereditary pancreatitis (Whitcomb et al. 1996).

This mutation produces a trypsin variant that cannot be degraded by the

acinar cell's protective enzymes. The consequent accumulation of active

trypsin could initiate activation of other enzymes, resulting in the

autodigestion of the pancreas.

Effect of Alcohol on Pancreatic Enzymes. Long-term alcohol consumption may

lead to premature activation of digestive enzymes in the acinar cell. In

this regard, it has been shown that alcohol increases the synthesis of

digestive enzymes in the pancreas ( et al. 1992; Apte et al. 1995) and

increases the fragility of the zymogen granules (Haber et al. 1994),

potentially allowing zymogens to leak into the cell. In addition, alcohol

consumption increases the fragility of lysosomes, structures that, like

zymogen granules, sequester lysosomal enzymes within the cell. The lysosomal

enzyme cathepsin B is capable of activating the digestive enzyme trypsinogen

to its active form, trypsin.

The increase in lysosomal fragility appears to be mediated by two compounds

known to accumulate in the pancreas after chronic alcohol consumption:

cholesteryl esters and fatty acid ethyl esters (FAEE's) ( et al. 1992;

Haber et al. 1993). The mechanism responsible for the alcoholinduced

increase in zymogen granule fragility is not yet understood. One possibility

is an alcohol-induced reduction in GP2 content of zymogen granule membranes

(as has been demonstrated recently in alcohol-fed rats [Apte et al. in press

b]). As noted earlier, GP2 is a major component protein of the zymogen

granule membrane and is postulated to play an important role in zymogen

granule maturation and stability.

Alcohol-Induced Oxidant Stress. Reactive oxygen species, or free radicals,

are unstable molecules that are generated as by-products of normal metabolic

processes. These molecules may damage cell membranes, proteins, and genetic

material through the process of oxidation. The cell is normally protected

from the disruptive effects of free radicals by chemical antioxidant

systems. An imbalance between free-radical production and the antioxidant

capability of a cell leads to oxidant stress within the cell.

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). Recent evidence demonstrates that cytochrome

P450 2E1 also is present in the pancreas and, moreover, is induced by

chronic alcohol administration (Norton et al. 1996). In addition, acute

alcohol administration increases levels of compounds formed by the reaction

of free radicals with membrane components (i.e., lipid peroxidation

products) in rat pancreas, thus providing direct evidence that alcohol

causes oxidant stress within the pancreas (Altomare et al. 1996).

Effects of Toxic Metabolites of Alcohol. Metabolism of alcohol by the

liver-with consequent production of toxic metabolites, such as acetaldehyde

and FAEE's-has been shown to play a central role in alcoholic liver disease

(Lieber 1991). Acetaldehyde binds to liver proteins, altering their function

and inducing a damaging immune response. FAEE's can disrupt membranes within

the cell.

Similar metabolic events may occur in the pancreas exposed to alcohol. A

recent study, using cultures of rat pancreatic acinar cells, has shown that

at intoxicating alcohol concentrations, acinar cells metabolize significant

amounts of alcohol (Haber et al. 1995b). The rate of this metabolism

approaches that of liver cells and can potentially contribute to pancreatic

cellular injury. In addition, both human and rat pancreas can synthesize

FAEE's in the presence of alcohol (Apte et al. in press a).

In summary, increasing evidence suggests that direct toxic effects of

alcohol or the products of its metabolism play a major role in alcoholic

pancreatitis. This knowledge has led to the concept of the " drinker's

pancreas " (figure 3) in which the effects of alcohol and its metabolic

by-products (including reactive oxygen species) lead to excessive

accumulation of digestive and lysosomal enzymes in the acinar cell (through

increased synthesis and, possibly, decreased secretion). In addition,

cholesteryl esters, FAEE's, and reactive oxygen species increase the

fragility of zymogen granules and lysosomes, thereby increasing the

potential for contact between digestive and lysosomal enzymes. These changes

occur in the absence of overt pancreatic damage, suggesting that an

additional trigger factor may be required to initiate injury.

FACTORS INFLUENCING INDIVIDUAL SUSCEPTIBILITY

An apparent clinical paradox exists with respect to the occurrence of

pancreatitis in alcoholics. Although it is well established that the risk of

developing pancreatitis rises with increasing alcohol consumption

(suggesting the presence of constant dose-related effects of alcohol on the

pancreas), it is also clear that only a small proportion of heavy drinkers

develop clinically significant pancreatitis. The latter observation raises

the possibility that a factor (or factors) other than alcoholism influence

the susceptibility of an alcoholic to pancreatitis. A number of factors that

may distinguish alcoholics who develop pancreatitis from those who do not

have been investigated (Haber et al. 1995a). These factors include diet,

amount and type of alcohol consumed, the pattern of alcohol consumption,

hereditary factors (e.g., blood group), fat intolerance, and smoking. Many

studies have provided conflicting results, probably because they compared

subjects with alcoholic pancreatitis (i.e., the experimental group) with

subjects from the general population (i.e., the control group). Thus, the

control and experimental groups differed from each other with respect to two

of the factors under study: alcoholism and pancreatitis.

The essential comparison in such studies must be between alcoholics with the

disease and alcoholics without the disease. Thus, the only difference

between the experimental and the control groups should be the presence or

absence of pancreatitis. When possible predisposing factors were studied in

this controlled fashion, no consistent association could be detected between

them and alcoholic pancreatitis (Haber et al. 1995a). Thus, the factors that

may make some heavy drinkers susceptible to pancreatitis have not yet been

identified. Possible predisposing factors that may be the subject of future

research include those that may influence the pathways of alcohol

metabolism, as well as those that may increase the likelihood of

enzyme-related injury to the pancreas, such as genetically determined

alterations in pancreatic digestive enzymes and their inhibitors.

CONCLUSION

Although the mechanism(s) responsible for the development of pancreatitis in

alcoholics need(s) to be fully clarified, significant progress in this

direction has been made in the past decade, particularly with respect to

understanding the direct toxic effects of alcohol on the pancreas. These

effects may create a " primed " setting within the pancreas, which, in the

presence of an additional (as yet unidentified) trigger factor, could lead

to acute, clinically evident pancreatic injury. Repeated episodes of acute

pancreatic injury may lead to chronic disease. Progression of alcoholic

pancreatitis may also be aided by alcohol-induced deposition of protein

plugs within small pancreatic ducts. Thus, the various theories of the

development of alcoholic pancreatitis need not be mutually exclusive.

Indeed, it is likely that a combination of the postulated mechanisms

described in this article is responsible for the manifestations of alcoholic

pancreatitis.

EDITORIAL NOTE

This article is accompanied by an abbreviated reference list. A complete

bibliography of sources consulted is available from the authors.

REFERENCES

AHLGREN, J.D. Epidemiology and risk factors in pancreatic cancer. Seminars

in Oncology 23: 241-250, 1996.

ALTOMARE, E.; GRATTAGLIANO, I.; VENDEMIALE, G.; PALMIERI, V.; AND

PALASCIANO, G. Acute ethanol administration induces oxidative changes in rat

pancreatic tissue. Gut 38:742-746, 1996.

AMMANN, R.W., AND MUELLHAUPT, B. Progression of alcoholic acute to chronic

pancreatitis. Gut 35(4):552-556, 1994.

ANDREN-SANDBERG, A., AND LOWENFELS, B. Etiologic links between chronic

pancreatitis and pancreatic cancer. Scandinavian Journal of Gastroenterology

32:97-103, 1997.

APTE, M.V.; WILSON, J.S.; MCCAUGHAN, G.W.; KORSTEN, M.A.; HABER, P.S.;

NORTON, I.D.; AND PIROLA, R.C. Ethanol-induced alterations in messenger RNA

levels correlate with glandular content of pancreatic enzymes. Journal of

Laboratory and Clinical Medicine 125:634-640, 1995.

APTE, M.V.; NORTON, I.D.; AND HABER, P.S. Both ethanol and protein

deficiency increase messenger RNA levels for pancreatic lithostathine. Life

Sciences 58(6):485-492, 1996.

APTE, M.V.; HABER, P.S.; AND APPLEGATE, T.L. Generation of fatty acid ethyl

esters by rat pancreatic acini: Comparison of oxidative and non-oxidative

ethanol metabolism. Gastroenterology in press a.

APTE, M.V.; NORTON, I.D.; AND HABER, P.S. Chronic ethanol administration

decreases rat pancreatic GP2 content. Biochimica et Biophysica Acta in press

b.

BERNARD, J.P.; ADRICH, Z.; AND MONTALTO, G. Inhibition of nucleation and

crystal growth of calcium carbonate by human lithostathine. Gastroenterology

103:1277-1284, 1992.

COMFORT, H.W.; GAMBILL, E.E.; AND BAGGENSTOSS, A.H. Chronic relapsing

pancreatitis: A study of 29 cases without associated disease of the biliary

or gastrointestinal tract. Gastroenterology 6:239-285, 1946.

DELCENSERIE, R.; YZET, T.; AND DUCROIX, J.P. Prophylactic antibiotics in

treatment of severe acute alcoholic pancreatitis. Pancreas 13: 198-201,

1996.

ELSASSER, H.P.; HAAKE, T.; GRIMMIG, M.; ADLER, G.; AND KERN, H.F. Repetitive

ceruleininduced pancreatitis and pancreatic fibrosis in the rat. Pancreas

7(3):385-390, 1992.

FREEDMAN, S.D.; SAKAMOTO, K.; AND VENU, R.P. GP2, the homologue to the renal

cast protein uromodulin, is a major component of intraductal plugs in

chronic pancreatitis. Journal of Clinical Investigation 92(1):83-90, 1993.

FRIEDREICH, N. Disease of the pancreas. Cyclopoedia of the Practice of

Medicine. New York: Wood, 1878.

GUMASTE, V.V.; DAVE, P.B.; WEISSMAN, D.; AND MESSER, J. Lipase/amylase

ratio: A new index that distinguishes acute episodes of alcoholic from

non-alcoholic acute pancreatitis. Gastroenterology 101:1361-1366, 1991.

HABER, P.S.; WILSON, J.S.; APTE, M.V.; AND PIROLA, R.C. Fatty acid ethyl

esters increase rat pancreatic lysosomal fragility. Journal of Laboratory

and Clinical Medicine 121:759-764, 1993.

HABER, P.S.; WILSON, J.S.; APTE, M.V.; KORSTEN, M.A.; AND PIROLA, R.C.

Chronic ethanol consumption increases the fragility of rat pancreatic

zymogen granules. Gut 35: 1474-1478, 1994.

HABER, P.; WILSON, J.; APTE, M.; KORSTEN, M.; AND PIROLA, R. Individual

susceptibility to alcoholic pancreatitis: Still an enigma. Journal of

Laboratory and Clinical Medicine 125(3): 305-312, 1995a.

HABER, P.S.; APTE, M.V.; NORTON, I.D.; KORSTEN, M.A.; PIROLA, R.C.; AND

WILSON, J.S. Ethanol oxidation by pancreatic acinar cells is comparable to

that of hepatocytes. Gastroenterology 110:A394, 1995b.

KING, L.G.; SEELIG, C.B.; AND RANNEY, J.E. The lipase to amylase ratio in

acute pancreatitis. American Journal of Gastroenterology 90:67-69, 1995

.. LE MOINE, O.; DEVASTER, J.M.; DEVIERE, J.; THIRY, P.; CREMER, M.; AND

OOMS, H.A. Trypsin activity: A new marker of acute alcoholic pancreatitis.

Digestive Diseases and Sciences 39:2634-2638, 1994.

LIEBER, C.S. Metabolism of ethanol and associated hepatotoxicity. Drug and

Alcohol Review 10:175-202, 1991. LIEBER, C.S. Metabolism of ethanol. In:

Lieber, C.S., ed. Medical and Nutritional Complications of Alcoholism:

Mechanisms and Management. New York: Plenum Publishing, 1992. pp. 1-35.

NORTON, I.; APTE, M.; AND HABER, P. P4502E1 is present in rat pancreas and

is induced by chronic ethanol administration. Gastroenterology 110:A1280,

1996.

PEDERZOLI, P.; BASSI, C.S.V.; AND CAMPEDILLI, C. A randomized multicenter

clinical trial of antibiotic prophylaxis of septic complications in acute

necrotizing pancreatitis with imipenem. Surgery Gynecology and Obstetrics

176:480-483, 1993.

STEINBERG, W., AND TENNER, S. Acute pancreatitis. New England Journal of

Medicine 330 (17):1198-1210, 1994.

WHITCOMB, D.C.; GORRY, M.C.; AND PRESTON, R.A. Hereditary pancreatitis is

caused by a mutation in the cationic trypsinogen gene. Nature Genetics

14:141-145, 1996.

WILSON, J.S.; APTE, M.V.; THOMAS, M.C.; HABER, P.S.; AND PIROLA, R.C.

Effects of ethanol, acetaldehyde and cholesteryl esters on pancreatic

lysosomes. Gut 33:1099-1104, 1992.

Data gathered from http://www.niaaa.nih.gov/