CAUSES OF ACUTE AND RECURRENT PANCREATITIS

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CAUSES OF ACUTE AND RECURRENT PANCREATITIS Clinical Considerations and Clues to Diagnosis Simmy Bank, MD, FRCP, and Anant Indaram, MD

The causes of acute and recurrent pancreatitis are conventionally tabulated either from their frequency (i.e., alcohol, gallstones, miscellaneous, or idiopathic) or the pathogenesis (e.g., obstructive, toxic, infective, 8, 24, 33, 4547 Clinically the idiopathic). Both categories are well a~cepted.~, cause either is obvious from the history and a few well-established investigations or may be exceedingly difficult to establish or even speculative. The major challenge at the moment is to try to understand better the mechanisms and clinical presentations of the more obvious causes and to whittle away at the group commonly referred to as idiopathic in an attempt to establish a cause, especially one that may be treatable. The idiopathic group still comprises 10% to 30% of all cases of pancreatitis despite the recognition of subtler entities, such as biliary sludge and microlithiasis, developmental abnormalities in pancreas divisum, genetic causes (i.e., cystic fibrosis), autoimmune causes, and occult neoplastic causes (i.e., mucinous duct ectasia). This article presents a clinically oriented approach to the cause. Table 1 shows the causes of acute and recurrent pancreatitis based on this clinical classification, and Table 2 shows the investigational profile (in phases) according to their value in ascertaining the causes.

From the Department of Gastroenterology, Long Island Jewish Medical Center, New Hyde Park; and the Department of Medicine, Albert Einstein College of Medicine, Bronx, New York

GASTROENTEROLOGY CLINICS OF NORTH AMERICA VOLUME 28 NUMBER 3 * SEPTEMBER 1999

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Table 1. CLINICALLY BASED ETIOLOGIC CLASSIFICATION OF ACUTE OR RECURRENT PANCREATITIS Usually Obvious on History or Phase I Testing Alcohol-induced Gallstones Hyperlipidemic Hypercalcemic Well-established toxins or drugs, eg., azathioprine, scorpion bites, valproic acid ERCP, stents, manometry Traumatic Postoperative, e.g., cardiac or abdominal surgery Nonalcoholic tropical in endemic areas Usually Evident After Phase II Testing Cancer of pancreas Mucinous duct ectasia Ampullary stenosis Pancreas divisum Other anatomic abnormalities Single stone in pancreatic duct Obstructive-periampullary lesions, e.g., Crohn’s, tuberculosis, cancer Perivaterian diverticula Choledochal cysts Usually Evident Only After Phase 111 Testing or Speculative Biliary sludge Biliary dyskinesia, pancreatic ampullary dyskinesia, sphincter of Oddi dysfunction Anecdotal drugs Infective: coxsackie, mumps, HIV, parasitic, worms Hereditary pancreatitis Cystic fibrosis Autoimmune pancreatitis With established disease: SLE, periarteritis Primary sclerosing pancreatitis with sclerosing cholangitis with Sjogren’s syndrome, primary biliary cirrhosis, thyroiditis, i.e., carbonic anhydrase I1 antibodies a,-Antitrypsin deficiency Thrombotic thrombocytopenic purpura ERCP virus; SLE

= Endoscopic retrograde cholangiopancreatography; HIV = = systemic lupus erythematosus.

human immunodeficiency

CAUSES USUALLY OBVIOUS ON HISTORY AND PHASE I INVESTIGATIONS Alcohol-Induced Pancreatitis

Although alcohol-induced pancreatitis has been championed by S a r l e as ~ ~an~ invariable ~ clinicopathologic chronic disease, other authors have demonstrated both functionally and pathologically that acute pancreatitis exists and that repeated attacks of the acute disease may evolve to a clinically chronic disease.34,35 Although the diagnosis is rarely in doubt, some patients are reluctant to admit to alcohol overindulgence. The amount of alcohol required to induce clinically acute pancreatitis is controversial. Studies by Sarles suggested that an average of 80 g of

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Table 2. PHASED INVESTIGATIVE PROFILE IN RELATION TO CAUSE Phase I Investigations* Serum chemistry and level of enzymes: Amylase >5 times normal value suggest gallstones or drug-induced disease. Levels less than 4-fold of normal range suggest alcohol, other causes of chronic pancreatitis, and hyperlipidemia. Ratio of lipase to amylase not established as indicative of alcohol Abdominal ultrasound Gallbladder: stones, sludge, thickened wall Pancreas: enlargement, calcification, pancreatic cyst Serum lipids, calcium CT scan for calcification, periampullary lesions, cancer of the pancreas Endoscopy for duodenal ulcer, ampullary cancer, duodenal disease Phase II Investigationsf ERCP after the first or second attack Biliary drainage for cholesterol and bilirubinate crystals MRI/MRCP (with or without gadolinium or secretin) if available for common duct stones, choledochal cyst, duct abnormalities Ultrasound with secretin (Warshaw’s test) for pancreas divisum Skinny needle (cytology or block), special stains for neuroendocrine tumor Endoscopic ultrasound (with or without biopsy) CA 19-9, CEA, C-reactive protein Phase 111 Investigations* Sphincter of Oddi manometry Pancreatic/biliary cytology and biopsy at ERCP Secretin: CCK pancreatic function test for chronicity Sweat electrolytes and CFTR gene studies Hereditary pancreatitis trypsin deletion gene study Viral studies: Toxoplusrnu, hepatitis profile a,-antitrypsin, immunoglobulins; antibodies to CA 11, Special radiologic techniques, three-dimensional CT scans, secretin MRI/MRCP *Noninvasive and commonly performed. tFurther investigations, often invasive. fLess commonly performed investigations. CT = Computed tomography; ERCP = endoscopic retrograde cholangiopancreatography; MRI/MRCP = magnetic resonance imaging/magnetic resonance cholangiopancreatography;CEA = carcinoembryonic antigen; CCK = cholecystokinin; CFTR = cystic fibrosis transmembrane conductance regulator.

alcohol (i.e., three quarters of a bottle of wine or five jiggers of hard liquor) needs to be taken daily for 5 to 15 years before the first attack occurs. Others believe that the acute attacks may occur with lesser and more intermittent consumption (i.e., weekend binging), and occasionally an acute attack appears to be induced by a sole precipitous large alcohol intake. Executive pancreatitis is a term coined by Marks and Bank3, 35 to characterize a group of executives and jet-setters who imbibe three to four drinks a night and whose abdominal pain is ascribed to hepatitis, gastritis, or another diagnosis until the pancreatic disease becomes evident. The mechanism of induction of alcohol-induced pancreatitis is unclear. Theories include the following, either alone or in combination: (1)Alcohol has a direct toxic effect on the acinar cells. (2) The effects of ethyl alcohol may be initiated by cholecystokinin (CCK) overstimulation (3) Ampullary stimulawith protein precipitation in the smaller

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tion occurs with activation of ampullary pancreatic reflexes affecting the acinar and vascular system, as championed by Guelrud et alZ8and Tiscomia et a1.& Other problems are whether lesser amounts of alcohol can induce pancreatitis in predisposed individuals (i.e., those taking drugs, those with hereditary pancreatitis, those with hyperlipidemia), and whether attacks of pancreatitis for which the cause has been eliminated (e.g., gallstones) render the pancreas more sensitive to the effect of alcohol, and whether alcohol needs to be discontinued in such patients. Most frustrating is that there is still not available a test for chronic alcohol consumption or an understanding of why pancreatitis may occur in one of two family members with the same exuberant alcohol consumption. Lastly, because of the ubiquitous use of alcohol, other remediable causes should always be investigated in alcoholic patients (at least phase I studies), especially for gallstones, drugs (cocaine, heroin), ampullary stenosis, cancer of the pancreas, and mucinous duct ectasia. Gallstone Pancreatitis

The diagnosis of gallstone pancreatitis is usually made during an attack of pancreatitis by the history and abdominal ultrasound. Past episodes of gallstone-like pain are frequent. The amylase is usually greater than fivefold the normal range, and raised bilirubin and liver function tests are suggestive of biliary origin. Epidemiologically, there appears to have been an almost exponential increase in gallstone pancreatitis over the years (Table 3); although improved diagnosis by endoscopic retrograde cholangiopancreatography (ERCP) (magnetic resonance [MR] imaging, MR cholangiopancreatography, and endoscopic ultrasound) has contributed, one has to wonder whether an increase in gallstones is due to sedentary lifestyle, increased obesity (35% in the United States), cultural attempts at weight loss (e.g., commercial weight loss programs, such as Nutrisystem), or use of cholesterol-lowering drugs (gemfibrozil and statins). The clinical dilemma is whether a stone has passed into the duode-

Table 3. CAUSES OF ACUTE AND RECURRENT PANCREATITIS (1978-1 997)*

Alcohol Gallstones Miscellaneous Idiopathic Total

1978-1 982

1983-1 987

1988-1 992

1993-1 997

No.

%

No.

%

No.

%

No.

%

8 26 26 15 75

11 35 35 20

17 35 18 8 78

22 45 23 10

17 95 39 26 177

10 53 22 15

57 90 81 51 279

20 32 29 18

m e causes of pancreatitis from 1978-1997 at Long Island Jewish Medical Center. Note that the incidence of idiopathic has remained relatively static.

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num or is still impacted in the ampulla?, l4 In populations in which there is a predominance of biliary pancreatitis, (as in Hong KongIs) ERCP is performed in all patients with pancreatitis, and therefore this does not constitute a dilemma. In the United States, however, clinicians are more conservative in using emergency ERCP only for patients with obvious cholangitis or clinical deterioration in the disease, withholding further 7,25 investigation until the attack has s~bsided.~,

Endoscopic Retrograde Choiangiopancreatography, Stents, and Sphincterotomy Although the cause of pancreatitis in patients who have undergone ERCP, stent placement, or sphincterotomy is obvious, the mechanism is not always clear (i.e., traumatic or reflex from the ampulla). In addition, pancreatitis not infrequently occurs despite a seemingly technically undemanding procedure. In experienced hands, some 50% of patients have a raised amylase level, pancreatitis occurs in some 7% to lo%, and 1% to 3% have a severe and even potentially fatal attack.21The question is whether there are any measures that would reduce this incidence. Pancreatitis is less likely in established chronic disease, but all those with a virgin gland seem to be equally vulnerable. The occurrence of post-ERCP pancreatitis is probably related to the experience of the endoscopist and perhaps by administration of preprocedure gabexate. Somatostatin, octreotide, steroids, misoprostol, and other medications have not lessened the incidence, and the platelet-activating factor inhibitor (lexipafant) is awaiting clinical trials. Although ERCP and stone extraction and sphincterotomy are among the great advances in medicine, the incidence of pancreatitis (and probably mortality) is probably considerably higher than reported by the various endoscopic societies who report data from only the most experienced endoscopists.

Drug-induced and Toxin-induced Pancreatitis Anecdotally, there is hardly a drug or toxin extant that has not been 47 The mechanism appears implicated as a cause of acute pan~reatitis.~, to be idiosyncratic (e.g., tetracycline) in some, whereas in others, it is dose dependent (i.e., 6-mercaptopurine). This situation is of little importance if the causative drug is an easily replaceable drug, such as tetracycline, allopurinol, or azulfidine, but the situation becomes quite problematic when there is less therapeutic choice (e.g., diuretics, valproic acid, chemotherapeutic agents, or anti-acquired immunodeficiency syndrome drugs). The clinician should attempt to change a possibly causative drug. Insect stings, such as scorpion stings, can result in acute pancreatitis. Parathion and other industrial poisons can cause pancreatitis; when such a case is encountered, the clinician should alert public health authorities.

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Traumatic and Postoperative Pancreatitis and Biochemical Causes Traumatic pancreatitis can be the result of either blunt trauma, such as handlebar injury on a bike, or a more obvious sharp injury, such as a bullet or stab wound. The most common pathology is disruption of the main pancreatic duct, which is best demonstrated by ERCP. Postoperative pancreatitis, particularly after cardiac or intra-abdominal surgery, appears to be becoming increasingly rare, but when it occurs, it is of undue severity with a high mortality. Hyperlipidemia type 1, 4, or 5 is often associated with the occurrence of fairly severe pancreatitis but rarely occurs with serum triglyceride values less than 1000 mg/dL and almost never with values less than 600 mg/dL unless there is an added 49 It is still a etiologic stimulus, such as estrogen therapy or alc~hol.~, truism that the presence of hyperlipidemia may mask the serum amylase elevation; this can be overcome by diluting the serum. Hypercalcemia is rarely overlooked as a cause of pancreatitis but is exceedingly u n c o m ~ n o n2o. ~ ~ ~

CAUSES EVIDENT ONLY AFTER SPECIAL TESTING (PHASE II TESTING) Cancer of the Pancreas and Mucinous Duct Ectasia Increased longevity and an unexplained increase in the prevalence of pancreatic cancer has highlighted its place as a cause of acute and recurrent pancreatitis, especially in the elderly, in whom gallstones, drug-induced disease, and idiopathic causes are also frequent. Greenberg et aIz4reported three severe cases of acute pancreatitis resulting from cancer, and Barkin et all2in a multicenter study have collected 35 cases. Today, unexplained pancreatitis in a patient 45 years or older requires that an underlying pancreatic carcinoma to be excluded. Two difficulties arise: (1) the frequent enlargement of the pancreatic head on computed tomography (CT) in all cases of pancreatitis and (2) the reluctance to do an ERCP after the first attack in many centers.2MR cholangiopancreatography or endoscopic ultrasound taken together with the C-reactive protein and CA 19-9 may assist with the diagnosis. The diagnosis of pancreatic carcinoma is somewhat philosophic because clinical cure or survival in the patients presenting with pancreatitis is unlikely because of the delay in its diagnosis. It is, however, extremely important to recognize mucinous duct ectasia because the intraductal papillary carcinoma characteristic of this type of lesion is amenable to surgical resection with more prolonged survival. The diagnosis may be made by CT scan showing a dilated pancreatic duct and intraductal lesions. ERCP is usually required, however, to show the distinctive umbilicated appearance of the ampulla, mucous discharge from the pancreatic duct, intra-

CAUSES OF ACUTE AND RECURRENT PANCREATITIS

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ductal lesions, and particularly dysplastic or neoplastic cytology obtained from the duct. Anatomic or Developmental Abnormalities

Extrapancreatic abnormalities (periampullary diverticula, blind loop after gastrectomy) and pancreatic abnormalities (pancreas divisum, ansa pancreatica, horseshoe duct, separate opening of cystic, bile, and pancreatic ducts at the ampulla) (Fig. 1) are usually diagnosed by ERCP, MR imaging or MR cholangiopancreatography.4, 53 Having demonstrated these abnormalities, of which pancreas divisum is clearly the most common occurring in 6% of routine autopsies, and their relationship to the patient’s disease, the question of the type and timing of therapy becomes problematic. Delayed resolution of ductal dilation that presents after secretin administration demonstrated by ultrasound (Warshaw’s test) may be helpful in demonstrating stenosis of the minor ampulla. A therapeutic trial of temporary stenting of the minor papilla to determine whether this procedure relieves symptoms may be a preliminary way of ascertaining whether sphincterotomy would be successful. Both endoscopic and surgical sphincterotomy of the minor papilla should be done only by those well versed in the disease and experienced in the technique.

Figure 1. Endoscopic retrograde cholangiopancreatography of cystic duct (arrowhead) opening into the ampulla in a 71-year-old man presenting with acute pancreatitis. (Courtesy of J. Farman, MD, Columbia-Presbyterian Hospital, New York.)

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Ampullary Stenosis True fibrosis and stenosis of the ampulla nearly always follows passage of a gallstone, cautery near or around the ampulla, or rarely sphincterotomy. The diagnosis is nearly always made by the finding of elevated liver enzymes and delayed emptying of dye from the biliary and pancreatic ducts. The question as to whether difficulty in cannulating the ampulla is a diagnostic sign is technique and operator dependent and thus not a clue to diagnosis. If tapering of the pancreatic and biliary tree is found, biopsy specimens should always be obtained to rule out an ampullary or bile duct tumor.

Perivaterian Diverticula, Obstructive Lesions, and cysts Compression of the pancreatic duct or entry of the duct into a perivaterian diverticulum was considered by the Manchester group to be a common cause of relapsing pancreatitis. It is probably no longer true except perhaps with large diverticula compressing the pancreatic duct.@Choledochal cysts (type I, 11, IV) are best diagnosed by sonography, CT, and ERCP, and obstructive lesions near the ampulla, such as Crohn’s disease and ampullary adenomas, should be recognized at endoscopy or CT scan.

CAUSATIVE GROUPS OFTEN REFERRED TO AS IDIOPATHIC UNTIL PHASE 111 TESTING Attempts to find a cause for the group of patients who are often referred to as having idiopathic pancreatitis after phase I1 investigations usually requires a consideration of less common causes. In some of these conditions, the relationship between pancreatitis and the cause is somewhat speculative and may first require a reevaluation of phase I and I1 causes and testing. Despite intensive investigation, the idiopathic group still comprises 10% to 30% of all cases. This situation is exemplified by Tables 3 and 4 showing the cause of acute and recurrent pancreatitis from 1978 through 1997 at the authors’ hospital divided into four yearly groups (i.e. 1978-1982, 1983-1987, 1988-1992, and 1993-1997). Although the causal incidence over the years varies considerably, the percentage of patients still labeled idiopathic even in the latest group from 1993-1997 (l8%), is not materially different from the 10% to 20% over the preceding years. Nevertheless, progress in attempting to find a cause for this difficult group continues, and it is probable that the cause will eventually be clarified by biochemical or genetic means. Table 4 shows the mortality according to the etiologic groups from 1978 through 1997. The mortality for idiopathic, alcohol, gallstones, and miscellaneous groups has decreased progressively, particularly after 1983, and in the

8 26 26 15

75

Alcohol Gallstones Miscellaneous Idiopathic

Total

No.

10 (13.5%)

2 (25%) 2 (8%) 3 (12%) 3 (20%)

Deaths

1976-1 982

17 35 18 8 78

No. 0 (0%) 1 (3%) 4 (22%) 2 (3%) 6 (8%)

Deaths

1983-1 987

177

3 (18%)

17 95 39 26

13 (7.3%)

1(4%)

4 (10%)

4 (4%)

Deaths

No.

1988-1 992

Table 4. MORTALITY OF ACUTE AND RECURRENT PANCREATITIS ACCORDING TO ETIOLOGIC GROUPS (1978-1997)

279

57 90 81 51

No.

10 (3.5%)

2 (3.5%) 5 (5.5%) 2 (2.5%) 1 (2%)

Deaths

1993-1 997

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BANK 81 INDARAM

latest period the mortality in the idiopathic group was low at 2%. In a study from Venu et a1,52idiopathic pancreatitis was reclassified as having a definitive diagnosis in 38% after ERCP or sphincter of Oddi manometry, and in studies from Spain and Seattle, 70% showed microlithiasis on biliary drainage.18,32 Lee et a1 state that a ”reduction in the frequency of attacks” occurred after sphincterotomy or cholecystectomy, a statement that bedevils the whole question of this difficult group of patients. Sludge

The available studies taken in conjunction with a response to ursodeoxycholic acid, endoscopic sphincterotomy, or laparoscopic cholecystectomy in some patients resulted in an almost universal acceptance of the sludge theory. Sludge is usually detected by its appearance on ultrasonography, and as observed by some authors, biliary sludge may eventually lead to stone formation. Sonography may not be sensitive in detecting sludge, and in one study, only 10 of 21 patients with sludge at ERCP were detected by s o n ~ g r a p h y The . ~ ~ most sensitive test is by microscopic examination of bile obtained either at ERCP or during duodenal aspiration after CCK administration. Lee and Ros found that more than 60% of patients with idiopathic pancreatitis had abnormal bile microscopy or sludge. Several authors, however, have found abnormal bile microscopy in healthy persons and in patients with unrelated disease^.'^, 18, 22, 32 Although two studies have shown a reduction in the frequency of recurrent episodes of acute pancreatitis, the disappointment that not infrequently occurs both for patient and for the endoscopist is that attacks recur after sphincterotomy or gallbladder removal. Although this disappointment is understandable, consolation is justified by the fact that everything possible has been done (i.e., phase I, 11, and I11 studies) to exclude other causes. Patient acceptance of this explanation is generally good, a fact that further justifies this approach. Conflicting reports, however, make this concept somewhat difficult to embrace. In the series by Marotta et a1,36in which there was a follow-up of patients for 43 months, 6 of 10 patients with sludge and 7 of 10 patients with no sludge remained asymptomatic, whereas 4 patients with sludge and 3 patients without sludge developed recurrent symptoms of pancreatitis. Other authors have reported recurrence rates of acute pancreatitis of 30% to 70% in patients with biliary sludge during a 2- to 3-year followup (Table 5).32,36 The main clinical dilemmas today are whether (1) to perform a sphincterotomy or cholecystectomy in the patient after the first or second or recurrent attacks with sludge demonstrated by sonogram, (2) to delay endoscopic or surgical intervention until attempts at low-fat diets and urso-deoxycholic acid therapy have been tried and failed, (3) to perform endoscopic or surgical intervention only in the patients with cholesterol or calcium bilimbinate crystals in duodenal aspirates or (4) to delay interventional therapy until there is sonographic evidence of sludge aggregates to obvious small stones. More long-term

NA = not available

Sludge Microscopy positive for bile crystals Gallstones detected on follow-up Recurrence of pancreatitis

2 (8%) NA

1

1

7 (33%) NA

1

2

Idiopathic Alcoholic Pancreatitis Pancreatitis ( n = 21) ( n = 25)

11 (35%) 21

NA NA

None None

NA

NA

3 (22%) None

Idiopathic Alcoholic Pancreatitis Pancreatitis ( n = 31) ( n = 14)

Lee et al (1992)33

1 (1.6%) NA

Control ( n = 63)

Marotta et al (1996)37

Table 5. SLUDGE AND BlLlARY MICROSCOPY IN PATIENTS WITH ACUTE PANCREATITIS

NA NA

NA 15

NA None 4

NA 5

NA

NA

NA 1

Idiopathic Alcoholic Pancreatitis Pancreatitis Control (n = 14) ( n = 15) ( n = 16)

Neoptolemos et al (1988)

27

10 (20%) 34

Idiopathic Pancreatitis ( n = 51)

Ros et al (1991)

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control studies are required to assess the real as opposed to the emotional role of sphincterotomy and cholecystectomy in patients with pancreatitis and sludge. In the meantime, most centers will undoubtedly continue this practice. The patient should be informed that the procedures might, in fact, not relieve further attacks. In the authors’ experience, about 20% of patients have been cured by one or other of these approaches, although pancreatitis can reappear later on. Recurrent Pancreatitis Without Sludge

If the question of sludge (and sphincter of Oddi dysfunction) is problematic, the question of whether to do a sphincterotomy or cholecystectomy in idiopathic recurrent pancreatitis after full investigation has been done, is even more difficult. The authors prefer to do three monthly sonograms to diagnose previously missed or possibly newly formed stones or sludge. In addition, ERCP, bile collection, and sphincterotomy are delayed until the second attack. ERCP is delayed because, first, acute pancreatitis is often a once-only disease and may have occurred as a result of the passage of a single stone or another isolated event. Second, although reported rates of complications ensuing from ERCP, sphincterotomy, and laparoscopic cholecystectomy by experts are low, the true complication rates of these procedures in the general community are not known. Caution must be exercised because litigation is frequent if patients with no established diagnosis develop post-ERCP or postlaparoscopic complications. Patients should always be made thoroughly aware of the risk-to-benefit ratio of blind sphincterotomy or cholecystectomy. Only about 10% of patients appear to be improved by these procedures as opposed to the higher rate that is reported. Sphincter of Oddi Dysfunction

The role of sphincter of Oddi dysfunction as a cause of pancreatitis and the place of biliary manometry in its diagnosis are undergoing evolution. Traditionally, sphincter of Oddi dysfunction is defined as an elevated basal pressure greater than 45 mm Hg and delayed drainage of contrast material from the pancreatic duct and common bile duct more than 7 minutes. There is a paradoxic response to CCK administration causing an increased basal sphincter of Oddi pressure. In the series by Venu et a1,52 only 17 of 116 patients (15%) with idiopathic recurrent pancreatitis had manometrically demonstrated criteria for sphincter of Oddi dysfunction; and of these 17,16 had a good response to sphincterotomy, whereas 35 of 40 patients with normal sphincter of Oddi pressure developed recurrent pancreatitis on follow-up. In another study by Touli et a1,5O 57% of patients with idiopafhic pancreatitis had sphincter of Oddi dysfunction. This highly variable incidence of sphincter of Oddi dysfunction among studies makes it difficult to conclude what the exact

CAUSES OF ACUTE AND RECURRENT PANCREATITIS

583

role of sphincter of Oddi dysfunction is as a cause of pancreatitis. Surgical sphincterotomy and septotomy performed many years ago by Doubilet in New York17 and Moody in Utah37for recurrent pancreatitis has been relegated to the scrapheap of medicine. This concept has been resurrected because of the relative ease of endoscopic sphincterotomy compared to operative sphincteroplasty and septotomy and use of manometry. Nardi’s relatively simple test of elevated liver enzymes or amylase (or both) after morphine/neostigmine provocation has been replaced because of its nonspecificity and sensitivity by sphincter of Oddi manometry. The Indiana group have attempted to classify sphincter of Oddi dysfunction and the need for manometry (Table 6). Manometry is probably not necessary in type I and is of some value in type I1 and type I11 patients because only 15%to 30% show some manometric abn0rrnality.5~ Sherman et a143bhave advocated manometry, sphincterotomy, or therapeutic stenting only in type I patients and had good results with sphincterotomy in 33% of their patients. The main problem is the lack of controls. The clinical outcome of sphincterotomy is not known when studies are restricted to patients with raised manometric pressures; what would be the clinical outcome in those with normal pressures? These and many other questions have to be addressed before universal manometry and sphincterotomy can be advised for patients with idiopathic recurrent pancreatitis. Genetic Diseases in Acute and Recurrent Pancreatitis

Hereditary Pancreatitis

Hereditary (familial) pancreatitis has been recognized for many years as a rare cause of chronic pancreatitis. Early studies by Gross et alZ6implicated aminoaciduria as the hereditary factor. Sarles et alrsaand Bank et allo reported a number of families with two or three family members among their large series, some siblings having alcohol-induced disease, whereas others were abstainers, and speculated whether genetic factors may contribute to the sensitivity to alcohol. Bank et al” investigated numerous factors (HLA status, immunoglobulins, ABO blood

Table 6. CLASSIFICATION OF SPHINCTER OF ODD1 DYSFUNCTION

Types

Findings

I

Pancreatic pain Dilated pancreatic duct Delayed emptying of pancreatic duct >7 min Elevated amylase and lipase values Pancreatic pain with one or two of the above findings Pancreatic pain with none of the above findings

I1 I11

Role of Biliary Manometry Usually not necessary

May be helpful May be helpful

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groups, urinary amino acids, chromosomal abnormalities, a,-antitrypsin). Although none could be regarded as definitive, there were HLA, ABO blood group, a,-antitrypsin, and other trends. A masterly demonstration by Whitcomb et a155,56 of the locus of the gene defect and trypsin deletion in hereditary pancreatitis on chromosome 7q35 has shown the hereditary (autosomal dominant) nature in affected families with pancreatitis, of whom 84% had acute attacks, 30% were diabetic, and 33% had cholecystectomies.This seminal finding has led to speculation regarding the frequency of these genes, not only in idiopathic pancreatitis, but also as a predisposing factor in alcohol-induced, drug-induced, tropical, and perhaps all pancreatitis. This finding is unlikely, and the pendulum will probably swing from exuberant enthusiasm to its rightful place in the genesis of pancreatitis. A number of centers are currently collaborating with Whitcomb and the Pittsburgh group in an attempt to clarify the proper place of genetics in idiopathic pancreatitis and pancreatitis with known causes. Cystic Fibrosis The story of cystic fibrosis parallels that of hereditary pancreatitis and demonstrates the remarkable role that marker genes currently hold in all diseases. Bank et allo reported on sweat tests carried out in 120 patients with chronic pancreatitis. Most of these had alcohol-induced pancreatitis and included five family members. Approximately 30% had raised sweat sodium and chloride, and the question was raised whether a heterozygous form of cystic fibrosis existed possibly to increase the sensitivity to alcohol and other pancreatoxins. Acute or recurrent painful pancreatitis and pancreatic calcification is exceedingly uncommon in homozygous florid cystic fibrosis, a fact that made the concept of occult cystic fibrosis being implicated as a cause of idiopathic pancreatitis or sensitizing the pancreas to alcohol somewhat unlikely.l6.38 Discovery of the CFTR gene, which is a now more precise diagnosis of cystic fibrosis, inevitably again raised the specter of cystic fibrosis being a possible cause of idiopathic pancreatitis. Studies on family members of patients with cystic fibrosis but without manifest cystic fibrosis who are CFTR gene positive have shown cohorts with acute or recurrent pancreatitis. In an attempt to determine the potential role of CFTR gene in the cause of hereditary pancreatitis, Ravnick et al" found a new alteration involving exon 7, causing an amino acid change from leucine to arginine at position 3;27 (L327R).These results indicate that CFTR gene mutations may be involved in the cause of hereditary pancreatitis. As an alternative to CFTR gene analysis, Iovanna et alZ9found pancreatitis-associated protein assay in blood useful as a screening for cystic fibrosis in neonates, with a high concordance rate between CFTR gene analysis and pancreatitis-associated protein assay. Desai et all5 found acute pancreatitis in five patients with definite cystic fibrosis and in six patients with chronic pancreatitis; the CFTR mutation was present in four patients. All of these patients were 21 to 50 years old. Although

CAUSES OF ACUTE AND RECURRENT PANCREATITIS

585

the studies of the relation of pancreatitis to CFTR are still in their infancy, it is currently moot whether a positive CFTR genetic study is worthwhile if the sweat test is negative. Because of the awareness of the possibility, it appears that certain groups are lowering their standards for a positive sweat test to the region of 40 mEq for chloride. Many studies are necessary to evaluate the exact frequency of formes fruste cystic fibrosis as a factor in what is now called idiopathic pancveatitis or, in fact, other forms of pancreatitis. AUTOIMMUNE DISEASE AND PROTEIN ABNORMALITIES IN ACUTE AND RECURRENT PANCREATITIS

Novis et a140 investigated a1-antitrypsin in patients with chronic calcific pancreatitis and found heterozygous al-antitrypsin deficiency in a number of patients. Bank et all1 found increased immunoglobulins (IgG) in a similar group of patients. These authors suggested that autoimmune factors and protein abnormalities might be involved in patients with acute pancreatitis and make the pancreas more vulnerable to the effect of alcohol and other toxins. Acute pancreatitis does occur in wellestablished autoimmune diseases, such as systemic lupus erythematosus and periarteritis, but these are probably on a vascular basis.1,30,41 Primary sclerosing pancreatitis may occur as an individual entity or in association with sclerosing cholangitis. More recently, Japanese workers have found an antibody to carbonic anhydrase I1 in patients with idiopathic pancreatitis associated with Sjogren’s syndrome and primary biliary ~ i r r h o s i s . ~ ~ The authors have seen a 55-year-old woman with a long history of pancreatitis, who already had had two sphincteroplasties and distal pancreatectomy, who 13 years later developed primary biliary cirrhosis, Sjogren’s syndrome, thyroiditis, and diabetes. These cases have been shown to have an abnormality of the T-cell subtypes for carbonic anhydrase II.27 Autoimmune pancreatitis appears to be characterized by a diffusely swollen pancreas on imaging studies and thumbprinting in the duct by infiltration of mononuclear cells and responds to steroids. The authors’ patient actually got worse on steroids. Other diseases in this group that have been associated with acute pancreatitis are thrombotic thrombocytopenic purpura, sickle cell anemia, and other conditions resulting from vascular insults. MISCELLANEOUS CAUSES

Pancreatitis resulting from ascaris and other helminths, fungi, and bacterial disease are usually fairly obvious. The question of a viral cause for some patients with idiopathic pancreatitis needs to be considered when all else seems to be negative. A viral cause is often not more than speculative, particularly in patients in whom the pancreatitis appears to

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be associated with other apparent viral syndromes, such as myocarditis and peripheral neuritis. In some, the presence of coxsackie virus can clearly be demonstrated, and it is likely that human immunodeficiency virus disease and cytomegalovirus might be implicated in some patients. In addition, mumps is a well-known cause of viral pancreatitis. Whether other viruses might be implicated is currently uncertain. TIMING OF PHASE I, II, OR 111 STUDIES IN ACUTE OR RECURRENT PANCREATITIS During the First Acute Attack

It is generally agreed that the presence of cholangitis, biochemical evidence of common bile duct obstruction, or severe pancreatitis as determined by Ranson's score, Bank's signs, or Apache signs mandates ERCP and subsequent removal of common bile duct stones if found or stenting. Patients with mild attacks of acute pancreatitis who are improving are usually observed until the attack has subsided. There is really no other cause than biliary that necessitates an immediate or urgent ERCP or other phase I1 studies. After the First Attack and No Obvious Cause After Phase I Investigations

Most clinicians delay phase I1 and I11 investigations until after the second attack.2,25 Acute pancreatitis is often a once-only disease, and the most common and important second-phase investigations are invasive (i.e., ERCP). Some authors, including Carr-Locke (personal communication) and Gregor and P0nich,2~believe that ERCP should be done even after the first attack. Perhaps the widespread availability and increasing resolution of MR cholangiopancreatography or gadolinium MR imaging would be helpful for clinicians reluctant to proceed with invasive procedures after only one attack of acute pancreatitis. After the Second Attack

Most authors agree that a second attack of acute pancreatitis or recurrent attacks mandate phase I1 and as many of phase I11 studies that are deemed necessary. This approach nearly always includes ERCP and noninvasive tests such as viral studies, antinuclear antibody, antimitochondrial antibodies, a sweat test, and perhaps hereditary pancreatitis gene studies in selected patients. Whether to proceed to sphincter of Oddi manometry and sphincterotomy should be given serious thought because in inexperienced hands, the incidence of pancreatitis is consider-

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able. It is hoped that this approach will maximize the diagnosis and minimize morbidity and mortality.

References 1. Antal L, Kavai M, Szabo G, et al: Immunological investigations in acute and chronic human pancreatitis. Digestion 2O:lOO-105, 1980 2. Ballinger AB, Barnes E, Alstead E M Is intervention necessary after first episode of acute idiopathic pancreatitis? Gut 3829S295, 1996 3. Banerjee AK, Steele RJC: Current views on the pathophysiology of acute biliary pancreatitis. Gut 38:803-804, 1996 4. Bank S: Acute pancreatitis. In Brandt CJ (ed): Clinical Practice of Gastroenterology. Philadelphia, Current Medicine, 21159-1169, 1999 5. Bank S Pancreatic endocrine-exocrine relationships in health and disease. Scand J Gastroenterol 7503-507, 1972 6. Bank S Acute and chronic pancreatitis. In Dent TL (ed): Pancreatic Disease: Diagnosis and Therapy. New York, Grune & Stratton, 1981, pp 167-188 7. Bank S Gall stone pancreatitis: Pathogenesis, concepts and clinical aspects. Post graduate course syllabus, Advances in Hepato-Biliary-Pancreatic Surgery. 8th World Congress of Gastroenterology, Stlo Paulo, Brazil, 1986, p 12 8. Bank S Chronic pancreatitis: Clinical features and medical management. Am J Gastroenterol 81:152-167, 1986 9. Bank S, Marks IN: Hyperlipaemic pancreatitis and the pill. Postgrad Med J 46:576578, 1970 10. Bank S, Marks IN, Novis BH: Sweat electrolytes in chronic pancreatitis. Dig Dis Sci 23178-181, 1978 11. Bank S, Novis BH, Peterson E, et al: Serum immunoglobulins in calcific pancreatitis. Gut 14:72S725, 1973 12. Barkin JS, Go VLW, Mujica V Acute pancreatitis due to pancreatic carcinoma: A multicenter study. Gastroenterology 112A427, 1997 13. Bess MA, Edis AJ, Van Heerden JA: Hyperparathyroidism and pancreatitis: Chance or a causal association? JAMA 243246-247, 1980 14. Curran FT, Neoptolemos JP: Acute biliary pancreatitis. Ann Ital Chir 66197-202,1995 15. Desai TK, Linerode M, Siddique N Forme fruste cystic fibrosis presenting as pancreatitis in adults. Gastroenterology 114:452, 1998 16. di-Sant-Agnes PA, Davis PB: Cystic fibrosis in adults: 75 cases and a review of 232 cases in the literature. Am J Med 66121-131, 1979 17. Doubilet H, Mulholland J H Eight year study of pancreatitis and sphincterotomy. JAMA 160:521-528,1956 18. Fan ST, Lai ECS, Mok FPT, et al: Early treatment of acute pancreatitis by endoscopic papillotomy. N Engl J Med 328228-232, 1993 19. Felicetta JV,Shah IA: Hyperparathyroid crisis with fatal pancreatitis. Journal of Resident and Staff Physician 417-21, 1998 20. Folsh U, Nitshe R, Ludtke R, et al, and German Study Group on Acute Biliary Pancreatitis: Early ERCP and papillotomy compared with conservative treatment for acute biliary pancreatitis. N Engl J Med 336:237-242, 1997 21. Fung HS, Tsiolos GG, Sarr MG: ERCP-induced acute necrotizing pancreatitis: Is it a more severe disease? Pancreas 15217-221, 1997 22. Juniper K, Burson E N Biliary tract studies: 11. The significance of biliary crystals. Gastroenterology 32:175-209, 1957 23. Greenberg RE, Bank S, Stark B Adenocarcinoma of the pancreas producing pancreatitis and pancreatic abscess. Pancreas 5:108-113, 1990 24. Greenberger NJ, Toskes PP, Isselbacher KJ: Acute and chronic pancreatitis. In Isselbacher KJ, Braunwald E, Wilson JD, et a1 (eds): Harrison’s Principles of Internal Medicine, ed 13. New York, McGraw-Hill, 1994, pp 1520-1532

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25. Gregor JC, Ponich TP: Should ERCP be routine after an episode of idiopathic pancreatitis-a cost utility analysis. Gastrointest Endosc 44:118-123, 1996 26. Gross JB, Ulrich JA, Jones J D Urinary excretion of amino acids in a kindred with hereditary pancreatitis and aminoaciduria. Gastroenterology 474148, 1964 27. Gordon SC, Quattrociocchi-Longe TM, Khan BA, et a1 Antibodies to carbonic anhydrase in patients with immune cholangiopathies. Gastroenterology 108:1802-1809, 1995 28. Guelrud M, Mendoza S, Rossler G, et al: Effect of local instillation of alcohol on sphincter of Oddi motor activity: Combined ERCP and manometry study. Gastrointest Endosc 37428-432, 1991 29. Iovanna JL, Ferec C, et al: The pancreatitis associated protein: A new candidate for neonatal screening of cystic fibrosis. C R Acad Sci I11 317561-564, 1994 30. Ito T, Nakano I, Koyanagi S, et al: Autoimmune pancreatitis as a new clinical entity. Dig Dis Sci 42:1458-1468, 1997 31. Kino-Ohsaki J, Nishimori I, Morita M, et al: Serum antibodies to carbonic anhydrase I and I1 in patients with idiopathic chronic pancreatitis and Sjogren’s syndrome. Gastroenterology 110:1579-1586, 1996 32. Lee S, Nocholls J, Park H Biliary sludge as a cause of acute pancreatitis. N Engl J Med 326:589-593, 1992 33. Marks IN: Etiology of pancreatitis. In Bank S, Bums G (eds): Disorders of the Pancreas. New York, McGraw-Hill, 1992, pp 17-23 34. Marks IN, Bank S: Chronic, chronic relapsing and calcific pancreatitis. In Bockus HL (ed): Gastroenterology, ed 2. Philadelphia, WB Saunders, 1985, pp 4020-4040 35. Marks IN, Bank S, Louw JH: Diagnosis and treatment of pancreatitis. In Jerzey Glass GB (ed): Progress in Gastroenterology, vol 1. New York, Grune and Stratton, 1968, pp 412-472 36. Marotta P, Gregor J, Taves D Biliary sludge: A risk factor for ”idiopathic” pancreatitis? Can J Gastroenterol6:385-388, 1996 37. Moody FG: Post cholecystectomy syndromes. In Moody FG (ed): Advances in Diagnosis of Surgical Treatment of Biliary Tract Disease. New York, Masson Publishing, 1983, pp 49-56 38. Moreno GE, lbanez AJ, et al: Recurrent acute pancreatitis as a complication of cystic fibrosis: A case report treated surgically. Ann Ital Chir 62345-347, 1991 39. Neoptolemos JP: Endoscopic sphincterotomy in acute gallstone pancreatitis. Br J Surg 80547-549, 1993 40. Novis BH, Young GO, Bank S, et al: Chronic pancreatitis and alpha-1-antitrypsin. Lancet 2:748-749, 1975 41. Ohsaki KJ, Nishimori I, Morita M, et al: Serum antibodies to carbonic anhydrase I and I1 in patients with idiopathic chronic pancreatitis and Sjogren’s Syndrome. Gastroenterology 110:1579-1586, 1996 42. Ravnick GM, Glavac D, di-Sant-Agnes P, et a1 Cystic fibrosis gene mutations detected in hereditary pancreatitis. Pflugers Arch 191-192, 1996 43. Ros E, Navarro S, Bru C, et al: Occult microlithiasis in idiopathic pancreatitis: Prevention of relapses by cholecystectomy or UDCA therapy. Gastroenterology 101:17011709, 1991 43a. Sarles H, Bernard JP, Johnson C: Pathogenisis and epidemiology of chronic pancreatitis. Ann Rev Med 40:453-468,1989 43b. Sherman S, Ruffolo TA, Hawes RH, et al: Complications of endoscopic sphincterotomy: A prospective series with emphasis on the increased risk associated with sphincter of Oddi dysfunction and nondilated bile ducts. Gastroenterology 101(4):1068-1075, 1991 44. Stark 8, Bank S, Greenberg R Duodenal diverticula and pancreatic-biliary disease: To stent or not to stent? Gastrointest Endosc 32:154, 1986 45. Steer ML, Waxman I, Freedman S Chronic panmatitis. N Engl J Med 33214821490, 1995 46. Steinberg WM: Acute pancreatitis. In Feldman M, Toskes P (eds): Gastroenterology and Hepatology: The Comprehensive Visual Reference. Vol 8. Pancreas. New York, Churchill Livingstone, 1998, pp 3.1-3.14

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47. Steinberg W, Tenner S Acute pancreatitis. N Engl J Med 330:119&1210, 1994 48. Tiscomia OM, Celener D, Perec C, et al: Physiopathogenic basis of alcoholic pancreatitis: The effects of elevated cholinergic tone and increased "pancreon" ecbolic response to CCK. Mt Sinai J Med 50:369-387,1983 49. Toskes PP: Approach to the patient with acute, relapsing pancreatitis. Gastrointest Dis Today 3:8-15, 1994 50. Touli J, Roberts-Thomson IC, Dent J, et al: Sphincter of Oddi motility disorders in patients with idiopathic pancreatitis. Br J Surg 72859-863, 1985 51. Tsui LC: The cystic fibrosis transmembrane conductance regulator gene. Am J Respir Crit Care Med 151:547-553, 1995 52. Venu RP, Geenen JE, Hogan L, et al: Idiopathic recurrent pancreatitis: An approach to diagnosis and treatment. Dig Dis Sci 3456-60, 1989 53. Warshaw AL, Simeone JF, Schapiro RH, et al: Evaluation and treatment of the dominant dorsal duct syndrome (pancreas divisum redefined). Am J Surg 159:59-66, 1990 54. Wehrmann T, Lembcke B, Jung M: Diagnostic and therapeutic possibilities in suspected Oddi's sphincter dysfunction. Gastroenterology 32694-701, 1994 55. Whitcomb DC, Gorry MC, Preson RA, et a1 Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat Genet 14141-145,1996 56. Whitcomb DC,Preson RA, Aston CE, et al: A gene for hereditary pancreatitis maps to chromosome 7q35. Gastroenterology 110:1975-1980, 1996

Address reprint requests to Simmy Bank, MD, FRCP Gastroenterology Long Island Jewish Medical Center 270-05 76thAvenue New Hyde Park, NY 11040