Recurrent pancreatitis

How can I be sure that the patient has recurrent pancreatitis?

Patients with pancreatitis typically present with abdominal pain that may or may not radiate to the back. This condition is accompanied typically by a three-fold or greater elevation of amylase and or lipase. If the clinician performs some imaging study (either a CT scan or MRI and, sometimes, ultrasound of the abdomen), he or she will see some inflammatory changes involving the pancreatic gland or the surrounding tissue. The physician needs at least two of the above three criteria to label a patient as having pancreatitis. (Ultrasound, generally, is not sensitive.)

Patients with recurrent acute pancreatitis present with repeated episodes of pain with variable frequency. The frequency is highly variable and might be influenced by genetic and environmental factors. In the absence of robust natural history data, it is difficult to predict the rates of recurrence.

In patients with both elevations of pancreatic enzymes and imaging evidence of pancreatitis, diagnosis is easy to make. In those patients with minimal elevations of enzymes and minimal or no changes of inflammation on imaging, it can be difficult to make a definitive diagnosis of recurrent pancreatitis.

Signs and symptoms

Abdominal pain with or without radiation to the back
Greater than or equal to 3-fold elevation of serum amylase and/or lipase
Imaging features suggestive of acute pancreatitis

In general, at least two of the above three features must be present to label a patient as having pancreatitis. In those patients with recurrent episodes and in patients who ultimately develop chronic pancreatitis, the peak level of amylase or lipase elevation may decrease over time and later episodes may have lesser degrees of elevation.

Pain is the most common presenting feature of pancreatitis. Typically, the pain is in the epigastrium/right upper quadrant with or without radiation to the back. Based on the severity of pancreatitis, other symptoms and signs of systemic inflammatory response might be seen.

Differential diagnoses

In addition to acute pancreatitis, many other conditions can cause severe acute abdominal pain. The differential diagnoses include:

Intestinal perforation with peritonitis
Acute intestinal obstruction
Acute cholecystitis
Acute appendicitis
Acute mesenteric ischemia
Pancreatic neoplasia

Pain is described as epigastric, severe – warranting evaluation by a health-care provider, and pain typically radiates to the back and sometimes to right upper quadrant, and could be worsened by oral intake.

Some patients may not have significant pain, may not have elevations in amylase or lipase and may not have imaging evidence of acute pancreatitis. Elderly patients with a rather atrophic pancreas might not have the classic findings of inflammation of the gland on imaging. Patients with recurrent episodes could at times experience pain with enzyme elevation that is less than 3 times the normal elevation of amylase or lipase. There is also a group of patients with pancreatic hyperenzymemia, with some pain but no radiological evidence of inflammation. With these types of patients, it is harder to make a diagnosis of pancreatitis.

How can I confirm the diagnosis?

A proper history and physical examination are very important. Most cases of recurrent pancreatitis are secondary to alcohol and biliary etiologies. Binge drinking of alcohol prior to the attack should be inquired about. It is reasonable to obtain the following diagnostic tests:

A plain X-ray of the abdomen in the erect posture, including the domes of the diaphragm to rule out gut perforation and intestinal obstruction in all patients with severe abdominal pain.
Contrast-enhanced CT scan of the abdomen (in the absence of renal failure) is very sensitive and will also show any necrosis of the pancreas and will rule out other etiologies of pancreatitis, including tumors. However, the CT should not be done early in the course of the disease if the diagnosis can be made in the presence of clinical features and elevation of amylase/lipase with or without the help of ultrasound. An ultrasound of the abdomen is useful since it is most sensitive and easily available to rule out acute cholecystitis. It is an excellent tool for gallstones, which might be the cause for pancreatitis.
Serum amylase and/or lipase should be ordered. Serum triglycerides should be checked on admission. Liver function tests could point toward a biliary etiology and should be evaluated; routine electrolytes and renal function should be checked.

Genetic mutations could be an etiological factor in recurrent pancreatitis, but routine testing is not recommended outside of clinical studies.

Algorithm 1

Diagnostic algorithm

– Plain X-ray of the abdomen and chest (to include domes of diaphragm) in standing posture.

– Blood chemistry (serum amylase, lipase, BUN, sugar, Na/K, Ca, bilirubin, ALT/AST, alkaline phosphatase, cholesterol, triglyceride.

– CECT scan of the abdomen.

– Ultrasound of the gall bladder, especially to rule out cholecystolithiasis and cholecystitis.

– MRCP

– EUS

– In patients with recurrent pancreatitis, serum amylase/lipase would suffice to confirm the episode of pain to be due to pancreatitis. Routine repetition of all the tests is not necessary and should be tailored individually

The next set of investigations is required to determine the etiology of recurrent pancreatitis. If the ultrasonography does not indicate gallstones, the patient has not been consuming significant amount of alcohol, and the chemistry results rule out hypercalcemia and hypertriglyceridemia, the patient would be tentatively labeled as having idiopathic recurrent acute pancreatitis. The investigations to establish the following common etiology include the following.

History of alcohol ingestion should be obtained again. An ultrasound of the gallbladder would help rule out cholelithiasis but not choledocholithiasis. Routine laboratory testing including liver function tests could be helpful to rule out biliary etiology. Hypertriglyceridemia and hypercalcemia could be excluded by routine testing. Despite these tests if a diagnosis is not made then it is reasonable to assume that the patient has Idiopathic Recurrent Acute Pancreatitis. Further testing and rationale for testing are as follows:

Etiology to be diagnosed and corresponding tests

Microlithiasis: EUS

Pancreas divisum: MRCP

Sphincter of Oddi (SO) dysfunction: ERCP and SO manometry

Early chronic pancreatitis: EUS

Endoscopic ultrasound is the most important test in patients with idiopathic pancreatitis. It can diagnose microlithiasis, pancreas divisum, early chronic pancreatitis, and pancreatic neoplasia which is a common cause of recurrent pancreatitis, especially as the age of the patient increases. The findings on EUS may include small stones in the gallbladder or bile duct that were missed with transabdominal ultrasound; absence of stack sign, suggesting pancreas divisum; or features of early chronic pancreatitis.

Certain features of imaging on EUS can suggest of chronic pancreatitis as validated in Rosemont criteria. Hyperechoic foci with shadowing and main pancreatic duct (PD) calculi and lobularity with honeycombing have been defined as major criteria, while the minor criteria for chronic pancreatitis include cysts, dilated duct at 3.5 mm or more, irregular PD contour, dilated side branches at 1 mm or more, hyperechoic duct wall, strands, nonshadowing hyperechoic foci, and lobularity with noncontiguous lobules. On this basis of these criteria, the findings are classified as “consistent with CP,” “suggestive of CP,” “indeterminate for CP,” or “normal.”

For pancreas divisum, MRCP is quite sensitive. Whether pancreas divisum is a cause of recurrent pancreatitis is controversial. However, it is reasonable because clinical data suggest that patients with divisum and recurrent pancreatitis or obstruction of the dorsal duct might benefit from therapeutic intervention of the dorsal duct to prevent recurrence of pancreatitis.

ERCP is reserved for therapeutic purpose and if MRCP is not available. ERCP should be done with caution as it can induce post-ERCP pancreatitis in patients. If ERCP is done, it should not be performed purely for ductography but for therapeutic intervention. It should be performed in centers with capabilities for sphincter of Oddi manometry. The role of sphincter of Oddi dysfunction is however, controversial.

Genetic mutations could be an etiological factor in recurrent pancreatitis, but routine testing is not recommended outside of clinical studies.

What other diseases, conditions, or complications should I look for in patients with recurrent pancreatitis?

History of significant alcohol intake (>3-5 drinks/day for >5 years), chronic smoking, hyperlipidemia, and hypercalcemia are risk factors for recurrent pancreatitis. Gallstones may be associated as a cause of recurrent pancreatitis.

Development of pseudocyst may be a local complication of recurrent pancreatitis. The patient may develop chronic pancreatitis after a variable period of time. Steatorrhea may be the presenting symptom.

Systemic complications in the form of organ failure are typically not seen in recurrent pancreatitis but should be considered.

Diabetes may be a late complication of recurrent pancreatitis.

Local complications and magnitude of risks

Pseudocyst : 10-30%
Portal/splenic vein thrombosis: 10%
Biliary obstruction: ~5%
Chronic pancreatitis: 47%*

Systemic complication

Diabetes: 10-25%

What is the right therapy for the patient with recurrent pancreatitis?

The treatment of recurrent pancreatitis can be divided into two parts:

1. Treatment of acute episode. In the acute episode, the major problem is abdominal pain. Pain relief can be achieved with intravenous non-steroidal anti-inflammatory drugs/narcotic analgesics/patient-controlled analgesia. Generally, patients are kept NPO. The physician should monitor the patient closely and provide sufficient fluid resuscitation. Early enteral nutrition is preferred over parenteral nutrition.

2. Prevention of recurrence of pancreatitis.

Identification of cause. The prevention depends on identification of the cause of recurrent pancreatitis. Once a cause is identified, appropriate measures may be taken, such as cholecystectomy for gallstones/microlithiaiss and ERCP, and endoscopic sphincterotomy of the minor papilla for pancreas divisum and sphincter of Oddi dysfunction. Again, cause association and response to therapy are debatable.
Alcohol and smoking. Because both alcohol and smoking are known risk factors for pancreatitis, the patients should be advised abstinence for both alcohol and smoking. Smoking is not well appreciated even by physicians as an important risk factor unlike alcohol and thus the patient needs to be given proper advice for cessation.
Additional therapy. If a patient develops features of chronic pancreatitis in the form of pancreatic ductal dilatation and calcification, then further therapy for prevention of recurrent attacks may be offered. This may include endoscopic therapy and even surgical therapy. Antioxidants may reduce pain. Enzyme supplements should be considered.

Medical therapy

Medical therapy consists of the following:

Management of an acute episode should be like the management of any episode of acute pancreatitis.

For prevention of recurrence:

Smoking cessation and avoidance of alcohol.
Avoidance of any precipitating cause (fatty foods) for hypertriglyceridemia, etc.
Trial of antioxidants and enzyme supplements for those patients with changes of chronic pancreatitis.

What is the most effective initial therapy?

Management of an acute episode is similar to management of any episode of acute pancreatitis: IV fluids, analgesics, nasojejunal feeding if no ileus, and management of any complications. Most pseudocysts resolve with time and, unless symptomatic, do not need intervention. Drainage is recommended only for those who are symptomatic or infected.

Listing of usual initial therapeutic options, including guidelines for use, along with expected result of therapy.

Because there is no good natural history data, and available clinical trials of therapeutic efficacy are small and only a few are randomized, it is difficult to come up with good evidence for clinical guidelines.

Avoidance of alcohol
Cholecystectomy for biliary pancreatitis, including microlithiasis
If pancreas divisum presents and the patient has recurrent pancreatitis, there is a small study that shows that serial stenting helps and a retrospective study that minor papillotomy helps reduce the risk of recurrence. If ERCP is done, the physician should place a temporary dorsal pancreatic duct stent to prevent post-ERCP pancreatitis.
If manometry is done and pressures either in the biliary and or pancreatic sphincter are elevated, sphincterotomy can help reduce recurrence. This is controversial. Data are limited. Again, these patients would benefit from temporary pancreatic duct stent placement.

A listing of a subset of second-line therapies, including guidelines for choosing and using these salvage therapies

Some physicians recommend empiric cholecystectomy, especially if sludge is seen in the gallbladder on ultrasound scans for presumed microlithiasis. This strategy was never systematically evaluated, although it might be a reasonable option in select individuals.

Listing of these, including any guidelines for monitoring side effects

N/A

How should I monitor the patient with recurrent pancreatitis?

Proper history and physical examination

Baseline laboratory and imaging data

Avoidance of trigger factors

EUS for etiology evaluation and development of chronic pancreatitis

What's the evidence?

Raty, S, Pulkkinen, J, Nordback, I. ” Can Laparoscopic Cholecystectomy Prevent Recurrent Idiopathic Acute Pancreatitis?: A Prospective Randomized Multicenter Trial”. Ann Surg. vol. 262. 2015. pp. 736(A randomized prospective trial in Finland showing laparoscopic cholecystectomy can prevent the recurrence of acute pancreatitis after other causes are ruled out, suggesting microlithiasis not detected on imaging methods may play a major role in recurrent pancreatitis).

Tenner, S, Baillie, J, DeWitt, J. ” American College of Gastroenterology Guideline: management of acute pancreatitis”. Am J Gastroenterol. vol. 108. 2013. pp. 1400(Most recent guidelines from ACG.)

Bhardwaj, P, Garg, PK, Maulik, SK. “A randomized controlled trial of antioxidant supplementation for pain relief in patients with chronic pancreatitis”. . vol. 136. 2009. pp. 149-159. (There is good evidence for use of antioxidants for pain reduction in patients with chronic pancreatitis.)

Garg, PK, Tandon, PK, Madan, M. “Is biliary microlithiasis a significant cause of idiopathic recurrent acute pancreatitis? A long-term follow-up study”. Clin Gastroenterol Hepatol. vol. 5. 2007. pp. 75-9. (This study showed that microlithiasis may not be a common cause of recurrent pancreatitis and recurrent pancreatitis may lead to chronic pancreatitis.)

Lans, JI, Greenen, JE, Johanson, JF, Hogan, WJ. “Endoscopic therapy in patients with pancreas divisum and acute pancreatitis: a prospective, randomized, controlled clinical trial”. Gastrointest Endosc. vol. 38. 1992. pp. 430-4. (Small studies show efficacy of therapy for pancreas divisum, using either stenting versus minor papillotony.)

Gerke, H, Byrne, MF, Stiffler, HL. “Outcome of endoscopic minor papillotomy in patient with symptomatic pancreas divisum”. JOP. vol. 5. 2004. pp. 122-31. (Endoscopic therapy for pancreas divisum and sphincter of Oddi dysfunction should be done preferably in centers with expertise and preferably under research protocol.)

Garg, PK, Khajuria, R, Kabra, M, Shastri, S. “Association of SPINK1 gene mutation and CFTR gene polymorphism in patients with pancreas divisum presenting with idiopathic pancreatitis”. J. Clin Gastroenterol. vol. 43. 2009. pp. 848-52. (This study shows that genetic mutations might be responsible for recurrent pancreatitis rather than pancreas divisum being the sole cause.)

Muthusamy, VR, Chandrasekhara, V, Ruben, Acosta. “The role of endoscopy in the diagnosis and treatment of inflammatory pancreatic fluid collections”. Gastrointest Endosc. vol. 83. 2016 Mar. pp. 481-8. (ASGE guidelines for the management of pancreatic fluid collections. Balanced recommendations.)

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