Gastroenterology Hepatology

Chronic pancreatitis

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

There are a number of clinical presentations of chronic pancreatitis. The disease usually is initially considered based on imaging findings or on symptoms. Abdominal pain is usually the earliest, most frequent, and most characteristic symptom. In many patients, the pain is often episodic early in the disease and becomes more constant and continuous over time. Pain is usually epigastric and radiation to the back is characteristic but not always present. Anorexia, nausea, and vomiting frequently accompany the pain, especially when it is severe. About 10% to 15% of patients do not experience abdominal pain and may instead present with features of exocrine (diarrhea or steatorrhea) or endocrine (diabetes) insufficiency.

Exocrine insufficiency ultimately develops in about two-thirds of patients with chronic pancreatitis. These patients note greasy or loose stools, weight loss, and may develop vitamin, mineral, and trace element deficiency. These patients may not have diarrhea despite sometimes massive steatorrhea. Exocrine insufficiency occurs when there has been substantial loss (>90%) of pancreatic exocrine function, which most commonly occurs 10 to 20 years after the onset of disease.

Endocrine insufficiency with hyperglycemia and clinical features of polyuria and polydipsia also occurs only after there has been loss of most of the endocrine function of the pancreas. It typically also occurs after 10 to 20 years of chronic pancreatitis.

Some patients will be discovered incidentally, usually with evidence of chronic pancreatitis on an imaging study (e.g., CT scan) performed for some other reason. The pancreas can develop chronic damage from a variety of insults, including smoking, alcohol (even social alcohol use), in the process of normal aging, and in the setting of many other diseases such as diabetes mellitus or chronic renal failure. This damage may be apparent on an imaging study in the absence of any symptoms, but it may not be accurate to label all these patients as having chronic pancreatitis. For example, many people who undergo endoscopic ultrasound (EUS) may have an abnormal-appearing pancreas (based on a lifetime of accumulated damage from the environmental exposures noted) but be without symptoms, and it would be inappropriate to label these patients as having the disease state chronic pancreatitis.

In patients with longstanding chronic pancreatitis, it is usually easy to make an accurate diagnosis. These patients usually have longstanding symptoms and have imaging studies (e.g., CT scan) that show characteristic features of chronic pancreatitis. In other patients, it can be quite challenging to be sure that a patient has chronic pancreatitis. In the early stages of chronic pancreatitis, these characteristic imaging features may be absent and the patient may have a relatively normal-appearing pancreas. This type of patient is usually being evaluated for an abdominal pain syndrome, and it can be difficult to determine whether the pain is in fact due to chronic pancreatitis or to some other condition.

Chronic pancreatitis can be caused by a number of different conditions, including toxins, trauma, previous severe acute pancreatitis, metabolic abnormalities, and genetic mutations. The management of patients requires not only that the diagnosis is established but also that the etiology of disease is identified because these impact therapy.

A tabular or chart listing of features and signs and symptoms of chronic pancreatitis

The symptoms and clinical presentations of chronic pancreatitis are not specific. In particular, a number of other conditions can cause episodic or chronic abdominal pain. The causes of abdominal pain are diverse and include other pancreatic diseases, as well as a huge variety of nonpancreatic conditions.

Acute pancreatitis may be difficult to distinguish from chronic pancreatitis in some patients, particularly in those who are evolving from acute to chronic. Pancreatic malignancy, including ductal adenocarcinoma, as well as intraductal papillary mucinous neoplasms (IPMN) and others, can mimic the features of chronic pancreatitis or can complicate preexisting chronic pancreatitis.

Diseases of the biliary tree, liver, abdominal viscera, abdominal wall, and abdominal vasculature may produce similar symptoms as chronic pancreatitis. A variety of functional pain syndromes can also cause chronic abdominal pain. Accurate diagnosis rests on a careful history and physical examination, supplemented by laboratory tests and imaging of the pancreas.

Abdominal pain is the most common symptom of chronic pancreatitis. The abdominal pain has no pathognomonic features but is usually dull, boring, and associated with nausea and occasionally vomiting. The pain may be felt anywhere in the upper abdomen but characteristically in the epigastrium. The pain is made worse by eating or sometimes by laying supine. Pain may be episodic or chronic with exacerbations. At least 80% of patients experience abdominal pain, and pain is often present for years before exocrine or endocrine insufficiency develops.

Chronic abdominal pain is a very common symptom, and chronic pancreatitis is relatively rare. Patients with chronic abdominal pain in whom no obvious cause is discovered may be inaccurately labeled as having chronic pancreatitis. This diagnostic error is possible because early in the clinical course of chronic pancreatitis, there may not be any obvious abnormalities of the pancreas on imaging studies such as CT. Often, these patients who are inaccurately labeled as having chronic pancreatitis instead suffer from functional abdominal pain or pain associated with gastrointestinal motility disorders.

There are hundreds of causes of abdominal pain. Most of these causes may be diagnosed by a careful history and physical, complemented by imaging studies and basic laboratory studies. Chronic pancreatitis, in its advanced stages, is also relatively easy to diagnose. The diagnostic challenges in these patients come in two major areas: (1) distinguishing other pancreaticobiliary conditions (particularly malignancy) from chronic pancreatitis and (2) accurately diagnosing chronic pancreatitis in those with less advanced disease, who have chronic abdominal pain but no obvious changes on cross-sectional imaging. Table I focuses on these two groups.

Table I. Differentiating features of chronic pancreatitis and other similar diseases
Disease Features allowing differentiation from chronic pancreatitis Comments
Pancreatic cancer and IPMN Abdominal pain and substantial weight loss very common in those with malignancy. Less commonly present with exocrine insufficiency. Jaundice much more common than chronic pancreatitis. New onset diabetes relatively common in patients with pancreatic adenocarcinoma. Imaging studies may demonstrate mass lesions or pancreatic ductal dilation but usually not pancreatic calcifications. More likely to have elevations in CA 19-9. IPMN may have more diffuse and severe pancreatic duct dilation and at endoscopy may have a massively dilated pancreatic duct orifice filled with gelatinous mucin. Chronic pancreatitis is a risk factor for pancreatic cancer and the 2 conditions may coexist. It can be very difficult to identify the presence of malignancy in some patients due to overlap in clinical characteristics and imaging features. EUS usually helpful in identifying underlying malignancy.
Biliary tract disease, including sphincter of Oddi dysfunction Elevations in liver chemistries more common than in chronic pancreatitis. Pain more likely to be episodic and felt in RUQ. Imaging studies demonstrate normal-appearing pancreas and may identify abnormalities (e.g., dilatation) of biliary system. Chronic pancreatitis can cause distal biliary obstruction. Autoimmune pancreatitis can also cause more proximal biliary tract strictures.
Chronic intestinal obstruction and ischemia Pain usually only post-prandially and usually lasts for hours. Nausea and vomiting more prominent than chronic pancreatitis. Imaging studies during episode may show dilated small bowel. Imaging studies of abdominal vessels show disease in at least 2 of 3 major arterial systems (celiac, SMA, IMA). Both intestinal obstruction and infarction can cause elevations in amylase and lipase.
Gastrointestinal motility disorders: gastroparesis and others Pain usually more episodic than continuous. Nausea, vomiting, bloating, distension more common than in chronic pancreatitis. Imaging studies may note gastric distension or retained gastric contents. Abnormal motility study (e.g., gastric emptying study). Gastroparesis and intestinal dysmotility syndromes can cause mild elevations in amylase and lipase. Patients with chronic pancreatitis often have coexistent gastroparesis.
Functional abdominal pain syndromes Pain may be indistinguishable. Weight loss uncommon. Do not develop endocrine or exocrine insufficiency. Most common situation in which chronic pancreatitis is misdiagnosed.
Abdominal wall (somatic) pain Pain is sharper in character, associated with dysesthesias. Pain made worse by movement. Pain usually dermatonal in distribution. May be due to both abdominal wall conditions (e.g., radiculopathy) or disease affecting peritoneal surfaces (e.g., adhesions or endometriosis).
Small bowel bacterial overgrowth Diarrhea and bloating more common than in chronic pancreatitis, pain usually less pronounced. Patients with chronic pancreatitis can frequently develop concomitant small bowel bacterial overgrowth.

Determining the etiology of chronic pancreatitis

Establishing the diagnosis of chronic pancreatitis also requires that the presumed etiology be identified. Environmental toxins, in particular alcohol and tobacco, are most commonly to blame. The role of tobacco is increasingly recognized and in many recent series now surpasses alcohol as the most common explanation. The characteristic features and approaches to determining etiology are summarized in Table II.

Table II. Etiology of and diagnostic approaches for chronic pancreatitis
Etiology Characteristics or unique features Approach to diagnosis
Alcohol No true threshold, but most patients have a history of more than 5 years, averaging more than 5 drinks daily. Women may develop chronic pancreatitis at lower levels of alcohol ingestion. Usually have numerous admissions for acute episodes of pain and then may develop more chronic pain. Commonly develop exocrine and endocrine insufficiency. History of chronic and sustained alcohol use; may need to obtain this history from family or friends. Imaging evidence usually reveals far advanced structural injury (e.g., pancreatic calcifications).
Smoking Threshold unknown, but most patients may have exposures to both tobacco and alcohol, which act synergistically to produce chronic pancreatitis. Many of these patients who smoke but do not drink may be labeled as "idiopathic" chronic pancreatitis. History of chronic tobacco use in the absence of other known etiologies.
Autoimmune May present as typical chronic pancreatitis, or may mimic pancreatic adenocarcinoma with obstructive jaundice. Pancreas may appear diffusely enlarged with delayed rim enhancement on CT with IV contrast. Commonly have extrapancreatic involvement, including biliary strictures, parotid or lacrimal gland enlargement, mediastinal lymphadenopathy, pseudotumors, renal lesions, and retroperitoneal fibrosis. Characteristic histology including periductal lymphoplasmacytic infiltrate with obliterative phlebitis and storiform fibrosis. Usually with many (>10/HPF) IgG4-positive plasma cells on histology. Prompt response to steroids but may relapse. Elevations in serum levels of IgG4 seen in about half of patients. May have positive ANA or other autoimmune markers. Biopsies (not cytology) of pancreas, ampulla, or other involved organs may demonstrate large numbers of IgG4-positive plasma cells. Prompt response to steroid therapy diagnostic.
Recurrent and severe pancreatitis One severe episode of acute pancreatitis, usually with pancreatic necrosis, or multiple repeated episodes often evolve to chronic pancreatitis. Commonly seen due to hypertriglyceridemia but also after severe acute pancreatitis.
Genetic Certain mutations in the cationic trypsinogen gene (PRSS1 gene) are autosomal-dominant and persist in many generations as hereditary pancreatitis. Other mutations in either the cystic fibrosis gene (CFTR), trypsin inhibitor gene (SPINK1), or chymotrypsin-C gene are permissive – they predispose to chronic pancreatitis but are not generally sufficient alone to cause chronic pancreatitis. Typically considered when other etiologies are excluded. A strong family history suggests a PRSS1 mutation. Mutations in CFTR are typically milder than the ones that cause classic cystic fibrosis. Patients with chronic pancreatitis associated with CFTR mutations may have other features of cystic fibrosis, including congenital bilateral absence of the vas deferens. The combination of a SPINK1 mutation and CFTR mutations appear to act synergistically to cause chronic pancreatitis. Genetic testing, if done, requires complete analysis of CFTR variants and mutations, not just the screening tests for typical cystic fibrosis.
Obstructive Chronic obstruction of the pancreatic duct by malignant or benign processes will lead to atrophy and chronic pancreatitis in the pancreatic parenchyma upstream from the stenosis. Malignant causes include pancreatic and ampullary carcinoma and IPMN. Benign causes include traumatic ductal strictures, celiac disease, stenosis or dysfunction of the sphincter of Oddi, and pancreas divisum. Malignant causes of chronic pancreatitis should not be overlooked. A good-quality MRI with MRCP or/and EUS are usually sufficient to exclude malignancy. Benign causes are often assessed with an MRI and MRCP as well. Patients with pancreas divisum and either acute or chronic pancreatitis usually have an associated genetic mutation (SPINK1 or CFTR) as a co-factor.
Idiopathic Many patients labeled as idiopathic may have smoked or have a genetic mutation predisposing to chronic pancreatitis. In many recent studies, idiopathic is the most common reported type of chronic pancreatitis rather than alcohol-induced. Genetic testing often considered prior to labeling a patient with idiopathic pancreatitis.

How can I confirm the diagnosis?

The diagnosis can best be confirmed utilizing various imaging tests. As chronic pancreatitis progresses, there is accumulating damage to the pancreatic parenchyma and duct. When substantial, this damage can be visualized by both cross-sectional imaging studies (CT, MRI), as well as by endoscopic evaluation by EUS or ERCP (endoscopic retrograde cholangiopancreatography). In less severe disease, the diagnosis can be difficult to make as these patients may not have developed significant damage to the gland that can be seen with CT or MRI. These patients with less advanced disease are sometimes labeled as having small-duct disease, in that the pancreatic duct is not dilated and the typical cross-sectional imaging features of chronic pancreatitis have not developed. This is in contradistinction to big-duct chronic pancreatitis, in which the pancreatic duct is dilated and obvious changes of chronic pancreatitis are visible on CT or MRI.

In most situations, a good-quality multidetector CT with pancreas protocol or an MRI with MRCP is the first tests to order.

Findings on CT which are most consistent with chronic pancreatitis include:

1. Focal or diffuse dilation of the pancreatic duct (>5mm, 4 mm, and 3mm in the head, body, and tail, respectively)

2. Pancreatic calcifications in the duct or parenchyma

3. Focal or diffuse atrophy of the gland

As an alternative, abdominal MRI with MRCP (magnetic resonance cholangiopancreatography) is comparable and perhaps superior to CT as the initial diagnostic test. MRI will demonstrate the same features as CT and MRCP provides better and more detailed imaging of the pancreatic duct. While ultrasound imaging may allow reasonable imaging of the pancreas, the ability to image the pancreas by ultrasound is more limited.

Diagnostic tests are usually divided into those that identify an abnormality of the structure of the pancreas (e.g., CT scans or ERCP) and those that identify an abnormality of function or secretory capacity of the pancreas (e.g., a fecal elastase test). Each of these tests can be useful, but no one test is able to accurately diagnose chronic pancreatitis at all stages of disease, and they vary in cost, risk, and availability.

In the early stages of chronic pancreatitis, there may not be sufficient accumulated structural damage to be easily visible on commonly used tests such as CT or MRI. These patients may have episodic or chronic pain, may have had episodes of more severe pain requiring hospitalization, and yet not have obvious findings on CT, such as a dilated pancreatic duct or pancreatic calcifications. In this group with early chronic pancreatitis (often called minimal change or small duct chronic pancreatitis), the diagnosis can be quite challenging. In more advanced disease, these structural changes have developed and diagnosis is relatively straightforward.

As imaging studies such as CT and MRI are widely available and reasonably safe, these are the initial tests to order. MRI will avoid undue radiation exposure, but, unfortunately, MRI may miss calcifications. Characteristic features on CT and MRI are noted in Table III. If these tests are indeterminate or negative, the next step usually is EUS.

Table III. Diagnostic tests for chronic pancreatitis
Diagnostic test Diagnostic features or criteria Comments
Abdominal ultrasound Pancreatic duct: dilation, irregularity, calcified ductal stones, increased echogenicity of ductal wall.Pancreatic parenchyma: focal or diffuse atrophy, cavities, parenchymal calcifications. Images often inadequate due to overlying intestinal gas. Sensitivity of approximately 50%. Changes detected on ultrasound often take years to develop.
CT scan Pancreatic duct: dilation, irregularity of main pancreatic duct or ductal side branches, calcified ductal stones, ductal stricture.Pancreatic parenchyma: focal or diffuse atrophy, cavities, parenchymal calcifications. Sensitivity of approximately 75-80%.
MRI with MRCP Pancreatic duct: dilation, irregularity of main pancreatic duct or ductal side branches, calcified ductal stones, ductal strictures.Pancreatic parenchyma: focal or diffuse atrophy, cavities, parenchymal calcifications. In some centers, secretin is administered at time of MRCP, which improves quality of imaging of pancreatic duct compared to standard MRI. Images of ductal anatomy with MRCP surpass images obtained with CT or US. Sensitivity of approximately 80%.
EUS Pancreatic duct: dilation, irregularity, hyperechoic ductal wall, visible side branches, ductal calcification.Pancreatic parenchyma: hyperechoic foci, hyperechoic strands, lobularity of contour, cysts, or cavities. Each of these 9 features is given 1 point if present and added. A total score of 0-2 is considered normal, a score of 5-9 is diagnostic of chronic pancreatitis, a score of 3 or 4 is considered indeterminate. A new scoring system called the Rosemont criteria has been proposed but is not in routine use.
ERCP Pancreatic duct: dilation of duct, irregularity, abnormalities of side duct branches (dilation, shortening, irregularity), ductal strictures, ductal stones or filling defects, cavities. ERCP images only the duct and not the parenchyma. In advanced disease, the duct is often dilated with multiple strictures (a chain of lakes appearance). ERCP is never needed for diagnosis but may be considered for therapy.
Pancreatic function testing The pancreas is stimulated with an injection of the hormone secretin, and pancreatic secretins are collected for an hour using either a tube (Dreiling tube) or an endoscope (endoscopic pancreatic function tests). The bicarbonate concentration of the fluid is measured every 15 minutes. The maximum value obtained (peak bicarbonate) should be >80 mEq/L. The most sensitive test for chronic pancreatitis in earlier stages (before the disease is easily detected by imaging tests such as CT) but not widely available.
Serum trypsin A blood test, which becomes abnormal in advanced and longstanding chronic pancreatitis. A value <20 ng/mL is abnormal. Abnormal only in far-advanced chronic pancreatitis.
Fecal elastase Less than 200 mcg/gm stool is abnormal. Abnormal only in far-advanced chronic pancreatitis with coexistent exocrine insufficiency.

EUS allows for a detailed image of the pancreatic parenchyma and duct. There are different systems used to classify the findings on EUS, based on specific ultrasonographic criteria. EUS is not perfect and many conditions that are not chronic pancreatitis can cause the same abnormalities in the pancreas that EUS can detect in patients with chronic pancreatitis. As such, the results of EUS are often reported as normal, consistent with chronic pancreatitis, suggestive of chronic pancreatitis, or indeterminate. The EUS criteria of chronic pancreatitis are noted in Table III.

If the EUS is indeterminate or inconclusive, two options remain. One option is to perform a pancreatic function test. This can be performed utilizing a duodenal tube collection system or an endoscopic-based approach, but both require the administration of a pancreatic secretagogue (secretin) and the collection of pancreatic secretions over the hour after administration of the secretin. These pancreatic function tests are best able to identify chronic pancreatitis in the earlier stages, when other tests are negative or inconclusive. Unfortunately, they are performed only at a small number of academic centers. The other option for diagnosis is observation because those patients with chronic pancreatitis will usually continue to evolve and, eventually, imaging studies will become abnormal enough to reach a diagnosis.

An approach to diagnosis includes the following steps:

1. Consider the disease in the appropriate patients: those with a pain syndrome consistent with chronic pancreatitis, with multiple episodes of acute pancreatitis, with risk factors for pancreatitis, or in patients with unexplained diarrhea or steatorrhea.

2. As an initial step, CT with pancreas protocol or MRI with MRCP is preferred.

3. If the diagnosis is still in doubt, proceed with EUS.

4. If the diagnosis is still in doubt, perform or refer for a pancreatic function test.

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

In most developed countries, the two major causes of chronic pancreatitis are alcohol and tobacco. These two toxins can cause chronic pancreatitis independently but act synergistically to cause chronic pancreatitis. Abstinence from alcohol and from tobacco slows the progression of chronic pancreatitis. Evidence demonstrates that an active approach to support abstinence is superior to the usual periodic advice given to patients in clinic. Referral to a program to support abstinence is recommended. Patients who continue to drink and/or smoke not only have more rapid progression of chronic pancreatitis but have increased mortality from the variety of diseases caused by these two toxins (e.g., malignancy, heart and lung disease, etc.).

Specific etiologies may have specific associated conditions. Autoimmune pancreatitis is often part of a systemic illness characterized by elevations in serum levels of IgG4 and by infiltration of a number of organs by inflammatory cells, including lymphocytes and plasma cells. These patients may have symptoms referable to the salivary glands, pseudotumors in various organs, tubulointerstitial nephritis, biliary strictures, retroperitoneal fibrosis, and others. These features may be helpful in suspecting this condition.

Chronic pancreatitis is a risk factor for pancreatic adenocarcinoma, and the two conditions may coexist. Some forms of chronic pancreatitis are more prone to malignancy than others. Genetic forms of pancreatitis due to mutations in the PRSS1 gene (hereditary pancreatitis) are at particular risk, with a lifetime risk of cancer ranging from 30% to 70%, depending on the pattern of inheritance and family history. Pancreatic cancer may also produce clinical symptoms and imaging features that are similar to chronic pancreatitis and the initial diagnostic approach emphasizing high-quality imaging studies is appropriate to help rule out the presence of pancreatic adenocarcinoma. IPMN, a malignant or pre-malignant condition of the pancreatic duct may produce ductal dilation, pancreatic gland atrophy, and exocrine insufficiency and can be mistaken for chronic pancreatitis. Differentiation can often be made with EUS although occasionally ERCP is needed.

As chronic pancreatitis progresses, patients may develop exocrine and/or endocrine insufficiency. Exocrine insufficiency usually occurs after more than 5 years of chronic pancreatitis. Patients may not report diarrhea but usually note oily or greasy stools. Steatorrhea can be substantial. Weight loss is not common as most patients increase intake. These patients may develop fat-soluble vitamin deficiency (especially vitamin D) and are at high risk of osteopenia and osteoporosis. The presence of steatorrhea and exocrine insufficiency may be difficult to diagnose. Typically, the presence of excess fat on a qualitative stool stain (Sudan stain), coupled with the appropriate history and an abnormally low fecal elastase (<200 mcg/gm stool) or serum trypsin (<20 ng/mL) is sufficient evidence to support initiating pancreatic enzyme replacement therapy for exocrine insufficiency.

Endocrine insufficiency also usually occurs after more than 5 years and often more than 10 years of chronic pancreatitis. Unlike patients with type I diabetes, the secretion of both insulin and glucagon are lost due to destruction of the entire islet. These patients are at increased risk of treatment-induced hypoglycemia. The diagnosis is established in the usual manner, with a fasting plasma glucose above 126 mg/dL or a HgbA1c above 6.5%. These can be periodically measured in patients with longstanding chronic pancreatitis.

A number of other complications may occur, including pancreatic pseudocysts, biliary obstruction, gastrointestinal bleeding, and duodenal obstruction. Pseudocysts occur in about one-quarter of patients with chronic pancreatitis. They may have an appearance similar to a cystic neoplasm, and the two types of cystic lesions must not be mistaken. Typically, those with a cystic neoplasm will not have a history of pancreatitis, are often middle-aged or elderly, and are often only minimally symptomatic.

Cystic neoplasms often have a thick wall and have internal nodules or septations. Cystic neoplasms can usually be differentiated from pseudocyst by EUS with FNA (fine needle aspiration) as well. Cystic neoplasms may demonstrate high levels in the cyst fluid of CEA (carcinoembryonic antigen), low levels of amylase, and cytology demonstrating mucin or atypical cells. The therapy of a cystic neoplasm is resection, not drainage.

Pseudocysts do not need therapy if they are not symptomatic, but if they are symptomatic or enlarging, they can be treated with drainage via surgical, endoscopic, or radiologic methods, depending on local expertise. The other complications are discussed in Table IV.

Table IV. Other complications associated with chronic pancreatitis
Complication Relative frequency or risk Clinical considerations
Exocrine insufficiency Typically occurs after 5-10 years of disease but may occur earlier in conditions that cause obstruction of the pancreatic duct. Ultimately, approximately 70% of patients will develop exocrine insufficiency after 10 or more years of disease. Diarrhea may not be present despite massive steatorrhea.Fat-soluble vitamin deficiency is common, especially vitamin D.
Endocrine insufficiency Typically occurs after 5-10 years of disease. Ultimately, approximately 50-60% of patients will develop endocrine insufficiency after 10 or more years of disease. Patients may develop type II diabetes earlier (as a consequence of obesity and metabolic syndrome, not chronic pancreatitis). These patients can be at high risk of treatment-induced hypoglycemia, which can be fatal.Pancreatic cancer may mimic the imaging features of chronic pancreatitis and also cause new-onset diabetes.
Secondary pancreatic carcinoma The overall lifetime risk in patients with chronic pancreatitis is 3-4%.In patients with hereditary pancreatitis, the risk is quite substantial and may approach a lifetime risk of 70% in those with a paternal inheritance pattern. Can be difficult to identify pancreatic cancer in the midst of a diseased pancreas. Serum CA 19-9 can be helpful but can be falsely elevated in patients with biliary obstruction and patients with pancreatitis. EUS is usually the most accurate way to identify mass lesions and sample them with FNA cytology. Surveillance programs (e.g., yearly CA 19-9 and EUS) are ineffective, except perhaps in those with hereditary pancreatitis. Prophylactic total pancreatectomy can be considered in some patients with hereditary pancreatitis.
Pancreatic pseudocysts These occur in around 25% of patients with chronic pancreatitis. Pseudocysts and cystic neoplasms of the pancreas have similar appearances but can be differentiated by historical features of the patient, usually complemented by EUS with FNA of the fluid.Pseudocysts may cause pain, obstruct a surrounding organ (stomach, duodenum, colon, or bile duct), become infected, or bleed. Symptomatic or complicated pseudocysts require therapy, which can include endoscopic, radiologic, or surgical drainage, depending on local expertise and location of pseudocyst.
Gastrointestinal bleeding Chronic pancreatitis may cause bleeding by producing thrombosis of the splenic vein or by causing a pseudoaneurysm to develop within a preexisting pseudocyst. These are rare occurrences in patients with chronic pancreatitis. Splenic vein thrombosis produces a segmental portal hypertension that causes gastric varices in the absence of esophageal varices. Bleeding is rare despite these varices and only occurs in about 4% of those patients who develop splenic vein thrombosis. Splenectomy is curative.Pseudoaneurysms of visceral arteries can occur in those with preexisting pseudocysts. Bleeding can be massive. The diagnosis is usually obvious on a CT with IV contrast. Angiographic embolization of the pseudoaneurysm is the preferred approach.
Biliary obstruction Occurs in about 10% of patients, from fibrous compression of the distal bile duct by the chronic pancreatitis. Patients usually develop jaundice but abnormal liver chemistries and jaundice may also occur from coexistent liver disease (e.g., alcoholic hepatitis). The bile duct stricture develops in the distal bile duct as it passes through the head of the pancreas. Additionally, more proximal bile duct strictures may be seen in patients with autoimmune pancreatitis. Surgical biliary bypass is the most durable therapy but long-term (12 months) placement of multiple plastic biliary stents or large-caliber, fully covered metal biliary stents at ERCP can resolve some distal biliary strictures due to chronic pancreatitis.
Duodenal obstruction Occurs in about 5% of patients. Usually occurs in those with large inflammatory mass of the head of the pancreas and often have coexistent biliary obstruction and relatively high-grade pancreatic duct obstruction. This same pattern can be seen in those with pancreatic adenocarcinoma of the head of the pancreas. Surgical therapy is generally required, often with resection of the pancreatic head.

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

Treatment of pain

Pain is the most common and most significant clinical problem in patients with chronic pancreatitis. Treatment is challenging, and many patients continue to have pain despite all efforts at treatment. (Table V lists pain therapies for patients with chronic pancreatitis.) Medical therapy is usually undertaken first and consists of active efforts to support abstinence from alcohol and tobacco, if applicable. Pain medications are often needed, and it is best to begin with a lower potency agent such as tramadol. More potent narcotics may be needed and there is a risk of addiction of around 10%. Evidence supports additional use of a gabapentoid (e.g., gabapentin or pregabalin) in those taking narcotics. The use of a selective serotonin reuptake inhibitor (SSRI) or tricyclic antidepressant (TCA) is a reasonable alternative to a gabapentoid. Some data demonstrate that antioxidants may be helpful in reducing pain and may be considered. Medical therapy alone is sufficient in less than half of patients. In those that remain symptomatic after medical therapy, endoscopic and surgical options can be considered.

Table V. Efficacy of various therapies for pain in chronic pancreatitis
Therapy for pain Patient selection Efficacy Comments
Abstinence Appropriate in all patients who drink or smoke. Stopping alcohol intake and/or tobacco use slows the progression of chronic pancreatitis. Stopping alcohol and tobacco use reduces the risk of cardiovascular disease and malignancy and prolongs life. Active and repeated interventions, including referral to abstinence support groups, are necessary.
Analgesics Appropriate in all patients with pain. Most patients require analgesics. The use of a lower-potency agent (tramadol) is equivalent to more potent narcotics and should be used as the initial agent, at a dose of up to 400 mg daily. More potent narcotics may be needed. Patients should maintain a pain diary so that the effect of analgesics can be assessed. The risk of addiction or dependency varies but is highest in those with a history of addictive behavior (including alcohol and tobacco). Referral to a pain clinic can be considered.
Adjunctive agents Appropriate in all patients who require narcotics for pain control. The gabapentoids (pregabalin or gabapentin) are useful adjuncts to narcotics. Other adjunctive agents such as selective serotonin reuptake inhibitors and tricyclic antidepressants may be effective. Adjunctive agents may allow the narcotic dose to be minimized.
Antioxidants Can be considered in patients with pain. A variety of mixtures of antioxidants, including vitamin E, vitamin C, β-carotene, selenium, and methionine, have been used. Modest efficacy in some studies. The most effective dose and mixture is not known. Some studies have documented some long-term risk of cardiovascular disease in patients on chronic antioxidants.
Pancreatic enzymes Can be considered in all patients with pain. Randomized trials of pancreatic enzymes for pain show mixed results. A meta-analysis of these trials did not show benefit for treating pain. Patients with exocrine insufficiency require pancreatic enzyme replacement therapy.
Endoscopic therapy Usually considered in those with persistent pain despite medical therapy and with a dilated pancreatic duct. Patients with an obstructing stone or stricture, usually in the head of the pancreas, with upstream dilation of the pancreatic duct are most amenable to endoscopic therapy. Endoscopic therapy can consist of pancreatic sphincterotomy, dilation of a pancreatic duct stricture, removal of pancreatic stones, and placement of a pancreatic duct stent. Pain relief is generally seen in 50-75% of carefully selected patients. A high degree of technical skill is required to perform these procedures. Advanced techniques including pancreatoscopy and lithotripsy may be required.
Surgical therapy Usually considered in those with persistent pain despite medical therapy and with a dilated pancreatic duct. A variety of surgical procedures are available, ranging from simple drainage operations (Puestow operation) to pancreatic resections (Whipple operation or distal pancreatectomy) to operations involving both resection and drainage (Beger, Frey, or Berne operation). A few small randomized trials have demonstrated that surgical therapy is more effective and more durable than endoscopic therapy. Total pancreatectomy with auto-islet cell transplantation is a last option but does not invariably relieve pain. Although most hospitals have surgeons adept at Puestow operations, performance of a Whipple operation or Beger, Frey, or Berne procedure require high levels of surgical, technical expertise.
Neurolysis Rarely considered in patients with chronic pancreatitis. Performance of a celiac plexus block or neurolysis, by CT or EUS guidance, has a very transitory effect and is rarely indicated in patients with chronic pancreatitis. Thoracoscopic splanchnicectomy also is rarely used and generally ineffective.  

Endoscopic options for pain include dilation and stenting of pancreatic duct strictures, removal of obstructing pancreatic duct stones, and celiac plexus block or neurolysis. Endoscopic therapy is usually considered in patients with a dilated pancreatic duct and a ductal obstruction caused by a stricture or stone. It is important in these patients to make sure that the stricture is not malignant. Strictures or stones in the head of the pancreas with upstream dilation are most amenable to endoscopic therapy at ERCP. These endoscopic therapies require highly advanced technical skills and may require lithotripsy of stones. In those undergoing endoscopic therapy, pain relief is seen in about half. EUS-guided celiac plexus block is rarely used in patients with chronic pancreatitis, as the duration of pain relief is short.

Surgical therapy is usually considered when medical therapy is insufficient. In most surgical procedures, a dilated pancreatic duct is a necessary prerequisite. The simplest operation involves incising the pancreas and pancreatic duct longitudinally, removing any ductal stones and incising any strictures, and overlaying this with a Roux limb. This operation, the lateral pancreaticojejunostomy, is called a Puestow operation. It leads to immediate pain relief in around 75% of patients, but this drops to less than 50% after 5 years of follow-up.

There are a number of other operations that can be performed that involve resection of part of the pancreas (usually the head) along with drainage of the pancreatic duct. These operations may be considered in patients with enlargement of the pancreatic head as well as a dilated pancreatic duct. These patients may have coexistent bile duct or duodenal obstruction from the enlarged pancreatic head. A number of different operations may be used. The traditional pancreaticoduodenectomy (Whipple operation), as well as variants that do not remove the duodenum (known as the Frey or Beger or Berne operations), are performed, and the choice depends on local surgical expertise. These operations involving resection of a portion of the pancreas have similar rates of immediate pain relief but better long-term pain relief, as the Puestow operation, although at the expense of increased surgical complications. Two very small randomized trials comparing endoscopic to surgical therapy for chronic pancreatitis have demonstrated that surgical therapy is more effective and more durable, although many patients still prefer a trial of endoscopic therapy before considering surgery.

Treatment of exocrine insufficiency

Treatment consists of exogenous pancreatic enzyme replacement therapy, coupled with nutritional advice and supplementation. (See Table VI, which lists enzyme treatment for exocrine insufficiency.) Although the lack of pancreatic enzymes in patients with chronic pancreatitis affects fat, protein, and carbohydrate digestion, fat maldigestion is the most significant. Pancreatic enzyme therapy requires delivering the right amount of enzyme at the proper time in the meal. Around 90,000 USP units of lipase are needed with each meal to assure normal digestion and absorption of fat and fat soluble vitamins. In many patients, the pancreas may still produce some enzymes, so less than the full 90,000 units may be sufficient. Enzymes are available in various strengths, measured in the number of USP units per pill. All currently available enzymes are enteric coated to release enzymes once they have passed the acidic environment of the stomach. Enzymes should be administered during and immediately after the meal for maximum effectiveness. Fat soluble vitamin and B12 deficiencies may develop and require supplementation, particularly vitamin D. Dietary changes (avoiding fat) are not required. The efficacy of therapy can be measured by weight gain and reduction in noticeable fat in stool. Formal 72-hour collections to measure fat absorption are rarely necessary.

Table VI. Enzyme treatment for exocrine insufficiency
Medication Dosages available (USP units of lipase/capsule) Comments
Zenpep® Enteric-coated10,00015,00020,000 Up to 90,000 USP units of lipase/meal is appropriate to treat exocrine insufficiency and steatorrhea. The pills should be administered half during the meal and half at the completion of the meal.
Creon® Enteric-coated6,00012,00024,000 Up to 90,000 USP units of lipase/meal is appropriate to treat exocrine insufficiency and steatorrhea. The pills should be administered half during the meal and half at the completion of the meal.
Pancreaze® Enteric-coated4,20010,00016,800021,000 Up to 90,000 USP units of lipase/meal is appropriate to treat exocrine insufficiency and steatorrhea. The pills should be administered half during the meal and half at the completion of the meal.
Ultresa® Enteric-coated13,80020,70023,000 Up to 90,000 USP units of lipase/meal is appropriate to treat exocrine insufficiency and steatorrhea. The pills should be administered half during the meal and half at the completion of the meal.
Viokace® Not enteric-coated10,44020,880 Up to 90,000 USP units of lipase/meal is appropriate to treat exocrine insufficiency and steatorrhea. The pills should be administered half during the meal and half at the completion of the meal. Non-enteric coated enzymes are susceptible to acid degradation so must be co-treated with agents to reduce gastric acid.

Treatment of endocrine insufficiency

Treatment may include both oral agents and insulin. In advanced chronic pancreatitis, insulin is often required as these patients have a deficiency of insulin, not insulin resistance. These patients are at high risk of treatment-induced hypoglycemia and may have brittle diabetes. Care should be taken to avoid hypoglycemia as these patients lack a glucagon surge to correct hypoglycemia. Referral to a specialist in diabetes care is often appropriate.

Treatment or prevention of complications of chronic pancreatitis

Pancreatic pseudocyst. Pseudocysts that develop in patients with chronic pancreatitis are generally mature, with a well-formed capsule at the time they are discovered. This can be confirmed by cross-sectional imaging utilizing CT or MR. MR is particularly helpful also at characterizing the contents of the cavity (liquid and solid components), which may have an impact on the choice of therapy. It is of paramount importance that a cystic neoplasm not be confused with a pseudocyst. Cystic neoplasms should be suspected when a cystic lesion is seen in a middle-aged or elderly individual with no previous history of pancreatitis. Pseudocysts are generally fluid-filled. The finding of a significant amount of solid material in the cyst usually means that this is an area of walled-off pancreatic necrosis, rather than a simple pseudocyst.

Pseudocysts often do not require treatment. Treatment is indicated for pseudocysts that are symptomatic (usually causing pain), are blocking an adjacent hollow organ (bile duct or duodenum), are infected, or are bleeding. Infected pseudocysts usually present with abdominal pain, fever, and leukocytosis. Bleeding may occur into the pseudocyst cavity and may ultimately reach the GI tract through the ampulla. Bleeding is discussed in a subsequent section.

Symptomatic or infected pseudocysts can be treated with surgical, endoscopic, or radiologic techniques. Surgery involves creating an anastomosis between the wall of the pseudocyst and an adjacent loop of small bowel or the stomach. Endoscopic treatment involves placement of transgastric or transduodenal stents, usually after EUS-guided puncture. Stents are left in place until the cyst is decompressed. Placement of a pancreatic duct stent via ERCP may also be used, either alone or in conjunction with the transluminal stent. Radiologic techniques involve percutaneous placement of a drain into the cavity. In most hospitals, endoscopic drainage is preferred but surgery is a reasonable treatment option as well.

Gastrointestinal bleeding. Bleeding may occur due to several different mechanisms. It may occur from routine causes not related to chronic pancreatitis. These causes might include peptic ulcer disease or erosive esophagitis. In addition, several specific types of bleeding need to be considered in patients with chronic pancreatitis. Many patients with chronic pancreatitis will develop splenic vein thrombosis due to inflammation of the splenic vein as it passes next to the pancreas. Splenic vein thrombosis causes varices to form in the gastric fundus, usually without coexistent esophageal varices. These gastric varices bleed rarely, in less than 10% of patients. No therapy is needed unless bleeding develops. In the acute bleed, therapy can include intravenous octreotide and, in some centers, endoscopic sclerotherapy of the varices using cyanoacrylate glue. This procedure of glue injection is not available at many hospitals. Splenectomy is curative and should be performed in any patient who has bled from gastric varices due to splenic vein thrombosis. Bleeding may also occur in association with a pseudocyst.

Some pseudocysts located adjacent to a major visceral artery will erode the artery, causing it to rupture into the pseudocyst cavity. This is called a pseudoaneurysm. These patients usually develop abdominal pain and melena. Blood can reach the intestine through the pancreatic duct, which communicates with the pseudocyst in many patients. Patients may initially develop a self-limited bleed, followed by a large volume and life-threatening hemorrhage. The diagnosis is usually made by CT scan with IV contrast, where IV contrast can be seen to be pooling in a pseudoaneurysm. Embolization of the pseudoaneurysm is the most effective therapy.

Nutritional complications. Patients with chronic pancreatitis and exocrine insufficiency may rarely develop protein-calorie malnutrition, usually in the setting of chronic alcoholism and limited intake coupled with severe exocrine insufficiency. More commonly, patients with exocrine insufficiency will develop deficiencies of vitamins and trace elements. Fat-soluble vitamins and B12 deficiencies are seen most commonly. Vitamin D in particular is of importance. Patients with chronic pancreatitis frequently suffer from osteopenia and osteoporosis, and fractures are as common in patients with chronic pancreatitis as in other gastrointestinal diseases with high rates of osteoporosis (inflammatory bowel diseases). Routine supplementation of vitamin D and calcium, along with other fat-soluble vitamins and trace elements, is appropriate.

Duodenal and biliary obstruction. Duodenal obstruction is rather uncommon, usually occurring in conjunction with biliary obstruction in patients with large inflammatory mass in the head of the pancreas. In these patients, the presentation is quite similar to pancreatic cancer and it may be difficult to differentiate the two. In most centers, these patients are evaluated in conjunction with a pancreatic surgeon and usually undergo extensive testing with EUS and CT and tumor markers. Duodenal obstruction, with or without biliary obstruction, usually requires surgical therapy with either a traditional Whipple operation or one of the other operations (Frey or Beger), which also achieves some resection of the head of the pancreas and decompression of the duodenal and bile duct obstruction.

Isolated bile duct obstruction is more common than duodenal obstruction, and presents as cholestasis or jaundice. Remember that cholestasis or jaundice can also occur from intrinsic liver disease, such as alcoholic hepatitis. In some patients, the biliary obstruction is due to edema from an acute attack of pancreatitis superimposed on chronic pancreatitis. In these patients, the biliary obstruction may resolve as the acute pancreatitis resolves. In most cases, however, the obstruction is more prolonged and more specific therapy is required.

Temporary biliary stenting with a plastic stent is appropriate as the first-line of therapy. It is also appropriate to perform either biliary cytologic brushings at the time of the index ERCP, or perform EUS with FNA, to determine if the biliary obstruction is due to a secondary carcinoma of the pancreas developing in the setting of chronic pancreatitis. If after a period of temporary stenting (6-8 weeks) the distal bile duct stenosis persists, treatment with either multiple plastic stents (usually 4-6), a fully covered removable metal stent, or surgical biliary bypass is appropriate. If endoscopic therapy is performed, it is usually continued for 6 to 12 months.

What is the most effective initial therapy?

Pain. Prior to initiating therapy for pain, it is critical to make sure that the diagnosis is correct. Second, it is essential to look for secondary complications of chronic pancreatitis that could cause pain and that have specific therapy. (See Figure 1.) These complications include a secondary pancreatic cancer complicating chronic pancreatitis, a pancreatic pseudocyst, duodenal obstruction, bile duct obstruction, and gastroparesis.

A good-quality CT or MRI is usually appropriate, both to the confirm the diagnosis and to assess for these types of complications. In those with coexistent features of gastroparesis (bloating or early satiety), a gastric emptying study can also be considered. This CT will also be able to determine if the patient has an enlarged pancreatic duct (big duct disease) or not (small duct disease). This distinction between big duct and small duct disease is very helpful in choosing therapy for pain.

All patients deserve attempts at encouraging abstinence and most require analgesics and adjunctive agents (e.g., pregabalin). It is also useful to have the patient keep a pain diary so that the effect of therapy can be more easily quantified.

In those with small duct disease, there are no endoscopic or surgical options and so therapy is medical. In those with small duct disease who do not respond to basic therapy as outlined, a trial of antioxidants could be considered. In a very select group of patients with small duct disease and intractable pain, total pancreatectomy with auto islet cell transplantation may be considered, although this does not invariably relieve pain. In those with big duct disease, referral to a center with expertise in endoscopic and surgical therapy of chronic pancreatitis is appropriate. The choice of endoscopic or surgical therapy depends on the ductal anatomy and on the available expertise, although accumulating evidence suggests that surgical therapy is more durable and more effective than endoscopic therapy.

Exocrine insufficiency. It can be difficult to determine if a patient has developed exocrine insufficiency. Exocrine insufficiency should be suspected in those with visible fat in stool, with weight loss or vitamin deficiency, in those with evidence of advanced chronic pancreatitis on imaging studies (pancreatic calcifications or a dilated pancreatic duct), or in those with a history of previous pancreatic surgery. Useful laboratory tests to confirm exocrine insufficiency include tests for serum trypsin (<20 ng/mL) or fecal elastase (< 200 mcg/gm stool). Treatment should be initiated with 75,000-90,000 USP units of lipase per meal, giving half the pills during the meal and half at the end. In some patients who do not show substantial improvement in fat absorption, the dose can be increased or an agent to suppress gastric acid (a proton pump inhibitor or H2-receptor antagonist) can be added, which improves fat digestion and absorption. Patients should be supplemented with good-quality multivitamins and receive vitamin D and calcium as well.

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

N/A

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

N/A

Listing of these, including any guidelines for monitoring side effects.

See again Figure 1, which lists initial and continued medical procedures for treating pain.

How should I monitor the patient with chronic pancreatitis?

Patients with chronic pancreatitis are at risk for a number of complications during the course of the disease. The disease tends to be progressive and, over time, patients will develop more substantial evidence of chronic pancreatitis on imaging studies (e.g., pancreatic calcifications) and more advanced functional derangements, such as exocrine and endocrine insufficiency. Pain may continue to worsen; however, in many patients, pain may stabilize or even improve.

It is appropriate to monitor pain over time, and a pain diary is helpful in this regard. If pain suddenly becomes worse during follow up, suspect a complication such as a pancreatic pseudocyst or the development of a secondary pancreatic carcinoma.

Exocrine insufficiency may worsen over time, so one should be alert to ask the patient about worsening steatorrhea or weight loss. Periodic monitoring of fecal elastase (yearly) can help identify patients who are developing exocrine insufficiency and who will need enzyme therapy. Those with exocrine insufficiency are at high risk of osteoporosis, so routine supplementation with vitamin D and calcium is appropriate, as is routine monitoring of bone density. Diabetes and endocrine insufficiency may also develop with time and can be detected by periodic monitoring of hemoglobin A1C (yearly).

Although the structural damage to the pancreas may progress over time, periodic imaging studies (e.g., CT or MRI) of the pancreas are not needed in the absence of any changes in symptoms.

What's the evidence?

Yadav, D, Timmons, L, Benson, JT. "Incidence, prevalence, and survival of chronic pancreatitis: a population based study". Am J Gastroenterol. 2011.

Chari, ST, Kloeppel, G, Zhang, L. "Histopathologic and clinical subtypes of autoimmune pancreatitis. The Honolulu consensus document". Pancreatology. vol. 10. 2010. pp. 664-72.

Cui, Y, Andersen, DK. "Pancreatogenic diabetes: special considerations for management". Pancreatology. vol. 11. 2011. pp. 279-94.

Raimondi, S, Lowenfels, AB, Morselli-Labate, AM. "Pancreatic cancer in chronic pancreatitis: aetiology, incidence, and early detection". Best Pract Res Clin Gastroenterol. vol. 24. 2010. pp. 349-58.

Dominguez-Munoz, JE. "Pancreatic exocrine insufficiency: diagnosis and treatment". J Gastroenterol Hepatol. vol. 26. 2011. pp. 12-12.

Braganza, JM, Lee, SH, McCloy, RF, McMahon, MJ. "Chronic pancreatitis". Lancet. vol. 377. 2011. pp. 1184-97.

LaRusch, J, Whitcomb, DC. "Genetics of pancreatitis". Curr Opin Gastroenterol. vol. 27. 2011. pp. 467-74.

Chauhan, S, Forsmark, CE. "Pain management in chronic pancreatitis: a treatment algorithm". Best Pract Res Clin Gastroenterol. vol. 24. 2010. pp. 323-35.

Lieb, JG, Forsmark, CE. "Review article: pain and chronic pancreatitis". Aliment Pharmacol Ther. vol. 29. 2009. pp. 706-19.

**The original author for this chapter was Chris Forsmark. The chapter was revised by Dr.Bruce R. Bacon.

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