Essentials

Patients with chronic pancreatitis usually come to medical attention with abdominal pain or maldigestion (diarrhoea, steatorrhoea, weight loss), but the frequency of chronic pancreatitis is underestimated because of inadequate investigation of these symptoms. The realization that impaired pancreatic exocrine function can occur without obvious dilatation of the main duct, i.e. ‘small-duct disease’, has greatly influenced management. Symptomatic variability and the many causes of this disease have made its classification difficult.

Three forms of chronic pancreatitis are now recognized: (1) chronic calcifying, (2) chronic obstructive, and (3) chronic inflammatory. Alcohol abuse and/or malnutrition are the most common causes of the calcifying type. Obstruction of the main pancreatic duct with secondary fibrosis in that part of the pancreas proximal to the obstruction leads to the obstructive type. Chronic inflammatory pancreatitis is not well characterized, and many patients with chronic pancreatitis of unknown cause fall into this group. Irreversible changes often occur in the gland, making a cure improbable. Nevertheless, the chief complaints of pain and/or maldigestion can be effectively treated.

Inflammation and sclerosis with progressive damage to the acini and ducts are the histological hallmarks of chronic pancreatitis. In advanced stages the gland may be fibrotic and calcified and the main duct may be dilated. Islet cells are usually lost more slowly than the exocrine part, hence diabetes is a late feature.

Aetiology

Table 1 classifies chronic pancreatitis into a number of different conditions associated with this disease. Chronic alcoholism and cystic fibrosis are the most frequent causes in adults and children, respectively. Gallstones rarely cause chronic pancreatitis because a cholecystectomy is almost always performed after the first or second attack of acute pancreatitis related to gallstones, after which the pancreas recovers. Hypertriglyceridaemia may cause chronic as well as acute pancreatitis. Some patients with chronic pancreatitis may have suffered autoimmune pancreatitis: they have had enlargement of the pancreas, strictures of the pancreatic duct, autoantibodies in the serum, elevated plasma immunoglobulins, and histology showing a dense lymphocytic infiltrate. Some respond to steroid therapy. Tropical pancreatitis (Africa and Asia) is characterized by calcific disease, glucose intolerance, and infrequent pain. Pancreatic exocrine impairment occurs in patients with haemochromatosis and α₁-antitrypsin deficiency, but the pancreatic disease is usually asymptomatic. Secondary pancreatic exocrine insufficiency may occur after gastric surgery, leading to postprandial asynchrony; usually the maldigestion is not very severe. Similarly, the acid hypersecretion associated with gastrinoma may irreversibly inactivate lipase, causing steatorrhoea. Hereditary pancreatitis and developmental anomalies leading to pancreatitis are discussed later.

Idiopathic chronic pancreatitis remains controversial and may account for up to 30% of cases, depending on the population. Many patients with this condition present solely with unexplained abdominal pain, with no evidence of maldigestion, and they have small-duct disease, often without overt radiographic abnormalities by CT or magneric resonance cholangiopancreatography (MRCP). It may be necessary to perform endoscopic ultrasonography or direct intubation (hormone stimulation) to identify this condition. Endoscopic retrograde cholangiopancreatography (ERCP), which is often used to diagnose chronic pancreatitis, may miss up to 30% of patients with chronic pancreatitis who have abnormal hormone stimulation tests. It is not know how many patients with unexplained abdominal pain may indeed suffer from small-duct chronic pancreatitis: some will be thought to have nonulcer dyspepsia, and others with idiopathic pancreatitis may present at an older age with painless diarrhoea, steatorrhoea, and secondary diabetes mellitus, and they often have pancreatic calcification.

Several investigators have documented mutations of the cystic fibrosis, transmembrane-conductance regulator gene (CFTR), which functions as a cAMP-regulated chloride channel, in idiopathic chronic pancreatitis. More than 1000 mutant alleles of the CFTR gene have been identified, which has hampered attempts to elucidate the relationship between the genotype and pancreatic manifestations. Two reports have shown cystic fibrosis gene mutations in 13 to 40% of patients with idiopathic chronic pancreatitis (the observed frequency of a single CFTR mutation was 11 times greater than expected); moreover, the frequency of two mutant alleles was increased 80-fold. Most of these patients were adults with chronic pancreatitis, none of whom had any clinical evidence of pulmonary disease, and the results of sweat chloride measurements were not diagnostic of cystic fibrosis. A further study examining all known CFTR mutations noted abnormalities in 55% of 16 patients, 14 of whom had idiopathic chronic pancreatitis. Some of these patients with either one or two mutations had evidence of defective CFTR-mediated ion transport in nasal epithelium. It is not yet clear whether these CFTR abnormalities are primarily responsible for chronic pancreatitis or whether they are, at least in some cases, unrelated.

Pathophysiology

Although alcohol-induced chronic pancreatitis has been studied extensively, it remains uncertain as to whether the biochemical and histological lesions are caused by a reduced secretion of pancreatic-stone protein or alcohol toxicity. Ingestion of alcohol may decrease stone protein secretion below a critical level, allowing calcium and other secretory components to precipitate and obstruct pancreatic ductules. Alcohol may also cause abnormalities in acinar cells, leading to an imbalance of proteases and their cognate inhibitors, resulting in the initiation of a necroinflammatory process. In tropical pancreatitis, a combination of protein deficiency and a dietary toxin that occurs in cassava or sorghum may be responsible. A primary defect in the permeability of the ductal epithelium to electrolytes in patients with cystic fibrosis reduces secretory fluxes such that the hyperconcentrated proteinaceous fluid precipitates and obstructs the pancreatic ducts. The pathophysiology of the other causes of chronic pancreatitis is not understood.

Although it is widely believed that when a patient develops their first attack of acute alcoholic pancreatitis they have already sustained chronic damage to the pancreas, some individuals who do not abuse alcohol regularly develop acute pancreatitis after ingesting uncommonly large quantities of alcohol (binge drinking).

Incidence

The exact prevalence and incidence of chronic pancreatitis is unknown. The prevalence in autopsy studies varies from 0.04 to 5.0%. The only prospective study (Copenhagen Pancreatic Study), which mainly reflected alcohol-induced pancreatitis, found a prevalence of 26.4 cases per 100 000 population and an incidence of 8.2 new cases per 100 000 per year.

Clinical features

Abdominal pain is the cardinal symptom of chronic pancreatitis, but its pattern, severity, and frequency vary considerably. Whereas the pain of acute pancreatitis is often located in the epigastrium and bores through to the back, the pain of chronic pancreatitis has no characteristic features and may be constant or intermittent. Eating often increases the severity of the pain, resulting in the avoidance of food and subsequent weight loss. The pain may be mild, requiring no therapy, or severe, leading to the frequent use of analgesics and narcotic addiction.

Patients with abdominal pain may develop steatorrhoea and/or diarrhoea, but this is not inevitable. Approximately 15% of patients never suffer with abdominal pain but present with steatorrhoea, diarrhoea, and weight loss. In those who only have abdominal pain, there are few physical findings except for abdominal tenderness and mild pyrexia. There is a marked disparity between the severity of the abdominal pain and the physical findings.

Signs and symptoms of liver disease may be present in patients with maldigestion and weight loss due to alcohol-induced pancreatitis. Clinically apparent deficiencies of fat-soluble vitamins or vitamin B₁₂ are uncommon.

Investigation and diagnosis

Table 2 lists selected tests of pancreatic function and structure, with abnormalities of function generally preceding abnormalities in structure.

Blood tests rarely contribute to a diagnosis of chronic pancreatitis. The plasma activities of pancreatic enzymes (amylase, lipase, trypsin) are usually normal, except in patients who have a pseudocyst of the pancreas. There may be evidence of cholestasis (elevated alkaline phosphatase, elevated bilirubin) caused by inflammatory reactions around the common bile duct. Some patients with severe disease may have raised fasting blood-glucose levels.

Calcification may be seen on a plain abdominal radiograph and by ultrasonography, with the latter also sometimes revealing dilatation of the pancreatic duct. CT scans may reveal diffuse enlargement of the pancreas and, occasionally, a pseudocyst). ERCP may reveal more subtle changes. Newer techniques for imaging the pancreas include MRCP and endoscopic ultrasonography (EUS). MRCP provides a satisfactory morphological assessment of the main pancreatic duct but does not provide detailed imaging of the secondary ducts, or even the main pancreatic duct if it is small. EUS provides detailed assessment of both the pancreatic duct and parenchyma. A total of nine abnormal features have been defined, with more than five of these criteria being required in most studies for a diagnosis of chronic pancreatitis. EUS may find abnormalities that are not depicted by CT or ERCP, and has replaced ERCP as a diagnostic modality in selected patients with suspected chronic pancreatitis. What is not yet clear is how sensitive and specific EUS is in defining abnormalities in patients considered to have early or mild chronic pancreatitis, or in those in whom only hormone stimulation testing has been found to be abnormal.

Currently, the most accurate means of detecting chronic pancreatitis is a combination of a hormone stimulation test and a structural test such as endoscopic ultrasonography or ERCP, but as many as 30% of patients with chronic pancreatitis may have a normal ERCP in combination with an abnormal hormone stimulation test, and occasionally the converse will be true. Two significant causes of a false-positive (abnormal) ERCP are normal ageing and recent acute pancreatitis, but ageing does not appear to affect the hormone stimulation test. Simple, noninvasive tests (bentiromide, pancreolauryl, serum trypsinogen, fecal elastase) are not sensitive and are used to confirm the clinical impression, and the same can be said for radiography other than endoscopic ultrasonography or ERCP.

Almost any test listed in Table 2 will identify patients with severe disease, but a hormone stimulation test is often needed to diagnose those with abdominal pain only. In comparison with the true ‘gold standard’—histological examination of the pancreas—the most discriminatory function after hormone stimulation testing is the maximum bicarbonate concentration, followed by volume and amylase output. In one study of 29 patients with histologically confirmed pancreatitis, the cholecystokinin–secretin test had a sensitivity of 79%, compared with 66% for ERCP. A simple, inexpensive test that has a sensitivity and specificity approaching that of hormone stimulation is needed but is not yet available. A cost-effective approach to the evaluation of patients suspected of having chronic pancreatitis would first be to use a simple noninvasive test like serum trypsinogen, bentiromide or fecal elastase, and initiate pancreatic enzyme therapy if the result is abnormal. However, if this first-ordered test is normal, the next step would be EUS or a hormone stimulation test, as further discussed below.

Management

The most important aspect of the medical management of chronic pancreatitis is the use of pancreatic enzyme formulations, which can be effective in treating both pain and steatorrhoea. A potent enzyme formulation must be used to ensure that the relevant enzymes (protease for pain, lipase for steatorrhoea) escape destruction by gastric acid and reach the duodenum.

Abstinence from alcohol is recommended. The diet should be moderate in fat (30%), high in protein (24%), and low in carbohydrate (40%). When required, non-narcotic analgesics are the pain-relieving medications of choice.

To date, three controlled trials have shown that pancreatic enzymes decrease abdominal pain in 75% of patients with chronic pancreatitis. Those most likely to respond have small-duct disease, i.e. a minimal to moderate impairment of exocrine function (normal fat absorption, abnormal hormone stimulation test, minimal abnormalities on ERCP. By contrast, patients with severe (large-duct) disease (steatorrhoea, abnormal hormone stimulation test, marked abnormalities on ERCP;  do not respond well to enzyme therapy for pain. These clinical observations fit well with findings in experimental animals and humans, which demonstrate the negative-feedback regulation of pancreatic secretion controlled by the amount of proteases within the proximal small intestine. Treatment comprising eight tablets or capsules of a potent, non-enteric-coated enzyme preparation should be given at mealtimes and at bedtime, with appropriate adjuvant therapy. Enteric-coated preparations are not the preparations of choice because they often release their proteases in the jejunum or ileum rather than the duodenum, thus failing to deliver to the feedback-sensitive segment of the intestine; these preparations may also cause acute colonic disease and rupture.

After other causes of abdominal pain have been excluded, ultrasonography should be performed. If no pseudocyst or mass is found, a hormone stimulation test should be performed; this will invariably be abnormal in patients with abdominal pain secondary to chronic pancreatitis. A 4-week trial of pancreatic enzymes (with adjuvant) is indicated, as described above. If pain is not relieved, ERCP is appropriate to characterize the pancreatitis as small- or large-duct disease, and possibly to define the surgical approach.

Bullet list 1 Frequently used pancreatic enzyme therapy

If there is large-duct disease (diameter of the main pancreatic duct >7 mm), a lateral pancreaticojejunostomy (Peustow procedure) should be performed. Immediate pain relief occurs in 80% of patients, with satisfactory pain relief sustained in about 50% at 1 to 3 years follow-up. If the ducts are not significantly dilated, most patients can eventually have their pain controlled by adjusting their enzyme and adjuvant therapy, e.g. substitution of a proton pump inhibitor for an H₂ receptor antagonist, total parenteral nutrition with no food orally for several weeks, or by performing a nerve block. It is now rare for a major pancreatic resection to be undertaken to control pain, but whether ductal decompression or major resection are performed, enzyme therapy for enhancing digestion should still be given. In some preliminary controlled trials, octreotide given subcutaneously in doses up to 200 µg three times daily has been effective in reducing pain in patients with severe chronic pancreatitis.

Endoscopic therapy for the pain of chronic pancreatitis—which has included dilatation or stenting of duct strictures, removal of calculi, and treatment of biliary obstruction—has been disappointing. With the exception of acute biliary decompression, none of these therapies has been shown to be effective. Complications such as bleeding, sepsis, pancreatitis, and perforation have occurred after stent placement; moreover, stents can induce progressive ductal changes similar to the abnormalities seen in chronic pancreatitis.

Steatorrhoea in chronic pancreatitis is a late finding and does not occur until lipase secretion is reduced by 90%. With eight conventional or three enteric-coated enzyme tablets or capsules (see Table 3), control of steatorrhoea and diarrhoea, and weight gain, can be readily achieved, even though some steatorrhoea persists. Formulations containing 25 000 units or more of lipase have recently been associated with the occurrence of colonic strictures in patients with cystic fibrosis who were taking large doses of these high-potency preparations. In the United States of America, all pancreatic enzyme preparations with more than 20 000 units of lipase per capsule have been taken out of clinical use.

Decreasing the amount of long-chain triglycerides in the diet and/or adding medium-chain triglycerides (which do not require pancreatic lipase for absorption) should decrease the steatorrhoea and enhance weight gain and energy.

Complications

Table 3 lists the structural and other complications of chronic pancreatitis. Inflammatory masses are common. Ultrasonography and CT greatly assist in discriminating phlegmon from a pseudocyst and from an abscess. The management of pseudocysts is currently being re-evaluated: most clinicians have hitherto recommended drainage if they persist for longer than 7 weeks, but the ability of pseudocysts to undergo late resolution may have been underestimated and the incidence of serious complications exaggerated. A mature pseudocyst that has benign radiological appearances should be observed in a patient who has minimal symptoms and is not actively abusing alcohol: nine out of ten such pseudocysts will resolve without complications.

Pancreatic ascites occurs when there is a rent in the pancreatic duct or a leaking pseudocyst. The amylase content in the ascitic fluid is extraordinarily high, averaging 20 000 IU/litre, which distinguishes this true pancreatic ascites from ‘reactive ascites’ in patients with pancreatitis. In reactive ascites the amylase content of the fluid is increased, but is not nearly as high as in the pancreatic ascites. Pancreatic stimulation should be avoided in patients with pancreatic ascites: they should receive total parenteral nutrition and no food by mouth; proton pump inhibitors or H₂ antagonists will reduce pancreatic stimulation resulting from gastric acid release into the duodenum. Surgery may be needed if the ascites persists after several weeks of conservative therapy, with ERCP sometimes required to determine the site of duct leakage.

Obstruction of the common bile duct is common, but may be temporary owing to the resolution of inflammation. Biliary obstruction due to fibrosis of the pancreas rarely leads to cholangitis. Conservative management is justified unless the alkaline phosphatase level remains very high or cholangitis develops. In a few patients obstruction may require surgical relief by anastomosis of the dilated common bile duct to the duodenum or jejunum.

Gastrointestinal bleeding may arise from portal hypertension associated with splenic vein thrombosis caused by inflammation of the tail of the pancreas. Bleeding may also occur if a pseudocyst erodes into the duodenum, or from a pseudoaneurysm within the wall of a pseudocyst. However, the most common cause of bleeding in chronic pancreatitis is a related duodenal ulcer or alcohol-induced gastritis.

Up to 30% of patients with chronic pancreatitis have impaired glucose tolerance. Although pancreatic diabetes is usually manageable, destruction of glucagon-containing cells may render hypoglycaemia more likely. Diabetic retinopathy occurs as often in pancreatic diabetes as in other types of diabetes mellitus, and retinopathy due to a zinc or vitamin A deficiency may also occur.

Cobalamin (vitamin B₁₂) malabsorption is common in chronic pancreatitis, but clinical vitamin B₁₂ deficiency is rare. It is caused by the failure to release free cobalamin by proteolysis of transcobalamin complexes. The exogenous administration of pancreatic enzymes corrects the maldigestion.

Familial and congenital diseases

Hereditary pancreatitis (OMIM 167800)

Familial or hereditary pancreatitis is an autosomal dominant disorder with approximately 80% penetrance that is responsible for about 1% of all cases of chronic pancreatitis. These patients often present in childhood with recurrent acute pancreatitis which causes chronic pancreatitis and often pancreatic insufficiency. The lifetime risk of developing pancreatic cancer is quite high. The genetic abnormality is a defect in the cationic trypsinogen gene (PRSS1), which appears to interfere with the inactivation of trypsin after it is cleaved. Mutations in the cystic fibrosis transmembrane conductance regulator gene (CTFR) and the pancreatic secretory trypsinogen inhibitor gene (SPINK1) are also linked to pancreatitis. 

Shwachman–Diamond syndrome (OMIM 260400)

This familial disorder is caused by homozygous or compound heterozygous mutations of the Shwachman–Bodian–Diamond syndrome gene (SBDS), whose function is not known. The condition affects the pancreas, bone marrow and skeletal system, and is second only to cystic fibrosis as a cause of pancreatic insufficiency in infants. Neonates present with severe steatorrhoea that can be well treated by pancreatic enzymes. The associated neutropenia leads to frequent infections, and there is a high lifetime risk of transformation into acute myeloid leukaemia. Severe skeletal defects result in dwarfism.

Isolated pancreatic enzyme deficiencies

Protease deficiencies result from a lack of enterokinase (proximal small-intestine mucosal enzyme) or trypsinogen. The addition of exogenous enterokinase to duodenal secretions will differentiate these two deficiencies; it will not activate duodenal secretions lacking trypsinogen. Both conditions respond to pancreatic enzyme therapy. Lipase and colipase deficiencies are also rare isolated deficiencies that cause steatorrhoea. Patients with these pancreatic lipase deficiencies retain a residual fat-absorbing capacity, presumably from the action of other lipases such as gastric lipase.

Developmental anomalies

Annular pancreas

A failure of the ventral and dorsal embryonic elements of the pancreas to unite produces a ring of pancreatic tissue encircling the duodenum. This may lead to intestinal obstruction in the neonate or the adult. Nonspecific symptoms of postprandial fullness, nausea, abdominal pain, and vomiting may be present for years before the diagnosis is made. Radiographs show fixed symmetrical dilatation of the proximal duodenum, with bulging of the recesses on either side of the annular band, effacement of the duodenal mucosa without obstruction of the mucosa, and accentuation of the findings in the right anterior oblique position. The differential diagnosis should include duodenal webs, tumours of the pancreas or duodenum, postbulbar peptic ulcer, Crohn’s disease of the proximal intestine, and adhesions. Patients with an annular pancreas have an increased incidence of pancreatitis and peptic ulcer. Surgery may be necessary because of these and other intestinal complications. Retrocolic duodenojejunostomy is the procedure of choice, although some surgeons prefer a Billroth II gastrectomy with gastroenterostomy and vagotomy.

Pancreas divisum

Pancreas divisum is the most common congenital anatomical abnormality of the human pancreas. It occurs when the ventral and dorsal parts of the pancreas fail to fuse, so that pancreatic drainage is accomplished mainly through the accessory papilla. Current evidence indicates that this anomaly predisposes, albeit infrequently, to the development of pancreatitis. The combination of a pancreas divisum and a small accessory orifice could result in dorsal-duct obstruction. The challenge is to identify this subset of patients. Cannulation of the dorsal duct by ERCP is not as easy as cannulation of the ventral duct. Patients with pancreatitis and pancreas divisum demonstrated by ERCP should be treated conservatively, including with pancreatic enzyme therapy. Many of them have idiopathic pancreatitis unrelated to the pancreas divisum and will respond well to pancreatic enzymes. Endoscopic or surgical intervention is indicated only when these methods fail. Surgical ductal decompression is indicated if marked dilatation of the dorsal duct can be demonstrated. However, the appropriate therapy for those patients without dilatation of the dorsal duct is not yet defined. It should be emphasized that the ERCP appearance of pancreas divisum (i.e. a small-calibre ventral duct with an arborizing pattern) may be confused with an obstructed main pancreatic duct caused by a pancreatic tumour.