4.1 Etiology and Pathogenesis

Inflammatory disease of the pancreas is a common problem in North America, with gallstones and alcohol being the major causes (Table 3). Pancreatitis tends to present with abdominal pain, which may improve with no sequelae or may run a more severe course that can lead to death. When the pancreas is continuously injured, such as with alcohol, a chronic condition results in obstruction and fibrosis of the gland, which leads to pancreatic insufficiency and chronic pain. Even one attack of pancreatitis from alcohol use can lead to some residual pancreatic damage.

Pancreatitis results from an autodigestive process. Pancreatic digestive enzymes, vasoactive materials and other toxic materials extravasate out of the pancreas into the surrounding areas, leading to a widespread chemical irritation resulting in simple edema to severe hemorrhage and necrosis. Serious complications include hypovolemia and hypotension. Trypsin and chymotrypsin are the initiating enzymes; their release can in turn result in the release and activation of other proenzymes (including proelastase, procollagenase and phospholipases). Trypsin damages endothelial cells and mast cells, resulting in the release of histamine. This major inflammatory mediator enhances vascular permeability, leading to edema, hemorrhage and the activation of the kallikrein system, which in turn results in the production of vasoactive peptides or kinins. The latter are thought to cause pain and further aggravate the inflammatory response. The other released enzymes destroy the supporting matrix of the gland and the plasma membrane of the acinar cell, precipitating further release of digestive enzymes, which in turn leads to further damage. Lysolecithin, which is released by the action of phospholipase on lecithin (a phospholipid found in bile), has also been implicated in pancreatic damage, because of its cytotoxic and hemolytic properties. When the pancreas is inflamed but remains viable, the condition is termed interstitial pancreatitis; this may occur in up to 80% of cases. In the remaining cases, there is significant pancreatic necrosis resulting from disruption of the microcirculation, destruction of the pancreatic parenchyma and peripancreatic necrosis. Although these enzymes result in pancreatic damage, the triggering mechanism is not well known. In the case of gallstones, the major theories include (1) reflux of bile into the pancreatic duct; (2) reflux of duodenal content into the pancreatic duct; and (3) distal obstruction of the pancreatic duct, with continued pancreatic secretion leading to increased ductal pressure and resulting in pancreatitis.

Although alcohol has been implicated as a major cause of acute pancreatitis, there is no evidence that an occasional bout of excessive alcohol intake can lead to an acute attack. It is suggested that chronic ingestion may lead to chronic damage and sensitization, which may result in acute pain even with small amounts of alcohol. Alcohol can cause direct damage to acinar cells in a manner similar to that in which it damages liver cells.

Hyperlipoproteinemia types I, IV and V are associated with the majority of lipid-associated cases of pancreatitis. The incidence of pancreatitis varies from 15-40% of patients. Hyperlipidemia has been suggested to be the cause of pancreatitis; however, recent evidence suggests that mild to moderate elevation of serum triglyceride levels is likely to be an epiphenomenon of the pancreatitis rather than the primary etiology. Hypercalcemia and hyperparathyroidism may also induce pancreatitis. Although the incidence of pancreatitis in patients with hyperparathyroidism was at one time shown to vary from 7-19%, recent findings suggest this variation to be closer to 1.5%. This discrepancy can be accounted for by the difference in the degree or duration of the hyperparathyroidism and by the earlier treatment of hypercalcemia. Other causes of pancreatitis are shown in Table 3.

4.2.1 CLINICAL MANIFESTATIONS 

The clinical spectrum of acute pancreatitis ranges from mild, self-limiting disease to fulminant lethal disease. Up to 80% of patients will have an uneventful recovery; the remainder will have serious complications with a high mortality rate. Objective measurements such as Ranson's criteria (Table 4) show a good correlation with the risk of major complications and death. The overall mortality rate of acute pancreatitis ranges from 7-20%. The mortality rate correlates well with complications such as shock and hemorrhage.

Pain from acute pancreatitis is a knife-like, steady, sharp pain that starts suddenly and reaches its zenith rapidly. It is commonly localized to the epigastric area and may radiate directly to the back. It improves on leaning forward and is frequently associated with nausea or vomiting. Depending on the location of the inflammation, the pain may be referred to either the left upper quadrant or the right upper quadrant. When the pancreatitis is severe, it may result in shock and may lead to death. Frequently the pain is dyspeptic in quality and aggravated by food. This is due partially to the fact that eating stimulates secretion. Classically the pain lasts between three and four days. When the pancreatitis is severe, it may result in peripheral circulatory failure; under these conditions, the mortality rate approaches 60%.

Recurrent nausea and vomiting may be due to a reflex mechanism secondary to pain and occurs in over 90% of the cases. Other causes include pseudo-obstruction secondary to ileus and distention or obstruction secondary to a pancreatic mass or pseudocyst. Since the common bile duct traverses the pancreatic head before entering the duodenum, jaundice may occur, often transiently.

Depending on the severity of pancreatitis, the patient may appear in distress or be in shock. Jaundice may be caused by edema of the head of the pancreas or by an obstructing stone. Tachycardia could be secondary to pain, volume depletion or the inflammatory process. Low-grade fever could be secondary to the inflammation in the pancreas or result from such complications as abscess formation.

Abdominal examination may reveal epigastric and abdominal tenderness with guarding or rigidity. Bluish discoloration of the flanks (Grey Turner's sign) or of the periumbilical area (Cullen's sign) indicates that blood from hemorrhagic pancreatitis has entered the fascial planes. The signs are not specific and may occur in any condition that causes retroperitoneal hemorrhage. Tender red and painful nodules that mimic erythema nodosum may appear over the extremities. These are often due to circulating lipases.

Since the signs and symptoms of acute pancreatitis may mimic those of surgically correctable intra-abdominal disorders, the diagnosis of acute pancreatitis is often one of exclusion. Other diseases to be considered are a perforated peptic ulcer, mesenteric thrombosis, intestinal obstruction, dissecting aneurysm, peritonitis, acute cholecystitis and appendicitis. The diagnostic process is complicated by the fact that hyperamylasemia can occur in disorders other than pancreatic inflammation (such as ectopic pregnancy, parotiditis, carcinoma of the lung, posterior penetrating ulcer, ruptured aortic aneurysm and opiate administration). Although amylase values greater than 1,000 units have been said to occur principally in conditions requiring surgery (e.g., biliary tract disease), this distinction is not absolute.

Local involvement of pancreatitis includes phlegmon (18%), pancreatic abscess (3%), pancreatic pseudocyst (10%) and thrombosis of the central portal system. Phlegmon is an area of edema, inflammation and necrosis without a definite structure (unlike an abscess). A phlegmon results from acute intrapancreatic inflammation with fat necrosis and pancreatic parenchymal and peripancreatic necrosis. This arises from the ischemic insult caused by decreased tissue perfusion and release of the digestive enzymes. When this damage is not cleared, further inflammation ensues, declaring itself by increased pain, fever and tenderness. In severe cases a secondary infection ensues, a process termed infected necrosis of the pancreas, which occurs within the first one to two weeks of the illness and carries a high mortality. This diagnosis can be made by computerized tomography (CT) and percutaneous aspiration of the area with subsequent bacterial staining and appropriate cultures. In 3% of acute pancreatitis an abscess develops, usually several weeks into the illness. An abscess is a well-defined collection of pus occurring after the acute inflammation has subsided.

A pseudocyst develops as a result of pancreatic necrosis and the escape of activated pancreatic secretions through pancreatic ducts. It contains blood and debris. This fluid coalesces and becomes encapsulated by an inflammatory reaction and fibrosis. These patients usually have pain and hyperamylasemia, but may be asymptomatic. They may present with an abdominal mass, causing compressive symptoms.

Systemic complications of acute pancreatitis are numerous (Table 5) and correlate well with the severity of the inflammatory process. They may be manifested by shock (circulatory collapse secondary to sequestration of retroperitoneal fluid or hemorrhage), respiratory and renal failure and profound metabolic disturbances.

Although acute pancreatitis may run a mild self-limiting course, severe pancreatitis occurs in up to 25% of acute attacks, with a mortality approaching 10%. The majority of deaths occur within the first week of hospital admission and are caused by local and systemic complications, including sepsis and respiratory failure. Most clinical studies in adults cite pancreatic infection as the most common cause of death, accounting for 70-80% of deaths.

The diagnosis of acute pancreatitis is based on a combination of clinical findings and the use of laboratory and radiographic techniques. Elevation of serum amylase in acute pancreatitis is short-lived. Amylase is rapidly cleared by the renal tubules and may return to normal within 24 hours from the time of onset. Although amylase-to-creatinine clearance was used in the past to diagnose pancreatitis, it is now rarely used. Lipase levels appear to be a more sensitive and specific method of diagnosing acute pancreatitis and may remain elevated for several days following the onset of pain. Immunologic assays for trypsinogen or immunolipase are experimental and do not add any more information than the serum lipase.

A plain film of the abdomen is very helpful. It may reveal calcification of the pancreas (indicative of a chronic process) or it may reveal gallstones (if calcified). The presence of free air suggests perforation, whereas the presence of thumb-printing in the intestinal wall may indicate a mesenteric ischemic process. A localizing ileus of the stomach, duodenum or proximal jejunum (all of which are adjacent to the pancreas) is highly suggestive of pancreatic inflammation. Similarly, when the transverse colon is also involved, air filling the transverse colon but not the descending colon (colon "cut-off" sign) may be seen. The chest x-ray can show atelectasis or an effusion, more often involving the left lower lobe.

Although clinical, biochemical and simple radiographic evaluation suffice for the diagnosis of pancreatitis, ultrasonographic and computerized tomography imaging are essential. These confirm the diagnosis, provide an early assessment regarding the course of the disease and detect complications such as phlegmon, pseudocyst and abscess formation. A pseudocyst or an abscess may also be drained percutaneously under CT or ultrasound guidance.

The most common ultrasonographic and CT finding in patients with acute pancreatitis is diffuse glandular enlargement. Ultrasonographically there is a decrease in echogenicity of the organ; on CT scan there is decreased attenuation from edema of the tissues. Frequently intravenous contrast is given, and this may demonstrate a uniform enhancement in the pancreatic parenchyma. A normal examination does not rule out the presence of acute disease. In up to 30% of uncomplicated cases of acute pancreatitis CT scan may be normal; these patients usually have a mild form of pancreatitis. When a stone or an obstruction of the distal common bile duct is present, the common bile duct and the intrahepatic biliary tree may be dilated.

Endoscopic retrograde cholangiopancreatography (ERCP) involves cannulating the ampulla of Vater and then injecting contrast material into the pancreatic duct and the biliary tree. This procedure is usually contraindicated during the acute phase, except when the pancreatitis is caused by an impacted common bile duct stone. Under those conditions, a sphincterotomy and stone removal may be performed. If performed as early as 24 hours following admission, this procedure may result in significant improvement in morbidity and mortality.

The aims of therapy of acute pancreatitis are (1) hemodynamic stabilization, (2) alleviation of pain, (3) stopping the progression of the damage, and (4) treatment of local and systemic complications. As yet there are no specific medical therapies capable of reducing or reversing the pancreatic inflammation. Hence therapeutic interventions are aimed at the complications of the disease.

Once the diagnosis is established with certainty, the patient's intravascular volume is replenished, and electrolytes, calcium, magnesium and blood sugar are closely monitored. Depending on the severity of the attack, an indwelling urinary catheter and close monitoring of urinary output may be necessary. Analgesics such as meperidine should be administered regularly during the first several days of the attack. This may alleviate the pain, decrease the patient's apprehension and improve respiration, thus preventing pulmonary complications such as atelectasis. The risk of narcotic addiction is minimal during the first days; most patients settle within 72 hours. The patient is kept off oral feeding; nasogastric suctioning is maintained if the disease is severe and complicated by vomiting and ileus. Mild cases with minimal symptoms may be managed without suctioning. The rationale behind nasogastric suctioning is to place the pancreas at rest by removing the acidic gastric juices. This suppresses secretin release and decreases pancreatic stimulation. The validity of this postulate has not been substantiated. Similarly, the use of acid-suppressive medications such as cimetidine has failed to show benefit in the treatment of acute pancreatitis. The use of enzyme inhibitors such as soybean trypsin inhibitor to prevent further damage is controversial, as is the use of prostaglandins and corticosteroids.

The routine administration of antibiotics does not improve the course of mild to moderate disease. However, when the development of pancreatic abscess is suspected from an increase in fever and abdominal pain, antibiotic therapy should be instituted using an aminoglycocide and cephalosporin.

Respiratory insufficiency may occur in up to 40% of the cases, usually in patients with severe or recurrent pancreatitis. In such patients, arterial oxygen saturation should be monitored and corrected. Fluid overload should be avoided. Intubation and ventilation may be required.

Peritoneal lavage has been advocated in patients with severe disease, such as those with marked hypovolemia or hypotension or those who continue to deteriorate despite appropriate medical therapy. Although this technique reduces the circulatory and renal complications, it does not seem to alter the local complications.

Intravenous hyperalimentation has been advocated in patients who continue to have pain and whose symptoms are aggravated postprandially. If during a trial of six weeks or longer, complications develop (such as an abscess or an enlargement of phlegmon), a surgical debridement may be warranted, albeit as a last resort.

Chronic pancreatitis is defined as a continued inflammation characterized by irreversible morphologic changes. These changes include fibrosis, ductal abnormality, calcification and cellular atrophy. Alcohol is the major etiologic factor, accounting for about 75% of the cases. Repeated attacks of gallstone-related pancreatitis rarely if ever result in chronic pancreatitis. Other causes include diabetes, protein-calorie malnutrition, hereditary pancreatitis, cystic fibrosis and idiopathic causes.

Alcohol presumably causes pancreatic injury by the intraductal formation of protein plugs secondary to increased protein concentration and precipitation, with or without calcification. These plugs lead to obstruction and secondary pancreatic damage caused by autodigestion. In developed countries chronic pancreatitis occurs after a long history (6 to 17 years) of alcohol ingestion of 150 to 170 g per day. Alcoholic pancreatitis is known to occur with much less consumption of alcohol, as low as 50 g per day. The mean age of a patient with new onset of disease is around 32 years, with a male predominance. Despite heavy drinking only a small number of alcoholics develop chronic pancreatitis, suggesting other factors that potentiate the injurious side effects of alcohol, including high-protein diet with either very high or very low fat content.

Chronic pancreatitis is characterized by irreversible injury to the pancreas and clinically by intractable abdominal pain and loss of exocrine and endocrine pancreatic function. The pain is localized to the upper abdomen, with radiation to subcostal regions and to the back. The pain is aggravated by meals and improves with fasting.

When more than 90% of exocrine pancreatic function is lost, maldigestion and malabsorption ensue. This is manifested by steatorrhea (fat malabsorption) associated with diarrhea and bloating, azotorrhea (protein malabsorption) and progressive weight loss. These patients frequently present with loss of adipose tissue, judged by hanging skin folds, and more objectively by demonstrating that the skin fold at the mid-triceps is less than 8 mm in males and less than 12 mm in females. In addition, patients manifest muscle wasting and edema, indicating protein deficiency. Latent fat-soluble vitamin deficiency (vitamins A, D, E and K) in addition to deficiencies of magnesium, calcium and essential fatty acids may occur and are closely related to dysfunction of fat digestion. Endocrine insufficiency presenting as diabetes mellitus may present at the same time as exocrine insufficiency or a few years later.

4.3.2 COMPLICATIONS

4.3.2.1 Pancreatic pseudocyst

Pancreatic pseudocyst is localized fluid collection occurring within a pancreatic mass or in the peripancreatic spaces following acute or chronic pancreatitis. The pseudocyst is usually surrounded by a non-epithelial-lined fibrous wall of granulation tissues. Its frequency varies from 10-50% of patients experiencing severe pancreatitis. When a pseudocyst is present for less than six weeks, it is considered acute; after that it becomes chronic. The pseudocyst may be asymptomatic or may present as an acute exacerbation of pancreatitis, with abdominal pain, nausea, vomiting and weight loss. These pseudocysts may obstruct intra-abdominal viscera, cause pancreatic ascites, rupture into viscera or the abdominal cavity, hemorrhage or become infected. Spontaneous resolution occurs in 20% of the cases within the first six weeks of the pseudocyst's development. Chronic pseudocysts or pseudocysts greater than 5 cm rarely improve. Asymptomatic patients with persistent psuedocysts should be observed and intervention may be considered if symptoms appear. Successful percutaneous catheter drainage may be accomplished by CT- or ultrasound-guided drainage techniques. The catheter may be required for up to six weeks and is frequently associated with infections. Surgical drainage is sometimes necessary for failed percutaneous drainage or for complicated pseudocysts. If the pseudocyst is in the head of the pancreas, drainage can be done via ERCP.

4.3.2.2 Pancreatic ascites

Pancreatic ascites results from the leakage of pancreatic juices into the peritoneal cavity through a fistula or ruptured pseudocyst. It presents with gradually increasing massive ascites, high levels of amylase, abdominal pain and weight loss. Painful areas of subcutaneous fat necrosis result from the high levels of circulating pancreatic lipase.

4.3.2.3 Common bile duct stricture

Common bile duct compression is another manifestation of chronic pancreatitis, but it rarely results in significant obstruction. As the distal common bile duct traverses the head of the pancreas, it may be narrowed secondary to inflammation, with edema or fibrosis of the gland.

Although pancreatic carcinoma was formerly thought to be increased in chronic pancreatitis, the incidence is now believed to be the same as in the general population. Pancreatic carcinoma may present as pancreatitis.

4.3.3 DIAGNOSTIC AND RADIOGRAPHIC EVALUATION

The diagnosis of chronic pancreatitis is straightforward in patients with advanced pancreatic disease, especially in the presence of radiologic evidence, such as calcification seen exclusively in the ductal system on plain radiographic abdominal films, by ultrasonography or on computerized tomography. This radiologic evidence may be seen in up to 30% of patients with chronic pancreatitis. Although ultrasonography may demonstrate pancreatic enlargement, ductal dilation or pseudocysts (Figure 5), these findings may be better seen on computerized tomography (Figure 6). Abnormalities of the ducts associated with chronic pancreatitis can also be demonstrated by endoscopic retrograde pancreatography. In mild to moderate disease these findings may be subtle and even normal. In more severe disease there is narrowing and dilation of the ducts, stenosis and filling of side ductules. Examination may reveal a tortuous main duct containing stones or protein plugs, or obstruction of the common bile duct (Figure 7). These changes may not be closely related to the degree of pancreatic insufficiency; hence the need for pancreatic function studies.

The only tests that appear to accurately measure pancreatic function in chronic pancreatitis are the direct tube tests that measure the response of the pancreas to various stimuli. The commonest manifestation is a decreased bicarbonate concentration (<50 mEq/L) and decreased volume of secretion.

4.3.4 TREATMENT

The ultimate goals of treatment in chronic pancreatitis are to alleviate pain, maintain adequate nutritional status, and reduce symptoms associated with steatorrhea such as abdominal pain, bloating and diarrhea.

The mechanism of pain in chronic pancreatitis is not known. Abstinence from alcohol may decrease the frequency and severity of painful attacks in patients with alcoholic pancreatitis. Large meals with foods rich in fat should be avoided. Analgesics should be given prior to meals, since the pain is maximal postprandially. The continuous use of narcotics often leads to drug addiction, which makes the management of pain more difficult. Large doses of pancreatic extracts may reduce the frequency and severity of the pain in patients with no demonstrable duct obstruction. These enzymes appear to suppress pancreatic exocrine output, thus putting the pancreas at rest and resulting in pain relief. Pancreatic replacement is given with meals and at bedtime. Patients who respond to this therapeutic regimen tend to be middle-aged women with idiopathic pancreatitis who suffer from mild or moderate disease. These patients tend to have a bicarbonate output greater than 55 mEq/L and normal fat absorption. Patients with more severe disease, whose peak bicarbonate output is less than 50 mEq/L, tend not to respond to this regimen.

Patients with intractable pain who fail to respond to medical therapy may benefit from surgical intervention. When there is a dilated pancreatic duct with obstructive areas, longitudinal pancreatojejunostomy (modified Pustow operation) may induce immediate pain relief. When the duct is small, partial surgical resection of the pancreas may control the pain in a certain percentage of patients. Although pain alleviation with surgery may be achieved in certain patients, its long-term benefit is limited since pain recurs in the majority of patients. An alternative to surgical drainage may be achieved by endoscopic insertion of an an endoprosthesis (stent) into the pancreatic duct. Although this approach is promising, its long-term benefit has not been proven.

Octreotide, a long-acting somatostatin analogue, appears to decrease the pain of chronic pancreatitis. Its action is mediated by suppressing pancreatic secretion, hence resting the pancreas. The role of octreotide remains uncertain.

Administration of high-potency, enteric-coated pancreatic enzymes remains the main therapy for the treatment of steatorrhea in the majority of patients with idiopathic and alcoholic pancreatitis. This will improve fat digestion, increase absorption and allow weight gain, although it will not correct the steatorrhea completely. Azotorrhea is more easily reversed than steatorrhea, since trypsin is more resistant to acid inactivation than lipases. It seems that the most important barrier preventing correction of steatorrhea is the destruction of enzymes in the stomach, which prevents the delivery of enough active enzyme into the duodenum.

Replacement pancreatic enzymes are made from hog pancreas and contain a mixture of proteases, lipase and amylase, along with a variety of enzymes normally present in pancreatic secretions. Different preparations vary in the amount of lipase activity and the method of enzyme delivery (e.g., tablets, capsules or enteric-coated microspheres). Treatment with these enzymes is lifelong. Pancreatic enzymes are inactivated by pH 4 or below; hence, enteric-coated preparations such as Pancrease^TM or Cotazym® may be appropriate. In patients who do not respond well, the use of histamine H₂-receptor antagonists (cimetidine, ranitidine or famotidine) or antacids with meals may overcome the detrimental effect of acid on the enzymes. The causes of failure to respond to pancreatic enzyme supplementation are shown in Table 6.

Hypersensitivity to pancreatic enzymes has been reported in patients who have hypersensitivity to pork proteins. Hyperuricosuria may occur in patients receiving high doses of pancreatic extracts, although recent reports have questioned this relationship. There appears to be a relationship between urinary urate concentration and the severity of pancreatitis. It appears that oral pancreatic enzymes may bind to folic acid, thereby impairing its absorption, but the clinical significance of this is not clear. Fat-soluble vitamins (e.g., vitamins A and E) are poorly absorbed when steatorrhea exceeds 20 g of fat loss per day. Vitamin D and calcium malabsorption leads to osteopenia and tetany. Vitamin K is also malabsorbed, but bleeding is rare. Malabsorption of vitamin B₁₂ occurs in up to 40% of patients with chronic pancreatitis, although vitamin B₁₂ deficiency is rare. This malabsorption is thought to be due to the failure of R factor to cleave from the vitamin B₁₂-intrinsic factor complex, resulting in failure to absorb vitamin B₁₂.