Chronic pancreatitis results from progressive destruction and fibrosis of the pancreas with ongoing inflammatory lesions. The exocrine pancreatic tissue and function are lost in the earlier stages, followed by the loss of endocrine parenchyma and function. The disease frequently is complicated in the early stages of its evolution by attacks of acute pancreatitis, which are responsible for recurrent pain. After several years of ongoing inflammation and fibrosis, pancreatic insufficiency develops, with resulting malabsorption, steatorrhea, and diabetes mellitus. Acute attacks decrease and pain usually disappears.
Chronic pancreatitis may be classified into two forms that present with specific lesions and have different causes.
Obstructive chronic pancreatitis is caused by the occlusion of pancreatic ducts, which precedes the onset of pancreatitis. The occlusion may be the result of tumors, scars of parenchymal inflammation, necrotic pseudocysts, or congenital anomalies (e.g., annular pancreas, pancreas divisum). The lesions are found in the part of the pancreas encompassing the occluded ducts. The ductal epithelium is relatively preserved, and intraductal protein plugs and stones are not present.
Infiltrative and autoimmune diseases such as hemochromatosis and SjГ¶gren’s syndrome may also involve the pancreas, resulting in pancreatic insufficiency.
Chronic calcifying pancreatitis is the most frequent cause (>95% of all instances) of chronic pancreatitis. It is significantly associated with chronic alcohol consumption and is exacerbated by cigarette smoking and by diets high in protein and high or low in fat.
Less frequently, Chronic calcifying pancreatitis occurs with hyperparathyroidism and hypercalcemia, and in some tropical countries (South India, Zaire, Nigeria, Brazil), it occurs in nonalcoholic young people (average age, 12-20 years) of both sexes living in areas where protein- and fat-poor diets are consumed. There is also a hereditary autosomal-dominant form of Chronic calcifying pancreatitis with variable penetrance. Pancreatic insufficiency from cystic fibrosis may resemble Chronic calcifying pancreatitis in morphology and presentation.
Chronic calcifying pancreatitis is characterized by the lobular, patchy distribution of lesions of different intensity in neighboring lobules. Protein plugs are always found in the ductal and acinar lumina, and in the later stages these form calcifications, or calculi (pancreatic calcification). Atrophy of the epithelium and stenosis of the ducts are common. Recurrent attacks of acute pancreatitis, retention cysts, pseudocysts, and perineural inflammation are frequently associated.
The first visible lesions are protein precipitates or plugs in the lumina of ducts and acini, which later calcify forming pancreatic stones. The ductal epithelium in contact with the protein plugs or stones loses its basement membrane, and the duct cells atrophy and disappear with the growth of periductal connective tissue and fibrosis leading to fibrotic strictures. Distal to the strictures, the exocrine tissue atrophies and disappears due to plugs, stones, and fibrosis. When a partially obstructed duct is distended by pancreatic juice under pressure of secretion, it may form an intrapancreatic cyst. These retention cysts may grow and extend into peripancreatic tissue, forming retention pseudocysts. Thus all lesions of chronic calcifying pancreatitis are thought to be secondary to the formation of protein plugs and stones in the pancreatic ducts and ductules, resulting in ductal obstruction, parenchymal inflammation, atrophy, and fibrosis.
The pathogenesis of pancreatic lithogenesis involves the precipitation of both a fibrillar protein – a form of pancreatic stone protein– and calcium carbonate.
Normally the pancreatic juice is saturated with calcium. The precipitation of calcium in the pancreatic juice is prevented by the presence of a group of proteins, pancreatic stone protein-S2-5, synthesized and secreted by the acinar cells. Pancreatic stone protein-S2-5 acts as a calcium stabilizer of the pancreatic juice by blocking the growth sites of crystals. In the pancreatic juice, pancreatic stone protein-S2-5 may be hydrolyzed by active trypsin to give a shorter protein, pancreatic stone protein-S, which is insoluble at physiologic pH and does not prevent calcium carbonate crystallization. Pancreatic stone protein extracted from pancreatic plugs and stones contains the same amino acid sequence as pancreatic stone protein-S1. The relative concentration of pancreatic stone protein is significantly decreased in the pancreatic juice of patients who have Chronic calcifying pancreatitis compared to normal controls; this is true even in the early stages of the disease, before the appearance of calcification on abdominal x-rays. This finding suggests that the formation of the calcified part of the stones is due to a decreased secretion of pancreatic stone protein, the stabilizer of calcium in pancreatic juice. Pancreatic stone protein secretion is also decreased in hereditary chronic pancreatitis as well as in idiopathic and alcoholic forms; thus the condition may be either congenital or acquired.
The lesions of the ductal epithelium caused by the protein plugs and stones lead to transudation of protein- and calcium-rich interstitial fluid into ductal lumina, increasing the calcium concentration in the pancreatic juice and resulting in increased intraductal calcium crystallization. As the diseased ducts become obstructed by the precipitated protein and calcifications, the acini and the lobule, which the ducts drain, become atrophic and fibrotic, resulting in pancreatic parenchymal loss in a patchy distribution throughout the pancreas.
Role of alcohol consumption and diet. Acute recurrent pancreatitis is thought to be a complication of the initial stages of Chronic calcifying pancreatitis. It occurs in chronic alcoholics who have recently increased their alcohol intake. Follow-up of these patients shows that in most of them, pancreatic calculi (calcifications) develop after a number of years.
Recurrent alcoholic pancreatitis progresses to overt pancreatic insufficiency at different rates in different people. However, there is a linear relation between the average daily consumption of alcohol and the logarithm of the risk. For a given amount of alcohol consumption, the risk increases with the increased duration of consumption. Even small quantities (1-20 g of alcohol per day) increase the risk. Rather than a statistical threshold of alcohol toxicity for the pancreas, there is a continuous spectrum of individual thresholds. The type of alcoholic beverage and the rhythm of alcohol consumption have no significant influence on the risk of development of Chronic calcifying pancreatitis.
Chronic alcohol ingestion increases the total protein concentration of protein in pancreatic juice but decreases the concentrations of pancreatic stone protein, citrate, bicarbonate, trypsin inhibitory protein, and the pH. Decreased citrate concentration increases calcium availability. It is thought that the increased viscosity of the pancreatic juice, due to increased protein content and decreased concentrations of pancreatic stone protein and citrate, leads to formation of protein plugs and calcifications in these patients.
Diagnosis of Chronic Pancreatitis
Chronic pancreatitis in a minority of patients may be complicated by the development of pancreatic pseudocysts, abscess, ascites, common bile duct obstruction, duodenal obstruction, and portal and splenic vein thrombosis. The incidence of pancreatic cancer is not increased in patients with chronic pancreatitis.
The treatment of chronic pancreatitis is mainly supportive and directed at the complications.
Management of pain
In alcohol-related disease, alcohol and tobacco consumption should be stopped. Patients should be advised to follow a diet with moderate fat and protein and high carbohydrate content.
In some instances pain relief may be obtained by small feedings and analgesics. Many patients require narcotics.
Feedback control. Oral treatment with large doses of pancreatic enzymes has been shown to decrease the abdominal pain experienced by patients with chronic pancreatitis by inhibiting pancreatic exocrine secretion and allowing the pancreas to rest. The presence of the proteases trypsin and chymotrypsin within the lumen of the proximal duodenum exerts a feedback control on pancreatic exocrine secretion. The patients in whom pain responds to pancreatic enzymes most readily are those with mild-to-moderate exocrine impairment. The use of pancreatic enzymes has also been shown to heal pancreatic fistulas and to decrease the frequency of attacks of acute, recurrent pancreatitis. The doses used are similar to those used for the treatment of malabsorption.
Percutaneous injection of alcohol to destroy the celiac ganglion has been reported to relieve pain in some patients for as long as 6 months. Long-term effects of this treatment have not been determined.
Surgery for relief of pancreatic pain is reserved for patients with intractable and disabling pain unresponsive to any other mode of therapy. The surgical procedures used depend on pancreatic and ductal anatomic abnormalities determined by preoperative computed tomography scan and endoscopic retrograde cholangiopancreatography findings. In most patients, pain relief is achieved for the short term. The long-term effectiveness of these procedures in relieving pain is debated.
Drainage procedures are used when there is generalized or localized pancreatic ductal dilatation, and partial resection of the gland is used when there is no ductal dilatation or the abnormality is confined to a segment of the pancreas.
Longitudinal pancreaticojejunostomy (the Puestow procedure). In this procedure, the dilated pancreatic duct is filleted open longitudinally over the length of the gland. A nonfunctioning segment of jejunum in a Roux-en-Y loop is also opened longitudinally and sewn over the open duct to allow for drainage of the pancreatic secretions.
Caudal pancreaticojejunostomy (DuVal procedure). When there is a ductal obstruction in the body of the pancreas with distal duct dilatation, the tail of the pancreas is resected and the remaining pancreas is placed in an end-to-end fashion into a nonfunctioning segment of jejunum.
Sphincteroplasty of the sphincter of Oddi or Santorini has been used in isolated strictures of these orifices (e.g., in pancreas divisum).
In the absence of ductal dilatation and when abnormalities are confined to portions of the pancreas, 40% to 95% of the gland may be resected. When the disease is confined to the head of the pancreas, the Whipple’s procedure (pancreaticoduodenectomy) may be used. Total pancreatectomy has been performed rarely when lesser procedures failed to relieve pain.
Although the short-term success of these procedures in relieving pain seems good, most patients experience pain recurrence. Also, pancreatic insufficiency and insulin-dependent diabetes mellitus become a problem after the resection of 50% of the gland in most patients. Surgical manipulation of the pancreas for relief of pancreatic pain should be reserved for truly refractory pain, and drainage procedures, when possible, are preferred to resection involving more than half of the gland.
Steatorrhea is often an earlier and more severe problem than azotorrhea in chronic pancreatitis, because secretion of lipase and colipase decreases earlier than that of the proteolytic enzymes. If steatorrhea is less than 10 g of fat per day, patients may do well with dietary restriction of fat. If the steatorrhea is greater than 10 g of fat per day, pancreatic enzyme supplementation is recommended in addition to dietary fat restriction.
Pancreatic enzyme supplements. Pancreatic extracts may be used for enzyme supplementation to reduce malabsorption. Table COMMERCIAL PANCREATIC ENZYME PREPARATIONS lists some of the commercially available pancreatic enzyme preparations.
To eliminate malabsorption, the concentration of enzymes delivered to the duodenum need only be 5% to 10% of the concentration that is secreted into the duodenum after maximal stimulation of the pancreas. This means that approximately 30,000 IU of lipase must be present in the duodenum with each meal. Most commercial preparations contain only 3,000 to 4,000 units of active lipase per tablet. Therefore, if no lipase is inactivated in the stomach, six to ten tablets are required per meal to eliminate steatorrhea. Lesser amounts diminish but do not abolish steatorrhea.
The enzyme preparations are commonly given before each meal at the following doses: Viokase, eight tablets; Cotazym, six capsules; Ilozyme, four capsules; Pancrease MT16, three capsules; Creon, three capsules; Entolase H.P., three capsules; and Zymase, three capsules. If the patient has pancreatic pain, another one to two doses are given at bedtime. Although pancreatic enzyme preparations are free of serious side effects, patients ingesting large doses may complain of nausea, abdominal cramps, and perianal excoriation. The high content of nucleic acids contained in the enzyme preparations may result in hyperuricemia and kidney stones in some patients, especially in children. Allergy to pork protein may develop and cause adverse reactions.
|TABLE. COMMERCIAL PANCREATIC ENZYME PREPARATIONS|
Pancreatic lipase is irreversibly inactivated by a pH less than 4.0; therefore, it is important to maintain the gastric pH above 4.0 for at least 1 hour postprandially. Because different patients have different rates of gastric acid secretion, those who are achlorhydric or hypochlorhydric do well with the preceding dosages. However, in patients with normal gastric acid secretion, higher dosages of the enzymes or adjuvant acid-suppressant therapy or both may be necessary to keep the intragastric pH above 4.0 to deliver adequate active enzyme concentrations to the small bowel.
Adjuvant acid-suppressant therapy may be used to increase the gastric luminal pH and improve the survival of the exogenous enzymes during transit from the stomach.
Sodium bicarbonate and aluminum hydroxide are the only antacids that are effective in reducing steatorrhea; they are administered before or at the beginning of the meal in a dosage that maintains intragastric pH above 4.0. This seems to be 16.6 g per 24 hours for sodium bicarbonate and 18.4 g per 24 hours for aluminum hydroxide gel. Other antacids, such as magnesium aluminum hydroxide or calcium carbonate, tend to increase steatorrhea.
Sodium bicarbonate 650 mg before and after meals has been effective, especially with Viokase. If the patient is receiving a nighttime dose of the enzymes, the dose of sodium bicarbonate is increased to 1,300 mg at bedtime. Hypercalcemia and the milk-alkali syndrome have not occurred with this regimen. Enteric-coated enzyme preparations should not be used with sodium bicarbonate. They may release the contents of the microspheres in the stomach with the loss of enzyme activity if used concomitantly with sodium bicarbonate.
Magnesium- and calcium-containing antacids effectively increase gastric pH but may aggravate steatorrhea by precipitating bile salts in the duodenum and forming calcium and magnesium soaps from the undigested free fatty acids, which increases intestinal secretion.
Gastric acid suppression with histamine-2 blockers or proton-pump inhibitors. Adjuvant therapy with histamine-2 (H2) blockers and proton-pump inhibitors may be used. However, concurrent use of a pH-sensitive, delayed-release pancreatic enzyme preparation and an H2 blocker or a proton-pump inhibitor could result in premature release of the enzymes in the stomach.
Enteric pH-coated preparations are effective if the intragastric pH remains at 4.0 to 5.0 and the duodenal pH above 6.0 to allow for dissolution of the coating and release of the active enzymes. These preparations have not been shown to be more advantageous than the other preparations. The newer preparations (e.g., Creon) with smaller microspheres may have better bioavailability in the duodenum.
Most patients with exocrine pancreatic insufficiency do quite well with adequate enzyme replacement. The dosage of the enzymes should be increased if symptoms are not alleviated.
Patients with chronic pancreatitis tolerate small but frequent feedings that are high in protein better than large feedings. In debilitated patients, dietary supplements rich in protein should be used. If patients cannot tolerate enteral feedings, parenteral nutrition may be given.
Medium-chain triglycerides may be substituted for long-chain triglycerides to increase the total fat intake, because Medium-chain triglycerides are hydrolyzed much more rapidly by pancreatic lipase, and some are absorbed while still intact into the portal vein. medium-chain triglycerides is sold as medium-chain triglycerides oil for food preparation.
Bacterial overgrowth. As many as 25% of patients with chronic pancreatitis have concomitant bacterial overgrowth in the small intestine. These patients may need both pancreatic enzymes and antimicrobial therapy (e.g., tetracycline 500 mg by mouth [p.o.] three or four times daily; metronidazole 250-500 mg p.o. three times daily for 7-14 days) before diarrhea and steatorrhea can be effectively treated.
Diabetes mellitus. Patients who have diabetes mellitus with insulin deficiency as a result of chronic pancreatitis also have concomitant glucagon deficiency. Thus, these patients are very susceptible to hypoglycemia, and their insulin dosage needs to be closely monitored.