Pancreatic Exocrine Dysfunction

In Western countries, the number of patients suffering from pancreatic exocrine insufficiency has increased. The most common cause is an increase in alcohol consumption with a concomitant increase of CP (FitzSimmons, 1993). The main goal of therapy for pancreatic exocrine dysfunction is to avoid fat maldigestion. Reasons for earlier and more severe impairment of fat digestion, compared with protein and carbohydrate digestion, in patients with pancreatic insufficiency are that 1) impairment of pancreatic lipase synthesis and secretion occurs earlier; 2) more rapid and complete inactivation of lipase occurs in the acidic duodenum as a result of impaired bicarbonate output; 3) proteolytic degradation of lipase occurs earlier during aboral transit than with amylase and proteases; 4) impairment of pancreatic bicarbonate secretion decreases duodenal pH, resulting in precipitation of glycine-conjugated bile acids and further deterioration of fat digestion; and 5) extrapancreatic sources of lipase are unable to compensate for loss of pancreatic lipase activity.

For all of the reasons listed, steatorrhea is the leading symptom in patients with pancreatic exocrine insufficiency.

Pancreatic Exocrine Enzyme Supplementation

When weight loss or steatorrhea (≥15 g/day) or both develop, supplementation of pancreatic enzymes is indicated. Dyspepsia, diarrhea, meteorism, and malabsorption of proteins and carbohydrates also have been cited as indications. Another interesting indication for pancreatic enzyme supplementation, although not formally studied, is in the treatment of pain (discussed in the next section). The main goal of the treatment of pancreatic exocrine dysfunction is to ensure that optimal amounts of lipase reach the duodenum with the delivered food. With the currently available pancreatic enzyme supplement preparations, azotorrhea (protein malabsorption) can be eliminated (Brady et al, 1991), whereas steatorrhea usually can be reduced but not totally corrected.

Four different types of pancreatic exocrine enzyme preparations are available. Uncoated preparations show only poor effects because of their inactivation by gastric acid. Huge doses of enzymes are required to have any effect on fat malabsorption. These preparations should be used only in patients with pancreatic exocrine insufficiency and hypochlorhydria or achlorhydria. The use of enteric-coated tablets is strongly discouraged, because these preparations are ineffective for decreasing fat excretion owing to erratic enzyme release. The superiority of enteric-coated microsphere preparations over conventional enzyme preparations with regard to decrease in stool fat excretion has been firmly established (Layer & Holtmann, 1994). Pancreatic enzymes in these preparations are protected at low pH by a special polymer coating. The release of the enzymes occurs only at a pH of at least 4.5. Simultaneous administration of antacids, H2-receptor antagonists, or proton pump inhibitors is unnecessary. Unfortunately, microencapsulation results in a considerable increase in costs. Another problem concerning enteric-coated microspheres might be considerable differences in the diameter of the microspheres and in their physical nature as a result of differences in the manufacturing process; however, clinical differences in the various enteric-coated microsphere preparations have not yet been proofed.

The use of enzyme preparations in combination with acid-reducing compounds also is not justified for many reasons, although additional administration of proton pump inhibitors or H2-receptor antagonists reduces fecal nutrient loss. These preparations are expensive, there is a variability of the effects owing to the acid-reducing therapy, and especially in children, the safety of long-term administration has not been firmly established (Lebenthal et al, 1994).

Certain bacterial and fungal lipases have shown no benefit in the treatment of pancreatic steatorrhea, although they are resistant against acid denaturation and proteolytic digestion. Decreased lipolytic activity of fungal lipase in the presence of bile acids could explain the fact that no superiority over enteric-coated microsphere preparations has been demonstrated to date (Griffin et al, 1989; Zentler-Munro et al, 1992).

Although rare, possible side effects of pancreatic exocrine enzyme supplementation are sourness of the mouth, perianal irritation, abdominal pain, diarrhea, constipation in infants, allergic reactions to pork proteins, hypersensitivity reactions after inhalation, and fibrosing colonopathy in cystic fibrosis patients (Lebenthal et al, 1994; Loser & Folsch, 1995). In regard to fibrosing colonopathy, it has been recommended that the maximum dose of lipase should not exceed 10,000 IU/kg body weight per day, or 2500 IU/kg body weight per meal.

Substitution Therapy in Chronic Pancreatitis

Approximately 80% of patients with CP can be managed by dietary means and pancreatic enzyme supplements. Some patients (10% to 15%) need oral supplements (polymeric or semielemental), 5% need enteral tube feeding, and approximately 1% need total parenteral nutrition (TPN). Reduction of steatorrhea and supplementation of calories are the main goals of nutritional therapy in CP. Treatment of exocrine insufficiency starts with dietary therapy and pancreatic enzyme supplementation (DiMagno, 1979).

Total abstinence from alcohol and partaking of frequent meals are basic dietary recommendations. The diet should be rich in proteins (1.0 to 1.5 g/kg body weight/day) and carbohydrates, although carbohydrates must be limited when diabetes mellitus is present. In addition, 30% to 40% of calories should be in the form of fats. Medium-chain triglycerides may be used to increase fat absorption, because they are absorbed directly across the small bowel into the portal vein, even in absence of lipase, co-lipase, and bile salts. Vitamins should be supplemented if serum levels indicate a deficiency (Havala et al, 1989). Patients with protein maldigestion and steatorrhea must be supplemented individually with exogenous pancreatic enzymes. Weight control, symptomatic relief of diarrhea, and a decrease in 72-hour fecal fat excretion are practical end points of therapy.

Enteral nutrition (EN) is indicated when a patient is unable to eat, has progressive weight loss despite an adequate dietary regimen, or develops acute complications; EN may also be indicated preoperatively and postoperatively. Only rarely is TPN indicated in patients with CP, such as when gastric emptying is blocked, when the patient needs gastric decompression, when the feeding tube cannot be introduced into the jejunum, or when a complicated fistula is present. In most cases, surgical intervention can solve these problems.

Conservative Treatment of Pain

Pain significantly reduces patients’ quality of life, and pain relief should be one of the main goals of conservative treatment in CP. Pain also may be treated interventionally or surgically, but medical treatment is generally the first-line therapy in patients with painful CP.

Different medical treatment options and therapeutic interventions are available, and these must be integrated into an individualized treatment plan. The pathogenesis of pain especially influences the therapeutic procedure. Two mechanisms are suggested for the generation of pain in the absence of local complications: 1) inflammatory changes of pancreatic parenchyma with intrapancreatic and peripancreatic neural alterations (Bockman et al, 1988; Ceyhan et al, 2009a, 2009b; Di Sebastiano et al, 1997), and 2) ductal and intraparenchymal hypertension (Di Sebastiano et al, 2003; Ebbehoj et al, 1990).

As for the second mechanism, options that reduce the intrapancreatic pressure may lead to a significant reduction of pancreatic pain. In the case of inflammation, a significant number of inflammatory mediators in pancreatic parenchyma and pancreatic nerves are detected in patients with pain (Ceyhan et al, 2009b; Di Sebastiano et al, 2000). Several medical, analgesic, and antiinflammatory treatment options are available, which may be combined with or supported by interventional methods.

Interventional Procedures to Treat Pancreatic Pain

Of patients with pancreatic pain, 40% to 70% seem to benefit from medical treatment (Ammann et al, 1984). This percentage may increase by combining medical therapy and interventional procedures (van der Hule et al, 1994). Pancreatic pain may also be improved by the combination of interventional endoscopy and lithotripsy, although a recent RCT demonstrated increased costs but no outcome benefit when systematic endoscopy was added to lithotripsy (Dumonceau et al, 2007). Some studies showed a significant difference in improvement of pain among patients with successful or unsuccessful lithotripsy (Delhaye et al, 1992; Costamagna et al, 1997; Johanns et al, 1996; Ohara et al, 1996; Sauerbruch et al, 1992; Schneider et al, 1994; Smits et al, 1996). Other studies did not report this difference (Adamek et al, 1999).

Celiac plexus neurolysis and celiac block involve injecting an agent at the celiac axis, with the aim of either selectively destroying the celiac plexus or temporarily blocking visceral afferent nociceptors. Agents most commonly used for this purpose include alcohol or phenol for neurolysis and bupivacaine and triamcinolone for a temporary block. Methods to administer such agents to the celiac ganglion include CT imaging, percutaneous ultrasound, fluoroscopy, or endoscopic ultrasound (EUS). Whereas the EUS-guided technique may be superior compared with the other methods, response rates in general are relatively low (Gress et al, 1999; Noble & Gress, 2006; Santosh et al, 2009).

Autoimmune Pancreatitis

A type of CP that might be caused by an autoimmune mechanism was first described by Sarles and collegues (1961) and was termed primary inflammatory sclerosis of the pancreas. Since then, a growing body of evidence suggests that autoimmune pancreatitis (AIP) is distinct from obstructive or calcifying forms of CP. Two clinical and histologic patterns of AIP can be distinguished (Park et al, 2009). Type 1 is characterized by the histologic key features of dense periductal lymphoplasmacytic infiltrate, swirling or storiform fibrosis, and obliterative venulitis; serum levels of the immunoglobulin G4 (IgG4) subclass of IgG are typically increased (Hamano et al, 2001). Type 1 AIP fits the classic description of the disease reported in Japan, also known as lymphoplasmacytic sclerosing pancreatitis. Type 1 AIP appears to be the pancreatic manifestation of a systemic disease that may also affect other organs, including the bile duct, retroperitoneum, kidney, lymph nodes, and salivary glands. Type 2 AIP is typically characterized by a duct-destructive pathology with infiltrating neutrophils, lymphocytes, and plasma cells. Typical serologic markers seen in type 1 AIP are not elevated in type 2 AIP (Park et al, 2009). Typical imaging features—a diffuse, sausage-shaped, enlarged pancreas with delayed and peripheral enhancement—only show up in about 50% of patients. Furthermore, classic features of lymphoplasmacytic sclerosing pancreatitis are found in just 20% of core biopsies, and false-positive IgG4 immunostaining has also been reported in the setting of cancer. Thus the preoperative differentiation from pancreatic carcinoma is a diagnostic challenge. In highly suspected or histologically confirmed cases of AIP, steroid therapy (prednisolone, initially 30 to 40 mg/day) may ameliorate symptoms and imaging findings within two weeks. Importantly, the similarity to pancreatic carcinoma and the absence of specific diagnostic parameters may result in surgical treatment of this disease. Because reports about patients misdiagnosed as having AIP are increasingly encountered, surgery should always be considered in doubtful cases (Gardner et al, 2009).

Decompression of Pancreatic Pseudocysts

Pancreatic pseudocysts are a late complication of CP. The main techniques for decompression of pancreatic pseudocysts include transgastric and transduodenal approaches (Sahel, 1990; Dohmoto & Rupp, 1992); these require a clear bulging of the cyst into the gastric or duodenal cavity to ensure a short distance between the cystic wall and the intestinal tract. In this context, endosonography has been shown to reduce the risk of cyst perforation and hemorrhage (Binmoeller et al, 1994; Etzkorn et al, 1995; Grimm et al, 1992).