CHRONIC PANCREATITIS

                                CHRONIC PANCREATITIS –

- is a self perpetuaring disease characterised by pain and ultimately by pancreatic exocrine or endocrine insufficiency.

Chronic inflammatory disease of the pancreas may present as episodes of acute inflammation in a previously injured pancreas or as chronic damage with persistent pain or malabsorption.

The causes of relapsing chronic pancreatitis are similar to those of acute pancreatitis (Table 294-1), except that there is an appreciable incidence of cases of undetermined origin. In addition, the pancreatitis associated with gallstones is predominantly acute or relapsing-acute in nature. A cholecystectomy is almost always performed in patients after the first or second attack of gallstone-associated pancreatitis.

Patients with chronic pancreatitis may present with persistent abdominal pain, with or without steatorrhea; some (~15%) present with steatorrhea and no pain.

Patients with chronic pancreatitis in whom there is extensive destruction of the pancreas (<10% of exocrine function remaining) have steatorrhea and azotorrhea.

Among American adults, alcoholism is the most common cause of clinically apparent pancreatic exocrine insufficiency, while cystic fibrosis is the most frequent cause in children. In up to 25% of American adults with chronic pancreatitis, the cause is not known; that is, they have idiopathic chronic pancreatitis. Indeed, idiopathic chronic pancreatitis is the leading cause of nonalcoholic chronic pancreatitis in adults in the United States. In a recent series, genetic testing was done on 39 patients with idiopathic chronic pancreatitis. Seventeen patients had CFTR mutations and 9 had mutations in a trypsin inhibitor gene (PSTI). Pancreatitis risk was increased 14-fold by having the PSTI mutation, 40-fold by having two abnormal copies of CFTR, and 600-fold by having both. Thus, the risk of pancreatitis showed complex inheritance and was highest in individuals who had abnormalities in both the pancreatic ducts (CFTR) and acini (PSTI). These findings suggest that PSTI is a modifier gene for CFTR-related idiopathic chronic pancreatitis. Current knowledge indicates that about 15% of patients with idiopathic chronic pancreatitis have a genetic basis for this disorder.

The therapeutic and prognostic implication of these findings remain to be determined.

In other parts of the world, severe protein-calorie malnutrition is a common cause.

In certain countries, particularly Japan and Italy, there has been an increased interest in autoimmune chronic pancreatitis. The Japanese describe a distinct entity that is associated with the presence of autoantibodies in the blood, elevated levels of serum IgG, association with other autoimmune disorders such as primary biliary cirrhosis and inflammatory bowel disease, diffuse enlargement of the pancreas, and irregular narrowing of the main pancreatic duct. Symptoms are usually mild without acute relapsing attacks of pancreatitis, and patients usually experience a good therapeutic response to glucocorticoids. It is noteworthy that pancreatic pseudocysts and calcification within the pancreas are unusual. Although this kind of pancreatitis is not very common in the United States, all major medical centers are seeing examples of autoimmune chronic pancreatitis.

Table  lists other causes of pancreatic exocrine insufficiency, but they are relatively uncommon.

TABLE 294-5 Causes of Pancreatic Exocrine Insufficiency

Alcohol, chronic alcoholism Idiopathic pancreatitis Cystic fibrosis Hypertriglyceridemia                     Severe protein-calorie malnutrition with hypoalbuminemia   Tropical pancreatitis (Africa, Asia) Pancreatic and duodenal neoplasms Pancreatic resection Gastric surgery   Subtotal gastrectomy with Billroth I anastomosis   Subtotal gastrectomy with Billroth II anastomosis   Truncal vagotomy and pyloroplasty Gastrinoma (Zollinger-Ellison syndrome) Hereditary pancreatitis Traumatic pancreatitis Autoimmune pancreatitis Abdominal radiotherapy Hemochromatosis Primary sclerosing cholangitis Primary biliary cirrhosis Shwachman's syndrome (pancreatic insufficiency and bone marrow dysfunction) Trypsinogen deficiency Enterokinase deficiency Isolated deficiencies of amylase, lipase, or proteases α1-Antitrypsin deficiency

PATHOPHYSIOLOGY

The events that initiate an inflammatory process in the pancreas are still not well understood, and the many hypotheses will not be reviewed here. In the case of alcohol-induced pancreatitis, it has been suggested that the primary defect may be the precipitation of protein (inspissated enzymes) in the ducts. The resulting ductal obstruction could lead to duct dilation, diffuse atrophy of the acinar cells, fibrosis, and eventual calcification of some of the protein plugs. However, the fact that some alcoholic patients with recurrent acute pancreatitis show no evidence of chronic pancreatitis does not support this hypothesis. In fact, experimental and clinical observations have shown that alcohol has direct toxic effects on the pancreas. While patients with alcohol-induced pancreatitis generally consume large amounts of alcohol, some consume very little (≤50 g/d). Thus prolonged consumption of “socially acceptable” amounts of alcohol is compatible with the development of pancreatitis. In addition, the finding of extensive pancreatic fibrosis in patients who died during their first attack of clinical acute alcohol-induced pancreatitis supports the concept that such patients already have chronic pancreatitis.

CLINICAL FEATURES

Patients with relapsing chronic pancreatitis may present with symptoms identical to those of acute pancreatitis, but pain may be continuous, intermittent, or absent. The pathogenesis of this pain is poorly understood.

Although the classic description is of

-        epigastric pain radiating through the back,

-        the pain pattern is often atypical; the pain may be worst in the right or left upper quadrant of the back or may be diffuse throughout the upper abdomen;

-        it may even be referred to the anterior chest or flank.

Characteristically it is persistent, deep-seated, and unresponsive to antacids. It often is worsened by ingestion of alcohol or a heavy meal (especially one rich in fat). Often the pain is severe enough to necessitate the frequent use of narcotics.

Weight loss, abnormal stools, and other signs or symptoms suggestive of malabsorption are common in chronic pancreatitis.

However, clinically apparent deficiencies of fat-soluble vitamins are surprisingly rare.

The physical findings in these patients are usually not impressive, so that there is a disparity between the severity of the abdominal pain and the physical signs (other than some abdominal tenderness and mild temperature elevation).

DIAGNOSTIC EVALUATION

In contrast to relapsing acute pancreatitis, the serum amylase and lipase levels are usually not elevated in chronic pancreatitis. Elevations of serum bilirubin and alkaline phosphatase levels may indicate cholestasis secondary to chronic inflammation around the common bile duct (Fig. 294-3).

Many patients demonstrate impaired glucose tolerance, and some have an elevated fasting blood glucose level.

View Figure

FIGURE 294-3 Radiologic abnormalities in chronic pancreatitis. A. Pancreatic calcification (arrows) and stenosis (tapering) of the intrahepatic portion of the common bile duct demonstrated by percutaneous transhepatic cholangiography. B. Pancreatic calcification (large white arrow) demonstrated by sonography. Note dilated pancreatic duct (thin white arrow) and splenic vein (open arrow). C. Pancreatic calcification (vertical arrows) and dilated pancreatic duct (horizontal arrow) demonstrated by CT scan. D. Endoscopic retrograde cholangiogram shows grossly dilated pancreatic ducts (arrows) in a patient with long-standing pancreatitis.

The classic triad of pancreatic calcification, steatorrhea, and diabetes mellitus usually establishes the diagnosis of chronic pancreatitis and exocrine pancreatic insufficiency but is found in fewer than one-third of chronic pancreatitis patients. Accordingly, it is often necessary to perform an intubation test such as the secretin stimulation test, which usually gives abnormal results when 60% or more of pancreatic exocrine function has been lost. Approximately 40% of patients with chronic pancreatitis have cobalamin (vitamin B₁₂) malabsorption, which can be corrected by the administration of oral pancreatic enzymes. There is usually a marked excretion of fecal fat (Chap. 275), which can be reduced by the administration of oral pancreatic enzymes. The serum trypsinogen (Chap. 293) and the D-xylose urinary excretion test are useful in patients with “pancreatic steatorrhea,” since the trypsinogen level will be abnormal, and D-xylose excretion is usually normal. A decreased serum trypsinogen (<20 ng/mL) or a fecal elastase level of <100 µg/mg of stool strongly suggests severe pancreatic exocrine insufficiency.

The radiographic hallmark of chronic pancreatitis is the presence of scattered calcification throughout the pancreas (Fig. 294-3). Diffuse pancreatic calcification indicates that significant damage has occurred and obviates the need for a secretin test. While alcohol is by far the most common cause, pancreatic calcification may also be seen in cases of severe protein-calorie malnutrition, hereditary pancreatitis, posttraumatic pancreatitis, hyperparathyroidism, islet cell tumors, and idiopathic chronic pancreatitis. A large prospective study has shown convincingly that pancreatic calcification decreases or even disappears spontaneously in one-third of patients with severe chronic pancreatitis; this outcome may also follow ductal decompression. Pancreatic calcification is a dynamic process that is incompletely understood.

Sonography, CT, and ERCP greatly aid the diagnosis of pancreatic disease. In addition to excluding pseudocysts and pancreatic cancer, sonography and CT may show calcification or dilated ducts associated with chronic pancreatitis (Fig. 294-4). ERCP and endoscopic ultrasound (EUS) are procedures that provide information about the main pancreatic duct and the smaller ducts. EUS is also useful in evaluating the pancreatic parenchyma. In patients with alcohol-induced pancreatitis, ERCP may reveal a pseudocyst missed by sonography or CT.

View Figure

FIGURE 294-4 Chronic pancreatitis and pancreatic calculi: CT scan and ERCP appearance. A. In this contrast-enhanced CT scan of the abdomen, there is evidence of an atrophic pancreas with multiple calcifications (arrows). Note the markedly dilated pancreatic duct seen in this section through the body and tail (open arrows). B. ERCP in the same patient demonstrates the dilated pancreatic duct as well as an intrapancreatic duct calculus (arrows). These findings correlate nicely with the CT scan appearance.

COMPLICATIONS OF CHRONIC PANCREATITIS

The complications of chronic pancreatitis are protean.

- Cobalamin (vitamin B₁₂) malabsorption occurs in 40% of patients with alcohol-induced chronic pancreatitis and in virtually all with cystic fibrosis. It is consistently corrected by the administration of pancreatic enzymes (containing proteases). It may be due to excessive binding of cobalamin by cobalamin-binding proteins other than intrinsic factor, which ordinarily are destroyed by pancreatic proteases and therefore do not compete with intrinsic factor for cobalamin binding.

- Although most patients show impaired glucose tolerance, diabetic ketoacidosis and coma are uncommon.

- Similarly, end-organ damage (retinopathy, neuropathy, nephropathy) is also uncommon, and the appearance of these complications should raise the question of concomitant genetic diabetes mellitus. A nondiabetic retinopathy, peripheral in location and secondary to vitamin A and/or zinc deficiency, is common in these patients. Effusions containing high concentrations of amylase may occur into the pleural, pericardial, or peritoneal space.

- Gastrointestinal bleeding may occur from peptic ulceration, gastritis, a pseudocyst eroding into the duodenum, or ruptured varices secondary to splenic vein thrombosis due to inflammation of the tail of the pancreas.

- Icterus may occur, caused either by edema of the head of the pancreas, which compresses the common bile duct, or by chronic cholestasis secondary to a chronic inflammatory reaction around the intrapancreatic portion of the common bile duct (Fig. 294-3). The chronic obstruction may lead to cholangitis and ultimately to biliary cirrhosis. Subcutaneous fat necrosis may appear as tender red nodules on the lower extremities. Bone pain may be secondary to intramedullary fat necrosis. Inflammation of the large and small joints of the upper and lower extremities may occur. The incidence of pancreatic carcinoma is increased in patients with chronic pancreatitis who have been followed for 2 or more years. Twenty years after the diagnosis of chronic pancreatitis, the cumulative risk of pancreatic carcinoma is 4%. Perhaps the most common and troublesome complication is addiction to narcotics.

TREATMENT

Supportive measures include diet restriction and pain medications. The diet should be moderate in fat (30%), high in protein (24%), and low in carbohydrate (40%). Restriction of long-chain triglyceride intake can help patients who do not respond satisfactorily to pancreatic enzyme therapy. Use of foods containing mainly medium-chain fatty acids, which do not require lipase for digestion, may be beneficial.

Therapy for patients with chronic pancreatitis is directed toward two major problems—pain and maldigestion.

Patients with intermittent attacks of pain are treated essentially like those with acute pancreatitis (see above). Patients with severe and persistent pain should avoid alcohol completely and avoid large meals rich in fat. Since the pain is often severe enough to require frequent use of narcotics (and hence addiction), a number of surgical procedures have been developed for pain relief. ERCP allows the surgeon to plan the operative approach. If there is a stricture of the pancreatic duct, a local resection may ameliorate the pain. Unfortunately, isolated localized strictures are not common. In most patients with alcohol-induced disease, the pancreas is diffusely involved, and surgically correctible localized ductal disease is rare. When there is primary ductal obstruction and dilation, ductal decompression may provide effective pain palliation. Short-term pain relief may be achieved in up to 80% of patients, while long-term pain relief occurs in approximately 50%. In some of these patients, however, pain relief can be achieved only by resecting 50 to 95% of the gland. Although pain relief is achieved in three-quarters of these patients, they tend to develop pancreatic endocrine and exocrine insufficiency and must be treated with pancreatic enzyme replacement therapy. It is important to screen patients carefully, for such radical surgery is contraindicated in those who are severely depressed or suicidal or who continue to drink. Procedures such as splanchnicectomy, celiac ganglionectomy, and nerve blocks usually bring only temporary relief and are not recommended. Endoscopic treatment of chronic pancreatitis may involve sphincterotomy of the minor or major pancreatic sphincter, dilatation of strictures, removal of calculi, or stenting of the ventral or dorsal pancreatic duct. Although many of these techniques are technically impressive, none has been subjected to a randomized trial in patients with chronic pancreatitis. In addition, significant complications—acute pancreatitis, pancreatic abscess, damage to the pancreatic duct, and death—have occurred in up to 36% of patients after stent placement.

Three double-blind trials have demonstrated that administration of pancreatic enzymes decreases abdominal pain in selected patients with chronic pancreatitis. In these trials, approximately 75% of the patients evaluated experienced pain relief. The patients most likely to respond are those with mild to moderate exocrine pancreatic dysfunction, as evidenced by an abnormal secretin test, normal fat absorption, and minimal abnormalities on ERCP examination. These clinical observations seem to fit with data from humans and experimental animals demonstrating a negative feedback regulation for pancreatic exocrine secretion controlled by the amount of proteases within the lumen of the proximal small intestine. It seems reasonable to use the following approach for patients with severe, persistent, or continuous abdominal pain thought to be caused by chronic pancreatitis. After other causes of abdominal pain (peptic ulcer, gallstones, etc.) have been excluded, a pancreatic sonogram should be done. If no mass is found, a secretin test may be performed, because its results are usually abnormal in cases of chronic pancreatitis with pain. If the results are abnormal (i.e., decreased bicarbonate concentration or volume output), a 3- to 4-week trial of pancreatic enzyme administration is appropriate. Four to eight conventional tablets or capsules are taken at meals and at bedtime. There are a number of studies suggesting that patients may have small-duct chronic pancreatitis and chronic abdominal pain with a normal appearance on radiographic evaluations (ultrasound, CT, ERCP) but abnormal results on hormone stimulation tests (secretin test) and/or abnormal pancreatic histology. Such minimal-change chronic pancreatitis may respond well to pancreatic enzyme therapy (non-enteric-coated) for relief of abdominal pain. If no relief is obtained, and especially if the volume secreted during the secretin test is very low, ERCP or EUS should be performed. If a pseudocyst or a localized ductal obstruction is found, surgery should be considered. A patient who has dilated ducts may be a candidate for a surgical ductal decompression procedure. This procedure provides short-term relief in up to 80% of patients, although long-term results are closer to 50%. Some studies have shown octreotide to be effective in decreasing abdominal pain in patients with severe large-duct disease. If no surgically remediable lesion is found and severe pain continues despite abstinence from alcohol, subtotal pancreatic resection may be necessary.

The treatment of maldigestion rests on the use of pancreatic enzyme replacement therapy. Diarrhea and steatorrhea are usually improved by this treatment, although the steatorrhea may not be completely corrected. The major problem is delivering enough active enzyme into the duodenum. Steatorrhea could be abolished if 10% of the normal amount of lipase could be delivered to the duodenum at the proper time. This concentration of lipase cannot be achieved with the current preparations of pancreatic enzymes, even if the latter are given in large doses. The reason for these poor results may be that lipase is inactivated by gastric acid, that food empties from the stomach faster than do the pancreatic enzymes, and that batches of commercially available pancreatic extracts vary in enzyme activity.

For the usual patient, two or three enteric-coated capsules or eight conventional (non-enteric-coated) tablets of a potent enzyme preparation should be administered with meals. The usual dose is 30000units of lipase in capsules (Kreon, mesim-forte).

Some patients using conventional tablets require adjuvant therapy to improve enzyme replacement treatment. H₂ receptor antagonists (ranitidine, 150 mg twice daiky), sodium bicarbonate (650 mg before and after meals), and proton pump inhibitors (e.g, omeprazole, 20-60 mg daily) are effective adjuvants.

Antacids containing calcium carbonate or magnesium hydroxide are not effective and may actually result in increased steatorrhea. Several publications have reported colonic strictures in patients with cystic fibrosis receiving extraordinarily high doses of high-potency pancreatic enzyme preparations. Such lesions have not been reported in adults with chronic pancreatitis.

Nonnarcotic analgesics should be emphasized (Baralgin 5,0 I|v or i|m, Spasmolgon 5,0 I|v or i|m). Patients taking narcotic drugs for pain relief often become addicted and continue to have pain.

Prognosis

Patients with severe exocrine pancreatic insufficiency secondary to alcohol who continue to drink have a high mortality rate (in one series, 50% of patients who were followed for 5 to 12 years died during this period) and significant morbidity (weight loss, lassitude, vitamin deficiency, and narcotic addiction).

Chronic pancreatitis carries significant medical and social costs. A recent study found that pancreatitis led to retirement in 11% of patients with the disease, accounting for 45% of all retirements. In 87% of patients with chronic pancreatitis unable to maintain gainful employment, alcoholism was a contributing factor. Patients with chronic pancreatitis also use substantial medical resources. In 1987 in the United States, this diagnosis accounted for 122,000 recorded outpatient visits and 56,000 hospital admissions. Pain may abate if progressive severe exocrine insufficiency continues. Patients who abstain from alcohol and use vigorous replacement therapy for maldigestion do reasonably well.

Medical management of the hyperlipidemias frequently associated with the condition may also prevent recurrent attacks of pancreatitis.