Cholelithiasis. Chronic cholecystitis and functional biliary disorders. Chronic pancreatitis.

І. CHRONIC CHOLECYSTITIS, CHOLEDOCHOLITHIASIS, CHOLANGITIS, DYSKINEZIA OF BILE DUCTS

(aetiology, diagnosis, treatment, complications).

Half of patients with gallstones experience no problems but 35% of patients with gallstones discovered by chance will require treatment over the next 10 years as a result of either pain or complications. A number of clinical conditions may develop as a result of gallstones depending upon their location (Fig. 1).

Fig. 1 Gallstones and the conditions they cause.

Acute cholecystitis. The abrupt onset of severe, right upper quadrant (RUQ) pain, which is constant and does not remit, points to acute cholecystitis. It is usually accompanied by pyrexia and leucocytosis and is a result of impaction of a gallstone in the cystic duct with associated infection in 50% of cases. Jaundice may develop if there is compression of the common bile duct (CBD) either because of the stone in the cystic duct or as result of surrounding inflammation (Mirizzi's syndrome). In seriously ill, elderly patients a similar picture may develop in the absence of gallstones and is termed acute acalculous cholecystitis and carries a poor prognosis.

Biliary pain / chronic cholecystitis

The symptoms are of intermittent, dull RUQ pain - constant or colicky. It may occur at any time and is not necessarily related to meals. It resolves spontaneously within a few hours and is not associated with systemic upset. These symptoms are a common indication for cholecystectomy, but it is difficult to determine that patients' symptoms are caused by their gallstones in this group. Symptoms of non-specific, post-prandial pain, bloating and fatty food intolerance are not good discriminators and 25% of patients who undergo cholecystectomy for these symptoms will experience continued discomfort postoperatively.

Choledocholithiasis

Stones which have migrated into or formed within the CBD may be asymptomatic and be discovered by an elevation in the alkaline phosphatase level. They are usually associated with biliary type pain and intermittent jaundice and can cause obstruction. Removal of these stones is essential as there is a high complication rate (Table 1).

Cholangitis

This occurs when there is infection in the biliary tree, usually as a result of CBD stones. Patients present with biliary pain, jaundice, fever and often rigors. The septicaemia is usually due to Gram-negative organisms, is frequently severe and may be lifethreatening.

Table 1 Conditions resulting from gallstones

Dyskinezia of bile ducts.

- Hypertonic, hyperkinetic type

- Hypotonic, hypokinetic type

- Mixed type.

The symptoms are of intermittent, dull RUQ pain – constant (hypotonic, hypokinetic type) or colicky (hypertonic, hyperkinetic type).

Less common complications

As stones pass the ampulla of Vater, they can induce a biliary pancreatitis. Stones may erode through the gallbladder wall into the ileum causing a choleeystenteric fistula. Gallbladder stones may be associated with calcification of the gallbladder wall ('porcelain' gallbladder), which carries a 20% risk of developing gallbladder cancer. Chronic cholelithiasis alone carries an increased but much lower risk of developing cancer.

AETIOLOGY

Bile is a super-saturated solution of cholesterol (Fig.2).

Fig.2 Cholesterol is solubilized in bile by the formation of mixed micelles that consist predominantly of bile salt and phospholipid. Micelles form when the concentration of bile salts in water is between 2 and 4 mM, the so-called critical micellar concentration (CMC). The negatively charged hydrophilic region of the bile salt molecule faces outward into the water phase, whereas the uncharged hydrophobic region is directed inward. These three components—bile salts, phospholipids, and cholesterol—exist in equilibrium between the free state and micelle constituents. At the CMC for bile salts, the equilibrium shifts strongly in the direction of the micelle. If bile salt concentrations are insufficient, the hydrophobic cholesterol molecules will precipitate to form a nidus for a gallstone.

Cholesterol does not crystallise out because of a combination of factors including: 1. the detergent activity of bile salts (paradoxically produced from cholesterol) and the polar lipid lecithin 2. gallbladder motility. Gallstones develop when these mechanisms fail and there is an originating nidus for stone formation which is often mucin or bacteria. 80% of gallstones are cholesterol or mixed cholesterol stones where cholesterol is the major constituent. Pigment stones form the bulk of the rest and comprise predominantly bile pigment and are most common in chronic haemolytic states (Tab.2, Fig. 3).

Table 2 Types of gallstones

Fig.3 Gall stones vary from pure cholesterol (white), through mixed, to bile salt predominant (black).

EPIDEMIOLOGY.

Incidence varies with age: 5% at age 20, rising to 30% over 50 (Fig.4).

Fig.4 Prevalence of gall stones according to age

There is a 2:1 predominance in females. There are wide ethnic variations with American Pima Indians having an incidence of 70% in females aged 20. Scandinavia also has high incidences excreted in the bile, subsequently being concentrated in the gallbladder. This shows gallstones as filling defects within the gallbladder and demonstrates that the cystic duct is not obstructed. Following a fatty meal, the ability of the gallbladder to contract can also be measured. A functioning gallbladder and a non-obstructed, cystic duct are prerequisites for consideration of bile dissolution therapy.

Risk factors for calculous cholecystitis mirror those for cholelithiasis and include the following:

· Female sex;

· Certain ethnic groups;

· Obesity or rapid weight loss;

· Drugs (especially hormonal therapy in women);

· Pregnancy;

· Increasing age.

Acalculous cholecystitis is related to conditions associated with biliary stasis, to include the following:

· Critical illness;

· Major surgery or severe trauma/burns;

· Sepsis;

· Long-term total parenteral nutrition (TPN);

· Prolonged fasting.

Other causes of acalculous cholecystitis include the following:

· Cardiac events, including myocardial infarction;

· Sickle cell disease;

· Salmonella infections;

· Diabetes mellitus;

· Patients with AIDS who have cytomegalovirus, cryptosporidiosis, or microsporidiosis.

Patients who are immunocompromised are at increased risk of developing cholecystitis from a number of different infectious sources. Idiopathic cases exist.

Pathogenesis

Ninety percent of cases of cholecystitis involve stones in the cystic duct (ie, calculous cholecystitis), with the other 10% of cases representing acalculous cholecystitis.

Acute calculous cholecystitis is caused by obstruction of the cystic duct, leading to distention of the gallbladder. As the gallbladder becomes distended, blood flow and lymphatic drainage are compromised, leading to mucosal ischemia and necrosis.

Although the exact mechanism of acalculous cholecystitis is unclear, several theories exist. Injury may be the result of retained concentrated bile, an extremely noxious substance. In the presence of prolonged fasting, the gallbladder never receives a cholecystokinin (CCK) stimulus to empty; thus, the concentrated bile remains stagnant in the lumen. A study by Cullen et al demonstrated the ability of endotoxin to cause necrosis, hemorrhage, areas of fibrin deposition, and extensive mucosal loss, consistent with an acute ischemic insult . Endotoxin also abolished the contractile response to CCK, leading to gallbladder stasis.

Clinical presentation

The most common presenting symptom of acute cholecystitis is upper abdominal pain. Signs of peritoneal irritation may be present, and in some patients, the pain may radiate to the right shoulder or scapula. Frequently, the pain begins in the epigastric region and then localizes to the right upper quadrant (RUQ). Although the pain may initially be described as colicky, it becomes constant in virtually all cases. Nausea and vomiting are generally present, and patients may report fever.

Most patients with acute cholecystitis describe a history of biliary pain. Some patients may have documented gallstones. Acalculous biliary colic also occurs, most commonly in young to middle-aged females. The presentation is almost identical to calculous biliary colic with the exception of reference range laboratory values and no findings of cholelithiasis on ultrasound. Cholecystitis is differentiated from biliary colic by the persistence of constant severe pain for more than 6 hours.

Patients with acalculous cholecystitis may present similarly to patients with calculous cholecystitis, but acalculous cholecystitis frequently occurs suddenly in severely ill patients without a prior history of biliary colic. Often, patients with acalculous cholecystitis may present with fever and sepsis alone, without history or physical examination findings consistent with acute cholecystitis.

Diagnosis

Delays in making the diagnosis of acute cholecystitis result in a higher incidence of morbidity and mortality. This is especially true for intensive care unit (ICU) patients who develop acalculous cholecystitis. The diagnosis should be considered and investigated promptly in order to prevent poor outcomes.

Example of diagnosis

Chronic non-calculous recurrent cholecystitis, acute phase, moderate severite. Hypotonic biliary dyskinesia

Laboratory tests and diagnostic studies

Although laboratory criteria are not reliable in identifying all patients with cholecystitis, the following findings may be useful in arriving at the diagnosis:

· Leukocytosis with a left shift may be observed in cholecystitis.

· Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels are used to evaluate the presence of hepatitis and may be elevated in cholecystitis or with common bile duct obstruction.

· Bilirubin and alkaline phosphatase assays are used to evaluate evidence of common duct obstruction.

· Amylase/lipase assays are used to evaluate the presence of pancreatitis. Amylase may also be elevated mildly in cholecystitis.

· An elevated alkaline phosphatase level is observed in 25% of patients with cholecystitis.

· Urinalysis is used to rule out pyelonephritis and renal calculi.

· All females of childbearing age should undergo pregnancy testing.

A retrospective study by Singer, aimed at determining a set of clinical and laboratory parameters that could be used to predict the outcome of hepatobiliary scintigraphy (HBS) in all patients with suspected acute cholecystitis, found that of 40 patients with pathologically confirmed acute cholecystitis, 36 (90%) did not have fever at the time of presentation and 16 (40%) did not have leukocytosis. The study also found that no combination of laboratory or clinical values was useful in identifying patients at high risk for a positive HBS finding.

Endoscopic retrograde cholangiopancreatography

(ERCP) is the technique of choice to demonstrate CBD stones as it also allows therapeutic interventions at the same time (Fig.5,6).

Fig.5 Endoscopic retrograde cholangiopancreatography reveals abnormalities in a patient with gallstones. Multiple radiolucent areas establish the diagnosis of stones in the gallbladder (broken arrow) and common bile duct (solid arrow).

Fig.6 This cholangiogram, obtained during endoscopic retrograde cholangiopancreatography, shows a normal gallbladder (black arrow) and a narrowed biliary tree with many areas of segmental stenosis (white arrows), diagnostic of primary sclerosing cholangitis.

Computerised tomography (CT) is not particularly helpful in gallstone disease but fine slice images may demonstrate CBD stones not seen at ultrasound. MR cholangiography is in its infancy and its place in hepatobiliary disease is being defined (Fig.7).

Fig.7 This magnetic resonance cholangiopancreatogram shows multiple gallstones (arrows) in the common bile duct (choledocholithiasis).

Ultrasonography is the important procedure for the diagnosis of chronic gallbladder disease. In 90% to 95% of cases of cholelithiasis, ultrasonography demonstrates the echo of the calculus and the acoustic shadow behind the calculus.

Fig.8 Ultrasound showing normal gallbladder

Fig.9 Ultrasound showing chronic cholecystitis.

Fig.10 Stone in the gallbladder.

VIDEO 3 (Ultrasonography. Stone in the gallbladder)

Fig.11 Ultrasound of the gallbladder showing, in the center of the image, a stone within the gallbladder with a triangular area of acoustic attenuation (“shadowing”) behind the gallstone.

Fig.12 Top: Ultrasound image of gall bladder with dark area (a) representing gall bladder and multiple white echoes (b) representing stones. Bottom: The gall bladder after cholecystectomy with multiple small stones.

Fig.13 Polyp in the gallbladder.

Fig.14 Radiograph of the right upper abdominal quadrant during upper GI barium study showing a calcified wall of the gallbladder (“porcelain“ gallbladder), ndicating chronic cholecystitis and a high risk of gallbladder cancer.

Fig.15 Cholecystography. Cholelithiasis.

TREATMENT

Cholecystitis

Acute cholecystitis requires analgesia, intravenous support and antibiotics, and usually settles with these measures. Subsequent cholecystectomy may then be performed when the acute episode has resolved. Careful selection of patients with chronic cholecystitis is important as not all patients are pain-free when the gallbladder is removed; symptoms may abate spontaneously and not recur; and there is an increasing, associated, operative mortality with advancing age. Laparoscopic cholecystectomy has increased the acceptability of the procedure for patients and has consequently become widely available. There appears to be an increased risk of bile duct injury at the time of the procedure, particularly when carried out by inexperienced surgeons. However, the replacement of a large subcostal scar with three porthole incisions reduces postoperative pain and hospital stay from 10 to less than 3 days.

Cholangitis

Acute cholangitis is a serious infection which may be life-threatening. Antibiotics such as third generation cephalosporins or amino-quinolones should be used. Careful attention should be paid to fluid balance, urine output and renal function. Cholangitis is usually caused by CBD stones and therefore ERCP is required early in its management, to allow confirmation of biliary stones and their extraction. Following sphincterotomy, the bile duct can be trawled with either an inflatable balloon or a basket to extract the stones. If it is not possible to clear the duct, then an endoscopic stent may be inserted to facilitate bile drainage and reduce the risk of further episodes of cholangitis. Subsequent attempts may be made to clear the bile duct or in the elderly these stents may be left in place. As long-term stents can occlude and further episodes of cholangitis can occur, stent replacement may be necessary.

Postcholecystectomy pain

Following cholecystectomy, some patients continue to experience symptoms such as bloating, fatty food intolerance and dyspepsia. These symptoms usually predated the surgery and are often due to the irritable bowel syndrome. There is also a group of patients who have convincing biliary pain after stones have been removed. Liver function tests may be abnormal and some patients may be jaundiced. ERCP shows a dilated CBD without stones and there may be delayed excretion of contrast medium. This points towards sphincter of Oddi dysfunction which in more severe cases may benefit from endoscopic sphincterotomy.

Medical management of gallbladder stones

Dissolution therapy can be considered in patients with uncomplicated gallstone disease who are unwilling or unfit for surgery. The prerequisites for treatment are that the stones should be non-calcified, the gallbladder should be functioning and the cystic duct not obstructed. The bile acids, chenodeoxycholic acid and ursodeoxycholic acid are available and need to be given for long periods to be successful. They have no effect on pigment stones.

ІІ. CHRONIC PANCREATITIS

(aetiology, classification, diagnosis, treatment, complications).

Definition

Pancreatitis is an inflammatory process in which pancreatic enzymes autodigest the gland.

Chronic pancreatitis is an often painful inflammatory condition of the pancreas characterized by progressive fibrosis that leads to irreversible destruction of exocrine and endocrine tissue, resulting eventually in exocrine and endocrine insufficiency. There is considerable heterogeneity in the presentation and natural history of the condition. Chronic pancreatitis is classified broadly into chronic calcifying pancreatitis, chronic obstructive pancreatitis, and chronic autoimmune pancreatitis. Chronic calcifying pancreatitis is characterized by recurrent bouts of clinically acute pancreatitis early in the course of the disease, with eventual development of intraductal stones later in the disease course. Eventually, steatorrhea and diabetes mellitus develop in the majority of patients. This is the clinical profile of the disease that readily comes to mind when the term chronic pancreatitis is used in clinical practice. Chronic obstructive pancreatitis results from obstruction of the pancreatic duct due to any cause. The disease affects only the organ distal to the obstruction. It generally is not associated with stone formation. Although often asymptomatic, partial obstruction can lead to recurrent bouts of clinically acute pancreatitis involving the obstructed part of the gland. Obstructive pancreatitis is commonly seen distal to pancreatic tumors (ductal adenocarcinoma and intraductal papillary mucinous tumor [IPMT]) and postinflammatory strictures following acute or traumatic pancreatitis. Chronic autoimmune pancreatitis is a unique form of chronic pancreatitis that can be defined as a systemic fibroinflammatory disease that afflicts not only the pancreas but also various other organs, including the bile duct, salivary glands, retroperitoneum, and lymph nodes. Organs affected by autoimmune pancreatitis have a lymphoplasmacytic infiltrate rich in IgG4-positive cells. The inflammatory process responds to corticosteroid therapy. The most common presentation of this form of chronic pancreatitis is with obstructive jaundice, and it rarely presents with clinically acute pancreatitis. Pancreatic calcification is not common. It is thought to be a systemic autoimmune disorder; its best known serologic marker is an increased level of IgG4. The rest of the discussion in this chapter is related to chronic calcifying pancreatitis. Several conditions are associated with chronic calcifying pancreatitis.The pathogenesis of chronic pancreatitis due to these presumed etiologic agents is largely unknown. In the West, the most common cause of chronic calcifying pancreatitis is chronic alcohol abuse.

Classification

Three groups have been described:

1. chronic calcified pancreatitis - fibrosis, intraductal protein plugs and stones result in ductal injury; alcohol is the major cause.

2. chronic obstructive pancreatitis - obstruction of the main duct with proximal, uniform, ductal dilatation and subsequent atrophy and fibrosis; this is much less common and is due to either an intraductal tumour or a stricture.

3. chronic inflammatory pancreatitis - fibrosis and a mononuclear infiltrate associated with conditions such as Sjogren's syndrome and primary sclerosing cholangitis.

Table 1. Classification

Cronic calcifield panreatitis	Chronic obstructive pancreatitis	Chronic inflammatory pancreatitis
Fibrosis, intraductal protein plugs and stones result in ductal injury; alcohol is the major cause	Obstruction of the main duct with proximal, uniform, ductal dilatation and subsequent atrophy and fibrosis; this is much less common and is due to either an intraductal tumour or a stricture	Fibrosis and a mononuclear infiltrate associated with conditions such as Sjogren's syndrome and primary sclerosing cholangitis

Epidemiology

· n population studies, males are affected more commonly than females (6.7 vs 3.2 per 100,000 population);

· Differences in the hospitalization rates of patients with chronic pancreatitis exist with respect to sex. Rates in males peak at age 45-54 years and then decline; female rates reach a plateau, which remains stable after age 35 years;

· Sex differences with respect to etiology also exist. Alcohol-induced illness is more prevalent in males, idiopathic and hyperlipidemic-induced pancreatitis is more prevalent in females, and equal sex ratios are observed in chronic pancreatitis associated with hereditary pancreatitis.

Etiology

The cause of chronic pancreatitis usually is metabolic in nature.

Excessive alcohol consumption is the most common cause, accounting for about 60% of all cases. Because fewer than 5-10% of people with alcoholism develop the disease, other factor(s) must place these individuals at risk. A mutation in the gene encoding the serine protease inhibitor, Kazal type 1, has been identified in patients with chronic pancreatitis. The N34S mutation was detected in 5.8% of 274 patients with alcoholic chronic pancreatitis compared to 1.0% of people with alcoholism without pancreatitis. Although all patients were heterozygous for the mutation, it provides evidence for abnormalities in the pancreatic protease/protease inhibitor system playing a role in the pathogenesis of alcoholic chronic pancreatitis.

Several inherited disorders also are considered metabolic in origin. Hereditary pancreatitis is an autosomal dominant disorder with an 80% penetrance, accounting for about 1% of cases. Research of families with hereditary pancreatitis has led to the identification of several mutations in the cationic trypsinogen gene on chromosome 7. These mutations apparently render the activated enzyme resistant to second-line proteolytic control mechanisms. Mutations were found in the pancreatic secretory serine protease inhibitor Kazal type 1 (SPINK1) gene in 18 of 96 patients with idiopathic or hereditary chronic pancreatitis.

Cystic fibrosis, one of the most common genetic abnormalities, is an autosomal recessive disorder accounting for a small percent of patients with chronic pancreatitis. The cystic fibrosis transmembrane regulator (CFTR) gene transcribes a protein important in regulating chloride transport across cellular membranes. Several hundred mutations of the CFTR gene have been identified, and the clinical manifestation of any given mutation depends on how severely it affects the protein's ability to regulate chloride transport. Different mutations in CFTR are associated with different functional statuses of the exocrine pancreas. Specific CFTR genotypes are significantly associated with pancreatitis. Patients with genotypes associated with mild phenotypic effects have a greater risk of developing pancreatitis than patients with genotypes associated with moderate-severe phenotype.

Hyperlipidemia (usually type I and type V) also may cause chronic pancreatitis; however, it usually presents with repeated attacks of acute pancreatitis.

Hypercalcemia due to hyperparathyroidism now is a rare cause of chronic pancreatitis, probably because automation of serum chemistries reveals hypercalcemia before it results in pancreatitis.

Nutritional, or tropical, chronic pancreatitis is rare in the United States, but it is an important cause of disease in other parts of the world.

Medications are an infrequent, or possibly underrecognized, cause of chronic pancreatitis.

Idiopathic chronic pancreatitis, which accounts for approximately 30% of cases, has been subdivided into early-onset and late-onset forms arbitrarily. While the cause is not yet known, some evidence points to atypical genetic mutations in CFTR, cationic trypsinogen, and possibly other proteins.

Obstruction of the flow of pancreatic juice can cause chronic pancreatitis. Obstructive forms account for less than 10% of cases and may be congenital or acquired.

Congenital abnormalities, such as pancreas divisum and annular pancreas divisum, are uncommon (even rare) causes of chronic pancreatitis and usually require an additional factor to induce chronic pancreatitis. For example, while pancreas divisum usually does not cause chronic pancreatitis, patients with divisum and minor papilla stenosis are at risk. In these patients, clear evidence of disease exists in the dorsal pancreas, whereas the ventral pancreas is normal histologically.

Acquired obstructive forms typically result from blunt abdominal trauma or accidents involving motor vehicles, bicycles, horses, and, on occasion, severe falls. In these cases, the pancreas is whiplashed against the spine, causing trauma to the ductal system, resulting in a stricture close to the surgical genu. In rare instances, chronic inflammatory conditions affecting the duodenum, or primarily the duodenal papilla, can induce fibrosis and papillary stenosis in a subset of patients, leading to chronic pancreatitis.

Autoimmune pancreatitis is uncommon and accounts probably for less than 1% of cases of chronic pancreatitis. Clinical characteristics include symptomatic or asymptomatic diffuse enlargement of the pancreas, diffuse and irregular narrowing of the main pancreatic duct, increased circulating levels of gamma globulin, the presence of autoantibodies, and a possible association with other autoimmune diseases. Fibrosis with lymphocytic infiltration is seen on pathology with an elevated level of IgG4. Secondary forms of autoimmune chronic pancreatitis are associated with primary biliary cirrhosis, primary sclerosing cholangitis, and Sjögren syndrome.

Table 1. Causes of Acute Pancreatitis

Alcohol ingestion (acute and chronic alcoholism)

Biliary tract disease (gallstones)

Postoperative state (after abdominal or nonabdominal operation)

Endoscopic retrograde cholangiopancreatography (ERCP), especially manometric studies of sphincter of Oddi

Trauma (especially blunt abdominal type)

Metabolic causes

Hypertriglyceridemia

Apolipoprotein CII deficiency syndrome

Hypercalcemia (e.g., hyperparathyroidism), drug-induced

Renal failure

After renal transplantation^a

Acute fatty liver of pregnancy^b

Hereditary pancreatitis

Infections

Mumps

Viral hepatitis

Other viral infections (coxsackievirus, echovirus, cytomegalovirus)

Ascariasis

Infections with Mycoplasma, Campylobacter, Mycobacterium avium complex, other bacteria

Drugs

Drugs for which association is definite

Azathioprine, 6-mercaptopurine

Sulfonamides

Thiazide diuretics

Furosemide

Estrogens (oral contraceptives)

Tetracycline

Valproic acid

Pentamidine

Dideoxyinosine (ddI)

Drugs for which association is probable

Acetaminophen

Nitrofurantoin

Methyldopa

Erythromycin

Salicylates

Metronidazole

Nonsteroidal anti-inflammatory drugs

Angiotensin-converting enzyme (ACE) inhibitors

Vascular causes and vasculitis

Vascular

Ischemic-hypoperfusion state (after cardiac surgery)

Atherosclerotic emboli

Aneurysm of celiac axis/hepatic artery

Connective tissue disorders with vasculitis

Systemic lupus erythematosus

Necrotizing angiitis

Thrombotic thrombocytopenic purpura

Penetrating peptic ulcer

Obstruction of the ampulla of Vater

Regional enteritis

Duodenal diverticulum

Pancreas divisum

Causes to be considered in patients having recurrent bouts of acute pancreatitis without an obvious cause

Occult disease of the biliary tree or pancreatic ducts, especially occult gallstones (microlithiasis, sludge)

Drugs

Hypertriglyceridemia

Pancreas divisum

Pancreatic cancer

Sphincter of Oddi dysfunction

Cystic fibrosis

Truly idiopathic

^a Pancreatitis occurs in 3% of renal transplant patients and is due to many factors, including surgery, hypercalcemia, drugs (glucocorticoids, zathioprine, L-asparaginase, diuretics), and viral infections.

^b Pancreatitis also occurs in otherwise uncomplicated pregnancy and is most often associated with cholelithiasis.

Table 1a. Causes of chronic pancreatitis

Table 2. 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

Abdominal radiotherapy

Hemochromatosis

Shwachman's syndrome (pancreatic insufficiency and bone marrow dysfunction)

Trypsinogen deficiency

Enterokinase deficiency

Isolated deficiencies of amylase, lipase, or proteases

₁-Antitrypsin deficiency

The cause of chronic pancreatitis usually is metabolic in nature. The proposed pathologic mechanisms of chronic pancreatitis are as follows:

• Intraductal plugging and obstruction - Eg, ethanol (ETOH) abuse, stones, tumors
• Direct toxins and toxic metabolites - These act on the pancreatic acinar cell to stimulate the release of cytokines, which stimulate the stellate cell to produce collagen and to establish fibrosis; cytokines also act to stimulate inflammation by neutrophils, macrophages, and lymphocytes (eg, ETOH, tropical sprue)
• Oxidative stress - Eg, idiopathic pancreatitis
• Necrosis-fibrosis - Recurrent acute pancreatitis that heals with fibrosis
• Ischemia - From obstruction and fibrosis; important in exacerbating or perpetuating disease rather than in initiating disease
• Autoimmune disorders - Chronic pancreatitis has been found in association with other autoimmune diseases, such as Sjögren syndrome, primary biliary cirrhosis, and renal tubular acidosis.
• Secondary forms of autoimmune chronic pancreatitis are associated with primary biliary cirrhosis, primary sclerosing cholangitis, and Sjögren syndrome.
• While alcohol greatly influences the understanding of its pathophysiology because it is the most common etiology (60-70%), approximately 20-30% of cases are idiopathic and 10% of cases are due to rare diseases.

Autoimmune pancreatitis is a more recently described entity. Clinical characteristics include symptomatic or asymptomatic, diffuse enlargement of the pancreas, diffuse and irregular narrowing of the main pancreatic duct, increased circulating levels of gamma globulin, the presence of autoantibodies, and a possible association with other autoimmune diseases. Fibrosis with lymphocytic infiltration is seen on pathology. The disorder is associated with elevated immunoglobulin G4 (IgG4) concentrations.

In a study of 51 patients with autoimmune pancreatitis, Kawa et al suggested that a strong link exists between pancreatic stone formation and the recurrence of autoimmune pancreatitis and that following several recurrences, this disease may develop into chronic pancreatitis. In the study, the authors found that during a long-term follow-up period, 21 patients suffered a recurrence of the condition and 9 of the 51 patients developed pancreatic stones

The investigators also found that the stones developed more frequently in the recurrence group (7 [33%] of 21 patients) than in the other patients (2 [7%] of 30 patients). In addition, within a group of 175 patients with ordinary chronic hepatitis, 13 patients were found to have high serum concentrations of IgG4.

Excessive alcohol consumption is the most common cause of pancreatitis, accounting for about 60% of all cases.

In the affected gland, alcohol appears to increase protein secretion from acinar cells while decreasing fluid and bicarbonate production from ductal epithelial cells. The resulting viscous fluid results in proteinaceous debris becoming inspissated within the lumen, causing ductular obstruction, upstream acinar atrophy, and fibrosis. GP2, which is secreted from the acinar cell and is homologous to a protein involved in renal tubular casts, is an integral component of these ductal plugs.

Lithostathine (formerly called pancreatic stone protein), which also is produced by acinar cells, accounts for about 5% of secretory protein and inhibits the growth of calcium carbonate crystals. Abnormal lithostathine S1, whether inherited or acquired through trypsin digestion, appears to play a role in stone formation; it is insoluble at the neutral pH of pancreatic juice and is the major constituent of pancreatic stones.

A competing theory suggests that the persistent demands of metabolizing alcohol (and probably other xenobiotics, such as drugs, tobacco smoke, environmental toxins, and pollution) cause oxidative stress within the pancreas and may lead to cellular injury and organ damage, especially in the setting of malnutrition. Oxidative and nonoxidative pathways metabolize ethanol. Alcohol dehydrogenase oxidatively metabolizes ethanol first to acetaldehyde and then to acetate. When the alcohol concentration increases, cytochrome P-450 2E1 is induced to meet the metabolic demands.

Although these reactions occur principally in the liver, further increases in ethanol concentration induce pancreatic cytochrome P-450 2E1, and the level of acetate within the pancreas begins to approach that observed in the liver. Reactive oxygen species produced by this reaction may overwhelm cellular defenses and damage important cellular processes.

Although nonoxidative metabolism of ethanol is a minor pathway, the fatty acid ethyl esters produced by this reaction may cause cellular injury and are synthesized in the pancreas to a greater extent than in other organ systems.

Because fewer than 5-10% of people with alcoholism develop chronic pancreatitis, another factor or factors must place these individuals at risk. Researchers have studied genetic polymorphisms of ethanol-oxidizing enzymes, but to date, none have correlated with a susceptibility to alcohol-induced pancreatitis.

A mutation in the gene encoding the serine protease inhibitor, Kazal type 1, has been identified in patients with chronic pancreatitis. The N34S mutation was detected in 5.8% of 274 patients with alcoholic chronic pancreatitis, compared with 1.0% of people with alcoholism without pancreatitis. Although all patients were heterozygous for the mutation, it provides evidence for abnormalities in the pancreatic protease/protease inhibitor system playing a role in the pathogenesis of alcoholic chronic pancreatitis.

Hereditary pancreatitis

Several inherited disorders also are considered metabolic in origin. Hereditary pancreatitis is an autosomal dominant disorder with an 80% penetrance, accounting for about 1% of cases. Research of families with hereditary pancreatitis has led to the identification of several mutations in the cationic trypsinogen gene on chromosome 7. These mutations apparently render the activated enzyme resistant to second-line proteolytic control mechanisms. Mutations were found in the pancreatic secretory serine protease inhibitor Kazal type 1 (SPINK1) gene in 18 of 96 patients with idiopathic or hereditary chronic pancreatitis.

Cystic fibrosis, one of the most common genetic abnormalities, is an autosomal recessive disorder accounting for a small percent of patients with chronic pancreatitis. The cystic fibrosis transmembrane regulator (CFTR) gene transcribes a protein important in regulating chloride transport across cellular membranes.

Several hundred mutations of the CFTR gene have been identified, and the clinical manifestation of any given mutation depends on how severely it affects the protein's ability to regulate chloride transport. Different mutations in CFTR are associated with different functional statuses of the exocrine pancreas.

Specific CFTR genotypes are significantly associated with pancreatitis. Patients with genotypes associated with mild phenotypic effects have a greater risk of developing pancreatitis than do patients with genotypes associated with moderate-severe phenotypes.

This form of chronic pancreatitis accounts for approximately 30% of cases. It has been arbitrarily divided into early onset and late-onset forms. While the cause of idiopathic chronic pancreatitis is not yet known, some evidence points to atypical genetic mutations in CFTR, cationic trypsinogen, and other proteins.

Congenital abnormalities, such as pancreas divisum and annular pancreas divisum, are uncommon (even rare) causes of chronic pancreatitis and usually require an additional factor to induce chronic pancreatitis. For example, while pancreas divisum usually does not cause chronic pancreatitis, patients with divisum and minor papilla stenosis are at risk. In these patients, clear evidence of disease exists in the dorsal pancreas, whereas the ventral pancreas is normal histologically.

Acquired obstructive forms typically result from blunt abdominal trauma or accidents involving motor vehicles, bicycles, horses, or, on occasion, severe falls. In these cases, the pancreas is whiplashed against the spine, causing trauma to the ductal system and resulting in a stricture close to the surgical genu. In rare instances, chronic inflammatory conditions affecting the duodenum, or primarily the duodenal papilla, can induce fibrosis and papillary stenosis in a subset of patients, leading to chronic pancreatitis.

Other causes of chronic pancreatitis include the following:

• Hyperlipidemia (usually type I and type V) - However, hyperlipidemia usually presents with repeated attacks of acute pancreatitis
• Hypercalcemia due to hyperparathyroidism - Now is a rare cause of chronic pancreatitis, probably because automation of serum chemistries reveals hypercalcemia before it results in pancreatitis
• Nutritional, or tropical, chronic pancreatitis - Rare in the United States, but an important cause of disease in other parts of the world
• Medications - An infrequent, or possibly underrecognized, cause of chronic pancreatitis
• Obstruction of the flow of pancreatic juice can cause chronic pancreatitis. Obstructive forms account for less than 10% of cases and may be congenital or acquired.

Predisposing factors

The proposed pathologic mechanisms of chronic pancreatitis are as follows:

· Intraductal plugging and obstruction (eg, ETOH abuse, stones, tumors);

· Direct toxins and toxic metabolites: These act on the pancreatic acinar cell to stimulate the release of cytokines, which stimulate the stellate cell to produce collagen and to establish fibrosis. Cytokines also act to stimulate inflammation by neutrophils, macrophages, and lymphocytes (eg, ETOH, tropical sprue);

· Oxidative stress (eg, idiopathic pancreatitis);

· Necrosis-fibrosis (recurrent acute pancreatitis that heals with fibrosis);

· Ischemia (from obstruction and fibrosis), which is important in exacerbating or perpetuating disease rather than in initiating disease;

· Autoimmune disorders: Chronic pancreatitis has been found in association with other autoimmune diseases, such as Sjögren syndrome, primary biliary cirrhosis, and renal tubular acidosis.

Pathogenesis

Grossly, the pancreas may be enlarged or atrophic, with or without cysts or calcifications. The ducts may be dilated, irregular, or strictured. Essential pathologic features include irregular and patchy loss of acinar and ductal tissue, chronic inflammation, ductal changes, and fibrosis.

Several important pathogenic theories have been developed, including the following: (1) oxidative stress; (2) toxic-metabolic; (3) stone and duct obstruction; and (4) necrosis-fibrosis. The premise of the oxidative stress hypothesis is that reactive by-products of hepatic mixed function oxidase activity damage the pancreas through chronic reflux of bile into the pancreatic duct. The toxic-metabolic theory is that alcohol is directly toxic to the acinar cell through a change in intracellular metabolism. This metabolic effect results in pancreatic lipid accumulation, fatty degeneration, cellular necrosis, and eventual widespread fibrosis. Proponents of the stone and duct obstruction theory have postulated that alcohol increases the lithogenicity of pancreatic juice, leading to stone formation. Chronic contact of the stones with duct epithelial cells produces ulceration and scarring. Eventually, atrophy and fibrosis result from chronic obstruction of the acini. The necrosis-fibrosis theory differs from other theories in that it emphasizes that acute and chronic pancreatitis represents a spectrum of disease. Inflammation from acute pancreatitis leads to scarring and extrinsic compression of the pancreatic ductules. Obstruction results in stasis, atrophy, and stone formation.

Discoveries about hereditary pancreatitis have supported the necrosis-fibrosis sequence. The genetic defect of hereditary pancreatitis produces recurrent acute pancreatitis beginning in early childhood, almost invariably leading to chronic pancreatitis in early adulthood. A major advance in understanding the underlying cellular mechanisms of pancreatic fibrogenesis is in the primary role of pancreatic stellate cells. Stimulated by alcohol and oxidative stress, activated stellate cells migrate to the periacinar areas to deposit collagen and fibronectin. Stellate cells are also stimulated by specific cytokines, many of which are emitted during the inflammatory phase of acute pancreatitis. Transforming growth factor beta 1 has received considerable attention as an important mediator of pancreatic fibrosis. The sentinel acute pancreatitis event hypothesis for CP pathogenesis incorporates many of these discoveries. Its major premise is that an episode of acute pancreatitis, the sentinel event, produces an inflammatory milieu, setting the stage for the attraction of collagen-secreting stellate cells.

CLINICAL FEATURES

The three important features of chronic pancreatitis are pain, steatorrhoea resulting from exocrine dysfunction and diabetes mellitus resulting from endocrine dysfunction.

Pain. The pain is usually located in the upper abdomen but is poorly localised. It is described as a boring, deep pain which may radiate to the back and is worsened after meals. It may be nocturnal. Its severity is not proportional to steatorrhoea and correlates poorly with loss of exocrine function or structural abnormality. The pain is the most difficult problem to treat and can be frustrating for both the patient and the physician.

Steatorrhoea. Lipase secretion has to be reduced to less than 10% of normal for steatorrhoea to develop and consequently this is a symptom which develops when the disease is advanced. Fat-soluble vitamins (A, D, E and K) are rarely sufficiently malabsorbed to cause symptoms. Stools are passed 2-3 times per day, are pale and may contain droplets of oil.

Diabetes. For overt diabetes to develop, more than 80% of the gland needs to be affected, which means that diabetes is also usually a late complication. However, abnormalities in the glucose tolerance test are detectable much earlier. The vast majority of patients will describe a heavy, sustained alcohol drinking habit and only rarely will there be a significant family history or associated medical history. Examination is usually normal although a mass may be palpable when a pseudocyst or cancer has developed. The spleen may be enlarged when the splenic vein has thrombosed.

Patients with chronic pancreatitis in whom there is extensive destruction of the pancreas (less than 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. Mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene have been documented in patients with idiopathic chronic pancreatitis. It has been estimated that in patients with idiopathic pancreatitis the frequency of a single CFTR mutation is 11 times the expected frequency and the frequency of two mutant alleles is 80 times the expected frequency. The results of sweat chloride testing are not diagnostic of cystic fibrosis in these patients. However, these patients have functional evidence of a defect in CFTR-mediated ion transport in nasal epithelium. It is suggested that up to 25% of patients with idiopathic chronic pancreatitis may have abnormalities of the CFTR gene. 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. Table 2 lists other causes of pancreatic exocrine insufficiency, but they are relatively uncommon.

Laboratory tests and diagnostic studies

Laboratory Studies

· Blood tests

Serum amylase and lipase levels may be slightly elevated in chronic pancreatitis; high levels are found only during acute attacks of pancreatitis. In the later stages of chronic pancreatitis, atrophy of the pancreatic parenchyma can result in normal serum enzyme levels, because of significant fibrosis of the pancreas, resulting in decreased concentrations of these enzymes within the pancreas.

While low concentrations of serum trypsin are relatively specific for advanced chronic pancreatitis, they are not sensitive enough to be helpful in most patients with mild-to-moderate disease.

Laboratory studies to identify causative factors include serum calcium and triglyceride levels.

When common etiologies are not found, research protocols are available to test for genetic mutations in cationic trypsinogen and CFTR.

· Fecal tests

Because maldigestion and malabsorption do not occur until more than 90% of the pancreas has been destroyed, steatorrhea is a manifestation of advanced chronic pancreatitis, and neither qualitative nor quantitative fecal fat analysis can detect early disease.

Assays of fecal chymotrypsin and human pancreatic elastase 1 have the same limitations but are useful in confirming advanced chronic pancreatitis with exocrine insufficiency.

· Pancreatic function tests

Direct tests: These tests are the most sensitive and can be used to detect chronic pancreatitis at its earliest stage; however, they are somewhat invasive, labor intensive, and expensive.

Determination in duodenal aspirates: Intubation of the duodenum usually is performed with a Dreiling tube, which allows for separate aspiration of gastric and duodenal contents. The methodology varies depending on the specific laboratory; however, exogenous secretin with cholecystokinin (CCK) is used to achieve maximal stimulation of the pancreas. The output of pancreatic bicarbonate, protease, amylase, and lipase then is measured in the duodenal aspirates. This test currently only is available in specialized centers. While the greatest sensitivity can be obtained in prolonged infusions of secretagogue to uncover a decreased pancreatic secretory reserve, it is impractical for general clinical use. Determination in pancreatic juice: This test generally is performed in conjunction with an endoscopic retrograde cholangiopancreatography (ERCP). The pancreatic duct is freely cannulated, an exogenous secretagogue is administered as above, and the pancreatic juice then is aspirated out of the

duct as it is produced. The output of pancreatic bicarbonate, protease, amylase, and lipase are measured.

Indirect tests: Noninvasive tests of pancreatic function have been developed for detecting chronic pancreatitis. In principle, these tests work via oral administration of a complex substance that is hydrolyzed by a specific pancreatic enzyme to release a marker substance. The intestine absorbs the marker, which then is measured in the serum or urine. These tests are capable of detecting moderate-to-severe chronic pancreatitis. The presence of renal, intestinal, and liver disease may interfere with the accuracy of these tests. Neither currently is freely available in the United States.

· Diagnosis of chronic pancreatitis requires morphologic abnormalities to appear on imaging procedures. Although advances in technology have improved the ability to detect these changes, most imaging procedures cannot depict early chronic pancreatitis because the structural changes they rely on are associated with moderate-to-advanced disease.

· Abdominal radiography: Pancreatic calcifications, often considered pathognomonic of chronic pancreatitis, are observed in approximately 30% of cases. Paired anteroposterior (AP) and oblique views are preferred because the vertebral column otherwise could obscure small flecks of calcium. The calcifications form within the ductal system—initially in the head, and later in the body and tail, of the gland. Calcium deposition is most common with alcoholic pancreatitis, hereditary pancreatitis, and tropical pancreatitis; however, it is rare in idiopathic pancreatitis.

· Computed tomography (CT) scanning: CT scanning, demonstrated in the images below, has the advantage of providing images of the pancreas of which interpretation is relatively intuitive. Although it excels at depicting the morphologic changes of advanced chronic pancreatitis described above, the subtle abnormalities of early-to-moderate chronic pancreatitis are beyond its resolution, and a normal finding on this study does not rule out chronic pancreatitis. This study is indicated to look for complications of the disease and is useful in planning surgical or endoscopic intervention. The sensitivity and the specificity of CT scan are 80% and 85%, respectively.

Endoscopic retrograde cholangiopancreatography: ERCP, demonstrated in the image below, provides the most accurate visualization of the pancreatic ductal system and has been regarded as the criterion standard for diagnosing chronic pancreatitis. Conversely, one limitation of ERCP is that it cannot be used to evaluate the pancreatic parenchyma, and histologically proven chronic pancreatitis has been documented in the setting of normal findings on pancreatogram. Pancreatograms can be interpreted and classified according to several schemes, such as the Cambridge criteria. A comparison of ERCP scoring with direct pancreatic function tests demonstrated good correlation. However, pancreatography tended to show significantly more severe changes. The problems with ERCP are that it is invasive, expensive, requires complete opacification of the pancreatic duct to visualize side branches, and carries a risk (operator-dependent) of pancreatitis.

Endoscopic ultrasonography: Studies suggest that endoscopic ultrasonography (EUS) may be the best test for imaging the pancreas but requires a highly skilled gastroenterologist.

Histologic Findings

· In the early stages of chronic pancreatitis, the parenchyma exhibits an increase in connective tissue around the ducts and between the lobules. The degree of inflammation is minimal to moderate, consisting mostly of T lymphocytes, and a patchy, focal process unevenly affects the pancreas. With increasing severity, the connective issue progresses between the acini, which gradually become distorted and tend to disappear. In advanced disease, fibrous tissue replaces the acinar tissue, and the pancreas becomes contracted, small, and hard. The islets of Langerhans are relatively spared until very late in the disease process.

· Patients can have severe histopathologic changes of chronic pancreatitis despite normal findings on imaging studies. In patients undergoing resection of the pancreas for chronic pancreatitis, focal necrosis is found in 11.9% and segmental fibrosis is observed in approximately 40% of cases.

· In chronic calcific pancreatitis, plugs of precipitated protein develop within the ductal system. While they may be observed in all types of chronic pancreatitis, in alcoholic and tropical forms, these plugs tend to evolve into calculi by deposition of calcium within them. The calcified pancreatic calculi are distributed irregularly, affecting ducts of various sizes, and may be associated with ulcerations of the ductal epithelium. Periductal connective tissue may encroach on the lumen and cause ductal stenoses, creating the "chain of lakes" pancreatogram appearance observed in advanced chronic calcific pancreatitis.

Evaluation tests of pancreatic exocrine function.

Table 3. Causes of Hyperamylasemia and Hyperamylasuria

PANCREATIC DISEASE

I. Pancreatitis

A. Acute

B. Chronic: ductal obstruction

C. Complications of pancreatitis

1. Pancreatic pseudocyst

2. Pancreatogenous ascites

3. Pancreatic abscess

II. Pancreatic trauma

III. Pancreatic carcinoma

NONPANCREATIC DISORDERS

I. Renal insufficiency

II. Salivary gland lesions

A. Mumps

B. Calculus

C. Irradiation sialadenitis

D. Maxillofacial surgery

III. "Tumor" hyperamylasemia

A. Carcinoma of the lung

B. Carcinoma of the esophagus

C. Breast carcinoma, ovarian carcinoma

IV. Macroamylasemia

V. Burns

VI. Diabetic ketoacidosis

VII. Pregnancy

VIII. Renal transplantation

IX. Cerebral trauma

X. Drugs: morphine

OTHER ABDOMINAL DISORDERS

I. Biliary tract disease: cholecystitis, choledocholithiasis

II. Intraabdominal disease

A. Perforated or penetrating peptic ulcer

B. Intestinal obstruction or infarction

C. Ruptured ectopic pregnancy

D. Peritonitis

E. Aortic aneurysm

F. Chronic liver disease

G. Postoperative hyperamylasemia

Elevation of ascitic fluid amylase occurs in acute pancreatitis as well as in (1) pancreatogenous ascites due to disruption of the main pancreatic duct or a leaking pseudocyst and (2) other abdominal disorders that simulate pancreatitis (e.g., intestinal obstruction, intestinal infarction, and perforated peptic ulcer). Elevation of pleural fluid amylase occurs in acute pancreatitis, chronic pancreatitis, carcinoma of the lung, and esophageal perforation.

Lipase may now be the single best enzyme to measure for the diagnosis of acute pancreatitis. Improvements in substrates and technology offer clinicians improved options, especially when a turbidimetric assay is used. The newer lipase assays have colipase as a cofactor and are fully automated.

An assay for trypsinogen (or for trypsin-like immunoreactivity) has a theoretical advantage over amylase and lipase determinations in that the pancreas is the only organ that contains this enzyme. The test appears to be useful in the diagnosis of both acute and chronic pancreatitis. Sensitivity and specificity are comparable to those of amylase and lipase determinations. Since trypsinogen is also excreted by the kidney, elevated serum values are found in renal failure, as is the case with serum amylase and lipase levels. No single blood test is reliable for the diagnosis of acute pancreatitis in patients with renal failure. Determining whether a patient with renal failure and abdominal pain has pancreatitis remains a difficult clinical problem. A recent study found that serum amylase levels were elevated in patients with renal dysfunction only when creatinine clearance was less than 50 mL/min. In such patients, the serum amylase level was invariably less than 500 IU/L in the absence of objective evidence of acute pancreatitis. In that study, serum lipase and trypsin levels paralleled serum amylase values.

A recent study evaluated the sensitivity and specificity of five assays used to diagnose acute pancreatitis: two for amylase, one for lipase, one for trypsin-like immunoreactivity (TLI), and one for pancreatic isoamylase. The data obtained (1) show that, if the best cutoff level is used, all these assays have similar specificities and (2) suggest that total serum amylase is as good an indicator of acute pancreatitis as any of the alternatives. However, inherent in many such studies is the problem that the recognition and diagnosis of acute pancreatitis hinge on the finding of an elevated serum amylase level. The question arises as to whether any diagnostic test result can be proved superior to the total serum amylase level if hyperamylasemia is required for the diagnosis. In other studies, when "objective" confirmation of the clinical diagnosis of pancreatitis was required (ultrasonography, CT, laparotomy), the sensitivity of the serum amylase has been found to be as low as 68%. With these limitations in mind, the recommended screening tests for acute pancreatitis are total serum amylase and serum lipase activities. Serum amylase values greater than three times normal are highly specific.

The diagnosis of acute pancreatitis is usually established by the detection of an increased level of serum amylase. Values threefold or more above normal virtually clinch the diagnosis if overt salivary gland disease and gut perforation or infarction are excluded. However, there appears to be no definite correlation between the severity of pancreatitis and the degree of serum amylase elevation. After 48 to 72 h, even with continuing evidence of pancreatitis, total serum amylase values tend to return to normal. However, pancreatic isoamylase and lipase levels may remain elevated for 7 to 14 days. It will be recalled that amylase elevations in serum and urine occur in many conditions other than pancreatitis (see Table 3). Importantly, patients with acidemia (arterial pH Ј7.32) may have spurious elevations in serum amylase. In one study, 12 of 33 patients with acidemia had elevated serum amylase, but only 1 had an elevated lipase value; in 9, salivary-type amylase was the predominant serum isoamylase. This finding explains why patients with diabetic ketoacidosis may have marked elevations in serum amylase without any other evidence of acute pancreatitis. Serum lipase activity increases in parallel with amylase activity, and measurement of both enzymes increases the diagnostic yield. An elevated serum lipase or trypsin value is usually diagnostic of acute pancreatitis; these tests are especially helpful in patients with nonpancreatic causes of hyperamylasemia (see Table 3). Markedly increased levels of peritoneal or pleural fluid amylase [>1500 nmol/L (> 5000 U/dL)] are also helpful, if present, in establishing the diagnosis.

Leukocytosis (15,000 to 20,000 leukocytes per microliter) occurs frequently. Patients with more severe disease may show hemoconcentration with hematocrit values exceeding 50% because of loss of plasma into the retroperitoneal space and peritoneal cavity. Hyperglycemia is common and is due to multiple factors, including decreased insulin release, increased glucagon release, and an increased output of adrenal glucocorticoids and catecholamines. Hypocalcemia occurs in approximately 25% of patients, and its pathogenesis is incompletely understood. Although earlier studies suggested that the response of the parathyroid gland to a decrease in serum calcium is impaired, subsequent observations have failed to confirm this idea. Intraperitoneal saponification of calcium by fatty acids in areas of fat necrosis occurs occasionally, with large amounts (up to 6.0 g) dissolved or suspended in ascitic fluid. Such "soap formation" also may be significant in patients with pancreatitis, mild hypocalcemia, and little or no obvious ascites. Hyperbilirubinemia [serum bilirubin >68 umol/L (> 4.0 mg/dL)] occurs in approximately 10% of patients. However, jaundice is transient, and serum bilirubin levels return to normal in 4 to 7 days. Serum alkaline phosphatase and aspartate aminotransferase (AST) levels are also transiently elevated and parallel serum bilirubin values. Markedly elevated serum lactic dehydrogenase (LDH) levels [>8.5 umol/L (> 500 U/dL)] suggest a poor prognosis. Serum albumin is decreased to Ј30 g/L (Ј3.0 g/dL) in about 10% of patients; this sign is associated with more severe pancreatitis and a higher mortality rate. Hypertriglyceridemia occurs in 15 to 20% of patients, and serum amylase levels in these individuals are often spuriously normal. Most patients with hypertriglyceridemia and pancreatitis, when subsequently examined, show evidence of an underlying derangement in lipid metabolism which probably antedated the pancreatitis. Approximately 25% of patients have hypoxemia (arterial PO2 Ј 60 mmHg), which may herald the onset of adult respiratory distress syndrome. Finally, the electrocardiogram is occasionally abnormal in acute pancreatitis with ST-segment and T-wave abnormalities simulating myocardial ischemia.

Diagnosis

The triad of pain, steatorrhoea and diabetes is unlikely to occur until late in the disease and patients more usually present with pain. There may be no signs of chronic liver disease as this too only develops in one-fifth of heavy drinkers. Simple blood tests are not usually helpful although there may be diabetes or at least an impaired glucose tolerance test. Serum lipase and amylase elevation is unusual and only tends to occur if the pancreatic duct is blocked or there is a pseudocyst. An obstructive pattern in the liver profile may occur if stricturing of the CBD has developed. The important differential diagnoses include peptic ulcer, biliary tract disease, mesenteric ischaemia and gastric or pancreatic malignancy, and appropriate investigation is necessary to exclude these.

Pancreatic function tests

Pancreatic function tests (Table 2) can be divided into the following:

1. Direct stimulation of the pancreas by intravenous infusion of secretin or secretin plus cholecystokinin (CCK) followed by collection and measurement of duodenal contents

2. Indirect stimulation of the pancreas using nutrients or amino acids, fatty acids, and synthetic peptides followed by assays of proteolytic, lipolytic, and amylolytic enzymes

3. Study of intraluminal digestion products, such as undigested meat fibers, stool fat, and fecal nitrogen

4. Measurement of fecal pancreatic enzymes such as elastase

The secretin test, used to detect diffuse pancreatic disease, is based on the physiologic principle that the pancreatic secretory response is directly related to the functional mass of pancreatic tissue. In the standard assay, secretin is given intravenously in a dose of 1 clinical unit (CU) per kilogram, as either a bolus or a continuous infusion. The results will vary with the secretin preparation used, the dose, the mode of administration, and the completeness with which the duodenal contents are collected. Normal values for the standard secretin test are (1) volume output >2.0 mL/kg per hour, (2) bicarbonate (HCO3-) concentration >80 meql/L, and (3) HCO3- output >10 meq/L in 1 h. The most reproducible measurement, giving the highest level of discrimination between normal subjects and patients with chronic pancreatitis, appears to be the maximal bicarbonate concentration.

The combined secretin-CCK test permits measurement of pancreatic amylase, lipase, trypsin, and chymotrypsin. Although there is overlap in the distributions of enzyme output in normal subjects and patients with pancreatitis in response to this test, markedly low enzyme outputs suggest advanced damage and destruction of acinar cells. With frank exocrine pancreatic insufficiency, there is usually an overall reduction in both HCO3- concentration and output of several enzymes. However, with lesser degrees of pancreatic damage there may be a dissociation between HCO3- concentration and enzyme output. There also may be a dissociation between the results of the secretin test and those of tests of absorptive function. For example, patients with chronic pancreatitis often have abnormally low outputs of HCO3- after secretin but have normal fecal fat excretion. Thus the secretin test measures the secretory capacity of ductular epithelium, while fecal fat excretion indirectly reflects intraluminal lipolytic activity. Steatorrhea does not occur until intraluminal levels of lipase are markedly reduced, underscoring the fact that only small amounts of enzymes are necessary for intraluminal digestive activities. An abnormal secretin test result suggests only that chronic pancreatic damage is present; it will not consistently distinguish between chronic pancreatitis and pancreatic carcinoma.

Another test of exocrine pancreatic function is the bentiromide test. This test is an indirect measure of pancreatic function and reflects intraluminal chymotrypsin activity. The test has excellent specificity but is not very sensitive. It no longer is available for clinical use in the United States.

The serum trypsinogen level, which is determined by radioimmunoassay, also has excellent specificity but is not very sensitive. It is a simple blood test that can detect severe damage to the exocrine pancreas. The normal values are 28 to 58 ng/mL, and any value below 20 ng/mL reflects pancreatic steatorrhea.

The amount of elastase in stool reflects the pancreatic output of this proteolytic enzyme. Decreased elastase activity in stool has been reported in patients with chronic pancreatitis and cystic fibrosis.

Table 2 Tests of exocrine pancreatic function

VIDEO 4 (Normal pancreatic secretion, digestion and absorption of food)

As a group, the tests have similar drawbacks in that they require accurate intubation of the duodenum and all depend on complete sample collection. The other major drawback is that a significantly abnormal test frequently does not develop until late in the condition when diagnostic uncertainty is often much less. They are of no use in monitoring the condition.

Imaging

Various imaging modalities are used, often in combination. Plain abdominal X-ray reveals pancreatic calcification or stones in up to two-thirds of patients. It may be necessary to perform a lateral Xray as vertebrae may obscure the view (Fig. 1).

Fig. 1 Plain X-ray of abdomen showing calcific pancreatitis.

Transabdominal ultrasound has the drawback that overlying bowel may obscure the view obtained, but it is moderately sensitive at detecting abnormalities of texture of the pancreas, variations in ductal calibre and pseudocysts.

.

Fig.2a

Fig. 2 B.

Fig. 2 Ultrasound investigation. A. Normal pancreas. B. Chronic pancreatitis: а) calcificates in the head of pancreas; б) Virsungov’s duct; в) pseudocyst of pancreas; г) increase of the head of pancreas; д) spleen vein;

VIDEO 5 (Ultrasonography. Chronic pancreatitis)

Fig. 3 Ultrasound investigation. chronic calcified pancreatitis а) virsungolithiasis б) dilated Virsungov’s duct.

Endoscopic ultrasound overcomes some of the visualisation problems and is probably more sensitive and specific. CT has a sensitivity of up to 90% and specificity of the same order. It will detect variation in ductal diameter, and ectatic side branches, changes in the parenchyma, calcification and complications of chronic pancreatitis such as pseudocyst formation (Fig. 4).

Fig. 4 CT scan with central pseudocyst.

Endoscopic retrograde cholangiopancreatography (ERCP) is probably the most sensitive imaging technique (Fig. 5-7) but still fails to correlate with functional tests in around 25% of cases.

Fig. 5 ERCP of chronic pancreatitis with distortion of the pancreatic duct.

Fig. 6 An endoscopic retrograde cholangiopancreatography image demonstrating massive pancreatic duct dilatation in a patient with bigduct chronic pancreatitis.

Fig. 7 An endoscopic retrograde cholangiopancreatography image demonstrating minimal pancreatic duct abnormalities in a patient with painful small-duct chronic pancreatitis.

An endoscopic ultrasound, which allows a highly detailed examination of the pancreatic parenchyma and pancreatic duct, routinely detects abnormalities in patients with chronic pancreatitis (high sensitivity), but the specificity and reproducibility of the test requires further study [see Figure 8].

Fig. 8 An endoscopic ultrasound image demonstrating a dilated pancreatic duct (markers) in a patient with advanced chronic pancreatitis.

Chronic pancreatitis usually is envisioned as an atrophic fibrotic gland with dilated ducts and calcifications. However, findings on conventional diagnostic studies may be normal in the early stages of chronic pancreatitis , as the inflammatory changes can be seen only by histologic examination

This endoscopic retrograde cholangiopancreatography (ERCP) shows advanced chronic pancreatitis. The pancreatogram has blunting of the lateral branches, dilation of the main pancreatic duct, and filling defects consistent with pancreatolithiasis. The cholangiogram also shows a stenosis of the distal bile duct and a dilated biliary tree.

This patient has recurrent abdominal pain. She used alcohol heavily in the past and was involved in a motor vehicle accident. The pancreatogram shows subtle blunting of side branches consistent with chronic pancreatitis. A stricture also is present in the body of the pancreas where it drapes over the spine, probably resulting from the trauma she sustained in the motor vehicle accident. Air in the stomach makes it difficult to observe that contrast is filling a pseudocyst on the other side of the stricture. These findings are not amenable to endoscopic intervention, and the patient was sent for a distal pancreatectomy.

By definition, chronic pancreatitis is a completely different process from acute pancreatitis .In acute pancreatitis, the patient presents with acute and severe abdominal pain, nausea, and vomiting. The pancreas is acutely inflamed (neutrophils and edema), and the serum levels of pancreatic enzymes (amylase and lipase) are elevated. Full recovery is observed in most patients with acute pancreatitis, whereas in chronic pancreatitis, the primary process is a chronic, irreversible inflammation (monocyte and lymphocyte) that leads to fibrosis with calcification.

The patient with chronic pancreatitis clinically presents with chronic abdominal pain and normal or mildly elevated pancreatic enzyme levels. When the pancreas loses its endocrine and exocrine function, the patient presents with diabetes mellitus and steatorrhea.

Criteria for diagnosis of the 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. 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.

Chronic pancreatitis is characterized by patchy fibrous replacement of whole lobules or parts of lobules, focal fat necrosis in different stages, and chronic inflammation.  Grossly, depending on the degree of injury, the gland may have a normal outline, lobular pattern, and color but be slightly firm, or it may be smaller than normal, bosselated, rock-hard, and display foci of fat necrosis, calcification, or fully developed calculi.

TREATMENT

It is important to try to minimise disease progression and this is best done by total alcohol avoidance particularly in those in whom alcohol is the cause.

The goals of medical treatment are as follows:

• Modify behaviors that may exacerbate the natural history of the disease
• Enable the pancreas to heal itself
• Determine the cause of abdominal pain and alleviate it
• Detect pancreatic exocrine insufficiency and restore digestion and absorption to normal
• Diagnose and treat endocrine insufficienc

Pain

Analgesia requirement should be titrated against need but often spirals upwards to considerable opiate requirement and subsequent addiction. Care should be taken in controlling associated side-effects such as constipation which can lead to abdominal pain inappropriately attributed to the pancreas. Pancreatic enzyme supplementation is usually used and may be helpful as may an anti-oxidant cocktail given daily. Coeliac axis nerve block may lead to temporary improvement in pain but frequently symptoms recur. Surgery including partial resections and drainage procedures may be helpful in the most severe cases but it is difficult to obtain controlled data for these procedures. Resection of tissue including endocrine cells results in brittle diabetes which is difficult to manage.

A number of factors may contribute to the pain in chronic pancreatitis, and the principal mechanisms of pain may change with the duration of disease. Sources of pain can include the following:

• Acute disease with inflammation and pseudocyst formation may be superimposed on chronic disease
• Obstruction of the pancreatic duct by strictures or stones may cause increased duct pressure and pain
• Pancreatic ischemia, with decreased pancreatic oxygenation and a decreased tissue pH, caused by a compartment syndrome may cause pain that is relieved by duct decompression
• Pancreatic and pancreatic nerves become enlarged, lose some of their cellular sheath, and are inflamed
• Obstruction of the duodenum or biliary tract may worsen with acute episodes and improve with time

Diagnostic tests may be necessary to identify an anatomic explanation for the pain and to plan appropriate treatment. If no anatomic explanation for abdominal pain can be found, medical therapy can be attempted. This therapy includes pain control with analgesic agents and a trial of noncoated pancreatic enzymes.

The impetus for using exogenous pancreatic enzymes to reduce pain begins with the hypothesis that stimulation of the pancreas by food causes pain. Cholecystokinin (CCK) is one of the possible mediators of this response.

CCK releasing factor (CRF) typically is secreted into the duodenum. During the interdigestive period, proteolytic enzymes within pancreatic juice rapidly degrade CRF. After a meal, the proteolytic enzymes are occupied with digesting dietary proteins, and enough CRF escapes to bind to duodenocytes, which stimulates CCK release, in turn stimulating pancreatic secretion.

In severe chronic pancreatitis with exocrine insufficiency, CCK levels may be high because proteolytic enzymes are low. When pancreatic enzyme supplements are administered in high doses, degradation of CRF is restored and the stimulus for CCK release is reduced.

This hypothesis is supported by one report that a CCK-receptor antagonist reduces pain in patients with chronic pancreatitis. The digestive products of a meal and the CCK-releasing factor stimulate CCK release from the duodenal mucosa. CCK acts directly on pancreatic cells and indirectly through neural pathways to stimulate the pancreas. Through unknown mechanisms, such stimulation has been hypothesized to cause pain.

When exogenous pancreatic enzymes are taken with a meal, CCK-releasing factors are degraded and CCK release in response to a meal is reduced, as indicated by the smaller CCK. This decreases pancreatic stimulation and pain. Any benefit from this treatment is likely limited to nonalcoholic patients with early chronic pancreatitis and requires the use of uncoated preparations.

Clinical trials investigating the benefits of this approach have provided mixed results. While 4 trials using enteric-coated enzyme preparations demonstrated no effect, these studies may have been flawed if the coating failed to release the enzymes into the feedback-sensitive portion of the duodenum. Two studies using non–enteric-coated tablets have demonstrated a reduction in pain compared with placebo. Female patients and those with idiopathic chronic pancreatitis appear to respond best.

If conventional medical therapy is unsuccessful and the patient has severe, intractable pain, celiac ganglion blockade can be considered. This approach tries to alleviate pain by modifying afferent sensory nerves in the celiac plexus, using agents that anesthetize, reduce inflammation, or destroy nerve fibers.

In a study in which alcohol injections were administered, 12 of 23 patients obtained complete pain relief, and 6 of 23 patients obtained partial pain relief. However, the mean pain-free interval was only 2 months; the longest pain-free interval was only 4 months. Repeated blocks generally were not effective.

Because of the risks of paralysis resulting from a transverse myelopathy and catastrophic hemorrhage resulting from injury to major abdominal vasculature, the use of alcohol blocks should be restricted to patients with intractable, severe pain due to terminal pancreatic cancer.

Percutaneous or endoscopic celiac nerve blocks with either alcohol or steroids have had only limited success in chronic pancreatitis and should be considered an unproven therapy.

Steatorrhoea

Dietary enzyme supplementation usually controls this. Lipase inactivation by gastric acid may result in more than the expected 30 000 units of lipase per meal estimated to be required to prevent steatorrhoea. Gelatin capsules and acid suppression therapy may help.

Diabetes

This is often brittle and wide fluctuations in blood glucose are seen with exogenous insulin.

Although reduced fat intake is often recommended in patients with chronic pancreatitis, the clinical benefit is unknown. Indeed, the efficiency of fat absorption in dogs increases with increased fat intake. Whether humans have a similar response is unknown.

Medium chain triglycerides are directly absorbed by the small intestine without a requirement for digestion by lipase or micellar solubilization. To supply lipids and calories, medium-chain triglycerides can be used in patients with severe fat malabsorption. There is occasionally sufficient loss of fat-soluble vitamins to cause disease.

Enteric-coated preparations protect lipase from inactivation by gastric acid. Uncoated preparations are often less costly and adequate to relieve steatorrhea. Reducing gastric acid secretion may enhance the effectiveness of uncoated preparations. Enzyme preparations with high lipase content are available and recombinant lipase preparations will probably soon be marketed. Some of the recombinant enzymes are resistant to acidic denaturation. To provide adequate mixing with food, enzymes should be ingested during and just after a meal.

The most serious adverse effects (ie, colonic strictures) were observed with coated preparations that contained high concentrations of enzymes. In recent years, this adverse effect has not been seen; this is probably due to a reformulation of enzyme preparations.

Cobalamin or vitamin B-12 is absorbed complexed to intrinsic factor in the terminal ileum. Some vitamin B-12 absorption that is independent of intrinsic factor occurs throughout the small bowel. When vitamin B-12 enters the stomach, it binds to a protein known as haptocorrin or R-protein. The haptocorrin is proteolytically degraded in the small intestine by pancreatic enzymes and released vitamin B-12 then binds to intrinsic factor. In patients with pancreatic insufficiency, vitamin B-12 can remain bound to haptocorrin and is not available for absorption by the terminal ileum. Although vitamin B-12 malabsorption can be demonstrated in patients with chronic pancreatitis, it rarely causes clinical vitamin B-12 deficiency.

Complications

Pseudocysts may occur in up to 25% of patients with chronic pancreatitis and if they are of significant size require drainage either surgically or endoscopically. Bleeding may occur into a pseudocyst or there may be erosion into surrounding vessels. Splenic vein thrombosis may occur resulting in gastric and oesophageal varices. Pancreatic cancer is more common in patients with chronic pancreatitis and represents the major differential diagnosis when obstructive jaundice occurs with a stricture of the CBD. Differentiation between the two conditions is difficult and serum markers (CA 19-9), CT and biopsy may all be necessary to confirm the diagnosis.

Depending on the individual case, the appropriate intervention may involve endoscopic, radiologic, or surgical techniques.

Prior to percutaneous drainage, performing pancreatography is important in order to understand the anatomy of the pancreatic ductal system and plan appropriate treatment. If a communication exists between the pancreatic ductal system and the pseudocyst, percutaneous drainage may create a persistent pancreaticocutaneous fistula, especially if the duct has a stricture downstream from the site of the disruption.

If the anatomy of the pseudocyst does not lend itself to transpapillary, transgastric, or transduodenal endoscopic drainage, then percutaneous drainage under ultrasonographic or CT scan guidance is an option. Transgastric pseudocyst drainage has been used to treat pancreatic pseudocysts successfully, but a high failure rate has been reported.

Successful treatment of alcoholism and tobacco addiction requires a team approach, including the involvement and expertise of a chemical dependency counselor and a psychologist trained in cognitive therapy.

In patients with uncontrolled abdominal pain, early referral to a pain management specialist may allow better pain control.

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