CCP is characterized by the lobular, patchy distribution of lesions of different intensity in neighboring lobules. Protein plugs are always found in the ductal and acinar lumina, and in the later stages these form calcifications, or calculi (pancreatic calcification). Atrophy of the epithelium and stenosis of the ducts are common. Recurrent attacks of acute pancreatitis, retention cysts, pseudocysts, and perineural inflammation are frequently associated.

The first visible lesions are protein precipitates or plugs in the lumina of ducts and acini, which later calcify forming pancreatic stones. The ductal epithelium in contact with the protein plugs or stones loses its basement membrane, and the duct cells atrophy and disappear with the growth of periductal connective tissue and fibrosis leading to fibrotic strictures. Distal to the strictures, the exocrine tissue atrophies and disappears due to plugs, stones, and fibrosis. When a partially obstructed duct is distended by pancreatic juice under pressure of secretion, it may form an intrapancreatic cyst. These retention cysts may grow and extend into peripancreatic tissue, forming retention pseudocysts. Thus all lesions of chronic calcifying pancreatitis are thought to be secondary to the formation of protein plugs and stones in the pancreatic ducts and ductules, resulting in ductal obstruction, parenchymal inflammation, atrophy, and fibrosis.

The pathogenesis of pancreatic lithogenesis involves the precipitation of both a fibrillar protein—a form of pancreatic stone protein (PSP)—and calcium carbonate.

Normally the pancreatic juice is saturated with calcium. The precipitation of calcium in the pancreatic juice is prevented by the presence of a group of proteins, PSP-S_2-5, synthesized and secreted by the acinar cells. PSP-S_2-5 acts as a calcium stabilizer of the pancreatic juice by blocking the growth sites of crystals. In the pancreatic juice, PSP-S_2-5 may be hydrolyzed by active trypsin to give a shorter protein, PSP-S, which is insoluble at physiologic pH and does not prevent calcium carbonate crystallization. PSP extracted from pancreatic plugs and stones contain the same amino acid sequence as PSP-S₁. The relative concentration of PSP is significantly decreased in the pancreatic juice of patients who have CCP compared to normal controls; this is true even in the early stages of the disease, before the appearance of calcification on abdominal x-rays. This finding suggests that the formation of the calcified part of the stones is due to a decreased secretion of PSP, the stabilizer of calcium in pancreatic juice. PSP secretion is also decreased in hereditary chronic pancreatitis as well as in idiopathic and alcoholic forms; thus the condition may be either congenital or acquired.

The lesions of the ductal epithelium caused by the protein plugs and stones lead to transudation of protein- and calcium-rich interstitial fluid into ductal lumina, increasing the calcium concentration in the pancreatic juice and resulting in increased intraductal calcium crystallization. As the diseased ducts become obstructed by the precipitated protein and calcifications, the acini and the lobule, which the ducts drain, become atrophic and fibrotic, resulting in pancreatic parenchymal loss in a patchy distribution throughout the pancreas.

Acute recurrent pancreatitis is thought to be a complication of the initial stages of CCP. It occurs in chronic alcoholics who have recently increased their alcohol intake. Follow-up of these patients shows that in most of them, pancreatic calculi (calcifications) develop after a number of years.

Recurrent alcoholic pancreatitis progresses to overt pancreatic insufficiency at different rates in different people. However, there is a linear relation between the average daily consumption of alcohol and the logarithm of the risk. For a given amount of alcohol consumption, the risk increases with the increased duration of consumption. Even small quantities (1-20 g of alcohol per day) increase the risk. Rather than a statistical threshold of alcohol toxicity for the pancreas, there is a continuous spectrum of individual thresholds. The type of alcoholic beverage and the rhythm of alcohol consumption have no significant influence on the risk of development of CCP.

Chronic alcohol ingestion increases the total protein concentration of protein in pancreatic juice but decreases the concentrations of PSP, citrate, bicarbonate, trypsin inhibitory protein, and the pH. Decreased citrate concentration increases calcium availability. It is thought that the increased viscosity of the pancreatic juice, due to increased protein content and decreased concentrations of PSP and citrate, leads to formation of protein plugs and calcifications in these patients.

accompanying chronic pancreatitis is described as a steady, boring, achy sensation usually associated with nausea with or without vomiting. It is commonly present in the mid-epigastrium, but it may also be perceived in the right or left upper quadrant or periumbilical area. It usually radiates to the back, increases in the supine position, and decreases on sitting up and leaning forward. Most patients require analgesics and may become addicted to narcotics.

The course of the pain of chronic pancreatitis differs in different patient groups. In most patients, it is a constant experience in the first 5 years after its diagnosis. Thereafter, in about two thirds of the patients, it may resolve spontaneously or diminish in severity and frequency.

Pancreatic exocrine function steadily diminishes with chronic pancreatitis.

a. Fat and protein malabsorption becomes apparent after the loss of 90% of the pancreatic secretory capacity. Protein malabsorption may be compensated for with increased oral intake of protein without additional abdominal discomfort to the patient. However, increased fat intake results in more diarrhea and abdominal pain. The steatorrhea of chronic pancreatitis consists mainly of triglycerides (esterified fats) in contrast to steatorrhea of sprue, which contains free fatty acids: The esterified fats are hydrolyzed by pancreatic lipase to free fatty acids, but they are not absorbed by the diseased intestinal mucosa. Stool volume is also smaller in chronic pancreatitis, again due to the presence of esterified fats, because hydroxylated free fatty acids are the secretagogues of colonic chloride and water secretion.

b. Carbohydrate malabsorption is rare in chronic pancreatitis, because loss of 97% of amylase secretion is necessary for maldigestion of starch.

c. Vitamin B₁₂ malabsorption. Decreased pancreatic exocrine function does not affect the absorption of bile salts, water- or fat-soluble vitamins, iron, or calcium. However vitamin B₁₂ malabsorption may occur in some patients due to diminished secretion of trypsin. As vitamin B₁₂ is ingested, a nonspecific protein (R protein) found in the upper gastrointestinal secretions binds with it and does not allow it to bind intrinsic factor (IF) from the stomach. Normally, trypsin in the second portion of the duodenum cleaves off the R protein and allows the association of vitamin B₁₂ to intrinsic factor.

The IF-vitamin B₁₂ complex is necessary for the active absorption of the vitamin B₁₂ at the terminal ileum. In chronic pancreatitis with diminished levels of pancreatic proteases, especially trypsin, in the duodenal lumen, the R protein is not cleaved off vitamin B₁₂ and IF-vitamin B₁₂ complex does not form, leading to vitamin B₁₂ malabsorption.

Along with exocrine insufficiency, endocrine insufficiency with diminished insulin and glucagon release develops in these patients. Seventy percent of the patients with pancreatic calcifications develop diabetes mellitus. Microangiopathy and nephropathy do not seem to complicate diabetes mellitus resulting from chronic pancreatitis. However, due to concomitant diminished glucagon secretion, these patients are very sensitive to exogenous insulin and may develop hypoglycemia even with low doses.

There are no specific findings in chronic pancreatitis. Some patients have epigastric tenderness. A mass may be palpable if a palpable pseudocyst exists. Patients with malabsorption may have weight loss but do not present with signs of fat-soluble vitamin deficiency (vitamins A, D, E, and K) such as night blindness, hypocalcemia, osteomalacia, and bleeding tendency. Jaundice may exist in patients with common bile duct obstruction due to scarring in the pancreatic head. In these patients, it may be difficult to differentiate pancreatic cancer from chronic pancreatitis.

There are no specific findings in the serum chemistry profile in patients with chronic pancreatitis. Even during acute attacks, the serum amylase or lipase level may not be elevated. The serum chemistry profile may reflect concomitant liver disease. With obstruction of the common bile duct, a cholestatic liver chemistry profile may emerge and should be confirmed by imaging techniques.