Chronic pancreatitis (CP) refers to chronic progressive inflammation of the pancreas, either localized or diffuse, caused by various factors. This condition is accompanied by irreversible damage to both the exocrine and endocrine functions of the pancreas. Clinically, it is characterized by recurrent or persistent abdominal pain, diarrhea or steatorrhea, weight loss, jaundice, abdominal masses, and diabetes.
Etiology and Pathogenesis
The etiology of CP is complex and involves multiple factors. Its development often requires an initial acute pancreatitis (AP) episode as a triggering event to initiate the inflammatory process. Subsequently, various causes or risk factors sustain the inflammatory response, leading to progressive fibrosis. Certain genetic mutations and autoimmune factors may promote the insidious onset of idiopathic CP without requiring an initial AP episode.
Diseases of the Biliary and Pancreatic Ducts
Infections, inflammation, or stones causing narrowing or obstruction at the lower end of the common bile duct or at the junction of the pancreatic and bile ducts can lead to obstruction of pancreatic juice outflow. This obstruction can result in recurrent acute pancreatitis (RAP), which gradually progresses to CP.
Alcohol
Alcohol consumption has long been considered a primary cause of CP. However, based on pathological and imaging findings, fewer than 10% of heavy drinkers ultimately develop CP. Clinical observations indicate that most individuals with long-term heavy alcohol consumption do not exhibit objective evidence of CP and may only present with dyspepsia. Experimental studies suggest that alcohol does not directly cause CP but can lead to alcohol-related RAP in the presence of factors such as pancreatic duct obstruction, eventually progressing to CP. Alcohol, in conjunction with other factors such as smoking, exacerbates pancreatic calcification.
Coxsackievirus B
This virus can cause acute pancreatitis, and higher viral titers increase the likelihood of acute pancreatitis. If tissue repair is insufficient, CP may develop. During Coxsackievirus B infection, alcohol consumption can exacerbate virus-induced pancreatitis, hinder pancreatic regeneration, and prolong tissue damage. The greater the alcohol intake and the longer its duration, the more difficult pancreatic regeneration becomes. Alcohol may facilitate chronic pancreatitis by enhancing viral infection or replication within tissues, impairing tissue healing, and promoting chronic inflammation.
Hereditary Pancreatitis
Patients often have a family history, with clinical features characterized by RAP, typically beginning in childhood. It frequently progresses to CP and is associated with a high risk of pancreatic cancer. Genetic analysis is an important diagnostic tool. This condition exhibits diverse manifestations, with most cases following an autosomal dominant inheritance pattern. Commonly involved genes include the cationic trypsinogen gene, serine protease inhibitor gene, and cystic fibrosis transmembrane conductance regulator (CFTR) gene. These genes contribute to the development of pancreatitis through mechanisms such as intrapancreatic trypsin activation, ductal obstruction, or protein misfolding.
Autoimmune Pancreatitis (AIP)
Patients with AIP produce various immune-related antibodies in their serum, such as IgG4, anti-carbonic anhydrase II and IV antibodies, anti-lactoferrin antibodies, antinuclear antibodies, anti-trypsin antibodies, and anti-secretory trypsin inhibitor antibodies. Humoral immunity, cellular immunity, the complement system, and lymphotoxins are involved in the pathogenesis.
Hypercalcemia
Elevated calcium concentrations in the blood and pancreatic parenchyma can activate pancreatic enzymes, increasing the risk of RAP in patients with persistent hypercalcemia. Hypercalcemia may impair the barrier function between pancreatic ducts and interstitial spaces, allowing more calcium ions to enter pancreatic secretions. High concentrations of calcium ions in alkaline pancreatic juice readily form deposits, promoting pancreatic duct stone formation.
Nutritional Factors
Diets rich in saturated fatty acids and low in protein may promote the development of CP or degenerative changes in the pancreas. Certain cases of tropical pancreatitis are associated with these dietary factors.
Idiopathic Pancreatitis
This diagnosis is considered after excluding other potential causes. It is often classified into two subtypes: early-onset (20–30 years old) and late-onset (60–70 years old). Possible contributing factors include smoking, mild genetic mutations, and anatomical abnormalities, though the exact causes remain uncertain.
Pathology
The pathological changes in chronic pancreatitis (CP) vary in severity. Inflammation may be localized to pancreatic lobules or involve the entire pancreas. The acinar cells undergo atrophy, and there is diffuse fibrosis or calcification. The pancreatic ducts exhibit multiple strictures and cystic dilations, with intraductal stones, calcifications, and protein plugs. Focal edema, inflammation, and necrosis may be observed in areas of ductal obstruction, sometimes accompanied by pseudocysts. These changes are progressive and irreversible. In advanced stages, the pancreas becomes hardened, pale, and irregularly nodular, with atrophy and reduced size. Fibrotic lesions often extend to the splenic and portal veins, leading to narrowing, obstruction, or thrombosis, which may result in left-sided portal hypertension.
Histologically, autoimmune pancreatitis (AIP) is characterized by non-calcifying destruction of pancreatic ducts and atrophy of acinar tissue. Type I AIP (IgG4-AIP) is marked by extensive lymphocyte and plasma cell infiltration around the ducts, patchy or storiform fibrosis in the pancreatic parenchyma, and abundant IgG4-positive cells on immunohistochemistry. These pathological changes may also occur in other organs, such as the bile ducts, gallbladder, kidneys, lungs, and salivary glands. Type II AIP is characterized by duct-centric pancreatitis with heavy neutrophilic infiltration, leading to microabscess formation within the pancreatic ducts, destruction of ductal epithelial cells, and ductal narrowing.
Clinical Manifestations
Symptoms
Abdominal Pain
Recurrent upper abdominal pain initially presents as intermittent but later becomes persistent. The pain worsens in the supine position and may improve with leaning forward, bending over, or lying curled on the side. The pain may radiate to the back or anterior chest and can sometimes involve the entire abdomen. The severity of abdominal pain varies, and in severe cases, analgesics or anesthetics may be required for relief. Pain is often triggered by alcohol consumption, overeating, or high-fat meals. During acute episodes, elevated serum amylase and lipase levels are commonly observed. The mechanism of pain is primarily related to increased ductal pressure caused by pancreatic duct obstruction and strictures, as well as inflammation, ischemia, pseudocysts, and associated neuritis.
Exocrine Pancreatic Insufficiency
In the later stages of CP, exocrine pancreatic dysfunction leads to symptoms such as loss of appetite, postprandial upper abdominal fullness, weight loss, malnutrition, edema, and deficiencies in vitamins A, D, E, and K. Some patients experience diarrhea due to significant exocrine insufficiency, with stools occurring 3–4 times per day, pale in color, voluminous, frothy, malodorous, and containing increased fat and undigested muscle fibers.
Endocrine Pancreatic Insufficiency
Chronic pancreatitis can cause destruction of pancreatic β-cells, and approximately half of patients develop diabetes.
Physical Signs
Most patients exhibit mild abdominal tenderness. In cases of pancreatic pseudocyst formation, an abdominal mass may be palpable. When the pancreatic head enlarges, pancreatic duct stones or cysts compress the common bile duct, leading to jaundice. AIP often presents with progressively worsening painless jaundice, which is easily misdiagnosed as pancreatic or bile duct cancer.
Auxiliary Examinations
Imaging
Abdominal X-ray
Calcifications or stones may be visible in the pancreatic region in some patients.
Abdominal Ultrasound and EUS
Findings include increased echogenicity of the pancreatic parenchyma, irregular narrowing or dilation of the main pancreatic duct, dilation of branch ducts, pancreatic duct stones, and pseudocysts. EUS, with its proximity to pancreatic tissue, provides more accurate information for diagnosing CP and differentiating it from pancreatic cancer.
Abdominal CT and MRI
Imaging may reveal pancreatic enlargement or atrophy, irregular contours, calcifications, irregular dilation of the pancreatic duct, or pseudocysts. In IgG4-AIP, the pancreas may appear "sausage-shaped" or exhibit localized nodular lesions in the pancreatic head, with localized narrowing of the main pancreatic duct.
ERCP and MRCP
ERCP is a key tool for the morphological diagnosis and staging of CP. Early features include dilation of pancreatic duct side branches. Additional findings include multifocal dilation, strictures, irregular morphology of the main and side ducts, filling defects caused by stones, and mucus plugs. MRCP can demonstrate the extent of ductal dilation and the location of stones, as well as clarify the etiology of some cases of CP. In recent years, MRCP has increasingly replaced diagnostic ERCP in CP evaluation.
Pancreatic Exocrine and Endocrine Function Tests
Blood glucose measurement, glucose tolerance tests, and serum insulin levels reflect endocrine pancreatic function. Decreased fecal elastase levels are evidence of exocrine pancreatic insufficiency.
Immunological Testing
In IgG4-AIP, serum IgG4 levels exceed 1,350 mg/L, and other antibodies, such as antinuclear antibodies and rheumatoid factors, may also be positive.
Diagnosis and Differential Diagnosis
The diagnostic approach involves first determining the presence of chronic pancreatitis (CP) and then identifying its underlying cause. When clinical manifestations suggest CP, imaging techniques are used to assess for pancreatic calcification, fibrosis, stones, ductal dilation, and atrophy, providing morphological evidence of CP. Further evaluation of pancreatic exocrine and endocrine function is conducted, while pancreatic tumors are excluded.
Common conditions requiring differentiation include biliary diseases, small intestinal malabsorption, and chronic liver diseases. Differentiating inflammatory pancreatic masses from pancreatic cancer is particularly important and challenging. Endoscopic ultrasound (EUS)-guided fine-needle aspiration biopsy or even exploratory laparotomy may be required in some cases.
Treatment
The goals of CP treatment are to eliminate the underlying cause, control symptoms, improve pancreatic function, manage complications, and enhance quality of life.
Abdominal Pain
Medications
Oral pancreatic enzyme supplements, subcutaneous octreotide injections, and non-opioid analgesics can relieve pain in some patients. For refractory, non-obstructive pain, celiac plexus blockade under CT or EUS guidance may be considered.
Endoscopic Treatment
Endoscopic interventions aim to relieve pancreatic duct obstruction and alleviate symptoms caused by increased intraductal pressure. Procedures such as endoscopic retrograde cholangiopancreatography (ERCP)-guided pancreatic sphincterotomy, stone removal, and stent placement have enabled many patients to avoid or delay surgical intervention, making endoscopic treatment a first-line option. For patients with pancreatic duct stones that cannot be removed endoscopically, extracorporeal shock wave lithotripsy (ESWL) or electrohydraulic lithotripsy may be considered.
Surgery
Surgery may be considered when endoscopic treatment fails or when pain recurs.
Exocrine Pancreatic Insufficiency
High-activity, enteric-coated pancreatic enzyme replacement therapy combined with dietary management is used. Pancreatic enzymes should be taken during meals, and proton pump inhibitors (PPIs) or H2 receptor antagonists (H2RAs) are used to suppress gastric acid secretion, reducing acid-mediated enzyme degradation and enhancing drug efficacy. The enzyme dosage can be adjusted based on the severity of diarrhea and bloating.
Diabetes
Diabetic patients are managed with a diabetic diet and oral hypoglycemic agents as much as possible to avoid insulin therapy. Since CP often results in glucagon deficiency, even low doses of insulin may induce hypoglycemia. Insulin dosages need to be individualized.
Autoimmune Pancreatitis (AIP)
Prednisone is commonly used, with an initial dose of 30–40 mg/day. After symptom relief, the dose is gradually tapered to 5–10 mg/day. While most patients achieve disease control, the morphological changes in the pancreas cannot be completely reversed.
Surgical Treatment
Indications for surgery in CP include:
- Pain unrelieved by medical or endoscopic management.
- Pancreatic duct stones or strictures causing ductal obstruction.
- Complications such as biliary obstruction, duodenal obstruction, portal hypertension, pancreatic ascites, or cysts.
Patient Education
Patients with CP must abstain from alcohol and smoking and avoid excessive intake of high-fat or high-protein diets. For patients with long-term steatorrhea, supplementation with fat-soluble vitamins, vitamin B12, folic acid, and trace elements is necessary.
Prognosis
Active treatment can alleviate symptoms but rarely achieves a cure. In advanced stages, most patients succumb to complications.