Chronic Pancreatitis

Etiology

The TIGAR-O classification system (Toxic-metabolic, Idiopathic, Genetic, Autoimmune, Recurrent and severe acute pancreatitis, and Obstructive) categorizes the causes of chronic pancreatitis using the acronym TIGAR (see Table. Modified TIGAR-O Pancreatitis Risk/Etiology Checklist): 

Table 1. Modified TIGAR-O Pancreatitis Risk/Etiology Checklist

Reference for the table.[8]

Abbreviations: ERCP, endoscopic retrograde cholangiopancreatography.

Additional causes of chronic pancreatitis include deficiencies in fat-soluble vitamins and antioxidants, and radiation therapy.[9][10] In adults, alcohol consumption is the most common cause of chronic pancreatitis, whereas in children, genetic conditions, especially cystic fibrosis, and anatomic variants are the primary causes (see Table 2. Genetic Polymorphisms Related to Chronic Pancreatitis).

Alcohol increases protein secretion from acinar cells, producing more viscous pancreatic fluid. This hyperviscosity leads to ductal obstruction, acinar fibrosis, and atrophy. However, fewer than 10% of individuals with alcohol use disorder develop chronic pancreatitis, suggesting that other factors, such as smoking, may also contribute to its development.

Table 2. Genetic Polymorphisms Related to Chronic Pancreatitis

Reference for the table.[11]

Epidemiology

Due to its slow progression, particularly when in alcohol-related cases, chronic pancreatitis is often diagnosed late. A 2014 epidemiological report estimated that its incidence has remained stable over the years, though its prevalence may be underestimated, warranting further studies.[12][13] 

In the United States, chronic pancreatitis is more common among Black individuals than White individuals. Risk factors also vary by sex—alcohol and tobacco use are the primary contributors in men, whereas idiopathic and obstructive causes are more common in women.[14] Overall, the condition is more prevalent in men, likely due to higher rates of alcohol and tobacco use. The median age at diagnosis is approximately 45 years, with onset occurring about a decade later in parts of China.[15]

Pathophysiology

The pathogenesis of chronic pancreatitis appears to be influenced by genetic and environmental factors. Studies have identified pancreatitis susceptibility genes associated with loss of function. Two main theories explain the development of chronic pancreatic disease.

The first theory suggests that impaired bicarbonate secretion fails to counterbalance increased pancreatic protein secretion. As a result, excess proteins form plugs within the lobules and ducts, leading to calcification and stone formation. The second theory involves the intraparenchymal activation of digestive enzymes within the pancreas, potentially triggered by genetic predisposition or external influences such as alcohol consumption.

Recent research suggests that alcohol diminishes the cell's ability to respond to calcium signaling. This reduced response disrupts the feedback mechanism and initiates a cycle of cellular damage, leading to cell death.[16][17] 

Exocrine pancreatic insufficiency, characterized by steatorrhea and azotorrhea, becomes clinically evident after over 90% of pancreatic function is lost.[1] This condition typically manifests at least 5 years after the diagnosis of chronic pancreatitis.

Recurrent episodes of acute pancreatitis increase the risk of developing chronic pancreatitis. Although the first and second episodes rarely lead to chronic disease, the likelihood rises from 16% to 50% after the third or fourth episode.

A proposed explanation is that alcoholic pancreatitis is more likely to recur than biliary pancreatitis, which typically occurs only once. Continued alcohol consumption contributes to progressive pancreatic damage. In addition, each recurrent episode causes further injury to an already compromised pancreas. By the third episode and beyond, acute pancreatitis tends to be more severe than the initial occurrences. Individuals with 3 or more episodes of acute pancreatitis often exhibit clinical, biochemical, and imaging findings consistent with chronic pancreatitis.[18]

A conceptual model outlining the progression of chronic pancreatitis has been published.[3] The model describes  the following distinct stages:

• At risk: Individuals are asymptomatic before the first pancreatic injury.

• Acute pancreatitis to recurrent acute pancreatitis: The first (sentinel) episode of acute pancreatitis occurs, followed by recurrent acute pancreatitis.

• Early chronic pancreatitis: Biomarkers of chronic pancreatitis become detectable. At this stage, the condition may either resolve or progress if further injury or stress occurs. 

• Established chronic pancreatitis to end-stage chronic pancreatitis: Disease features worsen unless therapeutic intervention leads to resolution.  

Key pathological changes include: 

• Immune dysregulation leading to fibrosis or sclerosis
• Acinar cell dysfunction leading to exocrine pancreatic insufficiency
• Islet cell dysfunction leading to pancreatogenic diabetes mellitus (T3c)
• Characteristic pain leading to chronic pain syndrome
• Metaplasia leading to pancreatic ductal adenocarcinoma (PDAC)

Histopathology

Histopathological examination of chronic pancreatitis reveals a significant increase in connective tissue surrounding the lobules and ducts. The acinar architecture is often distorted, with fibrosis becoming more prominent in later stages. Precipitated protein deposits may also be observed in the ducts. Distortion of the ductal system can produce a characteristic chain of lakes on computed tomography (CT) scans.

Pathologic fibrosis alone cannot serve as a definitive criterion for diagnosing chronic pancreatitis. Variations in histological presentation across different etiologies, along with the possibility of minimal or absent fibrosis in late-stage disease when biopsies are typically performed, limit its diagnostic reliability.[19][20] 

The histopathology of SPINK1-associated chronic pancreatitis closely resembles that of alcohol-induced chronic pancreatitis, showing a loss of exocrine parenchyma replaced by fibrosis.[21] In contrast, progressive lipomatous atrophy of the pancreas is observed with PRSS1-associated hereditary chronic pancreatitis, CFTR mutations, and hypertriglyceridemic chronic pancreatitis.[22]

History and Physical

Chronic pancreatitis typically presents with prolonged abdominal pain, often with intermittent pain-free periods. The pain may improve when leaning forward. However, some patients remain asymptomatic. Common symptoms include nausea, vomiting, diarrhea, steatorrhea (greasy, foul-smelling, difficult-to-flush stools), and weight loss. As the disease progresses, glucose intolerance or pancreatic diabetes may develop. During acute episodes of severe abdominal pain, patients may instinctively draw their knees towards their chest to alleviate discomfort.

On physical examination, focal or diffuse abdominal tenderness is commonly observed. In some cases, a palpable mass may indicate the presence of a pseudocyst. Signs of malnutrition are frequently observed in long-standing diseases.

Evaluation

When chronic pancreatitis is suspected, the new mechanistic definition can aid in diagnosis. This approach integrates clinical features (typical signs, symptoms, and family history) with risk factors (see Table. Modified TIGAR-O Pancreatitis Risk/Etiology Checklist). Biomarkers further support the diagnosis and may include the following: [23]

• Serum markers
  • Amylase
  • Lipase
  • Glucose
  • IgG4
  • Triglycerides
  • Tumor markers

• Nutritional deficiencies
  • Hypovitaminosis A, D, K, and B12

• Additional tests
  • Sweat chloride levels
  • Pancreatic biopsies

The 72-hour quantitative fecal fat collection is the most definitive test for advanced pancreatic insufficiency to evaluate steatorrhea. A fecal fat excretion of greater than 7 g/d confirms the diagnosis.

Alternatively, a fecal elastase-1 level can be performed using a single random stool sample to assess pancreatic insufficiency.[24]

• Normal fecal elastase level: > 500 µg/g of stool
• Borderline range: 200 to 500 µg/g (nonspecific, may be normal)
• Moderate exocrine pancreatic insufficiency: 100 to 200 µg/g 
• Severe exocrine pancreatic insufficiency: <100 µg/g

Although neither test is highly accurate, fecal elastase testing is less reliable than the 72-hour fecal fat collection but is more practical and widely used in clinical practice. For patients with a history of acute pancreatitis, chronic pancreatitis-related pain, and signs of maldigestion, such as steatorrhea or fat-soluble vitamin deficiencies, confirmatory imaging with CT or magnetic resonance cholangiopancreatography testing (MRCP) should be the initial diagnostic step.

Diagnostic Algorithm

• MRCP and CT are the preferred imaging modalities.
  • Detect calcifications (hallmark sign), pancreatic enlargement, and ductal obstruction or dilation.
  • MRCP is more sensitive and specific for chronic pancreatitis than transabdominal ultrasound or plain x-rays, though both can reveal calcifications.

• Endoscopic ultrasound (EUS) is an alternative, particularly for early chronic pancreatitis before fibrosis develops.
  • More invasive and less specific than MRCP or CT.
  • Reserved for cases where MRCP or CT is nondiagnostic but clinical suspicion remains high.[23][25][26]

• Secretin-enhanced MRCP may be used if standard imaging and EUS are inconclusive.

• Endoscopic retrograde cholangiopancreatography (ERCP) was the previous gold standard but is now largely supplanted by MRCP.
  • This technique is still used if therapeutic intervention, such as biliary or pancreatic sphincterotomy, stent placement, or stone extraction, is needed.

• Pancreatic biopsy is indicated if clinical suspicion is high, but imaging remains nondiagnostic. 

• Direct and indirect exocrine function tests can be performed at any point in the diagnostic process but should complement imaging studies rather than replace them.[24] 
  • Direct pancreatic function tests: 
    • The cholecystokinin (CCK) stimulation test measures trypsin or lipase and is sensitive to early exocrine pancreatic insufficiency. However, it is limited in availability and uncomfortable for patients. 
    • Endoscopic secretin stimulation test measures bicarbonate secretion but requires upper gastrointestinal endoscopy, making it costly and invasive.
  • Indirect pancreatic function tests:
    • The ¹³C-mixed triglyceride test is 90% sensitive but takes up to 6 hours to perform and is not widely available. 
  • The fecal elastase test is widely available and practical. 
  • Serum testing:
    • Trypsin or trypsinogen levels are no longer recommended, as they lack specificity and correlation with imaging findings. 

Treatment / Management

The primary goals of treatment are managing pain and improving malabsorption. Abdominal pain in chronic pancreatitis arises from inflammation, neuropathic mechanisms, and ductal obstruction. Once established, chronic pain is typically persistent and lifelong without intervention and can be debilitating.[27] (B2)

One of the most critical steps in management is encouraging alcohol cessation, as continued alcohol use can exacerbate pain and accelerate disease progression. Similarly, smoking cessation is vital and essential, as smoking is known to worsen the condition over time.  

Intervention is not clearly indicated when ductal strictures or stones are present, but the patient remains asymptomatic. However, if these obstructions cause symptoms, therapeutic options such as endoscopic procedures, surgical intervention, or extracorporeal shock wave lithotripsy (ESWL) may be considered.

Pain Management of Chronic Pancreatitis

Pain management in chronic pancreatitis involves medical, endoscopic, percutaneous, and surgical interventions. When imaging reveals ductal obstruction due to strictures or stones, the initial treatment approach should include endoscopy therapy or, in the case of stones, ESWL. Surgical intervention may be necessary if these interventions are unsuccessful or technically unfeasible. However, if no obstruction is identified, a trial of medical therapy is the recommended first-line approach.[28] (B3)

Medical management: The initial approach to pain management in chronic pancreatitis should prioritize non-opioid medications before considering opioids. First-line options include acetaminophen or paracetamol, nonsteroidal anti-inflammatory drugs, pregabalin, selective serotonin reuptake inhibitors, and tricyclic antidepressants.

Opioids should be avoided whenever possible due to the risks of dependence or addiction, tolerance, and adverse effects. However, they may be considered when non-opioid treatments prove ineffective or inadequate. Opioids should be prescribed in combination with non-opioid agents, particularly gabapentin, and initiated with a milder opioid such as tramadol, which has fewer gastrointestinal adverse effects and may be more effective when combined with pregabalin.

Antioxidant combinations—including selenium, ascorbic acid, β-carotene, L-methionine, and sometimes α-tocopherol—have demonstrated some effectiveness in pain relief in early chronic pancreatitis based on small studies. However, variability in formulations and dosages across studies limits definitive conclusions. Despite this, antioxidant therapy is safe and remains an option for some patients.[29][30](A1)

Pancreatic enzyme supplementation, although expensive, has not been proven effective in relieving pain associated with chronic pancreatitis.[31] However, it may still be beneficial for patients with exocrine pancreatic insufficiency to improve nutrient absorption and digestion(A1)

Endoscopic management: A celiac plexus block, involving the injection of a local anesthetic (typically bupivacaine), sometimes combined with a corticosteroid (typically triamcinolone), can be performed endoscopically using EUS or with CT guidance by a radiologist.[32] Pain relief from this procedure typically lasts 3 to 6 months and can be repeated as needed. (A1)

Obstructing pancreatic stones can be extracted using a basket, whereas balloons are rarely effective except in children, who may have softer stones. If traditional extraction methods fail, ESWL, pancreatoscopy-assisted laser, or electrohydraulic lithotripsy may be considered, particularly when a guidewire cannot be advanced past the stone(s).

For main pancreatic duct dilation, ERCP can help decompress ductal obstruction through pancreatic sphincterotomy, stone extraction, stricture dilatation, or stent placement, depending on diagnostic pancreatographic findings. However, when chronic pancreatitis is advanced enough to cause steatorrhea, ductal decompression via dilatation, stenting, or stone extraction offers limited benefit. During ERCP, ductal cytologic brushing can also be performed to evaluate for malignancy.

Pancreatic duct leaks may be treated with the temporary placement of a plastic stent to facilitate healing. Endoscopic drainage into the gastrointestinal tract, typically the stomach, can be performed using 1 or more lumen-apposing metal stents for peri-gastric pancreatic fluid collections such as pseudocysts or necrosis.[33]

Surgical management: Surgical decompression is preferred over ERCP when the main pancreatic duct is narrowed. Several surgical procedures are available based on the disease's location and severity:

• Puestow procedure (most commonly performed): Lateral pancreaticojejunostomy combined with a Roux-en-Y pancreaticojejunostomy to improve drainage.
• Beger procedure: Duodenal-preserving pancreatic head resection with a Roux-en-Y pancreaticojejunostomy, used for pancreatic head-dominant chronic pancreatitis.
• Frey procedure: A modification of the Puestow procedure that involves lateral pancreaticojejunostomy draining the pancreatic head and uncinate process. Unlike the Beger procedure, it preserves the pancreatic neck while removing part of the overlying pancreatic head.
• Distal pancreatectomy: Typically performed laparoscopically for tail-predominant disease. However, complications such as pancreatic fistulae and endocrine failure are relatively common.[34]
• Total pancreatectomy with islet autotransplant: Reserved for patients with refractory pain who have failed all other treatments. Although once used selectively, its application has been increasing in recent years.[35]
(B2)

Additional surgical indications for chronic pancreatitis include:

• Pancreatic abscess, fistula, or pseudocyst when endoscopic management fails
• Pancreatic ascites
• Stenosis of the duodenum leading to gastric outlet obstruction
• Gastric variceal bleeding due to splenic vein thrombosis when conservative therapy is ineffective [36]

In severe cases, inpatient care may be necessary, particularly for patients with chronic pain and anorexia, often requiring narcotics and nutritional support. Pancreatic enzyme supplementation, typically taken with meals, may help reduce pain, although its effectiveness remains uncertain.

Management of Exocrine Pancreatic Insufficiency

Chronic pancreatitis accompanied by weight loss, malnutrition, diarrhea, steatorrhea, osteopenia, or osteoporosis should raise suspicion of exocrine pancreatic insufficiency. Pancreatic enzyme replacement therapy is recommended for managing symptomatic exocrine pancreatic insufficiency. The potential benefits of pancreatic enzyme replacement therapy include improved symptoms, reduced morbidity related to maldigestion (especially bone fractures), better absorption of fat-soluble vitamins and trace elements, reduced fecal fat, weight gain, improved quality of life, and potentially lower mortality rates.[1]

A reduced fecal elastase level is the accessible diagnostic test for moderate-to-severe exocrine pancreatic insufficiency. Patients should avoid consuming a high-fiber diet (>25 g/d), as excessive fiber may interfere with enzyme activity. However, a low-fat diet is no longer recommended, as it may contribute to nutritional deficiencies.

Pancreatic enzyme replacement therapy should be taken at the start of each meal or snack, with additional supplementation added during or after the meal if needed (see Table 3. Dosage of Pancreatic Enzyme Replacement Therapy). Failure to respond to maximal doses of PERT raises several considerations. To maintain effectiveness, capsules must be appropriately stored at temperatures below 25 °C or 77 °F and kept away from direct sunlight, cars, or heat sources. In addition, inadequate response may indicate the need for acid suppression therapy with a histamine-2 receptor antagonist or proton pump inhibitor. If symptoms persist despite these measures, an alternative cause should be considered.[37]

Table 3. Dosage of Pancreatic Enzyme Replacement Therapy

Reference for the table.[37]

Differential Diagnosis

If symptoms of pancreatic insufficiency, such as diarrhea, steatorrhea, flatus, bloating, and abdominal pain, persist despite a dose of greater than 10,000 units of lipase/kg/d, several potential causes exist. These factors should be excluded before further increasing the pancreatic enzyme replacement therapy dose.[38] The differential diagnosis includes:

• Small bowel malabsorption
• Peptic ulcer disease
• Cholelithiasis
• Biliary obstruction
• Acute pancreatitis
• Pancreatic cancer
• Pancreatic pseudocyst
• Chronic mesenteric ischemia
• Small intestinal bacterial overgrowth
• Enteric bacterial infection
• Short bowel syndrome
• Inflammatory bowel disease
• Celiac disease
• Lactose or other food intolerances
• Bile acid malabsorption
• Parasites (especially giardia)

Other potential reasons for persistent symptoms include insufficient dosing, lack of compliance, inadequate timing of pancreatic enzyme replacement therapy administration, and poor diet.[38] A comprehensive review of the patient's medical history and lifestyle factors is essential to identify the underlying cause and tailor the treatment approach accordingly.

Prognosis

Several factors, including the age at diagnosis, ongoing alcohol and tobacco use, and the presence of comorbid conditions such as end-stage liver disease, influence the prognosis of chronic pancreatitis. Many individuals with chronic pancreatitis experience a diminished quality of life due to the high rates of complications associated with the condition.

A longitudinal study conducted between 1997 and 2019, which followed 161 patients who underwent operative management for chronic pain or local complications, found that long-term survival rates were generally favorable.[39] However, most deaths were attributed to alcohol- and smoking-related diseases rather than chronic pancreatitis itself,[39] highlighting the significant impact of lifestyle factors on the long-term prognosis of the disease.

Complications

Chronic pancreatitis can lead to various complications due to ongoing pancreatic damage and dysfunction. These complications include the following:

• Exocrine pancreatic insufficiency, which typically occurs later in the course of chronic pancreatitis, often no sooner than 5 years after diagnosis.
• Pseudocyst formation, which, if adjacent to the stomach, can be drained via EUS with pigtail stent placement; laparoscopic or open surgery is rarely necessary.
• Recurrent acute pancreatitis, especially in alcoholics who continue to drink and smoke.
• Splenic venous thrombosis is potentially complicated by gastric varices or gastric varices disproportionate to esophageal varices.
• Pancreatic ascites or pleural effusion (rare).
• Pseudoaneurysms (rarely involving vessels near the pancreas).
• Pancreatic diabetes occurs in about 30% of chronic pancreatitis patients.
• An increased risk of developing pancreatic ductal adenocarcinoma.