Chronic Pancreatitis

Definition, Etiology, PathogenesisTop

Chronic pancreatitis is a pathologic fibroinflammatory syndrome of the pancreas in individuals with genetic, environmental, and/or other risk factors who develop a chronic abnormal response to pancreatic parenchymal injury. Typical features of advanced chronic pancreatitis include pancreatic atrophy, fibrosis, pancreatic duct irregularities, calcifications, pain, exocrine and endocrine pancreatic dysfunction, and dysplasia. The pathogenesis has not been fully explained; most probably, the disease is a consequence of recurrent acute pancreatitis with subsequent fibrosis.

Causes (according to the TIGAR-O_V2 classification system; patients typically have multiple risk factors):

1) Toxic-metabolic: Alcohol related (alcohol affects the susceptibility to chronic pancreatitis and disease progression; accounts for up to 85% of cases).

Other less common factors contributing to the etiology include tobacco smoking, hypercalcemia (hyperparathyroidism, familial hypocalciuric hypercalcemia, multiple endocrine neoplasia type 1 [MEN 1] or MEN 2a), fasting triglyceride levels >300 mg/dL or incidental levels >500 mg/dL, drugs (>100 drugs may contribute to acute and/or recurrent pancreatitis, including azathioprine, methylprednisolone, fenofibrate, angiotensin-converting enzyme inhibitors, statins, estrogens, and valproic acid), toxins (other than alcohol and nicotine; oxidative stress–associated causes [related to radiotherapy or chemotherapy] or causing damage to pancreatic cells [eg, in stage 5 chronic kidney disease]), metabolic etiology (other than hypertriglyceridemia; related to diabetes, diet, or obesity).

2) Idiopathic.

3) Genetic: Gene mutations: PRSS1 (cationic trypsinogen), CFTR (cystic fibrosis), SPINK1 (serine protease inhibitors), or alpha1-antitrypsin deficiency.

4) Autoimmune (see Autoimmune Pancreatitis).

5) Recurrent and severe acute pancreatitis: Prior acute pancreatitis, recurrent acute pancreatitis.

6) Obstructive: Pancreas divisum, ampulla of Vater stenosis, main pancreatic duct stones, widespread pancreatic calcifications, stricture of the main pancreatic duct, or tumor causing duct obstruction.

Clinical Features and Natural HistoryTop

Chronic pancreatitis is an indolent condition. The dominant clinical features include abdominal pain (although in rare cases, particularly those of autoimmune etiology, the disease may be painless) and in more advanced disease also symptoms of exocrine and endocrine pancreatic insufficiency.

1. Pain: Located in the epigastrium, may be referred to the back, occurs after meals or often following alcohol use. May last from several hours to several days (usually <10 days) and recur with varying frequency or be constant with exacerbations. The pain may improve or disappear with the development of exocrine insufficiency.

2. Signs and symptoms of exocrine pancreatic insufficiency: Flatulence, sensation of epigastric distention, sometimes vomiting, chronic diarrhea (usually steatorrhea due to an impaired secretion of pancreatic lipase). Since meals exacerbate the symptoms, patients often limit their food intake, which together with the coexisting impaired digestion (and secondary malabsorption) and loss of appetite (frequent in alcohol misuse) results in body weight loss, malnutrition, or even cachexia.

3. Symptoms of endocrine pancreatic insufficiency: Impaired glucose tolerance or diabetes mellitus in advanced stages of chronic pancreatitis. Patients with diabetes are prone to hypoglycemia associated with insulin therapy and glucagon deficiency. In rare cases, ketoacidosis develops.

4. Signs: Epigastric tenderness (primarily during exacerbations); some patients develop a palpable abdominal mass (eg, a pseudocyst) or jaundice (usually mild, recurrent, caused by pancreatic head edema or stricture of the terminal portion of the common bile duct, which may be due to compression by the enlarged or fibrotic pancreatic head, or by pseudocysts).

DiagnosisTop

Diagnostic Tests

1. Laboratory tests: Serum amylase and lipase levels may be slightly elevated but are usually normal. Increased serum bilirubin and alkaline phosphatase (ALP) activity are seen in patients with common bile duct stricture due to pancreatic head swelling or fibrosis. In patients without a clear etiology in whom autoimmune pancreatitis is suspected clinically, tests for IgG4 levels or IgG4-positive plasma cells should be ordered as screening tests.

2. Genetic testing: Consider PRSS1, SPINK1, CFTR, CTRC, CPA1, and CEL gene testing in patients with early-onset chronic pancreatitis or positive family history (the test results may alter therapeutic management, have prognostic significance, and influence family planning)

3. Imaging studies:

1) Morphologic features indicating chronic pancreatitis: Irregular main pancreatic duct and branch ducts, with duct dilation or strictures in advanced cases (most frequently observed on endoscopic retrograde cholangiopancreatography [ERCP] or magnetic resonance cholangiopancreatography [MRCP]); pancreatic calcifications (sometimes visualized on plain abdominal radiographs); stones in pancreatic ducts.

2) Findings that are frequently observed in chronic pancreatitis but may occur in other diseases of the pancreas: Diffuse pancreatic edema (as in acute pancreatitis), pancreatic parenchymal fibrosis; pseudocysts; focal necrosis of the pancreas; pancreatic abscesses; portal vein thrombosis; pancreatic atrophy.

Ultrasonography and computed tomography (CT) are the first-line studies used in the assessment of the pancreatic parenchyma (size, presence of calcifications), the pancreatic duct (diameter, outline), and detection of pseudocysts. Endoscopic ultrasonography, MRCP (optimally with prior IV administration of secretin), and ERCP are more sensitive and specific than other imaging studies; due to a higher risk of complications, endoscopic ultrasonography (EUS) and ERCP are only performed in the case of diagnostic uncertainty or as therapeutic measures.

4. Functional tests: These are indicated when the diagnosis of chronic pancreatitis cannot be established on the basis of imaging studies:

1) The secretin-cholecystokinin test is the most sensitive test, but it is extremely costly and labor intensive and therefore rarely done as part of routine clinical practice. The lower limit of exocrine pancreatic sufficiency is defined as 20 mmol HCO3– per hour, trypsin 60 IU/h, lipase 130,000 IU/h, amylase 24,000 IU/h.

2) Fecal elastase 1 measurement: In chronic pancreatitis a result <100 microg/g of feces confirms the diagnosis of exocrine pancreatic insufficiency; a result of 100 to 200 microg/g of feces is inconclusive; a result of >500 microg/g excludes exocrine insufficiency (oral supplementation of pancreatic enzymes does not affect the test result).

Diagnostic Criteria

Diagnosis is based on history (usually involving alcohol consumption, presence of other risk factors, and abdominal pain), typical abnormalities observed on imaging studies of the pancreas (eg, calcifications and stones [see Diagnostic Tests, above]), or symptoms of exocrine or endocrine pancreatic insufficiency (chronic steatorrhea, diabetes mellitus). Confirmation of diagnosis in the early stages of the disease is difficult, as imaging studies usually reveal no abnormalities (except for EUS); in such cases the secretin-cholecystokinin test may prove useful. Sometimes diagnosis is made only after a longer follow-up. Since transabdominal ultrasonography only detects changes corresponding to advanced chronic pancreatitis, a CT or MRI is recommended as the first-line imaging modality in the setting of clinical suspicion of the disease, followed by EUS if findings are inconclusive. If a CT, MRI, and EUS are insufficient to confirm the diagnosis despite high clinical suspicion of chronic pancreatitis, consider secretin-enhanced MRCP (s-MRCP).

Differential Diagnosis

Differential diagnosis should include other causes of abdominal pain and of other symptoms (eg, pancreas cancer, pancreatic cystic neoplasias).

TreatmentTop

General Considerations

1. Treatment of the underlying condition: This is possible only in patients with autoimmune chronic pancreatitis, where oral glucocorticoid therapy results in improvement of symptoms, resolution of abnormalities observed on imaging studies, and improvement of laboratory test results. One should have a high index of suspicion of pancreatic cancer and cholangiocarcinoma before starting treatment of chronic pancreatitis.

2. Symptomatic treatment: Pain control, pancreatic enzyme replacement,Evidence 1Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of intervention). Quality of Evidence lowered due to sparse data (imprecision), as pancreatic enzymes for the management of chronic pancreatitis have been evaluated in 10 randomized trials including only 361 patients. Shafiq N, Rana S, Bhasin D, et al. Pancreatic enzymes for chronic pancreatitis. Cochrane Database Syst Rev. 2009 Oct 7;(4):CD006302. doi: 10.1002/14651858.CD006302.pub2. Review. PMID: 19821359. management of impaired glucose tolerance or diabetes mellitus, prevention of malnutrition, treatment of complications.

3. Treatment of exacerbations: Treatment as in acute pancreatitis is frequently necessary.

Long-Term Treatment

1. General measures:

1) Avoidance of alcohol.

2) Cessation of tobacco smoking.

3) A high-calorie (2500-3000 kcal/d) and high-protein diet. The fat intake should be adjusted to the individual tolerance of a patient receiving adequate enzyme replacement. In the case of severe fatty diarrhea persisting despite enzyme replacement, recommend a reduced fat intake (up to 60-70 g/d) and consumption of 5 or 6 smaller meals per day. If this management does not yield expected results, try medium-chain triglyceride (MCT) preparations and supplement essential unsaturated fatty acids. Patients receiving enzyme replacement therapy should avoid high-fiber foods, as fiber may inhibit the activity of exogenous pancreatic enzymes.Evidence 2Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to methodologic limitations. Poropat G, Giljaca V, Hauser G, Stimac D. Enteral nutrition formulations for acute pancreatitis. Cochrane Database Syst Rev. 2015 Mar 23;(3):CD010605. doi: 10.1002/14651858.CD010605.pub2. PMID: 25803695. Or Petrov MS, Loveday BP, Pylypchuk RD, McIlroy K, Phillips AR, Windsor JA. Systematic review and meta-analysis of enteral nutrition formulations in acute pancreatitis. Br J Surg. 2009 Nov;96(11):1243-52. doi: 10.1002/bjs.6862. PMID: 19847860.

2. Pain management: Introduce the following treatment methods in a stepwise manner: general recommendations (see above); pancreatic enzyme replacement; analgesics; invasive methods (see below). In case of changes in the nature of pain or development of constant pain, exclude complications of chronic pancreatitis and other causes of abdominal pain.

1) Pancreatic enzyme preparations (see below): These might reduce pancreatic stimulation and consequently alleviate the pain.Evidence 3Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of intervention). Quality of Evidence lowered due to heterogeneity and imprecision. de la Iglesia-García D, Huang W, Szatmary P, et al; NIHR Pancreas Biomedical Research Unit Patient Advisory Group. Efficacy of pancreatic enzyme replacement therapy in chronic pancreatitis: systematic review and meta-analysis. Gut. 2017 Aug;66(8):1354-1355. doi: 10.1136/gutjnl-2016-312529. Epub 2016 Dec 9. PMID: 27941156; PMCID: PMC5530474. Shafiq N, Rana S, Bhasin D, et al. Pancreatic enzymes for chronic pancreatitis. Cochrane Database Syst Rev. 2009 Oct 7;(4):CD006302. doi: 10.1002/14651858.CD006302.pub2. Review. PMID: 19821359.

2) Nonnarcotic analgesics (acetaminophen [INN paracetamol], nonsteroidal anti-inflammatory drugs [NSAIDs]) and spasmolytics; in patients not responding to treatment, use opioid analgesics (these must be administered with special care particularly in persons with alcohol use disorder due to the risk of developing dependence); coanalgesics, including pregabalin,Evidence 4Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision and indirectness. Gurusamy KS, Lusuku C, Davidson BR. Pregabalin for decreasing pancreatic pain in chronic pancreatitis. Cochrane Database Syst Rev. 2016 Feb 2;2(2):CD011522. doi: 10.1002/14651858.CD011522.pub2. PMID: 26836292; PMCID: PMC8265874. may prove useful (see Pain Management: Basic Principles). The use of antioxidants might slightly reduce pain; however, the clinical relevance is uncertain.Evidence 5Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to heterogeneity of results and some indirectness (“old” studies). Ahmed Ali U, Jens S, Busch OR, et al. Antioxidants for pain in chronic pancreatitis. Cochrane Database Syst Rev. 2014 Aug 21;8:CD008945. doi: 10.1002/14651858.CD008945.pub2. Review. PMID: 25144441.

3) Endoscopic treatment may include sphincterotomy of the major duodenal papilla (and sometimes also the minor papilla), stenting of the pancreatic duct, dilation of the pancreatic duct strictures, stone extraction, drainage of pseudocysts, and treatment of the common bile duct strictures. EUS-guided celiac plexus block (relieves pain for 3-6 months, allowing to reduce the dose of pain medications; to be considered in patients in whom other pain management methods are ineffective) or bilateral thoracoscopic splanchnicectomy yield satisfactory effects in some patients, but the pain tends to recur shortly, thus limiting the use of these methods.

4) Surgical treatment: Resection, decompression, or mixed surgical techniques. According to the American Gastroenterological Association (AGA), surgery should be considered as a first-line therapy for patients with painful chronic pancreatitis with pancreatic duct obstruction (endoscopic treatment is justified if there are contraindications to surgery or if preferred by the patient). For patients with obstructive chronic pancreatitis with a dilated pancreatic duct, surgical drainage procedures are preferred to endoscopic or conservative management.Evidence 6Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Ahmed Ali U, Pahlplatz JM, Nealon WH, van Goor H, Gooszen HG, Boermeester MA. Endoscopic or surgical intervention for painful obstructive chronic pancreatitis. Cochrane Database Syst Rev. 2012 Jan 18;1:CD007884. doi: 10.1002/14651858.CD007884.pub2. Review. Update in: Cochrane Database Syst Rev. 2015;3:CD007884. PMID: 22258975. In selected patients with pain that is resistant to treatment, total pancreatectomy with autologous islet cell transplant can be considered.

3. Treatment of exocrine pancreatic insufficiency:

1) Pancreatic enzyme replacement therapy is indicated in patients with a progressive body weight loss or fatty diarrhea. Therapy improves digestion and absorption of nutrients, reduces pain, and improves diabetes control. The body weight is the optimal clinical parameter used to assess the efficacy of the treatment. Lipase plays a key role; administer ≥25,000 to 50,000 IU during or immediately after meals and 25,000 IU during snacks between the main meals (the dose can later be adjusted to the size of and fat content in meals). It is recommended to use preparations that release their contents in the duodenum. The efficacy of pancreatic enzyme replacement can be enhanced by coadministration of gastric acid inhibitors: proton pump inhibitors (PPIs) or H2 blockers (agents and dosage: see Peptic Ulcer Disease), which reduce the inactivation of enzymes in the acidic environment (sometimes also in the duodenum).Evidence 7Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of intervention). Quality of Evidence lowered due to sparse data (imprecision), as pancreatic enzymes for the management of chronic pancreatitis have been evaluated in 10 randomized trials including only 361 patients. de la Iglesia-García D, Huang W, Szatmary P, et al; NIHR Pancreas Biomedical Research Unit Patient Advisory Group. Efficacy of pancreatic enzyme replacement therapy in chronic pancreatitis: systematic review and meta-analysis. Gut. 2017 Aug;66(8):1354-1355. doi: 10.1136/gutjnl-2016-312529. Epub 2016 Dec 9. PMID: 27941156; PMCID: PMC5530474. Shafiq N, Rana S, Bhasin D, et al. Pancreatic enzymes for chronic pancreatitis. Cochrane Database Syst Rev. 2009 Oct 7;(4):CD006302. doi: 10.1002/14651858.CD006302.pub2. Review. PMID: 19821359.

2) Supplementation of fat-soluble vitamins (particularly vitamins A and D) in patients with steatorrhea.

4. Treatment of endocrine pancreatic insufficiency:

1) Nutritional treatment of diabetes mellitus, generally without caloric restrictions.

2) If the diet alone is ineffective, start oral antidiabetic drugs. Use insulin with caution, as patients have low requirements for exogenous insulin and are prone to hypoglycemia; usually, the 2-injection regimen is followed, although in some patients with an inadequate diabetes control a more intensive insulin therapy may be required.

ComplicationsTop

Complications of chronic pancreatitis develop at various stages of the disease and in most cases require endoscopic or surgical treatment.

1. Pancreatic pseudocysts (see Pancreatic Cysts) develop in 20% to 40% of patients.

2. Stenosis or obstruction of the common bile duct occurs in 5% to 10% of patients; it causes postprandial abdominal pain and cholestatic liver injury (elevated liver enzyme levels with conjugated hyperbilirubinemia). Patients with duodenal stenosis experience early satiety.

3. Pancreatic ascites is caused by pancreatic duct rupture resulting in the formation of a peritoneal (or pleural) fistula, or by rupture of a pseudocyst draining into the peritoneal (or pleural) cavity. High amylase levels (>1000 IU/L) in the ascites fluid are typically observed.

4. Splenic vein thrombosis develops in 2% to 4% of patients; it causes secondary isolated portal hypertension and gastric varices, with possible upper gastrointestinal bleeding.

5. Pseudoaneurysms of peripancreatic vessels (eg, the splenic, gastroduodenal, or pancreaticoduodenal arteries) are rare.

6. Pancreatic cancer develops in 4% of patients with chronic pancreatitis and in up to 44% of patients with hereditary chronic pancreatitis <70 years (patients with hereditary chronic pancreatitis should be under oncologic surveillance).