Chronic pancreatitis

Chronic pancreatitis (CP) is characterized by progressive inflammation that results in irreversible damage to the structure and function of the pancreas. Chronic heavy alcohol use is the most common cause of CP, followed by pancreatic ductal obstruction. Approximately 30% of CP cases are idiopathic. Affected individuals may be asymptomatic or present with abdominal pain and features of exocrine pancreatic insufficiency (e.g., steatorrhea, weight loss) or endocrine pancreatic insufficiency (e.g., prediabetes, diabetes). Diagnosis is confirmed with imaging, which typically shows pancreatic calcifications, ductal strictures, and ductal dilations. Pancreatic function tests (e.g., fecal elastase-1 measurement, 72-hour fecal fat estimation) assess the degree of enzyme deficiency. Medical therapy should include patient counseling and education, pain management, and monitoring and management of complications (e.g., via oral pancreatic enzyme replacement therapy). Interventional therapy may be required for patients with intractable pain or other complications (e.g., celiac ganglion block, partial or complete pancreatic resection).

• Chronic heavy alcohol use (most common, esp. men) ^[1]
• Pancreatic ductal obstruction: strictures (e.g., due to trauma, stones)
• Tobacco use
• Idiopathic pancreatitis
• Hereditary pancreatitis ^[2]
  • PRSS1 gene mutation (autosomal dominant inheritance), SPINK1 gene mutation
  • Age of onset < 20 years
  • Characterized by a positive family history and the absence of other risk factors
• Autoimmune pancreatitis
• Systemic disease
  • Cystic fibrosis: ∼ 2% of cystic fibrosis patients develop chronic pancreatitis. ^[3]
  • Severe hypertriglyceridemia (levels > 1,000 mg/dL)
  • Primary hyperparathyroidism (hypercalcemia)
• Tropical pancreatitis
  • Most common cause in the tropics (esp. southern India)
  • Young age at onset

The TIGAR-O system categorizes etiologies of chronic pancreatitis: Toxic-Metabolic, Idiopathic, Genetic, Autoimmune, Recurrent acute/severe pancreatitis, and Obstructive. ^[4][5]

• Autodigestion and inflammation: damage to pancreatic acinar cells; (e.g., alcohol), outflow obstruction of pancreatic enzymes or premature activation of trypsinogen to trypsin; → intrapancreatic activation of digestive enzymes (e.g., amylase and lipase) → autodigestion of pancreatic tissue → inflammatory reaction
• Fibrosis: exposure to toxins and/or inflammatory mediators (e.g., alcohol, cytokines) → activation of pancreatic stellate cells

References:^[6]

• Epigastric abdominal pain (main symptom)
  • Pain radiates to the back, is relieved on bending forward, and is exacerbated after eating.
  • Pain is initially episodic and becomes persistent as the disease progresses.
  • Often associated with nausea and vomiting
• Features of pancreatic insufficiency: late manifestation (after 90% of the pancreatic parenchyma is destroyed)
  • Steatorrhea (exocrine enzyme deficiency)
    • Cramping abdominal pain, bloating, diarrhea
    • Can lead to a deficiency of fat-soluble vitamins (A, D, E, and K)
  • Malabsorption and weight loss
  • Pancreatic diabetes (endocrine hormone deficiency)

In the later stages of chronic pancreatitis, patients may not experience any pain.References:^[1][7]

Rule out underlying pancreatic malignancies before starting steroids for autoimmune pancreatitis; reassess for pancreatic malignancy in the case of autoimmune pancreatitis that does not respond to treatment. ^[8]

Approach ^{[4][11][12][13][14]}

There is no single test for the diagnosis of chronic pancreatitis; risk factors, clinical features, imaging studies, and pancreatic function tests may all be considered in the determination of a diagnosis.

• Initial survey: Identify findings raising suspicion for chronic pancreatitis.
  • Characteristic abdominal pain
  • Signs indicative of:
    • Exocrine pancreatic insufficiency (e.g., steatorrhea, weight loss)
    • Endocrine pancreatic insufficiency (e.g., diabetes)
  • Risk factors for chronic pancreatitis
• Initial studies
  • Imaging studies (most important) to confirm structural changes
  • Laboratory testing to assess for complications and identify the underlying cause
• Additional studies: if initial studies were nondiagnostic
  • Pancreatic function tests
  • Histology
  • Genetic testing

A STEP-wise approach to diagnosing chronic pancreatitis may include: Survey, Tomography/imaging, Endoscopic imaging, and Pancreatic function testing.

Imaging ^[4][11][15]

First-line imaging

• Abdominal CT (with and without contrast) or MRI/MRCP
  • Best initial imaging modalities to establish a diagnosis
  • Can exclude gastrointestinal malignancies (e.g., pancreatic carcinoma)
  • Supportive findings
    • Pancreatic ductal dilations and calcifications on plain CT (more sensitive than x-ray)
    • “Chain of lakes” appearance of the main pancreatic duct
    • Pancreatic atrophy

Additional imaging ^[4][16]

• Abdominal ultrasound ^[16]
  • Low sensitivity for detecting pancreatic pathologies
  • Findings
    • Indistinct margins and enlargement
    • Pancreatic calcifications
    • Ductal strictures, dilation, or stones
• Abdominal x-ray: visible pancreatic calcifications (highly specific, but only seen in ∼ 30% of cases) ^[17]
• Endoscopic ultrasound (EUS)
  • Can detect early changes that indicate chronic pancreatitis
  • Indication: reserved for cases in which a CT scan and/or MRI are nondiagnostic ^[4]
  • Findings include: ^[18]
    • Parenchymal lobularity and hyperechoic foci
    • Ductal dilation and calcification
• Secretin-enhanced MRCP
  • Improves visualization of pancreatic ducts ^{[19] [4]}
  • Indication: high clinical suspicion but inconclusive cross-sectional imaging and EUS
  • Findings: ductal strictures and dilations or ectasia
• ERCP: Not routinely recommended because of availability of noninvasive imaging, high risk, and cost ^[14]
  • Can simultaneously identify and treat early pathologies (e.g., duct dilation, stent insertion)
  • Findings
    • Ductal stones, which are visible as filling defects
    • “Chain of lakes” or “string of pearls” appearance (characteristic feature)
    • Irregularity and/or dilation of the main pancreatic duct ^[20]

Laboratory studies ^[11]

• Serum pancreatic enzyme levels: Lipase (specific) and amylase (nonspecific) are often normal.
• CBC: WBCs may be elevated in infection or abscess.
• Calcium: Hypercalcemia may suggest hyperparathyroidism, a rare cause of chronic pancreatitis.
• Triglycerides: Severe hypertriglyceridemia can cause pancreatitis.
• Liver enzymes and liver function tests: elevated in biliary or ductal obstruction
• Fasting plasma glucose and/or HbA1c: elevated levels could suggest type 3c diabetes (pancreatogenic diabetes mellitus)
• Fat-soluble vitamins and zinc: to identify deficiency and establish baseline

Pancreatic enzyme levels are often normal in chronic pancreatitis and cannot be used to confirm or rule out the diagnosis. In contrast, acute pancreatitis typically causes significant enzyme elevation.

Pancreatic function tests ^[4][11]

Consider for patients with features of exocrine pancreatic insufficiency or for those in whom diagnosis of chronic pancreatitis has not been confirmed by imaging.

• Fecal elastase-1 (FE-1): most common test
  • Can support a diagnosis of steatorrhea due to exocrine pancreatic insufficiency ^[21]
  • Interpretation (exact cutoffs are controversial) ^[4]
    • FE-1 < 200 mcg/g: abnormal, potential pancreatic exocrine insufficiency
    • FE-1 < 100 mcg/g: Suspect pancreatic exocrine insufficiency.
• 72-hour quantitative fecal fat estimation: confirmatory test for steatorrhea
  • Patients consume 100 g of fat per day for 72 hours.
  • Interpretation: Fecal fat > 7 g per day is diagnostic of steatorrhea.
• Serum trypsinogen: not routinely recommended ^[4]
  • May be elevated in acute pancreatitis, pain, cystic fibrosis
  • < 20 ng/mL is suggestive of severe pancreatic insufficiency.
• Direct tests of pancreatic function
  • Cholecystokinin analog (cerulein), secretin, or a combination, are administered parenterally.
  • Pancreatic enzyme and bicarbonate levels of duodenal fluid are measured.
  • Low amylase, lipase, trypsin, and bicarbonate levels are suggestive of exocrine pancreatic insufficiency.

The presence of exocrine pancreatic insufficiency (as confirmed by pancreatic function tests) is not required to establish a diagnosis of chronic pancreatitis but can further support the diagnosis.

Histology ^[4]

• Indications: reserved for high-risk patients if the diagnosis has not been established after thorough evaluation
• Characteristic findings ^[13]
  • Bands of interlobular fibrosis
  • Acinar atrophy
  • Intraductal concretions

Histology is rarely used to diagnose chronic pancreatitis because of procedural risks and the possibility of sampling errors that lead to false-negative results.

Genetic testing ^[22]

• Indications include:
  • Family history of chronic pancreatitis
  • Young patients with idiopathic pancreatitis
• Tests include:
  • PRSS1 gene mutations: diagnostic of hereditary pancreatitis
  • CFTR gene mutations: seen in ∼ 30% of patients with idiopathic chronic pancreatitis
  • SPINK1 gene mutations: seen in ∼ 20% of patients with hereditary or idiopathic chronic pancreatitis

Approach ^{[4][11][12][14]}

• Provide patient education: Chronic pancreatitis is a relapsing and remitting disease.
• Start treatment of pain
• Recommend abstinence from nicotine and alcohol for all patients. ^[13]
• Monitor for and manage complications of chronic pancreatitis (e.g., pancreatic enzyme replacement therapy for exocrine pancreatic insufficiency).
• Initiate directed treatment of the underlying etiology of chronic pancreatitis, e.g.:
  • Management of alcohol use disorder and nicotine addiction
  • Management of hypertriglyceridemia in adults
  • Management of hyperparathyroidism

Patients with CP may benefit from a multidisciplinary team providing individualized pain management and addressing psychosocial factors. ^[14]

Pharmacological pain management ^[4]

Provide pain management in a stepwise approach (see “Treatment of pain” for dosages).

• Start with nonopioid oral analgesics (e.g., NSAIDs and acetaminophen if not contraindicated).
• Consider adjuvant analgesics. ^[12]
  • Tricyclic antidepressants (e.g., amitriptyline)
  • SSRIs (e.g., fluoxetine)
  • SNRIs (e.g., duloxetine)
  • Gabapentinoids (e.g., pregabalin)
• Consider antioxidant therapy (e.g., combinations of selenium, ascorbic acid, beta carotene, and methionine).
• Limit opioid analgesics.

Pain management in chronic pancreatitis requires careful assessment and frequent reevaluation.

Interventional therapy

Endoscopic

• Indication: pain not adequately managed with pharmacotherapy
• Procedures
  • Celiac ganglion block repeated as needed (provides 3–6 months of relief)
  • Endoscopic papillotomy with ductal dilation, stent placement, and removal of stones if present
  • Extracorporeal shock wave lithotripsy (ESWL) to dissolve stones

Surgical ^[11]

• Indications
  • Intractable pain not adequately managed with pharmacotherapy or endoscopic procedures
  • Other: suspected malignancy, complications
• Procedures
  • Thoracoscopic bilateral splanchnicectomy ^[23]
  • Surgical decompression
    • Lateral pancreaticojejunostomy: if the main pancreatic duct is dilated (> 5 mm)
    • Sphincterotomy or sphincteroplasty
  • Surgical resection
    • Pancreaticoduodenectomy (Whipple procedure)
    • Distal pancreatectomy
    • Pylorus-preserving pancreaticoduodenectomy
    • Total pancreatectomy with islet autotransplant (TPIAT) (last-line curative therapy)

Total pancreatectomy is the only known cure for chronic pancreatitis; it should be reserved for select patients with chronic pain after all other measures have failed. ^[4]

Recurrent acute pancreatitis ^[11]

See “Acute pancreatitis.”

Exocrine pancreatic insufficiency ^[4][12]

Pathophysiology

Tissue atrophy and fibrosis → deficiency of lipase, amylase, and protease → maldigestion, steatorrhea, and malabsorption

Clinical features

• Long-standing chronic pancreatitis
• Weight loss, malnutrition
• Diarrhea, steatorrhea
• Osteoporosis or osteopenia

Diagnostics

• Clinical diagnosis
• Consider FE-1 testing for diagnostic confirmation (see also “Diagnostics”)

Management

• Advise small, frequent meals without fat restriction.
• Check indications for pancreatic enzyme replacement therapy (e.g., with pancrelipase ), which include: ^[14]
  • Typical symptoms of steatorrhea
  • Atypical symptoms of steatorrhea AND
    • FE-1 < 50 mcg/g of stool
    • OR micronutrient deficiency
  • Fecal fat > 15 g/day
• Screen for osteoporosis.
• Screen for fat-soluble vitamin deficiency (vitamins A, D, E, and K) and zinc.

Endocrine pancreatic insufficiency

• Pathophysiology: Destruction of beta cells leads to endocrine insufficiency with pancreatogenic diabetes (type 3c diabetes mellitus). ^[24]
• Clinical features: Brittle, insulin-dependent diabetes
• Diagnostics
  • Screen all patients annually with HbA1c or fasting plasma glucose measurement.
  • See “Diagnostics” in “Diabetes mellitus.”
• Treatment
  • Specialist consultation (endocrinology) is advised.
  • See “Antihyperglycemic treatment” in “Diabetes mellitus.”

Pancreatic pseudocysts ^[11][25]

Definition

Encapsulated collection of pancreatic fluid that develops 4 weeks after an acute attack of pancreatitis (can occur in both acute and chronic pancreatitis) ^[11]

Pathophysiology

Pancreatic secretions leak from damaged ducts → inflammatory reaction of surrounding tissue → encapsulation of secretions by granulation tissue

Clinical features ^[26]

• Often asymptomatic
• Painless abdominal mass
• Pressure effects
  • Gastric outlet obstruction (early satiety, nonbilious vomiting, abdominal pain)
  • Obstruction of the distal duodenum (bilious vomiting) may result in steatorrhea.
  • Bile duct obstruction with jaundice

Diagnostics ^[27]

• First line: CT abdomen with contrast
• Findings: Extrapancreatic fluid collection within well-defined wall or capsule with contrast enhancement
• Other imaging modalities
  • Transabdominal ultrasound
    • Fast and readily available
    • High sensitivity, but low negative predictive value
  • ERCP (gold-standard test): more invasive, but allows treatment to be performed
  • MRI/MRCP: highly sensitive and specific test, but associated with high cost

Treatment ^[28]

• Conservative management: asymptomatic patients with small pancreatic pseudocysts and no complications
  • Symptom management (e.g., nonopioid analgesics for pain, antiemetics for nausea)
  • Alcohol cessation
  • Low-fat diet with small, frequent meals
  • Imaging surveillance

• Endoscopic drainage
  • First-line treatment
  • Indications
    • Asymptomatic patients with chronic large pancreatic pseudocysts
    • Symptomatic cysts
      • Nausea and vomiting
      • Anorexia and weight loss
      • Persistent abdominal pain
    • Suspected malignancy
    • Complications
      • Gastric outlet, duodenal, or biliary obstruction (e.g., common bile duct stenosis)
      • Hemorrhage
      • Infection
      • Pancreatic pseudoaneurysm
      • Compression of large vessels
      • Pancreaticopleural fistula
• Percutaneous drainage: reserved for patients in whom endoscopic drainage is not technically feasible or was previously unsuccessful
• Surgical drainage
  • The cyst is drained into the stomach, duodenum, or jejunum (i.e., cystogastrostomy, cystoduodenostomy, cystojejunostomy).
  • Reserved for patients in whom endoscopic and/or percutaneous interventions were previously unsuccessful or where surgical access is useful to treat suspected complications (e.g., necrosis, infection) in addition to drainage
• ERCP transpapillary drainage: reserved for pseudocysts that connect with the pancreatic duct

Complications

• Infection: fever, abdominal pain, sepsis
• Pseudocyst rupture: pancreatic ascites/pancreaticopleural fistula
• Erosion into an abdominal vessel: hemorrhage into the cyst

Pancreatic ascites

Pathophysiology

Ductal disruption (due to an acute attack of pancreatitis, pancreatic surgery and/or trauma) or a pseudocyst leak/rupture → pancreatic ascites

Clinical features

• Abdominal distention; variable abdominal pain
• Dyspnea
• Peripheral edema
• Free fluid in the peritoneal cavity

Diagnostics

• Ascitic fluid analysis: exudate (high protein: > 3 g/dL; low SAAG: < 1.1 g/dL) with high amylase levels (> 1,000 IU/L)
• Imaging: ERCP, CECT, MRCP
  • Identify ascites and the site(s) of the leak
  • ERCP is preferred, as it allows treatment to be performed in the same sitting.

Management

• Conservative management
  • Indicated for all patients ^[29]
  • Nothing by mouth, IV fluids, parenteral nutrition
  • Somatostatin analogs (octreotide)
• Interventions
  • Repeated paracenteses
  • Stenting of the pancreatic duct: if ERCP shows ductal disruption ^[30]
  • Surgery: indicated in patients showing no improvement after 4 weeks of conservative management (see “Pancreatic and hepatic surgery”)
    • Pancreatic resection
    • Surgery for pancreatic pseudocyst
    • Lateral pancreaticojejunostomy

Splenic vein thrombosis ^[31]

• Epidemiology: Occurs in 10% of patients with chronic pancreatitis
• Pathophysiology: Inflammation of the splenic vein; → thrombus formation → left-sided portal hypertension → gastric varices
• Clinical features
  • Upper GI bleeding
  • Ascites
  • Splenomegaly
• Diagnostics
  • Ultrasound with doppler
  • CT/MR angiography
• Treatment
  • Acute: anticoagulation and/or thrombectomy
  • Chronic and symptomatic: splenectomy

Further complications

• Pancreatic abscess
• Portal vein thrombosis
• Pancreatic cancer (especially in patients with hereditary pancreatitis)

General screening for pancreatic cancer is not currently recommended. Screen patients (with a triphasic pancreas protocol CT) who develop weight loss, protracted abdominal pain, or functional decline. ^[4][11]

We list the most important complications. The selection is not exhaustive.