Chronic Pancreatitis

Acute Pancreatitis

• Nature of Injury: Acute pancreatitis represents a reversible, self-limiting inflammatory process of the pancreas.
• Clinical Presentation: Typically manifests with acute-onset mid-epigastric abdominal pain often radiating to the back, along with elevated serum levels of pancreatic enzymes such as amylase and lipase.
• Histology: Predominantly neutrophilic infiltration characterises the inflammation.
• Course: Resolution is expected with appropriate management and elimination of the inciting factor.
  
  

Chronic Pancreatitis

• Definition: A progressive fibroinflammatory disorder marked by irreversible structural changes in the pancreas, leading to permanent impairment of both exocrine and endocrine functions.
• Clinical Features: Patients may present with chronic or intermittent abdominal pain, steatorrhoea, malabsorption, weight loss, and diabetes mellitus. Some may remain asymptomatic for prolonged periods.
• Histology: Chronic inflammation with mononuclear cell infiltration, ductal distortion, acinar cell atrophy, and fibrosis.
• Functional Loss:
  • Exocrine insufficiency usually develops after loss of more than 90% of pancreatic tissue.
  • Endocrine dysfunction can lead to pancreatogenic (type 3c) diabetes.
• Imaging: Characteristic findings include pancreatic calcifications, atrophy, ductal strictures, and a “chain-of-lakes” appearance due to irregular dilation of pancreatic ducts.
  
  

Mechanistic Definition (2016 Consensus

• Ongoing inflammation,
• Fibrosis and parenchymal atrophy,
• Ductal distortion and strictures,
• Pain syndromes,
• Exocrine and endocrine insufficiency,
• Risk of dysplasia and pancreatic cancer.
  
  

Subtypes of Recurrent Pancreatitis

1. Recurrent Acute Pancreatitis: Caused by a known factor (e.g., gallstones, hypercalcaemia) but does not progress to chronic pancreatitis.
   
   
2. Idiopathic Pancreatitis: No identifiable cause despite exhaustive investigation; may represent early or chronic relapsing disease.
   
   
3. Chronic Relapsing Pancreatitis: Patients experience recurrent episodes of pancreatic pain without overt chronic changes but with histological evidence of damage.
   
   
4. Established Chronic Pancreatitis: Classical features such as exocrine insufficiency, diabetes, and calcifications are present.
   
   

Alcohol-Induced Pancreatitis

• Prevalence: Alcohol is the leading global cause, accounting for approximately 60–80% of chronic pancreatitis cases, although population-specific estimates vary.
• Dose-Response Relationship: Risk increases with consumption above 25 g/day. Most patients with chronic pancreatitis report daily consumption >150 g. However, fewer than 10% of chronic heavy drinkers develop the disease, indicating that alcohol alone is insufficient.
• Pathophysiology:
  • Alcohol increases acinar protein secretion while reducing ductal bicarbonate and fluid output, resulting in proteinaceous plug formation and ductal obstruction.
  • Lithostathine S1 and GP2, secreted from acinar cells, contribute to pancreatic stone formation and protein plug stabilisation.
  • Oxidative stress from alcohol metabolism (both oxidative via acetaldehyde and nonoxidative via fatty acid ethyl esters) leads to cellular injury, particularly when protective mechanisms are overwhelmed.
• Modifiers: Smoking, malnutrition, high-protein/high-fat diets, genetic polymorphisms (e.g., SPINK1), and viral infections such as coxsackievirus act as cofactors lowering the threshold for disease development.
  
  

Idiopathic Pancreatitis

• Frequency: Accounts for 20–30% of chronic pancreatitis cases.
• Subtypes:
  • Early-onset (<35 years): Often associated with genetic mutations (e.g., SPINK1, CFTR).
  • Late-onset (>35 years): May be linked with undiagnosed autoimmune or obstructive pathology.
• Genetic Susceptibility: Many idiopathic cases are reclassified as genetically mediated upon detailed molecular analysis.
  
  

Genetic Causes

• Key Genetic Mutations:
  • PRSS1 (cationic trypsinogen): Autosomal dominant; enhances trypsinogen autoactivation.
  • SPINK1: Autosomal recessive; loss of protease inhibitor activity.
  • CFTR: Affects bicarbonate transport; mutations linked with cystic fibrosis-related pancreatitis.
  • CTRC, CPA1, CEL, CASR, CLDN2: Involved in enzyme regulation, ductal ion transport, and cell signaling.
• Hereditary Pancreatitis: PRSS1 mutations have 80% penetrance; typically present in childhood or adolescence.
  
  

Autoimmune Pancreatitis (AIP)

• Subtypes:
  • Type I: IgG4-related disease with systemic manifestations.
  • Type II: Localised to the pancreas; often associated with inflammatory bowel disease.
• Features:
  • Painless obstructive jaundice, pancreatic enlargement, and diffuse ductal narrowing.
  • Histology shows lymphoplasmacytic infiltration and storiform fibrosis.
  • Elevated IgG4 levels and autoantibodies are typical.
• Prognosis: Recurrent episodes may result in progressive fibrosis and stone formation, evolving into chronic pancreatitis.
  
  

Obstructive Pancreatitis

• Congenital Abnormalities:
  • Pancreas divisum: Ductal drainage anomaly, often associated with stenosis of the minor papilla.
  • Annular pancreas: Can compress the duodenum, causing stasis and inflammation.
• Acquired Causes:
  • Post-traumatic ductal strictures, duodenal inflammation, or tumours obstructing the pancreatic duct.
• Pathogenesis: Mechanical obstruction leads to upstream ductal hypertension, acinar atrophy, and progressive fibrosis.
  
  

Metabolic and Nutritional Causes

• Hyperlipidaemia: Especially type I and V; frequent trigger for recurrent acute attacks evolving into chronic disease.
• Hypercalcaemia: Rare due to early detection in modern practice; classically associated with hyperparathyroidism.
• Tropical Pancreatitis: Occurs in developing regions; associated with malnutrition and potential genetic modifiers.
• Vitamin and Antioxidant Deficiency: May worsen oxidative injury and fibroinflammatory progression.
  
  

Autoimmune and Systemic Associations

• Associations: Sjögren syndrome, systemic lupus erythematosus, primary biliary cholangitis, and inflammatory bowel disease.
• Pathogenesis: Autoimmune activation leads to chronic lymphocytic infiltration, ductal obstruction, and fibrosis.
  
  

Drug-Induced Pancreatitis

• Examples include: azathioprine, corticosteroids, hydrochlorothiazide, didanosine, valproic acid, statins, oral contraceptives, ACE inhibitors, and interferon.
• Though typically causing acute pancreatitis, chronic forms may result from prolonged exposure or recurrent inflammation.
  
  

TIGAR-O Classification System

• Toxic-metabolic
  • Alcohol
  • Cigarette smoking
  • Hyperlipidaemia
  • Hypercalcaemia
  • Diabetes mellitus
  • End-stage renal disease
  • Specific medications (e.g., corticosteroids, thiazides, azathioprine)
    
    
• Idiopathic
  • Early-onset idiopathic chronic pancreatitis
  • Late-onset idiopathic chronic pancreatitis
    
    
• Genetic
  • PRSS1 (cationic trypsinogen)
  • SPINK1 (serine protease inhibitor, Kazal type 1)
  • CFTR (cystic fibrosis transmembrane conductance regulator)
  • CTRC (chymotrypsin C)
  • CPA1 (carboxypeptidase A1)
  • CEL (carboxyl ester lipase)
  • CASR (calcium-sensing receptor)
  • CLDN2 (claudin-2)
    
    
• Autoimmune
  • Type I autoimmune pancreatitis (IgG4-related)
  • Type II autoimmune pancreatitis
  • Systemic autoimmune diseases (e.g., Sjögren’s syndrome, systemic lupus erythematosus)
    
    
• Recurrent Acute Pancreatitis
  • Post-ERCP pancreatitis
  • Biliary pancreatitis
  • Traumatic causes
  • Other extrapancreatic conditions
    
    
• Obstructive
  • Congenital anomalies (e.g., pancreas divisum)
  • Acquired ductal strictures
  • Pancreatic duct stones
  • Mass lesions (e.g., tumours, pseudocysts)

Initiating Events and Early Cellular Injury

• Pancreatic ducts – as suggested by the primary duct hypothesis, which postulates a primary autoimmune or inflammatory reaction initiating in the ducts.
• Acinar cells – as described in the sentinel acute pancreatitis event hypothesis, where the initial insult occurs at the level of the acinar cells, resulting in the recruitment of inflammatory cells and cytokine secretion.
  
  

Fibrogenesis and Inflammatory Signalling

• Pancreatic stellate cell (PSC) activation: These normally quiescent cells are activated by inflammatory cytokines (e.g., TGF-β, TNF-α, IL-1β) and reactive oxygen species.
• Matrix production: Activated PSCs secrete extracellular matrix proteins such as collagen, fibronectin, and proteoglycans, contributing to parenchymal scarring.
• Chemokine involvement: Chemokines such as MCP-1 and RANTES further perpetuate inflammation and fibrogenesis.
  
  

Enzyme Activation and Ductal Obstruction

1. Protein Plug Theory: An imbalance between acinar protein hypersecretion and inadequate ductal bicarbonate output leads to proteinaceous plugs and eventual intraductal calcification.
2. Enzyme Activation Theory: Premature activation of digestive enzymes, particularly trypsinogen, within acinar cells causes autodigestion and cellular necrosis.
   
   

Role of Alcohol and Calcium Signalling

• Reducing the cell’s ability to buffer intracellular calcium, which is critical for zymogen granule integrity.
• Promoting oxidative stress and impairing mitochondrial function.
• Increasing ductal permeability and impairing bicarbonate secretion.

Progressive Staging of Chronic Pancreatitis

1. At Risk: Individuals have underlying genetic or environmental susceptibility but no symptoms or detectable changes.
2. Acute Pancreatitis: A first sentinel episode occurs, often resolving without progression.
3. Recurrent Acute Pancreatitis: Repeated acute episodes begin to cause irreversible damage.
4. Early Chronic Pancreatitis: Histological or biomarker evidence of disease becomes detectable.
5. Established to End-Stage Chronic Pancreatitis: Functional loss, fibrosis, and morphological changes become clinically overt and irreversible.

Pain Mechanisms

• Local inflammation and fibrosis increase intrapancreatic pressure.
• Ischaemia results from compression of intrapancreatic vasculature.
• Perineural inflammation and fibrosis can encase sensory nerves.
• Central sensitisation and altered nociceptive processing contribute to chronic pain syndromes.
• Extra-pancreatic complications such as pseudocysts or bile duct obstruction may also cause pain.
  
  

Functional Impairment and Sequelae

• Exocrine insufficiency: Loss of acinar cell mass leads to malabsorption, steatorrhoea, and nutritional deficiencies. Clinically apparent when >90% of function is lost.
• Endocrine insufficiency: Islet cell dysfunction results in pancreatogenic diabetes mellitus (type 3c), a form of insulinopenic diabetes.
• Neoplastic transformation: Chronic inflammation and epithelial metaplasia increase the risk of pancreatic ductal adenocarcinoma (PDAC).
  
  
  

Global Incidence and Prevalence

• Global Pooled Incidence: An estimated 9.62 cases per 100,000 person-years (95% CI: 7.86–11.78).
• Mortality Rate: Low, at approximately 0.09 deaths per 100,000 person-years (95% CI: 0.02–0.47).
• Prevalence Estimates:
  • General population studies report a prevalence ranging from 0.03% to 0.05%.
  • Autopsy series have found a higher prevalence, ranging from 0.04% up to 5%.
• Post-Acute Pancreatitis: A meta-analysis suggests that chronic pancreatitis develops in 10% of individuals after a single acute pancreatitis episode and in 36% after multiple episodes.
  
  

Geographical Variation

• Higher incidence rates are observed in European countries compared to North America and the Western Pacific.
• Hospital admission data show comparable frequencies across global urban centres (cases per 1,000 admissions):
  • Marseille: 3.1
  • Cape Town: 4.4
  • São Paulo: 4.9
  • Mexico City: 4.4
• Historical data (1945–1985) suggest a rising trend in chronic pancreatitis incidence over time.
  
  

Demographic Variation

• Overall Risk: Men are twice as likely as women to develop chronic pancreatitis.
• Risk Factors:
  • Alcohol and tobacco use are dominant in men.
  • Idiopathic and hyperlipidaemic causes are more common in women.
  • Equal male-to-female ratios are observed in hereditary forms.
    
    

• Median Age at Diagnosis: Around 45–46 years globally.
• Geographic Differences: Onset in China typically occurs a decade later than in Western populations.
• Age Peaks by Aetiology:
  • Hereditary: 10–14 years
  • Juvenile idiopathic: 19–23 years
  • Alcoholic: 36–44 years
  • Senile idiopathic: 56–62 years
    
    

Race and Ethnicity

• In the United States, Black individuals are hospitalised for chronic pancreatitis at three times the rate of White individuals.
• Socioeconomic factors, healthcare access, and risk factor prevalence (especially alcohol and smoking) likely contribute to these disparities.
  
  
  

Underdiagnosis and Reporting Limitations

• Chronic pancreatitis is frequently underdiagnosed due to its insidious onset and slow progression, particularly in alcohol-related cases.
• Disparities in diagnostic criteria, access to imaging, and differences in study designs further complicate incidence and prevalence estimates.
• Hospital discharge data in the U.S. estimate approximately 87,000 annual cases of pancreatitis, though not all are chronic.
  
  

Core Symptoms Identified on History

• Most Common Symptom: Present in over 80% of patients at the time of diagnosis.
• Character: Typically dull, located in the epigastric region, often radiates to the back. Pain may be relieved by leaning forward and worsened by lying supine.
• Temporal Pattern:
  • Postprandial exacerbation is common (~30 minutes after meals).
  • Episodic in early disease (type A: short, relapsing episodes).
  • Progresses to constant pain in some (type B: prolonged or continuous), especially in alcohol-related and early-onset idiopathic forms.
  • Pain may lessen over time with disease progression or calcification.
• Red Flags: Sudden change in pain pattern may indicate a complication (e.g., pseudocyst, pancreatic carcinoma, biliary obstruction).
  
  

• Symptom Description: Passage of oily, foul-smelling, floating stools.
• Timing: Develops after >90% exocrine pancreatic function is lost, usually over 5–10 years.
• Differential: Must exclude dietary mineral oil ingestion.
  
  

• Causes include:
  • Fear of eating due to pain.
  • Malabsorption from exocrine insufficiency.
  • Poor diabetes control.
• Micronutrient Deficiencies:
  • Commonly affects fat-soluble vitamins: A (14.5%), E (24.2%), D (up to 53%).
  • Consequences include visual impairment, neurological symptoms, and bone loss.
    
    

• Nausea and vomiting: May relate to altered gastric motility or opioid use.
• Bloating and excessive flatulence: Reflects fat malabsorption.
• Diarrhoea: Often linked to steatorrhoea and enzyme loss.
• Jaundice: Present in ~10%; usually due to bile duct compression.
• Shortness of breath: Can result from pleural effusions associated with pancreatic fluid leakage.
  
  

• Skin nodules: Subcutaneous fat necrosis due to circulating lipase.
• Joint pain: Seen in autoimmune pancreatitis or fat necrosis syndromes.
• Abdominal distension: May arise from pseudocysts, cancer, or pancreatic ascites.
• Low-trauma fractures: Related to bone density loss from malnutrition and chronic inflammation.
  
  
  

Historical Risk Factors for Chronic Pancreatitis

• Alcohol Use:
  • Most significant global risk factor (70–80%).
  • Risk increases with consumption above 25 g/day, especially in the presence of cofactors.
  • Pain is the typical presenting symptom in 77% of alcohol-related cases.
• Smoking:
  • Independent, dose-dependent risk factor.
  • Accelerates disease onset and progression, especially in combination with alcohol.
• Family History and Genetic Factors:
  • Important in early-onset idiopathic and tropical pancreatitis.
  • Associated mutations: PRSS1 (hereditary), SPINK1, CFTR, CTRC, CASR, CLDN2, CPA1.
  • Genetic counselling is advised in individuals with suggestive history.

• Coeliac Disease: Associated with idiopathic recurrent or chronic pancreatitis.
• Tropical Geography: Linked to tropical pancreatitis and SPINK1 mutations.

• Psoriasis: Preliminary evidence of increased risk.
• High-fat, high-protein diet: Requires further study.
• Autoimmune diseases: History suggestive of systemic lupus, Sjögren’s, or IgG4-related disorders can be relevant.
  
  
  

Natural History and Diagnostic Delays

• Time to Diagnosis:
  • Average time from symptom onset to diagnosis is ~62 months.
  • Longer delays (up to 81 months) are seen in non-alcoholic cases.
• Pain Evolution:
  • While many patients experience intermittent pain for years, a minority progress to constant pain.
  • Over time, some patients experience resolution of pain, coinciding with advanced disease (e.g., calcifications or glandular burnout).
    
    

General Observations on Physical Examination

• Limited Diagnostic Utility: Routine examination may be non-contributory in many patients, especially those with early-stage disease or mild symptoms.
• Characteristic Pain Posture:
  • During painful exacerbations, patients often adopt a forward-flexed position (e.g., lying on the left side, knees drawn to chest) to alleviate discomfort.
  • Pain is typically epigastric and may radiate to the back; however, tenderness on palpation is often absent unless complications have developed.
    
    

Abdominal Findings

• Epigastric Tenderness or Mass:
  • A tender, palpable mass in the epigastrium may suggest the presence of a pancreatic pseudocyst or inflammatory phlegmon.
  • Such findings are uncommon but significant and should prompt further imaging.
• Abdominal Distension:
  • May occur due to pancreatic ascites (resulting from ductal disruption), gastric outlet obstruction (from duodenal fibrosis or pseudocyst), or neoplastic progression.
  • Auscultation and percussion may reveal fluid shifts or tympanism depending on the underlying cause.
    
    

Nutritional and Cachectic Signs

• Subcutaneous Fat Loss:
  • Particularly noticeable in the temporal region, supraclavicular fossae, or interosseous spaces.
• Temporal Wasting and sunken cheeks suggest chronic malnutrition.
• Muscle Wasting (Sarcopenia):
  • May indicate advanced disease and correlates with poorer prognosis.
• Vitamin Deficiency Manifestations:
  • Vitamin A: Night blindness or dry eyes.
  • Vitamin D: Proximal muscle weakness, bone pain, increased risk of fractures.
  • Vitamin E: Neurological signs such as areflexia or ataxia.
  • Vitamin K: Easy bruising or prolonged clotting time (though subtle on examination).
    
    
    

Skin and Subcutaneous Signs

• Pancreatic Fat Necrosis:
  • Results from systemic lipase leakage.
  • Cutaneous Manifestations:
    • Painful or painless erythematous nodules typically on the lower limbs.
    • May be associated with fever and polyarthritis.
• Jaundice:
  • Seen in ~10% of cases due to compression of the common bile duct.
  • Scleral icterus and skin yellowing may be subtle and precede overt biochemical abnormalities.
  • Always evaluate for underlying malignancy in new-onset jaundice.
    
    

Pulmonary and Pleural Findings

• Pleural Effusion:
  • More common on the left side.
  • Results from leakage of pancreatic juice into the pleural space.
  • Clinical signs include:
    • Decreased breath sounds,
    • Stony dullness on percussion,
    • Reduced chest expansion.
  • May present as dyspnoea or orthopnoea.
    
    

Musculoskeletal Manifestations

• Joint Involvement:
  • May reflect metastatic fat necrosis or IgG4-related autoimmune pancreatitis.
  • Presents as painful, swollen joints with or without systemic inflammation.
• Fractures:
  • Low-impact or spontaneous fractures due to osteopenia or osteoporosis.
  • Particularly prevalent in patients with long-standing disease, alcohol abuse, and malnutrition.
  • Spinal or rib tenderness may suggest vertebral compression fractures.
    
    
    

Other Less Common Findings

• Ascites:
  • May be pancreatic in origin (due to ductal leak or pseudocyst rupture).
  • Distended abdomen with shifting dullness or fluid thrill may be detected.
• Signs of Endocrine Insufficiency:
  • Advanced disease may manifest with symptoms of diabetes mellitus (e.g., polydipsia, weight loss), though direct examination findings may be limited.
    
    

Initial Investigations

• Computed Tomography (CT):
  • Typically first-line imaging.
  • Identifies calcifications, ductal dilation, pseudocysts, and glandular atrophy.
  • Sensitivity: ~80%; specificity: ~85%.
  • Limitation: normal CT does not exclude early CP.
• Magnetic Resonance Imaging (MRI) / Magnetic Resonance Cholangiopancreatography (MRCP):
  • Preferred if CT findings are inconclusive or early CP is suspected.
  • Secretin-enhanced MRCP (s-MRCP) improves ductal detail and functional assessment.
  • More sensitive than CT for ductal abnormalities and mild CP.
    
    

Second-Line or Supplementary Imaging

• Superior spatial resolution for detecting early ductal and parenchymal changes.
• EUS criteria include:
  • Hyperechoic strands or foci
  • Lobularity
  • Ductal irregularity or dilation
  • Parenchymal calcifications
• Diagnosis is more specific when ≥5 features are present.
• Particularly useful when CT and MRCP are inconclusive.
  
  

• Formerly the gold standard; now reserved for therapeutic purposes.
• Visualises ductal abnormalities (e.g., stones, strictures, “chain-of-lakes” appearance).
• Invasive with a risk of post-ERCP pancreatitis.
• Limited in assessing parenchymal changes.
  
  
  

Functional Assessment

• Secretin or CCK-stimulated tests (via duodenal aspiration or ERCP):
  • Measure pancreatic enzyme and bicarbonate output.
  • Gold standard for detecting early functional impairment.
  • Availability is limited; invasive and resource-intensive.
    
    

• Faecal Elastase-1:
  • Most widely available test for exocrine insufficiency.
  • A level <100 μg/g of stool suggests severe insufficiency; 100–200 μg/g is indeterminate.
  • Less sensitive for mild to moderate disease.
• 72-hour Faecal Fat Quantification:
  • Gold standard for steatorrhoea confirmation.
  • 7 g/day of fat on 100 g fat intake confirms fat malabsorption.
  • Impractical for routine use.
• Steatocrit:
  • Quick gravimetric stool fat test; may substitute 72-hour test in select cases.
    
    

Laboratory and Serological Investigations

• Serum Amylase and Lipase:
  • Usually normal in chronic disease; may be mildly elevated during acute flares.
  • Normal levels do not exclude CP.
• Serum Calcium and Triglycerides:
  • Rule out hypercalcaemia and hyperlipidaemia as reversible causes.
• IgG4:
  • Elevated in autoimmune pancreatitis.
  • Consider testing when imaging shows diffuse glandular enlargement or ductal narrowing.
• Glucose and HbA1c:
  • Evaluate for pancreatogenic (type 3c) diabetes.
• Vitamin Levels:
  • Assess for deficiencies of fat-soluble vitamins A, D, E, and K.
  • Frequent in patients with steatorrhoea.
    
    

Genetic Testing

• Indicated in:
  • Early-onset or idiopathic CP.
  • Strong family history of pancreatic disorders.
• Genes commonly tested:
  • PRSS1 (cationic trypsinogen)
  • SPINK1 (serine protease inhibitor)
  • CFTR (cystic fibrosis transmembrane regulator)
  • CTRC, CASR, CPA1
• Identifying mutations aids in diagnosis, familial counselling, and potentially targeted management.
  
  
  

Histological Examination

• Gold Standard (but invasive):
  • Used in patients with diagnostic uncertainty despite comprehensive imaging and testing.
  • Helps differentiate CP from malignancy (especially when a mass is present).
• Histopathological findings:
  • Fibrosis, acinar atrophy, inflammatory infiltration.
  • Protein plugs and calcified ductal stones (especially in alcoholic or tropical CP).
    
    
    

Diagnostic Considerations in Children

• Diagnosis in paediatric populations requires:
  • Demonstration of irreversible morphological changes or functional impairment.
  • Imaging, PFTs, and genetic testing are crucial in the absence of classic features.
    
    

Gastrointestinal Causes

• Clues: Sudden onset epigastric pain, nausea, vomiting; may have systemic features like hypotension or renal dysfunction.
• Tests: Marked elevation of serum lipase (>3× upper limit); CT reveals pancreatic oedema or necrosis.
  
  

• Clues: Progressive pain, jaundice, anorexia, weight loss.
• Tests: Imaging (CT, MRI, EUS) reveals mass or ductal stricture; elevated CA 19-9 and CEA; diagnosis confirmed via biopsy.

• Clues: Palpable mass, worsening pain post-pancreatitis episode.
• Tests: CT or EUS showing fluid collection adjacent to pancreas.
  
  

• Clues: Epigastric pain relieved by food or antacids, nausea, melaena or haematemesis.
• Tests: Upper GI endoscopy or barium studies; response to PPI therapy is suggestive.
  
  

• Clues: Postprandial right upper quadrant pain (especially after fatty meals), radiates to shoulder.
• Tests: Abdominal ultrasound; may show gallstones or biliary sludge.
  
  

• Clues: Jaundice, dark urine, pale stools, pruritus.
• Tests: MRCP or ERCP for ductal imaging; elevated ALP, bilirubin.
  
  

• Clues: Diarrhoea, weight loss, iron-deficiency anaemia.
• Tests: tTG-IgA, duodenal biopsy showing villous atrophy.
  
  

• Clues: Chronic diarrhoea, abdominal pain, extraintestinal manifestations.
• Tests: Colonoscopy with biopsy; faecal calprotectin.
  
  

• Clues: Bloating, flatulence, diarrhoea, worsened after antibiotics or PPI use.
• Tests: Hydrogen or methane breath test.
  
  

• Clues: Bloating, flatulence, diarrhoea, associated with specific foods.
• Tests: Elimination diet; lactose hydrogen breath test.
  
  
  

Vascular and Ischaemic Conditions

• Clues:
  • Chronic: Postprandial pain, weight loss, "food fear".
  • Acute: Severe, sudden-onset abdominal pain, out of proportion to examination.
• Tests: CT angiography or mesenteric duplex ultrasound.
  
  

• Clues: Pulsatile mass, back pain, hypotension (if ruptured).
• Tests: Abdominal ultrasound or CT angiography.
  
  

Extra-Gastrointestinal Mimics

• Clues: Epigastric pain, nausea, diaphoresis, dyspnoea.
• Tests: ECG, cardiac enzymes.
  
  

• Clues: Flank pain radiating to groin, haematuria, dysuria.
• Tests: Non-contrast helical CT, urinalysis.
  
  

• Clues: Cramping abdominal pain, vomiting, abdominal distension, obstipation.
• Tests: Abdominal x-ray, CT scan.
  
  

• Clues: Dermatomal pain, allodynia, associated with prior zoster or spine pathology.
• Tests: Clinical diagnosis, confirmed by spine MRI or EMG.
  
  
  

Functional and Psychogenic Disorders

• Clues: Abdominal discomfort, alternating bowel habits, absence of alarm features.
• Tests: Diagnosis of exclusion based on Rome IV criteria.

• Clues: Nausea, early satiety, postprandial fullness, common in diabetes.
• Tests: Gastric emptying study.
  
  

• Clues: Focal tenderness at a scar site or over rectus sheath; pain may be reproducible or relieved with local anaesthetic injection.
• Tests: Ultrasound, response to trigger point injection.

• Clues: Multisystem symptoms without organic pathology; history of psychiatric disease.
• Tests: Clinical diagnosis.
  
  
  
  

General Lifestyle Measures

• Alcohol: Absolute abstinence is essential in all patients, regardless of aetiology, to delay disease progression and reduce recurrent inflammation.
• Tobacco: Strongly advised due to its role in accelerating progression and increasing the risk of pancreatic cancer.

• Diet:
  • Balanced, high-protein, energy-dense diet.
  • Small, frequent meals.
  • Avoid unnecessary low-fat diets as they increase the risk of fat-soluble vitamin deficiencies.
    
    
• Micronutrient Monitoring:
  • Monitor levels of vitamins A, D, E, K, B12, and trace minerals annually.
  • DEXA scan every 1–2 years to evaluate for osteoporosis.
    
    
• Enteral Feeding:
  • Indicated in patients with severe malnutrition or pain refractory to oral intake.
  • Nasojejunal feeding suppresses pancreatic secretion and may reduce pain.
    
    

Management of Pain

• Exclude complications (pseudocysts, duct obstruction, cancer).
• Imaging (CT/MRI) is essential before initiating chronic pain management.

• Stepwise Approach (WHO Ladder):
  • Step 1: Paracetamol and NSAIDs.
  • Step 2: Weak opioids (e.g., tramadol).
  • Step 3: Strong opioids (for refractory pain).
    
    
• Adjunctive Agents:
  • Tricyclic antidepressants (e.g., nortriptyline).
  • SNRIs (e.g., duloxetine).
  • Gabapentinoids (e.g., pregabalin, gabapentin).
  • Avoid polypharmacy; manage expectations (goal is pain reduction, not elimination).
    
    

• Combination of vitamin E, C, selenium, methionine, and beta-carotene may reduce pain in selected patients.
• Particularly useful in alcohol-associated or oxidative stress-predominant CP.
  
  

• Indicated for debilitating pain unresponsive to medication.
• Temporary relief (3–6 months); repeatable.
• Side effects include hypotension, diarrhoea; rare but serious complications include paraplegia.
  
  

Pancreatic Enzyme Replacement Therapy (PERT)

• Confirmed exocrine insufficiency (e.g., steatorrhoea, malabsorption, vitamin deficiencies).
  
  

• Start with 25,000–50,000 USP units of lipase per meal; adjust as needed.
• Maximum: 10,000 units/kg/day to avoid fibrosing colonopathy.
• Administer with meals (split dose if meal duration >20 minutes).
• Acid suppression (PPI or H2 blocker) may be needed with non-enteric-coated formulations.
  
  

• Clinical response (stool consistency, weight gain).
• Vitamin levels and nutritional parameters.
• Evaluate for alternative causes if inadequate response (e.g., SIBO, bile acid malabsorption).
  
  

Endocrine Insufficiency (Type 3c Diabetes)

• Characterised by insulin and glucagon deficiency.
• Management:
  • Prefer metformin for mild cases; insulin required for most.
  • Avoid tight glycaemic control due to high hypoglycaemia risk.
  • GLP-1 and DPP4 inhibitors generally avoided.
    
    

Endoscopic and Surgical Interventions

• Indications: Ductal obstruction by stricture or stone.
• Techniques:
  • ERCP with pancreatic sphincterotomy, stone removal, stenting.
  • Intraductal lithotripsy (mechanical or extracorporeal).
  • Endoscopic pseudocyst drainage.
  • EUS-guided transluminal drainage for inaccessible ducts or strictures.
    
    

• Drainage Procedures (for dilated ducts):
  • Lateral pancreaticojejunostomy (Puestow procedure).
  • Frey procedure (LPJ + limited head resection).
• Resection Procedures (for non-dilated ducts or mass lesions):
  • Pancreaticoduodenectomy (Whipple).
  • Duodenum-preserving pancreatic head resection (e.g., Beger or Frey).
  • Distal pancreatectomy (for tail-dominant disease).
• Total Pancreatectomy with Islet Autotransplantation (TPIAT):
  • Considered in young patients with intractable pain and diffuse disease.
  • Risk: universal exocrine insufficiency and high likelihood of diabetes.
    
    

Management of Complications

• Drain if symptomatic, increasing in size, or complicated.
• Options: Endoscopic (preferred), surgical, or percutaneous.

• Suspect if ALP >2× ULN persists >1 month.
• Endoscopic stenting preferred initially; surgery (e.g., Roux-en-Y choledochojejunostomy) if persistent.
  
  

• Suspect with persistent pain and ductal dilation.
• Endoscopic therapy first; surgery if failure.
  
  

• May be considered in selected cases with intractable pain.
• Benefit often short-lived (~2 years); around 50% respond.
  
  

Mortality and Survival

• Survival Rates:
  • 10-year survival: approximately 70%.
  • 20-year survival: approximately 45%.
  • 10-year mortality rate: 30%.
  • 20-year mortality rate: 55%.

• Standardised Mortality Ratio:
  • SMR ~3.6: patients with chronic pancreatitis have over threefold higher mortality compared to the general population.

• Median Life Expectancy:
  • Juvenile idiopathic CP: ~50 years.
  • Alcoholic CP: 55–72 years.
  • Senile idiopathic CP: 77–80 years.
  • Hereditary CP: ~44 years.

• Aetiology-specific Causes of Death:
  • Juvenile idiopathic CP: pancreatic carcinoma.
  • Late-onset idiopathic CP: cardiovascular disease, extra-pancreatic malignancy.
  • Alcoholic CP: cardiovascular disease, pancreatitis-related complications.
  • Hereditary CP: malignancy (pancreatic or extra-pancreatic).
    
    
• Impact of Lifestyle:
  • Continued alcohol and tobacco use significantly worsens prognosis.
  • Many deaths are related more to alcohol- and smoking-associated diseases than pancreatitis itself.
    
    

Risk of Pancreatic Cancer

• Approximately 4% of individuals with chronic pancreatitis develop pancreatic cancer within 20 years.
• Risk is highest in hereditary CP and in patients with longstanding disease or calcifications.

Pain Trajectory

• Natural Course:
  • Pain generally diminishes over time in many patients, irrespective of the aetiology.
  • Reported pain relief rates over long-term follow-up:
    • 67% in juvenile idiopathic CP (after 27 years).
    • 64% in late-onset idiopathic CP (after 13 years).
    • 77% in alcoholic CP (after 14 years).
      
      
• Factors Influencing Persistent or Recurrent Pain:
  • Pseudocysts and biliary or duodenal obstruction are associated with persistent or recurrent pain.
  • Pain may persist even in patients with end-stage disease due to central sensitisation.
    
    
    

Complications Impacting Prognosis

• Occur in ~10% of patients with CP.
• Arise from ductal disruptions, not peripancreatic fluid accumulations.
• Complications include:
  • Infection and abscess formation.
  • Obstruction of the bile duct, duodenum, or nearby vessels.
  • Rupture leading to pancreatic ascites or pleural effusion.
  • Rarely, pseudoaneurysm with life-threatening haemorrhage.
    
    

• Duodenal Obstruction:
  • Symptoms: postprandial pain, early satiety.
  • Caused by fibrosis or large pseudocysts in the pancreatic head.
    
    
• Biliary Obstruction:
  • Symptoms: jaundice, cholestatic liver enzyme abnormalities.
  • Caused by strictures or compression from inflammatory masses or pseudocysts.
    
    
    

• Result from ductal rupture or pseudocyst leakage.
• May lead to significant morbidity if unrecognised.
  
  

• Splenic Vein Thrombosis:
  • Can lead to isolated gastric varices and portal hypertension.
  • May require splenectomy if bleeding occurs.
• Pseudoaneurysm Formation:
  • Rare but serious complication involving splenic, hepatic, or gastroduodenal arteries.
  • May present with haemorrhage into the pancreatic duct (haemosuccus pancreaticus) or gastrointestinal tract.
    
    

Endocrine and Exocrine Dysfunction

• Diabetes Mellitus (Type 3c):
  • Occurs in ~33% of patients with CP.
  • Due to islet destruction; often brittle and prone to hypoglycaemia due to concurrent glucagon deficiency.
    
    
• Exocrine Pancreatic Insufficiency:
  • Typically manifests after >90% of glandular function is lost.
  • Leads to steatorrhoea, weight loss, and fat-soluble vitamin deficiencies.

Pancreatic Duct Disruption and Fluid Collections

• Prevalence: Occur in ~10% of patients with CP.
• Pathogenesis: Arise from ductal disruption rather than peripancreatic fluid accumulation, typically post-acute exacerbation.
• Characteristics: Well-encapsulated fluid collections with no solid material; lack epithelial lining.
• Clinical Features: Often asymptomatic; symptoms may include abdominal pain, early satiety, jaundice, or weight loss.
• Complications: Obstruction of adjacent structures, infection (10%), haemorrhage, fistula formation.
• Management:
  • Asymptomatic: observation.
  • Symptomatic or complicated: drainage (endoscopic or surgical).
    
    

• Mechanism: Result from ductal rupture or pseudocyst leakage.
• Presentation: Ascites (abdominal distension), pleural effusion (usually left-sided, causing dyspnoea).
• Diagnosis:
  • High fluid amylase (>1000 IU/L in ascitic fluid; >4000 IU/L in pleural fluid).
  • Low serum-ascites albumin gradient (SAAG) and high protein in ascitic fluid.
• Management:
  • Initial: octreotide, parenteral nutrition, and drainage.
  • Persistent cases: endoscopic stenting or surgery.
    
    

Obstructive Complications

• Incidence: 5–10%.
• Causes: Fibrosis or compression from a pseudocyst, especially in the pancreatic head.
• Symptoms: Jaundice, postprandial pain, abnormal liver enzymes, and cholangitis.
• Management:
  • Definitive: surgical bypass (e.g., choledochojejunostomy).
  • Temporary: endoscopic stenting (metal or plastic).
  • Pseudocyst-associated obstruction may resolve with drainage.
    
    

• Cause: Fibrosis around the head of the pancreas.
• Symptoms: Nausea, vomiting, early satiety, weight loss.
• Treatment: Surgical bypass or resection (Whipple or duodenum-preserving resection).
  
  
  

Vascular Complications

• Arteries Involved: Splenic (most common), gastroduodenal, pancreaticoduodenal.
• Presentation: Sudden pain, gastrointestinal bleeding, anaemia (haemosuccus pancreaticus).
• Diagnosis: Contrast-enhanced CT or MRI.
• Management:
  • First-line: angiographic embolisation.
  • Surgery: required for uncontrolled or recurrent bleeding.
    
    

• Prevalence: Up to 12%.
• Consequence: Segmental (left-sided) portal hypertension and gastric varices.
• Symptoms: Often asymptomatic; may present with upper GI bleeding.
• Treatment: Splenectomy for symptomatic variceal bleeding.
  
  

Functional Complications

• Prevalence:
  • At diagnosis: 8–22%.
  • After 13–26 years: up to 48%.
  • After 14–36 years: ~100%.
• Symptoms: Steatorrhoea, bloating, sarcopenia, fat-soluble vitamin deficiency.
• Complications: Osteopenia (40%), osteoporosis (25%), low-trauma fractures (~5%).
• Management: Pancreatic enzyme replacement therapy; vitamin D and calcium supplementation.
  
  

• Prevalence: Occurs in 37–44% of patients.
• Mechanism: Destruction of islets, loss of insulin, glucagon, and pancreatic polypeptide.
• Characteristics: "Brittle" diabetes with frequent hypoglycaemia, low risk of ketoacidosis.
• Management: Insulin therapy (with caution); annual screening with fasting glucose and HbA1c.
  
  

Structural and Neoplastic Complications

• Prevalence:
  • Early disease: 0–4%.
  • After 14–36 years: up to 91%.
• Pattern: Intraductal or parenchymal.
• Treatment: Extracorporeal shock wave lithotripsy (ESWL) for symptomatic ductal stones.
  
  

• Causes: Fibrosis, stones, pseudocyst, malignancy.
• Management: Endoscopic or surgical decompression.
  
  

• Risk:
  • Overall: ~4% at 20 years.
  • Increased in hereditary pancreatitis and smokers.
• Symptoms: Overlap with CP—jaundice, weight loss, worsening pain.
• Screening: Recommended only in hereditary pancreatitis (e.g., PRSS1 mutation carriers).
• Surveillance Tools: MRI/MRCP or endoscopic ultrasound.
  
  

Other Complications

• Incidence: 1–2%.
• Sites: Gastrointestinal tract, pleura, pericardium.
• Management: Most resolve conservatively; persistent cases may require endoscopic or surgical closure.
  
  

• Frequency: <1%.
• Often associated with pseudocyst rupture.
• Treatment: Octreotide, paracentesis, nutritional support; refractory cases need endoscopic or surgical intervention.
  
  

• Incidence: 3–8%.
• Causes: Peptic ulcer disease (secondary to duodenal acidity), variceal bleeding (due to portal hypertension), pseudoaneurysm rupture.
• Management: Endoscopic therapy, splenectomy, or embolisation as appropriate.

• Risk: High due to chronic pain.
• Management:
  • Long-acting opioids (e.g., methadone), buprenorphine, or naltrexone.
  • Emphasis on multimodal, opioid-sparing strategies.
    
    

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