Chronic Pancreatitis

Acute Pancreatitis

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

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)

This definition encompasses

• 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

Recurrent Acute Pancreatitis

• Caused by a known factor (e.g., gallstones, hypercalcaemia) but does not progress to chronic pancreatitis.

Idiopathic Pancreatitis

• No identifiable cause despite exhaustive investigation; may represent early or chronic relapsing disease.

Chronic Relapsing Pancreatitis

• Patients experience recurrent episodes of pancreatic pain without overt chronic changes but with histological evidence of damage.

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

Overview

• Chronic pancreatitis may be driven by monogenic or polygenic mutations affecting trypsin activation, protease inhibition, or ductal physiology.

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

Overview

• Chronic pancreatitis may occur in the context of broader systemic autoimmune conditions.

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

• Azathioprine, corticosteroids, hydrochlorothiazide, didanosine, valproic acid, statins, oral contraceptives, ACE inhibitors, and interferon.

Mechanism

• 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

• The earliest events involve cellular injury in either:
  • 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.
• Once initiated, if the injurious agent persists, these early events can progress through repeated cycles of injury, inflammation, and incomplete healing, ultimately leading to fibrosis.

Fibrogenesis and Inflammatory Signalling

• Fibrogenesis is the hallmark of chronic pancreatitis, involving a cascade of cellular responses:
  • 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.
• This process is typically self-perpetuating, such that even removal of a causative agent like alcohol may not reverse fibrosis once established.

Enzyme Activation and Ductal Obstruction

• Two dominant theories explain the intrapancreatic pathogenesis:
  • Protein Plug Theory: An imbalance between acinar protein hypersecretion and inadequate ductal bicarbonate output leads to proteinaceous plugs and eventual intraductal calcification.
  • Enzyme Activation Theory: Premature activation of digestive enzymes, particularly trypsinogen, within acinar cells causes autodigestion and cellular necrosis.
• Both mechanisms promote ongoing inflammation, necrosis-fibrosis cycles, and architectural disruption.

Role of Alcohol and Calcium Signalling

• Alcohol exacerbates these mechanisms by:
  • 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.
• These changes create an environment conducive to repetitive acinar cell damage and chronic inflammation.

Progressive Staging of Chronic Pancreatitis

• A conceptual model outlines disease progression across several stages:
  • At Risk: Individuals have underlying genetic or environmental susceptibility but no symptoms or detectable changes.
  • Acute Pancreatitis: A first sentinel episode occurs, often resolving without progression.
  • Recurrent Acute Pancreatitis: Repeated acute episodes begin to cause irreversible damage.
  • Early Chronic Pancreatitis: Histological or biomarker evidence of disease becomes detectable.
  • Established to End-Stage Chronic Pancreatitis: Functional loss, fibrosis, and morphological changes become clinically overt and irreversible.
• The transition to chronic disease accelerates with each acute episode, especially in alcohol-related pancreatitis, which tends to recur more frequently and severely than biliary pancreatitis.

Pain Mechanisms

• Chronic pancreatitis-associated pain is multifactorial:
  • 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

• The following pathological consequences result from structural and cellular disruption:
  • 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

Sex-Based Differences

• 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.

Age Distribution

• 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

Abdominal Pain

• 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).

Steatorrhoea

• 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.

Weight Loss and Nutritional Symptoms

• 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.

Gastrointestinal and Systemic Symptoms

• 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.

Other Less Common Historical Features

• 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

Strongly Associated Factors

• 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.

Moderately Associated Factors

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

Weak or Emerging Associations

• 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

Cross-Sectional Imaging

 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

Endoscopic Ultrasonography (EUS)

• 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.

Endoscopic Retrograde Cholangiopancreatography (ERCP)

• 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

Direct Pancreatic Function Tests (PFTs)

• 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.

Indirect Pancreatic Function Tests

 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

Acute Pancreatitis

• 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.

Pancreatic Cancer

• 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.

Pancreatic Pseudocyst

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

Peptic Ulcer Disease

• 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.

Cholelithiasis / Biliary Colic

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

Biliary Obstruction

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

Celiac Disease

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

Inflammatory Bowel Disease

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

Small Intestinal Bacterial Overgrowth (SIBO)

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

Lactose or Other Food Intolerances

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

Vascular and Ischaemic Conditions

Mesenteric Ischaemia

• 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.

Abdominal Aortic Aneurysm (AAA)

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

Extra-Gastrointestinal Mimics

Myocardial Infarction (Inferior Wall)

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

Nephrolithiasis

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

Intestinal Obstruction

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

Post-Herpetic Neuralgia / Radiculopathy

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

Functional and Psychogenic Disorders

Irritable Bowel Syndrome (IBS)

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

Gastroparesis

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

Abdominal Wall Pain

• 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.

Somatisation Disorders

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

General Lifestyle Measures

Alcohol and Tobacco Cessation

• 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.

Nutritional Support

• 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

Initial Evaluation

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

Analgesia Strategy

• 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).

Antioxidants

• 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.

Celiac Plexus Block (CPB)

• 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)

Indications

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

Dosing

• 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.

Monitoring and Adjustments

• 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

Endoscopic Drainage (for Dilated Duct ≥6 mm)

• 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.

Surgery for Refractory Pain or Failed Endoscopy

• 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

Pseudocysts

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

Biliary Obstruction

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

Pancreatic Ductal Obstruction

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

Denervation (Thoracoscopic Splanchnicectomy)

• 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

Pancreatic Pseudocysts

• 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.

Obstructive Complications

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.

Pancreatic Ascites and Pleural Effusion

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

Vascular Complications

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

Pancreatic Pseudocysts

• 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).

Pancreatic Ascites and Pleural Effusion

• 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

Biliary Obstruction

• 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.

Duodenal Obstruction

• 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

Pseudoaneurysm Formation

• 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.

Splenic Vein Thrombosis and Gastric Varices

• 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

Exocrine Pancreatic Insufficiency (EPI)

• 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.

Endocrine Pancreatic Insufficiency (Type 3c Diabetes)

• 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

Pancreatic Calcifications

• 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.

Pancreatic Duct Obstruction

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

Pancreatic Cancer

• 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

Fistula Formation

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

Ascites

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

Gastrointestinal Bleeding

• 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.

Opioid Use Disorder

• 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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