Acute pancreatitis

Acute pancreatitis is an acute inflammation of the pancreatic parenchyma, with about 15% of cases occurring against a background of chronic pancreatitis. Its incidence is approximately 10 cases per 100,000 inhabitants per year, occurring mainly in individuals aged 30 to 70 years, and 60% of cases are in men.

The two main etiologies are biliary lithiasis (about 50% of cases) and alcoholism (about 20 to 30% of cases). It is one of the main abdominal emergencies, with an overall mortality rate of 5 to 10%.

Pathophysiology and Etiologies

The mechanism of acute pancreatitis is still poorly understood. General assumed etiopathogenic mechanisms include:

• Disruption of acinar cell function → destruction → secondary release of activated enzymes
• Ductal obstruction with bile reflux → increased intraductal pressure → leakage of enzymes from the ducts into the interstitial space and secondary activation
• Worsening of lesions through alterations in microcirculation, inflammatory phenomena, bacterial translocations, oxidative stress, and systemic complications

Biliary Lithiasis (40 to 70% of cases)

3 to 10% of patients with biliary lithiasis will develop acute pancreatitis. Their prognosis is better than that of alcoholic pancreatitis.

Alcoholism (20 to 30% of cases - increasing)

10% of chronic alcoholics will develop acute pancreatitis. Smoking is an additional risk factor.

Various Causes

Hypertriglyceridemia, iatrogenic (post-ERCP, 6-mercaptopurine, aminosalicylates, sulfonamides, diuretics, valproate, tetracyclines, corticosteroids, azathioprine,...), abdominal trauma, hypercalcemia, infections, ischemia (vasculitis, shock, embolism,...), autoimmune, other causes of biliary obstruction...

Diagnosis

The diagnosis is established in clinical practice by the combination of acute abdominal pain and a serum lipase level more than three times the normal level or characteristic abnormalities on imaging (CT scan with contrast, MRI, or ultrasound).

• Abdominal Pain (relieved by painkillers) in the left upper quadrant, stabbing, sometimes epigastric in a band-like pattern but often diffuse. Possibly accompanied by vomiting (50%), ileus, dyspnea, shock (10%), oliguria or anuria, altered consciousness, hypovolemia, hypocalcemia, coagulation disorders, etc.
  • 10 to 15% of acute pancreatitis cases are fulminant.
  • History of lithiasis or alcoholism?
• Lipase more than 3 times the normal level
  • Elevation within 12 hours, returns to normal within 3 to 10 days
  • An elevation of amylase more than 3 times the normal level is sometimes also used. However, it is not very sensitive and, more importantly, not very specific (parotitis, biliary lithiasis, intestinal lesions, renal failure, etc.). However, it may be useful in the etiological workup.
  • Elevation of pancreatic enzymes may be lower in cases of renal insufficiency or acute exacerbation on a background of chronic pancreatitis.
• CT Scan with Contrast: Diagnostic role (in case of doubt) and, more importantly, prognostic role (Balthazar classification, more than 48 hours after the onset of pain). Alternatives: MRI (less available), ultrasound (less sensitive).
• Trypsinogen-2 (urine test):
  • Early elevation (12 hours), returns to normal within 3 days
  • Negative predictive value of 99% → mainly useful for ruling out acute pancreatitis

• Elastase (in stool) is the earliest marker of elevation but is rarely available routinely.

The differential diagnosis is that of acute abdominal pain.

Severity Markers

• Clinical evaluation (complications: infection, fistula, pseudoaneurysm, venous thrombosis, ascites, pleurisy, multiorgan failure, pseudocysts, hemorrhage, malnutrition) and history.
• Risk Factor Scores (valid for a short period—48 hours—and complex):
  • Glasgow, Apache II, etc.
  • Ranson Score (severity of acute pancreatitis): 11 points (score < 3 points: mild; 3 to 5 points: moderate (mortality of 10 to 20%); > 5 points: severe (mortality of 50%)
    • 1 point for each of these factors at admission:
      • 55 years old
      • Leukocytosis > 16,000/mm³
      • Blood glucose > 2 g/L (11 mmol/L)
      • LDH > 350 IU/L
      • AST > 250 IU/L
    • 1 point for each of these factors at 48 hours:
      • Hematocrit decrease of > 10%
      • Urea increase of > 1.8 mmol/L
      • Calcium < 80 mg/L (2 mmol/L)
      • PaO2 < 60 mmHg
      • Base deficit > 4 mmol/L
      • Estimated fluid retention > 6 L

• CRP is a nonspecific but very sensitive marker, and probably the best and most accessible marker of the severity of acute pancreatitis. Mild form if < 15 (for a norm < 1) at 48h, severe if > 150 mg/L.
• A Balthazar grade (established by CT scan with contrast) D or E on day 3 is correlated with increased mortality (10% without abdominal infection, 30% with abdominal infection… instead of 1% in grades A to C).
  • A: Normal-looking pancreas
  • B: Pancreatic hypertrophy or irregular contours
  • C: Infiltration of peripancreatic fat, pancreatic hypertrophy, and heterogeneity
  • D: Phlegmon or single collection = exudative pancreatitis
  • E: Phlegmon, multiple collections and/or intra- or peripancreatic gas

• TAP (Trypsin Activation Peptide) is a good indicator of severity and can be detected early in the urine but is not easily accessible routinely.
• IL 23, 6, and 8 are still debated.
• Elastase, rarely available routinely.
• Biological or clinical signs of organ failure: creatinine > 170, systolic blood pressure < 90, PaO2 < 60, Glasgow < 13, platelets < 80,000/mm³, etc.

Etiological Workup

Alcoholic and biliary etiologies represent 80% of the causes of acute pancreatitis. 10% are "idiopathic"… but before concluding this admission of ignorance, obstructive, metabolic, iatrogenic, genetic, traumatic, autoimmune, or infectious causes must also be excluded. Remember that "alcoholism" is common in our society… and pancreatitis with a completely different etiology often occurs in a "labeled alcoholic" context → do not label patients too quickly!

The basic etiological workup will include:

• Gallbladder ultrasound, CT scan, MRI/ERCP ± EUS
• Measurement of transaminases at admission, CDT, calcium, and triglycerides
• Various according to clinical presentation and history

Alcoholic Etiology

• CDT (Carboxy Deficient Transferrin) is the best marker of long-standing alcoholism.
• MCV (very low sensitivity, good specificity), GGT (low sensitivity, poor specificity), an increase in AST > ALT argues for an alcoholic origin.
• Withdrawal Test
• Some believe that acute alcoholic pancreatitis can only occur on a background of chronic alcoholic pancreatitis (contested) → monitor the patient, especially in case of recurrences.

Biliary Etiology

• Early elevation (returns to normal within 48 hours) of AST and ALT is a good marker of biliary lithiasis etiology. An ALT > AST ratio suggests a biliary origin.
• The Blamey score provides a score ranging from 0 to 5, corresponding to a probability of 0 to 100% of a lithiasis etiology:
  • Age > 50 years
  • Female gender (2 females for 1 male)
  • ALP > 300 IU/L
  • ALT (GPT) > 100 IU/L = 3x normal value = the major criterion.
  • Amylase > 4000 IU/L

• To demonstrate a lithiasis etiology:
  • Endoscopic ultrasound remains the reference examination
  • MRI/CT can be useful, although less sensitive.
  • If these are not available, an ultrasound should be performed within 24 hours (to avoid being misled by the formation of sludge) and repeated if negative. An urgent ERCP should be performed if cholangitis is suspected. If the ultrasound is negative, a follow-up endoscopic ultrasound should be performed.

Autoimmune Etiology

Mainly affects individuals between 30 and 40 years old.

A biological assessment may reveal:

• An increase in gamma-globulins.
• An increase in IgG4 (more specific) but with a low positive predictive value (not for screening, very useful for monitoring).
• The presence of various auto-antibodies (in 24% of cases).
  • Antinuclear antibodies, etc.
  • The presence of anti-carbonic anhydrase auto-antibodies is strongly correlated with the concomitant presence of Sjögren's syndrome.

Imaging typically shows irregular pancreatic ducts with multiple stenoses and an enlarged pancreas (cholestatic form)... however, the form can sometimes be pseudo-tumoral, in which case a challenging differential diagnosis is required!

Histology may be necessary.

Once this diagnosis is made, the presence of the following should be sought:

• Another autoimmune disease: Sjögren, UC, Crohn's disease, etc.
• Diabetes (association in nearly 50% of cases).

Treatment is based on corticosteroids, and immunosuppressants may be used if necessary.

Other Obstructive Etiologies

• Pancreatic cancers and dysplasias must be identified absolutely! Acute pancreatitis is often the first sign, and if the etiology is detected early, a curative treatment for these cancers, which generally have a poor prognosis, will be possible!

• Benign tumors.
• Calcifications and cystic lesions.

In all cases, the identification of such a mass will require a biopsy... because even a cystic or calcified lesion on imaging can reveal neoplasia on histology.

CA 19-9 is a pancreatic tumor marker with poor sensitivity (10% of the population is unable to synthesize it, often negative for small tumors, etc.) and low specificity (other pancreatic conditions, other tumors, cirrhosis, cholestasis, lithiasis, diabetes, etc.) → no diagnostic utility but of interest for monitoring and prognosis.

Metabolic Causes

• Hypercalcemia > 3 mmol/L
• Hypertriglyceridemia > 10 mmol/L
  • Toxic by itself
  • May be secondary to another cause of pancreatitis
• Alcoholism
• Decompensated diabetes
• Iatrogenic (β-blockers, protease inhibitors, etc.)

Sphincter of Oddi Dysfunction

Occurs mainly post-cholecystectomy. A cause of recurrent acute pancreatitis. Manifests as biliary/pancreatic pain + altered liver tests + bile duct dilation. Milwaukee classification may be used. Diagnosis is based on manometry/biliary scintigraphy (both exams can cause… pancreatitis). Treatment involves endoscopic sphincterotomy.

Iatrogenic Causes

Many drugs are implicated: azathioprime, 6-MP, mesalazine, antiretrovirals, valproate, salicylates, ACE inhibitors, asparaginase, cimetidine, corticosteroids, danazol, ergotamine, estrogens, furosemide, mercaptopurine, methyldopa, metronidazole, nitrofurantoin, pentamidine, ranitidine, sulfasalazine, tetracyclines, thiazides, etc. The diagnosis of drug-induced pancreatitis is generally difficult and is unfortunately established by observing improvement after excluding the suspected drug and recurrence upon reintroduction. Radiotherapy, ERCP, and parenteral nutrition are also occasional etiologies.

Genetic Etiologies

• Autosomal recessive:
  • CFTR (cystic fibrosis), SPINK1, α-1 antitrypsin deficiency
    • No family history, not always pulmonary manifestations
• Autosomal dominant:
  • PRSS1 (measure cationic trypsinogen)
    • Usually begins in childhood

Traumatic Etiologies

The context is usually suggestive and most often involves children.

Infectious Etiologies

Salmonella, Campylobacter, Legionella, Leptospira, mycobacteria, mycoplasma, brucellosis, Yersinia, Ascaris, microsporidia, Coxsackie, CMV, EBV, echovirus, hepatitis A/B/C/E, HIV, mumps, rubella, varicella, enterovirus, adenovirus, etc. In case of doubt, serologies should be performed.

Therapeutic Management - Treatments

General measures: management of complications, correction of metabolic and ionic disturbances.

Benign Forms (= edematous non-necrotic, 70 to 80% of cases)

• Fasting
• Massive IV rehydration, ++ 3 to 4 liters of G5-NaCl 0.45% (third space)
• Aspiration and nasogastric tube if paralytic ileus or intractable vomiting
• Pain relief: IV paracetamol + morphine derivatives: 10 mg of IV morphine per liter of infusion or pethidine (Dolantin) 50 to 100 mg IV every 2 to 6 hours or...
  • Opioids were traditionally avoided due to a presumed effect on the sphincter of Oddi. However, no study has ever shown a negative impact on the course of acute pancreatitis → do not hesitate to use them in cases of uncontrollable pain (increasingly, morphine is used directly in cases of paracetamol failure).
• Gradual refeeding (sugars then fats and proteins) within 48 hours in the absence of pain, maximum within 10 days.
• ERCP (with papillotomy, "drilling," and stone extraction) with extracorporeal lithotripsy if necessary within 24-(48) hours in cases of biliary pancreatitis. Considered an emergency in cases of cholangitis or obstructive jaundice.

Criteria for ICU admission: severe pancreatitis, HR > 150/min or < 40/min, SBP < 60 mmHg or DBP > 120 mmHg, RR > 35/min, natremia < 110 or > 170 mmol/L, kalemia < 2 or > 7 mmol/L, PaO2 < 50 mmHg, pH < 7.1 or > 7.7, calcium > 15 mg/dL, glucose > 800 mg/dL, anuria, coma.

Necrotizing-Hemorrhagic Forms (~20 to 30% of cases)

Same as above +:

• ICU admission + Swan-Ganz catheter.
• Increase caloric needs to 140%.
• Always maintain enteral nutrition (gastric or jejunal tube) (maintains digestive flow, minimizes infection risk, etc.) if possible.
• Antibiotics only in cases of documented infection, significant comorbidities, signs of sepsis, or >30% necrosis on CT and CRP > 15.
• Consider prophylactic antibiotic therapy (e.g., imipenem 4 x 500 mg/day for 7 to 10 days if necrosis on CT at 3 to 5 days with clinical deterioration despite good supportive treatment).
• Drain necrotic collections 4 to 6 weeks later (allow time for necrosis to liquefy and collect) or urgently in cases of persistent severe pain, impossible oral refeeding, or infected necrosis. Surgical debridement in extreme cases.

Natural Evolution and Complications

Acute pancreatitis can present as:

• Edematous:
  • Evolution towards an acute fluid collection (within the month)
    • Resolution
    • Evolution towards a pseudocyst
      • Infected
      • Sterile

• Necrotizing:
  • Evolution towards an acute fluid collection (within the month)
    • Resolution
      • Evolution towards a pseudocyst
        • Infected
        • Sterile
  • Evolution towards a post-necrotic collection (within the month)
    • Evolution towards a pseudocyst
      • Infected
      • Sterile
    • Evolution towards organized necrosis
      • Infected
      • Sterile

Infections

Acute pancreatitis with necrosis is complicated by infection in 30 to 50% of cases, with half occurring within 15 days but sometimes only within 2 months. The symptoms are non-specific (fever and leukocytosis can be attributed to SIRS), but attention should be paid to fever, hematocrit < 35%, base excess < 4 mmol/L, PaO2 < 60 mmHg, PaCO2 < 30 mmHg, albuminemia < 30 g/L, platelets > 450,000/mm³, a sudden increase in the Ranson score or CRP, organ failure, general deterioration, etc., in a patient with significant necrosis on CT scan (which may also, rarely, show late signs such as gas bubbles in the necrosis). The diagnosis is based on fine-needle aspiration of the collection under ultrasound or CT guidance → direct examination and cultures (including fungi in case of prior antibiotic therapy).

Local Digestive Complications

• Mesenteric and colonic infarctions: rare but serious (20% gangrene and perforations).
• Vascular complications (hemorrhage from pseudoaneurysm or pseudocyst, significant gastrointestinal bleeding).
• Venous thrombosis (mesenteric, portal, etc.).
• Pancreatic fistulas (ascites, pleural effusion): 10%.
• Subcutaneous necrosis.

Systemic Complications

SIRS (rapid release of inflammatory mediators), sepsis (later stage), multi-organ failure, septic or hypovolemic shock, ARDS, and renal failure (80% mortality!).

Functional Complications

Variable endocrine (hypoinsulinemic hyperglycemia) and exocrine insufficiency.

Pseudocysts (pancreatic fluid surrounded by a fibrous wall, no necrosis)

Secondary to the rupture of the pancreatic duct, they occur in 10 to 25% of necrotizing acute pancreatitis cases. If they are symptomatic (abdominal pain, weight loss, palpable mass) and do not resolve spontaneously (++ if > 5 cm): treatment at a distance by endoscopy, radiotherapy, or surgery. Complication: pseudocyst rupture.

Various

• (Definitive) diabetes may occur.
• Exocrine insufficiency is constant during the crisis but generally resolves. Perform functional tests if it persists.
• Look for ductal abnormalities in case of unexplained recurrent acute pancreatitis.
• Fistulas → medical or endoscopic treatment, surgery if unsuccessful.

In Summary…

• A diagnosis of acute pancreatitis should be considered first in case of abdominal pain with lipase levels > 3 times the normal.
• Upon admission: minimum = lipase, transaminases, calcium+, and triglycerides + ultrasound.
• A CT scan should be performed > 48 hours from the onset of pain to assess severity or immediately in case of diagnostic doubt or signs of complications.
• CRP (> 15 mg/dL = moderate, > 120 mg/dL = severe, with a normal value < 1) is the best marker of severity at 48 hours from symptom onset.
• A biliary etiology should be considered if ALT (GPT) > 3 times normal.
• An autoimmune etiology should be considered if IgG4 > 280 mg/dL.
• For pain relief, prefer paracetamol +/- morphine if necessary.
• An ERCP should be performed within 24 to 48 hours in case of biliary etiology.
• Outside of documented infection, antibiotic therapy is not justified. However, it can be discussed in cases of necrotizing acute pancreatitis with clinical deterioration despite well-conducted treatment.

Bibliography

EMC, Traité de Gastro-entérologie, Elsevier, 2018

Hawkey CJ et al., Textbook of clinical Gastroenterology and Hepatology, 2d edition, Wiley-BlackWell, 2012

Vege SS, Clinical manifestations and diagnosis of acute pancreatitis, UpToDate, 2023

Vege SS, Etiology of acute pancreatitis, UpToDate, 2023

Vege SS, Management of acute pancreatitis, UpToDate, 2023

Vege SS, Pathogenesis of acute pancreatitis, UpToDate, 2023

Vege SS, Predicting the severity of acute pancreatitis, UpToDate, 2023