Acute pancreatitis

Pancreatic inflammation secondary to inappropriate activation of enzymes and autodigestion

Epidemiology

• Increasing since 2000
• Up to 80% caused by gallstones/alcohol

Natural history

• 10-20% have a rapidly progressive inflammatory response - prolonged hospital stay, morbidity, mortality
• Risk of death in severe pancreatitis 10-50%, especially with MODS
• Mortality in the first two weeks is due to MODS
• Mortality after two weeks is from sepsis

Aetiology

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• Gallstones
  • Biliary sludge or gallstones on imaging
  • Dilated CBD (>=8mm in patients <75, >=10mm patients >75)
  • ALT>2x upper limit normal (PPV >95% for biliary aetiology, when pancreatitis has been diagnosed)
• Ethanol
  • Look for LFTs consistent with alcohol liver disease
• Trauma
  • Blunt abdo trauma
  • Bile duct injury
• Steroids
• Mumps + Viruses
  • HIV, coxsackie, CMV, mumps
• Autoimmune/anatomical
• Scorpions and other venoms/splenic embolisation
• Hypercalcaemia
• Hyperlipidaemia
  • Need lipids >11.3mmol/L
  • Suspect with trigs >25, and confirmed with trigs >50
  • Can see a pseudohyponatraemia in this setting
  • Consider risks
    • Primary hypertriglyceridaemia - familial syndromes
    • Secondary
      • Diabetes
      • Meds - tamoxifen etc, clomiphene, protease inhibitors, antiretroviral agents, propofol, olanzapine, mirtazapine, retinoids, thiazide diuretics, betablockers
      • Pregnancy
      • Alcohol
      • Hypothyroidism
    • Note that hypertriglyceridaemia secondary to hypothyroidism, DM or alcohol does not typically cause pancreatitis
• ERCP/surgery
  • 3% if surveillance, 5% if removal of stone, 25% if procedure on Sphincter of Oddi
  • More common in young females and prior history of ERCP pancreatitis
  • More common with multiple attempts at cannulation
  • Mild in 95% of patients
  • May be possible to prevent with use of indomethacin
• Drugs
  • Sulfonamides, metronidazole, erythromycin, tetracyclines, didanosine, thiazides, furosemide, statins, azathioprine, 6-mercaptopurine, 5-aminosalicyclic acid, sulfasalazine, valproic acid, HIV antiretroviral agents.

Pathophysiology

• Likely the result of inappropriate activation of proenzymes inside acinar cells
• Leads to autodigestion of normal pancreatic parenchyma, which triggers acinar cells releasing proinflammatory cytokines, propagating the response locally and systemically
• In severe cases, the local inflammatory response causes local haemorrhage and pancreatic necrosis
• SIRS can also worsen injury due to pancreatic ischaemia
• 80-90% of patients with acute pancreatitis have a self-limited inflammatory cascade -> mild pancreatitis
• Gallstones
  • Caused by either increased pancreatic duct back pressure, or bile salt reflux into the pancreas
  • Injury to acinar cells, triggering a cascade of pro-inflammatory changes
• Alcohol
  • Only seen in 5-10% of heavy drinkers
  • Risk factors - >100g/day for at least 5 years, smoking (RR 4.9), genetic predisposition
  • Alcohol probably causes pancreatic injury via a number of mechanisms, although it has not been fully delineated
    • Pancreatic processing of alcohol leads to damaging metabolites through both oxidative and non-oxidative pathways, such as acetaldehyde and fatty acid ethyl esters
    • Increased synthesis of digestive and lysosomal enzymes
    • Possible chronic sensitisation of acini to CCK
    • Precipitation and increased viscosity of pancreatic secretions - protein plugs in small ducts - progressive inflammation and fibrosis, leading to loss of acinar, islet and ductal cells
    • Premature activation of trypsinogen and other digestive and lysosomal enzymes
• Anatomical
  • Obstructed flow of pancreatic juice, secondary to tumour (uncommon), parasites, or congenital defects (pancreas divisum or annular pancreas)
• Hypercalcaemia - activation of trypsinogen, and intra-ductal precipitation of calcium leading to ductal obstruction
• Lipase release leads to fat necrosis and digestion, with subsequent reaction of fatty acids and calcium to create soaps, or 'saponification'

Presentation

• Epigastric or periumbilical pain, constant, radiating through to back (cardinal symptom)
• Nausea or vomiting that does not relieve pain
• Hypovolaemia
• Retroperitoneal bleeding:
  • Grey Turner sign - flank ecchymosis
  • Cullen sign - periumbilical ecchymosis
• Jaundice - can be choledocholithiasis or oedematous pancreatic head causing CBD obstruction
• Pleural effusion - most commonly left

Diagnosis:

• Two of the following (Atlanta criteria)

1. Clinical history/examination consistent with pancreatitis
2. Lipase/amylase >3 times upper limit of normal (lipase rises within 4-8 hours and peaks at 24 hours, and often stays high for 1-2 weeks. Lipase is better in EtOH pancreatitis, and has a slightly longer half-life (7-13.5 hours))
   1. Amylase rises within 6-12 hours of symptoms, and returns to normal in 3-5 days. It can also be elevated in PUD, mesenteric ischaemia, salpingitis and macroamylasaemia.
3. Radiological evidence pancreatitis

Imaging

• USS - useful to identify gallstones, not particularly good for seeing the pancreas
• CT portal venous phase
• MRCP indications: acute pancreatitis with no known aetiology to rule out pancreas divisum, IPMN, or a small ductal tumour

Scoring systems probably don't have clinical relevance

• Lots of systems, conflicting evidence
• The most useful approach:
  • During admission, use a three-dimensional approach to predict risk:
    • Risk factors (age, comorbidity, BMI)
    • Clinical risk stratification (persistent SIRS)
    • Monitoring response to initial therapy (persistent SIRS, BUN, creatinine)
  • Use BISAP, Atlanta or even just SIRS criteria
  • Apache II can be useful if patient is in ICU
  • Ignore Ranson/Glasgow
• SIRS criteria
  • Persistent SIRS from admission = mortality 25%
  • SIRS at admission but not persistent 8%
  • No SIRS 0%
  • 
• BISAP predicts mortality, quite simple, easy to use, performs on par with more extensive scores
  • Factors at admission (one point for each): BISAP
    • BUN: Urea >8.92mmol/L
    • Impaired mental status
    • SIRS criteria >=2
    • Age >60
    • Pleural effusion present
  • 0-2 points: mortality <2%
  • 3 or more points: mortality >15%
• Modified Atlanta:
  • 

• Atlanta radiographic classification:
  • Interstitial oedematous
  • Necrotising
  • Acute peripancreatic fluid
  • Pancreatic pseudocyst

• CT severity index
  • 
• APACHE II
  • Predicts ICU mortality, really only useful with ICU-style investigations e.g. arterial BP
• Glasgow-Imrie criteria (1984) predicts severity, but requires values from 48 hours after admission
  • Similar to Ranson
  • Not used any more
• Ranson predicts mortality (published 1974)
  • Disadvantage - needs scores at 0 and 48 hours post admission
  • Mainly used to rule out severe pancreatitis, but low PPV
  • 
  • 

Initial medical management:

• Analgaesia:
  • Don't give NSAIDs. ?PUD
  • Paracetamol probably IV if vomiting
  • Initial trial of endone + fluid resus, however often need PCA
  • No evidence opioids worsen outcomes, despite supposed sphincter of Oddi contraction
• Antiemetics
• IV PPI - prevent stress ulceration
• Early enteral feeding, unless ileus, pain or intubation
  • 20% of severe AP patients get recurrent pain after restarting diet
  • Enteral feeding reduces the need for surgery, but TPN can be considered if failing to meet requirements
  • NJT feeds if gastric outlet obstruction is present (according to Schein, if gastric aspirates are >250mL/6 hours). Start at 10mL/hr and increase gradually until 40mL/hr is reached)
• Investigate cause
  • USS vs MRCP to rule out biliary pathology
  • FBE, UEC, LFT, Lipase, CRP, CMP, fasting lipids (don't need to do it unless suspicious this is the cause - see above)
  • Consider INR if liver derangement
  • Erect CXR - rule out perf ulcer, plus check for ARDS
  • CT - only if unclear diagnosis or severe abdominal pain where perforated viscus or bowel ischaemia may be considered
• Strict FB - may need IDC if severe or does not respond to resuscitation
• Supplemental oxygen (to try and optimise perfusion)
• Correct fluids with CSL (vomiting, poor oral intake, increased resp losses, diaphoresis, oedema)
  • 5-10ml/kg/hr until HR<120, MAP 65-85, normal lactate and UO 0.5-1ml/kg/hr
  • Going to need a lot. Remember pancreatitis pain is worse if dehydrated. Be aggressive.
  • CSL better than saline with pancreatitis
• Correct electrolytes
• VTE prophylaxis
• ?Thiamine
• ?ICU if persistent shock for vasopressors after initial resuscitation
• Grade severity - Atlanta - mild/mod/severe - or use SIRS criteria on admission and again at 48/24
• Antibiotics if acute pancreatitis and an active infection (cholangitis, UTI, pneumonia, catheter-related infections, bacteraemia, infected necrosis)

Investigation for aetiology

• USS - to look for gallstones
• Trigs/calcium
• LFTs
• IgG4 - although UTD says don't need to do this, it seems to be standard of care in Australia if no other obvious cause
• Genetic testing in young (<35) or FHx - PRSS1, SPINK1, CFTR, CTRC, CASR, Claudin-2
  • But these would all be organised by geneticist, I think
  • Costs $300 and requires referral with justification
  • HPB surgeon says test it in young patients with recurrent presentations
• Consider cancer if other suggestions of it
• MRCP +/- secretin
• EUS - microlithiasis, ductal abnormalities, small tumours near ampulla

Course:

• Daily bloods including CRP
  • Don't repeat lipase
  • CRP >150 at 48 hours is reasonably predictive for severe course (sp 80%, se 76%)
• Early deaths - MODS from SIRS
• Late deaths - MODS from necrotic sepsis
• Feed early (once pain is better) in mild disease
• Consider enteral tube feeding around 72 hours in for severe AP (NGT and NJT are comparable, either is ok)
• CT 3-5 days after symptom onset if no improvement or deterioration (pancreatic necrosis typically becomes apparent 72 hours after onset)

Gallstone pancreatitis

Indications for ERCP:

• • Cholangitis
    • Cholangitis = fever + any of: CBD stones OR dilated CBD OR progressive cholestasis (bili >40). If cholangitis is suspected, aim ERCP within 24 hours.
  • Persistent CBD obstruction
    • Dilated CBD
    • Obstructing stone in CBD on MRCP (consider at 72 hours)
    • Increasing LFTs without cholangitis (do MRCP first - usually do it after 24-48 hours - give them a chance to improve on their own - could be just pancreatic head oedema)
• Urgent ERCP doesn't make a difference in patients with severe acute gallstone pancreatitis if they don't have cholangitis or significant cholestasis - might as well treat conservatively and take out GB after a few days if possible - Lancet article. Cholangitis will happen more often in conservatively-managed patients, but just do an ERCP at that point.
• ERCP and sphincterotomy effectively prevents recurrent biliary pancreatitis and is especially useful in elderly patients (according to Schein)

Cholecystectomy

• • If no cholecystectomy is done, there's a 25% risk of recurrence
  • Cholecystectomy in ALL medically fit patients once pancreatitis settled - during index admission if mild. Traditionally this has meant once pain and LFTs have normalised, but evidence is now suggesting we can do it at 48 hours or even earlier
  • Unclear at this time what the best thing to do is with moderate or severe pancreatitis - retrospective data says slightly higher risk profile if done during index admission, but no good evidence
  • Usual practice is, if complicated or severe disease, wait until all inflammation has resolved, and all pockets of fluid resolve or stabilise

In pregnant patients:

• • Can lead to complications: preterm labour, prematurity, in utero fetal death
  • First trimester is worst - low rate of term pregnancies, high rate of recurrence in same pregnancy - aim conservative treatment then lap chole
  • Second trimester - safest time to operate - can operate +/- ERCP
  • Third trimester - conservative treatment +/- ERCP, aim lap chole post-partum

Hypertriglyceridaemia pancreatitis:

• A patient with epigastric pain and high triglycerides (>20 or so) probably has hypertriglyceridaemia pancreatitis, even if their lipase is normal or only mildly elevated. The lipaemic blood can mess with the results and probably underestimates the true lipase level.
• Lipotoxicity caused by pancreatic metabolization of trigs into free fatty acids by pancreatic enzymes
• Most common in south Asian patients
• Anyone with triglycerides >11mmol/L is high-risk
  • 5% risk of developing it with trig > 11.3, 10-20% with trig > 22.6
• If 'worrisome features' (lactic acidosis, end-organ dysfunction, >= 2 SIRS criteria, or hypocalcaemia) need apharesis
• Otherwise treat with insulin infusion until triglycerides <5.6 mmol/L
  • BD triglycerides and K+
  • Set rate insulin infusion - generally 3 units per hour is reasonable, with concurrent 5% glucose, target BSL 6-15
  • Check BSL and ketones prior
  • NBM or clear fluids to start with
  • Once triglycerides down <10, common practice to cease infusion (sometimes switch to subcut insulin) and start fenofibrate/fish oil)
• Needs long-term follow-up with endocrinologist and medical r/v while inpatient for long-term lipid control

Autoimmune pancreatitis

• Uncommon overall
• Not commonly a cause of ACUTE pancreatitis
• Suspect in those with painless obstructive jaundice (most common) or diffusely enlarged pancreas on imaging, who have other autoimmune conditions
• Type 1
  • Associated with high IgG4 levels and obstructive jaundice in older men
  • Often seen as part of an IgG4-related disease syndrome
    • Sclerosing cholangitis
    • Retroperitoneal fibrosis
    • Sclerosing sialadenitis
• Type 2
  • Pancreas-specific disease - often presents with acute pancreatitis
  • Often have normal IgG4
  • Requires tissue sampling, as no biomarker
  • 'idiopathic duct-centric pancreatitis'
  • Often seen with IBD
• Diagnosis
  • Histology in the setting of supportive serologic studies
  • EUS and MRCP if suspected (also need to exclude pancreatic cancer)
• Treatment
  • Glucocorticoid - typically dramatic response - if no response you need to suspect cancer