Pancreatic Dz Flashcards
Autodigestion prevention in pancreas
- Zymogens: inactive when generated in RER and further modified and packaged in golgi and stored separately in granules (with suboptimal pH for autoactivation)
- Lysosomal hydrolases packaged and stored separately to zymogens
- Pancreatic secretory trypsin inhibitor (SPINK1) mops up any activated trypsin, colocalised with zymogen granules
- Zymogens released by exocytosis into duct, do not activate until reach duodenum where brush border enzymes do that. Flow in duct is unidirectional
Controls of pancreatic acinar and ductal cell secretion
Vagus nerve - ACh and VIP
S cell - secretin causes HCO3 release
I cell - CCK triggers GB contraction and zymogen granule release
Potential causes of intrapancreatic trypsin activation (3)
Blockage of acinar duct → colocalization and fusion of zymogen and lysosomal granules.
Oxidative stress or inflammation
Hypotension: The blood supply to the pancreas is very important for determining if oedema will progress to necrotising/haemorrhagic disease. Tissue hypoperfusion and diminished pancreatic microcirculation contributes to development of local and systemic complications
↓ microcirculation → prolonged retention of activated enzymes → further cellular necrosis
Ischaemia of pancreatic acinar cells (have a high metabolic rate so are very sensitive)
Inadequate pancreatic circulation → build up of toxic products → further injury.
6 mechanisms contributing to the pathogenesis of trypsin activation and pancreatitis
- deranged calcium signalling
- Colocalisation of lysosomes and zymogens (cathespin B mediated trypsin activation)
- Impaired Autophagy
- Endoplasmic reticulum stress (and maladaptive unfolded protein response)
- Oxidative stress
- Non-esterified FAs (released from digestion of visceral fat)
Risk Factors reviewed in Animals 2022 descriptive analysis Cridge et al
Breed: Min Schnauzer, miniature poodle, Dachshund, Cocker spaniel
(CKCS, Collies and Boxer for chronic panc)
Obesity - 2 retrospective studiies reported increased risk
Diet - not enough evidence of high fat diet being causative, likely multifactorial. Ingestion of unusual food had OR of 4.2x risk and garbage ingestion 13x risk in an association study (low LoE)
Hypercalcaemia - not much evidence
Drugs: Phenobarbitone, KBr
Azathioprine
Organophosphate toxicity (ACh esterase inhibitor causing functional duct obstruction)
Steroids - recent review suggest may be beneficial (multispecies), no relationship of cause and effect has been proven in past studies, only elevated DGGR lipase when administered
Dyslipidemias - limited evidence, and low prevalence of high TGs in AP dogs (18%). Though seems to be an assoc in Min Schnauzers (those that have had AP are more likely to be hyperTG)
Endocrine disease - limited evidence of HAC assoc though reports of elevated DGGR and cPLi in dogs with this disease
DM - may share risk factors, most likely AP causes DM.
Infections - E. canis and Babesia association, likely secondary injury and unknown significance.
Result of intracellular trypsinogen activation
trypsin autoactivates more trypsinogen triggering release of DAMPS and chemoattractants→ neutrophil infiltration (w/o neutrophils severity of inflam is reduced)
→ ROS, ET1 and phospholipase A3 release
→ shift from apoptosis to necrosis of pancreatic cells
→ increased vascular permeability and further disruption of microcirculation
Extent of damage is determined by cytokines, ROS and ox-redox status. Then the balance of these factors determines systemic symptoms.
Role of NF kB in pancreatitis
Intra-acinar NF-kB activation also occurs independent of trypsin.
Likely via deranged Ca signalling and endoplasmic reticulum stress
Unclear how activation occurs but is correlated with severity of disease in mice (and knock-out mice have less severe inflammation)
→ IL 6 → local and systemic signalling → more acute phase proteins from liver → complement activation
Role of pancreatic stellate cells and NEFAs in pancreatitis
Pancreatic stellate cells adjacent tot he acinar cells amplify the inflammatory signals released resulting in necroinflammatory amplification loop
Lipolysis of visceral fat by pancreatic lipase results in the formation of NEFA’s, which results in systemic inflammation and organ failure
Nonesterified fatty acids have been shown to alter the severity of AP, independent of the necroinflammatory response.
The mechanism of NEFA-induced organ failure is suspected to involve inhibition of mitochondrial complex I and V and release of intracellular calcium
cPL assay test principles and Sens/Spec for different available tests
Immunological assay using Ab targeted to cPL.
Spec cPLi is quantitative measure of how much enzyme present in sample. Sens 71-90%; Spec 74-100%. Good PPV in high risk pop and NPV good in low risk pop.
Sensitivity lower for chronic disease or if measured after commencing Tx
SNAP cPL - Sens 74-100%; Spec 59-78%.
Good agreement with normal spec, nut 88-92% agreement if abnormal.
Vetscan cPL - similar assay to SNAP, quantitative also. Sens 74-84%; Spec 77-88%. Higher coefficient of variation (17%) but good clinical agreement with cPL spec.
DGGR test principles and spec/sens and limitations
Catalytic assay that measures enzymatic activity in the sample.
older DiG lipase assays had poor sens/spec as other lipases can b/d the substrate.
Recent reports of Sens 81% and Spec 92%, but older studies report
66% and 73-93%. For differentiation of mild and severe pancreatitis sens and spec were moderate ~63%.
In EPI dogs DGGR activity is WNL which suggests extra-pancreatic source of lipase that can react with this substrate. Reducing its specificty
Also increased activity in critcally ill animals without pancreatitis
Comorbidities that impact pancreatic serology tests in dogs
Renal dz - increase all
Cardiac - increased cPLi reported in CHF, also increased cTN1 in AP with evidence of myocardial dysfunction on echo in recent study
Endocrine: up to 73% of dogs with DKA had elevated cPLi
HAC cPLi elevated (and DGGR) in 35% -> may indicate occult pancreatic injury
Infections
Recent Study on pred in AP og dogs
Steroids - prev avoided due to assoc with AP, recently removed from risk list. Anti-inflammatory and pro-apoptotic effects may be protective.
JSAP 2019 - unblinded non-random clinical study. 45 pred Tx vs 20 untreated (Tx based on time) and received otherwise relatively standard supportive Tx.
Pred group 89% survival, UnTx 58% survival at 1mo -
Faster decrease in CRP of Pred Tx group
UnTx group was older and had more Dach; also smaller
Did not use severity scoring systems
No way of knowing if CIRCI involved in pred-responsive dogs.
Retrospective study on AP induced EHBDO
JVIM 2020 46 dogs with AP EHBDO retro review. 79% survival (31/33 just with med mgmt). Taking up to 15d (median) for Tbili to normalise, often increasing initially despite clinical improvement.
Fuzapladib - MOA, justification and recent lit
LFA-1 inhibitor that prevents extravasation of neutrophils into tissue. Recently approved in Japan. Proof of concept study recently presented at ACVIM (experimentally induced pancreatitis)
JVIM 2023 - 61 dogs (35 for efficacy trial, all for safety) presumptive AP randomised masked PC trial.
Change in unvalidated clinical activity index was greater for Tx group but no other significant difference in secondary variables (validated CAPCSI, CRP, cPLi). Did not evaluate effects on survival/hosp
Funded by manufacturer.
Why is metoclopramide controversial in AP
effect of metoclopramide (dopamine inhibitor)on splanchnic perfusion is questionable and preference should be given to maropitant NK1 antagonist (also block substance P) and 5 HT3 antagonists (ondansetron
Dopamine protects against experimentally induced acute pancreatitis-especially if given before hand.
