Organ Failure due to Systemic Injury in Acute Pancreatitis

Potential mediators of systemic injury in AP:
Trypsin:
Trypsin generation is ubiquitous in AP 
56-59
in both rodents and humans
56, 59
. Being 
associated with the auto-digestive hypothesis of pancreatitis for over a hundred years
60
, 
trypsin has been an attractive target to reduce pancreatitis severity. The most direct proof of 
trypsin’s role as a mediator of systemic injury early on came from its intravenous (IV) 
infusion resulting in hypotension, shock
61, 62
and coagulopathy, which is consistent with the 
coagulation cascade being a series of proteolytic steps. In support of this observation, 
elevated D-dimer; a fibrin degradation products at admission has been shown to predict 
development of OF with a sensitivity, specificity, positive and negative predictive values of 
90%, 89%, 75% and 96% respectively
63
. Whether this coagulation cascade plays a role in 
splanchnic venous thrombosis, which is rare in the absence of necrosis, but occurs in about 
half of the patients with pancreatic necrosis
64
remains unknown. Trypsin infusion also 
causes lung injury
65
which is dependent on neutrophils (please see next section). More 
recent studies have identified the protease activated receptor-2 (PAR-2)
66
to be regulated by 
trypsin during pancreatitis. The most direct evidence comes from hypotension resulting from 
IV infusion of PAR-2 agonists, possibly via PAR-2 receptors on endothelial cells 
67
. 
Whether trypsin actually plays a major role in systemic injury during clinical pancreatitis 
remains debated, since small molecule trypsin inhibitors have not shown conclusive 
benefit
68-77
in improving systemic injury during AP and patients with hereditary pancreatitis 
due to trypsinogen gene mutations that result in its activation rarely develop systemic injury 
compared to other AP etiologies
78
. The interpretation of trypsin’s role is further complicated 
by circulating anti-proteases such as alpha-2 macroglobulin 
79, 80
which can inactivate it, 
and trypsin’s inherent tendency to auto-inactivate. Whether trypsin is indeed an initiator/
mediator of systemic severity during pancreatitis, therefore still remains inconclusive.