Organ Failure due to Systemic Injury in Acute Pancreatitis

Adipokines and Cytokines:
Previous clinical studies have shown that severe AP is associated with elevated serum levels 
of adipokines including resistin and visfatin 
119, 120
, and cytokines including IL-6 
121-124
, 
IL-
β
111
, IL-8
121, 124, 125
, MCP-1
126
, TNF-
α,
122
. Serum cytokines are part of the criteria for 
severity stratification 
111, 121-124, 126-128
. In a prospective study including 108 patients, IL-6 
was one of the best discriminators between mild and severe AP
129
. Another study showed 
that blood levels of IL-6 correlated with OF and mortality. At a cut-off value of 122 pg/mL 
on day 3, IL-6 predicted OF and severe pancreatitis with a sensitivity and specificity of 
81.8% and 77.7%, respectively
37
. While the increase in their levels is associated with worse 
local and systemic complications, the evidence to support them as potential mediators of 
clinically relevant end points of OF in pancreatitis is so far lacking. For example, while 
IL-1
β induces fever and myeloid infiltration into the lungs, it does not induce respiratory 
failure
47
. Neutrophil infiltration mediated by cytokines such as IL-8, CXCL1 has been 
shown to protect from lung infections 
88, 89130
Similarly, IL-6 infusion in humans inhibited 
endotoxin induced TNF-
α increase
131
and its long term infusion led to hypoferremia and 
anemia
132, 133
, but not systemic injury. IL-6
134
and TNF-
α
135
have also been shown to have 
a protective role in AP, and neither these or other cytokines have been shown to induce 
OF
136-140
. Therefore, targeting these cytokine alone may not improve outcomes in severe 
AP.
Coagulation pathway:
Vascular injury is an integral part of pancreatic inflammation and systemic injury. 
Endothelial activation, injury, increased vascular permeability, activation of coagulation, and 
increased leukocyte rolling, sticking and transmigration to pancreatic tissue have been 
demonstrated in AP. The inflammatory process and proteases like trypsin may activate the 
coagulation system leading to microvascular thrombosis. Whether this coagulation cascade 
contributes to systemic injury is unknown. As mentioned before, portal or splenic vein 
thrombosis can occur in about half of the patients with pancreatic necrosis
64
. Similarly while 
both anti-thrombin III and heparin have been shown to reduce the severity of AP in animal 
models, the clinical implications of this on systemic severity are unknown
141
.
Garg and Singh
Page 9
Gastroenterology. Author manuscript; available in PMC 2020 May 01.
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