Abstract
Acute pancreatitis (AP) is often accompanied by alterations in the acid-base balance, but how blood pH influences the outcome of AP is largely unknown. We studied the association between blood pH and the outcome of AP with meta-analysis of clinical trials, and aimed to discover the causative relationship between blood pH and AP in animal models. PubMed, EMBASE, and Cochrane Controlled Trials Registry databases were searched from inception to January 2017. Human studies reporting systemic pH status and outcomes (mortality rate, severity scores, and length of hospital stay) of patient groups with AP were included in the analyses. We developed a new mouse model of chronic metabolic acidosis (MA) and induced mild or severe AP in the mice. Besides laboratory blood testing, the extent of pancreatic edema, necrosis, and leukocyte infiltration were assessed in tissue sections of the mice. Thirteen studies reported sufficient data in patient groups with AP (n = 2,311). Meta-analysis revealed markedly higher mortality, elevated severity scores, and longer hospital stay in AP patients with lower blood pH or base excess (P < 0.001 for all studied outcomes). Meta-regression analysis showed significant negative correlation between blood pH and mortality in severe AP. In our mouse model, pre-existing MA deteriorated the pancreatic damage in mild and severe AP and, vice versa, severe AP further decreased the blood pH of mice with MA. In conclusion, MA worsens the outcome of AP, while severe AP augments the decrease of blood pH. The discovery of this vicious metabolic cycle opens up new therapeutic possibilities in AP.
Highlights
Acute pancreatitis (AP) is one of the most frequent gastrointestinal causes of hospitalization with significant morbidity and mortality in the US (Yadav and Lowenfels, 2013; Parniczky et al, 2016)
We revealed a strong association between blood pH and the outcome of AP with meta-analysis of human studies
Our analyses showed that lower blood pH predicts higher mortality rate, longer length of hospital stay (LOS), and worsens the severity of AP
Summary
Acute pancreatitis (AP) is one of the most frequent gastrointestinal causes of hospitalization with significant morbidity and mortality in the US (Yadav and Lowenfels, 2013; Parniczky et al, 2016). When pancreatic bicarbonate production is challenged by local or systemic acid load (i.e., metabolic acidosis, MA), the resulting lower pH can facilitate pancreatic enzyme activation and deteriorate cell damage (Reed et al, 2011). Beside an external acid load, the pancreatic pH balance can be compromised by tissue injury such as AP, which can lead to acidification of local tissues, deteriorate cell damage (Behrendorff et al, 2010). Multiple mechanisms have been implicated in AP which can lead to MA, including direct mechanisms such as the loss of bicarbonate-rich pancreatic juice via pancreatic fistula or drainage (Rice et al, 2014), as well as indirect ones through lactic acidosis which can sequentially occur in AP due to shock, sepsis, cardiovascular failure, or upper gastrointestinal bleeding (Zhan et al, 2015). The interaction between AP and systemic pH is still not fully clarified
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