*2.2.1 Inflammation*

Nutritional status during AP is affected by several factors, more importantly in the inflammation cascade. It is fed with increased secretion of tumor necrosis factor (TNF) secondary to hypotension, ischemia, endotoxin, hypoxemia, and reperfusion. Nitric oxide synthesis also increased activating the arachidonic acid pathway and inducing the activation of cyclooxygenase (COX). TNF and interleukin (IL) 1 are synergistic, leading to augmented neutrophil activation and permeability [29]. IL-1 also increases T-cell and macrophage activation, fever, and COX and nitric oxide synthase production [29]. IL-8 is an endogenous chemoattractant, present for a longer period, and is notably proinflammatory. IL-6 is frequently used as a biomarker of severity of the inflammatory response. It has both proinflammatory and anti-inflammatory activities [29]. However, the intestinal epithelial barrier is the first line of defense during AP and carries out the production of immunoglobulin A (IgA). Ap is also characterized by causing weakening of this defense system because of increased capillary leakage and decreased activity of tight junctions in preserving the integrity of intestinal barrier secondary to inflammatory mediators. When the intestinal barrier is compromised, intestinal bacteria can penetrate the bloodstream. Invading microorganisms are recognized in minutes by multiple components of innate immunity [29]. Peak inflammatory cytokine production is observed 24–36 hours after initial symptoms of pain, and subsequent systemic manifestations and distant organ failure 2–4 days later [30]. This dysregulation of the immune system leads to a major organic and systemic inflammation and immune paralysis, causing a worsening clinical course during AP [29].

### *2.2.2 Metabolic changes*

Inflammatory cytokines (TNF, IL 1, and 6) as well as stress hormones (cortisol, catecholamines, and glucagon) are produced during AP. As a result, a dysregulation of basal metabolism is similar to trauma or sepsis [23, 31, 32]. When overwhelming inflammation is observed, it produces augmented protein catabolism, characterized by a decremented production of gluconeogenesis by exogenous glucose, increased energy expenditure and insulin resistance, and an augmented dependence of fatty acid oxidation for energy substrates. Energy needs are in constant change according to the severity and stage of AP, comorbidities, as well as complications during the clinical course of AP [23, 32]. In the same sentence, impaired nutrient digestion and absorption occurred during AP produce nutritional deficiencies. This can be particularly severe in undernourished patients, as well as alcoholic patients, who are at great risk of AP. Without the correct and opportune nutritional support, patients develop malnutrition in a rapid manner, as well as water retention and decreased muscle function [33].

In patients with AP, resting energy expenditure (REE) measured by indirect calorimetry (IC) is increased by 61% and by 82% in complicated by infection ± SD of measured REE was 111% ± 15% in mild pancreatitis, 126% ± 10% in SAP, and 120% ± 11% in pancreatic sepsis, compared with predicted REE by Harris-Benedict equation [3]. The substrates for the production of acute-phase occurred during AP covered by amino acid released from protein breakdown observed in about 80% of patients with severe necrotizing pancreatitis [31]. In the same way, nitrogen loss can be up to 20–40 g/d and these patients have a tenfold higher death rate than those with normal balance [34]. Regarding carbohydrate metabolism, hyperglycemia is frequently observed in patients with AP, as a result of an imbalance of insulin resistance, increased hepatic glucose production, and impaired insulin secretion caused by beta-cell damage [35]. Hyperglycemia is associated with necrosis and its infectious complications. Clinical therapy should include blood glucose control in a strict manner [36]. Hypertriglyceridemia is also common during AP, and it can be caused by any complication related to AP, or it can produce pancreatitis. Elevated serum triglycerides and impaired lipid clearance are caused by lipid catabolism, resulting from decreased insulin secretion [36]. Severe hypertriglyceridemia is considered when serum triglycerides > 11.3 mmol/L, and in the absence of gallstones and significant alcohol consumption, it can cause AP [9, 36].

Micronutrient deficiencies are commonly observed in AP. On the other hand, chronic alcohol consumption can cause micronutrient deficiencies due to impaired storage and utilization of nutrients, inadequate intake, and decreased absorption. These deficiencies include vitamin B1, B2, B3, B12, C, A, folic acid, and zinc [37, 38]. Moreover, deficiencies in patients with severe complicated pancreatitis often require hospital admission.
