Towards a Novel Treatment Strategy for Acute Pancreatitis

Abstract

Despite more than a century of research endeavour, there is no specific medical treatment for acute pancreatitis and early mortality is high – 20% of fatalities by the day after admission. I do not see any realistic prospect that today’s focus on immunomodulation will provide a breakthrough either. The signs are that the outcome of acute pancreatitis is determined almost at its inception, and that those unfortunate individuals in whom the seeds for a precipitous course are sewn do not declare themselves until it is too late. This reappraisal of the evidence on disease aetiogenesis has been undertaken in an effort to fathom why this might be.

Towards a Novel Treatment Strategy for Acute Pancreatitis

“…2 The evolution of an attack of severe pancreatitis precipitated by percutaneous pancreatic biopsy two days after ERCP – with particular reference to blood antioxidant consumption in the first few days, despite prior antioxidant supplementation. As discussed in the text and in earlier reports [1, 2], the abrupt consumption of plasma ascorbate/vitamin C is best explained by histamine oxidation products: an anaphylactoid response of pancreatic mast cells may have been precipitated by pethidine and/or lignocaine. The patient is a man aged 41 years, fit until six months before presentation with incapacitating epigastric pain following two attacks, and computed tomography evidence of calcific chronic pancreatitis with a mass in the head of the gland.…”

“…As was observed in part 1 [1], the high early mortality of acute pancreatitis – 20% of deaths by the day after admission and 40% by the next day – is best rationalised in terms of mast cell pathology. Figure 1 illustrates how the concept links with the disease-initiating burst of free radical activity which paralyses the secretory pathway towards exocytosis in the acinar cell.…”

“…ZG = zymogen granules; L = lysosomes; V = vacuoles in cytoplasm; ROS = reactive oxygen species; RXS = reactive xenobiotic species generated via pancreatic cytochrome P450, alcohol/acetaldehyde dehydrogenases or prostaglandin synthase; N = nucleus; FROPs = free radical oxidation products; PAF = platelet activating factor; NO · = nitric oxide; LTB 4 and LTC 4 = leukotrienes; PGD 2 = prostaglandin D 2 ; IFN-α = interferon-α; IL-1,6,8 = interleukin series; TNF-α = tumour necrosis factor-α; EC = endothelial cell; PMN = neutrophil; P = platelet; MΦ = macrophage; PLA 2 = cell membrane-lysing form of phospholipase A 2 which could hydrolyse adipocyte membranes to facilitate lipase entry, and thus fat necrosis; tPA, uPA = tissue-type and urokinase plasminogen activator, respectively; PAR-2 proteinase activated receptor-2; C3 = complement subtype; ⊕ = activation; AO = antioxidants; LA-OP = linoleic acid oxidation products. Note that a high degree of oxidative stress (represented by the scales at the bottom) and the participation of reactive xenobiotic species – including those derived from linoleic acid and opiate analgesics [1, 2] – favours an anaphylactoid reaction of mast cells. …”

“…Schematic representation of the ‘free radical-mast cell’ template for the aetiogenesis of acute pancreatitis based on published information [1, 2]. The large cross symbol at the apical pole of the acinar cell indicates the disease-initiating blockade to exocytosis, which leads to a reversal in secretory polarity such that pro-inflammatory substances enter the interstitium along with the cell’s normal secretions.…”

“…Further, for this enzyme the increase seems to be selective for the development of acute pancreatitis – unusual when hyperamylasemia is asymptomatic – and its increment higher in severe than mild disease [16]. However, a clear increase in anionic trypsin-α 1 proteinase inhibitor complexes within serum is not seen until 24 h, when levels in severe pancreatitis are of the same order as in mild disease [16]: moreover it can be calculated that the active enzyme constitutes <10% of the circulating zymogen load [1]. This delay explains the lack of increase in the urinary concentration of the trypsinogen activation peptide (TAP) when sought at 4 h [17], but an increase at 24 h of the carboxypeptidase B activation peptide (CAPAP) [18], surrogate marker of trypsinogen activation [19].…”