Mononuclear Phagocyte Activation in Acute Pancreatitis: A Clinical and Experimental Study

McKay, Colin J (1996) Mononuclear Phagocyte Activation in Acute Pancreatitis: A Clinical and Experimental Study. MD thesis, University of Glasgow.

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The pathophysiology of the systemic illness seen in patients with acute pancreatitis is unknown but there are similarities with the systemic complications of sepsis, prompting the suggestion that similar endogenous mediators may be responsible. Central to this hypothesis is the role of activated mononuclear phagocytes. The long acting somatostatin analogue, octreotide (Sandostatin) has been shown to improve hepatic reticuloendothelial cell function, an effect which may be beneficial in acute pancreatitis by enhancing the clearance of endotoxin from portal blood and preventing systemic mononuclear phagocyte activation. This thesis addresses two main questions. Firstly the potential role of octreotide in the treatment of acute pancreatitis and secondly the role of mononuclear phagocyte activation in the pathophysiology of the systemic complications of acute pancreatitis. Octreotide in acute pancreatitis 58 patients with moderate or severe acute pancreatitis who were admitted to hospitals within the West of Scotland over an 18 month period were randomised to receive octreotide, 40mug/h by continuous intravenous infusion, or placebo in addition to standard supportive therapy. Patients were comparable in age, sex, aetiology and severity of disease on admission. There was no significant difference in the incidence of complications (53.6% octreotide group and 43.3% placebo group) or mortality (octreotide group 18%; placebo group 20%). The resuhs of this study indicate that octreotide is of little or no benefit in the treatment of acute pancreatitis. Mononuclear phagocyte activation in acute pancreatitis Monocytes were isolated from the peripheral blood of 28 patients with moderate or severe acute pancreatitis and the in-vitro secretion of these cytokines measured at intervals during the first week of illness. Sixteen patients (57%) developed systemic complications. Peak TNF? secretion was significantly higher in patients who developed systemic complications (median = 18.5ng/ml, IQR 5.5-28.5) than in those with an uncomplicated course (3.7ng/ml, 2.3-6.4, P<0.01). Similarly, peak IL-6 and peak IL-8 secretion were significantly higher in the complicated group (IL-6; complicated: median = 48.9ng/ml, IQR 12-71, uncomplicated 16.3ng/ml, 9.9-24.8, P<0.05; IL-8, complicated; median = 754ng/ml, IQR 683-857, uncomplicated; median = 602ng/ml, 496-756, P<0.05). No significant difference in peak IL-1 secretion was observed between the two groups. This study demonstrates that the systemic complications of acute pancreatitis are associated with a significant increase in monocyte secretion of TNFalpha, IL-6 and IL-8 suggesting that, as in sepsis, these cytokines play a central role in the pathophysiology of the disease. The role of IL-1beta and proteolytic degradation of parathyroid hormone (PTH) in the pathophysiology of pancreatitis-associated hypocalcaemia was studied. Serum levels of PTH, calcium and albumin were measured daily for five days in 41 selected patients with moderate to severe acute pancreatitis. PTH was measured by means of a two-site immunoradiometric assay specific for the intact peptide. A rise in PTH levels was observed more commonly in patients with a complicated or fatal outcome than in those with an uncomplicated course (complicated; 87.5% of 16 patients, uncomplicated; 24% of 25 patients, P<0.001, Chi-square test). In the presence of hypocalcaemia, although PTH levels were variable, raised levels of PTH were found more frequently in the complicated group (complicated; 7 of 8, uncomplicated; 2 of 7, P=0.035, Fisher's exact test). This study confirms that an appropriate rise in PTH occurs in response to the hypocalcaemic stimulus in patients with acute pancreatitis, with no evidence of significant PTH degradation. There was a significant negative correlation between serum calcium levels and the secretion of IL-1beta by monocytes but this was mainly a consequence of the resuhs obtained from one patient with very low serum calcium associated with high monocyte IL-1beta secretion. Increased production of pro-inflammatory cytokines by monocytes and mononuclear phagocytes would be expected to result in neutrophil activation and therefore raised plasma levels of polymorphonuclear elastase (PMNE). Measurement of PMNE in acute pancreatitis may therefore be a simple method of assessing the degree of leucocyte activation which would allow the early identification of patients at risk of developing systemic complications.

Item Type: Thesis (MD)
Qualification Level: Doctoral
Additional Information: Adviser: J N Baxter
Keywords: Medicine, Pathology
Date of Award: 1996
Depositing User: Enlighten Team
Unique ID: glathesis:1996-74952
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 27 Sep 2019 15:01
Last Modified: 27 Sep 2019 15:01

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