Influence of Copper, Iron, Zinc and Fe 3 + Haemoglobin Levels on the Etiopathogenesis of Chronic Calcific Pancreatitis—A Study in Patients with Pancreatitis

Abstract

Chronic pancreatitis is a serious condition associated with severe abdominal pain, and a significant percentage of patients progresses to irreversible calcification in pancreas. The present study evaluates the degree to which the levels of trace elements, copper, iron, selenium, zinc and haemoglobin-Fe(3+), in blood, serum and pancreas have any role to play in the calcification process associated with fibrosis in pancreas. Twenty-seven calcific (CCP) and 23 non-calcific chronic pancreatitis (CP) patients and equal number of age- and sex-matched normal volunteers (50) were enrolled in the study. Surgically removed pancreatic tissue and blood samples were analysed for copper, iron, selenium, zinc, protein, collagen and lipid peroxidation products in terms of malondialdehyde, protein carbonyls, glutathione, methemoglobin, methemoglobin reductase and ceruloplasmin activity levels. We could find that the pancreatic tissue levels of copper, iron, protein and collagen contents were significantly elevated in CCP patients when compared to CP patients. Serum levels of copper, free ionic copper and iron were also elevated in CCP patients. The serum and the pancreatic tissue level of zinc and selenium showed a significant decrease in CCP patients. The level of methemoglobin was elevated more significantly with the concomitant decline in the activity of methemoglobin reductase. There was a positive correlation between the pancreatic level of copper and iron with the collagen and protein levels. The results of the present study revealed that the levels of copper and iron, the pro-oxidants and zinc and selenium may influence calcification process in CCP patients. Hypoxia-related tissue injury due to the formation of oxidised haemoglobin may also contribute to the pathogenesis of calcification in pancreas.

Zinc/copper ratio: a predictor of pancreatic function in chronic pancreatitis?

“…Navarro et al showed that zinc deficiency is associated with collagen deposition and pancreatic fibrosis 16 . Supporting these findings, Geetha Armugam et al showed that reduced zinc levels and increased levels of copper and iron in the pancreatic tissue resected from CP patients may contribute to collagen deposition during the process of calcification 17 . Recently, ZnT2 (SLC30A2) has been implicated in Zn transport into zymogen granules of the pancreas which is required for the functioning of various proenzymes.…”

Micronutrient ('Antioxidant') Therapy for Chronic Pancreatitis: Basis and Clinical Experience

“…Table 1 is a distillate of many studies in patients with chronic pancreatitis, itemised in earlier reviews (16,18,23,34), now incorporating more recent observations in patients with mainly alcoholic disease (138,5). The findings are readily rationalized by the electrophilic stress concept (Figure 1), but not by any other theory on pathogenesis (34).…”

“…The information reveals that induction of the xenobiotic-processing machinery in liver and pancreas is not innocuous, despite mobilization of several natural antioxants (67,111). Studies on surgically resected specimens afford direct evidence of CYP induction (55,147,168), and also on-going oxidative stress : structural aberrations by microscopy ( Table 1) (24), FRA signals (155), increased FROP with decreased GSH (5,133), increased concentrations of prooxidant metals (copper, iron) but decreased levels of antioxidant metals (zinc, selenium) (5); and markers of the ER stress-UPR (123). The last finding might be expected to involve disrupted calcium homeostasis (177), but studies in isolated rat acini indicate that this is not a factor in toxicity from induced CYP (37).…”

“…Lower concentrations of selenium have been noted in serum / plasma of groups with chronic pancreatitis compared to control groups in diverse geographic areas (5,31,106,116,138,163,164,175), with subnormal GSH peroxidase activity when selenium level is very low (163). At Manchester the lowest selenium values accompanied painful disease, and levels fell progressively over four days upon repeated exposure to CYP substrates used for drug kinetic studies (31).…”

“…At the time of the studies at Soweto, it was not known that chlorzoxazone is a probe of CYP2E1 induction, as by ethanol (92): in these patients, with predominantly alcoholic disease, theophylline clearance was similar to that in healthy controls, but the impact of RXS evident from a fall in plasma GSH, increased oxidation of plasma ascorbic acid, decreased urinary inorganic sulphate and increased D-glucaric acid (138). A subnormal concentration of zinc in serum (5,138) and erythrocytes (62,116) correlates with reduced exocrine secretory capacity (62), rather than poor intake, and has no bearing on CYP function.…”