David Schofield

Evidence for early oxidative stress in acute pancreatitis

SummaryPancreatic oxidative stress with depletion of pancreatic glutathione is an early feature in all tested models of acute pancreatitis, and sooner or later the problem extends to the lung, irrespective of disease severity, whether toward spontaneous recovery or death from multisystem organ failure. We, therefore, sought evidence of oxidative stress in the human disease by analyzing admission blood samples. We found it from high concentrations of oxidatively altered linoleic acid in serum and vitamin C in plasma (p<0.001 vs controls or a group of other acute abdominal crises where the proportion of patients with admission Apache II scores 8 was similar). These changes were accompanied by subnormal levels of ascorbic acid in plasma (p<0.001); selenium (p<0.001), β-carotene (p<0.001), and α-tocopherol in serum (p=0.005 for its molar ratio to cholesterol). Paradoxically, the plasma concentration ofS-adenosylmethionine was elevated (p=0.02), suggesting that this proximate bioactive metabolite of the essential amino acid had backtracked because its intracellular metabolism down the methionine trans-sulfuration pathway toward glutathione synthesis was disrupted. The aberrations transcended putative etiological factor, duration of symptoms, or disease severity. We conclude: (1) that oxidative stress has pervaded the vascular compartment by the time of admission in patients with acute pancreatitis, and, (2) that blood micronutrient antioxidant profiles at this stage are consistent not only with compromised intracellular capacity to synthesize/refurbish glutathione, but also vulnerability of intra- and extracellular lipid targets.

Antioxidant therapy for recurrent pancreatitis : biochemical profiles in a placebo-controlled trial

The usefulness of micronutrient antioxidant therapy for recurrent (non‐gallstone) pancreatitis has recently been endorsed by a 20‐week double‐blind double‐dummy cross‐over trial in 20 patients. Treatment was delivered as two types of tablets, providing daily doses of 600 μ g organic selenium, 9000 i.u. β ‐carotene, 0.54 g vitamin C, 270 i.u. vitamin E and 2 g methionine. We report antioxidant profiles in blood samples collected before entry, at the cross‐over stage and upon completion of trial. Baseline serum concentrations of selenium, β ‐carotene and vitamin E in the patients were significantly lower than in healthy controls, were unaltered by placebo and normalized by active treatment, but reverted to basal values in the subgroup that received placebo subsequently. The baseline serum concentration of a free radical marker—the 9‐cis, II‐trans isomer of linoleic acid—was significantly higher in the patients than in controls, fell inexplicably in the placebo phase and fell further upon active treatment. Discriminant analysis eliminated the overlap in free radical marker and selenium concentrations between control sera on the one hand and baseline or post‐placebo samples from the patients on the other: antioxidant treatment normalized the relationship between these biochemical parameters. Subnormal baseline serum levels of S‐adenosylmethionine drifted downwards upon active treatment whereas a sharp rise was noted when a relapse of pancreatitis occurred during the placebo phase. The results confirm that adequate exposure to antioxidants in the active treatment phase was associated with amelioration of oxidative stress, and that there was no residual effect 10 weeks after switching over to placebo treatment. Furthermore, the paradoxical behaviour of S‐adenosylmethionine may imply that the beneficial effect of micronutrient antioxidants in recurrent pancreatitis is linked with preservation of the methionine trans‐sulfuration pathway in pancreatic acinar cells.

Placebo-Controlled Trials of Antioxidant Therapy Including S -Adenosylmethionine in Patients with Recurrent Nongallstone Pancreatitis

SummaryHaving shown in a 20-week placebo-controlled double-blind crossover trial that ‘global’ antioxidant supplementation - including selenium, β-carotene, vitamin C (ascorbic acid), vitamin E (tocopherol) and methionine - curbs symptoms while correcting oxidative stress in patients with recurrent nongallstone pancreatitis, we have investigated through two further trials the relative importance of methionine versus that of the other antioxidants in effecting this good outcome. 30 consecutive patients were entered into the second study in which therapeutic intervention involved only the active metabolite of methionine, S-adenosyl-methionine (SAMe), 2.4g per day in divided doses. Blood analysis showed that subnormal baseline levels of selenium, β-carotene and vitamins E and C were unchanged throughout and that drug treatment resulted in supranormal levels of SAMe in plasma. SAMe proved to be ineffective clinically as judged by attack rate and background pain, as well as biochemically as gauged by the percentages of oxidatively altered vitamin C and linoleic acid. The coadministration of selenium and β-carotene with SAMe was tested in the third study. This was abandoned when 3 patients had a clearcut attack of pancreatitis while on subsequent ‘open’ treatment. Analysis of clinical and biochemical information from 14 patients who had completed the 20-week trial confirmed the inefficacy of the combination, although active treatment normalised serum selenium and β-carotene concentrations while SAMe levels were again pushed into the supranormal range. The results show that SAMe on its own, or with additional selenium and β-carotene, is ineffective in patients with recurrent nongallstone pancreatitis. By a process of elimination with reference to biochemical measurements during the 3 trials, and considering experimental evidence of the importance of methionine for pancreatic integrity, we cautiously suggest that an effective antioxidant prescription should include SAMe (or methionine) as well as vitamin C, with additional compounds as indicated by blood measurements.