Towards a novel treatment strategy for acute pancreatitis. 2. Principles and potential practice.

In part 1 it was argued that a 'free radical-mast cell' template for the aetiogenesis of acute pancreatitis accommodates the evidence, whereas the prevailing 'trypsin-cytokine' template does not. In this sequel I examine the ramifications of the new philosophy in relation to speedier diagnosis, prognostic aids and, above all, a programme of active treatment which - once validated in experimental studies - could be implemented by the first medical respondent.

Towards a novel treatment strategy for acute pancreatitis. 1. Reappraisal of the evidence on aetiogenesis.

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.

A double-blind placebo-controlled trial of antioxidant therapy in limited cutaneous systemic sclerosis.

OBJECTIVE: To evaluate the effects of a combination of micronutrient antioxidants (selenium, beta-carotene, vitamin C, vitamin E and methionine) with allopurinol in patients with limited cutaneous systemic sclerosis (SSc). METHODS: The study was designed as a placebo-controlled double-blind crossover study. A carryover effect was detected retrospectively for some of the prescribed antioxidants, and so the data were analysed as: (a) a between group comparison of the first 10 week treatment period; and (b) a within group comparison of the first and second 10-week periods in those who received placebo treatment first. Study end-points were plasma von Willebrand factor (vWF), thermographic response to a standard cold challenge, frequency and duration of Raynaud's attacks, patient opinion, and specialised biochemical parameters (fatty acid profiles, antioxidants and markers of free radical injury). RESULTS: Thirty-three patients were recruited. The median duration of Raynaud's phenomenon was 10 years (range 2 to 50 years) in the active-first group and 10 years (range 4 to 53 years) in the placebo-first group. In the 10-week study, there were no differences between the active and placebo groups in the change from baseline for vWF, for the parameters of the rewarming curve, or for patients' symptoms. Despite a rise in circulating antioxidant levels, there was no fall in markers of free radical mediated injury. In the 20-week cross-over study, patients did not experience any clinical benefit from active treatment compared to placebo. CONCLUSION: No clinical benefit could be demonstrated from active treatment. There are several possible explanations for this negative result, including the short duration of therapy. It is possible that antioxidant therapy, to be effective, needs to be given early in the SSc disease process, before the onset of irreversible tissue damage.

APOE epsilon 4 influences the manifestation of Alzheimer's disease in adults with Down's syndrome.

BACKGROUND: Recent studies of the relationship between the apolipoprotein E (APOE) gene and Alzheimer's disease in adults with Down's syndrome have revealed inconsistent results. AIMS: To assess the role of the APOE gene in the manifestation of Alzheimer's disease in adults with Down's syndrome. METHOD: We studied the APOE genotypes of 24 adults with dementia and 33 non-demented adults with Down's syndrome over 35 years of age, and an additional group of 164 non-learning disabled adults. We also carried out a meta-analysis of all previously published studies of association between APOE and Down's syndrome, incorporating the current data. RESULTS: We observed a non-significant excess of APOE epsilon 4 and a reduction of epsilon 2 in adults with dementia compared with non-demented adults with Down's syndrome in our sample. However, meta-analysis showed a significantly higher frequency of epsilon 4 in adults with dementia compared with non-demented adults with Down's syndrome (odds ratio = 2.02, 95% CI 1.33-3.07, P = 0.001), but no significant reduction in the frequency of epsilon 2. CONCLUSIONS: The APOE epsilon 4 allele acts as a risk factor for the age-specific manifestation of Alzheimer's disease in people with Down's syndrome.

Comparison of rating scales for the diagnosis of dementia in adults with Down's syndrome.

Making a diagnosis of dementia, particularly in its early stages, in a person with intellectual disability can be difficult Some neuropsychological tests which were originally devised for the diagnosis of dementia in the non-intellectually disabled population have been modified for use in people with intellectual disability. Observer-rated scales have also been used for making a diagnosis of dementia in people with intellectual disability. Within the context of a genetic study, the rates of diagnosis of dementia according to different criteria, namely the clinician's diagnosis (ICD-10), the Dementia Questionnaire for Persons with Mental Retardation (DMR), the Dementia Scale for Down Syndrome (DSDS) and the Mini Mental State Examination (MMSE), were compared among 62 adults with Down's syndrome (26 demented and 36 non-demented adults according to the clinician's diagnosis). A comparison between the clinician's diagnosis and the diagnosis according to DMR criteria showed specificity and sensitivity at the 0.92 level for both categories. Similarly, a comparison between the clinician's diagnosis and the diagnosis according to the DSDS criteria showed a specificity of 0.89 and a sensitivity of 0.85. A good positive correlation was also shown between the scores of the DSDS and the DMR (Pearson's r = +0.868, P < 0.001). A similar positive correlation was found between the overall DSDS score and the scores in the main subcategories of the DMR. An MMSE could be performed in only 34 (55%) out of the 62 subjects with Down's syndrome. Out of the 30 subjects who had an MMSE score of less than 24 (the usual cut-off for the diagnosis of possible dementia), 23 (77%) did not have a diagnosis of dementia according to any criteria. It seems that the observer-rated scales, rather than the direct neuropsychological tests, are more useful for the diagnosis of dementia in people with an intellectual disability.

Prevention of recurrent pancreatitis in familial lipoprotein lipase deficiency with high-dose antioxidant therapy.

We describe a dramatic response to antioxidant therapy in three patients with familial lipoprotein lipase deficiency complicated by frequent severe episodes of pancreatitis who had failed to respond to other dietary and pharmacological measures. Antioxidant therapy may be an important advance in the management of this type of patient.

A framework for the aetiogenesis of chronic pancreatitis.

The traditional ductal model for the development of chronic pancreatitis leaves many questions unanswered and it has not facilitated management. An alternate philosophy centres on the acinar cell as the site of mounting oxidant stress, usually as a result of steady exposure to xenobiotics that induce cytochrome P450 mono-oxygenases while depleting glutathione: ductal changes are regarded as secondary, disease-compounding manifestations of the oxidant environment. Within this framework each burst of oxidant stress jeopardises exocytosis, to trigger an attack of pancreatitis by interfering with the methionine-to-glutathione transsulphuration pathway, which interacts closely with ascorbate and selenium. The resulting diversion of free radical oxidation products into the pancreatic interstitium causes mast cells to degranulate, thereby provoking inflammation, the activation of nociceptive axon reflexes, and profibrotic interactions.

Mutations of the cystic fibrosis gene in patients with chronic pancreatitis.

BACKGROUND: The pancreatic lesions of cystic fibrosis develop in utero and closely resemble those of chronic pancreatitis. Therefore, we hypothesized that mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene may be more common than expected among patients with chronic pancreatitis. METHODS: We studied 134 consecutive patients with chronic pancreatitis (alcohol-related disease in 71, hyperparathyroidism in 2, hypertriglyceridemia in 1, and idiopathic disease in 60). We examined DNA for 22 mutations of the CFTR gene that together account for 95 percent of all mutations in patients with cystic fibrosis in the northwest of England. We also determined the length of the noncoding sequence of thymidines in intron 8, since the shorter the sequence, the lower the proportion of normal CFTR messenger RNA. RESULTS: The 94 male and 40 female patients ranged in age from 16 to 86 years. None had a mutation on both copies of the CFTR gene. Eighteen patients (13.4 percent), including 12 without alcoholism, had a CFTR mutation on one chromosome, as compared with a frequency of 5.3 percent among 600 local unrelated partners of persons with a family history of cystic fibrosis (P<0.001). A total of 10.4 percent of the patients had the 5T allele in intron 8 (14 of 134), which is twice the expected frequency (P=0.008). Four patients were heterozygous for both a CFTR mutation and the 5T allele. Patients with a CFTR mutation were younger than those with no mutations (P=0.03). None had the combination of sinopulmonary disease, high sweat electrolyte concentrations, and low nasal potential-difference values that are diagnostic of cystic fibrosis. CONCLUSIONS: Mutations of the CFTR gene and the 5T genotype are associated with chronic pancreatitis.

Antibiotic accumulation and membrane trafficking in cystic fibrosis cells.

Cystic fibrosis (CF) results from mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) which is a regulated chloride channel. The deltaF508 mutation prevents the post-translational glycosylation and membrane insertion of the protein. Severe disease follows, with the formation of a viscous mucus and subsequent chronic bacterial infection of the lungs, necessitating frequent, and often long, periods of antibiotic treatment. The pharmacokinetics of antibiotics in CF patients are abnormal, with lower blood serum levels and higher clearance rates which have never been satisfactorily explained. We found that accumulation of gentamicin in nasal polyp tissue non-CF cells was subject to regulation by the effectors and inhibitors of CFTR function; regulation was lost in deltaF508 CF cells and accumulation was more than doubled because of the inhibition of exocytosis.

A pilot study of antioxidant intake in patients with cholesterol gallstones.

Whereas macronutrient intake has been extensively investigated in an attempt to unravel the pathogenesis of human cholesterol gallstones, theoretical considerations and animal models suggest that deficits in micronutrient antioxidants may be more relevant. We report a pilot study of this aspect. The plan was to obtain 7-d weighed food inventories over a 6-mo period from equal numbers of patients who had not consciously changed their diets, patients who were on low-fat diets and age- and gender-matched controls. Food tables would be used to derive daily intakes of 16 known antioxidants, essential amino acids, and essential fatty acids. Under-reporting of food intake, a recognized drawback of this dietary method, would be sought retrospectively by reference to a key publication giving minimum cut-off limits for ratios of energy intakes to basal metabolic rates. There were 18 pairs for study. Analysis of data for the 9 pairs involving patients on their normal diets showed no differences in the intakes of energy macronutrients, and cholesterol, but the patients ingested lower amounts of 10 among 16 antioxidants (P < 0.05 for methionine, alpha-tocopherol, manganese, and vitamin D; 0.05 < P < 0.10 for cysteine, beta-carotene, vitamin C, selenium, zinc, and phosphorus). Both subsets of patients ingested lower amounts of linoleic acid (diet unchanged P = 0.009, changed P = 0.026) and several essential amino acids than did matched controls. Institution of a low-fat diet caused the expected fall in intakes of energy and saturated fatty acids such that the deficit in alpha-tocopherol was amplified, but substitution of fruit and vegetables by the patients resulted in a fortuitous increase in vitamin C, beta-carotene, and manganese intake. Retrospective analysis confirmed under-reporting of food intake by all four subsets of subjects but there was no significant difference in the mean ratio of energy intake to estimated basal metabolic rate in the subset of patients who had not consciously altered their diets and the subset of matched controls. Furthermore, the lower daily intake of alpha-tocopherol and linoleic acid by these patients persisted when results were expressed relative to total fat consumption. The results support the hypothesis that insufficiency of dietary antioxidants, particularly alpha-tocopherol, may be germane to human gallstone disease; they also suggest that low intakes of linoleic acid and essential amino acids may be relevant. Because of the small sample sizes, however, these deductions should be regarded as tentative, pending confirmation by biochemical analysis of blood and especially of hepatic bile.

A pilot study of blood antioxidant and free radical marker profiles in patients awaiting coronary artery bypass grafting.

Coronary artery bypass grafting (CABG) carries a high risk of acute pancreatitis. We report a pilot study to investigate whether pre-existing oxidative stress might underlie this susceptibility, in that a burst of free radical activity not only accompanies the reperfusion stage of CABG but seems to be a pivotal step in the pathogenesis of pancreatitis. Samples of peripheral venous blood were obtained on the morning of surgery from 8 consecutive patients (age, median and range, 62, 35-70 years) with > 75% stenosis in at least three coronary vessels and a further 8 (64, 49-70 years) who had received 1200 mg allopurinol in divided doses in the previous 48 h: the results were compared with profiles of 8 healthy controls (56, 50-60 years) with normal exercise ECG. None of the patients or controls currently smoked cigarettes and the majority drank alcohol on a social basis. Compared with controls, untreated patients had lower levels of glutathione (P < 0.001) and ascorbate (P < 0.05) in plasma, alpha-tocopherol (vitamin E as molar ratio of cholesterol, P < 0.025 and beta-carotene (P < 0.05) in serum. There was no difference in serum selenium levels, but values in patients and controls were lower than in younger controls from this area (P < 0.02). Samples from the patients contained higher concentrations of lipid peroxides than control samples (P < 0.25) but there was no evidence of excessive isomerisation of linoleic acid or oxidation of ascorbate and erythrocytes showed normal ATP and energy charge with no increase in membrane lipid peroxidisability. Treatment with allopurinol did not alter this pattern, such that the ratio of oxidised to total glutathione in plasma was higher among the 16 patients than 8 controls (P < 0.025). Habitually inadequate intakes are the best explanation for the patients' deficits in aqueous phase antioxidants; prescribed low cholesterol diets would exacerbate any prior insufficiency of lipid-phase antioxidants. Correction of these deficits during the months leading up to surgery should reduce the risk of CABG-induced acute pancreatitis.

Dietary intake of micronutrient antioxidants in relation to blood levels in patients with systemic sclerosis.

OBJECTIVE: To document habitual intakes of micronutrient antioxidants in patients with systemic sclerosis (SSc) in light of studies reporting subnormal levels of ascorbate and selenium in this patient group. METHODS: Dietary intakes of vitamin C, selenium, alpha-tocopherol, beta-carotene, and sulfur amino acid precursors of glutathione were assessed using the 7 day weighed record in 12 patients with SSc and in 12 healthy control subjects. The intakes of the first 4 substances were examined in relation to plasma/serum levels, while intakes of sulfur amino acids were examined in relation to urinary inorganic sulfate. RESULTS: Antioxidant and sulfur amino acid intakes were similar in patients and controls, although the patients had lower levels of selenium (median 74 compared to 87 milligrams in controls; p = 0.014) and of vitamin C in plasma (median 6.0 compared to 11.1 milligrams/l in controls; p = 0.08). Inorganic sulfate concentration in urine was similar in patients and controls. CONCLUSION: Our results suggest that reduced blood levels of the water soluble antioxidants selenium and ascorbic acid in patients with SSc are not due to dietary deficiency. Other explanations must therefore be sought.

Iron, ascorbate and copper status of Sowetan Blacks with calcific chronic pancreatitis.

Vitamin C can be used to overcome oxidative stress and ease pain in chronic pancreatitis. But its use is deprecated in conditions of tissue iron overload, because its bioactive form, ascorbate, can accelerate free-radical reactions that are driven by transition metals. We measured iron, ascorbate and copper in Sowetan Blacks (RSA) with chronic pancreatitis, obtaining serum/plasma from 14 consecutive patients and 15 controls. Compared with data from corresponding groups in Manchester, African samples had less ascorbate (p < 0.0001), but more caeruloplasmin (p < 0.0001). African and British controls had comparable iron and iron-binding capacity. Plasma from African patients had less ascorbate than that from African controls (p < 0.005) and in six samples, ferritin exceeded 300 micrograms/l (677 pmol/l). Low-molecular-mass iron or copper, capable of participating in free radical reactions, was not detected. British patients, had similar caeruloplasmin levels to African patients but higher ascorbate levels. There is no evidence of iron overload in our African samples. Outwardly healthy controls from Soweto have elevated levels of caeruloplasmin, possibly to compensate for dietary deficiency of ascorbate. Persistent oxidative stress is a unifying feature of chronic pancreatitis, but its degree is higher in African than British patients. Supplements of vitamin C should be safe in Blacks of southern Africa.