Linda P. Hunt

APOLIPOPROTEINS (a), AI, AND B AND PARENTAL HISTORY IN MEN WITH EARLY ONSET ISCHAEMIC HEART DISEASE

Middle-aged men who had had a myocardial infarction were compared with controls matched for social background, age, cigarette-smoking, blood pressure, and alcohol consumption. Serum cholesterol, triglycerides, very low density lipoprotein, low density lipoprotein, high density lipoprotein (HDL), HDL2 and HDL3 cholesterol, and serum apolipoproteins (apo) (a), AI, and B were measured. Discriminant analysis showed that the combination of these variables that best distinguished patients from controls was provided by apo AI and apo B and a knowledge of parental history of early cardiac death, the most discriminating single factor being apo B. No other variable contributed more than these. Apo (a), however, could be substituted for parental history, which had a major influence on the serum concentration of apo (a). Apo (a) concentration accounted for much of the familial predisposition to cardiac ischaemia. These findings may prove valuable in the clinical assessment of genetic susceptibility to myocardial infarction. They also support the hypothesis that serum apo (a) concentration is a genetic trait that predisposes to arterial thrombosis. Apo B emerged as the main lipoprotein determinant of coronary disease risk.

A controlled trial of colchicine in primary biliary cirrhosis Trial design and preliminary report

Colchicine (1 mg/day), or an identical placebo, was given to 64 patients with primary biliary cirrhosis in a double-blind controlled trial. Due to a novel, pair-matched trial design, the two groups were exceptionally well matched at entry. In comparison with placebo, colchicine produced a beneficial effect on serum albumin and bilirubin levels at 3 months in patients who had abnormal liver function (bilirubin greater than 20 mumol/l) at entry: (albumin, P = 0.047; bilirubin, P = 0.022). In patients with normal liver function at entry (bilirubin less than 20 mumol/l), beneficial effects were noted on total globulin levels at 3 months (P = 0.013) and on immunoglobulin G levels at 3 and 6 months (P = 0.044 and 0.001, respectively). At 18 months, survival estimate in the colchicine and placebo groups were 84% and 69%, respectively. The difference did not reach significance. Colchicine produced an early improvement in liver function and immunoglobulin levels. Few serious side effects were encountered, and colchicine clearly merits long-term study in the treatment of primary biliary cirrhosis.

Serum lipoprotein(a) in patients heterozygous for familial hypercholesterolemia, their relatives, and unrelated control populations.

Serum lipoprotein(a) (Lp[a]) levels were significantly higher in 89 patients with heterozygous familial hypercholesterolemia (FH) (geometric mean, 22.7 mg/dl) than in 109 normocholesterolemic controls (10.0 mg/dl, p less than 0.05) and 40 controls (9.1 mg/dl, p less than 0.05) with similarly elevated low density lipoprotein cholesterol levels due to other primary hypercholesterolemias. To provide further evidence that the increased serum Lp(a) concentration was due to inheritance of the FH gene, 24 unaffected first-degree relatives were compared with their FH probands. Serum Lp(a) in affected individuals was significantly greater than in unaffected relatives (geometric means, 26.5 versus 13.7 mg/dl, respectively; p less than 0.05). Family membership exerted an effect on serum Lp(a) concentrations, indicating that other genetic influences were also operating, as is known to be the case in general populations. Serum Lp(a) in 30 of the FH patients, who had coronary heart disease, was not significantly different from 30 age- and sex-matched controls with FH but with coronary heart disease (geometric means, 23.6 versus 24.7 mg/dl, respectively). FH is associated with an increase in serum Lp(a). Elevated serum Lp(a) concentrations should probably now be regarded as a component of the clinical syndrome of FH. However, within our FH population Lp(a) did not distinguish those with clinically overt coronary heart disease from those without the disease.

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.

Influence of immunosuppressive therapy on lipoprotein(a) and other lipoproteins following renal transplantation

Coronary heart disease (CHD) is more common in patients with chronic renal failure and is a major cause of death after renal transplantation. Elevated serum levels of lipoprotein(a) (Lp(a)) are a known risk factor for CHD in the general population and levels have been reported to be increased in renal transplant recipients. It has been suggested that cyclosporin may elevate Lp(a) levels. We therefore measured the serum concentration of Lp(a) in 50 renal transplant recipients who were receiving cyclosporin alone as immunosuppressive therapy and 50 who were treated with azathioprine and prednisolone, but not cyclosporin. The patients attended two renal transplant centres, one where cyclosporin alone was used as immunosuppressive treatment when possible and another where many patients commenced on azathioprine and prednisolone remain on this medication rather than cyclosporin. Patients in each group were matched for age and sex, but the time since transplantation was greater in those not receiving cyclosporin. Transplant function, obesity and the underlying cause of renal disease were similar in both groups of patients. Median Lp(a) concentration in the cyclosporin monotherapy group was 32.0 (range <0.8-140.3) mg/dl and was significantly (p < 0.05) greater than that of the azathioprine and prednisolone group which was 18.3 (range <0.8-167.7) mg/dl. The serum high-density lipoprotein (HDL) cholesterol concentration, which was 1.24 +/- 0.39 mmol/l (mean +/- SD) in patients receiving cyclosporin, was significantly (p < 0.05) less than that of those treated with azathioprine and prednisolone in whom it was 1.41 +/- 0.40 mmol/l. The lower level in those on cyclosporin was due to a decrease in the HDL2 subfraction. Serum lipid and lipoprotein concentrations were otherwise similar in the two groups of patients. The serum level of Lp(a) after renal transplantation may be influenced by the choice of immunosuppressive therapy.

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.

Toward an animal model of chronic pancreatitis

SummaryThere is currently no reproducible model of the painful and lithogenic disease, chronic pancreatitis. Its biphasic evolution, from acinar cell hyperplasia and hyperactivity toward effacement of enzyme as well as bicarbonate secretory parenchyma, would be rationalized if it was linked to induction of cytochrome P450 mono-oxygenases (CYP): the increased oxidant load from long-term CYP induction eventually erodes micronutrient antioxidant defenses to injure cells. This philosophy would also rationalize the reported hepatobiliary aberrations associated with the human disease, including increases in free radical oxidation products in bile. Accordingly pancreatic and biliary secretions were studied in Syrian golden hamsters that were reared for 6 mo on low or high (16% corn oil) fat diets that were supplemented with a prototype inducer of CYP2 (200 ppm phenobarbitone) or CYP1 (100 ppm β naphthoflavone) enzyme families, with or without a putative enzyme inhibitor (400 ppm cimetidine). The drugs did not alter the reduction in flowrate or bicarbonate concentration of pancreatic juice caused by the high fat diet alone, but, in contrast, evoked pancreatic protein hypersecretion in a number of animals. β naphthoflavone, but not phenobarbitone, augmented the output of biliary lipid peroxidation products irrespective of dietary fat content and cimetidine cotreatment with either inducer did the same. We conclude: (1) that drug modifiers of CYP magnify the deleterious pancreatobiliary effects of corn oil-enriched diets and draw them closer to those found in human chronic pancreatitis; (2) that these functional derangements are accompanied by pancreatic lipoatrophy; and (3) that long-term CYP induction does not, of its own, cause fibrosis or the ductal abnormalities that generally accompany loss of pancreatic acinar cells in the human disease and, also in contrast, the changes that are caused appear to be painless.

On optimising the diagnostic yield of secretin pancreozymin tests

The results of 407 secretin-pancreozymin tests were analysed by a variety of statistical methods, in an attempt to optimize diagnostic yield. The best diagnostic yield accrued from selection of a point corresponding to 95% specificity and 60% sensitivity on each of two virtually superimposable receiver-operator curves--using either bicarbonate output or a discriminant function derived from multivariate analysis--and the anticipated yield approximated to that realised in a further prospective series of 150 cases. At a 25% hypothetical local prevalence of chronic pancreatic disease (including chronic pancreatitis and pancreatic cancer), the positive predictive value was 80%, the negative predictive value 88% and the efficiency was 86%--values that are not dissimilar to those reported in a study in which both hormones were given simultaneously by constant intravenous infusion for 105 min with multivariate analysis of the results. We conclude that (a) measurement of bicarbonate output in 30 min after an appropriate dose of secretin given as a bolus injection yields results that are comparable to those obtained when secretin and pancreozymin are given by constant intravenous infusion in doses to evoke maximal secretory responses; and (b) the yield of hormone tests using duodenal intubation is far from ideal.

Hypersecretion of biliary fatty acids in patients with exocrine pancreatic disease

SummaryThe fatty acid composition of bile secreted into the duodenum in the first 10 min after an intravenous (i.v.) injection of Boots secretin (2 CHRu kg-1) has been analysed by gas liquid chromatography in 11 healthy volunteers, 8 patients without pancreatic disease, 27 patients with exocrine pancreatic disease who had not altered their diet substantially (acute pancreatitis 8; chronic pancreatitis 16; cancer 3) and 11 patients with exocrine pancreatic disease on low fat intakes (40 g/day) for at least 6 months. The mean values for total fatty acid outputs (after back transformation of the logged data) were significantly higher in each subgroup of patients with pancreatic disease on their usual diets (acute 134, chronic 189, cancer 235 mg) than in the two subgroups of controls (30 and 55 mg), due to significant increases in the outputs of every fatty acid, C16:0 through to C22:5. This finding, which was usually not apparent in patients with pancreatic disease on low-fat diets, may reflect the combined influence of dietary fat intakes and hepatic enzyme induction. Comparison of the fatty acid outputs in endoscopically collected bile and duodenal juice after separate injections of secretin three hours apart indicate that: (a) analysis of duodenal juice within 10 min of stimulation by Boots secretin provides valuable information on the composition of hepatic bile; (b) the increased phospholipid output in the untreated patients is due to hypersecretion and does not merely represent a ‘washout’ phenomenon.

Insights into the development of alcoholic chronic pancreatitis at Soweto, South Africa: a controlled cross-sectional study.

Objective: We asked why so few working-class Africans of Soweto have chronic pancreatitis (CP) when alcoholism is the norm. Methods: Twenty-one alcoholics with acute psychosis but normal pancreas were investigated for lifestyle, micronutrient status, electrophilic stress, and iron overload. Results: Alcoholics consumed more ethanol daily than did 14 previously studied patients with CP (P = 0.003); cigarette usage was similar; both groups had even poorer vitamin C status than 14 healthy controls, and no participant had iron overload. The CP group had higher scores for exposure to occupational xenobiotics than did alcoholics (P < 0.05), with lower plasma glutathione (P = 0.047) and urinary inorganic sulfate (P = 0.009). Further analysis identified hyperhomocysteinemia in the alcoholic set, with lower vitamin B12 (P < 0.001), higher folic acid (P = 0.003), and similar vitamin B6 levels compared with controls. Conclusions: The transition from alcoholism to CP in Soweto is associated with occupational exposure to xenobiotics. Among detoxification systems that are strained thereby, glutathione and inorganic sulfate depend on methionine intake, which is ample in Sowetans, whereas vitamin C, which exerts a glutathione-sparing effect, is deficient. Hence, a daily tablet of vitamin C may enable community prophylaxis against the disease-but homocysteine status would need monitoring.