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J W Halliday

Publications and source records attributed to J W Halliday.

At least 55 records · Page 3Linked to original sources
PubMed1991

Fine mapping of a human chromosome 6 ferritin heavy chain pseudogene: relevance to haemochromatosis.

We have used a somatic cell hybrid regional mapping panel for the short arm of chromosome 6, linkage analysis and a population study to map in detail a previously described ferritin heavy chain pseudogene sequence on chromosome 6. Our results show that this sequence maps to the short arm of chromosome 6 centromeric to the glyoxylase locus. The ferritin pseudogene locus is thus distant from the locus for the iron storage disease haemochromatosis, confirming previous evidence that this sequence is not a candidate for the haemochromatosis gene.

Chromosome Mapping↗
PubMed1991

The effect of iron and ethanol on rat hepatocyte collagen synthesis.

1. Carbonyl iron (2.5% w/w) in rat chow was used to induce iron loading in rat hepatocytes. 2. Acute exposure of cultured hepatocytes from control and iron-loaded rats to ethanol (25-100 mM) resulted in a significant inhibition of protein synthesis. 3. Inhibition of protein synthesis in hepatocytes from iron-loaded rats was primarily due to impaired amino acid uptake by these cells. 4. High concentrations of ethanol stimulated the rate of protein degradation by hepatocytes from iron-loaded rats. 5. Acute administration of ethanol to hepatocytes from control animals did not stimulate the absolute rates of collagen biosynthesis nor induce Type I procollagen mRNA. 6. Acute administration of ethanol did not inhibit procollagen synthesis. 7. Iron overload induced Type I procollagen mRNA and increased the absolute rates of collagen synthesis in hepatocytes. 8. These findings may be relevant for the development of hepatic fibrosis in patients with genetic hemochromatosis who consume excess ethanol.

Amino Acids↗
PubMed1991

Intestinal transferrin receptors and iron absorption in the neonatal rat.

The transferrin receptor is a major protein found on the basolateral membranes of intestinal epithelial cells, yet its possible role in intestinal iron metabolism and also in iron absorption is unclear. We have studied intestinal transferrin receptor expression during the peri- and postnatal development of the small intestine of the rat using immunohistochemistry with a monoclonal antibody to the rat receptor. Two major changes in transferrin receptor expression in the developing small intestine were found, a decrease in receptor expression associated with birth, and an increase at the time of weaning. Around the time of weaning there was a large decrease in iron absorption, but there was no direct correlation between absorption and transferrin receptor expression. However, at both birth and weaning there were major changes in intestinal cell kinetics, and the distribution of receptor correlated well with the distribution of proliferating cell populations. In addition, as the intestinal epithelial cells differentiated and stopped dividing, there was a redistribution of transferrin receptors from the cell surface to intracellular sites. These data suggest that the most likely role of the transferrin receptor in the neonatal intestine is in the supply of iron to the developing epithelial cells in the crypts, and that the receptor does not play a direct role in iron transit across the intestinal epithelium.

Aging↗
PubMed1991

Effect of initial treatment of chronic inflammatory periodontal disease on the frequency of peripheral blood T-lymphocytes specific to periodontopathic bacteria.

Limit dilution analysis (LDA) was used to determine the effect of initial treatment of chronic inflammatory periodontal disease on the frequency of periodontopathic bacteria-specific T-cells in peripheral blood. Eleven marginal gingivitis (MG) and 8 adult periodontitis (AP) subjects took part in the study. The proliferative T-lymphocyte precursor (PTL-P) frequencies to Porphyromonas gingivalis and Actinomyces viscosus were determined using LDA and Poisson statistics both before and after treatment. Tetanus toxoid was used as a control antigen. Treatment resulted in a significant reduction in clinical disease parameters in both groups. The median peak PTL-P frequency for P. gingivalis was significantly higher in the AP group compared with the MG group before treatment. This was not the case after treatment nor with A. viscosus. In the MG group the median peak PTL-P frequency with both P. gingivalis and A. viscosus declined as a result of treatment. Although this decline was not statistically significant it may indicate an antigen-specific response in this group. In the AP group the median peak PTL-P frequency with P. gingivalis before treatment was 83.76 x 10(-6) (approximately 1 in 12,000) and after treatment it was 36.17 x 10(-6) (approximately 1 in 28,000). Dose-response relationships showed at each concentration of organisms/well this trend for a decline in PTL-P frequency after treatment, suggesting that any increased responsiveness to this organism in this group may be largely antigen-specific. However, there was no difference in this group in the median peak PTL-P frequency with A. viscosus before and after treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Actinomyces viscosus↗
PubMed1991

Current concepts in rational therapy for haemochromatosis.

Genetic haemochromatosis is characterised by an inappropriately high rate of iron absorption by the small intestine. The disease is transmitted as an autosomal recessive condition. The gene frequency in the Caucasian population is approximately 1 in 20 and the disease frequency is 1 in 400. Excessive iron deposition occurs in the liver, pancreas, heart, pituitary and joints and hepatic iron concentrations above approximately 400 mumol/g dry weight are always associated with fibrosis and usually with cirrhosis and progressive liver failure. Accurate diagnosis depends upon the demonstration of elevated hepatic iron stores. An hepatic iron index [hepatic iron concentration (in mumol/g dry weight) divided by patient age] of greater than 2.0 distinguishes homozygous subjects from the other conditions in which slight increases in hepatic iron concentration may occur, e.g. in a subject heterozygous for haemochromatosis or alcoholic liver disease. If cirrhosis is present, patients are at a high risk of developing hepatocellular carcinoma. Therefore, they should undergo regular abdominal ultrasound and alpha-fetoprotein estimation. In the absence of cirrhosis, phlebotomy restores life expectancy to normal. Venesection should be continued until all excess iron stores are removed as judged by failure of a rise in haemoglobin concentration on cessation of phlebotomy. Screening of first degree relatives should commence from a young age (e.g. 10 years). If serum ferritin or transferrin saturation are abnormal, liver biopsy should be undertaken. HLA typing of the family allows for the identification of those siblings who are most likely to develop the disease. Secondary iron overload is often multifactorial in origin. Iron chelation therapy with subcutaneous deferoxamine (desferrioxamine) should only commence after careful consideration of the potential benefits in each individual patient.

Bloodletting↗
PubMed1991

Markers of chronic alcohol ingestion in patients with nonalcoholic steatohepatitis: an aid to diagnosis.

We report here the use of the biochemical marker desialylated transferrin to aid in the diagnosis of nonalcoholic steatohepatitis. Conventional biochemical tests used for the detection of chronic alcohol consumption fail to differentiate nonalcoholic steatohepatitis patients from alcoholic subjects. In addition, even in those alcoholic subjects with alcoholic liver disease in whom biopsy has been performed, it is impossible to differentiate these two disease states on the basis of morphological examination alone. In this study we have examined two new markers of excessive alcohol intake, desialylated transferrin and mitochondrial AST in subjects with nonalcoholic steatohepatitis and in patients consuming excessive amounts of alcohol. All nonalcoholic steatohepatitis patients consumed minimal or no alcohol and were diagnosed by morphological criteria based on liver biopsy specimens. Alcoholic subjects were consuming in excess of 80 gm/day ethanol, often with clinical evidence of overt alcoholism. Control subjects included both healthy controls and patient controls with liver diseases unrelated to alcohol. The ratio of desialylated transferrin/total transferrin was elevated only in patients who consumed excessive amounts of alcohol, whereas the ratio of mitochondrial AST to total AST (mitochondrial AST/total AST) was not significantly different between alcoholic subjects and patients with nonalcoholic steatohepatitis. The sensitivity and specificity for the ratio desialylated transferrin/total transferrin was 81% and 98%, respectively, whereas the sensitivity for the mitochondrial AST/total AST ratio was 92%; the specificity was only 50%, indicating that there were a large number of false-positives. All the conventional markers were less sensitive and less specific than the ratio desialylated transferrin/total transferrin.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years.

Forty-two patients with nonalcoholic steatohepatitis were followed for a median of 4.5 yr (range = 1.5 to 21.5 yr). Except for two patients with lipodystrophy, all were obese; 35 of 42 were women, 26 of 32 were hyperlipidemic and 15 were hyperglycemic. Upper abdominal pain was the most common reason for presentation. Initial liver biopsy specimens showed the presence of macrovesicular fatty infiltration, lobular (acinar) inflammation, apoptosis, Mallory bodies (in four cases) and fibrosis (in 18 cases). Cirrhosis was present at initial diagnosis in one subject and in another two subjects liver biopsy showed marked fibrosis with disturbed architecture. Serial liver biopsy specimens revealed minimal or no apparent progression of the disorder in most of the patients, in keeping with their benign clinical course. However, one patient showed progression from fibrosis to cirrhosis during the 5-yr observation period, and in the patients with extensive fibrosis the liver disease evolved from one of active inflammation to one of inactive cirrhosis without fat or inflammation. The patient with cirrhosis later died of hepatocellular carcinoma. The severity or type of hepatic change did not correlate with the degree of obesity, hyperlipidemia or hyperglycemia. However, in individual patients, poorly controlled diabetes and rapid weight loss preceded the onset of steatohepatitis. We conclude that nonalcoholic steatohepatitis is a cause of hepatic inflammation histologically resembling that of alcohol-induced liver disease but usually slowly progressive and of low-grade severity. However, the disorder may ultimately result in cirrhosis. Nonalcoholic steatohepatitis should be distinguished from alcoholic steatohepatitis and recognized as a further cause of "cryptogenic cirrhosis."

Adolescent↗
PubMed1990

Identification of homozygous hemochromatosis subjects by measurement of hepatic iron index.

The value of measurement of hepatic iron concentration and determination of the hepatic iron index in distinguishing homozygotes from heterozygotes for hemochromatosis was examined. The study group included 42 homozygotes with an unequivocal diagnosis of hemochromatosis and six individuals who had initial equivocal results but were established as homozygous after extensive follow-up. These were compared with 15 heterozygotes with no sign of increasing body iron stores who had undergone liver biopsy because of an initial suspicion of raised iron levels. In these subjects a hepatic iron concentration of greater than 75 mumol/gm dry weight was clearly indicative of homozygous hemochromatosis. Body iron accumulation was age-related both in homozygotes and in these heterozygotes with mild biochemical abnormalities (r = 0.476; p = 0.001 and r = 0.689; p = 0.01, respectively), with a rate of accretion of approximately 5 mumol/gm dry weight/year in homozygotes and 0.9 mumol/gm dry weight/year in heterozygotes. Thus, lower values in young subjects may be consistent with homozygosity, and higher values in older individuals are consistent with heterozygosity. To overcome this problem, the hepatic iron index (hepatic iron concentration divided by age in years) was analyzed and found to separate the two groups effectively, with no homozygote having an index of less than 1.9 and no heterozygote having an index of greater than 1.5. These results in a series of patients who have been followed for a median of 3 yr (range = 1 to 30 yr) validate the use of the hepatic iron index to discriminate hemochromatosis homozygotes from heterozygotes with raised levels of serum ferritin, transferrin saturation or both.

Adolescent↗
PubMed1990

Transferrin receptor distribution and regulation in the rat small intestine. Effect of iron stores and erythropoiesis.

A combination of biochemical quantitation and immunohistochemistry has been used to examine in detail transferrin receptor distribution and expression in the rat small intestine and its relationship to iron absorption. Receptor numbers were quantitated by transferrin binding to preparations of basolateral or brush-border membranes. Receptors were demonstrated on the basolateral membranes of the gut cells, but not on the brush-border fraction. Apotransferrin demonstrated little binding to basolateral membranes at physiological pH. Dietary or parenteral iron loading of animals produced a significant decline in transferrin binding, whereas binding was increased in iron deficiency. These data were confirmed by immunohistochemical studies using a monoclonal antibody to the transferrin receptor. When iron absorption was increased threefold following acute hemolysis and without a decrease in body iron stores, there was no change in transferrin receptor number. These data indicate that intestinal transferrin receptors may be regulated by body iron stores but suggest that they are not directly involved in iron absorption.

Absorption↗
PubMed1990

Expression of hemochromatosis in homozygous subjects. Implications for early diagnosis and prevention.

This study looks at expression of genetic hemochromatosis in the homozygous and heterozygous states. Two hundred nine subjects in 40 families with confirmed hemochromatosis and clear evidence of HLA linkage in symptomatic individuals were studied prospectively for up to 24 yr. The study group consisted of 40 probands, 51 subjects sharing two HLA haplotypes with affected relatives (putative homozygotes), 98 putative heterozygotes, and 20 putative normal homozygotes. Forty-eight of 51 subjects predicted to be homozygous showed increased hepatic iron stores as assessed by liver biopsy and quantitative phlebotomy. If not evident initially, this developed in 1-8 yr. In the 3 subjects predicted by HLA typing to be homozygous but in whom there was no progressive iron accumulation, results of studies using another chromosome 6 genetic marker (Factor 13 A subunit) were consistent with chromosomal recombination, presumably separating one hemochromatosis allele from the HLA markers. No heterozygous subject developed overt hemochromatosis during the period of follow-up, although 1 showed evidence of iron overload at initial assessment. Genetic recombination is again thought to have separated the hemochromatosis allele from the HLA markers here. The present findings favor a location of the hemochromatosis locus telomeric to HLA-A. It is concluded that, in this population, hemochromatosis is apparently always HLA linked, and homozygous subjects will develop iron overload in the absence of chromosomal recombination or blood loss.

Adolescent↗
PubMed1990

Dose-dependent pharmacokinetics of caffeine in humans: relevance as a test of quantitative liver function.

Caffeine clearance was determined in 13 healthy control subjects and in 13 patients with histologically proven cirrhosis. On separate occasions, 70 mg, 200 mg, and 300 mg single doses of anhydrous caffeine were administered orally with decaffeinated coffee to each subject. Subjects were analyzed individually, acting as their own controls, thus reducing interindividual variability. The present study showed that caffeine exhibited dose-dependent pharmacokinetics, particularly in subjects who showed high initial clearance with the low dose (70 mg) of caffeine. There was a significant decrease in caffeine clearance with increasing dose from 70 mg to 300 mg (n = 26, p less than 0.01, Dunnett's test), indicating saturable caffeine metabolism in the dose range tested. These findings imply that if caffeine is to be used as a guide to deteriorating liver function, serial caffeine clearance estimations should be performed in each individual subject, with use of the same dose of caffeine each time.

Administration, Oral↗
PubMed1990

Clonal analysis of the effect of iron on human cytotoxic and proliferating T lymphocytes.

The immunoregulatory effect of non-transferrin-bound iron (Fe3+) on the proliferative and cytotoxic responses of normal human T lymphocytes was studied using a sensitive limit-dilution technique capable of detecting the responses of individual lymphocytes. Iron, present in the form of ferric citrate at concentrations from 0.03 to 1.0 mmol/L, significantly reduced the cloning frequency of peripheral blood T lymphocytes. The effect of iron appeared, however, to be targeted to individual clones in that some clones that did grow in the presence of iron achieved a normal rate of proliferation. Thus, iron was not non-specifically toxic. At these same concentrations ferric citrate also produced significant reductions in the cloning frequency of CD4+ CD8-precursor T lymphocytes. Reductions in the response of T lymphocyte precursors capable of cytotoxic activity occurred in the presence of ferric citrate from 0.1 to 1.0 mmol/L. These data support the hypothesis that non-transferrin-bound iron has an immunoregulatory role in cell-mediated immunity.

Antibodies, Monoclonal↗
PubMed1990

Prevalence of haemochromatosis amongst asymptomatic Australians.

We determined the prevalence of iron overload due to homozygous haemochromatosis in an asymptomatic Australian (predominantly Caucasian) population by surveying 1968 employees of two large corporations. Subjects were screened by measurement of transferrin saturation and serum ferritin concentration and, in all subjects with elevation of both indices, percutaneous liver biopsy was performed to establish whether significant iron overload was present. The prevalence of iron overload due to haemochromatosis in this population was 0.36%. The prevalence rate was not significantly different between males and females, suggesting that this autosomal recessive disease is expressed equally in females given an adequate dietary iron supply. The positive predictive value of a transferrin saturation consistently greater than 45% together with an elevated serum ferritin concentration was 64%. It is concluded that the prevalence of significant iron overload due to homozygous haemochromatosis warranting treatment is approximately 1:300 and that transferrin saturation should be included in existing adult health screening programmes.

Adolescent↗
PubMed1990

Effect of colchicine on the clearance of ferritin in vivo.

The effect of the microtubular inhibitor colchicine, administered at either 0.036 (dose 1) or 5 mumol/kg (dose 2), on hepatic ferritin uptake was determined over a 5-h period of ferritin infusion in normal and iron-loaded rats. In the absence of colchicine, the serum ferritin concentration of normal rats was reduced after 5 h to 20 +/- 9% and in iron-loaded rats to 30 +/- 1% of the expected values, indicating ferritin clearance. After colchicine (dose 1), a similar result was observed in normal rats; however, in iron-loaded rats, an increase in serum ferritin to 77 +/- 16% of the expected value indicated a decreased ferritin clearance and/or increased ferritin release. The administration of the higher dose to normal rats also resulted in an increase in serum ferritin to 72 +/- 2% of the expected value. In iron-loaded rats, after dose 2 the ferritin concentration rose to 359 +/- 108% of the expected value, consistent with the release of endogenous ferritin. Colchicine administration had no effect on biliary ferritin in normal rats; however, in iron-loaded rats, both doses resulted in a fivefold increase in the release of biliary ferritin. The results suggest that ferritin uptake is facilitated by receptor-mediated endocytosis, which is partially inhibited by colchicine. Release of ferritin also occurs as a result of colchicine administration, and this is dependent on both the dose of colchicine and the iron status of the animal.

Animals↗
PubMed1990

Sensitive and rapid colorimetric immunoenzymometric assay of ferritin in biological samples.

We describe a rapid and sensitive enzyme-linked immunosorbent assay (ELISA) for quantifying ferritin in human and rat biological fluids. We used chlorophenol red beta-D-galactopyranoside as the colorimetric substrate of beta-galactosidase (EC 3.2.1.23), which is coupled to specific antibodies to either human or rat liver ferritin. The assay is sensitive (detection limit for human assay = 0.58 micrograms/L and for rat assay = 0.37 micrograms/L), accurate (average recovery for human assay = 93% and for rat assay = 92%), and precise (total CVs for human assay = 2.3-12.2% and for rat assay = 5.6-11.3%). The results correlated well with those of an established immunoradiometric technique (r = 0.99691). This assay has a prolonged shelf-life, is inexpensive, and utilizes a stable colorimetric substrate that requires relatively short incubation.

Animals↗
PubMed1990

Desialylated transferrin and mitochondrial aspartate aminotransferase compared as laboratory markers of excessive alcohol consumption.

Concentrations of both desialylated transferrin (dTf) and the mitochondrial isoenzyme of aspartate aminotransferase (EC 2.6.1.1, mAST) have been claimed to be increased in sera of alcoholic subjects. To investigate the diagnostic usefulness of these new biochemical markers of alcoholism and to compare them with more conventional markers, we measured dTf and mAST in the sera of controls, alcoholic subjects, and patients with nonalcoholic liver diseases (NALD). Alcoholic subjects had significantly (P less than 0.001) higher ratios of dTf to total transferrin than did either healthy controls or patients with NALD (sensitivity 81%, specificity 97%). The mAST was increased in 92% of alcoholic subjects but also in 48% of patients with NALD. The mAST/total AST ratio differentiated the alcoholic subjects from those with NALD (P less than 0.001) with a sensitivity of 92%, but the specificity was only 70%. In contrast, the conventional markers were less sensitive and less specific. We conclude that the best available single laboratory marker for current heavy alcohol consumption is the ratio dTf/total transferrin.

Adult↗
PubMed1990

Factors affecting the concentrations of ferritin in serum in a healthy Australian population.

We measured by different techniques the ferritin concentration in serum in two large asymptomatic Australian population samples: 1367 bank employees and 601 insurance corporation employees. Ethanol intake, diet, the frequency of blood donation, smoking and exercise habits, and past medical history were documented. The median concentration of ferritin in serum varied according to age and sex, but was generally higher than in previously reported populations under age 65 years. Results for the two population samples were in close agreement. Apart from the blood donation status, the most important factors influencing the concentration of ferritin in serum were ethanol intake in men and diet in women. Heavy ethanol intake was associated with increased values, even among men without evidence of liver disease. We conclude that the reference range for ferritin concentration in serum in the Australian population should be significantly increased and should be related to age as well as sex. This study emphasizes the need to determine local reference ranges for ferritin concentrations in serum.

Adult↗