Genetic hemochromatosis.
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Chromosomes, Human, 6-12 and X↗
Biomedical subjects
J W Halliday
Publications and source records attributed to J W Halliday.
Chronic hepatitis. Aetiology and current management.
The entity of chronic hepatitis has long been an enigma, and its treatment confusing. Recent studies have indicated the importance of excluding causes such as drugs, Wilson's disease and alpha 1-antitrypsin deficiency. After excluding such causes, there are 3 major groups--'autoimmune', hepatitis B, and non-A, non-B (NANB) in all of which an immunological basis for pathogenesis exists. The autoimmune group has been subdivided into a milder type (chronic persistent hepatitis) and a more severe type (chronic active hepatitis) on histological grounds. Corticosteroids are indicated in chronic active hepatitis if cirrhosis or bridging necrosis is present. However, corticosteroids are contraindicated in disease due to the hepatitis B virus where chronic active hepatitis correlates with the presence of replicating virus (serum positive for e antigen, DNA polymerase and HBV-DNA), and in such cases antiviral agents and immunomodulation are being studied. Very little is known about NANB hepatitis in the absence of an assay and there may be more than a single agent. In hepatitis B, the development of serological markers, molecular probes (HBV-DNA), natural animal hepatitis with near-identical viruses, and delta antigen (a virus requiring co-infection with hepatitis B) have all extended our knowledge so dramatically that it is hoped that the enigma of chronic hepatitis will be solved when an assay for NANB hepatitis becomes available.
Adrenal Cortex Hormones↗
Are the causes and presentation of chronic hepatitis changing? An analysis of 104 cases over 15 years.
We describe the features at presentation of 104 patients with biopsy-proven chronic hepatitis who presented in Brisbane in the period 1968-32. The mean period of follow-up was 59 months. Sex ratio (female : male) was 70 : 34 and the mean age was 37 years (range 3-83). Eighty-five (82 per cent) were born in Australia. Serological evidence of hepatitis B (HBV) infection was present in 24 (23 per cent). Analysis of the HBV marker positive and negative (non-B) groups revealed that the clinical and laboratory features of HBsAg positive chronic hepatitis were much less florid than those of non-B patients. However, the disturbances seen in hepatic histopathology were similar in severity, and the mortality in the HBsAg positive group exceeded that in the non-B group. The relative risk calculated on an actuarial basis was higher in HBsAg positive patients. In contrast to the experience of others, severe chronic active hepatitis remains an important problem in Brisbane but some features of the disease are altering. Several changes may be attributable to the increasing incidence of HBV-associated disease, and in addition, patients aged under 20 with non-B chronic hepatitis are now rarely seen. This is of interest in view of recent reports of decreased incidence of another disease of disordered immune response, rheumatoid arthritis.
Adolescent↗
Diagnosis of hemochromatosis in young subjects: predictive accuracy of biochemical screening tests.
The reliability of serum iron, transferrin saturation, and serum ferritin in the detection of early iron overload in hemochromatosis was determined in 120 young (less than 35 yr old) relatives whose genetic susceptibility for the disease was determined by HLA typing of families. Serum ferritin and transferrin saturation demonstrated high levels of sensitivity and specificity, whereas serum iron concentration was an unreliable test in the detection of hemochromatosis. In hemochromatosis homozygotes there was an excellent correlation between serum ferritin and mobilized body iron (r = 0.92), 1 microgram/L of serum ferritin corresponding to approximately 7.5 mg of body iron stores. For a given age, serum ferritin values were higher in homozygotes compared with heterozygotes or homozygous-normal subjects and increased by approximately 65 micrograms/L X yr, reflecting the progressive accumulation of iron in hemochromatosis homozygotes. All hemochromatosis subjects with either hepatic fibrosis or cirrhosis had serum ferritin concentrations greater than 700 micrograms/L. We conclude that the combination of serum ferritin and transferrin saturation is a reliable screening regimen for the detection of hemochromatosis and for predicting the level of body iron stores in young hemochromatosis subjects.
Adolescent↗
Detection and isolation of a hepatic membrane receptor for ferritin.
A ferritin receptor has been detected on isolated rat hepatocytes and has been partially purified from rat liver using affinity chromatography. Isolated hepatocytes exhibit approximately 30,000 ferritin binding sites/cell with a binding association constant (Ka) of 1 x 10(8) mol-1 liter. A binding assay has been developed which utilizes a hepatic ferritin receptor coupled to a microparticulate support to facilitate separation of bound and free ligand. This method yielded a Ka of 3 x 10(8) mol-1 liter for the purified hepatic ferritin receptor. Binding of ferritin to the insolubilized receptor was partially inhibited by human lactoferrin but unaffected by 200-fold molar excess of bovine albumin, rat transferrin, or human asialoorosomucoid.
Animals↗
Mononuclear cell factors that inhibit fibroblast collagen synthesis. I. In vitro conditions determining their production and expression.
Peripheral blood mononuclear cells (PBMC) incubated either with phytohaemagglutinin-P (PHA) under serum-free conditions or with tuberculin purified protein derivative in the presence of 5% human blood group AB serum released into the culture medium factors that decreased collagen synthesis by dermal fibroblasts. These factors were first detected after incubation of PBMC with PHA for 24 h and were produced by non-adherent cells. The decrease in collagen synthesis was observed despite changes in conditions of fibroblast culture, the addition of a cross-linking inhibitor, and the use of different fibroblast cell lines.
Aminopropionitrile↗
Mononuclear cell factors that inhibit fibroblast collagen synthesis. II. Properties of the factors.
Supernatants harvested from peripheral blood mononuclear cells (PBMC) incubated either with the non-specific mitogen phytohaemagglutinin-P (PHA) or with the specific antigen tuberculin purified protein derivative for 72 h decreased collagen synthesis by dermal fibroblasts. PHA-induced mononuclear cell factors (PHA-MCF) responsible for decreases in collagen synthesis by dermal fibroblasts were localized by column chromatography on Sephacryl S-200 to fractions of 30,000-60,000 daltons. Proteolytic enzymes destroyed the activity of PHA-MCF, but after incubation with neuraminidase some activity of these factors remained. The activity of PHA-MCF was not inhibited by incubation with the monosaccharides L-fucose, L-rhamnose, N-acetylglucosamine, and alpha-methyl-D-mannoside but was partially destroyed by heating at 80 degrees C for 10 min. The factors were not mitogenic to PBMC. These factors did not appear to resemble any previously characterized factors produced by non-adherent mononuclear cells. The mechanism by which these factors decreased fibroblast collagen synthesis appeared complex. There was no detectable increase in the release of collagenase by fibroblasts, nor was a cytotoxic effect apparent. Increased PGE2 production by fibroblasts could not be related to the factor-induced decrease in fibroblast collagen synthesis.
Collagen↗
Demonstration of previously undetected hepatitis B viral determinants in an Australian Aboriginal population by monoclonal anti-hbs antibody radioimmunoassays.
High-affinity IgM and IgG monoclonal antibodies (anti-HBs) against hepatitis B surface antigen (HBsAg) determinants were used to study a confined Australian Aboriginal population, 51% of which showed evidence of exposure to hepatitis B virus (HBV). A conventional radioimmunoassay which uses polyvalent anti-HBs antisera indicated that 4.4% of the subjects were positive for HBsAg; a monoclonal IgM anti-HBs radioimmunoassay detected all these HBsAg-positive samples and showed enhanced binding activity in a further 5.4% of subjects. Detailed analysis of this binding activity in serum by different IgG and IgM monoclonal anti-HBs antibodies demonstrated additional HBsAg-associated determinants as well as remarkable homogeneity of the determinants in this population. It was concluded that there are HBV or HBV-like agents in this community not previously detected by conventional assays.
Adult↗
Idiopathic hemochromatosis: demonstration of homozygous-heterozygous mating by HLA typing of families.
In five families with idiopathic (hereditary) hemochromatosis, clinical and biochemical expression of the disease occurred in offspring of probands, suggesting an autosomal dominant mode of inheritance. However, HLA typing of subjects indicated that a homozygous-heterozygous mating almost certainly had occurred in four of the five families, resulting in homozygous offspring. Thus, in these families inheritance of the hemochromatosis trait was best explained in terms of an autosomal recessive or intermediate mode of inheritance. This study demonstrates the value of HLA typing in identifying homozygous-heterozygous matings in hemochromatosis families.
Adolescent↗
Immunoassay of ferritin in plasma.
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Antibodies↗
Congestive cardiomyopathy and haemochromatosis--rapid progression possibly accelerated by excessive ingestion of ascorbic acid.
We describe rapidly fatal cardiomyopathy in a young man. He had for twelve months ingested large amounts of ascorbic acid and was admitted with severe heart failure having been symptomatic for two months. He died after eight days. Idiopathic haemochromatosis was diagnosed at autopsy. The clinical and laboratory features are discussed and the possible implications of ascorbic acid ingestion are explored.
Adult↗
Iron, ferritin, and the liver.
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Chronic Disease↗
Ferritin synthesis in peripheral blood monocytes in idiopathic hemochromatosis.
RE ferritin synthesis in IHC was studied in M0s isolated from peripheral blood. Twelve phlebotomized hemochromatosis patients with normal body iron stores and 12 healthy control subjects were studied. M0s in culture were exposed to iron as either ferric ammonium citrate or iron dextran, and ferritin synthesis was determined by measurement of 3H-leucine incorporation after isolation of ferritin by a quantitative immunoadsorbent technique. Iron at concentrations of 150 and 300 microM induced de novo ferritin synthesis, increasing both 3H-leucine incorporation into ferritin and cellular ferritin content. However, no differences were observed between hemochromatosis and control M0s with respect to basal or iron-stimulated ferritin synthesis. The study has demonstrated that M0 ferritin synthesis in IHC does not differ from M0 ferritin synthesis in normal subjects and therefore suggests that the reported abnormalities in RE iron storage in IHC are not related to an inability of RE cells to synthesize ferritin.
Cells, Cultured↗
Idiopathic haemochromatosis in the Australian population: HLA linkage and recessivity.
Studies of 78 unrelated patients and 19 families with idiopathic haemochromatosis are reported. The unrelated patients showed a highly significant association between the disease and HLA-A3. There was a less strong association with HLA-B7 and HLA-DRw2 attributed to the linkage disequilibrium between HLA-A3, B7, and DRw2. Lod scores and haplotype analysis of the families indicated a recessive mode of inheritance for an idiopathic haemochromatosis susceptibility factor in close linkage with the HLA region. These results, for Australian caucasoid patients, are not in total agreement with those reported in studies of other populations.
Australia↗
Regulation of plasma ferritin by the isolated perfused rat liver.
The isolated perfused rat liver has been used to investigate the regulation of plasma ferritin in normal, iron-deficient and iron-overloaded states. Both 125I-labelled and non-labelled rat liver ferritins were rapidly cleared from the perfusion circuit with a half-life of approximately 30 min. Perfusion of livers from normal, iron-loaded or iron-deficient rats with blood obtained from normal, iron-loaded or iron-deficient rats showed that the liver takes up plasma ferritin, and releases ferritin into the perfusate to achieve a perfusate ferritin level appropriate to the iron stores of the animal from which the liver was taken. It is concluded that the liver is capable of both uptake and release of ferritin and that within the liver there resides a mechanism which maintains circulating ferritin concentrations at a level appropriate to body iron stores.
Animals↗
Serum prednisolone levels in Crohn's disease and coeliac disease following oral prednisolone administration.
Serum prednisolone levels have been measured following the oral administration of 20 mg prednisolone in 10 normal subjects, in 9 patients with Crohn's disease and in 6 with coeliac disease. Serum prednisolone levels showed more variation in patients with Crohn's disease when compared to normal subjects. In those patients with Crohn's disease who failed to respond to corticosteroid therapy, adequate serum levels of prednisolone were achieved. Patients with coeliac disease had levels similar to normal. Serum protein binding of prednisolone was not significantly different between the groups. We conclude that, even in the presence of mucosal damage, patients with coeliac disease and Crohn's disease achieve therapeutic serum prednisolone levels.
Administration, Oral↗
Iron absorption and iron overload.
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Anemia↗