ORCID Profile
0000-0003-0417-3411
Current Organisations
American Association for the Study of Liver Diseases
,
Curtin University
,
American Gastroenterological Association
,
Edith Cowan University
,
South Metropolitan Health Service
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Publications
Risk of Liver Cancer in HFE-Hemochromatosis
Publisher: Elsevier BV
Date: 11-2021
Diagnosing and preventing iron overload
Publisher: Wiley
Date: 22-03-2017
DOI: 10.1111/HDI.12555
Abstract: Absolute or functional iron (Fe) deficiency is an important determinant of anemia in hemodialysis patients and parenteral Fe is routinely used to treat this condition in conjunction with erythropoiesis stimulating agents. While restoration of hemoglobin toward the target range is a good outcome of Fe replacement, it is well known that Fe overload and toxicity may be adverse consequences of this therapy. Dialysis clinical practice guidelines recommend tailoring Fe therapy based on transferrin saturation and serum ferritin levels. Unfortunately, serum Fe markers may not accurately reflect the amount of Fe in the body, because factors such as infections, inflammation, or malignancy can alter serum ferritin levels. Some recent trials in dialysis patients receiving high intravenous Fe doses have shown increased cardiovascular morbidity and mortality and studies using magnetic resonance imaging (MRI) in this population have shown excessive tissue liver iron content (LIC) suggesting Fe overload. While LIC measured by MRI correlates well with LIC quantitated by liver biopsy, it only represents a surrogate marker for total body Fe and its clinical relevance in dialysis patients in terms of mortality and morbidity remains to be demonstrated. Nevertheless, these recent findings challenge the use of current serum Fe markers recommended by clinical guidelines to guide safe Fe therapy in dialysis patients. While not yet established for the routine screening of dialysis patients for Fe overload, MRI should be considered in patients who have received a high cumulative dose of intravenous Fe, or have long cumulative dialysis vintage. Further studies are needed to assess how MRI will alter management.
Liver and serum iron: Discrete regulators of hepatic hepcidin expression
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 24-06-2011
DOI: 10.1002/HEP.24449
Response to wang and kao
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2010
DOI: 10.1038/AJG.2009.591
Regular high‐frequency whole blood donation and risk of cardiovascular disease in middle‐aged and older blood donors in Australia
Publisher: Wiley
Date: 14-04-2023
DOI: 10.1111/TRF.17358
Abstract: Previous mixed findings on the associations between whole blood (WB) donation and risk of cardiovascular diseases (CVD) may in part reflect inadequate adjustment for the “healthy donor effect” (HDE). We used the Sax Institute's 45 and Up Study linked with blood donation history and other health‐related databases to examine the association between regular, high‐frequency WB donation and the risk of CVD. To mitigate the impact of HDE, we used a “5‐years qualification period,” in which donors must donate at least 1 WB donation in the 1st and 5th year of “qualification period.” We then compared the risk of CVD in the years following the “qualification period” between the regular high‐frequency WB donors (≥2 WB donation in each qualification year) and others using Cox proportional‐hazards models. Analyses were adjusted for potential confounders, such as sociodemographic, lifestyle, and health‐related variables, and results are reported separately for male and female donors. A total of 2736 male and 2917 female donors were included in the analyses. The median years of follow‐up per donor was 5.84 years (Q1‐Q3, 5.47–6.23). The rate of CVD hospitalization was 11.20 and 4.50 per 1000 person‐years for males and females, respectively. In fully adjusted models, the risk (hazard ratio) of CVD in regular high‐frequency donors compared to other donors was 0.93 (95% Confidence Interval (CI), 0.68–1.29) for males and 0.79 (95% CI, 0.49–1.28) for females. We did not observe a statistically significant reduction of CVD risk in regular, high‐frequency WB donors when adjusted for potential confounders.
Features of the metabolic syndrome in late adolescence are associated with impaired testicular function at 20 years of age
Publisher: Oxford University Press (OUP)
Date: 21-12-2019
Abstract: Are early signs of metabolic disorder in late adolescence associated with features of impaired testicular function many years before the majority seek parenthood? Adolescents with features of metabolic disorder at 17 years, or insulin resistance (IR) at 20 years of age, show impaired testicular function and altered hormone levels compared to those without metabolic disorder. Controversial evidence suggests a recent decline in sperm production potentially linked to environmental influences, but its cause remains unclear. Concomitant increases in obesity and diabetes suggest that lifestyle factors may contribute to this decline in testicular function. Although obesity has been associated with adverse testicular function in some studies, it remains unclear whether poor testicular function merely reflects, or causes, poor metabolic health. If metabolic disorder were present in adolescence, prior to the onset of obesity, this may suggest that metabolic disorder maybe a precursor of impaired testicular function. The Western Australian Pregnancy Cohort (Raine) Study is a longitudinal study of children born in 1989-1991 who have undergone detailed physical assessments since birth (1454 male infants born). At 17 years of age, 490 boys underwent a hepatic ultrasound examination, serum cytokine assessment (n = 520) and a metabolic assessment (n = 544). A further metabolic assessment was performed at 20 years (n = 608). Testicular assessment was performed at 20 years 609 had reproductive hormones measured, 404 underwent a testicular ultrasound and 365 produced a semen s le. Testicular volume was estimated by ultrasonography, and semen analysis was performed according to World Health Organization guidelines. Concentrations of LH, FSH and inhibin B (inhB) in serum were measured by immunoassay and total testosterone by liquid chromatography-mass spectrometry.At 17 years of age, a liver ultrasound examination was performed to determine the presence of non-alcoholic fatty liver disease (NAFLD), and serum analysed for the cytokines interleukin-18 and soluble tumour necrosis factor receptor 1 and 2 (sTNFR1, sTNFR2).At 17 and 20 years of age, fasting blood s les were analysed for serum liver enzymes, insulin, glucose, triglycerides (TG), total cholesterol, high density lipoprotein and low density lipoprotein cholesterol, high sensitivity C-reactive protein and uric acid. The homoeostatic model assessment (HOMA) was calculated and approximated IR was defined by a HOMA >4. Anthropometric data was collected and dual energy X-ray absorptiometry measurement performed for lean and total fat mass. As at this young age the prevalence of metabolic syndrome was expected to be low, a two-step cluster analysis was used using waist circumference, TGs, insulin, and systolic blood pressure to derive a distinct high-risk group with features consistent with the metabolic syndrome and increased cardiometabolic risk. Men at age 17 years with increased cardiometabolic risk had lower concentrations of serum testosterone (medians: 4.0 versus 4.9 ng/mL) and inhB (193.2 versus 221.9 pg/mL) (P < 0.001 for both) compared to those within the low risk metabolic cluster. Men with ultrasound evidence of NAFLD (n = 45, 9.8%) had reduced total sperm output (medians: 68.0 versus 126.00 million, P = 0.044), testosterone (4.0 versus 4.7 ng/mL, P = 0.005) and inhB (209.1 versus 218.4 pg/mL, P = 0.032) compared to men without NAFLD.Men with higher concentrations of sTNFR1 at 17 years of age had a lower sperm output and serum concentration of inhB, with an increase in LH and FSH (all P 4 was associated with a lower serum testosterone (P = <0.001) and inhB (P = 0.010) and an increase in serum FSH (P = 0.015). This study is limited by the s le size and multiple comparisons, and causality cannot be proven from an observational study. Due to a 3-year interval between some metabolic assessments and assessment of testicular function, we cannot exclude the introduction of a bias into the study, as some of the participants and their testicular function will not have been fully mature at the 17-year assessment. Irrespective of a proven causation, our study findings are important in that a significant minority of the men, prior to seeking parenthood, presented co-existent features of metabolic disorder and signs of testicular impairment. Of particular note is that the presence of NAFLD at 17 years of age, although only present in a minority of men, was associated with an almost 50% reduction in sperm output at 20 years of age, and that the presence of IR at 20 years was associated with a 20% reduction in testicular volume. This study was supported by Australian NHMRC (Grant Numbers 634457, 35351417 and 403981) and received support from the Raine Medical Research Foundation, The Telethon Kids Institute, University of Western Australia, Women and Infants Research Foundation, Curtin University and Edith Cowan University. D.A.D., J.E.D., N.M., L.A.A., R.-C.H., T.A.M., J.K.O., L.J.B. have nothing to declare. R.J.H. is Medical Director of Fertility Specialists of Western Australia, has equity interests in Western IVF, and has received grant support from MSD, Merck-Serono and Ferring Pharmaceuticals. RMcL has equity interests in the Monash IVF Group. R.J.N. has equity interests in FertilitySA, and has received grant support from Merck Serono and Ferring Pharmaceuticals. D.J.H. has received institutional grant funding (but no personal income) for investigator-initiated testosterone pharmacology studies from Lawley and Besins Healthcare and has provided expert testimony to anti-doping tribunals and for testosterone litigation.This abstract was awarded the Fertility Society of Australia clinical exchange award for the oral presentation at ESHRE, Barcelona, in 2018.
Visits to general practitioners after iron‐related deferrals from blood donation in middle‐aged and older Australian blood donors
Publisher: Wiley
Date: 07-10-2021
DOI: 10.1111/TRF.16701
Abstract: Australian Red Cross Lifeblood (Lifeblood) advises donors to visit their general practitioner (GP) for medical follow‐up if they are deferred from donating due to having a lower than acceptable level of hemoglobin (Hb) and/or serum ferritin (iron‐related deferrals). We used the Sax Institute's 45 and Up Study data linked to Lifeblood's donor datasets and other health administrative datasets. We examined the rate of visits to a GP after iron‐related deferral from donation, and investigated whether an early visit to a GP (within 30 days following the deferral) had an impact on return to make successful donation within 12, 18, and 24 months compared to a delayed or no GP visit. A total of 1928 donors underwent iron‐related deferral. The rate of visits to a GP in the first month after deferral was double the rate observed a month prior. However, only 52.4% of those deferred visited a GP early with slightly more than half of those receiving an iron‐monitoring test. Return to donate over the 24 months was lower in donors visiting their GP early (adjusted Hazard Ratio [aHR] 0.86, 95% CI 0.77–0.97). Early GP visitors were likely to have a relatively poorer health than the delayed or no GP visit group. Only half of the donors with an iron‐related deferral followed advice from Lifeblood and visited their GP within 30 days of deferral, and these donors have a significantly reduced likelihood of future successful blood donation which may be due to their relatively poorer health status.
Hereditary haemochromatosis: diagnosis and management in the gene era
Publisher: Wiley
Date: 04-1999
DOI: 10.1111/J.1478-3231.1999.TB00014.X
Abstract: Hereditary haemochromatosis is a common inherited disorder of iron metabolism in Caucasian populations. Two mutations in the HFE gene are strongly associated with hereditary haemochromatosis. One of these mutations (Cys282-->Tyr C282Y) is found homozygous in 90-95% of subjects with typical hereditary haemochromatosis. A second mutation (His63-->Asp H63D) has also been identified but is not associated with the same degree of iron overload as with the C282Y mutation. About 20% of subjects who are heterozygous for both mutations (C282Y, H63D-compound heterozygotes) can express typical hereditary haemochromatosis. A large number of patients with early disease are asymptomatic, and prompt diagnosis and treatment can result in normal life expectancy. The diagnosis can readily be confirmed by serum iron studies and genetic testing. For C282Y homozygotes or compound heterozygotes diagnosed under the age of 40 years and with no biochemical or clinical evidence of liver disease, phlebotomy therapy can be initiated without the need for liver biopsy. Liver biopsy should still be considered in all other patients with iron overload. Screening of first degree relatives should now be based on genotype assessment and measurement of serum iron parameters in order to determine phenotypic expression of the disease.
Utility and limitations of Hepascore and transient elastography to detect advanced hepatic fibrosis in HFE hemochromatosis
Publisher: Springer Science and Business Media LLC
Date: 19-07-2021
DOI: 10.1038/S41598-021-94083-X
Abstract: Aspartate aminotransferase-to-platelet ratio index (APRI) and Fibrosis-4 Index (Fib4) have been validated against liver biopsy for detecting advanced hepatic fibrosis in HFE hemochromatosis. We determined the diagnostic utility for advanced hepatic fibrosis of Hepascore and transient elastography compared with APRI and Fib4 in 134 newly diagnosed HFE hemochromatosis subjects with serum ferritin levels 300 µg/L using area under the receiver operator characteristic curve (AUROC) analysis and APRI- ( 0.44) or Fib4- ( 1.1) cut-offs for AHF, or a combination of both. Compared with APRI, Hepascore demonstrated an AUROC for advanced fibrosis of 0.69 (95% CI 0.56–0.83 sensitivity = 69%, specificity = 65% P = 0.01) at a cut-off of 0.22. Using a combination of APRI and Fib4, the AUROC for Hepascore for advanced fibrosis was 0.70 (95% CI 0.54–0.86, P = 0.02). Hepascore was not diagnostic for detection of advanced fibrosis using the Fib4 cut-off. Elastography was not diagnostic using either APRI or Fib4 cut-offs. Hepascore and elastography detected significantly fewer true positive or true negative cases of advanced fibrosis compared with APRI and Fib4, except in subjects with serum ferritin levels 1000 µg/L. In comparison with APRI or Fib4, Hepascore or elastography may underdiagnose advanced fibrosis in HFE Hemochromatosis, except in in iduals with serum ferritin levels 1000 µg/L.
Childhood adiposity trajectories and risk of nonalcoholic fatty liver disease in adolescents
Publisher: Wiley
Date: 23-12-2015
DOI: 10.1111/JGH.12666
Abstract: Nonalcoholic fatty liver disease (NAFLD) and its metabolic risk factors are recognized during childhood and adolescence. Identification of adolescents at risk of NAFLD from childhood anthropometry may expose opportunities to influence the hepatic and metabolic destinies of in iduals. We sought associations between NAFLD diagnosed during adolescence and earlier life trajectories of anthropometry, in a population-based cohort of predominantly Caucasian adolescents. Assessment for NAFLD, using questionnaires and liver ultrasound, was performed on 1170 adolescents, aged 17 years, from the population-based Raine cohort. We sought associations between NAFLD in adolescents and serial anthropometric measurements recorded from birth, childhood, and adolescence. NAFLD was diagnosed in 15.2% of adolescents. Birth anthropometry, including birth weight, skinfold thickness, and ponderal index, was not associated with NAFLD. However, adiposity differences between 17-year-old adolescents with NAFLD and those without NAFLD were apparent from age 3 years. Greater adiposity trajectories for weight, body mass index, skinfold thickness, mid-arm circumference, and chest circumference from age 3 years onwards, particularly in males, were associated with the diagnosis of NAFLD and severity of hepatic steatosis at age 17 years (P < 0.05). The strength of the associations increased with age after 3 years for each adiposity measure (all P < 0.001). Trajectories of childhood adiposity are associated with NAFLD. Adiposity attained by 3 years of age and older, but not at birth, was associated with the diagnosis and severity of hepatic steatosis in late adolescence. Exploration of clinically relevant risk factors and preventative measures for NAFLD should begin during childhood.
Attenuated liver progenitor (oval) cell and fibrogenic responses to the choline deficient, ethionine supplemented diet in the BALB/c inbred strain of mice
Publisher: Elsevier BV
Date: 2007
DOI: 10.1016/J.JHEP.2006.08.015
Abstract: Liver regeneration following chronic injury is associated with inflammation, the proliferation of liver progenitor (oval) cells and fibrosis. Previous studies identified interferon-gamma as a key mediator of oval cell proliferation. Interferon-gamma is known to regulate Th1 cell activities during immune challenge. Therefore, we hypothesised that progenitor cell-mediated regeneration is associated with a Th1 immune response. C57Bl/6 (normal Th1 response) and BALB/c mice (deficient in Th1 signalling) were placed on a carcinogenic diet to induce liver injury, progenitor cell proliferation and fibrosis. Serum transaminases and mortality were elevated in BALB/c mice fed the diet. Proliferation of liver progenitor cells was significantly attenuated in BALB/c animals. The pattern of cytokine expression and inflammation differed between strains. Liver fibrosis and hepatic stellate cell activation were significantly inhibited in BALB/c mice compared to C57Bl/6. In addition, interferon-gamma knockout mice also showed reduced fibrosis compared to wild type. These findings are in contrast to published results, in which interferon-gamma is shown to be anti-fibrogenic. Our data demonstrate that the hepatic progenitor cell response to a CDE diet is inhibited in mice lacking Th1 immune signalling and further show that this inhibition is associated with reduced liver fibrosis.
Non-Hfe Iron Overload: Is Phlebotomy the Answer?
Publisher: Springer Science and Business Media LLC
Date: 11-12-2012
Body mass index is a stronger predictor of alanine aminotransaminase levels than alcohol consumption
Publisher: Wiley
Date: 07-2008
DOI: 10.1111/J.1440-1746.2008.05451.X
Abstract: The relative effects of obesity compared to alcohol on liver injury are uncertain. We examined their effects on alanine aminotransferase (ALT) and gamma glutamyltransferase (GGT) levels in a population-based cohort. Adult residents (2610: 1326 males, 1284 females) from Busselton, Australia, participated in a cross-sectional survey determining alcohol intake as determined by a validated questionnaire, anthropometric measurements and serum analysis. Alcohol consumption was classified as never, light ( 420 g/week). The majority of subjects were either overweight (41%) or obese (17%). A minority of subjects were moderate (25%) or heavy drinkers (4%). Body mass index (BMI) and waist circumference were strongly associated with ALT and GGT (P < 0.0001 for all tests). Alcohol consumption was modestly associated with ALT in females (P = 0.01) but not in males (P = 0.9). In contrast, GGT was significantly associated with alcohol in both genders (P 0.2 for all tests). Excess weight is more common than excessive alcohol consumption in the community and confers a greater risk of elevated aminotransaminase levels.
Evaluation of Different Normalization and Analysis Procedures for Illumina Gene Expression Microarray Data Involving Small Changes.
Publisher: MDPI AG
Date: 21-05-2013
Antiproliferative effects of interferon alpha on hepatic progenitor cells in vitro and in vivo
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2006
DOI: 10.1002/HEP.21170
Abstract: Hepatic progenitor cells (called oval cells in rodents) proliferate during chronic liver injury. They have been suggested as targets of malignant transformation in chronic liver diseases, including chronic hepatitis C. Interferon alpha therapy reduces the risk of hepatocellular carcinoma (HCC) in chronic hepatitis C regardless of viral clearance. The aim of this study was to determine whether interferon alpha could reduce the risk of HCC by modifying preneoplastic events in the hepatic progenitor cell population. Pre- and post-treatment liver biopsies were evaluated for changes in t he hepaticprogenitor cell population in 16 patients with non-responding chronic hepatitis C Interferon alpha-based treatment significantly reduced the numbers of c-kit-positive hepatic progenitor cells by 50%. To determine the mechanism of cell number reduction, the effects of interferon alpha on murinehepatic progenitor cells were studied in vitro. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) proliferation assay and proliferating cell nuclear antigen staining showed that interferon alpha had a dose-dependent, anti-proliferative effect Interferon alpha stimulated hepatocytic and biliary differentiation of the oval cell lines reflected by increased expression of albumin and cytokeratin19 accompanied by decreased expression of alphafetoprotein and Thy-1. To validatethese results in vivo, mice were placed on the choline-deficient, ethionine-supplemented diet to induce liver injury and oval cell proliferation and treated with pegylated interferon alpha 2b for 2 weeks. This resulted in a significant four-fold reduction in the number of oval cells (P < .05). In conclusion, interferon alpha-based treatment reduced the number of hepatic progenitor cells in chronic liver injury by modulating apoptosis, proliferation, and differentiation. Supplementay material for this article can
Assessing Iron Overload: Are We There Yet?
Publisher: American Association for Cancer Research (AACR)
Date: 29-11-2012
DOI: 10.1158/1078-0432.CCR-12-2881
Abstract: Iron overload occurs in many hematologic disorders and causes significant morbidity. The advantages of MRI in quantifying liver iron concentration continue to mount, and the association between iron overload and increased mortality after allogeneic stem cell transplant needs further attention. Clin Cancer Res 18(23) 6395–7. ©2012 AACR.
Gamma' fibrinogen levels as a biomarker of COVID-19 respiratory disease severity
Publisher: Research Square Platform LLC
Date: 21-10-2022
DOI: 10.21203/RS.3.RS-2160004/V1
Abstract: Coronavirus disease 2019 (COVID-19) is characterized by a pro-inflammatory state associated with organ failure, thrombosis, and death. We investigated a novel inflammatory biomarker, γ' fibrinogen (GPF), in 103 hospitalized patients with COVID-19 and 19 healthy controls. We found significant associations between GPF levels and the severity of COVID-19 as judged by blood oxygen saturation (SpO 2 ). The mean level of GPF in the patients with COVID-19 was significantly higher than in controls (69.8 (95% CI 64.8–74.8) mg/dL compared with 36.9 (95% CI 31.4–42.4) mg/dL, p 0.0001), whereas C-reactive protein (CRP), lactate dehydrogenase (LDH), and total fibrinogen levels were not significantly different between groups. Mean GPF levels were significantly highest in patients with severe COVID-19 (SpO 2 ≤ 93%, GPF 75.2 (95% CI 68.7–81.8) mg/dL), compared to mild/moderate COVID-19 (SpO 2 93%, GPF 62.5 (95% CI 55.0–70.0) mg/dL, p = 0.01, AUC of 0.68, 95% CI 0.57–0.78 Youden's index cutpoint 62.9 mg/dL, sensitivity 0.64, specificity 0.63). In contrast, CRP, interleukin-6, ferritin, LDH, D-dimers, and total fibrinogen had weaker associations with COVID-19 disease severity (all ROC curves with lower AUCs). Thus, GPF may be a useful inflammatory marker of COVID-19 respiratory disease severity.
Sex differences between parental pregnancy characteristics and nonalcoholic fatty liver disease in adolescents
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 13-11-2018
DOI: 10.1002/HEP.29347
Abstract: Nonalcoholic fatty liver disease (NAFLD) is a complex chronic liver disorder. Examination of parental pregnancy‐related characteristics may provide insights into the origins of risk of NAFLD in offspring. We examined relationships between parental pregnancy‐related characteristics and NAFLD in 1,170 adolescent offspring aged 17 years participating in the Western Australian Pregnancy (Raine) Cohort Study. Fatty liver was diagnosed using liver ultrasound. NAFLD was diagnosed in 15.2% of adolescents at age 17 years. In univariate analysis, maternal factors associated with NAFLD in female offspring were younger maternal age ( P = 0.02), higher maternal prepregnancy BMI ( P 0.001), higher maternal weight gain by 18 weeks' gestation ( P 0.001), and maternal smoking during pregnancy ( P = 0.04). Paternal age or body mass index (BMI) were not associated with NAFLD in female offspring. In contrast, higher paternal BMI ( P 0.001), maternal prepregnancy BMI ( P 0.001), and lower family socioeconomic status (SES) at time of birth ( P = 0.001), but not parental age nor maternal gestational weight gain, were associated with NAFLD in male offspring. Using multivariate logistic regression, factors independently associated with NAFLD after adjusting for obesity in adolescent females included maternal obesity (odds ratio [OR], 3.46 95% confidence interval [CI], 1.49‐8.05 P = 0.004) and maternal weight gain ≥6.0 kg by the 18th week of gestation (OR, 1.10 95% CI, 1.04‐1.15 P 0.001). In adolescent males, family SES at the time of birth (OR, 9.07 95% CI, 1.54‐53.29 P = 0.02) remained significantly associated with NAFLD after multivariate modeling adjusted for adolescent obesity. Conclusion: Early‐life contributors to NAFLD show considerable sexual dimorphism. Maternal obesity and higher early‐mid gestational weight gain were associated with NAFLD in female offspring, whereas lower family SES at birth was associated with NAFLD in male offspring independent of adolescent obesity. (H epatology 2018 :108‐122).
Population-based study of the relationship between mutations in the hemochromatosis (HFE) gene and arthritis
Publisher: Wiley
Date: 03-2006
DOI: 10.1111/J.1440-1746.2006.04062.X
Abstract: Mutations in the hemochromatosis (HFE) gene are carried by one in three in iduals of British Isles descent and may result in increased iron stores. These increased iron stores could potentially induce or exacerbate diseases, such as arthritis, in which iron has a role in pathogenesis. Although arthritis is a well-known association of clinically overt hereditary hemochromatosis, controversy surrounds the role of mutations in the HFE gene as risk factors for arthritis. The aim of the present study was to determine whether mutations in the HFE gene are associated with an increased prevalence of arthritis. A population-based study was conducted in Busselton, Western Australia, of the prevalence of arthritis in 1372 in iduals of British Isles descent. Participants completed a questionnaire and general physical examination. Analysis for C282Y and H63D HFE mutations was undertaken. Unadjusted and adjusted odds ratios (OR) were calculated for the relationship between HFE mutations and the prevalence of self-reported, doctor-diagnosed arthritis. There was no association between the presence of HFE mutations and the prevalence of self-reported, doctor-diagnosed arthritis (C282Y/wild type (WT) adjusted OR = 1.041 (95% confidence interval (CI) 0.68-1.61), H63D/WT OR = 0.76 (95% CI 0.53-1.08), C282Y/C282Y OR = 0.39 (95% CI 0.04-3.63), C282Y/H 63D OR = 0.808 (95% CI 0.27-2.42), H63D/H63D OR = 0.419 (95% CI 0.13-1.36)). Overall adjusted OR for arthritis in participants with one or more HFE mutations was 0.81 (95% CI 0.61-1.09). Mutations of the HFE gene are not risk factors for arthritis in populations of British Isles descent.
Genetic haemochromatosis – preventable rust
Publisher: Wiley
Date: 12-1994
Low serum 25-hydroxyvitamin D concentrations associate with non-alcoholic fatty liver disease in adolescents independent of adiposity
Publisher: Wiley
Date: 15-05-2014
DOI: 10.1111/JGH.12541
Abstract: Non-alcoholic fatty liver disease (NAFLD) and serum 25-hydroxyvitamin D (s25[OH]D) concentrations are both associated with adiposity and insulin resistance (IR) and thus may be pathogenically linked. We aimed to determine the prevalence of vitamin D deficiency in adolescents with NAFLD and to investigate the prospective and cross-sectional associations between s25[OH]D concentrations and NAFLD. Participants in the population-based West Australian Pregnancy (Raine) Cohort had seasonally adjusted s25(OH)D concentrations determined at ages 14 and then 17 years. NAFLD was diagnosed at 17 years using liver ultrasonography. Associations were examined after adjusting for potential confounders. Odds ratios (ORs) and confidence intervals (CIs) are reported per standard deviation in s25(OH)D concentrations. NAFLD was present in 16% (156/994) of adolescents. The majority of participants with NAFLD had either insufficient (51%) or deficient (17%) vitamin D status. s25(OH)D concentrations at 17 years were inversely associated with risk of NAFLD (OR 0.74, 95% CI 0.56, 0.97 P = 0.029), after adjusting for sex, race, physical activity, television/computer viewing, body mass index, and IR. The effect of s25(OH)D concentrations at 17 years was minimally affected after further adjusting for s25(OH)D concentrations at 14 years (OR 0.76, 95% CI 0.56, 1.03 P = 0.072). Lower s25(OH)D concentrations are significantly associated with NAFLD, independent of adiposity and IR. Screening for vitamin D deficiency in adolescents at risk of NAFLD is appropriate, and clinical trials investigating the effect of vitamin D supplementation in the prevention and treatment of NAFLD may be warranted.
Critical Role of General Practitioners in Preventing Readmission Following Emergency Department Alcohol Screening and Brief Intervention Management of Alcohol-Related Problems
Publisher: SAGE Publications
Date: 2021
DOI: 10.1177/21501327211027437
Abstract: Alcohol screening and brief intervention (ASBI) strategies are useful in general practice (GP) but their effectiveness in the emergency department (ED) is unclear. We evaluated the effect of ED-based ASBI on re-admissions. 453 ED subjects exceeding the threshold score on the three-item Alcohol Use Disorders Identification Test-Consumption (females 3+: males 4+) were randomized. We conducted telephone follow-up at 1 and 3 months and recorded hospital events 6 months pre- and post-enrolment. Median weekly alcohol use was 20 standard drinks (interquartile range (IQR) 9-45) on enrolment. After 3 months, 247 (55%) were able to be re-interviewed. Median alcohol use was 10 drinks (IQR 4-26). Six months later, subjects receiving ED-ASBI without GP follow-up had significantly greater risk of re-admission compared with those having GP follow-up (OR 1.68, 95%CI 1.06-2.65 P = .028). ASBI reduces the likelihood of ED re-presentation only in subjects who have GP follow-up. The study has been registered as a clinical trial (Australian and New Zealand Clinical Trial Registry ACTRN12617001254381).
The acute effect of placentectomy and hysterectomy on peripheral plasma progesterone levels and ovarian progesterone secretion in the pregnant rat
Publisher: Bioscientifica
Date: 07-1983
Abstract: The role of placental luteotrophins in modulating plasma progesterone concentrations and ovarian progesterone secretion was examined in 16-day pregnant rats. In an initial experiment rats were placentectomized and their plasma progesterone concentrations monitored for 24 h the rats were conscious within 30 min of placentectomy. Relative to control values, progesterone concentrations fell significantly within 0·5 h. A venous outflow technique was then used to monitor rates of progesterone secretion from ovaries of hysterectomized and control rats maintained under anaesthesia. Hysterectomy had no apparent effect on either progesterone secretion or plasma progesterone concentrations for at least 2 h. A final experiment was carried out to compare the effects of hysterectomy on plasma progesterone concentrations in conscious rats with those of placentectomized rats of the first experiment. Progesterone concentrations did not change significantly in hysterectomized rats for 4 h but fell to very low values by 24 h. These results suggest that placental luteotrophins do not have an acute, direct role in the control of plasma progesterone levels but are needed to maintain progesterone secretion in the longer term and possibly inhibit uterine luteolysin release.
Oval cell-mediated liver regeneration: Role of cytokines and growth factors
Publisher: Wiley
Date: 20-12-2003
DOI: 10.1046/J.1440-1746.2003.02906.X
Abstract: In experimental models, which induce liver damage and simultaneously block hepatocyte proliferation, the recruitment of a hepatic progenitor cell population comprised of oval cells is invariably observed. There is a substantial body of evidence to suggest that oval cells are involved in liver regeneration, as they differentiate into hepatocytes and biliary cells. Recently, bone marrow cells were shown to be a source of a stem cells with the capacity to repopulate the liver. Presently, the relationship between bone marrow cells and oval cells is unclear. Investigations will be greatly assisted by the availability of in vitro models based on a knowledge of cytokines that affect oval cells. While the cytokines, which regulate the different hematopoietic lineages, are well characterized, there is relatively little information regarding those that influence oval cells. This review outlines recent developments in the field of oval cell research and focuses on cytokines and growth factors that have been implicated in regulating oval cell proliferation and differentiation.
Effects of HFE gene mutations and alcohol on iron status, liver biochemistry and morbidity
Publisher: Wiley
Date: 10-08-2005
DOI: 10.1111/J.1440-1746.2005.03967.X
Abstract: The aims of the present study were to determine: (i) whether alcohol consumption is greater in in iduals with HFE mutations and (ii) whether common HFE mutations modify the effects of alcohol on serum iron and liver biochemistry or morbidity. The residents of the town of Busselton in Western Australia were subject to cross-sectional health surveys between 1966 and 1983. In 1994/1995 all surviving participants of the earlier surveys were invited to take part in a follow-up survey. Logistic, linear and Poisson log-linear regression analyses were performed in 1490 men and 1452 women from the 1994/1995 survey to assess the relationships between HFE mutations, alcohol, iron levels, liver biochemistry and morbidity. Heavy or moderate alcohol consumption was present in 7% or 36% of men and 0.5% or 12% of women, respectively. Alcohol consumption strongly influenced levels of serum ferritin and gamma glutamyl transpeptidase (GGT) and mean cell volume (MCV) in men and women but only alanine aminotransferase (ALT) levels in women. These effects were independent of HFE gene mutations. Hospital admission rates for respiratory disorders were higher in men with the C282Y mutation. Alcohol consumption strongly influences serum ferritin and GGT levels and MCV in men and women but only ALT levels in women, and these effects are independent of HFE mutations. HFE gene mutations do not predispose to moderate or heavy alcohol consumption. The C282Y mutation is associated with increased respiratory admission rates in men.
Identification of a thalidomide derivative that selectively targets tumorigenic liver progenitor cells and comparing its effects with lenalidomide and sorafenib
Publisher: Elsevier BV
Date: 09-2016
DOI: 10.1016/J.EJMECH.2016.03.015
Abstract: The availability of non-tumorigenic and tumorigenic liver progenitor cell (LPC) lines affords a method to screen putative anti-liver cancer agents to identify those that are selectively effective. To prove this principle we tested thalidomide and a range of its derivatives and compared them to lenalidomide and sorafenib, to assess their growth-inhibitory effects. Cell growth, the mitotic and apoptotic index of cell cultures were measured using the Cellavista instrument (SynenTec) using commercially available reagents. Neither lenalidomide nor thalidomide (100 μM) affected tumorigenic LPCs but killed their non-tumorigenic counterparts. Sorafenib arrested growth in both cell types. All but two derivatives of thalidomide were ineffective of the two effective derivatives, one (thalidomide C1) specifically affected the tumorigenic cell line (10 μM). Mitotic and apoptotic analyses revealed that thalidomide C1 induced apoptotic cell death and not mitotic arrest. This study shows that screens incorporating non-tumorigenic and tumorigenic liver cell lines are a sound approach to identify agents that are effective and selective. A high throughput instrument such as the Cellavista affords robust and reproducible objective measurements with a large number of replicates that are reliable. These experiments show that neither lenalidomide nor thalidomide are potentially useful for anti-liver cancer therapy as they kill non-tumorigenic liver cells and not their tumorigenic counterparts. Sorafenib in contrast, is highly effective, but not selective. One tested thalidomide derivative has potential as an anti-tumor drug since it induced growth arrest and importantly, it selectively induced apoptotic cell death only in tumorigenic liver progenitor cells.
Transferrin receptor 2 mediates uptake of transferrin-bound and non-transferrin-bound iron
Publisher: Elsevier BV
Date: 02-2008
DOI: 10.1016/J.JHEP.2007.10.009
Abstract: Transferrin receptor 2 appears to have dual roles in iron metabolism one is signalling, the other is iron transport. It is sensitive to high levels of diferric transferrin, which is associated with disorders of iron overload. Also present in these disorders are increased levels of plasma non-transferrin-bound iron. This study sought to clarify the role of transferrin receptor 2 in the uptake of transferrin-bound and non-transferrin-bound iron. Variant Chinese Hamster Ovary (CHO) cells, transfected with transferrin receptor 2, were incubated with radio-labelled transferrin-bound or non-transferrin-bound iron. Competition studies were performed in the presence of unlabelled dimetallic transferrin knockdown was performed using specific siRNA. Cells expressing transferrin receptor 2 bound and internalised transferrin and transferrin-bound iron. Transferrin recycling occurred with an average cycling time of 11-15 min. Interestingly, the presence of transferrin receptor 2 was also associated with uptake of non-transferrin-bound iron which was inhibited by unlabelled transferrin-bound metals. Knockdown reduced transferrin-bound and non-transferrin-bound iron uptake by approximately 60%. Transferrin receptor 2 mediates transferrin-bound iron uptake by receptor-mediated endocytosis. It is also involved in the uptake of non-transferrin-bound iron and the inhibition of non-transferrin-bound iron uptake by diferric transferrin in CHO cells.
The Natural History of Serum Iron Indices for HFE C282Y Homozygosity Associated With Hereditary Hemochromatosis
Publisher: Elsevier BV
Date: 12-2008
DOI: 10.1053/J.GASTRO.2008.08.056
Abstract: There are few longitudinal studies of serum ferritin (SF) and transferrin saturation (TS) levels in in iduals homozygous for the C282Y mutation. We characterized the development of elevated iron measures in C282Y homozygotes followed for 12 years. From 31,192 people aged 40-69 years at baseline, we identified 203 C282Y homozygotes (95 males), of whom 116 had SF and fasting TS levels measured at baseline (mean age, 55 years) and 86 were untreated and had iron measures at follow-up (mean, 12 years later). The probabilities of SF at follow-up exceeding clinical thresholds were predicted from baseline SF and TS under a multivariate normal model. For C282Y homozygotes, at baseline, 84% of males and 65% of females had elevated SF and 37% of males and 3% of females had SF >1000 microg/L. For males with SF 300-1000 microg/L at baseline, the predicted probability of progressing to SF >1000 microg/L at follow-up was between 13% and 35% and, for females, between 16% and 22%. For C282Y homozygotes with normal baseline SF, 1000 microg/L if left untreated. The majority of C282Y homozygotes who are likely to develop SF levels sufficient to place them at risk of iron overload-related disease will have done so by mean age 55 years. TS >95% at mean age 55 years in males increases the likelihood that SF levels will be elevated at mean age 65 years, but this effect is absent in females, most likely because of physiologic blood loss associated with menstruation.
Serum alanine aminotransferase, metabolic syndrome, and cardiovascular disease in an Australian population
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-06-2009
DOI: 10.1038/AJG.2009.229
Abstract: Elevations of serum alanine aminotransferase (ALT) are common and have been associated with metabolic syndrome (Met S) and cardiovascular risk. The aim of this study was to determine whether elevated ALT concentrations are predictive of Met S or cardiovascular events. In 1994/95, surviving participants of the previously conducted Busselton health population surveys completed a series of clinical and biochemical assessments. Using the Western Australian Health Department data linkage system, admissions for cardiovascular disease (CVD) were determined for 15 years before the survey (from 1980 to 1994). Incident CVD events during the 10-year follow-up period to the end of 2004 were also ascertained. Met S was defined using NCEP ATP III (2005) criteria. 3,719 Subjects (1,544 men and 2,175 women), aged 25-84 years who did not have serologically diagnosable chronic liver diseases or excessive consumption of alcohol, had their levels of ALT measured. The prevalence of Met S was 17% in men and 15% in women. In age-adjusted analyses, ALT was significantly associated with Met S and each of its five components and the association with Met S remained significant after adjustment for insulin resistance. There was no positive association between ALT and incident CVD events over the 10-year follow-up period in age-adjusted or multivariate-adjusted analyses. The findings from this Australian population-based cohort study support a strong association between ALT concentration and Met S independent of insulin resistance. Serum ALT level does not appear to contribute significantly to cardiovascular risk assessment.
Cellular Plasticity in Liver Regeneration: Spotlight on Cholangiocytes
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 19-02-2019
DOI: 10.1002/HEP.30340
The western dietary pattern is prospectively associated with nonalcoholic fatty liver disease in adolescence
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2013
DOI: 10.1038/AJG.2013.95
Abstract: Poor dietary habits have been implicated in the development of nonalcoholic fatty liver disease (NAFLD) however, little is known about the role of specific dietary patterns in the development of NAFLD. We examined prospective associations between dietary patterns and NAFLD in a population-based cohort of adolescents. Participants in the Western Australian Pregnancy Cohort (Raine) Study completed a food frequency questionnaire at 14 years and had liver ultrasound at 17 years (n=995). Healthy and Western dietary patterns were identified using factor analysis and all participants received a z-score for these patterns. Prospective associations between the dietary pattern scores and risk of NAFLD were analyzed using multiple logistic regression. NAFLD was present in 15.2% of adolescents. A higher Western dietary pattern score at 14 years was associated with a greater risk of NAFLD at 17 years (odds ratio (OR) 1.59 95% confidence interval (CI) 1.17-2.14 P<0.005), although these associations were no longer significant after adjusting for body mass index at 14 years. However, a healthy dietary pattern at 14 years appeared protective against NAFLD at 17 years in centrally obese adolescents (OR 0.63 95% CI 0.41-0.96 P=0.033), whereas a Western dietary pattern was associated with an increased risk of NAFLD. A Western dietary pattern at 14 years in a general population s le was associated with an increased risk of NAFLD at 17 years, particularly in obese adolescents. In centrally obese adolescents with NAFLD, a healthy dietary pattern may be protective, whereas a Western dietary pattern may increase the risk.
Duration of Hepatic Iron Exposure Increases the Risk of Significant Fibrosis in Hereditary Hemochromatosis: A New Role for Magnetic Resonance Imaging
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2005
DOI: 10.1111/J.1572-0241.2005.41287.X
Abstract: Hepatic fibrosis is a complication of hereditary hemochromatosis. The aim of this study was to determine whether the product of the magnitude and duration of hepatic iron exposure is related to the risk of significant fibrosis. Receiver-operating characteristic curve analysis to determine the utility of hepatic iron concentration (HIC) and age in the diagnosis of low- or high-grade fibrosis was undertaken retrospectively in 60 subjects who had undergone liver biopsy for assessment of hereditary hemochromatosis. A prospective pilot study was then conducted in 10 additional subjects to evaluate utility of magnetic resonance imaging (MRI) measurements of HIC to predict fibrosis. Eighteen subjects had high-grade fibrosis while 42 subjects had low-grade fibrosis. Hepatic iron concentration alone was highly sensitive (100%) but of limited specificity (67%) in diagnosis of high-grade fibrosis. The product of [HIC x age] had a sensitivity and specificity of 100% and 86%, respectively, for diagnosis of high-grade fibrosis. Magnetic resonance imaging measurements also provided accurate assignment of subjects into fibrosis severity groups. Duration of exposure to iron is important in the development of hepatic fibrosis in hereditary hemochromatosis. The product of HIC and age is highly sensitive and specific for diagnosis of high-grade fibrosis and can be obtained using MRI.
Independence of ovarian progesterone secretion rate from arterial progesterone concentrations in the pregnant rat
Publisher: Bioscientifica
Date: 07-1982
Abstract: We have sought to determine whether the rate of ovarian progesterone secretion in pregnant rats is inversely related to the arterial plasma progesterone concentrations. For this purpose, rates of ovarian progesterone secretion were measured on day 16 of pregnancy in seven progesterone-treated and eight untreated rats. Treated rats received once-daily s.c. injections of 63·6 μmol progesterone in peanut oil on days 13 to 16. In a separate experiment, this treatment was found to produce a relatively stable fivefold increase in plasma progesterone concentrations. The rate of ovarian blood flow was increased in treated animals (mean ± s.e.m. treated, 0·63± 0·08 ml/min untreated, 0·43± 0·08 ml/min) but the progesterone secretion rate was unchanged (treated, 1·13 ± 0·20 μmol/day per ovary untreated, 1·05 ± 0·15 μmol/day per ovary). The stability of the progesterone secretion rate in the face of a fivefold increase in plasma progesterone concentration implies a lack of negative feedback from progesterone in plasma in the regulation of ovarian progesterone secretion.
Kupffer cell-monocyte communication is essential for initiating murine liver progenitor cell-mediated liver regeneration
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 31-07-2015
DOI: 10.1002/HEP.27977
Abstract: Liver progenitor cells (LPCs) are necessary for repair in chronic liver disease because the remaining hepatocytes cannot replicate. However, LPC numbers also correlate with disease severity and hepatocellular carcinoma risk. Thus, the progenitor cell response in diseased liver may be regulated to optimize liver regeneration and minimize the likelihood of tumorigenesis. How this is achieved is currently unknown. Human and mouse diseased liver contain two subpopulations of macrophages with different ontogenetic origins: prenatal yolk sac–derived Kupffer cells and peripheral blood monocyte–derived macrophages. We examined the in idual role(s) of Kupffer cells and monocyte‐derived macrophages in the induction of LPC proliferation using clodronate liposome deletion of Kupffer cells and adoptive transfer of monocytes, respectively, in the choline‐deficient, ethionine‐supplemented diet model of liver injury and regeneration. Clodronate liposome treatment reduced initial liver monocyte numbers together with the induction of injury and LPC proliferation. Adoptive transfer of monocytes increased the induction of liver injury, LPC proliferation, and tumor necrosis factor‐α production. Conclusion : Kupffer cells control the initial accumulation of monocyte‐derived macrophages. These infiltrating monocytes are in turn responsible for the induction of liver injury, the increase in tumor necrosis factor‐α, and the subsequent proliferation of LPCs. (H epatology 2015 :1272‐1284)
Clinical Expression of Hemochromatosis Gene (HFE) Variants
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2007
DOI: 10.1002/HEP.21957
Haemochromatosis
Publisher: Oxford University Press
Date: 10-2013
DOI: 10.1093/MED/9780199642489.003.0173
Abstract: The arthropathy of haemochromatosis is relatively common even in patients with hereditary haemochromatosis (HH) recruited from the community. It is a chronic, progressive arthropathy with a level of inflammatory activity that is both clinically and histopathologically intermediate between that of rheumatoid arthritis and osteoarthritis. There is a predilection for the finger metacarpophalangeal joints and it is variably, but not commonly accompanied by chondrocalcinosis. The precise mechanism responsible for tissue damage in affected joints remains unknown, however there is growing evidence that iron load is a major determinant of the arthropathy. HH arthropathy is variably responsive to phlebotomy. Whether earlier diagnosis and treatment targeted to achieve tight control of iron metabolism from an early age or as soon as possible after diagnosis could produce better outcomes remains to be determined. Novel and more effective approaches to management with a view to prevention of structural joint damage still need to be developed.
Should HFE p.C282Y homozygotes with moderately elevated serum ferritin be treated? A randomised controlled trial comparing iron reduction with sham treatment (Mi-iron)
Publisher: BMJ
Date: 08-2015
The Regulation of Cellular Iron Metabolism
Publisher: Informa UK Limited
Date: 2007
DOI: 10.1080/10408360701428257
Abstract: While iron is an essential trace element required by nearly all living organisms, deficiencies or excesses can lead to pathological conditions such as iron deficiency anemia or hemochromatosis, respectively. A decade has passed since the discovery of the hemochromatosis gene, HFE, and our understanding of hereditary hemochromatosis (HH) and iron metabolism in health and a variety of diseases has progressed considerably. Although HFE-related hemochromatosis is the most widespread, other forms of HH have subsequently been identified. These forms are not attributed to mutations in the HFE gene but rather to mutations in genes involved in the transport, storage, and regulation of iron. This review is an overview of cellular iron metabolism and regulation, describing the function of key proteins involved in these processes, with particular emphasis on the liver's role in iron homeostasis, as it is the main target of iron deposition in pathological iron overload. Current knowledge on their roles in maintaining iron homeostasis and how their dysregulation leads to the pathogenesis of HH are discussed.
Iron uptake from plasma transferrin by the duodenum is impaired in the Hfe knockout mouse
Publisher: Proceedings of the National Academy of Sciences
Date: 09-04-2002
Abstract: Hereditary hemochromatosis (HH) is a disorder of iron metabolism in which enhanced iron absorption of dietary iron causes increased iron accumulation in the liver, heart, and pancreas. Most in iduals with HH are homozygous for a C282Y mutation in the HFE gene. The function of HFE protein is unknown, but it is hypothesized that it acts in association with β 2 -microglobulin and transferrin receptor 1 to regulate iron uptake from plasma transferrin by the duodenum, the proposed mechanism by which body iron levels are sensed. The aim of this study was to test this hypothesis by comparing clearance of transferrin-bound iron in Hfe knockout (KO) mice with that observed in C57BL/6 control mice. The mice were fed either an iron-deficient, control, or iron-loaded diet for 6 weeks to alter body iron status. The mice then were injected i.v. with 59 Fe-transferrin, and blood s les were taken over 2 h to determine the plasma 59 Fe turnover. After 2 h, the mice were killed and the amount of radioactivity in the duodenum, liver, and kidney was measured. In both Hfe KO and C57BL/6 mice, plasma iron turnover and iron uptake from plasma transferrin by the duodenum, liver, and kidney correlated positively with plasma iron concentration. However, duodenal iron uptake from plasma transferrin was decreased in the Hfe KO mice compared with the control mice. Despite this difference in duodenal uptake, the Hfe KO mice showed no decrease in iron uptake by the liver and kidney or alteration in the plasma iron turnover when compared with C57BL/6 mice. These data support the hypothesis that HFE regulates duodenal uptake of transferrin-bound iron from plasma, and that this mechanism of sensing body iron status, as reflected in plasma iron levels, is impaired in HH.
Isolation and primary culture of rat Kupffer cells
Publisher: Wiley
Date: 08-1998
DOI: 10.1111/J.1440-1746.1998.TB00746.X
Abstract: The aim of this study was to describe a reproducible method for the isolation, purification and primary culture of rat Kupffer cells. Kupffer cells were isolated following sequential pronase/collagenase digestion of the liver and enrichment of a non-parenchymal cell fraction by a single-density gradient centrifugation step using 30% metrizamide. Kupffer cells were isolated and further purified from this cell fraction by centrifugal elutriation. Kupffer cells were isolated at 1017 g at 48-110 mL/min. All Kupffer cell fractions exhibited phagocytosis of 3 microm latex beads. Kupffer cell fractions isolated at 48 and 60 mL/min were predominantly ED2 negative while later fractions (80-110 mL/min) were ED2 positive. Kupffer cells were adherent in culture after 2 h. This method for Kupffer cell isolation resulted in a yield of 80-120 x 10(6) Kupffer cells per liver.
C-kit inhibition by imatinib mesylate attenuates progenitor cell expansion and inhibits liver tumor formation in mice.
Publisher: Elsevier BV
Date: 09-2008
DOI: 10.1053/J.GASTRO.2008.05.077
Abstract: Numerous studies have linked the proliferation of liver progenitor cells (LPCs) during chronic liver disease to the risk for development of hepatocellular carcinoma. Thus, selective inhibition of LPC growth during preneoplastic injury may prevent or delay the onset of liver cancer. Rats carrying a germ-line mutation in c-kit have an impaired LPC response to liver injury. Therefore, we hypothesized that the c-kit inhibitor imatinib mesylate (IM) would suppress LPC growth and, therefore, may exert antitumorigenic effects in the liver. Expression of IM target proteins was examined in chronically injured rodent and human livers. The effect of IM was examined in vitro using LPC lines and in vivo in mice fed a choline-deficient, ethionine-supplemented (CDE) diet. Livers were examined following short-term (up to 1 month) or long-term (up to 14 months) feeding of CDE diet and drug treatments. C-kit was significantly up-regulated in chronic injury and expressed by LPCs. IM was antiproliferative to LPC lines, and knockdown of c-kit reduced this response. IM treatment inhibited the LPCs response and early fibrogenesis induced by a short-term CDE diet. On the longer term, IM treatment reduced the extent of fibrosis and significantly inhibited tumor formation. Tyrosine kinase inhibitors, such as IM, may be suited for the prevention of hepatocellular carcinoma in the setting of chronic liver injury via antiproliferative effects on c-kit-expressing LPCs.
TWEAK/Fn14 signalling promotes cholangiocarcinoma niche formation and progression
Publisher: Elsevier BV
Date: 04-2021
DOI: 10.1016/J.JHEP.2020.11.018
Abstract: Cholangiocarcinoma (CCA) is a cancer of the hepatic bile ducts that is rarely resectable and is associated with poor prognosis. Tumour necrosis factor-like weak inducer of apoptosis (TWEAK) is known to signal via its receptor fibroblast growth factor-inducible 14 (Fn14) and induce cholangiocyte and myofibroblast proliferation in liver injury. We aimed to characterise its role in CCA. The expression of the TWEAK ligand and Fn14 receptor was assessed immunohistochemically and by bulk RNA and single cell transcriptomics of human liver tissue. Spatiotemporal dynamics of pathway regulation were comprehensively analysed in rat and mouse models of thioacetamide (TAA)-mediated CCA. Flow cytometry, qPCR and proteomic analyses of CCA cell lines and conditioned medium experiments with primary macrophages were performed to evaluate the downstream functions of TWEAK/Fn14. In vivo pathway manipulation was assessed via TWEAK overexpression in NICD/AKT-induced CCA or genetic Fn14 knockout during TAA-mediated carcinogenesis. Our data reveal TWEAK and Fn14 overexpression in multiple human CCA cohorts, and Fn14 upregulation in early TAA-induced carcinogenesis. TWEAK regulated the secretion of factors from CC-SW-1 and SNU-1079 CCA cells, inducing polarisation of proinflammatory CD206 These novel data provide evidence for the action of TWEAK/Fn14 on macrophage recruitment and phenotype, and cancer-associated fibroblast proliferation in CCA. Targeting TWEAK/Fn14 and its downstream signals may provide a means to inhibit CCA niche development and tumour growth. Cholangiocarcinoma is an aggressive, chemotherapy-resistant liver cancer. Interactions between tumour cells and cells that form a supportive environment for the tumour to grow are a source of this aggressiveness and resistance to chemotherapy. Herein, we describe interactions between tumour cells and their supportive environment via a chemical messenger, TWEAK and its receptor Fn14. TWEAK/Fn14 alters the recruitment and type of immune cells in tumours, increases the growth of cancer-associated fibroblasts in the tumour environment, and is a potential target to reduce tumour formation.
Reply
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 16-10-2015
DOI: 10.1002/HEP.28030
Factors That Affect Serum Levels of Ferritin in Australian Adults and Implications for Follow-Up
Publisher: Elsevier BV
Date: 2014
DOI: 10.1016/J.CGH.2013.07.019
Abstract: Serum levels of ferritin are commonly measured to assess iron stores but are affected by factors such as obesity and chronic disease. Published reference ranges have not changed in decades, and the number of patients whose levels exceed the upper limits has been increasing. As a result, more patients are evaluated for iron overload. We compared serum levels of ferritin in 1188 Australian adults who participated in the 2005 Busselton Population Survey with levels from the 1995 survey. Parametric regression was used to assess the effects of body weight and biochemical parameters on serum level of ferritin to derive contemporary population-appropriate reference ranges. In 2005, age-adjusted levels of ferritin were 21% higher in men (P < .0001) and 10% higher in women (P = .01) than in 1995 31% of men exceeded levels of 300 μg/L, compared with 23% in 1995. Body mass index (BMI) ≥25 kg/m(2) was associated with higher levels of ferritin in men ≥35 years old and in postmenopausal women (P ≤ .002). Serum level of γ-glutamyltransferase (GGT) correlated with serum level of ferritin (P < .0001). In men, the estimated 95th percentiles ranged from 353 to 495 μg/L (<35 years), from 350 to 511 μg/L (≥35 years, BMI <25 kg/m(2)), and from 413 to 696 μg/L (≥35 years, BMI ≥25 kg/m(2)) when GGT levels were 10-75 IU/L. In women, the 95th percentiles ranged from 106 to 235 μg/L (premenopausal), from 222 to 323 μg/L (postmenopausal, BMI <25 kg/m(2)), and from 249 to 422 μg/L (postmenopausal, BMI ≥25 kg/m(2)) when GGT levels were 8-45 IU/L. Serum levels of ferritin increased significantly between 1995 and 2005. Reference ranges that accommodate demographic and biomedical variations will assist clinicians in identifying in iduals who require further evaluation for iron overload.
Iron Overload in Blacks: Ironing Out The Issues
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2003
Reasons for noncompliance with five-yearly screening flexible sigmoidoscopy
Publisher: Informa UK Limited
Date: 10-2008
DOI: 10.2147/PPA.S4705
Utility of hepatic or total body iron burden in the assessment of advanced hepatic fibrosis in HFE hemochromatosis
Publisher: Springer Science and Business Media LLC
Date: 27-12-2019
DOI: 10.1038/S41598-019-56732-0
Abstract: Development of advanced hepatic fibrosis in HFE Hemochromatosis (HH) is influenced by hepatic iron concentration (HIC) and age. In patients with HH, it is important to assess the likelihood of cirrhosis and thus the need for confirmatory liver biopsy. Therapeutic phlebotomy also provides an estimate of mobilisable iron stores. We determined whether mobilisable iron stores may predict the presence of advanced fibrosis. Retrospective analysis of 137 male and 65 female HH subjects was undertaken. Biochemical, histological and phlebotomy data were available on all subjects. The mean values of HIC, HIC × [age], mobilisable iron, mobilisable iron × [age] and serum ferritin in the cohort were higher in the group with advanced fibrosis. HIC had an optimum sensitivity and specificity of 73% for the diagnosis of advanced liver fibrosis, with a cut-off HIC level of 200 µmol/g (AUROC 0.83, p 0.0001). AUROC for HIC was greater in females (0.93) than males (0.79). Mobilisable iron had an optimum sensitivity and specificity both of 83% at a cut-off of 9.6 g for the prediction of advanced fibrosis in all subjects (AUROC 0.92, p 0.0001). Mobilisable iron stores provide a simple, clinically useful indication of the risk of advanced fibrosis and should routinely be considered.
HFE Genotype in Patients with Hemochromatosis and Other Liver Diseases
Publisher: American College of Physicians
Date: 15-06-1999
DOI: 10.7326/0003-4819-130-12-199906150-00002
Abstract: Hereditary hemochromatosis is a common inherited disorder of iron metabolism. The gene HFE, which contains two missense mutations (C282Y and H63D), was recently identified. To determine how HFE genotyping for the C282Y and H63D mutations contributes to the diagnosis of hemochromatosis and to determine the prevalence of HFE mutations in a group of patients with liver disease. Cross-sectional study. Academic medical center. 66 patients with hereditary hemochromatosis and 132 referred patients with other liver diseases. At initial diagnosis, fasting transferrin saturation, ferritin level, routine chemistry panel, and complete blood count were determined. Percutaneous liver biopsy was done on all patients for histologic analysis and measurement of hepatic iron concentration and hepatic iron index. HFE genotyping for the C282Y and H63D mutations was done on all patients by using genomic DNA s les. Of the 66 patients with hemochromatosis diagnosed on the basis of serum iron studies and liver biopsy findings, 60 (91%) were C282Y homozygotes, 2 (3%) were compound heterozygotes, 1 (1.5%) was a C282Y heterozygote, 2 (3%) were H63D heterozygotes, and 1 (1.5%) was negative for both mutations. Of the 132 patients with liver disease, 6 (5%) were C282Y homozygotes, 8 (6%) were compound heterozygotes, 6 (5%) were C282Y heterozygotes, 5 (4%) were H63D homozygotes, 20 (15%) were H63D heterozygotes, and 87 (66%) were negative for both mutations. All 66 C282Y homozygotes had an elevated hepatic iron concentration, and 65 of the 66 patients (98%) had a transferrin saturation of at least 45%. Ten of the 66 patients (15% [95% CI, 7.5% to 26%]) had a hepatic iron index less than 1.9 mmol/kg per year hemochromatosis was not suspected in 6 of the 10 patients before genotyping. Cirrhosis or substantial hepatic fibrosis was not seen in any (0% [CI, 0% to 18%]) of the 19 patients younger than 40 years of age who were homozygous for the C282Y mutation. All 66 patients homozygous for the C282Y mutation of HFE had an elevated hepatic iron concentration, but approximately 15% of these patients did not meet a previous diagnostic criterion for hemochromatosis (hepatic iron index > 1.9 mmol/kg per year). Determination of HFE genotype is clinically useful in patients with liver disease and suspected iron overload and may lead to identification of otherwise unsuspected C282Y homozygotes.
Human Liver Progenitor Cell Lines Are Readily Established From Non-Tumorous Tissue Adjacent to Hepatocellular Carcinoma
Publisher: Mary Ann Liebert Inc
Date: 08-2010
Abstract: Non-tumorous liver tissue removed during surgery to resect hepatocellular carcinoma (HCC) is potentially a useful source of material from which cells, particularly liver progenitor/stem cells (LPCs), can be isolated to establish cell lines. The purpose of this study was to evaluate the applicability of the "plate-and-wait" method to derive LPCs from resections to remove HCC. Three independent non-tumorous liver s les from HCC resection and 3 s les from liver donors were used for LPC isolation. Staining for LPC markers, OV6, CK19, and EpCAM, in the above liver s les demonstrated staining in only 2 of the non-tumorous s les. We isolated 2 human liver epithelial cell lines (HLECs) from these 2 s les. These HLECs were positive for general stem cell markers CD133, EpCAM, and Oct4. They expressed the liver progenitor cell markers OV6, CK14, and M2PK but not CK19. They also expressed the hepatocellular markers albumin, CK8, CK18, HNF4-alpha, and the drug-metabolizing gene CYP3A4. These cells accumulated glycogen, indocyanine green, and synthesized urea. They produced colonies in soft agar that showed anchorage-independent growth and their tumorigenic status was confirmed when they produced tumors following transfer to athymic nude mice. In contrast, the third non-tumorous tissue and 3 normal liver s les did not produce cell lines. This study establishes a correlation between the presence of LPCs in the source liver tissue and the ability to derive cell lines from these tissues. The phenotypic similarities between the LPCs and the HLECs suggest that a precursor-product relationship may exist between the 2 cell types.
Stereological analysis of liver biopsy histology sections as a reference standard for validating non-invasive liver fat fraction measurements by MRI
Publisher: Public Library of Science (PLoS)
Date: 08-08-2016
HFE C282Y homozygotes are at increased risk of breast and colorectal cancer
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 30-11-2009
DOI: 10.1002/HEP.23448
Immune checkpoint inhibition: prospects for prevention and therapy of hepatocellular carcinoma.
Publisher: Wiley
Date: 11-2017
DOI: 10.1038/CTI.2017.47
Validation of fatty liver disease scoring systems for ultrasound diagnosed non-alcoholic fatty liver disease in adolescents
Publisher: Elsevier BV
Date: 06-2021
DOI: 10.1016/J.DLD.2020.11.037
Abstract: The incidence of non-alcoholic fatty liver disease (NAFLD) is increasing in young populations. However, there are inadequate data regarding diagnosis of NAFLD. We aimed to validate three scoring systems against a previous standard of suprailiac skinfold thickness for diagnosing NAFLD in population-based adolescents. Seventeen-year-old adolescents (n = 899), participating in the Raine Study, attended a cross-sectional follow-up. NAFLD was diagnosed using liver ultrasound. Scores for Fatty liver index (FLI), Hepatic Steatosis Index (HSI) and Zhejiang University index (ZJU index) were calculated. Diagnostic accuracy of these diagnostic tests was evaluated through discrimination and calibration. NAFLD was diagnosed 9% in males and 15% in females. The three scoring systems demonstrated better discrimination performance for NAFLD in males (AUC was FLI:0.82, HSI: 0.83 and ZJU index: 0.83) compared to females (AUC was FLI: 0.67, HSI: 0.67 and ZJU index: 0.67). Suprailiac skinfold performed better than the scoring systems (overall AUC: 0.82 male AUC:0.88 female AUC:0.73). FLI had best calibration performance. Suprailiac skinfold thickness was a better predictor of ultrasound-diagnosed NAFLD than the three diagnostic scoring systems investigated. The higher performance characteristics of the algorithmic scoring systems in males compared with females may have implications for use in population assessments.
Lymphotoxin-β receptor signaling regulates hepatic stellate cell function and wound healing in a murine model of chronic liver injury
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 22-08-2008
DOI: 10.1002/HEP.22597
Abstract: Lymphotoxin-beta (LTbeta) is a proinflammatory cytokine and a member of the tumor necrosis factor (TNF) superfamily known for its role in mediating lymph node development and homeostasis. Our recent studies suggest a role for LTbeta in mediating the pathogenesis of human chronic liver disease. We hypothesize that LTbeta co-ordinates the wound healing response in liver injury via direct effects on hepatic stellate cells. This study used the choline-deficient, ethionine-supplemented (CDE) dietary model of chronic liver injury, which induces inflammation, liver progenitor cell proliferation, and portal fibrosis, to assess (1) the cellular expression of LTbeta, and (2) the role of LTbeta receptor (LTbetaR) in mediating wound healing, in LTbetaR(-/-) versus wild-type mice. In addition, primary isolates of hepatic stellate cells were treated with LTbetaR-ligands LTbeta and LTbeta-related inducible ligand competing for glycoprotein D binding to herpesvirus entry mediator on T cells (LIGHT), and mediators of hepatic stellate cell function and fibrogenesis were assessed. LTbeta was localized to progenitor cells immediately adjacent to activated hepatic stellate cells in the periportal region of the liver in wild-type mice fed the CDE diet. LTbetaR(-/-) mice fed the CDE diet showed significantly reduced fibrosis and a dysregulated immune response. LTbetaR was demonstrated on isolated hepatic stellate cells, which when stimulated by LTbeta and LIGHT, activated the nuclear factor kappa B (NF-kappaB) signaling pathway. Neither LTbeta nor LIGHT had any effect on alpha-smooth muscle actin, tissue inhibitor of metalloproteinase 1, transforming growth factor beta, or procollagen alpha(1)(I) expression however, leukocyte recruitment-associated factors intercellular adhesion molecule 1 and regulated upon activation T cells expressed and secreted (RANTES) were markedly up-regulated. RANTES caused the chemotaxis of a liver progenitor cell line expressing CCR5. This study suggests that LTbetaR on hepatic stellate cells may be involved in paracrine signaling with nearby LTbeta-expressing liver progenitor cells mediating recruitment of progenitor cells, hepatic stellate cells, and leukocytes required for wound healing and regeneration during chronic liver injury.
Cost‐effectiveness of colorectal cancer screening: Comparison of community‐based flexible sigmoidoscopy with fecal occult blood testing and colonoscopy
Publisher: Wiley
Date: 12-12-2003
DOI: 10.1111/J.1440-1746.2004.03177.X
Abstract: To determine the cost-effectiveness of screening for colorectal cancer using flexible sigmoidoscopy once every 10 years, compared with annual and biennial rehydrated Hemoccult fecal occult blood testing and colonoscopy once every 10 years, or no screening. A Markov model was developed in order to simulate the progression of a cohort of asymptomatic, average-risk in iduals aged 55-64 years who were moving through a defined series of states towards death. The main outcome measures were: cases of colorectal cancer averted, colorectal cancer deaths averted, and cost per life-year saved. Colonoscopy averted the greatest number of cases of colorectal cancer (35%), followed by flexible sigmoidoscopy (25%), and annual (24%) and biennial (14%) fecal occult blood testing. Colonoscopy averted the greatest number of deaths from colorectal cancer (31%), followed by annual fecal occult blood testing (29%), flexible sigmoidoscopy (21%) and biennial fecal occult blood testing (19%). Flexible sigmoidoscopy was the most efficient in terms of cost per life-year saved (16,801 Australian dollars), followed by colonoscopy (19,285 Australian dollars), biennial (41,183 Australian dollars), and annual (46,900 Australian dollars) fecal occult blood testing. Flexible sigmoidoscopy and colonoscopy are cost-effective strategies for reducing the disease burden of colorectal cancer.
HFE p.C282Y homozygosity predisposes to rapid serum ferritin rise after menopause: A genotype‐stratified cohort study of hemochromatosis in Australian women
Publisher: Wiley
Date: 24-03-2017
DOI: 10.1111/JGH.13621
Differential findings for CD14‐positive hepatic monocytes/macrophages in primary biliary cirrhosis, chronic hepatitis C and nonalcoholic steatohepatitis
Publisher: Wiley
Date: 25-05-2006
DOI: 10.1111/J.1478-3231.2006.01255.X
Abstract: Endotoxin-responsive monocytes/macrophages (CD14-positive) are potential sources of profibrogenic factors. The aims of this study were to determine (1) whether hepatic CD14-positive cells are present in various forms of chronic liver disease, and (2) the relationship between CD14-positive cells, myofibroblasts, and fibrosis in these diseases. Liver specimens from control subjects (n = 12) and those with primary biliary cirrhosis (n = 18), chronic hepatitis C (n = 13), or nonalcoholic steatohepatitis (n = 13) were immunostained for CD14, CD68, and alpha-smooth muscle actin (SMA) and the number of cells expressing these antigens was determined. Fibrosis and inflammation were also assessed. The total number of hepatic CD68-positive cells was similar in diseased and control livers. The number of CD14-positive cells was increased in advanced fibrosis in primary biliary cirrhosis and hepatitis C but not in nonalcoholic steatohepatitis. The number of CD14-positive cells was also increased in hepatitis C specimens with high inflammatory activity. CD14-positive cells were often associated with alpha-SMA-positive myofibroblasts in fibrous septa. The number of hepatic CD14-positive cells is increased in advanced fibrosis in subjects with primary biliary cirrhosis and hepatitis C but not in nonalcoholic steatohepatitis. In primary biliary cirrhosis and hepatitis C, CD14-positive macrophages are found in close proximity to fibrous septa and myofibroblasts. In hepatitis C, an increased number of CD14-positive cells are associated with high inflammatory activity.
Gender-specific differences in adipose distribution and adipocytokines influence adolescent nonalcoholic fatty liver disease
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2011
DOI: 10.1002/HEP.24097
Abstract: Nonalcoholic fatty liver disease (NAFLD) is a predominantly adult-diagnosed disorder. Knowledge regarding the epidemiology, phenotype, and metabolic risk factors, during adolescence is limited. We sought to determine the prevalence, phenotype, and predictors of NAFLD in 1170 community-based adolescents in the Western Australian Pregnancy Cohort (Raine) Study (the Raine Cohort) who underwent a cross-sectional assessment that included questionnaires, anthropometry, cardiovascular examinations, blood tests, and abdominal ultrasound examinations. Among the 1170 adolescents assessed, the prevalence of NAFLD was 12.8%. Females compared with males had a significantly higher prevalence of NAFLD (16.3% versus 10.1%, P = 0.004) and central obesity (33.2% versus 9.9%, P < 0.05). The severity of hepatic steatosis was associated with the body mass index, waist circumference, subcutaneous adipose tissue thickness (SAT), serum leptin level, homeostasis model assessment for insulin resistance score (P < 0.001 for all), and serum alanine aminotransferase level (P < 0.005) in both genders, but it was associated with increasing visceral adipose tissue thickness (VAT P < 0.001) and decreasing serum adiponectin levels (P 0.05) however, in comparison with females with NAFLD, males with NAFLD had greater VAT, a more severe metabolic phenotype with higher glucose levels and systolic blood pressure and lower adiponectin and high-density lipoprotein cholesterol levels (P < 0.001 for all), and greater measures of liver injury (alanine aminotransferase and aspartate aminotransferase, P < 0.001 for all). Similarly, metabolic syndrome was more common in males than females with NAFLD (24% versus 8%, P = 0.01). Suprailiac skinfold thickness predicted NAFLD independently of the body mass index, insulin resistance, and VAT. Gender differences in adolescent NAFLD are related to differences in adipose distribution and adipocytokines. The male phenotype of NAFLD is associated with more adverse metabolic features and greater visceral adiposity than the female phenotype despite the lower prevalence of NAFLD.
Genetics of hereditary hemochromatosis: A clinical perspective
Publisher: Informa UK Limited
Date: 05-2009
DOI: 10.1586/EEM.09.9
Abstract: Hereditary hemochromatosis due to homozygosity for the C282Y mutation in the HFE gene product is the most common autosomal recessive genetic disorder in populations of northern European descent, where it attains a maximum prevalence of approximately one in 200. Cross-sectional and longitudinal studies have revealed that clinically significant iron-overload disease develops in at least 28% of male and 1% of female HFE C282Y homozygotes. The relatively low clinical penetrance is largely unexplained. Current evidence suggests a limited role for digenic inheritance of mutations in iron homeostasis genes in modifying the penetrance of hemochromatosis. Male gender is a strong genetic factor, promoting expression of clinical disease. Dietary intake of alcohol and noncitrus fruit may also act as important environmental modifiers of penetrance. With genetic analyses becoming simpler to perform, new genetic modifiers of hepatic iron loading and liver fibrogenesis are likely to be forthcoming.
The investigation and management of disturbed iron metabolism
Publisher: Elsevier BV
Date: 2009
Monitoring quality of care in hepatocellular carcinoma: A modified Delphi consensus
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 25-09-2022
DOI: 10.1002/HEP4.2089
Abstract: Although there are several established international guidelines on the management of hepatocellular carcinoma (HCC), there is limited information detailing specific indicators of good quality care. The aim of this study was to develop a core set of quality indicators (QIs) to underpin the management of HCC. We undertook a modified, two‐round, Delphi consensus study comprising a working group and experts involved in the management of HCC as well as consumer representatives. QIs were derived from an extensive review of the literature. The role of the participants was to identify the most important and measurable QIs for inclusion in an HCC clinical quality registry. From an initial 94 QIs, 40 were proposed to the participants. Of these, 23 QIs ultimately met the inclusion criteria and were included in the final set. This included (a) nine related to the initial diagnosis and staging, including timing to diagnosis, required baseline clinical and laboratory assessments, prior surveillance for HCC, diagnostic imaging and pathology, tumor staging, and multidisciplinary care (b) thirteen related to treatment and management, including role of antiviral therapy, timing to treatment, localized ablation and locoregional therapy, surgery, transplantation, systemic therapy, method of response assessment, and supportive care and (c) one outcome assessment related to surgical mortality. Conclusion : We identified a core set of nationally agreed measurable QIs for the diagnosis, staging, and management of HCC. The adherence to these best practice QIs may lead to system‐level improvement in quality of care and, ultimately, improvement in patient outcomes, including survival.
Genotyping as a diagnostic aid in genetic haemochromatosis
Publisher: Wiley
Date: 05-1999
DOI: 10.1046/J.1440-1746.1999.01884.X
Abstract: Two mutations in a newly described gene, HFE, have been proposed as genetic markers for the inherited iron overload disease, genetic haemochromatosis. We assessed the frequency of both mutations in a cohort of genetic haemochromatosis patients and compared these with a control population. The patients were genetic haemochromatosis patients from Western Australia whose diagnosis met strict criteria for phenotypic expression. Control patients had other liver disease where iron overload was excluded. Genomic DNA of 72 genetic haemochromatosis patients and 69 controls was examined for the C282Y and H63D mutations of the HFE gene using polymerase chain reaction lification and restriction enzyme digestion. In genetic haemochromatosis patients, the C282Y mutation was homozygous in 64 of 72, giving a sensitivity of 89% (95% confidence interval 82-96%), heterozygous in five (7%) and absent in another three (4%), whereas none of the control subjects were homozygous. The H63D mutation was present in one genetic haemochromatosis patient and was not useful as a diagnostic marker. In this cohort of Western Australian patients with phenotypic expression of genetic haemochromatosis, the specificity of a homozygous C282Y mutation for genetic haemochromatosis was 100%. The results indicate that genotyping for the C282Y mutation is a useful test for the diagnosis of genetic haemochromatosis in clinical practice.
Higher concentrations of serum iron and transferrin saturation but not serum ferritin are associated with cancer outcomes
Publisher: Elsevier BV
Date: 09-2016
Abstract: Although the carcinogenic potential of iron has been shown, evidence from observational studies that have linked serum iron variables and cancer outcomes has been inconsistent. We investigated whether higher iron concentrations increased risk of cancer outcomes. A prospective examination of iron biomarkers as independent risk factors for cancer was assessed in 1597 men and 1795 women aged 25-79 y who participated in the 1994/1995 Busselton Health Survey and had relevant data, no history of cancer before the survey, and serum ferritin concentrations ≥20 μg/L. Follow-up for incident cancers and death from cancer was available to 2010. Proportional hazards regression modeling was performed to investigate if iron status predicted cancer incidence and mortality. After adjustments for age, smoking, drinking, anthropometric and biochemical variables, or menopausal status (breast cancer), higher serum iron concentrations and transferrin saturation were associated with increased risks of incident nonskin cancer [HR for iron: 1.83 (95% CI: 1.21, 2.76 P < 0.01) HR for transferrin saturation: 1.68 (95% CI: 1.18, 2.38 P < 0.01)] including breast cancer [HR for iron: 2.45 (95% CI:1.12, 5.34 P < 0.05) HR for transferrin saturation: 1.90 (95% CI:1.02, 3.56 P < 0.05)] in women. Transferrin saturation was also associated with a greater risk of cancer death (HR: 2.48 95% CI: 1.28, 4.82 P < 0.01). In men, higher iron concentrations were associated with reduced risks of incident nonskin cancer (HR: 0.65 95% CI: 0.42, 0.99 P < 0.05) including colorectal cancer (HR: 0.34 95% CI: 0.12, 0.95 P < 0.05). There was no association between serum iron and colorectal cancer risk in women. Serum ferritin was not associated with cancer risk or cancer death. Higher transferrin saturation or serum iron concentrations were associated with increased nonskin cancer risk and increased risk of cancer death. Conversely, in men, higher serum iron concentrations were associated with decreased risk of nonskin cancer. The molecular basis for the observed differences in the association between serum iron and nonskin cancer risk is unclear.
Brain transcriptome perturbations in the transferrin receptor 2 mutant mouse support the case for brain changes in iron loading disorders, including effects relating to long-term depression and long-term potentiation
Publisher: Elsevier BV
Date: 04-2013
DOI: 10.1016/J.NEUROSCIENCE.2013.01.014
Abstract: Iron abnormalities within the brain are associated with several rare but severe neurodegenerative conditions. There is growing evidence that more common systemic iron loading disorders such as hemochromatosis can also have important effects on the brain. To identify features that are common across different forms of hemochromatosis, we used microarray and real-time reverse transcription polymerase chain reaction (RT-PCR) to assess brain transcriptome profiles of transferrin receptor 2 mutant mice (Tfr2(mut)), a model of a rare type of hereditary hemochromatosis, relative to wildtype control mice. The results were compared with our previous findings in dietary iron-supplemented wildtype mice and Hfe(-/-) mice, a model of a common type of hereditary hemochromatosis. For transcripts showing significant changes relative to controls across all three models, there was perfect (100%) directional concordance (i.e. transcripts were increased in all models or decreased in all models). Comparison of the two models of hereditary hemochromatosis, which showed more pronounced changes than the dietary iron-supplemented mice, revealed numerous common molecular effects. Pathway analyses highlighted changes for genes relating to long-term depression (6.8-fold enrichment, p=5.4×10(-7)) and, to a lesser extent, long-term potentiation (3.7-fold enrichment, p=0.01), with generalized reductions in transcription of key genes from these pathways, which are involved in modulating synaptic strength and efficacy and are essential for memory and learning. The agreement across the models suggests the findings are robust and strengthens previous evidence that iron loading disorders affect the brain. Perturbations of brain phenomena such as long-term depression and long-term potentiation might partly explain neurologic symptoms reported for some hemochromatosis patients.
Non-invasive measurement and imaging of liver iron concentrations using proton magnetic resonance
Publisher: American Society of Hematology
Date: 15-01-2005
DOI: 10.1182/BLOOD-2004-01-0177
Abstract: Measurement of liver iron concentration (LIC) is necessary for a range of iron-loading disorders such as hereditary hemochromatosis, thalassemia, sickle cell disease, aplastic anemia, and myelodysplasia. Currently, chemical analysis of needle biopsy specimens is the most common accepted method of measurement. This study presents a readily available noninvasive method of measuring and imaging LICs in vivo using clinical 1.5-T magnetic resonance imaging units. Mean liver proton transverse relaxation rates (R2) were measured for 105 humans. A value for the LIC for each subject was obtained by chemical assay of a needle biopsy specimen. High degrees of sensitivity and specificity of R2 to biopsy LICs were found at the clinically significant LIC thresholds of 1.8, 3.2, 7.0, and 15.0 mg Fe/g dry tissue. A calibration curve relating liver R2 to LIC has been deduced from the data covering the range of LICs from 0.3 to 42.7 mg Fe/g dry tissue. Proton transverse relaxation rates in aqueous paramagnetic solutions were also measured on each magnetic resonance imaging unit to ensure instrument-independent results. Measurements of proton transverse relaxivity of aqueous MnCl2 phantoms on 13 different magnetic resonance imaging units using the method yielded a coefficient of variation of 2.1%.
Previous liver regeneration induces fibro-protective mechanisms during thioacetamide-induced chronic liver injury
Publisher: Elsevier BV
Date: 05-2021
Texture-based classification of liver fibrosis using MRI
Publisher: Wiley
Date: 18-12-2015
DOI: 10.1002/JMRI.24536
Abstract: To investigate the ability of texture analysis of MRI images to stage liver fibrosis. Current noninvasive approaches for detecting liver fibrosis have limitations and cannot yet routinely replace biopsy for diagnosing significant fibrosis. Forty-nine patients with a range of liver diseases and biopsy-confirmed fibrosis were enrolled in the study. For texture analysis all patients were scanned with a T2 -weighted, high-resolution, spin echo sequence and Haralick texture features applied. The area under the receiver operating characteristics curve (AUROC) was used to assess the diagnostic performance of the texture analysis. The best mean AUROC achieved for separating mild from severe fibrosis was 0.81. The inclusion of age, liver fat and liver R2 variables into the generalized linear model improved AUROC values for all comparisons, with the F0 versus F1-4 comparison the highest (0.91). Our results suggest that a combination of MRI measures, that include selected texture features from T2 -weighted images, may be a useful tool for excluding fibrosis in patients with liver disease. However, texture analysis of MRI performs only modestly when applied to the classification of patients in the mild and intermediate fibrosis stages.
Fecal occult blood and flexible sigmoidoscopy screening for colorectal cancer: Modeling the impact on colonoscopy requirements and cancer detection rates
Publisher: Wiley
Date: 04-2001
DOI: 10.1046/J.1440-1746.2001.02458.X
Abstract: The aim of this study was to estimate the colonoscopy requirements and the likely impact of fecal occult blood and flexible sigmoidoscopy screening on the detection of colorectal cancer by using previously published data. Fecal occult blood and flexible sigmoidoscopy screening programs were applied to the 2.04 million subjects aged 50-65 years, at a participation rate of 40%. The following strategies were evaluated: Fecal occult blood testing with colonoscopy follow up of all positive tests flexible sigmoidoscopy with colonoscopy follow up of all adenomatous polyps and flexible sigmoidoscopy with colonoscopy follow up of all adenomatous polyps > 10 mm in size. The fecal occult blood program detected 5.6% of all colorectal cancer cases at a rate of 2,914 colonoscopies ercentage of detection of colorectal cancer. The flexible sigmoidoscopy program detected 14% of all colorectal cancer cases at a rate of 8,160 colonoscopies ercentage of detection of colorectal cancer. The flexible sigmoidoscopy program with follow up of adenomatous polyps > 10 mm in size detected 13% of all colorectal cancer cases at a rate of 1,230 colonoscopies ercentage of detection of colorectal cancer. Flexible sigmoidoscopy screening followed by colonoscopic follow up of adenomatous polyps > 10 mm in size is the most efficient screening strategy in terms of colonoscopies generated and cases of colorectal cancer detected.
PAHA model: An alternative non-invasive predictor of liver cirrhosis in patients with chronic hepatitis B infection
Publisher: Wiley
Date: 22-12-2010
Iron-Overload–Related Disease inHFEHereditary Hemochromatosis
Publisher: Massachusetts Medical Society
Date: 17-01-2008
DOI: 10.1056/NEJMOA073286
Iron absorption and hepatic iron uptake are increased in a transferrin receptor 2 (Y245X) mutant mouse model of hemochromatosis type 3
Publisher: American Physiological Society
Date: 2007
Abstract: Hereditary hemochromatosis type 3 is an iron (Fe)-overload disorder caused by mutations in transferrin receptor 2 (TfR2). TfR2 is expressed highly in the liver and regulates Fe metabolism. The aim of this study was to investigate duodenal Fe absorption and hepatic Fe uptake in a TfR2 (Y245X) mutant mouse model of hereditary hemochromatosis type 3. Duodenal Fe absorption and hepatic Fe uptake were measured in vivo by 59 Fe-labeled ascorbate in TfR2 mutant mice, wild-type mice, and Fe-loaded wild-type mice (2% dietary carbonyl Fe). Gene expression was measured by real-time RT-PCR. Liver nonheme Fe concentration increased progressively with age in TfR2 mutant mice compared with wild-type mice. Fe absorption (both duodenal Fe uptake and transfer) was increased in TfR2 mutant mice compared with wild-type mice. Likewise, expression of genes participating in duodenal Fe uptake ( Dcytb, DMT1) and transfer (ferroportin) were increased in TfR2 mutant mice. Nearly all of the absorbed Fe was taken up rapidly by the liver. Despite hepatic Fe loading, hepcidin expression was decreased in TfR2 mutant mice compared with wild-type mice. Even when compared with Fe-loaded wild-type mice, TfR2 mutant mice had increased Fe absorption, increased duodenal Fe transport gene expression, increased liver Fe uptake, and decreased liver hepcidin expression. In conclusion, despite systemic Fe loading, Fe absorption and liver Fe uptake were increased in TfR2 mutant mice in association with decreased expression of hepcidin. These findings support a model in which TfR2 is a sensor of Fe status and regulates duodenal Fe absorption and liver Fe uptake.
Lymphotoxin-beta production following bile duct ligation: Possible role for Kupffer cells
Publisher: Wiley
Date: 12-10-2005
DOI: 10.1111/J.1440-1746.2005.04065.X
Abstract: Lymphotoxin-beta (LT-beta) may play a role in the pathogenesis of chronic liver injury. The aim of this study was to determine in an animal model of bile duct ligation liver injury whether LT-beta expression is induced and whether Kupffer cells are an intrahepatic source of LT-beta. Sprague-Dawley rats were ided into two groups: one group received a single dose of GdCl (a Kupffer cell-blocking agent, 10 mg/kg i.v.), whereas the other group received saline. One day later, the groups underwent bile duct ligation or a sham operation. Liver tissue was obtained on days 1, 3, 5, and 8 for assessment of Kupffer cell numbers, early fibrogenic events and LT-beta gene expression. Kupffer cells were isolated using pronase/collagenase perfusion and centrifugal elutriation. Hepatic LT-beta mRNA expression increased early following bile duct ligation. Pretreatment of bile duct-ligated animals with GdCl significantly reduced the number of Kupffer cells, delayed the rise in LT-beta expression, but had no effect on fibrogenesis. Recovery of the Kupffer cell population in these animals was accompanied by increased hepatic LT-beta expression. The LT-beta ligand and receptor were expressed by isolated normal Kupffer cells. Hepatic LT-beta expression is induced early following bile duct ligation. Kupffer cells may be an intrahepatic source of LT-beta.
SNP selection for genes of iron metabolism in a study of genetic modifiers of hemochromatosis
Publisher: Springer Science and Business Media LLC
Date: 20-03-2008
Inhibition of adult liver progenitor (oval) cell growth and viability by an agonist of the peroxisome proliferator activated receptor (PPAR) family member gamma, but not alpha or delta
Publisher: Oxford University Press (OUP)
Date: 25-05-2005
Abstract: Multifaceted evidence links the development of liver tumours to the activation and proliferation of adult liver progenitor (oval) cells during the early stages of chronic liver injury. The aim of this study was to examine the role of the peroxisome proliferator activated receptors (PPARs): PPARalpha, delta and gamma, in mediating the behaviour of liver progenitor cells during pre-neoplastic disease and to investigate their potential as therapeutic targets for the treatment of chronic liver injury. We observed increased liver expression of PPARalpha and gamma in concert with expanding oval cell numbers during the first 21 days following commencement of the choline deficient, ethionine supplemented (CDE) dietary model of carcinogenic liver injury in mice. Both primary and immortalized liver progenitor cells were found to express PPARalpha, delta and gamma, but not gamma2, the alternate splice form of PPARgamma. WY14643 (PPARalpha agonist), GW501516 (PPARdelta agonist) and ciglitazone (PPARgamma agonist) were tested for their ability to modulate the behaviour of p53-immortalized liver (PIL) progenitor cell lines in vitro. Both PPARdelta and gamma agonists induced dose-dependent growth inhibition and apoptosis of PIL cells. In contrast, the PPARalpha agonist had no effect on PIL cell growth. None of the drugs affected the maturation of PIL cells along either the hepatocytic or biliary lineages, as judged by their patterns of hepatic gene expression prior to and following treatment. Administration of the PPARgamma agonist ciglitazone to mice fed with the CDE diet for 14 days resulted in a significantly diminished oval cell response and decreased fibrosis compared with those receiving placebo. In contrast, GW501516 did not affect oval cell numbers or liver fibrosis, but inhibited CDE-induced hepatic steatosis. In summary, PPARgamma agonists reduce oval cell proliferation and fibrosis during chronic liver injury and may be useful in the prevention of hepatocellular carcinoma.
Prior oral proton‐pump inhibitor use is associated with reduced severity of aspirin‐related upper gastrointestinal bleeding in older people
Publisher: Wiley
Date: 04-2022
DOI: 10.1111/IMJ.15732
Abstract: Low‐dose aspirin is commonly used for primary or secondary prophylaxis against cardiovascular disease in older people. However, the potential risk of upper gastrointestinal (UGI) ulceration and bleeding associated with low‐dose aspirin use is often not appreciated by prescribers and older consumers. Among 133 serial patients with UGI bleeding, aspirin‐users aged ≥70 years had a ninefold increased likelihood of overt UGI bleeding compared with non‐users, reducing by 90% in regular proton‐pump inhibitor users (adjusted odds ratio 0.10). We recommend risk‐versus‐benefit discussions when recommending aspirin to older people.
The C282Y polymorphism of the hereditary hemochromatosis gene is associated with increased sex hormone-binding globulin and normal testosterone levels in men.
Publisher: Springer Science and Business Media LLC
Date: 15-02-2010
DOI: 10.1007/BF03346645
HFECys282Tyr homozygotes with serum ferritin concentrations below 1000 μg/L are at low risk of hemochromatosis
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2010
DOI: 10.1002/HEP.23786
Tumor necrosis factor-like weak inducer of apoptosis is a mitogen for liver progenitor cells.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-03-2010
DOI: 10.1002/HEP.23663
Abstract: Liver progenitor cells (LPCs) represent the cell compartment facilitating hepatic regeneration during chronic injury while hepatocyte-mediated repair mechanisms are compromised. LPC proliferation is frequently observed in human chronic liver diseases such as hereditary hemochromatosis, fatty liver disease, and chronic hepatitis. In vivo studies have suggested that a tumor necrosis factor family member, tumor necrosis factor-like weak inducer of apoptosis (TWEAK), is promitotic for LPCs whether it acts directly is not known. In our murine choline-deficient, ethionine-supplemented (CDE) model of chronic liver injury, TWEAK receptor [fibroblast growth factor-inducible 14 (Fn14)] expression in the whole liver is massively upregulated. We therefore set out to investigate whether TWEAK/Fn14 signaling promotes the regenerative response in CDE-induced chronic liver injury by mitotic stimulation of LPCs. Fn14 knockout (KO) mice showed significantly reduced LPC numbers and attenuated inflammation and cytokine production after 2 weeks of CDE feeding. The close association between LPC proliferation and activation of hepatic stellate cells in chronic liver injury prompted us to investigate whether fibrogenesis was also modulated in Fn14 KO animals. Collagen deposition and expression of key fibrogenesis mediators were reduced after 2 weeks of injury, and this correlated with LPC numbers. Furthermore, the injection of 2-week-CDE-treated wildtype animals with TWEAK led to increased proliferation of nonparenchymal pan cytokeratin-positive cells. Stimulation of an Fn14-positive LPC line with TWEAK led to nuclear factor kappa light chain enhancer of activated B cells (NFkappaB) activation and dose-dependent proliferation, which was diminished after targeting of the p50 NFkappaB subunit by RNA interference. TWEAK acts directly and stimulates LPC mitosis in an Fn14-dependent and NFkappaB-dependent fashion, and signaling via this pathway mediates the LPC response to CDE-induced injury and regeneration.
Oncostatin M induces an acute phase response but does not modulate the growth or maturation-status of liver progenitor (oval) cells in culture.
Publisher: Elsevier BV
Date: 05-2005
DOI: 10.1016/J.YEXCR.2005.02.010
Abstract: Following acute injury, the liver regenerates through hepatocyte ision. If this pathway is impaired, liver repair depends on the recruitment of adult liver progenitor (oval) cells. Mice fed a choline deficient, ethionine supplemented (CDE) diet possess substantial numbers of oval cells, which can be isolated, or examined in vivo. Oncostatin M (OSM) has been shown to induce maturation of murine fetal hepatoblasts into hepatocytes. We recently confirmed this in human fetal liver cultures. Here, we show that liver OSM expression increases in mice fed a CDE diet and CDE-derived oval cell isolates express OSM and its receptor (OSMR). Oval cell lines (PIL cells), as well as primary oval cell cultures, displayed STAT-3 phosphorylation following OSM stimulation. OSM had no effect on the growth of primary oval cells, but it was pro-apoptotic to PIL cells, suggesting that the two cell models are not directly comparable. Expression of PCNA and cyclin D1 was not affected by OSM treatment. No evidence was obtained to suggest an effect on oval cell maturation with OSM treatment. However, decreased albumin production, accompanied by increased expression of haptoglobin and fibrinogen, suggests that OSM induced an acute phase reaction in cultured oval cells.
Detection of HFE Haemochromatosis in the clinic and community using standard erythrocyte tests
Publisher: Elsevier BV
Date: 02-2019
DOI: 10.1016/J.BCMD.2018.10.003
Abstract: Detection of HFE Haemochromatosis (HH) is challenging in the absence of clinical features. HH subjects have elevated erythrocyte parameters compared to those without HH, but it remains unclear how this could be applied in clinical practice. Thus, we determined the sensitivity, specificity and clinical utility of erythrocyte parameters in 144 HH subjects with (n = 122) or without (n = 22) clinical and/or biochemical expression of iron overload, 1844 general population controls, and 700 chronic disease subjects. For both expressing and non-expressing HH subjects, the mean pre- and post-phlebotomy values of mean cell volume (MCV) and mean cell haemoglobin (MCH) were always significantly higher when compared to all other groups and demonstrated excellent diagnostic utility for detection of HH in men and women (AUROC 0.83-0.9 maximal sensitivity and specificity 82% and 78%) using cut-off values for MCV >91 fL or MCH >31 pg, respectively. Between 34 and 62% of all HH subjects would be detected, and 94 fL or 32.2 pg, respectively, were evaluated.
Comparison of the cardiometabolic profiles of adolescents conceived through ART with those of a non-ART cohort
Publisher: Oxford University Press (OUP)
Date: 28-05-2022
Abstract: Is the cardiometabolic health of adolescents conceived through ART worse than that of their counterparts conceived without ART? The majority of cardiometabolic and vascular health parameters of adolescents conceived through ART are similar or more favourable, than those of their counterparts of similar age and conceived without ART. It has been proposed that the cardiometabolic health of offspring conceived with ART may be unfavourable compared to that of their counterparts conceived without ART. The literature pertaining to cardiometabolic health of offspring conceived after ART is contradictory, but generally suggests unfavourable cardiometabolic health parameters, such as an increase in blood pressure (BP), vascular dysfunction and adiposity, as well as unfavourable glucose and lipid profiles. With over 8 million children and adults born through ART worldwide, it is important to investigate whether these early signs of adverse cardiometabolic differences persist into adolescence and beyond. The Growing Up Healthy Study (GUHS) is a prospective cohort study that recruited 303 adolescents and young adults conceived after ART (aged 13–21 years) and born between 1991 and 2001 in Western Australia. Their health parameters, including cardiometabolic factors, were assessed and compared with counterparts from the Raine Study Generation 2 (Gen2). The 2868 Gen2 participants were born 1989–1992 and are representative of the Western Australian adolescent population. At ∼17 years of age (2013–2017), 163 GUHS participants replicated assessments previously completed by Gen2 at a similar age. Cardiometabolic parameters were compared between a total of 163 GUHS and 1457 Gen2 adolescents. Separate male (GUHS n = 81, Gen2 n = 735) and female (GUHS n = 82, Gen2 n = 722) analyses were conducted. Assessments consisted of a detailed questionnaire including health, lifestyle and demographic parameters, anthropometric assessments (height, weight, BMI, waist circumference and skinfold thickness), fasting serum biochemistry, arterial stiffness and BP (assessed using applanation tonometry). Abdominal ultrasonography was used to assess the presence and severity of hepatic steatosis, and thickness of abdominal fat compartments. Non-alcoholic fatty liver disease (NAFLD) was diagnosed if there was sonographic fatty liver in the absence of significant alcohol consumption. Chi2, Fisher’s exact and Mann–Whitney U tests, performed in SPSS V25, examined cohort differences and generalized estimating equations adjusted for the following covariates: singleton vs non-singleton pregnancy, birthweight (z-score), gestational age, BMI, smoking, alcohol consumption in the past 6 months and parent cardiovascular status. Arterial stiffness measures and waist circumference were additionally adjusted for height, and female analyses were additionally adjusted for use of oral contraceptives in the preceding 6 months. In adjusted analyses, GUHS females had a lower BMI (22.1 vs 23.3 kg/m2, P = 0.014), and thinner skinfolds (triceps, subscapular, mid-abdominal 16.9 vs 18.7 mm, P = 0.021, 13.4 vs 15.0 mm, P = 0.027, 19.7 vs 23.2 mm, P & 0.001, respectively), whereas males were not significantly different. Waist circumference was lower in GUHS adolescents (males: 78.1 vs 81.3 cm, P = 0.008, females: 76.7 vs 83.3 cm, P = 0.007). There were no significant differences between the two groups in glucose, insulin, homeostatic model assessment for insulin resistance, low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), alanine aminotransferase and high-sensitivity C-reactive protein in both sexes. In females, serum triglycerides were lower in GUHS adolescents (1.0 vs 1.2 mmol/l, P = 0.029). GUHS males had higher serum HDL-C (1.1 vs 1.0 mmol/l, P = 0.004) and a lower TC/HDL-C ratio (3.2 vs 3.6, P = 0.036). There were no significant differences in the prevalence of NAFLD or steatosis severity scores between the cohorts in males and females. GUHS females had less subcutaneous adipose tissue (9.4 vs 17.9 mm, P & 0.001), whereas GUHS males had greater visceral adipose thickness (44.7 vs 36.3 mm, P & 0.001). There was no significant difference in pre-peritoneal adipose thickness. Pulse wave velocity was lower in GUHS males (5.8 vs 6.3 m/s, P & 0.001) and heart rate corrected augmentation index was lower in GUHS females (−8.4 vs −2.7%, P = 0.048). There were no significant differences in BP or heart rate in males or females between the two groups. Despite the substantial study size and the unique study design of the ART cohort, we were unable to differentiate between different types of ART, due to the low number of ICSI cycles (e.g. IVF vs ICSI), draw definite conclusions, or relate the outcomes to the cause of infertility. Considering the differences in time points when both cohorts were studied, external factors could have changed, which could not be accounted for. Given the observational nature of this study, causation cannot be proven. Contrary to our hypothesis and previous findings focussing mainly on childhood, this study reports mostly similar or favourable cardiometabolic markers in adolescents conceived with ART compared to those conceived without ART. The greater visceral adipose thickness, particularly present in males, requires further investigation. While these findings are generally reassuring, future well-designed and appropriately powered studies are required to definitively address the issue of cardiometabolic health in ART adults. This project was supported by NHMRC project grant number 1042269 and R.J.H. received education grant funding support from Ferring Pharmaceuticals. R.J.H. is the Medical Director of Fertility Specialists of Western Australia and a shareholder in Western IVF. He has received educational sponsorship from MSD, Merck-Serono and Ferring Pharmaceuticals. P.B. is the Scientific Director of Concept Fertility Centre, Subiaco, Western Australia. J.L.Y. is the Medical Director of PIVET Medical Centre, Perth, Western Australia. N/A.
Clinical practice guidelines on hemochromatosis: Asian Pacific Association for the Study of the Liver
Publisher: Springer Science and Business Media LLC
Date: 17-04-2023
Screening for hemochromatosis: Patients with liver disease, families, and populations
Publisher: Springer Science and Business Media LLC
Date: 2004
DOI: 10.1007/S11894-004-0025-2
Abstract: Hereditary hemochromatosis is a common autosomal- recessive disorder of iron overload usually occurring in in iduals who are homozygous for a C282Y mutation in the hemochromatosis (HFE) gene. Current screening methods can detect affected in iduals early in disease pathogenesis, enabling early institution of effective treatment that can restore normal life expectancy. Phenotypic screening of adults using transferrin saturation and serum ferritin levels identifies the majority of in iduals who develop iron overload. HFE genotyping, when combined with serum biochemical measurements, has reduced reliance on liver biopsy as a diagnostic tool and is the preferred initial screening modality for families with an affected in idual. Genetic testing has altered previously held views regarding the high level of penetrance of the disease. Although the majority of C282Y homozygotes develop increased body iron stores, end-organ damage occurs much less frequently than previously thought. Screening is recommended in high-risk groups and in those with a high index of clinical suspicion. Opportunistic screening during routine health assessments may also be recommended. However, large-scale screening of the average-risk population is not recommended on the basis of current evidence.
Murine precision-cut liver slices as an ex vivo model of liver biology
Publisher: MyJove Corporation
Date: 14-03-2020
DOI: 10.3791/60992
Single-nucleus RNA sequencing of pre-malignant liver reveals disease-associated hepatocyte state with HCC prognostic potential
Publisher: Elsevier BV
Date: 05-2023
HCV, Iron, and Oxidative Stress: The New Choreography of Hepcidin
Publisher: Elsevier BV
Date: 2008
Higher ferritin levels, but not serum iron or transferrin saturation, are associated with Type 2 diabetes mellitus in adult men and women free of genetic haemochromatosis
Publisher: Wiley
Date: 23-07-2015
DOI: 10.1111/CEN.12529
Abstract: Iron overload predisposes to diabetes and higher ferritin levels have been associated with diabetes. However, it is unclear whether ferritin reflects differences in iron-related parameters between diabetic and nondiabetic persons. We examined associations of serum ferritin, iron and transferrin saturation with Type 2 diabetes in adults without genetic predisposition to iron overload. Cross-sectional analysis of community-dwelling men and women aged 17-97 years from the Busselton Health Survey, Western Australia. Men and women carrying genotypes associated with haemochromatosis (C282Y/C282Y or C282Y/H63D) were excluded. Serum ferritin, iron and transferrin saturation were assayed. There were 1834 men (122 with diabetes, 6·6%) and 2351 women (141 with diabetes, 6%). In men, higher serum ferritin was associated with diabetes after adjusting for age, smoking, alcohol, cardiovascular history, body mass index (BMI), waist, blood pressure, lipids, C-reactive protein (CRP), adiponectin, alanine transaminase (ALT) and gamma-glutamyl transpeptidase (GGT) [odds ratio (OR): 1·29 per 1 unit increase log ferritin, 95% confidence interval (CI) = 1·01-1·65, P = 0·043]. In women, higher serum ferritin was associated with diabetes [fully adjusted OR: 1·31 per 1 unit increase log ferritin, 95% CI = 1·04-1·63, P = 0·020 1·84 for tertile (T) 3 vs T1, 95% CI = 1·09-3·11]. Neither iron levels nor transferrin saturation were associated with diabetes risk in men or women. Higher ferritin was not associated with insulin resistance in nondiabetic adults. In adults, higher ferritin levels are independently associated with prevalent diabetes while iron and transferrin saturation are not. Ferritin is a robust biomarker for diabetes risk, but further investigation is needed to clarify whether this relationship is mediated via iron metabolism.
Evaluation of the Cellscreen system for proliferation studies on liver progenitor cells.
Publisher: Elsevier BV
Date: 12-2006
DOI: 10.1016/J.EJCB.2006.08.006
Abstract: Proliferation studies on mammalian cells have been disadvantaged by the limited availability of non-invasive assays as the majority of approaches are based on chemical treatment, s ling or staining of cells removed from culture. In this study, we utilised the Cellscreen system (Innovatis AG, Bielefeld, Germany), a non-invasive automated technique for measuring proliferation of adherent and suspension cells over time. We have evaluated the ability of the Cellscreen system to monitor and quantify growth of adherent liver progenitor cells over time and tested several applications, (i) serum reduction or (ii) treatment with a cytokine. Our results demonstrate that the Cellscreen system reproducibly documents pro- and anti-proliferative effects of cytokines and growth factors and quantifies changes by providing cell-doubling times for control and test cultures. However, we found that for the conversion of cell density values into absolute cell numbers different conversion factors, which better suit the in idual growth phases, need to be established. Collectively, these findings reveal that the Cellscreen system is applicable for the determination of cell proliferation of adherent and suspension cells in response to a variety of (growth) factors. It minimises operator participation and thus enables more rapid and larger screens and, being non-invasive, permits multiple assays on the same culture of cells. Hence, this technique proves superior to the common proliferation assays opening up new dimensions of proliferation studies in cell biology.
Jekyll and Hyde: evolving perspectives on the function and potential of the adult liver progenitor (oval) cell
Publisher: Wiley
Date: 2005
DOI: 10.1002/BIES.20311
Abstract: The liver progenitor cell (LPC) has enormous potential for use in cell therapy to treat liver disease. Since liver regenerates readily from pre-existing hepatocytes, a role for LPCs and, indeed, their existence have been questioned. Research during the last decade has established that LPCs are an important alternative source of cells for liver regeneration. Their utility for cell therapy lies in their ability to generate both hepatocytes and cholangiocytes. However, they are observed in liver diseases that often lead to cancer and there is experimental evidence that implicates LPCs as the source of tumours. This article provides a brief history of the studies that established the functional importance of LPCs in liver disease. It focuses on mouse models that have led to the identification of factors that regulate LPC growth and differentiation and discusses LPCs derived from different sources. Recent promising results from both in vitro and vivo studies suggest that LPCs could be useful for cell therapy. In the context of liver disease, LPCs may indeed be the cell of the future and understandably "our favourite cell".
The Murine Choline-Deficient, Ethionine-Supplemented (CDE) Diet Model of Chronic Liver Injury
Publisher: MyJove Corporation
Date: 21-10-2017
DOI: 10.3791/56138
Gastric intraepithelial neoplasia in a Western population
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2012
Prevalence, characteristics, and prognostic significance of HFE gene mutations in type 2 diabetes: The fremantle diabetes study
Publisher: American Diabetes Association
Date: 09-2008
DOI: 10.2337/DC08-0248
Abstract: OBJECTIVE—To examine the relationship between iron status, hereditary hemochromatosis (HFE) gene mutations, and clinical features and outcomes of type 2 diabetes in a well-characterized representative s le of community-based patients. RESEARCH DESIGN AND METHODS—HFE genotype data were available for 1,245 type 2 diabetic patients from the longitudinal observational Fremantle Diabetes Study (FDS), representing 96.2% of the total FDS type 2 diabetes cohort. Data were collected at recruitment between 1993 and 1996 and annually until the end of June 2001. Hospitalization and mortality data were available until the end of June 2006. The presence of the C282Y HFE mutation was determined in all subjects and H63D in C282Y heterozygotes. Fasting serum iron, transferrin, and ferritin were measured in all C282Y homozygotes and C282Y/H63D heterozygotes and in 286 randomly selected wild-type subjects. Multiple logistic regression analysis was performed to determine independent baseline associates of prevalent complications (myocardial infarction, cerebrovascular disease, retinopathy, neuropathy, and nephropathy), as was Cox proportional hazards modeling to determine predictors of incident complications and mortality. RESULTS—Although there were expected positive associations between HFE gene mutations and serum iron and transferrin saturation, there were no independent positive associations between HFE gene status and either microvascular or macrovascular complications in cross-sectional and longitudinal analyses. HFE gene status did not independently predict cardiac or all-cause mortality. Measures of iron metabolism including serum ferritin were not associated with combined microvascular or macrovascular end points. CONCLUSIONS—Directed screening for iron overload and/or HFE mutations appears unwarranted in patients with type 2 diabetes.
Hereditary hemochromatosis is characterized by a clinically definable arthropathy that correlates with iron load
Publisher: Wiley
Date: 28-12-2010
DOI: 10.1002/ART.30094
Abstract: To determine the frequency and character of arthropathy in hereditary hemochromatosis (HH) and to investigate the relationship between this arthropathy, nodal interphalangeal osteoarthritis, and iron load. Participants were recruited from the community by newspaper advertisement and assigned to diagnostic confidence categories for HH (definite robable or possible/unlikely). Arthropathy was determined by use of a predetermined clinical protocol, radiographs of the hands of all participants, and radiographs of other joints in which clinical criteria were met. An arthropathy considered typical for HH, involving metacarpophalangeal joints 2-5 and bilateral specified large joints, was observed in 10 of 41 patients with definite or probable HH (24%), all of whom were homozygous for the C282Y mutation in the HFE gene, while only 2 of 62 patients with possible/unlikely HH had such an arthropathy (P=0.0024). Arthropathy in definite robable HH was more common with increasing age and was associated with ferritin concentrations>1,000 μg/liter at the time of diagnosis (odds ratio 14.0 [95% confidence interval 1.30-150.89], P=0.03). A trend toward more episodes requiring phlebotomy was also observed among those with arthropathy, but this was not statistically significant (odds ratio 1.03 [95% confidence interval 0.99-1.06], P=0.097). There was no significant association between arthropathy in definite robable HH and a history of intensive physical labor (P=0.12). An arthropathy consistent with that commonly attributed to HH was found to occur in 24% of patients with definite robable HH. The association observed between this arthropathy, homozygosity for C282Y, and serum ferritin concentrations at the time of diagnosis suggests that iron load is likely to be a major determinant of arthropathy in HH and to be more important than occupational factors.
TWEAK/Fn14 Signalling Regulates the Tissue Microenvironment in Chronic Pancreatitis
Publisher: MDPI AG
Date: 16-03-2023
Abstract: Chronic pancreatitis increases the risk of developing pancreatic cancer through the upregulation of pathways favouring proliferation, fibrosis, and sustained inflammation. We established in previous studies that the ligand tumour necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) signals through its cognate receptor fibroblast growth factor-inducible 14 (Fn14) to regulate these underlying cellular processes in the chronic liver injury niche. However, the role of the TWEAK/Fn14 signalling pathway in pancreatic disease is entirely unknown. An analysis of publicly available datasets demonstrated that the TWEAK receptor Fn14 is upregulated in pancreatitis and pancreatic adenocarcinoma, with single cell RNA sequencing revealing pancreatic ductal cells as the main Fn14 producers. We then used choline-deficient, ethionine-supplemented (CDE) diet feeding of wildtype C57BL/6J and Fn14 knockout littermates to (a) confirm CDE treatment as a suitable model of chronic pancreatitis and (b) to investigate the role of the TWEAK/Fn14 signalling pathway in pancreatic ductal proliferation, as well as fibrotic and inflammatory cell dynamics. Our time course data obtained at three days, three months, and six months of CDE treatment reveal that a lack of TWEAK/Fn14 signalling significantly inhibits the establishment and progression of the tissue microenvironment in CDE-induced chronic pancreatitis, thus proposing the TWEAK/Fn14 pathway as a novel therapeutic target.
Characterisation of hepatic and cardiac iron deposition during standard treatment of anaemia in haemodialysis.
Publisher: Wiley
Date: 08-01-2016
DOI: 10.1111/NEP.12735
Abstract: Parenteral iron is integral in the treatment of anaemia of chronic kidney disease patients on haemodialysis (HD). However, increased liver iron concentration (LIC) can result from such treatment, and this correlates poorly with serum ferritin or transferrin saturation values. It is unclear whether increased cardiac iron concentration also occurs in this setting. We aimed to evaluate the relationship of intravenous iron supplementation to hepatic and cardiac iron deposition in chronic HD subjects. A cohort of 10 patients on chronic HD for at least 1 year underwent MRI-based quantitation of hepatic and cardiac iron content to evaluate the relationship between intravenous iron supplements and hepatic and cardiac iron deposition. The results were compared against the cumulative parenteral iron dose and serum iron markers. The median age was 61 years (95% confidence interval (CI) 50-71), HD time 2.5 years (95%CI 2.0-5.3) and cumulative iron dose 4300 mg (95%CI 2110-9045). Hepatic iron concentration was elevated in eight of 10 subjects (median 46 mmol/kg, range 31-76). Cardiac iron levels were within the reference range in all subjects. There was poor correlation between conventional haematinic values and either LIC or cardiac iron levels. None of the study subjects exhibited elevated cardiac iron concentration. Whilst HD patients receiving standard parenteral iron therapy have elevated LICs, this is not associated with cardiac iron deposition. Transferrin saturation and serum ferritin levels are poor markers of either liver or cardiac iron deposition in HD subjects.
Hemochromatosis
Publisher: Massachusetts Medical Society
Date: 08-12-2022
Impact of modern antiviral therapy of chronic hepatitis B and C on clinical outcomes of liver disease
Publisher: Baishideng Publishing Group Inc.
Date: 07-08-2021
Iron and the response to treatment of hepatitis C
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2002
Quantitative assay of urinary hepcidin using MALDI-TOF mass spectrometry
Publisher: Royal Society of Chemistry (RSC)
Date: 2010
DOI: 10.1039/B9AY00130A
NAFLD as a risk factor for the development of diabetes and the metabolic syndrome : an eleven-year follow-up study
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 17-03-2009
DOI: 10.1038/AJG.2009.67
Abstract: Non-alcoholic fatty liver disease (NAFLD) uncommonly results in cirrhosis and liver-related death however, its impact on the development of metabolic complications remains unclear. We sought to determine whether NAFLD with elevated aminotransaminase (ALT) levels was a risk factor for incident diabetes or the metabolic syndrome (MS) over an 11-year period. Adult residents of Busselton, Western Australia underwent assessment in 1994-1995 as part of the Busselton Health Survey. NAFLD was diagnosed on the basis of a raised ALT (>40 IU/l) after the exclusion of alcohol, viral, metabolic, and autoimmune liver disease. NAFLD and non-NAFLD subjects were reassessed in 2005 for liver complications, diabetes, and the MS. A total of 358 subjects, 68% male (109 NAFLD, 249 non-NAFLD), mean age (s.d.) 59.9 (11.6) years, attended follow-up 11.1 years after the initial assessment. After excluding subjects with diabetes at baseline, those with NAFLD were more likely to have developed diabetes on follow-up (20/106, 18.9% vs. 15/246, 6.1% P<0.001). After excluding subjects with MS at baseline, those with NAFLD were more likely to have developed MS at follow-up (27/81, 33.3% vs. 51/226, 22.6% P=0.056). However, in multivariate logistic regression models, NAFLD was no longer a significant independent predictor of the development of diabetes or MS after adjusting for baseline waist circumference, hypertension, and insulin resistance. None of the subjects developed liver complications. Subjects with NAFLD and elevated ALT levels are at an increased risk of developing diabetes and the MS. This may be because of the presence of associated metabolic risk factors.
γ′ fibrinogen levels as a biomarker of COVID-19 respiratory disease severity
Publisher: Elsevier BV
Date: 07-2023
Blood transfusion in acute upper gastrointestinal bleeding: is giving more blood always better?
Publisher: AME Publishing Company
Date: 07-06-2017
Interferon-gamma exacerbates liver damage, the hepatic progenitor cell response and fibrosis in a mouse model of chronic liver injury
Publisher: Elsevier BV
Date: 12-2007
DOI: 10.1016/J.JHEP.2007.06.022
Abstract: Several previous studies have suggested that interferon gamma (IFNgamma) may play a key role during hepatic progenitor cell (HPC) mediated liver regeneration. However to date, no studies have directly tested the ability of IFNgamma to mediate the HPC response in an in vivo model. Administration of IFNgamma to mice receiving a choline deficient, ethionine (CDE) supplemented diet to induce chronic injury resulted in an augmented HPC response. This was accompanied by increased inflammation, altered cytokine expression and hepatic fibrosis. Serum alanine aminotransferase activity, hepatocyte apoptosis and Bak staining were significantly increased in IFNgamma-treated, CDE-fed mice, demonstrating that liver damage was exacerbated in these animals. Administration of IFNgamma to control diet fed mice did not induce liver damage, however it did stimulate hepatic inflammation. Our results suggest that IFNgamma increases the HPC response to injury by stimulating hepatic inflammation and aggravating liver damage. This is accompanied by an increase in hepatic fibrogenesis, supporting previous reports which suggest that the HPC response may drive fibrogenesis during chronic liver injury.
Nomenclature of the finer branches of the biliary tree: Canals, ductules, and ductular reactions in human livers
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2004
DOI: 10.1002/HEP.20130
Abstract: The work of liver stem cell biologists, largely carried out in rodent models, has now started to manifest in human investigations and applications. We can now recognize complex regenerative processes in tissue specimens that had only been suspected for decades, but we also struggle to describe what we see in human tissues in a way that takes into account the findings from the animal investigations, using a language derived from species not, in fact, so much like our own. This international group of liver pathologists and hepatologists, most of whom are actively engaged in both clinical work and scientific research, seeks to arrive at a consensus on nomenclature for normal human livers and human reactive lesions that can facilitate more rapid advancement of our field.
A long-term study of the interaction between iron and alcohol in an animal model of iron overload
Publisher: Elsevier BV
Date: 06-1995
DOI: 10.1016/0168-8278(95)80222-3
Abstract: The hypothesis that chronic alcohol ingestion potentiates iron-associated liver injury was investigated in the 'carbonyl iron-overload rat model'. Newborn male and female Wistar-Furth rats (seven per group) were used to investigate iron-alcohol interaction over a 26-week period. Groups 1 and 2 were iron loaded from birth, while the others received normal diet. At 10 weeks all rats commenced Lieber-DeCarli liquid diet additional treatments were: group 1 6 g carbonyl iron/1000 ml diet plus alcohol group 2 carbonyl iron in the liquid diet group 3 alcohol in the liquid diet group 4, the controls, received liquid diet only. This study confirmed our previous observation that iron-loading from birth resulted in grade III-IV siderosis, in both male and female rats, and caused fibrosis associated with periportal macrophages. Alcohol-feeding, in addition to iron-feeding for 26 weeks significantly lowered the hepatic iron concentration in both male and female rats compared to those fed iron only (p < 0.05). Alcohol feeding did increase hepatic fibrosis in the iron-loaded animals. However, serum alanine aminotransferase activity was significantly higher in the iron-alcohol group than in the other groups (p < 0.05). Thus, contrary to expectation, chronic alcohol feeding failed to potentiate hepatic fibrosis in iron-overloaded rats, although there was rather more hepatocyte necrosis, and the serum alanine aminotransferase activity was significantly higher in the iron-alcohol group than in the other groups.
Diagnostic Performance of a Rapid Magnetic Resonance Imaging Method of Measuring Hepatic Steatosis
Publisher: Public Library of Science (PLoS)
Date: 21-03-2013
Hepatic iron concentration as a predictor of response to interferon alfa therapy in chronic hepatitis C
Publisher: Elsevier BV
Date: 04-1995
DOI: 10.1016/0016-5085(95)90209-0
Abstract: It has been reported that hepatic iron concentration (HIC) may influence response to therapy in chronic viral hepatitis. The aim of this study was to determine the relationship between HIC and response to interferon alfa therapy in patients with chronic hepatitis C. HIC was measured in liver biopsy specimens from 58 patients with chronic hepatitis C treated at three centers. Three patients had mild chronic hepatitis C, 35 had moderate to severe chronic hepatitis C, and 20 had active cirrhosis. Serum ferritin levels were measured in 51 of these 58 patients. Response to therapy was defined as normalization of alanine aminotransferase levels at the end of treatment. Twenty-four patients (41%) responded to therapy. HICs were generally within the normal range (< 1500 micrograms/g). The mean HIC in nonresponders (860 +/- 100 micrograms/g range, 116-2296 micrograms/g) was significantly higher than in responders (548 +/- 85 micrograms/g range, 29-1870 micrograms/g) (P 1100 micrograms/g and 87% of patients with an elevated serum ferritin concentration did not respond to interferon alfa therapy. HIC seems to influence response to interferon alfa therapy among patients with chronic hepatitis C. A subgroup of patients with chronic hepatitis C has been identified for which an HIC of > 1100 micrograms/g predicted nonresponse in 88% of patients.
Significant association between thyroid hormones and erythrocyte indices in euthyroid subjects
Publisher: Wiley
Date: 04-01-2012
DOI: 10.1111/J.1365-2265.2011.04228.X
Abstract: Hypothyroidism and hyperthyroidism are each associated with anaemia, but relationships between thyroid function and erythrocyte indices in euthyroid subjects have not been examined. The aim of this study was to examine these relationships in a community-based cohort. Linear regression models with free T4, free T3 and TSH as predictors of erythrocyte indices and serum iron parameters were fitted to data from a cohort of 1179 participants in the 1994 Busselton health study and a subset of 1011 euthyroid participants. All models were adjusted for age, age(2), sex and an age-sex interaction. In the full cohort and euthyroid subset, there were significant, positive linear relationships between free T4 and each of haemoglobin, haematocrit and erythrocyte count (P < 0·01 for each), such that in euthyroid participants, each 1·0 pM increase in free T4 was associated with an increase in haemoglobin of 0·39 g/l. There were significant relationships between free T3 and each of haemoglobin, haematocrit and erythrocyte count (P < 0·001 for each), with the best model fits obtained using free T3(2), indicating curved relationships. TSH had a significant (P < 0·05) inverse relationship with serum iron and transferrin saturation in the full cohort and the euthyroid subset. Serum iron concentrations were lower in participants with subclinical hypothyroidism (n = 87) than euthyroid subjects [mean (SD) 15·9 (4·7) vs 18·4 (6·0) μM, P = 0·001]. In euthyroid subjects, small differences in thyroid function are associated with significant differences in erythrocyte indices.
Serum Iron Markers Are Inadequate for Guiding Iron Repletion in Chronic Kidney Disease
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2011
DOI: 10.2215/CJN.04190510
Abstract: Iron (Fe) overload may complicate parenteral Fe therapy used to enhance the efficacy of erythropoietic-stimulating agents in the treatment of anemia of chronic kidney disease. However, serum Fe markers are influenced by inflammation or malignancy and may not accurately reflect the amount of body Fe. We studied the relationship between parenteral Fe therapy, conventional serum Fe markers, and liver iron concentration (LIC) measured using magnetic resonance R2 relaxometry (FerriScan) in 25 Fe-deficient predialysis chronic kidney disease patients before and 2 and 12 weeks after single high-dose intravenous Fe and in 15 chronic hemodialysis patients with elevated serum ferritin ( μg/L). In predialysis patients, there was strong dose dependency between the administered Fe dose and changes in LIC at weeks 2 and 12 however, no dose dependency between Fe dose and changes in ferritin or transferrin saturation (TSAT) were observed. In hemodialysis patients, LIC correlated with the cumulative Fe dose and duration of dialysis but not with current ferritin or TSAT. The cumulative Fe dose remained a significant independent predictor of LIC in a multiple regression model. Two dialysis patients who received g parenteral Fe had substantially elevated LIC μmol/g, which is associated with hemochromatosis. In Fe-deficient predialysis patients, intravenous Fe therapy is associated with increases in LIC unrelated to changes in conventional Fe markers. In hemodialysis patients, TSAT and ferritin are poor indicators of body Fe load, and some patients have LICs similar to those found in hemochromatosis.
A comparison of self‐reported and record‐linked blood donation history in an Australian cohort
Publisher: Wiley
Date: 19-04-2011
DOI: 10.1111/J.1537-2995.2011.03141.X
Abstract: Questionnaire-based studies investigating blood donation history rely on the accurate recall of information from participants for results to be valid. This study aimed to retrieve electronic records from a national blood donation service and link them to self-reported history of donation to assess agreement between the two sources. Between 2004 and 2006, a s le of participants of northern European descent was selected from the Melbourne Collaborative Cohort Study (n = 31,192) to participate in the "HealthIron" study (n = 1438). A total of 1052 participants completed questionnaires that included questions about blood donation history. In 2009, consenting participants' records were linked to the Australian Red Cross Blood Service (ARCBS) to provide information on blood donations made between 1980 and follow-up (2004-2006). Those who commenced blood donation before 1980 were excluded. A total of 718 participants were available for analysis. Of these, 394 (55%) provided signed consent, including 182 (82%) of the 227 participants who self-reported ever donating blood. The two data sources were concordant for 331 (87%) of participants, with a κ statistic of 0.74 (SE, 0.05) indicating a high level of agreement. Participants tended to overstate by a factor of 2.0 (95% confidence interval, 1.7-2.2) the number of donations they had made when compared with ARCBS records. Participants in studies assessing self-reported blood donation history are likely to correctly indicate whether or not they have ever donated blood. Quantitative estimates are potentially inaccurate and could benefit from validating a s le of records to quantify the bias.
The relationship between abdominal pain and emotional wellbeing in children and adolescents in the Raine Study
Publisher: Springer Science and Business Media LLC
Date: 03-02-2020
DOI: 10.1038/S41598-020-58543-0
Abstract: Abdominal pain is a common reason for medical visits. We examined the prevalence, gastrointestinal, and emotional significance of abdominal pain in a population-based cohort serially followed up from birth to 17 years. Children and adolescents from Generation 2 of the Raine Study participated in comprehensive cross-sectional assessments at ages 2, 5, 8, 10, 14 and 17 years. At 17 years, medical history, general health, gastrointestinal symptoms, medications, health practitioner attendance, and self-rated unhappiness were recorded. Longitudinal data regarding abdominal pain or unhappiness, from serial questionnaires, were analysed to identify factors associated with abdominal pain and adverse emotional health at age 17 years. Females experienced more abdominal pain than males at all ages (p 0.05). Seventeen-year-old adolescents with abdominal pain reported a higher prevalence of depression, anxiety, being bullied at school, and poorer health status than those without abdominal pain (p 0.05 for all). Abdominal pain and unhappiness during childhood and mid-adolescence were prospectively associated with recurrent abdominal pain, anxiety, depression and unhappiness during late adolescence (p 0.05 for all). In conclusion, abdominal pain in children and adolescents associates with depression, anxiety, being bullied, unhappiness and reduced overall health-rating during adolescence. Awareness of these factors may guide management decisions.
Hepatic oval cell response to the choline-deficient, ethionine supplemented model of murine liver injury is attenuated by the administration of a cyclo-oxygenase 2 inhibitor
Publisher: Oxford University Press (OUP)
Date: 12-12-2006
Abstract: Oval cell proliferation precedes neoplasia in many rodent models of hepatocellular carcinoma and prevention of this proliferative response can reduce the risk of subsequent carcinoma. This study aimed to determine whether a selective cyclo-oxygenase-2 (COX-2) inhibitor, SC-236, affects (i) the oval cell response to liver injury in a mouse model of hepatocarcinogenesis and (ii) an oval cell line. Four-week-old mice were fed either normal chow or a choline deficient, ethionine supplemented (CDE) diet in the presence or absence of SC-236. Liver histology and oval cell numbers were determined after 2, 4, 12 and 52 weeks of treatment. Oval cells were scored using morphological criteria and positive immuno-staining for the M(2)-isozyme of pyruvate kinase (M2PK) or A6. An immortalized oval cell line (PIL-2) was used to study the in vitro effects of SC-236 on oval cell proliferation, apoptosis and Akt phosphorylation. The percentage of M2PK-positive oval cells and COX-2-positive cells was reduced by 80% and 45%, respectively, in CDE-fed mice receiving SC-236 compared with CDE-fed animals not receiving SC-236. Some M2PK-positive oval cells were also COX-2 positive. The percentage of A6-positive cells was not affected by SC-236 administration to CDE-fed mice. Administration of SC-236 increased apoptosis as evidenced by a 73% increase in the number of TUNEL-positive cells at 2 weeks in CDE-fed mice. Primary oval cells and PIL-2 cells expressed COX-2. In vitro treatment of PIL-2 cells with SC-236 resulted in a dose-dependent preferential death of A6-negative cells. Administration of 25 and 50 microM Prostaglandin E(2) partially attenuated SC-236 induced cell death by 25%. In vitro oval cell death was associated with apoptosis and a 70% reduction in Akt phosphorylation. These results suggest that the SC-236 induced reduction of M2PK-positive oval cell numbers may be due to COX-2 dependent inhibition of Akt phosphorylation and induction of apoptosis.
Divergent Inflammatory, Fibrogenic, and Liver Progenitor Cell Dynamics in Two Common Mouse Models of Chronic Liver Injury
Publisher: Elsevier BV
Date: 07-2016
DOI: 10.1016/J.AJPATH.2016.03.005
Abstract: Complications of end-stage chronic liver disease signify a major cause of mortality worldwide. Irrespective of the underlying cause, most chronic liver diseases are characterized by hepatocellular necrosis, inflammation, fibrosis, and proliferation of liver progenitor cells or ductular reactions. Vast differences exist between experimental models that mimic these processes, and their identification is fundamental for translational research. We compared two common murine models of chronic liver disease: the choline-deficient, ethionine-supplemented (CDE) diet versus thioacetamide (TAA) supplementation. Markers of liver injury, including serum alanine transaminase levels, apoptosis, hepatic fat loading, and oxidative stress, as well as inflammatory, fibrogenic and liver progenitor cell responses, were assessed at days 3, 7, 14, 21, and 42. This study revealed remarkable differences between the models. It identified periportal injury and fibrosis with an early peak and slow normalization of all parameters in the CDE regimen, whereas TAA-treated mice had pericentral patterns of progressive injury and fibrosis, resulting in a more severe hepatic injury phenotype. This study is the first to resolve two different patterns of injury and fibrosis in the CDE and TAA model and to indisputably identify the fibrosis pattern in the TAA model as driven from the pericentral vein region. Our data provide a valuable foundation for future work using the CDE and TAA regimens to model a variety of human chronic liver diseases.
Iron overload impairs pro‐inflammatory cytokine responses by Kupffer cells
Publisher: Wiley
Date: 04-2001
DOI: 10.1046/J.1440-1746.2001.02456.X
Abstract: The aim of the present study was to determine the effect of chronic iron overload on Kupffer cell cytokine production. Kupffer cells were isolated from rats that were fed either a control or iron-supplemented diet for 12 months. Cytokine mRNA and protein levels were determined by using a ribonuclease protection assay and ELISA, respectively. Baseline levels of tumor necrosis factor-alpha, transforming growth factor-beta1, interleukin-6 and granulocyte macrophage colony stimulating factor were similar in iron-loaded and control Kupffer cells. Following the addition of lipopolysaccharide to control cells, tumor necrosis factor-alpha, interleukin-1alpha and interleukin-6 mRNA levels increased. Tumor necrosis factor-alpha mRNA and protein levels were reduced by 40 and 60%, respectively, in iron-loaded cells compared with controls following the addition of lipopolysaccharide. Interleukin-6 mRNA levels in iron-loaded Kupffer cells were also reduced. Granulocyte macrophage colony stimulating factor mRNA levels remained unchanged in controls, but were significantly elevated in iron-loaded cells. Tumor growth factor-beta1 mRNA and protein levels were similar in control and iron-loaded cells. Deposition of iron in Kupffer cells in chronic dietary iron overload results in an impaired pro-inflammatory cytokine response to lipopolysaccharide. Our observations may have relevance to the altered immune function observed in chronic iron-overload syndromes.
Distal colonic neoplasms predict proximal neoplasia in average‐risk, asymptomatic subjects
Publisher: Wiley
Date: 1999
DOI: 10.1046/J.1440-1746.1999.01804.X
Abstract: Flexible sigmoidoscopy has been recommended as a screening method to reduce the incidence of colorectal cancer in asymptomatic, average-risk subjects through the early detection and removal of polyps. However, the association between distal and proximal colonic neoplasia and, hence, the requirement for colonoscopic follow up of screen-detected distal neoplasms is unclear. Our aims were: (i) to evaluate the risk of having proximal neoplasms in those with distal colonic neoplasms and (ii) to determine whether the risk was dependent on the number, size, histology or morphology of the distal lesions. We prospectively evaluated asymptomatic subjects in a flexible sigmoidoscopy based screening programme. Those with rectosigmoid neoplasia underwent colonoscopy. The number, size, histology and morphology of the polyps were recorded. Advanced lesions were defined as adenomas > 1 cm or with a villous component or severe dysplasia, carcinoma in situ or cancer. Adenomatous polyps were found in 17% (135) of screening flexible sigmoidoscopies. At colonoscopy, up to 30% of subjects with distal colonic neoplasms had synchronous proximal lesions at colonoscopy and up to 20% had advanced proximal lesions. The risk of proximal colonic neoplasia was increased in those with distal sessile colonic neoplasms but appeared independent of distal lesion size, number or morphology. In conclusion, distal colonic neoplasia predicts proximal neoplasia in up to 30% of subjects and these were advanced lesions in up to 20%. We recommend that all subjects with biopsy proven distal colonic neoplasia undergo colonoscopy.
Brain transcriptome perturbations in the Hfe -/- mouse model of genetic iron loading
Publisher: Elsevier BV
Date: 04-2012
DOI: 10.1016/J.BRAINRES.2012.02.006
Abstract: Severe disruption of brain iron homeostasis can cause fatal neurodegenerative disease, however debate surrounds the neurologic effects of milder, more common iron loading disorders such as hereditary hemochromatosis, which is usually caused by loss-of-function polymorphisms in the HFE gene. There is evidence from both human and animal studies that HFE gene variants may affect brain function and modify risks of brain disease. To investigate how disruption of HFE influences brain transcript levels, we used microarray and real-time reverse transcription polymerase chain reaction to assess the brain transcriptome in Hfe(-/-) mice relative to wildtype AKR controls (age 10 weeks, n≥4/group). The Hfe(-/-) mouse brain showed numerous significant changes in transcript levels (p<0.05) although few of these related to proteins directly involved in iron homeostasis. There were robust changes of at least 2-fold in levels of transcripts for prominent genes relating to transcriptional regulation (FBJ osteosarcoma oncogene Fos, early growth response genes), neurotransmission (glutamate NMDA receptor Grin1, GABA receptor Gabbr1) and synaptic plasticity and memory (calcium/calmodulin-dependent protein kinase IIα Camk2a). As previously reported for dietary iron-supplemented mice, there were altered levels of transcripts for genes linked to neuronal ceroid lipofuscinosis, a disease characterized by excessive lipofuscin deposition. Labile iron is known to enhance lipofuscin generation which may accelerate brain aging. The findings provide evidence that iron loading disorders can considerably perturb levels of transcripts for genes essential for normal brain function and may help explain some of the neurologic signs and symptoms reported in hemochromatosis patients.
Potential protective effects of zinc in iron overload
Publisher: Wiley
Date: 16-01-2007
Differential DNA methylation of steatosis and non-alcoholic fatty liver disease in adolescence
Publisher: Springer Science and Business Media LLC
Date: 03-02-2023
DOI: 10.1007/S12072-022-10469-7
Abstract: Epigenetic modifications are associated with hepatic fat accumulation and non-alcoholic fatty liver disease (NAFLD). However, few epigenetic modifications directly implicated in such processes have been identified during adolescence, a critical developmental window where physiological changes could influence future disease trajectory. To investigate the association between DNA methylation and NAFLD in adolescence, we undertook discovery and validation of novel methylation marks, alongside replication of previously reported marks. We performed a DNA methylation epigenome-wide association study (EWAS) on DNA from whole blood from 707 Raine Study adolescents phenotyped for steatosis score and NAFLD by ultrasound at age 17. Next, we performed pyrosequencing validation of loci within the most 100 strongly associated differentially methylated CpG sites (dmCpGs) for which ≥ 2 probes per gene remained significant across four statistical models with a nominal p value 0.007. EWAS identified dmCpGs related to three genes ( ANK1, MIR10a , PTPRN2 ) that met our criteria for pyrosequencing. Of the dmCpGs and surrounding loci that were pyrosequenced ( ANK1 n = 6, MIR10a n = 7, PTPRN2 n = 3), three dmCpGs in ANK1 and two in MIR10a were significantly associated with NAFLD in adolescence. After adjustment for waist circumference only dmCpGs in ANK1 remained significant. These ANK1 CpGs were also associated with γ-glutamyl transferase and alanine aminotransferase concentrations. Three of twenty-two differentially methylated dmCpGs previously associated with adult NAFLD were associated with NAFLD in adolescence (all adjusted p 2.3 × 10 –3 ). We identified novel DNA methylation loci associated with NAFLD and serum liver biochemistry markers during adolescence, implicating putative dmCpG/gene regulatory pathways and providing insights for future mechanistic studies.
Pathological relationships involving iron and myelin may constitute a shared mechanism linking various rare and common brain diseases
Publisher: Informa UK Limited
Date: 2016
Cholesteryl ester transfer protein gene polymorphisms increase the risk of fatty liver in females independent of adiposity
Publisher: Wiley
Date: 21-08-2012
Hepcidin predicts response to IV iron therapy in patients admitted to the intensive care unit
Publisher: Springer Science and Business Media LLC
Date: 10-09-2018
Dietary Iron Enhances Colonic Inflammation and IL-6/IL-11-Stat3 Signaling Promoting Colonic Tumor Development in Mice
Publisher: Public Library of Science (PLoS)
Date: 06-11-2013
Limited iron export by hepatocytes contributes to hepatic iron-loading in the Hfe knockout mouse
Publisher: Elsevier BV
Date: 2006
DOI: 10.1016/J.JHEP.2005.08.012
Abstract: In hereditary hemochromatosis, iron-loading of hepatocytes is associated with increased iron uptake while little is known about iron release. This study aims to characterise iron release and ferroportin expression by Hfe knockout hepatocytes to determine if they contribute to iron overload in haemochromatosis. Iron release by hepatocytes from Hfe knockout, non-iron-loaded and iron-loaded wild-type mice was measured after incubation with nontransferrin-bound iron as iron-citrate. Iron release and ferroportin expression by hepatocytes from Hfe knockout, non-iron-loaded and in vivo iron-loaded wild-type mice were similar although, nontransferrin-bound iron uptake was significantly increased in Hfe knockout hepatocytes and decreased in iron-loaded wild-type hepatocytes compared with non-iron-loaded wild-type cells. When expressed as a percentage of total iron uptake, iron release was decreased in Hfe knockout hepatocytes (4.6+/-0.7 versus 13.7+/-1.2%, P<0.0001) and increased in iron-loaded wild-type hepatocytes (29.5+/-0.5 versus 13.5+/-0.7% P<0.0001) compared with wild-type hepatocytes. In contrast, in vitro iron-loading increased iron release and ferroportin expression by both Hfe knockout and wild-type hepatocytes. Hfe knockout hepatocytes accumulate iron as a result of limited iron export and enhanced iron uptake. The correlation between iron release and ferroportin expression suggests that iron export in hepatocytes is mediated by ferroportin.
Perioperative management of a common disorder: hereditary haemochromatosis
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2000
DOI: 10.1097/00001503-200006000-00018
Abstract: Hereditary haemochromatosis is the commonest autosomal recessive disorder affecting Caucasian populations, and is readily diagnosed on the basis of elevated total body iron stores and genetic testing. Increased awareness of this disease in the community will hopefully prompt earlier testing and diagnosis. Treatment with regular phlebotomy is simple and effective and can prevent significant morbidity and mortality. Preoperative evaluation of patients with this disorder should consider the potential multisystem involvement in iron overload.
Iron and Hepatic Carcinogenesis
Publisher: Begell House
Date: 2013
DOI: 10.1615/CRITREVONCOG.2013007759
Abstract: Iron is an essential co-factor for life however, a physiologically optimal balance is critical. Too much or too little iron can have detrimental effects on human health. In this article, we explore the relationships between iron and hepatocellular carcinoma (HCC). Iron can act as a modulating co-factor in a range of chronic liver diseases and can accelerate the development of liver injury, fibrosis, cirrhosis, and ultimately HCC. Iron can, however, also act as a sole factor in the causation of liver cirrhosis and HCC in in iduals with hereditary hemochromatosis (HH). We overview the regulation of normal iron metabolism and the role of iron in wound healing and associated cell types as well as in pathophysiologies that predispose to HCC. We review how these injury processes are inextricably linked, providing a mechanistic basis for understanding how iron and hepatic injury potentially result in HCC.
Decreased Physical Working Capacity in Adolescents With Nonalcoholic Fatty Liver Disease Associates With Reduced Iron Availability
Publisher: Elsevier BV
Date: 06-2020
DOI: 10.1016/J.CGH.2019.10.017
Abstract: Non-alcoholic fatty liver disease (NAFLD) is common and related to obesity and insulin resistance. Iron metabolism is impaired in obese in iduals and iron deficiency has been associated with physical inactivity. We investigated whether iron bioavailability is reduced in patients with NAFLD and contributes to reduced cardiorespiratory fitness. We collected information on weight-adjusted, submaximal physical work capacity (PWC), ultrasound-determined hepatic steatosis, iron indices, and hematologic and metabolic parameters from 390 female and 458 male participants of the Raine Study-a longitudinal study of disease development in 2868 children in Western Australia. X Fourteen percent of the cohort had NAFLD. PWC was significantly reduced in adolescents with NAFLD compared to adolescents without NAFLD (reduction of 0.17 W/kg, P = .0003, adjusted for sex and body mass index [BMI]). Iron bioavailability (assessed by mean corpuscular volume [MCV], mean corpuscular haemoglobin [MCH], transferrin saturation, and serum levels of iron) was inversely correlated with BMI in adolescents with NAFLD (P ≤ .01 for all, adjusted for sex) but not in adolescents without NAFLD (P > .30). MCV and MCH correlated with PWC (MCV, P = .002 for female and P = .0003 male participants MCH, P = .004 for female and P = .01 for male participants), irrespective of NAFLD status. Reduced PWC was associated with lower transferrin saturation in adolescents with NAFLD (reduction of 0.012 W/kg per unit decrease in transferrin saturation, P = .007) but not in adolescents without NAFLD (reduction of 0.001 W/kg, P = .40), adjusted for sex. This association was independent of MCV or MCH. In a well-defined cohort of adolescents, we found NAFLD to be associated with decreased cardiorespiratory fitness, independent of BMI. The relationship between transferrin saturation and PWC in adolescents with NAFLD indicates that functional iron deficiency might contribute to reductions in cardiorespiratory fitness.
An in vitro model for the study of phagocytosis of damaged hepatocytes by rat Kupffer cells
Publisher: Wiley
Date: 10-1999
DOI: 10.1111/J.1478-3231.1999.TB00071.X
Abstract: One function of Kupffer cells is the phagocytosis of nonviable hepatocytes. Our aims were to develop a model for phagocytosis of damaged hepatocytes by rat Kupffer cells in vitro, and to characterise prostaglandin E2 (PGE2), prostacyclin (PGI), and tumour necrosis factor-alpha (TNF) production in this model. Kupffer cells were incubated alone or with damaged hepatocytes for up to 18 h, then washed and cultured for up to 66 h. To compare mediator responses produced during inert particle phagocytosis, Kupffer cells were also incubated with latex beads. Phagocytic uptake of hepatocyte debris was confirmed in at least 50% of Kupffer cells. A dissociation between TNF and PGI responses was found for both latex beads and damaged hepatocytes, such that a TNF secretory response was not triggered by either stimulus whereas PGI production was increased for both. Although phagocytosis of beads increased PGE2 production, phagocytosis of hepatocytes did not. Phagocytosis of damaged hepatocytes by Kupffer cells results in the production of PGI but not PGE2 or TNF.
Ensuring donor safety: is venesecting therapeutic donors to haemoglobin levels below Blood Service guidelines safe?
Publisher: Wiley
Date: 20-02-2020
DOI: 10.1111/VOX.12900
Associations between Prenatal Exposure to Phthalates and Features of the Metabolic Syndrome in Males from Childhood into Adulthood
Publisher: MDPI AG
Date: 18-11-2022
Abstract: Phthalate metabolites are detectable within the majority of the population. Evidence suggests that a prenatal exposure to phthalates may be associated with the subsequent risks of obesity and elevated blood pressure. We hypothesised that a prenatal exposure to phthalates would lead to an increase in adverse cardiometabolic parameters through childhood and adulthood. The maternal serum phthalate measurements from the stored s les taken from Gen1 mothers at 18 and 34 weeks gestation were examined in relation to the cardiometabolic measures in 387 male offspring from the Raine Study. Data from the Gen2 follow-ups between 3 and 27 years were used. The primary outcomes were analysed longitudinally using linear mixed models for the repeated measures. Non-alcoholic fatty liver disease (NAFLD) was assessed at 17 years using logistic regression. A consistent positive relationship was observed between a prenatal exposure to mono-carboxy-iso-octyl phthalate (MCiOP) through adolescence into adulthood with systolic blood pressure. There were no other consistent cardiovascular associations. Mid-levels of prenatal exposures to Mono-n-butyl phthalate (MnBP) were associated with a greater incidence of NAFLD. Detectable Mono-3-carboxypropyl phthalate (MCPP) was associated with a lower serum HDL-C through late childhood into adulthood, while a higher prenatal exposure to mono-iso-butyl phthalate (MiBP), was associated with a higher LDL-C at 22 years of age. A mid-level prenatal exposure to mono-2-ethylhexyl phthalate (MEHP) metabolites was associated with higher insulin in adulthood, while a higher prenatal exposure to the sum of the Di-(2-ethyl-hexyl) phthalate (DEHP) and Di-iso-nonyl phthalate (DiNP) metabolites was associated with higher fasting serum glucose in adulthood. In conclusion, our study demonstrated that higher prenatal phthalate exposures to some phthalate metabolites was associated with some adverse metabolic profiles through adolescence into adulthood, although the consistent themes were limited to a few metabolites and the outcomes of systolic blood pressure, fasting insulin and glucose.
Long-term outcome of a school-based, universal approach to prevention of depression in adolescents
Publisher: American Psychological Association (APA)
Date: 2005
Screening for hereditary haemochromatosis
Publisher: Elsevier BV
Date: 02-2012
Taurocholate Induces Biliary Differentiation of Liver Progenitor Cells Causing Hepatic Stellate Cell Chemotaxis in the Ductular Reaction Role in Pediatric Cystic Fibrosis Liver Disease
Publisher: Elsevier BV
Date: 12-2017
DOI: 10.1016/J.AJPATH.2017.08.024
Abstract: Cystic fibrosis liver disease (CFLD) in children causes progressive fibrosis leading to biliary cirrhosis however, its cause(s) and early pathogenesis are unclear. We hypothesized that a bile acid-induced ductular reaction (DR) drives fibrogenesis. The DR was evaluated by cytokeratin-7 immunohistochemistry in liver biopsies, staged for fibrosis, from 60 children with CFLD, and it demonstrated that the DR was significantly correlated with hepatic fibrosis stage and biliary taurocholate levels. To examine the mechanisms involved in DR induction, liver progenitor cells (LPCs) were treated with taurocholate, and key events in DR evolution were assessed: LPC proliferation, LPC biliary differentiation, and hepatic stellate cell (HSC) chemotaxis. Taurocholate induced a time-dependent increase in LPC proliferation and expression of genes associated with cholangiocyte differentiation (cytokeratin 19, connexin 43, integrin β4, and γ-glutamyltranspeptidase), whereas the hepatocyte specification marker HNF4α was suppressed. Functional cholangiocyte differentiation was demonstrated via increased acetylated α-tubulin and SOX9 proteins, the number of primary cilia
Mutations in the HFE Gene and Cardiovascular Disease Risk
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2008
DOI: 10.1161/CIRCGENETICS.108.773176
Abstract: Background— Whether mutations in the hemochromatosis (HFE) gene increase cardiovascular disease risk is still undetermined. The main reason is the low frequency of the mutations, in particular of the compound C282Y/H63D genotype. We combined the data of 11 observational studies for an in idual patient data meta-analysis. Methods and Results— In idual patient data were obtained from published as well as unpublished studies that had information available on the C282Y mutation as well as the H63D mutation in relation to coronary heart disease risk. In idual records were provided on each of the 53 880 participants in 11 studies. In total, 10 541 patients with coronary events were documented, of whom 5724 had an acute myocardial infarction. The crude and adjusted association between HFE genotypes and coronary events was examined by logistic regression analysis. We explored potential effect modification of the association between traditional cardiovascular risk factors and coronary events by HFE genotypes. After full adjustment, the odds ratio for coronary heart disease was 1.12 (95% CI, 0.92 to 1.37) for subjects with the compound heterozygous (C282Y/H63D) genotype relative to those with the wild-type/wild-type genotype. The odds ratios for C282Y/C282Y, C282Y/wild-type, H63D/H63D, and H63D/wild-type were 0.78 (95% CI, 0.49 to 1.26), 0.98 (95% CI, 0.90 to 1.07), 1.16 (95% CI, 0.97 to 1.38), and 1.07 (95% CI, 1.00 to 1.14), respectively. There was no evidence for effect modification. Conclusions— The results of this large in idual patient data meta-analysis do not support the view that HFE gene mutations are associated with an increased risk of coronary heart disease or acute myocardial infarction.
Brain changes in iron loading disorders
Publisher: Springer Vienna
Date: 2012
Detection of liver injury in IBD using transient elastography
Publisher: Oxford University Press (OUP)
Date: 07-2014
DOI: 10.1016/J.CROHNS.2013.12.006
Abstract: Up to 5% of inflammatory bowel disease (IBD) patients are thought to have clinically significant liver disease due to multifactorial causes, however, this figure may be an underestimate due to reliance on abnormal liver tests (LTs) and/or liver biopsies. Our aim was to evaluate the prevalence of clinically significant liver disease in IBD patients as defined by an increased liver stiffness measurement (LS) ≥8kPa using transient elastography (TE). 110 IBD patients, and 55 non-IBD control subjects, had their LS recorded using FibroScan® (EchoSense, Paris, France) by a single blinded operator trained in TE. 71 Crohn's disease and 39 ulcerative colitis subjects were included. All demographic variables were similar between the IBD and control groups apart from a significantly higher proportion of IBD patients who smoked (17.3% vs 3.6%, P=0.013). Seven IBD patients (6.4%) had an LS over 8 kPa and 3 had persistently elevated LS 6 months later. One patient had compensated cirrhosis. No significant differences in overall LS were observed between the IBD and control groups. Increased BMI and age, however, were independently associated with a higher LS in the IBD but not in the control group (P<0.001 and 0.010 respectively). Using TE, the prevalence of clinically significant liver disease in IBD patients is low. The association of increased BMI and age with increased LS in IBD suggests fatty liver disease being the prevailing aetiology in these patients.
Effects of body iron stores and haemochromatosis genotypes on coronary heart disease outcomes in the Busselton health study
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2002
Bowel patterns, gastrointestinal symptoms, and emotional well-being in adolescents: A cohort study
Publisher: Wiley
Date: 07-2019
DOI: 10.1111/JGH.14699
Abstract: Bowel patterns are varied in the general population. Gastrointestinal symptoms are common reasons for clinical visits. We aimed to examine the usual bowel pattern and the prevalence and significance of gastrointestinal symptoms in a population-based cohort of Australian adolescents. Seventeen-year-old adolescents (n = 1279) in the Western Australian Pregnancy Cohort (Raine) Study participated in a cross-sectional assessment, involving health questionnaires. Questions included medical history, diet, bowel patterns, and gastrointestinal symptoms. Data were analyzed to identify patterns of bowel motions, gastrointestinal symptoms, and factors associated with these in adolescents. Multivariate logistic regression analysis was used to determine predictors of poorer self-rated health status. The dominant pattern of bowel motions was passage of stool that was "not too hard and not too soft" (Bristol stool types 3 and 4) in 90% and occurring between three and seven times per week in 74%. The most prevalent gastrointestinal symptoms included abdominal bloating (72%), abdominal pain (36%), nausea (25%), and constipation (20%). A "Western" dietary pattern was associated with abdominal bloating, constipation, and nausea (P < 0.05). Apart from diarrhea, gastrointestinal symptoms were more prevalent in female adolescents than male adolescents (P < 0.05 for all). Female sex (odds ratio [OR] 1.87, 95% confidence interval [CI] 1.16-3.02, P = 0.01), nausea (OR 3.18, 95% CI 2.03-4.98, P < 0.001), and depression (OR 6.68, 95% CI 3.65-12.22, P = 0.03) were independently associated with poorer self-rated health status, after adjusting for other gastrointestinal symptoms. In adolescents, bowel patterns and gastrointestinal symptoms are erse and show sex differences. Nausea, depression, and female sex are significant factors for poorer self-rated health.
A Population-Based Study of the Clinical Expression of the Hemochromatosis Gene
Publisher: Massachusetts Medical Society
Date: 02-09-1999
Aldehydic products of lipid peroxidation do not directly activate rat hepatic stellate cells
Publisher: Wiley
Date: 07-2002
DOI: 10.1046/J.1440-1746.2002.02798.X
Abstract: Activation of hepatic stellate cells (HSC) results in the transdifferentiation of the resting (quiescent) phenotype to one characterized by loss of vitamin A droplets, increased alpha-smooth muscle actin (SMA) expression and increased collagen production. Aldehydic products of lipid peroxidation have been shown to increase collagen production by cultured fibroblasts and by passaged HSC, but it is unclear whether these products of lipid peroxidation can initiate the activation of HSC. In the present study the effects were examined of two aldehydic products of lipid peroxidation, malondialdehyde (MDA) and 4-hydroxynonenal (HNE), on activation of rat HSC in early culture as measured by SMA and desmin expression, and collagen production. The HSC from normal rat liver were plated in plastic wells and exposed to either MDA (5-200 micromol/L), HNE (0.1-20 micromol/L) or vehicle for either 3 or 7 days. The cells were then harvested SMA and desmin levels were measured by western blotting. Collagen production was measured by radiolabeled proline incorporation after 6 h of aldehyde exposure. Malondialdehyde (100 and 200 micromol/L) decreased SMA expression during the 3-day and 7-day exposures compared with controls. 4-Hydroxynonenal (20 micromol/L) decreased SMA expression significantly while no effects were observed with lower concentrations compared with controls during the 3-day exposure. Seven-day exposure to HNE (0.1-20 micromol/L) failed to alter SMA expression compared with controls. Exposure to MDA or HNE did not influence desmin expression or collagen production. Aldehydic products of lipid peroxidation do not directly activate HSC in early culture and alternative pathways may be responsible for HSC activation during oxidative stress.
Adverse metabolic phenotype of adolescent girls with non-alcoholic fatty liver disease plus polycystic ovary syndrome compared with other girls and boys
Publisher: Wiley
Date: 28-04-2016
DOI: 10.1111/JGH.13241
Abstract: Non-alcoholic fatty liver disease (NAFLD) and polycystic ovary syndrome (PCOS) share risk associations of adiposity and insulin resistance. We examined the impact of a PCOS diagnosis on the metabolic phenotype of adolescent girls with NAFLD and compared this to girls without PCOS or NAFLD and to age-matched boys. Community-based adolescents from the Raine Cohort participated in assessments for NAFLD (572 girls and 592 boys) and PCOS (244 girls). One hundred and ninety-nine girls attended both assessments. Amongst the 199 girls, PCOS was diagnosed in 16.1% and NAFLD in 18.6%. NAFLD was diagnosed in 10.1% of the boys. NAFLD was more prevalent in girls with PCOS than girls without PCOS (37.5% vs 15.1%, P = 0.003). Girls with NAFLD plus PCOS had greater adiposity (waist circumference, body mass index, suprailiac skinfold thickness [SST], serum androgens, high-sensitivity C-reactive protein, ferritin, homeostasis model assessment for insulin resistance (HOMA-IR), and lower serum sex hormone binding globulin levels than girls with NAFLD without a PCOS diagnosis (all P < 0.05). Girls with NAFLD plus PCOS had similar adiposity, HOMA-IR, and adiponectin levels to boys with NAFLD, but more adiposity, serum leptin and HOMA-IR than both girls and boys without NAFLD. PCOS (odds ratios 2.99, 95% confidence intervals 1.01-8.82, P = 0.048) and SST (odds ratios 1.14, 95% confidence intervals 1.08-1.20, P < 0.001) independently predicted NAFLD in adolescent girls, however, serum androgens and HOMA-IR levels did not. Adolescent girls with NAFLD plus PCOS have a similar metabolic phenotype to boys with NAFLD. Increasing SST and pre-existing PCOS independently predict NAFLD in adolescent girls.
Haemochromatosis HFE gene polymorphisms as potential modifiers of hereditary nonpolyposis colorectal cancer risk and onset age
Publisher: Wiley
Date: 16-03-2009
DOI: 10.1002/IJC.24304
Abstract: Hereditary nonpolyposis colorectal cancer (HNPCC) is characterized by germline mutations in DNA mismatch repair genes however, variation in disease expression suggests that there are potential modifying factors. Polymorphisms of the HFE gene, which cause the iron overload disorder hereditary haemochromatosis, have been proposed as potential risk factors for the development of colorectal cancer (CRC). To understand the relationship between HNPCC disease phenotype and polymorphisms of the HFE gene, a total of 362 in iduals from Australia and Poland with confirmed causative MMR gene mutations were genotyped for the HFE C282Y and H63D polymorphisms. A significantly increased risk of developing CRC was observed for H63D homozygotes when compared with combined wild-type homozygotes and heterozygotes (hazard ratio = 2.93, p = 0.007). Evidence for earlier CRC onset was also observed in H63D homozygotes with a median age of onset 6 years earlier than wild type or heterozygous participants (44 vs. 50 years of age). This effect was significant by all tests used (log-rank test p = 0.026, Wilcoxon p = 0.044, Tarone-Ware p = 0.035). No association was identified for heterozygosity of either polymorphism and limitations on power-prevented investigation of C282Y homozygosity or compound C282Y/H63D heterozygosity. In the Australian s le only, women had a significantly reduced risk of developing CRC when compared with men (hazard ratio = 0.58, p = 0.012) independent of HFE genotype for either single nucleotide polymorphisms. In conclusion, homozygosity for the HFE H63D polymorphism seems to be a genetic modifier of disease expression in HNPCC. Understanding the mechanisms by which HFE interrelates with colorectal malignancies could lead to reduction of disease risk in HNPCC.
Lower fructose intake may help protect against development of nonalcoholic fatty liver in adolescents with obesity
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2014
TWEAK and LTβ Signaling during Chronic Liver Disease
Publisher: Frontiers Media SA
Date: 2014
Noncitrus fruits as novel dietary environmental modifiers of iron stores in people with or without HFE gene mutations
Publisher: Elsevier BV
Date: 05-2008
DOI: 10.4065/83.5.543
Abstract: To investigate whether citrus fruit, noncitrus fruit, and other dietary factors act as environmental modifiers of iron status in the absence or presence of hemochromatotic HFE gene mutations. Iron studies, HFE genotypic analyses, and dietary data from a survey conducted from March 21, 1994, through December 15, 1995, were analyzed for a group of 2232 residents (1105 men, 1127 women) aged 20 to 79 years recruited from the community electoral roll of Busselton in Western Australia. Data were analyzed by linear regression analysis and analysis of covariance. Higher levels of fresh fruit intake (excluding citrus fruits and citrus juices) had a significant protective effect (P=.002) against high body iron status as gauged by ferritin levels in men, irrespective of HFE genotype. Consumption of 2 or more pieces of fruit per day on average reduced mean serum ferritin levels by 20% compared with average consumption of less than 1 piece of fruit per day. This effect was not observed in women. Consumption of citrus fruits and citrus juices had no significant effects in either sex. No protective effects were observed for tea consumption or any other dietary factors studied. Red meat and alcohol consumption correlated with high body iron stores (P .05). Noncitrus fruits are environmental modifiers of iron status independent of HFE genotype. This could have important implications for the provision of evidence-based dietary advice to patients with other iron-storage disorders.
Authors' response.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2015
Reduction of body iron in HFE -related haemochromatosis and moderate iron overload (Mi-Iron): a multicentre, participant-blinded, randomised controlled trial
Publisher: Elsevier BV
Date: 12-2017
Oval cell numbers in human chronic liver diseases are directly related to disease severity
Publisher: Elsevier BV
Date: 02-1999
Nontransferrin-bound iron uptake by hepatocytes is increased in the Hfe knockout mouse model of hereditary hemochromatosis
Publisher: American Society of Hematology
Date: 09-2004
DOI: 10.1182/BLOOD-2003-11-3872
Abstract: Hereditary hemochromatosis (HH) is an iron-overload disorder caused by a C282Y mutation in the HFE gene. In HH, plasma nontransferrin-bound iron (NTBI) levels are increased and NTBI is bound mainly by citrate. The aim of this study was to examine the importance of NTBI in the pathogenesis of hepatic iron loading in Hfe knockout mice. Plasma NTBI levels were increased 2.5-fold in Hfe knockout mice compared with control mice. Total ferric citrate uptake by hepatocytes isolated from Hfe knockout mice (34.1 ± 2.8 pmol Fe/mg protein/min) increased by 2-fold compared with control mice (17.8 ± 2.7 pmol Fe/mg protein/min P & .001 mean ± SEM n = 7). Ferrous ion chelators, bathophenanthroline disulfonate, and 2′,2-bipyridine inhibited ferric citrate uptake by hepatocytes from both mouse types. Divalent metal ions inhibited ferric citrate uptake by hepatocytes, as did diferric transferrin. Divalent metal transporter 1 (DMT1) mRNA and protein expression was increased approximately 2-fold by hepatocytes from Hfe knockout mice. We conclude that NTBI uptake by hepatocytes from Hfe knockout mice contributed to hepatic iron loading. Ferric ion was reduced to ferrous ion and taken up by hepatocytes by a pathway shared with diferric transferrin. Inhibition of uptake by alent metals and up-regulation of DMT1 expression suggested that NTBI uptake was mediated by DMT1.
mTOR Inhibitors Induce Erythropoietin Resistance in Renal Transplant Recipients.
Publisher: Frontiers Media SA
Date: 22-02-2022
Abstract: To elucidate the role of mTOR inhibitors on iron, hepcidin and erythropoietin-mediated regulation of hemopoiesis in stable renal transplant recipients (RTR). Impaired hemopoiesis is common following renal transplantation managed using mTOR inhibitors. The mechanisms responsible are uncertain but include direct effects on iron, hepcidin or erythropoietin-mediated hemopoiesis. We conducted a single center prospective case-control study of 26 adult RTR with stable allograft function. RTR received stable mTOR dosing (cases, 11/26 [42%]) or stable tacrolimus dosing (controls, 15/26 [58%]). Baseline demographics, full blood count, renal function, iron studies, hepcidin-25, Interleukin-6 (IL-6) and erythropoietin (EPO) levels were determined. There were no differences in age, gender or allograft function. Mean daily sirolimus dose for cases was 1.72 mg, with mean trough level of 8.46 ng/mL. Mean daily tacrolimus dose for controls was 4.3 mg, with mean trough level of 5.8 ng/mL. There were no differences in mean hemoglobin (143 vs. 147 g/L p = 0.59), MCV (88 vs. 90 fL p = 0.35), serum ferritin (150 vs. 85.7 μg/L p = 0.06), transferrin saturation (26 vs. 23.3% p = 0.46), IL-6 (11 vs. 7.02 pg/ml p = 0.14) or hepcidin-25 (3.62 vs. 3.26 nM p = 0.76) between the groups. EPO levels were significantly higher in the group receiving mTOR therapy (16.8 vs. 8.49 IU/L p = 0.028). On logistic regression analysis EPO level was the only variable that had a significant impact providing an odds ratio of 0.84 (95%CI 0.66–0.98). The area under the receiver operator characteristic curve (ROC) for the analysis was 0.77 (95%CI 0.54–0.94) with p = 0.04. Conclusion: Higher levels of EPO in the absence of deranged iron biochemistry or hepcidin-25 levels suggest that EPO resistance rather than impaired iron metabolism may contribute to the impaired hemopoiesis previously demonstrated in RTR on mTOR therapy.
Iron: An emerging factor in colorectal carcinogenesis
Publisher: Baishideng Publishing Group Inc.
Date: 2010
Natural history of HFE simple heterozygosity for C 282Y and H 63D : A prospective 12‐year study
Publisher: Wiley
Date: 16-03-2015
DOI: 10.1111/JGH.12804
Range of Normal Liver Stiffness and Factors Associated With Increased Stiffness Measurements in Apparently Healthy Individuals
Publisher: Elsevier BV
Date: 2019
DOI: 10.1016/J.CGH.2018.08.069
Abstract: Transient elastography (TE) is a noninvasive technique used to measure liver stiffness to estimate the severity of fibrosis. The range of liver stiffness measurements (LSMs) in healthy in iduals is unclear. We performed a systematic review to determine the range of LSMs, examined by TE, in healthy in iduals and in iduals who are susceptible to fibrosis. We collected data from 16,082 in iduals, in 26 cohorts, identified from systematic searches of Embase, Ovid MEDLINE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews for studies of liver stiffness measurements. Studies analyzed included apparently healthy adults (normal levels of liver enzymes, low-risk alcohol use patterns, and negative for markers of viral hepatitis). The presence of diabetes, hypertension, dyslipidemia, or steatosis, based on ultrasound examination, was known for most participants. We performed a meta-analysis of data from in idual participants. The cohort was ided into 4 groups participants with a body mass index <30 kg/m We established LSM ranges for healthy in iduals measured with both probes-these did not change significantly in sensitivity analyses of in iduals with platelets ≥150,000/mm In a systematic review and meta-analysis of data from in idual participants, we established a comprehensive set of LSM ranges, measured by TE in large cohorts of healthy in iduals and persons susceptible to hepatic fibrosis. Regression analyses identified factors associated with increased LSMs obtained by TE with the medium and extra-large probes.
A prospective cohort examination of haematological parameters in relation to cancer death and incidence
Publisher: Springer Science and Business Media LLC
Date: 03-09-2018
A novel association between a SNP in CYBRD1 and serum ferritin levels in a cohort study of HFE hereditary haemochromatosis
Publisher: Wiley
Date: 14-09-2009
The role of liver progenitor cells during liver regeneration, fibrogenesis, and carcinogenesis
Publisher: American Physiological Society
Date: 02-2016
Abstract: The growing worldwide challenge of cirrhosis and hepatocellular carcinoma due to increasing prevalence of excessive alcohol consumption, viral hepatitis, obesity, and the metabolic syndrome has sparked interest in stem cell-like liver progenitor cells (LPCs) as potential candidates for cell therapy and tissue engineering, as an alternative approach to whole organ transplantation. However, LPCs always proliferate in chronic liver diseases with a predisposition to cancer they have been suggested to play major roles in driving fibrosis, disease progression, and may even represent tumor-initiating cells. Hence, a greater understanding of the factors that govern their activation, communication with other hepatic cell types, and bipotential differentiation as opposed to their potential transformation is needed before their therapeutic potential can be harnessed.
Differential DNA methylation of steatosis and non-alcoholic fatty liver disease in adolescence.
Publisher: Research Square Platform LLC
Date: 06-10-2022
DOI: 10.21203/RS.3.RS-2114814/V1
Abstract: BACKGROUND AND AIMS : Epigenetic modifications are associated with hepatic fat accumulation and non-alcoholic fatty liver disease (NAFLD). However, few epigenetic modifications directly implicated in such processes have been identified during adolescence, a critical developmental window where physiological changes could influence future disease trajectory. To investigate the association between DNA methylation and NAFLD in adolescence we undertook discovery and validation of novel methylation marks, alongside replication of previously reported marks. APPROACH & RESULTS: We performed a DNA methylation epigenome-wide association study (EWAS) on DNA from whole blood from 707 Raine Study adolescents phenotyped for steatosis score and NAFLD by ultrasound at age 17. Next, we performed pyrosequencing validation of loci within the most 100 strongly associated differentially-methylated CpG sites (dmCpGs) for which ≥2 probes per gene remained significant across four statistical models with a nominal p-value .007. EWAS identified dmCpGs related to three genes ( ANK1, MIR10a , PTPRN2 ) that met our criteria for pyrosequencing. Of the dmCpGs and surrounding loci that were pyrosequenced ( ANK1 n =6, MIR10a n =7, PTPRN2 n =3), three dmCpGs in ANK1 and two in MIR10a were significantly associated with NAFLD in adolescence. After adjustment for waist circumference only dmCpGs in ANK1 remained significant. These ANK1 CpGs were also associated with γ-glutamyl transferase and alanine aminotransferase concentrations. Three of twenty-two differentially methylated dmCpGs previously associated with adult NAFLD were associated with NAFLD in adolescence (all adjusted p .3 x 10 -3 ). CONCLUSIONS: We identified novel DNA methylation loci associated with NAFLD and serum liver biochemistry markers during adolescence, implicating putative dmCpG/gene regulatory pathways and providing insights for future mechanistic studies.
Iron overload
Publisher: Elsevier BV
Date: 08-2005
DOI: 10.1016/J.CCCN.2005.02.022
Abstract: Iron overload disorders represent a heterogenous group of conditions resulting from inherited and acquired causes. With the discovery of new proteins and genetic defects we have gained greater insight into their causation at the molecular level and the complex mechanisms of normal and disordered iron homeostasis. Here we review the normal mechanisms and regulation of gastrointestinal iron absorption and liver iron transport and their dysregulation in iron overload states. Advances in the understanding of the natural history of iron overload disorders and new methods for clinical detection and management of hereditary hemochromatosis are also reviewed.
Concordance of transient elastography and shear wave elastography for measurement of liver stiffness
Publisher: Wiley
Date: 19-09-2017
DOI: 10.1002/SONO.12122
Genotype–Phenotype Relationship in Hereditary Hemochromatosis
Publisher: Wiley
Date: 08-12-2013
Serum testosterone levels correlate with haemoglobin in middle-aged and older men
Publisher: Wiley
Date: 08-2009
DOI: 10.1111/J.1445-5994.2008.01789.X
Abstract: Lower testosterone levels are associated with anaemia in older men and women. The relation between testosterone and haemoglobin (Hb) in younger and middle-aged men is less well defined. The aim of the study was to examine the association between testosterone and Hb levels in men spanning middle to older ages. A cross-sectional analysis of 492 men aged 30.7-94.5 years from the Busselton Health Survey, Western Australia, was carried out. Haemoglobin (Hb), early-morning serum total testosterone and sex hormone-binding globulin (SHBG) were measured. Free testosterone was calculated using mass action equations. Haemoglobin correlated to total and free testosterone concentrations (r= 0.13, P= 0.003 and r= 0.20, P < 0.001, respectively). Hb and SHBG were inversely correlated (r=-0.14, P= 0.001). Hb increased across lowest to highest quartiles of total testosterone (P= 0.02) and free testosterone (P < 0.001), but not SHBG. After adjusting for age, waist circumference, smoking status, alcohol consumption, renal function and ferritin, total testosterone was associated with Hb (beta= 0.037, P= 0.003) as was free testosterone (beta= 2.32, P < 0.001), whereas SHBG was not associated. Testosterone concentration modulates Hb levels in community-dwelling men across a wide age range. Further studies are needed to clarify implications of this association between testosterone and Hb in men.
Importance of cardiometabolic risk factors in the association between nonalcoholic fatty liver disease and arterial stiffness in adolescents
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-08-2013
DOI: 10.1002/HEP.26495
Abstract: Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide and is regarded as the hepatic manifestation of the metabolic syndrome. In adults, NAFLD is a determinant of arterial stiffness and cardiovascular risk, independent of the metabolic syndrome. Our aim was to ascertain if NAFLD is associated with arterial stiffness, independent of cardiometabolic factors in a population-based cohort of adolescents. The 17-year-olds (n = 964) from an Australian birth cohort had measures of anthropometry, blood pressure, fasting insulin, glucose, lipids, and NAFLD by ultrasound. Two-step cluster analysis identified youth at high metabolic risk. Measures of arterial stiffness (pulse wave velocity [PWV] and augmentation index corrected for heart rate [AI@75]) were obtained using applanation tonometry. The overall prevalence of NAFLD was 13.3%. The "high risk" metabolic cluster at age 17 years included 16% males and 19% females. Compared to "low risk," the "high risk" cluster participants had greater waist circumference, triglycerides, insulin, systolic blood pressure, and lower high-density lipoprotein (HDL) cholesterol (all P < 0.0001). Those who had NAFLD but were not in the "high risk" metabolic cluster did not have increased PWV or AI@75. However, males and females who had NAFLD in the presence of the metabolic cluster had greater PWV (b = 0.20, 95% confidence interval [CI] 0.01 to 0.38, P = 0.037). Males who had NAFLD in the presence of the metabolic cluster had greater AI@75 (b = 6.3, 95% CI 1.9 to 10.7, P = 0.005). NAFLD is only associated with increased arterial stiffness in the presence of the "high risk" metabolic cluster. This suggests that arterial stiffness related to the presence of NAFLD is predicated on the presence of an adverse metabolic profile in adolescents.
Characteristics of the arthropathy described in hereditary hemochromatosis
Publisher: Wiley
Date: 28-12-2011
DOI: 10.1002/ACR.20501
Alcohol Consumption and Cardiovascular Outcomes in Patients With Nonalcoholic Fatty Liver Disease
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 20-12-2022
DOI: 10.1002/HEP4.1828
Abstract: Low‐level alcohol consumption is associated with reduced cardiovascular disease (CVD) in the general population. It is unclear whether this association is seen in patients with nonalcoholic fatty liver disease (NAFLD) who have an increased risk of CVD. We examined the association between alcohol consumption and CVD‐related outcomes in subjects with NAFLD from a general population cohort. Subjects participating in the 1994‐1995 Busselton Health survey underwent clinical and biochemical assessment. NAFLD was identified using the Fatty Liver Index of , and alcohol consumption quantified using a validated questionnaire. CVD hospitalizations and death during the ensuing 20 years were ascertained using the Western Australian data linkage system. A total of 659 of 4,843 patients were diagnosed with NAFLD. The average standard drinks per week was 8.0 for men and 4.0 for women. Men consuming 8‐21 drinks per week had a 38% (hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.43‐0.90) lower risk of CVD hospitalization as compared with men consuming 1‐7 drinks per week. With both men and women combined, consumption of 8‐21 drinks per week was associated with a 32% (HR 0.68, 95% CI 0.49‐0.93) reduction in CVD hospitalization in minimally adjusted and 29% (HR 0.71, 95% CI 0.51‐0.99) in fully adjusted models. No protective association was observed with binge drinking. There was no association between alcohol consumption and CVD death. Conclusion: Low to moderate alcohol consumption is associated with fewer CVD hospitalizations but not CVD death in subjects with NAFLD.
Transdifferentiation of pancreatic progenitor cells to hepatocyte-like cells is not serum-dependent when facilitated by extracellular matrix proteins.
Publisher: Springer Science and Business Media LLC
Date: 12-03-2018
DOI: 10.1038/S41598-018-22596-Z
Abstract: The rising prevalence of chronic liver disease, coupled with a permanent shortage of organs for liver transplantation, has sparked enormous interest in alternative treatment strategies. Previous protocols to generate hepatocyte-like cells (HLCs) via pancreas-to-liver transdifferentiation have utilised fetal bovine serum, introducing unknown variables and severely limiting study reproducibility. Therefore, the main goal of this study was to develop a protocol for transdifferentiation of pancreatic progenitor cells to HLCs in a chemically defined, serum-free culture medium. The clonal pancreatic progenitor cell line AR42J-B13 was cultured in basal growth medium on uncoated plastic culture dishes in the absence or presence of Dexamethasone on uncoated, laminin- or fibronectin-coated culture substrata, with or without serum supplementation. The hepatocytic differentiation potential was evaluated: (i) morphologically through bright-field and scanning electron microscopy, (ii) by assessing pancreatic and hepatic marker expression and (iii) by determining the function of HLCs through their ability to synthesise glycogen or take up and release indocyanine green. Here we demonstrate for the first time that transdifferentiation of pancreatic cells to HLCs is not dependent on serum. These results will assist in converting current differentiation protocols into procedures that are compliant with clinical use in future cell-based therapies to treat liver-related metabolic disorders.
Association between serum hepcidin-25 and primary resistance to erythropoiesis-stimulating agents in chronic kidney disease: a secondary analysis of the HERO trial
Publisher: Wiley
Date: 15-06-2017
DOI: 10.1111/NEP.12815
Abstract: Pentoxifylline has been shown to increase haemoglobin levels in patients with chronic kidney disease (CKD) and erythropoietin-stimulating agent (ESA)-hyporesponsive anaemia in the Handling Erythropoietin Resistance with Oxpentifylline multicentre double-blind, randomized controlled trial. The present sub-study evaluated the effects of pentoxifylline on the iron-regulatory hormone hepcidin in patients with ESA-hyporesponsive CKD. This sub-study included 13 patients in the pentoxifylline arm (400 mg daily) and 13 in the matched placebo arm. Hepcidin-25 was measured by ultra performance liquid chromatography/quadrupole time-of-flight mass spectrometry following isolation from patient serum. Serum hepcidin-25, serum iron biomarkers, haemoglobin and ESA dosage were compared within and between the two groups. Hepcidin-25 concentration at 4 months adjusted for baseline did not differ significantly in pentoxifylline versus placebo treated patients (adjusted mean difference (MD) -7.9 nmol, P = 0.114), although the difference between the groups mean translated into a >25% reduction of circulating hepcidin-25 due to pentoxifylline compared with the placebo baseline. In paired analysis, serum hepcidin-25 levels were significantly decreased at 4 months compared with baseline in the pentoxifylline group (-5.47 ± 2.27 nmol/l, P < 0.05) but not in the placebo group (2.82 ± 4.29 nmol/l, P = 0.24). Pentoxifylline did not significantly alter serum ferritin (MD 55.4 mcg/l), transferrin saturation (MD 4.04%), the dosage of ESA (MD -9.93 U/kg per week) or haemoglobin concentration (MD 5.75 g/l). The reduction of circulating hepcidin-25 due to pentoxifylline did not reach statistical significance however, the magnitude of the difference suggests that pentoxifylline may be a clinically and biologically meaningful modulator of hepcidin-25 in dialysis of patients with ESA-hyporesponsive anaemia.
Hepatic expression of the tumor necrosis factor family member lymphotoxin‐β is regulated by interleukin (IL)‐6 and IL‐1β: transcriptional control mechanisms in oval cells and hepatoma cell lines
Publisher: Wiley
Date: 20-05-2005
DOI: 10.1111/J.1478-3231.2005.01080.X
Abstract: Lymphotoxin-beta (LT-beta) plays an important role in inflammation and its promoter contains a functional nuclear factor-kappaB (NF-kappaB) element, rendering it a likely target of pro-inflammatory cytokines. Inflammatory cytokines play a central role in liver regeneration resulting from acute or chronic liver injury, with interleukin (IL)-6 signaling essential for liver regeneration induced by partial hepatectomy. In hepatic oval cells observed following chronic liver injury, LT-beta levels are upregulated, suggesting a link between LT-beta and liver regeneration. The expression of LT-beta in hepatic oval cell and hepatocellular carcinoma cell lines was further investigated, along with its responsiveness to IL-6 and IL-1beta. Key regulatory cis-acting elements of the LT-beta promoter that mediate IL-6 responsiveness (Sp/BKLF, Ets, NF-kappaB and Egr-1/Sp1) and IL-1beta responsiveness (NF-kappaB and Ets) of hepatic LT-beta expression were identified. The novel binding of basic Kruppel-like factor (BKLF) proteins to an apparent composite Sp/BKLF site of the LT-beta promoter was shown to mediate IL-6 responsiveness. Binding of NF-kappaB p65 50 heterodimers and Ets-related transcription factors to their respective sites mediates responsiveness to IL-1beta. The identification of IL-6 and IL-1beta as activators of LT-beta supports their involvement in LT-beta signaling in liver regeneration associated with chronic liver damage.
Liver inflammation and cytokine production,but not acute phase protein synthesis, accompany the adult liverprogenitor (oval) cell response to chronic liver injury
Publisher: Wiley
Date: 08-2005
DOI: 10.1111/J.1440-1711.2005.01346.X
Abstract: Oval cells are facultative liver progenitor cells, which are invoked during chronic liver injury in order to replenish damaged hepatocytes and bile duct cells. Previous studies have observed inflammation and cytokine production in the liver during chronic injury. Further, it has been proposed that inflammatory growth factors may mediate the proliferation of oval cells during disease progression. We have undertaken a detailed examination of inflammation and cytokine production during a time course of liver injury and repair, invoked by feeding mice a choline-deficient, ethionine-supplemented (CDE) diet. We show that immediately following initial liver injury, B220-expressing leucocytes transiently infiltrate the liver. This inflammatory response occurred immediately before oval cell numbers began to expand in the liver, suggesting that the two events may be linked. Two waves of liver cytokine production were observed during the CDE time course. The first occurred shortly following commencement of the diet, suggesting that it may represent a hepatic acute phase response. However, examination of acute phase marker expression in CDE-fed mice did not support this hypothesis. The second wave of cytokine expression correlated with the expansion of oval cell numbers in the liver, suggesting that these factors may mediate oval cell proliferation. No inflammatory signalling was detected following withdrawal of the injury stimulus. In summary, our results document a close correlation between inflammation, cytokine production and the expansion of oval cells in the liver during experimental chronic injury.
Pharmacokinetics and safety of deferasirox in subjects with chronic kidney disease undergoing haemodialysis.
Publisher: Wiley
Date: 25-02-2013
DOI: 10.1111/NEP.12035
Abstract: Treatment of chronic kidney disease (CKD) includes parenteral iron therapy, and these infusions can lead to iron overload. Secondary iron overload is typically treated with iron chelators, of which deferasirox is one of the most promising. However, it has not been studied in patients with CKD and iron overload. A pilot study was conducted to evaluate the pharmacokinetics and safety of deferasirox in eight haemodialysis-dependent patients, who were receiving intravenous iron for treatment of anaemia of CKD. Deferasirox was administered at two doses (10 mg/kg and 15 mg/kg), either acute (once daily for 2 days) or steady-state (once daily for 2 weeks). A dose of 10 mg/kg in either protocol was not sufficient to achieve a plasma concentration in the therapeutic range (acute peak 14.1 and steady-state 22.8 μmol/L), while 15 mg/kg in either protocol maintained plasma concentration well above this range (acute peak 216 and steady-state 171 μmol/L). Plasma concentration observed at 15 mg/kg was well above that expected for this dose (40-50 μmol/L), although no adverse clinical events were observed. This study highlights the need to profile drugs such as deferasirox in specific patient groups, such as those with CKD and iron overload.
Iron uptake from plasma transferrin by a transferrin receptor 2 mutant mouse model of haemochromatosis.
Publisher: Elsevier BV
Date: 03-2010
Infant nutrition and maternal obesity influence the risk of non-alcoholic fatty liver disease in adolescents
Publisher: Elsevier BV
Date: 09-2017
DOI: 10.1016/J.JHEP.2017.03.029
Abstract: The pathway to non-alcoholic fatty liver disease (NAFLD) in adolescents may have its origins in adiposity gains, nutrition and sedentary lifestyle established during childhood. There is inadequate knowledge regarding the associations between infant nutrition and subsequent NAFLD. We examined the association of maternal factors and infant nutrition, with the subsequent diagnosis of NAFLD in adolescents. Adolescents aged 17years in the Western Australian Pregnancy (Raine) Cohort study had fatty liver assessment using liver ultrasound. Prospectively recorded data on maternal pregnancy and infant feeding were examined against a NAFLD outcome during late adolescence. NAFLD was diagnosed in 15.2% of the 1,170 adolescents examined. Ninety-four percent had been breastfed as infants. The duration of breastfeeding before starting supplementary milk was ⩾4months in 54.4% and ⩾6months in 40.6%. Breastfeeding without supplementary milk ⩾6months (adjusted odds ratio [OR]: 0.64 95% confidence interval [CI]: 0.43-0.94, p=0.02), maternal pre-pregnancy obesity (adjusted OR: 2.29 95% CI: 1.21-4.32, p=0.01) and adolescent obesity (adjusted OR: 9.08 95% CI: 6.26-13.17, p<0.001) were associated with NAFLD independent of a Western dietary pattern at 17years of age. Adolescents with NAFLD who had been breastfed for ⩾6months had a less adverse metabolic profile compared with adolescents breastfed for <6months. Supplementary milk intake starting before 6months was associated with a higher prevalence and ultrasound severity of NAFLD compared with intake starting after 6months (17.7% vs. 11.2%, p=0.003 and 7.8% vs. 3.4%, p=0.005 respectively). Though NAFLD is generally mediated through adiposity gains, breastfeeding for at least 6months, avoidance of early supplementary formula milk feeding, and normal maternal pre-pregnancy BMI may reduce the odds of a NAFLD diagnosis during adolescence. Non-alcoholic fatty liver disease (NAFLD) is a common liver disorder in which there is too much fat in the liver of people who do not consume excessive amounts of alcohol. In this large study, we found that infants who consumed breast milk for less than 6months before starting infant formula milk, infants who were obese as teenagers or had mothers who were obese at the start of pregnancy, were much more likely to have NAFLD at 17years of age. Based on our findings we consider that reducing the risk of NAFLD in teenagers needs to start before birth, by encouraging normal body mass index before pregnancy, as well as breastfeeding without infant formula milk consumption for the first 6months of life.
Role of TWEAK in coregulating liver progenitor cell and fibrogenic responses
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 27-01-2014
DOI: 10.1002/HEP.26701
Overexpression of miRNA-25-3p inhibits Notch1 signaling and TGF-β-induced collagen expression in hepatic stellate cells
Publisher: Springer Science and Business Media LLC
Date: 12-06-2019
DOI: 10.1038/S41598-019-44865-1
Abstract: During chronic liver injury hepatic stellate cells (HSCs), the principal source of extracellular matrix in the fibrotic liver, transdifferentiate into pro-fibrotic myofibroblast-like cells - a process potentially regulated by microRNAs (miRNAs). Recently, we found serum miRNA-25-3p (miR-25) levels were upregulated in children with Cystic Fibrosis (CF) without liver disease, compared to children with CF-associated liver disease and healthy in iduals. Here we examine the role of miR-25 in HSC biology. MiR-25 was detected in the human HSC cell line LX-2 and in primary murine HSCs, and increased with culture-induced activation. Transient overexpression of miR-25 inhibited TGF-β and its type 1 receptor (TGFBR1) mRNA expression, TGF-β-induced Smad2 phosphorylation and subsequent collagen1α1 induction in LX-2 cells. Pull-down experiments with biotinylated miR-25 revealed Notch signaling (co-)activators ADAM-17 and FKBP14 as miR-25 targets in HSCs. NanoString analysis confirmed miR-25 regulation of Notch- and Wnt-signaling pathways. Expression of Notch signaling pathway components and endogenous Notch1 signaling was downregulated in miR-25 overexpressing LX-2 cells, as were components of Wnt signaling such as Wnt5a. We propose that miR-25 acts as a negative feedback anti-fibrotic control during HSC activation by reducing the reactivity of HSCs to TGF-β-induced collagen expression and modulating the cross-talk between Notch, Wnt and TGF-β signaling.
Arthritis Prediction of Advanced Hepatic Fibrosis in HFE Hemochromatosis
Publisher: Elsevier BV
Date: 09-2022
DOI: 10.1016/J.MAYOCP.2022.02.017
Abstract: To evaluate whether arthritis predicts the likelihood of advanced hepatic fibrosis in HFE hemochromatosis. We conducted a retrospective, cross-sectional analysis of 112 well-characterized patients with HFE hemochromatosis and liver biopsy-validated fibrosis staging recruited between January 1, 1983, and December 31, 2013. Complete clinical, biochemical, hematologic, and noninvasive serum biochemical indices (aspartate aminotransferase to platelet ratio index [APRI] and fibrosis 4 index [FIB4]) were available. Scheuer fibrosis stages 3 and 4, APRI greater than 0.44, or FIB4 greater than 1.1 were used to define advanced hepatic fibrosis. Comparisons between groups were performed using categorical analysis, unpaired or paired t test. Male (n=76) and female (n=36) patients were similar in age. Nineteen patients had advanced hepatic fibrosis, and 47 had hemochromatosis arthritis. Arthritis was significantly associated with the presence of advanced hepatic fibrosis as determined by liver biopsy (sensitivity, 84%, [95% CI, 62% to 95%] negative predictive value, 95% [95% CI, 87% to 99%] relative risk, 7.4 [95% CI, 2.5 to 23] P<.001), APRI (sensitivity, 75% [95% CI, 55% to 88%] negative predictive value, 91% [95% CI, 81% to 96%] relative risk, 4.5 [95% CI, 2.0 to 10.2] P<.001), or FIB4 (sensitivity, 61% [95% CI, 41% to 78%] negative predictive value, 67% [95% CI, 68% to 90%] relative risk, 2.2 [95% CI, 1.1 to 4.6] P=.03). Mean cell volume values were significantly higher pretreatment in patients with F3-4 fibrosis (96.7±1.1 fL) compared with F0-2 fibrosis (93.4±0.5 fL P=.004) and declined following treatment (F3-4, 93.2±0.9 fL, P=.01 F0-2, 91.7±0.6 fL, P=.01). Advanced hepatic fibrosis is strongly associated with arthritis in HFE hemochromatosis. The absence of arthritis predicts a low likelihood of advanced hepatic fibrosis, supporting its use as a clinical marker for advanced hepatic fibrosis in HFE hemochromatosis.
Upregulation of lymphotoxin beta expression in liver progenitor (oval) cells in chronic hepatitis C
Publisher: BMJ
Date: 09-2003
Abstract: Bipotent liver progenitor (oval) cells with the ability to differentiate into hepatocytes and biliary epithelium have recently been identified in human subjects with hepatitis C. Animal studies suggest that members of the tumour necrosis factor family, including lymphotoxin beta (LT-beta), regulate oval cell proliferation in liver disease, but its role in human liver disease is unclear. This study seeks to establish a role for LT-beta in hepatitis C related liver injury and to provide evidence that its increased expression is related to the presence of oval cells. Liver biopsy specimens were obtained from patients with chronic hepatitis C virus (HCV) infection (n=20). Control liver s les (n=5) were obtained from liver resection or transplant surgery. LT-beta expression in liver biopsy specimens was studied using quantitative real time polymerase chain reaction and immunohistochemistry. LT-beta mRNA levels were similar in control and HCV liver in the absence of fibrosis. In subjects with portal fibrosis, LT-beta mRNA levels were elevated 2.2-fold over control liver levels (p=0.04). In subjects with bridging fibrosis, LT-beta mRNA levels increased 4.4-fold over control liver levels (p=0.02). LT-beta mRNA levels in subjects with established cirrhosis were increased 3.3-fold compared with controls and 2.6-fold compared with mild liver damage (p=0.02). Immunohistochemical analysis established that LT-beta was expressed by oval cells, inflammatory cells, and small portal hepatocytes. In chronic HCV infection, LT-beta expression is observed in multiple hepatic cell types, including oval cells. LT-beta expression is significantly increased when fibrosis or cirrhosis is present, suggesting a role for LT-beta in the pathogenesis of chronic hepatitis C and a possible role in oval cell mediated liver regeneration.
Hereditary hemochromatosis in the post-HFEera
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2008
DOI: 10.1002/HEP.22507
Screening forHFEand Iron Overload
Publisher: Georg Thieme Verlag KG
Date: 2005
Abstract: Type 1 hereditary hemochromatosis is a common disorder of iron overload occurring in in iduals homozygous for the C282Y HFE gene mutation. It can be a progressive and fatal condition. Early detection and phlebotomy prior to the onset of cirrhosis can reduce morbidity and normalize life expectancy. It is readily identified through biochemical testing for iron overload using serum transferrin saturation and genetic testing for C282Y homozygosity. General population screening has been waived in preference to targeting high-risk groups such as first-degree relatives of affected in iduals and those with clinical features suggestive of iron loading. This screening strategy is likely to continue until uncertainties regarding the natural history of the disease, age-related penetrance, and management of asymptomatic in iduals are clarified. Potential ethical, legal, and psychosocial issues arising through application of genetic screening programs also must be resolved prior to implementation of general population screening programs.
Hepatic iron loading in mice increases cholesterol biosynthesis.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-04-2010
DOI: 10.1002/HEP.23712
Abstract: Iron and cholesterol are both essential metabolites in mammalian systems, and too much or too little of either can have serious clinical consequences. In addition, both have been associated with steatosis and its progression, contributing, inter alia, to an increase in hepatic oxidative stress. The interaction between iron and cholesterol is unclear, with no consistent evidence emerging with respect to changes in plasma cholesterol on the basis of iron status. We sought to clarify the role of iron in lipid metabolism by studying the effects of iron status on hepatic cholesterol synthesis in mice with differing iron status. Transcripts of seven enzymes in the cholesterol biosynthesis pathway were significantly up-regulated with increasing hepatic iron (R(2) between 0.602 and 0.164), including those of the rate-limiting enzyme, 3-hydroxy-3-methylglutarate-coenzyme A reductase (Hmgcr R(2) = 0.362, P < 0.002). Hepatic cholesterol content correlated positively with hepatic iron (R(2) = 0.255, P < 0.007). There was no significant relationship between plasma cholesterol and either hepatic cholesterol or iron (R(2) = 0.101 and 0.014, respectively). Hepatic iron did not correlate with a number of known regulators of cholesterol synthesis, including sterol-regulatory element binding factor 2 (Srebf2 R(2) = 0.015), suggesting that the increases seen in the cholesterol biosynthesis pathway are independent of Srebf2. Transcripts of genes involved in bile acid synthesis, transport, or regulation did not increase with increasing hepatic iron. This study suggests that hepatic iron loading increases liver cholesterol synthesis and provides a new and potentially important additional mechanism by which iron could contribute to the development of fatty liver disease or lipotoxicity.
Hereditary haemochromatosis: to screen or not to screen?
Publisher: Elsevier BV
Date: 07-2005
Phenotypic expression of hereditary hemochromatosis: What have we learned from the population studies?
Publisher: Springer Science and Business Media LLC
Date: 26-01-2010
DOI: 10.1007/S11894-009-0078-3
Abstract: Profound advances in our knowledge of hereditary hemochromatosis (HH) during the past 150 years have resulted in two distinct "iron ages": the pre-HFE gene era and the post-HFE gene era. During these periods, family studies, HLA association studies, and ultimately HFE gene studies in various populations informed us of the genotypic prevalence as well as the clinical and biochemical penetrance of HH. We learned that HH has a highly variable clinical penetrance in susceptible in iduals of Northern European ancestry. Further, we now recognize that the natural history of HH is not as discrete as previously believed, because genetic and environmental modifiers of disease penetrance are increasingly identified as influencing the clinical expression of HH.
Fine-needle aspiration biopsy for the measurement of hepatic iron concentration
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-1992
Abstract: The potential application of fine-needle aspiration liver biopsy in the documentation of hepatic iron overload has been assessed in iron-loaded rats. Fine-needle aspiration and standard liver biopsy specimens were obtained from three groups of animals supplemented with oral and parenteral iron for 2 to 6 mo. The mean dry weights of standard and fine-needle biopsy specimens were 7.41 +/- 0.77 (+/- S.E.M.) and 0.57 +/- 0.54 mg, respectively. Hepatic iron in fine-needle aspiration biopsy specimens correlated significantly with hepatic iron in standard liver biopsy specimens as measured by biochemical determination, computerized image analysis and histological grading (r greater than 0.9, p less than 0.001). In conclusion, we have shown that fine-needle aspiration biopsy of the liver can obtain sufficient tissue for biochemical measurement of the hepatic iron concentration in an animal model of iron overload. The clinical applications of fine-needle aspiration liver biopsy in human beings with iron overload is currently being investigated.
Differential effects of gadolinium chloride on Kupffer cells in vivo and in vitro
Publisher: Elsevier BV
Date: 03-2004
DOI: 10.1016/J.BIOCEL.2003.08.004
Abstract: Gadolinium chloride (GdCl) is commonly used to study the role of Kupffer cells in liver disease in vivo. The in vitro effects of GdCl on cultured Kupffer cells are poorly characterised. The aim of this study was to characterise rat Kupffer cell TNFalpha production, phagocytic function, and ED1 and ED2 antigen expression following the administration of GdCl. For in vivo experiments, rats received 10mg/kg GdCl IV or sterile saline. Lipopolysaccharide 3mg/kg IP (LPS) was administered 4h prior to sacrifice on Days 1-3, 5 or 8 following GdCl injection. Hepatic ED1 and ED2 positive macrophage numbers and TNFalpha mRNA levels were determined. For in vitro experiments, Kupffer cells were cultured in the presence of 0-270 microM GdCl for 24h following which viability, TNFalpha protein production in response to LPS (10 ng/ml), phagocytosis, and ED1 and ED2 staining were evaluated. In vivo, the proportion of ED1 positive cells which were ED2 positive was reduced from 87 to 3% and hepatic TNFalpha mRNA levels following LPS declined by 60% over Days 1-5 after injection of GdCl (P<0.01). In vitro, phagocytosis declined with increasing concentrations of GdCl. GdCl (0-27 microM) did not effect cultured Kupffer cell viability, TNFalpha production, ED1 or ED2 staining. We conclude that GdCl significantly reduces ED2 expression by Kupffer cells in vivo. In vitro, GdCl has a dose dependent effect on phagocytosis but only effects viability and TNFalpha production at high concentrations. ED2 expression of cultured Kupffer cells is not affected by GdCl.
The role of Hfe in transferrin-bound iron uptake by hepatocytes
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-04-2008
DOI: 10.1002/HEP.22180
Abstract: HFE-related hereditary hemochromatosis results in hepatic iron overload. Hepatocytes acquire transferrin-bound iron via transferrin receptor (Tfr) 1 and Tfr1-independent pathways (possibly Tfr2-mediated). In this study, the role of Hfe in the regulation of hepatic transferrin-bound iron uptake by these pathways was investigated using Hfe knockout mice. Iron and transferrin uptake by hepatocytes from Hfe knockout, non-iron-loaded and iron-loaded wild-type mice were measured after incubation with 50 nM (125)I-Tf-(59)Fe (Tfr1 pathway) and 5 microM (125)I-Tf-(59)Fe (Tfr1-independent or putative Tfr2 pathway). Tfr1 and Tfr2 messenger RNA (mRNA) and protein expression were measured by real-time polymerase chain reaction and western blotting, respectively. Tfr1-mediated iron and transferrin uptake by Hfe knockout hepatocytes were increased by 40% to 70% compared with iron-loaded wild-type hepatocytes with similar iron levels and Tfr1 expression. Iron and transferrin uptake by the Tfr1-independent pathway was approximately 100-fold greater than by the Tfr1 pathway and was not affected by the absence of Hfe. Diferric transferrin increased hepatocyte Tfr2 protein expression, resulting in a small increase in transferrin but not iron uptake by the Tfr1-independent pathway. Tfr1-mediated iron uptake is regulated by Hfe in hepatocytes. The Tfr1-independent pathway exhibited a much greater capacity for iron uptake than the Tfr1 pathway but it was not regulated by Hfe. Diferric transferrin up-regulated hepatocyte Tfr2 protein expression but not iron uptake, suggesting that Tfr2 may have a limited role in the Tfr1-independent pathway.
Screening for genetic haemochromatosis in a rheumatology clinic
Publisher: Wiley
Date: 02-1994
DOI: 10.1111/J.1445-5994.1994.TB04420.X
Abstract: Recent data indicate that the prevalence of genetic haemochromatosis (GH) is greater than previously recognised and suggest that this disease is underdiagnosed. To determine the prevalence of GH in rheumatology clinic population. Over a 12 month period 339 consecutive patients, mean age 67.0 years, attending a rheumatology clinic were screened for iron overload. Twenty three patients had elevated initial screening tests (transferrin saturation [Tf%] > 55% ferritin > 500 micrograms/L). Repeat fasting Tf% and ferritin concentrations were obtained in 20 of these patients. Twelve patients had persistently elevated results, and of these patients four had liver biopsy tissue hepatic iron indices consistent with GH. One patient in the group had the diagnosis established by liver biopsy just before the screening commenced. Thus, the prevalence of GH in this population was 1.5%--five times that anticipated for the general population. Three of the patients with GH presented with an arthropathy which was not characteristic of the disease. The increased prevalence of GH in this group of patients with peripheral arthropathy provides an excellent justification for the routine screening of patients with peripheral arthritis for the exclusion of iron overload.
Utility of Serum Biomarker Indices for Staging of Hepatic Fibrosis Before and After Venesection in Patients With Hemochromatosis Caused by Variants in HFE
Publisher: Elsevier BV
Date: 07-2021
Pentoxifylline improves haemoglobin and interleukin-6 levels in chronic kidney disease.
Publisher: Wiley
Date: 30-03-2010
DOI: 10.1111/J.1440-1797.2009.01203.X
Abstract: To assess whether pentoxifylline improves anaemia of chronic kidney disease (CKD) via suppression of interleukin-6 (IL-6) and improved iron mobilization. CKD patients may have elevated IL-6 and tumour necrosis factor alpha levels. These cytokines can increase hepcidin production, which in turn reduces iron release from macrophages resulting in reduced availability of iron for erythropoiesis. In experimental models, pentoxifylline was shown to reduce IL-6 expression. We studied 14 patients with stages 4-5 CKD (glomerular filtration rate <30mL/min per 1.73 m(2)) due to non-inflammatory renal diseases. None of the patients had received immunosuppressive or erythropoietin-stimulating agents or parenteral iron. Patients had weekly blood tests for iron studies and cytokines during a control run-in period of 3 weeks and during 4 weeks of pentoxifylline treatment. Ten patients (eGFR 23 + or - 6 mL/min) completed the study. At the end of the run-in period average haemoglobin was 111 + or - 5 g/L, ferritin 92 + or - 26 microg/L, transferrin saturation 15 + or - 3% and circulating IL-6 10.6 + or - 3.8 pg/mL. Tumour necrosis factor alpha values were below threshold for detection. Treatment with pentoxifylline reduced circulating IL-6 (6.6 + or - 1.6 pg/mL, P < 0.01), increased transferrin saturation (20 + or - 5%, P < 0.003) and decreased serum ferritin (81 + or - 25 microg/L, P = NS). Haemoglobin increased after the second week of pentoxifylline, reaching 123 + or - 6 g/L by week 4 (P < 0.001). Pentoxifylline reduces circulating IL-6 and improves haemoglobin in non-inflammatory moderate to severe CKD. These changes are associated with changes in circulating transferrin saturation and ferritin, suggesting improved iron release. It is hypothesized that pentoxifylline improves iron disposition possibly through modulation of hepcidin.
Relationship between brain R(2) and liver and serum iron concentrations in elderly men.
Publisher: Wiley
Date: 23-01-2010
DOI: 10.1002/MRM.22263
Abstract: Studies of iron overload in humans and animals suggest that brain iron concentrations may be related in a regionally specific way to body iron status. However, few quantitative studies have investigated the associations between peripheral and regional brain iron in a normal elderly cohort. To examine these relationships, we used MRI to measure the proton transverse relaxation rate (R(2)) in 13 gray and white matter brain regions in 18 elderly men (average age, 75.5 years) with normal cognition. Brain R(2) values were compared with liver iron concentrations measured using the FerriScan MRI technique and serum iron indices. R(2) values in high-iron gray matter regions were significantly correlated (positively) with liver iron concentrations (globus pallidus, ventral pallidum) and serum transferrin saturation (caudate nucleus, globus pallidus, putamen) measured concurrently with brain R(2), and with serum iron concentrations (caudate nucleus, globus pallidus) measured three years before the current study. Our results suggest that iron levels in specific gray matter brain regions are influenced by systemic iron status in elderly men.
The nexus of iron and inflammation in hepcidin regulation: SMADs, STATs, and ECSIT
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2006
DOI: 10.1002/HEP.21526
Abstract: Hereditary hemochromatosis, characterized by iron overload in multiple organs, is one of the most common genetic disorders among Caucasians. Hepcidin, which is synthesized in the liver, plays important roles in iron overload syndromes. Here, we show that a Cre-loxP-mediated liver-specific disruption of SMAD4 results in markedly decreased hepcidin expression and accumulation of iron in many organs, which is most pronounced in liver, kidney, and pancreas. Transcript levels of genes involved in intestinal iron absorption, including Dcytb, DMT1, and ferroportin, are significantly elevated in the absence of hepcidin. We demonstrate that ectopic overexpression of SMAD4 activates the hepcidin promoter and is associated with epigenetic modification of histone H3 to a transcriptionally active form. Moreover, transcriptional activation of hepcidin is abrogated in SMAD4-deficient hepatocytes in response to iron overload, TGF-beta, BMP, or IL-6. Our study uncovers a novel role of TGF-beta/SMAD4 in regulating hepcidin expression and thus intestinal iron transport and iron homeostasis [corrected]
CD14‐positive hepatic monocytes/macrophages increase in hereditary hemochromatosis
Publisher: Wiley
Date: 10-2004
DOI: 10.1111/J.1478-3231.2004.0943.X
Abstract: Iron overload in hereditary hemochromatosis (HH) may result in hepatic fibrosis and cirrhosis, primarily due to collagen production by hepatic stellate cells that become activated to myofibroblasts. Endotoxin-responsive monocytes/macrophages (CD14-positive) are potential sources of profibrogenic factors. The aims of this study were to determine (1) whether CD14-positive monocytes/macrophages are present in the livers of patients with HH and (2) the potential relationship between CD14-positive cells and hepatic fibrosis in HH. HH was diagnosed using standard clinical, biochemical and genotypic parameters. Liver specimens from HH patients and control subjects were immunostained for CD14, CD68 and alpha-smooth muscle actin (alpha-SMA) and the number of cells expressing these antigens was determined. Fibrosis was assessed by routine histological methods. The total number of hepatic CD68-positive monocytes/macrophages was similar in HH patients and control subjects however, there was a nine-fold increase in the number of CD14-positive monocytes/macrophages in HH patients. Control subjects had very low levels of hepatic CD14 expression. In HH livers with advanced fibrosis, CD14-positive monocytes/macrophages were often associated with fibrous septa containing myofibroblasts expressing alpha-SMA. There was a substantial increase in hepatic CD14-positive monocytes/macrophages in HH and, in livers with advanced fibrosis, these cells were often associated with fibrous septa and septal myofibroblasts. The total number of monocytes/macrophages was similar in HH and control livers. In control human liver, Kupffer cells had a very low expression of CD14. These findings suggest that CD14-positive monocytes/macrophages may contribute to the process of hepatic fibrogenesis in HH.
Prospective dietary polyunsaturated fatty acid intake is associated with trajectories of fatty liver disease: an 8 year follow-up study from adolescence to young adulthood
Publisher: Springer Science and Business Media LLC
Date: 03-07-2022
DOI: 10.1007/S00394-022-02934-8
Abstract: Dietary fat intake has long been associated with fatty liver. Our study aimed to determine the effect of dietary fats on longitudinal fatty liver index (FLI) trajectories from adolescence to young adulthood. Nine hundred eighty-five participants in the Raine Study, Perth, Western Australia, Australia, had cross-sectional assessments at ages 14, 17, 20 and 22 years, during which anthropometric measurements and blood tests were obtained. FLI trajectories were derived from the longitudinal FLI results. Dietary fat intake was measured with a semi-quantitative food frequency questionnaire at 14 years and log multinominal regression analyses were used to estimate relative risks. Three FLI trajectories were identified and labelled as stable-low (79.1%, N = 782), low-to-high (13.9%, N = 132), and stable-high (7%, N = 71). The low-to-high group associated with an increased intake of the long-chain polyunsaturated fatty acids EPA, DPA and DHA (RR 1.27, 95% CI 1.10–1.48) relative to the stable-low group. Compared to the stable-low group, omega-6 and the ratio of omega-6 to omega-3 in the stable-high group were associated with an increased relative risk of 1.34 (95% CI 1.02–1.76) and 1.10 (95% CI 1.03–1.16), respectively. For those at high risk of fatty liver in early adolescence, high omega-6 fatty acid intake and a high ratio of omega-6 to omega-3 fatty acids are associated with increased risk of fatty liver. There should be caution in assuming these associations are causal due to possible undetected and underestimated confounding factors.
HFEC282Y/H63D compound heterozygotes are at low risk of hemochromatosis-related morbidity
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 19-03-2009
DOI: 10.1002/HEP.22972
Disruption of hemochromatosis protein and transferrin receptor 2 causes iron-induced liver injury in mice.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-06-2012
DOI: 10.1002/HEP.25689
Abstract: Mutations in hemochromatosis protein (HFE) or transferrin receptor 2 (TFR2) cause hereditary hemochromatosis (HH) by impeding production of the liver iron-regulatory hormone, hepcidin (HAMP). This study examined the effects of disruption of Hfe or Tfr2, either alone or together, on liver iron loading and injury in mouse models of HH. Iron status was determined in Hfe knockout (Hfe(-/-)), Tfr2 Y245X mutant (Tfr2(mut)), and double-mutant (Hfe(-/-) ×Tfr2(mut) ) mice by measuring plasma and liver iron levels. Plasma alanine transaminase (ALT) activity, liver histology, and collagen deposition were evaluated to assess liver injury. Hepatic oxidative stress was assessed by measuring superoxide dismutase (SOD) activity and F(2)-isoprostane levels. Gene expression was measured by real-time polymerase chain reaction. Hfe(-/-) ×Tfr2(mut) mice had elevated hepatic iron with a periportal distribution and increased plasma iron, transferrin saturation, and non-transferrin-bound iron, compared with Hfe(-/-), Tfr2(mut), and wild-type (WT) mice. H 1 expression was reduced to 40% (Hfe(-/-) and Tfr2(mut) ) and 1% (Hfe(-/-) ×Tfr2(mut)) of WT values. Hfe(-/-) ×Tfr2(mut) mice had elevated plasma ALT activity and mild hepatic inflammation with scattered aggregates of infiltrating inflammatory cluster of differentiation 45 (CD45)-positive cells. Increased hepatic hydoxyproline levels as well as Sirius red and Masson's Trichrome staining demonstrated advanced portal collagen deposition. Hfe(-/-) and Tfr2(mut) mice had less hepatic inflammation and collagen deposition. Liver F(2) -isoprostane levels were elevated, and copper/zinc and manganese SOD activities decreased in Hfe(-/-) ×Tfr2(mut), Tfr2(mut), and Hfe(-/-) mice, compared with WT mice. Disruption of both Hfe and Tfr2 caused more severe hepatic iron overload with more advanced lipid peroxidation, inflammation, and portal fibrosis than was observed with the disruption of either gene alone. The Hfe(-/-) ×Tfr2(mut) mouse model of iron-induced liver injury reflects the liver injury phenotype observed in human HH.
Isolation, culture and immortalisation of hepatic oval cells from adult mice fed a choline-deficient, ethionine-supplemented diet.
Publisher: Elsevier BV
Date: 2007
DOI: 10.1016/J.BIOCEL.2007.06.008
Abstract: Oval cells have great potential for use in cell therapy to treat liver disease, however this cannot be achieved until the factors which govern their proliferation and differentiation are better understood. We describe a method to establish primary cultures of murine oval cells, and the derivation of two novel lines from these. Primary cultures from the livers of wildtype or TAT-GRE lacZ transgenic mice subjected to a choline-deficient, ethionine-supplemented diet comprised up to 80% oval cells at day 7 based on A6 or CK19 staining. Cell lines were clonally derived, which underwent spontaneous immortalisation following prolonged maintenance in culture. Immunostaining and RT-PCR demonstrated they express hepatocytic and biliary markers and they were therefore termed "bipotential murine oval liver" (BMOL) cells. Under proliferating culture conditions, BMOL or BMOL-TAT cells abundantly expressed oval cell and biliary markers, whereas mature hepatocytic markers were upregulated when the growth conditions were changed to facilitate differentiation. Hepatic differentiation of BMOL-TAT cells could be traced by measuring the expression of their lacZ transgene, which is driven by a promoter element from tyrosine aminotransferase (TAT), a marker of adult hepatocytes. Interestingly, haematopoietic markers were upregulated in superconfluent cultures, indicating a possible multipotentiality. None of the cell lines grew in semi-solid agar, nor did they form tumours in nude mice, suggesting they are non-tumourigenic. These novel murine oval cell lines, together with a reliable method for isolation and culture of primary oval cells, will provide a useful tool for investigating the contribution of oval cells to liver regeneration.
Computerized measurement of iron in liver biopsies: A comparison with biochemical iron measurement
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-1990
Abstract: The measurement of stainable hepatic iron using a microcomputer image analysis system was compared with standard biochemical measurements of liver iron content in 103 liver biopsy specimens--29 of idiopathic hemochromatosis, 51 of alcoholic liver disease and 23 of various nonalcoholic liver diseases. Sections were stained using Perls' method for iron the mean area staining positively for iron was measured and expressed as a percentage of the area of biopsy measured. Biochemical (biochemical hepatic iron [mumol/gm dry wt]/age) and morphometrical (morphometrical hepatic iron [%]/age x 100) hepatic iron indices were calculated. Patients in the idiopathic hemochromatosis group had significantly higher biochemical hepatic iron concentrations (p less than 0.001) compared with the alcoholic liver disease and nonalcoholic liver disease groups: 284 (range = 119 to 631), 21 (range = 2 to 65) and 15 (range = 3 to 31) mumol/gm dry wt, respectively. The biochemical hepatic iron index was also significantly higher (p less than 0.001) in the hemochromatosis group compared with the alcoholic liver disease and nonalcoholic liver disease groups: 5.8 (range = 2.1 to 13.7), 0.4 (range = 0 to 1.6) and 0.4 (range = 0 to 1.1), respectively. Computerized measurements were significantly higher in the hemochromatosis group (p less than 0.001) compared with the alcoholic liver disease and nonalcoholic liver disease groups: 9.72% (range = 1.50% to 29.26%), 0.13% (range = 0% to 1.20%) and 0.03% (range = 0% to 0.40%), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Porphyria Cutanea Tarda in The Hfe -Gene and Hepatitis C Virus Era
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2000
Long-term mortality risks associated with mild anaemia in older persons: the Busselton Health Study
Publisher: Oxford University Press (OUP)
Date: 27-09-2012
Abstract: up to 25% of older people in the USA and other Western countries are anaemic by World Health Organization (WHO) criteria. The objective of this study was to examine the long-term relationships of haemoglobin concentration with all-cause and cause-specific mortality in a community-based s le of Australian adults surveyed in 1978. a community survey of 2,194 adults aged 40+ years in Busselton, Western Australia in 1978 with mortality follow-up to 2001. Cox regression models were used to investigate the relationships of haemoglobin as a continuous measure and anaemia by WHO criteria (women <12 g/dl (7.5 mmol/l) men 10 g/dl) and normocytic. There was an increased risk of death from all causes and from cancer for men with low haemoglobin. Cancers were predominantly of the prostate and genito-urinary organs, and to a lesser extent the gastrointestinal tract. There was no increased risk of all cause or cancer death in women. mild, normocytic anaemia is associated with survival reductions in middle-aged and older men, where it often occurs with prostate, gastrointestinal and other cancers, and should be investigated to exclude treatable causes.
Colonial health transitions: Aboriginal and ‘poor white’ infant mortality compared, Victoria 1850–1910
Publisher: Informa UK Limited
Date: 15-03-2011
Single Nucleus RNA Sequencing of Pre-Malignant Liver Reveals Disease-Associated Hepatocyte State with HCC Prognostic Potential
Publisher: Cold Spring Harbor Laboratory
Date: 27-03-2022
DOI: 10.1101/2022.03.25.485695
Abstract: Current approaches to stage chronic liver diseases have limited utility to directly predict liver cancer risk. Here, we employed single nucleus RNA sequencing (snRNA-seq) to characterize the cellular microenvironment of healthy and chronically injured pre-malignant livers using two distinct mouse models. Analysis of 40,748 hepatic nuclei unraveled a previously uncharacterized disease-associated hepatocyte transcriptional state (daHep). These cells were absent in healthy livers, but were increasingly prevalent as chronic liver disease progressed towards hepatocarcinogenesis. Gene expression deconvolution of 1,439 human liver transcriptomes from publicly available datasets revealed that daHep frequencies highly correlate with current histopathological liver disease staging systems. Importantly, we show that high daHep levels precede carcinogenesis in mice and humans and predict a higher risk of hepatocellular carcinoma (HCC) development. This novel transcriptional signature with diagnostic and, more importantly, prognostic significance has the potential to change the way chronic liver disease patients are staged, surveilled and risk-stratified.
Molecular pathogenesis of iron overload
Publisher: BMJ
Date: 08-2002
DOI: 10.1136/GUT.51.2.290
Abstract: Our current understanding of iron absorption under normal conditions is presented, together with an overview of the clinical disorders of iron overload and the molecular processes that contribute to increased iron deposition in iron overload. Recently, a number of new genes involved in iron metabolism have been identified which is allowing the molecular mechanisms of iron absorption to be elucidated.
The ancestral haplotype markers HLA -A3 and B7 do not influence the likelihood of advanced hepatic fibrosis or cirrhosis in HFE hemochromatosis
Publisher: Springer Science and Business Media LLC
Date: 13-05-2023
DOI: 10.1038/S41598-023-35028-4
Abstract: Advanced hepatic fibrosis occurs in up to 25% of in iduals with C282Y homozygous hemochromatosis. Our aim was to determine whether human leukocyte antigen (HLA)-A3 and B7 alleles act as genetic modifiers of the likelihood of advanced hepatic fibrosis. Between 1972 and 2013, 133 HFE C282Y homozygous in iduals underwent clinical and biochemical evaluation, HLA typing, liver biopsy for fibrosis staging and phlebotomy treatment. Hepatic fibrosis was graded according to Scheuer as F0–2 (low grade hepatic fibrosis), F3–4 (advanced hepatic fibrosis), and F4 cirrhosis. We analysed associations between the severity of fibrosis and HLA-A3 homozygosity, heterozygosity or absence, with or without the presence of HLA-B7 using categorical analysis. The mean age of HLA-A3 homozygotes (n = 24), heterozygotes (n = 65) and HLA-A3 null in iduals (n = 44) was 40 years. There were no significant differences between the groups for mean(± SEM) serum ferritin levels (1320 ± 296, 1217 ± 124, 1348 ± 188 $$\\upmu$$ μ g/L), hepatic iron concentration (178 ± 26, 213 ± 22, 199 ± 29 $$\\upmu$$ μ mol/g), mobilizable iron stores (9.9 ± 1.5, 9.5 ± 1.5, 11.5 ± 1.7 g iron removed via phlebotomy), frequency of advanced hepatic fibrosis (5/24[12%], 13/63[19%], 10/42[19%]) or cirrhosis (3/24[21%], 12/63[21%], 4/42[24%]), respectively. The presence or absence of HLA-B7 did not influence the outcome. Thus, HLA-A3 and HLA-B7 alleles are not associated with the risk of advanced hepatic fibrosis or cirrhosis in C282Y hemochromatosis.
The role of transferrin receptor 1 and 2 in transferrin-bound iron uptake in human hepatoma cells
Publisher: American Physiological Society
Date: 12-2009
DOI: 10.1152/AJPCELL.00649.2008
Abstract: Transferrin receptor (TFR) 1 and 2 are expressed in the liver TFR1 levels are regulated by cellular iron levels while TFR2 levels are regulated by transferrin saturation. The aims of this study were to 1) determine the relative importance of TFR1 and TFR2 in transferrin-bound iron (TBI) uptake by HuH7 human hepatoma cells and 2) characterize the role of metal-transferrin complexes in the regulation of these receptors. TFR expression was altered by 1) incubation with metal-transferrin (Tf) complexes, 2) TFR1 and TFR2 small interfering RNA knockdown, and 3) transfection with a human TFR2 plasmid. TBI uptake was measured using 59 Fe- 125 I-labeled Tf and mRNA and protein expression by real-time PCR and Western blot analysis, respectively. Fe 2 Tf, Co 2 Tf, and Mn 2 Tf increased TFR2 protein expression, indicating that the upregulation was not specifically regulated by iron-transferrin but also other metal-transferrins. In addition, Co 2 Tf and Mn 2 Tf upregulated TFR1, reduced ferritin, and increased hypoxia-inducible factor-1α protein expression, suggesting that TFR1 upregulation was due to a combination of iron deficiency and chemical hypoxia. TBI uptake correlated with changes in TFR1 but not TFR2 expression. TFR1 knockdown reduced iron uptake by 80% while TFR2 knockdown did not affect uptake. At 5 μM transferrin, iron uptake was not affected by combined TFR1 and TFR2 knockdown. Transfection with a hTFR2 plasmid increased TFR2 protein expression, causing a 15–20% increase in iron uptake and ferritin levels. This shows for the first time that TFR-mediated TBI uptake is mediated primarily via TFR1 but not TFR2 and that a high-capacity TFR-independent pathway exists in hepatoma cells.
Association between remnant lipoprotein cholesterol levels and non-alcoholic fatty liver disease in adolescents
Publisher: Elsevier BV
Date: 12-2020
Brain iron accumulation affects myelin-related molecular systems implicated in a rare neurogenetic disease family with neuropsychiatric features
Publisher: Springer Science and Business Media LLC
Date: 05-01-2016
DOI: 10.1038/MP.2015.192
Assessment of liver fibrosis markers in people with rheumatoid arthritis on methotrexate.
Publisher: Wiley
Date: 16-03-2022
DOI: 10.1111/IMJ.15125
Abstract: Up to 3% of methotrexate (MTX)-treated rheumatoid arthritis (RA) patients might develop liver fibrosis or cirrhosis, requiring effective screening algorithms. To assess the utility of non-invasive liver fibrosis assessment in RA patients on MTX. Fifty-six patients were recruited from rheumatology outpatient clinics in a public tertiary centre from July 2017 to October 2018. Clinical data was collected. Screening for hepatic fibrosis was performed using transient elastography (TE), aminoaspartate transaminase to platelet ratio index (APRI), Hepascore and Fibrosis-4 index (FIB-4). Those with suspected significant liver fibrosis based on these screening tests were assessed by a hepatologist. Twenty-seven patients were suspected to have liver fibrosis on screening, including 10/56 (18%) by TE, 20/56 (36%) by Hepascore, 2/56 by APRI (4%) and 1/56 by FIB-4 (2%). Of these 27 patients, 11 were reviewed by a hepatologist and one diagnosed with significant liver fibrosis. TE, but not APRI, Hepascore or FIB-4, was found to have 100% sensitivity and 84% specificity (P = 0.029) for hepatologist-diagnosed liver fibrosis. Liver fibrosis develops in a minority of MTX-treated RA patients. The present study suggests that TE is a more sensitive screening test than APRI, FIB-4 or Hepascore in the identification of people with RA at risk of hepatic fibrosis.
Serum Ferritin and Cardiovascular Disease: A 17-Year Follow-up Study in Busselton, Western Australia
Publisher: Oxford University Press (OUP)
Date: 15-07-2003
DOI: 10.1093/AJE/KWG121
Abstract: The association between serum ferritin level and coronary heart disease (CHD) and stroke events was evaluated in a long-term Western Australia prospective study in 1981-1998. The cohort consisted of the 1612 men and women aged 40-89 years who participated in the 1981 Busselton Health Survey and who were free of cardiovascular disease at that time. Serum ferritin levels were obtained from serum s les stored frozen since 1981. The outcomes of interest were time to first CHD event (hospital admission or death) and time to first stroke event. Case-cohort s ling was used to reduce costs and preserve serum but still allow efficient analysis. Ferritin assays were performed for 217 CHD cases, 118 stroke cases, and a random s le of 450 of the total cohort. Proportional hazards regression models were used to obtain age-adjusted and multivariate-adjusted hazard ratios for ferritin level in relation to CHD and stroke. The hazard ratio for the highest tertile group compared with the lowest group was 0.96 (95% confidence interval: 0.60, 1.53) for CHD and 1.43 (95% confidence interval: 0.78, 2.64) for stroke. Little or no evidence was found that ferritin level was a risk factor for cardiovascular disease.
Clinical penetrance of C282Y homozygousHFEhemochromatosis
Publisher: Informa UK Limited
Date: 12-2008
Abstract: Following the discovery of the HFE gene, it became apparent that C282Y homozygous HFE hemochromatosis is the most common autosomal recessive genetic disorder in populations of northern European descent, where it attains a maximum prevalence of approximately 1 in 200. Cross-sectional studies have revealed that the clinical penetrance of symptoms of iron-loading disease is relatively low and highly variable. Although there is no standard definition of clinical penetrance, large studies of newly diagnosed C282Y homozygotes that have specifically assessed liver disease have obtained data showing that penetrance occurs in between 24 and 43% of males and 1 and 14% of females. This relatively low clinical penetrance is largely unexplained. Current evidence suggests a limited role for digenic inheritance of mutations in iron homeostasis genes in modifying the penetrance of HFE hemochromatosis. Currently, the single most important environmental and genetic variables promoting penetrance are alcohol consumption and male gender, respectively. With genetic analyses becoming simpler to perform, new genetic modifiers of hepatic iron loading and liver fibrogenesis await identification.
Natural History and Management ofHFE-Hemochromatosis
Publisher: Georg Thieme Verlag KG
Date: 08-2011
Abstract: Advances in our knowledge of hereditary hemochromatosis (HH) over the past 150 years have revealed new insights into this common genetic disorder. Meticulous family and HLA association studies followed ultimately by cloning of the HFE gene have dramatically changed our understanding of the natural history and manifestations of HH. Cross-sectional studies demonstrated that HH had a highly variable clinical and biochemical penetrance in susceptible in iduals of northern European descent. "State-of-the-art" large longitudinal population studies have accurately defined the natural history. We now recognize that HH is not as discreet an entity as previously thought because genetic and environmental modifiers of disease penetrance are increasingly identified as influencing the clinical course of HH. While phlebotomy remains the cornerstone of therapy, our diagnostic approach has been refined to incorporate new biochemical, genetic, and noninvasive methods that complement more traditional approaches. This review aims to encapsulate this new knowledge in a framework that addresses commonly raised issues relating to the current natural history, diagnosis, and management of HH patients.
Histological evaluation of iron in liver biopsies: relationship to mutations
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2000
Outcomes for women in a flexible sigmoidoscopy‐based colorectal cancer screening programme
Publisher: Wiley
Date: 03-10-2007
DOI: 10.1111/J.1445-5994.2007.01468.X
Abstract: There are concerns that technical and anatomical factors can reduce the potential benefit of flexible sigmoidoscopy (FS) as a colorectal cancer (CRC) screening tool in women compared with men. Our aim was to review the outcomes for female participants in a community-based CRC screening project using FS. In 1995, a programme of unsedated FS-based screening of asymptomatic average-risk in iduals aged 55-64 years was established at Fremantle Hospital, Western Australia. Insertion depths, pathological findings and site of adenomas and subject-rated pain scores have been prospectively recorded. Later diagnoses of malignancy were determined by linkage of the cohort with the West Australian Cancer Registry. Between 1995 and 2005, 3402 primary screening FS examinations had been carried out (women 41%). Mean age of participants was 59.6 years. Women were more likely to undergo a FS with insertion depth less than 40 cm (17 vs 6%, P < 0.0001). Mean pain score was 2.9 for men and 4.0 for women (P < 0.0001). Women were less likely to have any neoplasia detected, independent of pain score or insertion depth (odds ratio 0.5, 95% confidence interval 0.4-0.6). Increasing insertion depth from 50 to 60 cm in a woman would only have a 0.4% chance of detecting any additional neoplasia. An insignificant trend to higher incidence of later interval CRC was observed in women with normal sigmoidoscopy. Women probably undergo FS with more discomfort and lesser insertion depth than men. It is unlikely that moderate increases in insertion depth would have a substantial benefit.
Association of Transferrin Saturation With the Arthropathy of Hereditary Hemochromatosis
Publisher: Elsevier BV
Date: 10-2017
Predicting Iron Overload in Hyperferritinemia
Publisher: Elsevier BV
Date: 03-2009
DOI: 10.1016/J.CGH.2008.11.010
Abstract: Hyperferritinemia is a common abnormality. This study determined the prevalence of hepatic iron overload in subjects of northern European origin with hyperferritinemia. Fifty-two consecutive subjects referred for evaluation of suspected iron overload (serum ferritin level >350 microg/L) were ided into 3 groups: group 1, increased transferrin saturation and no significant hemochromatosis gene product (HFE) mutations (N = 17) group 2, increased transferrin saturation and C282Y homozygosity or C282Y/H63D compound heterozygosity (N = 22) and group 3, normal transferrin saturation and no significant HFE mutations (N = 13). All subjects underwent magnetic resonance R2 relaxometry for quantitation of hepatic iron concentration (HIC). The HIC was significantly higher in group 2 subjects (123 +/- 22 micromol/g) compared with groups 1 and 3 subjects (39 +/- 4 and 36 +/- 5 micromol/g, respectively) (P < .01). Nine of 22 subjects in group 2 had an increase of their HIC to greater than 3 times the upper limit of normal compared with none in the other 2 groups (P < .01). An increase of HIC to greater than 3 times the upper limit of normal is highly unlikely in hyperferritinemic subjects who do not have HFE-related hereditary hemochromatosis or causes of secondary iron overload.
22 Hepatitis C and iron
Publisher: Elsevier
Date: 2000
A population-based study of the biochemical and clinical expression of the H63D hemochromatosis mutation
Publisher: Elsevier BV
Date: 03-2002
DOI: 10.1016/S0016-5085(02)80116-0
Abstract: Two major mutations are defined within the hemochromatosis gene, HFE. Although the effects of the C282Y mutation have been well characterized, the effects of the H63D mutation remain unclear. We accessed a well-defined population in Busselton, Australia, and determined the frequency of the H63D mutation and its influence on total body iron stores. Serum transferrin saturation and ferritin levels were correlated with the H63D mutation in 2531 unrelated white subjects who did not possess the C282Y mutation. Sixty-two subjects (2.1%) were homozygous for the H63D mutation, 711 (23.6%) were heterozygous, and 1758 (58.4%) were wild-type for the H63D mutation. Serum transferrin saturation was significantly increased in male and female H63D homozygotes and heterozygotes compared with wild-types. Serum ferritin levels within each gender were not influenced by H63D genotypes. Elevated transferrin saturation > or = 45% was observed in a greater proportion of male H63D carriers than male wild-types. Male H63D homozygotes (9%) and heterozygotes (3%) were more likely to have both elevated transferrin saturation and elevated ferritin > or = 300 ng/mL than male wild-types (0.7%). Homozygosity for H63D was not associated with the development of clinically significant iron overload. Presence of the H63D mutation results in a significant increase in serum transferrin saturation but does not result in significant iron overload. In the absence of the C282Y mutation, the H63D mutation is not clinically significant.
Is HFE involved in increased hepcidin expression and hypoferremia in inflammation and anemia of chronic disease?
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2005
DOI: 10.1002/HEP.20652
Hepatic iron concentration correlates with insulin sensitivity in nonalcoholic fatty liver disease
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 27-04-2018
DOI: 10.1002/HEP4.1190
Abstract: Rodent and cell‐culture models support a role for iron‐related adipokine dysregulation and insulin resistance in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) however, substantial human data are lacking. We examined the relationship between measures of iron status, adipokines, and insulin resistance in patients with NAFLD in the presence and absence of venesection. This study forms part of the Impact of Iron on Insulin Resistance and Liver Histology in Nonalcoholic Steatohepatitis (IIRON2) study, a prospective randomized controlled trial of venesection for adults with NAFLD. Paired serum s les at baseline and 6 months (end of treatment) in controls (n = 28) and patients who had venesection (n = 23) were assayed for adiponectin, leptin, resistin, retinol binding protein‐4, tumor necrosis factor α, and interleukin‐6, using a Quantibody, customized, multiplexed enzyme‐linked immunosorbent assay array. Hepatic iron concentration (HIC) was determined using MR FerriScan. Unexpectedly, analysis revealed a significant positive correlation between baseline serum adiponectin concentration and HIC, which strengthened after correction for age, sex, and body mass index (rho = 0.36 P = 0.007). In addition, there were significant inverse correlations between HIC and measures of insulin resistance (adipose tissue insulin resistance (Adipo‐IR), serum insulin, serum glucose, homeostasis model assessment of insulin resistance, hemoglobin A1c, and hepatic steatosis), whereas a positive correlation was noted with the insulin sensitivity index. Changes in serum adipokines over 6 months did not differ between the control and venesection groups. Conclusion: HIC positively correlates with serum adiponectin and insulin sensitivity in patients with NAFLD. Further study is required to establish causality and mechanistic explanations for these associations and their relevance in the pathogenesis of insulin resistance and NAFLD. ( Hepatology Communications 2018 :644‐653)
Red blood cell transfusion is associated with further bleeding and fresh-frozen plasma with mortality in nonvariceal upper gastrointestinal bleeding
Publisher: Wiley
Date: 31-12-2016
DOI: 10.1111/TRF.13446
Abstract: Blood products are commonly transfused for patients with nonvariceal upper gastrointestinal bleeding (NVUGIB). While concerns exist about further bleeding and mortality in subsets of patients receiving red blood cell (RBC) transfusion, the impact of non-RBC blood products has not previously been systematically investigated. The aim of the study was to investigate the associations between blood products transfusion, further bleeding, and mortality after acute NVUGIB. A retrospective cohort study examined further bleeding and 30-day and 1-year mortality in adult patients who underwent gastroscopy for suspected acute NVUGIB between 2008 and 2010 in three tertiary hospitals in Western Australia. Survival analysis was performed. A total of 2228 adults (63% male) with 2360 hospital admissions for NVUGIB met the inclusion criteria. Median age at presentation was 70 years (range, 19-99 years). Thirty-day mortality was 4.9% and 1-year mortality was 13.9%. Transfusion of 4 or more units of RBCs was associated with greater than 10 times the odds of further bleeding in patients with a hemoglobin level of more than 90 g/L (odds ratio, 11.9 95% confidence interval [CI], 3.1-45.7 p ≤ 0.001), but was not associated with mortality. Administration of 5 or more units of fresh-frozen plasma (FFP) was associated with increased 30-day (hazard ratio, 2.8 95% CI, 1.3-5.9 p = 0.008) and 1-year (hazard ratio, 2.6 95% CI, 1.3-5.0 p = 0.005) mortality after adjusting for coagulopathy, comorbidity, Rockall score, and other covariates. In this large, multicenter study of NVUGIB, RBC transfusion was associated with further bleeding but not mortality, while FFP transfusion was associated with increased mortality in a subset of patients.
Redox cycling metals: Pedaling their roles in metabolism and their use in the development of novel therapeutics
Publisher: Elsevier BV
Date: 04-2016
DOI: 10.1016/J.BBAMCR.2016.01.026
Abstract: Essential metals, such as iron and copper, play a critical role in a plethora of cellular processes including cell growth and proliferation. However, concomitantly, excess of these metal ions in the body can have deleterious effects due to their ability to generate cytotoxic reactive oxygen species (ROS). Thus, the human body has evolved a very well-orchestrated metabolic system that keeps tight control on the levels of these metal ions. Considering their very high proliferation rate, cancer cells require a high abundance of these metals compared to their normal counterparts. Interestingly, new anti-cancer agents that take advantage of the sensitivity of cancer cells to metal sequestration and their susceptibility to ROS have been developed. These ligands can avidly bind metal ions to form redox active metal complexes, which lead to generation of cytotoxic ROS. Furthermore, these agents also act as potent metastasis suppressors due to their ability to up-regulate the metastasis suppressor gene, N-myc downstream regulated gene 1. This review discusses the importance of iron and copper in the metabolism and progression of cancer, how they can be exploited to target tumors and the clinical translation of novel anti-cancer chemotherapeutics.
Reduced mortality due to phlebotomy in moderately iron-loaded HFE haemochromatosis? The need for clinical trials
Publisher: Elsevier BV
Date: 07-2015
Association between liver-specific gene polymorphisms and their expression levels with nonalcoholic fatty liver disease
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2013
DOI: 10.1002/HEP.26184
Abstract: Genetic factors account for a significant proportion of the phenotypic variance of nonalcoholic fatty liver disease (NAFLD) however, very few predisposing genes have been identified. We aimed to (1) identify novel genetic associations with NAFLD by performing a genome-wide association study (GWAS), and (2) examine the biological expression of the strongest genetic associations in a separate cohort. We performed GWAS of a population-based cohort (Raine Study) of 928 adolescents assessed for NAFLD by ultrasound at age 17. Expression of genes with single nucleotide polymorphisms (SNPs) that were associated with NAFLD at a significance level of P < 10(-5) was examined in adults with NAFLD and controls by quantifying hepatic messenger RNA (mRNA) expression and serum levels of protein. After adjustment for sex and degree of adiposity, SNPs in two genes expressed in liver were associated with NAFLD adolescents: group-specific component (GC) (odds ratio [OR], 2.54 P = 1.20 × 10(-6)) and lymphocyte cytosolic protein-1 (LCP1) (OR, 3.29 P = 2.96 × 10(-6)). SNPs in two genes expressed in neurons were also associated with NAFLD: lipid phosphate phosphatase-related protein type 4 (LPPR4) (OR, 2.30 P = 4.82 × 10(-6)) and solute carrier family 38 member 8 (SLC38A8) (OR, 3.14 P = 1.86 × 10(-6) ). Hepatic GC mRNA was significantly reduced (by 83%) and LCP1 mRNA was increased (by 300%) in liver biopsy s les from patients with NAFLD compared to controls (P < 0.05). Mean serum levels of GC protein were significantly lower in patients with NAFLD than controls (250 ± 90 versus 298 ± 90, respectively P = 0.004) GC protein levels decreased with increasing severity of hepatic steatosis (P < 0.01). The association between GC and LCP1 SNPs and NAFLD as well as altered biological expression implicate these genes in the pathogenesis of NAFLD.
Related Organisations
American Association For The Study Of Liver Diseases
Location: United States of America
Edith Cowan University School Of Medical And Health Sciences
Location: Australia
American Gastroenterological Association
Location: United States of America
American Association For The Study Of Liver Diseases
Location: No location found
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