DOCSLIB.ORG

Physiopathology of Iron Overload in Hemochromatosis

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Physiopathology of Iron Overload in Hemochromatosis Emocromatosi ed Iperferritinemie Alberto Piperno Università di Milano-Bicocca Dipartimento di Medicina e Chirurgia Centro Malattie Rare ASST-Monza, Ospedale S.Gerardo Learning Objectives • Cos’è l’emocromatosi • Cos’è l’iperferritinemia • La diagnosi di emocromatosi • L’intrico diagnostico delle iperferritinemie • Take home messages Emocromatosi Iperferritinemia Un gruppo di malattie Può essere espressione di: ereditarie caratterizzate da: • accumulo di ferro da cause • elevata saturazione della diverse (genetiche e transferrina acquisite) • iperferritinemia • accumulo di ferro di entità Più frequentemente è dovuta a: variabile • diverse condizioni (genetiche • sviluppo di complicanze con e acquisite) non associate ad variabile penetranza ed un corrispondente incremento espressione dei depositi di ferro Hereditary Hemochromatosis diseases, genes and proteins Disease Gene Protein Hemochromatosis type 1 HFE HFE Hemochromatosis type 2a (JH) HAMP Hepcidin Hemochromatosis type 2b (JH) HJV Hemojuvelin Hemochromatosis type 3 TFR2 Transferrin receptor 2 Hemochromatosis type 4 SLC40A1 Ferroportin Gene Phenotype Allele frequency 1000G ESP6500 ExAC Recessive Recessive Recessive Recessive Dominant Wallace & Subramaniam Genet Med 2016;18:618-626; Piperno A. Expert Opin. Med. Diagn. 2013;7:161-177; Pietrangelo A. Hepatology 2007;,46::1291-1301; Piperno et al doi: 10.21037/tgh.2019.11.15 Hemochromatosis proteins and iron homeostasis Blood and tissue iron status LSECs I II TF-Fe - - 2 BMP2 BMP6 Erythropoietic TFR2 BMPR BMPR HFE HJV HIF IL-6 TFR1 Hypoxia IL-6R TMPRSS6 PDGF-BB ERK1/2? activity Inflammation SMAD4 ERFE STAT3 Nucleus ? Hepatocyte HAMP Duodenal Macrophage cell Hepcidin Ferroportin Ferroportin Iron release in blood Modified from Expert Opin Med Diagn 2013; Silvestri et al 2019; Tangudu et al 2019 Hemochromatosis type 1, 2 and 3 a quantitative defect of hepcidin production HFE HJV-HAMP TFR2 Hepcidin Inadequate production Reduced production Adult Juvenile Type 3 Hemochromatosis Hemochromatosis Hemochromatosis 120 100 epcidin 80 h 60 40 /mg creatinine) /mg 20 urinary ng 0 Controls HFE TfR2 HFE2 HAMP ( Piperno et al WJG 2009;15:513 HH type-4: gain-of-function mutations of SLC40A1 gene causes hepcidin resistence • Genetics: autosomal dominant; gain-of-function mutations; incomplete penetrance and variable expression at biochemical and clinical level • Clinics: similar to hemochromatosis type-1 • Laboratory: variably increased TSAT and serum ferritin Hepcidin resistence 30-year-old men Tf saturation 88%; SF 5600 µg/L; macrophage LIC 14.5 mg Fe/g dry wt Fe Enterocyte RBC RBC Cp Mut FP FP FP Mut FP Heph High Fe High TS Hepatocellular IOL Pietrangelo et al. N Engl J Med 1999; Pietrangelo A Haematologica 2017; Le Lan et al. Gastroenterology 2011 Physiopathology of iron overload in Hemochromatosis Type 1, 2, 3, and 4 HH: increased iron absorption and macrophage release § High serum iron RES involvement § Increased Tf saturation (TSAT) RES occurs in advanced § Formation of NTBI in the plasma liver IOL and favours fibrosis Hepatocellular IOL §High serum ferritin Excess iron overwhelms hepatocyte capacity Diabetes Hypogonadism Cardiopathy Liver damage Systemic IOL Arthropathy NTBI, non-transferrin-bound iron; RES, reticuloendothelial system; Tf, transferrin. Transl Gastroenterol Hepatol 2020;5:25 Ferritin: the iron storage protein • In mammalian ferritins, 24 subunits assemble to form a hollow symmetrical protein with a molecular weight of about 480 kDa. The cavity contains up to 4,500 iron atoms. • Three different types of monomer are in mammalian cells: – H (FtH, heavy, ~21 kDa) and L (FtL, light,~19 kDa) monomers variably assemble to form the most abundant cytosolic ferritins (isoferritins). – The mitochondrial subunit (FtMt, ~21 kDa) is found exclusively in the mitochondria (FtMt). Arch Toxicol (2014) 88:1787–1802 Tissue and serum ferritin Serum ferritin in humans ferritin appears to consist of l- L-ferritin ferritin, a glycosylated Iron leakage L-ferritin form of L termed G- ferritin, a truncated ferritin G-ferritin (smaller) form of L (S- S-ferritin ferritin) and trace secretion H-ferritin amounts of H-ferritin. Cytokines Serum ferritin is iron- poor compared to intracellular ferritin Hepatocytes, Macrophages, Myocytes, other cells Cell Serum Metallomics 2014;6:748; Arch Toxicol 2014;88:1787; Blood. 2010;116:1574-84. Physiopathology of hyperferritinemia Iron overload Cell necrosis L-ferritin ferritin Iron leakage L-ferritin G-ferritin ferritin S-ferritin secretion H-ferritin Cytokines Inflammation Synthesis Altered/variable Altered/variable Metabolic dis. dysregulation secretion? scavenging? Hypertyroidism Cell Serum Arch Toxicol (2014) 88:1787–1802; J Biol Chem 2020;295:15727; J Neural Transm (2011) 118:337–347 Hyperferritinemia is not a reliable index of iron overload Serum ferritin as an index of iron overload shows marked variability according to different clinical situations Olynik et al Clin Gastroenterol Hepatol 2009 Hyperferritinemia is not a reliable index of iron overload No iron overload Systemic iron overload Acquired Inflammation Primary iron overload Hepatocellular necrosis Hemochromatosis (type 1, 2 and 3) Metabolic disorders (DHF) Hemochromatosis type 4 High alcohol intake Hyperthyroidism Secondary iron overload Inherited Iron-loading anemias Hereditary hyperferritinemia-cataract Transfusional iron overload Benign hyperferritinemia End-stage liver disease Chronic liver diseases Local iron overload [Mostly mild to moderate with prevalent Other iron overload diseases reticuloendothelial or mixed distribution] Acquired Acquired Neonatal hemochromatosis (GALD) Chronic liver diseases (viral, ASH, NASH) African iron overload Metabolic disorders (DIOS) Inherited Inherited DMT1 deficiency Ferroportin disease Hypotransferrinemia Gaucher’s disease Aceruloplasminemia Modified from Expert Opin. Med. Diagn. 2013;7:161; Transl Gastroenterol Hepatol 2020;5:25 Hyperferritinemia should be classified according to transferrin saturation <45% Transferrin saturation No iron overload Inflammatory tests Inflammation Liver function tests Hepatocellular necrosis Glucose, Lipid tests, OGTT Metabolic disorders (DHF) History High alcohol intake Familial and personal history of early cataract, Hereditary hyperferritinemia-cataract genetic test Benign hyperferritinemia Exclusion diagnosis, genetic test Iron overload (mostly mild to moderate) Chronic liver diseases (viral, ASH, NASH) Liver function tests Metabolic disorders (DIOS) Glucose, Lipid tests, OGTT Hemolytic anemias Hemolytic tests Transfusional iron overload (early stages) History, number of transfusions Parenteral iron administration (inadequate) History, number of inadequate infusion Ferroportin disease Family recurrence, genetic test Aceruloplasminemia Measure serum ceruloplasmin Gaucher’s disease Platelet, splenomegaly, biochemical test Modified from Expert Opin. Med. Diagn. 2013;7:161-177; Transl Gastroenterol Hepatol 2020;5:25 Causes of hyperferritinemia macrophage 2+ Transfusion-dependent: Fp Fe Early RES iron loading -> Cp Fe2+ hyperferritinemia with 3+ Tf-Fe TfR1 hepatocyte normal TSAT; Fp Cp Fe3+ Later TSAT oversaturation -> systemic parenchimal TF > TSAT iron overload enterocytes RES Iron retention: macrophage Inflammation (cytokine 2+ mediated: hepcidin and Fe Fe2+ GR Cp Fp ferritin up-regulation) Fp GR Heph Ferroportin disease (Loss- GR of-function mutations) Tf Hyperferritinemia with reduced or normal TSAT Metabolic-associated hyperferritinemia, and iron overload: a pathologic continuum Metabolic syndrome DIOS Insulin Local Altered hepcidin inflammation NAFLD production? Hepatic damage Hepatic and Sinusoidal iron Serum ferritin cellular iron retention? Genetic background Hepcidin-mediated J Hepatol 2007;46:549–552 Causes of Hyperferritinemia: aceruloplasminemia Apo-Ceruloplasmin Iron accumulation 6-Cu Brain Ceruloplasmin Iron accumulation Ferroportin High s-ferritin liver, pancreas Fe3+ Transferrin Low serum iron, Increased iron Low transferrin saturation absorption Stomach Iron deficient erythropoiesis Hepcidin Duodenum suppression Mild microcytic anemia Hyperferritinemia should be classified according to transferrin saturation Transferrin saturation >45% Primary iron overload Genetic tests Hemochromatosis (type 1, 2 and 3) Hemochromatosis type 4 Secondary iron overload Inherited/acquired ineffective erythropoiesis: Iron-loading anemias anemia, bone marrow aspiration/biopsy, genetics End-stage liver disease Liver function and instrumental tests History, number of transfusions Transfusional iron overload (later stages) Other iron overload diseases Severe microcytic anemia; measure serum DMT1 deficiency transferrin; Genetic tests Hypotransferrinemia Severe liver failure Neonatal hemochromatosis African iron overload Modified from Expert Opin. Med. Diagn. 2013;7:161-177 Diagnosis of hemochromatosis (and other iron overload disorders) • Define the presence and the amount of iron overload • Genetic testing if appropriate • Define appropriate tests for clinical stadiation (when and how) • Define adequate therapy • Define adequate follow-up Defining and monitoring the amount of iron overload Biochemical indices § Transferrin saturation (n.v. 16-45%) Qualitative, not quantitative index [s-Iron (µg/dL)/s-Transferrin (mg/dL)*1.42] § Serum ferritin (n.v. varies according Correlates with body iron, but to sex and age: children 12/30-100 influenced by many factors ng/mL; young women 12/30-160 ng/mL; post-menopausal women 12/30-250 ng/mL; men 12/30-400) Non-invasive methods Reliable, can
Load more

Recommended publications
  • Primary Liver Cancer: Epidemiological And
    PRIMARY LIVER CANCER: EPIDEMIOLOGICAL AND BIOMARKER DISCOVERY STUDIES Nimzing Gwamzhi Ladep Imperial College London Department of Medicine December 2013 Thesis submitted for Doctor of Philosophy 1 THESIS ABSTRACT With previous reports indicating changes in mortality, risk factors and management of primary liver cancer (PLC), evaluation of current trends in the incidence and mortality rates was indicated. Late diagnosis has been implicated to be a major contributor to the high fatality rates of PLC. This work aimed at: studying trends of PLC by subcategories globally in general, and in England and Wales, in particular; investigating liver-related morbidities of HIV infected patients in an African setting; and discovering urinary biomarkers of hepatocellular carcinoma. The World Health Organisation (WHO) and Small Area Health Statistics Unit (SAHSU) databases were interrogated respectively, in order to achieve the first aim. The second aim was achieved through utilisation of databases of an African-based HIV treatment programme- AIDS Prevention Initiative in Nigeria (APIN), located in Jos, Nigeria. The European Union-funded Prevention of Liver Fibrosis and Cancer in Africa (PROLIFICA) case-control study in three West African countries was the platform through which urinary metabolic profiling was accomplished. Proton nuclear magnetic resonance spectroscopy (NMR) and parallel ultra-performance liquid chromatography mass spectrometry (UPLC-MS) were used for biomarker discovery studies. Mortality rates of intrahepatic bile duct carcinoma (IHBD) increased in all countries that were studied. Misclassification of hilar cholangiocarcinoma accounted for only a small increase in the rate of IHBD in England and Wales. With over 90% screening rate for viral hepatitides, the rates of hepatitis B (HBV), hepatitis C (HCV) and 2 HBV/HCV in HIV-infected patients in the APIN programme were 17.8%, 11.3% and 2.5% respectively.
    [Show full text]
  • Secondary Hemochromatosis As a Result of Acute Transfusion-Induced Iron Overload in a Burn Patient Michael Amatto1 and Hernish Acharya2*
    Amatto and Acharya Burns & Trauma (2016) 4:10 DOI 10.1186/s41038-016-0034-z CASE REPORT Open Access Secondary hemochromatosis as a result of acute transfusion-induced iron overload in a burn patient Michael Amatto1 and Hernish Acharya2* Abstract Background: Red blood cell transfusions are critical in burn management. The subsequent iron overload that can occur from this treatment can lead to secondary hemochromatosis with multi-organ damage. Case Presentation: While well recognized in patients receiving chronic transfusions, we present a case outlining the acute development of hemochromatosis secondary to multiple transfusions in a burn patient. Conclusions: Simple screening laboratory measures and treatment options exist which may significantly reduce morbidity; thus, we believe awareness of secondary hemochromatosis in those treating burn patients is critical. Keywords: Secondary hemochromatosis, Transfusion, Iron overload, Burn patients Background of parental iron or RBC transfusions, neonatal iron over- Acute and chronic treatment of the severely burned indi- load, aceruloplasminemia, and African iron overload [6, 7]. vidual is often complex due to many physical and psycho- Hemochromatosis is a disease characterized by iron logical factors [1, 2]. Resuscitation involving packed red accumulation in tissues. Initial symptoms and signs in- blood cell (RBC) transfusion is often essential [3]. How- clude skin pigmentation, fatigue, erectile dysfunction, ever, RBC transfusion carries potential risks including and arthralgia while later stages of the disease result in hemolytic reactions and infections, as well as other com- cardiomyopathy, diabetes mellitus, hypogonadism, hypo- plications that are often overlooked such as iron overload pituitarism, and hypoparathyroidism, as well as liver fi- [4, 5]. Each unit of RBCs contains 200–250 mg of iron, brosis and cirrhosis which can lead to hepatocellular and with no physiologic excretion mechanism, multiple carcinoma [6].
    [Show full text]
  • Orphanet Report Series Rare Diseases Collection
    Marche des Maladies Rares – Alliance Maladies Rares Orphanet Report Series Rare Diseases collection DecemberOctober 2013 2009 List of rare diseases and synonyms Listed in alphabetical order www.orpha.net 20102206 Rare diseases listed in alphabetical order ORPHA ORPHA ORPHA Disease name Disease name Disease name Number Number Number 289157 1-alpha-hydroxylase deficiency 309127 3-hydroxyacyl-CoA dehydrogenase 228384 5q14.3 microdeletion syndrome deficiency 293948 1p21.3 microdeletion syndrome 314655 5q31.3 microdeletion syndrome 939 3-hydroxyisobutyric aciduria 1606 1p36 deletion syndrome 228415 5q35 microduplication syndrome 2616 3M syndrome 250989 1q21.1 microdeletion syndrome 96125 6p subtelomeric deletion syndrome 2616 3-M syndrome 250994 1q21.1 microduplication syndrome 251046 6p22 microdeletion syndrome 293843 3MC syndrome 250999 1q41q42 microdeletion syndrome 96125 6p25 microdeletion syndrome 6 3-methylcrotonylglycinuria 250999 1q41-q42 microdeletion syndrome 99135 6-phosphogluconate dehydrogenase 67046 3-methylglutaconic aciduria type 1 deficiency 238769 1q44 microdeletion syndrome 111 3-methylglutaconic aciduria type 2 13 6-pyruvoyl-tetrahydropterin synthase 976 2,8 dihydroxyadenine urolithiasis deficiency 67047 3-methylglutaconic aciduria type 3 869 2A syndrome 75857 6q terminal deletion 67048 3-methylglutaconic aciduria type 4 79154 2-aminoadipic 2-oxoadipic aciduria 171829 6q16 deletion syndrome 66634 3-methylglutaconic aciduria type 5 19 2-hydroxyglutaric acidemia 251056 6q25 microdeletion syndrome 352328 3-methylglutaconic
    [Show full text]
  • Essential Trace Elements in Human Health: a Physician's View
    Margarita G. Skalnaya, Anatoly V. Skalny ESSENTIAL TRACE ELEMENTS IN HUMAN HEALTH: A PHYSICIAN'S VIEW Reviewers: Philippe Collery, M.D., Ph.D. Ivan V. Radysh, M.D., Ph.D., D.Sc. Tomsk Publishing House of Tomsk State University 2018 2 Essential trace elements in human health UDK 612:577.1 LBC 52.57 S66 Skalnaya Margarita G., Skalny Anatoly V. S66 Essential trace elements in human health: a physician's view. – Tomsk : Publishing House of Tomsk State University, 2018. – 224 p. ISBN 978-5-94621-683-8 Disturbances in trace element homeostasis may result in the development of pathologic states and diseases. The most characteristic patterns of a modern human being are deficiency of essential and excess of toxic trace elements. Such a deficiency frequently occurs due to insufficient trace element content in diets or increased requirements of an organism. All these changes of trace element homeostasis form an individual trace element portrait of a person. Consequently, impaired balance of every trace element should be analyzed in the view of other patterns of trace element portrait. Only personalized approach to diagnosis can meet these requirements and result in successful treatment. Effective management and timely diagnosis of trace element deficiency and toxicity may occur only in the case of adequate assessment of trace element status of every individual based on recent data on trace element metabolism. Therefore, the most recent basic data on participation of essential trace elements in physiological processes, metabolism, routes and volumes of entering to the body, relation to various diseases, medical applications with a special focus on iron (Fe), copper (Cu), manganese (Mn), zinc (Zn), selenium (Se), iodine (I), cobalt (Co), chromium, and molybdenum (Mo) are reviewed.
    [Show full text]
  • Genetic Disorder
    Genetic disorder Single gene disorder Prevalence of some single gene disorders[citation needed] A single gene disorder is the result of a single mutated gene. Disorder Prevalence (approximate) There are estimated to be over 4000 human diseases caused Autosomal dominant by single gene defects. Single gene disorders can be passed Familial hypercholesterolemia 1 in 500 on to subsequent generations in several ways. Genomic Polycystic kidney disease 1 in 1250 imprinting and uniparental disomy, however, may affect Hereditary spherocytosis 1 in 5,000 inheritance patterns. The divisions between recessive [2] Marfan syndrome 1 in 4,000 and dominant types are not "hard and fast" although the [3] Huntington disease 1 in 15,000 divisions between autosomal and X-linked types are (since Autosomal recessive the latter types are distinguished purely based on 1 in 625 the chromosomal location of Sickle cell anemia the gene). For example, (African Americans) achondroplasia is typically 1 in 2,000 considered a dominant Cystic fibrosis disorder, but children with two (Caucasians) genes for achondroplasia have a severe skeletal disorder that 1 in 3,000 Tay-Sachs disease achondroplasics could be (American Jews) viewed as carriers of. Sickle- cell anemia is also considered a Phenylketonuria 1 in 12,000 recessive condition, but heterozygous carriers have Mucopolysaccharidoses 1 in 25,000 increased immunity to malaria in early childhood, which could Glycogen storage diseases 1 in 50,000 be described as a related [citation needed] dominant condition. Galactosemia
    [Show full text]
  • Diseases of the Liver and Biliary System
    Diseases of the Liver and Biliary System SHEILA SHERLOCK DBE, FRS MD (Edin.), Hon. DSc (Edin., New York, Yale), Hon. MD (Cambridge, Dublin, Leuven, Lisbon, Mainz, Oslo, Padua, Toronto), Hon. LLD (Aberd.), FRCP, FRCPE, FRACP, Hon. FRCCP, Hon. FRCPI, Hon. FACP Professor of Medicine, Royal Free and University College Medical School University College London, London JAMES DOOLEY BSc, MD, FRCP Reader and Honorary Consultant in Medicine, Royal Free and University College Medical School, University College London, London ELEVENTH EDITION Blackwell Science DISEASES OF THE LIVER AND BILIARY SYSTEM Diseases of the Liver and Biliary System SHEILA SHERLOCK DBE, FRS MD (Edin.), Hon. DSc (Edin., New York, Yale), Hon. MD (Cambridge, Dublin, Leuven, Lisbon, Mainz, Oslo, Padua, Toronto), Hon. LLD (Aberd.), FRCP, FRCPE, FRACP, Hon. FRCCP, Hon. FRCPI, Hon. FACP Professor of Medicine, Royal Free and University College Medical School University College London, London JAMES DOOLEY BSc, MD, FRCP Reader and Honorary Consultant in Medicine, Royal Free and University College Medical School, University College London, London ELEVENTH EDITION Blackwell Science © 1963, 1968, 1975, 1981, 1985, 1989, 1993, 1997, 2002 by Blackwell Science Ltd a Blackwell Publishing Company Editorial Offices: Osney Mead, Oxford OX2 0EL, UK Tel: +44 (0)1865 206206 108 Cowley Road, Oxford OX4 1JF, UK Tel: +44 (0)1865 791100 Blackwell Publishing USA, 350 Main Street, Malden, MA 02148-5018, USA Tel: +1 781 388 8250 Iowa State Press, a Blackwell Publishing Company, 2121 State Avenue, Ames,
    [Show full text]
  • Essentials of Medical Genetics for Health Professionals
    59605_Gunder_FM_00i_xii_3 8/27/10 12:58 PM Page i Essentials of Medical Genetics for Health Professionals Laura M. Gunder, DHSc, MHE, PA-C Assistant Professor Physician Assistant Department School of Allied Health Sciences Medical College of Georgia Augusta, Georgia Adjunct Faculty Doctor of Health Sciences Program Arizona School of Health Sciences A.T. Still University Mesa, Arizona Staff Clinician Peachtree Medical Center Edgefield County Hospital Ridge Spring, South Carolina Scott A. Martin, MS, PhD, PA-C Dean Life Sciences Division Athens Technical College Athens, Georgia Clinical Professor Physician Assistant Department School of Allied Health Sciences Medical College of Georgia Augusta, Georgia Staff Clinician Family Medicine Athens, Georgia 59605_Gunder_FM_00i_xii_3 8/27/10 12:58 PM Page ii World Headquarters Jones & Bartlett Learning Jones & Bartlett Learning Canada Jones & Bartlett Learning International 40 Tall Pine Drive 6339 Ormindale Way Barb House, Barb Mews Sudbury, MA 01776 Mississauga, Ontario L5V 1J2 London W6 7PA 978-443-5000 Canada United Kingdom [email protected] www.jblearning.com Jones & Bartlett Learning books and products are available through most bookstores and online booksellers. To contact Jones & Bartlett Learning directly, call 800-832-0034, fax 978-443-8000, or visit our website, www.jblearning.com. Substantial discounts on bulk quantities of Jones & Bartlett Learning publications are available to corporations, profes- sional associations, and other qualified organizations. For details and specific discount information, contact the special sales department at Jones & Bartlett Learning via the above contact information or send an email to [email protected]. Copyright © 2011 by Jones & Bartlett Learning, LLC All rights reserved. No part of the material protected by this copyright may be reproduced or utilized in any form, electronic or mechanical, including photocopying, recording, or by any information storage and retrieval system, without written permission from the copyright owner.
    [Show full text]
  • Measurements of Iron Status and Survival in African Iron
    -. MEASUREMENTS OF IRON STATUS garnma-glutamyl transpeptidase concentration. There was a AND SURVIVAL IN AFRICAN IRON strong correlation between serum ferritin and hepatic iron concentrations OVERLOAD (r = 0.71, P '= 0.006). After a median follow-up of 19 months, A Patrick MacPhail, Eberhard M Mandishona, Peter D Bloom, 6 (26%) of the subjects had died. The risk of mortality Alan C Paterson, Tracey A RouauIt, Victor R Gordeuk correlated significantly with both the hepatic iron concentration and the serum ferritin concentration. Conclusions. Indirect measurements of iron status (serum ferritin concentration and transferrin saturation) are usetul Introduction. Dietary iron overload is common in southern in the diagnosis of African dietary iron overload. When ~ Africa and there is a misconception that the condition is dietary iron overload becomes symptomatic it has a high benign. 'Early descriptions of the condition relied on mortality, Measures to prevent and treat this condition are autopsy studies, and the use of indirect measurements of needed. iron status to diagnose this form of iron overload has not been clarified. 5 Afr Med J1999; 89: 96&-972. Methods. The study involved 22 black subjects found to have iron overload on liver biopsy. Fourteen subjects African iron overload, first described in 1929/ has not been well presented to hospital with liver disease and were found to characterised in living subjects. Early studies were based on have iron overload on percutaneous liver biopsy. Eight autopsy findings and documented an association with chronic subjects, drawn from a family study, underwent liver liver disease/''' specifically portal fibrosis and cirrhosis. Later biopsy because of elevated serum ferritin concentrations studies also described associations with diabetes mellitus,' suggestive of iron overload.
    [Show full text]
  • Defining the Molecular, Genetic and Transcriptomic Mechanisms
    Defining the molecular, genetic and transcriptomic mechanisms underlying the variation in glycation gap between individuals Fakhra Naseem. FHEA. A thesis submitted in partial fulfilment of the requirements of the University of Wolverhampton for the degree of Doctor of Philosophy. This work or any part thereof has not previously been presented in any form to the University or to any other body whether for the purposes of assessment, publication or for any other purpose (unless otherwise indicated). Save for any express acknowledgements, references and/or bibliographies cited in the work, I confirm that the intellectual content of the work is the result of my own efforts and of no other person. The right of Fakhra Naseem to be identified as an author of this work is asserted in accordance with ss.77 and 78 of the Copyright, Designs and Patents Act 1988. At this date, copyright is owned by the author. Signature: Fakhra Naseem Date: 23/10/2019 1 Abstract The discrepancy between HbA1c and fructosamine estimations in the assessment of glycaemia has frequently been observed and is referred to as the glycation gap (G- gap). This could be explained by the higher activity of the fructosamine-3-kinase (FN3K) deglycating enzyme in the negative G-gap group (patients with lower than predicted HbA1c for their mean glycaemia) as compared to the positive G-gap group. This G-gap is linked with differences in complications in patients with diabetes and this potentially happens because of dissimilarities in deglycation. The difference in deglycation rate in turn leads to altered production of advanced glycation end products (AGEs).
    [Show full text]
  • For Hemochromatosis (Atransferrinemia/Hemosiderosis/Iron Absorption) C
    Proc. Natl. Acad. Sci. USA Vol. 84, pp. 3457-3461, May 1987 Medical Sciences Tissue distribution and clearance kinetics of non-transferrin-bound iron in the hypotransferrinemic mouse: A rodent model for hemochromatosis (atransferrinemia/hemosiderosis/iron absorption) C. M. CRAVEN*, J. ALEXANDERt, M. ELDRIDGE*, J. P. KUSHNERt, S. BERNSTEINt, AND J. KAPLAN*§ Departments of *Pathology and tMedicine, University of Utah College of Medicine, Salt Lake City, UT 84132; and tThe Jackson Laboratories, Bar Harbor, ME 04609 Communicated by Gilbert Ashwell, January 29, 1987 (receivedfor review October 28, 1986) ABSTRACT Genetically hypotransferrinemic mice accumu- (S.B., unpublished data; see refs. 9-11). These mice (HP) late iron in the liver and pancreas. A similar pattern oftissue iron were found to have a hypochromic microcytic anemia and accumulation occurs in humans with hereditary hemohroma- were growth-retarded at birth. Neonatal HP homozygotes die tosis. In both disorders, there is a decreased plasma concentration soon after birth but can be life-spared by weekly injections of of apotransferrin. To test the hypothesis that nontransferrin- whole mouse serum or Tf, even though the serum Tf levels bound iron exists and is cleared by the parenchymal tissues, the in the life-spared animals rarely exceeded 1% of normal tissue distribution of "9Fe was studied in animals lacking values. The life-spared adults develop parenchymal iron apotransferrin. Two groups of animal were used: normal rats overload with massive iron deposition in the liver and and mice whose transferrin had been saturated by an intravenous pancreas. The parenchymal iron accumulation was not injection of nonradiolabeled iron, and mice with congenital caused simply by the serum injections, as increased tissue hypotransferrinemia.
    [Show full text]
  • Opinion of the Scientific Committee on Food on The
    Vitamin D OPINION OF THE SCIENTIFIC COMMITTEE ON FOOD ON THE TOLERABLE UPPER INTAKE LEVEL OF VITAMIN D (EXPRESSED ON 4 DECEMBER 2002) FOREWORD This opinion is one in the series of opinions of the Scientific Committee on Food (SCF) on the upper levels of vitamins and minerals. The terms of reference given by the European Commission for this task, the related background and the guidelines used by the Committee to develop tolerable upper intake levels for vitamins and minerals used in this opinion, which were expressed by the SCF on 19 October 2000, are available on the Internet at the pages of the SCF, at the address: http://www.europa.eu.int/ comm/food/fs/sc/scf/index_en.html. 1. INTRODUCTION The principal physiological function of vitamin D in all vertebrates including humans is to maintain serum calcium and phosphorus concentrations in a range that support cellular processes, neuromuscular function, and bone ossification. Vitamin D accomplishes this goal by enhancing the efficiency of the small intestine to absorb dietary calcium and phosphorous, and by mobilising calcium and phosphorus from the bone (Holick, 1999; Holick et al, 1998). The last couple of decades it has become increasingly apparent that vitamin D also has other important functions in tissues not primarily related to mineral metabolism (Brown et al, 1999; Holick, 1999). One example is the haematopoietic system, in which vitamin D affects cell differentiation and proliferation including such effects also in cancer cells. Vitamin D furthermore participates in the process of insulin secretion. The active metabolite of vitamin D, 1,25(OH)2D, regulate the transcription of a large number of genes through binding to a transcription factor, the vitamin D receptor (VDR).
    [Show full text]
  • The Postnatal Hypotransferrinemia of Early Preterm Newborn Infants
    Pediat. Res. 10: 1 18-120 (1976) Bacteriostasis newborn infection serum iron transferrin The Postnatal Hypotransferrinemia of Early Preterm Newborn Infants SAMUEL GALET AND HERBERT M. SCHULMAN'Z6' Lady Davis Institute for Medical Research, Jewish General Hospital and Biology Department, McGill University, Montreal, Quebec, Canada HARRY BARD Perinatal Service, Centre de Recherche, Hospital Ste. Justine, and Department de Pediatrie, Universire de Montreal, Montreal, Quebec, Canada Extract ble to infection, the aim of this study was to examine the transferrin levels in the sera of these infants during their first few Preterm newborns were found to be markedly hypotransfer- months of life. rinemic when compared with normal term infants. At birth the concentration of transferrin in sera from preterm infants of gestational age equal to or less than 32 weeks is 45% of that found MATERIALS AND METHODS in normal term infant sera. The preterm infant transferrin levels slowly rise so that 7-8 weeks after birth they are 78% of the level Transferrin was purified from a pool of outdated human blood found in the sera of normal term infants. We also found that the se- by a modification of a method described previously (16). Eight rum transferrin concentrations at birth correlate with gestational hundred milliliters of plasma were diluted in the cold with 800 ml age. Therefore, the transferrin levels postnatally in early preterm 0.01 M Tris-HCI, pH 8.8. Nonglobulin proteins were precipitated infants reflect postconceptional rather than postnatal age. by the addition of 1,600 ml of 0.6% Rivanol in 0.01 M Tris-HCI, pH 8.8.
    [Show full text]