Skip to main content
SpringerLink
Log in

Altered metal metabolism in patients with HCV-related cirrhosis and hepatic encephalopathy

  • Original Article
  • Published:
Metabolic Brain Disease Aims and scope Submit manuscript

Abstract

Dysfunctional metal homeostasis contributes to oxidative stress and neuronal damage. These have been implicated in hepatic encephalopathy pathogenesis. To investigate whether altered metal metabolism is associated with hepatic encephalopathy. Twenty-one controls and 34 HCV-cirrhotic patients (ENC/NEC patients according to presence/absence of previous overt episodes of hepatic encephalopathy) and a control group were studied. Serum iron, copper, ceruloplasmin, ceruloplasmin activity, transferrin, and ceruloplasmin/transferrin ratio were determined. Neuropsychological tests were performed by the repeatable battery of neuropsychological status. Magnetic resonance assessed basal ganglia volumes and metal deposition (pallidal index and T2*). Cirrhotic patients performed worse than controls at cognitive tests, especially ENC patients,. At biochemical analysis copper concentrations, ceruloplasmin activity and transferrin levels were lower in ENC than in NEC patients and controls (p < 0.05 and p < 0.01, respectively). Ceruloplasmin/transferrin ratio was higher in ENC compared to NEC patients (p < 0.05), and controls (p < 0.01). By brain magnetic resonance, ENC patients showed reduced caudate and globus pallidus volumes compared to controls (p < 0.05), and ENC and NEC patients an increased pallidal index compared to controls (p < 0.01). In ENC patients, ceruloplasmin activity correlated with caudate volume and pallidal index (ρ = 0.773 and ρ = −0.683, p < 0.05). Altered metal metabolism likely contributes to cirrhotic hepatic encephalopathy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Altamura C, Squitti R, Pasqualetti P et al (2009) Ceruloplasmin/Transferrin system is related to clinical status in acute stroke. Stroke 40:1282–1288

    Article  CAS  PubMed  Google Scholar 

  • Andersen JK (2004) Oxidative stress in neurodegeneration: Cause or consequence? Nat Med 10:S18–S25

    Article  PubMed  Google Scholar 

  • Arciello M, Gori M, Balsano C (2013) Mitochondrial dysfunctions and altered metals homeostasis: new weapons to counteract HCV-related oxidative stress. Oxid Med Cell Longev 971024

  • Arias JL, Aller MA, Sánchez-Patan F et al (2006) The inflammatory bases of hepatic encephalopathy. Eur J Gastroenterol Hepatol 18:1297–1310

    Article  PubMed  Google Scholar 

  • Bajaj JS, Schubert CM, Heuman DM (2010) Persistence of cognitive impairment after resolution of overt hepatic encephalopathy. Gastroenterology 138:2332–2340

    Article  PubMed Central  PubMed  Google Scholar 

  • Bandmann O, Weiss KH, Kaler SG (2015) Wilson’s disease and other neurological copper disorders. Lancet Neurol 14:103–113

    Article  CAS  PubMed  Google Scholar 

  • Bemeur C, Desjardins P, Butterworth RF (2010) Evidence for oxidative/nitrosative stress in the pathogenesis of hepatic encephalopathy. Metab Brain Dis 25:3–9

    Article  CAS  PubMed  Google Scholar 

  • Bosoi CR, Rose CF (2013) Oxidative stress: a systemic factor implicated in the pathogenesis of hepatic encephalopathy. Metab Brain Dis 28:175–178

    Article  CAS  PubMed  Google Scholar 

  • Brewer GJ, Kanzer SH, Zimmerman EA et al (2010) Copper and ceruloplasmin abnormalities in Alzheimer’s disease. Am J Alzheimers Dis Other Demen 25:490–497

    Article  PubMed  Google Scholar 

  • Butterworth RF (2010) Metal toxicity, liver disease and neurodegeneration. Neurotox Res 18:100–105

    Article  PubMed  Google Scholar 

  • Butterworth RF (2015) (2015) Pathogenesis of hepatic encephalopathy and brain edema in acute liver failure. J Clin Exp Hepatol 5:S96–S103

    Article  PubMed  Google Scholar 

  • Büyükaşik NS, Nadır I, Akin FE et al (2011) Serum iron parameters in cirrhosis and chronic hepatitis: detailed description. Turk J Gastroenterol 22:606–611

    PubMed  Google Scholar 

  • Chang Y, Woo ST, Kim Y et al (2010) Pallidal index measured with three-dimensional T1-weighted gradient echo sequence is a good predictor of manganese exposure in welders. J Magn Reson Imaging 31:1020–1026

    Article  PubMed  Google Scholar 

  • Devrajani BR, Ur Rahman AA, Ali Shah SZ et al (2012) Serum trace metals and enzyme activity in patients with hepatic encephalopathy. World Appl Sci J 16:1053–1059

  • Dringen R, Bishop GM, Koeppe M, Dang TN, Robinson SR (2007) The pivotal role of astrocytes in the metabolism of iron in the brain. Neurochem Res 32:1884–1890

    Article  CAS  PubMed  Google Scholar 

  • Ferenci P, Lockwood A, Mullen K et al (2002) Hepatic encephalopathy--definition, nomenclature, diagnosis, and quantification: finalreport of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology 35:716–721

    Article  PubMed  Google Scholar 

  • Fleming RE, Ponka P (2012) Iron overload in human disease. N Engl J Med 366:348–359

    Article  CAS  PubMed  Google Scholar 

  • Gluud LL, Dam G, Borre M et al (2013) Lactulose, rifaximin or branched chain amino acids for hepatic encephalopathy: what is the evidence? Metab Brain Dis 28:221–225

    Article  CAS  PubMed  Google Scholar 

  • Görg B, Qvartskhava N, Bidmon HJ et al (2010) Oxidative stress markers in the brain of patients with cirrhosis and hepatic encephalopathy. Hepatology 52:256–265

    Article  PubMed Central  PubMed  Google Scholar 

  • Guo CH, Chen PC, Lin KP et al (2012) Trace metal imbalance associated with oxidative stress and inflammatory status in anti-hepatitis C virus antibody positive subjects. Environ Toxicol Pharmacol 33:288–296

  • Healy J, Tipton K (2007) Ceruloplasmin and what it might do. J Neural Transm 114(6):777–781

    Article  CAS  PubMed  Google Scholar 

  • Hellman NE, Gitlin JD (2002) Ceruloplasmin metabolism and function. Annu Rev Nutr 22:439–458

    Article  CAS  PubMed  Google Scholar 

  • Jayakumar AR, Rama Rao KV, Norenberg MD (2015) Neuroinflammation in hepatic encephalopathy: mechanistic aspects. J Clin Exp Hepatol 5:S21–S28

    Article  PubMed  Google Scholar 

  • Jurczyk K, Wawrzynowicz-Syczewska M, Boroń-Kaczmarska A et al (2001) Serum iron parameters in patients with alcoholic and chronic cirrhosis and hepatitis. Med Sci Monit 7:962–965

    CAS  PubMed  Google Scholar 

  • Jursa T, Smith DR (2009) Ceruloplasmin alters the tissue disposition and neurotoxicity of manganese, but not its loading onto transferrin. Toxicol Sci 107:182–193

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kell DB (2009) Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular and other progressive inflammatory and degenerative diseases. BMC Med Genomics 2:2

    Article  PubMed Central  PubMed  Google Scholar 

  • Koziarska D, Wunsch E, Milkiewicz M et al (2013) Mini-Mental State Examination in patients with hepatic encephalopathy and liver cirrhosis: a prospective, quantified electroencephalography study. BMC Gastroenterol 13:107

    Article  PubMed Central  PubMed  Google Scholar 

  • Kozlov AV, Sergienko VI, Vladimirov Iu A et al (1984) The antioxidant system of transferrin-ceruloplasmin in experimental hypercholesterolemia. Biulleten’ eksperimental’noi biologii i meditsiny 98:668–671

    CAS  PubMed  Google Scholar 

  • Krieger D, Krieger S, Jansen O et al (1995) Manganese and chronic hepatic encephalopathy. Lancet 346:270–274

    Article  CAS  PubMed  Google Scholar 

  • Kristinsson J, Snaedal J, Tórsdóttir G, Jóhannesson T (2012) Ceruloplasmin and iron in Alzheimer's disease and Parkinson's disease: a synopsis of recent studies. Neuropsychiatr Dis Treat 8:515–521

    PubMed Central  CAS  PubMed  Google Scholar 

  • Lauridsen MM, Schaffalitzky de Muckadell OB, Vilstrup H (2015) Minimal hepatic encephalopathy characterized by parallel use of the continuous reaction time and portosystemic encephalopathy tests. Metab Brain Dis

  • Layrargues GP, Shapcott D, Spahr L, Butterworth RF (1995) Accumulation of manganese and copper in pallidum of cirrhotic patients: role in the pathogenesis of hepatic encephalopathy? Metab Brain Dis 10:353–356

    Article  CAS  PubMed  Google Scholar 

  • Li SJ, Jiang L, Fu X et al (2014) Pallidal index as biomarker of manganese brain accumulation and associated with manganese levels in blood: a meta-analysis. PLoS One 9, e93900

    Article  PubMed Central  PubMed  Google Scholar 

  • Lin WC, Chou KH, Chen CL et al (2012) Significant volume reduction and shape abnormalities of the basal ganglia in cases of chronic liver cirrhosis. AJNR Am J Neuroradiol 33:239–245

    Article  CAS  PubMed  Google Scholar 

  • López-Prieto J, González-Reimers E, Alemán-Valls MR et al (2013) Iron and proinflammatory cytokines in chronic hepatitis C virus infection. Biol Trace Elem Res 155:5–10

    Article  PubMed  Google Scholar 

  • Macfarlane S, Macfarlane GT, Cummings JH (2006) Review article: prebiotics in the gastrointestinal tract. Aliment Pharmacol Ther 24:701–714

    Article  CAS  PubMed  Google Scholar 

  • Maeda H, Sato M, Yoshikawa A et al (1997) Brain MR imaging in patients with hepatic cirrhosis: relationship between high intensity signal in basal ganglia on T1-weighted images and elemental concentrations in brain. Neuroradiology 39:546–550

    Article  CAS  PubMed  Google Scholar 

  • Mariani S, Ventriglia M, Simonelli I, Bucossi S et al. (2015) Association between sex, systemic iron variation and probability of Parkinson's Disease. Int J Neurosci

  • McNeill A, Pandolfo M, Kuhn J et al (2008) The neurological presentation of ceruloplasmin gene mutations. Eur Neurol 60:200–205

    Article  PubMed  Google Scholar 

  • Melgari JM, Marano M, Quattrocchi CC et al (2015) Movement disorders and brain iron overload in a new subtype of aceruloplasminemia. Parkinsonism Relat Disord 21:658–660

    Article  PubMed  Google Scholar 

  • Montoliu C, Cauli O, Urios A et al (2011) 3-nitro-tyrosine as a peripheral biomarker of minimal hepatic encephalopathy in patients with liver cirrhosis. Am J Gastroenterol 106:1629–1637

    Article  CAS  PubMed  Google Scholar 

  • Mooney S, Hasssanein TI, Hilsabeck RC et al (2007) Utility of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) in patients with end-stage liver disease awaiting liver transplant. Arch Clin Neuropsychol 22:175–186

    Article  PubMed  Google Scholar 

  • Nangliya V, Sharma A, Yadav D et al (2015) Study of trace elements in liver cirrhosis patients and their role in prognosis of disease. Biol Trace Elem Res 165:35–40

    Article  CAS  PubMed  Google Scholar 

  • O’Leary DH, Polak JF, Kronmal RA et al (1999) Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. N Engl J Med 340:14–22

    Article  PubMed  Google Scholar 

  • Pal A, Siotto M, Prasad R, Squitti R (2015) Towards a unified vision of copper involvement in Alzheimer’s disease: a review connecting basic, experimental, and clinical research. J Alzheimers Dis 44:343–354

    CAS  PubMed  Google Scholar 

  • Patel BN, David S (1997) A novel glycosylphosphatidylinositol-anchored form of ceruloplasmin is expressed by mammalian astrocytes. J Biol Chem 272:20185–20190

    Article  CAS  PubMed  Google Scholar 

  • Péran P, Hagberg G, Luccichenti G et al (2007) Voxel-based analysis of R2* maps in the healthy human brain. J Magn Reson Imaging 26:1413–1420

    Article  PubMed  Google Scholar 

  • Rama Rao KV, Norenberg MD (2014) Glutamine in the pathogenesis of hepatic encephalopathy: the trojan horse hypothesis revisited. Neurochem Res 39:593–598

    Article  CAS  PubMed  Google Scholar 

  • Randolph C, Hilsabeck R, Kato A et al (2009) International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN). Neuropsychological assessment of hepatic encephalopathy: ISHEN practice guidelines. Liver Int 29:629–635

    Article  PubMed  Google Scholar 

  • Riggio O, Amodio P, Farcomeni A et al (2015) A Model for Predicting Development of Overt Hepatic Encephalopathy in Patients With Cirrhosis. Clin Gastroenterol Hepatol 13:1346–1352

    Article  PubMed  Google Scholar 

  • Rovira A, Alonso J, Córdoba J (2008) MR imaging findings in hepatic encephalopathy. AJNR Am J Neuroradiol 29:1612–1621

    Article  CAS  PubMed  Google Scholar 

  • Sayed HA, El Ayyat A, El Dusoki H et al (2005) A cross sectional study of hepatitis B, C, some trace elements, heavy metals, aflatoxin B1 and schistosomiasis in a rural population, Egypt. J Egypt Public Health Assoc 80:355–388.

  • Schliess F, Görg B, Häussinger D (2009) RNA oxidation and zinc in hepaticencephalopathy and hyperammonemia. Metab Brain Dis 24:119–134

    Article  CAS  PubMed  Google Scholar 

  • Siotto M, Bucossi S, Squitti R (2010) Copper status abnormalities and how to measure them in neurodegenerative disorders. Recent Pat CNS Drug Discov 5:182–194

    Article  CAS  PubMed  Google Scholar 

  • Siotto M, Pasqualetti P, Marano M, Squitti R (2014) Automation of o-dianisidine assay for ceruloplasmin activity analyses: usefulness of investigation in Wilson’s disease and in hepatic encephalopathy. J Neural Transm 121:1281–1286

    Article  PubMed  Google Scholar 

  • Squitti R, Salustri C, Siotto M et al (2010) Ceruloplasmin/Transferrin ratio changes in Alzheimer’s disease. Int J Alzheimers Dis 2011:231595

    PubMed Central  PubMed  Google Scholar 

  • Ward RJ, Zucca FA, Duyn JH et al (2014) The role of iron in brain ageing and neurodegenerative disorders. Lancet Neurol 13:1045–1060

    Article  CAS  PubMed  Google Scholar 

  • White KN, Conesa C, Sanchez L et al (2012) The transfer of iron between ceruloplasmin and transferrins. Biochim Biophys Acta 1820:411–416

    Article  CAS  PubMed  Google Scholar 

  • Zorov DB, Juhaszova M, Sollott SJ (2014) Mitochondrial reactive oxygen species (ROS) and ROS-inducedROS release. Physiol Rev 94:909–950

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Financial disclosures

All the co-authors and I deny any financial disclosure or funding.

Author information

Authors and Affiliations

  1. Neurology, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 200, 00128, Rome, Italy

    Massimo Marano, Claudia Altamura & Fabrizio Vernieri

  2. Internal Medicine and Hepatology, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 200, 00128, Rome, Italy

    Umberto Vespasiani Gentilucci & Antonio Picardi

  3. Radiology, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 200, 00128, Rome, Italy

    Federico Greco, Laura Scarciolla & Carlo Cosimo Quattrocchi

  4. Clinical psychology, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 200, 00128, Rome, Italy

    Livia Quintiliani & Simone Migliore

  5. Don Carlo Gnocchi foundation ONLUS, Milan, Italy

    Mariacristina Siotto

  6. Fatebenefratelli Foundation, AFaR Division, Fatebenefratelli Hospital, Isola Tiberina, Rome, Italy

    Rosanna Squitti

  7. Laboratorio di Neurodegenerazione, IRCCS San Raffaele Pisana, Rome, Italy

    Rosanna Squitti & Serena Bucossi

Authors
  1. Massimo Marano
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Umberto Vespasiani Gentilucci
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Claudia Altamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mariacristina Siotto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rosanna Squitti
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Serena Bucossi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Livia Quintiliani
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Simone Migliore
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Federico Greco
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Laura Scarciolla
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Carlo Cosimo Quattrocchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Antonio Picardi
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Fabrizio Vernieri
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Massimo Marano.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Marano, M., Vespasiani Gentilucci, U., Altamura, C. et al. Altered metal metabolism in patients with HCV-related cirrhosis and hepatic encephalopathy. Metab Brain Dis 30, 1445–1452 (2015). https://doi.org/10.1007/s11011-015-9721-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11011-015-9721-x

Key words

Search

Navigation