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Minimal portosystemic encephalopathy: A new nosological entity in patients with hereditary haemorrhagic telangiectasia

  • Author Footnotes
    1 Equally contributed to the manuscript.
    Michele Barone
    Correspondence
    Corresponding author.
    Footnotes
    1 Equally contributed to the manuscript.
    Affiliations
    Gastroenterology Unit, Department of Emergency and Organ Transplantation, (D.E.T.O.), University of Bari Aldo Moro, Policlinico University Hospital, Piazza G. Cesare 11, 70124 Bari, Italy
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  • Author Footnotes
    1 Equally contributed to the manuscript.
    Patrizia Suppressa
    Footnotes
    1 Equally contributed to the manuscript.
    Affiliations
    “Frugoni” Internal Medicine Unit, Centre for Rare Diseases, Interdepartmental Centre for Hereditary Haemorrhagic Telangiectasia, Interdisciplinary Department of Medicine (D.I.M.), VascERN HHT Reference Centre, University of Bari Aldo Moro, Policlinico University Hospital, Bari, Italy
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  • Maria Teresa Viggiani
    Affiliations
    Gastroenterology Unit, Department of Emergency and Organ Transplantation, (D.E.T.O.), University of Bari Aldo Moro, Policlinico University Hospital, Piazza G. Cesare 11, 70124 Bari, Italy
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  • Gennaro Mariano Lenato
    Affiliations
    “Frugoni” Internal Medicine Unit, Centre for Rare Diseases, Interdepartmental Centre for Hereditary Haemorrhagic Telangiectasia, Interdisciplinary Department of Medicine (D.I.M.), VascERN HHT Reference Centre, University of Bari Aldo Moro, Policlinico University Hospital, Bari, Italy
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  • Arnaldo Scardapane
    Affiliations
    Interdisciplinary Department of Medicine-Radiology Unit, University of Bari Aldo Moro, Policlinico University Hospital, Bari, Italy
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  • Luigi Chiumarulo
    Affiliations
    Neuroradiology Unit, Policlinico University Hospital, Bari, Italy
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  • Nicola Ambrosini
    Affiliations
    “Frugoni” Internal Medicine Unit, Centre for Rare Diseases, Interdepartmental Centre for Hereditary Haemorrhagic Telangiectasia, Interdisciplinary Department of Medicine (D.I.M.), VascERN HHT Reference Centre, University of Bari Aldo Moro, Policlinico University Hospital, Bari, Italy
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  • Alfredo Di Leo
    Affiliations
    Gastroenterology Unit, Department of Emergency and Organ Transplantation, (D.E.T.O.), University of Bari Aldo Moro, Policlinico University Hospital, Piazza G. Cesare 11, 70124 Bari, Italy
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  • Carlo Sabbà
    Affiliations
    “Frugoni” Internal Medicine Unit, Centre for Rare Diseases, Interdepartmental Centre for Hereditary Haemorrhagic Telangiectasia, Interdisciplinary Department of Medicine (D.I.M.), VascERN HHT Reference Centre, University of Bari Aldo Moro, Policlinico University Hospital, Bari, Italy
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  • Author Footnotes
    1 Equally contributed to the manuscript.

      Highlights

      • Hepatic vascular malformations (HVMs) observed in HHT include portosystemic shunts.
      • The presence of radiologically undetectable HVMs is reported in the literature.
      • HVMs can cause portosystemic encephalopathy (PSE).
      • Using specific neurological tests we identified subclinical PSE in HHT patients.
      • These neurological tests should be adopted in HHT surveillance protocols.

      Abstract

      Background. Portosystemic shunts in Hereditary Haemorrhagic Telangiectasia (HHT) are often overlooked by conventional imaging although they could reduce hepatic clearance of gut-derived toxins.
      Aims. To evaluate, the presence of subclinical neurological alterations (SNAs), that we named “minimal portosystemic encephalopathy” (mPSE) in HHT patients without advanced liver disease (ALD).
      Methods. In this cross sectional study, consecutive HHT outpatients were firstly screened by critical flicker frequency (CFF) test (abnormal ≤39Hz), and the simplified animal naming test (S-ANT1) (abnormal <15) was used to confirm the diagnosis of mPSE. Furthermore, we evaluated the effect of lactulose administration on mPSE. Multi-slice CT, cerebral dynamic magnetic resonance, laboratory analyses and transient elastography were also used.
      Results. None of the 37 enrolled patients showed portosystemic shunts at imaging techniques. However, 33 patients had normal CFF values (CFF-) and 4 displayed CFF alterations (37.0±0.7Hz, CFF+). The S-ANT1 confirmed an impaired neurological performance (10.2±2.8) in CFF+ patients thus confirming the presence of mPSE. Noteworthy, lactulose administration determined a CFF increase (39.1±0.4Hz) and S-ANT1 normalization in these patients. Neither mPSE- nor mPSE+ patients had ALD and showed similar demographic, clinical and laboratory parameters. Finally, no mPSE+ patient showed radiologically-detectable brain vascular malformations or other brain abnormalities at imaging.
      Conclusions. HHT patients represent a human model of mPSE secondary to portosystemic shunts escaping radiological detection. mPSE evaluation should be incorporated in HHT surveillance protocols since it can affect both health-related/social aspects and pharmacokinetics of orally administered drugs with a narrow therapeutic index and high hepatic first-pass uptake.

      Graphical abstract

      Key words

      Abbreviations:

      HHT (Hereditary Haemorrhagic Telangiectasia), HVMs (hepatic arteriovenous malformations), CFF (critical flicker frequency), MSCT (multi-slice computed tomography), MRA (magnetic resonance angiography), HE (hepatic encephalopathy), mHE (minimal hepatic encephalopathy), mPSE (minimal portosystemic encephalopathy), SNAs (subclinical neurological alterations), ALD (advanced liver disease), S-ANT1 (simplified animal naming test.)
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