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Ammonia rises from the ashes!

  • Nicolas Weiss
    Affiliations
    Sorbonne Université, AP-HP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, Département de Neurologie, Unité de Médecine Intensive Réanimation à Orientation Neurologique, Paris, France & Brain Liver Pitié-Salpêtrière (BLIPS) Study Group, INSERM UMR_S 938, Centre de Recherche Saint-Antoine, Maladies Métaboliques, Biliaires et Fibro-inflammatoire Du Foie, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France & Groupe de Recherche Clinique en REanimation et Soins Intensifs Du Patient en Insuffisance Respiratoire AiguE (GRC-RESPIRE) Sorbonne Université, Paris, France
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  • Dominique Thabut
    Correspondence
    Corresponding author. Address: Sorbonne Université, Service d’hépato-gastroentérologie, AP-HP, Sorbonne Université, Hôpital Pitié-Salpêtrière, 47-83, boulevard de l’hôpital, 75013 Paris, France. Tel.: +33(0)1.42.16.00.00, fax : +33(0)1.42.16.00.01.
    Affiliations
    Sorbonne Université, AP-HP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, Service D’hépato-gastroentérologie, Unité de Soins Intensifs D’hépatologie, Paris, France & Brain Liver Pitié-Salpêtrière (BLIPS) Study Group, INSERM UMR_S 938, Centre de Recherche Saint-Antoine, Maladies Métaboliques, Biliaires et Fibro-inflammatoire Du Foie, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France
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Open AccessPublished:August 17, 2022DOI:https://doi.org/10.1016/j.jhepr.2022.100559
      To the Editor:
      We read with great interest the study by Hadjihambi et al.
      • Hadjihambi A.
      • Cudalbu C.
      • Pierzchala K.
      • Simicic D.
      • Donnelly C.
      • Konstantinou C.
      • et al.
      Abnormal brain oxygen homeostasis in an animal model of liver disease.
      showing that oxygen concentrations were reduced in the brains of rats with cirrhosis, which was probably mediated by hyperammonemia. The authors suggest that this brain hypoxia could participate in the pathogenesis of hepatic encephalopathy (HE), which is still a matter of debate.
      • Weiss N.
      • Jalan R.
      • Thabut D.
      Understanding hepatic encephalopathy.
      With respect to this, we would like to report our clinical experience of a 35-year-old woman who was admitted to the intensive care unit (ICU) for coma (Glasgow coma scale at 3), variceal bleeding and shock, revealing decompensated alcohol-related cirrhosis. Control of bleeding was rapidly obtained by vasoactive drugs and banding. She displayed hyperammonemia at 106 mmol/L. Neurological examination was unremarkable; specifically, there were no focal signs and an electroencephalogram showed diffuse slowing without any epileptic discharge. Coma was rapidly resolutive with symptomatic ICU measures and lactulose through the nasogastric tube. Surprisingly, brain MRI revealed a diffuse cortical hypersignal (Fig. 1A). The patient was discharged at day 15 with mild neurological impairment, short-span memory loss and attention complaints. She stopped alcohol and was monitored regularly in our outpatient clinics. Control brain MRI performed 3 months after ICU discharge showed partial disappearance (Fig. 1B) and the one performed at 6 months the total disappearance of cortical hypersignals (Fig. 1C). Currently, cirrhosis is recompensated and all cognitive complaints have disappeared.
      Figure thumbnail gr1
      Fig. 1Brain MRI
      (A) MRI imaging in ICU showing diffuse cortical hypersignals on both FLAIR and diffusion-weighted sequences. T2∗ weighted sequence was normal (B) Partial disappearance of the cortical hypersignals at 3 months; (C) Total disappearance of the cortical hypersignals at 6 months. FLAIR, fluid attenuated inversion recovery; ICU, intensive care unit.
      Diffuse cortical hypersignals on T2-weighted or FLAIR-weighted sequences are classically observed on brain MRI in a limited number of circumstances almost all associated with hypoxemia: cardiac arrest, severe hypoglycemia, status epilepticus or mitochondrial disease.
      • Koksel Y.
      • Benson J.
      • Huang H.
      • Gencturk M.
      • McKinney A.M.
      Review of diffuse cortical injury on diffusion-weighted imaging in acutely encephalopathic patients with an acronym: ‘crumpled’.
      Rarely those abnormalities are observed in Creutzfeld-Jakob disease. Very similar abnormalities have been described in some case reports in HE, but their pathogenesis was unclear.
      • Arnold S.M.
      • Els T.
      • Spreer J.
      • Schumacher M.
      Acute hepatic encephalopathy with diffuse cortical lesions.
      We hypothesize that cortical hypersignals on brain MRI in HE are related to decreased cortical oxygenation mediated by hyperammonemia, as described by Hadjihambi et al.,
      • Hadjihambi A.
      • Cudalbu C.
      • Pierzchala K.
      • Simicic D.
      • Donnelly C.
      • Konstantinou C.
      • et al.
      Abnormal brain oxygen homeostasis in an animal model of liver disease.
      potentially compromising brain energy metabolism as previously shown by us and others.
      • Clément M.A.
      • Bosoi C.R.
      • Oliveira M.M.
      • Tremblay M.
      • Bémeur C.
      • Rose C.F.
      Bile-duct ligation renders the brain susceptible to hypotension-induced neuronal degeneration: implications of ammonia.
      ,
      • Weiss N.
      • Barbier Saint Hilaire P.
      • Colsch B.
      • Isnard F.
      • Attala S.
      • Schaefer A.
      • et al.
      Cerebrospinal fluid metabolomics highlights dysregulation of energy metabolism in overt hepatic encephalopathy.
      We would like to outline that brain lesions were reversible in our case with strict control of ammonemia, together with control of bleeding and symptomatic ICU management.
      The reversibility of HE is debated after liver transplantation, even if neuropsychological sequalae do not perfectly mimic HE symptoms.
      • Campagna F.
      • Montagnese S.
      • Schiff S.
      • Biancardi A.
      • Mapelli D.
      • Angeli P.
      • et al.
      Cognitive impairment and electroencephalographic alterations before and after liver transplantation: what is reversible?.
      The combination of long periods of hyperammonemia before transplantation and a second hit (namely hypovolemia which is inherent to the liver transplantation procedure, especially the anhepatic phase) could be responsible for altered brain oxygenation. Hence, a strict control of ammonia levels before transplantation could be an appealing strategy to avoid neurological sequalae.
      • Weiss N.
      • Thabut D.
      Neurological complications occurring after liver transplantation: role of risk factors, hepatic encephalopathy, and acute (on chronic) brain injury.
      Finally, hyperammonemia and its clinical consequences have been completely revisited lately, in both acute and outpatient settings.
      • null Shalimar
      • Sheikh M.F.
      • Mookerjee R.P.
      • Agarwal B.
      • Acharya S.K.
      • Jalan R.
      Prognostic role of ammonia in patients with cirrhosis.
      ,
      • Tranah T.H.
      • Ballester M.P.
      • Carbonell-Asins J.A.
      • Ampuero J.
      • Alexandrino G.
      • Caracostea A.
      • et al.
      Plasma ammonia levels predict hospitalisation with liver-related complications and mortality in clinically stable outpatients with cirrhosis.
      Going back to basics, we provide evidence of the utility of strict ammonia control in clinical situations favoring hypoxia, which are very frequent in patients with decompensated cirrhosis.

      Financial support

      The authors received no financial support to produce this manuscript.

      Authors’ contributions

      Nicolas Weiss and Dominique Thabut wrote this manuscript and reviewed it critically.

      Conflicts of interest

      The authors have nothing to disclosure.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

      The following is the supplementary data to this article:

      References

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      Linked Article

      • Abnormal brain oxygen homeostasis in an animal model of liver disease
        JHEP ReportsVol. 4Issue 8
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          Increased plasma ammonia concentration and consequent disruption of brain energy metabolism could underpin the pathogenesis of hepatic encephalopathy (HE). Brain energy homeostasis relies on effective maintenance of brain oxygenation, and dysregulation impairs neuronal function leading to cognitive impairment. We hypothesised that HE is associated with reduced brain oxygenation and we explored the potential role of ammonia as an underlying pathophysiological factor.
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