Systemic inflammation is associated with increased intrahepatic resistance and mortality in alcohol-related acute-on-chronic liver failure

Authors

  • Gautam Mehta,

    1. UCL Institute for Liver and Digestive Health, Division of Medicine, UCL Medical School, Royal Free Hospital, London
    Search for more papers by this author
  • Rajeshwar P Mookerjee,

    1. UCL Institute for Liver and Digestive Health, Division of Medicine, UCL Medical School, Royal Free Hospital, London
    Search for more papers by this author
  • Vikram Sharma,

    1. UCL Institute for Liver and Digestive Health, Division of Medicine, UCL Medical School, Royal Free Hospital, London
    Search for more papers by this author
  • Rajiv Jalan

    Corresponding author
    1. UCL Institute for Liver and Digestive Health, Division of Medicine, UCL Medical School, Royal Free Hospital, London
    • Correspondence

      Rajiv Jalan, UCL Institute for Liver and Digestive Health, UCL Medical School, Division of Medicine, Royal Free Hospital, Rowland Hill Street, NW3 2PF London.

      Tel./Fax: +442074332795

      e-mail: r.jalan@ucl.ac.uk

    Search for more papers by this author

Abstract

Background & Aims

Acute-on-chronic liver failure (ACLF) is characterized by acute deterioration of cirrhosis, systemic inflammation and multi-organ failure. Inflammation is also key to the pathobiology of portal hypertension. This study aims to define the relationship between systemic and hepatic haemodynamics in patients with ACLF.

Methods

Sixty patients with alcoholic cirrhosis were prospectively enrolled – stable cirrhosis (SC, n = 27), acute decompensation without ACLF (AD, n = 14) and ACLF (n = 19) – and managed with standard therapy. Systemic and hepatic haemodynamic studies were performed, and patients were followed up for 3 months. Plasma norepinephrine, cytokine profile, nitrate/nitrite and malondialdehyde levels were measured.

Results

Three-month mortality was as follows: SC – none; AD – 14%; ACLF – 47.2% (P < 0.001). Mean arterial pressure was lowest in the ACLF group (P < 0.001). ACLF patients had significantly higher hepatic vein pressure gradient (HVPG), while the hepatic blood flow was markedly reduced with an increase in intrahepatic resistance, which predicted mortality (AUROC: 0.87, P < 0.0001). In ACLF, the severity of intrahepatic resistance correlated with markers of inflammatory response, norepinephrine levels, creatinine levels and severity of encephalopathy. Modelling data showed that the high norepinephrine levels in ACLF may contribute to the right shift of the HVPG–hepatic blood flow relationship and its levels correlated with inflammatory markers and mortality (AUROC: 0.90; P < 0.0001).

Conclusions

The disturbances in systemic and hepatic haemodynamics in alcohol-related ACLF are associated with dysregulated inflammation, multi-organ failure and marked activation of the sympathetic nervous system. These abnormalities predict high mortality rates in alcohol-related ACLF patients.

Ancillary