Vaquero, J. et al. Infection and the progression of hepatic encephalopathy in acute liver failure. Gastroenterology 125, 755-764

Division of Gastroenterology and Hepatology , Northwestern University, Evanston, Illinois, United States
Gastroenterology (Impact Factor: 13.93). 09/2003; 125(3):755-64. DOI: 10.1016/S0016-5085(03)01051-5
Source: PubMed

ABSTRACT Progression of hepatic encephalopathy (HE) is a major determinant of outcome in acute liver failure (ALF). Our aim was to identify predictive factors of worsening HE, including the relation of encephalopathy with the systemic inflammatory response (SIRS) and infection.
We included 227 consecutive patients with stage I-II HE prospectively enrolled in the U.S. Acute Liver Failure Study. Univariate and multivariate analysis of 27 variables at admission were performed separately for acetaminophen (n = 96) and nonacetaminophen (n = 131) etiologies.
On multivariate analysis, acquisition of infection during stage I-II HE (P < 0.01), increased leukocyte levels at admission (P < 0.01), and decreased platelet count (P < 0.05) were predictive factors of worsening HE in the acetaminophen group. By contrast, only increased pulse rate (P < 0.05) and AST levels (P < 0.05) at admission were predictors in nonacetaminophen patients. In patients who progressed to deep HE, the first confirmed infection preceded progression in 15 of 19 acetaminophen patients compared with 12 of 23 nonacetaminophen patients. In patients who did not demonstrate positive microbiologic cultures, a higher number of components of SIRS at admission was associated with more frequent worsening of HE (25% vs. 35% vs. 50% for 0, 1, and >or=2 components of SIRS, P < 0.05). CONCLUSIONA: This prospective evaluation points to infection and/or the resulting systemic inflammatory response as important factors contributing to worsening HE in ALF, mainly in patients with acetaminophen- induced ALF. The use of prophylactic antibiotics in these patients and the mechanisms by which infection triggers hepatic encephalopathy require further investigation.

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Available from: Javier Vaquero, Jul 27, 2015
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    • "Immune dysregulation is central to the pathogenesis of ALF, in which massive leucocyte infiltration of the injured liver is contrasted by a depletion and dysfunction of immune cells in the circulation [2]. From a clinical perspective, it is widely accepted that the mortality in ALF is a consequence of profound activation of systemic inflammatory responses (SIRS) and its attendant complications of recurrent sepsis and extra-hepatic organ dysfunction [3] [4]. "
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    ABSTRACT: Acute liver failure (ALF) is a condition with a high mortality and morbidity for which new treatments are desperately required. We contend that although the initial event in ALF is liver cell death, the clinical syndrome of ALF and its complications including multi-organ dysfunction and sepsis, are largely generated by the immune response to liver injury. Hepatic macrophages fulfil a diversity of roles in ALF, from pro-inflammatory to pro-resolution. Their inherent plasticity means the same macrophages may have a variety of functions depending on the local tissue environment at different stages of disease. A better understanding of the mechanisms that regulate macrophage plasticity during ALF will be an essential step towards realising the potential of immune-modulating therapies that re-orientate macrophages to promote the desirable functions of attenuating liver injury and promoting liver repair/regenerative responses. The key dynamics: temporal (early vs. late phase), regional (hepatic vs. systemic), and activation (pro-inflammatory vs. pro-resolution) are discussed and the potential for novel ALF therapies that modulate monocyte/macrophage function are described.
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    • "Pathophysiologically, astrocyte metabolism of ammonia produces accumulation of osmotically active glutamine to produce brain oedema and intracranial hypertension (Haussinger et al. 1994; Cordoba et al. 1996; Tofteng et al. 2006). In patients with ALF, SIRS (often secondary to infection) correlates with advancing stages of HE and intracranial hypertension (Rolando et al. 2000; Vaquero et al. 2003). We have previously reported a correlation between intracranial hypertension and both circulating and brain levels of proinflammatory cytokines in ALF patients (Jalan et al. 2004; Wright et al. 2007a). "
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    • "HE patients usually have advanced chronic liver disease and thus have many of the physical and laboratory stigmata associated with severe hepatic dysfunction. Physical features may include muscle wasting, jaundice, ascites, palmar erythema, edema, spider telangiectasias, and fetor hepaticus [15] [16]. However, some of these features (such as muscle wasting, spider telangiectasias, and palmar erythema) are usually absent in HE patients with fulminant hepatic failure who are previously healthy, because the development of these features requires a relatively longer period of hepatic dysfunction. "
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