Hepatic encephalopathy: A central neuroinflammatory disorder?

Hepatology. 2011 Apr;53(4):1372-6

Authors: Butterworth RF

Encephalopathy and brain edema are serious central nervous system complications of liver failure. Recent studies using molecular probes and antibodies to cell-specific marker proteins have demonstrated the activation of microglial cells in the brain during liver failure and confirmed a central neuroinflammatory response. In animal models of ischemic or toxic liver injury, microglial activation and concomitantly increased expression of genes coding for proinflammatory cytokines in the brain occur early in the progression of encephalopathy and brain edema. Moreover, the prevention of these complications with mild hypothermia or N-acetylcysteine (two treatments known to manifest both peripheral and central cytoprotective properties) averts central neuroinflammation due to liver failure. Recent studies using anti-inflammatory agents such as ibuprofen and indomethacin have shown promise for the treatment of mild encephalopathy in patients with cirrhosis, whereas treatment with minocycline, a potent inhibitor of microglial activation, attenuates the encephalopathy grade and prevents brain edema in experimental acute liver failure. The precise nature of the signaling mechanisms between the failing liver and central neuroinflammation has yet to be fully elucidated; mechanisms involving blood-brain cytokine transfer and receptor-mediated cytokine signal transduction as well as a role for liver-related toxic metabolites such as ammonia have been proposed. The prevention of central proinflammatory processes will undoubtedly herald a new chapter in the development of agents for the prevention and treatment of the central nervous system complications of liver failure. (HEPATOLOGY 2011;).

PMID: 21480337 [PubMed - in process]

Autoimmune acute liver failure: Proposed clinical and histological criteria.

Hepatology. 2011 Feb;53(2):517-526

Authors: Stravitz RT, Lefkowitch JH, Fontana RJ, Gershwin ME, Leung PS, Sterling RK, Manns MP, Norman GL, Lee WM,

Identifying autoimmune hepatitis as the etiology of acute liver failure (ALF) is potentially important, because administering corticosteroids might avoid the need for liver transplantation. However, clinical and histological criteria of autoimmune ALF (AI-ALF) have not been defined. Liver sections (biopsies and explants) from a 72-patient subset of the ALF Study Group Registry with indeterminate ALF were reviewed by a pathologist blinded to all clinical data and were diagnosed with probable AI-ALF based on four features suggestive of an autoi mmune pathogenesis: distinctive patterns of massive hepatic necrosis (present in 42% of sections), presence of lymphoid follicles (32%), a plasma cell-enriched inflammatory infiltrate (63%), and central perivenulitis (65%). Forty-two sections (58%) were considered probable for AI-ALF; this group demonstrated higher serum globulins (3.7 ± 0.2 g/dL versus 3.0 ± 0.2 g/dL; P = 0.037) and a higher prevalence of antinuclear and/or anti-smooth muscle antibodies (73% versus 48%; P = 0.034) compared to those without histology suggestive of probable AI-ALF. Thirty patients concordant for autoantibodies and probable AI-ALF upon histological analysis were more likely to have the classical autoimmune hepatitis phenotype (female predominance [72% versus 48%; P < 0.05], higher globulins [3.9 ± 0.2 g/dL versus 3.0 ± 0.2 g/dL; P < 0.005], and higher incidence of chronic hepatitis in long-term follow-up [67% versus 17%, P = 0.019]) compared to the population without concordant AI-ALF histology and autoantibodies. Conclusion: Patients with indeterminate ALF often have features of autoimmune disease by histological analysis, serological testing, and clinical recurrence during follow-up. In contrast to classical autoimmune hepatitis, histological features of AI-ALF predominate in the centrilobular zone. (HEPATOLOGY 2011;53:517-526).

PMID: 21274872 [PubMed - as supplied by publisher]

Unrecognized acetaminophen toxicity as a cause of indeterminate acute liver failure.

Hepatology. 2010 Nov 4;

Authors: Khandelwal N, James LP, Sanders C, Larson AM, Lee WM,

Despite extensive investigations, the cause of liver injury in 14% of patients with acute liver failure remains unknown (indeterminate). In a pilot study using a novel assay, highly specific acetaminophen-cysteine adducts were detected in 7 of 36 indeterminate patients (19%). To extend these observations, sera from 110 subjects enrolled in the Acute Liver Failure Study Group registry with indeterminate acute liver failure were analyzed with a similar but more efficient and sensitive adduct assay. As positive controls, another 199 patients with known or presumed acetaminophen-induced liver failure were assessed for the presence and quantity of adducts. Clinical, laboratory, and outcome data were compared for the two groups. On the basis of previous data for known therapeutic exposures and acetaminophen overdoses, an adduct concentration ?1.0 nmol/mL of serum indicated a definite acetaminophen overdose. Among the 110 indeterminate cases, 18% had assay values ?1.0 with a median level of 9.2 nmol/mL; 94.5% of the positive controls (known acetaminophen cases) had values ?1.0 nmol/mL. Regardless of the initial diagnosis, subjects with elevated adduct levels demonstrated the clinical profile and hyperacute biochemical injury pattern associated with acetaminophen overdose: a predominance of female gender, very high aminotransferase levels, and low bilirubin levels. Conclusion: These data confirm and extend previous observations regarding the high (18%) prevalence of unrecognized or uncertain acetaminophen toxicity among subjects with indeterminate acute liver failure. N-Acetylcysteine use was limited in this group, presumably because of the lack of a specific diagnosis of acetaminophen toxicity. (HEPATOLOGY 2011;.).

PMID: 21225650 [PubMed - as supplied by publisher]