The Efficacy and Safety of N-acetyl-L-cysteine (NAC) as Adjuvant Therapy in Acute on Chronic Liver Failure (ACLF) A Randomized Double Blind Placebo Controlled Pilot Trial

Introduction:

Acute on Chronic Liver Failure (ACLF) is a relatively new entity, characterized by complications of cirrhosis and high rate of organ failures. Short term mortality at 28 days is high (>15%). ACLF is multifactorial in its etiology and there is no consensus about the definitions between different parts of the world. The Asian Pacific Association for the Study of the Liver (APASL) consensus defines ACLF as "Acute hepatic insult manifesting as jaundice (serum bilirubin ≥ 5mg/dl and coagulopathy (INR≥1.5 or prothrombin activity <40% complicated within 4 weeks by clinical ascites and/or encephalopathy in a patient with previously diagnosed or undiagnosed chronic liver disease or cirrhosis, and is associated with a high 28-day day mortality. Another definition of ACLF defines it as "an acute deterioration of pre-existing chronic liver disease, usually related to a precipitating event and associated with increased mortality at 3 months due to multi-system organ failure". This definition also includes a high mortality at 28 days and organ failures.

Events known to precipitate ACLF include Acute alcoholic hepatitis, acute hepatotrophic viral infections , reactivation of hepatitis B virus infection, Drug induced liver injury (DILI), Gastrointestinal bleeding, sepsis, ischemia to the liver and portal vein thrombosis.

An enhanced pro-inflammatory cytokine environment has been shown to be present in ACLF. These are chronically primed neutrophils which are energy depleted and unable to carry out the phagocytosis function, leading to a functional failure in combating infections.

Cytokines also play a key role in the pathogenesis of the inflammatory response. Elevated serum levels of TNF-α, sTNF-αR1, sTNF-αR2, interleukin (IL)-2, IL-2R, IL-4, IL-6, IL-6,IL-8, IL-10 and interferon-γ have been described. Raised levels of these pro-inflammatory cytokines can be due to necrotic liver cells, reduced clearance by the liver or most importantly, from activation of toll-like receptors (TLRs). These receptors activate Kupffer cells (KCs), which play a key role I the pathogenesis of liver injury by activating signaling cascades, transcription of pro-inflammatory cytokines and super oxide agents. The resulting oxidative stress releases proteolytic enzymes and vasoactive substances like endothelin-1 (ET-1), thromboxane A2, nitric oxide (NO), and prostaglandins which lead to microcirculatory dysfunction. The entire cascade ultimately results in hepatocyte death and liver dysfunction.