Acute-on-chronic liver failure: Terminology, mechanisms and management

Abstract

Acute-on-chronic liver failure is an acute deterioration of liver function manifesting as jaundice and coagulopathy with the development of ascites, with a high probability of extrahepatic organ involvement and high 28-day mortality. The pathogenesis involves extensive hepatic necrosis, which is associated with severe systemic inflammation and subsequently causes the cytokine storm, leading to portal hypertension, organ dysfunction, and organ failure. These patients have increased gut permeability, releasing lipopolysaccharide (LPS) and damage-associated molecular patterns (DAMPS) in the blood, leading to hyper-immune activation and the secretion of cytokines, followed by immune paralysis, causing the development of infections and organ failure in a proportion of patients. Early detection and the institution of treatment, especially in the "Golden Window" period of 7 days, gives an opportunity for reversal of the syndrome. Scores like the Asian Pacific Association for the Study of the Liver (APASL) ACLF research consortium (AARC) score, a model for end stage liver disease (MELD), and the CLIF Consortium acute-on-chronic liver failure (CLIF-C ACLF) score can help in the prediction of mortality. Treatment strategy includes treatment of acute insult. Patients should be considered for early transplant with MELD score >28, AARC score >10, high-grade hepatic encephalopathy, and in the absence of >2 organ failure or overt sepsis to improve survival of up to 80% at five years. Patients, with no option of transplant, can be treated with emerging therapies like faecal microbial transplant, plasma exchange, etc., which need further evaluation.

Keywords: Acute-on-chronic liver failure; Bile acid and salts; Organ failure; Plasma exchange and support system.

Figure 1.

Various definitions of liver failure. Illustrating the differences in the definition by various societies and its basis and time frame. APASL, Asian Pacific Association for the Study for the Liver; EASL, European Association for the Study of the Liver; NASCELD-ACLF, North American Consortium for the Study of End-Stage Liver Disease's definition of acute-on-chronic liver failure; GI, gastro-intestinal bleed; HE, hepatic encephalopathy; HRS, Hepatorenal syndrome; AK, acute kidney injury).

Figure 2.

Insights into of Pathophysiology of Acute on Chronic Liver Failure. Figure illustrates the importance of Gut-liver axis and immune activation, causing SIRS which leads to various organ failures. Above figure shows Dysbiosis with release of products leads to release of DAMPS/HMGB1/ATP/IL-1a/IL-33/S100 protein superfamily and also release of mitochondrial DNA, N-formyl peptides causes PRR/TLR activation. Subsequently leads to activation of innate immune system with abnormal phagocytosis and cell damage along with mitochondrial dysfunction leading to NLRP3 inflammasome. Later immune activation and molecular cascade causes TLR4–CD14–Lymphoctye antigen 96 (Ly-96 also known as MD2) receptor complex assembly followed by recruitment of the adaptor molecules, myeloid-differentiation factor 88 (MYD88) and TIR domain-containing adaptor molecule 1 (TRIF) which can result in recovery or death based on improvement in the inflammatory response. LPS, lipopolysaccharides; DAMP, damage associated molecular pattern’s; PAMP’S, pathogen associated molecular patterns; PRR/TLR, pattern recognition receptors/TOLL like receptors; i-NOS, Nitric oxide synthase; ER- endoplasmic reticulum; NLRP3, NLR family pyrin domain containing 3; RAAS, Renin-angiotensin-aldosterone system; HMGB1, High mobility group box 1 protein.

Figure 3.

Concept of Golden window. This period may be considered as the initial 1-week period of the disease presentation. An acute hepatic insult leading to hepatic decompensation is the main driver resulting in the subsequent extra-hepatic organ failure. This is essentially due to the failure of recovery or regeneration. The period from acute insult and the development of immune paralysis and subsequent the development of sepsis is considered as the golden window of opportunity. Prevention of SIRS or its progression to sepsis and using immune modulation in the golden window period provides therapeutic opportunity and may benefit the patient [1,31].

Figure 4.

Photomicrograph showing the histological patterns of ACLF with Hematoxycillin and Eosin satining and maisson trichrome sataining (magnification, 10x) showing the appearance of two patterns described [34]. ACLF, acute-on-chronic liver failure.

Figure 5.

Algorithmic approach for treatment. AH, alcoholic hepatitis; AIH, auto-immune hepatitis; FMT, fecal microbiota transplant; LT, liver transplantation; GM-CSF, granulocyte and monocyte colony stimulating factor; MELD, Model for End-Stage Liver Disease; APASL, Asian Pacific Association for Study of Liver; ACLF, acute-on-chronic liver failure; AARC, APASL ACLF Research Consortium; OF, organ failures; CST, continue same treatment; PE, plasma exchange.