Future directions in acute liver failure

Abstract

Acute liver failure (ALF) describes a clinical syndrome of rapid hepatocyte injury leading to liver failure manifested by coagulopathy and encephalopathy in the absence of pre-existing cirrhosis. The hallmark diagnostic features are a prolonged prothrombin time (ie, an international normalized ratio of prothrombin time of ≥1.5) and any degree of mental status alteration (HE). As a rare, orphan disease, it seemed an obvious target for a multicenter network. The Acute Liver Failure Study Group (ALFSG) began in 1997 to more thoroughly study and understand the causes, natural history, and management of ALF. Over the course of 22 years, 3364 adult patients were enrolled in the study registry (2614 ALF and 857 acute liver injury-international normalized ratio 2.0 but no encephalopathy-ALI) and >150,000 biosamples collected, including serum, plasma, urine, DNA, and liver tissue. Within the Registry study sites, 4 prospective substudies were conducted and published, 2 interventional ( N -acetylcysteine and ornithine phenylacetate), 1 prognostic [ 13 C-methacetin breath test (MBT)], and 1 mechanistic (rotational thromboelastometry). To review ALFSG's accomplishments and consider next steps, a 2-day in-person conference was held at UT Southwestern Medical Center, Dallas, TX, entitled "Acute Liver Failure: Science and Practice," in May 2022. To summarize the important findings in the field, this review highlights the current state of understanding of ALF and, more importantly, asks what further studies are needed to improve our understanding of the pathogenesis, natural history, and management of this unique and dramatic condition.

Trial registration: ClinicalTrials.gov NCT00518440 NCT00004467 NCT00896025 NCT01548690 NCT02786836.

FIGURE 1

Etiologies of ALF as determined by the ALF Study Group site principal investigator and the Causality Committee; patients with ALI not included. January 1998 and August 2019. Total N = 2614 patients. Abbreviation: ALF, acute liver failure.

FIGURE 2

Outcomes according to study day in patients with ALF according to etiology with hyperacute ALF (APAP overdose; A) or subacute ALF (eg, AIH; B). Diagrammatic representation of events by day after registry enrollment/listing. For APAP, essentially all outcomes have occurred by day 4. Abbreviations: AIH, autoimmune hepatitis; ALF, acute liver failure; ALFSG, Acute Liver Failure Study Group; APAP, acetaminophen.

FIGURE 3

Histological injury patterns in ALF. (A) Zonal necrosis due to APAP. There is coagulative necrosis in zone 3 with preserved zone 1 hepatocytes showing steatosis. Only minimal inflammation is present (H&E, ×40) (B) Fulminant hepatic necrosis due to acute hepatitis B. There is near-complete necrosis of hepatocytes with ductular reaction and lympho-plasmacellular inflammation (H&E, ×100) C. Sinusoidal obstruction syndrome-veno-occlusive disease. A central vein, marked by the blue collagen rim, is occluded by loose connective tissue and red blood cells. The adjacent parenchyma is hemorrhagic and necrotic (Masson trichrome, ×400) (D) Diffuse microvesicular steatosis due to fialuridine toxicity. The hepatocytes are enlarged and foamy, as a result of mitochondrial toxicity (H&E, ×400). Abbreviations: ALF, acute liver failure; APAP, acetaminophen.

FIGURE 4

Molecular mechanisms of non-APAP liver injury. Low-magnitude toxic, metabolic, and pathogenic stress can be compensated for by molecular adaptive responses (listed in text) and the capacity of the liver to regenerate. However, when injury passes a certain threshold, the liver fails to adapt, and its compensatory mechanisms fall short, leading to cell death. The type of cell death signal and the signaling pathways that are activated dictate the cell death subroutine. While multiple cell death pathways exist, apoptosis, pyroptosis, MPT-driven necrosis, and necroptosis are the best studied. Apoptosis is the dominant cell death pathway in the liver, except in the case of APAP, which is clearly MPT-driven necrosis. While theoretically possible, to date no conclusive evidence for other cell death subroutines has been presented in hepatocytes. Abbreviations: APAP, acetaminophen; ARE, antioxidant response elements; Caspase, cysteine-dependent aspartate-directed proteases; ER, endoplasmic reticulum; GSH, glutathione; KEAP, Kelch-like ECH-associated protein; MOMP, mitochondrial outer membrane pore opening; MPT, mitochondrial permeability transition; NRF2, NF-E2–related factor 2; ROS, reactive oxygen species; TCR, T-cell receptor; UPR, unfolded protein response.

FIGURE 5

Mechanisms of liver regeneration and recovery after APAP overdose. Studies show that survival after APAP overdose depends on the extent of stimulation of the compensatory liver regeneration. Following moderate overdose, timely initiation of compensatory cell proliferation is driven by activation of pro-mitogenic signaling involving cytokines, growth factors, bile acids, and pathways such as Wnt/beta-catenin. This is further supported by timely GSH replenishment that mitigates the oxidative stress, improves mitochondrial health, and accelerates DNA repair, which is a key regulator of cell cycle progression. During severe overdose, these mechanisms are actively inhibited due to extensive oxidative stress and tremendous DNA damage, which inhibit cell cycle progression and induce cellular senescence. A 2-fold approach involving mitigation of oxidative and DNA damage along with supplementation of pro-mitogenic signals could be the key to successful regenerative therapies against APAP overdose. Abbreviations: APAP, acetaminophen; GSH, glutathione.