Continuing research is changing perspectives on acute-on-chronic liver failure. Better understanding of the pathogenesis and natural history of ACLF is suggesting new prognostic and management approaches.
Infection is the most common precipitating event, said Gynogyi Szabo, MD, PhD, FAASLD, Worcester Foundation for Biomedical Research Endowed Chair and Professor of Medicine at the University of Massachusetts Medical School. But nearly half of cases develop with no clear trigger.
“We know survival is reduced by the occurrence of infection during ACLF,” Dr. Szabo said. “And for those who have ACLF, the probability of infection is increased. There is an underlying problem of immune dysfunction due to sustained low-grade stimulation and inflammation which alters response to new danger signals.”
Dr. Szabo explored the relationship between ACLF, infection and immune dysfunction during the ACLF Special Interest Group symposium on Friday. ACLF-associated infections can be exogenous, such as pneumonia or nosocomial infection, or host-derived from periodontal disease and translocation from the gut due to intestinal dysbiosis commonly seen in cirrhosis.
Immune and molecular recognition of infection is trigged by pathogen-associated molecular pattern (PAMP), and damage-associated molecular pattern (DAMP). PAMPs and DAMPs induce innate and immune responses to inflammation, triggering a cytokine storm and sepsis, which trigger emergency granulopoiesis, immune exhaustion, sepsis, multi-organ failure and death, she explained.
This systemic inflammatory response syndrome (SIRS) is a clinical response to a nonspecific insult that can be triggered by ischemia, inflammation, trauma, infection or the combined effect of multiple insults. There are early suggestions that granulocyte-colony stimulating factor (G-CSF) may interrupt this cascade and allow for immune repair and hepatic regeneration, she said.
The gut microbiome offers another route to assess and manage ACLF. New work suggests that changes to the gut microbial community may be one of the factors that potentiate infection. Other factors include intestinal barrier failure, the active and adaptive immune deficits common in cirrhosis, clinical factors and genetic factors.
“If you have Clostridium Incertae sedis, Lachnospiraceae and Ruminococcaceae in your gut, this is a good thing,” said Jasmohan S. Bajaj, MD, FAASLD, Associate Professor of Medicine, Virginia Commonwealth University. “Patients with cirrhosis have a predominance of other species in their gut. This cirrhosis-associated dysbiosis parallels cirrhosis severity. The stool microbiome at admission can predict organ failure and 30-day mortality.”
One clear step in managing ACLF is to rationalize and deescalate antimicrobial therapy, Dr. Bajaj said. Drug resistant microbes and fungi are strongly associated with mortality in cirrhosis, emphasizing the appropriate use of antimicrobials.
It is also important to withdraw unneeded proton pump inhibitors, he noted. PPIs modify the gut microbiota in ways that can enhance infection.
Treating periodontal disease can also improve liver outcomes by eliminating a common source of infection and inflammation.
“Beneficial microbiota changes could improve outcomes in our patients,” Dr. Bajaj said. “There is a pandemic of antibiotic resistance that has to be faced head on.”