Acute Liver Injury (Deis, 10/29/25)

 A recording of this presentation is available HERE.

Many thanks to Dr. Faith Deis for an awesome presentation this week on Acute Liver Injury (ALI). For those impatient folks out there, the most important take home points are: 

1) While the combination of alcohol and acetaminophen can actually be hepato-protective, a pattern of heavy ETOH use + fasting followed by moderate to high dose of APAP can be particularly hepatotoxic and make vulnerable patients more susceptible to ALI. 

2) N-Acetylcysteine (NAC) replenishes glutathione with is hepatoprotective and shows benefit for ALI of multiple etiologies (not just APAP intoxication); when in doubt and/or when in the midst of a work-up, give NAC empirically for any undifferentiated ALI, even if APAP level is normal.

A few more pearls from Dr. Deis's talk follow. . .

Acute Liver Failure= Acute liver injury (as indicated by elevation in AST/ALT) + Coagulopathy (INR>1.5) + Hepatic Encephalopathy

Much like many of us use LactMed for breastfeeding safety, there is an excellent NIH source, LiverTox, which compiles all the evidence we have on liver toxicity of medications. Just last night while precepting, a resident and I used this resource to understand whether GLP-1 medications may be implicated in rising transaminases in a patient with poorly controlled DM2. This is a great resource!

Dr. Deis introduced us to the idea of using the "R factor" to help distinguish between intrahepatic and cholestatic patterns of liver injury.

From the 2021 ACG Guidelines. You can see how both the LiverTox and the R factor are involved in your clinical decision about 1st line testing for abnormal liver enzymes:

A little physiology and pathophysiology of APAP Toxicity, which you will note involves the CYP-2E1 pathway (5-9% of hepatic metabolism of APAP) and NAPQI, which leads to hepatocyte necrosis. In APAP overdose, more of the pathway is pushed to the NAPQI pathway! This is important in consideration the mechanism of action of NAC, which actually helps to replenish glutathione, and therefore shift the ASAP metabolism pathway away from the toxic one and back to the healthy one.

Dr. Deis also shared an interesting set of studies on the interaction between APAP and Alcohol on liver metabolism. This is super interesting! It turns out that if APAP and alcohol are ingested simultaneously, alcohol's metabolism actually has a protective effect on the liver's metabolism of APAP, keeping it in the non-toxic pathway. BUT if alcohol is ingested prior to APAP administration (and particularly in the setting of prolonged fasting, which is not uncommon during an alcohol binge), then the use of APAP is pushed toward the NAPQI pathway and is more likely to be hepatotoxic. Practically speaking, then, if a patient has an alcohol binge, and then consumes even moderate doses of APAP at the tail end/after the binge, those moderate doses may lead to a disproportionately toxic impact on the liver. This means, then, that you can have acute liver injury (and even failure) from a therapeutic dose of APAP. 

What about NAC?

Turns out that NAC's protective effect on the liver extends beyond APAP ingestion. In a 2021 Metanalysis , authors found a small but stastitically significant mortality benefit in patients with non-APAP induced liver injury and improved mortality (see table below). There are actually few downsides to NAC (the only absolute contraindication is allergy to NAC itself, care with volume needed to infuse for patients for whom volume could be problematic). In sum,  American College of Gastroenterology 2024 Guidelines actually recommend NAC be administered to all patients with ALI while work-up is in progress. 

A bit on Alcoholic Hepatitis (which may be on your ddx in someone with binge drinking behaviors)

-Remember the Alcoholic hepatitis rarely has AST/ALT elevated above 400-500 and the AST/ALT ratio should be somewhere around 1.5 and the Total Bilirubin is almost always >3.

The 2024 ACG guidelines on alcohol associated liver disease have a really nice set of flowsheets (for those of you who love flowsheets) that nicely outline the evaluation of Alcoholic hepatitis and the subsequent decision tree around using (or not using) steroids, remembering that steroids have downsides (infection, GI bleed, hyperglycemia, AKI, psych) and should only be used in appropriate candidates. 

 

On a final note, we must be careful with patients with ALI who also undergo alcohol withdrawal. Phenobarbital, which has become widely used in our institution in the last year, is relatively contraindicated, as are sedating medications (e.g. benzos). That being said, alcohol withdrawal is a dangerous condition that could result in ICU transfer and/or even death, so we need to be treating them. A reminder that librium/chlordiazepoxide, which has widely fallen out of favor, may be the best option in these patients. 

So much good learning!

Thanks for making it to the end.

Dr. Deis' references:

ACG Guidelines 2024

LiverTox

AASLD

Ghosh, A., Berger, I., & Remien, C. H. (2020). The role of alcohol consumption on acetaminophen-induced liver injury: Implications from a mathematical model. Journal of Theoretical Biology, 510, 110559. https://doi.org/10.1016/j.jtbi.2020.110559 ouci.dntb.gov.ua+1

Forget, P., Wittebole, X., & Laterre, P.-F. (2009). Therapeutic dose of acetaminophen may induce fulminant hepatitis in the presence of risk factors: A report of two cases. British Journal of Anaesthesia, 103(6), 899-900. https://doi.org/10.1093/bja/aep322 OUP Academic

Ghosh, A., Berger, I., Remien, C. H., & Mubayi, A. (2020). The role of alcohol consumption on acetaminophen-induced liver injury: Implications from a mathematical model. Journal of Theoretical Biology, 510, 110559. https://doi.org/10.1016/j.jtbi.2020.110559. (Note: duplicate to #1 – keep one)

Lee, W. M., Kaplowitz, N., et al. (2020). Acute liver injury with therapeutic doses of acetaminophen (≤ 6 g/day): A prospective study. Hepatology, (in press). https://pubmed.ncbi.nlm.nih.gov/33306215/ PubMed+1

Whitcomb, D. C., & Block, G. D. (1994). Association of acetaminophen hepatotoxicity with fasting and ethanol use. JAMA, 272(23), 1845-1850. https://doi.org/10.1001/jama.272.23.1845 (from PubMed 7990219)