Is there a role for NAC outside of paracetamol overdose?

N-acetyl-cysteine (NAC) has been a cornerstone of paracetamol-induced acute liver failure (ALF) for almost fifty years, since a series of landmark studies demonstrated its mortality benefit (1–3). The mechanism is clear: the small proportion of paracetamol metabolised to N-acetyl-p-benzoquinone imine (NAPQI) is detoxified by glutathione. In paracetamol overdose, NAC supplements glutathione stores and prevents the hepatocyte necrosis brought on by NAPQI accumulation (4).

The role of NAC outside of paracetamol overdose, whether that be ALF from other aetiologies or decompensated chronic liver disease, remains unclear. Anecdotally, I see colleagues differ significantly in their practice, with some touting the perceived lack of evidence and others arguing, ‘what harm could it do?’. Any signal, whether in favour of benefit or harm, may be difficult to tease out given the heterogeneity in this ‘all but paracetamol’ population. Equally, the biological rationale underpinning any difference associated with NAC in these patients is far less explicit, unlike NAPQI in paracetamol overdose.

Here I look to unpick the available evidence for or against NAC in these circumstances, and try to tease out the likely biology behind any difference.

The overall picture

Acute liver failure

Very few prospective RCTs have addressed this question in non-paracetamol-induced ALF. In one study from India, where acute viral hepatitis is a common precipitant of ALF, NAC improved mortality rates in non-paracetamol-induced ALF from 53% to 28% compared with placebo. When stratified by precipitant, drug-induced ALF was the only aetiology that had a significant mortality benefit associated with NAC (5). A further American study showed that NAC improved transplant-free survival in those with low-grade hepatic encephalopathy from 30% to 52%; it made no difference to overall mortality (6).

The most recent EASL and AASLD guidelines both recommend NAC in non-paracetamol-induced ALF given a potential signal of improving transplant-free survival. EASL notably stipulates that NAC should be limited to the first five days of admission given the anti-inflammatory properties of NAC and the risk of nosocomial infection. The takeaway message from a 2020 Cochrane review is that the evidence is inconclusive; however, this is likely due to the paucity of eligible RCTs. Notably, the 2017 study showing a mortality benefit was not included in their analysis (5, 7). A 2024 meta-analysis that did include that study did not find improved mortality or transplant-free survival associated with NAC (8).

Decompensated chronic liver disease

In chronic liver disease, NAC administration in those with cirrhosis and an acute variceal bleed reduced rates of ischaemic hepatitis by one third, likelihood of death from subsequent acute-on-chronic liver failure (ACLF) by two thirds, and developing an AKI by more than 40% compared with a volume-matched placebo. There was no difference in all-cause mortality, however; the majority of observed deaths were attributed to sepsis (9). The renoprotective properties of NAC have also been shown in a cohort of hepatorenal syndrome patients with mixed liver aetiologies (10).

Alcohol-related hepatitis

In severe alcohol-related hepatitis (sAH), NAC for the first five days in combination with prednisolone yielded differences that really made me pause for thought. This study narrowly missed its primary endpoint of improved mortality at 6 months (p = 0.07), however mortality was significantly lower in the NAC arm at 1 month. At 6 months, mortality from hepatorenal syndrome had more than halved following NAC treatment compared with steroids alone (9% vs 22%). Moreover, bilirubin levels had significantly improved by day 14 in those treated with NAC and steroids versus steroids alone. Staggeringly, rates of infection were down by two thirds in the NAC cohort, but mortality associated with infection was no different between the two arms (11). Although not assessed in this study, NAC in sAH may afford a window for transplant in countries where these patients are eligible for organs.

Sepsis and SIRS

A meta-analysis of 41 studies of patients with sepsis and/or a systemic inflammatory response syndrome (SIRS) demonstrated no benefit of NAC versus placebo in these patients (12). A study of early versus late NAC (before or after 24 hours) demonstrated increased mortality associated with late NAC versus placebo (13).

The underlying mechanisms

Haemodynamics

NAC increased stroke volume and oxygen extraction in those with paracetamol-induced and non-paracetamol-induced ALF, although to a lesser degree in the non-paracetamol cohort (14). Interestingly, in the same patients once they had recovered, the findings were not reproducible, suggesting a specific pathology-modifying action rather than a generalised positive inotropic and vasodilatory action. The same group went on to show that in a mixed-aetiology ALF cohort (42% non-paracetamol-induced; 58% late-presenting paracetamol-induced) NAC increases serum cGMP, likely causing vasodilation via the nitric oxide pathway, and improved microvascular flow (15). Unlike their initial study, however, they did not separate out data based on the ALF aetiology.

NAC has also been shown to improve cardiac output and oxygen extraction in critically unwell patients with a range of hepatic disorders incorporating paracetamol-induced ALF, autoimmune hepatitis, acute viral hepatitis, ACLF and post-transplant graft dysfunction (16).

An increased cardiac output and improved oxygen delivery following NAC treatment has also been shown in sepsis patients, suggesting that its haemodynamic properties may extend more generally to the shocked patient. Interestingly, NAC directly improved hepatic blood flow and improved liver function (17, 18). However, another study found that NAC was concerningly negatively inotropic in patients with early septic shock, with reductions in cardiac index, left ventricular stroke work index and mean arterial pressure over 48 hours compared with placebo (19).

Immunomodulation

An immunomodulatory function may explain some of the changes seen associated with NAC in non-paracetamol-induced ALF with lower-grade encephalopathy. IL-17 was positively associated with grade of encephalopathy, and those who went on to have an emergency transplant or die had significantly higher serum IL-17 than those who recovered without transplant. Interestingly, those who received NAC had a significant reduction in IL-17 compared with those who received placebo (20).

Although not directly shown in patients, NAC had an immunosuppressive effect by impairing T-cell responses to bacterial cues at the level of dendritic cells through inhibition of the NF-κB pathway (21). A study in rats showed that NAC dampened TNF-α release, again via NF-κB inhibition (22). Together, these suggest that NAC could restrict the cytokine storm seen in early ALF. As reflected in the EASL ALF guidelines, late administration of NAC (greater than 5 days) may coincide with the progressive endogenous immune paralysis seen in liver failure patients and increase the risk of infection.

Conclusions

The body of evidence evaluating the role of NAC outside of paracetamol-induced ALF is broadly slim and heterogeneous. In non-paracetamol-induced ALF, NAC may be associated with increased transplant-free survival, but any reduced mortality in these patients does not hold up in meta-analyses. That being said, there appears to be a role for NAC in reducing short-term mortality, renal failure and infection in patients with decompensated chronic liver disease and sAH. I think it is hard to deny that there is a positive role for NAC in patients with sAH.

Crucially, NAC may be seen as an adjunct in these patients but it certainly should not delay referral to tertiary hepatology and/or transplant centres.

In septic and SIRS patients, at best there are no mortality benefits in giving NAC, and at worst evidence of harm, particularly when NAC is given later in admission. NAC is certainly not a blanket therapy appropriate for all critically unwell patients.

Whereas in paracetamol overdose NAC exerts a large effect through its antioxidant properties, across other aetiologies its cardiovascular and immunomodulatory actions are far more prominent. It would be beneficial to see a multicentre, international RCT of NAC such that it reflects the global aetiology mix of liver failure syndromes. Any trial should also have a smaller mechanistic study nested within it to drill down on the hypotheses generated over the last forty years.