N-Acetylcysteine: Effect on the Liver and Kidneys

N-acetylcysteine is considered one of the main “liver” agents, and in the sports community often also a protector of the kidneys. The editorial team analyzed how NAC acts on these organs at the level of biochemistry, where its effect is proven, and where large clinical trials refuted the initial hopes.

Biochemistry: from cysteine to glutathione

Glutathione is the main intracellular antioxidant and “neutralizer” of reactive metabolites. It consists of three amino acids: glutamate, cysteine, and glycine. The rate of its synthesis in the cell is usually limited precisely by the availability of cysteine.

NAC is a convenient source of cysteine: after absorption the acetyl group is cleaved off, and free cysteine is used for glutathione synthesis. This process proceeds especially actively in the liver, which is the main “producer” of glutathione in the body.

The direct antioxidant properties of NAC itself are relatively weak compared with glutathione. The review by Rushworth and Megson emphasizes that most of the clinically significant effects of NAC are connected precisely with replenishing intracellular glutathione, rather than with the direct “quenching” of free radicals.

The bioavailability of NAC when taken orally is low due to intensive metabolism in the intestine and liver. This is not a problem for the liver, which the substance reaches first, but it limits the effects in other organs.

Liver: proven effect in paracetamol poisoning

The strongest evidence for NAC's action on the liver concerns paracetamol overdose. The toxic metabolite NAPQI depletes glutathione and damages hepatocytes. NAC restores glutathione reserves and thereby prevents massive necrosis.

The classic studies by Prescott and colleagues (1979) and Smilkstein and colleagues (1988) showed that timely treatment with NAC sharply reduces the frequency of severe liver damage. The effect is maximal when started in the first hours after poisoning and decreases over time.

This treatment is carried out exclusively in a hospital according to standardized protocols with monitoring of paracetamol concentration and liver tests. Taking NAC tablets at home on your own does not replace medical care in case of poisoning.

In acute liver failure not related to paracetamol, a study by Lee and colleagues (2009) showed improved transplant-free survival in patients at early stages. This is also a hospital situation with intravenous administration.

Liver: other situations

For fatty liver disease, alcoholic hepatitis, and drug-induced injury from other substances, the data are much weaker. Small studies with varying results have been conducted, but there is no convincing evidence base for routine use.

In alcoholic hepatitis, NAC was studied in combination with corticosteroids; individual results were encouraging regarding short-term survival, but this is a narrow, specialized application under the supervision of a hepatologist.

In the sports community, NAC is taken “for the liver” during the use of hepatotoxic substances. There is no scientifically grounded data that NAC prevents the cholestatic damage caused by 17α-alkylated steroids: the mechanism of their toxicity is connected not with glutathione depletion, as with paracetamol, but mainly with impaired bile transport.

Kidneys: the story about creatinine

Interest in NAC as a nephroprotector arose after the study by Tepel and colleagues in 2000, in which the drug reduced the rise in creatinine after administration of a radiocontrast agent. Dozens of subsequent studies gave contradictory results.

One of the explanations came from the work of Hoffmann and colleagues in 2004: in healthy volunteers, NAC lowered serum creatinine levels without changes in cystatin C. That is, the drug could affect the marker itself rather than the actual filtration function of the kidneys.

The large randomized PRESERVE trial (Weisbord et al., 2018) with several thousand patients showed that NAC does not reduce the risk of death, dialysis, or persistent worsening of kidney function after angiography. Since then, prophylactic prescription for this purpose has not been recommended.

For athletes, an important practical lesson follows from this: a decrease in creatinine while taking NAC should not be interpreted as “improved kidney function”. For an objective assessment it is better to use cystatin C or a combination of markers.

Safety for the liver and kidneys

NAC itself, when taken orally at the doses used as a mucolytic, is usually well tolerated and is not hepato- or nephrotoxic. The most common side effects are nausea, stomach discomfort, diarrhea, and an unpleasant smell.

With intravenous administration at high doses, which is used in poisoning, anaphylactoid reactions are possible — rash, bronchospasm, a drop in blood pressure. Therefore such therapy is carried out only under medical supervision.

NAC and its metabolites are excreted predominantly by the kidneys. In people with severe kidney failure, dosing is determined by a doctor.

To assess the real state of the organs while taking NAC, it is worth focusing on the following indicators:

• ALT, AST, GGT, alkaline phosphatase, bilirubin — for the liver;
• creatinine together with cystatin C and a urinalysis — for the kidneys;
• creatine kinase — to distinguish the muscular origin of enzymes after training.

Editorial conclusions

NAC acts on the liver primarily as a supplier of cysteine for glutathione synthesis. The strongest evidence concerns paracetamol poisoning, where it saves lives, but it is used in a hospital.

For other liver diseases and for “protection” against toxic substances, the evidence is weak or absent.

The idea of nephroprotection was not confirmed in a large randomized trial, and the decrease in creatinine while taking NAC may be a laboratory artifact rather than a real effect.

We also recommend reading “Tests While Taking N-Acetylcysteine”, “Who Should Not Take N-Acetylcysteine” and “TUDCA: Effect on the Liver and Kidneys”.

References

1. Rushworth GF, Megson IL. Existing and potential therapeutic uses for N-acetylcysteine: the need for conversion to intracellular glutathione for antioxidant benefits. Pharmacol Ther. 2014;141(2):150–159.
2. Prescott LF, Illingworth RN, Critchley JA, et al. Intravenous N-acetylcystine: the treatment of choice for paracetamol poisoning. Br Med J. 1979;2(6198):1097–1100.
3. Smilkstein MJ, Knapp GL, Kulig KW, Rumack BH. Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. N Engl J Med. 1988;319(24):1557–1562.
4. Lee WM, Hynan LS, Rossaro L, et al. Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure. Gastroenterology. 2009;137(3):856–864.
5. Tepel M, van der Giet M, Schwarzfeld C, et al. Prevention of radiographic-contrast-agent-induced reductions in renal function by acetylcysteine. N Engl J Med. 2000;343(3):180–184.
6. Hoffmann U, Fischereder M, Krüger B, et al. The value of N-acetylcysteine in the prevention of radiocontrast agent-induced nephropathy seems questionable. J Am Soc Nephrol. 2004;15(2):407–410.
7. Weisbord SD, Gallagher M, Jneid H, et al. Outcomes after angiography with sodium bicarbonate and acetylcysteine. N Engl J Med. 2018;378(7):603–614.