DNC News

N-acetyl-cysteine and Liver Transplantation:

Jacob Schor, ND
12/19/00

It was recently suggested in our clinical support network that N-acetylcysteine (NAC) might be a useful supplement to use in patients undergoing liver transplants. I have done a literature search and read through what abstracts I could find related to this subject. The use of NAC appears to have sparked the interest of a number of research groups. The focus of the research has been whether or not NAC could decrease the amount of damage that occurs to the transplanted liver. NAC is the classic antidote for acetominophen poisoning[1. 2] and it also appears to be particularly useful for protecting the liver and is recommended ("This study suggests that N-acetyl-cysteine administration should be considered in all patients with acute liver failure.") in cases of hepatic failure[.3]

There have been a number of studies looking at whether NAC could improve the outcomes in liver transplants.

In January of 1995 American researchers published an experiment using pig livers that suggested that pretreatment of the liver with NAC improved outcome of transplantation. ("ATP recovery, bile output, and survival were all better in the treatment groups than in the control group. Pretreatment with NAC helps maintain hepatic glutathione during warm ischemia; given after ischemia, NAC is effective in replenishing depleted glutathione stores. Adjunctive use of NAC was associated with improved glutathione homeostasis, improved bile output and ATP regeneration, and increased survival.") [4]

In August of 1995, French doctors reported that NAC appeared useful in a rat experiments.[ 5]

In May of 1996 German Researchers published findings that NAC was useful in a rat model. ("We conclude that high-dose therapy with NAC in OLT attenuates manifestations of microvascular perfusion failure early after reperfusion and should be considered as a means to reduce reperfusion injury.") [6]

In July, 1996, French Researchers reported that NAC was useful in protecting Rat livers from injury during transplantation("....the NAC pretreatment also significantly reduced hepatocellular as well as sinusoidal oxidative stress, resulting in improvement of hepatocellular integrity relative to a control dextrose.")[7]

This was followed by a Japanese report in February 1998, again using rats. (".... NAC prevented hepatic injury and improved liver integrity after a cold ischaemic-reperfusion injury, by acting not as a substrate for glutathione synthesis but as a direct free radical scavenger.")[8] In 1998 an pilot study of 30 human liver transplant patients and an equal number of controls reported that: "In the NAC group we observed a distinct reduction in ischemia/reperfusion injury and improved liver function with less elevated peak transaminases, better macrocirculation, improved liver synthesis function and a lower incidence of primary nonfunction compared with the control group. We conclude that NAC is a very promising substance for reducing graft dysfunction in clinical liver transplantation."[9] Not all the studies have been positive. Several have been unsuccessful at showing benefit to using NAC.[10 11 12 13]

None of the studies have demonstrated any harm in using it.

None of the studies have used oral NAC.
Only one is on human subjects, the rest are rats (well, one pig study).
In the animal studies the livers about to be transplanted were instilled, injected, perfused or somehow basted with large amounts of NAC. Most abstracts do not give the concentrations, though one mentions 400 mg/ kg (a 100 Kg person would get 40 gms of NAC!) though it wasn't clear whether Kg was body weight or liver weight.

In the Thies study, the study using human subjects, it is unclear from the abstract how the NAC was administered and at what amounts. This is one journal article worth looking up in its entirety.

So how does this apply to what naturopathic physicians can do to help their patients as they undergo liver transplants (or other organ transplants for that matter)? I'm not sure. Here's what IÕm thinking. If I have any control of the person who will donate the liver prior to surgery, I'll try to have them take supplemental NAC. What dose? Probably as much as they can. I donÕt know whether giving NAC to the recipient will do much good, but it won't hurt so I'll suggest the same just before surgery and ASAP post surgery.

In looking for these abstracts I stumbled through a few other interesting references on the same subjects.

1. Liver transplant patients typically get cardiovascular problems. No surprise but they have high homocysteine levels which respond to the standard, B-12 and folic acid combination. Is it surprising that a liver transplant might deplete B-12 stores?[14]

2. Use of NAC for MIs seems to accepted practice in some parts of the world as reported in an Australian nursing journal: "Previously administered in cases of acetaminophen toxicity, N-Acetylcysteine (NAC) is now also being used in the management of acute myocardial ischemia and reperfusion injury. NAC potentiates the beneficial effects of nitrates such as nitroglycerin and reduces oxidative stress on the heart. The critical care nurse plays an important role in optimizing the therapeutic benefits of NAC and minimizing its potential harmful effects."[15]

3. One method being investigated or used to help protect the liver before it is transplanted is called ischemic preconditioning. Apparently subjecting the liver to short ischemic episodes prior to the transplant hardens the liver making it more resistant to damage. This apparently is due to increasing Nitrous Oxide (NO) production. Arginine seems to increase the production of NO and increases the effectiveness of the preconditioning. (" ..... L-arginine synergized with short-term ischemic pre conditioning..... to increase the survival of rats that received a liver graft ....").[16]

references:
1. Gastroenterol Hepatol 1999 Aug;14(8):817-21 Paracetamol overdose in a liver transplantation centre: an 8-year experience. Gow PJ, Smallwood RA, Angus PW
2. Emerg Med 2000 Apr;35(4):363-8 Shorter duration of oral N-acetylcysteine therapy for acute acetaminophen overdose. Woo OF, Mueller PD, Olson KR, Anderson IB, Kim SY
3. Hepatogastroenterology 2000 May-Jun;47(33):786-9 N-acetylcysteine in acute hepatic failure (non-paracetamol-induced). Ben-Ari Z, Vaknin H, Tur-Kaspa R
4. Transplantation 1995 Jan 15;59(1):6-9 N-acetylcysteine ameliorates reperfusion injury after warm hepatic ischemia. Fukuzawa K, Emre S, Senyuz O, Acarli K, Schwartz ME, Miller CM
5. Hepatology 1995 Aug;22(2):539-45 Protective effects of N-acetylcysteine on hypothermic ischemia-reperfusion injury of rat liver. Nakano H, Boudjema K, Alexandre E, Imbs P, Chenard MP, Wolf P, Cinqualbre J, Jaeck D
6. Transplantation 1996 May 15;61(9):1397-402 Impact of N-acetylcysteine on the hepatic microcirculation after orthotopic liver transplantation. Koeppel TA, Lehmann TG, Thies JC, Gehrcke R, Gebhard MM, Herfarth C, Otto G, Post S
7. Eur Surg Res 1996 Jul-Aug;28(4):245-55 Amelioration of hepatocellular integrity and inhibition of sinusoidal oxidative stress by N-acetylcysteine pretreatment in cold ischemia-reperfusion injury of rat liver. Nakano H, Boudjema K, Jaeck D, Alexandre E, Imbs P, Chenard MP, Nagasaki H, Kumada K, Wolf P, Cinqualbre
8. Eur J Surg 1998 Feb;164(2):139-46Efficacy of preconditioning with N-acetylcysteine against reperfusion injury after prolonged cold ischaemia in rats liver in which glutathione had been reduced by buthionine sulphoximine.Nagasaki H, Nakano H, Boudjema K, Jaeck D, Alexandre E, Baek Y, Kitamura N, Yamaguchi M, Kumada K
9. Transpl Int 1998;11 Suppl 1:S390-2The efficacy of N-acetylcysteine as a hepatoprotective agent in liver transplantation.Thies JC, Teklote J, Clauer U, Tox U, Klar E, Hofmann WJ, Herfarth C, Otto G
10. Transplantation 1999 Aug 15;68(3):327-30 N-acetylcysteine in pig liver transplantation from non-heart-beating donors. Manika A, Trinh T, Lagace G, Dugas MA, Proulx F, Lepage G, Champagne J, Lavoie JC, Cousineau J, Russo P, Chartrand C, Yandza T
11. Liver Transpl Surg 1998 Mar;4(2):152-7Does N-acetylcysteine improve hemodynamics and graft function in liver transplantation?Steib A, Freys G, Collin F, Launoy A, Mark G, Boudjema K
12. Br J Anaesth 1995 Sep;75(3):352-4 Effects of intraoperative N-acetylcysteine in orthotopic liver transplantation.Bromley PN, Cottam SJ, Hilmi I, Tan KC, Heaton N, Ginsburg R, Potter DR
13. Transpl Int 1995;8(4):317-23 N-acetylcysteine failed to improve early microcirculatory
14. Liver Transpl 2000 Sep;6(5):614-8Hyperhomocysteinemia in liver transplant recipients: prevalence and multivariate analysis of predisposing factors. Herrero JI, Quiroga J, Sangro B, Beloqui O, Pardo F, Cienfuegos JA, Prieto J
15. Dimens Crit Care Nurs 1997 May-Jun;16(3):122-31 Managing patients with acute myocardial ischemia and reperfusion injury with N-acetylcysteine. Stewart S, Ryan C, Poropat S
16. Transplantation 1998 Jul 27;66(2):152-7 Protective effect of ischemic preconditioning on liver preservation-reperfusion injury in rats.Yin DP, Sankary HN, Chong AS, Ma LL, Shen J, Foster P, Williams JW


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