Appleyard et al. Journal of Medical Case Reports 2010, 4:311 http://www.jmedicalcasereports.com/content/4/1/311 autoimmune diseases, and length of exposure. In addi- tion to nitrofurantoin, other drugs such as methyldopa, dihydralazine and minocycline are also implicated in inducing immune-mediated liver disease. In drug- induced autoimmune liver disease it is believed that drug metabolites act as haptens and covalently bind to macromolecular protein carriers. In those genetically predisposed, the altered proteins are perceived as foreign and consequently provoke an immunological attack on normal hepatocellular components [13]. Nitrofurantoin-induced hepatitis is commonly asso- ciated with hyper-gammaglobulinemia [14] and with anti-nuclear and anti-smooth muscle antibodies [6]. Our first patient demonstrated both these antibodies, our second patient had a widely positive autoimmune screen and our third patient had anti-nuclear antibodies alone. This heterogeneity of auto-antibody production is also seen in patients with autoimmune hepatitis and no known drug trigger. The auto-antibody status of the three patients prior to nitrofurantoin exposure is unknown. None of these three patients had any record of liver auto-antibodies being checked before the onset of their liver disease. The natural history of nitrofurantoin-induced hepatitis is variable. There are certainly patients who have progressed to fatal liver disease or transplant [7-9], but it is also likely that many cases are sub-clinical and remain undiagnosed. Management of nitrofurantoin-triggered hepatitis depends firstly on recognition of the causal relationship. Prognosis is generally good if nitrofurantoin is withdrawn early, and sometimes simply withdrawing nitrofurantoin is sufficient to reverse the hepatic damage [7]. However, corticosteroids are useful in patients who had persistently abnormal liver biochemistry despite withdrawal of nitro- furantoin. In the cases reported here, our patients had been on nitrofurantoin for considerable periods of time and since the biochemical, serological and histopathologi- cal data supported an immunologically-mediated disease process, simple withdrawal of nitrofurantoin without the use of immunosuppressive drugs was deemed insufficient. Thus all three of our patients were treated with predniso- lone, resulting in a rapid improvement in the first two cases, but a rather slow improvement in the third. Immu- nosuppression with corticosteroids may fail to improve patients diagnosed at a very advanced or fulminant stage of disease. Such fatal outcomes have occurred when nitro- furantoin either has been continued after liver dysfunction was identified, or has been reintroduced after liver damage was first detected [6,7]. Future re-challenge with nitrofurantoin should be avoided since the recurrent liver dysfunction may be persistent and even fatal. In one case repeat administra- tion of nitrofurantoin 17 years after the initial exposure led to recurrent liver disease [15]. Page 4 of 5 Hepatitis is not the only potentially serious side- effect of nitrofurantoin; it has also been associated with pulmonary, hematological and neurological com- plications. Nitrofurantoin induced pulmonary disease and liver injury can occur together and it may well be that these share a common autoimmune mechanism [16,17]. The pulmonary disease is often the predomi- nant feature and so those patients with interstitial pneumonitis should have liver function tests to check for occult hepatitis. Conclusions Nitrofurantoin is widely used in the long term prophy- laxis of recurrent urinary tract infection. Serious hepatic injury remains rare, but recognition of harm from nitro- furantoin is crucial since early withdrawal of the drug has been shown to result in improved prognosis. Con- sideration should be given to monitoring liver function tests during long term nitrofurantoin therapy. Consent Written informed consent was obtained from the three patients for publication of these case reports and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal. Authors’ contributions SA collated patient data regarding the liver disease, and prepared the first manuscript draft. RS performed the histological examination of the liver biopsies. DG redrafted the manuscript and acted as corresponding author. All authors read and approved the final manuscript. Competing interests The authors declare that they have no competing interests. Received: 22 January 2010 Accepted: 23 September 2010 Published: 23 September 2010 References 1. Hoyumpa AM Jr, Connell AM: Methyldopa hepatitis. Report of three cases. Am J Dig Dis 1973, 18:213-222. 2. 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