Nitrofurantoin-induced liver failure

Discussion

In the case presented, the likely cause of liver failure was chronic use of nitrofurantoin, supported by liver histology corroborating a drug-induced cause. The Naranjo Adverse Drug Reaction Probability Score was used to assess causality.⁴ Although the Naranjo scale is not specific to liver injury, it is the most extensively used adverse drug reaction causality assessment tool.⁵ Her Naranjo score was 6 out of 13, indicating a probable adverse drug reaction to nitrofurantoin, receiving points for previously documented conclusive reports on this reaction (+1), the adverse event appearing after the suspected drug was administered (+2), there being no alternative causes that on their own could have caused the reaction (+2), and the adverse event being confirmed by objective evidence (+1). Her transaminase levels declined following nitrofurantoin discontinuation, with continued bilirubin level ascension. This likely represented further liver dysfunction secondary to “burnout,” and therefore a point was not included for this.

We used MeSH terms nitrofurantoin, drug induced liver injury, and case reports to search for previous reports.

The first published report of nitrofurantoin-induced liver injury was in 1961,⁶ with an appreciable number of reports since then.^7-15 Nitrofurantoin has been shown to cause a spectrum of hepatic injury ranging from mild hepatitis to fulminant liver failure and death.^9,10 Despite this, the overall incidence of liver injury is very rare, reported at 0.0003%.¹⁶ It is likely this rarity that leads to this reaction being forgotten.

Nitrofurantoin-induced acute liver injury generally presents days to weeks after initiation of the drug.^17,18 It is characterized by a predominant hepatocellular enzyme elevation with possible symptoms of fever, rash, jaundice, abdominal pain, nausea, malaise, and anorexia.¹⁷ Chronic injury is more insidious and usually presents after 6 months of therapy.^16,17 Clinical and laboratory features might resemble acute injury; however, patients generally lack the immunoallergic symptoms of fever and rash.¹⁶ Patients also typically manifest abnormal liver function, including elevated international normalized ratio and bilirubin levels, suggesting greater hepatic damage. Additionally, chronic injury often demonstrates histologic and autoimmune-like serologic features including positive ANA and anti–smooth muscle antibody levels, and hypergammaglobulinemia.^3,19 A thorough medication history is essential, as immunology and histology findings often resemble primary autoimmune hepatitis.³ Our patient presented with jaundice 1 year after continuous nitrofurantoin therapy and was found to have liver enzyme elevations, and histologic and autoimmune-like serologic features including positive ANA and mildly elevated IgA levels.

Risk factors for nitrofurantoin-induced liver injury include older age, female sex, and duration of use.^3,17,20,21 A genetic predisposition with HLA-B8 has also been suggested.^10,21 Correlation between the dose and development of liver injury is inconsistent. Lower doses of nitrofurantoin appear to be as effective as higher doses for long-term prophylaxis.²² However, our patient was taking a cystitis-treatment dose (100 mg twice daily) for 1 year for prophylaxis for recurrent cystitis. The prophylactic dose is typically 50 to 100 mg daily for 6 months.² This reminds all care providers of the importance of reassessing a patient’s medication regimen at each encounter.

The decision to initiate prophylactic antimicrobials for recurrent cystitis is controversial but should be based on individual patient assessment and a discussion of risks versus benefits.²³ Considerations for initiating nitrofurantoin prophylaxis should include the risk of hepatotoxicity and appropriate monitoring, particularly if any of the above risk factors are present. While no guidelines exist, we suggest a pragmatic approach of monitoring hepatic enzymes after 1 month for subacute reactions, followed by every 3 months during continuous therapy.^24,25 Upon recognition of enzyme elevation, nitrofurantoin should be discontinued to prevent further inflammation and damage, enzyme levels should be monitored for improvement, and alternative explanations should be explored. Hepatotoxicity is reversible if recognized early and nitrofurantoin is stopped; however, continuation of the drug after clinical illness can be fatal.^3,11,18 Nitrofurantoin should not be re-challenged, as accelerated hepatic injury might occur.³