Drug-induced autoimmune-like hepatitis.

The clinical phenotype of classical autoimmune hepatitis can be mimicked by idiosyncratic drug-induced liver injury, and differentiation can be difficult. The goals of this review are to enumerate the major agents of drug-induced autoimmune-like hepatitis, describe the clinical findings and risk factors associated with it, detail the clinical tools by which to assess causality, discuss putative pathogenic mechanisms, and describe treatment and outcome. The frequency of drug-induced autoimmune-like hepatitis among patients with classical features of autoimmune hepatitis is 9%. Minocycline and nitrofurantoin are implicated in 90% of cases. Female predominance, acute onset, and absence of cirrhosis at presentation are important clinical manifestations. Genetic factors affecting phase I and phase II transformations of the drug, polymorphisms that protect against cellular oxidative stress, and human leukocyte antigens that modulate the immune response may be important pathogenic components. Clinical judgment is the mainstay of diagnosis as structured diagnostic methods for drug-induced liver injury are imperfect. The covalent binding of a reactive drug metabolite to a hepatocyte surface protein (commonly a phase I or phase II enzyme), formation of a neoantigen, activation of CD8 T lymphocytes with nonselective antigen receptors, and deficient immune regulatory mechanisms are the main bases for a transient loss of self-tolerance. Discontinuation of the offending drug is the essential treatment. Spontaneous improvement usually ensues within 1 month. Corticosteroid therapy is warranted for symptomatic severe disease, and it is almost invariably effective. Relapse after corticosteroid withdrawal probably does not occur, and its absence distinguishes drug-induced disease from classical autoimmune hepatitis.

Irreversible photobinding of nitrofurantoin and of nitrofurfural to plasma proteins in vitro.

Allergic reactions form a serious problem in therapy with the urinary antiseptic nitrofurantoin (NFT). The formation of conjugates between NFT and plasma proteins is considered to be a first step in the development of such reactions. We investigated the possibility that UV-A irradiation of NFT in the presence of plasma proteins results in covalent binding. Binding to blood cell proteins was +/- 100X less. Efficient photobinding to albumin was demonstrated for NFT (up to 50 nmol mg-1 protein) and its photoproduct 5-nitrofurfural. Incubation of photodecomposition products from these two nitrofurans with plasma proteins also resulted in irreversible binding. Protein amino and, to a lesser extent, thiol groups proved to be targets for binding. Furthermore, upon photolysis both compounds induced a significant decrease in the iso-electric point of albumin. Photobinding, along with such alterations in the structure of plasma proteins, may well be able to trigger immunological responses when taking place in vivo. In this manner activation of nitrofurantoin by light may be a cause of allergic reactions by nitrofurantoin.