Anti-Tuberculosis Drug Induced Liver Injury and Ursodeoxycholic Acid

Hepatotoxicity induced by standard anti-tuberculosis drugs (isoniazid, rifampicin, pyrazinamide) can result in significant morbidity and, rarely, even mortality. This major adverse side-effect of anti-tuberculosis treatment has a negative impact on patient adherence and patient outcomes as well as on tuberculosis control. Early recognition and prompt withdrawal of the offending drugs are the most critical interventions in the management of anti-tuberculosis drug-induced liver injury. No drug or herbal extract has been shown until recently to prevent or reverse anti-tuberculosis drug-induced hepatotoxicity. Ursodeoxycholic acid is the only FDA approved drug for the treatment of primary biliary cholangitis and has also been successfully used in various cholestatic liver diseases. Although still experimental, recent controlled clinical studies suggested that oral administration of ursodeoxycholic acid may prevent the onset of anti-tuberculosis drug-induced liver injury and accelerate the recovery of liver injury. These clinical data are supported by experimental models of anti-tuberculosis drug-induced hepatotoxicity. There is an urgent need for further randomized clinical trials to document the promising hepatoprotective properties of ursodeoxycholic acid.


Introduction
Hepatotoxicity is a frequent and potentially serious adverse effect of standard first line anti-tuberculosis drug (ATD) regimens containing the hepatotoxic compounds isoniazid, rifampicin, and pyrazinamide. There is a wide variety in the reported incidence of ATD-induced liver injury in different studies (2% to 28%). This may be attributable to patient characteristics, the drug regimen involved, or the threshold of liver function tests used to define hepatoxicity. The most widely used definitions of ATD-induced liver injury rely on serum alanine aminotransferase activities (ALT) (more than 5 times the upper limit of normal (ULN) and bilirubin concentrations (more than 2 times ULN without symptoms) or ALT levels more than 3 times ULN with clinical symptoms of hepatotoxicity [1] [2] [3].
The clinical presentations of ATD-induced liver injury vary from asymptomatic rises in serum transaminases, to acute hepatitis or even fatal liver failure. The high morbidity and mortality of ATD-induced severe liver injury may require interruption or modification of anti-tuberculosis treatment and reduce the efficacy of tuberculosis therapy. Discontinuation of first line drugs or nonadherence to treatment regimens may cause treatment failure, relapse and drug-resistance which can significantly reduce TB control [4] [5].
The pathogenesis underlying ATD-induced liver injury is poorly understood. Direct toxicity of the primary compound or its metabolites is the main cause but an immunologically mediated response may also play a role [6]. Once hepatotoxicity is diagnosed, all ATDs are temporarily withdrawn and sequential re-challenge of the involved drugs is used to identify the drug causing hepatotoxicity [7]. This can be a time-consuming effort for both patients and caregivers. No hepatoprotective agent has been proved beyond any doubt to be effective in ameliorating ATD-induced hepatotoxicity [8] [9] [10]. New therapies are needed to reduce the incidence and severity of ATD-induced hepatotoxicity.
Ursodeoxycholic acid (UDCA) has been successfully used for the treatment of primary biliary cholangitis and pregnant intrahepatic cholestasis [11]. Since UDCA has a favorable safety profile it seemed reasonable to treat cholestatic drug-induced liver injury (DILI) in a variety of diseases [12]. The usefulness of UDCA as a novel hepatoprotective agent for drug-induced hepatotoxicity was largely demonstrated by case reports and observational studies [13]- [21].
This narrative review describes the available experience with this drug in TB patients receiving standard first line treatment.

UDCA and ATD-Induced Liver Injury
UDCA is the major bile acid of the bile of black bears and has been used for centuries in traditional Chinese medicine as a remedy for cholestatic liver disease [22]. The therapeutic effects of UDCA for ATD-induced hepatotoxicity have been recognized but the data reported (case reports, case series,) are scarce and inconsistent [23] [24] [25].
We carried out a prospective pilot study to evaluate the hepatoprotective ef- orally administered UDCA 30 minutes before isoniazid and rifampicin. UDCA pre-treatment significantly alleviated hepatic apoptosis. The UDCA-mediated protective effects seemed to be associated with its antioxidative and anti-apoptotic effects.
UDCA was well tolerated. None of these prospective clinical studies reported any relevant adverse effects of mid-to long-term UDCA therapy in humans.

Mechanisms of Action of UDCA
The specific mechanisms underlying the protective effect of UDCA on anti-TB-DILI are unknown.
UDCA acts on the liver through a variety of complex and complementary mechanisms. The main effects are: 1) protection of hepatocytes against bile-acid induced apoptosis 2) protection of cholangiocytes against cytotoxicity of hydrophobic bile acids 3) stimulation of hepatobiliary secretion of bile acids, 4) suppression of immune responses, and 5) anti-inflammatory effects [12] [28].
Perspective of UDCA in TB treatment UDCA is an inexpensive and well tolerated medication that has shown the potential to alleviate DILI from standard TB regimens in a small number of prospective studies. In most TB patients raised liver functions tests entail a stop and rechallenge strategy which can be a burden for patients and their treating physicians. Prevention of hepatoxicity by UDCA facilitates patient management and may result in better adherence, especially in an out-patient setting.

Conclusion
UDCA is a promising therapeutic option for the prevention and treatment of DILI. Further clinical studies are required to validate these results.

Authors' Contributions
All authors have made substantial contributions to: 1) the analysis and interpretation of data; 2) drafting the article or revising it critically for intellectual content;