Tuberculosis is an infectious disease with a major global impact, ranked in the top 10 mortality causes worldwide. In an immunocompetent individual, the host defence mechanisms control Mycobacterium tuberculosis infection and induce the latent form of the disease. However, in the presence of diseases or therapies, which exert an immunosuppressive effect, latent tuberculosis can be re-activated. Psoriasis is an immune-mediated, inflammatory disease, and its treatment has rapidly evolved over the last few years. It has long been recognized that the tumour necrosis factor (TNF)-α inhibitors are associated with increased risk of reactivation of latent tuberculosis infection. Thus, international guidelines have been suggesting tuberculosis screening before starting the treatment with all biological agents since then. In addition, the institution of chemoprophylaxis in the presence of latent tuberculosis and the annual screening for tuberculosis thereafter have also been indicated. However, anti-tuberculosis treatments can have significant side-effects and there are currently several contraindications to their use. The risk benefit of starting anti-tuberculous treatment should be carefully weighed up. The emergence of new biological drugs for the treatment of psoriasis, such as interleukin (IL)-17 and IL-23 inhibitors, has reignited the subject of tuberculosis reactivation as it is possible that IL-17 and 23 blockade do not carry the same risk of TB reactivation as TNF-α inhibitors. Although preclinical studies have shown that cytokines IL-17 and IL-23 have a possible role against infection with M. tuberculosis, data from clinical trials and post-marketing surveillance with drugs that inhibit these cytokines appear to suggest that they are not crucial to this response. In this article, we review the available data on tuberculosis reactivation after the treatment of psoriasis with IL-17 and IL-23 inhibitors, and its possible impact on the way we currently manage latent tuberculosis infection before or after starting treatment with these new drugs.

The antituberculosis drugs isoniazid (INH), rifampicin (RMP), pyrazinamide (PZA), and ethambutol (EMB) usually expose patients to the risk of fulminant hepatic failure (FHF). This report presents a case of liver transplantation in antituberculosis drugs-induced FHF and reviews the relevant literature. A 39-year-old woman with pelvic and salpinx tuberculosis experienced complex pelvic exenteration. After the operation, she was administrated INH, RMP, PZA, and EMB to prevent tuberculosis. Two months later, examination revealed severe FHF and the antituberculosis therapy regimen was changed to ciprofloxacin and streptomycin. Subsequently, urgent orthotopic liver transplantation was performed. Posttransplantation, her serum transaminases improved gradually, but her total bilirubin level and direct bilirubin level continued to worsen, which may have been related to the rejection. However, irreversible damage from antituberulosis drugs was note excluded. Two liver biopsies and histological examinations were performed. One year after transplantation, she died as a consequence of ischemic cholangitis and pulmonary infection. A literature review revealed 9 other published cases of antituberculosis drugs-associated FHF with liver transplantation.This report suggests that, in most cases of antituberculosis drugs-induced FHF, discontinuation of toxic drugs and orthotopic liver transplantation are always sufficient treatment.

Drug-induced liver injury (DILI) is an underrecognized cause of pediatric liver disease, accounts for almost 20% of pediatric acute liver failure cases, and is a major reason for liver transplantation in the USA. This article reviews the pathogenesis of DILI, approach to diagnosis and management, and highlights recent pediatric DILI case series.

Select individuals have an increased propensity to develop DILI. Known genetic polymorphisms of enzymes and host factors play an important role in medication management and influence the clinical outcome in 20-25% of all drug therapies. Children are more likely to have mitochondrial dysfunction from drugs, increasing their susceptibility to severe liver injury or acute liver failure. Antibiotics and central nervous system agents account for the majority of pediatric DILI in the West, although herbals are becoming more common.

Clinical features of DILI vary and overlap so exclusion of other conditions, identification of latency period and risk factors, and use of a searchable database can aid evaluation. Treatment consists of cessation of the offending agent and supportive care. Areas needing further research include elucidating mechanisms, identifying at risk individuals, and therapeutic interventions.

Progressive liver failure is rarely seen in tuberculosis chemoprophylaxis with isoniazid. We present a case of a 32-year-old woman admitted to our clinic reporting abdominal pain, nausea and vomiting for 2 days. The initial diagnosis was fulminant toxic hepatitis due to isoniazid chemoprophylaxis, which was treated successfully with living donor transplantation. Tuberculosis continues to be a significant public health problem. Isoniazid-related hepatotoxicity is extremely rare in adults. The only treatment in cases of fulminant liver failure is orthotopic liver transplantation from a deceased or living donor. If a deceased donor is not available or the patient refuses this treatment, living donor transplantation is the only choice. Although rare, isoniazid used as protective therapy for pulmonary tuberculosis can lead to fulminant liver failure. When cadaveric liver transplantation is not available, living donor liver transplantation is vital.

Medications are a major cause of acute liver failure (ALF) in the United States, but no population-based studies have evaluated the incidence of ALF from drug-induced liver injury. We aimed to determine the incidence and outcomes of drug-induced ALF in an integrated health care system that approximates a population-based cohort.

We performed a retrospective cohort study using data from the Kaiser Permanente Northern California (KPNC) health care system between January 1, 2004, and December 31, 2010. We included all KPNC members age 18 years and older with 6 months or more of membership and hospitalization for potential ALF. The primary outcome was drug-induced ALF (defined as coagulopathy and hepatic encephalopathy without underlying chronic liver disease), determined by hepatologists who reviewed medical records of all KPNC members with inpatient diagnostic and laboratory criteria suggesting potential ALF.

Among 5,484,224 KPNC members between 2004 and 2010, 669 had inpatient diagnostic and laboratory criteria indicating potential ALF. After medical record review, 62 (9.3%) were categorized as having definite or possible ALF, and 32 (51.6%) had a drug-induced etiology (27 definite, 5 possible). Acetaminophen was implicated in 18 events (56.3%), dietary/herbal supplements in 6 events (18.8%), antimicrobials in 2 events (6.3%), and miscellaneous medications in 6 events (18.8%). One patient with acetaminophen-induced ALF died (5.6%; 0.06 events/1,000,000 person-years) compared with 3 patients with non-acetaminophen-induced ALF (21.4%; 0.18/1,000,000 person-years). Overall, 6 patients (18.8%) underwent liver transplantation, and 22 patients (68.8%) were discharged without transplantation. The incidence rates of any definite drug-induced ALF and acetaminophen-induced ALF were 1.61 events/1,000,000 person-years (95% confidence interval, 1.06-2.35) and 1.02 events/1,000,000 person-years (95% confidence interval, 0.59-1.63), respectively.

Drug-induced ALF is uncommon, but over-the-counter products and dietary/herbal supplements are its most common causes.

The standard antitubercular treatment (ATT), which consists of isoniazid (INH), rifampicin (RIF), ethambutol, and pyrazinamide (PZA), is the best available treatment for tuberculosis (TB). However, the hepatotoxicity of INH and PZA can be severe, and even after drug withdrawal, patients may require liver transplantation (LT). In these cases, the strategy for the treatment of TB is poorly defined. Between 1986 and 2008, 14 patients presented at our department with severe hepatitis secondary to INH and PZA treatment. Four of these patients were immunosuppressed: 2 after renal transplantation and 2 because of human immunodeficiency virus infection. In seven of the 14 patients an alternative ATT was begun on admission, which was well tolerated. Hepatitis improved spontaneously in 5 patients, and alternative ATT was continued for 9.3 ± 4.2 months; 1 patient deteriorated and underwent LT, and 1 patient died. ATT was stopped definitively in 2 patients. Six patients required urgent LT, and alternative ATT was started after transplantation and was successful. Five patients receiving RIF had an episode of acute rejection. In conclusion, hepatitis secondary to ATT can be successfully treated with alternative anti-TB regimens. The use of RIF in LT patients may lead to acute rejection. RIF should therefore be avoided in these patients.

Hepatotoxic effects attributable to antituberculosis therapy are considered unique among drug-related liver problems because almost all first-line antituberculosis medications have such adverse effects, which vary in severity according to the drug and the regimen. In addition, all regimens for the treatment of active tuberculosis include a combination of medications that must typically be administered for at least 6 months to ensure complete cure of the disease and to minimize the development of drug-resistant bacterial strains. Hepatotoxic effects are a serious problem in patients who are undergoing treatment for tuberculosis, not only because of the morbidity and mortality they directly cause, but also because the liver symptoms can necessitate interruption of therapy or affect a patient's adherence to it, which can limit the efficacy of the antitubercular regimen.

Antituberculosis therapy (ATT)-associated acute liver failure (ATT-ALF) is the commonest drug-induced ALF in South Asia. Prospective studies on ATT-ALF are lacking. The current study prospectively evaluated the magnitude, clinical course, outcome, and prognostic factors in ATT-ALF. From January 1986 to January 2009, 1223 consecutive ALF patients were evaluated: ATT alone was the cause in 70 (5.7%) patients. Another 15 (1.2%) had ATT and simultaneous hepatitis virus infection. In 44 (62.8%) patients, ATT was prescribed empirically without definitive evidence of tuberculosis. ATT-ALF patients were younger (32.87 [+/-15.8] years), and 49 (70%) of them were women. Most had hyperacute presentation; the median icterus encephalopathy interval was 4.5 (0-30) days. The median duration of ATT before ALF was 30 (7-350) days. At presentation, advanced encephalopathy and cerebral edema were present in 51 (76%) and 29 (41.4%) patients, respectively. Gastrointestinal bleed, seizures, infection, and acute renal failure were documented in seven (10%), five (7.1%), 26 (37.1%), and seven (10%) patients, respectively. Compared with hepatitis E virus (HEV) and non-A non-E-induced ALF, ATT-ALF patients had nearly similar presentations except for older age and less elevation of liver enzymes. The mortality rate among patients with ATT-ALF was high (67.1%, n = 47), and only 23 (32.9%) patients recovered with medical treatment. In multivariate analysis, three factors independently predicted mortality: serum bilirubin (>or=10.8 mg/dL), prothrombin time (PT) prolongation (>or=26 seconds), and grade III/IV encephalopathy at presentation.

ATT-ALF constituted 5.7% of ALF at our center and had a high mortality rate. Because the mortality rate is so high, determining which factors are predictors is less important. A high proportion of patients had consumed ATT empirically, which could have been prevented.

Mycobacterium tuberculosis (MTB) causes substantial morbidity and mortality in liver transplant recipients. We examined the efficacy of isoniazid latent Mycobacterium tuberculosis infection (LTBI) treatment in liver transplant recipients and reviewed systematically all cases of active MTB infection in this population. We found 7 studies that evaluated LTBI treatment and 139 cases of active MTB infection in liver transplant recipients. Isoniazid LTBI treatment was associated with reduced MTB reactivation in transplant patients with latent MTB risk factors (0.0% versus 8.2%, P = 0.02), and isoniazid-related hepatotoxicity occurred in 6% of treated patients, with no reported deaths. The prevalence of active MTB infection in transplant recipients was 1.3%. Nearly half of all recipients with active MTB infection had an identifiable pretransplant MTB risk factor. Among recipients who developed active MTB infection, extrapulmonary involvement was common (67%), including multiorgan disease (27%). The short-term mortality rate was 31%. Surviving patients were more likely to have received 3 or more drugs for MTB induction therapy (P = 0.003) and to have been diagnosed within 1 month of symptom onset (P = 0.01) and were less likely to have multiorgan disease (P = 0.01) or to have experienced episodes of acute transplant rejection (P = 0.02). Compared with the general population, liver transplant recipients have an 18-fold increase in the prevalence of active MTB infection and a 4-fold increase in the case-fatality rate. For high-risk transplant candidates, isoniazid appears safe and is probably effective at reducing MTB reactivation. All liver transplant candidates should receive a tuberculin skin test, and isoniazid LTBI treatment should be given to patients with a positive skin test result or MTB pretransplant risk factors, barring a specific contraindication. Liver Transpl 15:894-906, 2009. (c) 2009 AASLD.

Transmission of infection from donor to recipient is a potential complication of transplantation. More data on this issue are needed to expand the insufficient donor pool. This study evaluates the incidence of donor nonviral infection, transmission from infected donors and the effect of donor infection on 30-day recipient survival. Data from 211 infected donors contributing to 292 (8.8%) of 3322 consecutive transplant procedures within RESITRA (Spanish Research Network for the Study of Infection in Transplantation) were prospectively compiled and analyzed. Lung was the most likely transplanted organ carried out with an infected donor and Staphylococcus aureus was the most commonly isolated microorganism. In more than a half of donors, the lung was the site of infection. Donor-to-host transmission was documented in 5 patients out of 292 (1.71%), 2 of whom died of the acquired infection (40%). Nonetheless, there was no difference in 30-day patient survival when comparing transplant procedures performed with organs from infected or uninfected donors. In conclusion, donor infection is not an infrequent event, but transmission to the recipient is quite low. Hence, with careful microbiological surveillance and treatment, the number of organs available for transplantation may be increased.

Drug-induced acute liver failure (ALF) accounts for approximately 20% of ALF in children and a higher percentage of ALF in adults. Although most patients experience milder drug hepatotoxic reactions such as hepatitis, cholestasis, or asymptomatic enzyme elevation, it is important to recognize the potential for progression to ALF. The most common cause of drug-induced ALF in children is acetaminophen (15% of all ALF in children in the United Kingdom and the United States), whereas other drugs such as antituberculous and antiepileptic therapy account for 5%. The pathogenesis of liver injury includes direct hepatotoxicity and idiosyncratic reactions for most drugs, although for others the mechanism of injury is assumed on the basis of clinical presentation and hepatic histological findings. We review the adult and pediatric literature of drug-induced hepatotoxicity and ALF, with special attention to commonly used or offending medications, mechanism of the toxicity, clinical presentation, diagnosis, treatment, and prognosis. Although most of the available information is based on experience in adult patients, we have included that which is applicable to children, or we have cited pediatric examples. Enhanced awareness of the potential hepatotoxicity of commonly prescribed medications may minimize the frequency of serious hepatotoxicity and ALF in pediatric patients.

The management of patients with pre-existing tuberculosis (TB) undergoing liver transplantation is challenging. Cautious immunosuppression is required to prevent reactivation of disease, and second-line anti-tuberculous treatment may be necessary to prevent graft hepatotoxicity. Furthermore, liver transplantation in the context of isoniazid-resistant TB has seldom been reported. We report on a 44-year-old man with recent isoniazid-resistant extra-pulmonary TB who developed subacute hepatic failure requiring emergency liver transplantation and treatment with second-line anti-tuberculous therapy. We demonstrate that patients who have pre-existing TB can be successfully treated with alternative anti-tuberculous medication while under immunosuppression post transplantation. Pre-existing TB, including resistant strains, should not be an absolute contraindication to liver transplantation.

Isoniazid (INH) therapy for tuberculosis carries a known risk for hepatoxicity, and leads to hepatic failure in a small subset of patients. This incidence has been described for adults, but is uncertain in children. Our aim was to estimate the incidence of pediatric referrals for INH-related liver failure, and to describe the characteristics and outcomes of these patients.

The 84 U.S. centers performing pediatric liver transplants between 1987 and 1997 were surveyed regarding patients with INH-induced liver failure. Additional transplant statistics were obtained from the United Network for Organ Sharing. Estimates of the number of children taking preventive INH were derived from a nationwide public health database.

Twenty cases of INH-related liver failure were found during a 10-year period. Four patients (20%) recovered spontaneously; 10 (50%) underwent orthotopic liver transplantation (OLT), while six (30%) died awaiting OLT. Mean age at presentation was 9.8 years (range 1.3-17). Mean length of INH therapy was 3.3 months (range 0.5-9). Notably, five patients seen for symptoms of hepatitis were initially told not to stop treatment. INH-associated liver failure accounted for 0.2% (8 of 4679) of all pediatric OLTs, and 14% (8/56) of transplants for drug hepatoxicity. The estimated incidence of liver failure was up to 3.2/100,000 for children on prophylactic INH.

While INH-associated liver failure in children is rare, discontinuation at the onset of symptoms does not assure recovery. This indicates a need for increased awareness of hepatotoxicity risk, expanded biochemical monitoring for children receiving INH, and prompt withdrawal in symptomatic patients.

Treatment of latent tuberculosis infection with isoniazid (INH) or rifampin (RIF) is controversial in liver transplant candidates due to potential hepatotoxicity. In this study, treatment of latent tuberculosis during transplant candidacy period is explored, and relevant literature is reviewed.

Liver transplant candidates with latent tuberculosis infection by positive tuberculin skin test (>5 mm) were prospectively enrolled and treated with 9 months of INH or 4 months of RIF, and were monitored monthly for their liver enzyme profiles, adverse effects, compliance, and completion rate.

Four of nine patients with INH had asymptomatic, mild elevations of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) versus none of five patients in the RIF group. Two cases of elevations were attributed to INH. Two other cases were attributed to alcoholism or active chronic hepatitis B virus infection. Only one patient in the INH group experienced symptoms possibly attributed to INH hepatotoxicity. Compliance was 100% per patient reporting. Completion rates were 79% for INH and 100% for RIF. No fulminant hepatic failure or death was observed.

Treatment of latent tuberculosis in liver transplant patients during their candidacy with INH or RIF appears to be a safe, viable option, if carefully monitored for adverse effects and liver enzymes.

Tuberculosis remains one of the most serious infections after organ transplantation. Isoniazid prophylaxis for liver transplant recipients with a history of tuberculosis is generally recommended. However, its benefit is controversial because of potential hepatotoxicity of isoniazid. It is crucial to determine appropriate post-transplant managements for the recipients with a history of tuberculosis. The purpose of this study was to investigate the necessity of isoniazid prophylaxis for liver transplant recipients who had a history of tuberculosis. The medical records of 1116 liver transplant recipients were studied, of whom seven had a history of tuberculosis (0.63%). One who underwent living-donor liver transplantation for fulminant hepatic failure was excluded from evaluation because of early death, caused by bacterial sepsis two months after transplantation, although reactivation of tuberculosis was not observed. The median observation period after transplantation was 25.5 months (range 12-82). Reactivation of tuberculosis did not occur in any of these six patients. In conclusion, we could not find rationale for isoniazid prophylaxis in liver transplant recipients with past diagnosis of tuberculosis, when the disease is considered to be inactive. Tuberculosis should be considered as cause of post-transplant infections, and careful post-transplant observations are essential for an early diagnosis.

Isoniazid, pyrazinamide and rifampicin have hepatotoxic potential, and can lead to such reactions during antituberculosis chemotherapy. Most of the hepatotoxic reactions are dose-related; some are, however, caused by drug hypersensitivity. The immunogenetics of antituberculosis drug-induced hepatotoxicity, especially inclusive of acetylaor phenotype polymorphism, have been increasingly unravelled. Other principal clinical risk factors for hepatotoxicity are old age, malnutrition, alcoholism, HIV infection, as well as chronic hepatitis B and C infections. Drug-induced hepatic dysfunction usually occurs within the initial few weeks of the intensive phase of antituberculosis chemotherapy. Vigilant clinical (including patient education on symptoms of hepatitis) and biochemical monitoring are mandatory to improve the outcomes of patients with drug-induced hepatotoxicity during antituberculosis chemotherapy. Some fluoroquinolones like ofloxacin/levofloxacin may have a role in constituting non-hepatotoxic drug regimens for management of tuberculosis (TB) in the presence of hepatic dysfunction. Isoniazid administration is currently the standard therapy for latent TB infection. Rifamycins like rifampicin or rifapentine, alone or in combination with isoniazid, may also be considered as alternatives, pending accumulation of further clinical data. During treatment of latent TB infection, regular follow up is essential to ensure adherence to therapy and facilitate clinical monitoring for hepatic dysfunction. Monitoring of liver chemistry is also required for those patients at risk of drug-induced hepatotoxicity.

Standard antituberculous therapy including isoniazid, rifampin, ethambutol, and pyrazinamide is widely used for the treatment of active tuberculosis. Its most important side effect is hepatotoxicity, ranging from asymptomatic transaminitis to fulminant hepatic failure. A 19-year-old woman was admitted to our unit due to jaundice and unconsciousness. According to her past medical history, she was diagnosed as having extrapulmonary tuberculosis and had been prescribed standard antituberculous therapy. The patient became icteric and unconscious on the fourth day after therapy initiation. She was diagnosed with drug-induced acute fulminant hepatic failure and underwent living-related liver transplantation. Nonhepatotoxic antituberculous therapy (cycloserine, ciprofloxacin, streptomycin, and ethambutol) and low-dose immunosuppressive therapy were started after transplantation. Currently the patient is very well with normal graft function 42 months after transplantation. Here we report a case of a patient with acute fulminant hepatic failure caused by isoniazid, rifampicin, or both, who was successfully treated with living-related liver transplantation and a relatively less hepatotoxic antituberculous therapy. In conclusion, liver transplantation is a feasible therapy for individuals with standard antituberculous therapy-induced hepatic failure. Nonhepatotoxic antituberculous therapy may achieve control of active tuberculosis in such individuals after transplantation.

Antituberculous treatment is a well-known cause of fulminant hepatic failure (FHF). This could lead to liver transplantation as the only possible treatment, which on the other hand could be contraindicated due to active tuberculosis. The risk of aggressive dissemination of the disease after transplantation is not clearly determined by the current second-line antituberculous therapies. We report a case of vertebral tuberculosis treated with rifampin, isoniazid and pyrazinamide. He developed an FHF that was treated with urgent liver transplantation. Despite the immunosuppression, the disease was well controlled with ciprofloxacin, ethambutol and streptomycin and the patient is in good health 23 months after transplantation. In conclusion, active extrapulmonary tuberculosis should perhaps be considered for liver transplantation when FHF develops due to anti-tuberculous drugs.