BACKGROUND & AIMS:

The inclusion of protease inhibitors in 3-drug highly active antiretroviral regimens for treating patients who are infected with human immunodeficiency virus-1 has had a significant impact in increasing survival and decreasing morbidity. However, the effectiveness of this class of drugs may be compromised by the occurrence of drug-related hepatotoxicity, which is problematic especially in individuals co-infected with hepatitis viruses. Based on its clinical and pharmacologic profile, especially its unique pattern of resistance, nelfinavir has been used frequently as a first-line protease-inhibitor therapy for human immunodeficiency virus-1-infected patients. The aim of this study was to identify the relative potential for developing hepatotoxicity for nelfinavir vs other protease inhibitors.

METHODS:

An exploratory meta-analysis of liver enzyme level increases was conducted in a combined total of 4268 patients derived from 3 large recently conducted prospective and retrospective clinical trials and a prospective cohort study.

RESULTS:

The results indicate that among 4 commercially available protease inhibitors and a 2-protease inhibitor combination, nelfinavir and indinavir are associated with the lowest rates of occurrence of severe hepatotoxicity (ie, combined estimates of liver enzyme level increases of 2.9% and 3.1%, respectively). The low rate of occurrence of severe hepatotoxicity for nelfinavir was shown even among patients co-infected with hepatitis viruses.

CONCLUSIONS:

In conclusion, these data provide support for the conclusion that differences in the potential for hepatotoxicity do exist among the commercially available protease inhibitors.

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OBJECTIVE:

To report a case of acute elevation of hepatic enzyme levels as a probable adverse reaction associated with pregabalin.

CASE SUMMARY:

A 59-year-old man with a history of mantle cell lymphoma developed neuropathic pain and was treated with pregabalin 25 mg daily. Fourteen days after beginning pregabalin therapy, he developed left ankle edema and elevation of liver enzyme levels. Peak values were aspartate transaminase 907 U/L, alanine transaminase 1582 U/L, and γ-glutamyltransferase 510 U/L. Pregabalin was discontinued and hepatic enzyme levels returned gradually (over 4 months) to baseline levels.

DISCUSSION:

Many medications are commonly associated with liver injury; few cases of pregabalin-associated hepatotoxicity have been documented. A MEDLINE search (1966-November 2010) revealed 2 reports of acute liver injury with the initiation of pregabalin. In our patient, with hemosiderosis after hematopoietic cell transplantation, pregabalin worsened the underlying liver injury. The low pregabalin dosage and the short time to elevation of liver enzyme levels suggest an idiosyncratic reaction. According to the Naranjo probability scale and the Council for International Organizations of Medical Sciences probability scale, this reaction was probably due to pregabalin.

CONCLUSIONS:

Prescribers should be alert to the possibility of idiosyncratic hepatotoxicity associated with pregabalin use.

Cyclophosphamide, a potent alkylating agent, is effective therapy for some rheumatic diseases. Despite primary hepatic activation of the drug, hepatic toxicity has been reported only in one case. We have reported two episodes of hepatic dysfunction associated with oral cyclophosphamide administration in patients with systemic rheumatic diseases.

BACKGROUND:

Elderly persons have the highest rates of tuberculosis (TB) in the United States compared to all other age groups. A systematic literature review was conducted to determine if older age was a risk factor for hepatotoxicity resulting from treatment with first-line drugs used to treat active (TB) and latent tuberculosis (LTBI).

METHODS:

A systematic review of MEDLINE, Cochrane Controlled Trial Registry, CINAHL(®), and Science Citation Index Expanded (from 1970 to 2011) was performed to determine the risk of hepatotoxicity, comparing those over 60 with those under 60. A meta-analysis was performed using a random effects model along with log odds ratios and the chi-square test.

FINDINGS:

Thirty-eight studies (40,034 participants; 1208 cases of hepatotoxicity) met the selection criteria. For active TB, an overall mean effect of 0.277 (p = 0.024, 95% CI.: 0.037-0.517) was observed, which is equivalent to an odds ratio of 1.32 (95% CI.: 1.04-1.68). For LTBI, an overall mean effect of 1.42 (p < 0.001, 95% CI.: 0.794-2.05) was observed, which translates to an odds ratio of 4.14 (95% CI.: 2.21-7.74).

INTERPRETATION:

Our analysis revealed that patients older than 60 had significantly more risk of hepatotoxicity. These studies suggest that a gentler regimen of treatment for older individuals could benefit health outcomes in this population of TB patients and minimize risks to the public's health.

Although used widely and recognized as a safe drug at therapeutic dose, acetaminophen has a narrow therapeutic margin. Its hepatotoxic potential differs for each individual and depends essentially on associated risk factors which could lead to a severe hepatotoxicity even at therapeutic doses. A systematic screening of these risk factors is essential for an accurate risk stratification and selection of the most adapted treatment strategy. In this article, we review the principal risk factors and propose an approach to aminotranferase elevation in patients using acetaminophen.

Objetivo: identificar los medicamentos y determinar las principales características asociadas con hepatotoxicidad por medicamentos en el embarazo. Método: revisión estructurada en PubMed/Medline, EMBASE y Web of Science utilizando los términos: Drug induced liver injury OR Hepatotoxicity AND Pregnancy. La búsqueda incluyó artículos en inglés, español, humanos, entre 2005 y 2015, con información sobre hepatotoxicidad por medicamentos en el embarazo. Fueron excluidos los artículos sin relación con embarazo o hepatotoxicidad, asociados con otras causas de enfermedad hepática o con hepatotoxicidad por otras sustancias. La información del medicamento y las características de los pacientes fueron registradas en una tabla. La probabilidad de la aparición de hepatotoxicidad fue valorada y agrupada en tres categorías: definida, probable y posible; para algunos medicamentos fue determinada por el método RUCAM. Resultados: fueron identificados 488 artículos, de los cuales 46 fueron seleccionados. Fueron identificados también 12 medicamentos (acetaminofeno, alfametildopa, labetalol, metotrexato, saquinavir, nevirapina, propiltiouracilo, metimazol, carbimazol, nitrofurantoína, ácido acetilsalicílico y piperidolato) con probabilidad de causar hepatotoxicidad en el embarazo. Algunas características asociadas con los fármacos fueron: tiempo de aparición de las reacciones, semanas de embarazo (3-36), factores de riesgo (edad y enfermedades crónicas), manifestaciones clínicas (elevación de transaminasas, prurito, ictericia) y desenlaces (trasplante de hígado, muertes materna y fetal). Conclusión: los medicamentos acetaminofeno, alfametildopa, labetalol, metotrexato, saquinavir, nevirapina, propiltiouracilo, metimazol, carbimazol, nitrofurantoína, ácido acetilsalicílico y piperidolato podrían causar hepatotoxicidad en pacientes embarazadas. Además de la dosis y del tiempo de exposición al fármaco, la edad y el tiempo de gestación podrían influir en la presentación y gravedad de la hepatotoxicidad

This review critically analyzes the clinical data of patients with suspected kava hepatotoxicity and suggests recommendations for minimizing risk. Kava is a plant (Piper methysticum) of the pepper family Piperaceae, and its rhizome is used for traditional aqueous extracts in the South Pacific Islands and for commercial ethanolic and acetonic medicinal products as anxiolytic herbs in Western countries. A regulatory ban for ethanolic and acetonic kava extracts was issued in 2002 for Germany on the basis of reports connecting liver disease with the use of kava, but the regulatory causality assessment was a matter of international discussions. Based on one positive reexposure test with the kava drug, it was indeed confirmed that kava is potentially hepatotoxic. In subsequent studies using a structured, quantitative and hepatotoxicity specific causality assessment method in 14 patients with liver disease described worldwide, causality for kava +/- comedicated drugs and dietary supplements including herbal ones was highly probable (n = 1), probable (n = 4) or possible (n = 9) regarding aqueous extracts (n = 3), ethanolic extracts (n = 5), acetonic extracts (n = 4), and mixtures containing kava (n = 2). Risk factors included overdose, prolonged treatment, and comedication with synthetic drugs and dietary supplements comprizing herbal ones in most of the 14 patients. Hepatotoxicity occurred independently of the used solvent, suggesting poor kava raw material quality as additional causative factor. In conclusion, in a few individuals kava may be hepatotoxic due to overdose, prolonged treatment, comedication, and probably triggered by an unacceptable quality of the kava raw material; standardization is now required, minimizing thereby hepatotoxic risks.

Diclofenac sodium is one of the most prescribed NSAIDs in the world which is frequently used in therapy of musculosceletal diseases. Therefore it is important to justify clinical and literary data about diclofenac hepatotoxicity. We searched for diclofenac versus placebo investigations performed in patients with osteoarthrosis. A method of the search included international databases such as EMBASE, Cochrane Database, databases of medical publishers and search engines. Total amount of patients in all trials was 1121. 583 patients took diclofenac and 538 ones took placebo. Meta-analysis was performed in StatsDirect software. We estimated 95% confidence interval, Q and 12 criteria, Mantel-Haenszel and DerSimonian-Laird statistics and relative risk of adverse reactions. Relative risk of hepatitis in diclofenac group did not differ from placebo. Hereby the fact of diclofenac hepatotoxicity needs more detailed study and genetic factors of risk should be taken into account.