OBJECTIVE:

To evaluate the incidence of Ketoconazole associated hepatotoxicity and related factor.

METHODS:

Literature retrieval was conducted by using multi-databases for meta-analysis on Ketoconazole associated hepatotoxicity. The data were collected with a standardized form. Overall estimation of incidence of hepatotoxicity for specific study type was calculated by using a DerSimonian-Laird random-effects model owing to the substantial differences among the studies.

RESULTS:

Totally 204 eligible studies were included in the analysis. The incidence of Ketoconazole associated hepatotoxicity was 3.6%-4.2%. The dosage and duration specific subgroup analyses did not show any significant difference among groups, while the age specific subgroup analysis showed the incidence in children and people aged >60 years was 1.4% (95% CI.: 0.5%-4.2%) and 3.2% (95% CI.: 1.1%-8.7%) respectively. Additionally, the incidence of the hepatotoxicity was higher in people who had oral administration of ketoconazole beyond the provisions of the usage instructions, and the incidence was 5.7% (95% CI.: 4.5%-7.2%).

CONCLUSION:

Ketoconazole associated hepatotoxicity was common. Off-label use might increase the risk of liver damage. Well-designed large sample studies are needed to identify the risk factors in future.

Resumen: Introducción: la hepatotoxicidad inducida por fármacos y otros agentes es una forma frecuente de injuria hepática, superando en algunos países a las hepatitis virales. La presentación es variable, desde una alteración aislada del funcional hepático hasta formas graves con fallo hepático agudo fulminante. Se presenta un caso de lesión hepática aguda luego de un ciclo corto con altas dosis de metilprednisolona intravenosa. Caso clínico: sexo femenino, 45 años. Antecedentes personales de esclerosis múltiple, con último empuje 40 días previo a la consulta, tratada con bolos de metilprednisolona intravenosa. Consulta por ictericia de una semana de evolución, dolor abdominal, vómitos, anorexia, astenia y adinamia en el último mes. De la paraclínica se destaca: hiperbilirrubinemia mixta, elevación de las transaminasas, tiempo de protrombina descendido. Se descarta etiología viral, autoinmune y metabólica. Se plantea hepatotoxicidad por metilprednisolona que se confirma con la evolución favorable, y normalización a los 3 meses del enzimograma hepático y tiempo de protrombina tras la suspensión del tratamiento con metilprdnisolona. Discusión: el primer paso para el diagnóstico de hepatotoxicidad es descartar otras causas de injuria hepática. En segundo lugar, se debe demostrar la relación temporal entre la exposición al fármaco y el daño hepático. Por último, la suspensión del medicamento suele acompañarse de mejoría del cuadro clínico y analítico. Para diagnosticar esta entidad es necesario tener un alto índice de sospecha. El tratamiento con dosis altas de metilprednisolona puede inducir hepatitis severa que recurre con la re-exposición a la droga. Los pacientes con enfermedades autoinmunes tienen mayor riesgo de desarrollar hepatotoxicidad, lo que plantea un desafío terapéutico.

El perfil clínico de la hepatotoxicidad inducida por fármacos antituberculosos es variable y la reintroducción de la terapia a los pacientes que la han desarrollado es controversial. Se presentan 5 casos pediátricos atendidos en un periodo de 10 años en el Servicio de Pediatría del Hospital Nacional Hipólito Unanue. 2 casos mostraron elevación asintomática de transaminasas, 2 presentaron hepatitis y 1 presentó insuficiencia hepática fulminante. La mayoría fueron escolares del sexo femenino y como factores de riesgo se encontró la desnutrición y la continuación de la terapia una vez que el daño hepático se inicia. Proponemos un esquema de reintroducción escalonada de estos agentes luego de la recuperación de la hepatitis.

BACKGROUND:

Non-steroidal anti-inflammatory drugs have been implicated in reports of liver injury. However, the precise risk of non-steroidal anti-inflammatory drugs for this rare complication is unknown.

AIM:

To review systematically the published literature of population-based epidemiological studies reporting the incidence or comparative risk of non-steroidal anti-inflammatory drugs for liver injury resulting in clinically significant events, defined as hospitalization or death.

DATA EXTRACTION:

Duplicate extraction of the methodological quality, design, source, population, years studied, particular non-steroidal anti-inflammatory drugs studied, definitions, patient counts and follow-up, and the adjustment for confounders.

RESULTS:

Seven articles met inclusion criteria. The comparative risk of liver injury resulting in hospitalization for current non-steroidal anti-inflammatory drug users compared with past non-steroidal anti-inflammatory drug users ranged from 1.2 to 1.7, but none was statistically significant. The incidence of liver injury resulting in hospitalization ranged from 3.1 to 23.4/100,000 patient-years of current use of non-steroidal anti-inflammatory drugs, with an excess risk compared with past non-steroidal anti-inflammatory drugs users of 4.8-8.6/100,000 patient-years of exposure. There were zero deaths from liver injury associated with non-steroidal anti-inflammatory drugs use in over 396,392 patient-years of cumulative exposure.

CONCLUSION:

These findings allow for the possibility of a small increase in the risk of clinically relevant hepatotoxicity with non-steroidal anti-inflammatory drugs use, but do not document that such a risk occurs.

AIM:

Hepatic toxicity of chemotherapy for colorectal cancer and its complications after hepatic metastasis surgery are unclear. Studies reporting hepatic lesions after chemotherapy for colorectal cancer and published before July 2009 have been identified by searching the Medline database. Data concerning these hepatic lesions and outcome after surgery are resumed in this review.

RESULTS:

Studies concerning the link between hepatic steatosis and chemotherapy have contradictory results but steatosis is clearly associated to an increase of postoperative morbidity. Steatohepatitis, especially due to irinotecan, is associated with increased postoperative mortality. Sinusoidal obstruction syndrome, a severe form of vascular hepatic lesion, associated to oxaliplatin, seems to be linked with an increase of postoperative morbidity, but not mortality. Bevacizumab would not increase, when used in combination with oxaliplatin, the rate of postoperative complications. Some studies suggest a decrease of vascular hepatic lesions when bevacizumab is administered with chemotherapy. The literature concerning hepatic toxicity of anti-EGF-R antibody is freak.

CONCLUSION:

The fact that irinotecan may be linked to an increased risk of hepatic failure and postoperative death, which is not the case of oxaliplatine, must be taken in consideration in the choice of the preoperative chemotherapy before resection of hepatic metastasis of colorectal cancer.

Herbal hepatotoxicity is a rare and poorly described disease because reported cases are mostly scattered and lack an appropriate causality assessment. We now describe in detail the clinical picture of herbal hepatotoxicity by extracts of Greater Celandine (GC), syn. Chelidonium majus L. from the Papaveraceae family, which contain more than 20 ingredients including various biologically active isoquinoline alkaloids. For this purpose, we analyzed and reviewed published cases of 16 patients from various European countries. In all patients, herbal hepatotoxicity was of probable and highly probable causality for GC, using the original and updated scale of CIOMS (Council for International Organizations of Medical Sciences). GC associated hepatotoxicity usually has an acute clinical course exhibiting a hepatocellular pattern of injury and is correlated to an idiosyncratic reaction with its metabolic subtype. Jaundice combined with high values of serum aminotransferases was present in virtually all cases with favourable outcome despite severe clinical course. In conclusion, GC hepatotoxicity is a typical herbal hepatotoxicity with a sound causality track for GC, but there is uncertainty regarding the respective causative compound(s). The present detailed review of GC hepatotoxicity may serve as an example for clinical causality assessments of future cases of liver injury due to other herbs.

BACKGROUND:

To examine chronic viral hepatitis (CVH) as a risk factor for hepatotoxicity during isoniazid (INH) treatment for latent tuberculosis infection (LTBI).

METHODS:

A search of MEDLINE (1966-May 2008) was conducted using the terms 'tuberculosis', 'antitubercular', 'therapeutics', 'treatment', 'prevention', 'prophylaxis', 'hepatitis', 'toxic hepatitis', 'hepatotoxic', 'liver' and 'injury'. Peer-reviewed, English-language articles describing the relationship between a history of CVH and occurrence of hepatotoxicity during LTBI treatment were selected. We limited CVH diagnoses to reports with positive serological test or biopsy for hepatitis B or C. Risk ratios and 95% confidence intervals were abstracted or derived.

RESULTS:

We reviewed 486 abstracts, and 11 studies met the selection criteria. Populations included in the studies were the general population (n = 6) and transplant recipients (n = 5). The variability in study designs and case finding practices precluded performing a quantitative meta-analysis. Two studies of former or current drug users reported a consistent, positive association between chronic hepatitis C infection and INH hepatotoxicity. Other risk ratios did not significantly or consistently show any association between CVH in patients treated for LTBI and the development of INH hepatotoxicity.

CONCLUSION:

Owing to the limited number of published papers, CVH was not established as a risk factor for INH hepatotoxicity during LTBI treatment. Controlled studies are needed to define the safety and tolerability of LTBI treatment in those with CVH and to provide an evidence base for recommendations for LTBI treatment in persons with CVH.

PURPOSE:

The main aim of this study was to determine the most frequently reported drugs to the Serbian Pharmacovigilance Database (SPD) with suspected induced hepatotoxicity. Additionally, reasons for the low reporting rate of adverse drug reactions (ADRs) in Serbia were identified.

METHODS:

Retrospective observational study of spontaneously reported ADRs recorded in the SPD from January 1995 to December 2008 was performed. The Medical Dictionary for Regulatory Activities (MedDRA) was used to identify cases of hepatobiliary disorders (HD). Drugs were classified using the Anatomical Therapeutic Chemical (ATC) classification. Medline and WHO-UMC databases were used to address specific queries suggested by our results. The questionnaire was used to investigate the health care professionals' knowledge and practice related to spontaneous reporting.

RESULTS:

Among the 1804 reports of ADRs recorded in the SPD between 1995 and 2008, 70 (3.9%) cases of HD were identified. Drugs most frequently associated with hepatotoxicity were anti-infectives for systemic use, drugs affecting the nervous system, herbal products, hypolipemics, and anticoagulant drugs (26.83, 24.39, 12.20, 9.76, and 8.54% cases, respectively). Four cases (5.71%) of liver injury resulted in death, which accounted for 10.26% of all ADR fatalities reported to the SPD. The main reasons for not reporting ADRs were lack of reporting knowledge (30.26%), well-known ADRs (29.89%), and insecurity about causality relationship (15.50%).

CONCLUSIONS:

Anti-infectives, nervous system drugs, and herbal products were the most common drug classes reported for hepatotoxicity in Serbia. There is a need for additional education about ADRs, and enhanced reporting by health care professionals.

RESUMEN Objetivo: Describir las características clínicas de la injuria hepática inducida por antituberculosos (IHIA) en pacientes con tuberculosis multirresistente (MDR-TB). Materiales y métodos: Estudio retrospectivo de pacientes hospitalizados con TB-MDR e IHIA. Se utilizó los criterios de la DILI-Expert Working Group, y el instrumento de análisis de causalidad fue el RUCAM (Roussel Uclaf Causality Assessment Method). La asociación específica de la IHIA con un antituberculoso fue por un proceso de reexposición o suspensión y recuperación. Resultados: Reportamos 7 casos de MDR-TB e IHIA; la edad media (desviación estándar) fue de 39,1 (3,3) años. La media de la IHIA apareció después de 30,4 (27,70) días de iniciar el tratamiento. Tres (43,00 %) pacientes presentaron ictericia. En cuanto al patrón, en 4 (57,00 %) fue hepatocelular y en 3 (43,00 %), colestásico. En 4 pacientes, la IHIA fue leve, y moderada en 3. En todos los casos estuvo involucrada la pirazinamida (pirazinamida sola, 4; pirazinamida y etionamida, 1; pirazinamida, rifampicina e isoniazida, 1; pirazinamida y rifampicina, 1). La estancia hospitalaria media fue de 48,10 (48,70) días. Los promedios de fosfatasa alcalina (FA), alanina aminotransferasa (ALT) y gamma-glutamiltranspeptidasa (GGT) sérica fueron 2,40 (1,10), 7,9 (7,10) y 5,60 (3,70) veces el límite superior normal (NUL), respectivamente. La bilirrubina total media fue 2,30 (2,10), rango de 0,50 a 6,40 mg/dl. Como parte del esquema de alta del paciente, se administraron quinolonas a 7 pacientes (levofloxacino, 6; ofloxacino, 1), y en un paciente se agregó ácido amoxicilina/ácido clavulánico. Conclusiones: La IHIA en pacientes con TB-MDR puede aparecer después del primer mes de tratamiento. El patrón de lesión común fue hepatocelular, y la pirazinamida fue el antimicobacteriano involucrado con mayor frecuencia.

The available literature assessing Chelidonium majus L. (CM) hepatotoxicity potential, and its risk to benefit assessment has been reviewed in this paper. Identification of significant scientific literature was performed via the following research databases: Cochrane Central, Google Scholar, EMBASE, Medline, Science Direct, Scopus, Web of Science, using the following keywords: "Chelidonium majus", "greater celandine", "Hepatotoxicity", "Liver" "Injury", "Toxicity" individually investigated and then again in association. CM named also greater celandine, swallow-wort, or bai-qu-cai (Chinese), has been used for a long time in traditional Chinese medicine and phytotherapy. Its extracts have been claimed to display a wide variety of biological activities: antimicrobial, anti-inflammatory, spasmolytic, antineoplastic, hepatoprotective, and analgesic. Moreover, herbal medicine suggests this plant have numerous additional effects which have not yet been scientifically evaluated, such as antitussive, diuretic, and eye-regenerative. However, despite its claimed hepatoprotective effects, several hepatotoxicity cases have been reported to be probably or highly probably connected with CM exposure, after their evaluation through liver-targeted causality assessment methods. CM hepatotoxicity has been defined as a distinct form of herb-induced liver injury (HILI), due to an idiosyncratic reaction of the metabolic type. This evidence has to be considered in relationship with the absence of considerable benefits of CM therapy. Therefore, the risk to benefit ratio of the use of herbal products containing greater celandine can actually be considered as negative.