Liver Toxicity In Patients Research Articles

Aminotransferase Elevations Tied to Acetaminophen

A new study has found abnormal aminotransferase elevations in healthy adults taking 4 g of acetaminophen per day, the maximum recommended daily dose. The new findings were published July 5, 2006 in the Journal of the American Medical Association. Historically, the potential for liver toxicity in patients treated for pain was first noted during a clinical trial of a novel hydrocodone-acetaminophen combination. Initially, scientists had assumed the risk came from the hydrocodone component. That study was stopped prematurely because of the frequency and magnitude of ALT elevations in the active treatment versus the placebo groups. “Because ALT elevations had generally not been reported in adults receiving recommended doses of acetaminophen, there was concern that opioids might increase susceptibility to acetaminophen liver toxicity. This new study was, therefore, designed to investigate hepatotoxicity among participants receiving acetaminophen alone, opioid/acetaminophen combinations, or placebo,” the JAMA authors note. Each participant received either placebo (n = 39), 1 of 3 acetaminophen-opioid combinations (n = 80), or acetaminophen alone (n = 26). Each treatment included 4 g of acetaminophen daily, the upper limit of recommended acetaminophen dosing, for 14 days. Serum hepatic biochemical tests and trough acetaminophen concentrations were measured daily through Day 8, and at 1- or 2-day intervals thereafter. None of the 39 participants assigned to placebo had a maximum ALT of more than 3 times the upper limit of normal, the authors report. In contrast, the incidence of maximum ALT of more than 3 times the upper limits of normal was 31% to 44% in the 4 treatment groups receiving acetaminophen, including those participants treated with acetaminophen alone. Compared with placebo, treatment with acetaminophen was associated with a markedly higher median maximum ALT (ratio of medians, 2.78; 95% confidence interval, 1.47–4.09; P <.001). Trough acetaminophen concentrations did not exceed therapeutic limits in any participant and, after active treatment was discontinued, often decreased to undetectable levels before ALT elevations resolved. “None of the patients in the placebo group had a maximum ALT measurement of more than 3 times the upper limit of normal,” said Dr. Paul B. Watkins, study senior author and Professor of Medicine and director of the General Clinical Research Center at the University of North Carolina at Chapel Hill. “This clearly showed that it had nothing to do with the opiate. It was a previously unrecognized but remarkable effect of acetaminophen alone when taken as directed for 4 days.” Acetaminophen is contained in many over-the-counter pain relievers, including Tylenol. (McNeil Consumer Healthcare, Fort Washington, PA) According to Watkins, the study recommends that doctors investigate a patient’s history of acetaminophen intake when unexplained elevations in aminotransferase levels are found. “A history of acetaminophen ingestion should be considered in the differential diagnosis of serum aminotransferase elevations, even in the absence of measurable serum acetaminophen concentrations,” he said. “Because acetaminophen has been shown to be safe when taken as directed, the study also raises questions concerning the reliability of commonly used liver blood tests,” Watkins added. He noted that when physicians have observed aminotransferase abnormalities to the extent found in the study, “this has indicated there is significant liver injury or damage occurring. But since we have decades of experience and know the safety of acetaminophen, perhaps the tests are not good predictors as to which drugs are going to be associated with liver problems.” Watkins also pointed out that it may be possible that a number of past tests may have been misinterpreted, incorrectly attributing aminotransferase elevations to a drug other than acetaminophen. “Treatment with other drugs suspected to cause liver problems, such as lipid-lowering medicines, may have been stopped unnecessarily.” For more details, see “Aminotransferase Elevations in Healthy Adults Receiving 4 Grams of Acetaminophen Daily: A Randomized Controlled Trial,” JAMA 2006;296:87–93.

Low incidence of severe liver toxicity in patients receiving antiretroviral combinations including atazanavir

Low incidence of severe liver toxicity in patients receiving antiretroviral combinations including atazanavir

Amifostine does not protect against liver toxicity in patients receiving dose-escalated IV busulfan (IVBU) and standard dose cyclophosphamide in auto BMT

Amifostine does not protect against liver toxicity in patients receiving dose-escalated IV busulfan (IVBU) and standard dose cyclophosphamide in auto BMT

MTHFR-A1298C Polymorphism Is Associated with Veno-Occlusive Disease (VOD) and Liver Toxicity after Busulfan/Cyclophosphamide Conditioning Followed by Allogeneic Hematopoietic Stem Cell Transplantation (HSCT).

Purpose: The aim of our study was to evaluate the impact of genomic polymorphisms of methylene-tetrahydrofolate-reductase (MTHFR) and glutathione S-transferases (GST) on liver toxicities seen in patients receiving busulfan and cyclophoshamide conditioning followed by allogeneic HSCT.Background: Polymorphisms of methylene-tetrahydrofolate-reductase (MTHFR) have been shown to potentially influence toxicity (e.g. mucositis) in HSCT. Additionally, many chemotherapeutics that have been linked to veno-occlusive disease (VOD) and liver toxicity (e.g. Busulfan) are metabolised by glutathione S-transferases (GST). Little is known about the impact of gene polymorphisms of MTHFR and various GSTs on VOD and liver toxicity in allogeneic HSCT.Methods: 84 adult patients were enrolled in this retrospective study. The majority of the patients had chronic myelogenous leukemia (CML) in 1st chronic phase (94%). 2 patients suffered from acute myelogenous leukemia (AML-M4), 2 from myelodysplastic syndrome (MDS) and 1 patients from Farber's disease. DNA was isolated from leucocytes of stem cell recipients collected prior to HSCT. Common gene polymorphisms of glutathione S-transferases (GSTP1-Ile105Val, GSTA1*A/B, GSTM1, GSTT1) and methylene-tetrahydofolate-reductase (MTHFR-C677T, MTHFR-A1298C) were detected by PCR-RFLP. All patients were treated with busulfan/cyclophosphamide as conditioning regimen and received cyclosporine and short-course MTX for GvHD prophylaxis. 67 patients (80%) received additionally anti-thymocyte globulin (ATG). Assessment of liver toxicities was based on appearance of VOD according to the Baltimore criteria, maximum bilirubin levels within 20 days after HSCT and duration of hyperbilirubinaemia > 2 mg/dl.Results: Analyses revealed statistical significant association between the MTHFR-A1298C polymorphism and liver toxicities. There was significant higher incidence of VOD in patients that are homozygous for the C allele (p = 0,04). Independently of VOD, patients carrying the MTHFR-1298CC genotype demonstrated higher median maximum levels of bilirubin with 6.8 mg/dl than MTHFR-1298AC and MTHFR-1298AA patients (3,0 mg/dl and 3,4 mg/dl) (p = 0,004). Furthermore, elevation of bilirubin levels > 2 mg/dl lasted longer in MTHFR-1298CC patients with a median of 14 days compared to 3 and 6 days in patients harbouring the MTHFR-1298AC and MTHFR-1298AA genotype (p = 0,004). Interestingly, the common MTHFR-C677T polymorphism did not reach statistical significance in accordance to liver toxicity in our study population. No significant associations between GSTP1-Ile105Val, GSTA1*A/B, GSTM1 and GSTT1 polymorphisms and liver toxicity were found in this study.Conclusion: Our data suggest that the MTHFR-A1298C polymorphism is associated with VOD and hyperbilirubinaemia in patients treated with busulfan/cyclophosphamide as conditioning regimen followed by allogeneic HSCT. To the best of our knowledge this the first report linking the MTHFR-A1298C polymorphism to liver toxicity in patients receiving allogeneic HSCT.

Incidence, risk factors and clinical course of thiopurine‐induced liver injury in patients with inflammatory bowel disease

The incidence of thiopurine-induced hepatotoxicity in patients with inflammatory bowel disease varies in different studies. To assess the rate of thiopurine-induced liver toxicity in patients with inflammatory bowel disease; to determine the predictive factors and to characterize its clinical course and management. A cohort of 161 patients was prospectively followed for a median of 271 days. Hepatotoxicity was established when alanine transaminase or alkaline phosphatase plasma levels were greater than twice the upper normal limit. Abnormal liver function was detected in 21 patients (13%; 95% CI: 7-18). Hepatotoxicity occurred in 16 patients (10%; 95% CI: 6-16) after a median of 85 days. In five cases, treatment was withdrawn due to hepatotoxicity. Use of corticosteroids was associated with hepatotoxicity (OR: 4.94; 95% CI: 1.01-23.98) with antitumour necrosis factor concomitant therapy showing a protective role (OR: 0.3; 95% CI: 0.1-3.1). gamma-Glutamyl transferase plasma levels at the onset of hepatotoxicity showed the best predictive value for treatment withdrawal (area under the receiver operating characteristic curve: 0.95). The incidence of hepatotoxicity in inflammatory bowel disease patients receiving thiopurines is relevant, mainly in patients co-treated with corticosteroids. gamma-Glutamyl transferase plasma level is a useful biomarker in therapy withdrawal prediction.

Incidence of Liver Injury After Beginning Antiretroviral Therapy with Efavirenz or Nevirapine

Objective: To compare the incidence and define the risk factors associated with liver toxicity in patients beginning treatment with nevirapine (NVP) and efavirenz (EFZ). Method: This was a retrospective chart review of all HIV-infected patients starting any antiretroviral regimen containing at least two nucleoside analogues plus either NVP or EFZ between January 1998 and January 2000. Liver toxicity was defined as an increase in transaminase levels 5-fold above the upper limits of normal if they were normal at baseline or 3.5-fold above baseline levels if they werepreviously elevated. Results: Out of 298 patients included in the study, 162 received NVP and 136 EFZ. Overall, 75% were men, and 45% were coinfected with the hepatitis C virus (HCV). Median (interquartile range) time on follow-up was 10 (6-12) months. Liver toxicity was more frequently associated with NVP (12%) than with EFZ (4%) (p = .016). Overall, it was first recognized at a median time of 5.5 months (2.7-9.2) on therapy, with no differences between treatment arms. Both univariate and multivariate analyses identified the use of NVP, HCV coinfection, alcohol abuse, and female gender as independent risk factors for liver toxicity. Conclusion: Liver damage is three times more common in patients receiving NVP than in those taking EFZ. In both groups of patients, it is recognized late, after an average of 5.5 months on therapy. Coinfection with HCV, alcohol abuse, and female gender increase the risk for developing liver toxicity with both drugs.

Incidence of Liver Injury After Beginning Antiretroviral Therapy with Efavirenz or Nevirapine

Objective: To compare the incidence and define the risk factors associated with liver toxicity in patients beginning treatment with nevirapine (NVP) and efavirenz (EFZ). Method: This was a retrospective chart review of all HIV-infected patients starting any antiretroviral regimen containing at least two nucleoside analogues plus either NVP or EFZ between January 1998 and January 2000. Liver toxicity was defined as an increase in transaminase levels 5-fold above the upper limits of normal if they were normal at baseline or 3.5-fold above baseline levels if they werepreviously elevated. Results: Out of 298 patients included in the study, 162 received NVP and 136 EFZ. Overall, 75% were men, and 45% were coinfected with the hepatitis C virus (HCV). Median (interquartile range) time on follow-up was 10 (6-12) months. Liver toxicity was more frequently associated with NVP (12%) than with EFZ (4%) (p = .016). Overall, it was first recognized at a median time of 5.5 months (2.7-9.2) on therapy, with no differences between treatment arms. Both univariate and multivariate analyses identified the use of NVP, HCV coinfection, alcohol abuse, and female gender as independent risk factors for liver toxicity. Conclusion: Liver damage is three times more common in patients receiving NVP than in those taking EFZ. In both groups of patients, it is recognized late, after an average of 5.5 months on therapy. Coinfection with HCV, alcohol abuse, and female gender increase the risk for developing liver toxicity with both drugs.

Liver injury after beginning antiretroviral therapy in HIV/hepatitis C virus co-infected patients is not related to immune reconstitution

Transaminase elevations occur more frequently after beginning antiretroviral therapy in HIV-positive patients co-infected with hepatitis C virus (HCV). The mechanism of liver injury in these individuals is unknown, although immune reconstitution phenomena have been postulated. In 42 HIV/HCV co-infected individuals followed after beginning potent antiretroviral therapy, the development of liver injury was not associated with significant changes in serum HCV-RNA levels nor with greater CD4 cell increases. Underlying chronic hepatitis may thus increase the risk of liver toxicity by other mechanisms.

Severe liver toxicity in patients receiving two nucleoside analogues and a non-nucleoside reverse transcriptase inhibitor

Severe liver toxicity in patients receiving two nucleoside analogues and a non-nucleoside reverse transcriptase inhibitor

Severe liver toxicity in patients receiving two nucleoside analogues and a non-nucleoside reverse transcriptase inhibitor

Severe liver toxicity in patients receiving two nucleoside analogues and a non-nucleoside reverse transcriptase inhibitor

前立腺癌患者に対するフルタミド投与前後の肝機能の検討

The incidence of flutamide-induced liver toxicity was studied in 30 consecutive patients with prostate cancer who were treated with total androgen blockage (TAB) therapy (luteinizing hormone releasing hormone [LHRH] analogue and flutamide) in our hospital during the last 3 years and in 20 consecutive patients with prostate cancer who were treated by partial androgen blockage (PAB) therapy (LHRH analogue alone). Liver function test, including measurement of serum levels of aspartate aminotransferase (AST) alanine aminotransferase (ALT), total cholesterol, total bilirubin, gamma-glutamyl transpeptidase (gamma-GTP), and cholinesterase were performed at regular interval. The incidence of liver toxicity in patients receiving TAB (10 cases of 25 patients) was significantly higher than in patients receiving PAB (2 of 18 patients). Two patients in whom severe liver toxicity developed after receiving TAB were hospitalized. However, after flutamide was discontinued all patients with liver damage recovered with normalization of AST and ALT levels. Levels of total cholesterol and gamma-GTP did not differ significantly in either patient group. In two patients receiving TAB total bilirubin levels showed slight, transient elevations after maximum elevations of AST and ALT. In 80% of patients receiving TAB serum levels of cholinesterase were significantly higher than those in patients receiving PAB. These data suggest that the risk of flutamide-induced liver toxicity is significant in patients receiving TAB. However, this damage can be normalized after flutamide has been discontinued. Serum levels of cholinesterase also increase significantly in patients receiving TAB. This previously unreported phenomenon suggests an unknown effect of flutamide on liver function in patients with prostate cancer.

High doses of aminoglycosides did not produce liver toxicity in patients with cystic fibrosis

Liver disease is common in patients with cystic fibrosis, but the pathogenesis is poorly understood. The chronic colonization of bacteria in the lower airways leads to repeated treatments with antibiotics, especially aminoglycosides in high dosages. To investigate the possible role of aminoglycoside treatment in the natural history of liver disease in cystic fibrosis, five patients were studied for 3 years. Four of the patients received repeated courses of antibiotics, in two of the patients at the time of the liver biopsies. One patient did not receive any aminoglycosides. Light and electron microscopical morphometry was done on liver biopsy specimens. The contents of fat and lysosomes were quantified and expressed as volume density of liver cell volume (%). The amount of fat calculated in this way (13-35%) was highest in one patient who had not received any aminoglycosides. The two patients being treated with aminoglycosides at the time of the biopsy showed small amounts of fat in their liver cells (0.2-1.5%); similar values were noted in some patients who had not been treated for years. The lysosomes did not show the specific changes previously reported to occur in the kidney, nor did the morphometrical quantitation reveal any abnormalities which could be related to the administration of aminoglycosides. The present study did not find liver toxicity related to aminoglycosides in repeated high therapeutic dosages given to patients with cystic fibrosis.

Methotrexate and histologic hepatic abnormalities: A meta-analysis

To determine the risk of liver toxicity from the long-term administration of methotrexate in patients with rheumatoid arthritis or psoriatic arthritis. A meta-analysis of 15 studies examining the relationship between long-term, low-dose methotrexate administration and biopsy evidence of liver fibrosis. A total of 636 patients from 15 studies. The incidence of progression of liver disease (defined as worsening of at least one grade on the histologic classification of Roenigk) among 636 patients was 27.9% (95% confidence intervals 24.3 to 31.6). The rate of progression of liver disease in the 15 studies was associated with the cumulative dose of methotrexate (p = 0.01). Patients on average had a 6.7% (95% confidence intervals 2.1 to 11.4) chance of progressing at least one histologic grade on liver biopsy for each gram of methotrexate taken. The overall incidence of advanced pathologic changes on liver biopsy (grades IIIB or IV) among 636 patients was 5.0% (95% confidence intervals 3.5 to 7.0). The development of advanced histologic changes was not associated with the cumulative dose of methotrexate (p = 0.08). Patients who according to their history were heavy drinkers (at least 100 g of alcohol per week) were more likely to have advanced changes on liver biopsy (17.8% versus 4.5%, p = 0.0003) and to show histologic progression (73.3% versus 25.9%, p = 0.0002). Patients with psoriasis were more likely than patients with rheumatoid arthritis to have advanced changes (7.7% versus 2.7%, p = 0.003) and histologic progression (33.1% versus 24.3%, p = 0.02). The risk of liver toxicity in patients undergoing long-term, low-dose methotrexate therapy is substantial, and that risk increases with the total cumulative dose and with heavy consumption of alcohol. Heavy users of alcohol should not receive long-term methotrexate therapy. For most patients who are not heavy users of alcohol, liver biopsies should be done periodically to monitor for the occurrence of liver toxicity.

Methotrexate and histologic hepatic abnormalities: A meta-analysis

study objective: To determine the risk of liver toxicity from the long-term administration of methotrexate in patients with rheumatoid arthritis or psoriatic arthritis. design: A meta-analysis of 15 studies examining the relationship between long-term, low-dose methotrexate administration and biopsy evidence of liver fibrosis. patients: A total of 636 patients from 15 studies. results: The incidence of progression of liver disease (defined as worsening of at least one grade on the histologic classification of Roenigk) among 636 patients was 27.9% (95% confidence intervals 24.3 to 31.6). The rate of progression of liver disease in the 15 studies was associated with the cumulative dose of methotrexate (p = 0.01). Patients on average had a 6.7% (95% confidence intervals 2.1 to 11.4) chance of progressing at least one histologic grade on liver biopsy for each gram of methotrexate taken. The overall incidence of advanced pathologic changes on liver biopsy (grades IIIB or IV) among 636 patients was 5.0% (95% confidence intervals 3.5 to 7.0). The development of advanced histologic changes was not associated with the cumulative dose of methotrexate (p = 0.08). Patients who according to their history were heavy drinkers (at least 100 g of alcohol per week) were more likely to have advanced changes on liver biopsy (17.8% versus 4.5%, p = 0.0003) and to show histologic progression (73.3% versus 25.9%, p = 0.0002). Patients with psoriasis were more likely than patients with rheumatoid arthritis to have advanced changes (7.7% versus 2.7%, p = 0.003) and histologic progression (33.1% versus 24.3 %, p = 0.02). conclusions: The risk of liver toxicity in patients undergoing long-term, low-dose methotrexate therapy is substantial, and that risk increases with the total cumulative dose and with heavy consumption of alcohol. Heavy users of alcohol should not receive long-term methotrexate therapy. For most patients who are not heavy users of alcohol, liver biopsies should be done periodically to monitor for the occurrence of liver toxicity.