Risk Factors For Liver Injury Research Articles

Hypertension exacerbates liver injury and hepatic fibrosis induced by a choline-deficient L-amino acid-defined diet in rats

The effect of hypertension on non-alcoholic fatty liver disease (NAFLD) remains unclear at the molecular level. In this study, we investigated the effects of hypertension on the degree of hepatic steatosis, liver injury and hepatic fibrosis induced by a choline-deficient L-amino acid-defined (CDAA) diet in spontaneously hypertensive rats (SHRs). Seven-week-old male SHRs were fed standard chow with high or normal salt concentrations for 7 weeks, followed by a CDAA diet containing high or normal salt for an additional 8 or 24 weeks. Hepatic steatosis was assessed using hepatic triglyceride levels and Oil red O staining. Hepatic fibrosis was evaluated using Sirius red and Azan staining. Systolic blood pressure (SBP) gradually increased with a high-salt diet and was significantly higher after 7 weeks of feeding with high-salt vs. normal-salt chow. After 8 weeks on the CDAA diet, the degree of hepatic steatosis did not differ between the high-salt and normal-salt groups; however, alanine aminotransferase and fasting blood glucose levels were significantly higher and hepatic mRNA levels for interleukin (IL)-10 and heme oxygenase (HO)-1 were significantly lower in the high-salt group compared with the normal-salt group. After 24 weeks on the CDAA diet, the high-salt group had significantly more severe hepatic fibrosis and a higher hepatic mRNA expression of α-smooth muscle actin and lower hepatic IL-10 and HO-1 mRNA levels compared with the normal-salt group. In conclusion, our results indicate that hypertension is a potential risk factor for liver injury and hepatic fibrosis through glucose intolerance and decreased IL-10-mediated or HO-1-induced anti-inflammatory mechanisms.

Decreased activities of daily living is a strong risk factor for liver injury by anti‐tuberculosis drugs

We evaluated the association between activities of daily living and drug-induced liver injury by anti-tuberculosis drugs. This retrospective cohort study included adult inpatients with newly diagnosed smear-positive lung tuberculosis treated with standard regimen in two hospitals. (n = 346; 63.6 ± 20.3 years old; 106 (30.6%) females). Activities of daily living was divided into 'independent' (Barthel Index (BI) 80-100, 60.4%) and 'decreased' (BI 0-75, 39.6%) categories. Liver injury was defined as the withdrawal or change of treatment regimen on the basis of the following criteria: serum transaminase concentrations were more than three times the upper limit of normal range with jaundice and/or hepatitis symptoms, or more than five times the upper limit of the normal range. Compared with 'independent' patients, patients with 'decreased' activities of daily living had odds ratios for liver injury of 4.2 (P < 0.001) in univariate analysis and 5.7 (P = 0.002) in logistic regression analysis after adjusting for other risk factors. Decreased activity of daily living is a strong risk factor for liver injury among adult inpatients with newly diagnosed smear-positive lung tuberculosis treated using a standard regimen.

Risk Factors for Liver Injury with an Elevated Serum Bilirubin Concentration Caused by Antituberculous Drugs

No studies have so far sufficiently investigated the risk factors for drug-induced liver injury (DILI) with an elevated serum bilirubin concentration. We conducted a historical cohort study observing inpatients admitted to two hospitals in Japan. A decreased level of activities of daily living (ADL) was defined as a Barthel Index score of <80. The patients were treated with standard regimens under a directly observed treatment short-course strategy. The cohort of 356 patients comprised 244 men (68.5%) and 112 women (31.5%), with a mean age of 63.8±20.2 years. Compared with the patients who did not experience DILI with a bilirubin level of ≥2.0 mg/dL, the patients who experienced DILI with a bilirubin level of ≥2.0 mg/dL more often had a decreased level of ADLs, were more likely to suffer from chronic cardiac disease, had lower serum albumin levels and were less often treated with four-drug regimens involving pyrazinamide (PZA). In a logistic regression analysis in which these five factors acted as independent variables, a decreased level of ADLs was the strongest predictor for DILI with a bilirubin level of ≥2.0 mg/dL, with an odds ratio of 16.5 (95%CI: 1.7-159; p=0.015), followed by chronic cardiac disease, with an odds ratio of 4.0 (95%CI: 1.2-12.6; p=0.020). A decreased level of ADLs and chronic cardiac disease are strong risk factors for DILI with a bilirubin level of ≥2.0 mg/dL resulting from the use of antituberculous drugs. Physicians should pay close attention to the possibility of DILI with a bilirubin level of ≥2.0 mg/dL when treating tuberculosis patients with a decreased level of ADLs and/or chronic heart disease.

Evidence for liver injury in the setting of obstructive sleep apnea

Introduction. Obstructive sleep apnea (OSA) and non-alcoholic fatty liver disease (NAFLD) are both strongly associated with obesity. Whether OSA is an independent risk factor for liver injury is uncertain.Objective. To assess the hypothesis that OSA is associated with liver injury independent of obesity.Materials and methods. We reviewed the histories of 73 consecutive patients referred to a hospital-based sleep lab because of suspected OSA. OSA was determined to be present if the apnea-hypopnea index was > 10. Obesity was defined as a BMI ≥ 30 kg/m2. Patients were included for analysis if they had aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels obtained within 60 days of sleep study. Patients with evidence of viral hepatitis, autoimmune-, metabolic-or established alcoholic-liver disease were excluded. Patients who reported alcohol intake equivalent to a dose ≥ 20 g/day were also excluded. 53 of 73 patients met study criteria. Patients were subdivided for analysis into groups meeting or not meeting OSA and obesity criteria, and having or not having elevated aminotransferase levels.Results. 35/53 patients (66%) had OSA. 31/53 (58%) patients were obese. 15 (28%) and 12 (23%) patients had elevated AST and ALT, respectively. Mean age, gender distribution, mean BMI and percentage with either diabetes or hyperlipi-demia were not significantly different in those with or without OSA. Elevated ALT was found in 11/35 (31%) patients with OSA, compared to 1/18 patients without OSA (p = 0.041). Frequency of elevated AST [obese 11/31 (35%); non-obese 4/22 (18%)] or ALT [obese 10/31 (32%); non-obese 2/22 (9%)] was not significantly different in the obese and non-obese cohorts.Conclusions. OSA may be a risk factor for liver injury independent of obesity. The prevalence and nature of liver disease in the setting of OSA should be determined with larger, prospective studies. The impact of OSA treatment, if any, on liver injury should be similarly evaluated.

Pathologic role of stressed-induced glucocorticoids in drug-induced liver injury in mice

We previously reported that acetaminophen (APAP)-induced liver injury (AILI) in mice is associated with a rise in serum levels of the glucocorticoid (GC), corticosterone. In the current study, we provide evidence that endogenous GC play a pathologic role in AILI. Specifically, pretreatment of mice with the GC receptor (GCR) inhibitor, RU486 (mifepristrone), protected normal but not adrenalectomized mice from AILI, while pretreatment with dexamethasone, a synthetic GC, exacerbated AILI. RU486 did not affect the depletion of whole liver reduced GSH or the formation of APAP–protein adducts. It also had no effects on the formation of reactive oxygen species or the depletion of mitochondrial GSH or ATP. While RU486 pretreatment also protected against halothane-induced liver injury, it exacerbated concanavalin A (ConA)- and carbon tetrachloride (CCl 4)-induced liver injury, demonstrating the complexity of GC effects in different types of liver injury. Conclusion: These results suggest that under certain conditions, elevated levels of GC might represent a previously unappreciated risk factor for liver injury caused by APAP and other drugs through the diverse biological processes regulated by GCR.

Trunk Fat Is Associated With Increased Serum Levels of Alanine Aminotransferase in the United States

Liver injury is associated with obesity and related measures, such as body mass index (BMI) and waist circumference. The relationship between liver injury and body composition has not been evaluated in a population-based study. Using data from a US population-based survey, we examined the contributions of body composition, measured by dual-energy x-ray absorptiometry (DXA), to increased serum alanine aminotransferase (ALT) activity among 11,821 adults without viral hepatitis. Trunk fat, extremity fat, trunk lean, and extremity lean mass were divided by height squared and used to categorize subjects into quintiles; logistic regression odds ratios (OR) were calculated for increased ALT. Increased ALT was associated with higher measures of fat and lean mass (P < .001) after adjustment for alcohol consumption and other liver injury risk factors in separate models for each DXA measure. Trunk fat was associated with increased ALT (P < or = .001) in models also including any 1 of the other 3 measures. Extremity fat was independently inversely associated among women (P < .001). Trunk and extremity lean mass were not independently related to increased ALT. In models that contained all 4 DXA measures, the OR (95% confidence interval [CI]) for increased ALT for the highest, relative to lowest, quintile of trunk fat/height squared was 13.8 (95% CI: 5.4-35.3) for men and 7.8 (95% CI: 3.9-15.8) for women. When BMI, waist circumference, and trunk fat were considered together, only trunk fat remained independently associated with increased ALT. Trunk fat is a major body composition determinant of increased ALT, supporting the hypothesis that liver injury can be induced by metabolically active intraabdominal fat.

Fatal Hepatitis After Long-Term Pulse Itraconazole Treatment for Onychomycosis

To report the occurrence of acute cytolytic hepatitis in a patient exposed to pulse itraconazole therapy for 24 weeks and provide a concise review of the literature on cases of itraconazole-induced hepatitis. A 61-year-old woman with no apparent risk factors for liver injury developed acute hepatitis one week after the final dose of a long-term course of pulse itraconazole therapy (200 mg orally twice daily, 1 wk on, 3 wk off, for 24 wk) for onychomycosis. Monitoring of liver enzymes was not performed during the treatment period. Serologic evaluations on presentation ruled out infectious diseases or other etiological factors. Liver function tests showed alanine aminotransferase 3330 U/L, aspartate aminotransferase 3250 U/L, and bilirubin 21 mg/dL. Liver function continued to deteriorate, and the patient underwent liver transplantation 17 days after admission. Her liver displayed reduced volume and there was a mild accumulation of ascitic fluid in the retroperitoneal cavity. Histologic evaluation showed massive panlobular necrosis. Complications occurred after transplantation and a rejection crisis worsened the clinical picture until the patient died about 4 months later. Use of the Naranjo probability scale showed the relationship of itraconazole therapy and the occurrence of acute hepatitis as probable. Itraconazole pulse therapy for onychomycosis appears to be at least as effective as and safer than a continuous treatment regimen, particularly from the perspective of potential liver damage. Only one case of severe symptomatic hepatitis occurring after pulse therapy with itraconazole for onychomycosis and requiring transplantation has been reported previously. In that case, as well as the one reported here, hepatitis symptoms occurred after completion of long-term treatment in patients who were asymptomatic both before and during therapy. Prolonged exposure to itraconazole, administered either continuously or intermittently, may precipitate severe and irreversible hepatotoxic events. Accordingly, careful monitoring of liver function parameters should be performed both during and after treatment when onychomycosis requires prolonged itraconazole administration, even in asymptomatic patients lacking apparent risk factors of hepatic injury.

Liver injury in long‐term methotrexate treatment in psoriasis is relatively infrequent

Methotrexate-induced liver damage in psoriasis has led to dermatologic guidelines that stipulate monitoring of liver injury by means of serial liver biopsies. Recent literature data suggest that methotrexate may be considerably less hepatotoxic than previously assumed. To evaluate prevalence and development of liver injury in methotrexate treated psoriasis. Retrospective chart review (1976-2005). Hundred and twenty-five patients (F58/M67; mean age 45.0, SD 12.7 years) received a median cumulative methotrexate dose of 2,113 mg (range 180-20 235) over a median period of 228 weeks (range 16-1763). Two hundred and seventy eight liver biopsies were analysed and 71% were classified as Roenigk grade I, 14% as Roenigk II, 14% grade IIIa, 2% grade IIIB and 2% grade IV. Liver injury was not associated with cumulative dose, weekly prescribed dose, age or duration of treatment. Obesity and diabetes were significant risk factors for liver injury. A total of 68 patients had multiple biopsies, 3% improved, 72% did not change and in 25% liver histology deteriorated. The majority of cases (84%) that progressed to Roenigk 2 had a cumulative dose of 1,500-6,000 mg. Methotrexate-related liver injury is less frequent than previously thought and mostly occurred at cumulative dose of <6,000 mg. Diabetes and being overweight are significantly correlated with liver injury.

Causes and risk factors for liver injury following bone marrow transplantation.

A retrospective study of pretransplantation risk factors predisposing to liver injury following bone marrow transplantation (BMT). Liver complications are a major cause of morbidity and mortality following BMT. Determination of the pretransplantation factors that are likely to lead to liver injury may allow earlier diagnosis after BMT and may possibly improve prognosis. Medical records of BMT patients were reviewed, and results of serial liver function tests and HBV/HCV serology during the pre- and posttransplantation 1-year period were noted. Presence of liver injury was defined as alanine aminotransferase levels twice the upper limit of normal. Forty-four allogeneic and 17 autologous BMTs, performed between 1990 and 2000, were analyzed in the study. One-year survival was 77% (34 of 44 patients) for allogeneic BMT and 52% (9 of 17 patients) for autologous BMT. Seventy-two percent (32 of 44) of allogeneic transplant recipients and 47% (8 of 17) of autologous transplant recipients had liver injury during the first year of BMT. The most frequent causes of liver injury were graft-versus-host disease and drug hepatotoxicity for allogeneic BMT and drug hepatotoxicity for autologous BMT. Fulminant hepatic failure occurred in one allogeneic transplant recipient who was a pretransplantation HBV carrier and led to death. Multivariate regression analysis showed that pretransplantation HBV/HCV positivity and pretransplantation elevated liver enzyme levels of any cause were predictive risk factors for post-BMT liver injury, and close follow-up, early diagnosis, and treatment are highly recommended for BMT patients with these risk factors.

Long term effects of phlebotomy on biochemical and histological parameters of chronic hepatitis C

OBJECTIVES: There is considerable evidence that iron is a risk factor for liver injury in chronic hepatitis C. Known as iron reduction therapy, phlebotomy reduces serum ALT activity. This effect might continue with maintenance phlebotomy and result in slower progression of liver fibrosis. METHODS: We examined the biochemical parameters and liver histology of patients with chronic hepatitis C treated by maintenance phlebotomy. For biochemical evaluation, 25 patients were treated by initial phlebotomy to reduce serum ferritin levels to 10 ng/ml or less and then observed for 5 yr with maintenance phlebotomy to maintain the iron-deficient state. For histological evaluation, liver biopsies were performed before and after the study period in 13 of the patients. Thirteen patients who were virological nonresponders to interferon alone and had undergone second liver biopsies after more than 3 yr served as histological controls. RESULTS: Serum aminotransferase levels were decreased significantly by initial phlebotomy and remained at the same levels during the study period ( p < 0.05). The grading scores were improved significantly in the study group ( p < 0.05) and unchanged in the controls. The staging scores remained unchanged in the study group but were increased in the controls ( p < 0.005). Disease progression was significantly different between the two groups ( p < 0.05). CONCLUSIONS: These results suggest that phlebotomy with maintenance lowers serum aminotransferase levels, improves liver inflammation, and suppresses the progression of liver fibrosis in chronic hepatitis C.

Role of non-alcoholic steatohepatitis in methotrexate-induced liver injury.

Hepatotoxicity, especially liver fibrosis, is the major concern with long-term, 'low-dose' oral methotrexate (MTX) therapy for psoriasis. The histological features are non-specific and resemble those of non-alcoholic steatohepatitis (NASH). Moreover, most of the risk factors of MTX-induced liver injury are also associated with NASH. In this study, we investigate whether NASH contributes to the prevalence and progression of MTX-induced liver injury in patients receiving MTX for psoriasis. Clinical details, including MTX dosage schedules and risk factors for liver injury, was documented for 24 patients on long-term MTX therapy for psoriasis. Serial liver biopsies were graded according to the Roenigk classification scale and a recently proposed grading and staging system for NASH. Thirteen of the 17 patients who had a NASH-like pattern of liver injury also had the risk factors for NASH obesity and/or diabetes, and all had progressive liver injury. The other four patients had no risk factors, but a mean cumulative dose of 6.5 g. Seven patients, who did not have a NASH-like pattern of injury, had a mean cumulative dose of 3.8 g. There was a positive correlation between the cumulative dose, risk factors and progression when the biopsies were scored by the modified grading and staging classification for NASH, but not with the Roenigk system. Non-steatohepatitis, probably aggravated by MTX, is an important cause of liver injury in patients on long-term, 'low-dose' MTX treatment for psoriasis. In addition, MTX alone can cause a NASH-like pattern of injury that is at least, in part, caused by a higher cumulative dose.