Drug-induced liver injury: Is chronic liver disease a risk factor and a clinical issue?

Introduction: Clinicians and practitioners caring for patients with chronic liver disease are often unsure whether drug therapy is a hazard that increases their patient’s risk for drug-induced liver injury (DILI).

Areas covered: We searched for reports of drug induced liver injury, both idiosyncratic and intrinsic, in patients with chronic liver disease including non-alcoholic and alcoholic liver disease, and cirrhosis. Reports we analyzed include statin treatment in patients with fatty liver, acetaminophen use in alcoholic fatty liver, antituberculous drugs in patients with tuberculosis and viral hepatitis, antiviral medications in hepatitis and antiretroviral medications in HIV/AIDS. The most challenging cases we found are drug therapy in patients with decompensated liver cirrhosis.

Expert opinion: We identified many case reports and case series discussing a potential increased risk of DILI in patients with pre-existing liver disease. However, most of these reports were retrospective and ambiguous. With few exceptions, we conclude that drugs seem to be well tolerated by the majority of patients with pre-existing, non-cirrhotic chronic liver diseases. Special care is needed for some therapies, however, including antiviral therapy in chronic hepatitis B and C and in decompensated liver cirrhosis with impaired drug metabolism. Prospective studies are warranted to valid our conclusions.     

Clomipramine N-demethylation metabolism in human liver microsomes

目的：研究ＣＹＰ４５０选择性抑制剂对体外氯米帕明（Ｃｌｏ）Ｎ去甲基代谢的影响．方法：应用米氏方程计算肝微粒体中ＣｌｏＮ去甲基代谢的动力学参数，比较加入抑制剂前后这些参数的改变．结果：Ｋｍ１，Ｋｍ２，Ｖｍａｘ１，Ｖｍａｘ２，Ｖｍａｘ１／Ｋｍ１和Ｖｍａｘ２／Ｋｍ２分别为（０１１±００６），（２４±１１）μｍｏｌ·Ｌ－１，（１１４±４７），（４２８±１８８）ｎｍｏｌ·ｇ－１·ｍｉｎ－１，（１８±１６）和（００１９±０００５）Ｌ·ｇ－１·ｍｉｎ－１．后四个参数的个体差异分别可达２５，７３，３４和１８倍．二硫卡钠（Ｄｉｔ）、美芬妥英（Ｍｅｐ）、呋拉茶碱（Ｆｕｒ）、醋竹桃霉素（Ｔｒｏ）和Ｆｕｒ＋Ｔｒｏ的抑制率分别为２７０％，３２９％，６３９％，６６４％和７８３％．Ｔｒｏ和Ｆｕｒ的ＩＣ５０分别为４２１和２７７μｍｏｌ·Ｌ－１．结论：人肝微粒体中存在高、低亲合力ＣｌｏＮ脱甲基酶．在低浓度下，ＣｌｏＮ去甲基代谢主要由ＣＹＰ３Ａ４和ＣＹＰ１Ａ２催化，其次由ＣＹＰ２Ｃ１９介导．     

Stereoselective metabolism of metoprolol in isolated rat liver

目的：研究美托洛尔光学异构体在离体大鼠肝灌流上的药物动力学的立体选择性差异．方法：美托洛尔光学异构体在离体大鼠肝灌流中作循环式灌流，用高效液相色谱法进行定量分析．结果：０１６，０３２和０６４ｍｇ三种不同剂量的美托洛尔光学异构体在离体大鼠肝脏中消除过程，经叠加原则认为不存在饱和机制，符合单室模型一级动力学过程，在三种剂量下，两种异构体间的动力学参数Ｔ１／２，Ｋ和Ｃｌ均存在着显著性差异（Ｐ＜００１），其Ｓ（－）Ｍｅｔ／Ｒ（＋）Ｍｅｔ的Ｃｌ比值为０１４－０１７．结论：离体大鼠肝脏对美托洛尔两种光学异构体的代谢具有立体选择性，其肝消除符合线性动力学过程．     

Which treatment for nonalcoholic fatty liver disease?

Subjects with nonalcoholic fatty liver disease are at risk of progressive liver failure. Lifestyle changes including weight-loss strategies and increased physical activity remain the first-line approach, but a few pharmacological treatments have also been successfully tested. Several drugs improve biochemistry, only a few improve histology; in all cases, the results were not sustained after treatment stop. Pharmacological treatment is not so far indicated outside controlled clinical trials with histological outcomes.     

Aluminum in liver cells – the element species matters

Abstract

Aluminum (Al) can be ingested from food and released from packaging and can reach key organs involved in human metabolism, including the liver via systemic distribution. Recent studies discuss the occurrence of chemically distinct Al-species and their interconversion by contact with biological fluids. These Al species can vary with regard to their intestinal uptake, systemic transport, and therefore could have species-specific effects on different organs and tissues. This work aims to assess the in vitro hepatotoxic hazard potential of three different relevant Al species: soluble AlCl₃ and two nanoparticulate Al species were applied, representing for the first time an investigation of metallic nanoparticles besides to mineral bound γ-Al₂O₃ on hepatic cell lines. To investigate the uptake and toxicological properties of the Al species, we used two different human hepatic cell lines: HepG2 and differentiated HepaRG cells. Cellular uptake was determined by different methods including light microscopy, transmission electron microscopy, side-scatter analysis, and elemental analysis. Oxidative stress, mitochondrial dysfunction, cell death mechanisms, and DNA damage were monitored as cellular parameters. While cellular uptake into hepatic cell lines occurred predominantly in the particle form, only ionic AlCl₃ caused cellular effects. Since it is known, that Al species can convert one into another, and mechanisms including ‘trojan-horse’-like uptake can lead to an Al accumulation in the cells. This could result in the slow release of Al ions, for which reason further hazard cannot be excluded. Therefore, individual investigation of the different Al species is necessary to assess the toxicological potential of Al particles.     

Unbound liver concentration is the true inhibitor concentration that determines cytochrome P450-mediated drug–drug interactions in rat liver

1.?In order to identify the best inhibitor concentration for the accurate prediction of magnitude of a hepatic cytochrome P450 (CYP)-mediated drug–drug interaction (DDI), the DDI between nifedipine, the CYP substrate probe, and fluconazole, ketoconazole, or ritonavir, the CYP inhibitors, in in situ rat liver perfusion system and rats were investigated.

2.?In in situ system, the intrinsic clearance (CLint) of nifedipine was decreased after co-infusion of the CYP inhibitors. The decrease in in situ CLint of nifedipine was most comparable to that in in vitro CLint in rat liver microsomes calculated by using the unbound liver concentrations of inhibitors ([I]liver,u). The ratios of unbound liver concentration to unbound hepatic vein concentration (Kp,uu) of ketoconazole and ritonavir were 4.0–8.0 and 18.4–21.1, suggesting a concentrative uptake of them into liver.

3.?In rats, the DDI effects of orally administered nifedipine with constant infusion of the inhibitors were investigated. The most accurate prediction of magnitude of DDI was achieved when [I]liver,u was applied as the inhibitor concentration.

4.?These results indicated that [I]liver,u is the most reliable inhibitor concentration for CYP-mediated DDI and it is necessary to consider the concentrative uptake of inhibitors into liver for the quantitative prediction of DDI.     

Single-agent immunosuppression after liver transplantation: what is possible?

Orthotopic liver transplantation is a life saving and life enhancing procedure. The development of immunosuppressive drugs has contributed to the high rate of success in terms of both patient and graft survival. However, the considerable adverse effects of these therapies are affecting long-term outcomes of transplant recipients. Complications related to immunosuppression are responsible for the majority of deaths in patients surviving more than 1 year. Therefore, the search for an optimal immunosuppressive regimen has become of paramount importance. The liver has proved to be an 'immunologically privileged' organ, capable in several animal models to be accepted as an allograft without any intervention on the immune system of the recipient. In some human liver allografts acceptance of the new organ is recognised after withdrawal of immunosuppressants, but prior identification of such individuals is not yet possible, thus negating this management option. Graft-recipient interaction is peculiar in liver transplantation: acute cellular rejection does not always need to be treated, and if it is not severe, appears to be associated with a better survival of both patient and graft. In the last decade there has been an evolution of immunosuppressive protocols, driven by empirical observation and a deeper understanding of immunological events after transplant. However, most modifications have been made because of the necessity to reduce long-term drug related morbidity and mortality. Withdrawal of corticosteroids has proven to be safely achievable in most patients, with no deleterious effects on patient or graft survival but with a great benefit in terms of reduction of incidence of metabolic and cardiovascular complications. Long-term 'steroid-free' regimens are therefore now widely used. Patients with stable graft function can be easily maintained using a single drug usually after 6 or 12 months and usually with a calcineurin inhibitor. The more evolved step of using monotherapy ab initio has also proven to be effective in a few studies and needs to be explored further. In the future new strategies will be designed to help the development of tolerance of the allograft, selectively stimulating instead of suppressing the immune reaction of the recipient.     

CYP3A activity in severe liver cirrhosis correlates with Child–Pugh and model for end-stage liver disease (MELD) scores

Aims

Impaired liver function often necessitates drug dose adjustment to avoid excessive drug accumulation and adverse events, but a marker for the extent of the required adjustment is lacking. The aim of this study was to investigate whether Child–Pugh (CP) and model for end-stage liver disease (MELD) scores correlate with drug clearance.

Methods

Midazolam was used as a CYP3A probe and its pharmacokinetics were analyzed in 24 patients with mild to severe liver cirrhosis (n = 4, 10 and 10 with CP class A, B and C, respectively) and six patients without liver disease.

Results

Both scores correlated well with unbound midazolam clearance (CL_u), unbound midazolam fraction and half-life (all P < 0.01), whereas the unbound steady-state volume of distribution was not significantly changed. In patients with severe liver cirrhosis unbound midazolam clearance was only 14% of controls (CP C: CL_u = 843 ± 346 l h⁻¹, MELD ≥ 15: CL_u = 805 ± 474 l h⁻¹, controls: CL_u = 5815 ± 2649 l h⁻¹, P < 0.01).

Conclusion

The correlation with unbound midazolam clearance suggests that either score predicts the metabolic capacity of CYP3A, the most relevant drug metabolizing enzyme subfamily in humans.     

Does therapeutic use of acetaminophen cause acute liver failure?

STUDY OBJECTIVE: To compare the reported occurrence of liver failure in subjects in prospective trials with that in patients in retrospective reports after repeated use of therapeutic dosages of acetaminophen. DESIGN: Systematic review of the medical literature. DATA SOURCE: MEDLINE and EMBASE biomedical and pharmacologic databases. SUBJECTS: Adults who received repeated dosing of acetaminophen 4 g/day or lower for at least 24 hours. MEASUREMENTS AND MAIN RESULTS: Articles written in several languages were abstracted by trained personnel using a structured abstraction form. Data were categorized by methodology (prospective vs retrospective), acetaminophen dosage, and type of liver effect. A total of 791 articles were identified, which included 30,865 subjects in prospective studies and 9337 patients in retrospective reports. The prospective studies reported no cases of fulminant hepatic injury, liver transplantation, or death due to acetaminophen. Of the 30,865 subjects in these studies, 129 (0.4%) were identified who had a serum aminotransferase level that exceeded the upper limit of normal, including 61 subjects in randomized trials in which the proportion of serum aminotransferase level increase was the same as or less than that in the placebo group and 68 subjects in trials without a placebo group. In addition, 4263 (13.8%) received the maximum recommended therapeutic dosage (3.9-4 g/day). In the retrospective reports, 96 patients (1.0%) had a serum alanine aminotransferase level that exceeded the upper limit of normal, one (0.01%) underwent liver transplantation, and six (0.06%) died. Causality relationship of acetaminophen for each retrospective case was assessed with the Naranjo adverse drug reaction probability scale. The mean +/- SD Naranjo score for all 103 retrospective cases was 3.2 +/- 1.9, indicating a possible relationship between the increased aminotransferase levels and acetaminophen use. Some retrospective reports contained information suggesting that the patient had ingested an overdose despite a history of therapeutic use. CONCLUSION: Prospective studies indicated that repeated use of a true therapeutic acetaminophen dosage may slightly increase the level of serum aminotransferase activity, but hepatic failure or death was not reported. Retrospective reports indicated a higher rate of increased serum aminotransferase levels, and several reported associated liver injury and death. The differing results and presence of evidence indicating inaccurate acetaminophen dosage information in some case reports suggests that these cases may be inadvertent overdoses, rather than true therapeutic dosages.     

Does arsenic exposure increase the risk for liver cancer?

Arsenic has been well documented as the major risk factor for development of blackfoot disease (BFD), a unique peripheral vascular disease that was once endemic to the southwestern coast of Taiwan, where residents imbibed artesian well water containing high concentrations of arsenic for more than 50yr. Long-term arsenic exposure has also been reported to be associated with increased incidence of liver cancer in a dose-responsive manner. A tap-water supply system was implemented in the early 1960s in the BFD endemic areas. Artesian well water was no longer used for drinking and cooking after the mid-1970s. The objective of this study was to examine whether liver cancer mortality rates were altered after the consumption of high-arsenic artesian well water ceased and, if so, when the reduction occurred. Standardized mortality ratios (SMRs) for liver cancer were calculated for the BFD endemic area for the years 1971-2000. Cumulative-sum techniques were used to detect the occurrence of changes in the SMRs. The study results show that mortality from liver cancer in females declined starting 9yr after the cessation of consumption of high-arsenic artesian well water. However, data show fluctuations in male liver cancer mortality rates. Based on the reversibility criterion, the association between arsenic exposure and liver cancer mortality is likely to be causal for females but not in males.     

Vasopressin in liver disease--should we turn on or off?

Arginine vasopressin is a naturally occurring peptide with established physiological functions acting as a vasoconstrictor through V1 receptors or an aquagenic agent allowing free water retention through V2 receptors in the kidney. Portal haemodynamic changes of chronic liver disease are responsible for the lethal consequences of cirrhosis--bleeding oesophageal varices and hepatorenal syndrome. Increasing hepatic vascular resistance to blood flow coupled with central hypovolaemia and a hyperdynamic circulation driven by changes in nitric oxide responsiveness disturbs the normal circulatory physiology raising portal pressure. Vasopressin and its analogues are potent vasoconstrictors and can be utilised in the management of the complications of cirrhosis. Hyponatraemia is common in end stage liver disease due in part to sodium retention and a decreased free water clearance. Diuretic therapy often leads to a worsening of the sodium status and have little true effect on improving free water clearance. Recently a new class of drugs, V2 receptor antagonists, have been evaluated in chronic liver disease whereby increasing free water clearance they may reduce ascitic fluid development. This review addresses the pharmacology of both vasopressin agonists and antagonists, their clinical application and future potential roles in managing patients with acute on chronic liver failure.     

Statins and nonalcoholic fatty liver disease: a bright future?

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease affecting up to 30% of adults in Western countries. NAFLD and mainly nonalcoholic steatohepatitis (NASH) are independent cardiovascular disease (CVD) risk factors; more of these patients are expected to die from CVD rather than from liver disease. The effect of statins on newer risk factors that may influence the pathobiology of liver damage in NASH is considered. These include microparticles, inflammasomes, gut–liver axis abnormalities and dietary lipids. Evidence suggests that statins induce NAFLD/NASH resolution and substantially improve symptom-free survival from CVD to a greater extent than in patients without NAFLD. However, large randomized clinical trials are needed to verify these findings.     

New therapeutic approaches to liver fibrosis: a practicable route?

The progress of research on the molecular pathogenesis of liver fibrosis and the consequent discoveries are likely to open new possibilities for therapeutic approaches to the management of this disease in the future. A key step towards this goal is a deeper comprehension of both the complex molecular and cellular mechanisms and the signaling involved in the development of hepatic fibrosis. It is not yet clear, in fact, what role apoptosis, cytokines, oxidants and other molecules play and what relationships exist between them in favouring or delaying the onset of these adverse mechanisms. At present, a unique mechanism is recognized to be the main reason for the cause and development of liver fibrosis: sustained hepatic stellate cell activation and transformation. Therefore, in this review, after considering the cause, development of fibrosis and interrelation between molecular and cellular profibrotic mechanisms, the part played in counteracting both of these actions by some anti-oxidants and anti-fibrotic molecules such as cytokines, prostacyclin and others will be taken into consideration. The gene therapy and the possible therapeutic use of liver stem cells and tissue engineering will also be dealt with briefly. At the moment, however, the efficacy of these novel strategies still needs to be further validated in animal studies and confirmed in clinical trials. Some data that are already available from in vitro and animal studies demonstrating the effectiveness of novel approaches to inhibiting or treating liver fibrosis can only offer moderate hope.