Drugs and the liver

The liver is a major organ with multiple functions. A number of drugs are metabolized by the liver during phase 1 and 2 reactions which include complex processes involving cytochrome P450 enzymes. Genetic and acquired variability in cytochrome P450 activity may have profound effects on pharmacokinetics. Additionally, drugs can also modify how the liver functions and cause dysfunction or even failure of the organ both by a direct effect on the liver or by alteration in liver blood flow. It is important to recognize the signs and symptoms of liver failure in patients and identify possible causes including drug interactions. Furthermore, once a patient has been recognized to be suffering with liver dysfunction or failure drug choice and dosing regime will need to be rationalized.Paracetamol overdose can have severe and life-threatening consequences for patients due to its effect on liver function. It is the leading cause of acute liver failure in the UK,¹ Correct and early management is crucial and will be discussed within this article.     

Drugs and the liver

The liver is a major organ with multiple functions. A number of drugs are metabolized by the liver during phase 1 and 2 reactions which include complex processes involving cytochrome P450 enzymes. Genetic and acquired variability in cytochrome P450 activity may have profound effects on pharmacokinetics. Additionally, drugs can also modify how the liver functions and cause dysfunction or even failure of the organ both by a direct effect on the liver or by alteration in liver blood flow. It is important to recognize the signs and symptoms of liver failure in patients and identify possible causes including drug interactions. Furthermore, once a patient has been recognized to be suffering with liver dysfunction or failure drug choice and dosing regime will need to be rationalized.Paracetamol overdose can have severe and life threatening consequences for patients due to its effect on liver function. It is the leading cause of acute liver failure in the UK,¹ Correct and early management is crucial and will be discussed within this article.     

供受体CYP3A5基因多态性与肝移植患者术后他克莫司浓度/剂量比的关系

目的研究肝移植供、受体CYP3A5基因多态性对受者术后他克莫司浓度/剂量比的影响。方法研究对象为2009年2月至6月期间在中山大学附属第三医院肝移植中心接受肝移植手术的32例受者及其对应供体。记录患者术后1周、2周、4周、12周他克莫司用量,并测定相应时间点的他克莫司谷浓度值,计算他克莫司浓度/剂量比。采用聚合酶链反应-限制性内切酶片段长度多态性方法对肝移植供、受体进行CYP3A5基因分型,比较不同基因型对受者术后他克莫司浓度/剂量比的影响。结果供、受者基因型分布比较差异均无统计学意义（P〉0.05）。CYP3A5＊3等位基因总发生频率为76%（97/128）,CYP3A5＊1等位基因总发生频率为24%（31/128）。受者术后2、4、12周他克莫司浓度/剂量比与供体CYP3A5基因型明显相关,与供体为携带＊3/＊3基因型的受者比较,供体为＊1/＊1和＊1/＊3基因型的受者该值明显降低,比较差异有统计学意义（均为P〈0.05）,后两者比较差异无统计学意义（P〉0.05）。术后1、2、4、12周,不同CYP3A5基因型受体的他克莫司浓度/剂量比比较,差异均无统计学意义（均为P〉0.05）。结论供体CYP3A5基因多态性是影响肝移植术后患者他克莫司血药浓度的重要遗传因素。供体携带＊1等位基因,其受者需更高剂量他克莫司才能达到目标血药浓度。     

Hepatocellular metabolic change after orthotopic liver transplantation in rats

The hepatocellular metabolic change after liver transplantation following 2 hr cold ischemia was investigated. Of 55 orthotopic liver transplantations in male Wistar rats, 47 animals were sacrificed at 3 hr, and 1, 2, 7 and 30 days to determine hepatic metabolite levels, in the form of adenine nucleotides, lactate and glycogen. Using the other 8 recipients, biochemical examinations were done at 1, 3, 5, 7, 30 and 60 days and metabolic levels estimated at 60 days. The SGOT and SGPT levels decreased gradually after a remarkable increase on the first postoperative day, while the alkaline phosphatase level revealed a peak value at 30 days. All levels recovered to within the normal range in 60 days. The total adenine nucleotide level reached the normal range within 3 hr following the blood reflow and remained at a normal level thereafter. However, all the metabolic levels apart from total adenine nucleotides deteriorated to reach their worst level at 7 days. The results of this investigation indicate that the posttransplanted deterioration of metabolic levels were possibly caused by the imperfect oxygenation due to cellular edema after blood reflow. However, the levels of these metabolites recovered within 60 days after transplantation.     

Long‐term outcome following liver transplantation for paracetamol overdose

Paracetamol overdose (POD) is a major cause of acute liver failure (ALF) requiring liver transplantation in the United Kingdom. To characterize the early and late outcome after orthotopic liver transplantation (OLT) for POD in the Scottish Liver Transplant Unit over a 14‐year period (1992–2006). Data were obtained from a prospective database combined with case‐note review. Of 127 liver transplants performed for ALF, 44 were for POD. The median age was 30 (range 18–51). In 18 patients (63.7%), POD was associated with alcohol/other drugs, nine (20.5%) had a staggered overdose and four patients (9.1%) accidentally overdosed. Nineteen patients (43.2%) had a history of previous overdose/psychiatric illness. Post‐transplant mortality during the index admission was 30% (13 patients), whilst five patients died during follow‐up. The actuarial 5‐year patient survival was 54.5%, whilst graft survival was 49.5%. Some 23% of the patients were re‐transplanted: primary nonfunction (1), hepatic artery thrombosis (3) and chronic rejection (2). Three patients had a subsequent transplant; three patients had two further transplants. Nine patients (35%) continue to have social/psychiatric issues. OLT for POD is associated with significant early and late morbidity and mortality. A multidisciplinary approach is required to identify the suitable candidates, in whom transplantation should be pursued promptly.     

体外生物人工肝系统对暴发性肝衰竭兔的支持作用

目的探讨培养肝细胞用于生物人工肝及其作为肝移植辅助支持手段的可能性。方法以培养人肝细胞和中空纤维反应器为主要材料构成体外生物人工肝系统,对Ｄ-氨基半乳糖诱导的暴发性肝衰竭（ＦＨＦ）免进行人工肝支持实验。结果尽管两组实验动物的存活时间没有明显差异,但支持治疗组兔的血清转氨酶、总胆红素和肌酐水平均低于对照组,肝组织病理检查见肝细胞坏死程度明显轻于对照组,实验所用肝细胞保持较好的活力和贴壁能力。结论所用体外生物人工肝支持系统已发挥出培养肝细胞的生物作用,能够部分代偿ＦＨＦ兔的肝脏功能。【关键词】##4人工肝;;支持;;暴发性肝衰竭;;兔     

Acute liver failure

Acute liver failure (ALF) is a rare but life-threatening disease with varying aetiologies worldwide. Drug-induced liver injury, including paracetamol poisoning, is the main cause in Europe and the USA. Whereas in the developing world, viral hepatitis is most common. ALF is a multisystem illness that leads to development of hepatic encephalopathy, cerebral oedema, vasodilatory shock, coagulopathy, hypoglycaemia and multiple-organ failure. Early referral to a specialist liver unit is essential. The core principles of ALF management are to identify/treat the underlying cause, provide supportive care and treat any complications. Optimal management will allow time for spontaneous liver regeneration or liver transplantation, and result in improved survival rates. This article provides an overview of the key concepts in ALF diagnosis and management.     

Paracetamol-induced fulminant hepatic failure in a child after 5 days of therapeutic doses

We report the case of a two and a half year-old girl who developed fulminant hepatic failure following 5 days of regular oral ingestion of paracetamol, approximately 90 mg x kg-1 x day-1. She presented with the typical findings of hepatomegaly, encephalopathy, high ammonia levels, high transaminases, hypoglycaemia and lactic acidosis. After stabilization, she was transferred to a specialist paediatric liver failure unit and fortunately she made a full recovery with intensive medical management.     

Relationship of deranged energy metabolism in liver and kidney to arterial ketone body ratio following liver ischemia in rats

Changes in energy metabolism in the liver and kidney in liver ischemia induced in rats were simultaneously studied, in terms of energy charge (EC) and mitochondrial oxidoreduction state. Mean arterial blood pressure, glucose and lactate, total ketone bodies (acetoacetate+β-hydroxybutyrate) and the ketone body ratio in arterial blood (KBR) were also investigated. During and after liver ischemia, both organs showed similar patterns of reversibility, and KBR, which reflects the mitochondrial oxidoreduction state, correlated well with EC, in both organs. Referring to the mortality and changes in substrates above mentioned, KBR is a pertinent parameter for detection of viability following induced liver ischemia. It was also suggested that KBR may indicate a regulation role by the liver, in kidney energy metabolism.     

细胞色素酶CYP3A4基因多态性研究进展

背景 药物代谢酶的基因多态性是导致药物在体内处置和反应存在明显个体差异的重要因素之一,而细胞色素酶P450家族的CYP3A4 (cytochrome P450 3A4)酶是药物及外源性物质的主要代谢酶.CYP3A4基因多态性是导致这些药物代谢个体差异的主要原因.目的 就CYP3A4基因多态性对药物代谢的影响作一综述.内容 CYP3A4主要分布于肝脏和小肠内,其基因结构、酶活性的个体差异以及遗传多态性的种族差异,是导致药物作用和副作用个体差异的主要原因,甚至与许多疾病包括肿瘤等的发病有关.趋向 对CYP3A4基因多态性的研究将有助于提高药物疗效,避免副作用发生,预防和治疗某些疾病尤其是肿瘤等疾病.     

Propofol inhibits lidocaine metabolism in human and rat liver microsomes

Purpose.When two drugs are metabolized by similar P450 isoforms, one drug inhibits the metabolism of the other when both the present. The metabolism of lidocaine and propofol can be mediated by similar P450 isoforms. Therefore, we investigated the relationship in the metabolism between lidocaine and propofol in both rat and human liver microsomal P450 (CYP) systems in vitro. Methods.(1) Propofol, 4µg·ml^–1, as the substrate and lidocaine (between 0.5 and 8µg·ml^–1) and (2) lidocaine, 4.7µg·ml^–1, as the substrate and propofol (between 0.5 and 40µg·ml^–1) were reacted separately with human and rat microsomes. The concentrations of lidocaine, its major metabolite (monoethylglycinexylidide, MEGX) and propofol were measured using high-pressure liquid chromatography. The metabolism of lidocaine was presented as a reaction activity (MEGX/lidocaine). Results.The dose-dependent inhibitory effects of propofol on lidocaine metabolism were observed in both the human and rat groups. The IC50 (the concentration producing 50% maximal inhibition) of propofol was 5.0µg·ml^–1 and 0.70µg·ml^–1 in the human and the rat groups, respectively. The propofol concentration of 5.0µg·ml^–1 is within the range of clinical doses for humans. On the other hand, lidocaine did not change propofol metabolism. Conclusion.Propofol possesses a dose-dependent inhibitory effect on the metabolism of lidocaine in both human and rat CYP systems in vitro.     

肝移植受者CYP3A5基因多态性对他克莫司血药浓度与剂量比值的影响

目的 研究CYP3A5基因多态性对肝移植受者术后他克莫司血药浓度与剂量比值（C/D比值）的影响.方法 选取2011年1月至2012年12月在上海交通大学医学院附属仁济医院肝脏外科接受原位肝移植术的86例受者,记录其术后1,2周和1,2,3,6个月他克莫司剂量,并测定相应时间点的他克莫司血药谷浓度,计算他克莫司C/D比值.检测肝移植受者CYP3A5基因多态性,观察不同基因型对他克莫司C/D比值的影响.结果 86例受者中,5例为CYP3A5＊1/＊1型（5.8%）,38例为CYP3A5＊1/＊3型（44.2%）,43例为CYP3A5＊3/＊3型（50%）.受者术后1,2周和1,2,3个月他克莫司C/D比值与CYP3A5基因型明显相关,携带CYP3A5＊1等位基因受者的C/D比值低于CYP3A5＊3/＊3型受者,差异有统计学意义（P〈0.05）.结论 CYP3A5基因多态性是影响肝移植受者术后他克莫司血药浓度的重要遗传因素.CYP3A5＊1/＊1型和CYP3A5＊1/＊3型受者需要比CYP3A5＊3/＊3型受者服用更高剂量的他克莫司才能达到相似的血药浓度.用药前检测受者基因型可以更有效地对他克莫司进行剂量调整.     

Artificial liver: Review and Cedars-Sinai experience

During the past decade, whole organ transplantation has become the only clinically effective method of treating fulminant hepatic failure and chronic liver failure due to specific genetic, hepatocellular, and anatomic defects of liver function. However, wider application of liver transplantation is restricted by shortage of organ donors, high cost, relatively high morbidity, and need for life-long immunosuppression. As a result, investigators have attempted to develop alternative methods to treat liver insufficiency. These ranged from use of plasma exchange to utilization of detoxification columns and extracorporeal devices loaded with various liver tissue preparations. Recently, advances in hepatocyte isolation and culture techniques, improved understanding of hepatocyte-matrix interactions, availability of new biomaterials, improved hollow-fiber technology, and better understanding of flow and mass transport across semipermeable membranes have resulted in the development of a new generation of liver assist devices. Some of these devices, including the one developed by the authors, are currently being tested in the clinical setting. In this paper, the past experience with liver support systems is reviewed, the present status of the field is critically examined, and the results of a phase I clinical trial with the bioartificial liver, utilizing primary porcine hepatocytes, are summarized. Received for publication on Feb. 2, 1998; accepted on Feb. 2, 1998     

Fulminant hepatic failure post liver transplantation: clinical syndromes,correlations and outcomes

This paper reports the clinical syndrome of fulminant hepatic failure (FHF) following liver transplantation. FHF was defined as the sudden onset of liver failure [encephalopathy and prolonged International Normalised Ratio (INR)] without arterial thrombosis in the setting of a liver allograft. FHf post-transplant was seen in 8/154 (5.2%) adult patients undergoing transplantation. These eight patients developed a clinical syndrome characterised by: (a) a rapid rise in ALT levels to above 1000 U/l (mean maximum 1600 U/l), (b) a sudden increase in the INR to above 5 (mean maximum 5.6), (c) the development of high fever, (d) the persistence of thrombocytopenia (mean nadir 40×10⁹/dl), (e) a progressive rise in the bilirubin (mean maximum 400 mol/l) and (f) the development of hepatic encephalopathy. In seven cases this syndrome occurred following good initial graft function at day 6 post (mean)-transplant. In one case the above syndrome developed immediately after liver transplantation. Four of the eight patients developed multiorgan failure associated with systemic acidosis (mean pH 6.84). All of these patients died (mean day 11). Four patients developed systemic alkalosis. Two of these four patients underwent successful retransplantation (on days 12 and 13) and remain alive at a mean of 11 months post-transplant. Six of the eight patients received OKT3 therapy without any apparent affect on clinical outcome. Compared to a control group of patients (n=28), 2/8 versus 2/28 had a positive crossmatch with donor lymphocytes (P=NS), 1/8 versus 7/28 were ABO-non-identical (P=NS), 3/8 versus 10/21 had total MHC mismatches (P=NS) and 5/7 versus 6/16 had UW ischemic times above 10 h (P=NS). No patients had main hepatic artery thrombosis on angiography although four patients had evidence of intrahepatic microthrombi or arterial necrosis at autopsy. In all cases the histology showed massive haemorrhagic necrosis. Three cases had evidence of veno-occlusive lesions whilst foam cell arteriopathy was seen in two cases. Immunofluorescence was performed in three cases. In two cases there was evidence of immunoglobulin, complement and fibrin deposition in blood vessels. In conclusion, we describe an uncommon clinical syndrome occurring post liver transplant. This syndrome represents humorally mediated allograft rejection but there seems to be no relationship with tissue matching (antibody, ABO, MHC) or donor ischaemic times. If recognised earlier in the absence of multiorgan failure, urgent retransplantation seems to be the only effective therapy.     

Changes in liver regenerative factors in a case of living-related liver transplantation

Liver regeneration in a patient with fulminant hepatic failure (FHF) who underwent living-related partial liver transplantation (LRLT) was investigated regarding hepatic growth factors. The patient was a 16-yr-old Japanese male who developed severe subacute FHF. LRLT was performed using an extended left lobe of the ABO matched patient's mother. In the recipient, the pre-transplant levels of both plasma hepatocyte growth factor (HGF) and transforming growth factor (TGF)-beta were extremely high and rapidly decreased following the liver replacement. The liver volume evaluated using a CAT scan increased 195% after 2 wk in graft liver and 110% after 2 wk in the hepatectomized donor. The explanted liver (FHF liver), the liver from donor (normal liver), and the graft liver [the 3rd post-transplant day (POD 3)] were all investigated immunohistochemically. FHF liver: No liver regeneration was observed [proliferative cell nuclear antigen (PCNA) labeling index (L.I.): 0%]. In the liver, both HGF in the hepatocytes and c-met on the membrane of the hepatocytes were positive. TGF-beta was positive in the hepatocytes and no apoptosis was detected by the TUNEL method. Donor liver (POD 0): Few PCNA stained hepatocytes were detected. No HGF was detected but c-met was clearly detected on the cell membrane of the hepatocytes. Neither TGF-beta nor apoptosis was detected. Graft liver (POD 3): The PCNA L.I. was conspicuous at 40%. HGF was positive in non-parenchymal cells and c-met was positive in the cytoplasm of the hepatocytes. TGF-beta was negative while apoptosis was positive in the zone 3 hepatocytes. In conclusion, these findings suggested that the liver of the patient with FHF did not respond to liver regenerative stimulus, in part, through involvement of inhibitor TGF-beta. On POD 3, the transplanted graft was in a vigorous regenerative status in comparison to that in the hepatectomized donor. The HGF/c-met system is thought to be involved in the mechanism of regeneration. Intrahepatic apoptosis was detected in the graft on the 3rd post-transplant day probably due to transient ischemia in the liver, which was not related to the Fas/Fas-ligand system.     

Xenobiotic metabolism, genetic polymorphisms and male infertility

Male reproductive function may be impaired by various occupational and environmental chemical agents. The majority of these xenobiotics, however, require metabolic activation in order to exert adverse effects via covalent interactions between intermediate metabolites and cellular macromolecules such as DNA or protein. In addition, metabolization may alter endocrine-disrupting properties of xenobiotics. Thus tissue-specific expression and regulation of multiple xenobiotic-metabolizing enzymes are likely to play an important role in chemically induced disorders of male reproductive organs. Recent studies suggest that genetic polymorphisms underlying inter-individual and inter-ethnic variability of xenobiotic metabolism modulate susceptibility to male reproductive disorders. For cytochrome P450 1A1 (CYP1A1), a key enzyme in extra-hepatic metabolic activation of lipophilic xenobiotics, increased frequencies of two genetically linked polymorphisms have been found among infertile men.     

Bioartificial liver support devices: historical perspectives

Fulminant hepatic failure (FHF) is an important cause of death worldwide. Despite significant improvements in critical care therapy there has been little impact on survival with mortality rates approaching 80%. In many patients the cause of the liver failure is reversible and if short-term hepatic support is provided, the liver may regenerate. Survivors recover full liver function and a normal life expectancy. For many years the only curative treatment for this condition has been liver transplantation, subjecting many patients to replacement of a potentially self-regenerating organ, with the lifetime danger of immunosuppression and its attendant complications, such as malignancy. Because of the shortage of livers available for transplantation, many patients die before a transplant can be performed, or are too ill for operation by the time a liver becomes available. Many patients with hepatic failure do not qualify for liver transplantation because of concomitant infection, metastatic cancer, active alcoholism or concurrent medical problems. The survival of patients excluded from liver transplantation or those with potentially reversible acute hepatitis might be improved with temporary artificial liver support. With a view to this, bioartificial liver support devices have been developed which replace the synthetic, metabolic and detoxification functions of the liver. Some such devices have been evaluated in clinical trials. During the last decade, improvements in bioengineering techniques have been used to refine the membranes and hepatocyte attachment systems used in these devices, in the hope of improving function. The present article reviews the history of liver support systems, the attendant problems encountered, and summarizes the main systems that are currently under evaluation.     

Continuous peritransplant assessment of consciousness using bispectral index monitoring for patients with fulminant hepatic failure undergoing urgent liver transplantation

Hwang S, Lee SG, Park JI, Song GW, Ryu JH, Jung DH, Hwang GS, Jeong SM, Song JG, Hong SK, Lim YS, Kim KM. Continuous peritransplant assessment of consciousness using bispectral index monitoring for patients with fulminant hepatic failure undergoing urgent liver transplantation.
Clin Transplant 2010: 24: 91–97. © 2009 John Wiley & Sons A/S. Abstract: Background: Rapid deterioration of consciousness is a critical situation for patients with fulminant hepatic failure (FHF). Bispectral (BIS) index was derived from electroencephalography parameters, primarily to monitor the depth of unconsciousness. Aim: To assess the usability of peritransplant BIS monitoring in patients with FHF. Methods: A prospective study using peritransplant BIS monitoring was performed in 26 patients with FHF undergoing urgent liver transplantation (LT). Results: Pre‐transplant Child‐Pugh score was 12.2 ± 1.0; model for end‐stage liver disease score was 32.4 ± 4.4; Glasgow coma score (GCS) was 9.9 ± 1.3; and BIS index was 44.0 ± 6.7. Pre‐transplant sedation significantly decreased BIS index. After LT, all patients having endotracheal intubation recovered consciousness within one to three d and showed progressive increase in BIS index, which appeared slightly earlier and was more evident than the increase in derived GCS score. There was a significant correlation between BIS index and derived GCS scores (r² = 0.648). Timing of eye opening to voice was matched with BIS index of 66.3 ± 10.4 and occurred 12.7 ± 8.3 h after passing BIS index of 50. Conclusion: These results suggest that BIS monitoring is a non‐invasive, simple, easy‐to‐interpret method, which is useful in assessing peritransplant state of consciousness. BIS monitoring may therefore be a useful tool during peritransplant intensive care for patients with FHF showing hepatic encephalopathy.