药物引起的急性肾功能衰竭

据卫生部药品不良反应监察中心报告 :我国近年来每年约有 19 2万人死于药物不良反应 ,药源性疾病的死亡人数已达到主要传染病死亡人数的 10倍以上。因此 ,药源性疾病日趋严重的情况应引起临床工作者的高度重视。在机体各个脏器中 ,肾脏是机体中对药物高积聚、高代谢、高排泄的主要脏器之一 ,故而肾脏对药物不良反应具有高度的易感性。目前已经发现的药源性肾脏疾病几乎包括了各种类型的肾脏疾病[1] ,其中 ,药物引起的急性肾衰竭由于发病急骤、临床表现复杂多样、已逐渐成为危害病人生命的主要药源性肾脏疾病之一。根据我院近 5年来 194例肾…     

Drug-induced acute liver failure: results of a U.S. multicenter, prospective study

Acute liver failure (ALF) due to drug-induced liver injury (DILI), though uncommon, is a concern for both clinicians and patients. The Acute Liver Failure Study Group has prospectively collected cases of all forms of acute liver failure since 1998. We describe here cases of idiosyncratic DILI ALF enrolled during a 10.5-year period. Data were collected prospectively, using detailed case report forms, from 1198 subjects enrolled at 23 sites in the United States, all of which had transplant services. A total of 133 (11.1%) ALF subjects were deemed by expert opinion to have DILI; 81.1% were considered highly likely, 15.0% probable, and 3.8% possible. Subjects were mostly women (70.7%) and there was overrepresentation of minorities for unclear reasons. Over 60 individual agents were implicated, the most common were antimicrobials (46%). Transplant-free (3-week) survival was poor (27.1%), but with highly successful transplantation in 42.1%, overall survival was 66.2%. Transplant-free survival in DILI ALF is determined by the degree of liver dysfunction, specifically baseline levels of bilirubin, prothrombin time/international normalized ratio, and Model for End-Stage Liver Disease scores. Conclusion: DILI is an uncommon cause of ALF that evolves slowly, affects a disproportionate number of women and minorities, and shows infrequent spontaneous recovery, but transplantation affords excellent survival.     

Drug-induced heart failure

Heart failure is a clinical syndrome that is predominantly caused by cardiovascular disorders such as coronary heart disease and hypertension. However, several classes of drugs may induce heart failure in patients without concurrent cardiovascular disease or may precipitate the occurrence of heart failure in patients with preexisting left ventricular impairment. We reviewed the literature on drug-induced heart failure, using the MEDLINE database and lateral references. Successively, we discuss the potential role in the occurrence of heart failure of cytostatics, immunomodulating drugs, antidepressants, calcium channel blocking agents, nonsteroidal anti-inflammatory drugs, antiarrhythmics, beta-adrenoceptor blocking agents, anesthetics and some miscellaneous agents. Drug-induced heart failure may play a role in only a minority of the patients presenting with heart failure. Nevertheless, drug-induced heart failure should be regarded as a potentially preventable cause of heart failure, although sometimes other priorities do not offer therapeutic alternatives (e.g., anthracycline-induced cardiomyopathy). The awareness of clinicians of potential adverse effects on cardiac performance by several classes of drugs, particularly in patients with preexisting ventricular dysfunction, may contribute to timely diagnosis and prevention of drug-induced heart failure.     

Flutamide-associated acute liver failure

The nonsteroidal antiandrogenic drug flutamide [4'-nitro-3'-(trifluoromethyl)isobutyranilide] is a safe and generally well-tolerated drug used for the treatment of prostate cancer. We describe the case of a 74-year-old male who developed life-threatening acute liver failure during flutamide therapy. Other causes of acute liver failure were appropriately ruled out and there was no evidence of active prostate cancer or liver metastases. The use of the Naranjo probability scale indicated a highly probable relationship between the development of acute liver failure and flutamide therapy. Severe liver dysfunction has been rarely documented in patients treated with flutamide, even though cases of fulminant liver failure have been described. A few cases have been reported also among patients with hirsutism being treated with flutamide. The mechanisms responsible for the occurrence of hepatotoxicity during treatment with flutamide are unknown. Mitochondrial dysfunction seems to be implicated. The potential of flutamide to act as a potent hepatotoxin should be borne in mind when treatment with this drug is being planned.     

儿童急性肝衰竭

儿童急性肝衰竭是一种以肝性脑病、黄疸、凝血障碍和腹水为主要表现的临床综合征,常导致多器官功能障碍,病死率较高,是重症医学面临的救治难题。由于儿童这个群体的特殊性,儿童急性肝衰竭和成人相比在定义、病因以及诊治过程中均有其独特性。近年来随着医学技术的发展,尤其是重症医学的发展使得急性肝衰竭的预后有所改善。儿童肝移植的发展也为儿童急性肝衰竭的治疗提供了更多的机会。     

Autoimmune acute liver failure: an emerging etiology for intractable acute liver failure

Diagnosis of acute onset autoimmune hepatitis (AIH) is the most challenging task because of atypical clinicopathological features. We examined the nature of acute onset AIH consisting of nonsevere, severe, and fulminant AIH based on our published data and other published papers, and propose how to diagnose and treat this intractable hepatitis. We analyzed clinical, biochemical, immunological, radiological, and histological features of acute onset AIH. Thirty percent of fulminant hepatitis was due to AIH and autoimmune acute liver failure (ALF) was not rare. The important characteristic of acute onset AIH is its histological, radiological, and clinical heterogeneity. Sometimes acute onset AIH develops into ALF in a sub-acute clinical course without appropriate diagnosis and treatment, and becomes resistant to immunosuppressive therapy and has poor prognosis. Unenhanced computed tomography (CT) often shows heterogeneous hypoattenuation in autoimmune ALF. The revised original scoring system (1999) performed better in patients with acute onset AIH than the simplified scoring system (2008). Liver regeneration from periportal progenitor cells to mature hepatocytes was impaired in ALF, resulting in resistance to immunosuppressive therapy. Precise histological evaluation (the presence of centrilobular necrosis/collapse) along with the revised original scoring system and CT findings of heterogeneous hypoattenuation after systematic exclusion of other causes 36 plays an important role in the diagnosis. The most important strategy for autoimmune ALF is to diagnose and treat acute onset AIH before its development into ALF. Liver transplantation should be considered before the occurrence of infectious complications in the case of fulminant liver failure.     

Renal failure in acute liver failure.

Renal failure develops in approximately 55% of all patients referred to specialized centres with acute liver failure. The renal failure may be secondary to the liver failure itself (and is termed the hepatorenal syndrome) or the renal failure may be a secondary insult that directly affects both liver and kidney alike (for example paracetamol overdose). The pathogenesis of the hepatorenal syndrome involves the development of a hyperdynamic circulation, with a lowering of renal perfusion pressure, the activation of the sympathetic nervous system, which renders the kidneys more susceptible to modest decreases in perfusion pressure, and increased synthesis of a variety of vasoactive mediators. These mediators can cause renal vasoconstriction, but more importantly they can also decrease the glomerular capillary ultrafiltration coefficient (Kf), thus causing a decline of glomerular filtration rate over and above that caused by renal vasoconstriction alone. The treatment of the renal failure in acute liver failure involves the optimization of renal haemodynamics and haemofiltration. Renal failure will always recover when there is recovery of liver function, and in the absence of a spontaneous hepatic recovery, liver transplantation will reverse the hepatorenal syndrome.     

Drug-induced liver disease

Opinion statement  

Drug-induced liver diseases

About 1000 drugs produced world-wide may lead to clinically relevant hepatotoxic reactions which are unpredictable at normal doses and occur at various frequencies. Among these are well established therapeutic drugs which have been in use for years or decades as well as newly introduced drugs, the number of which is steadily increasing. For the development of drug-induced liver disease, various pathogenetic mechanisms, many risk factors and variable latency periods are known. The histological picture may imitate practically all known non-toxic liver diseases from which toxic liver disease needs to be differentiated. Patients under drug therapy require regular medical follow-up with regard to the development of toxic liver disease since the prognosis is only good with early recognition and immediate withdrawal of the alleged drug. Specific therapeutic modalities to prevent toxic liver disease are limited to paracetamol overdosage which is treated by the application of N-acetylcysteine. For other drug-induced liver diseases characterised by a prolonged course, therapy with ursodeoxycholic acid or steroids may be helpful. When fulminant drug-induced liver failure occurs, liver transplantation is the therapy of choice with a better prognosis than a conventional therapy. Despite this therapeutic option more than 40 different drugs are known to have caused lethal forms of toxic liver disease. Physicians have therefore to be alert to early recognize drug-induced liver disease and to withdraw the drug at first suspicion of the diagnosis.     

Drug-induced liver disease

Drug-induced liver disease may account for between 10% and 50% of adult patients with elevated enzymes, especially in patients over age 50 years. It accounts for nearly 25% of patients with fulminant hepatic failure. Liver injury can be cytotoxic, cholestatic, or mixed. A variety of systemic manifestations can accompany drug-induced hepatotoxicity. Drug-induced liver disease can mimic autoimmune hepatitis or it can evolve to cirrhosis. It can also mimic veno-occulusive disorders. The plethora of herbal and traditional agents currently ingested by many people should always be considered in any patient with abnormal hepatic biochemistry.     

Drug-induced liver disease

Drug-induced liver injury (DILI), also known as hepatotoxicity, refers to liver injury caused by drugs or other chemical agents, and represents a special type of adverse drug reaction. It has been estimated that more than 600 drugs and chemicals have been associated with significant liver injury. Many previous reviews have focused on DILI pathogenesis or have outlined the clinical features of liver injury linked to different drugs. This article briefly touches on several areas that are potentially vexing for both the novice and cognoscenti, with the goal of guiding the consultant through one of the most challenging areas of hepatology.     

药物性肝病

药物性肝病是指由药物或其代谢产物引起的肝损害。迄今为止,可造成肝脏不同程度损害的药物多达800余种,几乎遍及各类药物。近年来,随着新药的不断开发与应用,该类疾病的发病率亦呈逐年上升趋势。药物性肝病约占黄疸住院患者的2%~5%,非病毒性肝炎的20%~50%。其发病为药物的内在毒性与宿主性别、遗传、免疫易感性等因素相互作用所致,目前仍缺乏特异性诊断指标。1发病机制肝脏对药物及其代谢产物的代谢作用主要分为第1相反应(也称为药物降解)和第2相反应(结合反应),前者包括对药物的氧化、还原和水解反应,多数药物被灭活,亦有变为活性或毒性产…     

Auxiliary liver transplantation for acute liver failure

BACKGROUND: In patients with acute liver failure (ALF) who fulfil criteria, liver transplantation is the only effective treatment which can substitute metabolic and excretory function of the liver. Auxiliary liver transplantation was developed because a significant minority of patients with ALF who fulfil transplant criteria can have a complete morphological and functional recovery of their liver. The favourable outcome reported in European series using auxiliary partial orthotopic liver transplantation (APOLT), the greater experience as well as the lessons from split liver and from living related donors have revived interest in this approach. In selected patients aged <40 years without haemodynamic instability, the use of ABO-compatible, non-steatotic grafts harvested from young donors with normal liver function can restore liver function and prevent the occurrence of irreversible brain damage. In the majority of cases the auxiliary graft is a right graft which is placed orthotopically after a right hepatectomy in the recipient. After standard immunosuppression, the recovery of the native liver is assessed by biopsies, hepatobiliary scintigraphy and computed tomography. When, on the basis of histological, scintigraphical and morphological data, there is evidence of sufficient regeneration of the native liver, immunosuppression can be discontinued progressively. Complete regeneration of the native liver can be observed in >50% of patients, who can be withdrawn from immunosuppression. Therefore the advantages of auxiliary transplantation seem to balance favourably with the potential inconvenience of this technique in selected patients.     

Viral hepatitis-related acute liver failure

OBJECTIVES: Viral hepatitis has previously been the major cause of acute liver failure (ALF) in the United States. We aimed to determine the incidence of viral hepatitis-related ALF and to compare the outcome and clinical and biochemical variables in patients with hepatitis A and B. METHODS: A total of 354 patients with ALF from multiple centers were screened for possible acute viral etiology. RESULTS: Forty-three patients (12.1% of all ALF cases) had acute viral hepatitis: hepatitis A (n = 16), hepatitis B (n = 26), and herpes simplex virus infection (n = 1). There was no difference between groups with regard to age, gender, body mass index, admission or peak coma grade, symptom duration, admission mean arterial pressure, temperature, or biochemical liver tests, creatinine, arterial pH, or rate of infections. Platelet count was significantly higher in hepatitis A patients than in hepatitis B patients. The transplantation-free (spontaneous) survival rate was significantly higher for hepatitis A patients (69%) than for hepatitis B patients (19%, p = 0.007), whereas the liver transplantation rate was higher in hepatitis B patients (62%) than in hepatitis A patients (19%, p = 0.017). Spontaneous survivors had significantly higher mean arterial pressure, higher platelet count, and lower AST/ALT ratio than patients who did not survive spontaneously. CONCLUSIONS: Viral hepatitis now comprises only one-eighth of all ALF cases in the United States. The marked difference in spontaneous survival between hepatitis A and B cannot be explained by the severity of hepatic dysfunction on admission but may rather be an inherent feature of the infections or a bias toward transplanting patients with hepatitis B.     

Etiologies of acute liver failure

Acute liver failure is present when any type of rapid-onset liver insult results in a common systemic pathophysiologic picture: altered mental status, vasodilation, renal and pulmonary failure, frequent infection, and poor outcome without transplantation. Identifying which of the many different causes is a first step in understanding prognosis and options for treatment. However, identifying the correct cause can be difficult and sometimes impossible. Any discussion of etiologies must take a historical perspective; there have been several evolving trends nationally and internationally over the past three decades. Etiologies also vary worldwide with considerable differences apparent between Western countries and the developing world. In Europe and North America a large proportion of cases are due to acetaminophen and to idiosyncratic drug reactions, whereas reports from emerging countries in Asia and Africa feature viral illnesses, particularly hepatitis B and E. Determining etiology is important for two reasons: specific antidotes or therapies may be indicated once the diagnosis is known, and knowing the cause provides a reasonably valid guide to predicting outcome.     

Thrombopoietin in acute liver failure

Thrombopoietin (TPO) is the primary regulator of platelet production. TPO is produced in the liver and levels are low in patients with cirrhosis. Because thrombocytopenia is common in patients with acute liver failure (ALF), we measured TPO concentrations (normal TPO range, 31 to 136 pg/mL) in 51 patients with ALF to determine if low levels were associated with thrombocytopenia. TPO levels from hospital day 2 were elevated in 43% of patients, normal in 47%, and decreased in 10% of patients. Levels were higher in acetaminophen-induced than in non-acetaminophen-induced ALF, 160 (12 to 549) pg/mL versus 73 (18 to 563) pg/mL, respectively, P =.031. TPO levels did not correlate with platelet count and were not related with survival or infection. We analyzed daily TPO levels for the first week of hospitalization in 12 patients with acetaminophen-induced ALF and observed a gradual increase from a median admission level of 50 (5 to 339) pg/mL to a median peak level of 406 (125 to 1,081) pg/mL occurring on day 5 (3 to 6). Platelets were reduced in 11 of the 12 patients with a nadir platelet count of 52 (19 to 156) x 10(9) cells/L occurring on day 5.5 (1 to 6). The peak TPO level did not correlate with the nadir platelet count (P =.43). In conclusion, the normal inverse relationship between platelet count and TPO levels was not observed in ALF. Despite severe hepatic dysfunction, serum TPO levels were initially normal and increased during hospitalization in acetaminophen-induced ALF, but did not prevent the development of thrombocytopenia.