Pre-existing Liver Dysfunction Research Articles

High voriconazole trough levels in relation to hepatic function: how to adjust the dosage?

High voriconazole trough levels in relation to hepatic function: how to adjust the dosage?

Part II: Liver function in oncology: towards safer chemotherapy use

The liver is fundamentally important in drug metabolism. In oncology, the astute clinician must not only understand the meaning and limitations of commonly ordered liver biochemical tests, but also be aware of which anticancer agents might induce liver dysfunction, and of the strategies for appropriate dosing of patients with pre-existing liver dysfunction. In part I of our Review, we highlighted both the importance and inadequacies of identifying serum biochemical liver abnormalities in oncology; we also discussed a lack of routine formal investigation of liver function. We summarised chemotherapy-related hepatotoxicity and other causes of liver toxic effects in patients with cancer. Here in part II, we discuss trials that have specifically assessed chemotherapy dosing strategies in the setting of overt biochemical liver dysfunction and we note their recommendations. Furthermore, we review other assessments of liver metabolic and excretory function, particularly in the setting of chemotherapy drug handling. We discuss the potential use of these metabolic probes in practice.

Darunavir en la coinfección por VIH/VHB y/o VHC

Darunavir/ritonavir is indicated in combination with other antiretroviral drugs for the treatment of HIV-1 infection in pre-treated adult patients. In hepatitis B or C co-infected patients, the virological response rate to darunavir/ritonavir appeared to be unaffected and, except for increased liver enzymes, the incidence of adverse events was not higher than in patients without co-infection. Drug-induced hepatitis has been reported in 0.5% of patients receiving combination therapy with darunavir/ritonavir. Patients with pre-existing liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities including severe hepatic adverse events. Therefore AST/ALT monitoring should be considered in patients with underlying chronic hepatitis, (HVB/HCV) like it is recommended in all patients receiving boosted PIS. Darunavir is primarily metabolized by the liver. The steady-state pharmacokinetic parameters of darunavir are similar in patients with normal liver function, mild hepatic impairment (Child-Pugh Class A), and moderate hepatic impairment (Child-Pugh Class B). The effect of severe hepatic impairment on the pharmacokinetics of darunavir has not been evaluated. No dose adjustment is required in patients with mild or moderate hepatic impairment. There are no data on the use of darunavir in patients with severe hepatic impairment and consequently this drug is not recommended in this group of patients.

Metabolic Issues in Liver Transplantation

Patients who undergo orthotopic liver transplantation (OLT), almost by definition, have end-stage liver disease. One cannot examine the metabolic changes observed during OLT without insight into the profound effects of preexisting liver dysfunction. Because the liver plays a central role in regulation of whole-body metabolism, its disease leads to major alterations in glucose metabolism. Most patients presenting for OLT have chronic liver disease which has gradually progressed to the point where replacement surgery is indicated. The endocrine and metabolic changes associated with chronic cirrhosis are well described. A small subset of patients presents for OLT with fulminant liver failure which may or may not have been preceded by chronic liver disease. Evidence describing metabolic alterations of patients with fulminant disease, because of its unstable nature, is much less complete than that for patients with chronic disease. Many of the underlying endocrine and metabolic alterations are exacerbated by the OLT procedure itself. After OLT, full normalization of glucose metabolism is delayed and corrects in stages. Certain primary inherited diseases (‘‘inborn errors’’) of metabolism, which can be corrected by OLT, present unique issues that are beyond the scope of this review. Patients with end-stage liver disease exhibit disturbances in lipid, amino acid, and protein metabolism; and also poor clearance of drugs whose elimination or biotransformation depends on hepatic function. However, these subjects are also outside of the scope of the present review. This review focuses on the intertwined derangements of glucose metabolism, acid-base balance, and serum electrolyte concentrations that appear in patients before OLT, then describes changes which occur intraoperatively and persist in the postoperative setting. The endocrine environment that in part mediates the metabolic response is presented first.

Esophageal Perforation: Principles of Diagnosis and Surgical Management

Esophageal perforation (EP) is still associated with a high mortality rate, even after surgical repair. We reviewed 17 cases of EP to evaluate the management of this major surgical problem. We reviewed the medical records of all patients treated for EP in our department between November 2001 and November 2004. Therapy was based on various patient-related factors. Seventeen patients, with a mean age of 63 years, presented with EP mostly caused by iatrogenic incidents (11/17). In nine patients, the perforation was located in the thoracic segment, with a mean size of 2.5 +/- 0.6 cm. Thoracic computed tomography (CT) was performed in all patients to assess the periesophageal inflammation precisely. More than 50% showed signs of systemic inflammation indicative of sepsis, reflected by a dramatic increase in serum C-reactive protein and leukocytosis. Treatment consisted of debridement and drainage (n = 3), primary repair (n = 3), reinforced repair (n = 4), esophageal resection (n = 5), and conservative measures (n = 2). All patients, except for three with pre-existing liver dysfunction and other comorbidities, survived, representing a mortality rate of 17.6% (14/17). An analysis of the literature (2000-2005) revealed an overall mortality rate of 19.7% (101/521), ranging from 3% to 67%. Our data support the individualized surgical management of EP, based on careful evaluation of various patient-related factors, including CT findings.

わが国における<I>Vibrio vulniificus</I>感染症患者誌上調査

Vibrio vulnificus is found globally in marine coastal waters. Infection with this organism, via ingestion of raw shellfish or exposure to marine water, can cause necrotizing fasciitis and sepsis, which have high mortality and short latency. In Japan, many cases have been reported since 1980, mainly from hospitals in western prefectures. However, because of the sporadic nature of infection outbreaks, a thorough epidemiologic survey has not been done. We studied the epidemiological and clinical characteristics of Vibrio vulnificus infections reported in Japan from 1975 to 2005. We identified 185 cases using the medical article search engines Ichushi (Japan Medical Abstracts Society), CiNii (Citation Information by National Institute of Informatics), and PubMed over 30 years. The median age of patients was 59. The number of male patients was eight times the number of female patients; however, no significant difference in mortality was found between genders. In yearly distributions of patients, 20 cases were reported in 2001, a year in which we experienced more rainfall and a longer rainy season in Northern Kyushu. In monthly distribution, about 80% of cases were reported from July to September when sea water temperatures rise. About 40% of cases were reported in four prefectures around the Ariake Sea. The underlying disease indicated liver dysfunction in 90% of patients, but mortality was the same regardless of the infection pathway (oral ingestion or wound). Because of its rapid aggravation and high mortality rate, public education is important to prevent new cases. It is also highly recommended that patients with preexisting liver dysfunction avoid raw fish and limit exposure to marine water during the summer.

Repeat anaesthesia: hepatic injury

Hepatic injury following repeat anaesthesia is a rare complication that may be precipitated by several of the commonly used volatile anaesthetic agents. Halothane is the most common culprit, causing either a mild dysfunction or a more severe fulminant liver injury. Similar immune-mediated reactions may occur with enflurane, isoflurane and desflurane. There are no investigations that can accurately predict who will be affected, therefore those with a history of recent halothane anaesthesia or unexplained fever or jaundice after a previous anaesthetic should avoid repeat volatile anaesthesia. No cases of propofol-induced liver failure in adults have been published, therefore total intravenous anaesthesia may be suitable for these patients. Postoperative hepatic injury has profound effects on the future conduct of anaesthesia. The injury ranges from asymptomatic derangement of liver enzymes to fatal liver failure. The major precipitants are non-anaesthetic such as sepsis, hypotension, hypoxaemia, transfusion-related viral infection (hepatitis B, hepatitis C, cytomegalovirus, herpes virus), transfusion reaction, surgical trauma to the liver or biliary tract, prolonged nutritional deficiency, or a combination of factors in patients with pre-existing liver dysfunction. Aside from the usual measures to minimize physiological stress by careful attention to oxygenation, blood pressure and fluid status, there is little the anaesthetist can do to prevent recurrent hepatic injury during repeat anaesthesia.

Risk of hepatic failure after transcatheter arterial chemoembolization for hepatocellular carcinoma: predictive value of the monoethylglycinexylidide test.

Transcatheter arterial chemoembolization (TACE) is the major treatment modality for patients with unresectable hepatocellular carcinoma (HCC). Hepatic failure after TACE is relatively common in patients with preexisting liver dysfunction. The purpose of this study was to evaluate whether the monoethylglycinexylidide test and other parameters might predict hepatic failure after TACE in HCC patients. One hundred forty-two HCC patients undergoing TACE were enrolled into this study. Before TACE, their venous blood was collected 15 min after a bolus injection of lidocaine (1 mg/kg body weight). A fluorescence polarization immunoassay was used to measure monoethylglycinexylidide oncentrations in their sera. Univariate and multivariate analyses were performed on the monoethylglycinexylidide test and other parameters between patients with and without hepatic failure after TACE. Nineteen patients (13.4%) suffered hepatic failure after TACE. Univariate analysis revealed that the monoethylglycinexylidide concentration (17.7+/-5.8 vs 43.9+/-13.2 ng/ml), Child-Pugh score (6.9+/-0.6 vs 6.0+/-0.7), indocyanine green retention ratio at 15 min (32.4+/-6.5% vs 15.7+/-5.8%), prolonged PT, and serum total bilirubin and albumin showed significant differences between patients with and without hepatic failure after TACE. After a multiple logistic regression, only the monoethylglycinexylidide test was an independent predictor of hepatic failure (OR = 1.68, 95% CI = 1.07-2.65, p = 0.026). Among the 19 hepatic failure patients, three (15.8%) died of hepatic failure associated with TACE within 1 month after this procedure. As a predictor of hepatic failure after TACE, the monoethylglycinexylidide test is better than conventional liver function tests and clinical parameters. The monoethylglycinexylidide test may be used to select patients with relatively good liver reserves for safe TACE treatment.

Risk of hepatic failure after transcatheter arterial chemoembolization for hepatocellular carcinoma: predictive value of the monoethylglycinexylidide test

OBJECTIVES: Transcatheter arterial chemoembolization (TACE) is the major treatment modality for patients with unresectable hepatocellular carcinoma (HCC). Hepatic failure after TACE is relatively common in patients with preexisting liver dysfunction. The purpose of this study was to evaluate whether the monoethylglycinexylidide test and other parameters might predict hepatic failure after TACE in HCC patients. METHODS: One hundred forty-two HCC patients undergoing TACE were enrolled into this study. Before TACE, their venous blood was collected 15 min after a bolus injection of lidocaine (1 mg/kg body weight). A fluorescence polarization immunoassay was used to measure monoethylglycinexylidide concentrations in their sera. Univariate and multivariate analyses were performed on the monoethylglycinexylidide test and other parameters between patients with and without hepatic failure after TACE. RESULTS: Nineteen patients (13.4%) suffered hepatic failure after TACE. Univariate analysis revealed that the monoethylglycinexylidide concentration (17.7 ± 5.8 vs 43.9 ± 13.2 ng/ml), Child-Pugh score (6.9 ± 0.6 vs 6.0 ± 0.7), indocyanine green retention ratio at 15 min (32.4 ± 6.5% vs 15.7 ± 5.8%), prolonged PT, and serum total bilirubin and albumin showed significant differences between patients with and without hepatic failure after TACE. After a multiple logistic regression, only the monoethylglycinexylidide test was an independent predictor of hepatic failure (OR = 1.68, 95% CI = 1.07–2.65, p = 0.026). Among the 19 hepatic failure patients, three (15.8%) died of hepatic failure associated with TACE within 1 month after this procedure. CONCLUSIONS: As a predictor of hepatic failure after TACE, the monoethylglycinexylidide test is better than conventional liver function tests and clinical parameters. The monoethylglycinexylidide test may be used to select patients with relatively good liver reserves for safe TACE treatment.

Liver disease during the first post-transplant year in bone marrow transplantation recipients: retrospective study

Liver dysfunction is a common problem in BMT recipients and it is important to determine the etiology in order to institute appropriate therapy. The purpose of this study was to evaluate the possible causes of liver dysfunction during the first post-transplant year in BMT recipients and to identify a possible relationship between pre-existing liver dysfunction and viral hepatitis with prognosis after BMT. We reviewed liver status before and after BMT in 130 consecutive patients at the Catholic Hematopoietic Stem Cell Transplantation Center. Liver dysfunction during the first post-transplant year occurred in 85 out of 101 (84. 2%) allogeneic BMT recipients and 13 out of 29 (44.8%) autologous BMT recipients. In allogeneic BMT, GVHD and drug hepatotoxicity were major causes. In autologous BMT, drug hepatotoxicity was the most common cause. Eighteen out of 130 patients (13.8%) had abnormal liver function tests before BMT. These patients did not have an increased risk of post-transplant liver dysfunction, GVHD, and death compared to patients who had normal liver function tests prior to BMT. Nine patients were hepatitis B antigen positive and three patients were anti-HCV positive prior to BMT. There was no significant increase in the incidence of post-transplant liver dysfunction, GVHD, and death in these patients.

Tamoxifen in liver disease: Potential exacerbation of hepatic dysfunction

Tamoxifen, a non-steroidal anti-estrogen, has been used successfully for a decade as post-operative adjuvant therapy for breast cancer. Tamoxifen is generally well tolerated with few side effects, especially at the typical dose of 10 mg twice daily. However, hepatic effects have been reported after tamoxifen administration and are usually found to be cholestatic in nature. Although previous reports concentrate on tamoxifen as a probable cause of drug-induced hepatotoxicity, very little attention has been focused on the use of tamoxifen in patients with pre-existing liver dysfunction and the possible need for dose adjustment. We present the case of a 48-year-old woman with an acute exacerbation of her pre-existing liver dysfunction and subsequent elevations of tamoxifen blood levels after approximately one year of tamoxifen therapy for adjuvant treatment of breast cancer. Tamoxifen dosing was adjusted based on serum levels.

Hepatic resection in the elderly.

From 1986 to 1995 a total of 97 patients > 65 years of age underwent hepatic resections at the Department of General Surgery, Hospital Lainz, Vienna, Austria. The population consisted of 39 men and 58 women with a mean age of 74.0 +/- 5.5 years. Primary neoplasia of the liver was the cause of resection in 35 patients, gallbladder cancer in 16 patients, and metastatic disease to the liver (due to colorectal cancer in 70%) in 40 patients. The rate of major resections (> or = 3 liver segments) was 96% for primary neoplasia of the liver, 70% for metastatic disease to the liver, and 50% for gallbladder cancer; the associated mortality rates were 23%, 2.5%, and 25%, respectively. The magnitude of the resection had a significant influence on survival for gallbladder cancer (p = 0.02) and for primary neoplasia of the liver (p = 0.002) but not for metastatic disease to the liver. This reflects the high rate of cirrhosis in hepatocellular and cholangiocellular carcinoma (88%) and gallbladder cancer (37.5%). Both pre- and postoperative severe liver dysfunction had a significantly higher risk for postoperative mortality and morbidity, which showed an incremental risk with age. Another organ system able to predict outcome at the beginning of treatment by its moderate severe dysfunction were the lungs. Overall, only right and extended right lobectomies carried a significantly higher risk for postoperative mortality and morbidity. Postoperative complications were recorded in 43% of our patients, with infection the most frequent problem in nearly all of these patients (95%). Pneumonia was the leading complication associated patient survival. All patients who developed pneumonia as a late complication during a complicated postoperative course died postoperatively. The postoperative Goris score of the patients who died was 6.9 +/- 2.9 (range 3-11), whereas the surviving patients' score averaged 2.2 +/- 1.9 (range 0-9), which was significantly different (p = 0.0003). None of the 54 patients with a GORIS score < or = 2 died postoperatively, whereas 5 of 6 patients with a score > or = 9 died (p = 0.0001). Severe liver dysfunction rather than the extent of resection influences clinical mortality. Patients > 80 years of age with a preoperative severe liver dysfunction showed a postoperative mortality of 57%, and all of these patients developed postoperative complications. Therefore resection cannot be recommended for those patients. Cirrhosis led to an unacceptable mortality of 44% after hepatic resection of > or = 5 liver segments for primary neoplasia of the liver. Major resections cannot be recommended in the aged with gallbladder cancer because 50% of the patients died after such operations. Overall, only resection of > or = 5 liver segments with segments I to III or less remaining were found to pose a major risk for clinical mortality and morbidity, but the cause of death was preexisting liver dysfunction and cirrhosis in all of these patients. Major resections of large neoplasia of the liver can be recommended even in the aged, but a preoperative preselection of patients with respect to liver function and pulmonary function preoperatively may help lower the postoperative morbidity and mortality, especially in patients who will undergo resection of > or = 5 liver segments. Major hepatic resection for metastatic disease to the liver in the elderly carries no additional survival risk. Patients > 65 years of age and especially those > 80 years of age are more liable to succumb to postoperative organ failure and complications, especially infections.