Monitoring Of Liver Function Tests Research Articles

Period of onset and lack of clinical manifestation of hepatotoxicity after commencing highly active antiretroviral therapy

The period of onset of hepatotoxicity varies between cohorts as do their clinical manifestations. Clinical manifestations of hepatotoxicity that have been previously reported include fatal portal hypertension, dress syndrome, and lipodystrophy syndrome. The aim of this study was to determine the period of onset and clinical manifestation of hepatotoxicity after commencing HAART. This study was carried out on patients with HIV on HAART attending infectious disease clinic, gastroenterology clinic or admitted into the medical wards of University of Benin Teaching Hospital. Patients with HIV but not on HAART were used as controls. A clinical evaluation and relevant laboratory investigations were done. Hepatotoxicity was defined using a standardized toxicity grade scale. A total of 84 cases and 42 controls were studied. The mean ages were 35.2 ± 9.9 years and 35.5 ± 9.0 years for the cases and the controls respectively. Over 70% of the study population and controls were females. The overall incidence of hepatotoxicity was 17.85% and severe hepatotoxicity occurred in 10.71% of the patients. Over 80% of liver enzyme elevations occurred within 3 months, most of which were asymptomatic. This study shows that over 80% of enzyme elevations occurred within 3 months and were mostly asymptomatic. There is a need for regular monitoring of liver function tests at short intervals in HIV patients starting HAART since most of the cases of hepatotoxicity found in this study occurred early and were asymptomatic.

Kava extract drug

Background There is an increasing widespread use of complementary and alternative medicine in the treatment of psychiatric symptoms and disorders worldwide. Kava extract is a useful herbal medicine for treatment of insomnia and anxiety. However, a number of case reports have raised serious concerns about kava’s safety regarding liver toxicity. Aim of the work To examine the putative hepatotoxic effect of prolonged administration of a commercial kava extract drug on albino rats. Materials and methods Thirty adult male rats were randomly divided into three equal groups: 10 rats each. Group (negative control group) rats were kept in the same environment without handling. Group (vehicle group) rats were gavaged with 1.5 ml of corn oil. Group III (kava group) rats received 2 g/kg (600mg kavalactones) orally for 60 days. The anesthetized animals were sacrificed after blood collection (for liver function tests and statistical analysis) and dissected; livers were prepared for light and electron microscopic examinations. Results The kava-treated rats showed a significant reduction in their final body weights accompanied with a significant increase in both the absolute and the relative liver weight. Analysis of sera from the kava group depicted significant elevations in γ-glutamyl transferase, aspartate transaminase, alanine transaminase, alkaline phosphatase, total bilirubin, and calculated globulin levels associated with a significant decrease in the total protein, albumin, and the albumin/globulin ratio in comparison with the control values. These biochemical alterations were confirmed by the presence of different morphological changes such as degeneration and necrosis of some hepatocytes, mononuclear inflammatory cell infiltration, increased collagen fibers in the liver interstitium, loss of microvilli of hepatocytes in Disse’s space, large activated Kupffer cell, and collagen fibrils in Disse’s space in the examined liver sections. Conclusion These potentially hepatotoxic effects of kava should be taken into consideration, with close monitoring of liver function tests at frequent intervals during drug use for a long time.

Hepatitis C virus infection prevalence and liver dysfunction in a cohort of B-cell non-Hodgkin's lymphoma patients treated with immunochemotherapy

Several studies have reported a higher prevalence of hepatitis C virus (HCV) infection in patients with B-cell non-Hodgkin's lymphoma (NHL) than in the general population. Treatment for NHL includes the use of chemotherapeutic agents such as cytotoxic drugs, corticosteroids, and rituximab, which can be immunosuppressive and hepatotoxic. While reactivation of hepatitis B virus (HBV) when undergoing immunosuppressive therapy for haematological malignancies is a well-documented complication, data on HCV reactivation or liver function impairment after chemotherapy for NHL are controversial. From January 2006 to December 2009, 207 consecutive NHL patients treated with chemotherapy without rituximab (CHOP) or with rituximab (R-CHOP) were observed; screening for HCV infection and baseline liver function tests were performed in all patients. The prevalence of HCV infection was 9.2%. This prevalence is higher than that observed in the general population in Italy (3%). Among the HCV-infected subjects, the incidence of hepatitis flares was 26.3% vs 2.1% among the HCV-uninfected individuals. Although less frequent and less severe than in HBV-infected subjects, liver dysfunction can occur as a consequence of rituximab-containing regimens in HCV-infected patients with NHL. In the cases considered in this study, no patient treated with chemotherapy without rituximab developed hepatitis flares. The frequency and the severity of this complication vary in different reports. Therefore, we recommend the assessment of liver function and the screening of all patients with NHL for HCV infection before starting chemotherapy; we also recommend monitoring of liver function tests and HCV-RNA serum levels during treatment.

Serum nevirapine and efavirenz concentrations and effect of concomitant rifampicin in HIV infected children on antiretroviral therapy

To determine factors affecting serum levels of Efavirenz and Nevirapine and analyze the effect of Rifampicin on Nevirapine drug levels. A cross-sectional study was conducted on 30 HIV infected children on Antiretroviral therapy (ART) with Nevirapine or Efavirenz. Patients on simultaneous Rifampicin and Nevirapine were given higher doses of Nevirapine with regular monitoring of liver function tests. Trough levels (before morning dose of Nevirapine) and levels after 2 hours of administration of Nevirapine and levels of Efavirenz were assessed using HPLC and were checked to see if they fall within the therapeutic range. Thirty patients (14 males) were enrolled in the study with 20 on Nevirapine and 10 (33.3%) on Efavirenz. Seven (23.3%) patients were simultaneously taking rifampicin. The mean Nevirapine dose given to the patients was 350.9±59.8 mg/m2/day (on simultaneous rifampicin) and 309.2±54.6 mg/m2/day (not on concurrent rifampicin). Thirteen (81.3%) of the 16 patients with trough Nevirapine had values in the normal range, 1 (6.3%) had low Nevirapine trough levels and 2 (12.5%) had high Nevirapine trough levels. Of the post 2 hours Nevirapine levels, 1 (5%) had low levels and 3 (15%) had high Nevirapine blood levels. Factors like age (P=0.4, P=0.4087), nourishment (P=0.2679, P=0.4132), ART combination (P=0.4199, P=0.4132), form of the drug (tablet/syrup) (P=0.1964, P=0.4696) or if it was being given as single or in a fixed dose combination (P=0.4179, P=0.4696) and even concurrent rifampicin administration (P=0.284, P=0.472) did not significantly affect the trough and post 2 hours Nevirapine values, respectively. All the five patients being given concurrent rifampicin had normal trough and post 2 hours levels of Nevirapine. The Efavirenz drug levels were 1.9±1.1 g/mL. Of the 10 patients on Efavirenz, 2 (20%) had high and 1 (10%) had low blood levels. Concurrent Rifampicin administration does not alter blood levels of Nevirapine; provided the dose of Nevirapine is increased by 20-30%. Formulation of drugs does not alter the blood levels provided drug administered is in the recommended dose.

Sitaxentan-related acute liver failure in a patient with pulmonary arterial hypertension

To the Editors: Liver toxicity is a well recognised side-effect of endothelin receptor antagonists (ERAs) (bosentan, sitaxentan and ambrisentan) and long-term monthly monitoring of liver function tests (LFTs) is mandatory. Sitaxentan is thought to be less commonly associated with liver toxicity compared with the older agent bosentan and has been used as an alternative in patients who develop liver dysfunction on bosentan 1–3. However, several recently published cases of sitaxentan-related liver injury have raised concerns that the potential of sitaxentan to cause serious liver toxicity has been underestimated. To date , there are six such cases reported in the medical literature, including two deaths (one patient was on a higher dose of 300 mg twice daily in the pre-marketing stage and the other patient died from pneumonia 2 months after drug withdrawal) and one patient requiring liver transplantation (patient was also on another potentially hepatotoxic drug) 4–6. We would like to report a case of a young patient with idiopathic pulmonary arterial hypertension (IPAH) who developed acute liver failure while taking sitaxentan. Her LFTs had always been and were normal, last tested 1 month before the development of acute liver failure, which was within the timescale of the LFT monitoring procedure currently recommended. This 19-yr-old patient diagnosed with severe IPAH was treated with sildenafil 50 mg three times daily with an initial response. She had no other comorbid conditions, in particular had no pre-existing liver disease. Her exertional symptoms progressed a few months later and sitaxentan 100 …

Imatinib and Panax Ginseng: A Potential Interaction Resulting in Liver Toxicity

To report a case of imatinib-induced hepatotoxicity after concurrent ginseng ingestion in a patient with chronic myelogenous leukemia (CML). A 26-year-old man with CML who had taken imatinib 400 mg daily for 7 years with no complications presented with right upper quadrant pain. Laboratory test results included alanine aminotransferase 1069 U/L, aspartate aminotransferase 481 U/L, alkaline phosphatase 124 IU/L, total bilirubin 1.4 mg/dL, albumin 4.0 g/dL, and international normalized ratio 1.08. Liver biopsy showed acute lobular hepatitis favoring a drug-induced etiology, and a diagnosis of imatinib-induced hepatotoxicity was made. The patient's only lifestyle modification prior to the diagnosis of hepatotoxicity was daily ingestion of Panax ginseng via energy drinks for the past 3 months. Both imatinib and ginseng were discontinued, and the patient was treated with a short course of corticosteroids. Imatinib was later restarted at the same dose with no recurrent elevations in his liver enzyme levels. Imatinib-associated hepatotoxicity usually presents within 1-2 years of therapy initiation, with the median time to hepatotoxicity being 100 days. Ginseng is an herb that is not known to be hepatotoxic. In vivo, ginseng is known to inhibit CYP3A4, the primary enzyme involved in the metabolism of imatinib. We propose that our patient's late-onset imatinib-associated hepatotoxicity was due to an interaction between ginseng and imatinib through CYP3A4. Based on the Naranjo probability scale, it is probable that imatinib caused this patient's hepatotoxicity, and the Horn drug interaction probability scale also indicates a probable interaction between imatinib and ginseng. This case emphasizes the importance of continuous monitoring of liver function tests even after several years of imatinib therapy and the importance of advising patients to avoid ginseng and any other over-the-counter herbal supplements that may interact with imatinib.

The Achilles heel of endothelin receptor therapy for pulmonary arterial hypertension

To the Editors: We were interested to read the letter from Lavelle et al . 1, together with the accompanying editorial 2, regarding liver toxicity in patients receiving endothelin receptor antagonist therapy (ERA) for pulmonary arterial hypertension. Both of these articles highlight the potential for severe liver toxicity in patients receiving sitaxentan and stress the continued need for regular monitoring of liver function tests in all patients receiving ERAs. In fact, the details of the reported cases show that severe liver toxicity can occur …

Sitaxentan-induced hepatic failure in two patients with pulmonary arterial hypertension

To the Editor: Sitaxentan sodium is an endothelin receptor antagonist (ERA) recently approved for the management of pulmonary arterial hypertension (PAH) 1. While hepatotoxicity is a recognised side-effect of treatment with the ERA bosentan, it is considered to be less common with sitaxentan 2–4. We recently admitted two patients with severe hepatotoxicity on sitaxentan to the Pulmonary Hypertension Unit at the Mater Misericordiae University Hospital (Dublin, Ireland). The first patient was a 47-yr-old male with PAH associated with congenital heart disease. He had a past history of ventricular septal defect closure at 12 yrs of age and was referred to our service with a history of gradual diminishing exercise capacity. His right heart catherisation demonstrated a pulmonary artery systolic pressure of 80 mmHg and a normal pulmonary capillary wedge pressure. He was commenced on sitaxentan 100 mg q.d. Initial liver function tests (LFTs) were normal, and the patient continued to undergo monthly LFT monitoring. At 3 months, he was experiencing an improvement in his symptoms and 6-min walking distance. However, 1 month later, he became generally unwell, with nausea, vomitting, anorexia and weight loss. He denied abdominal pain or pruritis. …

Ambrisentan, an endothelin receptor type A-selective endothelin receptor antagonist, for the treatment of pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a disease of the pulmonary vasculature characterized by vasoconstriction and vascular proliferation, which leads to right heart failure and death. Prostacyclin, NO and endothelin are felt to be key mediators in the development of PAH. We present the available published and presented data about ambrisentan, an ETA-selective endothelin receptor antagonist (ERA) and newest ERA agent to be approved by the FDA for the treatment of PAH in patients with WHO functional class II and III symptoms. Randomized, placebo-controlled trials have demonstrated a significant improvement in exercise capacity and decrease in time to clinical worsening, along with evidence to support an improvement in WHO functional class and quality of life for patients receiving ambrisentan. Long-term data have shown a 1-year survival of 95%; of the survivors, 94% remained on ambrisentan monotherapy. Endothelin receptor antagonists as a drug class have previously been associated with peripheral edema, aminotransferases abnormalities and a teratogenic risk to a developing fetus. Peripheral edema was observed in patients receiving ambrisentan; however, a greater percentage was experienced in patients aged > 65 years. In contrast, significant aminotransferase abnormalities were not observed with ambrisentan treatment in the placebo-controlled trials, and in all clinical trials combined the 1-year risk seems to be low (< 3%). Despite these data, the FDA requires monthly liver function tests monitoring. As with other ERAs, monthly pregnancy testing is required in all women of child bearing potential.

Effects of simvastatin 40 mg daily on muscle and liver adverse effects in a 5-year randomized placebo-controlled trial in 20,536 high-risk people

BackgroundSimvastatin reduces cardiovascular mortality and morbidity but, as with other HMG-CoA reductase inhibitors, can cause significant muscle toxicity and has been associated with elevations of liver transaminases.MethodsMuscle and liver adverse effects of simvastatin 40 mg daily were evaluated in a randomized placebo-controlled trial involving 20,536 UK patients with vascular disease or diabetes (in which a substantial reduction of cardiovascular mortality and morbidity has previously been demonstrated).ResultsThe excess incidence of myopathy in the simvastatin group was < 0.1% over the 5 years of the trial, and there were no significant differences between the treatment groups in the incidence of serious hepatobiliary disease.ConclusionAmong the many different types of high-risk patient studied (including women, older individuals and those with low cholesterol levels), there was a very low incidence (< 0.1%) of myopathy during 5 years treatment with simvastatin 40 mg daily. The risk of hepatitis, if any, was undetectable even in this very large long-term trial. Routine monitoring of liver function tests during treatment with simvastatin 40 mg is not useful.Trial RegistrationISRCTN48489393

Clozapine-Induced Fatal Fulminant Hepatic Failure: A Case Report

Fulminant hepatic failure (FHF) refers to the rapid development of severe acute liver injury with impaired synthetic function and encephalopathy in a person who previously had a normal liver or had wellcompensated liver disease. The potential causes of FHF are numerous, but viral or toxin-induced hepatitis are the most common. Clozapineinduced hepatotoxicity has rarely been reported in the literature, occurs via an unknown mechanism and results in liver biochemical abnormalities that are usually of no clinical significance. In approximately 30% to 50% of patients treated with clozapine, there is an asymptomatic rise in serum aminotransaminase levels; however, there are no current guidelines for routine monitoring of liver function tests and liver enzymes during its use. Fatal fulminant hepatitis has only been reported in three patients receiving clozapine. A case of fatal FHF that occurred in a schizophrenic woman who began clozapine therapy shortly before her illness developed is described.

Abacavir-induced hepatotoxicity: a report of two cases

Hepatotoxicity induced by antiretroviral therapy occurs in 5–10% [1] of patients. It is most commonly seen in patients taking didanosine, zalcitabine, stavudine, nevirapine or protease inhibitors. A variety of mechanisms including direct hepatotoxicity, lactic acidosis, and hypersensitivity have been implicated [1,2]. In the well described hypersensitivity reaction (HSR) caused by abacavir, minor elevations in transaminase levels are common; however, there are few reported cases of abacavir-induced liver injury in the context of a negative HLA B*5701 test [3]. We describe two cases of abnormal liver function tests occurring in young HLA B*5701-negative women shortly after switching to abacavir, with no history of underlying liver abnormalities or concurrent risk factors for liver disease. In both cases, biochemical abnormalities and symptoms resolved promptly on cessation of abacavir. Case 1 is a 26-year-old Zimbabwean woman who switched from combivir/nevirapine to kivexa/nevirapine after 3 years on initial therapy to avoid long-term toxicity from zidovudine. She tested negative for the HLA B*5701 allele, had no history of liver problems and, was hepatitis A Ab IgG positive, hepatitis B surface antigen negative, surface antibody more than 1000 and negative for hepatitis C Ab. Her baseline alanine aminotransferase (ALT) was 21 IU/l (ULN 37 IU/l) and, at 6 weeks after starting abacavir, it was still within normal range at 36 IU/l. She contacted the clinic a month later with symptoms of nausea, fatigue and myalgia but did not attend for further assessment until 2 months later, when the ALT had risen to 433 IU/l. Hep B DNA, Hep C RNA and autoantibody screen were negative, and there was no history of excessive alcohol intake. Initially, nevirapine was thought to be the causative agent and was switched to Kaletra. Due to lack of any subsequent improvement, a liver biopsy was performed that showed severe hepatitis with grossly abnormal architecture and liver cell loss, likely to be drug-induced. Following this, kivexa was stopped, the patient remained on kaletra monotherapy, and her symptoms and biochemical indices resolved within 4 weeks. Case 2 is a 34-year-old Spanish woman who switched to kivexa/nevirapine after 4 years on combivir/nevirapine, again because of concerns about the risk of lipodystrophy from zidovudine. As in case 1, she was HLA B*5701 negative, had no history of liver problems, and serology for hepatitis A, B and C viruses was negative. Her baseline ALT was 10 IU/l and, 6 weeks later, this remained normal at 21 IU/l. However, blood taken at day 98 showed a marked rise in ALT to 580 IU/l and, on repeat, was 423 IU/l. Plasma Hep B DNA, Hep C RNA and autoantibody screen were negative. The patient remained asymptomatic throughout. Despite our advice to switch therapy, it was not until 5 weeks later that the patient agreed and kivexa was switched to truvada. The ALT returned to normal within 4 weeks. Abacavir-induced liver injury in the context of a negative HLA B*5701 test is rare. A handful of cases of clinically suspected HSR with negative testing have been reported [4]. Here, the diagnosis of abacavir HSR was considered in both cases, but thought to be unlikely due to negative HLA B*5701 results, the fact that abnormalities in liver function only developed after more than 6 weeks of treatment with abacavir, and because liver biopsy findings suggested otherwise in case 1. Clinicians should be aware of the possibility that abacavir can cause impaired liver function and should remain alert for signs of hepatitis. Patients should be encouraged to report even mild symptoms at their onset and close monitoring of liver function tests is recommended.

Healy's law and the pediatric liver allograft

Although the long-term care of children who have undergone liver transplantation has a relatively short history, such care has already evolved. This evolution has largely been driven by the availability of new therapies. The biggest current problems are the seemingly conflicting requirements that graft integrity be maintained and that side effects of therapy, most notably renal toxicity, be minimized. Several strategies have shown promise with respect to reducing nephrotoxicity, although long-term data are still awaited. Given the complexity of today's pharmacopoeia, the care of the graft remains a major concern. LFT, liver function test; SPLIT, Studies of Pediatric Liver Transplantation. More fundamental than drug-choice issues, however, as addressed by Ekong et al.1 in this issue of Liver Transplantation, is this question: how should we best monitor the graft? Ekong et al.1 present a summary of their biopsy findings in 63 of 222 long-term (>3 years) liver transplant recipients. Biopsy was prompted in 32 by clinical-laboratory test result [liver function test (LFT)] abnormalities; in this group, unsurprisingly, inflammation and fibrosis were seen. Biopsy to assess liver status in the absence of LFT abnormalities (surveillance biopsy) was offered to 118 longer term (>5 years) survivors, of whom 87 declined. Among the 31 patients who underwent surveillance biopsy at >5 years, 8 had substantial fibrosis, a finding of concern for graft outcome over decades. In addition, longer intervals since transplantation were associated with increased fibrosis. These data confirm those assembled in Birmingham, United Kingdom, by Evans et al.2 The English cohort included, at 5-year survival, 148 patients still considered pediatric who were followed at the reporting institution. Of these, 3 were judged to be poor candidates for liver biopsy, and 10 declined the procedure. Among the 135 who underwent biopsy prompted not specifically by LFT abnormalities but instead by the study schedule (protocol biopsy), 58 had chronic hepatitis, and 47 of these had substantial fibrosis (4 with cirrhosis). At 10-year survival, 68 patients were eligible for protocol biopsy; 1 was judged to be a poor candidate, and 3 declined the procedure. Of the 64 biopsy specimens obtained, 41 showed chronic hepatitis, and 37 of these had substantial fibrosis (6 with cirrhosis). LFTs did not distinguish between patients with and without hepatitis and fibrosis. These 2 reports thus establish that, as in adults,3 surveillance or protocol biopsy in children will identify inflammation and scarring in the engrafted liver and that these will worsen over time. They also establish that LFT monitoring alone does not reflect the status of the allograft liver in children and that liver biopsy is required for an accurate assessment of that status. Bernadine Healy in 1997 wrote: “Don't order a test if you lack the facts to know how to interpret the result.”4 Is it time to apply Healy's Law in pediatric posttransplant liver care? What shall we do, after all, with the information on the liver's status that we obtain at protocol or surveillance biopsy? Shall we intervene when hepatitis or fibrosis is found, stepping in to augment immunosuppressive regimens, with their side effects? Can we act to improve graft outcome, and if we can, how can we? Neither Evans et al.2 nor Ekong et al.1 tell us. To answer these questions requires that, should protocol biopsy find abnormalities, assignation to intervention or to watchful waiting be at random and that allograft status, with other indices of health or morbidity, be assessed periodically thereafter. Can such a study be justified? Should such a study even be attempted, or should we proceed from the assumption that inflammation and scarring found at protocol biopsy require intervention? Probably no single care team attends enough liver-transplanted children to answer these questions. The Studies of Pediatric Liver Transplantation (SPLIT) consortium5 is at least positioned to consider the questions, and perhaps the study by Ekong et al.,1 confirming the observations of Evans et al.,2 will provide the impetus for SPLIT or another consortium to decide whether it wishes to set the agenda for further work in this field.

Hereditary angioedema: a current state-of-the-art review, V: attenuated androgens for the treatment of hereditary angioedema

To provide a summary of the literature regarding the use of attenuated androgens during the past 40 to 50 years for the treatment of hereditary angioedema (HAE). MEDLINE and PubMed were searched to identify studies involving the treatment of HAE with androgens. Studies were selected based on their relevance to the use of androgens for the treatment of HAE. Attenuated androgens have proven successful for the short- and long-term treatment of HAE. Adverse effects are still concerning, and their use in children and pregnant women must be undertaken with great caution. Scheduled monitoring of liver function tests and lipid profiles in patients treated with these medications is critical. Attenuated androgens have been successful in the short- and long-term treatment of HAE, and they are still the most frequently used medications in the United States for the treatment of this disease. There is a lack of readily available options for the treatment of acute HAE attacks apart from the administration of fresh frozen plasma or safe prophylactic therapies; however, several appropriate agents currently in clinical trials in the United States appear promising.

Results From a 2-Year Centralized Tolcapone Liver Enzyme Monitoring Program

Tolcapone, administered with levodopa/carbidopa to patients with Parkinson disease, is an effective and generally well-tolerated adjunctive therapy. However, 4 early cases of hepatotoxicity causing 3 deaths in patients not properly monitored gave rise to more rigorous liver function test monitoring guidelines and a liver function test monitoring program in which blood samples from tolcapone-treated patients were tested and results were collected in a central database. We analyzed these results to determine the percentages of patients with at least 1 aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation above the upper limit of normal (ULN) and at least 1 elevation greater than 2 times the ULN. This retrospective, observational analysis included all AST and ALT values recorded in the database from 11,883 samples from patients who received tolcapone for up to 2 years or longer (January 1999-January 2001). Of 1725 patients who had at least 1 AST or ALT measurement, 3.9% (n = 67) had elevations above the ULN. Less than 1% (15/1725) of patients had AST or ALT elevations greater than 2 times the ULN. Most values returned to normal during continued tolcapone treatment. In 472 patients monitored biweekly while receiving tolcapone for 20 to 114 consecutive weeks, only 0.6% (n = 3) had an AST or ALT value greater than 2 times the ULN; no significant elevations occurred in the remaining 469 (99.4%). This analysis of results from the central monitoring program suggests that significant transaminase elevations are rare, typically transient, and may return to normal in the face of continued tolcapone therapy in most patients.

Statins and Monitoring of Liver Function Tests

Statins and Monitoring of Liver Function Tests

Imatinib mesylate-induced acute hepatitis in a patient treated for gastrointestinal stromal tumour

We report the first case of hepatocellular injury occurring in a patient treated for metastatic gastrointestinal stromal tumour (GIST) with imatinib mesylate, with two positive rechallenges including one with 2.5% of the current therapeutic dosage. The patient could be treated later with sunitinib without liver toxicity. Grade 3-4 liver toxicity could occur in one out of 40 treated patients with imatinib for GIST, and fatalities have been reported. Regular monitoring of liver function tests is essential in patients treated with imatinib.

Levodopa/Carbidopa/Entacapone for the Treatment of Parkinson’s Disease

The triple combination levodopa/carbidopa/entacapone tablet provides the clinical benefits of adding entacapone therapy to carbidopa/levodopa while affording the convenience of fewer pills. Entacapone is a catechol-O-methyl transferase inhibitor that slows the peripheral metabolism of levodopa, thereby increasing its central bioavailability. Clinically, the addition of entacapone to levodopa/carbidopa in Parkinson's disease patients with wearing-off fluctuations increases ‘on’ time, improves motor function and activities of daily living, and allows for a reduction of the levodopa dose. Levodopa/carbidopa/entacapone is indicated for use in patients with idiopathic Parkinson's disease who are being treated with immediate-release levodopa and experiencing the signs and symptoms of end-of-dose wearing-off. Clinical trial data in levodopa-treated Parkinson's disease patients who are not experiencing wearing-off demonstrate that the addition of entacapone is associated with a mild but significant improvement in activities-of-daily- living and quality-of-life measures. Entacapone is well tolerated and safe and, unlike the catechol-O-methyl transferase inhibitor tolcapone, does not require liver function test monitoring. Levodopa/carbidopa/entacapone is available in 50, 100 and 150 mg levodopa tablets that also contain carbidopa in a 1:4 ratio to levodopa, plus entacapone 200 mg. Based on preclinical studies demonstrating that concomitant administration of entacapone with levodopa/carbidopa delays the development of dyskinesias, a worldwide multicenter trial is in progress comparing the initiation of levodopa/carbidopa/entacapone versus levodopa/carbidopa in Parkinson's disease patients who require levodopa treatment.

Lamivudine prophylaxis and treatment of hepatitis B Virus-exposed recipients receiving reduced intensity conditioning hematopoietic stem cell transplants with alemtuzumab

Individuals with past exposure to hepatitis B virus (HBV) may reactivate HBV following bone marrow transplantation. Alemtuzumab (CAMPATH)-based reduced intensity conditioning bone marrow transplantation has been associated with a high incidence of viral infections. Lamivudine prophylaxis for HBV should be instituted in this setting. The management of 240 CAMPATH-based reduced intensity conditioning bone marrow transplantation, carried out over an 8-year period at Kings College Hospital, was reviewed. Hepatitis B core total antibody (anti-HBc) testing identified recipients and donors with previous HBV exposure. Fifteen donor-recipient pairs were identified as being at risk of HBV reactivation. Eight recipients of anti-HBc negative donors were HBsAg negative, anti-HBc positive pre-transplantation. Five anti-HBc negative recipients received transplants from HBsAg negative, anti-HBc positive donors. Two HBV carrier recipients had one anti-HBc negative and one positive donor, respectively. Pre-transplant lamivudine prophylaxis was given to 8/10 (80%) anti-HBc positive recipients. Although HBsAg and HBV DNA were detected 4 months after bone marrow transplantation in one patient who did not receive prophylaxis, a good antiviral response was documented on starting lamivudine. The two HBV carrier recipients had stopped lamivudine at 8 and 31 months post-bone marrow transplantation, respectively, and died of liver failure with a sharp rise in HBV DNA levels. The five anti-HBc negative recipients with anti-HBc positive donors remained HBsAg and HBV DNA negative. Although lamivudine prophylaxis prevented HBV reactivation, it is unclear at what stage post-transplantation prophylaxis can be discontinued. Close monitoring of liver function tests (LFTs), HBsAg, and HBV DNA must be undertaken even after stopping antiviral prophylaxis.

Hepatitis A

Hepatitis A infection is typically transmitted by the fecal-oral route. Symptomatic infection is highly dependent on the age of the patient and usually follows a self-limited course. Once diagnosed, clinical and biochemical follow-up in the outpatient setting is generally appropriate. Treatment aims are to achieve symptomatic relief and to maintain adequate hydration and caloric intake. In patients with more severe disease, hospitalization may be needed to accomplish aggressive symptomatic therapy and close monitoring of liver function tests and mental status. Prompt evaluation for liver transplantation is appropriate in the rare case where fulminant liver failure develops. Given the absence of specific therapy for hepatitis A virus infection, the most important health care intervention is prevention of infection and/or transmission, which can be accomplished with the safe and effective use of immune globulin and commercially available vaccines.