Fulminant liver failure associated with clarithromycin

OBJECTIVE: To report a patient developing fulminant liver failure while being treated with clarithromycin for pneumonia. CASE SUMMARY: A 58-year-old white woman developed fulminant liver failure while being treated with the macrolide antibiotic clarithromycin for pneumonia. Comedication included N-acetylcysteine, atenolol, and isradipine. Other causes of liver failure, such as viral hepatitis, autoimmune hepatitis, toxins, and heart failure, were excluded by appropriate diagnostic means. All drugs were stopped, and the patient was transferred to another hospital for liver transplantation. She recovered spontaneously within several days, making transplantation unnecessary. A liver biopsy obtained 10 days after the initial presentation revealed centroacinar necrosis and beginning fibrous reorganization, compatible with recent centroacinar damage. DISCUSSION: Since no other cause could be identified, liver injury was considered to be drug related. Fulminant liver failure has not previously been described with concomitant use of atenolol and N-acetylcysteine. Although isradipine has been associated with hepatocellular injury, there are no reports of fulminant liver failure with this agent, and our patient had been treated for >2 years without signs of toxicity. The most likely cause of liver failure in this patient was, therefore, clarithromycin, which undergoes hepatic metabolism and has been reported to cause fulminant hepatic failure. A second possibility is an interaction between clarithromycin and isradipine, potentially increasing the hepatic toxicity of isradipine. CONCLUSIONS: Clarithromycin may be a cause of fulminant liver failure either alone or by inhibiting the metabolism of other drugs.     

Living related liver transplantation for acute fulminant hepatitis B: experience from two possible hyper-acute cases

Fulminant hepatic failure, which is represented by fulminant hepatitis, is fatal in most cases unless prompt liver transplantation is performed. Even if liver transplantation is performed, irreversible neurological damage is often complicated. In this case report, we describe two cases of fulminant hepatitis induced by acute hepatitis B virus infection, both of which were successfully rescued by living related liver transplantation without significant complications. The case 1 was a 45-year-old Japanese male. He complained general malaise and anorexia. His local physician diagnosed him as acute hepatitis B, and referred to our hospital. Due to severe coagulopathy, plasma exchange was performed 3 times. However, his hepatic coma progressed rapidly along with rapid decrease of both his direct/indirect bilirubin (D/T) ratio and serum blood urea nitrogen (BUN) levels. Living related liver transplantation was performed under the diagnosis of acute fulminant hepatitis B. The case 2 was a 34-year-old Japanese male. His complaints were fever and skin rush. He was referred to our hospital under the diagnosis of acute hepatitis B. On the second day after admission, he developed grade II hepatic coma, which deteriorated into grade III in spite of intensive therapy including plasma exchange. He also demonstrated rapid decrease of both D/T ratio and serum BUN level. Living related liver transplantation was performed on the next day. Both cases recovered without any evidence of neurological sequelae. In general, it is extremely difficult to rescue fulminant hepatitis by conservative treatments, particularly in cases with rapid progression. Although emergency liver transplantation may be an only option to rescue in such a case, living related liver transplantation has an advantage in view of urgent organ donation over cadeveric transplantation.     

Role of hepatitis C virus infection in German patients with fulminant and subacute hepatic failure

To investigate the possible role of hepatitis C virus (HCV) in fulminant and subacute liver failure, we tested serum and liver of 13 patients undergoing orthotopic liver transplantation for the presence of HCV RNA. HCV RNA was detected in specimens from two out of eight patients negative for all viral markers with suspected hepatitis non-A, non-B infection and in one out of four patients with hepatitis B virus infection. Only in this patient replication of HCV could be demonstrated. We conclude, that fulminant and subacute hepatic failure is induced by hepatitis C virus only in few patients with hepatitis non-A, non-B.     

Outcome of Orthotopic Liver Transplantation in the Aetiological and Clinical Variants of Acute Liver Failure

Thirty-three patients with acute liver failure underwent orthotopicliver transplantation, including 16 with fulminant hepatic failure,15 with late–onset hepatic failure and two with severeacute liver failure (coagulopathy without encephalopathy). Twenty–three(70 per cent) survived to leave hospital and 21 of these arecurrently alive and well. Outcome correlated with the serumbilirubin level before transplantation (p<0.05) but no correlationwas found with the variant of acute liver failure, grade ofencephalopathy, cerebral oedema, serum creatinine, white cellcount, prothrombin time or platelet count at the time of transplantation.Severe coagulation factor deficiencies did not constitute aclinical problem. One patient developed a neurological deficitsecondary to cerebral oedema, but otherwise the morbidity reflectedthat observed in the general population after transplantation.Careful monitoring of intracranial pressure and surveillance(with early aggressive therapy) for bacterial and fungal infectionsis very important in achieving a successful outcome after transplantation.     

Efficacy and limitation of apheresis therapy in critical care.

Apheresis therapy such as plasma exchange and plasma adsorption has become therapeutic tools in critical care. The indications for apheresis therapy in ICU patients include fulminant hepatic failure, thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), autoimmune disease, and sepsis. During the past 11 years, 150 patients with various kinds of critical illnesses were treated with apheresis therapy in our ICU, and the overall survival rate was 50%. Apheresis therapy is especially useful in the treatment of a patient with fulminant hepatic failure because liver transplantation is seldom performed in Japan; therefore, the patient should be treated with artificial liver support. When plasma exchange is performed on the critically ill, continuous hemodiafiltration should be performed simultaneously to overcome the adverse effects of plasma exchange such as hypernatremia, metabolic alkalosis, and abrupt changes in colloid osmotic pressure and to enhance the removal rate of the causative middle molecular weight substances of hepatic failure or hepatic coma.     

The current endeavors to understand the pathogenesis of intractable liver diseases

The death due to liver diseases accounts for more the 35,000 cases every year in Japan for decades. Among these liver diseases, the Ministry of Health, Labor, and Welfare of Japan has named both fulminant hepatitis and primary biliary cirrhosis (PBC) as intractable liver diseases, since the precise mechanism of these diseases are unclear. Accordingly, there are no effective medical treatments other than liver transplantation toward these diseases. However, still the number of the liver transplantation performed in Japan is small. Thus, we have focused on the pathogenesis of these two intractable conditions. The fulminant hepatitis is a distinct form of acute hepatitis, and hepatitis B virus infection accounts for 20~30% of this lethal condition. Only tiny proportions of patients with acute HBV infection develop fulminant hepatitis (less than 10%). It has been widely believed both viral and host factors contribute for fulminant hepatitis, although still unknown factors are expected to be involved. On the other hand, PBC is a chronic progressive cholestatic liver disease. Clinical features of PBC include female predominance (80 to 90%), the presence of antimitochondrial antibody (up to 95%), and elevated serum levels of immunoglobulin M. Eventually, patients with PBC will develop liver failure due to biliary cirrhosis in spite of medical interventions. Immune-mediated processes are believed to be responsible for the pathogenesis, although the precise mechanism is yet to be determined. In this review article, our endeavors to understand the mechanism of these intractable liver diseases are discussed.     

Fulminant hepatic failure

Most cases of fulminant hepatic failure (FHF) are related to viral hepatitis or to drugs and toxins. With improvement in supportive intensive care, the overall survival has increased, but specific forms of temporary hepatic support pending hepatic regeneration have been disappointing. With the widespread availability of orthotopic liver transplantation, this has become a viable option for those patients with FHF who are unlikely to survive with conservative treatment, although patient selection and timing of transplantation still presents a clinical dilemma.     

Successful treatment of refractory cerebral oedema in ecstasy/cocaine-induced fulminant hepatic failure using a new high-efficacy liver detoxification device (FPSA-Prometheus)

Ecstasy-induced fulminant hepatic failure is associated with high mortality. If complicated by cerebral oedema, orthotopic liver transplantation is the only established treatment. We report a case of combined ecstasy/cocaine-induced fulminant hepatic failure presenting with severe rhabdomyolysis, myocardial infarction and multiorgan failure. Transplantation was declined by the transplant surgeons because of a history of intravenous drug abuse. As excessive hyperammonaemia (318 mumol/l) and refractory transtentorial herniation developed, treatment with a new liver detoxification device combining high-flux haemodialysis and adsorption (FPSA-Prometheus) was initiated. Within a few hours of treatment, ammonia levels normalised. Cerebral oedema was greatly reduced by day 4 and hepatic function gradually recovered. Following neurologic rehabilitation for ischaemic sequelae of herniation, the patient was discharged from hospital with only minimal deficits. In conclusion, efficient extracorporeal detoxification may be an option for reversal of hyperammonaemia and refractory cerebral oedema in ecstasy/cocaine-induced acute liver failure.     

Methanobactin reverses acute liver failure in a rat model of Wilson disease

In Wilson disease (WD), functional loss of ATPase copper-transporting β (ATP7B) impairs biliary copper excretion, leading to excessive copper accumulation in the liver and fulminant hepatitis. Current US Food and Drug Administration– and European Medicines Agency–approved pharmacological treatments usually fail to restore copper homeostasis in patients with WD who have progressed to acute liver failure, leaving liver transplantation as the only viable treatment option. Here, we investigated the therapeutic utility of methanobactin (MB), a peptide produced by Methylosinus trichosporium OB3b, which has an exceptionally high affinity for copper. We demonstrated that ATP7B-deficient rats recapitulate WD-associated phenotypes, including hepatic copper accumulation, liver damage, and mitochondrial impairment. Short-term treatment of these rats with MB efficiently reversed mitochondrial impairment and liver damage in the acute stages of liver copper accumulation compared with that seen in untreated ATP7B-deficient rats. This beneficial effect was associated with depletion of copper from hepatocyte mitochondria. Moreover, MB treatment prevented hepatocyte death, subsequent liver failure, and death in the rodent model. These results suggest that MB has potential as a therapeutic agent for the treatment of acute WD.     

Telbivudine in the treatment of chronic hepatitis B

Introduction  The treatment of chronic hepatitis B virus (HBV) infection has been revolutionized in the past decade by the increased availability of effective antiviral agents. Telbivudine is an L-nucleoside that is structurally related to lamivudine and has recently been approved for use in patients with chronic HBV infection. Telbivudine is highly selective for HBV DNA and inhibits viral DNA synthesis with no effect on human DNA or other viruses. This article reviews the pharmacology, pharmacokinetics, therapeutic efficacy and safety of telbivudine, and discusses its place in the current armamentarium against HBV. Methods  Relevant publications were identified from searches of Medline and PubMed between 2000 and 2008, using the search terms “hepatitis B/HBV,” “telbivudine/LdT,” “β-L-thymidine,” “pharmacokinetics,” “safety,” “adverse events,” and “resistance.” The reference lists of retrieved articles were searched for relevant studies. Results  Phase 3 clinical studies demonstrate that telbivudine is superior to lamivudine over a 2-year period in hepatitis B e-antigen (HBeAg)-positive and HBeAg-negative patients. Telbivudine was associated with a statistically signficantly greater reduction in HBV DNA, greater proportion of alanine aminotransferase normalization, and greater histological response than lamivudine. Furthermore, telbivudine use resulted in fewer cases of treatment failure and less virological resistance than lamivudine. However, after 2 years of therapy, telbivudine resistance was appreciable (25%) and considerably higher than that seen with other new antivirals such as tenofovir and entecavir. Overall, telbivudine was found to be safe, although grade 3 or 4 adverse events, including elevations in creatine kinase, were more commonly found in patients receiving telbivudine than lamivudine. Telbivudine is not active against lamivudine-resistant HBV. Conclusions  Telbivudine is a new antiviral agent joining the armamentarium against HBV. It is superior to lamivudine in terms of therapeutic response and resistance profile. However, concerns about resistance with long-term use, along with inferior cost-effective analyses, have relegated telbivudine to a second-line agent in the management of chronic HBV infection.     

Pediatric liver transplantation: Part I. Choosing and caring for the transplant candidate

Liver transplantation is now an accepted modality of treatment for acute fulminant hepatic failure, end-stage chronic liver disease and certain hepatic-based inborn errors of metabolism in children. This paper reviews the criteria used in selecting appropriate candidates for transplantation based on a knowledge of the natural history of the underlying disease and the individual patient's condition. Important clinical, laboratory, radiologic and histologic data used to make decisions regarding transplantation are reviewed. Nutritional assessment and management are emphasized as part of the comprehensive evaluation and therapeutic plan to prepare a patient for transplantation.     

Acute hepatic failure: the emerging role of orthotopic liver transplantation

From 1985 through 1987, we diagnosed acute hepatic failure in 13 patients. Spontaneous recovery occurred in three of these patients. Eight patients underwent liver transplantation, five of whom survived and three of whom died. In addition, two patients died before undergoing transplantation. The survival rate of 62% was better than that among our previous series of similar patients. This improvement seems to be related to the use of orthotopic liver transplantation as a therapeutic alternative among these patients. One of the three patients who died after liver transplantation had normal liver function, but respiratory failure caused by Pneumocystis carinii developed 4 months after the transplantation. The surgical procedure was less difficult in patients with acute fulminant hepatitis than in those with chronic liver disease because fewer problems arose from adhesions, venous collaterals, and ascites. The emerging role of orthotopic liver transplantation in patients with acute hepatic failure is demonstrated by the improvement of survival rates observed by various groups, including ours, when this therapeutic modality is available.     

Levofloxacin-induced acute fulminant hepatic failure in a patient with chronic hepatitis B infection

OBJECTIVE: To report a case of possible levofloxacin-induced acute fulminant hepatic failure. CASE SUMMARY: An unconscious 55-year-old woman was hospitalized with the diagnosis of hepatic encephalopathy. The patient had received levofloxacin 500 mg daily for 10 days because of an upper respiratory infection. Her past medical history revealed hepatitis B surface antigen positivity as an asymptomatic hepatitis B virus carrier for 10 years. After hospitalization, treatment included plasmapheresis and supportive care. The patient's consciousness improved on the second day of treatment. Other etiologies of fulminant hepatic failure were ruled out, suggesting levofloxacin-induced fulminant hepatic failure. Although the patient received supportive treatment, her condition gradually deteriorated and she died 12 weeks after admission to our hospital. An objective causality assessment revealed that the adverse event was possibly related to levofloxacin. DISCUSSION: Levofloxacin is widely used because of its broad spectrum of antimicrobial activity. As of August 9, 2005, to our knowledge, only one case of fulminant hepatic failure in relation to levofloxacin has previously been published. We believe that, in our patient, the relationship between levofloxacin and her illness is clear because of the negative results in the etiological studies, the short time between the drug's administration and the development of disease, and the pathologic findings suggestive of drug-induced hepatitis. CONCLUSIONS: Clinicians should be aware of the possibility of severe hepatic injury associated with levofloxacin when prescribing this drug.     

Energy expenditure in acetaminophen-induced fulminant hepatic failure

OBJECTIVE: To determine energy expenditure in critically ill patients suffering from acetaminophen-induced fulminant hepatic failure and compare it with values obtained in matched, healthy control subjects and in patients studied during the anhepatic period of elective liver transplantation. DESIGN: Prospective, controlled, observational study. SETTING: A ten-bed intensive therapy unit and a liver transplant unit at a University teaching hospital. PATIENTS AND SUBJECTS: Sixteen patients suffering from acetaminophen-induced fulminant hepatic failure who were sedated, paralyzed, and mechanically ventilated; 16 age-, gender-, and weight-matched, awake, healthy control subjects; and 16 patients with chronic liver disease, undergoing elective liver transplantation, who were studied during the anhepatic period of surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The mean energy expenditure was calculated in each case for a 30-min period, using indirect calorimetry. In the patients undergoing liver transplantation, measurements were performed after clamping the hepatic veins and recipient hepatectomy. Energy expenditure was markedly increased in the fulminant hepatic failure group (mean energy expenditure, 4.05 [SD 0.52] kJ x kg(-1) x hr(-1)), in comparison with healthy control subjects (mean, 3.44 [0.27] kJ x kg(-1) x hr(-1); mean difference, 18%; p < .001) and in comparison with patients during the anhepatic period of liver transplantation (mean, 3.15 [0.61] kJ x kg(-1) x hr(-1); mean difference, 29%; p < .001). These differences were even more pronounced when a correction factor for differences in core temperature was included in the calculation. Harris-Benedict predictions of energy expenditure were unreliable in the patients with acute liver failure. No correlations were found among energy expenditure and hemodynamic variables, the requirement for vasoconstrictors, or the presence of renal failure. CONCLUSIONS: Despite the loss of functioning liver cell mass, the metabolic rate is substantially increased in patients with acetaminophen-induced fulminant hepatic failure. This finding is consistent with the marked systemic inflammatory response, which accompanies acute hepatic failure. The Harris-Benedict equation is unreliable when an estimation of energy expenditure is required in patients with this condition.     

Severe hepatotoxicity associated with use of a dietary supplement containing usnic acid

Dietary supplements containing usnic acid are marketed for weight loss and have been associated with hepatotoxicity. The specific ingredient responsible for the hepatotoxicity is currently unknown. We describe 2 patients who developed severe hepatotoxicity within 3 months of taking a dietary supplement containing usnic acid. One patient developed fulminant hepatic failure requiring emergency liver transplantation; the other developed submassive hepatic necrosis but did not require transplantation. Thorough investigation, including histopathological examination of the liver, revealed no other cause of acute liver injury. Usnic acid hepatotoxicity should be considered as a possible etiologic factor in patients presenting with fulminant hepatic failure, especially if they have been taking dietary supplements for weight reduction.     

Headache in kidney transplantation

The aim of this retrospective study was to determine the relevance of the symptom “headache” in kidney transplanted patients, since few studies have considered headache as a clinically significant complication in this condition. A total of 83 consecutive kidney transplant patients underwent to neurological examination and a detailed headache history was taken. The headache history considered the period before kidney disease, during renal failure, during dialysis treatment and after transplantation. Diagnosis was made according to International Headache Criteria (ICDH-II) (2004). Our results reveal an occurrence of headache after kidney transplantation in 44.5% of the patients, which is higher than rates reported for the general population and in the only specific comparable study on liver transplant patients. These data suggest the need for prospective studies to explore the causal mechanisms by which headache develops with frequency in kidney transplant patients, and in particular to determine the role of immunosuppressive therapy.     

Telaprevir: a new hope in the treatment of chronic hepatitis C?

More than 180 million people worldwide have chronic hepatitis C (CHC) virus infection, a major cause of liver cirrhosis and its life-threatening complications including liver failure, portal hypertension, and hepatocellular carcinoma. With the current standard of care of pegylated interferon-alpha and ribavirin (PEG-IFN-α/RBV), the chances of sustained viral clearance or “cure” are only 40%–50% for genotype 1 infection, which is the most common genotype in western populations. Consequently, there has been a drive to develop new agents specifically targeting essential components of the viral life cycle, such as the hepatitis C virus (HCV) NS3/4A serine protease. Perhaps the most advanced HCV protease inhibitor in clinical development is telaprevir, which has been shown to improve treatment outcomes when combined with PEG-IFN-α/RBV in genotype 1 infection, and is currently undergoing phase 3 study. In this review, we summarize the pharmacology, pharmacokinetics, and results of phase 1 and 2 clinical trials of telaprevir, and discuss the likely role of this agent in the future management of CHC.     

Adrenal-exhaustion syndrome in patients with liver disease

Objective Adrenal failure is emerging as an important cause of excess morbidity and mortality in critically ill patients. We have recently reported the high incidence of adrenal failure in patients with liver disease, the so called “hepato-adrenal syndrome.” It has been noted that patients who on initial testing may have “normal” adrenal function subsequently progress to overt adrenal failure, the adrenal-exhaustion syndrome. The goal of this study was to further characterize this syndrome. Design Retrospective review of the “Hepatic Cortisol Research and Adrenal Pathophysiology Study” database. Setting Liver transplant ICU of a tertiary care university hospital. Patients and methods Patients who on initial testing had “normal” adrenal function were followed, and adrenal function testing was repeated in those who failed to improve. The patients were grouped as follows: (1) patients who developed adrenal failure on follow-up testing; and (2) patients who had normal adrenal function during their ICU stay. The incidence and risk factors for the development of adrenal-exhaustion syndrome were determined. Measurements and results The study cohort consisted of 221 patients, of whom 120 (54%) were diagnosed with adrenal insufficiency on initial diagnostic testing and were excluded from further analysis. The remaining 101 patients comprised those who made up the group of interest. On follow-up, 16 (16%) of these developed adrenal failure a mean of 3 days after initial testing. The only factor that predicted the development of adrenal-exhaustion syndrome was a low HDL level (p < 0.001). Conclusion This study demonstrates that adrenal failure is a dynamic process and that repeat adrenal function testing is indicated in patients who remain hemodynamically unstable or fail to improve with aggressive supportive treatment. Low HDL levels may be pathogenetically linked to the development of adrenal failure. The author has no financial interest in any of the products mentioned in this paper.     

Abnormal Platelet Function and Ultrastructure in Fulminant Hepatic Failure

Evidence in favour of an acquired platelet defect in fulminanthepatic failure has been provided by studies of in vitro plateletaggregation with adenosine diphosphate (ADP). Platelets fromsix patients required a higher concentration (threshold concentration)of ADP to reach second phase aggregation than those from controls(12·3 compared with 2·2x10^–6 M). Plateletsfrom another six patients failed to show second phase aggregationat the highest concentration of ADP used (3·2x10^–6M). The degree of aggregation at a fixed concentration (3·2x^–6M) was significantly less than in controls (34·2 percent compared with 57·5 per cent). Capillary bleedingtimes correlated positively with the abnormalities of plateletaggregation. In crossover studies, platelet poor plasma fromthese patients did not inhibit platelet aggregation in controls,nor did platelet poor plasma from controls enable patients'platelets to reach second phase aggregation suggesting thatfactors other than the plasma were responsible for this abnormalplatelet function. Some relationship between the severity of hepatic necrosis andplatelet dysfunction can be deduced as platelet function wasnormal in 16 patients with virus hepatitis or liver damage followingparacetamol overdose who were ill enough to warrant hospitaladmission, but who did not develop fulminant hepatic failure. Electron microscopy of platelets from patients with fulminanthepatic failure showed many structural abnormalities includingnumerous pseudopods, vacuoles and blurred plasma membranes.Most striking were the numbers of platelets showing microtubules,and the increased microtubular content per platelet. As patientsrecovered from fulminant hepatic failure, platelet functionimproved and platelets with normal ultrastructure appeared amongstthe abnormal ones. The abnormal-looking platelets may be responsible for the abnormalitiesof platelet function, but kinetic studies are required to elucidatetheir source and fate.     

Current status and perspective of pediatric liver transplantation in Japan

In Japan, the annual number of pediatric liver transplantation (LT) has been stable around 140 in the last few years. Almost all of them are from living donors. Three fourth are indicated for cholestatic liver diseases, mainly biliary atresia. One year patient survival rate after pediatric LT in Japan is 85 %. In comparison to other indications, patient survival of the infants with fulminant hepatic failure is quite poor. Weaning protocol of immunosuppression in pediatric LT in Japan is going in many institutions, and has succeeded to obtain some number of recipients with complete tolerance. More attenuated immunosuppresion and intimate monitoring for EB virus infection using the real-time PCR has been effective to decrease the incidence of post-transplant lymphoproliferative disorder.