Geoffrey Haydon

Tacrolimus and cyclosporin doses and blood levels in hepatitis C and alcoholic liver disease patients after liver transplantation

Hepatitis C virus (HCV)‐induced cirrhosis is the most common indication for liver transplantation (LT). However, graft reinfection is nearly universal. The choice of immunosuppression, including the calcineurin inhibitor (CNI), may have some effect on severity of recurrence and graft survival. In addition, HCV recurrence may have some impact on metabolism of immunosuppressive drugs. In this retrospective study, we examined the dose and blood levels of tacrolimus (TAC) and cyclosporin A (CYA) in HCV patients consecutively undergoing transplantation (TAC, n = 44; CYA, n = 60) and surviving 12 months post‐LT. In addition, we examined the CNI dose and blood levels in an age‐ and gender‐matched comparison group of patients who were transplanted for alcoholic liver disease (ALD) (TAC, n = 44; CYA, n = 47). During the 12‐month period of observation, TAC levels were significantly higher for HCV than for ALD patients (P = 0.002). The dose of TAC decreased over time for both HCV and ALD patients (P < 0.001), but the reduction was greater for HCV patients (P = 0.03). CYA dose decreased over time for both groups (P < 0.001) but a greater reduction was observed for the HCV group (P = 0.007). For both HCV and ALD patients, CYA levels decreased over time (P < 0.001) but there was no significant difference between HCV and ALD patients. Thus, to maintain comparable blood levels, a greater reduction of dose was required for HCV than for ALD patients. In conclusion, our observations demonstrate a likely effect of HCV infection on CNI metabolism, an effect that is not clearly due to graft damage. Physicians need to be alert to this interaction and to the need to respond quickly to changes in CNI levels that may be associated with HCV infection and with HCV clearance during antiviral therapy. Liver Transpl 14:81–97, 2008.

Multiorgan failure is the commonest cause of death in fulminant hepatic failure: a single centre experience

To the editor: The incidence of cerebral oedema as a complication of fulminant liver failure (FHF) has been reported to be as high as 80% (1). Recently, there has been a significant improvement in the supportive treatment of FHF and an observed fall in the incidence of cerebral oedema (61% in 1987 to 45% in 1993) (2). In this retrospective analysis of trends in mortality from FHF, we aimed to determine the extent of cerebral oedema as the primary cause of death in FHF during 6 years of follow-up in a single centre. The Queen Elizabeth Hospital Birmingham serves a large area of England and Wales. Transfer of FHF patients to the Liver Unit is based on local guidelines. Between 1/1/1996 and 31/12/ 2001, 503 FHF patients were admitted, 118 died (62 males; median age: 44 years, range: 19–73; liver transplant recipients: 24) and were included in this study. All 118 had grade III/IV hepatic encephalopathy, were electively ventilated and admitted to ITU. Treatment for prevention of raised intracranial pressure (ICP) included the routine insertion of ICP bolts in all patients at risk of cerebral oedema (29 patients (25%)). Data were collected from medical notes, the Liver Unit database and autopsy reports (33 patients). A broad definition of death associated with cerebral oedema was used, this included patients who had: (i) subdural bolts recording intracranial hypertension (ICH), (ii) subdural bolts and intermittent ICH without another cause of death, (iii) autopsy evidence of cerebral oedema/ICH, (iv) clinical signs of ICH, (v) a hyperacute presentation without sepsis, pneumonia, adult respiratory distress syndrome (ARDS), disseminated intravascular coagulation (DIC) or gastrointestinal haemorrhage. Multiorgan failure (MOF) was considered the cause of death if three of the following were present: (i) renal failure requiring continuous veno-venous haemofiltration (CVVH), (ii) sepsis with positive blood culture(s), (iii) respiratory failure secondary to pneumonia/ARDS, (iv) persistent DIC despite treatment in the context of systemic sepsis. The most common cause of FHF was paracetomol overdose (POD) (n5 57; 48.3%) followed by non-A–non-B hepatitis (n5 37; 31.3%). MOF was the cause of death in 80 (67.7%) and cerebral oedema in 29 (24.5%). Of these, 14 had an ICP bolt showing ICH, and 13 had autopsy findings consistent with ICH. Figure 1 shows the causes of death for each aetiology of FHF. POD patients were significantly more likely to die of MOF (n5 33; 57.9%) than cerebral oedema (n5 20; 35.1%; Po0.05) as were nonA–non-B hepatitis patients (n5 28; 75.6% vs. n5 4; 10.8%). This study demonstrates that MOF is the most common cause of death in FHF and that this is independent of the aetiology of FHF. The overall incidence of cerebral oedema continues to fall and there are several possible explanations. Firstly, a change in guidelines has led to earlier referral and earlier treatment with N-acetyl-cysteine (NAC). Indeed, even late administration of NAC in paracetomol-induced FHF, improves outcome (3–5) and decreases the incidence of cerebral oedema (4). Secondly, the supportive medical management of FHF has also improved, guided by local protocols. Finally, current transplant criteria encourage early listing of patients with FHF, before they are at risk of developing cerebral oedema. In conclusion, this study both reiterates the prominence of MOF as a cause of death in FHF and the falling incidence of death from cerebral oedema. Our findings emphasise the importance Liver International 2004: 24: 702–703 Printed in Denmark. All rights reserved Copyright r Blackwell Munksgaard 2004

Thrombocytosis in liver transplant recipients: Prevalence, natural history, and impact

The prevalence, natural history, and implications of reactive thrombocytosis after liver transplantation (LT) are unknown. Prospectively collected data from July 2000 to February 2006 were analyzed. Post–LT thrombocytosis was defined as a platelet count of >450 × 103/μL lasting for >7 days and starting within 8 weeks of transplantation. In patients who survived >8 weeks, graft and patient outcomes were compared with liver transplant recipients who survived >8 weeks and did not develop any thrombocytosis. Post‐LT thrombocytosis was seen in 92 (14.7%) of 627 patients. The median onset was on day 13 (range, days 1‐44) and the peak platelet count was seen on day 17 (range, days 3‐110). The median duration of thrombocytosis was 25 days (range, 7‐1,253 days), with a median peak platelet count of 625 × 10/μL (range, 472‐1,381 × 10/μL). Seronegative fulminant hepatic failure was the indication for transplantation in 18% of patients with post‐LT thrombocytosis compared with 3% of controls (P < 0.001). There was a lower proportion of patients transplanted for hepatitis C–related cirrhosis in the thrombocytosis group (10% vs. 18%, P = 0.04). The occurrence of hepatic arterial thrombosis was similar in the 2 groups (5% vs. 4%, P = NS). None of the 4 patients with platelet count higher than 1,000 × 10/μL developed thrombotic complications. Post‐LT thrombocytosis is more often associated with seronegative fulminant hepatic failure, and there is a negative association with hepatitis C–related cirrhosis. Post‐LT thrombocytosis does not increase the risk of hepatic artery thrombosis, and patients without thrombotic complications should not be treated. Liver Transpt 13: 1598–1602. 2007.

Haematological malignancies presenting with acute liver injury: a single-centre experience.

INTRODUCTION Early recognition and identification of the underlying cause of acute liver injury (ALI) is crucial in instituting medical treatment and assessing the need for liver transplantation. Haematological malignancies have been reported to present as ALI with progression to acute liver failure but experience is limited. AIM Review our experience of ALI secondary to haematological malignancies. PATIENTS AND METHODS Patients admitted to the liver unit with ALI secondary to a haematological malignancy between 1996 and 2006 were identified. A retrospective review was made of their case notes and our database. RESULTS Of the 752 cases of ALI, six cases of ALI secondary to haematological malignancy were identified. Common features were a prodromal illness (median duration of 5 weeks; range 2-6 weeks) and jaundice (median bilirubin 208 micromol/l; range 112-238 micromol/l). The majority of patients (5/6) had hepatomegaly. Liver biopsy was performed in two patients and confirmed the diagnosis in both cases. In other cases, the diagnosis was made following lymph node biopsy (1), bone marrow examination (2) or from post-mortem examination (1). Median time from jaundice to encephalopathy was 12 days; range 1-22 days. A single patient underwent liver transplantation but died in the immediate post-operative period. All patients died soon after admission with a median survival of 8 days (range 3-26 days). CONCLUSION Haematological malignancy should be considered in ALI patients presenting with a prodromal illness, jaundice and hepatomegaly. Biopsy is essential to confirm the diagnosis but the benefit of definitive therapy such as chemotherapy and/or transplantation in this setting is unclear and survival is poor.

Genetically modified interferon: is there a consensus yet?

 Current national and international guidelines for the treatment of chronic hepatitis C infection recommend combination therapy with 3 MU interferon alpha-2b tiw and ribavirin 1000–1200 mg/day for 6 or 12 months duration. The best second-line treatment for non-responders to combination therapy remains uncertain. Sustained biochemical and virological response rates to treatment with consensus interferon vary according to the characteristics of the treated population. A role for consensus interferon has yet to be defined. Further controlled studies that compare consensus interferon with combination antiviral therapy, or evaluate its use as a component of combination therapy, are required. The treatment of patients with chronic hepatitis C virus infection has evolved during the last decade from interferon monotherapy to combination therapy with interferon and ribavirin. National and international guidelines recommend either 6 or 12 months of interferon/ribavirin combination therapy depending on the pre-treatment virological status of the patient. However, the choice for second-line treatment of patients who do not achieve sustained viral clearance with combination therapy has yet to be defined. This commentary examines previously published studies of the use of consensus interferon for hepatitis C virus infected patients. The characteristics of the treated populations and response to treatment are examined. The current and potential roles for this type of interferon in the treatment of hepatitis C virus infection are considered.