Focus
Article Outline
- Clevudine induced myopathy
- Albumin dialysis for intractable pruritus
- Increased incidence of gastrointestinal carcinomas in PSC patients with a dominant bile duct stenosis: Fact or co-incidence?
- Conflicts of interest
- References
- Copyright
Clevudine induced myopathy
During the last decade, the development of several potentially potent anti-viral agents against hepatitis B virus (HBV) infection was discontinued for a variety of reasons. Among them was Clevudine, a drug which interferes in a number of steps in the HBV replication cycle. Clevudine distinguished itself due to several attractive properties including its sustained suppression of circulating HBV-DNA observed after 24
weeks of treatment discontinuation as well as a reduction in intrahepatic cccDNA. Despite these properties, phase III studies came to a halt in most countries due to initially anecdotal reports of Clevudine associated myopathy and fear of mitochondrial toxicity as well as early selection of an rt181T mutation also observed in resistance to lamivudine and adefovir. Yet, following the successful completion of a 24week placebo controlled trial in HBeAg positive and negative HBV patients, Korea, remained the only country in which Clevudine was licensed for chronic HBV infection (CHB). Since 2009, more than 10 reports from Korea appeared in the literature describing various aspects of Clevudine associated myopathy.
In this issue of the Journal, Dr. Tak and co-workers report their experience in 363 CHB patients treated with Clevudine, 30mg/day for more than 24weeks and closely followed prospectively for a mean period of 18.0months (9–24) for the clinical signs of myopathy and neuropathy. The diagnosis of myopathy was established in 10% of the patients and was mainly based on clinical signs of lower limb proximal muscle weakness, elevated muscle enzymes, and in the majority of cases a muscle biopsy was also taken. Evidence for myopathy was supported by electrophysiologic studies and elevated lactic acid levels. Fortunately, symptoms and signs of myopathy were reversible in all patients within 2–9months following cessation of Clevudine. Statistical analysis was not provided but the investigators were unable to identify distinct risk factors or findings in patients with myopathy as compared to those without. Although the presented data are not new, this study, conducted in a relatively large cohort of prospectively followed patients, provides solid clinical information which should be useful to clinicians treating patients with anti-viral agents with potential mitochondrial toxicity. The relatively high incidence of myopathy identified after the completion of the licensure trials, strengthens the importance of post licensure surveillance despite initial satisfactory safety results in phase III clinical evaluations of anti-viral agents. The exact mechanism of the presumed mitochondrial toxicity induced by Clevudine remains unknown. In the discussion, the authors make an interesting comparison between Clevudine associated myopathy and Telbivudine induced neuropathy. Finally, in view of the plethora of new and potent anti-viral agents against HBV that thus far display a better safety record, there is little justification for continuous use of Clevudine which, apparently, is limited to Korea only.
Albumin dialysis for intractable pruritus
The controversy regarding the use of molecular adsorbent recirculating system (MARS) in patients with acute or chronic liver failure, and the impact of treatment by albumin dialysis on survival is still unresolved. Yet, cumulative experience with this procedure suggests that some palliation may be achieved in defined clinical situations.
A number of cholestatic syndromes including primary biliary cirrhosis, primary sclerosing cholangitis, benign recurrent intrahepatic cholestasis, cholestasis of pregnancy, drug induced cholestasis, liver associated graft versus host disease (GVHD), and others may lead to severe pruritus which occasionally is not relieved by cholestyramine, colestipol, ursodecholic acid, rifampicin, and naloxone.
There are at least 11 case reports describing between 1 and 7 patients with severe pruritus in whom MARS therapy leads to complete or partial amelioration of symptoms for a limited period. Yet, large scale studies with a defined protocol have not been conducted. In view of the promising initial results obtained through treatment with MARS in a very limited number of patients, it is important to capture any available experience in this difficult to treat population who often have a miserable quality of life which does not necessarily correlate with the severity of underlying liver disease. In this issue of the Journal, Dr. Pares and co-workers have summarized the clinical experience gained in two centers in Spain who successfully treated 19/20 patients with severe pruritus by albumin dialysis coupled with hemodialysis (HD) or continuous renal replacement therapy (CRRT). Most patients received two sessions of treatment within 2days and 5 patients were treated with additional sessions (1–3) within 4–43days from initiation. The severity of pruritus before and after intervention was assessed by two different scoring methods, namely a visual analogue scale (VAS) and a semiquantitative scoring system converted later to the VAS. A rapid improvement in severity of pruritus was documented already after two treatment sessions and the severity score improved in 72% of patients immediately, remaining at 51% at four weeks post-initiation of treatment. This effect usually lasted for about 4weeks in about one half of patients and was accompanied by a transient decrease in biochemical markers of cholestasis, including bile acid levels which dropped in 41% of patients immediately after treatment and this effect was still present after 4weeks in 37% of patients. The impact of treatment on long-term survival was variable with this invasive procedure but no treatment associated serious adverse events were reported during the observation period. The study has however a number of limitations, including among others the somewhat different protocols used by the two participating centers, the different pruritus scoring systems, the choice of the MARS coupled procedures (HD or CRRT), the number and duration of treatment sessions, the lack of a control group, the somewhat heterogenous patient population, and the cost. Nevertheless, the information provided through this observational case series study will be useful in the palliative treatment of patients with cholestatic syndromes (including GVHD) with intractable pruritus who did not respond to conventional therapy.
Increased incidence of gastrointestinal carcinomas in PSC patients with a dominant bile duct stenosis: Fact or co-incidence?
Patients with primary sclerosing cholangitis (PSC) are at increased risk ranging from 7% to 13% for developing cholangiocarcinoma (ChC) [1]. In addition, 25–90% of patients with PSC also have inflammatory bowel disease (IBD). The presence of ulcerative colitis is by itself associated with a 14–31% risk of developing colorectal carcinoma (CrC) at 10 and 20years of follow-up, respectively [2]. In recent years, and for some unclear reasons yet, the incidence of intrahepatic ChC is rising while the rate of extrahepatic ChC is dropping worldwide [2], [3], [4]. It is therefore important to identify the risk factors which affect these findings. Rudolph and co-workers have previously reported a reduced liver transplantation free survival in a cohort of 97/171 PSC patients with dominant bile duct stenosis who were followed prospectively for up to 20years in Germany [5]. In this issue of the Journal, these investigators analyzed the impact of a dominant bile duct stenosis in IBD patients in the same cohort of PSC patients, as well as the incidence of ChC, CrC, and gall bladder carcinoma. During the follow-up period (up to 20years), ChC was detected in 6 patients, CrC in 6 patients, and gallbladder carcinoma in 2 patients with PSC with a dominant stricture who also had IBD. In contrast, none of the PSC/IBD patients without a dominant stricture developed ChC or gall bladder carcinoma and only one had CrC. Furthermore, actuarial liver transplantation free survival at 18years was only 23% in PSC patients with IBD and a dominant bile duct stricture as compared to 77.8% in the patients without IBD who had a dominant bile duct stricture. Interestingly, the overall prevalence of bile duct carcinoma was relatively low at only 3%, rising to 6.2% in patients with a dominant bile duct stricture. The investigators conclude that presence of a dominant bile duct stenosis in PSC patients with IBD is associated with an increased risk for developing a carcinoma which most probably contributes to a reduced survival free of liver transplantation. The results of this study justify a close follow-up of such PSC/IBD patients with dominant bile duct stenosis and who are at risk for developing malignant transformation. Yet caution is advised in the over-interpretation of data for a number of reasons: (i) The number of patients with ChC, CrC, and gallbladder carcinoma identified during the follow-up is relatively small. (ii) It is difficult to explain why the actuarial liver transplantation free survival at 18years of follow-up was lower (although not statistically significant) in those PSC patients without IBD and without a dominant bile duct stenosis as compared to patients with IBD. (iii) PSC patients were treated with variable doses of ursodecholic acid which at least in theory may confound the risk for development of cancer. (iv) Newer treatment protocols for IBD such as anti-TNFα introduced during the past decade may affect the risk for developing a carcinoma.
Conflicts of interest
The author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
References
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- . High lifetime risk of cancer in primary sclerosing cholangitis. J Hepatol. 2009;50:158–164
- . Worldwide trends in mortality from biliary tract malignancies. BMC Cancer. 2002;2:10
- . Rising incidence of intrahepatic cholangiocarcinoma in the United States: a true increase?. J Hepatol. 2004;40:472–477
- . Influence of dominant bile duct stenoses and biliary infections on outcome in primary sclerosing cholangitis. J Hepatol. 2009;51:149–155
PII: S0168-8278(10)00387-9
doi:10.1016/j.jhep.2010.04.005
© 2010 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.
