Duloxetine hepatotoxicity: a case-series from the drug-induced liver injury network

Aliment Pharmacol Ther 2010; 32: 1174–1183Case reports suggest that duloxetine hepatotoxicity may arise, but risk factors, presenting features and clinical course are not well-described.To describe the presenting features and outcomes of seven well-characterized patients with suspected duloxetine hepatotoxicity.Patients enrolled in the Drug-Induced Liver Injury Network Prospective Study underwent an extensive laboratory and clinical evaluation to exclude competing aetiologies of liver injury as well as a standardized assessment for causality and disease severity.Between 1/2006 and 9/2009, six of the seven cases of DILI attributed to duloxetine were assessed as definite or very likely. Median patient age was 49 years, six (86%) were women and the median latency from drug initiation to DILI onset was 50 days. Six patients developed jaundice and the median peak alanine aminotransferase in the five patients with acute hepatocellular injury was 1633 IU/L. Ascites developed in one patient and acute renal dysfunction in two others (29%). All patients recovered without liver transplantation even though three had pre-existing chronic liver disease. Liver histology in four cases demonstrated varying patterns of liver injury.Duloxetine hepatotoxicity developed within 2 months of drug intake and led to clinically significant liver injury. A spectrum of laboratory, histological and extra-hepatic features were noted at presentation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/79147/1/j.1365-2036.2010.04449.x.pd

Development and Pilot of a Checklist for Management of Acute Liver Failure in the Intensive Care Unit

Introduction Acute liver failure (ALF) is an ideal condition for use of a checklist. Our aims were to develop a checklist for the management of ALF in the intensive care unit (ICU) and assess the usability of the checklist among multiple providers. Methods The initial checklist was developed from published guidelines and expert opinion. The checklist underwent pilot testing at 11 academic liver transplant centers in the US and Canada. An anonymous, written survey was used to assess the usability and quality of the checklist. Written comments were used to improve the checklist following the pilot testing period. Results We received 81 surveys involving the management of 116 patients during the pilot testing period. The overall quality of the checklist was judged to be above average to excellent by 94% of users. On a 5-point Likert scale, the majority of survey respondents agreed or agreed strongly with the following checklist characteristics: the checklist was easy to read (99% agreed/agreed strongly), easy to use (97%), items are categorized logically (98%), time to complete the checklist did not interfere with delivery of appropriate and safe patient care (94%) and was not excessively burdensome (92%), the checklist allowed the user the freedom to use his or her clinical judgment (80%), it is a useful tool in the management of acute liver failure (98%). Web-based and mobile apps were developed for use of the checklist at the point of care. Conclusion The checklist for the management of ALF in the ICU was shown in this pilot study to be easy to use, helpful and accepted by a wide variety of practitioners at multiple sites in the US and Canada

Safety, tolerability, and pharmacokinetics of l‐ornithine phenylacetate in patients with acute liver injury/failure and hyperammonemia

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142428/1/hep29621.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142428/2/hep29621-sup-0001-suppinfo1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142428/3/hep29621_am.pd

Coagulopathy, Bleeding Events, and Outcome According to Rotational Thromboelastometry in Patients With Acute Liver Injury/Failure

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/169284/1/hep31767_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/169284/2/hep31767-sup-0001-Supinfo.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/169284/3/hep31767.pd

Human Amniotic Epithelial Cell Transplantation Induces Markers of Alternative Macrophage Activation and Reduces Established Hepatic Fibrosis

Chronic hepatic inflammation from multiple etiologies leads to a fibrogenic response that can progress to cirrhosis and liver failure. Transplantation of human amniotic epithelial cells (hAEC) from term delivered placenta has been shown to decrease mild to moderate hepatic fibrosis in a murine model. To model advanced human liver disease and assess the efficacy of hAEC therapy, we transplanted hAEC in mice with advanced hepatic fibrosis. Immunocompetent C57BL/6 mice were administered carbon tetrachloride (CCl4) twice weekly resulting in bridging fibrosis by 12 weeks. hAEC (2×106) were infused via the tail vein at week 8 or weeks 8 and 10 (single and double dose, respectively). Human cells were detected in mouse liver four weeks after transplantation showing hAEC engraftment. CCl4 treated mice receiving single or double hAEC doses showed a significant but similar decrease in liver fibrosis area associated with decreased activation of collagen-producing hepatic stellate cells and decreased hepatic protein levels of the pro-fibrogenic cytokine, transforming growth factor-beta1. CCl4 administration caused hepatic T cell infiltration that decreased significantly following hAEC transplantation. Hepatic macrophages play a crucial role in both fibrogenesis and fibrosis resolution. Mice exposed to CCl4 demonstrated increased numbers of hepatic macrophages compared to normal mice; the number of macrophages decreased significantly in CCl4 treated mice given hAEC. These mice had significantly lower hepatic protein levels of the chemokine monocyte chemoattractant protein-1 than mice given CCl4 alone. Alternatively activated M2 macrophages are associated with fibrosis resolution. CCl4 treated mice given hAEC showed increased expression of genes associated with M2 macrophages including YM-1, IL-10 and CD206. We provide novel data showing that hAEC transplantation induces a wound healing M2 macrophage phenotype associated with reduction of established hepatic fibrosis that justifies further investigation of this potential cell-based therapy for advanced hepatic fibrosis

Best radiological response to trans‐arterial chemoembolization for hepatocellular carcinoma does not imply better outcomes

AbstractIntroductionRegional therapy with trans‐arterial chemoembolization (TACE) is a common treatment for unresectable hepatocellular carcinoma (HCC). Outcomes were examined in patients with the best radiological response (BR) after the initial TACE.MethodsThis was a retrospective cohort study of patients who underwent TACE as the initial treatment for HCC between the years 2000 and 2010. BR was defined as complete disappearance of the tumour or no enhancement with contrast on the first cross‐sectional imaging study after the initial TACE.ResultsSeventy‐eight out of 104 total consecutive patients were identified with the potential for a BR to TACE therapy for unresectable HCC, and 24 met the criteria for BR. Patients with BR had a median survival of 12.8 months (2.2–54.9) compared with 18.9 months(1.3–56.7) for the entire cohort (P= 0.313). The median time to progression was 10.6 months (1.2–24.3) in the BR group and 3.2 months (0.7–49.2) in the patients without a BR (P= 0.003).DiscussionBR to initial TACE for unresectable HCC is associated with comparable survival to those without BR in spite of a longer time to cancer progression. It may be reasonable to consider further therapy such as repeat TACE or biological/systemic therapy in patients with HCC even when the radiological response to the initial TACE is favourable